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

The Adaptor Protein AP-3 Is Required for CD1d-Mediated Antigen Presentation of Glycosphingolipids and Development of Vα14i NKT Cells

Relatively little is known about the pathway leading to the presentation of glycolipids by CD1 molecules. Here we show that the adaptor protein complex 3 (AP-3) is required for the efficient presentation of glycolipid antigens that require internalization and processing. AP-3 interacts with mouse CD1d, and cells from mice deficient for AP-3 have increased cell surface levels of CD1d and decreased expression in late endosomes. Spleen cells from AP-3–deficient mice have a reduced ability to present glycolipids to natural killer T (NKT) cells. Furthermore, AP-3–deficient mice have a significantly reduced NKT cell population, although this is not caused by self-tolerance that might result from increased CD1d surface levels. These data suggest that the generation of the endogenous ligand that selects NKT cells may also be AP-3 dependent. However, the function of MHC class II–reactive CD4+ T lymphocytes is not altered by AP-3 deficiency. Consistent with this divergence from the class II pathway, NKT cell development and antigen presentation by CD1d are not reduced by invariant chain deficiency. These data demonstrate that the AP-3 requirement is a particular attribute of the CD1d pathway in mice and that, although MHC class II molecules and CD1d are both found in late endosomes or lysosomes, different pathways mediate their intracellular trafficking

Neutrality of the canonical NF-kappaB-dependent pathway for human and murine cytomegalovirus transcription and replication in vitro

Cytomegalovirus (CMV) is known to rapidly induce activation of nuclear factor �B (NF-�B) after infection of fibroblast and macrophage cells. NF-�B response elements are present in the enhancer region of the CMV major immediate-early promoter (MIEP), and activity of the MIEP is strongly upregulated by NF-�B in transient-transfection assays. Here we investigate whether the NF-�B-dependent pathway is required for initiating or potentiating human and murine CMV replication in vitro. We show that expression of a dominant negative mutant of the inhibitor of NF-�B-alpha (I�B�M) does not alter the replication kinetics of human or mouse CMV in cultured cells. In addition, mouse embryo fibroblasts genetically deficient for p65/RelA actually showed elevated levels of MCMV replication. Mutation of all NF-�B response elements within the enhancer of the MIEP in a recombinant mouse CMV containing the human MIEP (hMCMV-ES), which we have previously shown to replicate in murine fibroblasts with kinetics equivalent to that of wild-type mouse CMV, did not negatively affect replication in fibroblasts. Taken together, these data show that, for CMV replication in cultured fibroblasts activation of the canonical NF-�B pathway and binding of NF-�B to the MIEP are dispensable, and in the case of p65 may even interfere, thus uncovering a previously unrecognized level of complexity in the host regulatory network governing MIE gene expression in the context of a viral infection

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