The unfolded protein response in immunity and inflammation.

The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.This work was supported by the Netherlands Organization for Scientific Research Rubicon grant 825.13.012 (J.G.); US National Institutes of Health (NIH) grants DK044319, DK051362, DK053056 and DK088199, and the Harvard Digestive Diseases Center (HDDC) grant DK034854 (R.S.B.); National Institutes of Health grants DK042394, DK088227, DK103183 and CA128814 (R.J.K.); and European Research Council (ERC) Starting Grant 260961, ERC Consolidator Grant 648889, and the Wellcome Trust Investigator award 106260/Z/14/Z (A.K.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nri.2016.6

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Search for strongly interacting massive particles generating trackless jets in proton–proton collisions ats=13 TeV\sqrt{s} = 13\,\text {TeV}

A search for dark matter in the form of strongly interacting massive particles (SIMPs) using the CMS detector at the LHC is presented. The SIMPs would be produced in pairs that manifest themselves as pairs of jets without tracks. The energy fraction of jets carried by charged particles is used as a key discriminator to suppress efficiently the large multijet background, and the remaining background is estimated directly from data. The search is performed using proton–proton collision data corresponding to an integrated luminosity of 16.1fb$^{-1}$, collected with the CMS detector in 2016. No significant excess of events is observed above the expected background. For the simplified dark matter model under consideration, SIMPs with masses up to 100GeV are excluded and further sensitivity is explored towards higher masses

Measurement of single-diffractive dijet production in proton–proton collisions at s=8 TeV\sqrt{s} = 8\,\text {Te}\text {V} with the CMS and TOTEM experiments

Measurements are presented of the single-diffractive dijet cross section and the diffractive cross section as a function of the proton fractional momentum loss ξ ξ and the four-momentum transfer squared t. Both processes p p → p X p p → p X and p p → X p p p → X p , i.e. with the proton scattering to either side of the interaction point, are measured, where X X includes at least two jets; the results of the two processes are averaged. The analyses are based on data collected simultaneously with the CMS and TOTEM detectors at the LHC in proton–proton collisions at s √ =8TeV s=8TeV during a dedicated run with β ∗ =90m β∗=90m at low instantaneous luminosity and correspond to an integrated luminosity of 37.5nb −1 37.5nb−1 . The single-diffractive dijet cross section σ p X jj σjj p X , in the kinematic region ξ<0.1 ξ<0.1 , 0.03<|t|<1GeV 2 0.03<|t|<1GeV2 , with at least two jets with transverse momentum p T >40GeV pT>40GeV , and pseudorapidity |η|<4.4 |η|<4.4 , is 21.7±0.9(stat) +3.0 −3.3 (syst)±0.9(lumi)nb 21.7±0.9(stat)−3.3+3.0(syst)±0.9(lumi)nb . The ratio of the single-diffractive to inclusive dijet yields, normalised per unit of ξ ξ , is presented as a function of x, the longitudinal momentum fraction of the proton carried by the struck parton. The ratio in the kinematic region defined above, for x values in the range −2.9≤log 10 x≤−1.6 −2.9≤log10⁡x≤−1.6 , is R=(σ p X jj /Δξ)/σ jj =0.025±0.001(stat)±0.003(syst) R=(σjj p X /Δξ)/σjj=0.025±0.001(stat)±0.003(syst) , where σ p X jj σjj p X and σ jj σjj are the single-diffractive and inclusive dijet cross sections, respectively. The results are compared with predictions from models of diffractive and nondiffractive interactions. Monte Carlo predictions based on the HERA diffractive parton distribution functions agree well with the data when corrected for the effect of soft rescattering between the spectator partons

A Deep Neural Network for Simultaneous Estimation of b Jet Energy and Resolution

We describe a method to obtain point and dispersion estimates for the energies of jets arising from b quarks produced in proton-proton collisions at an energy of s = 13 TeV at the CERN LHC. The algorithm is trained on a large sample of simulated b jets and validated on data recorded by the CMS detector in 2017 corresponding to an integrated luminosity of 41 fb - 1 . A multivariate regression algorithm based on a deep feed-forward neural network employs jet composition and shape information, and the properties of reconstructed secondary vertices associated with the jet. The results of the algorithm are used to improve the sensitivity of analyses that make use of b jets in the final state, such as the observation of Higgs boson decay to b b ¯

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Search for light long-lived neutral particles from Higgs boson decays via vector-boson-fusion production from pp collisions at √s = 13 TeV with the ATLAS detector

A search is reported for long-lived dark photons with masses between 0.1 GeV and 15 GeV, from exotic decays of Higgs bosons produced via vector-boson-fusion. Events that contain displaced collimated Standard Model fermions reconstructed in the calorimeter or muon spectrometer are probed. This search uses the full LHC Run 2 (2015–2018) data sample collected in proton–proton collisions at √s = 13 TeV, corresponding to an integrated luminosity of 139 f b − 1 . Dominant backgrounds from Standard Model processes and non-collision sources are estimated using data-driven techniques. The observed event yields in the signal regions are consistent with the expected background. Upper limits on the Higgs boson to dark photon branching fraction are reported as a function of the dark photon mean proper decay length or of the dark photon mass and the coupling between the Standard Model and the potential dark sector. This search is combined with previous ATLAS searches obtained in the gluon–gluon fusion and WH production modes. A branching fraction above 10% is excluded at 95% CL for a 125 GeV Higgs boson decaying into two dark photons for dark photon mean proper decay lengths between 173 and 1296 mm and mass of 10 GeV