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<context> Lysine methylation of histones is associated with both transcriptionally active chromatin and with silent chromatin, depending on what residue is modified. Histone methyltransferases and demethylases ensure that histone methylations are dynamic and can vary depending on cell cycle- or developmental stage. This approach identified Txr1p as a histone methyltransferase in Tetrahymena thermophila and characterized the relationships of the Txr1p and Ezl2p methyltransferases to histone H3 modification. Histone methyltransferases catalyze site-specific deposition of methyl groups, enabling recruitment of transcriptional regulators. In mammals, trimethylation of lysine 4 in histone H3, a modification localized at the transcription start sites of active genes, is catalyzed by six enzymes (SET1a and SET1b, MLL1-MLL4) whose specific functions are largely unknown. Epigenetic regulation of gene expression by covalent modification of histones is important for germ line cell development. In mammals, histone H3 lysine 9 (H3K9)-specific histone methyltransferases (HMTases), such as G9a, SETDB1, and SUV39H, play critical roles, but the contribution of H3K9-specific HMTases in Drosophila remains to be clarified, especially in male sperm. Histone acetyltransferases (HATs), histone deacetylases (HDACs), kinases, and histone methyltransferases (HMTs) are all responsible for the addition/removal of covalent modifications on the histone tails [35-37]. Histone methyltransferases (HMTs) can methylate arginine residues such as 2, 8, 17, and 26 on H3 and residue 3 on H4. HMTs can also methylate specific lysine residues such as 4, 9, 27, 36, and 79 on H3 and residue 20 on H4 which serve as markers for the recruitment of chromatin organization complexes [41-43]. Historically, the methylation of H3-K9 has been linked to functionally repressed chromatin [33,44,45]. By analyzing the distribution of histone modifications in nuclei using quantitative fluorescence microscopy, we found that H4K16 acetylation (H4K16ac) is underrepresented and H4K20 monomethylation (H4K20me1) is enriched on hermaphrodite X chromosomes in a DCC-dependent manner. Here, we found the epigenetic modification of the BZLF1 promoter in latent Raji cells by histone H3 lysine 27 trimethylation (H3K27me3), H3K9me2/me3, and H4K20me3. Although DNA methyltransferases have been shown to interact with histone methyltransferases such as EZH2 (which methylates histone H3 on lysine 27) and G9a (which methylates histone H3 on lysine 9), the relationship between DNA methylation and repressive histone marks has not been fully studied. Np95 or its human homolog ICBP90/UHRF1 were reported to interact with the histone deacetylase HDAC1 and the histone methyltransferase G9a and to mediate silencing of a viral promoter, suggesting a role of Np95 in gene silencing through histone modification (13,23,24). Methylation of histone H4 lysine 20 (H4K20me) plays critical roles in diverse cellular processes such as gene expression, cell cycle progression and DNA damage repair, with each of the three degrees of methylation (mono-, di- and tri-methylation) making a unique contribution. The trithorax proteins Trithorax (TRX) and Absent, small or homeotic 1 (ASH1) also catalyze modifications of nucleosomal histones, including the methylation of lysine 4 of histone H3 (H3K4) [18],[19],[20],[21],[22]. It has been reported that both ASH1 and TRX methylate H3K4 [18],[19],[20]; this covalent modification of chromatin is enriched near the promoters of many genes and is thought to recruit factors required for early events in the transcription cycle [23]. Histone H3-lysine (K) 4, H3-K9 and H3-K27 modifications in all these four genes were examined by chromatin immunoprecipitation (ChIP) assay in HCC cell lines. The histone H4 N-terminal tail has long been regarded as a major regulator in chromatin structure and function. Gene transcription is critically influenced by chromatin structure and the modification status of histone tails. Methylation of lysine residues in histone tails is dynamically regulated by the opposing activities of histone methyltransferases and histone demethylases. The SAS3-dependent NuA3 histone acetyltransferase complex was originally identified on the basis of its ability to acetylate histone H3 in vitro. Consistent with the histone code, it has been revealed that the methylation of histone H3 lysine 9 (H3 K9), a modification associated with transcriptionally silent heterochromatin, is critical for long-range chromatin regulatory processes [26,27]. SU(VAR)3-9 like histone methyltransferases control heterochromatic domains in eukaryotes. Methylation of position-specific lysine residues in histone N termini is a central modification for regulating epigenetic transitions in chromatin. Each methylatable lysine residue can exist in a mono-, di-, or trimethylated state, thereby extending the indexing potential of this particular modification. One of these modifications, histone lysine methylation, has been shown to be highly stable and to represent an epigenetic alteration. Primarily because of the recent discovery of the SET domain-depending H3-specific histone methyltransferases SUV39H1 and Suv39h1, which selectively methylate lysine 9 of the H3 N terminus, this posttranslational modification has regained scientific interest. Set9, a novel histone H3 methyltransferase that facilitates transcription by precluding histone tail modifications required for heterochromatin formation. Our results suggest that the methylation of histone tails can have distinct effects on transcription, depending on its chromosomal location, the combination of posttranslational modifications, and the enzyme (or protein complex) involved in the particular modification. Among the different groups of enzymes known to catalyze the covalent modification, the most recent additions are the histone methyltransferases (HMTases), whose functions are now being characterized. </context> <question> How do histone methyltransferases cause histone modification? </question> <answer> Histone methyltransferases (HMTs) are responsible for the site-specific addition of covalent modifications on the histone tails, which serve as markers for the recruitment of chromatin organization complexes. There are two major types of HMTs: histone-lysine N-Methyltransferases and histone-arginine N-methyltransferases. The former methylate specific lysine (K) residues such as 4, 9, 27, 36, and 79 on histone H3 and residue 20 on histone H4. The latter methylate arginine (R) residues such as 2, 8, 17, and 26 on histone H3 and residue 3 on histone H4. Depending on what residue is modified and the degree of methylation (mono-, di- and tri-methylation), lysine methylation of histones is linked to either transcriptionally active or silent chromatin. </answer>
<context> However, in general, HMTs have no widely accepted high-throughput screening (HTS) assay format, and reference inhibitors are not available for many of the enzymes. Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms in Plasmodium falciparum. We synthesized a compound library based upon a known specific inhibitor (BIX-01294) of the human G9a histone methyltransferase. Two compounds, BIX-01294 and its derivative TM2-115, inhibited P. falciparum 3D7 parasites in culture with IC(50) values of ~100 nM, values at least 22-fold more potent than their apparent IC(50) toward two human cell lines and one mouse cell line. Together, these results suggest that BIX-01294 and TM2-115 inhibit malaria parasite histone methyltransferases, resulting in rapid and irreversible parasite death. Synthesis and structure-activity relationship investigation of adenosine-containing inhibitors of histone methyltransferase DOT1L. A total of 55 adenosine-containing compounds were designed and synthesized, among which several potent DOT1L inhibitors were identified with K(i) values as low as 0.5 nM. Several new reagents and assays were developed to aid in the identification of EZH2 inhibitors, and these were used to execute two high-throughput screening campaigns. Of the five histone methyltransferases known to mediate methylation of the lysine 9 residue of histone H3 (H3K9), euchromatic histone-lysine N-methyltransferase 2 (EHMT2; also known as G9a) has been shown to be a primary mediator of H3K9 dimethylation; BIX-01294 has been shown to be a specific inhibitor of EHMT2 We hypothesised that inhibition of EHMT2 by BIX-01294 would result in reduced levels of H3K9 dimethylation and compromised embryo development. We also demonstrate that peptides that mimic SET1 family Win motif sequences inhibit H3K4 dimethylation by the MLL1 core complex with varying degrees of efficiency. Studies of H3K4me3 demethylation by KDM5B/Jarid1B/PLU1 reveals strong substrate recognition in vitro and identifies 2,4-pyridine-dicarboxylic acid as an in vitro and in cell inhibitor. Inhibition studies of ccKDM5B showed both in vitro and in cell inhibition of ccKDM5B by 2,4-pyridinedicarboxylic acid (2,4-PDCA) with a potency similar to that reported for the HDM KDM4C. Treatment with 3-deazaneplanocin A (DZNep), an inhibitor of H3K27me3 and H4K20me3, significantly enhanced the BZLF1 transcription in Raji cells when in combination with an HDAC inhibitor, trichostatin A (TSA). All assays allowed profiling of known SET7/9 and LSD1 inhibitors. The results demonstrate that the optimized LANCE Ultra and AlphaLISA assay formats provide a relevant biochemical screening approach toward the identification of small-molecule inhibitors of HMTs and HDMs that could lead to novel epigenetic therapies. Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies. We used structure- and mechanism-based design to discover several potent inhibitors of DOT1L with IC(50) values as low as 38 nM. Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: implications for adoptive immunotherapy of cancer. Short hairpin RNAs were used to inhibit several histone methyltransferases (KMT) and histone demethylases (KDM) that mediate histone methylation and repress gene expression. DZNep, a pharmacologic inhibitor of KMT6 expression, recapitulated the effects of KMT6 knockdown. Recent evidence shows that S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors (AHI) such as 3-deazaneplanocin A (DZNep) modulate chromatin through indirect inhibition of histone methyltransferases including EZH2. We investigated the biological effects of AdoHcy hydrolase inhibition using DZNep and its structural analogues 3-deazaadenosine (DZA) and neplanocin A (Nep A) in breast cancer cells. A chemiluminescence-based method for identification of histone lysine methyltransferase inhibitors. The method is particularly well suited for detection of inhibitors acting by the desired histone peptide competitive mechanism and is applicable to testing other HMTs, demonstrated here with the G9a homolog EHMT1, also known as GLP. RESULTS: We found that GE can reactivate ERα expression and this effect was synergistically enhanced when combined with a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), in ERα-negative MDA-MB-231 breast cancer cells. This study reports the pharmacokinetics and tissue distribution of a novel histone deacetylase and DNA methyltransferase inhibitor, psammaplin A (PsA), in mice. Human diet contains many histone deacetylase (HDAC) inhibitors, such as the bioactive component sulforaphane (SFN), whose epigenetic effects on MSTN gene in satellite cells are unknown. Indeed, treatment with the histone deacetylase inhibitors trichostatin A (TSA) or suberoxylanilide hydroxamic acid (SAHA) led to a suppression of AXL mRNA expression (Figure 4E). We found that DNA methyltransferase inhibitor (5-Aza-2'-deoxycytidine) and histone deacetylase inhibitor (trichostatin A) reduced leptin receptor expression. However, histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butyrate (NaBt) significantly increased Wnt5a mRNA expression in SW620. </context> <question> Which are the inhibitors of histone methyltransferases? </question> <answer> BIX-01294; TM2-115; 2,4-pyridinedicarboxylic acid', '2,4-PDCA; 3-deazaneplanocin A', 'DZNep; Trichostatin A', 'TSA; Psammaplin A', 'PsA; Sulforaphane', 'SFN </answer>
<context> We found a very significant increase in average longevity (17%) of the cyclists when compared with the general population. The age at which 50% of the general population died was 73.5 vs. 81.5 years in Tour de France participants. Our major finding is that repeated very intense exercise prolongs life span in well trained practitioners. Competitive exercise does not induce cardiac damage in individuals with healthy hearts, but does induce physiological functional and structural cardiac adaptations which have positive effects on life expectancy. Medallists lived an average of 2.8 years longer than controls. Medallists in eight of the nine country groups had a significant survival advantage compared with controls. Gold, silver, and bronze medallists each enjoyed similar sized survival advantages. Medallists in endurance sports and mixed sports had a larger survival advantage over controls at 30 years (1.13, 1.09 to 1.17; 1.11, 1.09 to 1.13) than that of medallists in power sports (1.05, 1.01 to 1.08). CONCLUSIONS: Olympic medallists live longer than the general population, irrespective of country, medal, or sport. This study was not designed to explain this effect, but possible explanations include genetic factors, physical activity, healthy lifestyle, and the wealth and status that come with international sporting glory. Long-term endurance training induces in elderly subjects an increased HRV and a higher exercise working capacity, which are well-established predictors of cardiovascular and overall mortality. VO(2max) is positively associated with telomere length, and we found that long-term endurance exercise training may provide a protective effect on muscle telomere length in older people. Sports activity in adolescents and young adults was associated with an increased risk of SD, both in males and females. Sports, per se, was not a cause of the enhanced mortality, but it triggered SD in those athletes who were affected by cardiovascular conditions predisposing to life-threatening ventricular arrhythmias during physical exercise. </context> <question> is intense physical activity associated with longevity ? </question> <answer> yes </answer>
<context> Molecular tests such as the 21 gene expression test (Oncotype DX(TM)) and 70 gene microarray test (MammaPrint(®)) have revolutionized the predictive and prognostic tools in the clinic. By stratifying the risk of recurrence for patients, the tests are able to provide clinicians with more information on the treatment outcomes of using chemotherapy, HER2 targeted therapy or endocrine therapy or the combination of the therapies for patients with particular genetic expressions. Gene expression profiling tests are used in an attempt to determine the right treatment for the right person with early-stage breast cancer that may have spread to nearby lymph nodes but not to distant parts of the body. These new diagnostic approaches are designed to spare people who do not need additional treatment (adjuvant therapy) the side effects of unnecessary treatment, and allow people who may benefit from adjuvant therapy to receive it. In the present review we discuss in detail the major diagnostic tests available such as MammaPrint dx, Oncotype dx, PAM50, Mammostrat, IHC4, MapQuant DX, Theros-Breast Cancer Gene Expression Ratio Assay, and their potential clinical applications. Oncotype DX, PAM50, and MammaPrint are multigene tests that are being used clinically for early-stage breast cancer to predict recurrence risk and guide adjuvant chemotherapy decisions. We critically evaluated the available evidence on genomic tests in breast cancer to define their prognostic ability and likelihood to determine treatment benefit. METHODS: Independent evaluation of six genomic tests [Oncotype Dx™, MammaPrint(®), Genomic Grade Index, PAM50 (ROR-S), Breast Cancer Index, and EndoPredict] was carried out by a panel of experts in three parameters: analytical validity, clinical validity, and clinical utility based on the principles of the EGAPP criteria. PANEL Gene expression profiling (GEP) is being used increasingly for risk stratification to identify women with lymph node-negative, estrogen receptor-positive, early stage breast cancer who are most likely to benefit from adjuvant chemotherapy. The authors of this report evaluated the cost effectiveness of recurrence score-guided treatment using 2 commercially available GEP tests, Oncotype DX (Genomic Health, Redwood City, Calif) and MammaPrint (Agendia Inc., Irvine, Calif), from a third-party payer's perspective. genomic tumor signatures that predict a patient's risk of breast cancer recurrence and response to chemotherapy. The paper builds on empirical evidence from the two trials to explore the emergence of diverse regulatory-scientific hybrids; that is, the paper discusses configurations of genomic practice and bioclinical work that depend on linkages between technical, commercial, patient, clinical, and legal interests and institutions. The development of the genomic signatures for each trial--Oncotype DX and MammaPrint--has followed quite different routes. In addition to examining the relationship between the molecular subtypes of breast cancer identified in this study and various clinical parameters, our classifier genes were also applied to the other two published independent breast cancer datasets for confirmation [10,24]. In addition, we used the reported genes of the OncotypeDX [8] and MammaPrint [3] predictors to assess the risk of distant recurrence for cases in all three datasets. Real-time RT-PCR confirmed the 5-gene prognostic signature that was distinct from an FDA-cleared 70-gene signature of MammaPrint panel and from the Oncotype DX recurrence score assay panel. These data suggest that neoadjuvant immunotherapy in patients with high risk of relapse may reduce tumor recurrence by inducing the immune function genes. We will review the primary tools in clinical use: Adjuvant!, Oncotype DX, and MammaPrint as well as intrinsic subtypes and the plans for their further assessment in the clinical trial setting. The expected benefit from these models are that treatment recommendations for women with early-stage breast cancer will become more individualized and thereby appropriate by combining standard clinicopathologic and molecular features. newer prognostic markers with a focus on the 21-gene recurrence score (Oncotype DX(™)), 70-gene prognosis profile (Mammaprint(®)), and Adjuvant! Online. Conclusion: These techniques differ in their execution and application and have been demonstrated to provide further data on risk stratification as compared with conventional breast-cancer-risk factors. diagnostic tools such as MammaPrint and oncotype-DX are beginning to have impact on clinical practice of breast cancer. They are based on gene expression profiling, i.e., gene expression analysis of a large number of genes. Their unique characteristic is the use of a score calculated from expression values of a number of genes, for which the Food and Drug Administration (FDA) created a new diagnostic category entitled "in vitro diagnostic multivariate index assay (IVDMIA)." the gene expression signatures that define specific prognostic subtypes in other breast cancer datasets, such as luminal A and B, basal, normal-like, and ERBB2+, and prognostic signatures including MammaPrint and Oncotype DX, predicted genomic instability in our samples. </context> <question> What is the use of MammaPrint and Oncotype DX? </question> <answer> The MammaPrint and Oncotype DX assays are used to predict breast cancer recurrence risk and guide adjuvant chemotherapy decisions. </answer>
<context> Real-time RT-PCR confirmed the 5-gene prognostic signature that was distinct from an FDA-cleared 70-gene signature of MammaPrint panel and from the Oncotype DX recurrence score assay panel. MammaPrint is the first FDA approved, gene expression-based prognostic test which assess patients’ risk for distant metastasis in women under age 61 with Stage I-II lymph node negative breast cancer. The test was developed by Agendia, a gene expression-based diagnostic company in Amsterdam (http://www.agendia.com/), and was approved by the FDA in February 2007 as an Agendia-only offered service. a clinical assay MammaPrint® has recently been cleared by FDA. </context> <question> Is MammaPrint cleared by the United States Food and Drug Administration? </question> <answer> yes </answer>
<context> Survivin (BIRC5) is one of the members of IAP-family apoptosis inhibitors. The BIRCS gene is expressed in most human embryonic tissues and malignant tumors but not in normal differentiated tissues of adult human. Survivin is an inhibitor of apoptosis that is undetectable in most terminally differentiated normal human tissues, strongly expressed in embryonic and fetal organs and is strongly expressed in many different human cancers. Survivin is a member of the inhibitor apoptosis family that is overexpressed in many malignancies. It has five known alternative splice forms, some of which differ in their antiapoptotic properties and expression levels in human cancers. survivin is usually not expressed in normal adult tissues, AZD1152-hQPA induced caspase-dependent apoptosis of some cell lines, demonstrated by loss of mitochondrial membrane potential, activation of caspase-9, followed by activation of caspase-3. This effect was accompanied by the inhibition of survivin expression. In vivo efficacy was determined in NOD/SCID/γc(null) mice implanted with the Ramos human BL cell line. AZD1152 had anti-tumour effects in this murine xenograft model. There preclinical data suggest that the inhibition of Aurora B kinase is a potentially useful therapeutic strategy in BL and HL. Survivin, an anti-apoptotic protein encoded by BIRC5, to perform immunostaining on a melanoma progression tissue microarray (TMA). This TMA contained 480 cores of tumor tissues representing benign nevi, thin and thick primary cutaneous melanoma, as well as lymph node and visceral melanoma metastasis. As shown in Figure 3C, Survivin expression was low to absent in the majority of the benign nevi but was significantly elevated in all melanomas (p<0.0001, χ2). a novel antiapoptosis gene, i.e., survivin, was identified as a structurally unique member of the inhibitor of apoptosis protein family. Survivin expression is turned off during fetal development and not found in non-neoplastic adult human tissues but is again turned on in the most common human cancers. The antiapoptotic properties of survivin might provide a significant growth advantage in tumors and possibly also contribute to chemoresistance of cancer. Further comparison of the distribution of PDEF with other widely recognized cancer-associated molecules showed that PDEF has more restricted distributions than Her-2/neu, Bcl-2, survivin or telomerase in cDNA libraries from normal human tissues and more increased distribution than Her-2/neu, CA-125, Bcl-2, survivin and telomerase in cDNA libraries from brain (except survivin), breast, lung and ovarian tumors. These data together show a better tumor-association for PDEF and suggest that PDEF is a more suitable target for developing specific cancer therapies. Aggressive (Group 2) melanomas were characterized by upregulation of genes associated with cell cycle progression, DNA replication and repair, and altered expression of apoptosis-related genes including upregulation of the antiapoptotic gene BIRC5/survivin [49] and downregulation of the novel stress-associated apoptosis inducer TRIB3 [50] (Table 1). we identified decreased FHIT expression resulting in apoptosis inhibition and decreasing apoptosis associated with abnormal levels of some pro- and anti-apoptotic proteins (Bax, Bcl-2 and Survivin) by TUNEL and TMA. Our results demonstrated that the mutation in the FHIT gene significantly reduced FHIT expression in human CRC. Both TUNEL and TMA experiments demonstrated significantly inhibited apoptosis by down-regulation of Bax and up-regulation of Survivin and Bcl-2. Collectively, these studies identify the mechanism by which an important tumor suppressor gene, FHIT, inactivated specifically in human CRC, and contributes to our understanding of the mechanism of colorectal carcinogenesis. </context> <question> Is it possible to detect survivin protein expression in normal human adult tissues? </question> <answer> no </answer>
<context> Malfunction of the circadian clock has been linked to the pathogenesis of a variety of diseases. We show that mice lacking the core clock components Cryptochrome-1 (Cry1) and Cryptochrome-2 (Cry2) (Cry-null mice) show salt-sensitive hypertension due to abnormally high synthesis of the mineralocorticoid aldosterone by the adrenal gland. The Cryptochrome 1 and 2 genes are indispensable for molecular core oscillator function, as evident from the arrhythmic wheel-running behavior and lack of rhythmic clock gene expression in mCry1/mCry2 double-mutant mice in constant darkness. Among the components driving the mammalian circadian clock are the Period 1 and 2 (mPer1 and mPer2) and Cryptochrome 1 and 2 (mCry1 and mCry2) genes. A mutation in the mPer2 gene leads to a gradual loss of circadian rhythmicity in mice kept in constant darkness (DD). Here we show that inactivation of the mCry2 gene in mPer2 mutant mice restores circadian rhythmicity and normal clock gene expression patterns. Thus, mCry2 can act as a nonallelic suppressor of mPer2, which points to direct or indirect interactions of PER2 and CRY2 proteins. In marked contrast, inactivation of mCry1 in mPer2 mutant mice does not restore circadian rhythmicity but instead results in complete behavioral arrhythmicity in DD, indicating different effects of mCry1 and mCry2 in the clock mechanism Consistent with their central role in circadian rhythm generation, genetic inactivation of both cryptochromes (cry1,2-/-) results in circadian arrhythmicity in mice [22,23]. Cryptochrome 1 and 2 gene products act in the negative feedback loop and are indispensable for molecular core oscillator function, as evident from the arrhythmic wheel running behaviour and absence of cyclic clock gene expression in mCry1/mCry2 double mutant mice in constant darkness. , when mCry-deficient mice are housed in normal light-dark cycles, a single non-circadian peak in neuronal activity can be detected in SCN slices prepared two hours after the beginning of the day. This light-induced increase in electric activity of the SCN suggests that deletion of the mCry genes converts the core oscillator in an hour-glass-like timekeeper and may explain why in normal day-night cycles mCry-deficient mice show apparently normal behaviour. Cryptochrome 1 and 2 act as essential components of the central and peripheral circadian clocks for generation of circadian rhythms in mammals cryptochrome-1 mRNA was found in DA cells, immunocytochemistry was extended to other components of the circadian clock machinery. This analysis showed that DA cells contain the most common clock-related proteins. Cryptochrome 1 and cryptochrome 2 proteins are core components of the mammalian circadian clock and mice mutated in both genes are arrhythmic. a domain in the extreme C terminus of BMAL1 that plays an essential role in the rhythmic control of E-box-mediated circadian transcription. Remarkably, the last 43 aa of BMAL1 are required for transcriptional activation, as well as for association with the circadian transcriptional repressor CRYPTOCHROME 1 (CRY1), depending on the coexistence of CLOCK protein. circadian rhythm protein cryptochrome 1 (CRY1). CRY1 is a master regulator of circadian rhythm that regulates the extracellular calcification of MSCs. Studying mouse fibroblasts, we demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Thus, phosphorylation by AMPK enables cryptochrome to transduce nutrient signals to circadian clocks in mammalian peripheral organs. Cytoplasmic hnRNP D levels displayed a pattern that was reciprocal to the mcry1 oscillation. Knockdown of hnRNP D stabilized mcry1 mRNA and resulted in enhancement of the oscillation amplitude and a slight delay of the phase. Our results suggest that hnRNP D plays a role as a fine regulator contributing to the mcry1 mRNA turnover rate and the modulation of circadian rhythm. more than three mutations of conserved PER2 residues impaired not only binding to CRY1 but also subsequent nuclear translocation, although mutations of non-conserved residues did not affect interaction with CRY1. Thus, the conserved amino acid residues of 1179-1198 in PER2 are apparently responsible for binding to CRY1. Cryptochrome 1 and 2 (Cry1 and Cry2) are considered essential for generating circadian rhythms in mammals. The role of Cry1 and Cry2 in circadian rhythm expression and acute light-induced suppression of pineal melatonin was assessed using Cry1 and Cry2 double-deficient mice (Cry1(-/-) /Cry2(-/-) ) developed from the C3H strain that synthesizes melatonin. Cryptochrome 1 (Cry1), an essential clock component, displays evening-time expression and serves as a strong repressor at morning-time elements (E box/E' box). A genetic complementation assay in Cry1(-/-):Cry2(-/-) cells revealed that substantial delay of Cry1 expression is required to restore circadian rhythmicity, and its prolonged delay slows circadian oscillation. Taken together, our data suggest that phase delay in Cry1 transcription is required for mammalian clock function. the 24-h mRNA rhythms of the following genes were suppressed in db/db mice compared with control mice: the clock genes period homolog 1/2 (Per1/2) and cryptochrome 1/2 (Cry1/2) and their target genes D site albumin promoter-binding protein (Dbp) and peroxisome proliferator-activated receptor-γ (Pparg) in the aorta and mesenteric arteries; Dbp in the heart; Per1, nuclear receptor subfamily 1, group D, member 1 (Rev-erba), and Dbp in the kidney; and Per1 in the suprachiasmatic nucleus. In mammals, circadian rhythms in behavior and physiology are controlled by a central pacemaker, the SCN, and subordinated clocks throughout the body. On the molecular level, these clocks are based on transcriptional/translational feedback loops involving a set of clock genes that regulate their own transcription. Among the components driving the mammalian circadian clock are the Period 1 and 2 (Per1 and Per2) and Cryptochrome 1 and 2 (Cry1 and Cry2) genes. I circadian rhythm protein CRY1. The mammalian clock protein, cryptochrome 1 (CRY1), is degraded via the FBXL3-mediated ubiquitination pathway, suggesting that it is also likely to be targeted by the deubiquitination pathway. Here, we identified that USP2a, a circadian-controlled deubiquitinating enzyme, interacts with CRY1 and enhances its protein stability via deubiquitination upon serum shock. Depletion of Usp2a by shRNA greatly enhances the ubiquitination of CRY1 and dampens the oscillation amplitude of the CRY1 protein during a circadian cycle. By stabilizing the CRY1 protein, USP2a represses the Per2 promoter activity as well as the endogenous Per2 gene expression. We also demonstrated that USP2a-dependent deubiquitination and stabilization of the CRY1 protein occur in the mouse liver. The clock gene Period2 (per2)-knockout mice are sensitive to carbon tetrachloride-induced hepatotoxicity [18], but are less sensitive to acetaminophen hepatotoxicity when injected at night-time (20∶00) with a decreased expression of Cyp1a2, a P450 enzyme gene implicated in acetaminophen bioactivation [19]. Only cryptochrome 1(Cry1) mRNA exhibited marked fluctuation with a 17-fold peak/trough ratio for females and 27-fold peak/trough radio for males during the dark phase. These clock gene expression patterns indicate that the outbred KM mouse livers had typical circadian rhythms and were valid for further investigations. Interestingly, except for Cry1 and Dbp, other four clock genes were highly expressed in females. Mammalian circadian clocks are based on a transcription and translation feedback loop in which a heterodimer of the transcription factors circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1) drives transcription from E-box elements, including that of their own repressors, the Period (Per1, Per2 and Per3) and Cryptochrome (Cry1 and Cry2) genes2. whether Cry1 can interact with two NRs known to modulate clock function—the retinoid-related orphan receptors (ROR α/β/γ) and Reverb α/β. Unexpectedly, we find robust association between Cry1 and RORα and γ but not with RORβ or Reverb α/β though we did reproduce the reported association of PER2 with Reverb α16 (Fig. 1A–B). discovered a robust physical association of Cry1 with the glucocorticoid and androgen receptors (GR and AR, respectively) ( Cry1 represses the ability of GR to drive expression of a luciferase reporter from a GRE-containing promoter (Fig. 1G). Finally, we used a series of deletion mutants of GR to demonstrate that Cry1 interacts with the C-terminus of GR (Fig. 1H), which is required for either activation or repression of transcription in response to ligand. Steroid hormones (glucocorticoids, testosterone, progesterone and aldosterone) are critical regulators of metabolic and reproductive physiology so the possibility that they could be directly regulated by cryptochromes suggests a new mechanism by which circadian clocks modulate physiological rhythms. Cry1 and Cry2, central regulators of the circadian clock, also directly oppose Dex-induced GR activation. The mammalian circadian clock is composed of interlocking feedback loops. Cryptochrome is a central component in the core negative feedback loop, whereas Rev-Erbα, a member of the nuclear receptor family, is an essential component of the interlocking loop. By analyzing the Fbxl3 and Cryptochrome 1 double-mutant mice, we found that FBXL3 also regulates the amplitudes of E-box-driven gene expression. These two separate roles of FBXL3 in circadian feedback loops provide a mechanism that contributes to the period determination and robustness of the clock. </context> <question> What is the function of cryptochrome-1 in mouse? </question> <answer> component of the central and peripheral circadian clocks for generation of circadian rhythms in mice </answer>
<context> The human phospholamban Arg14-deletion mutant localizes to plasma membrane and interacts with the Na/K-ATPase. Moreover, PLN-R14Del did not co-immunoprecipitate with SERCA2a (as did WT-PLN), n this review, we attempted to highlight the functional significance of PLN in vertebrate cardiac physiology. We will refer to the huge literature on mammals in order to describe the molecular characteristics of this protein, its interaction with SERCA2a There is clear evidence for direct regulatory protein-protein interactions between phospholamban (PLN) and the Ca2+-ATPase of cardiac sarcoplasmic reticulum (SERCA2a) in cytoplasmic domains These results suggest that PLN modulates the apparent Ca2+ affinity of SERCA2a through intramembrane interactions, which are disrupted at long range and in concert with disruption of the well characterized cytoplasmic interactions. Phospholamban (PLN), a homopentameric, integral membrane protein, reversibly inhibits cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity through intramembrane interactions. The concentration of this inhibited complex is determined by the dissociation constant for the PLN pentamer (which is mutation-sensitive) and by the dissociation constant for the PLN/SERCA2a heterodimer (which is likely to be mutation-sensitive). These results support the proposal that PLN inhibition of SERCA2a involves, first, depolymerization of PLN and, second, the formation of inhibitory interactions between monomeric PLN and SERCA2a. SLN and PLN appear to bind to the same regulatory site in SERCA. However, in a ternary complex, PLN occupies the regulatory site and SLN binds to the exposed side of PLN and to SERCA. Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit SERCA2a. . Conversely, using anti-SERCA2a antibody, both PLN and acylphosphatase were co-immunoprecipitated with SERCA2a, and the PLN amount in the precipitate decreased with increasing acylphosphatase concentrations. Reconstitution of the cytoplasmic interaction between phospholamban and Ca(2+)-ATPase of cardiac sarcoplasmic reticulum. Phospholamban (PLN) reversibly inhibits the Ca(2+)-ATPase of cardiac sarcoplasmic reticulum (SERCA2a) through a direct protein-protein interaction, playing a pivotal role in the regulation of intracellular Ca(2+) in heart muscle cells. Phospholamban (PLN) is a key regulator of Ca(2+) homeostasis and contractility in the heart. Its regulatory effects are mediated through its interaction with the sarcoplasmic reticulum Ca(2+)-ATPase, (SERCA2a), resulting in alterations of its Ca(2+)-affinity In a co-immunoprecipitation of PLN with SERCA2a, the physical interaction between the two proteins was increased in PUGNAc-treated cardiomyocytes. </context> <question> Does Serca2a bind PLN in the heart? </question> <answer> yes </answer>
<context> UGT1A1*28/*28 genotype was associated with more than fourfold (odds ratio (OR)=4.79, 95% confidence intervals (CI): 3.28-7.01; P<0.00001) and threefold (OR=3.44, 95% CI: 2.45-4.82; P<0.00001) increases in the risk of neutropenia when compared with wild type and with at least one UGT1A1*1 allele, respectively. Differences in TR, PFS and OS for any genotype comparison, UGT1A1*28/*28 versus (vs) UGT1A1*1/*1 (homozygous model), UGT1A1*1/*28 vs UGT1A1*1/*1 (heterozygous model), and UGT1A1*28/*28 vs all others (recessive model, only for TR) were not statistically significant. UGT1A1*28 polymorphism cannot be considered as a reliable predictor of TR and PFS in CRC patients treated with IRI-based chemotherapy. The OS relationship with UGT1A1*28 in the patients with lower-dose IRI chemotherapy requires further validation. These variants are associated with greater risk of serious toxicity. Homozygous carriers of UGT1A1*28 as well as those with additional UGT1A variants can suffer from severe irinotecan toxicity </context> <question> Is the UGT1A1*28 polymorphism associated with irinotecan response in Caucasians? </question> <answer> yes </answer>
<context> Our findings establish that p43 is an important regulator of glucose homeostasis and pancreatic β-cell function and provide evidence for the first time of a physiological role for a mitochondrial endocrine receptor. The p43(-/-) mice had a major defect in insulin secretion both in vivo and in isolated pancreatic islets and a loss of glucose-stimulated insulin secretion. We demonstrated that treatment of primary cultures of rat pancreatic islets with T3 results in augmented β-cell vitality with an increase of their functional properties. Nonetheless, the insulin secretion is sensibly augmented after T3 stimulation. Plasma glucose concentration of the fetal hypothyroid group during intravenous glucose tolerance test was significantly higher (p=0.003) at 5-20 min as compared to the control group, whereas plasma insulin concentration was significantly lower (p=0.012) at 5-20 min Although adult offspring born from hypothyroid mothers were euthyroid, their glucose tolerance and glucose stimulated insulin secretion of islets were altered hyroid hormones modulate the immune system and metabolism, influence insulin secretion Only T(3) concentrations higher than 250 microM were able to decrease cell viability and proliferation rate, to increase the rate of apoptosis and to reduce glucose-induced insulin secretion. Islets preincubated with glucose (3.3 mmol/l) and glucagon (1.4 mumol/l) plus theophylline (10 mmol/l), ACTH (0.11 nmol/l), bovine GH (0.46 mumol/l), prolactin (0.2 mumol/l) or tri-iodothyronine (1.0 nmol/l) have significantly lower Ca(2+)-ATPase activity than those preincubated with only 3.3 mmol glucose/l. All these hormones increased the release of insulin significantly. T3 (0.2 nM) did not affect insulin secretion in the absence or presence of glucose or in the presence of secretagogues (potassium and glyceraldehyde). In the perfused rat pancreas, the addition of thyroxine (10 micrograms/dL) or 3,5,3'-triiodothyronine (150 ng/dL) to the perfusing medium did not affect insulin secretion. The administration of thyroxine (40 micrograms/kg, s.c.) in vivo increased the plasma insulin level from 11 +/- 2 microUnits/mL (mean +/- SD) to 30 +/- 7 microUnits/mL Addition of T3 to the incubation medium, significantly modified the insulin release, but its effect varied according to the glucose concentration in the medium, i.e. it enhanced the insulin release at a glucose concentration between 2 to 8 mmol/l; it has no effect at 12 mmol/glucose, and significantly inhibited the secretion of insulin in the presence of 16.6 mmol/l glucose. Both T3 and T4 inhibited insulin secretion </context> <question> Does triiodothyronine play a regulatory role in insulin secretion from pancreas? </question> <answer> yes </answer>
