Global assessment of dengue Virus-Specific CD4+ T cell responses in Dengue-Endemic areas

Background: Dengue is a major public health problem worldwide. Assessment of adaptive immunity is important to understanding immunopathology and to define correlates of protection against dengue virus (DENV). To enable global assessment of CD4+ T cell responses, we mapped HLA-DRB1-restricted DENV-specific CD4+ T cell epitopes in individuals previously exposed to DENV in the general population of the dengue-endemic region of Managua, Nicaragua. Methods: HLA class II epitopes in the population of Managua were identified by an in vitro IFNγ ELISPOT assay. CD4+ T cells purified by magnetic bead negative selection were stimulated with HLA-matched epitope pools in the presence of autologous antigen-presenting cells, followed by pool deconvolution to identify specific epitopes. The epitopes identified in this study were combined with those previously identified in the DENV endemic region of Sri Lanka, to generate a “megapool” (MP) consisting of 180 peptides specifically designed to achieve balanced HLA and DENV serotype coverage. The DENV CD4MP180 was validated by intracellular cytokine staining assays. Results: We detected responses directed against a total of 431 epitopes, representing all 4 DENV serotypes, restricted by 15 different HLA-DRB1 alleles. The responses were associated with a similar pattern of protein immunodominance, overall higher magnitude of responses, as compared to what was observed previously in the Sri Lanka region. Based on these epitope mapping studies, we designed a DENV CD4 MP180 with higher and more consistent coverage, which allowed the detection of CD4+ T cell DENV responses ex vivo in various cohorts of DENV exposed donors worldwide, including donors from Nicaragua, Brazil, Singapore, Sri Lanka, and U.S. domestic flavivirus-naïve subjects immunized with Tetravalent Dengue Live-Attenuated Vaccine (TV005). This broad reactivity reflects that the 21 HLA-DRB1 alleles analyzed in this and previous studies account for more than 80% of alleles present with a phenotypic frequency ≥5% worldwide, corresponding to 92% phenotypic coverage of the general population (i.e., 92% of individuals express at least one of these alleles). Conclusion: The DENV CD4 MP180 can be utilized to measure ex vivo responses to DENV irrespective of geographical location

What is the Oxygen Isotope Composition of Venus? The Scientific Case for Sample Return from Earth’s “Sister” Planet

Venus is Earth’s closest planetary neighbour and both bodies are of similar size and mass. As a consequence, Venus is often described as Earth’s sister planet. But the two worlds have followed very different evolutionary paths, with Earth having benign surface conditions, whereas Venus has a surface temperature of 464 °C and a surface pressure of 92 bar. These inhospitable surface conditions may partially explain why there has been such a dearth of space missions to Venus in recent years.The oxygen isotope composition of Venus is currently unknown. However, this single measurement (Δ17O) would have first order implications for our understanding of how large terrestrial planets are built. Recent isotopic studies indicate that the Solar System is bimodal in composition, divided into a carbonaceous chondrite (CC) group and a non-carbonaceous (NC) group. The CC group probably originated in the outer Solar System and the NC group in the inner Solar System. Venus comprises 41% by mass of the inner Solar System compared to 50% for Earth and only 5% for Mars. Models for building large terrestrial planets, such as Earth and Venus, would be significantly improved by a determination of the Δ17O composition of a returned sample from Venus. This measurement would help constrain the extent of early inner Solar System isotopic homogenisation and help to identify whether the feeding zones of the terrestrial planets were narrow or wide.Determining the Δ17O composition of Venus would also have significant implications for our understanding of how the Moon formed. Recent lunar formation models invoke a high energy impact between the proto-Earth and an inner Solar System-derived impactor body, Theia. The close isotopic similarity between the Earth and Moon is explained by these models as being a consequence of high-temperature, post-impact mixing. However, if Earth and Venus proved to be isotopic clones with respect to Δ17O, this would favour the classic, lower energy, giant impact scenario.We review the surface geology of Venus with the aim of identifying potential terrains that could be targeted by a robotic sample return mission. While the potentially ancient tessera terrains would be of great scientific interest, the need to minimise the influence of venusian weathering favours the sampling of young basaltic plains. In terms of a nominal sample mass, 10 g would be sufficient to undertake a full range of geochemical, isotopic and dating studies. However, it is important that additional material is collected as a legacy sample. As a consequence, a returned sample mass of at least 100 g should be recovered.Two scenarios for robotic sample return missions from Venus are presented, based on previous mission proposals. The most cost effective approach involves a “Grab and Go” strategy, either using a lander and separate orbiter, or possibly just a stand-alone lander. Sample return could also be achieved as part of a more ambitious, extended mission to study the venusian atmosphere. In both scenarios it is critical to obtain a surface atmospheric sample to define the extent of atmosphere-lithosphere oxygen isotopic disequilibrium. Surface sampling would be carried out by multiple techniques (drill, scoop, “vacuum-cleaner” device) to ensure success. Surface operations would take no longer than one hour.Analysis of returned samples would provide a firm basis for assessing similarities and differences between the evolution of Venus, Earth, Mars and smaller bodies such as Vesta. The Solar System provides an important case study in how two almost identical bodies, Earth and Venus, could have had such a divergent evolution. Finally, Venus, with its runaway greenhouse atmosphere, may provide data relevant to the understanding of similar less extreme processes on Earth. Venus is Earth’s planetary twin and deserves to be better studied and understood. In a wider context, analysis of returned samples from Venus would provide data relevant to the study of exoplanetary systems

