Epstein-Barr Virus LMP2A Reduces Hyperactivation Induced by LMP1 to Restore Normal B Cell Phenotype in Transgenic Mice

Epstein-Barr virus (EBV) latently infects most of the human population and is strongly associated with lymphoproliferative disorders. EBV encodes several latency proteins affecting B cell proliferation and survival, including latent membrane protein 2A (LMP2A) and the EBV oncoprotein LMP1. LMP1 and LMP2A signaling mimics CD40 and BCR signaling, respectively, and has been proposed to alter B cell functions including the ability of latently-infected B cells to access and transit the germinal center. In addition, several studies suggested a role for LMP2A modulation of LMP1 signaling in cell lines by alteration of TRAFs, signaling molecules used by LMP1. In this study, we investigated whether LMP1 and LMP2A co-expression in a transgenic mouse model alters B cell maturation and the response to antigen, and whether LMP2A modulates LMP1 function. Naïve LMP1/2A mice had similar lymphocyte populations and antibody production by flow cytometry and ELISA compared to controls. In the response to antigen, LMP2A expression in LMP1/2A animals rescued the impairment in germinal center generation promoted by LMP1. LMP1/2A animals produced high-affinity, class-switched antibody and plasma cells at levels similar to controls. In vitro, LMP1 upregulated activation markers and promoted B cell hyperproliferation, and co-expression of LMP2A restored a wild-type phenotype. By RT-PCR and immunoblot, LMP1 B cells demonstrated TRAF2 levels four-fold higher than non-transgenic controls, and co-expression of LMP2A restored TRAF2 levels to wild-type levels. No difference in TRAF3 levels was detected. While modulation of other TRAF family members remains to be assessed, normalization of the LMP1-induced B cell phenotype through LMP2A modulation of TRAF2 may be a pathway by which LMP2A controls B cell function. These findings identify an advance in the understanding of how Epstein-Barr virus can access the germinal center in vivo, a site critical for both the genesis of immunological memory and of virus-associated tumors

Sex- and Diet-Specific Changes of Imprinted Gene Expression and DNA Methylation in Mouse Placenta under a High-Fat Diet

Changes in imprinted gene dosage in the placenta may compromise the prenatal control of nutritional resources. Indeed monoallelic behaviour and sensitivity to changes in regional epigenetic state render imprinted genes both vulnerable and adaptable

Exploring new physics frontiers through numerical relativity

The demand to obtain answers to highly complex problems within strong-field gravity has been met with significant progress in the numerical solution of Einstein's equations - along with some spectacular results - in various setups. We review techniques for solving Einstein's equations in generic spacetimes, focusing on fully nonlinear evolutions but also on how to benchmark those results with perturbative approaches. The results address problems in high-energy physics, holography, mathematical physics, fundamental physics, astrophysics and cosmology

Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis.

Contains fulltext : 89753.pdf (publisher's version ) (Closed access)Stimulants used to treat attention-deficit/hyperactivity disorder (ADHD) have been well researched, but comparisons among stimulants are hindered by the absence of direct comparative trials. The goal of this work was to compare the efficacy of methylphenidate and amfetamine formulations through a meta-analysis of double-blind placebo-controlled trials. We analyzed recent published literature on the stimulant therapy of ADHD to describe the variability of drug-placebo effect sizes. A literature search was conducted to identify double-blind, placebo-controlled studies of ADHD in children and adolescents published after 1979. Meta-analysis regression assessed the influence of medication type and study design features on medication effects. Twenty-three trials met criteria and were included in this meta-analysis. These trials studied 11 drugs using 19 different outcome measures of hyperactive, inattentive, or impulsive behavior. We found significant differences between amfetamine and methylphenidate products, even after correcting for study design features that might have confounded the results. Our analyses indicate that effect sizes for amfetamine products are significantly, albeit moderately, greater than those for methylphenidate. We found that most measures of effect from all studies were statistically significant. Our findings suggest that amfetamine products may be moderately more efficacious than methylphenidate products, even after controlling for potentially confounding study design features. This difference in effect size may be due to differences between amfetamine and methylphenidate in the molecular mechanisms involved in facilitating the dopaminergic neurotransmission.1 april 201