Enzymatic Blockade of the Ubiquitin-Proteasome Pathway

Ubiquitin-dependent processes control much of cellular physiology. We show that expression of a highly active, Epstein-Barr virus-derived deubiquitylating enzyme (EBV-DUB) blocks proteasomal degradation of cytosolic and ER-derived proteins by preemptive removal of ubiquitin from proteasome substrates, a treatment less toxic than the use of proteasome inhibitors. Recognition of misfolded proteins in the ER lumen, their dislocation to the cytosol, and degradation are usually tightly coupled but can be uncoupled by the EBV-DUB: a misfolded glycoprotein that originates in the ER accumulates in association with cytosolic chaperones as a deglycosylated intermediate. Our data underscore the necessity of a DUB activity for completion of the dislocation reaction and provide a new means of inhibition of proteasomal proteolysis with reduced cytotoxicity.National Institutes of Health (U.S.)EMBO (long term Fellowship 2008-379)Boehringer Ingelheim Fond

Release of Enzymatically Active Deubiquitinating Enzymes upon Reversible Capture by Disulfide Ubiquitin Reagents

Chemical Immunolog

Impact of grazing management on hibernating caterpillars of the butterfly melitaea cinxia in calcareous grasslands

Contains fulltext : 103431.pdf (publisher's version ) (Open Access)12 p

The XENONnT dark matter experiment.

The multi-staged XENON program at INFN Laboratori Nazionali del Gran Sasso aims to detect dark matter with two-phase liquid xenon time projection chambers of increasing size and sensitivity. The XENONnT experiment is the latest detector in the program, planned to be an upgrade of its predecessor XENON1T. It features an active target of 5.9 tonnes of cryogenic liquid xenon (8.5 tonnes total mass in cryostat). The experiment is expected to extend the sensitivity to WIMP dark matter by more than an order of magnitude compared to XENON1T, thanks to the larger active mass and the significantly reduced background, improved by novel systems such as a radon removal plant and a neutron veto. This article describes the XENONnT experiment and its sub-systems in detail and reports on the detector performance during the first science run

HIV-1 Vpu Neutralizes the Antiviral Factor Tetherin/BST-2 by Binding It and Directing Its Beta-TrCP2-Dependent Degradation

Host cells impose a broad range of obstacles to the replication of retroviruses. Tetherin (also known as CD317, BST-2 or HM1.24) impedes viral release by retaining newly budded HIV-1 virions on the surface of cells. HIV-1 Vpu efficiently counteracts this restriction. Here, we show that HIV-1 Vpu induces the depletion of tetherin from cells. We demonstrate that this phenomenon correlates with the ability of Vpu to counteract the antiviral activity of both overexpressed and interferon-induced endogenous tetherin. In addition, we show that Vpu co-immunoprecipitates with tetherin and β-TrCP in a tri-molecular complex. This interaction leads to Vpu-mediated proteasomal degradation of tetherin in a β-TrCP2-dependent manner. Accordingly, in conditions where Vpu-β-TrCP2-tetherin interplay was not operative, including cells stably knocked down for β-TrCP2 expression or cells expressing a dominant negative form of β-TrCP, the ability of Vpu to antagonize the antiviral activity of tetherin was severely impaired. Nevertheless, tetherin degradation did not account for the totality of Vpu-mediated counteraction against the antiviral factor, as binding of Vpu to tetherin was sufficient for a partial relief of the restriction. Finally, we show that the mechanism used by Vpu to induce tetherin depletion implicates the cellular ER-associated degradation (ERAD) pathway, which mediates the dislocation of ER membrane proteins into the cytosol for subsequent proteasomal degradation. In conclusion, we show that Vpu interacts with tetherin to direct its β-TrCP2-dependent proteasomal degradation, thereby alleviating the blockade to the release of infectious virions. Identification of tetherin binding to Vpu provides a potential novel target for the development of drugs aimed at inhibiting HIV-1 replication

First Dark Matter Search with Nuclear Recoils from the XENONnT Experiment

We report on the first search for nuclear recoils from dark matter in the form of weakly interacting massive particles (WIMPs) with the XENONnT experiment, which is based on a two-phase time projection chamber with a sensitive liquid xenon mass of 5.9 ton. During the (1.09±0.03)  ton yr exposure used for this search, the intrinsic $^{85}$Kr and $^{222}$Rn concentrations in the liquid target are reduced to unprecedentedly low levels, giving an electronic recoil background rate of (15.8±1.3)  events/ton yr keV in the region of interest. A blind analysis of nuclear recoil events with energies between 3.3 and 60.5 keV finds no significant excess. This leads to a minimum upper limit on the spin-independent WIMP-nucleon cross section of 2.58×10$^{47}$  cm$^2$ for a WIMP mass of 28  GeV/c$^2$ at 90% confidence level. Limits for spin-dependent interactions are also provided. Both the limit and the sensitivity for the full range of WIMP masses analyzed here improve on previous results obtained with the XENON1T experiment for the same exposure