Insights into the high-energy γ-ray emission of Markarian 501 from extensive multifrequency observations in the Fermi era

We report on the γ-ray activity of the blazar Mrk 501 during the first 480 days of Fermi operation. We find that the average Large Area Telescope (LAT) γ-ray spectrum of Mrk 501 can be well described by a single power-law function with a photon index of 1.78 ± 0.03. While we observe relatively mild flux variations with the Fermi-LAT (within less than a factor of two), we detect remarkable spectral variability where the hardest observed spectral index within the LAT energy range is 1.52 ± 0.14, and the softest one is 2.51 ± 0.20. These unexpected spectral changes do not correlate with the measured flux variations above 0.3 GeV. In this paper, we also present the first results from the 4.5 month long multifrequency campaign (2009 March 15-August 1) on Mrk 501, which included the Very Long Baseline Array (VLBA), Swift, RXTE, MAGIC, and VERITAS, the F-GAMMA, GASP-WEBT, and other collaborations and instruments which provided excellent temporal and energy coverage of the source throughout the entire campaign. The extensive radio to TeV data set from this campaign provides us with the most detailed spectral energy distribution yet collected for this source during its relatively low activity. The average spectral energy distribution of Mrk 501 is well described by the standard one-zone synchrotron self-Compton (SSC) model. In the framework of this model, we find that the dominant emission region is characterized by a size ≲0.1 pc (comparable within a factor of few to the size of the partially resolved VLBA core at 15-43 GHz), and that the total jet power (≃1044 erg s-1) constitutes only a small fraction (∼10-3) of the Eddington luminosity. The energy distribution of the freshly accelerated radiating electrons required to fit the time-averaged data has a broken power-law form in the energy range 0.3 GeV-10 TeV, with spectral indices 2.2 and 2.7 below and above the break energy of 20 GeV. We argue that such a form is consistent with a scenario in which the bulk of the energy dissipation within the dominant emission zone of Mrk 501 is due to relativistic, proton-mediated shocks. We find that the ultrarelativistic electrons and mildly relativistic protons within the blazar zone, if comparable in number, are in approximate energy equipartition, with their energy dominating the jet magnetic field energy by about two orders of magnitude. © 2011. The American Astronomical Society

Global assessment of dengue virus-specific CD4+ T Cell responses in dengue-endemic areas

10.3389/fimmu.2017.01309Frontiers in Immunology8OCT130

Safety and efficacy of non-steroidal anti-inflammatory drugs to reduce ileus after colorectal surgery

Background: Ileus is common after elective colorectal surgery, and is associated with increased adverse events and prolonged hospital stay. The aim was to assess the role of non-steroidal anti-inflammatory drugs (NSAIDs) for reducing ileus after surgery. Methods: A prospective multicentre cohort study was delivered by an international, student- and trainee-led collaborative group. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The primary outcome was time to gastrointestinal recovery, measured using a composite measure of bowel function and tolerance to oral intake. The impact of NSAIDs was explored using Cox regression analyses, including the results of a centre-specific survey of compliance to enhanced recovery principles. Secondary safety outcomes included anastomotic leak rate and acute kidney injury. Results: A total of 4164 patients were included, with a median age of 68 (i.q.r. 57\u201375) years (54\ub79 per cent men). Some 1153 (27\ub77 per cent) received NSAIDs on postoperative days 1\u20133, of whom 1061 (92\ub70 per cent) received non-selective cyclo-oxygenase inhibitors. After adjustment for baseline differences, the mean time to gastrointestinal recovery did not differ significantly between patients who received NSAIDs and those who did not (4\ub76 versus 4\ub78 days; hazard ratio 1\ub704, 95 per cent c.i. 0\ub796 to 1\ub712; P = 0\ub7360). There were no significant differences in anastomotic leak rate (5\ub74 versus 4\ub76 per cent; P = 0\ub7349) or acute kidney injury (14\ub73 versus 13\ub78 per cent; P = 0\ub7666) between the groups. Significantly fewer patients receiving NSAIDs required strong opioid analgesia (35\ub73 versus 56\ub77 per cent; P < 0\ub7001). Conclusion: NSAIDs did not reduce the time for gastrointestinal recovery after colorectal surgery, but they were safe and associated with reduced postoperative opioid requirement