Protein C Mutation (A267T) Results in ER Retention and Unfolded Protein Response Activation

BACKGROUND: Protein C (PC) deficiency is associated with a high risk of venous thrombosis. Recently, we identified the PC-A267T mutation in a patient with PC deficiency and revealed by in vitro studies decreased intracellular and secreted levels of the mutant. The aim of the present study was to characterize the underlying mechanism(s). METHODOLOGY/PRINCIPAL FINDINGS: CHO-K1 cells stably expressing the wild-type (PC-wt) or the PC mutant were generated. In order to examine whether the PC mutant was subjected to increased intracellular degradation, the cells were treated with several inhibitors of various degradation pathways and pulse-chase experiments were performed. Protein-chaperone complexes were analyzed by treating the cells with a cross-linker followed by Western blotting (WB). Expression levels of the immunoglobulin-binding protein (BiP) and the phosphorylated eukaryotic initiation factor 2α (P-eIF2α), both common ER stress markers, were determined by WB to examine if the mutation induced ER stress and unfolded protein response (UPR) activation. We found no major differences in the intracellular degradation between the PC variants. The PC mutant was retained in the endoplasmic reticulum (ER) and had increased association with the Grp-94 and calreticulin chaperones. Retention of the PC-A267T in ER resulted in UPR activation demonstrated by increased expression levels of the ER stress markers BiP and P-eIF2α and caused also increased apoptotic activity in CHO-K1 cells as evidenced by elevated levels of DNA fragmentation. CONCLUSIONS/SIGNIFICANCE: The reduced intracellular level and impaired secretion of the PC mutant were due to retention in ER. In contrast to other PC mutations, retention of the PC-A267T in ER resulted in minor increased proteasomal degradation, rather it induced ER stress, UPR activation and apoptosis

Orthopaedic management of Hurler’s disease after hematopoietic stem cell transplantation: a systematic review

The introduction of hematopoietic stem cell transplantation (HSCT) has significantly improved the life-span of Hurler patients (mucopolysaccharidosis type I-H, MPS I-H). Yet, the musculoskeletal manifestations seem largely unresponsive to HSCT. In order to facilitate evidence based management, the aim of the current study was to give a systematic overview of the orthopaedic complications and motor functioning of Hurler's patients after HSCT. A systematic review was conducted of the medical literature published from January 1981 to June 2010. Two reviewers independently assessed all eligible citations, as identified from the Pubmed and Embase databases. A pre-developed data extraction form was used to systematically collect information on the prevalence of radiological and clinical signs, and on the orthopaedic treatments and outcomes. A total of 32 studies, including 399 patient reports were identified. The most frequent musculoskeletal abnormalities were odontoid hypoplasia (72%), thoracolumbar kyphosis (81%), genu valgum (70%), hip dysplasia (90%) and carpal tunnel syndrome (63%), which were often treated surgically during the first decade of life. The overall complication rate of surgical interventions was 13.5%. Motor functioning was further hampered due to reduced joint mobility, hand dexterity, motor development and longitudinal growth. Stem cell transplantation does not halt the progression of a large range of disabling musculoskeletal abnormalities in Hurler's disease. Although prospective data on the quantification, progression and treatment of these deformities were very limited, early surgical intervention is often advocated. Prospective data collection will be mandatory to achieve better evidence on the effect of treatment strategies

Running of the top quark mass from proton-proton collisions at \sqrt{s} = 13 TeV

The running of the top quark mass is experimentally investigated for the first time. The mass of the top quark in the modified minimal subtraction \bar{MS} renormalization scheme is extracted from a comparison of the differential top quark-antiquark (t\bar{t}) cross section as a function of the invariant mass of the (t\bar{t}) system to next-to-leading-order theoretical predictions. The differential cross section is determined at the parton level by means of a maximum-likelihood fit to distributions of final-state observables. The analysis is performed using (t\bar{t}) candidate events in the e^{±} μ^{∓} channel in proton-proton collision data at a centre-of-mass energy of 13 TeV recorded by the CMS detector at the CERN LHC in 2016, corresponding to an integrated luminosity of 35.9 fb^{-1}. The extracted running is found to be compatible with the scale dependence predicted by the corresponding renormalization group equation. In this analysis, the running is probed up to a scale of the order of 1 TeV

