Conserved Central Intraviral Protein Interactome of the Herpesviridae Family

Protein interactions are major driving forces behind the functional phenotypes of biological processes. As such, evolutionary footprints are reflected in system-level collections of protein-protein interactions (PPIs), i.e., protein interactomes. We conducted a comparative analysis of intraviral protein interactomes for representative species of each of the three subfamilies of herpesviruses (herpes simplex virus 1, human cytomegalovirus, and Epstein-Barr virus), which are highly prevalent etiologic agents of important human diseases. The intraviral interactomes were reconstructed by combining experimentally supported and computationally predicted protein-protein interactions. Using cross-species network comparison, we then identified family-wise conserved interactions and protein complexes, which we defined as a herpesviral “central” intraviral protein interactome. A large number of widely accepted conserved herpesviral protein complexes are present in this central intraviral interactome, encouragingly supporting the biological coherence of our results. Importantly, these protein complexes represent most, if not all, of the essential steps required during a productive life cycle. Hence the central intraviral protein interactome could plausibly represent a minimal infectious interactome of the herpesvirus family across a variety of hosts. Our data, which have been integrated into our herpesvirus interactomics database, HVint2.0, could assist in creating comprehensive system-level computational models of this viral lineage

Evaluation of the therapeutic potential of ant-TLR4-antibody MTS510 in experimental stroke and significa of different routes of application

Toll-like receptors (TLRs) are central sensors for the inflammatory response in ischemia-reperfusion injury. We therefore investigated whether TLR4 inhibition could be used to treat stroke in a standard model of focal cerebral ischemia. Anti-TLR4/MD2-antibody (mAb clone MTS510) blocked TLR4-induced cell activation in vitro, as reported previously. Here, different routes of MTS510 application in vivo were used to study the effects on stroke outcome up to 2d after occlusion of the middle cerebral artery (MCAO) for 45 min in adult male C57Bl/6 wild-type mice. Improved neurological performance, reduced infarct volumes, and reduced brain swelling showed that intravascular application of MTS510 had a protective effect in the model of 45 min MCAO. Evaluation of potential long-term adverse effects of anti-TLR4-mAb-treament revealed no significant deleterious effect on infarct volumes nor neurological deficit after 14d of reperfusion in a mild model of stroke (15 min MCAO). Interestingly, inhibition of TLR4 resulted in an altered adaptive immune response at 48 hours after reperfusion. We conclude that blocking TLR4 by the use of specific mAb is a promising strategy for stroke therapy. However, long-term studies with increased functional sensitivity, larger sampling sizes and use of other species are required before a clinical use could be envisaged

Theoretical uncertainties for measurements of alpha_s from electroweak observables

One of the most precise measurements of the strong coupling constant alpha_s(MZ) is obtained in the context of global analyses of precision electroweak data. This article reviews the sensitivity of different electroweak observables to alpha_s and describes the perturbative uncertainties related to missing higher orders. The complete renormalisation scale dependence for the relevant observables is calculated at next-to-next-to-leading order and a new method is presented to determine the corresponding perturbative uncertainty for measurements of alpha_s based on these observables.Comment: v4: Revised version with new tables and figure

Deep-coverage spatiotemporal proteome of the picoeukaryote Ostreococcus tauri reveals differential effects of environmental and endogenous 24-hour rhythms.

The cellular landscape changes dramatically over the course of a 24 h day. The proteome responds directly to daily environmental cycles and is additionally regulated by the circadian clock. To quantify the relative contribution of diurnal versus circadian regulation, we mapped proteome dynamics under light:dark cycles compared with constant light. Using Ostreococcus tauri, a prototypical eukaryotic cell, we achieved 85% coverage, which allowed an unprecedented insight into the identity of proteins that facilitate rhythmic cellular functions. The overlap between diurnally- and circadian-regulated proteins was modest and these proteins exhibited different phases of oscillation between the two conditions. Transcript oscillations were generally poorly predictive of protein oscillations, in which a far lower relative amplitude was observed. We observed coordination between the rhythmic regulation of organelle-encoded proteins with the nuclear-encoded proteins that are targeted to organelles. Rhythmic transmembrane proteins showed a different phase distribution compared with rhythmic soluble proteins, indicating the existence of a circadian regulatory process specific to the biogenesis and/or degradation of membrane proteins. Our observations argue that the cellular spatiotemporal proteome is shaped by a complex interaction between intrinsic and extrinsic regulatory factors through rhythmic regulation at the transcriptional as well as post-transcriptional, translational, and post-translational levels