<context> In diabetic vs. nondiabetic patients T(1)AM concentration was significantly increased (0.232 ± 0.014 vs. 0.203 ± 0.006 pmol/ml, P = 0.044), Our results are consistent with the hypothesis that circulating T(1)AM is produced from thyroid hormones and encourage further investigations on the potential role of T(1)AM in insulin resistance exogenous T3 lowered blood glucose in db/db mice, a model of type 2 diabetes. T3 potentiated insulin signaling, improved insulin sensitivity, and increased insulin synthesis, which may contribute to its anti-diabetic effects. TRalpha P398H mutation is associated with visceral adiposity and insulin resistance </context> <question> How does thyroid hormone affect insulin resistance in the heart? </question> <answer> T3 potentiates insulin signaling and improves insulin sensitivity. In addition, T3 lowers blood glucose in a model of type 2 diabetes. TRalpha P398H mutation is associated with insulin resistance. Circulating T(1)AM is produced from thyroid hormones and is found to be increased in diabetic patients. </answer>
<context> The results indicate that mutations in TPM2 may cause nemaline myopathy as well as cap disease with a dominant mode of inheritance. Autosomal recessive inheritance had been verified or appeared likely in all nebulin cases Most cases were sporadic, but in addition there were instances of both autosomal dominant and autosomal recessive inheritance, while two families showed mosaicism for dominant mutations. Finding the causative mutation(s) determines the mode of inheritance We conclude that in the Finnish CNM patients, the mode of inheritance appears to be recessive. Apart from a few instances of dominant inheritance, most cases published also seem compatible with recessive inheritance. </context> <question> What is the mode of inheritance of nemaline myopathy? </question> <answer> autosomal dominant' 'autosomal recessive </answer>
<context> loss of Thra protects mice from high-fat diet-induced hepatic steatosis and hepatic and peripheral insulin resistance. liganded TR(alpha) plays a critical role in beta-cell replication and in expansion of the beta-cell mass during postnatal development. Thus, liganded TR(alpha) may be a target for therapeutic strategies that can induce the expansion and regeneration of beta-cells. the TRalpha P398H mutation is associated with visceral adiposity and insulin resistance </context> <question> What is the role of thyroid hormone receptor alpha1 in insulin secretion? </question> <answer> Liganded TR(alpha) plays a critical role in beta-cell replication and in expansion of the beta-cell mass. the TRalpha P398H mutation which cannot bind T3, is associated with insulin resistance. Loss of Thra protects mice from high-fat diet-induced hepatic and peripheral insulin resistance. </answer>
<context> These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2-dependent mechanisms. The improved cardiac function was associated with decreased atrial natriuretic peptide mRNA levels in the metformin-treated group (50% reduction compared with MI, P < 0.05). Molecular analyses suggested that altered AMP kinase phosphorylation status and low insulin levels mediate the salutary effects of metformin. AMP-activated protein kinase (AMPK) is a key sensor of cellular energy. The activation of AMPK by metformin prevents cardiac remodeling after myocardial infarction (MI). These results suggest that AMPK activation by metformin and the subsequent suppression of TLRs activity could be considered as a target in protecting the infarcted heart, which may indicate a link between AMPK and TLRs. Specifically, AMPK plays a central role in myocardial remodeling by attenuating the growth and proliferation of cardiac fibroblasts. In a mouse model of postinfarction HF, metformin treatment for 4 weeks improved ventricular function, an effect that was mediated through activation of AMPK and eNOS </context> <question> What is the role of AMPK kinase in myocardial remodeling after myocardial infarction </question> <answer> AMP-activated protein kinase (AMPK) is a key sensor of cellular energy. The activation of AMPK by metformin prevents cardiac remodeling after myocardial infarction (MI). \nAdiponectin protects the heart from ischemia-reperfusion injury through an AMPK-dependent mechanism.\nAMPK activation by metformin and the subsequent suppression of TLRs activity could be considered as a target in protecting the infarcted heart. </answer>
<context> We demonstrated that thyroid hormone T3 rapidly induces Akt activation in pancreatic beta cells rRINm5F and hCM via thyroid hormone receptor (TR) beta1. The silencing of TRbeta1 expression through RNAi confirmed this receptor to be crucial for the T3-induced activation of Akt. T3 is able to specifically activate Akt in the islet beta cells rRINm5F and hCM through the interaction between TRbeta1 and PI3K p85alpha, demonstrating the involvement of TRbeta1 in this novel T3 non-genomic action in islet beta cells. </context> <question> Does thyroid hormone receptor beta1 affect insulin secretion? </question> <answer> no </answer>
<context> our data suggests that TRbeta1-mediated down regulation of hepatic LDLr gene may play a critical role in iodine excess-induced hypercholesterolemic effects. These data suggest that ChREBP mRNA expression is positively regulated by TR-beta1 and TH at the transcriptional level in mammals. This novel observation indicates that TH fine-tunes hepatic lipogenesis via regulating SREBP-1c and ChREBP gene expression reciprocally. In contrast treatment with L-T3 produced an increase in S14 and ME but no change in TR beta-/- mice. From these results, it can be concluded that regulation of HR and EE are independent of TR beta. With the exception of serum cholesterol concentration and liver ME mRNA accumulation, all other markers of TH action examined during TH deprivation exhibited the expected responses in the absence of TR beta. However, the T3-activated expression of the GH gene in GH3-PV and ME gene in SK-Hep-1-PV was repressed by approximately 30% and 90%, respectively, indicating the lack of correlation of PV/TRpbeta1 protein ratio with the dominant negative potency of mutant PV. Transient cotransfection of P450R promoter/chloramphenicol acetyl transferase (CAT) constructs and the thyroid hormone receptor beta1 (TR beta1) expression plasmid into rat hepatoma H4IIE cells resulted in a 2.4-fold induction of promoter activity that was both T3 and TR beta1 dependent. At the molecular level, we detected a dose-dependent attenuation of hepatic low density lipoprotein receptor (LDLr) and thyroid hormone receptor beta1 (TRbeta1) expression in parallel to the change of serum cholesterol. </context> <question> Which genes does thyroid hormone receptor beta1 regulate in the liver? </question> <answer> LDL receptor; ChREBP', 'Carbohydrate response element binding protein; ME', 'malic enzyme; cytochrome P450 oxidoreductase </answer>
<context> Mice expressing the mutant thyroid hormone receptor TRalpha1R384C, which has a 10-fold reduced affinity to the ligand T(3), exhibit hypermetabolism due to an overactivation of the sympathetic nervous system. To define the consequences in the liver, we analyzed hepatic metabolism and the regulation of liver genes in the mutant mice. Our results showed that hepatic phosphoenolpyruvate-carboxykinase was up-regulated and pyruvate kinase mRNA down-regulated, contrary to what observed after T(3) treatment Remarkably, there was an obligatory requirement for a TR, whether TRbeta or TRalpha1, for any detectable D1 expression in liver. Liver and kidney D1 mRNA and activity levels were reduced in TRbeta(-/-) but not TRalpha1(-/-) mice </context> <question> Which genes does thyroid hormone receptor alpha1 regulate in the liver? </question> <answer> phosphoenolpyruvate-carboxykinase; pyruvate kinase; D1', 'deiodinase 1 </answer>
<context> e show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a. On the other hand, T₃ treatment increased miR-350 expression. Through a bioinformatics screening using TargetScan, we identified thyroid hormone receptor β1 (TRβ1), which negatively regulates β-MHC transcription, as a target of miR-27a hese findings suggested that miR-27a regulates β-MHC gene expression by targeting TRβ1 in cardiomyocytes. We found that a cardiac-specific microRNA (miR-208) encoded by an intron of the alphaMHC gene is required for cardiomyocyte hypertrophy, fibrosis, and expression of betaMHC in response to stress and hypothyroidism. Moreover, miR-27a was demonstrated to modulate β-MHC gene regulation via thyroid hormone signaling and to be upregulated during the differentiation of mouse embryonic stem (ES) cells or in hypertrophic hearts in association with β-MHC gene upregulation. </context> <question> Does thyroid hormone signaling affect microRNAs expression in the heart? </question> <answer> yes </answer>
<context> The ethanolic extract of Cucumis sativus Linn, Cucumis melo utilissimum Roxb, Cucumis melo Linn, Benincasa hispida Thunb Cogn and Tricosanthes anguina Nees, when administered in 250 mg/kg dose, orally to rats failed to lower blood sugar or to depress the peak value, after glucose load. Ethanolic extract of Tricosanthes dioica Roxb plant caused a significant lowering of blood sugar in fasted rats and depressed the peak value in glucose loaded single and longterm fed groups of rats. The ethanolic extract of the aerial part of T. dioica also induced significant depression in the peak values in the glucose loaded models. The amount of sucrose in ordinary marinated foods, such as herring, cucumber, and common beet was negligible Dietary saponins of sea cucumber ameliorate obesity, hepatic steatosis, and glucose intolerance in high-fat diet-fed mice. In this study, we investigated the effects of saponins of sea cucumber (SSC) on high-fat diet-induced obesity, insulin resistance, and fatty liver in mice. Mice administrated with 0.1% SSC had significantly decreased serum glucose and insulin levels, lower homeostatic model assessment for insulin resistance index, and area under the blood glucose curve, suggesting that insulin sensitivity is enhanced by dietary SSC. [Effects of sea cucumber cerebroside and its long-chain base on lipid and glucose metabolism in obese mice]. OBJECTIVE: To investigate the effect of sea cucumber cerebroside(SCC) and its long-chain base(LCB) on lipid and glucose metabolism in obese mice. CONCLUSIONS: Sea cucumber cerebroside and its long-chain base can improve the glucose and lipid metabolism in obese mice. Evaluation of the Hypoglycemic Activity of Cucumis metuliferus (Cucurbitaceae) Fruit Pulp Extract in Normoglycemic and Alloxan-Induced Hyperglycemic Rats. The hitherto unknown glucose regulating role of three vegetable peels from cucurbitaceae family was evaluated. In a preliminary study, effects of ethanolic extracts of Cucurbita pepo, Cucumis sativus and Praecitrullus fistulosus peels were studied at 250 and 500 mg kg(-1) d(-1) for 15 days in the alterations in serum glucose and in hepatic lipid peroxidation (LPO) in male mice. All the three peel extracts nearly reversed most of these changes induced by alloxan suggesting their possible role in ameliorating diabetes mellitus and related changes in serum lipids. Antidiabetic activity of aqueous fruit extract of Cucumis trigonus Roxb. in streptozotocin-induced-diabetic rats. Cucumis trigonus Roxb. (Cucurbitaceae) fruit is used in the Indian traditional medicine for the treatment of diabetes. Based on a number of reports on the blood glucose level reduction and the other complications of diabetes associated with some Cucurbitaceae plants, the antidiabetic effect of Cucumis trigonus fruit was investigated. The antidiabetic activity of aqueous extract of Cucumis trigonus fruit was evaluated by using normal and streptozotocin-induced-diabetic rats. The aqueous fruit extract of Cucumis trigonus has had beneficial effects in reducing the elevated blood glucose level and lipid profile of STZ-induced-diabetic rats. Possible amelioration of atherogenic diet induced dyslipidemia, hypothyroidism and hyperglycemia by the peel extracts of Mangifera indica, Cucumis melo and Citrullus vulgaris fruits in rats. Hitherto unknown efficacy of the peel extracts of Mangifera indica (MI), Cucumis melo (CM) and Citrullus vulgaris (CV) fruits in ameliorating the diet-induced alterations in dyslipidemia, thyroid dysfunction and diabetes mellitus have been investigated in rats. Rats, treated simultaneously with either of the peel extracts reversed the CCT-diet induced increase in the levels of tissue LPO, serum lipids, glucose, creatinine kinase-MB and decrease in the levels of thyroid hormones and insulin indicating their potential to ameliorate the diet induced alterations in serum lipids, thyroid dysfunctions and hyperglycemia/diabetes mellitus. Role of pectin from cucumber (Cucumis sativus) in modulation of protein kinase C activity and regulation of glycogen metabolism in rats. The regulatory role of protein kinase C (PKC) in glycogen metabolism in pectin fed rats was investigated. Administration of pectin (5 g/kg body wt/day) from cucumber (Cucumis sativius L.) led to inhibitory effects on PKC activity in the liver of rats. In the brain and pancreas, PKC activity was significantly higher in pectin-treated rats as compared to the control group. Level of blood glucose was significantly lowered and the level of glycogen in the liver was significantly increased in pectin-administered rats. Addition of fermented milk (yogurt) and pickled cucumber to a breakfast with a high-glycemic index bread significantly lowered postprandial glycemia and insulinemia compared with the reference meal. In contrast, addition of regular milk and fresh cucumber had no favorable effect on the metabolic responses. Tolbutamide, Cucurbita ficifolia, Phaseolus vulgaris, Opuntia streptacantha, Spinacea oleracea, Cucumis sativus and Cuminum cyminum decrease significantly the area under the glucose tolerance curve and the hyperglycemic peak. Two unsaturated fatty acids with potent α-glucosidase inhibitory activity purified from the body wall of sea cucumber (Stichopus japonicus). In this study, 2 fatty acids with strong α-glucosidase-inhibitory activity, 7(Z)-octadecenoic acid and 7(Z),10(Z)-octadecadienoic acid, were purified and identified from sea cucumber. Therefore, sea cucumber fatty acids can potentially be developed as a novel natural nutraceutical for the management of type-2 diabetes. </context> <question> Does cucumber lower blood sugar in diabetics? </question> <answer> yes </answer>
<context> In the traditional model at least two different families of MTases were proposed to exist in eukaryotes: one family that is required for de novo methylation of DNA targeting un-methylated DNA, while the other family is specific for hemi-methylated DNA copying the methylation pattern in every replication cycle [2], [12]. In fact this traditional model holds mostly true, however, the de novo DNA nucleotide methyltransferases (DNMT3a/3b) and the maintenance DNA nucleotide methyltransferases (DNMT1) have partially overlapping functions and are supported by a number of other proteins [4], [13], [14]. However, there is also a third family of eukaryotic DNA nucleotide methyltransferases (DNMT2) that is widely distributed and highly conserved [19], [20]. Broadly, eukaryotic DNA methyltransferases can be classified into the Dnmt1 and Dnmt3 families with several subfamilies [3], [4], [5], [6]. The Dnmt2 proteins contain all the sequence motifs characteristic for DNA-(cytosine C5)-MTases and the Dnmt2 structure strongly resemble prokaryotic DNA MTases [14], [15], but in contrast to all other mammalian DNA MTases, Dnmt2 does not possess a large N-terminal regulatory domain. However, if such transition happened at all, it must have occurred long before the development of eukaryotic cells, because the wide distribution of the Dnmt1, Dnmt2 and Dnmt3 enzyme families in eukaryotes clearly indicates that all these enzymes were present already in the last eukaryotic common ancestor (LECA) (Fig. 6). I Most likely, the eukaryotic Dnmt2, Dnmt1 and Dnmt3 families of methyltransferases had an independent origin in the prokaryotic DNA methyltransferase sequence space and all were derived from MTases of RM systems. Of the DNMTs, DNMT1 and DNMT3a are most highly expressed in postmitotic neurons. DNA methyltransferase 3B (Dnmt3b) belongs to a family of enzymes responsible for methylation of cytosine residues in mammals. Bovine DNA methylation imprints are established in an oocyte size-specific manner, which are coordinated with the expression of the DNMT3 family proteins. The specific transfer of methyl groups to form 5mC is catalyzed by members of the DNA methyltransferase (DNMT) protein family. Three classes of DNMTs have been identified in mammals: DNMT1, DNMT2 and DNMT3 (including DNMT3a, DNMT3b and DNMT3L isoforms) (3,4). All of them share homologous catalytic domains but differ in their regulatory, protein–DNA- and protein–protein-binding regions. .There are three enzymes in the DNA (cytosine-5-)-methyltransferase (DNMT) family: DNMT1, DNMT 3 alpha (DNMT3A), and DNMT 3 beta (DNMT3B). All catalyze DNA methylation activity. DNMT1 is a member of the maintenance-type methyltransferase family, which is responsible for the maintenance of DNA methylation patterns [5]. DNMT3A and the closely related DNMT3B are de novo methyltransferases, which are responsible for the establishment of new methylation patterns [2], [5]. The DNMT3B de novo DNA methyltransferase (DNMT) plays a major role in establishing DNA methylation patterns in early mammalian development, but its catalytic mechanism remains poorly characterized. Genome-wide patterns of DNA methylation in mammals are established and maintained by a family of three enzymatically active DNA methyltransferases: DNMT1, DNMT3A and DNMT3B, and a fourth catalytically inactive co-factor, DNMT3L. This de novo methylation function is assigned primarily to the DNMT3 family of DNA methyltransferases (DNMTs) [9]. This family comprises the two active DNMT3A and DNMT3B enzymes, which are highly expressed at specific developmental times in germ cells and during early development, and mediate genome-wide acquisition of DNA methylation. Dnmt2 proteins are the most conserved members of the DNA methyltransferase enzyme family, but their substrate specificity and biological functions have been a subject of controversy. Occurring exclusively at cytosine within CpG dinucleotides in mammals, DNA methylation is coordinated by a family of DNA methyltransferases (DNMTs)5 comprising DNMT1, -3A, -3B, and -3L. DNMT1 is the “maintenance” methyltransferase that ensures faithful transmission of methylation profile from maternal to daughter cells during cell division. In contrast, DNMT3A and -3B are de novo methyltransferases that show a degree of specificity in both target sequence and temporal activity (reviewed in Ref. 1). DNMT3L (DNMT3-like) lacks catalytic activity and has a very restricted gene expression profile (2). This promoter hypermethylation may be mediated not only by DNMT-1 but also by an entire family of de novo DNA-methyltransferases, such as DNA-methyltransferase-3a (DNMT-3a) and -3b (DNMT-3b). Within the family of DNA methyltransferases (Dnmts), Dnmt3a and 3b establish methylation marks during early development, while Dnmt1 maintains methylation patterns after DNA replication. The maintenance function of Dnmt1 is regulated by its large regulatory N-terminal domain that interacts with other chromatin factors and is essential for the recognition of hemi-methylated DNA. In this study, we examined a role for the DNA methyltransferase DNMT3B, in particular, the truncated isoform DNMT3B7, which is generated frequently in cancer. Methylation is carried out by 5-cytosine DNA-methyltransferases (5 mC DNA MTases; EC 2.1.1.37) DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. Figure 5.Tet1 negatively regulates de novo DNA methyltransferase Dnmt3b. DNA methyltransferases (DNMTs) are a family of related proteins that both catalyze the de novo formation of 5-methylcytosine and maintain these methylation marks in cell-specific patterns in virtually all mitotic cells of the body. Moreover, recent genome-wide bisulfite sequencing efforts have revealed clear local sequence preferences for cytosine methylation in A. thaliana, an organism that harbors two de novo DNA methyltransferases distantly related to the mammalian DNMT3A and DNMT3B enzymes [26], [27]. This methylation is critical for imprinting; a reduction in the DNA methyltransferase DNMT1 causes a widespread loss of imprinting. Occurring exclusively at cytosine within CpG dinucleotides in mammals, DNA methylation is coordinated by a family of DNA methyltransferases (DNMTs)5 comprising DNMT1, -3A, -3B, and -3L. DNA methyltransferase 3B (DNMT3B) is the key methyltransferase in DNA methylation regulations. DNA methyltransferases (DNMTs) are a family of enzymes that methylate DNA at the C5 position of cytosine residues, and their inhibition is a promising strategy for the treatment of various developmental and proliferative diseases, particularly cancers. DNA methylation is mediated by a family of DNA methyltransferases. These results suggest that DNMT1 and DNMT3B regulate BAG-1 expression via insulator protein DNA-binding and chromatin dynamics by regulating histone dimethylation. Here we show that human miR-148 represses DNA methyltransferase 3b (Dnmt3b) gene expression through a region in its coding sequence. DNA methylation is catalyzed by a family of DNA methyltransferases (DNMTs) including the maintenance enzyme DNMT 1 and de novo methyltransferases DNMT 3a and DNMT 3b. Among the reported down-regulated miRNAs in lung cancer, the miRNA (miR)-29 family (29a, 29b, and 29c) has intriguing complementarities to the 3'-UTRs of DNA methyltransferase (DNMT)3A and -3B (de novo methyltransferases), two key enzymes involved in DNA methylation, that are frequently up-regulated in lung cancer and associated with poor prognosis. Furthermore, we have examined the roles of the de novo methyltransferases (Dnmt3a and Dnmt3b) and related protein (Dnmt3L) in this process. DNA methyltransferase 1 (DNMT1) has been reported to interact with a wide variety of factors and to contain intrinsic transcriptional repressor activity. Inactivation of both Dnmt3a and Dnmt3b, DNA methyltransferases essential for the initiation of de novo DNA methylation, abolished the establishment of DNA methylation and the silencing of Rhox cluster genes in the embryo proper. Rather, in vitro analysis indicates that Dnmt3L stimulates DNA methylation by both Dnmt3a and Dnmt3b through direct binding to these proteins. BackgroundThe epigenetic modification of DNA by the addition of a methyl group to the 5 position of cytosine is an important mechanism for control of gene expression in vertebrates. OBJECTIVE: To investigate the association between single nucleotide polymorphism (SNP) in promoter of the DNA methyltransferase 3B (DNMT3B) gene and risk for development and lymphatic metastasis of gastric cardiac adenocarcinoma (GCA). Methylation at the 5-position of DNA cytosine on the vertebrate genomes is accomplished by the combined catalytic actions of three DNA methyltransferases (DNMTs), the de novo enzymes DNMT3A and DNMT3B and the maintenance enzyme DNMT1. There are two major categories of DNA methyltransferases: de novo and maintenance. Some, but not all, murine H1 subtypes interact with DNA methyltransferases DNMT1 and DNMT3B. </context> <question> Which are the families of mammalian DNA-(cytosine-5)-methyltransferases? </question> <answer> DNMT1; DNMT2; DNMT3 </answer>
<context> Administration of debutyl-dronedarone (DBD), a TRα1 antagonist abolished the T3-limiting effect on reperfusion injury: Dron affected TR expression in the RA similarly by decreasing TRalpha 1 and beta 1 expression by about 50%. In the LVW, AM and Dron decreased TRbeta 1 Hypothyroid heart displays a phenotype of cardioprotection against ischemia and this study investigated whether administration of dronedarone, an amiodarone-like compound that has been shown to preferentially antagonize thyroid hormone binding to thyroid hormone receptor alpha1 (TRalpha1), dronedarone treatment results in cardioprotection by selectively mimicking hypothyroidism. The in vitro and in vivo findings suggest that dronedarone via its metabolite debutyldronedarone acts as a TRalpha(1)-selective inhibitor. Amiodarone resulted in increased T4, T4/T3 and rT3, whereas dronedarone did not alter the thyroid hormone profile in normal animals. </context> <question> How does dronedarone affect thyroid hormone signaling in the heart? </question> <answer> Dronedarone via its metabolite debutyldronedarone acts as a TRalpha(1)-selective inhibitor and selectively mimicks hypothyroidism.\nDronedarone decreases TRalpha 1 and beta 1 expression by about 50% in the right atrium (RA) while in the left ventricle, only TRbeta1 is found to be decreased. </answer>
<context> Amiodarone resulted in increased T4, T4/T3 and rT3, whereas dronedarone did not alter the thyroid hormone profile in normal animals. Fifty-five Wistar rats were randomly allocated to a 2-week oral treatment with either vehicle (n=18), amiodarone (30 mg/kg, n=20), or dronedarone (30 mg/kg, n=17). Thyroid function was similar in the 3 groups. Plasma levels of T3, T4, and rT3 were changed after SR 33589 treatment except a decrease in T4 level at the highest dose whilst the T4 T3 ratio and the level of rT3 were dose-dependently increased by amiodarone treatment. </context> <question> Does dronedarone affect T3 and T4 levels? </question> <answer> no </answer>
<context> AM and Dron affected TR expression in the RA similarly by decreasing TRalpha 1 and beta 1 expression by about 50% In the LVW, AM and Dron decreased TRbeta 1 and, interestingly, AM increased TRalpha 1. n the apex, AM also increased TRalpha 2. Both in treated and untreated mice, TRalpha2 mRNA had the highest density in mouse heart, whereas TRbeta2 mRNA had the lowest density. Amiodarone dose-dependently downregulated the levels of TRalpha1 and beta1 mRNA in comparison to the control. amiodarone subtype selectively downregulates the TR mRNA levels in mouse myocardium in a dose-dependent manner. Western blot analysis revealed no change in the expression of the ThR protein. Amiodarone and T3, respectively, downregulated T3R alpha 1, T3R beta 1, T3R beta 2 (p < 0.05), but did not affect the levels of T3R alpha 2. Amiodarone and T3, added together, upregulated T3R alpha 2 and T3R beta 1 (p < 0.05) as compared to amiodarone or T3 alone. </context> <question> Does amiodarone affect thyroid hormone receptors in the myocardium? </question> <answer> yes </answer>
<context> treatment of the cells with T(3) for 2 d induced the expression of thyroid hormone receptor-beta and caspase-3, and this thyroid hormone receptor-beta induction was drastically repressed by xTNF-alpha. </context> <question> How does TNF affect thyroid hormone receptors? </question> <answer> TNF-alpha inhibits the T3-induced expression of thyroid hormone receptor-beta </answer>
<context> PE, in the absence of T3, resulted in 5.0 fold increase in TRalpha1 expression in nucleus and 2.0 fold decrease in TRalpha1 expression in cytosol, P<0.05. nuclear TRalpha1 is overexpressed after prolonged activation of the alpha1- adrenergic signalling by PE. This response seems to be an ERK kinase dependent process. </context> <question> How does adrenergic signaling affect thyroid hormone receptors? </question> <answer> alpha1- adrenergic signalling increases TRalpha1 expression in nucleus and decreases TRalpha1 expression in cytosol. </answer>
<context> Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer Regions of focal hypermethylation in the tumor were located primarily at CpG islands and were concentrated within regions of long-range (>100 kb) hypomethylation. These hypomethylated domains covered nearly half of the genome and coincided with late replication and attachment to the nuclear lamina in human cell lines the confluence of hypermethylation and hypomethylation Comparison of CpG island hypermethylation and repetitive DNA hypomethylation in premalignant stages of gastric cancer CpG island hypermethylation and genomic DNA hypomethylation are found not only in gastric cancers but also in associated premalignant lesions Methylation of repetitive DNA elements in gastric lesions generally decreased with progression of the gastric lesion along the multistep carcinogenesi our findings suggest that CpG island hypermethylation and repetitive DNA hypomethylation are enhanced with progression of the gastric lesion DNA hypomethylation arises later in prostate cancer progression than CpG island hypermethylation Hypomethylation of CpG dinucleotides in genomic DNA was one of the first somatic epigenetic alterations discovered in human cancers. DNA hypomethylation is postulated to occur very early in almost all human cancers, perhaps facilitating genetic instability and cancer initiation and progression. Contrary to the prevailing view that global DNA hypomethylation changes occur extremely early in all human cancers, we show that reductions in (5me)C content in the genome occur very late in prostate cancer progression, appearing at a significant extent only at the stage of metastatic disease These findings provide evidence that DNA hypomethylation changes occur later in prostate carcinogenesis than the CpG island hypermethylation changes and occur heterogeneously during prostate cancer progression and metastatic dissemination. revealed a high incidence of hypermethylation only in poorly differentiated (early and late) tumors. In contrast to gene hypermethylation, genomic DNA hypomethylation, including hypomethylation of repetitive elements and loss of genomic 5-methyldeoxycytidine, occurred in both early and late stages of prostate cancer. Tumors have reduced levels of genomic DNA methylation and contain hypermethylated CpG islands The results are consistent with a specific defect in methylation of repetitive DNA sequences in human cancer. Both hypomethylation and hypermethylation in a 0.2-kb region of a DNA repeat in cancer Differential DNA hypermethylation and hypomethylation signatures in colorectal cancer Cancer cells are characterized by a generalized disruption of the DNA methylation pattern involving an overall decrease in the level of 5-methylcytosine together with regional hypermethylation of particular CpG islands We conclude that DNA hypermethylation and hypomethylation are independent processes and appear to play different roles in colorectal tumor progression </context> <question> Is cancer related to global DNA hypo or hypermethylation? </question> <answer> Global hypomethylation is coupled with focal hypermethylation at CpG islands </answer>
<context> Etoposide is effective as an anti-tumour drug by inhibiting eukaryotic DNA topoisomerase II via establishing a covalent complex with DNA benzoxazoles, benzimidazoles and related fused heterocyclic compounds, which exhibited significant eukaryotic DNA topoisomerase II inhibitory activity F14512, a polyamine-containing inhibitor of DNA topoisomerase II F14512, an epipodophyllotoxin derivative equipped with a spermine moiety, is selectively taken up by the polyamine transport system over-active in tumor cells Recent reports have proposed topoisomerase II alpha (TOP2A) biomarker status as a potential predictor of tumor responsiveness to doxorubicin (DOX) therapy F14512 combines an epipodophyllotoxin core-targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. The polyamine tail supports three complementary functions: (a) facilitate formulation of a water-soluble compound, (b) increase DNA binding to reinforce topoisomerase II inhibition, and (c) facilitate selective uptake by tumor cells via the PTS Twenty previously synthesized fused heterocyclic DNA-topoisomerase II (Topo II)-inhibiting compounds were investigated for their potential efficacy in various human cancer cell lines that were derived from different tumor entities In conclusion, compounds BD 13, BD 14, BD 16, D 23 and D 24 may be useful for the treatment of different multidrug-resistant cancer cells with cross resistance against "classical" Topo II-targeting drugs. ATPase domain of eukaryotic DNA topoisomerase II. Inhibition of ATPase activity by the anti-cancer drug bisdioxopiperazine and ATP/ADP-induced dimerization We tested the effects of two DNA topoisomerase II poisons, etoposide and doxorubicin the bisdioxopiperazine topoisomerase II catalytic inhibitor ICRF-187 Bisdioxopiperazine drugs such as ICRF-187 are catalytic inhibitors of DNA topoisomerase II, with at least two effects on the enzyme: namely, locking it in a closed-clamp form and inhibiting its ATPase activity These findings suggest that the difference in drug sensitivities to doxorubicin and etoposide in human lung cancer cell lines might not be explainable by the topoisomerase II alpha levels and topoisomerase II catalytic activity Reduced expression of DNA topoisomerase II confers resistance to etoposide (VP-16) in small cell lung cancer cell lines topoisomerase II-targeting anticancer agents, etoposide (VP-16) and teniposide (VM-26) the anti-cancer DNA topoisomerase II poison etoposide (VP-16 New DNA topoisomerase II inhibitors less prone to redox reactions, such as mitoxantrone and more recently the anthrapyrazoles, were developed to circumvent this toxicity Two anthrapyrazoles currently in clinical evaluation, DuP 941 (Losoxantrone) and DuP 937, were compared to other topoisomerase II inhibitors Among topoisomerase II inhibitors, the cytostatic potency was by decreasing order: mitoxantrone; doxorubicin, which was slightly greater than DuP 941, azatoxin; DuP 937; and amsacrine, which was much greater than VP-16 n an attempt to clarify the role of drug-induced protein-associated DNA breaks (i.e., DNA topoisomerase II-mediated DNA cleavage) in the cytotoxic activity of doxorubicin and etoposide The effect of combinations of the anthracycline aclarubicin and the topoisomerase II targeting drugs 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucopyra noside) (VP-16) and 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) was investigated in a clonogenic assay Antagonistic effect of aclarubicin The effect of combinations of the anthracyclines aclarubicin and daunorubicin was investigated in a clonogenic assay using the human small cell lung cancer cell line OC-NYH and a multidrug-resistant (MDR) murine subline of Ehrlich ascites tumor (EHR2/DNR+) the DNA topoisomerase II inhibitors doxorubicin and etoposide in both types of cancer cell lines the DNA topoisomerase II inhibitors doxorubicin and etoposide in human lung cancer cell lines cells are cross-resistant to some drugs that interact with topoisomerase II but not mitoxantrone suramin decreases the phosphorylation of Topo II mediated by PKC. This effect of suramin might cause the inhibition of Topo II activity resulting in the growth inhibition of tumor cells. </context> <question> Which anticancer drugs target human topoisomerase II? </question> <answer> Etoposide (VP-16); Teniposide (VM-26); Doxorubicin; Daunorubicin; Aclarubicin; Mitoxantrone; Amsacrine (m-AMSA) </answer>
<context> our study established a novel approach utilizing high-resolution SNP array to identify lincRNA candidates, which could functionally link to tumorigenesis lincRNAs have been increasingly acknowledged for their expressional dynamics and likely functional associations with cancers HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer HOTAIR knockdown in L3.6pL cells inhibited tumor growth in mouse xenograft model, further demonstrating the pro-oncogenic function of HOTAIR in pancreatic cancer Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis We hypothesized that altered HOTAIR expression may be involved in human cancer by promoting genomic relocalization of Polycomb complex and H3K27 trimethylation enforced expression of HOTAIR in four different breast cancer cell lines increased cancer cell invasion through Matrigel, a basement-membrane like extracellular matrix Long non-coding RNAs (lncRNAs) are pervasively transcribed in the genome and are emerging as new players in tumorigenesis due to their various functions in transcriptional, posttranscriptional and epigenetic mechanisms of gene regulation Long non-coding RNA H19 increases bladder cancer metastasis These data suggest that upregulated H19 enhances bladder cancer metastasis by associating with EZH2 and inhibiting E-cad expression lncRNA H19 is essential for human tumor growth Previous reports have demonstrated that HOTAIR associates with chromatin modifications in cooperation with the Polycomb complex PRC2, and promotes breast and colorectal cancer metastasis although the clinical significance of HOTAIR expression in HCC may not be as pronounced as that in breast and colorectal cancers, the current study demonstrates that HOTAIR expression is associated with HCC progression, warranting further studies. Long non-coding RNA HOTAIR is an independent prognostic marker for nasopharyngeal carcinoma progression and survival CRNDE is the gene symbol for Colorectal Neoplasia Differentially Expressed (non-protein-coding), a long non-coding RNA (lncRNA) gene that expresses multiple splice variants and displays a very tissue-specific pattern of expression We present evidence that the human lincRNA-RoR (RoR) is a strong negative regulator of p53 A major function of long non-coding RNAs (lncRNAs) is regulating gene expression through changes in chromatin state. Experimental evidence suggests that in cancer, they can influence Polycomb Repressive Complexes (PRC) to retarget to an occupancy pattern resembling that of the embryonic state. the expression level of lncRNA in the HOX locus, including HOTAIR, is a predictor of breast cancer metastasis A genetic variant in long non-coding RNA HULC contributes to risk of HBV-related hepatocellular carcinoma in a Chinese population Recently, several studies reported that lncRNAs were dysregulated in different caners reported the association between polymorphisms in lncRNAs and prostate cancer this is the first study that has provided evidence that common SNPs in lncRNAs might be associated with HCC susceptibility Long non-coding RNA influences radiosensitivity of colorectal carcinoma cell lines by regulating cyclin D1 expression A central role for long non-coding RNA in cancer Long non-coding RNA urothelial carcinoma associated 1 (UCA1) promotes human bladder cancer cell proliferation, but the underlying mechanism remains unknown UCA1 regulated cell cycle through CREB via PI3K-AKT dependent pathway in bladder cancer. Long non-coding RNA UCA1 regulated cell cycle distribution via CREB through PI3-K dependent pathway in bladder carcinoma cells overexpression of Yiya promotes cell cycle progression at the G1/S transition, therefore identifying Yiya as a cell-cycle-associated long non-coding RNA Human cancer long non-coding RNA transcriptomes The well-studied HOX antisense intergenic RNA (HOTAIR), for example, is highly expressed in breast cancers and breast cancer metastases and plays a role in retargeting chromatin remodeling complexes The long noncoding RNA HOTAIR has been reported as a poor prognostic biomarker in patients with breast cancer. The aim of the present study is to examine the expression pattern of HOTAIR in hepatocellular carcinoma (HCC) and its clinical significance as well as its biological role in tumor progression The high expression level of HOTAIR in HCC could be a candidate biomarker for predicting tumor recurrence in HCC patients who have undergone liver transplant therapy and might be a potential therapeutic target Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene A 42 kb region on human chromosome 9p21 encodes for three distinct tumor suppressors, p16(INK4A), p14(ARF) and p15(INK4B), and is altered in an estimated 30-40% of human tumors These results advance our understanding of the role of lncRNA-LET as a regulator of hypoxia signaling and offer new avenues for therapeutic intervention against cancer progression. Silencing MALAT1 is a potential novel therapeutic approach for this cancer. </context> <question> Do lincRNAs play a role in human cancer? </question> <answer> yes </answer>
