68 research outputs found

    Spontaneous HIV expression during suppressive ART is associated with the magnitude and function of HIV-specific CD4+ and CD8+ T cells.

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    Spontaneous transcription and translation of HIV can persist during suppressive antiretroviral therapy (ART). The quantity, phenotype, and biological relevance of this spontaneously "active" reservoir remain unclear. Using multiplexed single-cell RNAflow-fluorescence in situ hybridization (FISH), we detect active HIV transcription in 14/18 people with HIV on suppressive ART, with a median of 28/million CD4 <sup>+</sup> T cells. While these cells predominantly exhibit abortive transcription, p24-expressing cells are evident in 39% of participants. Phenotypically diverse, active reservoirs are enriched in central memory T cells and CCR6- and activation-marker-expressing cells. The magnitude of the active reservoir positively correlates with total HIV-specific CD4 <sup>+</sup> and CD8 <sup>+</sup> T cell responses and with multiple HIV-specific T cell clusters identified by unsupervised analysis. These associations are particularly strong with p24-expressing active reservoir cells. Single-cell vDNA sequencing shows that active reservoirs are largely dominated by defective proviruses. Our data suggest that these reservoirs maintain HIV-specific CD4 <sup>+</sup> and CD8 <sup>+</sup> T responses during suppressive ART

    Enhanced detection of antigen-specific T cells by a multiplexed AIM assay.

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    Broadly applicable methods to identify and characterize antigen-specific CD4 <sup>+</sup> and CD8 <sup>+</sup> T cells are key to immunology research, including studies of vaccine responses and immunity to infectious diseases. We developed a multiplexed activation-induced marker (AIM) assay that presents several advantages compared to single pairs of AIMs. The simultaneous measurement of four AIMs (CD69, 4-1BB, OX40, and CD40L) creates six AIM pairs that define CD4 <sup>+</sup> T cell populations with partial and variable overlap. When combined in an AND/OR Boolean gating strategy for analysis, this approach enhances CD4 <sup>+</sup> T cell detection compared to any single AIM pair, while CD8 <sup>+</sup> T cells are dominated by CD69/4-1BB co-expression. Supervised and unsupervised clustering analyses show differential expression of the AIMs in defined T helper lineages and that multiplexing mitigates phenotypic biases. Paired and unpaired comparisons of responses to infections (HIV and cytomegalovirus [CMV]) and vaccination (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) validate the robustness and versatility of the method

    Outcomes of Patients with Asymptomatic Aortic Stenosis Followed Up in Heart Valve Clinics

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    Importance: The natural history and the management of patients with asymptomatic aortic stenosis (AS) have not been fully examined in the current era. Objective: To determine the clinical outcomes of patients with asymptomatic AS using data from the Heart Valve Clinic International Database. Design, Setting, and Participants: This registry was assembled by merging data from prospectively gathered institutional databases from 10 heart valve clinics in Europe, Canada, and the United States. Asymptomatic patients with an aortic valve area of 1.5 cm2 or less and preserved left ventricular ejection fraction (LVEF) greater than 50% at entry were considered for the present analysis. Data were collected from January 2001 to December 2014, and data were analyzed from January 2017 to July 2018. Main Outcomes and Measures: Natural history, need for aortic valve replacement (AVR), and survival of asymptomatic patients with moderate or severe AS at entry followed up in a heart valve clinic. Indications for AVR were based on current guideline recommendations. Results: Of the 1375 patients included in this analysis, 834 (60.7%) were male, and the mean (SD) age was 71 (13) years. A total of 861 patients (62.6%) had severe AS (aortic valve area less than 1.0 cm2). The mean (SD) overall survival during medical management (mean [SD] follow up, 27 [24] months) was 93% (1%), 86% (2%), and 75% (4%) at 2, 4, and 8 years, respectively. A total of 104 patients (7.6%) died under observation, including 57 patients (54.8%) from cardiovascular causes. The crude rate of sudden death was 0.65% over the duration of the study. A total of 542 patients (39.4%) underwent AVR, including 388 patients (71.6%) with severe AS at study entry and 154 (28.4%) with moderate AS at entry who progressed to severe AS. Those with severe AS at entry who underwent AVR did so at a mean (SD) of 14.4 (16.6) months and a median of 8.7 months. The mean (SD) 2-year and 4-year AVR-free survival rates for asymptomatic patients with severe AS at baseline were 54% (2%) and 32% (3%), respectively. In those undergoing AVR, the 30-day postprocedural mortality was 0.9%. In patients with severe AS at entry, peak aortic jet velocity (greater than 5 m/s) and LVEF (less than 60%) were associated with all-cause and cardiovascular mortality without AVR; these factors were also associated with postprocedural mortality in those patients with severe AS at baseline who underwent AVR (surgical AVR in 310 patients; transcatheter AVR in 78 patients). Conclusions and Relevance: In patients with asymptomatic AS followed up in heart valve centers, the risk of sudden death is low, and rates of overall survival are similar to those reported from previous series. Patients with severe AS at baseline and peak aortic jet velocity of 5.0 m/s or greater or LVEF less than 60% have increased risks of all-cause and cardiovascular mortality even after AVR. The potential benefit of early intervention should be considered in these high-risk patients

