The enzymes LSD1 and Set1A cooperate with the viral protein HBx to establish an active hepatitis B viral chromatin state

Indexación: Web of ScienceWith about 350 million people chronically infected around the world hepatitis B is a major health problem. Template for progeny HBV synthesis is the viral genome, organized as a minichromosome (cccDNA) inside the hepatocyte nucleus. How viral cccDNA gene expression is regulated by its chromatin structure; more importantly, how the modulation of this structure impacts on viral gene expression remains elusive. Here, we found that the enzyme SetDB1 contributes to setting up a repressed cccDNA chromatin state. This repressive state is activated by the histone lysine demethylase-1 (LSD1). Consistently, inhibiting or reducing LSD1 levels led to repression of viral gene expression. This correlates with the transcriptionally repressive mark H3K9 methylation and reduction on the activating marks H3 acetylation and H3K4 methylation on viral promoters. Investigating the importance of viral proteins we found that LSD1 recruitment to viral promoters was dependent on the viral transactivator protein HBx. Moreover, the histone methyltransferase Set1A and HBx are simultaneously bound to the core promoter, and Set1A expression correlates with cccDNA H3K4 methylation. Our results shed light on the mechanisms of HBV regulation mediated by the cccDNA chromatin structure, offering new therapeutic targets to develop drugs for the treatment of chronically infected HBV patients.http://www.nature.com/articles/srep2590

Ballistic performance of thermoplastic composite laminates made from aramid woven fabric and polypropylene matrix

The ballistic behavior of multi-layer Kevlar (R) aramid fabric/polypropylene (PP) composite laminate (CL) and plain layered aramid fabric (AF) impact specimens was investigated. It was found that the thermoplastic PP matrix increases the ballistic performance of CL targets when compared to AF targets with similar areal density, resulting in less aramid fabric needed to obtain the same level of protection when the PP matrix is incorporated. It was found that the improved ballistic performance of CL targets is due to the fact that the thermoplastic matrix enables energy absorbing mechanisms such as fabric/matrix debonding and delamination. The ballistic limit and penetration threshold energy of the CL configurations, which were predicted using an empirical model, were found to be higher than those of the AF targets. These results show that aramid fabric/PP laminates should be further studied for improved ballistic performance at lower costs. (C) 2012 Elsevier Ltd. All rights reserved

Psychometric properties of a test in evidence based practice: the Spanish version of the Fresno test

<p>Abstract</p> <p>Background</p> <p>Validated instruments are needed to evaluate the programmatic impact of Evidence Based Practice (EBP) training and to document the competence of individual trainees. This study aimed to translate the Fresno test into Spanish and subsequently validate it, in order to ensure the equivalence of the Spanish version against the original English version.</p> <p>Methods</p> <p>Before and after study performed between October 2007 and June 2008. Three groups of participants: (a) Mentors of family medicine residents (expert group) (n = 56); (b) Family medicine physicians (intermediate experience group) (n = 17); (c) Family medicine residents (novice group) (n = 202); Medical residents attended an EBP course, and two sets of the test were administered before and after the course. The Fresno test is a performance based measure for use in medical education that assesses EBP skills. The outcome measures were: inter-rater and intra-rater reliability, internal consistency, item analyses, construct validity, feasibility of administration, and responsiveness.</p> <p>Results</p> <p>Inter-rater correlations were 0.95 and 0.85 in the pre-test and the post-test respectively. The overall intra-rater reliability was 0.71 and 0.81 in the pre-test and post-test questionnaire, respectively. Cronbach's alpha was 0.88 and 0.77, respectively. 152 residents (75.2%) returned both sets of the questionnaire. The observed effect size for the residents was 1.77 (CI 95%: 1.57-1.95), the standardised response mean was 1.65 (CI 95%:1.47-1.82).</p> <p>Conclusions</p> <p>The Spanish version of the Fresno test is a useful tool in assessing the knowledge and skills of EBP in Spanish-speaking residents of Family Medicine.</p

The Antibacterial Activity of Honey Derived from Australian Flora

Chronic wound infections and antibiotic resistance are driving interest in antimicrobial treatments that have generally been considered complementary, including antimicrobially active honey. Australia has unique native flora and produces honey with a wide range of different physicochemical properties. In this study we surveyed 477 honey samples, derived from native and exotic plants from various regions of Australia, for their antibacterial activity using an established screening protocol. A level of activity considered potentially therapeutically useful was found in 274 (57%) of the honey samples, with exceptional activity seen in samples derived from marri (Corymbia calophylla), jarrah (Eucalyptus marginata) and jellybush (Leptospermum polygalifolium). In most cases the antibacterial activity was attributable to hydrogen peroxide produced by the bee-derived enzyme glucose oxidase. Non-hydrogen peroxide activity was detected in 80 (16.8%) samples, and was most consistently seen in honey produced from Leptospermum spp. Testing over time found the hydrogen peroxide-dependent activity in honey decreased, in some cases by 100%, and this activity was more stable at 4°C than at 25°C. In contrast, the non-hydrogen peroxide activity of Leptospermum honey samples increased, and this was greatest in samples stored at 25°C. The stability of non-peroxide activity from other honeys was more variable, suggesting this activity may have a different cause. We conclude that many Australian honeys have clinical potential, and that further studies into the composition and stability of their active constituents are warranted

An?lisis de los elementos cr?ticos para el desarrollo de proveedores en empresas de la gran miner?a en el Per?

