Virus Targeting of the Tumor Necrosis Factor Superfamily

AbstractHerpesviruses appear to peacefully coexist with their natural hosts, with infection typically manifested as a benign, but lifelong process. However, coexistence depends on active resistance by innate and specific immune defenses as revealed in the striking virulence of herpesviruses when immunity fails. This pattern of infection is characteristic of a viral pathogen, such as cytomegalovirus, that has evolved efficient strategies targeted at host defense systems. Targeting members of the tumor necrosis factor (TNF)/lymphotoxin (LT) superfamily of cytokines is a strategy found in all herpesviruses, which suggests the existence of an intimate evolutionary link in their host–parasite relationship. Here we examine some of the strategies used by herpesvirus that target members of the TNF superfamily and discuss a recent study that revealed a novel mechanism that links LT-related ligands and interferons (IFN) to the establishment of coexistence between herpesvirus and its host cell

In-Materio Extreme Learning Machines

Nanomaterial networks have been presented as a building block for unconventional in-Materio processors. Evolution in-Materio (EiM) has previously presented a way to congure and exploit physical materials for computation, but their ability to scale as datasets get larger and more complex remains unclear. Extreme Learning Machines (ELMs) seek to exploit a randomly initialised single layer feed forward neural network by training the output layer only. An analogy for a physical ELM is produced by exploiting nanomaterial networks as material neurons within the hidden layer. Circuit simulations are used to eciently investigate diode-resistor networks which act as our material neurons. These in-Materio ELMs (iM-ELMs) outperform common classication methods and traditional articial ELMs of a similar hidden layer size. For iM-ELMs using the same number of hidden layer neurons, leveraging larger more complex material neuron topologies (with more nodes/electrodes) leads to better performance, showing that these larger materials have a better capability to process data. Finally, iM-ELMs using virtual material neurons, where a single material is re-used as several virtual neurons, were found to achieve comparable results to iM-ELMs which exploited several dierent materials. However, while these Virtual iM-ELMs provide signicant exibility, they sacrice the highly parallelised nature of physically implemented iM-ELMs

Cytomegalovirus exploits IL-10–mediated immune regulation in the salivary glands

The salivary glands represent a major site of cytomegalovirus replication and transmission to other hosts. Despite control of viral infection by strong T cell responses in visceral organs cytomegalovirus replication continues in the salivary glands of mice, suggesting that the virus exploits the mucosal microenvironment. Here, we show that T cell immunity in the salivary glands is limited by the induction of CD4 T cells expressing the regulatory cytokine interleukin (IL)-10. Blockade of IL-10 receptor (IL-10R) with an antagonist antibody dramatically reduced viral load in the salivary glands, but not in the spleen. The mucosa-specific protection afforded by IL-10R blockade was associated with an increased accumulation of CD4 T cells expressing interferon γ, suggesting that IL-10R signaling limits effector T cell differentiation. Consistent with this, an agonist antibody targeting the tumor necrosis factor receptor superfamily member OX40 (TNFRSF4) enhanced effector T cell differentiation and increased the number of interferon γ–producing T cells, thus limiting virus replication in the salivary glands. Collectively, the results indicate that modulating effector T cell differentiation can counteract pathogen exploitation of the mucosa, thus limiting persistent virus replication and transmission

Precise Doppler Monitoring of Barnard's Star

We present 248 precise Doppler measurements of Barnard's Star (Gl 699), the second nearest star system to Earth, obtained from Lick and Keck Observatories during 25 years between 1987 and 2012. The early precision was 20 \ms{} but was 2 \ms{} during the last 8 years, constituting the most extensive and sensitive search for Doppler signatures of planets around this stellar neighbor. We carefully analyze the 136 Keck radial velocities spanning 8 years by first applying a periodogram analysis to search for nearly circular orbits. We find no significant periodic Doppler signals with amplitudes above $\sim$2 \ms{}, setting firm upper limits on the minimum mass (\msini) of any planets with orbital periods from 0.1 to 1000 days. Using a Monte Carlo analysis for circular orbits, we determine that planetary companions to Barnard's Star with masses above 2 \mearth{} and periods below 10 days would have been detected. Planets with periods up to 2 years and masses above 10 \mearth{} (0.03 \mjup) are also ruled out. A similar analysis allowing for eccentric orbits yields comparable mass limits. The habitable zone of Barnard's Star appears to be devoid of roughly Earth-mass planets or larger, save for face-on orbits. Previous claims of planets around the star by van de Kamp are strongly refuted. The radial velocity of Barnard's Star increases with time at $4.515\pm0.002$ \msy{}, consistent with the predicted geometrical effect, secular acceleration, that exchanges transverse for radial components of velocity.Comment: 21 pages & 11 figures; accepted to ApJ for publication; revision comments: the conclusions and results remain unchanged, removed the last paragraph in section 4.2, a few minor changes to the text, replaced figure 7 with figures 7 and 8, corrected typos in the rv data tables (tables 2 and 3, data downloadable from ApJ

N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death.