<context> The Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome with facial abnormalities, broad thumbs, broad big toes and mental retardation as the main clinical features Many patients with RTS have been shown to have breakpoints in, and microdeletions of, chromosome 16p13.3 these breakpoints are restricted to a region that contains the gene for the human CREB binding protein (CBP), a nuclear protein participating as a co-activator in cyclic-AMP-regulated gene expression RTS was shown to be associated with disruption of the CREB-binding protein gene CBP (CREBBP), either by gross chromosomal rearrangements or by point mutations Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease A certain level of CREB-binding protein is essential for normal development, since inactivation of one allele causes Rubinstein-Taybi syndrome (RSTS) In 92 patients, we were able to identify a total of 36 mutations in CBP We extended the search for mutations to the EP300 gene and showed that mutations in EP300 also cause this disorder. Mutations in the CREBBP (CREB-binding protein gene) cause Rubinstein-Taybi syndrome (RSTS). Heterozygous CREBBP mutations were identified in 12 of the 21 patients: five frameshift mutations, three nonsense mutations, two splice-site mutations, and two missense mutations. It could be possible that genetic heterogeneity is related with novel mutations in other genes. identified a novel CREBBP missense mutation, c.2728A > G (predicting p.Thr910Ala) The p.Thr910Ala variant is outside the crucial histone acetyltransferase domain, and this may explain the mild and variable phenotype Rubinstein-Taybi syndrome (RSTS), a developmental disorder comprising abnormalities that include mental retardation, an unusual facial appearance, broad thumbs and big toes is frequently associated with molecular lesions in the CREB-binding protein gene, CREBBP Direct sequencing of CREBBP performed in 13 RSTS patients identified the three zinc fingers (CH1, CH2, CH3) and HAT domain as mutational hotspots in which ten novel pathogenic mutations were localized Chromosomal 16p microdeletion in Rubinstein-Taybi syndrome detected by oligonucleotide-based array comparative genomic hybridization bout 55% of patients have cytogenetic or molecular abnormalities in the Crebbp or E1A binding protein p300 (Ep300) gene, leaving the diagnosis in 45% of patients to rest on clinical features only It is caused by either a microdeletion at 16p13.3 or mutations in the CREB-binding protein (CREBBP or CBP) or EP300 gene (at 22q13 Novel cAMP binding protein-BP (CREBBP) mutation in a girl with Rubinstein-Taybi syndrome Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant disorder (prevalence 1:125,000) characterised by broad thumbs and halluces, facial dysmorphism, psychomotor development delay, skeletal defects, abnormalities in the posterior fossa and short stature. The known genetic causes are point mutations or deletions of the cAMP-response element binding protein-BP (CREBBP) (50-60% of the cases) and of the homologous gene E1A-binding protein (EP300) (5%) </context> <question> What is the genetic basis of Rubinstein-Taybi syndrome? </question> <answer> Mutations or/and deletions in the genes of the cAMP-response element binding protein-BP (CREBBP) (50-60% of the cases) and of the homologous gene E1A-binding protein (EP300) at 22q13 (5%). </answer>
<context> Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease To further explore the therapeutic potential of HDAC inhibitors, we have conducted preclinical trials with suberoylanilide hydroxamic acid (SAHA), a potent HDAC inhibitor, in the R6/2 HD mouse model. We show that SAHA crosses the blood-brain barrier and increases histone acetylation in the brain SAHA dramatically improved the motor impairment in R6/2 mice, clearly validating the pursuit of this class of compounds as HD therapeutics. dministration of histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) consistently shows therapeutic potential in HD models The molecular mechanisms by which SAHA exerts its beneficial and toxic effects are currently not clear chronic administration of SAHA decreases Hdac7 mRNA expression levels in mouse brain irrespective of the HD genotype. SAHA treatment selectively suppresses expression of HDAC7 in vitro SAHA resulted in the specific down-regulation of HDAC7 at the mRNA level SAHA has been reported to inhibit the eleven Zn2+ dependent HDAC enzymes Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage Suberoylanilide hydroxamic acid (SAHA) was the first HDAC inhibitor approved by the Food and Drug Administration for the sole use of cancer therapy. The purpose of this study was to explore the potential new indications of SAHA for therapy of neurodegenerative diseases in in vitro Parkinson's disease models The novel neurotrophic and neuroprotective effects of SAHA demonstrated in this study suggest that further study of this HDAC inhibitor could provide a new therapeutic approach to the treatment of neurodegenerative diseases SAHA displayed dose- and time-dependent prolongation of the survival and protection against neurotoxin-induced neuronal death of dopaminergic neurons neuroprotective effects of SAHA were mediated in part by promoting release of neurotrophic factors from astroglia through inhibition of histone deacetylation SAHA decreases HDAC 2 and 4 levels in vivo and improves molecular phenotypes in the R6/2 mouse model of Huntington's disease SAHA was shown to inhibit members of class I and class II HDACs at nanomolar concentrations SAHA can lead to the degradation of class IIa HDACs 4 and 5 via RANBP2 mediated proteasome degradation in vitro SAHA administration decreased HDAC4 protein levels in the cortex and brain stem but not in the hippocampus like HDAC4, SAHA decreased HDAC2 protein levels in cortex SAHA is predominantly an inhibitor of class I HDACs [23]. However, it can also bind to class IIa HDACs [24],[25] and has been shown to degrade class IIa HDACs at the protein level in vitro we might speculate that the mechanism through which SAHA leads to a reduction in HDAC4 is through RANBP2-mediated proteasome degradation as determined for cancer cell lines </context> <question> What is the effect of SAHA treatment in Huntington's disease? </question> <answer> Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage. SAHA is predominantly an inhibitor of class I HDACs. However, it can also bind to class IIa HDACs and has been shown to degrade class IIa HDACs at the protein level in vitro. The neuroprotective effects of SAHA were mediated in part by promoting release of neurotrophic factors from astroglia through inhibition of histone deacetylation. SAHA can lead to the degradation of class IIa HDACs 4 and 5 via RANBP2 mediated proteasome degradation in vitro. </answer>
<context> The peptide is bound in the conventional manner; i.e., the methyl-lysine is oriented on the opposite surface of SMYD3 from the SAM/Sinefungin methyl donor, with a narrow channel connecting the two surfaces of the SET domain. For radioactive based assays, 2 µCi S-adenosyl-L–[methyl-3H] methionine (SAM; Amersham Biosciences) was included as a methyl donor. While SAMe is a methyl donor, MTA is an inhibitor of methylation. SAMe can convert to MTA spontaneously, so the effect of exogenous SAMe may be mediated by MTA. Based on known SET domain structures, the mutations likely affect either the lysine-substrate binding pocket, the binding site for the adenosylmethionine methyl donor, or a critical tyrosine predicted to interact with the substrate lysine epsilon-amino group Also, S-adenosylhomocysteine or methyl donor deficiency inhibits RIZ1 and other H3 lysine 9 methylation activities. Angiosperms synthesize S-methylmethionine (SMM) from methionine (Met) and S-adenosylmethionine (AdoMet) in a unique reaction catalyzed by Met S-methyltransferase (MMT). SMM serves as methyl donor for Met synthesis from homocysteine, catalyzed by homocysteine S-methyltransferase (HMT). Plants synthesize S-methylmethionine (SMM) from S-adenosylmethionine (AdoMet), and methionine (Met) by a unique reaction and, like other organisms, use SMM as a methyl donor for Met synthesis from homocysteine (Hcy). AtHMT-1 and -2 both utilize l-SMM or (S,S)-AdoMet as a methyl donor in vitro and have higher affinities for SMM. When the serine residue is mutated to glutamic acid, which mimics the phosphorylated serine residue, the mutant CARM1 exhibits diminished ability to bind the methyl donor adenosylmethionine and diminished histone methylation activity. S-adenosylmethionine (SAMe), the major methyl donor for DNA and histone methylation was fed with ethanol for 1month in order to modify the effects of ethanol on rat liver. To investigate if tumor growth is dependent on the enzymatic activity of Ezh2, we developed a potent and selective small molecule inhibitor, EI1, which inhibits the enzymatic activity of Ezh2 through direct binding to the enzyme and competing with the methyl group donor S-Adenosyl methionine. The enzyme was capable of transferring methyl groups to selected lysine residues in a substrate protein using S-adenosyl-l-methionine (SAM) as the methyl donor. All the structures have the lone pair of electrons on Nξ of target lysine well aligned with the methyl donor group of AdoMet. SAM is the main methyl group donor for methyltransferases to modify DNA, RNA, protein, metabolites, or phospholipid target substrates. To control the enzymatic activity of vSET in vivo with an engineered S-adenosyl-l-methionine (SAM) analogue as methyl donor cofactor, we have carried out structure-guided design, synthesis, and characterization of orthogonal vSET methyltransferase mutant/SAM analogue pairs using a "bump-and-hole" strategy. Protein lysine methyltransferases are important regulators of epigenetic signaling. One of the well-studied PTMs, arginine methylation, is catalyzed by protein arginine methyltransferases (PRMTs) with SAM as the methyl donor. One class of such enzymes is SAM-dependent methyltransferases, a broad group of enzymes that have one property in common, the use of S-adenosylmethionine (SAM) as methyl group donor. While SAMe is a methyl donor, MTA is an inhibitor of methylation. The purified cytochrome can act as a methyl acceptor for a methyltransferase activity in the cell extract that uses S-adenosylmethionine as methyl donor. This enzyme utilizes S-adenosyl-L-methionine as the methyl donor. </context> <question> Which is the methyl donor of histone methyltransferases? </question> <answer> ['S-adenosyl-L–methionine' 'SAM' 'AdoMet' 'S-Adenosylmethionine' 'adenosylmethionine' 'S-Adenosyl methionine'] </answer>
<context> For robustness evaluation, we apply bootstrap and jackknife techniques to input data. An alignment confidence score capturing robustness to guide tree uncertainty. We build on the widely used bootstrap method for perturbing the phylogenetic tree. SuperTRI: A new approach based on branch support analyses of multiple independent data sets for assessing reliability of phylogenetic inferences. To overcome these limitations, we propose a new approach, called SuperTRI, which is based on the branch support analyses of the independent data sets, and where the reliability of the nodes is assessed using three measures: the supertree Bootstrap percentage and two other values calculated from the separate analyses: the mean branch support (mean Bootstrap percentage or mean posterior probability) and the reproducibility index. A variety of methods and computer programs are available for aligning multiple sequences, reconstructing phylogenetic trees, and estimating evolutionary parameters. Because true phylogenetic relationships are rarely known with certainty (cf. Hillis et al. 1992; Sousa et al. 2008), simulated data are used to investigate the accuracy and efficiency of phylogenetic reconstruction methods (e.g., Gaut and Lewis 1995; Huelsenbeck 1995), ancestral sequence reconstruction methods (e.g., Blanchette et al. 2004), or methods of sequence alignment (e.g., Nuin et al. 2006). They can also be used in parametric bootstrap analysis to calculate confidence intervals for parameter estimates or to estimate the null distribution for hypothesis testing (e.g., Goldman 1993). In contrast to other similar software, the program FreeTree (available at http://www.natur.cuni.cz/~flegr/programs/freetree or http://ijs.sgmjournals.org/content/vol51/issue3/) can also assess the robustness of the tree topology by bootstrap, jackknife or operational taxonomic unit-jackknife analysis. Unlike any previous tool for inferring phylogenies from rearrangement data, TIBA uses novel methods of robustness estimation to provide support values for the edges in the inferred tree. ImOSM: intermittent evolution and robustness of phylogenetic methods. Fast and accurate phylogenetic reconstruction from high-resolution whole-genome data and a novel robustness estimator. Moreover, whereas phylogenetic analyses from sequence data are deemed incomplete unless bootstrapping scores (a measure of confidence) are given for each tree edge, no equivalent to bootstrapping exists for rearrangement-based phylogenetic analysis. We also describe a novel approach to estimate the robustness of results-an equivalent to the bootstrapping analysis used in sequence-based phylogenetic reconstruction. However, with the latest program version of RAxML implementing partitioned analysis, rapid bootstrap functions, and the ability of parallel analyses, even very large data sets, can be analyzed in a reasonable amount of time. The standard deviation also suggests the reliability level of the branch order. Assessment of the reliability of a given phylogenetic hypothesis is an important step in phylogenetic analysis. The reliability of the phylogenetic trees was probed with the bootstrapping of 100 replicates of the original sequence alignments. </context> <question> By which methods can we evaluate the reliability of a phylogenetic tree? </question> <answer> bootstrap; jackknife </answer>
<context> We isolated human mononucleosomes bound by the bromodomain-containing proteins Brd2, Brd3 and Brd4, and by the chromodomain-containing heterochromatin proteins HP1 beta and HP1 alpha. Their hallmark is the presence of a chromodomain at the C-terminus of the integrase. The chromodomain exhibits structural characteristics similar to proteins of the heterochromatin protein 1 (HP1) family, which mediate the binding of each chromovirus type to specific histone variants. Chromodomain helicase DNA-binding protein 2 affects the repair of X-ray and UV-induced DNA damage. Chromodomain helicase DNA-binding proteins (CHD) belong to a group of highly conserved chromatin remodeling proteins that are implicated in regulation of transcription. In an effort to understand the physiological role of one of the CHD members in a mammalian model system, we developed a mutant mouse model for the Chd2 gene. Crystal structure of the chromodomain helicase DNA-binding protein 1 (Chd1) DNA-binding domain in complex with DNA. Because, in plants, DNA methylation can serve as a signal for H3-lysine9-dimethylation (H3K9me2), and subsequently for non-CG-context DNA methylation, SET-domain histone methyltransferase and chromodomain dna methyltransferase 3 (cmt3) mutations were introgressed. In suvh4 suvh5 suvh6 and cmt3 mutants, H3K9me2 associated with lacO repeats is diminished, but homologous pairing persists. Mutations in CHD7, the gene encoding chromodomain helicase DNA binding protein 7, are present in 60-80% of individuals with the CHARGE syndrome. Chromodomain is present in the integrase structures of blastopia and 412 subgroup LTR-retrotransposons and may facilitate the process of non-specific integration. Most fungal transposons of the Ty3/Gypsy superfamily are classified as Chromoviridae because of the presence of a chromointegrase (an integrase with a C-terminal chromodomain) [14]. The CHARGE syndrome is a multiple congenital malformation syndrome that usually results from deletion or heterozygous loss of function mutations of the chromodomain helicase DNA-binding protein 7 (CHD7) gene at 8q12.1. Mutations in critical residues of the chromodomain (F11A and W32A, Figure S2) or deletion of the Pc-box (ΔPc) inhibited the ability of CBX7 to extend the life span of cells [20]. In the present study, we also found that the deletion of Pc-box or chromodomain mutations only partially abolished the repressive effect of CBX7 on transcription of p16 in the transiently transfected cell lines. CHD5 is one of the nine members of the chromodomain helicase DNA-binding (CHD) family of enzymes that belong to the ATP-dependent chromatin remodeling protein SNF2 superfamily [8]. CHD protein structure is characterized by two N-terminal chromodomains and a SNF2-like ATPase central domain that defines the chromodomain remodeling proteins [9,10]. A causative mutation within the chromodomain helicase DNA-binding protein-7 gene, which plays an important role in the embryonic development, is present in 2/3 of affected patients. CHD1 is a subfamily member of the CHD family, which possesses a chromodomain, a helicase domain, and a DNA-binding domain. The chromatin organizer modifier domain (chromodomain) is present in proteins that contribute to chromatin organization and mediates their binding to methylated histone H3. Mass spectrometric analysis revealed serine-42, a conserved amino acid in the chromodomain, as a phosphorylation site of Cbx2. Phosphorylation of the chromodomain of Cbx2 on this residue in vitro resulted in a reduced level of binding to an H3 peptide containing trimethylated lysine-9 as well as an increase in the extent of binding to an H3 peptide containing trimethylated lysine-27, suggesting that such phosphorylation changes the binding specificity of Cbx2 for modified histone H3. Phosphorylation of the chromodomain of Cbx2 may therefore serve as a molecular switch that affects the reading of the histone modification code and thereby controls epigenetic cellular memory. Here we identify the ATP-dependent chromatin remodeling factor chromodomain helicase DNA-binding protein 8 (CHD8) as a novel coregulator of androgen-responsive transcription. According to the model, histone methyltransferase enzymes (HMTases) methylate the histone H3 at lysine 9 (H3K9me), creating selective binding sites for themselves and for the chromodomain of HP1a [12]. As Figure 1E shows, we found that only the HP1a fragments containing the chromodomain are capable of producing a gel shift of RNA. These results strongly suggest that the chromodomain region is required for the direct binding of HP1a to RNA transcripts.I Our data show that, among its multiple functions, HP1a is also involved in upregulation of many euchromatic genes at the postranscriptional level by an association of its chromodomain with the corresponding transcripts.T Mutations in CHD7, a chromodomain gene, are present in a majority of individuals with CHARGE syndrome, a multiple anomaly disorder characterized by ocular Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital hypoplasia and Ear anomalies. Two new chromodomain-containing proteins that associate with heterochromatin in Sciara coprophila chromosomes. Both proteins, ScoHET1 of 37 kDa and ScoHET2 of 44 kDa, display two chromodomain motifs that contain the conserved residues essential for the recognition of methylated histone H3 at lysine 9. In this study, we present a detailed histomorphologic characterization of mice containing a mutation in the chromodomain helicase DNA-binding protein 2 (Chd2). Specificity of the chromodomain Y chromosome family of chromodomains for lysine-methylated ARK(S/T) motifs. Previous studies have shown two homologous chromodomain modules in the HP1 and Polycomb proteins exhibit discriminatory binding to related methyllysine residues (embedded in ARKS motifs) of the histone H3 tail. In vertebrates, HP1-like chromodomains are also present in the chromodomain Y chromosome (CDY) family of proteins adjacent to a putative catalytic motif. The human genome encodes three CDY family proteins, CDY, CDYL, and CDYL2. The CDY chromodomain exhibits discriminatory binding to lysine-methylated ARK(S/T) motifs, whereas the CDYL2 chromodomain binds with comparable strength to multiple ARK(S/T) motifs. Interestingly, subtle amino acid changes in the CDYL chromodomain prohibit such binding interactions in vitro and in vivo. We assessed mRNA transcript abundance of seven genes that code for proteins with established roles in epigenetically-mediated gene silencing [transcriptional co-repressor SIN3A, DNA (cytosine-5-) methyltransferase 1, methyl CpG binding protein 2, chromodomain helicase DNA binding protein 4, histone binding protein rbbp4, histone deacetylase 1 and nuclear receptor co-repressor 2] using qRT-PCR. CHD7 is a member of the chromodomain helicase DNA binding domain (CHD) family of ATP-dependent chromatin remodelling enzymes. The cysteine-rich CXXC domains of MBD1 bound to Ring1b and the chromodomain of hPc2. Methylation of lysine 9 within histone H3 and the subsequent binding of the chromodomain protein heterochromatin protein 1 (HP1) are thought to initiate heterochromatin formation in vivo and to propagate a heterochromatic state lasting through several cell divisions. Here, we show that the SNF2-like chromodomain helicase protein CHD8 interacts with the insulator binding protein CTCF. C For example, PC recognizes K27 methylation of H3 via its chromodomain. The chromodomain protein Corto [35,36] and the HMGB protein DSP1 [37] also behave as ETP. We showed previously that the only noticeable domain of the 550 amino acid Corto protein is a chromodomain located in the NH2-terminal half (aminoacids 107 to 203) [36]. The chromodomain (CD) of the Drosophila Polycomb protein exhibits preferential binding affinity for histone H3 when trimethylated at lysine 27. Despite a high degree of conservation, the Cbx chromodomains display significant differences in binding preferences. This particular element has been designated cenH, for centromeric homology (11). cenH facilitates heterochromatin formation in the mating-type region by recruiting the histone methyltransferase (HMT) Clr4 and the chromodomain protein Swi6 (12–15). In addition to Ago1, RITS contains the Tas3 protein, the chromodomain protein Chp1 and 20–22 nt RNA molecules (siRNA) mostly originating from centromeric dh and dg repeats (21–23). Ago1 associates with the chromodomain protein Chp1 in the RITS complex (21). Three-dimensional solution structures of the chromodomains of cpSRP43. Recently, three functionally distinct chromodomains (CDs) have been identified in cpSRP43. The C-terminal helical segment typically found in the nuclear chromodomains is absent in CD1. Critical comparison of the structures of the chromodomains of cpSRP43 with those found in nuclear chromodomain proteins revealed that the diverse protein-protein interactions mediated by the CDs appear to stem from the differences that exist in the surface charge potentials of each CD. Characterization and functional analysis of CReMM, a novel chromodomain helicase DNA-binding protein. The present study describes a newly identified protein named CReMM (chromatin-related mesenchymal modulator). The protein was studied by bioinformatic means and classified as a member of the third subfamily of chromodomain helicase DNA-binding proteins (CHD). In silico translation defined CReMM as a multiple domains protein including two chromodomains, SNF2/ATPase, helicase C domain and an A/T-DNA-binding domain (DBD). Identification and analysis of chromodomain-containing proteins encoded in the mouse transcriptome. The chromodomain is 40-50 amino acids in length and is conserved in a wide range of chromatic and regulatory proteins involved in chromatin remodeling. Chromodomain-containing proteins can be classified into families based on their broader characteristics, in particular the presence of other types of domains, and which correlate with different subclasses of the chromodomains themselves. Here we show that the chromodomain of CMT3 can directly interact with the N-terminal tail of histone H3, but only when it is simultaneously methylated at both the H3K9 and H3K27 positions. In addition to the canonical MYST HAT catalytic domain, both TgMYST-A and -B possess an atypical C2HC zinc finger and a chromodomain. Clr7 and Clr8 are required for localization of the Swi6 chromodomain protein and for histone H3 lysine 9 methylation, thereby influencing not only mating-type switching but also transcriptional silencing in all previously characterized heterochromatic regions, chromosome segregation, and meiotic recombination in the mating-type region. MRG15, a novel chromodomain protein, is present in two distinct multiprotein complexes involved in transcriptional activation. MRG15 is a novel chromodomain protein that is a member of a family of genes related to MORF4. MORF4 (mortality factor on chromosome 4) induces senescence in a subset of human tumor cell lines. Analysis of deletion mutants of MRG15 indicated that the leucine zipper at the C-terminal region of MRG15 was important for the protein associations in MAF1 and that the N-terminal chromodomain was required for the assembly of the MAF2 protein complex. Consistent with these data was the fact that a histone acetyltransferase activity associated with MRG15 was lost when the chromodomain was deleted and that both mutant MRG15 proteins failed to activate the B-myb promoter. The various mechanisms by which MRG15 could activate gene transcription are discussed. The chromodomain (CD) is a highly conserved motif present in a variety of animal and plant proteins, and its probable role is to assemble a variety of macromolecular complexes in chromatin. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. The chromodomain of the HP1 family of proteins recognizes histone tails with specifically methylated lysines. Here, we present structural, energetic, and mutational analyses of the complex between the Drosophila HP1 chromodomain and the histone H3 tail with a methyllysine at residue 9, a modification associated with epigenetic silencing. The histone tail inserts as a beta strand, completing the beta-sandwich architecture of the chromodomain. The methylammonium group is caged by three aromatic side chains, whereas adjacent residues form discerning contacts with one face of the chromodomain. The MORF4-Related Gene on chromosome 15 (MRG15) is a member of a novel family of genes originally identified in studies to reveal cell senescence-inducing factors. MRG15 contains several predicted protein motifs, including a nuclear localization signal, a helix-loop-helix region, a leucine zipper, and a chromodomain. Four alleles of dMi-2 mutants were further characterized in molecular nature; dMi-2(BL1) was found to have a mutation in the ATP-binding motif of the ATPase domain, dMi-2(BL7) in the core histidine of the first plant homeodomain zinc finger and dMi-2(BL12) in a conserved serine in the chromodomain. These analyses also suggest that the msl-3/MRG15 duplication occurred after the fungus/animal split, while an independent duplication occurred in plants. The proteins encoded by these genes have similar structures, including a putative chromodomain close to their N-terminal end and a putative leucine zipper at their C-terminus. CHD1 interacts with SSRP1 and depends on both its chromodomain and its ATPase/helicase-like domain for proper association with chromatin. Interaction between an integral protein of the nuclear envelope inner membrane and human chromodomain proteins homologous to Drosophila HP1. A mammalian DNA-binding protein that contains a chromodomain and an SNF2/SWI2-like helicase domain. A Southern blot analysis indicated that this protein, which we have named CHD-1, for chromodomain-helicase-DNA-binding protein, is present in most, if not all, mammalian species. Here we show that chromodomain helicase DNA-binding protein 4 (Chd4) forms a complex with Gata3 in Th2 cells that both activates Th2 cytokine transcription and represses the Th1 cytokine IFN-γ. Chromodomain helicase DNA-binding protein 4 (CHD4), the defining subunit of the nucleosome remodeling and deacetylase (NuRD) complex, is a nucleosome-remodeling protein of the SNF2/ISWI2 family, members of which contain two chromo domains and an ATP-dependent helicase module. Among those proteins with >40% regulation were Macrophage Capping protein (CAPG) and Chromodomain Helicase DNA binding protein 4 (CHD4) proteins which were significantly upregulated by pp32r1 and pp32r1Y140H overexpression. This heterochromatin coordinates expression levels by associating with a chromodomain protein Chp1 and an antisilencing factor Epe1. Within NCCs, Brg1 partners with chromatin remodeler Chromodomain-helicase-DNA-binding protein 7 (Chd7) on the PlexinA2 promoter to activate PlexinA2, which encodes a receptor for semaphorin to guide NCCs into the OFT. Chromodomain Helicase DNA binding protein 5 (CHD5) is a tumor suppressor mapping to 1p36, a genomic region that is frequently deleted in human cancer. Here, we identify ENHANCED PHOTOMORPHOGENIC1 (EPP1), previously known as PICKLE (PKL), an ATP-dependent chromatin remodeling factor of the chromodomain/helicase/DNA binding family, as a repressor of photomorphogenesis in Arabidopsis thaliana. In this study, the structure of the chromodomain of human SUV39H1 was determined by X-ray crystallography. BACKGROUND: Mutations in the chromodomain helicase DNA binding protein 7 gene (CHD7) lead to CHARGE syndrome, an autosomal dominant multiple malformation disorder. Chromodomain on Y-like (CDYL) is a chromodomain protein that has sequence homology to members of the enoyl CoA hydratase family. Our previous structural work demonstrated that a coiled-coil interaction between MBD2 and GATA zinc finger domain containing 2A (GATAD2A/p66α) proteins recruits the chromodomain helicase DNA-binding protein (CHD4/Mi2β) to the NuRD complex and is necessary for MBD2-mediated DNA methylation-dependent gene silencing in vivo (Gnanapragasam, M. N., Scarsdale, J. N., Amaya, M. L., Webb, H. D., Desai, M. A., Walavalkar, N. M., Wang, S. Z., Zu Zhu, S., Ginder, G. D., and Williams, D. C., Jr. (2011) p66α-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex. Sequence analysis showed that NlElp3 contains GNAT-type HAT domain and Radical SAM domain, and NlMof contains chromodomain and MOZ-SAS acetyltransferase domain. [32], [34] Chd8-S contains a single chromodomain (C1). We show here that the Corto chromodomain binds RPL12K3me3. We examined requirements for individual domains of chromodomain helicase DNA-binding protein 4 (CHD4), a core catalytic component of NuRD complexes, as well as the NuRD subunit methyl-binding domain protein 2 (MBD2) and methylated DNA, for NuRD function in the context of tissue-specific transcription. OBJECTIVE: Chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1L) is an SNF2-like transcription factor involved in the development of human hepatocellular carcinoma (HCC). BACKGROUND: Our recent studies suggested that the chromodomain helicase DNA binding protein 1-like (CHD1L) gene plays an oncogenic role in human hepatocellular carcinoma. RESULTS: We isolated human mononucleosomes bound by the bromodomain-containing proteins Brd2, Brd3 and Brd4, and by the chromodomain-containing heterochromatin proteins HP1 beta and HP1 alpha. Twelve rare copy number variants segregate with talipes equinovarus in multiplex pedigrees, and contain the developmentally expressed transcription factors and transcriptional regulators PITX1, TBX4, HOXC13, UTX, CHD (chromodomain protein)1, and RIPPLY2. OBJECTIVE: Chromodomain helicase DNA-binding protein 5 (CHD5) plays a role in normal neural development and in tumorigenesis of various human cancers. The chromodomain, helicase, DNA-binding protein 5 (CHD5) is a chromatin remodeling enzyme which is implicated in tumor suppression. The methyl-mark determines a highly flexible and very dynamic interaction of the chromodomain of hHP1β with the H3-tail. To test this hypothesis, we performed a comprehensive molecular dynamics study in which we analyzed a crystallographically defined complex that involves the HP1 chromodomain and an H3 tail peptide. Whereas the molecular target of the MRG15 chromodomain (CD) has been suggested to be H3K36me(2/3), the precise molecular target of the Pf1 plant homeodomain 1 (PHD1) has remained elusive. Chp1, a chromodomain (CD) protein, forms the Ago1-containing RNA-induced transcriptional silencing (RITS) complex and recruits siRNA-bound RITS to methylated histone H3 lysine 9 (H3K9me) via its CD. In addition, cells expressing S473A also displayed defective mobilization of the HP1-β chromodomain protein. CHD7 is a chromodomain-containing, ATP dependent helicase protein that is highly expressed in the developing ear and is required for semicircular canal development in both humans and mice. Moreover, the LTR retrotransposon fraction in BAC clones harboring genes is disproportionately composed of chromodomain-containing Gypsy LTR retrotransposons ('chromoviruses'), and the majority of the intact chromoviruses contain tandem chromodomain duplications. Stimulated by positively charged residues in the hinge region, RNA competes with methylated histone H3K9 for binding to the chromodomain of HP1(Swi6). CHD7 is one of the nine members of the chromodomain helicase DNA-binding family of ATP-dependent chromatin remodeling enzymes. Therefore, p53, ZNF237, and Chromodomain helicase DNA-binding protein 3 inhibit the function ER Ca²⁺ leak channels to regulate both ER and cytoplasmic Ca²⁺ levels and may potentially control Ca²⁺-signaling function of PS1. Chd5 knock-down was associated with hyperproliferation and reduced apoptosis and senescence, primarily through the p19Arf/p53 pathway [2].CHD5 belongs to the chromodomain helicase DNA binding domain (CHD) family, which is a subclass of the Swi/Snf proteins [3,4]. We show that chromodomain helicase DNA-binding domain 2 (Chd2), a SNF2 chromatin remodelling enzyme family member, interacts with MyoD and myogenic gene regulatory sequences to specifically mark these loci via deposition of the histone variant H3.3 prior to cell differentiation. Analysis of the Neurospora crassa chromodomain protein CDP-2, a component of a newly characterized HP1-containing complex, reveals a second gene-silencing mechanism and provides insights into the dynamic nature of chromatin domains that possess shared components. We state that the non-tumorogenic potential of bitumen transformant in nude/SCID mice can be attributed to the downregulation of galectin-1, chromodomain helicase DNA-binding protein 1-like gene, and membrane-associated guanylate kinase 2 protein. Yellow: histone H1 peptide; Gray: Cbx3 chromodomain in Cbx3-histone H1K26me2 complex. Mutagenesis of Tf1 integrase revealed that the complete Tf1 integrase protein (excluding its chromodomain) is required for stimulating the Tf1 RT primer removal activity. About 80% of patients with a clinical diagnose, have a mutation or a deletion in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). The binding of HP1 to the telomeres is independent of the chromodomain and H3K9me3. Owing to different polyadenylation sites and alternative splicing events, the human CBX2 locus produces two transcripts: a 5-exon transcript that encodes the 532-amino acid CBX2-1 isoform that contains the conserved chromodomain and Pc box and a 4-exon transcript encoding a shorter isoform, CBX2-2, lacking the Pc box but still possessing a chromodomain. Co-occupancy is thought to be a consequence of recruitment of PRC1 via interaction of the chromodomain in the PRC1 protein PC (mammalian homologs CBX2/4/6/7/8) with PRC2-dependent H3K27me3. Chromodomain helicase DNA-binding protein 4 (Chd4) is the core catalytic subunit of the nucleosome remodeling and deacetylase (NuRD) chromatin remodeling complex. These proteins have a DNA-binding domain as well as a chromodomain motif that can directly effect chromatin structure and gene transcription. Chromodomain helicase DNA-binding proteins (CHD) belong to a group of highly conserved chromatin remodeling proteins that are implicated in regulation of transcription. Here, we report that chromodomain helicase DNA-binding protein 4 (CHD4) is a novel BRIT1 binding partner that regulates the HR repair process. Here, we report that the chromodomain-containing protein MRG-1 is an important factor for genomic integrity in meiosis in Caenorhabditis elegans. The chromodomain protein, Chromator, can be divided into two main domains, a NH(2)-terminal domain (NTD) containing the chromodomain (ChD) and a COOH-terminal domain (CTD) containing a nuclear localization signal. A single cDNA clone encoding chromodomain-helicase-DNA binding protein 8 (CHD8) was independently identified on separate screenings by two different patients' sera. Chromodomain helicase DNA binding protein 5 (CHD5) is a potent tumor suppressor that serves as a master regulator of a tumor-suppressive network. By high-resolution tiling array CGH, the smallest common deletion targeted just one gene, the chromatin remodeler chromodomain helicase DNA-binding protein 1 (CHD1). Here we report direct evidence for presynaptic pairing activity intrinsic to non-PC regions, which is facilitated by a conserved chromodomain protein, MRG-1. The chromodomain of MPP8 recognizes the dimethylated Dnmt3aK44me2. Members of the chromodomain helicase DNA-binding (CHD) family of proteins are thought to regulate gene expression. It has been shown that the methylation mark of vertebrate histone H1 is specifically recognized by the chromodomain of HP1. Mutation of Tyr47 in the chromodomain of TIP60 abolished its binding to H3K9me3 (ref. RITS contains the chromodomain protein Chp1, the GW protein Tas3 and the argonaute protein Ago1 in complex with a small RNA. Chromodomain helicase DNA binding proteins solely produce from trinucletotide EST-SSRs in cancerous tissue.(XLS)Click To this end, we have performed mutation studies on the Drosophila HP1α chromodomain, which binds H3K9Me(2) and H3K9Me(3) with approximately equal affinities. We are interested in defining which elements of the chromodomain helicase DNA-binding protein 1 (Chd1) remodeler are necessary and sufficient for sliding nucleosomes. Chromatin remodelers are ATP-dependent machines that dynamically alter the chromatin packaging of eukaryotic genomes by assembling, sliding, and displacing nucleosomes. Ocular coloboma, heart malformation, choanal atresia, retardation of growth and/or development, genital hypoplasia, and ear anomalies associated with deafness (CHARGE) syndrome is a rare, usually sporadic, autosomal dominant disorder, caused by mutations within the CHD7 (chromodomain helicase DNA-binding protein 7) gene, in nearly 70% of cases. 1Overall structure of hMPP8 chromodomain.(A) Here we report that the chromodomain-containing protein CDYL specifically recognizes di- and tri-methylated H3K27 (H3K27me2 and H3K27me3) and directly interacts with EZH2, the catalytic subunit of PRC2. Murine Chd1 (chromodomain helicase DNA-binding protein 1), a chromodomain-containing chromatin remodeling protein, is necessary for embryonic stem (ES) cell pluripotency. Among those genes, zinc finger helicase (ZFH), also termed chromodomain-helicase-DNA-binding protein 3 (Chd3), was one of the highly expressed transcripts in tentative cementoblasts. UNLABELLED: Emerging evidence implicates the chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) as a specific oncogene in human hepatocellular carcinoma (HCC). Here, we investigate the function of chromodomain helicase DNA binding protein 7 (chd7) during zebrafish somitogenesis. Heterozygous mutations in the gene encoding chromodomain-DNA-binding-protein 7 (CHD7) cause CHARGE syndrome, a multiple anomaly condition which includes vestibular dysfunction and hearing loss. BACKGROUND: The CHD5 gene located on 1p36 encodes a protein-chromodomain helicase DNA-binding protein 5. CHD5 has been shown to be a tumor suppressor gene candidate. Because, in plants, DNA methylation can serve as a signal for H3-lysine9-dimethylation (H3K9me2), and subsequently for non-CG-context DNA methylation, SET-domain histone methyltransferase and chromodomain dna methyltransferase 3 (cmt3) mutations were introgressed. Previously, we have shown that the chromodomain protein Chriz and the zinc-finger protein Z4 are essentially required for the maintenance of polytene chromosome structure. In brain, Family with sequence similarity 174 member b (Fam174b) had increased expression in 318 females, whereas Chromodomain helicase DNA binding protein 2 (Chd2-2) had reduced expression in 318 males. The canonical chromodomain contains three β-strands that correspond to the middle three β-strands of the Tudor, MBT and PWWP domains, and a C-terminal α-helix. RESULTS: Here we demonstrated that chromobox protein homolog 3 (Cbx3) is crucial for SMC differentiation from stem cells and that the chromodomain and chromoshadow domain of Cbx3 are responsible for Cbx3-induced SMC differentiation. Fractionation of the extract identified a single protein, chromodomain helicase DNA binding protein 1 (Chd1), capable of the remodeling activity. Chromodomain helicase DNA-binding protein 5 (CHD5) has been found to be a candidate tumor suppressor gene (TSG) in malignant neural tumors. In contrast, the Saccharomyces cerevisiae protein Chd1 appears to act as a monomer (Tran et al, 2000) and dissecting how the accessory domains within this protein direct the activity of its Snf2 domain is a more tractable problem.Chd1, or chromodomain helicase DNA-binding protein 1, is conserved from yeast to humans. Similarly, CenH3-GFP distribution was altered in the absence of HP1, the chromodomain protein that binds to H3K9me3. ChIP-Seq reveals that KDM5B is predominantly targeted to intragenic regions and that it is recruited to H3K36me3 via an interaction with the chromodomain protein MRG15. OBJECTIVE: Chromodomain helicase DNA-binding protein (CHD) is a regulator of the chromatin remodelling process. We determined the crystal structure of MPP8 chromodomain in complex with H3K9me3 peptide. On this gene the chromodomain protein HP1γ, frequently defined as a transcriptional repressor, facilitates inclusion of the alternative exons via a mechanism involving decreased RNA polymerase II elongation rate. Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core component of the NuRD complex and contains a nucleosome remodeling ATPase domain along with two chromodomains and two plant homeodomain (PHD) fingers. H3-Lys-9-Me2 interacts with the chromodomain of Swi6/HP1. The chromodomain (CD) of HP1 proteins specifically recognizes the methyl mark on H3 peptides, but the same extent of specificity is not observed within chromatin. We have performed simulations on models of chromodomain helicase DNA-binding protein 1 complexed with a variety of histone H3 modifications. Also, there are no apparent differences between the recruitment of chromodomain-mutated CHD1 and wild-type CHD1. CHARGE syndrome is an autosomal dominant multisystem disorder caused by mutation in the CHD7 gene, encoding chromodomain helicase DNA-binding protein 7. Molecular diagnostic testing for CHD7 mutation has been available in a clinical setting since 2005. In this work we identified Kismet, a chromodomain-containing protein of the SNF2-like family of ATPases, as a novel component of the hedgehog transcriptional repression mechanism in anterior compartment cells. Mouse heterochromatin protein 1-beta (NM_007622) chromodomain-containing region of amino acids 1–185 was expressed as a recombinant protein with N-terminal GST tag (GST-HP1β). Human M-phase phosphoprotein (NM_017520) chromodomain-containing region of amino acids 50–120 was expressed as a recombinant protein with either an N-terminal GST tag (GST-MPP8) or N-terminal His6 tag (His-MPP8). Human chromodomain-containing protein, Y-linked, 2B (NM_001001722) chromodomain-containing region of amino acids 5–101 was expressed as a recombinant protein with N-terminal GST tag (GST-CDY2B). Human chromodomain helicase DNA-binding protein 1 (NM_001270) chromodomain-containing region of amino acids 251–467 was expressed as a recombinant protein with N-terminal GST tag (GST-CHD1). </context> <question> In which proteins is the chromodomain present? </question> <answer> HP1 alpha; CHD proteins', 'Chromodomain helicase DNA-binding protein; CReMM; cmt3; chromointegrases; Polycomb group (PcG) proteins; Cbx2; TgMYST-A; MRG15; MSL3; Swi6; Chp1; dMi-2; Corto; ScoHET1; cpSRP43; CDY', 'chromodomain Y chromosome; transposable elements; like heterochromatin protein', 'LHP1; ADP/ATP translocase 1; CDYL', 'CDY-like protein; CHD1L', 'CHD1-like; NlMof; TIP60; Kismet; Chriz; PICKLE', 'PKL; HP1 beta; HP1 gamma; TgMYST –B; Cbx4; Cbx6; Cbx7; Cbx8; ScoHET2; Cbx3; MPP8; MRG1 </answer>