The XENONnT Dark Matter Experiment

The multi-staged XENON program at INFN Laboratori Nazionali del Gran Sasso aims to detect dark matter with two-phase liquid xenon time projection chambers of increasing size and sensitivity. The XENONnT experiment is the latest detector in the program, planned to be an upgrade of its predecessor XENON1T. It features an active target of 5.9 tonnes of cryogenic liquid xenon (8.5 tonnes total mass in cryostat). The experiment is expected to extend the sensitivity to WIMP dark matter by more than an order of magnitude compared to XENON1T, thanks to the larger active mass and the significantly reduced background, improved by novel systems such as a radon removal plant and a neutron veto. This article describes the XENONnT experiment and its sub-systems in detail and reports on the detector performance during the first science run.Comment: 32 pages, 19 figure

The Triggerless Data Acquisition System of the XENONnT Experiment

The XENONnT detector uses the latest and largest liquid xenon-based timeprojection chamber (TPC) operated by the XENON Collaboration, aimed atdetecting Weakly Interacting Massive Particles and conducting other rare eventsearches. The XENONnT data acquisition (DAQ) system constitutes an upgraded andexpanded version of the XENON1T DAQ system. For its operation, it reliespredominantly on commercially available hardware accompanied by open-source andcustom-developed software. The three constituent subsystems of the XENONnTdetector, the TPC (main detector), muon veto, and the newly introduced neutronveto, are integrated into a single DAQ, and can be operated both independentlyand as a unified system. In total, the DAQ digitizes the signals of 698photomultiplier tubes (PMTs), of which 253 from the top PMT array of the TPCare digitized twice, at $\times10$ and $\times0.5$ gain. The DAQ for the mostpart is a triggerless system, reading out and storing every signal that exceedsthe digitization thresholds. Custom-developed software is used to process theacquired data, making it available within $\mathcal{O}\left(10\text{ s}\right)$for live data quality monitoring and online analyses. The entire system withall the three subsystems was successfully commissioned and has been operatingcontinuously, comfortably withstanding readout rates that exceed $\sim500$ MB/sduring calibration. Livetime during normal operation exceeds $99\%$ and is$\sim90\%$ during most high-rate calibrations. The combined DAQ system hascollected more than 2 PB of both calibration and science data during thecommissioning of XENONnT and the first science run.<br

Searching for Heavy Dark Matter near the Planck Mass with XENON1T

Multiple viable theoretical models predict heavy dark matter particles with a mass close to the Planck mass, a range relatively unexplored by current experimental measurements. We use 219.4 days of data collected with the XENON1T experiment to conduct a blind search for signals from Multiply-Interacting Massive Particles (MIMPs). Their unique track signature allows a targeted analysis with only 0.05 expected background events from muons. Following unblinding, we observe no signal candidate events. This work places strong constraints on spin-independent interactions of dark matter particles with a mass between 1$\times$10$^{12}\,$GeV/c$^2$ and 2$\times$10$^{17}\,$GeV/c$^2$. In addition, we present the first exclusion limits on spin-dependent MIMP-neutron and MIMP-proton cross-sections for dark matter particles with masses close to the Planck scale.Comment: 7 pages, 6 figure

Design and performance of the field cage for the XENONnT experiment

The precision in reconstructing events detected in a dual-phase time projection chamber depends on an homogeneous and well understood electric field within the liquid target. In the XENONnT TPC the field homogeneity is achieved through a double-array field cage, consisting of two nested arrays of field shaping rings connected by an easily accessible resistor chain. Rather than being connected to the gate electrode, the topmost field shaping ring is independently biased, adding a degree of freedom to tune the electric field during operation. Two-dimensional finite element simulations were used to optimize the field cage, as well as its operation. Simulation results were compared to $^{83m} Kr$ calibration data. This comparison indicates an accumulation of charge on the panels of the TPC which is constant over time, as no evolution of the reconstructed position distribution of events is observed. The simulated electric field was then used to correct the charge signal for the field dependence of the charge yield. This correction resolves the inconsistent measurement of the drift electron lifetime when using different calibrations sources and different field cage tuning voltages