487 research outputs found

    Structure of the human TSC:WIPI3 lysosomal recruitment complex.

    Get PDF
    Tuberous sclerosis complex (TSC) is targeted to the lysosomal membrane, where it hydrolyzes RAS homolog-mTORC1 binding (RHEB) from its GTP-bound to GDP-bound state, inhibiting mechanistic target of rapamycin complex 1 (mTORC1). Loss-of-function mutations in TSC cause TSC disease, marked by excessive tumor growth. Here, we overcome a high degree of continuous conformational heterogeneity to determine the 2.8-Å cryo-electron microscopy (cryo-EM) structure of the complete human TSC in complex with the lysosomal recruitment factor WD repeat domain phosphoinositide-interacting protein 3 (WIPI3). We discover a previously undetected amino-terminal TSC1 HEAT repeat dimer that clamps onto a single TSC wing and forms a phosphatidylinositol phosphate (PIP)-binding pocket, which specifically binds monophosphorylated PIPs. These structural advances provide a model by which WIPI3 and PIP-signaling networks coordinate to recruit TSC to the lysosomal membrane to inhibit mTORC1. The high-resolution TSC structure reveals previously unrecognized mutational hotspots and uncovers crucial insights into the mechanisms of TSC dysregulation in disease

    Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

    Get PDF
    The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

    Study of the reaction e^{+}e^{-} -->J/psi\pi^{+}\pi^{-} via initial-state radiation at BaBar

    Get PDF
    We study the process e+eJ/ψπ+πe^+e^-\to J/\psi\pi^{+}\pi^{-} with initial-state-radiation events produced at the PEP-II asymmetric-energy collider. The data were recorded with the BaBar detector at center-of-mass energies 10.58 and 10.54 GeV, and correspond to an integrated luminosity of 454 fb1\mathrm{fb^{-1}}. We investigate the J/ψπ+πJ/\psi \pi^{+}\pi^{-} mass distribution in the region from 3.5 to 5.5 GeV/c2\mathrm{GeV/c^{2}}. Below 3.7 GeV/c2\mathrm{GeV/c^{2}} the ψ(2S)\psi(2S) signal dominates, and above 4 GeV/c2\mathrm{GeV/c^{2}} there is a significant peak due to the Y(4260). A fit to the data in the range 3.74 -- 5.50 GeV/c2\mathrm{GeV/c^{2}} yields a mass value 4244±54244 \pm 5 (stat) ±4 \pm 4 (syst)MeV/c2\mathrm{MeV/c^{2}} and a width value 11415+16114 ^{+16}_{-15} (stat)±7 \pm 7(syst)MeV\mathrm{MeV} for this state. We do not confirm the report from the Belle collaboration of a broad structure at 4.01 GeV/c2\mathrm{GeV/c^{2}}. In addition, we investigate the π+π\pi^{+}\pi^{-} system which results from Y(4260) decay

    Observation of associated near-side and away-side long-range correlations in √sNN=5.02  TeV proton-lead collisions with the ATLAS detector

    Get PDF
    Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

    Changing behaviour 'more or less'-do theories of behaviour inform strategies for implementation and de-implementation? A critical interpretive synthesis

    Get PDF
    BACKGROUND: Implementing evidence-based care requires healthcare practitioners to do less of some things (de-implementation) and more of others (implementation). Variations in effectiveness of behaviour change interventions may result from failure to consider a distinction between approaches by which behaviour increases and decreases in frequency. The distinction is not well represented in methods for designing interventions. This review aimed to identify whether there is a theoretical rationale to support this distinction. METHODS: Using Critical Interpretative Synthesis, this conceptual review included papers from a broad range of fields (biology, psychology, education, business) likely to report approaches for increasing or decreasing behaviour. Articles were identified from databases using search terms related to theory and behaviour change. Articles reporting changes in frequency of behaviour and explicit use of theory were included. Data extracted were direction of behaviour change, how theory was operationalised, and theory-based recommendations for behaviour change. Analyses of extracted data were conducted iteratively and involved inductive coding and critical exploration of ideas and purposive sampling of additional papers to explore theoretical concepts in greater detail. RESULTS: Critical analysis of 66 papers and their theoretical sources identified three key findings: (1) 9 of the 15 behavioural theories identified do not distinguish between implementation and de-implementation (5 theories were applied to only implementation or de-implementation, not both); (2) a common strategy for decreasing frequency was substituting one behaviour with another. No theoretical basis for this strategy was articulated, nor were methods proposed for selecting appropriate substitute behaviours; (3) Operant Learning Theory makes an explicit distinction between techniques for increasing and decreasing frequency. DISCUSSION: Behavioural theories provide little insight into the distinction between implementation and de-implementation. Operant Learning Theory identified different strategies for implementation and de-implementation, but these strategies may not be acceptable in health systems. Additionally, if behaviour substitution is an approach for de-implementation, further investigation may inform methods or rationale for selecting the substitute behaviour

    Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

    Get PDF
    A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of s=7  TeV \sqrt{s}=7\;\mathrm{TeV} proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40

    Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

    Get PDF
    This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}andcorrespondtoanintegratedluminosityof and correspond to an integrated luminosity of 4.6\;{\rm f}{{{\rm b}}^{-1}}.ThemeasurementisperformedbyreconstructingtheboostedWorZbosonsinsinglejets.ThereconstructedjetmassisusedtoidentifytheWandZbosons,andajetsubstructuremethodbasedonenergyclusterinformationinthejetcentreofmassframeisusedtosuppressthelargemultijetbackground.ThecrosssectionforeventswithahadronicallydecayingWorZboson,withtransversemomentum. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum {{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}andpseudorapidity and pseudorapidity |\eta |\lt 1.9,ismeasuredtobe, is measured to be {{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques

    Microbial Co-occurrence Relationships in the Human Microbiome

    Get PDF
    The healthy microbiota show remarkable variability within and among individuals. In addition to external exposures, ecological relationships (both oppositional and symbiotic) between microbial inhabitants are important contributors to this variation. It is thus of interest to assess what relationships might exist among microbes and determine their underlying reasons. The initial Human Microbiome Project (HMP) cohort, comprising 239 individuals and 18 different microbial habitats, provides an unprecedented resource to detect, catalog, and analyze such relationships. Here, we applied an ensemble method based on multiple similarity measures in combination with generalized boosted linear models (GBLMs) to taxonomic marker (16S rRNA gene) profiles of this cohort, resulting in a global network of 3,005 significant co-occurrence and co-exclusion relationships between 197 clades occurring throughout the human microbiome. This network revealed strong niche specialization, with most microbial associations occurring within body sites and a number of accompanying inter-body site relationships. Microbial communities within the oropharynx grouped into three distinct habitats, which themselves showed no direct influence on the composition of the gut microbiota. Conversely, niches such as the vagina demonstrated little to no decomposition into region-specific interactions. Diverse mechanisms underlay individual interactions, with some such as the co-exclusion of Porphyromonaceae family members and Streptococcus in the subgingival plaque supported by known biochemical dependencies. These differences varied among broad phylogenetic groups as well, with the Bacilli and Fusobacteria, for example, both enriched for exclusion of taxa from other clades. Comparing phylogenetic versus functional similarities among bacteria, we show that dominant commensal taxa (such as Prevotellaceae and Bacteroides in the gut) often compete, while potential pathogens (e.g. Treponema and Prevotella in the dental plaque) are more likely to co-occur in complementary niches. This approach thus serves to open new opportunities for future targeted mechanistic studies of the microbial ecology of the human microbiome.National Institutes of Health (U.S.) (grant CA139193)Fonds Wetenschappelijk Onderzoek – VlaanderenJuvenile Diabetes Research Foundation InternationalNational Institutes of Health (U.S.) (grant NIH U54HG004969)Crohn's and Colitis Foundation of AmericaNational Science Foundation (U.S.) (NSF DBI-1053486)United States. Army Research Office (ARO W911NF-11-1-0473)National Institutes of Health (U.S.) (grant NIH 1R01HG005969

    Flavor tagged time-dependent angular analysis of the B0s → J/ψϕ decay and extraction of ΔΓs and the weak phase ϕs in ATLAS

    Get PDF
    A measurement of the B0s→J/ψϕ decay parameters, updated to include flavor tagging is reported using 4.9  fb−¹ of integrated luminosity collected by the ATLAS detector from √s=7  TeV pp collisions recorded in 2011 at the LHC. The values measured for the physical parameters are ϕs=0.12±0.25(stat)±0.05(syst)  rad ΔΓs=0.053±0.021(stat)±0.010(syst)  ps−¹ Γs=0.677±0.007(stat)±0.004(syst)  ps−¹ |A∥(0)|2=0.220±0.008(stat)±0.009(syst) |A0(0)|2=0.529±0.006(stat)±0.012(syst) δ⊥=3.89±0.47(stat)±0.11(syst)  rad where the parameter ΔΓs is constrained to be positive. The S-wave contribution was measured and found to be compatible with zero. Results for ϕs and ΔΓs are also presented as 68% and 95% likelihood contours, which show agreement with the Standard Model expectations
    corecore