<context> support of this view, CaMKII activity was also increased in hearts of transgenic mice overexpressing a gain-of-function Na(v)1.5 mutant (N(1325)S). The effects of both ATX-II and the N(1325)S mutation were reversed by either I(NaL) inhibition (with ranolazine or tetrodotoxin) or CaMKII inhibition (with KN93 or autocamtide 2-related inhibitory peptide). Such changes were related to enhanced Ca(2+)/calmodulin kinase II (CaMKII) activity and increased phosphorylation of its targets. Ranolazine at therapeutic concentrations partially reversed the HCM-related cellular abnormalities via I(NaL) inhibition, with negligible effects in controls. By shortening the action potential duration in HCM cardiomyocytes, ranolazine reduced the occurrence of early and delayed afterdepolarizations. Finally, as a result of the faster kinetics of Ca(2+)(i) transients and the lower diastolic Ca(2+)(i), ranolazine accelerated the contraction-relaxation cycle of HCM trabeculae, ameliorating diastolic function. </context> <question> How does ranolazine affect kinase signaling activation in the heart? </question> <answer> Ranolazine inhibits Ca(2+)/calmodulin kinase II (CaMKII) activity </answer>
<context> Ranolazine and lidocaine (10 μM) similarly reduced Ca2+i overload and improved left ventricle work recovery in whole-heart models of IR injury or exposure to ouabain (80 μM). Ranolazine (10 μM), but not lidocaine (10 μM), reduced RM NCX1.1-mediated Ca2+i overload in ventricular myocytes. Blockade of the late inward sodium current, late I(Na), offers another target for the treatment of ischemia. Blockade of late I(Na) reduces the sodium and calcium overload that follows ischemia. Ranolazine, a late I(Na) inhibitor, has been shown to provide both anti-anginal and anti-ischemic benefits without significant alterations in the heart rate and blood pressure in patients with stable coronary artery disease. Ranolazine is a new antianginal drug that reduces intracellular sodium and calcium accumulation during ischemia, thus potentially limiting myocardial ischemia. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca(2+) with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca(2+) response and cross-bridge kinetics. Ran reduces P(o) of RyR2, desensitizes Ca(2+)-dependent RyR2 activation, and inhibits Ca(i) oscillations, Ranolazine may provide functional protection of the heart during IR injury by reducing cCa2+ and mCa2+ loading secondary to its effect to block the late Na+ current. Ranolazine is a novel antianginal medication that acts by ameliorating disturbed sodium and calcium homeostasis. By preventing myocyte sodium and calcium overload, ranolazine also have potential beneficial effects on myocardial function. Reduction by RAN of I(Na,L)-induced dysregulation of calcium cycling could contribute to the antiarrhythmic actions of this agent in both reentrant and triggered arrhythmias. Moreover, in rabbit myocytes the increases in late I(Na), [Na(+)](i) and [Ca(2+)](i) caused by ATX-II, were significantly blunted by ranolazine. These results suggest that ranolazine may be of therapeutic benefit in conditions of diastolic dysfunction due to elevated [Na(+)](i) and diastolic [Ca(2+)](i). Ranolazine is a selective inhibitor of the late sodium current relative to peak sodium channel current, and via this mechanism, it may decrease sodium-dependent intracellular calcium overload during ischemia and reperfusion. he beneficial effects of ranolazine in reducing Ca2+ overload and LV mechanical dysfunction during ischemia/reperfusion is consistent with the inhibition of late INa mechanism of action. Ranolazine is a novel agent that inhibits the late sodium current thereby reducing cellular sodium and calcium overload Ranolazine selectively inhibits late I(Na), reduces [Na(+)](i)-dependent calcium overload and attenuates the abnormalities of ventricular repolarisation and contractility that are associated with ischaemia/reperfusion and heart failure. The results indicate that ranolazine, at concentrations which have significantly beneficial effects during ischaemic episodes, only greatly affects whole cell calcium current when facilitated by beta-adrenoceptor or histamine receptor activation. Ranolazine had only a small effect on the basal calcium current </context> <question> How does ranolazine affect calcium handling in the heart </question> <answer> Ranolazine has only a small effect on the basal calcium current, while it greatly affects whole cell calcium current when facilitated by beta-adrenoceptor or histamine receptor activation.\nRanolazine is a novel agent that inhibits the late sodium current thereby reducing cellular sodium and calcium overload.\nRanolazine reduces Ca2+ overload and LV mechanical dysfunction during ischemia/reperfusion.\nranolazine decreases I(Na,L)-induced dysregulation of calcium cycling that contributes to the antiarrhythmic actions of this agent.\nranolazine desensitizes Ca(2+)-dependent RyR2 activation, and inhibits Ca(i) oscillations.\nranolazine ameliorates the Ca(2+) response and cross-bridge kinetics of cardiac myofilaments. </answer>
<context> High-glucose treatment resulted in increased intracellular calcium ([Ca2+]i) which was mobilized to the mitochondria. Concomitant intra-mitochondrial calcium ([Ca2+]m) increase resulted in enhanced reactive oxygen and nitrogen species generation. These events led to mitochondrial dysfunction and apoptosis. The novel findings of the study reveal that high glucose induces apoptosis by both mitochondria-dependent and independent pathways via concomitant rise in intracellular calcium. Diabetes-induced myocardial dysfunction has been attributed, in part, to calcium overload within individual myocytes. It seems that intracellular calcium overload is intimately involved in the development of diabetic cardiomyopathy; BACKGROUND: It has been suggested that intracellular Ca2+ overload in cardiac myocytes leads to the development of diabetic cardiomyopathy. The results from the alloxan-rat model of diabetes support the view that membrane abnormalities with respect to Ca2+ handling may lead to the occurrence of intracellular Ca2+ overload and the development of diabetic cardiomyopathy. It seems that intracellular calcium overload is intimately involved in the development of diabetic cardiomyopathy; however, a concentrated research effort is required to understand the primary biochemical lesion in the pathogenesis of cardiac dysfunction in diabetes. It has been suggested that the occurrence of an intracellular Ca2+ overload may result in the development of diabetic cardiomyopathy, which is associated with depletion of high-energy phosphate stores and a derangement of ultrastructure and cardiac dysfunction. </context> <question> Is calcium overload involved in the development of diabetic cardiomyopathy? </question> <answer> yes </answer>
<context> The data suggest that trimetazidine significantly improves cardiac function in db/db mice by attenuating lipotoxicity and improving the oxidation status of the heart. Activation of AMPK and decreased expression of PGC-1 alpha were involved in this process. the results demonstrated that TMZ is cardioprotective when administered before reperfusion and that this protection appears to be mediated by activation of p38 mitogen-activated protein kinase and Akt signaling. The study emphasizes the importance of administering TMZ before reflow to prevent reperfusion-mediated cardiac injury and dysfunction. TMZ induced cardioprotection did not involve p38 MAPK and JNKs. Phospho-p38 MAPK and JNKs levels after I/R were not changed with TMZ treatment. Trimetazidine also caused AMPK activation and reduced PGC-1 alpha expression in the hearts of db/db mice. </context> <question> How does trimetazidine affect intracellular kinase signaling in the heart? </question> <answer> Trimetazidine activates AMPK in diabetic myocardium. Trimetazidine when administered before reperfusion results in activation of p38 mitogen-activated protein kinase and Akt signaling. Trimetazidine when administered during reperfusion does not affect p38MAPK and JNK activation. </answer>
<context> diabetes leads to cardiomyopathy in later stages with hypocontractility and reduced SERCA activity Previous studies with diabetes type 1 models have shown a down-regulation of SERCA2a in the heart associated with a decrease in systolic and diastolic function. the up-regulation of SERCA2a in the early phase of type 2 diabetes is an important physiological adaptation of the heart diabetic cardiomyocytes displayed reduced SERCA activity and Ca2+ sequestration, as well as impaired NCX function Compared with control group, [Ca(2+)](i) and the expression of CaSR, RyR and SERCA/PLN were decreased, while PKC-α and PLN were significantly increased in a time-dependent manner in diabetic group Diabetic rats showed impaired cardiac structure and function compared with control rats. The expression of PKC, PLB increased significantly, while the PPI-1, SERCA-2 and RyR expression decreased. Treatment with breviscapine could reverse the cardiac dysfunction and structure changes in diabetic cardiomyopathy rats, and decrease the expression of PKC and PLB, as well as increase the expression of PPI-1, SERCA-2 and RyR. Although decreased SR Ca2+ uptake exists, it is offset by an increase in action-potential duration, thereby ensuring that SR Ca2+ content is maintained. Diabetic Ren-2 rats developed impairment of both active and passive phases of diastole, accompanied by reductions in SERCA-2a ATPase and phospholamban along with activation of the fetal gene program. The levels of SERCA and GLUT4, but not PLB, were significantly reduced in diabetic hearts compared with controls. CONCLUSIONS: CASQ2, FKBP12.6 and SERCA2a were down-regulated in diabetic cardiomyopathy. Reduced sarcoplasmic calcium ATPase (SERCA2a) expression has been shown to play a significant role in the cardiac dysfunction in diabetic cardiomyopathy. Depressed sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a) and Ca(2+)-release channels (ryanodine receptor RyR2) are involved in diabetic cardiomyopathy, however, the implication of intracellular calcium handling proteins in SR is undefined. The depressed sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) and Ca2+-release channels (ryanodine receptor RyR2) are involved in the diabetic cardiomyopathy. Slowed relaxation in diabetic cardiomyopathy (CM) is partially related to diminished expression of the sarcoplasmic reticulum (SR) Ca2+-ATPase SERCA2a. Reduced sarcoplasmic calcium ATPase (SERCA2a) expression has been shown to play a significant role in the cardiac dysfunction in diabetic cardiomyopathy. </context> <question> What is the role of SERCA in diabetic cardiomyopathy? </question> <answer> Diabetic cardiomyopathy is accompanied by reduced SERCA levels and activity in later stages. The up-regulation of SERCA2a in the early phase of type 2 diabetes is an important physiological adaptation of the heart. </answer>
<context> Our results further substantiate that gene scanning of all relevant RET exons is a powerful tool in the management of MEN2 patients, We identified RET mutations in seven of 13 MTCs: five RET-positive cases revealed a mutation in exon 16 (M918T) and two a mutation in exon 10 (C618S and C620S). In four of the RET-positive cases, the mutation was inherited, out of which three were reportedly associated with a multiple endocrine neoplasia type 2 (MEN2) syndrome, i.e. MEN2A (C618S), MEN2A/familial MTC (FMTC) (C620S), and MEN2B (M918T). RET gene mutation carries a risk of MEN2 and MTC in all ethnic groups in South Africa Mutational screening of the RET gene identified a common mutation (C618R) in all 8 (7 FMTC and 1 MEN2A) Gene mutation in the RET-620 position carries significant risk and may be part of a targeted investigation of high-risk areas in HSCR Activating germline RET mutations are presented in patients with familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia (MEN) types 2A and 2B, whereas inactivating germline mutations in patients with Hirschsprung's disease (HSCR). The aim of this study was to evaluate genotype-phenotype correlations of the frequently discussed Tyr791Phe mutation in exon 13 of the RET proto-oncogene. Screening of three groups of patients was performed (276 families with medullary thyroid carcinoma (MTC), 122 families with HSCR, and 29 patients with pheochromocytoma). We found this mutation in 3 families with apparently sporadic MTC, 3 families with FMTC/MEN2, 1 patient with pheochromocytoma, and 3 families with HSCR. Multiple endocrine neoplasia type 2 (MEN2) is an inherited, autosomal-dominant disorder caused by deleterious mutations within the RET protooncogene. MEN2 RET mutations are mainly heterozygous, missense sequence changes found in RET exons 10, 11, and 13-16 Medullary thyroid carcinoma (MTC) occurs both sporadically and in the context of autosomal dominantly inherited multiple endocrine neoplasia type 2 (MEN2) syndromes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC), which are caused by activating germline mutations in the RET proto-oncogene. The germline mutation was detected because of the systematic genetic screening of the RET proto-oncogene, which is useful for genetic counseling of potential risk of HSCR and MTC in other family members. This family could be added to the small worldwide cohort of families with MEN2A/FMTC-HSCR. Germline mutations of the ret protooncogene are the underlying cause of the MEN2 syndromes and a proportion of cases of HSCR. In this report, we describe a new kindred in which the MEN2 and HSCR phenotypes are associated with a single C620S point mutation at one of the cysteine codons of the extracellular domain of the ret protooncogene. Medullary thyroid carcinoma (MTC) occurs both sporadically and in the autosomal dominantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical management of both the patient and family. The susceptibility gene for MEN 2 is the RET proto-oncogene. </context> <question> What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease? </question> <answer> Ret </answer>
<context> Using a chemical carcinogenesis model in Sparc-deficient mice and their wild-type littermates, we found that loss of SPARC accelerated the development of urothelial preneoplasia (atypia and dysplasia), neoplasia, and metastasis and was associated with decreased survival. Our studies showed that inhibition of HDAC decreased NB proliferation, and induced caspase activity and G1 growth arrest. Expression patterns of cancer-related genes were modulated by VPA. The expression of THBS1, CASP8, SPARC, CDKN1A, HIC1, CDKN1B, and HIN1 was upregulated, and that of MYCN and TIG1 was downregulated. In this study, we demonstrate that expression of SPARC inhibits medulloblastoma cell proliferation. Concomitantly, SPARC was upregulated in all ccRCC cells, suggesting that Ukrain could also affect cell proliferation by cell cycle inhibition, as supported by the cell cycle analysis, as SPARC also acts as a cell cycle inhibitor. SPARC silencing in IM-R cells restored imatinib sensitivity, whereas enforced SPARC expression in imatinib-sensitive cells promoted viability as well as protection against imatinib-mediated apoptosis. Notably, we found that the protective effect of SPARC required intracellular retention inside cells We found that depletion of SPARC induces G2/M cell cycle arrest and tumor growth inhibition with activation of p53 and induction of p21(Cip1/Waf1) acting as a checkpoint, preventing efficient mitotic progression. Knockdown of SPARC expression in H322 and A549 cells led to suppression of cell invasion, comparable to that observed in KLF4-transfected cells. Moreover, retrovirus-mediated restoration of SPARC expression in KLF4-transfected cells abrogated KLF4-induced anti-invasion activity. Together, our results indicate that KLF4 inhibits lung cancer cell invasion by suppressing SPARC gene expression. To validate the potential of SPARC as a therapeutic target, we examined the effect of the knockdown of SPARC with SPARC-specific siRNA on the growth of human melanoma cell lines. SPARC siRNAs exerted a potent knockdown effect. Silencing of SPARC resulted in growth inhibition with G(1) arrest accompanied by accumulation of p21, a G(1) cyclin-dependent kinase inhibitor, in MeWo and CRL1579 cells. Moreover, the induction of p53 was observed in MeWo cells, but not in CRL1579 cells. Conditioned media containing SPARC from MeWo cells could not restore the growth of SPARC-silenced MeWo cells. This result suggests that intracellular SPARC, but not secreted SPARC, is involved in cell proliferation The SPARC expression reduced xenograft growth with reduced vascularity in an orthotopic medulloblastoma model. We also demonstrated that SPARC expression inhibits VEGF-mediated angiogenesis by altering MMP-9 expression, thereby leading to reduced angiogenesis. In summary, we showed that inhibition of endogenous SPARC enhances the malignant phenotype of PDAC cells and showed that endogenous SPARC expression is regulated by FGFR1 domain III isoform expression. On the basis of these observations, we conclude that endogenous SPARC levels can contribute to the reversion of the malignant phenotype and may, therefore, act as a tumour suppressor in human PDAC cells. In vivo experiments revealed that SPARC overexpression in HCC cells inhibited their tumorigenic capacity and increased animal survival through a mechanism that partially involves host macrophages. Our data suggest that SPARC overexpression in HCC cells results in a reduced tumorigenicity partially through the induction of mesenchymal-to-epithelial transition (MET). Finally, we demonstrated that SPARC, which has been previously associated with meningioma invasiveness, was increased in aggressive meningiomas. We found that the leukemic cells of AML patients with MLL gene rearrangements express low to undetectable amounts of SPARC whereas normal hematopoietic progenitors and most AML patients express this gene. SPARC RNA and protein levels were also low or undetectable in AML cell lines with MLL translocations. Consistent with its tumor suppressive effects in various solid tumor models, exogenous SPARC protein selectively reduced the growth of cell lines with MLL rearrangements by inhibiting cell cycle progression from G1 to S phase. These data indicate that SPARC plays an essential role in tumor evasion from immune surveillance through the inhibition of the antitumor PMN activity. We conclude that SPARC is inhibitory to human breast cancer cell proliferation, and does not stimulate migration, in contrast to its stimulatory effects reported for melanoma (proliferation and migration) and glioma (migration) cells. Similar growth repression by SPARC has been reported for ovarian cancer cells, and this may be a common feature among carcinomas. Furthermore, SPARC delayed but did not inhibit tumor growth. The patterns of invasion and the extent of growth delay correlated with the level of SPARC expression. </context> <question> What is the correlation between SPARC expression and growth inhibition in human cancer? </question> <answer> Secreted protein acidic and rich in cysteine (SPARC) is a multi-faceted protein-modulating cell-cell and cell-matrix interactions. SPARC seems to act as a tumour suppressor, as it has been found that loss of SPARC accelerates the development of certain types of cancer, whereas its expression impairs tumor growth. However it has also been associated with a aggressive phenotypes of some tumours. The role of SPARC may depend on its subcellular localization. </answer>
<context> Evidence for the novel expression of human kallikrein-related peptidase 3, prostate-specific antigen, in the brain. Human kallikrein-related peptidase 3 (hK3), also known as prostate-specific antigen (PSA), is a 33 kDa single chain glycoprotein belonging to the kallikrein family of serine proteases. </context> <question> Which are the synonyms of prostate-specific antigen? </question> <answer> human kallikrein-related peptidase 3; hK3 </answer>
<context> This unit describes how to use the gene-finding programs GeneMark.hmm-E and GeneMark-ES for finding protein-coding genes in the genomic DNA of eukaryotic organisms. this paper we present an implementation of three computational pipelines (Fgenesh++, PSF and Fprom) for automatic identification of protein coding genes, pseudo-genes and promoters in eukaryotic genomes YACOP parses and combines the output of the three gene-predicting systems Criticia, Glimmer and ZCURVE. In this paper we have explored the benefits of combining predictions from already existing gene prediction programs. We have introduced three novel methods for combining predictions from programs Genscan and HMMgene We describe the data sets on which the experiments were performed, the approaches employed by the five algorithms: GenScan, HMMGene, GeneMark, Pombe and FFG, the methodology of our evaluation, and the results of the experiments. Phat is based on a generalized hidden Markov model (GHMM) similar to the models used in GENSCAN, Genie and HMMgene. We present an independent comparative analysis of seven recently developed gene-finding programs: FGENES, GeneMark.hmm, Genie, Genescan, HMMgene, Morgan, and MZEF. We have explored the effectiveness when the results of several gene-finding programs were re-analyzed and combined. We studied several methods with four programs (FEXH, GeneParser3, GEN-SCAN and GRAIL2) JIGSAW, GeneZilla, and GlimmerHMM: puzzling out the features of human genes in the ENCODE regions The gene prediction tools tested were Ensembl, SGP2 and TWINSCAN. Ensembl is a homology-based method, which builds gene-models using species-specific known sequences and proteins from other species aligned to the genome [13]. SGP2 and TWINSCAN are de novo comparative gene predictors whose only inputs are the genome to be annotated and a second informant genome [3,4,14-16] FGENES; Gene-Mark.hmm; Genie; Genescan; HMMgene; Morgan and MZEF, The gene sets are labelled as follows: AU: AUGUSTUS, MG: MGENE, CR: CRAIG, AG: Agene, EU: EUGENE, FPC: Fgenesh++C, FP: Fgenesh++, FG: Fgenesh, GE: GeneID, GM: GeneMark.hmm, GX: GENOMIX, GS: GESECA, GN: GLEAN, GL: GlimmerHMM, GR: Gramene, JW: JIGSAW, MK: MAKER (using SNAP), MG: MGENE, NS: N-SCAN, SG: SGP2, SN: SNAP, EX: ExonHunter, EV: Evigan. </context> <question> Name five popular computer programs used to identify genes in genomic sequences </question> <answer> Genscan; Glimmer; Fgenesh; Augustus; GeneID </answer>
<context> Deer are the key hosts of the vector (Ixodes ricinus) that transmits LIV to red grouse Lagopus lagopus scoticus, causing high mortality. n Europe the primary arthropod vectors of zoonotic diseases are ticks, which transmit Borrelia burgdorferi sensu lato (the agent of Lyme disease), tick-borne encephalitis virus and louping ill virus between humans, livestock and wildlife. Ixodes ricinus ticks and reported tick-borne disease cases are currently increasing in the UK Many vector-borne pathogens whose primary vectors are generalists, such as Ixodid ticks, can infect a wide range of host species and are often zoonotic. Tick-borne encephalitis virus (TBEV) and Louping ill virus (LIV) are viruses in the Mammalian tick-borne virus group/genus Flavivirus, causing central nervous system disease. The complex pathogen-host-vector system of the tick-borne louping-ill virus causes economic losses to sheep and red grouse in upland United Kingdom. For pathogens transmitted by biting vectors, one of the fundamental assumptions is often that vector bites are the sole or main route of host infection. Here, we demonstrate experimentally a transmission route whereby hosts (red grouse, Lagopus lagopus scoticus) became infected with a member of the tick-borne encephalitis virus complex, louping ill virus, after eating the infected tick vector. We used Susceptible Infected Recovered (SIR) models parameterized for the tick-borne louping ill virus (LIV) system. This study has examined the efficacy following intramuscular administration of a recombinant Semliki Forest virus (rSFV) vaccine, encoding the prME and NS1 proteins of louping ill virus (LIV), in sheep. Since the recognition that louping-ill, known for well over 100 years as an epizootic disease of sheep in Scotland, was caused by a virus transmitted by arthropods, many other arthropod-borne viruses capable of causing encephalitis in domestic animals or man have been discovered. </context> <question> Which is the vector of Louping ill virus? </question> <answer> Ixodes ricinus </answer>
<context> Dual binding of chromomethylase domains to H3K9me2-containing nucleosomes directs DNA methylation in plants. CHG methylation by CHROMOMETHYLASE3 (CMT3) depends on histone H3K9 dimethylation (H3K9me2), but the mechanism underlying this relationship is poorly understood. Here, we report multiple lines of evidence that CMT3 interacts with H3K9me2-containing nucleosomes. CMT3 genome locations nearly perfectly correlated with H3K9me2, and CMT3 stably associated with H3K9me2-containing nucleosomes. Thirdly, CHROMOMETHYLASES (CMTs), a plant-specific DNA methyltransferase family, are involved primarily in the maintenance of symmetrical CHG methylation (Lindroth et al., 2001; Papa et al., 2001). Furthermore, CMTs also play a role in de novo methylation (Cao et al., 2003; Chan et al., 2005). CMT is characterized by a chromatin-associated domain (chromodomain) embedded within the catalytic motifs I and IV of the protein (Henikoff and Comai, 1998). The presence of this plant-specific methyltransferase provides an explanation for the high levels of CHG methylation in plant genomes relative to animals. In Arabidopsis, the targeting of AtCMT3 methylation is accomplished by short interfering RNA (siRNA) pathways (Zilberman et al., 2003; Chan et al., 2004, 2006) and histone methylation H3K9, H3K27 (Jackson et al., 2002; Lindroth, 2004). In conclusion, CHROMOMETHYLASE, a gene involved in both maintenance and de novo DNA methylation has been characterized in P. oceanica, whose genome information is still very limited. A role for CHROMOMETHYLASE3 in mediating transposon and euchromatin silencing during egg cell reprogramming in Arabidopsis. We also demonstrated that CHROMOMETHYLASE 3 (CMT3) is required for H3K9 dimethylation in the egg cell and for normal embryogenesis during the first few divisions of the zygote. Subsequent analysis of CMT3 mutants points to a key role in egg cell reprogramming by controlling silencing in both transposon and euchromatic regions. A speculative model of the CMT3-induced egg cell silencing is presented here, based on these results and current data from the literature suggesting the potential involvement of small RNAs targeted to the egg cell, a process conceptually similar to the division of labor described in the male gametophyte for which we show that H3K9 modifications and TFL2 localization are reminiscent of the female gametophyte. Expression analysis of eight putative tomato DNA methyltransferases encoding genes showed that one chromomethylase (CMT) and two rearranged methyltransferases (DRMs) are preferentially expressed in the pericarp during fruit growth and could be involved in the locus-specific increase of methylation observed at this developmental phase in the pericarp. In this study, we investigated the functional targets of the maize chromomethylase ZMET2 in multiple inbred lines to determine whether epigenetic changes conditioned by this chromomethylase are conserved or variable within the species. These include a promising allelic series for a chromomethylase gene that had been previously implicated in non-CpG DNA methylation, whose counterpart in Arabidopsis is responsible for epigenetic gene silencing and genome surveillance. Plant chromomethylases have received considerable recent attention. For example, studies of other mutations affecting CpNpG methylation reveal the first links between DNA methylation, histone methylation [27] and the small interfering RNA (siRNA) machinery [28] in a higher eukaryote. A methylation profiling study has revealed that transposons are in vivo targets of CMT3-dependent methylation [29]. Locus-specific control of asymmetric and CpNpG methylation by the DRM and CMT3 methyltransferase genes. However, at the SUPERMAN locus, asymmetric methylation was only completely abolished in drm1 drm2 chromomethylase 3 (cmt3) triple mutant plants. The drm1 drm2 cmt3 triple mutant plants did not affect CpG methylation at any locus tested, suggesting that the primary CpG methylases are encoded by the MET1 class of genes. Although neither the drm1 drm2 double mutants nor the cmt3 single mutants show morphological defects, drm1 drm2 cmt3 triple mutant plants show pleiotropic effects on plant development. Our results suggest that the DRM and CMT3 genes act in a partially redundant and locus-specific manner to control asymmetric and CpNpG methylation. Arabidopsis has two types of methyltransferases with demonstrated maintenance activity: MET1, which maintains CpG methylation and is homologous to mammalian DNMT1, and CHROMOMETHYLASE 3 (CMT3), which maintains CpNpG (N = A, T, C, or G) methylation and is unique to the plant kingdom. Maize chromomethylase Zea methyltransferase2 is required for CpNpG methylation. The sequence of ZMET2 is similar to that of the Arabidopsis chromomethylases CMT1 and CMT3, with C-terminal motifs characteristic of eukaryotic and prokaryotic DNA methyltransferases. Our research shows that chromomethylase Zmet2 is required for in vivo methylation of CpNpG sequences. Arabidopsis cmt3 chromomethylase mutations block non-CG methylation and silencing of an endogenous gene. The cmt3 mutants displayed enhanced expression and reduced methylation of the reporter, particularly at non-CG cytosines. CNG methylation was also reduced at repetitive centromeric sequences. Thus, CMT3 is a key determinant for non-CG methylation. The lack of CMT homologs in animal genomes could account for the observation that in contrast to plants, animals maintain primarily CG methylation. The 791 residue "chromomethylase" (CMT1) is encoded by a floral transcript that is spliced from 20 exons and is present at only approximately 1/10(-7) of total mRNA. Conversely, several SUVH proteins seem to control the deposition of non-CpG methylation, mediated by the CMT3 chromomethylase, at distinct loci (27–29,31). </context> <question> What is the role of chromomethylases in plants? </question> <answer> Chromomethylases (CMTs), which constitute a plant-specific DNA (cytosine-5)-methyltransferase family, are involved primarily in the maintenance of symmetrical CpNpG (N = A, T, C, or G) methylation and they also play a role in de novo methylation. CMTs are characterized by the presence of a chromatin-associated domain (chromodomain) inserted within the catalytic protein motifs I and IV. CMTs have likely evolved because of the high levels of CpNpG methylation present in plant genomes relative to animal genomes. The targeting of CMT methylation is accomplished by short interfering RNA (siRNA) pathways and histone methylation (H3K9, H3K27). It has been shown that transposons are in vivo targets of CMT-dependent methylation, suggesting that CMTs play a role in the plant genome surveillance. In Arabidopsis, CMTs play a key role in egg cell reprogramming and normal embryogenesis during the first few divisions of the zygote by mediating transposon and euchromatin epigenetic gene silencing. In tomatoes, CMTs are preferentially expressed in the pericarp during fruit development which suggests involvement of CMTs in the locus-specific control of methylation in the pericarp during fruit growth. </answer>
<context> The human selenoproteome consists of 25 selenoproteins. </context> <question> How many selenoproteins are encoded in the human genome? </question> <answer> 25 </answer>
<context> We show that treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model. Our results show that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target We further found that ATO targets AME via both myelodysplastic syndrome 1 (MDS1) and EVI1 moieties and degrades EVI1 via the ubiquitin-proteasome pathway and MDS1 in a proteasome-independent manner. Our results suggest that ATO could be used as a part of targeted therapy for AME-, AML1/MDS1-, MDS1/EVI1-, and EVI1-positive human cancers. Previously we had shown the synergic effect of bortezomib and thiostrepton in breast cancer cells in vitro, where sub-apoptotic concentrations of both proteasome inhibitors resulted in synergic increase in cell death when combined as a treatment. Here, we administered such a combination to MDA-MB-231 xenograft tumors in vivo, and found that the effect of complementary proteasome inhibitors reduced tumor growth rates more efficiently than compared with when administered alone. Addition of a proteasome inhibitor to anti-hormonal therapy resulted in a clinical benefit rate of 22% in a limited number of patients with endocrine resistant and progressive metastatic breast cancer. Here we show that the water-soluble analog of curcumin #12, but not curcumin, in combination with bortezomib could enhance the proteasome-inhibitory effect in multiple myeloma cells. Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications. BU-32 is a highly selective and potent inhibitor of 26S proteasome. Preclinical studies currently being conducted by the National Cancer Institute against a panel of 60 cell lines show that BU-32 has broad anti-tumor activity (data not shown), and numerous biochemical studies are currently ongoing to investigate its efficacy as a single agent and in combination with other active anti-tumor agents against a variety of malignancies. Bortezomib has minimal activity as a single-agent in the treatment of recurrent platinum-sensitive EOC/PPC Our study indicates a molecular mechanism by which the sensitivity of thyroid cancer cells is regulated by the level of GRP78 as well as preferential induction of GRP78 or CHOP upon treatment with proteasome inhibitors. Our experiments therefore suggest a novel approach toward sensitization of thyroid cancer cells to proteasome inhibitors. Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. Given the results of this trial, it is safe and reasonable to recommend treatment with PS341 on the schedule used in this trial at 1.56 mg/m2/dose in Phase II trials. Particular care should be taken with patients with preexisting neuropathy The successes of proteasome inhibitors in MM are now being translated to other hematologic malignancies, including acute leukemia Such efforts have led to bortezomib, the first FDA approved proteasome inhibitor now used as a frontline treatment for newly diagnosed multiple myeloma (MM), relapsed/refractory MM and mantle cell lymphoma We recently reported the impact and mechanisms of carfilzomib and oprozomib, second-in-class proteasome inhibitors with higher specificities and reduced toxicities, against head and neck squamous cell carcinoma (HNSCC). Carfilzomib and oprozomib potently inhibit HNSCC cell survival and the growth of HNSCC tumors </context> <question> Are proteasome inhibitors good candidates for treatment of leukemia and solid tumors? </question> <answer> yes </answer>
<context> Many plant, animal, and fungal genomes contain cytosine DNA methylation in asymmetric sequence contexts (CpHpH, H = A, T, C). However, at the SUPERMAN locus, asymmetric methylation was only completely abolished in drm1 drm2 chromomethylase 3 (cmt3) triple mutant plants. Although neither the drm1 drm2 double mutants nor the cmt3 single mutants show morphological defects, drm1 drm2 cmt3 triple mutant plants show pleiotropic effects on plant development. Arabidopsis cmt3 chromomethylase mutations block non-CG methylation and silencing of an endogenous gene. The lack of CMT homologs in animal genomes could account for the observation that in contrast to plants, animals maintain primarily CG methylation. Dual binding of chromomethylase domains to H3K9me2-containing nucleosomes directs DNA methylation in plants. A role for CHROMOMETHYLASE3 in mediating transposon and euchromatin silencing during egg cell reprogramming in Arabidopsis. During embryogenesis there is a major switch from dependence upon maternally-deposited products to reliance on products of the zygotic genome. Expression analysis of eight putative tomato DNA methyltransferases encoding genes showed that one chromomethylase (CMT) and two rearranged methyltransferases (DRMs) are preferentially expressed in the pericarp during fruit growth and could be involved in the locus-specific increase of methylation observed at this developmental phase in the pericarp. Natural variation for alleles under epigenetic control by the maize chromomethylase zmet2. Arabidopsis has two types of methyltransferases with demonstrated maintenance activity: MET1, which maintains CpG methylation and is homologous to mammalian DNMT1, and CHROMOMETHYLASE 3 (CMT3), which maintains CpNpG (N = A, T, C, or G) methylation and is unique to the plant kingdom. Maize chromomethylase Zea methyltransferase2 is required for CpNpG methylation. A cytosine DNA methyltransferase containing a chromodomain, Zea methyltransferase2 (Zmet2), was cloned from maize. The sequence of ZMET2 is similar to that of the Arabidopsis chromomethylases CMT1 and CMT3, with C-terminal motifs characteristic of eukaryotic and prokaryotic DNA methyltransferases. We have detected a chromodomain embedded within the catalytic region of a predicted Arabidopsis DNA methyltransferase that is diverged from other eukaryotic enzymes. The 791 residue "chromomethylase" (CMT1) is encoded by a floral transcript that is spliced from 20 exons and is present at only approximately 1/10(-7) of total mRNA. </context> <question> Are chromomethylases present in animal genomes? </question> <answer> no </answer>