Search for dijet resonances using events with three jets in proton-proton collisions at \sqrt{s} = 13 TeV

A search for a narrow resonance with a mass between 350 and 700 GeV, and decaying into a pair of jets, is performed using proton-proton collision events containing at least three jets. The data sample corresponds to an integrated luminosity of 18.3 fb^{−1} recorded at \sqrt{s} = 13 TeV with the CMS detector. Data are collected with a technique known as “data scouting”, in which the events are reconstructed, selected, and recorded at a high rate in a compact form by the high-level trigger. The three-jet final state provides sensitivity to lower resonance masses than in previous searches using the data scouting technique. The spectrum of the dijet invariant mass, calculated from the two jets with the largest transverse momenta in the event, is used to search for a resonance. No significant excess over a smoothly falling background is found. Limits at 95% confidence level are set on the production cross section of a narrow dijet resonance and compared with the cross section of a vector dark matter mediator coupling to dark matter particles and quarks. Translating to a model where the narrow resonance interacts only with quarks, upper limits on this coupling range between 0.10 and 0.15, depending on the resonance mass. These results represent the most stringent upper limits in the mass range between 350 and 450 GeV obtained with a flavor-inclusive dijet resonance search

Observation of the Λ_{b}^{0} → J/ψΛφ decay in proton-proton collisions at \sqrt{s} = 13 TeV

The observation of the Λ_{b}^{0} → J/ψΛφ decay is reported using proton-proton collision data collected at \sqrt{s} = 13 TeV by the CMS experiment at the LHC in 2018, corresponding to an integrated luminosity of 60 fb^{-1}. The ratio of the branching fractions B(Λ_{b}^{0} → J/ψΛφ)/B(Λ_{b}^{0} → J/ψ(2s)Λ) is measured to be 8.26 ± 0.90(stat) ± 0.68 (syst) ± 0.11(B)) x 10^{-2}, where the first uncertainty is statistical, the second is systematic, and the last uncertainty reflects the uncertainties in the world-average branching fractions of φ and ψ(2s) decays to the reconstructed final states

Measurements of differential Z boson production cross sections in proton-proton collisions at \sqrt{s} = 13 TeV

Measurements are presented of the differential cross sections for Z bosons produced in proton-proton collisions at \sqrt{s} = 13 TeV and decaying to muons and electrons. The data analyzed were collected in 2016 with the CMS detector at the LHC and correspond to an integrated luminosity of 35.9 fb^{-1}. The measured fiducial inclusive product of cross section and branching fraction agrees with next-to-next-to-leading order quantum chromodynamics calculations. Differential cross sections of the transverse momentum p_{T}, the optimized angular variable ϕ^{*}_{η}, and the rapidity of lepton pairs are measured. The data are corrected for detector effects and compared to theoretical predictions using fixed order, resummed, and parton shower calculations. The uncertainties of the measured normalized cross sections are smaller than 0.5% for ϕ^{*}_{η} < 0.5 and for p^{Z}_{T} < 50 GeV

Search for supersymmetry in pp collisions at \sqrt{s} = 13 TeV with 137 fb^{-1} in final states with a single lepton using the sum of masses of large-radius jets

Results are reported from a search for new physics beyond the standard model in proton-proton collisions in final states with a single lepton; multiple jets, including at least one jet tagged as originating from the hadronization of a bottom quark; and large missing transverse momentum. The search uses a sample of proton-proton collision data at \sqrt{s} = 13 TeV, corresponding to 137 fb^{-1}, recorded by the CMS experiment at the LHC. The signal region is divided into categories characterized by the total number of jets, the number of bottom quark jets, the missing transverse momentum, and the sum of masses of large-radius jets. The observed event yields in the signal regions are consistent with estimates of standard model backgrounds based on event yields in the control regions. The results are interpreted in the context of simplified models of supersymmetry involving gluino pair production in which each gluino decays into a top quark-antiquark pair and a stable, unobserved neutralino, which generates missing transverse momentum in the event. Scenarios with gluino masses up to about 2150 GeV are excluded at 95% confidence level (or more) for neutralino masses up to 700 GeV. The highest excluded neutralino mass is about 1250 GeV, which holds for gluino masses around 1850 GeV