Electroweak corrections to Higgs production through ZZ fusion at the linear collider

We present the full order alpha electroweak radiative corrections to e+e- -> e+e-H. The computation is performed with the help of GRACE-loop. The extraction of the full QED corrections is performed, these are quite large at threshold. The genuine weak corrections, for the linear collider energies, when expressed in the G_mu scheme are of order -2 to -4 for Higgs masses preferred by the latest precision data. We also extract the m_t^2 type corrections and make a comparison with the weak corrections for the process e+e- ->nu nu H.Comment: 16 pages and 6 figure

Full one-loop electroweak radiative corrections to single Higgs production in e+ e-

We present the full ${{\cal O}}(\alpha)$ electroweak radiative corrections to single Higgs production in \epemt. This takes into account the full one-loop corrections as well as the effects of hard photon radiation. We include both the fusion and Higgs-strahlung processes. The computation is performed with the help of {\tt GRACE-loop} where we have implemented a generalised non-linear gauge fixing condition. The latter includes 5 gauge parameters that can be used for checks on our results. Besides the UV, IR finiteness and gauge parameter independence checks it proves also powerful to test our implementation of the 5-point function. We find that for a 500GeV machine and a light Higgs of mass 150GeV, the total ${{\cal O}}(\alpha)$ correction is small when the results are expressed in terms of $\alpha_{{\rm QED}}$. The total correction decreases slightly for higher energies. For moderate centre of mass energies the total ${{\cal O}}(\alpha)$ decreases as the Higgs mass increases, reaching -10% for $M_H=350$GeV and $\sqrt{s}=500$GeV. In order to quantify the genuine weak corrections we have subtracted the universal virtual and bremsstrahlung correction from the full ${{\cal O}}(\alpha)$. We find, for $M_H=150$GeV, a weak correction slowly decreasing from -2% to -4% as the energy increases from $\sqrt{s}=300$GeV to $\sqrt{s}=1$TeV after expressing the tree-level results in terms of $G_\mu$Comment: 16 pages, 3 figures. Only correction is a reference to a web-pag

Intermittent bulk release of human cytomegalovirus

Human Cytomegalovirus (HCMV) can infect a variety of cell types by using virions of varying glycoprotein compositions. It is still unclear how this diversity is generated, but spatio-temporally separated envelopment and egress pathways might play a role. So far, one egress pathway has been described in which HCMV particles are individually enveloped into small vesicles and are subsequently exocytosed continuously. However, some studies have also found enveloped virus particles inside multivesicular structures but could not link them to productive egress or degradation pathways. We used a novel 3D-CLEM workflow allowing us to investigate these structures in HCMV morphogenesis and egress at high spatio-temporal resolution. We found that multiple envelopment events occurred at individual vesicles leading to multiviral bodies (MViBs), which subsequently traversed the cytoplasm to release virions as intermittent bulk pulses at the plasma membrane to form extracellular virus accumulations (EVAs). Our data support the existence of a novel bona fide HCMV egress pathway, which opens the gate to evaluate divergent egress pathways in generating virion diversity

Electron Bio-Imaging Centre (eBIC): the UK national research facility for biological electron microscopy

The recent resolution revolution in cryo-EM has led to a massive increase in demand for both time on high-end cryo-electron microscopes and access to cryo-electron microscopy expertise. In anticipation of this demand, eBIC was set up at Diamond Light Source in collaboration with Birkbeck College London and the University of Oxford, and funded by the Wellcome Trust, the UK Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC) to provide access to high-end equipment through peer review. eBIC is currently in its start-up phase and began by offering time on a single FEI Titan Krios microscope equipped with the latest generation of direct electron detectors from two manufacturers. Here, the current status and modes of access for potential users of eBIC are outlined. In the first year of operation, 222 d of microscope time were delivered to external research groups, with 95 visits in total, of which 53 were from unique groups. The data collected have generated multiple high- to intermediate-resolution structures (2.8–8 Å), ten of which have been published. A second Krios microscope is now in operation, with two more due to come online in 2017. In the next phase of growth of eBIC, in addition to more microscope time, new data-collection strategies and sample-preparation techniques will be made available to external user groups. Finally, all raw data are archived, and a metadata catalogue and automated pipelines for data analysis are being developed