628 research outputs found

    The role of the PQC system in managing misfolded protein in motoneuronal and muscular models of ALS and SBMA

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    Motorneuronal diseases are fatal neurodegenerative diseases which include spinobulbar muscular atrophy (SBMA). Recent studies have demonstrated that both motorneuron and muscle cells are directly affected in SBMA patients. SBMA is caused by a poliglutammine stretch in the N-terminal region of the androgen receptor (AR) protein. In presence of testosterone ARpolyQ lose the proper conformation, misfolds and becomes toxic to cells. The protein quality control (PQC) system is in charge of protein homeostasis. The chaperone system maintains proteins in the proper conformation; if it fails misfolded proteins are directed to the degradative systems: the ubiquitin proteasome system (UPS) and the autophagy. We have already demonstrated that autophagy stimulation reduces protein aggregation in motorneuronal models of SBMA. Here we studied the involvement of the PQC system in the muscular response to misfolded toxic proteins and in the removal of aggregates, hallmark of the disease. We tried to potentiate the autophagic response with trehalose in muscle C2C12 cells stably expressing AR with a stretch of 100 glutamine (C2C12_ARQ100). By filter retardation assay (FRA) we observed that ARpolyQ aggregation was reverted by trehalose. By RTq-PCR analysis we found that trehalose increased the expression of the small heat shock protein B8 a molecular chaperone involved in the autophagic machinery. Overexpression of HspB8 in C2C12_ARQ100, interestingly, caused a significative reduction of ARpolyQ aggregation in FRA. We extend our findings to a SBMA-related motorneuronal disease: the amyotrophic lateral sclerosis (ALS). As model of sporadic ALS we studied the TAR-DNA-Binding Protein of 43 kDa (TDP43) and its truncated form TDP43-25 that aggregates in the cytoplasm. Trehalose treatment of muscle C2C12 cells expressing both TDP43 and TDP43-25 caused no aggregate reduction. In conclusion we demonstrate that the enhancement of autophagy is a possible therapeutical strategy for treating SBMA; in the case of sporadic ALS other degradative pathways should to be investigated as autophagic facilitation can not prevent aggregate formation. GRANTS: Regione Lombardia; AFM-TELETHON, FRANCE; FONDAZIONE TELETHON, ITALY; FONDAZIONE CARIPLO, ITALY; FONDAZIONE ARISLA, ITALY; Ministero della Sanit\ue0, ITALY

    The contribution of protein quality control in the pathogenesis of SBMA

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    Spinal and bulbar muscular atrophy (SBMA) is a motoneuronal diseases caused by an elogated polyglutamine (polyQ) tract in the androgen receptor (AR). The intracellular accumulation of ARpolyQ, induced by the ligand testosterone, altered the protein quality control system (PQC) and impaired the protective mechanisms deputed to refolding and clearance of misfolded proteins. Emerging evidence reveal that ARpolyQ toxicity is not related only to motoneuron degeneration but also to skeletal muscle damage. Using SBMA knock-in mice (113Q SBMA mice), we analysed the role of PQC in skeletal muscle. All mice were analysed both at a pre-symptomatic stage (8 weeks) and at symptomatic stage (24 weeks). At symptomatic stages, the skeletal muscle of SBMA mice showed an increased expression of muscular markers (MYOG, TGF-beta1, AchR) suggesting that there is atrophy accompanied by denervation. In this condition, we have analysed the transcriptional regulation of several proteins involved in the PQC system. We found no variations of the autophagic master key regulator TFEB expression, while all autophagic markers analysed were specifically induced in skeletal muscle of symptomatic tg SBMA male mice (p62, LC3 Beclin-1 ATG10). Moreover, we have analysed the expression of HSPB8, a pro-autophagic chaperone, and of the co-chaperones BAG3 and BAG1, involved in the autophagic and proteasomal removal of the misfolded proteins, respectively. We found that HSPB8, BAG1 and BAG3 were transcriptionally up-regulated in symptomatic tg SBMA male mice. Moreover, the ratio BAG3:BAG1, index of which PQC degradative pathways is preferred to clear misfolded proteins, was increased in favor of the BAG3. Collectively, these data might suggest that in the skeletal muscle of SBMA mice autophagy is highly activated and the data might elucidate how muscle responds to ARpolyQ toxicity. GRANTS: Fondazione AriSLA; Fondazione Cariplo; AFM Telethon France; Regione Lombardia; UNIMI; Telethon Italy

