VASP, zyxin and TES are tension-dependent members of Focal Adherens Junctions independent of the α-catenin-vinculin module

Mechanical forces are integrated at cadherin-based adhesion complexes to regulate morphology and strength of cell-cell junctions and organization of associated F-actin. A central mechanosensor at the cadherin complex is α-catenin, whose stretching recruits vinculin to regulate adhesion strength. The identity of the F-actin regulating signals that are also activated by mechanical forces at cadherin-based junctions has remained elusive. Here we identify the actin-regulators VASP, zyxin and TES as members of punctate, tensile cadherin-based junctions called Focal Adherens Junctions (FAJ) and show that they display mechanosensitive recruitment similar to that of vinculin. However, this recruitment is not altered by destroying or over-activating the α-catenin/vinculin module. Structured Illumination Microscopy (SIM) indicates that these tension sensitive proteins concentrate at locations within FAJs that are distinct from the core cadherin complex proteins. Furthermore, localization studies using mutated versions of VASP and zyxin indicate that these two proteins require binding to each other in order to localize to the FAJs. We conclude that there are multiple force sensitive modules present at the FAJ that are activated at distinct locations along the cadherin-F-actin axis and regulate specific aspects of junction dynamics

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Overview of the JET preparation for deuterium-tritium operation with the ITER like-wall

For the past several years, the JET scientific programme (Pamela et al 2007 Fusion Eng. Des. 82 590) has been engaged in a multi-campaign effort, including experiments in D, H and T, leading up to 2020 and the first experiments with 50%/50% D-T mixtures since 1997 and the first ever D-T plasmas with the ITER mix of plasma-facing component materials. For this purpose, a concerted physics and technology programme was launched with a view to prepare the D-T campaign (DTE2). This paper addresses the key elements developed by the JET programme directly contributing to the D-T preparation. This intense preparation includes the review of the physics basis for the D-T operational scenarios, including the fusion power predictions through first principle and integrated modelling, and the impact of isotopes in the operation and physics of D-T plasmas (thermal and particle transport, high confinement mode (H-mode) access, Be and W erosion, fuel recovery, etc). This effort also requires improving several aspects of plasma operation for DTE2, such as real time control schemes, heat load control, disruption avoidance and a mitigation system (including the installation of a new shattered pellet injector), novel ion cyclotron resonance heating schemes (such as the three-ions scheme), new diagnostics (neutron camera and spectrometer, active Alfven eigenmode antennas, neutral gauges, radiation hard imaging systems...) and the calibration of the JET neutron diagnostics at 14 MeV for accurate fusion power measurement. The active preparation of JET for the 2020 D-T campaign provides an incomparable source of information and a basis for the future D-T operation of ITER, and it is also foreseen that a large number of key physics issues will be addressed in support of burning plasmas

Chemical erosion of carbon at ITER relevant plasma fluxes:results from the linear plasma generator Pilot-PSI

\u3cp\u3eThe chemical erosion of carbon was investigated in the linear plasma device Pilot-PSI for ITER divertor relevant hydrogen plasma flux densities 10 \u3csup\u3e23\u3c/sup\u3e < Γ < 10\u3csup\u3e25\u3c/sup\u3e m\u3csup\u3e-2\u3c/sup\u3e s\u3csup\u3e-1\u3c/sup\u3e. The erosion was analyzed in situ by optical emission spectroscopy and post mortem by surface profilometry. The experiments indicate a threshold for the absolute carbon erosion rate as a function of plasma temperature T\u3csub\u3ee\u3c/sub\u3e around 0.7 eV, a peak of the surface temperature around 550 °C, and no dependence on plasma flux density. The latter implies a flux dependence of the chemical erosion yield as Γ\u3csup\u3e-1\u3c/sup\u3e. The value of the chemical erosion yield at the surface temperature of maximum erosion and Γ = 1 × 10\u3csup\u3e24\u3c/sup\u3e m\u3csup\u3e-2\u3c/sup\u3e s\u3csup\u3e-1\u3c/sup\u3e was 0.9% for T\u3csub\u3ee\u3c/sub\u3e < 0.5 eV as determined by surface profilometry.\u3c/p\u3

Low-temperature, atmospheric pressure reverse water-gas shift reaction in dielectric barrier plasma discharge, with outlook to use in relevant industrial processes

Plasma discharges offer a direct way to convert electrical to chemical energy and to store volatile renewable energy sources. Converting CO2 in this way can contribute to reducing the greenhouse effect, and provide additional opportunity for chemical processing, e.g., on-site or on a small scale. The CO2 hydrogenation to CO via the reverse water-gas shift reaction (RWGS) generates synthesis gas for use as feedstock to different fuels and chemicals. The RWGS reaction carried out in a Dielectric Barrier Discharge (DBD) plasma reactor benefits from operation at ambient pressure and mild temperature, as compared to the harsher conditions of conventional RWGS processing. To develop that with outlook to real-life uses, e.g., toward methanol synthesis, key performances need to be achieved; that is, i.a., a threshold CO2 conversion, a high CO selectivity at low impurity (low CH4 selectivity), and a high (H2 − CO2)/(CO + CO2) ratio (favourable for high reaction rates) as well as tolerable energy efficiency. Central plasma process parameters for this are the feed gas ratio, residence time, and uniformly distributed microdischarges. The optimisation of an individual key performance can be adverse to the other so that the process exploration is a task. This gives room to introduce new plasma operation types, and the burst mode was applied for the first time to the RWGS reaction in the present work. By this fast (millisecond) periodic switching on and off the plasma, the process temperature can be reduced as well as a better microdischarge distribution can be achieved. The residence time is not only set by the flow rate, as commonly done, but also by taking the discharge gap as an additional parameter of freedom, which also impacts the reducing distribution. As a result of relevant process conditions, at CO selectivity of 98%, 337 mmol/kWh is obtained as the energy efficiency of CO formation. Whereas the best CO2 conversion of 50% and the (H2 − CO2)/(CO + CO2) ratio of 2 were obtained at respective optimum process parameters