    The present and future status of heavy neutral leptons

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    The existence of nonzero neutrino masses points to the likely existence of multiple Standard Model neutral fermions. When such states are heavy enough that they cannot be produced in oscillations, they are referred to as heavy neutral leptons (HNLs). In this white paper, we discuss the present experimental status of HNLs including colliders, beta decay, accelerators, as well as astrophysical and cosmological impacts. We discuss the importance of continuing to search for HNLs, and its potential impact on our understanding of key fundamental questions, and additionally we outline the future prospects for next-generation future experiments or upcoming accelerator run scenarios

    Feebly-interacting particles: FIPs 2022 Workshop Report

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    Particle physics today faces the challenge of explaining the mystery of dark matter, the origin of matter over anti-matter in the Universe, the origin of the neutrino masses, the apparent fine-tuning of the electro-weak scale, and many other aspects of fundamental physics. Perhaps the most striking frontier to emerge in the search for answers involves new physics at mass scales comparable to familiar matter, below the GeV-scale, or even radically below, down to sub-eV scales, and with very feeble interaction strength. New theoretical ideas to address dark matter and other fundamental questions predict such feebly interacting particles (FIPs) at these scales, and indeed, existing data provide numerous hints for such possibility. A vibrant experimental program to discover such physics is under way, guided by a systematic theoretical approach firmly grounded on the underlying principles of the Standard Model. This document represents the report of the FIPs 2022 workshop, held at CERN between the 17 and 21 October 2022 and aims to give an overview of these efforts, their motivations, and the decadal goals that animate the community involved in the search for FIPs

    Proteome Profiling in Murine Models of Multiple Sclerosis: Identification of Stage Specific Markers and Culprits for Tissue Damage

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    The identification of new biomarkers is of high interest for the prediction of the disease course and also for the identification of pathomechanisms in multiple sclerosis (MS). To specify markers of the chronic disease phase, we performed proteome profiling during the later phase of myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE, day 35 after immunization) as a model disease mimicking many aspects of secondary progressive MS. In comparison to healthy controls, high resolution 2 dimensional gel electrophoresis revealed a number of regulated proteins, among them glial fibrilary acidic protein (GFAP). Phase specific up-regulation of GFAP in chronic EAE was confirmed by western blotting and immunohistochemistry. Protein levels of GFAP were also increased in the cerebrospinal fluid of MS patients with specificity for the secondary progressive disease phase. In a next step, proteome profiling of an EAE model with enhanced degenerative mechanisms revealed regulation of alpha-internexin, syntaxin binding protein 1, annexin V and glutamate decarboxylase in the ciliary neurotrophic factor (CNTF) knockout mouse. The identification of these proteins implicate an increased apoptosis and enhanced axonal disintegration and correlate well the described pattern of tissue injury in CNTF −/− mice which involve oligodendrocyte (OL) apoptosis and axonal injury