    Search for composite and exotic fermions at LEP 2

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    A search for unstable heavy fermions with the DELPHI detector at LEP is reported. Sequential and non-canonical leptons, as well as excited leptons and quarks, are considered. The data analysed correspond to an integrated luminosity of about 48 pb^{-1} at an e^+e^- centre-of-mass energy of 183 GeV and about 20 pb^{-1} equally shared between the centre-of-mass energies of 172 GeV and 161 GeV. The search for pair-produced new leptons establishes 95% confidence level mass limits in the region between 70 GeV/c^2 and 90 GeV/c^2, depending on the channel. The search for singly produced excited leptons and quarks establishes upper limits on the ratio of the coupling of the excited fermio

    Search for charginos in e+e- interactions at sqrt(s) = 189 GeV

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    An update of the searches for charginos and gravitinos is presented, based on a data sample corresponding to the 158 pb^{-1} recorded by the DELPHI detector in 1998, at a centre-of-mass energy of 189 GeV. No evidence for a signal was found. The lower mass limits are 4-5 GeV/c^2 higher than those obtained at a centre-of-mass energy of 183 GeV. The (\mu,M_2) MSSM domain excluded by combining the chargino searches with neutralino searches at the Z resonance implies a limit on the mass of the lightest neutralino which, for a heavy sneutrino, is constrained to be above 31.0 GeV/c^2 for tan(beta) \geq 1.Comment: 22 pages, 8 figure

    Search for lightest neutralino and stau pair production in light gravitino scenarios with stau NLSP

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    Promptly decaying lightest neutralinos and long-lived staus are searched for in the context of light gravitino scenarios. It is assumed that the stau is the next to lightest supersymmetric particle (NLSP) and that the lightest neutralino is the next to NLSP (NNLSP). Data collected with the Delphi detector at centre-of-mass energies from 161 to 183 \GeV are analysed. No evidence of the production of these particles is found. Hence, lower mass limits for both kinds of particles are set at 95% C.L.. The mass of gaugino-like neutralinos is found to be greater than 71.5 GeV/c^2. In the search for long-lived stau, masses less than 70.0 to 77.5 \GeVcc are excluded for gravitino masses from 10 to 150 \eVcc . Combining this search with the searches for stable heavy leptons and Minimal Supersymmetric Standard Model staus a lower limit of 68.5 \GeVcc may be set for the stau mas

    Hadronization properties of b quarks compared to light quarks in e+e- -> q qbar from 183 to 200 GeV

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    The DELPHI detector at LEP has collected 54 pb^{-1} of data at a centre-of-mass energy around 183 GeV during 1997, 158 pb^{-1} around 189 GeV during 1998, and 187 pb^{-1} between 192 and 200 GeV during 1999. These data were used to measure the average charged particle multiplicity in e+e- -> b bbar events, _{bb}, and the difference delta_{bl} between _{bb} and the multiplicity, _{ll}, in generic light quark (u,d,s) events: delta_{bl}(183 GeV) = 4.55 +/- 1.31 (stat) +/- 0.73 (syst) delta_{bl}(189 GeV) = 4.43 +/- 0.85 (stat) +/- 0.61 (syst) delta_{bl}(200 GeV) = 3.39 +/- 0.89 (stat) +/- 1.01 (syst). This result is consistent with QCD predictions, while it is inconsistent with calculations assuming that the multiplicity accompanying the decay of a heavy quark is independent of the mass of the quark itself.Comment: 13 pages, 2 figure

    Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

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    A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

    Jet size dependence of single jet suppression in lead-lead collisions at sqrt(s(NN)) = 2.76 TeV with the ATLAS detector at the LHC

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    Measurements of inclusive jet suppression in heavy ion collisions at the LHC provide direct sensitivity to the physics of jet quenching. In a sample of lead-lead collisions at sqrt(s) = 2.76 TeV corresponding to an integrated luminosity of approximately 7 inverse microbarns, ATLAS has measured jets with a calorimeter over the pseudorapidity interval |eta| < 2.1 and over the transverse momentum range 38 < pT < 210 GeV. Jets were reconstructed using the anti-kt algorithm with values for the distance parameter that determines the nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of the jet yield is characterized by the jet "central-to-peripheral ratio," Rcp. Jet production is found to be suppressed by approximately a factor of two in the 10% most central collisions relative to peripheral collisions. Rcp varies smoothly with centrality as characterized by the number of participating nucleons. The observed suppression is only weakly dependent on jet radius and transverse momentum. These results provide the first direct measurement of inclusive jet suppression in heavy ion collisions and complement previous measurements of dijet transverse energy imbalance at the LHC.Comment: 15 pages plus author list (30 pages total), 8 figures, 2 tables, submitted to Physics Letters B. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HION-2011-02

    Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

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    This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio

    Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

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    The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter
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