<context> MicroRNAs are a class of small non-coding RNAs that negatively regulate gene expression by interacting with the 3'UTR of protein-coding mRNA. MicroRNAs are implicated in nearly all major biological and cellular events, and recent findings further link microRNA deregulation to human carcinogenesis. MiR-657 promotes tumorigenesis in hepatocellular carcinoma by targeting transducin-like enhancer protein 1 through NF-κB pathways. MicroRNAs (miRNAs), which are small non-coding RNAs, are involved in diverse biological functions and carcinogenesis. Moreover, we demonstrated that miR-106b downregulates APC expression by directly targeting the 3'-untranslated region of APC messenger RNA. MicroRNAs (miRNAs) are endogenous 19–25 nucleotide non-coding single-stranded RNAs that regulate gene expression by blocking the translation or decreasing the stability of mRNAs [1]. In fact, almost one-third of the protein-coding genes are susceptible to miRNA regulation [2]. Therefore, many miRNAs seem to play pivotal roles in many biological processes, including cellular proliferation, differentiation and apoptosis [3]. In recent years, accumulating evidence indicates that dysregulation of miRNAs is associated with the initiation and progression of cancer. Several studies have shown that unique miRNA expression profiles are present in lots of cancers, such as breast, lung, oesophageal, prostate and pancreatic cancer, gastric cancer and colon cancer, suggesting that miRNAs may act as oncogenes or cancer suppressors [4]. Furthermore, miRNAs present a mechanism by which genes with diverse functions on multiple pathways can be simultaneously regulated at the post-transcriptional level. However, little is known about the cancer-related pathways through which cancer-associated miRNAs (CA-miRNAs) regulate these processes representing either positive or negative functions in carcinogenesis. MicroRNAs, known as small noncoding MiRNAs, 19 to 24 nt in length, are important gene regulators and recognized as key players in carcinogenesis. The mechanism lies in that the MiRNAs can conjugate with their targeted mRNA and then lead to the targeted mRNA degradation or repress their translation. Bioinformatic analysis indicates that each MiRNA can regulate hundreds of gene targets and could serve functionally as "oncogenes" or "tumor suppressor genes", and therefore regulate multiple cellular processes relevant to carcinogenesis and cancer progression. miRNAs are a class of noncoding RNAs 18 to 25 nucleotides long that negatively regulate gene expression by binding to the 3'-UTR of target messenger mRNAs, causing translational repression or degradation. Deregulation of miRNAs has been demonstrated to play roles in the pathogenesis of human diseases, including malignancy [1,2]. Some miRNAs have been identified from cancers and appear to play crucial roles in proliferation, differentiation, and apoptosis [3-5]. One of these, microRNA-21 (miR-21), is a key player. As an anti-apoptosis factor, aberrantly expressed miR-21 compromises tumor suppressor-mediated apoptosis of cancer cells [6,7]. microRNAs (miRs) are endogenous small non-coding RNAs that are aberrantly expressed in various carcinomas. While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown. In the last years, microRNAs (miRNA) have emerged as new molecular players involved in carcinogenesis. Deregulation of miRNAs expression has been shown in different human cancer but the molecular mechanism underlying the alteration of miRNA expression is unknown. These are microRNAs (miRNAs), a class of noncoding RNAs, 20-23 nucleotides in length, that can up or downregulate gene expression of downstream gene targets (including transcription factors, oncogenes, and tumour suppressor genes) at the post-transcriptional level. Some members of this new class of genes seem to have the potential to act simultaneously either as oncogenes or as tumour suppressor genes depending on the molecular microenvironment of the cell. MicroRNAs can also be affected by chromosomal alterations and thus contribute to carcinogenesis. Mechanisms and role of microRNA deregulation in cancer onset and progression. MicroRNAs (miRNAs) are a group of small RNAs, with around 19 to 25 nucleotides, resulting from cleavage of larger non-coding RNAs. Recent studies have emphasized the importance of understanding the mechanism of mRNA regulation by studying changes in miRNA expression in a variety of human pathological conditions, including cancers (Vanderboom et al., 2008). Given their importance in development, it was to be expected that miRNAs would also have a significant role in tumorigenesis. Since their discovery close to 3000 publications, including over 700 reviews, documented associations between miRNAs and cancer, (Garofalo and Croce, 2010; Medina and Slack, 2008).T It is now recognized that miRNA also have a primary role in cancer onset and progression. Oncomir is the term used to describe an miRNA involved in cancer. Such miRNAs were initially linked to tumorigenesis due to their proximity to chromosomal breakpoints (Calin et al., 2004b) and their dysregulated expression levels in many malignancies (Calin et al., 2004a). Abnormal gene expression by miRNAs has been correlated with several types of tumors, and such genes may function as oncogenes or tumor-suppressing genes (Figure 2). In humans, 50% of the miRNA genes are located at genomic sites associated with cancer-specific chromosomal rearrangements. The strongest evidence for an association between miRNAs and cancer was demonstrated by a sequence of three concurrent studies published in Nature in June 2005 (He et al., 2005; Lu et al., 2005; O’Donnell et al., 2005). Several classes of deregulated miRNAs have also been shown to be differentially expressed in breast cancer, compared with healthy breast tissue (Volinia et al., 2006). Moreover, the expression signatures of informative miRNA subsets have enabled better molecular classification than mRNA expression profiles in several types of human cancer (Lu et al., 2005).Among the miRNAs differentially expressed in breast cancer, miR-10b, miR-125, miR-145, miR-21 and miR-155 have consistently presented the highest degree of deregulation. Downregulation of miR-10b, miR-125b and miR-145 and upregulation of miR-21 and miR-155 suggest that these miRNAs may play an important role as tumor-suppressors or oncogenes (Blenkiron et al., 2007). In line with this, novel molecular classifications of tumors based on their miRNA expression, have provided a wealth of new resources for predictive and prognostic biomarkers for clinical applications in cancer. Regulation of hepatocarcinogenesis by microRNAs. MicroRNAs are implicated in nearly all major biological and cellular events, and recent findings further link microRNA deregulation to human carcinogenesis. MicroRNAs (miRNAs), which are small non-coding RNAs, are involved in diverse biological functions and carcinogenesis. miR-106b downregulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma. MiR-101 is involved in human breast carcinogenesis by targeting Stathmin1. However, little is known about the cancer-related pathways through which cancer-associated miRNAs (CA-miRNAs) regulate these processes representing either positive or negative functions in carcinogenesis. Combined with previous cancer studies, the analysis of the relevance between functions of CA-miRNAs and cancer-related pathways exploring different internal carcinogenesis stimuli also revealed the potential of the top five pathways to regulate core carcinogenesis processes. MicroRNAs, known as small noncoding MiRNAs, 19 to 24 nt in length, are important gene regulators and recognized as key players in carcinogenesis. MicroRNA-34a and microRNA-21 play roles in the chemopreventive effects of 3,6-dihydroxyflavone on 1-methyl-1-nitrosourea-induced breast carcinogenesis. As an anti-apoptosis factor, aberrantly expressed miR-21 compromises tumor suppressor-mediated apoptosis of cancer cells [6,7]. Downregulation of the tumor-suppressor miR-16 via progestin-mediated oncogenic signaling contributes to breast cancer development. Despite the undeniable role of progestins in breast cancer progression, progestin-mediated regulation of miRNAs has only recently been explored [49]. Bearing in mind the importance of progestins in breast cancer growth, we hypothesized that progestins may also govern a set of miRNAs that regulate the expression of genes relevant to breast cancer growth Endometrial Cancer and Hypermethylation: Regulation of DNA and MicroRNA by Epigenetics. miRNAs have been found to be downregulated by methylation of DNA in various cancers, and these miRNAs are referred to as tumor suppressor miRNAs (TS-miRNAs) [25, 26]. Androgen pathway stimulates microRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis. Deregulation of microRNAs (miRNAs) is common in advanced human hepatocellular carcinoma (HCC); however, the ones involved in early carcinogenesis have not yet been investigated. MiR-185 targets the DNA methyltransferases 1 and regulates global DNA methylation in human glioma. However, whether and how miR-185 could regulate DNMT1 expression and affect the genomic DNA methylation, contributing to the development of human glioma, has not been systemically explored. More importantly, our findings indicate that miR-185 can directly target DNMT1, thereby leading to a reduction in global DNA methylation (GDM) and regulating the expression of the promoter-hypermethylated genes in glioma cells. MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo. MicroRNAs (miRNAs) are believed to have fundamental roles in tumorigenesis and have great potential for the diagnosis and treatment of cancer. However, the roles of miRNAs in hepatocellular carcinogenesis are still not fully elucidated. Growing evidence indicates that deregulation of microRNAs (miRNAs) contributes to tumorigenesis. UNLABELLED: Deregulation of microRNAs (miRNAs) is common in advanced human hepatocellular carcinoma (HCC); however, the ones involved in early carcinogenesis have not yet been investigated. Deregulation of miRNAs expression has been shown in different human cancer but the molecular mechanism underlying the alteration of miRNA expression is unknown. </context> <question> What is the mechanism of microRNA deregulation in carcinogenesis? </question> <answer> MicroRNAs (miRNAs) are endogenous non-protein coding single-stranded RNAs (19–25 nucleotides in length) generated from cleavage of larger non-coding RNAs by the ribonuclease III enzyme Dicer. They become part of the RNA-induced silencing complex and negatively regulate gene expression by binding to homologous 3\'-UTR region of target protein-coding mRNAs as an imperfect match, causing translational repression or degradation. Approximately one-third of the protein-coding genes are susceptible to miRNA regulation. Accumulating evidence indicates that deregulated miRNA expression is associated with the onset and progression of a number of human cancers. Therefore, cancer-associated miRNAs (CA-miRNAs) could regulate target genes by acting either as "oncogenes" or "tumor suppressor miRNA (TS-miRNAs)". In line with this, numerous cancers (e.g. breast, lung, oesophageal, prostate, pancreatic, gastric and colon cancer) have been classified based on their unique miRNA expression profile. </answer>
<context> Moreover, the identification of uric acid precipitates in P. falciparum- and P. vivax-infected erythrocytes obtained directly from malaria patients underscores the in vivo and clinical relevance of our findings. lasmodium falciparum the main causative agent of malaria is an important public health vector. Moreover, the identification of uric acid precipitates in P. falciparum- and P. vivax-infected erythrocytes obtained directly from malaria patients underscores the in vivo and clinical relevance of our findings. Plasmodium falciparum the main causative agent of malaria is an important public health vector. < Plasmodium falciparum is the causative agent of malaria, a disease that kills almost one million persons each year, mainly in sub-Saharan Africa. P. falciparum is transmitted to the human host by the bite of an Anopheles female mosquito, and Anopheles gambiae sensus stricto is the most tremendous malaria vector in Africa, widespread throughout the afro-tropical belt. Fluorescence imaging microscopy of erythrocytes infected with Plasmodium falciparum, a causative agent of malaria in humans, showed that only the parasite was stained. Human malaria is among the most ubiquitous and destructive tropical, parasitic diseases in the world today. The causative agent, Plasmodium falciparum, contains an unusual, essential organelle known as the apicoplast. Overcoming antigenic variation is one of the major challenges in the development of an effective vaccine against Plasmodium falciparum, a causative agent of human malaria. [The vivax malaria causative agent Plasmodium ovale: the present global area, intraspecies polymorphism, importation to the Russian Federation (1992-2011)]. The global area for Plasmodium ovale is small as compared with that for other species of human malaria pathogens. Parasites that have been described to affect the central nervous system (CNS), either as the dominant or as a collateral feature, include cestodes (Taenia solium (neurocysticerciasis), Echinococcus granulosus (cerebral cystic echinococcosis), E. multilocularis (cerebral alveolar echinococcosis), Spirometra mansoni (neurosparganosis)), nematodes (Toxocara canis and T. cati (neurotoxocariasis), Trichinella spiralis (neurotrichinelliasis), Angiostrongylus cantonensis and A. costaricensis (neuroangiostrongyliasis), Gnathostoma spinigerum (gnathostomiasis)), trematodes (Schistosoma mansoni (cerebral bilharziosis), Paragonimus westermani (neuroparagonimiasis)), or protozoa (Toxoplasma gondii (neurotoxoplasmosis), Acanthamoeba spp. or Balamuthia mandrillaris (granulomatous amoebic encephalitis), Naegleria (primary amoebic meningo-encephalitis), Entamoeba histolytica (brain abscess), Plasmodium falciparum (cerebral malaria), Trypanosoma brucei gambiense/rhodesiense (sleeping sickness) or Trypanosoma cruzi (cerebral Chagas disease)) Plasmodium falciparum, the causative agent of the deadliest form of malaria, and human immunodeficiency virus type-1 (HIV-1) are among the most important health problems worldwide, being responsible for a total of 4 million deaths annually. Plasmodium falciparum is the causative agent of malaria, a deadly infectious disease for which treatments are scarce and drug-resistant parasites are now increasingly found. In contrast, it has been thought that Plasmodium spp., the causative agent of malaria, rely mainly on cytosolic glycolysis but not mitochondrial oxidative phosphorylation for energy production during blood stages. Whereas no biological activity was previously identified for 1, the material derived from the efficient synthesis enabled additional bioactivity tests leading to the identification of a notable activity against insect cells and Plasmodium falciparum, the causative agent of malaria. Plasmodium falciparum, the causative agent of malaria, encodes an SSB protein that localizes to the apicoplast and likely functions in the replication and maintenance of its genome. Fingerprinting the substrate specificity of M1 and M17 aminopeptidases of human malaria, Plasmodium falciparum. Malaria is one of the deadliest infectious diseases of humans in the world. It is endemic in tropical and subtropical regions, with about 500 million cases of malaria infections and 1.4–2.6 million deaths each year [1]. Four Plasmodium species commonly infect humans (P. vivax, P. malariae, P. falciparum and P. ovale) [2], [3]. Among them P. falciparum is of special interest because it is the most lethal and responsible for most deaths, particularly in pregnant women and children under the age of five. While observing cells by time-lapse imaging is a standard procedure in many systems, this technique was until recently not available for blood stages of Plasmodium falciparum, the causative agent of the most severe form of human malaria. The causative agent of malaria, Plasmodium, possesses three translationally active compartments: the cytosol, the mitochondrion and a relic plastid called the apicoplast. One of the world's deadliest diseases, malaria, is caused by protozoan parasites of the genus Plasmodium, which are transmitted by Anopheles mosquitoes. The innate immune system of Anopheles, this malaria vector's main line of defense against the Plasmodium parasite, is engaged at multiple stages of parasite infection [1]–[3]. The merozoite surface protein (MSP)-1 of Plasmodium falciparum, the causative agent of malaria tropica, is considered to be a promising vaccine candidate. Plasmodium vivax has been long neglected as a major malaria parasite since it is the causative agent of benign malaria, in favor of Plasmodium falciparum that causes fatal cerebral malaria. However, P. vivax is the second leading cause of malaria outside Africa inflicting about 40% of the world population. In Asia, P. vivax accounts for about 50% of malaria cases [1]. In the case of P. falciparum, the causative agent of the most severe form of malaria in humans, this involves at least two protein families. The genus Plasmodium, the causative agent of malaria, has the smallest mt genome in the form of a tandemly repeated, linear element of 6 kb. The culminating step of the intraerythrocytic development of Plasmodium falciparum, the causative agent of malaria, is the spectacular release of multiple invasive merozoites on rupture of the infected erythrocyte membrane. Plasmodium falciparum, the causative agent of human malaria, lacks a conventional tricarboxylic acid cycle and depends exclusively on glycolysis for ATP production. Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. The Hsp90 protein from the parasite Plasmodium falciparum, the causative agent of malaria, is critical for this organism's survival; the anti-Hsp90 drug geldanamycin is toxic to P. falciparum growth. A novel family of 1H-imidazol-2-yl-pyrimidine-4,6-diamines has been identified with potent activity against the erythrocyte-stage of Plasmodium falciparum (Pf), the most common causative agent of malaria. The Plasmodium parasite, causative agent of malaria, infects RBC that are phagocytosed by DC and macrophages during the course of infection. Plasmodium falciparum is the causative agent of malaria, a disease where new drug targets are required due to increasing resistance to current anti-malarials. Malaria is one of the deadliest infectious diseases, threatening half a billion humans worldwide with a yearly death toll of 1 to 2 million people, mainly in developing countries (World Malaria Report 2005, Geneva, World health Organization, WHO/UNICEF; 2005). Malaria is due to infections by protozoan parasites of the Plasmodium genus, transmitted by bites of female Anopheles mosquitoes. Of the four species that infect humans, P. falciparum causes the greatest incidence of illness and death [1]. Plasmodium falciparum, the causative agent of human malaria, invades host erythrocytes using several proteins on the surface of the invasive merozoite, which have been proposed as potential vaccine candidates. Few studies have investigated the pathophysiologic mechanisms responsible for what seems to be a possible interaction between Plasmodium falciparum, the causative agent of malaria, and HIV-1 in dually infected patients. We show that orthochromatic cells are the earliest stages that may be invaded by Plasmodium falciparum, the causative agent of fatal human malaria. Infection by Plasmodium, the causative agent of malaria, is associated with hemolysis and therefore with release of hemoglobin from RBC. Plasmodium falciparum, the causative agent of malignant malaria, is among the most severe human infectious diseases Plasmodium falciparum, the most important causative agent of human malaria, undergoes antigenic variation as a means of prolonging infection and ensuring transmission between hosts. Despite the clinical and economic significance of the human malaria parasite, Plasmodium falciparum, the energy metabolism of this organism is still poorly understood. L-Malate dehydrogenase (PfMDH) from Plasmodium falciparum, the causative agent for the most severe form of malaria, has shown remarkable similarities to L: -lactate dehydrogenase (PfLDH). Although malaria has long been a devastating killer for the most vulnerable populations in countries of sub-Saharan Africa and other developing nations, our understanding of the early host-parasite interactions underlying this infectious disease remains far from complete. In fact, the first stage of a malaria infection, which occurs in the liver once the Plasmodium parasite has been delivered through the bite of an infected female Anopheles mosquito, is still clearly under-studied today. FQ is able to overcome the chloroquine (CQ) resistance problem, an important limit to the control of Plasmodium falciparum, the principal causative agent of malaria. Plasmodium falciparum, the main causative agent of this parasitic disease, develops drug resistance and no effective vaccine is available. In recent years, Plasmodium falciparum, the most virulent malaria parasite species that infects humans, has developed increasing resistance to anti-malarial drugs in use. The causative agent of malaria, Plasmodium falciparum posses a single aquaglyceroporin (PfAQP) which represents a potential drug target for treatment of the disease. An essential requisite for transmission of Plasmodium, the causative agent of malaria, is the successful completion of a complex developmental cycle in its mosquito vector. In Plasmodium falciparum, the causative agent of cerebral malaria, silent information regulator 2 (Sir2) has been implicated in pathogenesis through its role in var gene silencing. Plasmodium falciparum, the causative agent of human malaria, is totally dependent on de novo pyrimidine biosynthetic pathway. Plasmodium falciparum, the causative agent of the fatal form of malaria, synthesizes GMP primarily from IMP and, hence, needs active GMPS (GMP synthetase) for its survival. Plasmodium falciparum is the causative agent of the most severe type of malaria, a life-threatening disease affecting the lives of over three billion people. Plasmodium falciparum, the causative agent of the most serious form of malaria, infects about 5-10% of the world human population per year. Plasmodium vivax is an important human pathogen causing malaria in more temperate climates of the world. Similar to Plasmodium falciparum, the causative agent for malaria tropica, drug resistance is beginning to emerge for this parasite species and this hampers adequate treatment of infection. Malaria kills more than one million people a year, and understanding the historical association between its most notorious causative agent, Plasmodium falciparum, and its mosquito vectors is important in fighting the disease. We show here that macrophages are mandatory for NK cell IFN-gamma secretion in response to erythrocytes infected with Plasmodium falciparum (Pf), a causative agent of human malaria. The lethal form of human malaria is caused by the infection with the obligate intracellular protozoan parasite Plasmodium falciparum, which displays a developmental life cycle alternating between a vertebrate and an invertebrate host. Plasmodium falciparum is the causative agent of the most severe and mortal type of malaria. Plasmodium falciparum is the main causative agent of tropical malaria, the most severe parasitic disease in the world. Growing resistance of Plasmodia towards available drugs is an increasing problem in countries where malaria is endemic. The presence of antisense RNA in Plasmodium falciparum, the causative agent of severe malaria, remains controversial. Plasmodium falciparum, the causative agent of malaria, is sensitive to oxidative stress and therefore the family of antioxidant enzymes, peroxiredoxins (Prxs) represent a target for antimalarial drug design. In the Republic of Yemen, Plasmodium falciparum is the predominant causative agent of malaria and is associated with adverse consequences for pregnant women and their babies. Plasmodium falciparum, the causative agent of the most lethal form of human malaria, uses multiple ligand-receptor interactions to invade host red blood cells (RBCs). Comparative genomic analysis of the malaria causative agent, Plasmodium falciparum, with other eukaryotes for which the complete genome is available, revealed that the genome from P. falciparum was more similar to the genome of a plant, Arabidopsis thaliana, than to other non-apicomplexan taxa. Plasmodium falciparum, the causative agent of the most lethal form of human malaria, totally depends on de novo pyrimidine biosynthetic pathway. Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Plasmodium falciparum is the causative agent of the most severe form of human malaria. The rapid multiplication of the parasite within human erythrocytes requires an active production of new membranes. Seven sPLA(2)s from groups IA, IB, IIA and III, were tested here in different culture conditions for inhibition of the in vitro intraerythrocytic development of Plasmodium falciparum, the causative agent of the most severe form of human malaria Plasmodium falciparum, the causative agent of the most lethal form of human malaria, relies on de novo pyrimidine biosynthesis. In spite of research efforts to develop vaccines against the causative agent of human malaria, Plasmodium falciparum, effective control remains elusive. Plasmodium, the causative agent of malaria, has to undergo sexual differentiation and development in anopheline mosquitoes for transmission to occur. For Plasmodium falciparum, a causative agent of tropical malaria, TrxR is an essential protein which has been validated as a drug target. Plasmodium, the causative agent of malaria, must first infect hepatocytes to initiate a mammalian infection. As the causative agent of malaria, Plasmodium sp. claims between one and two million human lives annually worldwide. Plasmodium falciparum is particularly lethal and causes cerebral malaria [1]. Cyclin dependent protein kinases (CDKs) have become attractive drug targets in an effort to identify effective inhibitors of the parasite Plasmodium falciparum, the causative agent of the most severe form of human malaria. Human malaria is caused by four species of the parasitic protozoan genus Plasmodium. Of these four species, Plasmodium falciparum is responsible for the vast majority of the 300–500 million episodes of malaria worldwide and accounts for 0.7–2.7 million annual deaths. It is well established that protection against one such disease, malaria, requires strong CD8(+) T cell responses targeted against the liver stages of the causative agent, Plasmodium spp. A novel method for the in vitro detection of the protozoan Plasmodium, the causative agent of malaria, has been developed. Trypanosomes do not inhabit or grow in anopheles mosquitoes, the vector for the transmission of Plasmodium parasites the causative agent for malaria. The genome sequence of Plasmodium falciparum, the causative agent of the most severe form of malaria in humans, rapidly approaches completion, but our ability to genetically manipulate this organism remains limited. It is caused by a number of species of the genus Plasmodium, and Plasmodium falciparum is the causative agent of the most lethal form. To complete its life cycle in the mosquito, Plasmodium, the causative agent of malaria, has to traverse the epithelia of the midgut and salivary glands. In Plasmodium falciparum, the causative agent of human malaria, the catalytic subunit gene of cAMP-dependent protein kinase (Pfpka-c) exists as a single copy. Sulfadoxine is the most extensively used drug of this group of drugs and is usually combined with pyrimethamine (Fansidar), particularly for the control of Plasmodium falciparum, the causative agent of the most lethal form of malaria. Resistance to the sulfadoxine/pyrimethamine combination is widespread. A putative glutathione peroxidase gene (Swiss-Prot accession number Z 68200) of Plasmodium falciparum, the causative agent of tropical malaria, was expressed in Escherichia coli and purified to electrophoretic homogeneity. Apical membrane antigen 1 (AMA1) is an asexual blood-stage protein expressed in the invasive merozoite form of Plasmodia species, which are the causative agent of malaria. In the case of Plasmodium falciparum, the causative agent of malaria tropica, this approach is especially interesting, because here both key enzymes, ODC and AdoMetDC, are combined in a bifunctional protein, ODC/AdoMetDC. Plasmodium falciparum, the causative agent of the most lethal form of human malaria, is incapable of de novo purine synthesis, and thus, purine acquisition from the host is an indispensable nutritional requirement. A laboratory model of circulation of the malaria causative agent P. gallinaceum has been used to show that the effect of precocene (antijuvenoid) leads to a statistically significant reduction in the proportion of infected females developing eggs after blood suction. A cell-free incubation system prepared from asexual erythrocytic stages of Plasmodium falciparum, the causative agent of malaria in humans, is capable of synthesizing the same spectrum of GPIs as that found in metabolically labelled parasites. The Plasmodium falciparum malaria parasite is the causative agent of malaria tropica. The gene of an NADP+-specific glutamate dehydrogenase was cloned from Plasmodium falciparum, the causative agent of tropical malaria. This study describes the synergistic interaction of two calcium channel blockers, verapamil (VR) and SR33557 or fantofarone (SR), in reversing chloroquine resistance in Plasmodium falciparum, the causative agent of human malaria. Plasmodium falciparum is the major causative agent of malaria, a disease of worldwide importance. Two enzymes were purified to homogeneity from the intraerythrocytic malarial parasite Plasmodium falciparum: glutathione disulfide reductase, an antioxidative enzyme, which appears to play an essential role for parasite growth and differentiation, and glutamate dehydrogenase, an enzyme not occurring in the host erythrocyte. The paper provides evidence that the An. sacharovi females which do not develop mature eggs after blood-sucking on the malaria-infected donor could not be infected by the bird malaria agent P. gallinaceum. Plasmodium falciparum is the causative agent of malaria tropica in man. Plastid origin of an extrachromosomal DNA molecule from Plasmodium, the causative agent of malaria. [New models of the circulation of the causative agent of malaria Plasmodium gallinaceum using malarial mosquitoes in the fauna of the USSR]. [Experimental research on the effect of biologically active substances on the susceptibility of mosquitoes to the causative agent of malaria. 3. Algae, fertilizers]. On a model pair Aedes aegypti--Plasmodium gallinaceum in has been shown that changes in the conditions of larvae development caused by the addition into the water medium of the live culture of Synochocystis sp. cyanobacteria or green seaweeds Chlorella vulgaris, acetone extracts from the live culture precipitate or Chlorella powder, as well as nitrogen-containing fertilizer--ammonium chloride did not lower the sensitivity of the imago flying to malaria parasites. The mechanism of chloroquine resistance has not been known but recent evidence from Plasmodium falciparum, the causative agent of the most severe form of human malaria, suggested similarities to the multidrug resistance phenotype (MDR) of mammalian tumour cells which is mediated by a protein molecule termed P-glycoprotein. The feasibility was determined of influencing Ae. aegypti sensitivity to bird malaria agent P. gallinaceum by sublethal concentrations of herbicides (ordram and propanide) and fungicides (fundozol and blue vitriol) introduced into the larvae habitation medium or into the imago feed. [An experimental study of the effect of different biologically active substances on the susceptibility of mosquitoes to the causative agent of malaria. 1. Insect development regulators]. It has been shown on the model pair Ae. aegypti-P. gallinaceum that dimilin, an inhibitor of insect chitin synthesis has practically no effect on female sensitivity to malaria agent. [The absence of an action of the pyrethroids deltamethrin and cypermethrin on mosquito susceptibility to the causative agent of malaria]. Mosquitos Ae. aegypti and An. stephensi contact with sublethal doses of deltametrin and cypermetrin pyretroids at larval stage and in grown state, when diet includes sugar with pyretroids, had no influence on the sensitivity of survived females to malaria agents P. gallinaceum and P. berghei. This prompted us to purify and characterize the topoisomerases I and II present in the erythrocytes of protozoan parasites of the genus Plasmodium, the causative agent of malaria, in order to later use these enzymatic systems in antimalarial drug assays. The problem of drug resistance of Plasmodium falciparum, the causative agent of tropical malaria and its role in the general system of malaria control are discussed. [Effect of mosquito contact with DDT and their susceptibility to the causative agent of malaria]. [Lack of an effect from repeated blood sucking by mosquitoes on their infectivity with the causative agent of malaria]. The lack of repeated bloodsucking does not affect essentially the infection of Ae. aegypti mosquitoes with malaria agent, P. gallinaceum. High resolution 31P-NMR has been used for the non-invasive observation of metabolites and metabolic rates in blood of normal mice and of mice infected with Plasmodium berghei, the causative agent of malaria. BACKGROUND: Plasmodium falciparum the main causative agent of malaria is an important public health vector. Plasmodium falciparum is the causative agent of malaria, a disease that kills almost one million persons each year, mainly in sub-Saharan Africa. The causative agent, Plasmodium falciparum, contains an unusual, essential organelle known as the apicoplast. In this study bioinformatic analyses indicated a single copy orthologue of the putative SM synthase from the apicomplexan Plasmodium falciparum (the causative agent of malaria) was a bona fide sphingolipid synthase in the related model parasite, Toxoplasma gondii (TgSLS). The effectiveness of methylene blue (MB) combined with pyrimethamine (PYR), chloroquine (CQ) or quinine (Q) was examined in a classical four-day suppressive test against a causative agent of rodent malaria, Plasmodium berghei. Infection by Plasmodium species, the causative agent of malaria, is currently treated with drug-based therapies, but an increase in drug resistance has led to the need for new methods of treatment. IntroductionOne of the world's deadliest diseases, malaria, is caused by protozoan parasites of the genus Plasmodium, which are transmitted by Anopheles mosquitoes. BACKGROUND: The merozoite surface protein (MSP)-1 of Plasmodium falciparum, the causative agent of malaria tropica, is considered to be a promising vaccine candidate. The 23-megabase genome of Plasmodium falciparum, the causative agent of severe human malaria, contains ∼5300 genes, most of unknown function or lacking homologs in other organisms. IntroductionPlasmodium vivax has been long neglected as a major malaria parasite since it is the causative agent of benign malaria, in favor of Plasmodium falciparum that causes fatal cerebral malaria. Results of the present study indicate that malaria is endemic in Nouakchott and that P. vivax is the principal causative agent. Like Plasmodium falciparum, the causative agent of malaria in humans, Babesia species generate asexual merozoites through binary fission of red blood cells (RBCs) after infection. Malaria remains one of the most devastating infectious diseases in the world. Plasmodium vivax was the main causative agent followed by Plasmodium falciparum. Toxoplasma gondii is a member of the phylum Apicomplexa that includes several important human pathogens, such as Cryptosporidium and Plasmodium falciparum, the causative agent of human malaria. Plasmodium falciparum, the major causative agent of human malaria, contains three separate genomes. Plasmodium parasites, the causative agent of malaria, are transmitted through the bites of infected Anopheles mosquitoes resulting in over 250 million new infections each year. Malaria is due to infections by protozoan parasites of the Plasmodium genus, transmitted by bites of female Anopheles mosquitoes. The genus Plasmodium, causative agent of malaria, of the phylum Apicomplexa, has the smallest mt genome in the form of a circular and/or tandemly repeated linear element of 6 kb, encoding only three protein genes (cox1, cox3, and cob). Plasmodium falciparum is the causative agent of the most lethal form of human malaria. In Plasmodium falciparum, the causative agent of the most lethal form of malaria, fatty acid biosynthesis occurs in the apicoplast organelle during the liver stage of the parasite life cycle. Plasmodium falciparum, the causative agent of malignant malaria, is among the most severe human infectious diseases. For transmission to occur, Plasmodium, the causative agent of malaria, must complete a complex developmental cycle in its mosquito vector. FQ is able to overcome the CQ resistance problem, an important limit to the control of Plasmodium falciparum, the principal causative agent of malaria. Some lycorine ester derivatives including LT1 were examined for their inhibitory activity against Trypanosoma brucei brucei, the parasite associated with sleeping sickness, and against Plasmodium falciparum, the causative agent of malaria. A three-dimensional structure of histo-aspartic protease (HAP), a pepsin-like enzyme from the causative agent of malaria Plasmodium falciparum, is suggested on the basis of homologous modeling followed by equilibration by the method of molecular dynamics. BACKGROUND: Understanding gene regulation in Plasmodium, the causative agent of malaria, is an important step in deciphering its complex life cycle as well as leading to possible new targets for therapeutic applications. Plasmodium falciparum, the causative agent of malaria, relies on a complex protein-secretion system for protein targeting into numerous subcellular destinations. We have evaluated a technology called transcriptionally active PCR (TAP) for high throughput identification and prioritization of novel target antigens from genomic sequence data using the Plasmodium parasite, the causative agent of malaria, as a model. </context> <question> Which is the causative agent of malaria? </question> <answer> Plasmodium species' 'Plasmodium spp. </answer>
<context> Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Nine genes that are mutated at significant frequencies were identified, including four with established roles in chronic lymphocytic leukemia (TP53 in 15% of patients, ATM in 9%, MYD88 in 10%, and NOTCH1 in 4%) and five with unestablished roles (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X). SF3B1, which functions at the catalytic core of the spliceosome, was the second most frequently mutated gene (with mutations occurring in 15% of patients). </context> <question> Which genes are more frequently affected by somatic mutations in Chronic Lymphocytic Leukemia </question> <answer> TP53; ATM; NOTCH1; XPO1; MYD88; KLHL6; SF3B1; ZMYM3; MAPK1; FBXW7; DDX3X </answer>
<context> The problem of finding an optimal structural alignment for a pair of superimposed proteins is often amenable to the Smith-Waterman dynamic programming algorithm, which runs in time proportional to the product of lengths of the sequences being aligned. The similarities between sequences can be determined by computing their optimal local alignments using the dynamic programming based on the Smith-Waterman (SW) algorithm [1,2]. However, the quadratic time complexity of this algorithm makes it computationally demanding, which is further compounded by the exponential growth of sequence databases While this result is not an asymptotic improvement over the original Smith-Waterman algorithm, its complexity is characterized in terms of some sparse features of the matrix and it yields the fastest software implementation to date for such searches. If we use N, M and C to represent the size of an amino acid sequence, the size of a structure template, and the maximum cut size of long-range interactions, respectively, the algorithm finds an optimal structure-sequence alignment in O(21C NM) time, a polynomial function of N and M when C = O(log(N + M)). When running on structure-sequence alignment problems without long-range intersections, i.e. C = 0, the algorithm achieves the same asymptotic computational complexity of the Smith-Waterman sequence-sequence alignment algorithm. The algorithm is based on fractional programming and its running time is O(n2log n). In practice, normalized local alignment is only 3-5 times slower than the standard Smith-Waterman algorithm. </context> <question> Which is the execution time (complexity) of the Smith-Waterman algorithm for the alignment of two sequences </question> <answer> quadratic </answer>
<context> For instance, they are used to determine expression profiles of miRNAs, 20–24 nt long RNA molecules, that have emerged in recent years as important post-transcriptional regulators in all known multicellular organisms and that are known to play roles in development, tumorigenesis and viral infection (Bartel, 2004). Besides miRNAs other small non-coding RNA (ncRNA) classes such as piRNAs (Aravin et al., 2001), snoRNAs (Bachellerie et al., 2002) or scaRNAs (Gerard et al., 2010) have been investigated Most ncRNAs have very specific structural properties that have been used to classify them (Will et al., 2007), e.g. tRNAs possess a cloverleaf structure, whereas miRNA precursors form stable hairpins. Distance information also helps to distinguish miRNAs from degradation products of other abundant RNA species such as tRNAs or snRNAs (Fig. 1). Since there are only very few unique snRNAs, snoRNAs and rRNAs, we only considered miRNAs and tRNAs for evaluation egulatory RNAs such as miRNAs, piRNAs or siRNAs are believed to recognize their targets by a short complementary region (seed) Some of these RNA classes, in particular microRNAs and snoRNAs, undergo maturation processes that lead to the production of shorter RNAs. </context> <question> Name the major classes of small non coding RNAs in mammalians? </question> <answer> miRNA; snRNA; snoRNAs; scaRNAs; piRNAS </answer>
