The rna-binding ubiquitin ligase mex3a affects glioblastoma tumorigenesis by inducing ubiquitylation and degradation of rig-i

Glioblastoma multiforme (GB) is the most malignant primary brain tumor in humans, with an overall survival of approximatively 15 months. The molecular heterogeneity of GB, as well as its rapid progression, invasiveness and the occurrence of drug-resistant cancer stem cells, limits the efficacy of the current treatments. In order to develop an innovative therapeutic strategy, it is mandatory to identify and characterize new molecular players responsible for the GB malignant phenotype. In this study, the RNA-binding ubiquitin ligase MEX3A was selected from a gene expression analysis performed on publicly available datasets, to assess its biological and still-unknown activity in GB tumorigenesis. We find that MEX3A is strongly up-regulated in GB specimens, and this correlates with very low protein levels of RIG-I, a tumor suppressor involved in differentiation, apoptosis and innate immune response. We demonstrate that MEX3A binds RIG-I and induces its ubiquitylation and proteasome-dependent degradation. Further, the genetic depletion of MEX3A leads to an increase of RIG-I protein levels and results in the suppression of GB cell growth. Our findings unveil a novel molecular mechanism involved in GB tumorigenesis and suggest MEX3A and RIG-I as promising therapeutic targets in GB

Endogenous human cytomegalovirus gB is efficiently presented by MHC class II molecules to CD4+ CTL

Human cytomegalovirus (HCMV) infects endothelial, epithelial, and glial cells in vivo. These cells can express MHC class II proteins, but are unlikely to play important roles in priming host immunity. Instead, it seems that class II presentation of endogenous HCMV antigens in these cells allows recognition of virus infection. We characterized class II presentation of HCMV glycoprotein B (gB), a membrane protein that accumulates extensively in endosomes during virus assembly. Human CD4+ T cells specific for gB were both highly abundant in blood and cytolytic in vivo. gB-specific CD4+ T cell clones recognized gB that was expressed in glial, endothelial, and epithelial cells, but not exogenous gB that was fed to these cells. Glial cells efficiently presented extremely low levels of endogenous gB--expressed by adenovirus vectors or after HCMV infection--and stimulated CD4+ T cells better than DCs that were incubated with exogenous gB. Presentation of endogenous gB required sorting of gB to endosomal compartments and processing by acidic proteases. Although presentation of cellular proteins that traffic into endosomes is well known, our observations demonstrate for the first time that a viral protein sorted to endosomes is presented exceptionally well, and can promote CD4+ T cell recognition and killing of biologically important host cells

The structure of Herpesvirus Fusion Glycoprotein B-Bilayer Complex reveals the protein-membrane and lateral protein-protein interaction

Glycoprotein B (gB) is a key component of the complex herpesvirus fusion machinery. We studied membrane interaction of two gB ectodomain forms and present an electron cryotomography structure of the gB-bilayer complex. The two forms differed in presence or absence of the membrane proximal region (MPR) but showed an overall similar trimeric shape. The presence of the MPR impeded interaction with liposomes. In contrast, the MPR-lacking form interacted efficiently with liposomes. Lateral interaction resulted in coat formation on the membranes. The structure revealed that interaction of gB with membranes was mediated by the fusion loops and limited to the outer membrane leaflet. The observed intrinsic propensity of gB to cluster on membranes indicates an additional role of gB in driving the fusion process forward beyond the transient fusion pore opening and subsequently leading to fusion pore expansion

Oxfam GB: Accountability Starter Pack

This guide is for those staff who would like to learn more about how to implement activities that are accountable to people and communities. It is primarily aimed at country-level staff responsible for implementing development or humanitarian projects and programmes. The pack begins with an introduction to Oxfam GB's approach to accountability. This is followed by Oxfam International's Accountability Matrix. The Matrix shows the commitments to accountability found within Oxfam International's Programme Standards, and the different levels programmes can achieve in each area. Following this is an explanation of Oxfam GB's Minimum Standards on Accountability.The rest of the pack is divided into four sections - one for each of the four Standards that Oxfam GB is focussing on. For each Standard, there is a brief explanation as to why this Standard is important, then some 'How-To' Guidelines and a Good Practice example from one of Oxfam's programmes. We have also added an extra section on how to improve greater financial transparency as we have had so many requests for guidance specifically on this

Transmission transparency and potential convergence of optical network solutions at the physical layer for bit rates from 2.5 Gb·s-1 to 256 Gb·s-1

In this paper, we investigate optical network recommendations GPON and XG-PON with triple-play services in terms of physical reach, number of subscribers, transceiver design, modulation format and implementation cost. Despite trends to increase the bit rate from 2.5 Gb s1 to 10 Gb s1 and beyond, TDMPONs cannot cope with bandwidth requirements of future networks. TDM and WDM techniques can be combined, resulting in improved scalability. Longer physical reach can be achieved by deploying active network elements within the transmission path. We investigate these options by considering their potential coexistence at the physical layer. Subsequently, we analyse the upgrade of optical channels to 100 Gb s1 and 256 Gb s1 by using advanced modulation formats, which combine polarization division multiplexing with coherent detection and digital signal processing. We show that PDMQPSK format is suitable for 100 Gb s1 systems and PDM-16QAM is more beneficial at 256 Gb s1. Simulations are performed in the OptSim software environment