    Feebly Interacting Particles: FIPs 2022 workshop report

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    Particle physics today faces the challenge of explaining the mystery of dark matter, the origin of matter over anti-matter in the Universe, the origin of the neutrino masses, the apparent fine-tuning of the electro-weak scale, and many other aspects of fundamental physics. Perhaps the most striking frontier to emerge in the search for answers involves new physics at mass scales comparable to familiar matter, below the GeV-scale, or even radically below, down to sub-eV scales, and with very feeble interaction strength. New theoretical ideas to address dark matter and other fundamental questions predict such feebly interacting particles (FIPs) at these scales, and indeed, existing data provide numerous hints for such possibility. A vibrant experimental program to discover such physics is under way, guided by a systematic theoretical approach firmly grounded on the underlying principles of the Standard Model. This document represents the report of the FIPs 2022 workshop, held at CERN between the 17 and 21 October 2022 and aims to give an overview of these efforts, their motivations, and the decadal goals that animate the community involved in the search for FIPs

    SND@LHC: The Scattering and Neutrino Detector at the LHC

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    SND@LHC is a compact and stand-alone experiment designed to perform measurements with neutrinos produced at the LHC in the pseudo-rapidity region of 7.2<η<8.4{7.2 < \eta < 8.4}. The experiment is located 480 m downstream of the ATLAS interaction point, in the TI18 tunnel. The detector is composed of a hybrid system based on an 830 kg target made of tungsten plates, interleaved with emulsion and electronic trackers, also acting as an electromagnetic calorimeter, and followed by a hadronic calorimeter and a muon identification system. The detector is able to distinguish interactions of all three neutrino flavours, which allows probing the physics of heavy flavour production at the LHC in the very forward region. This region is of particular interest for future circular colliders and for very high energy astrophysical neutrino experiments. The detector is also able to search for the scattering of Feebly Interacting Particles. In its first phase, the detector will operate throughout LHC Run 3 and collect a total of 250 fb1\text{fb}^{-1}

    The SHiP experiment at the proposed CERN SPS Beam Dump Facility

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    The Search for Hidden Particles (SHiP) Collaboration has proposed a general-purpose experimental facility operating in beam-dump mode at the CERN SPS accelerator to search for light, feebly interacting particles. In the baseline configuration, the SHiP experiment incorporates two complementary detectors. The upstream detector is designed for recoil signatures of light dark matter (LDM) scattering and for neutrino physics, in particular with tau neutrinos. It consists of a spectrometer magnet housing a layered detector system with high-density LDM/neutrino target plates, emulsion-film technology and electronic high-precision tracking. The total detector target mass amounts to about eight tonnes. The downstream detector system aims at measuring visible decays of feebly interacting particles to both fully reconstructed final states and to partially reconstructed final states with neutrinos, in a nearly background-free environment. The detector consists of a 50 m long decay volume under vacuum followed by a spectrometer and particle identification system with a rectangular acceptance of 5 m in width and 10 m in height. Using the high-intensity beam of 400 GeV protons, the experiment aims at profiting from the 4 x 10(19) protons per year that are currently unexploited at the SPS, over a period of 5-10 years. This allows probing dark photons, dark scalars and pseudo-scalars, and heavy neutral leptons with GeV-scale masses in the direct searches at sensitivities that largely exceed those of existing and projected experiments. The sensitivity to light dark matter through scattering reaches well below the dark matter relic density limits in the range from a few MeV/c(2) up to 100 MeV-scale masses, and it will be possible to study tau neutrino interactions with unprecedented statistics. This paper describes the SHiP experiment baseline setup and the detector systems, together with performance results from prototypes in test beams, as it was prepared for the 2020 Update of the European Strategy for Particle Physics. The expected detector performance from simulation is summarised at the end

    Feebly-interacting particles: FIPs 2022 workshop report

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    Particle physics today faces the challenge of explaining the mystery of dark matter, the origin of matter over anti-matter in the Universe, the origin of the neutrino masses, the apparent fine-tuning of the electro-weak scale, and many other aspects of fundamental physics. Perhaps the most striking frontier to emerge in the search for answers involves new physics at mass scales comparable to familiar matter, below the GeV-scale, or even radically below, down to sub-eV scales, and with very feeble interaction strength. New theoretical ideas to address dark matter and other fundamental questions predict such feebly interacting particles (FIPs) at these scales, and indeed, existing data provide numerous hints for such possibility. A vibrant experimental program to discover such physics is under way, guided by a systematic theoretical approach firmly grounded on the underlying principles of the Standard Model. This document represents the report of the FIPs 2022 workshop, held at CERN between the 17 and 21 October 2022 and aims to give an overview of these efforts, their motivations, and the decadal goals that animate the community involved in the search for FIPs
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