68 research outputs found

    α-Synuclein is a Novel Microtubule Dynamase.

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    α-Synuclein is a presynaptic protein associated to Parkinson's disease, which is unstructured when free in the cytoplasm and adopts α helical conformation when bound to vesicles. After decades of intense studies, α-Synuclein physiology is still difficult to clear up due to its interaction with multiple partners and its involvement in a pletora of neuronal functions. Here, we looked at the remarkably neglected interplay between α-Synuclein and microtubules, which potentially impacts on synaptic functionality. In order to identify the mechanisms underlying these actions, we investigated the interaction between purified α-Synuclein and tubulin. We demonstrated that α-Synuclein binds to microtubules and tubulin α2β2 tetramer; the latter interaction inducing the formation of helical segment(s) in the α-Synuclein polypeptide. This structural change seems to enable α-Synuclein to promote microtubule nucleation and to enhance microtubule growth rate and catastrophe frequency, both in vitro and in cell. We also showed that Parkinson's disease-linked α-Synuclein variants do not undergo tubulin-induced folding and cause tubulin aggregation rather than polymerization. Our data enable us to propose α-Synuclein as a novel, foldable, microtubule-dynamase, which influences microtubule organisation through its binding to tubulin and its regulating effects on microtubule nucleation and dynamics

    AHR2 Mutant Reveals Functional Diversity of Aryl Hydrocarbon Receptors in Zebrafish

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    The aryl hydrocarbon receptor (AHR) is well known for mediating the toxic effects of TCDD and has been a subject of intense research for over 30 years. Current investigations continue to uncover its endogenous and regulatory roles in a wide variety of cellular and molecular signaling processes. A zebrafish line with a mutation in ahr2 (ahr2hu3335), encoding the AHR paralogue responsible for mediating TCDD toxicity in zebrafish, was developed via Targeting Induced Local Lesions IN Genomes (TILLING) and predicted to express a non-functional AHR2 protein. We characterized AHR activity in the mutant line using TCDD and leflunomide as toxicological probes to investigate function, ligand binding and CYP1A induction patterns of paralogues AHR2, AHR1A and AHR1B. By evaluating TCDD-induced developmental toxicity, mRNA expression changes and CYP1A protein in the AHR2 mutant line, we determined that ahr2hu3335 zebrafish are functionally null. In silico modeling predicted differential binding of TCDD and leflunomide to the AHR paralogues. AHR1A is considered a non-functional pseudogene as it does not bind TCCD or mediate in vivo TCDD toxicity. Homology modeling, however, predicted a ligand binding conformation of AHR1A with leflunomide. AHR1A-dependent CYP1A immunohistochemical expression in the liver provided in vivo confirmation of the in silico docking studies. The ahr2hu3335 functional knockout line expands the experimental power of zebrafish to unravel the role of the AHR during development, as well as highlights potential activity of the other AHR paralogues in ligand-specific toxicological responses

    The Forward Physics Facility at the High-Luminosity LHC

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    Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

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    A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

    First neutrino interaction candidates at the LHC

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    FASERν\nu at the CERN Large Hadron Collider (LHC) is designed to directly detect collider neutrinos for the first time and study their cross sections at TeV energies, where no such measurements currently exist. In 2018, a pilot detector employing emulsion films was installed in the far-forward region of ATLAS, 480 m from the interaction point, and collected 12.2 fb1^{-1} of proton-proton collision data at a center-of-mass energy of 13 TeV. We describe the analysis of this pilot run data and the observation of the first neutrino interaction candidates at the LHC. This milestone paves the way for high-energy neutrino measurements at current and future colliders.Comment: Auxiliary materials are available at https://faser.web.cern.ch/fasernu-first-neutrino-interaction-candidate

    The FASER Detector

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    FASER, the ForwArd Search ExpeRiment, is an experiment dedicated to searching for light, extremely weakly-interacting particles at CERN's Large Hadron Collider (LHC). Such particles may be produced in the very forward direction of the LHC's high-energy collisions and then decay to visible particles inside the FASER detector, which is placed 480 m downstream of the ATLAS interaction point, aligned with the beam collisions axis. FASER also includes a sub-detector, FASERν\nu, designed to detect neutrinos produced in the LHC collisions and to study their properties. In this paper, each component of the FASER detector is described in detail, as well as the installation of the experiment system and its commissioning using cosmic-rays collected in September 2021 and during the LHC pilot beam test carried out in October 2021. FASER will start taking LHC collision data in 2022, and will run throughout LHC Run 3

    Measurement of jet fragmentation in Pb+Pb and pppp collisions at sNN=2.76\sqrt{{s_\mathrm{NN}}} = 2.76 TeV with the ATLAS detector at the LHC