<context> Our analyses indicate that lncRNAs are generated through pathways similar to that of protein-coding genes, with similar histone-modification profiles, splicing signals, and exon/intron lengths. In contrast to protein-coding genes, however, lncRNAs display a striking bias toward two-exon transcripts hey are predominantly localized in the chromatin and nucleus, and a fraction appear to be preferentially processed into small RNAs. They are under stronger selective pressure than neutrally evolving sequences-particularly in their promoter regions, which display levels of selection comparable to protein-coding genes. Comprehensive analysis of their expression in multiple human organs and brain regions shows that lncRNAs are generally lower expressed than protein-coding genes, and display more tissue-specific expression patterns, with a large fraction of tissue-specific lncRNAs expressed in the brain. .Compared with protein-coding sequences and small RNAs (e.g., miRNA and snoRNA), lncRNAs are weakly conserved: only approximately 5% of the bases have been estimated to be evolutionarily constrained (Marques and Ponting 2009) A comparative analysis of the expression patterns of intergenic transcripts in brain, heart, testis, and lymphoblastoid cell lines of human and chimpanzee has revealed a tissue-specific conservation pattern, which is similar to that of protein-coding genes. LincRNA exons and their putative promoters were found by Guttman et al. [10] to be better conserved than introns, which is suggestive of the action of purifying selection. he proportion of conserved sequence (4.1%-5.5%) in these macroRNAs is comparable to the density of exons within protein-coding transcripts (5.2%). These macroRNAs, taken together, thus possess the imprint of purifying selection, thereby indicating their functionality. </context> <question> Other than protein coding potential, what features set apart long non-coding RNAs from protein coding genes? </question> <answer> Compared to protein coding genes, long non-coding RNAs (lncRNAs) display a bias towards two-exon transcripts. They are predominantly localized in the chromatin and nucleous. They are lower expressed and display a more tissue-specific expression pattern. LncRNAs are overall more weakly conserved than protein coding genes. </answer>
<context> ecently, we have shown [19] that one fly, Drosophila willistoni, lacks selenoprotein genes, being the first animal reported to lack these proteins. More recently Lobanov et al. have reported that other insect genomes also appear to lack selenoproteins [20] We have also analyzed the sequences of all other available insect genomes (the mosquitoes Anopheles gambiae and Aedes aegypti, the honey bee Apis mellifera, the wasp Nasonia vitripennis, the beetle Tribolium castaneum and the silkworm Bombyx mori), and found that, while mosquitoes share the selenoprotein complement of D. melanogaster, selenoproteins have been lost in the wasp, the honey bee, the silkworm and the beetle Analysis of available sequence data from other arthropoda (including cDNA, EST, protein and genomic data) suggests that the loss of selenoproteins has been confined to the infraclass Endopterygota, affecting species of all orders investigated (Hymenoptera, Lepidoptera, Diptera and Coleoptera). </context> <question> Which metazaon species or taxa are known to lack selenoproteins </question> <answer> Some insect genomes have lost the capacity of synthesizing selenoproteins. Species without selenoproteins have been identified within Diptera, Lepidoptera, Hymenoptera and Coleoptera. </answer>
<context> , as splicing is often cotranscriptional, a complex picture emerges in which splicing regulation not only depends on the balance of splicing factor binding to their pre-mRNA target sites but also on transcription-associated features such as protein recruitment to the transcribing machinery and elongation kinetics. recent evidence shows that chromatin structure is another layer of regulation that may act through various mechanisms hese span from regulation of RNA polymerase II elongation, which ultimately determines splicing decisions, to splicing factor recruitment by specific histone marks. Chromatin may not only be involved in alternative splicing regulation but in constitutive exon recognition as well Moreover, splicing was found to be necessary for the proper 'writing' of particular chromatin signatures, giving further mechanistic support to functional interconnections between splicing, transcription and chromatin structure. These links between chromatin configuration and splicing raise the intriguing possibility of the existence of a memory for splicing patterns to be inherited through epigenetic modifications. Whereas the historical view of splicing envisioned a cascade of temporal events initiated by transcription, followed by polyadenylation, and finalized with splicing and export of mRNAs from the nucleus, it is now clear that these pathways are not independent from one another but rather are functionally coupled. trong evidence in both yeast and higher eukaryotes demonstrates that recruitment of the spliceosome to intron-containing transcripts occurs co-transcriptionally [3]–[6], mediated at least in part by physical associations between the C-terminal domain (CTD) of RNA polymerase II and the U1 snRNP [7] A growing body of evidence also indicates that the landscape of chromatin modifications encountered by transcribing polymerase molecules can dictate the activity of the spliceosome at various splice sites. Spliceosome assembly occurs co-transcriptionally, raising the possibility that DNA structure may directly influence alternative splicing. upporting such an association, recent reports have identified distinct histone methylation patterns, elevated nucleosome occupancy and enriched DNA methylation at exons relative to introns Moreover, the rate of transcription elongation has been linked to alternative splicing. ere we provide the first evidence that a DNA-binding protein, CCCTC-binding factor (CTCF), can promote inclusion of weak upstream exons by mediating local RNA polymerase II pausing both in a mammalian model system for alternative splicing, CD45, and genome-wide We recently showed that cotranscriptional splicing occurs efficiently in Drosophila, In recent years it became apparent that splicing is predominantly cotranscriptional To determine the prevalence of cotranscriptional splicing in Drosophila, we sequenced nascent RNA transcripts from Drosophila S2 cells as well as from Drosophila heads. Eighty-seven percent of the introns assayed manifest >50% cotranscriptional splicing. The remaining 13% are cotranscriptionally spliced poorly or slowly, with ∼3% being almost completely retained in nascent pre-mRNA. We estimate that > or =90% of endogenous yeast splicing is posttranscriptional, consistent with an analysis of posttranscriptional snRNP-associated pre-mRNA. Notably, the topoisomerase I inhibitor camptothecin, which stalls elongating Pol II, increased cotranscriptional splicing factor accumulation and splicing in parallel. This provides direct evidence for a kinetic link between transcription, splicing factor recruitment and splicing catalysis. Recent evidence indicates that transcriptional elongation and splicing can be influenced reciprocally: Elongation rates control alternative splicing and splicing factors can, in turn, modulate pol II elongation. The presence of transcription factors in the spliceosome and the existence of proteins, such as the coactivator PGC-1, with dual activities in splicing and transcription can explain the links between both processes and add a new level of complexity to the regulation of gene expression in eukaryotes. </context> <question> Are transcription and splicing connected? </question> <answer> yes </answer>
<context> One of the most reliable prognostic markers in chronic lymphocytic leukemia (CLL) is the mutational status of immunoglobulin heavy variable (IGHV) genes, which defines 2 subsets, mutated CLL (M-CLL) and unmutated CLL (U-CLL), with different clinical courses. Mutational status of the immunoglobulin heavy chain variable regions (IGHVs) of CLL cells offers useful prognostic information for high-risk patients but time and economical costs originally prevented it from being routinely used in a clinical setting. Instead, alternative markers of IGHV status, such as zeta-associated protein (ZAP70) or messenger RNA levels are often used Patients with unmutated IgV(H) gene show a shorter progression-free and overall survival than patients with immunoglobulin heavy chain variable regions (IgV(H)) gene mutated </context> <question> Which is the most important prognosis sub-classification in Chronic Lymphocytic Leukemia? </question> <answer> The mutational status of the IGHV genes. </answer>
<context> Nucleosomes preferentially are located at the ends of exons, thus protecting splice junctions, with the N9 positions of guanines of the GT and AG junctions oriented toward the histones. Nucleosomes were found to be preferentially positioned within constitutive exons and/or constitutive portions of alternative exons, which was not associated with gene expression or states of cells but was based on sequence and positively related with the sequence conservation of splicing sites Here, we discuss the evidence supporting these ideas, from the first proposal of chromatin affecting alternative splicing, performed 20 years ago, to the latest findings including genome-wide evidence that nucleosomes are preferentially positioned in exons. a large number of histone modifications showed higher levels across exons which, for the most part, could be accounted for by nucleosome distribution, with well-positioned nucleosomes on exons accounting for these patterns he general link between nucleosome and gene exon–intron architecture has been suggested in previous studies (11,12). Andersson et al. (13) have reported that nucleosomes are well positioned in exons and carry characteristic histone modifications, and Schwartz et al. (14) have described that the chromatin organization marks the exon–intron structure. We found the common feature that the nucleosome occupation potential is significantly stronger in exons but weaker in their adjacent intron regions Here we show, by analysis of data sets from human sperm and T cells and medaka (Japanese killifish, Oryzias latipes) blastulae, that internal exons of genes are characterized by sharply elevated average nucleosome occupancy in comparison to flanking intronic sequences. sing public data, we here show that there is a higher nucleosome-positioning signal in internal human exons and that this positioning is independent of expression. We observed a similarly strong nucleosome-positioning signal in internal exons of Caenorhabditis elegans. we have found stable nucleosome occupancy within human and Caenorhabditis elegans exons that is stronger in exons with weak splice sites. This confirms previously reported findings about preferential positioning of splice junctions within the nucleosomes. </context> <question> What is the relationship between nucleosomes and exons? </question> <answer> Nucleosomes are preferentially located within exons compared to nearby intronic sequences. Preferential positioning within the exons is indepedent of gene expression levels, stronger in exons with weak splice sites and conserved through metazoan evolution. </answer>
<context> We found that several types of histone modifications including H3K36me3 were associated with the inclusion or exclusion of alternative exons. Furthermore, we observed that the levels of H3K36me3 and H3K79me1 in the cell lines were well correlated with the differences in alternative splicing patterns between the cell lines. Here we find that elevated levels of trimethylation of histone H3 on Lys9 (H3K9me3) are a characteristic of the alternative exons of several genes including CD44. he first report shows that a physiological stimulus such as neuron depolarization promotes intragenic histone acetylation (H3K9ac) and chromatin relaxation, causing the skipping of exon 18 of the neural cell adhesion molecule gene. Using small interfering RNAs (siRNAs), we increased the levels of H3K9me2 and H3K27me3 in the proximity of alternative exon 33 of the human fibronectin gene, favoring its inclusion into mature messenger RNA (mRNA) through a mechanism that recalls RNA-mediated transcriptional gene silencing. Among the 38 histone modifications analyzed in man, H3K36me3, H3K79me1, H2BK5me1, H3K27me1, H3K27me2, and H3K27me3 had evidently higher signals in internal exons than in the following introns and were clearly related to exon expression We also observe a novel pattern: exons are preferentially marked with H3K36me3 relative to introns. H3K36me3 exon marking is dependent on transcription and is found at lower levels in alternatively spliced exons, supporting a splicing-related marking mechanism Histone modifications such as H3K36me3, H3K79me1, H2BK5me1, H3K27me1, H3K27me2, and H3K27me3 were found to be related with exon expression Other histone methylations, such as H3K4me1, H3K4me3, H3K27me3 and H3K9me1, H3K4me3 was suggested to affect the AS events of CHD1 [21], and H3K9me3 was found to be associated with the multiple exon skipping of CD44 [22] Among the histone methylations we investigate, H3K36me3 (Figure 2a) is the only one that is significantly associated with all types of ASE in all regions, The level of H3K4 methylations, including H3K4me1, H3K4me2, and H3K4me3 (Figure 2b-d), is almost all significantly higher in A3SS and A5SS except that the significance of the association of H3K4me3 with ASE is in between 0.01 and 0.05 in some regions. For the other histone methylations, the level of H4K20me1 (Figure 2e) is significantly higher in A3SS, A5SS and IR; the level of H3K27me3 (Figure 2f) is significantly higher in the exonic region of ES; the level of H3K79me1 (Figure 2g) is significantly higher in A3SS and A5SS, and slightly higher in the intronic region of ES; the level of H3K79me2 (Figure 2h) is significantly higher in ME, A3SS and A5SS, and most region of IR; the level of H3K9me1 (Figure 2i) is significantly higher in A3SS, A5SS and most regions of IR. However, H3K9me3 (Figure 2j) is not significantly associated with any type of ASE. the strongest univariate candidates [8], [9], [10], [11] e.g. H3K79me1, H3K79me3 and H3K36me3, were all selected as significant by the MCFS, but only H3K36me3 succeeding and preceding the exon were among the 20 highest ranked modifications and thus included in the rule model. investigation of the fibroblast growth factor receptor 2 (FGFR2) locus revealed cell line-specific enrichment of histone H3 lysine 36 trimethylation (H3K36me3), which was shown to be required to promote the exclusion of one exon of the gene H3K36me3 exhibited a spatially reciprocal relationship with H3K79me2, clearly peaking at internal exons. H3K27me1 was present within active genes20, but exhibited little if any change with respect to exons (Supplementary Fig. 2). Across the genome, normalizing ChIP-seq data by MNase-seq data largely removed exon-centered enrichment for most marks (e.g. H3K79me2), but H3K36me3 remained enriched after normalization, peaking near exons and extending on average a few kilobases downstream As a control for comparison, H3K27me1 showed little difference up- and downstream of exons or ECRs (Supplementary Fig. 5). </context> <question> Which histone modifications have been associated to alternative splicing? </question> <answer> H3K36m3 has been systematically associated to exon inclusion in almost all published studies. Other marks have been associated as well in specific studies to exon expression, but it can not be concluded that the effect of these marks in exon expression it is not a consequence of their effect in gene expression. </answer>
<context> A member of the p53 family, p73, has several isoforms and differentially regulates transcription of genes involved in the control of the cell cycle and apoptosis. The Trp73 gene belongs to the p53 family of transcription factors and, like the other members, is transcribed into different isoforms [1-4]. TP73 gene contains two promoters, encoding the transcriptional domain-containing (TAp73) and the amino deleted (ΔNp73) isoforms [5, 6]. Furthermore alternative splicing at the 3'-end (to generate α, β, γ, etc isoforms) and 5'-end (to generate Δ2, Δ3 and Δ2-3 isoforms) results in generation of at least 14 different transcripts, with different abilities to promote or repress apoptosis [7, 8]. Due to the presence in the 5' flanking region of two promoters, there are two N-terminal variants, TAp73, which retains a fully active transactivation domain (TA), and ΔNp73, in which the N terminus is truncated. In addition, extensive 3' splicing gives rise to at least seven distinctive isoforms; TAp73-selective knockout highlights its role as a regulator of cell death, senescence and tumor suppressor. The p73 gene, a homologue of the p53 tumor suppressor, is expressed as TA and ΔN isoforms. TAp73 has similar activity as p53 and functions as a tumor suppressor whereas ΔNp73 has both pro- and anti-survival functions. The ΔNp73 isoforms that are derived from an internal promoter, antagonize the growth suppressing, pro-apoptotic functions of p53 and of the full length TAp73 isoforms in a dominant negative way by competing for the respective binding sites (2). TAp73 isoforms have been reported to play a role in DNA damage pathways, since p73 is activated by ionizing irradiation and cisplatin through c-Abl, thereby inducing apoptosis (10–12). Transcription from two different promoters on the p73 gene results in generation of transcriptionally active TAp73 isoforms and dominant negative DeltaNp73 isoforms with opposing pro- and anti-apoptotic functions. Given that the transactivation activity resides in the protein's N-terminus, TAp63 isoforms function as transcription factors inducing cell cycle arrest and apoptosis. TAp63γ is the most potent transcription activator [1], [2]. We have evaluated the differential expression and subcellular localization of the functionally distinct apoptotic (TA) and anti-apoptotic (DeltaN) isoforms of p73 in non-small cell lung cancer (NSCLC), their possible association with p53 expression and determined the methylation status of the two p73 gene promoters (P1 and P2) in this tumor type. The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73(-/-)) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73(-/-) mice show a high incidence of spontaneous tumors. p73 is a member of the p53 family of transcription factors, existing as numerous NH2- and COOH-terminal isoforms (1,2) The NH2-terminal variant, known as the deltaNp73 (DNp73), is generated from an internal intronic promoter and lacks the NH2-terminal transactivation (TA) domain, and hence, has been suggested to bind to and counter the tumour-suppressive properties of the TA proficient full-length TAp73 forms (3,4). The COOH-terminal variants arise due to alternate splicing resulting in multiple isoforms that exhibit varying degrees of TApotential (6,7). The longest isoform, the TAp73α, generally shows weaker activity than TAp73β and TAp73γ that exhibit stronger TA potential (7,8). TAp73 isoforms, harbouring a transactivating domain (TA), are known to transactivate p53 responsive genes and to induce apoptosis and growth arrest, whereas N-terminal truncated ΔNp73 isoforms, lacking the TA domain, can act as dominant-negative towards p53 and TAp73 (14,15). Alternative promoters and N-terminal splicing result in the transcription and processing of either full-length (TA) or N-terminally truncated (deltaN) p73 isoforms. TAp73 possesses pro-apoptotic functions, while deltaNp73 has anti-apoptotic properties via functional inhibition of TAp73 and p53. The p73 gene is able to encode transcriptionaly active TAp73, as well as a dominant-negatively acting DeltaNp73 transcript isoforms. Since some mutant p53 proteins and ΔNp73 isoforms form heterocomplexes with TAp73, we asked whether p53 isoforms can do the same and potentially act as dominant-negative inhibitors of TAp73. p73, a p53 family tumor suppressor, is expressed as TA and ΔN isoforms. p73 is expressed as TA and ΔN isoforms, both of which are implicated in tumor suppression and/or promotion. TP73 gene contains two promoters, encoding the transcriptional domain-containing (TAp73) and the amino deleted (ΔNp73) isoforms [5, 6]. We found that TAp73 isoforms are down regulated in oocytes from women older than 38 years. p73 possesses an extrinsic P1 promoter and an intrinsic P2 promoter controlling the expression of the pro-apoptotic TAp73 isoforms and the anti-apoptotic ΔΝp73 isoforms respectively. BRCA1-deficient ovarian carcinoma cells exhibit hypermethylation within a p73 regulatory region, which includes the binding site for the p73 transcriptional repressor ZEB1, leading to the abrogation of ZEB1 binding and increased expression of transactivating p73 isoforms (TAp73). In this study, we investigated the expression and subcellular distribution of two N-terminal isoforms, TAp73 and ΔNp73, in medulloblastoma cells using immunofluorescence microscopy. Proteasomal degradation of p73 is mediated by polyubiquitination-dependent and -independent processes both of which appear, thus far, to lack selectivity for the TAp73 and DeltaNp73 isoforms. In general, TAp73 isoforms show proapoptotic activities, whereas members of the N-terminally truncated (ΔN) p73 subfamily that lack the transactivation domain show antiapoptotic functions. The p73 gene possesses an extrinsic P1 promoter and an intrinsic P2 promoter, resulting in TAp73 and DeltaNup73 isoforms, respectively. Mice with a complete deficiency of p73 have severe neurological and immunological defects due to the absence of all TAp73 and DeltaNp73 isoforms. Moreover, we also found that subcellular location of p73 isoforms changes with the culture density increases. Moreover, ectopic expression of DeltaNp73alpha (but not other p73 isoforms) increased alphaB-crystallin mRNA levels in the absence of p53. Like wt p53, TAp63 and TAp73 isoforms transactivate target genes that activate apoptosis signaling pathways. The TP73 gene gives rise to transactivation domain-p73 isoforms (TAp73) as well as DeltaNp73 variants with a truncated N terminus. In contrast, antiapoptotic DeltaNp73 isoforms lack the TA domain and are dominant-negative inhibitors of p53 and TAp73. The isoforms TAp63 and TAp73 transactivate p53 target genes and induce apoptosis, whereas the isoforms DeltaNp63 and DeltaNp73 lack transactivation and might have dominant-negative effects in p53 family members. The expression of all 5 N-terminal isoforms (TAp73, DeltaNp73, DeltaN'p73, Ex2p73 and Ex2/3p73) was measured by real-time RT-PCR and p53 status was analyzed by immunohistochemistry. TAp73, DeltaNp73 and DeltaN'p73 were significantly upregulated in tumors. Consequently, different p73 isoforms can be degraded by calpains, i.e., both N-terminal isoforms (TAp73 and DeltaNp73) as well as the C-terminal isoforms (alpha, beta, gamma, delta). Variants lacking the TA domain (DeltaN isoforms) are induced by TAp73 and by p53, and inhibit their transcriptional activity. Indeed, tazarotene modulates the expression of the p73 gene in immortalized keratinocyte cell lines by inducing the pro-apoptotic and anti-proliferative TAp73 isoforms and by repressing the anti-apoptotic and pro-proliferative DeltaNp73 isoforms. p73, the first p53 gene homologue, encodes an array of p73 proteins including p73 alpha full-length (TAp73 alpha) and amino-truncated isoforms (Delta Np73 alpha), two proteins with opposite biological functions. We further showed that DeltaNp73 is a potent transdominant inhibitor of wild-type p53 and TAp73 in cultured human tumor cells by efficiently counteracting their target gene transactivations, apoptosis, and growth suppression functions (A. In developing sympathetic neurons of mice, p73 is predominantly expressed as a truncated anti-apoptotic isoform (DeltaNp73), which antagonizes both p53 and the full-length p73 protein (TAp73). Interestingly, expression of the Delta Np73 is strongly up-regulated by the TA isoforms and by p53, thus creating a feedback loop that tightly regulates the function of TAp73 and more importantly of p53. </context> <question> How many TAp73 isoforms have been identified in humans? </question> <answer> seven' '7 </answer>
<context> We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. Comparative functional genomic analysis identified a signature of Notch activation in 30% of HCC samples from patients. Mutations in NOTCH2, a gene required for marginal-zone (MZ) B cell development, represent the most frequent lesion in SMZL, accounting for ∼20% of cases. Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines. Exon resequencing of CMML patient specimens (Suppl. Table 3) identified a substantial fraction (6 novel mutations in 5 out of 42 patients) harboring somatic heterozygous mutations in multiple Notch pathway genes including NCSTN, APH1, MAML1 and NOTCH2 We found activating mutations in Notch in more than 30% of ATL patients. These activating mutations are phenotypically different from those previously reported in T-ALL leukemias and may represent polymorphisms for activated Notch in human cancers. We detected Notch1 missense mutations in 8.3% of the tumors (only in the posterior fossa location and in case of 9q33-34 gain). Importantly, mutations of the Notch protein and components of its signaling pathway have been implicated in an array of human diseases (T-cell leukemia and other cancers, Multiple Sclerosis, CADASIL, Alagille Syndrome, Spondylocostal Dysostosis). Here, we demonstrate that endothelial-specific deletion of Jag1 leads to cardiovascular defects in both embryonic and adult mice that are reminiscent of those in Alagille syndrome. In this study, analysis of 21 Vietnamese ALGS individuals led to the identification of 19 different mutations (18 JAG1 and 1 NOTCH2), 17 of which are novel, including the third reported NOTCH2 mutation in Alagille Syndrome. Genetics of Holoprosencephaly (HPE), a congenital malformation of the developing human forebrain, is due to multiple genetic defects. Most genes that have been implicated in HPE belong to the sonic hedgehog signaling pathway. Here we describe a new candidate gene isolated from array comparative genomic hybridization redundant 6qter deletions, DELTA Like 1 (DLL1), which is a ligand of NOTCH. Four genes causing a subset of autosomal recessive forms of this disease have been identified: DLL3 (SCDO1: MIM 277300), MESP2 (SCDO2: MIM 608681), LFNG (SCDO3: MIM609813) and HES7 (SCDO4). These genes are all essential components of the Notch signalling pathway, which has multiple roles in development and disease. Previously, only a single SCD-causative missense mutation was described in HES7. In this study, we have identified two new missense mutations in the HES7 gene in a single family, Here we have used autozygosity mapping to identify a mutation in a fourth Notch pathway gene, Hairy-and-Enhancer-of-Split-7 (HES7), in an autosomal recessive SCD family. Alagille syndrome (AGS) is caused by mutations in the gene for the Notch signaling pathway ligand Jagged1 (JAG1), which are found in 94% of patients. To identify the cause of disease in patients without JAG1 mutations, we screened 11 JAG1 mutation-negative probands with AGS for alterations in the gene for the Notch2 receptor (NOTCH2). We found NOTCH2 mutations segregating in two families and identified five affected individuals. Mutations in the JAG1 (Jagged 1) gene, coding a ligand in the evolutionarily conserved Notch signaling pathway, are responsible for AGS. Here we present sixteen different JAG1 gene mutations, among them twelve novel, not described previously. Altogether 226 different JAG1 mutations have been described in association with AGS, including our novel 36 mutations. Previous studies have demonstrated that a wide spectrum of JAG1 mutations result in AGS. These include total gene deletions, protein truncating, splicing and missense mutations which are distributed across the coding region of the gene. Here we present results of JAG1 mutation screening by SSCP and FISH in 105 patients with AGS. For these studies, new primers were designed for 12 exons. Mutations were identified in 63/105 patients (60%) We have screened 54 AGS probands and family members to determine the frequency of mutations in JAG1. Three patients (6%) had deletions of the entire gene. Of the remaining 51 patients, 35 (69%) had mutations within JAG1, identified by SSCP analysis. Of the 35 identified intragenic mutations, all were unique, with the exceptions of a 5-bp deletion in exon 16, seen in two unrelated patients, and a C insertion at base 1618 in exon 9, also seen in two unrelated patients. Analyses of many patients with cytogenetic deletions or rearrangements have mapped the gene to chromosome 20p12, although deletions are found in a relatively small proportion of patients (< 7%). We have mapped the human Jagged1 gene (JAG1), encoding a ligand for the developmentally important Notch transmembrane receptor, to the Alagille syndrome critical region within 20p12. </context> <question> What type of cancers and inherited diseases have been associated to mutations in the Notch pathway? </question> <answer> Alagille syndrome; spondylocostal dysostosis; CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy); T-cell acute lymphoblastic leukemia </answer>
<context> HTPB significantly inhibits cancer cell metastasis in vivo JNJ-26481585 also fully inhibited the growth of C170HM2 colorectal liver metastases, whereas again 5-fluorouracil/Leucovorin showed modest activity. Although not meeting the RECIST response criteria for adequate single-agent activity, the observed tolerable toxicities and the potential for clinical benefit in terms of stable disease suggest that further assessment of vorinostat as a part of combination therapy with either chemotherapeutic or targeted agents in metastatic breast might be undertaken. Treatments of different structural classes of HDACi simultaneously induced cell death and promoted cell migration and metastasis in multiple cancer cell types. Suppression of HDACi-induced PKCs leads to development of low toxic and long-term therapeutic strategies to potentially treat cancer as a chronic disease. mRNA expression analysis of lung tumor bearing mice suggested that the enhanced chemopreventive activity of the combination is related to atorvastatin modulation of DNA repair, SAHA modulation of angiogenesis, and both drugs modulating invasion and metastasis pathways. Histone deacetylase (HDAC) inhibitors induced morphologic differentiation, cell-cycle exit, and a shift to a differentiated, melanocytic gene expression profile in cultured UM cells. VPA inhibited the growth of UM tumors in vivo. When both drugs were used in concert additive effects were observed on the migratory and invasive behavior but not on tumor-endothelium and tumor-matrix interaction. Separate mTOR or HDAC inhibition slows processes related to tumor metastasis. The RAD001-VPA combination showed advantage over VPA monotreatment with particular respect to migration and invasion. In conclusion, sequential treatments of mice with MS-275 followed by TRAIL may target multiple pathways to reverse EMT and inhibit tumor progression, angiogenesis, and metastasis and represent a novel therapeutic approach to treat cancer. In vivo, AA98 synergized with vorinostat to inhibit tumor growth and metastasis. We report the first preclinical data for the prevention of brain metastasis of triple-negative breast cancer. Vorinostat is brain permeable and can prevent the formation of brain metastases by 62%. Its mechanism of action involves the induction of DNA double-strand breaks, suggesting rational combinations with DNA active drugs or radiation. Combining vorinostat with radiation may be a potential treatment option for patients with breast cancer who develop brain metastases. Although single-agent PCI-24781 had modest effects on STS growth and metastasis, marked inhibition was observed when combined with chemotherapy. In a 4T1 metastatic breast carcinoma model, AN-7 inhibited the formation of lung lesions by 76% and AN-9 by 47%, further demonstrating the greater efficacy of AN-7 compared to AN-9 (P<0.02). Both AN-7 and AN-9 exhibited antimetastatic and antiangiogenic activities by reducing vascularization, bFGF expression and HIF-1alpha. Since prolonged oral administration with 50 mg/kg or a single oral dose of 1.2 g/kg AN-7 did not cause adverse effects and the former exhibited significant anticancer activity, AN-7 is likely to display a high therapeutic index and may be beneficial for prostate cancer patients. We show that apicidin significantly inhibits H-ras-induced invasive phenotype of MCF10A human breast epithelial cells in parallel with a specific downregulation of matrix metalloproteinase (MMP)-2, but not MMP-9. We also show that apicidin induces a morphological reversal and growth inhibition of H-ras MCF10A cells similar to that induced by other HDAC inhibitors. We also found that NaB induced three genes, which are known metastatic suppressors, and downregulated 11 genes, which have been shown to promote metastasis. </context> <question> Are histone deacetylase (HDAC) inhibitors good candidates to control metastasis of solid tumors? </question> <answer> yes </answer>
<context> The prediction of the complete structure of genes is one of the very important tasks of bioinformatics, especially in eukaryotes. A crucial part in the gene structure prediction is to determine the splice sites in the coding region. Identification of splice sites depends on the precise recognition of the boundaries between exons and introns of a given DNA sequence. This problem can be formulated as a classification of sequence elements into 'exon-intron' (EI), 'intron-exon' (IE) or 'None' (N) boundary classes. The proposed WPSS method poses efficient results compared with the performance of many methods proposed in the literature. SCGPred: a score-based method for gene structure prediction by combining multiple sources of evidence. Moreover, computational gene finding in newly sequenced genomes is especially a difficult task due to the absence of a training set of abundant validated genes. Here we present a new gene-finding program, SCGPred, to improve the accuracy of prediction by combining multiple sources of evidence. Therefore, SCG-Pred can serve as an alternative gene-finding tool for newly sequenced eukaryotic genomes. The program is freely available at http://bio.scu.edu.cn/SCGPred/. For example, the TICO tool [14,24] was developed to refine prokaryotic gene structure annotations generated by the GLIMMER program [25,26]. MetWAMer.gthXML is a special-purpose variant of the software, specifically tailored to refine gene structure predictions generated by the GenomeThreader [30] and GeneSeqer [31] programs for spliced alignment-based gene structure annotation. WebScipio: an online tool for the determination of gene structures using protein sequences. A normal usage would be to call a series of functions in order to arrive at a gene structure and a visualization: SearchSpecies, SearchGenomes, Query, GetSvg. Incorporation of splice site probability models for non-canonical introns improves gene structure prediction in plants. We pursued one such approach and describe the training and implementation of GC-donor splice site models for Arabidopsis and rice, with the goal of exploring whether specific modeling of non-canonical introns can enhance gene structure prediction accuracy. Source code for the updated versions of GeneSeqer and SplicePredictor (distributed with the GeneSeqer code) isavailable at http://bioinformatics.iastate.edu/bioinformatics2go/gs/download.html. Web servers for Arabidopsis, rice and other plant species are accessible at http://www.plantgdb.org/PlantGDB-cgi/GeneSeqer/AtGDBgs.cgi, http://www.plantgdb.org/PlantGDB-cgi/GeneSeqer/OsGDBgs.cgi and http://www.plantgdb.org/PlantGDB-cgi/GeneSeqer/PlantGDBgs.cgi, respectively. A SplicePredictor web server is available at http://bioinformatics.iastate.edu/cgi-bin/sp.cgi. Software to generate training data and parameterizations for Bayesian splice site models is available at http://gremlin1.gdcb.iastate.edu/~volker/SB05B/BSSM4GSQ/ Prediction of splice sites with dependency graphs and their expanded bayesian networks. A crucial part in the gene structure prediction is to determine the precise exon-intron boundaries, i.e. the splice sites, in the coding region. Software (a program called DGSplicer) and datasets used are available at http://csrl.ee.nthu.edu.tw/bioinf/ BACKGROUND: cclu@ee.nthu.edu.tw. Gene structure prediction from consensus spliced alignment of multiple ESTs matching the same genomic locus. Accurate gene structure annotation is a challenging computational problem in genomics. The splice site prediction tool (SplicePredictor) is distributed with the GeneSeqer code. A SplicePredictor web server is available at http://bioinformatics.iastate.edu/cgi-bin/sp.cgi We have developed a software tool, Transcript Assembly Program (TAP), to delineate gene structures using genomically aligned EST sequences. GeneBuilder: interactive in silico prediction of gene structure. In the case of low homology, GeneBuilder is still able to predict the gene structure. The GeneBuilder system has been tested by using the standard set (Burset and Guigo, Genomics, 34, 353-367, 1996) and the performances are: 0.89 sensitivity and 0.91 specificity at the nucleotide level. The computer program SeqHelp organizes information from database searches, gene structure prediction, and other information to generate multiply aligned, hypertext-linked reports to allow for fast analysis of molecular sequences. Identification of human gene structure using linear discriminant functions and dynamic programming. Development of advanced technique to identify gene structure is one of the main challenges of the Human Genome Project. A gene structure prediction system FGENE has been developed based on the exon recognition functions. Analysis of uncharacterized human sequences based on our methods for splice site (HSPL, RNASPL), internal exons (HEXON), all type of exons (FEXH) and human (FGENEH) and bacterial (CDSB) gene structure prediction and recognition of human and bacterial sequences (HBR) (to test a library for E. coli contamination) is available through the University of Houston, Weizmann Institute of Science network server and a WWW page of the Human Genome Center at Baylor College of Medicine. We adhered to the nomenclature established in the literature aimed to the evaluation of gene structure prediction tools, even if the definition of specificity that we use here is called positive predictive value in statistical literature [28]. In the bioinformatics field, many computer algorithmic and data mining technologies have been developed for gene prediction, protein-protein interaction analysis, sequence analysis, and protein folding predictions, to name a few. Gene prediction algorithms that take into account protein coding information have been shown to perform better than those that rely only on signals present in the splice sites (29). Computational gene prediction tools are now essential components of every genome sequencing project. The HTML output provides tight links to the visualization tools, GeneNest (EST resource and visualization) as well as SpliceNest (gene structure and alternative splice visualization), which allows a detailed inspection of candidate genes and transcripts. DF carried out the splice site prediction. Indeed, due to their common origin, genes from the same family quite often share the same gene intron–exon structure. The accurate prediction of intron boundaries largely facilitates the correct prediction of gene structure in nuclear genomes. </context> <question> Which are the bioinformatics tools for gene structure prediction? </question> <answer> WPSS; SCGPred; TICO; GLIMMER; MetWAMer; WebScipio; GeneSeqer; SplicePredictor; DGSplicer; TAP; GeneBuilder; SeqHelp; FGENE', 'FGENEH; HSPL; RNASPL; HEXON; CDSB; HBR </answer>
<context> Diabetic animals developed low triiodothyronine syndrome. They also showed that diabetes during the final 8 weeks (i) caused a marked impairment in the performance of perfused hearts ex vivo of hypertensive rats but had no measurable effect in the normotensive WKY, (ii) had no effect on arterial pressure of either the normotensive or the hypertensive rats but reduced heart rate of hypertensive animals in vivo, and (iii) caused equivalent hyperglycemia, hypoinsulinemia, and hypothyroidism (depressed serum T3 and T4 levels) of hypertensive and normotensive rats. Treatment of diabetic RVH rats with T3 (10 micrograms.kg-1.day-1) in vivo was nearly as effective as insulin therapy (10 U.kg-1.day-1) in preventing the cardiac dysfunction ex vivo and was as effective as insulin therapy in preventing the bradycardia in vivo and the decline loss the diabetic state in rats is associated with lowered T3 (triiodothyronine) and T4 levels Thyroid status of diabetic animals was normalized by T3 alone or in combination with myo-inositol but not by myo-inositol alone. T3 treatment alone did not prevent cardiac dysfunction in diabetic rats. Untreated diabetic rats exhibited a decrease in spontaneous heart rate and myocardial cytochrome c concentrations concurrent with depressed plasma T3 values compared with untreated controls. T3 treatment did not improve in vitro cardiac performance (assessed as cardiac output times peak systolic pressure per gram dry heart weight) in hearts from diabetic rats perfused with glucose alone. Addition of octanoate reversed this depression and improved cardiac function to a greater extent in treated than in untreated diabetic animals. As triiodothyronine (T3) treatment has been shown to normalize depression of cardiac myosin ATPase in diabetic rats While diabetic rats treated with T3 alone did not show significant improvement of myocardial function when compared with untreated diabetics, the function of those treated with both T3 and methyl palmoxirate was not significantly different from that in control rat hearts Although the plasma level of thyroid hormone was decreased in the diabetic rat, thyroid hormone treatment did not restore microsomal calcium transport in the diabetic animals. </context> <question> How are thyroid hormones involved in the development of diabetic cardiomyopathy? </question> <answer> The diabetic state is associated with lowered T3 and T4 levels. Thyroid hormone treatment in diabetic cardiomyopathy may partially reverse cardiac dysfunction </answer>