En esta investigaci?n se describen las caracter?sticas de los elementos cr?ticos para el desarrollo de proveedores en empresas de la gran miner?a en el Per?. Como parte de la gesti?n de las relaciones con proveedores, las empresas realizan desarrollo de proveedores cuando participan activamente en esfuerzos para mejorar el desempe?o y capacidades de sus proveedores. Sobre la base del marco de referencia para el desarrollo de proveedores de Sucky y Durst (2013), se definen las variables que describen las condiciones influyentes, factores de ?xito, estrategias e impactos del desarrollo de proveedores en una muestra de seis empresas representativas de la gran miner?a peruana. Para ello se realizan entrevistas semiestructuradas a ejecutivos de log?stica, compras y contratos, as? como revisiones de reportes de sostenibilidad y otros documentos. El estudio concluye que la estrategia de las empresas es desarrollar las capacidades de sus proveedores locales, con el objetivo de mantener una buena relaci?n con las comunidades de sus ?reas de influencia directa. La baja capacidad del proveedor local representa la principal condici?n influyente, y la actitud estrat?gica hacia el proveedor es el principal factor de ?xito. Finalmente, el desarrollo de proveedores tiene impactos positivos en las empresas y en sus proveedores locales

The secreted triose phosphate isomerase of Brugia malayi is required to sustain microfilaria production in vivo

Human lymphatic filariasis is a major tropical disease transmitted through mosquito vectors which take up microfilarial larvae from the blood of infected subjects. Microfilariae are produced by long-lived adult parasites, which also release a suite of excretory-secretory products that have recently been subject to in-depth proteomic analysis. Surprisingly, the most abundant secreted protein of adult Brugia malayi is triose phosphate isomerase (TPI), a glycolytic enzyme usually associated with the cytosol. We now show that while TPI is a prominent target of the antibody response to infection, there is little antibody-mediated inhibition of catalytic activity by polyclonal sera. We generated a panel of twenty-three anti-TPI monoclonal antibodies and found only two were able to block TPI enzymatic activity. Immunisation of jirds with B. malayi TPI, or mice with the homologous protein from the rodent filaria Litomosoides sigmodontis, failed to induce neutralising antibodies or protective immunity. In contrast, passive transfer of neutralising monoclonal antibody to mice prior to implantation with adult B. malayi resulted in 60–70% reductions in microfilarial levels in vivo and both oocyte and microfilarial production by individual adult females. The loss of fecundity was accompanied by reduced IFNγ expression by CD4+ T cells and a higher proportion of macrophages at the site of infection. Thus, enzymatically active TPI plays an important role in the transmission cycle of B. malayi filarial parasites and is identified as a potential target for immunological and pharmacological intervention against filarial infections

Impact of massive neutrinos on the Higgs self-coupling and electroweak vacuum stability

The presence of right-handed neutrinos in the type I seesaw mechanism may lead to significant corrections to the RG evolution of the Higgs self-coupling. Compared to the Standard Model case, the Higgs mass window can become narrower, and the cutoff scale become lower. Naively, these effects decrease with decreasing right-handed neutrino mass. However, we point out that the unknown Dirac Yukawa matrix may impact the vacuum stability constraints even in the low scale seesaw case not far away from the electroweak scale, hence much below the canonical seesaw scale of 10^15 GeV. This includes situations in which production of right-handed neutrinos at colliders is possible. We illustrate this within a particular parametrization of the Dirac Yukawas and with explicit low scale seesaw models. We also note the effect of massive neutrinos on the top quark Yukawa coupling, whose high energy value can be increased with respect to the Standard Model case.Comment: 17 pages, 7 figures, minor revisions, version to appear in JHE

Different rates of spontaneous mutation of chloroplastic and nuclear viroids as determined by high-fidelity ultra-deep sequencing

[EN] Mutation rates vary by orders of magnitude across biological systems, being higher for simpler genomes. The simplest known genomes correspond to viroids, subviral plant replicons constituted by circular non-coding RNAs of few hundred bases. Previous work has revealed an extremely high mutation rate for chrysanthemum chlorotic mottle viroid, a chloroplastreplicating viroid. However, whether this is a general feature of viroids remains unclear. Here, we have used high-fidelity ultra-deep sequencing to determine the mutation rate in a common host (eggplant) of two viroids, each representative of one family: the chloroplastic eggplant latent viroid (ELVd, Avsunviroidae) and the nuclear potato spindle tuber viroid (PSTVd, Pospiviroidae). This revealed higher mutation frequencies in ELVd than in PSTVd, as well as marked differences in the types of mutations produced. Rates of spontaneous mutation, quantified in vivo using the lethal mutation method, ranged from 1/1000 to 1/800 for ELVd and from 1/7000 to 1/3800 for PSTVd depending on sequencing run. These results suggest that extremely high mutability is a common feature of chloroplastic viroids, whereas the mutation rates of PSTVd and potentially other nuclear viroids appear significantly lower and closer to those of some RNA viruses.This work was supported by the European Research Council (erc.europa.eu; ERC-2011-StG-281191-VIRMUT to RS), the Spanish Ministerio de Economia y Competitividad (www.mineco.gob.es; BFU2013-41329 grant to RS, BFU2014-56812-P grant to RF, and a predoctoral fellowship to ALC), and the Spanish Junta de Comunidades de Castilla-La Mancha (www.castillalamancha.es;postdoctoral fellowship to CB). 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