Interphase phosphorylation of H1.4 in transcriptional control

Core histone variants such as H2A.X and H3.3 serve specialized roles in chromatin processes that depend on the genomic distributions and amino acid sequence differences of the variant proteins. Modifications of the variants alters interactions with other chromatin components and thus the protein’s functions. Similarly, growing evidence suggests that amino acid sequence variance also modifies the functions of H1 linker histone family members, altering their effects on transcription, differentiation and development. These data are contrary to the notion that linker histones are redundant repressors. For example, complete loss of H1 does not result in an overall increase in transcription, implying that not all H1 variants are associated with repression. Furthermore, certain modifications of H1 variants can confer distinct roles. On the one hand, phosphorylation of H1 reportedly results in its release from chromatin and subsequent transcription of HIV-1 genes. On the other hand, recent evidence has shown that the phosphorylated H1 may in fact be associated with active promoters. This conflict suggests that different H1 isoforms may play distinct functional roles. Here, we provide the first genome- wide evidence that when phosphorylated, H1.4 remains associated with active promoters and may even play a role in transcription activation. Using novel, highly specific antibodies, we generated the first genome-wide view of the H1.4 isoform phosphorylated at serine 187 (pS187-H1.4) in estradiol-inducible MCF7 cells. We observe that pS187-H1.4 is enriched primarily at the transcription start sites (TSSs) of genes activated by estradiol treatment, and depleted from those that are repressed. We also show that pS187-H1.4 strongly associates with ‘early estrogen response’ genes and co-localizes with active RNA polymerase signals. Based on observations presented here, we propose that interphase phosphorylation at S187 by CDK9 represents an early event required for gene activation. This event may also be involved in release of promoter proximal polymerases to begin elongation by interacting directly with the polymerase or other parts of the transcription machinery. Although we focused on estrogen- responsive genes, taking into account previous evidence of H1.4 enrichment at promoters of pluripotency genes, we propose that H1.4 phosphorylation for gene activation may be a more general and global phenomenon

Targeting proteases and proteolytic processing of unusual N-terminal extensions of Plasmodium proteins: parasite peculiarity

More than sesquicentennial years of malarial research, however the unique malarial parasite, Plasmodium still bewilders us with its atypical characteristic features. Elimination strategies, deeper knowledge of the parasite biology and pathways can help combat this global health concern that affects ∼250 million people annually. In this review, we unveil an unusual phenomenon observed in the parasite proteome, N-terminal extensions in proteins and highlight that the proteases that may be involved in their processing events, are potential candidates to target this pathogen. Plasmodium encodes larger proteins as compared to its eukaryotic counterparts with homology regions present in the C-terminus of the protein. In contrast, the function of unusual extensions in the N-terminus remains mostly elusive. This novelty observed in Plasmodium proteins is collated here with a focus on replication proteins. The plausible functions and prevalence of these extensions, despite the reduction in genome size, through the parasite evolution are also mentioned. We hypothesize that these extensions, propagated via the energy consuming cellular processes in the otherwise host-dependent obligate parasite, are beneficial to the parasite in ways that are yet to be explored. Consequently, targeting the proteolytic processing of these proteins and the involved proteases would serve as a new drug development regimen to tackle the emerging resistance in parasites to existing antimalarials

Class I histone deacetylases in retinal progenitors and differentiating ganglion cells

Background The acetylation state of histones has been used as an indicator of the developmental state of progenitor and differentiating cells. The goal of this study was to determine the nuclear localization patterns of Class I histone deacetylases (HDACs) in retinal progenitor cells (RPCs) and retinal ganglion cells (RGCs), as the first step in understanding their potential importance in cell fate determination within the murine retina. Results The only HDAC to label RPC nuclei at E16 and P5 was HDAC1. In contrast, there was generally increased nuclear localization of all Class I HDACs in differentiating RGCs. Between P5 and P30, SOX2 expression becomes restricted to Müller glial, cholinergic amacrine cells, and retinal astrocytes. Cholinergic amacrine showed a combination of changes in nuclear localization of Class I HDACs. Strikingly, although Müller glia and retinal astrocytes express many of the same genes, P30 Müller glial cells showed nuclear localization only of HDAC1, while retinal astrocytes were positive for HDACs 1, 2, and 3. Conclusion These results indicate there may be a role for one or more of the Class I HDACs in retinal cell type-specific differentiation