APO2L/TRAIL (TNF-related apoptosis-inducing ligand) induces death of tumor cells through two agonist receptors, TRAIL-R1 and TRAIL-R2. We demonstrate here that N-linked glycosylation (N-glyc) plays also an important regulatory role for TRAIL-R1-mediated and mouse TRAIL receptor (mTRAIL-R)-mediated apoptosis, but not for TRAIL-R2, which is devoid of N-glycans. Cells expressing N-glyc-defective mutants of TRAIL-R1 and mouse TRAIL-R were less sensitive to TRAIL than their wild-type counterparts. Defective apoptotic signaling by N-glyc-deficient TRAIL receptors was associated with lower TRAIL receptor aggregation and reduced DISC formation, but not with reduced TRAIL-binding affinity. Our results also indicate that TRAIL receptor N-glyc impacts immune evasion strategies. The cytomegalovirus (CMV) UL141 protein, which restricts cell-surface expression of human TRAIL death receptors, binds with significant higher affinity TRAIL-R1 lacking N-glyc, suggesting that this sugar modification may have evolved as a counterstrategy to prevent receptor inhibition by UL141. Altogether our findings demonstrate that N-glyc of TRAIL-R1 promotes TRAIL signaling and restricts virus-mediated inhibition

Scenario-based sustainable water management and urban regeneration

Copyright © ICE PublishingDeployable output (source availability) from water resources in north west England is predicted to decrease over the next 25 years. Alternative supply management strategies are planned to help avoid a deficit in the supply–demand balance within the region but have yet to be considered in detail. This paper assesses the contribution of such an alternative supply strategy at local level on the water resource supply–demand balance at regional level based on a proposed urban regeneration site in north west England. Various water conservation and reuse measures are investigated considering local and regional conditions and constraints. Four future scenarios are presented and used to describe how the future might be (rather than how it will be), to allow an assessment to be made of how current ‘sustainable solutions’ might cope whatever the future holds. The analysis determines the solution contributions under each future and indicates that some strategies will deliver their full intended benefits under scenarios least expected but most needed. It is recommended that to help reduce the regional supply–demand deficit and maximise system resilience to future change, a wide range of water demand management measures should be incorporated on this and other sites

A multifaceted study of stigma/style cysteine-rich adhesin (SCA)-like Arabidopsis lipid transfer proteins (LTPs) suggests diversified roles for these LTPs in plant growth and reproduction

Lily stigma/style cysteine-rich adhesin (SCA), a plant lipid transfer protein (LTP) which is secreted into the extracellular matrix, functions in pollen tube guidance in fertilization. A gain-of-function mutant (ltp5-1) for Arabidopsis LTP5, an SCA-like molecule, was recently shown to display defects in sexual reproduction. In the current study, it is reported that ltp5-1 plants have dwarfed primary shoots, delayed hypocotyl elongation, various abnormal tissue fusions, and display multibranching. These mutant phenotypes in vegetative growth are recessive. No abnormality was found in ltp5-1/+ plants. In a phylogenetic analysis of plant LTPs, SCA-like Arabidopsis LTPs were classified with conventional plant LTPs. Homology modelling-based electrostatic similarity index (ESI) clustering was used to show diversity in spatial distributions of electrostatic potentials of SCA-like LTPs, suggestive of their various roles in interaction in the extracellular matrix space. β-Glucuronidase (GUS) analysis showed that SCA-like Arabidopsis LTP genes are diversely present in various tissues. LTP4 was found specifically in the guard cells and LTP6 in trichomes as well as in other tissues. LTP1 levels were specifically abundant in the stigma, and both LTP3 and LTP6 in the ovules. LTP2 and LTP4 gene levels were up-regulated in whole seedlings with 20% polyethylene glycol (PEG) and 300 mM NaCl treatments, respectively. LTP5 was up-regulated in the hypocotyl with 3 d dark growth conditions. LTP6 was specifically expressed in the tip of the cotyledon under drought stress conditions. The results suggest that SCA-like Arabidopsis LTPs are multifunctional, with diversified roles in plant growth and reproduction

Systemic hematogenous maintenance of memory inflation by MCMV infection.

Several low-grade persistent viral infections induce and sustain very large numbers of virus-specific effector T cells. This was first described as a response to cytomegalovirus (CMV), a herpesvirus that establishes a life-long persistent/latent infection, and sustains the largest known effector T cell populations in healthy people. These T cells remain functional and traffic systemically, which has led to the recent exploration of CMV as a persistent vaccine vector. However, the maintenance of this remarkable response is not understood. Current models propose that reservoirs of viral antigen and/or latently infected cells in lymph nodes stimulate T cell proliferation and effector differentiation, followed by migration of progeny to non-lymphoid tissues where they control CMV reactivation. We tested this model using murine CMV (MCMV), a natural mouse pathogen and homologue of human CMV (HCMV). While T cells within draining lymph nodes divided at a higher rate than cells elsewhere, antigen-dependent proliferation of MCMV-specific effector T cells was observed systemically. Strikingly, inhibition of T cell egress from lymph nodes failed to eliminate systemic T cell division, and did not prevent the maintenance of the inflationary populations. In fact, we found that the vast majority of inflationary cells, including most cells undergoing antigen-driven division, had not migrated into the parenchyma of non-lymphoid tissues but were instead exposed to the blood supply. Indeed, the immunodominance and effector phenotype of inflationary cells, both of which are primary hallmarks of memory inflation, were largely confined to blood-localized T cells. Together these results support a new model of MCMV-driven memory inflation in which most immune surveillance occurs in circulation, and in which most inflationary effector T cells are produced in response to viral antigen presented by cells that are accessible to the blood supply