Disease-relevant proteostasis regulation of cystic fibrosis transmembrane conductance regulator

Mismanaged protein trafficking by the proteostasis network contributes to several conformational diseases, including cystic fibrosis, the most frequent lethal inherited disease in Caucasians. Proteostasis regulators, as cystamine, enable the beneficial action of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators in \u394F508-CFTR airways beyond drug washout. Here we tested the hypothesis that functional CFTR protein can sustain its own plasma membrane (PM) stability. Depletion or inhibition of wild-type CFTR present in bronchial epithelial cells reduced the availability of the small GTPase Rab5 by causing Rab5 sequestration within the detergent-insoluble protein fraction together with its accumulation in aggresomes. CFTR depletion decreased the recruitment of the Rab5 effector early endosome antigen 1 to endosomes, thus reducing the local generation of phosphatidylinositol-3-phosphate. This diverts recycling of surface proteins, including transferrin receptor and CFTR itself. Inhibiting CFTR function also resulted in its ubiquitination and interaction with SQSTM1/p62 at the PM, favoring its disposal. Addition of cystamine prevented the recycling defect of CFTR by enhancing BECN1 expression and reducing SQSTM1 accumulation. Our results unravel an unexpected link between CFTR protein and function, the latter regulating the levels of CFTR surface expression in a positive feed-forward loop, and highlight CFTR as a pivot of proteostasis in bronchial epithelial cells

Search for supersymmetry in hadronic final states with missing transverse energy using the variables αT and b-quark multiplicity in pp collisions at [Formula: see text].

An inclusive search for supersymmetric processes that produce final states with jets and missing transverse energy is performed in pp collisions at a centre-of-mass energy of 8 TeV. The data sample corresponds to an integrated luminosity of 11.7 fb-1 collected by the CMS experiment at the LHC. In this search, a dimensionless kinematic variable, αT, is used to discriminate between events with genuine and misreconstructed missing transverse energy. The search is based on an examination of the number of reconstructed jets per event, the scalar sum of transverse energies of these jets, and the number of these jets identified as originating from bottom quarks. No significant excess of events over the standard model expectation is found. Exclusion limits are set in the parameter space of simplified models, with a special emphasis on both compressed-spectrum scenarios and direct or gluino-induced production of third-generation squarks. For the case of gluino-mediated squark production, gluino masses up to 950-1125 GeV are excluded depending on the assumed model. For the direct pair-production of squarks, masses up to 450 GeV are excluded for a single light first- or second-generation squark, increasing to 600 GeV for bottom squarks

Search for physics beyond the standard model in events with τ leptons, jets, and large transverse momentum imbalance in pp collisions at [Formula: see text].

A search for physics beyond the standard model is performed with events having one or more hadronically decaying τ leptons, highly energetic jets, and large transverse momentum imbalance. The data sample corresponds to an integrated luminosity of 4.98 fb-1 of proton-proton collisions at [Formula: see text] collected with the CMS detector at the LHC in 2011. The number of observed events is consistent with predictions for standard model processes. Lower limits on the mass of the gluino in supersymmetric models are determined

Measurement of masses in the [Formula: see text] system by kinematic endpoints in pp collisions at [Formula: see text].

A simultaneous measurement of the top-quark, W-boson, and neutrino masses is reported for [Formula: see text] events selected in the dilepton final state from a data sample corresponding to an integrated luminosity of 5.0 fb-1 collected by the CMS experiment in pp collisions at [Formula: see text]. The analysis is based on endpoint determinations in kinematic distributions. When the neutrino and W-boson masses are constrained to their world-average values, a top-quark mass value of [Formula: see text] is obtained. When such constraints are not used, the three particle masses are obtained in a simultaneous fit. In this unconstrained mode the study serves as a test of mass determination methods that may be used in beyond standard model physics scenarios where several masses in a decay chain may be unknown and undetected particles lead to underconstrained kinematics

Performance of photon reconstruction and identification with the CMS detector in proton-proton collisions at √s = 8 TeV

A description is provided of the performance of the CMS detector for photon reconstruction and identification in proton-proton collisions at a centre-of-mass energy of 8 TeV at the CERN LHC. Details are given on the reconstruction of photons from energy deposits in the electromagnetic calorimeter (ECAL) and the extraction of photon energy estimates. The reconstruction of electron tracks from photons that convert to electrons in the CMS tracker is also described, as is the optimization of the photon energy reconstruction and its accurate modelling in simulation, in the analysis of the Higgs boson decay into two photons. In the barrel section of the ECAL, an energy resolution of about 1% is achieved for unconverted or late-converting photons from Hγγ decays. Different photon identification methods are discussed and their corresponding selection efficiencies in data are compared with those found in simulated events

Measurement of jet multiplicity distributions in [Formula: see text] production in pp collisions at [Formula: see text].

The normalised differential top quark-antiquark production cross section is measured as a function of the jet multiplicity in proton-proton collisions at a centre-of-mass energy of 7[Formula: see text] at the LHC with the CMS detector. The measurement is performed in both the dilepton and lepton+jets decay channels using data corresponding to an integrated luminosity of 5.0[Formula: see text]. Using a procedure to associate jets to decay products of the top quarks, the differential cross section of the [Formula: see text] production is determined as a function of the additional jet multiplicity in the lepton+jets channel. Furthermore, the fraction of events with no additional jets is measured in the dilepton channel, as a function of the threshold on the jet transverse momentum. The measurements are compared with predictions from perturbative quantum chromodynamics and no significant deviations are observed

Probing color coherence effects in pp collisions at [Formula: see text].

A study of color coherence effects in pp collisions at a center-of-mass energy of 7[Formula: see text] is presented. The data used in the analysis were collected in 2010 with the CMS detector at the LHC and correspond to an integrated luminosity of 36 pb[Formula: see text]. Events are selected that contain at least three jets and where the two jets with the largest transverse momentum exhibit a back-to-back topology. The measured angular correlation between the second- and third-leading jet is shown to be sensitive to color coherence effects, and is compared to the predictions of Monte Carlo models with various implementations of color coherence. None of the models describe the data satisfactorily