<context> Inhibition of MEF2A using siRNA attenuated HB-EGF-induced COX-2, ANF expression and cell size. This genetic reprogramming coincides with a pronounced increase in expression of the estrogen receptor (ER)alpha gene, which we show to be a direct MEF2 target gene cardiac calsequestrin gene (casq2) Functional studies demonstrated that site-directed mutagenesis of the proximal MEF-2 and CArG box sites significantly decreased the transcription of the gene in cardiac and skeletal muscle cells, indicating that they are important to drive cardiac and skeletal muscle-specific transcription of the casq2 gene. DTEF-1 also interacts with MEF- 2 by coimmunoprecipitation and independently or cooperatively (with MEF-2) trans-activates the cTnT promoter An 85-bp region within the enhancer is highly conserved between human and mouse and contains a central AT-rich site, which is essential for enhancer activity. This site binds myocyte enhancer factor (MEF)2 factors, principally MEF2D and MEF2A in cardiocyte nuclear extracts. These results are discussed in the context of MEF2 activity and of the regulation of the alpha-cardiac actin locus. The cis-acting elements, MEF-2, E boxes and A/T rich elements present in the enhancer region of the mouse MCK gene are known to regulate the expression of the gene The sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs) belong to a family of active calcium transport enzymes encoded by the SERCA1, 2, and 3 genes. In this study, we describe the complete structure of the human SERCA2 gene and its 5 -regulatory region. Among the DNA cis-elements present in these two regulatory regions there are potential binding sites for: GATA-4, -5, -6, Nkx-2.5/Csx, OTF-1, USF, MEF-2, SRF, PPAR/RXR, AP-2, and TREs. Upstream from position -1.5 kb, there is no significant homology among the SERCA2 genes cloned. The cardiac calsequestrin gene consists of 11 exons and its 5' flanking region is characterized by the presence of a TATA-like box, muscle specific promoter elements such as 7 E-boxes, 1 MEF-2, 1 MCBF and 1 Repeat (musS) motifs, as well as several muscle non-specific transcriptional elements (AP-2A, NRE1, NRE2, p53, Spel and TFI-IIA). our laboratory identified a 28 bp HF-la/MEF-2 element in the MLC-2v promoter region, which confers cardiac ventricular chamber-specific gene expression during murine cardiogenesis, In this study, we investigated T3R alpha 1-vs. T3R beta 1-specific interactions with the myocyte enhancer-specific factor-2 (MEF-2) on the expression of the SERCA 2 gene in transient transfection assays in embryonal heart-derived H9c2 cells. point to T3R isoform-specific interactions with a cell type-specific transcription factor (MEF-2) in the regulation of SERCA 2 gene expression. In multiple independent transgenic mouse lines, we found that both a 250 base pair myosin light chain-2 ventricular promoter fragment, as well as a dimerized 28 bp sub-element (HF-1) containing binding sites for HF1a and HF1b/MEF2 factors, directed ventricular-specific reporter expression from as early as the endogenous gene, at day 7.5-8.0 post coitum. Myocyte-specific enhancer-binding factor (MEF-2) regulates alpha-cardiac myosin heavy chain gene expression in vitro and in vivo In the MLC-2 gene, an AT-rich element (HF-1b) which contains a consensus MEF-2 site is required for cardiac tissue-specific expression. Role of myocyte-specific enhancer-binding factor (MEF-2) in transcriptional regulation of the alpha-cardiac myosin heavy chain gene. In order to analyze the transcriptional regulation of the muscle-specific subunit of the human phosphoglycerate mutase (PGAM-M) gene, chimeric genes composed of the upstream region of the PGAM-M gene These observations define the PGAM-M enhancer as the only cardiac- and skeletal-muscle-specific enhancer characterized thus far that is mainly activated through MEF-2. Transcription of each gene is independently controlled but coordinately regulated. During each embryogenesis, the beta-MHC gene is expressed as part of the cardiac myogenic program under the control of NKX-2.5, MEF-2C, and GATA-4/5/6. We have characterized the specific DNA regulatory elements responsible for the function of the human cardiac troponin C gene (cTnC) muscle-specific enhancer in myogenic cells. We used functional transient transfection assays with deletional and site-specific mutagenesis to evaluate the role of the conserved sequence elements. Gel electrophoresis mobility shift assays (EMSA) demonstrated the ability of the functional sites to interact with nuclear proteins. We demonstrate that three distinct transcription activator binding sites commonly found in muscle-specific enhancers (a MEF-2 site, a MEF-3 site, and at least four redundant E-box sites) all contribute to full enhancer activity but a CArG box does not. </context> <question> Which genes are regulated by MEF-2 in the heart? </question> <answer> COX-2; ANF; estrogen receptor (ER)alpha gene; calsequestrin gene', 'casq2; cTnT; MCK; alpha-cardiac actin; sarco(endo)plasmic reticulum Ca2+-ATPase', 'SERCA; MLC-2; alpha-cardiac myosin heavy chain gene; phosphoglycerate mutase', 'PGAM-M; cardiac troponin C', 'cTnC </answer>
<context> n FM the reduced mRNA expression of ARB1 (p<0.05, -37%) and ARB2 (p<0.05, -42%) was associated with a reduction of the messenger for TRalpha1 (p<0.05, -85%) and TRalpha2 (p<0.05, -73%). hese data reveal that in human heart failure the reduction of beta-adrenergic receptors is associated with reduced expression of both TRalpha1 and TRalpha2 isoforms of thyroid hormone receptors. Mitigating TRalpha1 effects, both TRalpha2 and TRbeta1 attenuate TRalpha1-induced myocardial growth and gene expression by diminishing TAK1 and p38 activities, respectively. Selective ablation of TRalpha2 resulted in an inevitable, concomitant overexpression of TRalpha1. These data reveal that in human heart failure the reduction of beta-adrenergic receptors is associated with reduced expression of both TRalpha1 and TRalpha2 isoforms of thyroid hormone receptors. </context> <question> Which genes are regulated by TRalpha2 in the heart? </question> <answer> ARB1; ARB2; TAK1; p38; TRalpha1 </answer>
<context> We used a polymerase chain reaction (PCR)-based mRNA differential display (DD) analysis to obtain a profile of thyroid hormone-responsive genes in osteoblast-like cells At the 2-hour time point, 1 true-positive novel clone was identified and shown to be the mitochondrial gene, subunit 6 of ATP synthase (ATPase-6). We studied the coordination of the two genomes by measuring transcript levels for nuclear (IV, Va, and VIc) and mitochondrial (II and III) subunits of cytochrome-c oxidase after altering the mitochondrial content of rat muscle and liver by altering the thyroid state of the animals. Tissue levels of these mRNAs were generally decreased in hypothyroid animals and were up-regulated again after thyroid hormone (T3) treatment. Following this procedure, we now report the identification of the mitochondrial NADH dehydrogenase subunit 3 (ND3) gene as target of thyroid hormone. Sequencing and electrophoretic mobility shift assays confirmed the presence of a thyroid hormone receptor (TR)/c-erbA specific binding site in the mitochondrial ND3 gene. </context> <question> Which mitochondrial genes are regulated by thyroid hormone? </question> <answer> subunit 6 of ATP synthase', 'ATPase-6; mitochondrial II and III subunits of cytochrome-c oxidase; NADH dehydrogenase subunit 3', 'ND3 </answer>
<context> We recently reported that diabetes depresses AMP-activated protein kinase (AMPK) activity, inhibits MAPK8/JNK1-BCL2 signaling Activation of AMPK directly phosphorylates MAPK8, which mediates BCL2 phosphorylation and subsequent BECN1-BCL2 dissociation, leading to restoration of cardiac autophagy, protection against cardiac apoptosis, and ultimately improvement in cardiac structure and function. We hypothesized that AMPK-induced autophagy ameliorates diabetic cardiomyopathy by inhibiting cardiomyocyte apoptosis and examined the effects of AMPK on the interaction between Beclin1 and Bcl-2, a switch between autophagy and apoptosis, in diabetic mice and high glucose-treated H9c2 cardiac myoblast cells. Conversely, activation of AMPK by metformin stimulated JNK1-Bcl-2 signaling and disrupted the Beclin1-Bcl-2 complex. We concluded that dissociation of Bcl-2 from Beclin1 may be an important mechanism for preventing diabetic cardiomyopathy via AMPK activation that restores autophagy and protects against cardiac apoptosis. studies were shown that p38 MAPK stimulates glucose uptake through the AMPK activation. Taken together, it is suggested that the modulation of AT-1R/AMPK-MAPK pathway might play crucial roles for the pathogenesis of diabetic cardiomyopathy and it could become an important therapeutic target to ameliorate the diabetic cardiomyopathy. We conclude that AMPK activation protects cardiac structure and function by increasing cardiac autophagy in the diabetic heart. Genetic inhibition of AMPK in cardiomyocytes attenuates cardiac autophagy, exacerbates cardiac dysfunction and increases mortality in diabetic mice. our findings demonstrate that decreased AMPK activity and the subsequent reduction in cardiac autophagy are central to the development of diabetic cardiomyopathy. Metformin prevents diabetic cardiomyopathy by stimulating AMPK activity and enhancing autophagic capacity. Thus, stimulation of AMPK may represent a novel approach to treat diabetic cardiomyopathy. Oxidative stress and lipid deposition were markedly increased in the myocardium, concomitant with inactivation of AMPK and increased expression of peroxisome proliferator-activated receptor coactivator-1 alpha (PGC-1 alpha). Trimetazidine also caused AMPK activation and reduced PGC-1 alpha expression in the hearts of db/db mice. The data suggest that trimetazidine significantly improves cardiac function in db/db mice by attenuating lipotoxicity and improving the oxidation status of the heart. Activation of AMPK and decreased expression of PGC-1 alpha were involved in this process. Our findings highlight a role of PP2C and AMPK in the derangements of cardiac lipid metabolism in obesity and provide new insights as to the mechanisms of the liporegulatory disorder leading to lipotoxic cardiomyopathy. We conclude that dissociation of BCL2 from BECN1 through activation of MAPK8-BCL2 signaling may be an important mechanism by which AMPK activation restores autophagy, protects against cardiac apoptosis, and prevents diabetic cardiomyopathy. Thus, stimulation of AMPK may represent a novel approach to treat diabetic cardiomyopathy. Both the AMPK activator resveratrol and the antioxidant N-acetylcysteine mimicked the UCF-101-induced beneficial effect in STZ-induced diabetic cardiomyocytes. UCF-101 protects against STZ-induced cardiomyocyte contractile dysfunction, possibly via an AMPK-associated mechanism. </context> <question> What is the role of AMPK in diabetic cardiomyopathy? </question> <answer> AMPK activation protects cardiac structure and function by increasing cardiac autophagy in the diabetic heart. Decreased AMPK activity and the subsequent reduction in cardiac autophagy are central to the development of diabetic cardiomyopathy. In fact, dissociation of Bcl-2 from Beclin1 may be an important mechanism for preventing diabetic cardiomyopathy via AMPK activation that restores autophagy and protects against cardiac apoptosis. In addition, genetic inhibition of AMPK in cardiomyocytes attenuates cardiac autophagy, exacerbates cardiac dysfunction and increases mortality in diabetic mice. The modulation of AT-1R/AMPK-MAPK pathway might play crucial roles for the pathogenesis of diabetic cardiomyopathy and it could become an important therapeutic target to ameliorate the diabetic cardiomyopathy. Stimulation of AMPK by metformin or trimetazidine administration may represent a novel approach to treat diabetic cardiomyopathy. </answer>
<context> IFT often is associated with a systemic extracervical fibrotic process and tobacco use. Attempted thyroid resection often results in postoperative complications. Long-term follow-up showed no deaths fro Riedel's invasive fibrous thyroiditis is a rare disorder of unknown origin with progressive extension and invasion of adjacent structures. Clinically it is impossible to distinguish between Riedel's/thyroiditis and other diseases as undifferentiated carcinoma, Hashimoto's disease etc... Surgical treatment depends on the stage of the disease, when both lobes are involved generous wedge resection of the isthmus may be the treatment of choice to relieve tracheal compression; in earlier stages radical operation are considered. Corticosteroid treatment in Riedel's thyroiditis, as multifocal disease has been successfully used. Other drugs with antifibrosing actions have also utilised in small groups of patients with encouraging results. </context> <question> What is the treatment of Riedel disease (thyroiditis)? </question> <answer> Riedel thyroiditis is a rare disorder related to a systemic extracervical fibrotic process of unknown origin. The tratment of choice is the surgical treatment: Corticosteroids may be also useful </answer>
<context> 5IFNα can commonly induce thyroiditis, which is classified as either autoimmune or non-autoimmune interferon-induced thyroiditis (IIT).6 Autoimmune IIT manifests as Hashimoto's thyroiditis, which is defined by an emerge of or worse in antithyroid antibody levels with or without hypothyroidism. In rare cases, autoimmune IIT also manifests as Graves' disease, which is defined by antithyroid antibodies with hyperthyroidism. Non-autoimmune IIT presents as destructive thyroiditis and hypothyroidism.6Hashimoto's thyroiditis is diagnosed in up to 40% of patients, and hypothyroidism can be triggered by IFNα.7 Hypothyroidism frequently escapes diagnosis due to the overlap of its symptoms with those induced by IFNα itself, such as fatigue, somnolence and depression. Rarely, IFNα induces Graves' disease, the diagnosis of which is based on hyperthyroidism with goiter and the presence of thyroid stimulating hormone receptor antibodies.7 Its treatment demands precaution due to the hepatotoxic and hematologic side effects of antithyroid drugs.Destructive thyroiditis represents a form of non-autoimmune IIT characterized by self-limited thyrotoxicosis with a triphasic evolution similar to that of subacute thyroiditis. In the first phase, the patient shows thyrotoxicosis, low radioiodine uptake and the absence of antithyroid antibodies. Hypothyroidism follows euthyroidism within a few weeks to months. . Based on these findings, we diagnosed the patient with interferon-induced destructive thyroiditis and prescribed propranolol 20 mg/d for one month. The diagnosis of Graves' disease was made, and the patient started treatment with methimazole and propranolol. The most common clinical manifestation of IIT is Hashimoto's thyroiditis. In addition, cases 10 and 14 had subclinical hypothyroidism which resolved with time and did not require thyroxine at any stage, Table 2. Similarly, case 13 was in the hypothyroid phase of the thyroiditis at the end of treatment, was treated expectantly and resolved without thyroxine Most series report hypothyroidism as the commonest thyroid disorder in this setting but our experience has been that of thyroiditis almost exclusively the long term outcome of interferon induced thyroiditis appears benign. There is no long term risk of hypothyroidism </context> <question> What is the treatment of interferon-induced thyroiditis? </question> <answer> An altered thyroid function is frequently observed during interferon treatment with a pattern similar to Hashimoto Thyroiditis or Graves disease.\nVery frequently the alterations of thyroid hormones related to interferon-induced thyroiditis spontaneosly diseapper in a few months\nTreatment when necessary is propanolol and antithyroid drugs for the Graves like form and thyroxine for chronic hypothyroidism indiced by interferon </answer>
<context> The terminal dinucleotides GT and AG at the 5' and 3' end of introns, respectively, are nearly universal [4-6]. However, compilation of introns with non-consensus splice sites [7,8] led to the discovery of a minute class of introns. These introns contained an extended and nearly invariant 5' splice site (ATATCCTT at +1 to +8 positions starting from the 5' junction), a more pronounced Branch Point Site (BPS, TCCTTAAC), and an AC acceptor site The U12 consensus sequences for the donor site, RTATCCTTT, and branch point, TTCCTTRAY, are highly conserved and distinct from the U2 consensi (9). he acceptor site is unique in that the 3′-most nucleotide of the U12 acceptor site is more tolerant of substitutions, especially in those introns that begin with AT; AT–AC, AT–AA, AT–AG and AT–AT combinations have been observed (14,15). About 1-2% of introns are non-canonical, with the most abundant subtype of non-canonical introns being characterized by GC and AG dinucleotides at their 5'- and 3'-termini, respectively. Our results indicate that the incorporation of non-canonical splice site models yields dramatic improvements in annotating genes containing GC-AG and AT-AC non-canonical introns If we assume that approximately the same situation is true for the whole set of annotated mammalian non-canonical splice sites, then the 99.24% of splice site pairs should be GT-AG, 0.69% GC-AG, 0.05% AT-AC and finally only 0.02% could consist of other types of non-canonical splice sites. </context> <question> What are the most frequent non-canonical sequence motifs at the donor and acceptor splice sites in vertebrates? </question> <answer> There are two major exceptions to the canonical GT-AG dinucleotides at donor and acceptor sites: the GG-AG splice site pairs, recognized through the typical U2 splicing machinery, and the AT-AC splice pairs recognized by the U12 splicing machinery. </answer>
<context> Most lncRNAs are under lower sequence constraints than protein-coding genes and lack conserved secondary structures, making it hard to predict them computationally. hey are under stronger selective pressure than neutrally evolving sequences-particularly in their promoter regions, which display levels of selection comparable to protein-coding genes. bout one-third seem to have arisen within the primate lineage. Indeed, even well-known examples of functional mammalian lncRNAs, such as Gomafu [11], Evf-2 [12], XIST [13], Air [14], and HOTAIR [9], exhibit poor sequence conservation across species. </context> <question> Are long non coding RNAs as conserved in sequence as protein coding genes? </question> <answer> no </answer>
<context> Although in this study we focused on the antagonistic function of AIMP2-DX2 against the pro-apoptotic activity of AIMP2-F via p53 in response to DNA damage, it may also influence the normal activity of AIMP2 in these two other pathways with a similar mode of action, namely, through the competitive binding to the target proteins Apoptosis promoted by UV in cells lacking p53 is prevented when the change in AS of the apoptotic gene bcl-x is reverted, confirming the relevance of this mechanism. We demonstrate that E2F1 requires SC35 to switch the alternative splicing profile of various apoptotic genes such as c-flip, caspases-8 and -9 and Bcl-x, towards the expression of pro-apoptotic splice variants. Finally, we provide evidence that E2F1 upregulates SC35 in response to DNA-damaging agents and show that SC35 is required for apoptosis in response to these drugs. This analysis revealed that DNA damage resulted in changes in splicing activity that modified the splicing pattern of Fas, a key pro-apoptotic, p53-inducible death receptor. Bortezomib induces mitochondrial damage in native cells and also activates the UPR by splicing of Xbp-1 and induction of CHOP, which is significantly reduced by silencing of MUC4. The tumour-suppressor protein p53 is an important activator of apoptosis. Although p53-deficient cancer cells are less responsive to chemotherapy, their resistance is not complete, which suggests that other apoptotic pathways may exist. A p53-related gene, p73, which encodes several proteins as a result of alternative splicing, can also induce apoptosis. Induction of apoptosis was significantly reduced in P388/SPR cells, as indicated by minimal DNA fragmentation. Analysis of oncogenes regulating apoptotic cell death revealed a marked decrease of bcl-2 in combination with a moderate reduction of bax protein, but a striking overexpression of the long form of the bcl-X protein. </context> <question> Is alternative splicing of apoptotic genes playing a role in the response to DNA or mitochondrial damage? </question> <answer> yes </answer>
<context> The Alu element has been a major source of new exons during primate evolution. Thousands of human genes contain spliced exons derived from Alu elements. More than 25% of Alu exons analyzed by RNA-Seq have estimated transcript inclusion levels of at least 50% in the human cerebellum, indicating widespread establishment of Alu exons in human genes. his study presents genomic evidence that a major functional consequence of Alu exonization is the lineage-specific evolution of translational regulation. Our data suggests that lineage-specific exonization events should be determined by the combination event of the formation of splicing sites and protection against site-specific mutation pressures. These evolutionary mechanisms could be major sources for primate diversification. n human, most of the exons that originated from TEs are from the primate-specific transposon called Alu. he new exons generated from Alu elements are usually alternatively spliced; these exons comprise ∼5% of alternatively spliced exons in the human transcriptome his implies that novelties added to established genes (within established coding sequences, CDSs) are under lower purifying selection if they do not interfere with the original coding sequence, compared to those events that change the original CDS. . We found that exonizations occur preferentially in the beginning of protein coding sequences. Effects of TE exonization within the first intron are usually neutral with respect to the protein sequence, but can affect signal sequences [41].10.1371/journal.pone.0010907.g001Figure 1Bias toward exonization at the 5′ end of the CDS. e previously suggested that the majority of the TE-derived exons are non-symmetrical because they are still young in evolutionary terms and thus have not yet undergone purifying selection, which eliminates deleterious exonizations. Given a sufficient period of time, some of the currently non-symmetrical exons that are only mildly deleterious will eventually become symmetrical (through small deletions/insertions) and thus will add coding capacity into already established genes. Examples of functional TE-exonizations are exon 8 of ADAR2 gene [60] and exon 8 of NARF gene [47]. Exonization of Alu elements creates primate-specific genomic diversity more than 5% of the alternatively spliced internal exons in the human genome are derived from Alu, and to the best of our knowledge all Alu-driven exons originated from exonization of intronic sequences Alternatively spliced Alu exons thus enrich the transcriptome, the coding capacity, and the regulatory versatility of primate genomes with new isoforms, without compromising the integrity and the original repertoire of the transcriptome and its resulting proteome. Several indications imply that Alu insertions can add new functionality to proteins we also observed a higher exonization level within human genome: 0.05% exonization in human both in coding and non-protein-coding genes, versus 0.03% and 0.02% in mouse coding and non-protein-coding genes, respectively (χ2; P < 10-16 [degrees of freedom = 1] for protein-coding genes and P < 10-22 [degrees of freedom = 1] for non-protein-coding genes; see Additional data file 1). Our data show that, once acquired, some exonizations were lost again in some lineages. In general, Alu exonization occurred at various time points over the evolutionary history of primate lineages, and protein-coding potential was acquired either relatively soon after integration or millions of years thereafter. Once integrated, they have the potential to become exapted as functional modules, e.g., as protein-coding domains via alternative splicing. This particular process is also termed exonization and increases protein versatility alternative "Alu-exons" also carry the potential to greatly enhance genetic diversity by increasing the transcriptome of primates chiefly via alternative splicing. ere, we report a 5' exon generated from one of the two alternative transcripts in human tumor necrosis factor receptor gene type 2 (p75TNFR) that contains an ancient Alu-SINE, which provides an alternative N-terminal protein-coding domain. </context> <question> Can protein coding exons originate from ALU sequences? </question> <answer> yes </answer>
<context> The tRNASec and the SECIS element, an RNA hairpin in the 3′UTR of selenoprotein mRNAs, and two trans-acting proteins, the specialized translation elongation factor eEFSec and the SECIS Binding Protein 2 (SBP2), are the key players of the recoding machinery ( Specialized protein complexes that involve SECp43, the Phosphoserine tRNASec Kinase (PSTK) and the Sec synthase are recruited to the tRNASec to ensure proper selenocysteine synthesis (2–4). Ribosomal protein L30 has also been implicated in this mechanism and shown to compete with SBP2 for SECIS binding (5). SPS2 is the selenophosphate synthetase involved in selenocysteine biosynthesis The process requires the Sec insertion sequence (SECIS) element, tRNASec, and protein factors including the SECIS binding protein 2 (SBP2) Taken together, these data establish the role of SECp43 and SLA in selenoprotein biosynthesis through interaction with tRNA([Ser]Sec) in a multiprotein complex. Selenophosphate synthetase (SelD) generates the selenium donor for selenocysteine biosynthesis in eubacteria. One homologue of SelD in eukaryotes is SPS1 (selenophosphate synthetase 1) and a second one, SPS2, was identified as a selenoprotein in mammals. These in vivo studies indicate that SPS2 is essential for generating the selenium donor for selenocysteine biosynthesis in mammals, whereas SPS1 probably has a more specialized, non-essential role in selenoprotein metabolism. </context> <question> Name the factors required for selenoprotein synthesis in eukaryotes </question> <answer> eFSec; SBP2; SECp43; PSTK; Sec synthase', 'Sec S', 'SLA/LP; SPS2', 'SelD; tRNASec; SECIS element; (L30); SPS1 </answer>
<context> We identify a novel mutation in PHC1, a human orthologue of the Drosophila polyhomeotic member of polycomb group (PcG), which significantly decreases PHC1 protein expression, increases Geminin protein level and markedly abolishes the capacity to ubiquitinate histone H2A in patient cells. In clinical specimens of head and neck cancer, we found that coamplification of BMI1 and AURKA correlated with poorer prognosis. Mutations of EZH2, RUNX1, TP53, and ASXL1 were associated with shorter overall survival independent of the LR-PSS. In this study, we show the high frequency of spontaneous γδ T-cell leukemia (T-ALL) occurrence in mice with biallelic deletion of enhancer of zeste homolog 2 (Ezh2). Distribution of mutations of JAK2, EZH2, TET2, IDH1 or IDH2 genes in CMML patients are represented in Figure 1 and further detailed in Table S4. A total of 15 out of 24 patients (65%) showed TET2 gene mutations. In 4 patients, a JAK2V617F gene mutation was found while only 1 patient showed a mutation of EZH2. We found recurrent deletions encompassing the EZH210–12 and SUZ1213,14 loci Subsequently, analysis of deletion profiles of other PRC2 members revealed frequent losses of genes such as EZH2, AEBP2, and SUZ12; however, the deletions targeting these genes were large. We also identified two patients with homozygous losses of JARID2 and AEBP2. We observed frequent codeletion of AEBP2 and ETV6, and similarly, SUZ12 and NF1. A total of 25 different EZH2 mutations were detected in 5.9% of PMF, 1.2% of PPV-MF, and 9.4% of PET-MF patients; most were exonic heterozygous missense changes. In the present investigation we have focused on the candidate region in 6p23, a region that have been found linked to CL/P in several investigations, in the attempt to find out the susceptibility gene provisionally named OFC1. Gene expression experiments in mice embryo of positional candidate genes revealed that JARID2 was highly and specifically expressed in epithelial cells in merging palatal shelves. High expression of EZH2 and amplification of EZH2 was found in 54.1% and 12.0% of ESCCs, respectively. We also observed that HOXA9 levels were significantly inversely correlated with survival and that BMI-1 was overexpressed in cases with 11q23 rearrangements, suggesting that p19(ARF) suppression may be involved in MLL-associated leukemia. We demonstrate that in multiple experimental models of metastatic prostate cancer both BMI1 and Ezh2 genes are amplified and gene amplification is associated with increased expression of corresponding mRNAs and proteins. he EZH2 gene amplification was significantly (P < 0.05) associated with increased EZH2 protein expression. The third tumor showed a t(6p;10q;10p) as the sole karyotypic abnormality, leading to the fusion of PHF1 with another partner, the enhancer of polycomb (EPC1) gene from 10p11; EPC1 has hitherto not been associated with neoplasia. </context> <question> Have mutations in the Polycomb group been found in human diseases? </question> <answer> yes </answer>
<context> tau hyperphosphorylation were dramatically reduced in hUCB-MSC transplanted APP/PS1 mice Administration of 7-nitroindazole to CMS-exposed old rats significantly (p=0.002) increased GAD activity, decreased glutamate levels (7.19+/-3.19 vs. 763.9+/-91 micromol/g tissue protein; p=0.0005), and decreased phosphorylation of tau proteins compared to CMS exposed rats. Changes in glutamate decarboxylase enzyme activity and tau-protein phosphorylation in the hippocampus of old rats exposed to chronic mild stress: reversal with the neuronal nitric oxide synthase inhibitor 7-nitroindazole. Involvement of I2PP2A in the abnormal hyperphosphorylation of tau and its reversal by Memantine. Full reversal of Alzheimer's disease-like phenotype in a mouse model with conditional overexpression of glycogen synthase kinase-3. Here, we show that transgene shutdown in symptomatic mice leads to normal GSK-3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK-3 inhibitors for AD therapeutics. These effects can be combined with the beneficial effects of these compounds on some other major hallmarks of Alzheimer's disease (AD) (e.g. tau hyperphosphorylation and paired helical filaments [PHF]; and loss of cholinergic function conducive to cognitive impairments.) The M1 muscarinic agonists AF102B (Cevimeline, EVOXACTM: prescribed in USA and Japan for Sjogren's Syndrome), AF150(S) and AF267B--1) are neurotrophic and synergistic with neurotrophins such as nerve growth factor and epidermal growth factor; 2) elevate the non-amyloidogenic amyloid precursor protein (alpha-APPs) in vitro and decrease beta-amyloid (A beta) levels in vitro and in vivo; and 3) inhibit A beta- and oxidative-stress-induced cell death and apoptosis in PC12 cells transfected with the M1 muscarinic receptor </context> <question> List some ways to reverse Tau hyperphosphorylation in Tauopathies? </question> <answer> Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) transplantation; Administration of 7-nitroindazole (neuronal nitric oxide synthase inhibitor); Administration of Memantine (un-competitive inhibitor of N-methyl-D-aspartate receptors); Administration glycogen synthase kinase-3 (GSK-3) inhibitors; Administration of M1 muscarinic agonists such as AF150(S) and AF267B </answer>
<context> activating mutations in KRAS are identified in most pancreatic cancers Mutations at codon 12 of the K-ras gene are present in 65%-100% of carcinomas of human exocrine pancreas and could be used as a potential tumor marker at the tissue level. K-RAS mutation is observed in a third of IPMN adenomas and its mutation frequency increases with lesion grade Activating point mutations in the K-Ras oncogene are among the most common genetic alterations in pancreatic cancer, occurring early in the progression of the disease. Activating K-ras mutations are found in approximately 90% of pancreatic carcinomas and may contribute to the poor prognosis of these tumors. Five of the seven duct lesions harbored activating point mutations in codon 12 of K-ras; a G to A transition was found in four and a G to C transversion in one. Ki-RAS mutations in 38% of the overall series KRAS exon 2 mutations were detected in a total of 62 patients with the two methods combined, comprising 11 different mutant alleles. the frequencies for MASI (of all types) varied between individual oncogenes, being relatively high for EGFR (75%) and KRAS (58%) and lower for BRAF (38%) and PIK3CA (8%). gain-of-function mutations in ras genes were the first specific genetic alterations identified in human cancer A heterozygous G to T substitution at nucleotide position 34 (Gly to Cys) was found in 3 patients. The other three mutations also corresponded to the k-ras amino acid 12 substitution mutation, </context> <question> Which is the molecular mechanism underlying K-ras alterations in carcinomas? </question> <answer> Point mutations </answer>
<context> Rett syndrome is caused by mutations in the gene coding for methyl CpG-binding protein 2 (MeCP2). Rett syndrome is one of the most common causes of complex disability in girls. It is characterized by early neurological regression that severely affects motor, cognitive and communication skills, by autonomic dysfunction and often a seizure disorder. It is a monogenic X-linked dominant neurodevelopmental disorder related to mutation in MECP2, which encodes the methyl-CpG-binding protein MeCP2. Recently, this syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of still unknown target genes. Here we report a detailed mutational analysis of 62 patients from UK and Italian archives, representing the first comparative study among different populations and one of the largest number of cases so far analyzed. Out of the 365 cases, 315 had MECP2 gene mutations and 3 had de novo CDKL5 gene mutations. No patients had FOXG1 mutation. Mutations were detected in ≈ 70% of classic and ≈ 21% of variant RTT, respectively. Amongst MR cases, 2.1% carried MECP2 mutations. Mutations in the MECP2 gene were detected in 13 of the 20 (65 percent) RS patients. This multicenter investigation into the phenotypic correlates of MECP2 mutations in Rett syndrome has provided a greater depth of understanding than hitherto available about the specific phenotypic characteristics associated with commonly occurring mutations Mutation screening revealed 31 different mutations in 68 patients and 12 non-pathogenic polymorphisms. In this study, the MECP2 sequences in 121 unrelated Chinese patients with classical or atypical RTT were screened for deletions and mutations. In all, we identified 45 different MECP2 mutations in 102 of these RTT patients. Mutations in MECP2 were found in about 55% We identified mutations in the MECP2 gene and documented the clinical manifestations in 65 Rett syndrome patients to characterize the genotype-phenotype spectrum. We searched for mutations by sequencing the MECP2 coding region in 45 sporadic cases (35 with classic RTT, eight with variant forms and two males) and in seven families with two or more affected females. Following our previous report of mutations in two families and eight sporadic cases, we here present 18 additional mutations. The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) mutations have been found, with multiple recurrences. Mutations were identified in 44/55 (80%) unrelated classical sporadic and familial RTT patients, but only 1/5 (20%) sporadic cases with suggestive but non-diagnostic features of RTT Collectively, we tested 228 unrelated female patients with a diagnosis of possible (209) or classic (19) RTT and found MECP2 mutations in 83 (40%) of 209 and 16 (84%) of 19 of the patients, respectively. Thirty-two different mutations were identified (8 missense, 9 nonsense, 1 splice site, and 14 frameshifts), of which 12 are novel and 9 recurrent in unrelated patients. Mutations in MECP2 were identified from most of the patients with classical and variant RTT (25 of 27 cases) In our series, 19 different de novo MECP2 mutations, eight of which were previously unreported, were found in 35 out of 50 Rett girls (70%) Causative mutations in the MeCP2 gene were identified in 63% of patients, representing a total of 30 different mutations. Mutations were identified in 72% of patients with classical RTT and one third of atypical cases studied (8 of 25). We have identified 15 different MECP2 mutations in 26 of 30 Danish RTT patients. </context> <question> Which is the neurodevelopmental disorder associated to mutations in the X- linked gene mecp2? </question> <answer> Rett syndrome </answer>
<context> Half of the human genome is composed of repeated DNA, and some types are mobile within our genome (transposons and retrotransposons). Despite their abundance, only a small fraction of them are currently active in our genome (Long Interspersed Element-1 (LINE-1), Alu, and SVA elements). Since certain types of retrotransposons, particularly members of the Alu, L1, and SVA families, are still active, their recent and ongoing propagation generates a unique and important class of human genomic diversity/polymorphism Alu elements are the most successful SINEs (Short INterspersed Elements) in primate genomes and have reached more than 1,000,000 copies in the human genome 1 and Alu represent the most prolific human LINE and SINE families, respectively. Only a few Alu elements are able to retropose, and the factors determining their retroposition capacity are poorly understood. </context> <question> What are the major classes of retrotransposons active in the human genome? </question> <answer> LINE-1', 'L1; Alu; SVA </answer>
<context> discovery that genes targeted by either p53 or E2F were respectively activated or repressed through repression of E6 and E7 The ability of high-risk HPV E6 and E7 protein to promote the degradation of p53 and pRb, respectively, has been suggested as a mechanism by which HPV oncogenes induce cellular transformation. E6 and E7 abrogate cell cycle checkpoints and induce genomic instability that leads to malignant conversion The results showed that tumorigenicity and decreased serum requirement were associated with the ability of E6 to bind to p53, although the subsequent degradation of p53 was not required for these functions The E7 mutants chosen had either an in-frame deletion in the conserved region 2 (CR2) domain, which is required for binding of the retinoblastoma tumor suppressor protein (pRb) and pRb-like proteins, or an in-frame deletion in the E7 CR1 domain. The recognition of a causal relationship between human papillomaviruses and cancer almost 30 years ago led to a rapid expansion of knowledge in the field, resulting in the description of the main mediators of HPV-induced carcinogenesis, the viral proteins E6 and E7. These oncoproteins show a remarkable pleiotropism in binding host-cell proteins, with the tumour suppressor genes p53 and pRb as their major targets. First, we found that human papillomavirus E6 and E7 oncogenes, which block the function of the p53 and Rb tumor suppressors, respectively, and SV40 small t antigen were required to allow mutant K-Ras(12D) growth transformation In recent years, it has become clear that in addition to E6-induced degradation of p53 tumor suppressor protein, other targets of E6 are required for mammary epithelial cells immortalization. a general requirement for oncoproteins such as human papillomavirus E6 and E7 has suggested that the p53 and Rb pathways are targeted. Transformation by the human papillomavirus (HPV) early gene products, E6 and E7, involves their interaction with cellular proteins p53 and Rb. The results from this study support the theory that p53 protein binds HPV-16/18 E6 protein in the cell cytoplasm, thus preventing p53 from exerting its tumor-suppressor function in the nucleus. Hence, inactivation of wild-type p53 by p53-E6 complex formation in cervical cancer may be a critical step in malignant transformation. the E7-RbAB interaction involves multiple motifs within the N-terminal domain of E7 and at least two conserved interaction surfaces in RbAB. Based on these studies we present a mechanistic model for how E7 displaces E2F from pRb The E7 protein of human papillomavirus type 16 contains an element that binds to pRB and appears to be functionally homologous to the E1A sequences Several of the biological activities of HPV16 E7 are mediated by inactivation of the members of the pocket protein family, pRb, p107 and p130. </context> <question> What is the main mechanism by which human papillomavirus proteins E6 and E7 contribute to cell transformation? </question> <answer> Although they may have other targets, human papillomavirus proteins E6 and E7 interact with and block the function of p53 and pRb, respectively, therefore deregulating cell cycle and leading to cellular transformation. </answer>