A study of nutritional assessment of newly diagnosed tuberculosis patients in a tertiary care hospital of Tripura, India

Background: Tuberculosis kills more than any infection in India. TB is a serious public health problem in India. Tuberculosis causes immense morbidity. The mortality rate of this disease is also very high. Tuberculosis causes a great distress to the patients. To control this infection is a challenge to the health care facility of India. A lot of steps are being taken at various levels to end this disease. Still a huge number of patients are dying everyday from these deadly diseases. Out of so many recognised risk factors, malnutrition is considered to be as one of the most important among them. The immunity of a malnourished patient is suppressed. When the patient’s immunity is ineffective, the conversion of latent tuberculosis to diseases happens. Malnutrition invites tuberculosis and tuberculosis again causes morbidity, so there is a complex relation between this two. Malnutrition and tuberculosis are both problems of considerable magnitude in most of the underdeveloped regions of the world.Methods: In this cross sectional hospital based study involving 400 newly diagnosed Tuberculosis cases were taken. Their nutritional status was measured by BMI.Results: It was found that 66% of the study population is having malnutrition (BMI <18.5kg/m2). Malnutrition was more in females (71%). Mean BMI is 17.9Kg/m2. Mean height of the population is 1.53 meters.Conclusions: Nutritional supplementation may represent a novel approach for fast recovery in tuberculosis patients. In addition, raising nutritional status of population may prove to be an effective measure to control tuberculosis in underdeveloped areas of world. This study has demonstrated that half of newly diagnosed adult TB patients were malnourished at the time of starting treatment, with more than a quarter having moderate to severe malnutrition

Epigenetic suppression of human telomerase ( hTERT ) is mediated by the metastasis suppressor NME2 in a G-quadruplex–dependent fashion

Transcriptional activation of the human telomerase reverse transcriptase (hTERT) gene, which remains repressed in adult somatic cells, is critical during tumorigenesis. Several transcription factors and the epigenetic state of the hTERT promoter are known to be important for tight control of hTERT in normal tissues, but the molecular mechanisms leading to hTERT reactivation in cancer are not well-understood. Surprisingly, here we found occupancy of the metastasis suppressor non-metastatic 2 (NME2) within the hTERT core promoter in HT1080 fibrosarcoma cells and HCT116 colon cancer cells and NME2-mediated transcriptional repression of hTERT in these cells. We also report that loss of NME2 results in up-regulated hTERT expression. Mechanistically, additional results indicated that the RE1-silencing transcription factor (REST)–lysine-specific histone demethylase 1 (LSD1) co-repressor complex associates with the hTERT promoter in an NME2-dependent way and that this assembly is required for maintaining repressive chromatin at the hTERT promoter. Interestingly, a G-quadruplex motif at the hTERT promoter was essential for occupancy of NME2 and the REST repressor complex on the hTERT promoter. In light of this mechanistic insight, we studied the effects of G-quadruplex–binding ligands on hTERT expression and observed that several of these ligands repressed hTERT expression. Together, our results support a mechanism of hTERT epigenetic control involving a G-quadruplex promoter motif, which potentially can be targeted by tailored small molecules

Metastases suppressor NME2 associates with telomere ends and telomerase and reduces telomerase activity within cells

Analysis of chromatin-immunoprecipitation followed by sequencing (ChIP-seq) usually disregards sequence reads that do not map within binding positions (peaks). Using an unbiased approach, we analysed all reads, both that mapped and ones that were not included as part of peaks. ChIP-seq experiments were performed in human lung adenocarcinoma and fibrosarcoma cells for the metastasis suppressor non-metastatic 2 (NME2). Surprisingly, we identified sequence reads that uniquely represented human telomere ends in both cases. In vivo presence of NME2 at telomere ends was validated using independent methods and as further evidence we found intranuclear association of NME2 and the telomere repeat binding factor 2. Most remarkably, results demonstrate that NME2 associates with telomerase and reduces telomerase activity in vitro and in vivo, and sustained NME2 expression resulted in reduced telomere length in aggressive human cancer cells. Anti-metastatic function of NME2 has been demonstrated in human cancers, however, mechanisms are poorly understood. Together, findings reported here suggest a novel role for NME2 as a telomere binding protein that can alter telomerase function and telomere length. This presents an opportunity to investigate telomere-related interactions in metastasis suppression

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely