Combination immunotherapy with anti-PD-L1 antibody and depletion of regulatory T cells during acute viral infections results in improved virus control but lethal immunopathology

Combination immunotherapy (CIT) is currently applied as a treatment for different cancers and is proposed as a cure strategy for chronic viral infections. Whether such therapies are efficient during an acute infection remains elusive. To address this, inhibitory receptors were blocked and regulatory T cells depleted in acutely Friend retrovirus-infected mice. CIT resulted in a dramatic expansion of cytotoxic CD4+ and CD8+ T cells and a subsequent reduction in viral loads. Despite limited viral replication, mice developed fatal immunopathology after CIT. The pathology was most severe in the gastrointestinal tract and was mediated by granzyme B producing CD4+ and CD8+ T cells. A similar post-CIT pathology during acute Influenza virus infection of mice was observed, which could be prevented by vaccination. Melanoma patients who developed immune-related adverse events under immune checkpoint CIT also presented with expanded granzyme-expressing CD4+ and CD8+ T cell populations. Our data suggest that acute infections may induce immunopathology in patients treated with CIT, and that effective measures for infection prevention should be applied

An analysis of interplanetary solar radio emissions associated with a coronal mass ejection

Coronal mass ejections (CMEs) are large-scale eruptions of magnetized plasma that may cause severe geomagnetic storms if Earth-directed. Here we report a rare instance with comprehensive in situ and remote sensing observa- tions of a CME combining white-light, radio, and plasma measurements from four different vantage points. For the first time, we have successfully applied a radio direction-finding technique to an interplanetary type II burst detected by two identical widely separated radio receivers. The derived locations of the type II and type III bursts are in general agreement with the white light CME recon- struction. We find that the radio emission arises from the flanks of the CME, and are most likely associated with the CME-driven shock. Our work demon- strates the complementarity between radio triangulation and 3D reconstruction techniques for space weather applications

Safety and Feasibility of Long-term Intravenous Sodium Nitrite Infusion in Healthy Volunteers

BACKGROUND: Infusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion. METHODOLOGY: Healthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate. Twelve subjects (5 males, 7 females; mean age, 38.8±9.2 years (range, 21-56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 µg/kg/hr; maximal dose of 533.8 µg/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed. FINDINGS: The maximal tolerated dose for intravenous infusion of sodium nitrite was 267 µg/kg/hr. Dose limiting toxicity occurred at 446 µg/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood. CONCLUSION: Sodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov; NCT00103025

DNA content of a functioning chicken kinetochore

© The Author(s) 2014. In order to understand the three-dimensional structure of the functional kinetochore in vertebrates, we require a complete list and stoichiometry for the protein components of the kinetochore, which can be provided by genetic and proteomic experiments. We also need to know how the chromatin-containing CENP-A, which makes up the structural foundation for the kinetochore, is folded, and how much of that DNA is involved in assembling the kinetochore. In this MS, we demonstrate that functioning metaphase kinetochores in chicken DT40 cells contain roughly 50 kb of DNA, an amount that corresponds extremely closely to the length of chromosomal DNA associated with CENP-A in ChIP-seq experiments. Thus, during kinetochore assembly, CENP-A chromatin is compacted into the inner kinetochore plate without including significant amounts of flanking pericentromeric heterochromatin. © 2014 The Author(s).Wellcome Trust [grant number 073915]; Wellcome Trust Centre for Cell Biology (core grant numbers 077707 and 092076); Darwin Trust of Edinburg

The STAR Silicon Strip Detector (SSD)

The STAR Silicon Strip Detector (SSD) completes the three layers of the Silicon Vertex Tracker (SVT) to make an inner tracking system located inside the Time Projection Chamber (TPC). This additional fourth layer provides two dimensional hit position and energy loss measurements for charged particles, improving the extrapolation of TPC tracks through SVT hits. To match the high multiplicity of central Au+Au collisions at RHIC the double sided silicon strip technology was chosen which makes the SSD a half million channels detector. Dedicated electronics have been designed for both readout and control. Also a novel technique of bonding, the Tape Automated Bonding (TAB), was used to fullfill the large number of bounds to be done. All aspects of the SSD are shortly described here and test performances of produced detection modules as well as simulated results on hit reconstruction are given.Comment: 11 pages, 8 figures, 1 tabl

A protocol for manual segmentation of medial temporal lobe subregions in 7 Tesla MRI

Recent advances in MRI and increasing knowledge on the characterization and anatomical variability of medial temporal lobe (MTL) anatomy have paved the way for more specific subdivisions of the MTL in humans. In addition, recent studies suggest that early changes in many neurodegenerative and neuropsychiatric diseases are better detected in smaller subregions of the MTL rather than with whole structure analyses. Here, we developed a new protocol using 7 Tesla (T) MRI incorporating novel anatomical findings for the manual segmentation of entorhinal cortex (ErC), perirhinal cortex (PrC; divided into area 35 and 36), parahippocampal cortex (PhC), and hippocampus; which includes the subfields subiculum (Sub), CA1, CA2, as well as CA3 and dentate gyrus (DG) which are separated by the endfolial pathway covering most of the long axis of the hippocampus. We provide detailed instructions alongside slice-by-slice segmentations to ease learning for the untrained but also more experienced raters. Twenty-two subjects were scanned (19–32 yrs, mean age = 26 years, 12 females) with a turbo spin echo (TSE) T2-weighted MRI sequence with high-resolution oblique coronal slices oriented orthogonal to the long axis of the hippocampus (in-plane resolution 0.44 × 0.44 mm2) and 1.0 mm slice thickness. The scans were manually delineated by two experienced raters, to assess intra- and inter-rater reliability. The Dice Similarity Index (DSI) was above 0.78 for all regions and the Intraclass Correlation Coefficients (ICC) were between 0.76 to 0.99 both for intra- and inter-rater reliability. In conclusion, this study presents a fine-grained and comprehensive segmentation protocol for MTL structures at 7 T MRI that closely follows recent knowledge from anatomical studies. More specific subdivisions (e.g. area 35 and 36 in PrC, and the separation of DG and CA3) may pave the way for more precise delineations thereby enabling the detection of early volumetric changes in dementia and neuropsychiatric diseases

Phase-space dependence of particle-ratio fluctuations in Pb+Pb collisions from 20A to 158A GeV beam energy

A novel approach, the identity method, was used for particle identification and the study of fluctuations of particle yield ratios in Pb+Pb collisions at the CERN Super Proton Synchrotron (SPS). This procedure allows to unfold the moments of the unknown multiplicity distributions of protons (p), kaons (K), pions ($\pi$) and electrons (e). Using these moments the excitation function of the fluctuation measure $\nu_{\text{\text{dyn}}}$[A,B] was measured, with A and B denoting different particle types. The obtained energy dependence of $\nu_{\text{dyn}}$ agrees with previously published NA49 results on the related measure $\sigma_{\text{dyn}}$. Moreover, $\nu_{\text{dyn}}$ was found to depend on the phase space coverage for [K,p] and [K,$\pi$] pairs. This feature most likely explains the reported differences between measurements of NA49 and those of STAR in central Au+Au collisions

Energy dependence of kaon-to-proton ratio fluctuations in central Pb+Pb collisions from sNN\sqrt{s_{NN}} = 6.3 to 17.3 GeV

Kaons and protons carry large parts of two conserved quantities, strangeness and baryon number. It is argued that their correlation and thus also fluctuations are sensitive to conditions prevailing at the anticipated parton-hadron phase boundary. Fluctuations of the $(\mathrm{K}^+ + \mathrm{K}^-)/(\mathrm{p}+\bar{\mathrm{p}})$ and $\mathrm{K}^+/\mathrm{p}$ ratios have been measured for the first time by NA49 in central Pb+Pb collisions at 5 SPS energies between $\sqrt{s_{NN}}$= 6.3 GeV and 17.3 GeV. Both ratios exhibit a change of sign in $\sigma_{\mathrm{dyn}}$, a measure of non-statistical fluctuations, around $\sqrt{s_{NN}}$ = 8 GeV. Below this energy, $\sigma_{\mathrm{dyn}}$ is positive, indicating higher fluctuation compared to a mixed event background sample, while for higher energies, $\sigma_{\mathrm{dyn}}$ is negative, indicating correlated emission of kaons and protons. The results are compared to UrQMD calculations which which give a good description at the higher SPS energies, but fail to reproduce the transition to positive values.Comment: 5 pages, 4 figure