204 research outputs found

    ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R–mediated apoptosis

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    Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF-related apoptosis–induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor-bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs

    Status of Muon Collider Research and Development and Future Plans

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    The status of the research on muon colliders is discussed and plans are outlined for future theoretical and experimental studies. Besides continued work on the parameters of a 3-4 and 0.5 TeV center-of-mass (CoM) energy collider, many studies are now concentrating on a machine near 0.1 TeV (CoM) that could be a factory for the s-channel production of Higgs particles. We discuss the research on the various components in such muon colliders, starting from the proton accelerator needed to generate pions from a heavy-Z target and proceeding through the phase rotation and decay (π→μνμ\pi \to \mu \nu_{\mu}) channel, muon cooling, acceleration, storage in a collider ring and the collider detector. We also present theoretical and experimental R & D plans for the next several years that should lead to a better understanding of the design and feasibility issues for all of the components. This report is an update of the progress on the R & D since the Feasibility Study of Muon Colliders presented at the Snowmass'96 Workshop [R. B. Palmer, A. Sessler and A. Tollestrup, Proceedings of the 1996 DPF/DPB Summer Study on High-Energy Physics (Stanford Linear Accelerator Center, Menlo Park, CA, 1997)].Comment: 95 pages, 75 figures. Submitted to Physical Review Special Topics, Accelerators and Beam

    Stellar Coronal and Wind Models: Impact on Exoplanets

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    Surface magnetism is believed to be the main driver of coronal heating and stellar wind acceleration. Coronae are believed to be formed by plasma confined in closed magnetic coronal loops of the stars, with winds mainly originating in open magnetic field line regions. In this Chapter, we review some basic properties of stellar coronae and winds and present some existing models. In the last part of this Chapter, we discuss the effects of coronal winds on exoplanets.Comment: Chapter published in the "Handbook of Exoplanets", Editors in Chief: Juan Antonio Belmonte and Hans Deeg, Section Editor: Nuccio Lanza. Springer Reference Work

    Feedback Effects on Low-Mass Star Formation

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    Protostellar feedback, both radiation and bipolar outflows, dramatically affects the fragmentation and mass accretion from star-forming cores. We use ORION, an adaptive mesh refinement gravito-radiation-hydrodynamics code, to simulate the formation of a cluster of low-mass stars, including both radiative transfer and protostellar outflows. We ran four simulations to isolate the individual effects of radiation feedback and outflow feedback as well as the combination of the two. Outflows reduce protostellar masses and accretion rates each by a factor of three and therefore reduce protostellar luminosities by an order of magnitude. Thus, while radiation feedback suppresses fragmentation, outflows render protostellar radiation largely irrelevant for low-mass star formation above a mass scale of 0.05 M_sun. We find initial fragmentation of our cloud at half the global Jeans length, ~ 0.1 pc. With insufficient protostellar radiation to stop it, these 0.1 pc cores fragment repeatedly, forming typically 10 stars each. The accretion rate in these stars scales with mass as predicted from core accretion models that include both thermal and turbulent motions. We find that protostellar outflows do not significantly affect the overall cloud dynamics, in the absence of magnetic fields, due to their small opening angles and poor coupling to the dense gas. The outflows reduce the mass from the cores by 2/3, giving a core to star efficiency ~ 1/3. The simulation with radiation and outflows reproduces the observed protostellar luminosity function. All of the simulations can reproduce observed core mass functions, though they are sensitive to telescope resolution. The simulation with both radiation and outflows reproduces the galactic IMF and the two-point correlation function of the cores observed in rho Oph.Comment: 20 pages, 20 figure

    Addressing the welfare needs of farmed lumpfish: knowledge gaps, challenges and solutions

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    Lumpfish (Cyclopterus lumpus L.) are increasingly being used as cleaner fish to control parasitic sea lice, one of the most important threats to salmon farming. However, lumpfish cannot survive feeding solely on sea lice, and their mortality in salmon net pens can be high, which has welfare, ethical and economic implications. The industry is under increasing pressure to improve the welfare of lumpfish, but little guidance exists on how this can be achieved. We undertook a knowledge gap and prioritisa tion exercise using a Delphi approach with participants from the fish farming sector, animal welfare, academia and regulators to assess consensus on the main challenges and potential solutions for improving lumpfish welfare. Consensus among participants on the utility of 5 behavioural and 12 physical welfare indicators was high (87–89%), reliable (Cronbach's alpha = 0.79, 95CI = 0.69–0.92) and independent of participant background. Participants highlighted fin erosion and body damage as the most use ful and practical operational welfare indicators, and blood parameters and behav ioural indicators as the least practical. Species profiling revealed profound differences between Atlantic salmon and lumpfish in relation to behaviour, habitat preferences, nutritional needs and response to stress, suggesting that applying a common set of welfare standards to both species cohabiting in salmon net-pens may not work well for lumpfish. Our study offers 16 practical solutions for improving the welfare of lumpfish and illustrates the merits of the Delphi approach for achieving consensus among stakeholders on welfare needs, targeting research where is most needed and generating workable solutions.info:eu-repo/semantics/publishedVersio

    Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

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    Background: Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world. Methods and Findings: 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72–1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39–0.64 for women; HR 0.79, CI 0.62–1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12–2.04; p = 0.007). Conclusion: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen

    Impact Factor: outdated artefact or stepping-stone to journal certification?

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    A review of Garfield's journal impact factor and its specific implementation as the Thomson Reuters Impact Factor reveals several weaknesses in this commonly-used indicator of journal standing. Key limitations include the mismatch between citing and cited documents, the deceptive display of three decimals that belies the real precision, and the absence of confidence intervals. These are minor issues that are easily amended and should be corrected, but more substantive improvements are needed. There are indications that the scientific community seeks and needs better certification of journal procedures to improve the quality of published science. Comprehensive certification of editorial and review procedures could help ensure adequate procedures to detect duplicate and fraudulent submissions.Comment: 25 pages, 12 figures, 6 table
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