<context> Measures of RNA abundance are important for many areas of biology and often obtained from high-throughput RNA sequencing methods such as Illumina sequence data. These measures need to be normalized to remove technical biases inherent in the sequencing approach, most notably the length of the RNA species and the sequencing depth of a sample. These biases are corrected in the widely used reads per kilobase per million reads (RPKM) measure. Pyicos EA can have read counts or reads per kilobase per million reads (RPKM) (Mortazavi et al., 2008) as input; o predict DE genes, we considered for each Ensembl locus the mean of the values for read counts or RPKM for the corresponding Ensembl transcripts in the locus DESeq and edgeR are run in combination with BEDTools. (d) ROC curves of the different normalization methods: read counts (Counts), TMM-normalized counts (TMM counts), RPKMs and TRPKs, for the microarray benchmarking Both methods, DEGseq and Pyicos, can accept as input read counts or RPKM values for each gene; Expression levels are quantified using the RPKM (reads per kilobase of exon model per million mapped reads) method proposed by Mortazavi et al. (17). The distribution of 32,361 UCs’ average expression levels in the 24 samples showed that half of the UCs were expressed at less than 0.19 FPKM (fragments per kilobase of exon model per million mapped reads) and three-quarters of the UCs were expressed at less than 4.81 FPKM (Additional file 1: Figure S10). .Sequencing-based transcript profilingThe RNA levels in the three cell lines were analyzed using digital RNA-seq based on >20 million separate reads for each cell line and the RPKM values (reads per kilobase of exon model per million mapped reads) were calculated for each gene. </context> <question> What is a popular mesaure of gene expression in RNA-seq experiments? </question> <answer> Reads Per Kilobase per Million mapped reads (RPKM) </answer>
<context> we find that using an anti-PD-1 antibody (CT-011) PD-1 blockade by CT-011, anti-PD-1 antibody, . Presence of CT-011, an anti-PD1 antibody, CT-011, a novel monoclonal anti-PD-1 antibody CT-011, a humanized antibody interacting with PD-1, Anti-PD1 (nivolumab and MK-3475) anti-PD-1 antibodies MK-3475 </context> <question> The antibodies MK-3475 and CT-011 have shown promising results in treating malignancies. Which protein are they targeting? </question> <answer> PD-1 </answer>
<context> ILK knockdown had no effect on the viability or survival pathway activity pattern of MM cells. We conclude that ILK does not play a prominent role in the promotion or sustenance of established MM. Defective granulation tissue formation in mice with specific ablation of integrin-linked kinase in fibroblasts Here, we show that fibroblast-restricted inactivation of ILK in mice leads to impaired healing due to a severe reduction in the number of myofibroblasts, whereas inflammatory infiltrate and vascularization of the granulation tissue are unaffected. in fibroblasts, ILK is crucial for limiting RhoA activity, thus promoting TGFβ1 production, which is essential for dermal repair following injury. Our results show that ILK is important for the function, but not the differentiation, of osteoclasts. Osteoclast-specific inactivation of the integrin-linked kinase (ILK) inhibits bone resorption. ack of ILK in the hepatocytes imparts prolonged proliferative response not only to stimuli related to liver regeneration but also to xenobiotic chemical mitogens, such as PB. Liver-specific ablation of integrin-linked kinase in mice results in enhanced and prolonged cell proliferation and hepatomegaly after phenobarbital administration. Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase. ILK deficiency caused an aberrant distribution of nephrin and alpha-actinin-4 in podocytes, whereas the localization of podocin and synaptopodin remained relatively intact. Targeted ablation of ILK from the murine heart results in dilated cardiomyopathy and spontaneous heart failure. Here we show that targeted ablation of the integrin-linked kinase (ILK) expression results in spontaneous cardiomyopathy and heart failure by 6 wk of age. Together, these results suggest that ILK plays a central role in protecting the mammalian heart against cardiomyopathy and failure. Our results show for the first time in vivo the significance of ILK and hepatic ECM-signaling for regulation of hepatocyte proliferation and differentiation. Liver-specific ablation of integrin-linked kinase in mice results in abnormal histology, enhanced cell proliferation, and hepatomegaly. Integrin-linked kinase is required for radial sorting of axons and Schwann cell remyelination in the peripheral nervous system. </context> <question> What are the effects of ILK ablation? </question> <answer> Ablation of ILK in heart results in dilated cardiomyopathy and spontaneous heart failure; Ablation of ILK in fibroblasts leads to impaired healing due to a severe reduction in the number of myofibroblasts; Ablation of ILK in osteoclasts inhibits bone resorption; Ablation of ILK in liver results in enhanced and prolonged cell proliferation and hepatomegaly after phenobarbital administration and in abnormal histology; Ablation of ILK in podocytes caused an aberrant distribution of nephrin and alpha-actinin-4 </answer>
<context> reduction in Na+,K+ATPase activity has been demonstrated in red blood cells (RBCs), as well as an inverse correlation between this enzymatic action and free triiodothyronine (FT3) levels. The restoration of normal FT3 values also brings about a normalization of Na+,K+ATPase activity in erythrocytes. at hyperthyroid patients have decreased red cell Na/K-ATPase activity and provide direct evidence that erythrocyte ATPase activity is increased in hypothyroid patients. The change in enzyme activity in patients with nonthyroidal illness and decreased circulating T3 levels was comparable to that in hypothyroidism. The effect of triiodothyronine (T3) on Na+,K(+)-ATPase activity of K562 human erythroleukemic cell was studied to understand why the erythrocyte sodium pump activity is decreased in hyperthyroidism. We conclude that T3 stimulates Na+,K(+)-ATPase activity of K562 cells and in the presence of T3 during differentiation, the enzyme activity remains high. </context> <question> Does triiodothyronine stimulate red blood cell sodium potassium pump? </question> <answer> no </answer>
<context> Iodothyronine deiodinase in vitro activity studies in the chicken showed the presence of type I and type III iodothyronine deiodinase activity in both liver and kidney. In embryonic chicken liver (ECL) two types of iodothyronine deiodinases are expressed: D1 and D3. In liver homogenates, D1 activity was not correlated with age, whereas D3 activity showed a strong negative correlation with age (r -0.84), with high D3 activities in preterm infants and (except in 1 infant of 35 weeks) absent D3 activity in full-term infants. In microsomes, D1 activities amounted to 4.3-60 pmol/min/mg protein in fetal livers and to 170-313 pmol/min/mg protein in adult livers, whereas microsomal D3 activities were 0.15-1.45 pmol/min/mg protein in fetuses and <0.1 pmol/min/mg protein in all but one adult. high D1 and D3 activities in fetal human liver, and high D1 and mostly absent D3 activities in adult human liver. </context> <question> Which deiodinase is known to be present in liver? </question> <answer> Type 1 deiodinase' 'type 3 deiodinase </answer>
<context> Thyroxine (T4) is transported through the blood-brain barrier and converted to triiodothyronine (T3) to bind and activate thyroid hormone receptors (TR). This pathway is catalyzed by type 2 deiodinase (D2) in glial cells [3], [4], [5] from which T3 exits for uptake into TR-containing neurons to establish a transcriptional footprint [6]. However, regulation of thyroid hormone economy in the CNS also utilizes a second deiodinase, type 3 deiodinase (D3), that inactivates thyroid hormone in neurons In brain, the presence of type III iodothyronine deiodinase (D3) seems to be important to maintain homeostasis of T(3) levels. We were able to detect a protein fragment corresponding to the expected molecular mass (30 kDa) for type III deiodinase by means of Western blot analysis. RT-PCR as well as Northern blot analysis confirmed the presence of D3 mRNA in the cerebellum. The presence of 5D (type-III) together with our previous report of 5'-deiodinase (type-I in euthyroidism and type-II in hypothyroidism) shows that the isozymes of deiodinases in the neurohypophysis are quite similar to those in the brain. </context> <question> Which deiodinases are best known to be present in brain? </question> <answer> Type 2 deiodinase; Type 3 deiodinase </answer>
<context> Type 2 deiodinase (D2), the thyroid hormone (TH)-activating enzyme, is sharply upregulated during myoblast differentiation The iodothyronine deiodinases D1, D2, and D3 enable tissue-specific adaptation of thyroid hormone levels in response to various conditions, such as hypothyroidism or fasting. The possible expression of D2 mRNA in skeletal muscle is intriguing because this enzyme could play a role in systemic as well as local T3 production Human skeletal muscle D2 mRNA expression is modulated by fasting and insulin, but not by hypothyroidism. SM had very low D2 activity and again no differences were found between groups; D3 activity in SM was higher in NTIS than controls Deiodinase activities were then assayed in cell sonicates. The ratio of T3 production in cell sonicates (catalytic efficiency) was multiplied by the tissue activities reported in human liver (D1) and skeletal muscle (D2) </context> <question> Which deiodinases are present in skeletal muscle? </question> <answer> Type 2 deiodinase; Tipe 3 deiodinase </answer>
<context> Iodothyronine deiodinase in vitro activity studies in the chicken showed the presence of type I and type III iodothyronine deiodinase activity in both liver and kidney. Co-expression of the deiodinases was also found in the kidney. high ID-I activities were found in liver, kidney the kidney microsome 5'-deiodinase is type I. </context> <question> Which dediodinases are present in kidney? </question> <answer> Type 1 deiodinase; Tipe 3 deiodinase </answer>
<context> Enteroviruses (EV) are an important cause of neonatal disease including hepatitis, meningoencephalitis, and myocarditis that can lead to death or severe long-term sequelae Enteroviruses have been considered to be the most common cause of acute myocarditis and possible consequence of dilated cardiomyopathy. n our study the adenovirus genome was found to be the most frequent virus genome in explanted heart tissues. Coxsackie B viruses (types 1 to 5) are the most frequent reported cause of acute viral myocarditis. </context> <question> Which viruses are best known to cause myocarditis? </question> <answer> Enterovirus; Adenovirus; Coxsackie B virus </answer>
<context> ibuprofen 400 mg twice a day as therapy Acute fulminant myocarditis commonly manifests itself as severe, rapidly progressive hemodynamic deterioration and circulatory collapse that may be resistant to high doses of inotropic agents and steroids and to mechanical support by intra-aortic balloon pump the TandemHeart percutaneous ventricular assist device, can enable patients to recover in a few days. he authors report a typical case of fulminating myocarditis with electromechanical dissociation, which recovered completely after a period of circulatory assistance. To clarify the effects of Astragalus Membranaceus (AM) combined with taurine and/or coenzyme Q10(CoQ10) on coxsackievirus B3 (CVB3) murine myocarditis AM, taurine and CoQ10 have some curative effects on CVB3 murine myocarditis, AM combined with taurine and CoQ10 is the best. </context> <question> What is the treatment of acute myocarditis? </question> <answer> antiinflammatory steroid and non steroid drugs; inotropic agents; mechanical support </answer>
<context> Recurrences develop in up to 20-50% of patients with acute pericarditis. Although different causes of recurrent pericarditis have been identified, the etiology remains obscure in most cases which are therefore labelled as idiopathic. A poor response to colchicine treatment and/or a steroid-dependence may be the clue to investigate TNFRSF1A mutations in patients with idiopathic recurrent pericarditis. intravenous infusion of inotropic agents medical treatment may be changed in these patients with a slower tapering of the dosage of steroidal and non-steroidal antiinflammatory drugs. The incidence of purulent pericarditis has decreased considerably since the antibiotic era. It is typically an acute and potentially lethal disease, necessitating rapid diagnosis and adequate therapy to improve prognosis. Standard treatment combines appropriate antibiotic therapy with surgical drainage. We report successful treatment of a non-resolving fibrino-purulent pericardial effusion by combined intrapericardial irrigation of fibrinolytics and systemic corticosteroids administration as an alternative to pericardectomy. Prednisolone (20-30 mg/d) was used in addition to antituberculous chemotherapy in 11 of the 17 patients with effusive pericarditis antibiotic therapy has been initiated. Use of appropriate parenterally administered antibiotics, in combination with early surgical pericardial drainage or partial pericardiectomy, should minimize morbidity and mortality and prevent acute constrictive sequelae. </context> <question> What is the treatment of acute pericarditis? </question> <answer> A multidisciplinary approach is frequently necessary to treat acute pericarditis; the most frequent treatments are: antiinflammatory steroid and non-steroid drugs, antibiotic therapy, pericardial drainage and, less frequently ,intrapericardial irrigation of fibrinolytics; antituberculous chemotherapy in presence of Tuberculous Agent </answer>
<context> Current therapeutic options include use of proton-pump inhibitors, immunosuppressive drugs, elimination diets, and esophageal dilatation. Aerosolized, swallowed fluticasone leads to a histologic but not a symptomatic response in adults with EoE OVB is an effective treatment of pan-esophageal disease in children with EoE. OVB improves symptoms and endoscopic and histologic features. Proton pump inhibitor single therapy did not significantly improve esophageal eosinophilia or symptoms of EoE. </context> <question> Which drugs are utilized to treat eosinophilic esophagitis? </question> <answer> proton pump inhibitors; immunosoppressive drugs; budesonide </answer>
<context> good response to anti-thyroid drugs and steroid therapy The disease course of amiodarone-induced thyrotoxicosis is usually benign and remits with timely administration of anti-thyroid medications, with or without corticosteroids. RIT may be a safe and useful method of AIT therapy in patients with low RAIU, in whom other treatment methods are contraindicated. Treatment consists in the use of a high dose of anti-thyroid drugs and steroids in an isolated form or in combination. the addition of lithium carbonate to the two other drugs resulted in a successful and safety therapy in controlling amiodarone-induced thyrotoxicosis. lithium is a useful and safe medication for treatment of iodine-induced thyrotoxicosis caused by amiodarone. Two patients with amiodarone-induced thyrotoxicosis were treated successfully with potassium perchlorate and carbimazole while treatment with amiodarone was continued. Amiodarone-induced thyrotoxicosis seems to be a transient condition that can be treated successfully with a short course of antithyroid drugs without stopping amiodarone treatment. Both patients were successfully treated with propylthiouracil (PTU) and dexamethasone (DXT). </context> <question> Which drugs are utilized to treat amiodarone-induced thyroitoxicosis? </question> <answer> Antithyroid drugs; Corticosteroids; Lithium; Radioiodine </answer>
<context> Prednisone remains the preferred treatment modality of AIT type 2, because perchlorate given alone or in combination with prednisone had no better outcomes. Total thyroidectomy, by rapidly restoring euthyroidism, may improve cardiac function and reduce the risk of mortality in AIT patients with severe LV dysfunction. Prednisone restores euthyroidism in most type 2 AIT patients, irrespective of amiodarone continuation or withdrawal. However, continuing amiodarone increases the recurrence rate of thyrotoxicosis, causing a delay in the stable restoration of euthyroidism and a longer exposure of the heart to thyroid hormone excess. Steroid therapy should be started when findings indicate type II or mixed-type AIT. Beta blockers may prevent heart thyrotoxicosis and recurrence of primary arrhythmia if amiodarone is discontinued. Glucocorticoids are the first-line treatment in type 2 AIT, whereas thionamides play no role in this destructive thyroiditis. iopanoic can be used to rapidly lower FT(3) levels and to treat symptoms of thyrotoxicosis in a preoperative setting. The patient responded to iopanoic acid with a rapid decrease in his FT(3) level and slight increase in his FT(4) level. In patients with type-2 AIT, RAI treatment may be the therapy of choice for thyroid gland ablation. In type 1 AIT thionamides represent the treatment of choice for North Americans as well as for Europeans, Glucocorticoids are the selected treatment for type 2 AIT, alone (62%vs. 46% in Europe, P < 0.05) or in association with thionamides After restoration of euthyroidism, thyroid ablation in the absence of recurrent thyrotoxicosis is recommended in type 1 AIT less frequently by North Americans. </context> <question> What is the treatment of amiodarone-induced thyrotoxicosis? </question> <answer> Treatment of amiodarone-induced thyrotoxicosis is complex and may include drugs such as antithyroid drugs, beta-blockers, corticosteroids lithium as well as iopanoic acid in preparation of thyroidectomy. Total thyroidectomy and radioiodine represent alternative treatment options </answer>
<context> Triple therapy, which has been the mainstay of treatment in many countries over the last decade, now has suboptimal results in many parts of the world. equential therapy and quadruple therapy (either bismuth-based or non-bismuth-based) are the best current options to replace initial treatment with triple therapy. olecular tests can be used to detect H. pylori and clarithromycin and/or fluoroquinolone resistance in gastric biopsies without necessitating culture. In regions of high clarithromycin resistance, such as France, sequential treatment or bismuth-containing quadruple therapies are replacing standard triple therapies for the first-line empirical treatment. The evidence in favour of bismuth compounds for treating infected children is still not clear. Chitosan microspheres with multiple Eudragit L100 cores were easily prepared by a new emulsification/coagulation encapsulating method. the multi-core chitosan microspheres could serve as a satisfactory vehicle for stomach-specific delivery of hydrophilic antibiotics. Treatment consisted of a one-week regimen containing a PPI twice daily, amoxicillin (A) 1 g twice daily and rifabutin (R) 300 mg once daily (PPI-AR). Pretreatment antibiotic susceptibility to metronidazole, clarithromycin and A was evaluated using a validated epsilometer test. four different strategies for prevention of rebleeding in patients with peptic ulcer hemorrhage: 1) test for H. pylori and treatment, if positive; 2) proton pump inhibitor maintenance; 3) no preventive treatment; 4) empirical H. pylori eradication immediately after bleeding. Empirical H. pylori eradication was the dominant strategy: its estimated rate of recurrent bleeding was lower (6.1%) than those of strategies 1 (7.4%), 2 (11.1%), and 3 (18.4%) and it was the least expensive strategy. The results remained stable when variables were changed inside a wide range of plausible values. In patients with bleeding peptic ulcer, empirical treatment of H. pylori infection immediately after feeding is restarted is the most cost-effective strategy for preventing recurrent hemorrhage. </context> <question> Which are the best treatment options to treat Helicobacter pylori? </question> <answer> amoxicillin; metronidazole; claritromycin; Proton pump inhibithors; rifabutin; Eudragit L100 </answer>
<context> Three patients met the criteria for free T3 toxicosis and three had subclinical hyperthyroidism. All six patients had either multinodular glands or a single nodule on thyroid exam. Four patients were treated with radioactive iodine or surgery, resulting in reversal of the TSH suppression in three cases. 6 months treatment with propranolol (160 mg/day) in eight patients with T3 (triiodothyronine) toxicosis. Serum total T3 concentrations showed a significant (p less than 0.01) and sustained fall to approximately 80% of pre-treatment values. Both patients responded to therapy with propylthiouracil. </context> <question> What is the treatment of triiodothyronine toxicosis? </question> <answer> Propyltiouracil; Radioiodine; beta blockers; thyroidectomy </answer>
<context> Some miRNAs as miR-1, miR-133 and miR-208a are highly expressed in the heart and strongly associated with the development of cardiac hypertrophy. Recent data indicate that these miRNAs as well as miR-206 change their expression quickly in response to physical activity. the miR-494 content significantly decreased after endurance exercise in C57BL/6J mice, accompanied by an increase in expression of mtTFA and Foxj3 proteins. These results suggest that miR-494 regulates mitochondrial biogenesis by downregulating mtTFA and Foxj3 during myocyte differentiation and skeletal muscle adaptation to physical exercise. 1) c-miRNA up-regulated by acute exercise before and after sustained training (miR-146a and miR-222), (2) c-miRNA responsive to acute exercise before but not after sustained training (miR-21 and miR-221), (3) c-miRNA responsive only to sustained training (miR-20a), MicroRNA 1 expression was decreased independent of the training modality, and was paralleled by an increased expression of IGF-1 representing a potential target. we investigated the expression of these myomiRs, including miR-1, miR-133a, miR-133b and miR-206 in muscle biopsies from vastus lateralis of healthy young males (n = 10) in relation to a hyperinsulinaemic–euglycaemic clamp as well as acute endurance exercise before and after 12 weeks of endurance training. In resting biopsies, endurance training for 12 weeks decreased basal expression of all four myomiRs (P < 0.05) In this study, we found that down-regulation of miR-23 is associated with a significant increase in PGC-1α mRNA expression and protein content in quadriceps of C57Bl/6J male mice three hours following an acute bout of endurance exercise In addition, we report a significant induction in miR- 107, 1 and 181 in the skeletal muscle of male mice subjected to endurance exercise. These results suggest that miR-494 regulates mitochondrial biogenesis by downregulating mtTFA and Foxj3 during myocyte differentiation and skeletal muscle adaptation to physical exercise. </context> <question> Which microRNAs are involved in exercise adaptation? </question> <answer> miR-1; miR-133; miR-208a; miR-206; miR-494; miR-146a; miR-222; miR-21; miR-221; miR-20a; miR-133a; miR-133b; miR-23; miR-107; miR-181 </answer>
<context> Our major finding is that repeated very intense exercise prolongs life span in well trained practitioners. Death rates declined with increased levels of total activity (estimated in kilocalories), and declined also with increased intensity of effort measured as from none, to light, to moderately vigorous or vigorous sports play. Death rates at any given quantity of physical exercise were lower for men playing moderately intense sports than for less vigorous men. he purpose of this study was to investigate if jogging, which can be very vigorous, is associated with increased all-cause mortality in men and women. This long-term study of joggers showed that jogging was associated with significantly lower all-cause mortality and a substantial increase in survival for both men and women. Light activities (<4 multiples of resting metabolic rate (METs)) were not associated with reduced mortality rates, moderate activities (4-<6 METs) appeared somewhat beneficial, and vigorous activities (> or =6 METs) clearly predicted lower mortality rates (p, trend = 0.72, 0.07, and <0.001, respectively). These data demonstrate a graded inverse relationship between total physical activity and mortality. Furthermore, vigorous activities but not nonvigorous activities were associated with longevity. The capacity for prolonged and vigorous physical exercise, particularly if the exercise is recreational, is a strong indicator of longevity. </context> <question> Is intense physical activity associated with longevity? </question> <answer> yes </answer>
<context> POM121 is involved in the fusion of inner and outer nuclear membranes in vitro. In this study, we show that the transmembrane Nup, POM121, but not the Nup107–160 complex, is required for the juxtapositioning of the INM and ONM Untreated cells and cells overexpressing Ndc1-GFP, another transmembrane Nup shown to be critical for NPC assembly POM121 is a single-pass transmembrane protein containing a small luminal domain of ∼50 amino acids, with the majority of the protein exposed to the nucleoplasmic/cytoplasmic sides of the NE (Fig. 3 A) the lumenal and nucleoplasmic sequences were joined after removing transmembrane segments because NET FGs could also interact with many FG repeats on the transmembrane Nup gp210 that occurs in the NE lumen. We investigated the interplay between import receptors and the transmembrane nucleoporin Pom121 the transmembrane nucleoporin POM121 is critical for the incorporation of the Nup107/160 complex into new assembly sites specifically during interphase. The transmembrane nucleoporin NDC1 NDC1 is a transmembrane nucleoporin that is required for NPC assembly and nucleocytoplasmic transport. The only protein known to localize to and be important in the assembly of both of these yeast structures is the integral membrane protein, Ndc1p. However, no homologues of Ndc1p had been characterized in metazoa. Here, we identify and analyze NDC1 homologues that are conserved throughout evolution. We show that the overall topology of these homologues is conserved. Each contains six transmembrane segments in its N-terminal half and has a large soluble C-terminal half of approximately 300 amino acids. Although it is not known whether vertebrate NDC1 protein localizes to nuclear pores like its yeast counterpart, the human homologue contains three FG repeats in the C-terminus, a feature of many nuclear pore proteins. we bring together data from another study to demonstrate that the human homologue of NDC1 is the known inner nuclear membrane protein, NET3. NDC1 also localizes to NPCs in higher eukaryoteshNDC1 was previously identified in a proteomics screen as NE transmembrane protein 3 (Net3; Schirmer et al., 2003). To determine its intracellular localization at a higher resolution, we expressed NH2- and COOH-terminal GFP fusions of hNDC1 in HeLa cells (Fig. S2, available at http://www.jcb.org/cgi/content/full/jcb.200601001/DC1). At low or moderate expression levels, a clear colocalization with NPCs was observed, suggesting that NDC1 is also a Nup in human cells. The number and orientation of the transmembrane segments (TMSs) determine which parts of hNDC1 are exposed to the cytoplasmic/NPC side of the membrane and, hence, are available for interaction with other Nups NDC1: a crucial membrane-integral nucleoporin of metazoan nuclear pore complexes POM121 and gp210 (Gerace et al., 1982; Hallberg et al., 1993) have, so far, been the only known membrane-integral constituents of vertebrate NPCs, but they are both absent from fungi. POM121 and gp210 were the only known membrane-integral Nups found in vertebrates Typical of a multimembrane-spanning protein, hNDC1 migrates faster on SDS-gels than expected from its calculated molecular mass NDC1 is now the third known membrane-integral Nup in vertebrate NPCs, and its presence may be one possible explanation as to why NPCs can still form in the virtual absence of POM121 and gp210, which are the other two integral constituents (Stavru et al., 2006). Instead, they typically contain several membrane-integral Nups (e.g., three different ones in either yeast or mammals). Genomic data indicate that two of them, gp210 and NDC1, are evolutionary conserved (Mans et al., 2004). we now face the puzzling problem that none of the remaining membrane-integral Nups possesses any significant luminal parts: the luminal loops of NDC1 are so short that they will hardly protrude from the membrane. For POM121, it is even unlikely that any part is exposed to the lumen. The conserved transmembrane nucleoporin NDC1 we characterize vertebrate NDC1--a transmembrane nucleoporin conserved between yeast and metazoans In the list of metazoan nucleoporins, there are only two integral membrane proteins, gp210 [4-6] and POM121 The 121-kDa pore membrane protein POM121 [7,8] is located in the pore membrane domain of the NPC with a short (29 residues) N-terminal tail protruding into the lumen of the nuclear envelope, with the C-terminus facing the cytoplasm In vertebrates, the NPC has a mass of ∼125 MD and contains over 30 different proteins (nucleoporins), including two integral proteins (gp210 and POM121) that in part protrude into the lumenal space adjacent to the NPC and are thought to help tether the NPC to the pore membrane Because movement to the INM is strongly inhibited by antibodies to the transmembrane nucleoporin gp210 Our first experiment targeted gp210, a major transmembrane glycoprotein of the NPC These proteins include POM121, a type II integral membrane protein of the nuclear pore membrane we found that it is potently blocked by antibodies to the nuclear pore membrane protein gp210. gp210 is a major constituent of the nuclear pore complex (NPC) with possible structural and regulatory roles. It interacts with components of the NPC via its C-terminal domain (CTD), which follows a transmembrane domain and a massive ( approximately 200 kDa) N-terminal region that resides in the lumen of the perinuclear space. The membrane-spanning glycoprotein gp210 is a major component of the nuclear pore complex. This nucleoporin contains a large cisternal N-terminal domain, a short C-terminal cytoplasmic tail, and a single transmembrane segment. We propose that gp210 is organized into the pore membrane as a large array of gp210 dimers that may constitute a luminal submembranous protein skeleton. Patients with primary biliary cirrhosis (PBC) frequently produce autoantibodies against gp210, an integral glycoprotein of the nuclear pores. this protein consists of three main domains: a large glycosylated lumenal domain, a single hydrophobic transmembrane segment and a short cytoplasmic tail. Patients with primary biliary cirrhosis frequently develop autoantibodies directed to gp210, a major glycoprotein of the nuclear pore complex. This protein contains a large glycosylated cisternal domain, a single transmembrane segment, and a short cytoplasmic tail. Autoantibodies from patients with primary biliary cirrhosis recognize a restricted region within the cytoplasmic tail of nuclear pore membrane glycoprotein Gp210 Patients with primary biliary cirrhosis (PBC) frequently have autoantibodies against a 210-kD integral glycoprotein of the nuclear envelope pore membrane. This protein, termed gp210, has a 1,783-amino acid amino-terminal domain located in the perinuclear space, a 20-amino acid transmembrane segment, and a 58-amino acid cytoplasmic carboxy-terminal tail. S. cerevisiae Pom33 and Per33 and human TMEM33 are evolutionarily conserved NE/ER-associated proteins. these data therefore indicate that Pom33 behaves as a dynamic transmembrane Nup. In this paper, we provide evidence that the transmembrane nucleoporin (Nup), POM121, but not the Nup107-160 complex, is present at new pore assembly sites at a time that coincides with inner nuclear membrane (INM) and outer nuclear membrane (ONM) fusion. We investigated the interplay between import receptors and the transmembrane nucleoporin Pom121. Conversely, the transmembrane nucleoporin POM121 is critical for the incorporation of the Nup107/160 complex into new assembly sites specifically during interphase. Human NDC1 (hNDC1) likely possesses six transmembrane segments, and it is located at the nuclear pore wall. Here, we characterize vertebrate NDC1--a transmembrane nucleoporin conserved between yeast and metazoans. In order to identify factors regulating GP210, the genomic organization of human GP210 was analyzed in silico. Here, we report the solution structure of the human gp210 CTD as determined by various spectroscopic techniques. Using human gp210 isolated from HeLa cells we found the lumenal domain as the major target. This protein, termed gp210, has a 1,783-amino acid amino-terminal domain located in the perinuclear space, a 20-amino acid transmembrane segment, and a 58-amino acid cytoplasmic carboxy-terminal tail. In vertebrate cells, GLYCOPROTEIN OF 210 kD (gp210), PORE MEMBRANE PROTEIN OF 121 kD (Pom121), and NUCLEAR DIVISION CYCLE1 (NDC1) have been identified as integral pore membrane proteins (Cronshaw et al., 2002). POM121 (Hallberg et al., 1993) is less conserved than gp210 and is found only in vertebrates. Membrane-integral Nups anchor NPCs within the nuclear membrane. Two of them, gp210 and POM121, were previously identified in vertebrate NPCs. gp210 forms homodimers and possesses a cleavable signal sequence, an ∼200-kD luminal domain, followed by a stop-transfer sequence that serves as membrane anchor and a short cytoplasmic tail (Gerace et al., 1982; Wozniak et al., 1989; Greber et al., 1990; Favreau et al., 2001). gp210 is evolutionary well conserved and is found in metazoans, such as vertebrates (Gerace et al., 1982), insects (Berrios et al., 1995), or nematodes (Cohen et al., 2003), in several protozoa, such as Dictyostelium discoideum, and in plants (Mans et al., 2004). Several studies have been performed on the metazoan transmembrane Nups GP210 and POM121, although results pertaining to their function in NPC assembly are somewhat conflicting. This suggests that Ndc1p is required both for efficient nuclear transport and for NPC assembly, although Pom152p can partially compensate for the loss of Ndc1p in NPC assembly. </context> <question> Which are the known human transmembrane nucleoporins? </question> <answer> NDC1', 'TMEM48', 'NET3', 'hNDC1; POM121', 'Nup121; GP210', 'Nuclear pore membrane glycoprotein 210', 'Nuclear envelope pore membrane protein POM 210', 'POM210', 'Nup210; TMEM33', 'DB83 </answer>
<context> These proteins are targeted by chaperones and delivered to lysosomes where they are translocated into the lysosomal lumen and degraded via the lysosome-associated membrane protein type 2A (LAMP-2A) Macroautophagy is followed by chaperone-mediated autophagy (CMA), in which Hsc70 (Heat shock cognate 70) selectively binds proteins with exposed KFERQ motifs and pushes them inside lysosomes through the LAMP-2A (Lysosome-associated membrane protein type 2A) receptor. Chaperone-mediated autophagy (CMA) is a lysosomal pathway for selective removal of damaged cytosolic proteins (reviewed in [27]). CMA effects direct transmembrane import of cytosolic proteins into the endolysosomal system. The LAMP-2 isoform LAMP-2A functions as a receptor for cytosolic proteins and also as essential component of the CMA translocation complex [28]. Cytosolic substrate proteins bind to monomers of LAMP-2A, which then multimerizes to form the complex required for substrate transmembrane import. CMA activity has been shown to be proportional to levels of the CMA receptor Lamp-2a. Mammalian LAMP2, which is localized in the lysosomal membrane, consists of three splicing isoforms (LAMP2A, B, C) that are alternatively spliced in their carboxyl termini [23]. Among the isoforms, only LAMP2A is involved in CMA as a lysosomal receptor for CMA substrates [24]. Single-cell monitoring of CMA activity by visualizing lysosomal accumulation of a CMA substrate using the HaloTag systemIn the process of CMA, cytosolic substrate proteins for CMA are recognized by heat shock cognate protein 70 (Hsc70), a molecular chaperone. The substrates are then transferred to the lysosome, where they are translocated through lysosome-associated membrane protein type 2A (LAMP2A) and subsequently degraded by lysosomal proteases Lysosomes from livers of lipid-challenged mice had a marked decrease in the levels of the CMA receptor, the lysosome-associated membrane protein type 2A, We report that Bcl-2-related early rod apoptosis was associated with the upregulation of autophagy markers including chaperone-mediated autophagy (CMA) substrate receptor LAMP-2 Once delivered to the lysosomal membrane by Hsc70, the misfolded cargo proteins are translocated to the lysosomal cavity with the help of Lamp2A, a rate limiting factor of CMA we examined gene expression levels of lysosome-associated membrane 2 (LAMP-2), a CMA receptor In chaperone-mediated autophagy (CMA), substrates are recognized by a chaperone complex containing Hsc70 (heat shock cognate of 70 kD) and delivered into lysosomes through interactions with LAMP-2A (lysosome-associated membrane protein 2A) The lysosomal-membrane protein type 2A (LAMP-2A) acts as the receptor for the substrates of chaperone-mediated autophagy (CMA) Chaperone-mediated autophagy (CMA) is a selective type of autophagy by which specific cytosolic proteins are sent to lysosomes for degradation. Substrate proteins bind to the lysosomal membrane through the lysosome-associated membrane protein type 2A (LAMP-2A), one of the three splice variants of the lamp2 gene, and this binding is limiting for their degradation via CMA. Substrate proteins only bind to monomeric LAMP-2A, while the efficient translocation of substrates requires the formation of a particular high-molecular-weight LAMP-2A complex We recently reported that UCH-L1 physically interacts with LAMP-2A, the lysosomal receptor for chaperone-mediated autophagy (CMA In this study, we found that UCH-L1 physically interacts with LAMP-2A, the lysosomal receptor for CMA, We have previously described an age-related decline in chaperone-mediated autophagy (CMA), a selective form of autophagy, by which particular cytosolic proteins are delivered to lysosomes after binding to the lysosome-associated membrane protein type 2A (LAMP-2A), a receptor for this pathway. Chaperone-mediated autophagy (CMA) is a selective pathway for the degradation of cytosolic proteins in lysosomes. CMA declines with age because of a decrease in the levels of lysosome-associated membrane protein (LAMP) type 2A, a lysosomal receptor for this pathway. Oxidation-induced activation of CMA correlates with higher levels of several components of the lysosomal translocation complex, but in particular of the lumenal chaperone, required for substrate uptake, and of the lysosomal membrane protein (lamp) type 2a, previously identified as a receptor for this pathway. We now demonstrate that this protease activity triggers the degradation of the lysosome-associated membrane protein type 2a (lamp2a), a receptor for chaperone-mediated autophagy (CMA). We have previously identified this receptor as the lysosome-associated membrane protein type 2a (lamp2a) Lamp2a acts as a receptor in the lysosomal membrane for substrate proteins of chaperone-mediated autophagy. These characteristics may be important for lamp2a to act as a receptor for chaperone-mediated autophagy. A progressive age-related decrease in the levels of the lysosome-associated membrane protein type 2a that acts as a receptor for chaperone-mediated autophagy Among the isoforms, only LAMP2A is involved in CMA as a lysosomal receptor for CMA substrates [24]. Hsc70 and Hsp40 are members of a molecular chaperone complex required for protein transport into the lysosome during chaperone-mediated autophagy (CMA). The second pathway, chaperone mediated autophagy (CMA), transports proteins that contain a KFERQ like recognition sequence across the lysosomal membrane sequence into the lysosomal lumen. This transport is assisted by cytosolic and lysosomal chaperones as well as LAMP2a. Once there, substrate proteins bind to the lysosome-associated membrane protein type 2 isoform A (LAMP2A), inducing assembly of this receptor protein into a higher molecular weight protein complex that is used by the substrate proteins to reach the lysosomal lumen. Protein substrates bind to a receptor in the lysosomal membrane, the lysosome-associated membrane protein (lamp) type 2a. </context> <question> Which is the receptor for substrates of Chaperone Mediated Autophagy? </question> <answer> LAMP2A' 'Lysosome-associated membrane protein 2 isoform A </answer>