Protease effects on the structure of acetylcholine receptor membranes from Torpedo californica.

Protease digestion of acetylcholine receptor-rich membranes derived from Torpedo californica electroplaques by homogenization and isopycnic centrifugation results in degradation of all receptor subunits without any significant effect on the appearance in electron micrographs, the toxin binding ability, or the sedimentation value of the receptor molecule. Such treatment does produce dramatic changes in the morphology of the normally 0.5- to 2-microns-diameter spherical vesicles when observed by either negative-stain or freeze-fracture electron microscopy. Removal of peripheral, apparently nonreceptor polypeptides by alkali stripping (Neubig et al. 1979, Proc. Natl. Acad. Sci. U. S. A. 76:690-694) results in increased sensitivity of the acetylcholine receptor membranes to the protease trypsin as indicated by SDS gel electrophoretic patterns and by the extent of morphologic change observed in vesicle structure. Trypsin digestion of alkali-stripped receptor membranes results in a limit degradation pattern of all four receptor subunits, whereupon all the vesicles undergo the morphological transformation to minivesicles. The protein-induced morphological transformation and the limit digestion pattern of receptor membranes are unaffected by whether the membranes are prepared so as to preserve the receptor as a disulfide bridged dimer, or prepared so as to generate monomeric receptor

The influence of 'significant others' on persistent back pain and work participation: a qualitative exploration of illness perceptions

Background Individual illness perceptions have been highlighted as important influences on clinical outcomes for back pain. However, the illness perceptions of 'significant others' (spouse/partner/close family member) are rarely explored, particularly in relation to persistent back pain and work participation. The aim of this study was to initiate qualitative research in this area in order to further understand these wider influences on outcome. Methods Semi-structured interviews based on the chronic pain version of the Illness Perceptions Questionnaire-Revised were conducted with a convenience sample of UK disability benefit claimants, along with their significant others (n=5 dyads). Data were analysed using template analysis. Results Significant others shared, and perhaps further reinforced, claimants' unhelpful illness beliefs including fear of pain/re-injury associated with certain types of work and activity, and pessimism about the likelihood of return to work. In some cases, significant others appeared more resigned to the permanence and negative inevitable consequences of the claimant's back pain condition on work participation, and were more sceptical about the availability of suitable work and sympathy from employers. In their pursuit of authenticity, claimants were keen to stress their desire to work whilst emphasising how the severity and physical limitations of their condition prevented them from doing so. In this vein, and seemingly based on their perceptions of what makes a 'good' significant other, significant others acted as a 'witness to pain', supporting claimants' self-limiting behaviour and statements of incapacity, often responding with empathy and assistance. The beliefs and responses of significant others may also have been influenced by their own experience of chronic illness, thus participants lives were often intertwined and defined by illness. Conclusions The findings from this exploratory study reveal how others and wider social circumstances might contribute both to the propensity of persistent back pain and to its consequences. This is an area that has received little attention to date, and wider support of these findings may usefully inform the design of future intervention programmes aimed at restoring work participation

Is social stress in the first half of life detrimental to later physical and mental health in both men and women?

This study examined gender differences in the associations between affection- and status-related stressors encountered in the first half of life and physical and mental health problems later on. Based on the theory of Social Production Functions (SPF) two hypotheses have been formulated, which were tested in a representative sample of 446 men and 514 women (aged 40–79). Main outcome measures were number of chronic somatic diseases and level of psychological distress. As expected, regression analyses showed no gender differences in the associations between affection-related stressors and physical and mental health problems later on. In contrast, but as also expected, status-related stressors encountered in the first half of life were associated with later physical and mental health for men only. It is concluded that the gender differences in the associations between earlier social stressors and later health problems may be more complex than the common assumption that men are only affected by status stress and women only by affection stress. This study contributes to the knowledge on gender differences concerning the link between social stress and health, and it indicates that social experiences encountered earlier in life are of importance for being healthy and happy in later life

Induction of epigenetic variation in Arabidopsis by over-expression of DNA METHYLTRANSFERASE1 (MET1)

Epigenetic marks such as DNA methylation and histone modification can vary among plant accessions creating epi-alleles with different levels of expression competence. Mutations in epigenetic pathway functions are powerful tools to induce epigenetic variation. As an alternative approach, we investigated the potential of over-expressing an epigenetic function, using DNA METHYLTRANSFERASE1 (MET1) for proof-of-concept. In Arabidopsis thaliana, MET1 controls maintenance of cytosine methylation at symmetrical CG positions. At some loci, which contain dense DNA methylation in CG- and non-CG context, loss of MET1 causes joint loss of all cytosines methylation marks. We find that over-expression of both catalytically active and inactive versions of MET1 stochastically generates new epi-alleles at loci encoding transposable elements, non-coding RNAs and proteins, which results for most loci in an increase in expression. Individual transformants share some common phenotypes and genes with altered gene expression. Altered expression states can be transmitted to the next generation, which does not require the continuous presence of the MET1 transgene. Long-term stability and epigenetic features differ for individual loci. Our data show that over-expression of MET1, and potentially of other genes encoding epigenetic factors, offers an alternative strategy to identify epigenetic target genes and to create novel epi-alleles

TET family dioxygenases and DNA demethylation in stem cells and cancers

The methylation of cytosine and subsequent oxidation constitutes a fundamental epigenetic modification in mammalian genomes, and its abnormalities are intimately coupled to various pathogenic processes including cancer development. Enzymes of the Ten-eleven translocation (TET) family catalyze the stepwise oxidation of 5-methylcytosine in DNA to 5-hydroxymethylcytosine and further oxidation products. These oxidized 5-methylcytosine derivatives represent intermediates in the reversal of cytosine methylation, and also serve as stable epigenetic modifications that exert distinctive regulatory roles. It is becoming increasingly obvious that TET proteins and their catalytic products are key regulators of embryonic development, stem cell functions and lineage specification. Over the past several years, the function of TET proteins as a barrier between normal and malignant states has been extensively investigated. Dysregulation of TET protein expression or function is commonly observed in a wide range of cancers. Notably, TET loss-of-function is causally related to the onset and progression of hematologic malignancy in vivo. In this review, we focus on recent advances in the mechanistic understanding of DNA methylation-demethylation dynamics, and their potential regulatory functions in cellular differentiation and oncogenic transformation

Measurement of the tt¯tt¯ production cross section in pp collisions at √s=13 TeV with the ATLAS detector

A measurement of four-top-quark production using proton-proton collision data at a centre-of-mass energy of 13 TeV collected by the ATLAS detector at the Large Hadron Collider corresponding to an integrated luminosity of 139 fb−1 is presented. Events are selected if they contain a single lepton (electron or muon) or an opposite-sign lepton pair, in association with multiple jets. The events are categorised according to the number of jets and how likely these are to contain b-hadrons. A multivariate technique is then used to discriminate between signal and background events. The measured four-top-quark production cross section is found to be 26+17−15 fb, with a corresponding observed (expected) significance of 1.9 (1.0) standard deviations over the background-only hypothesis. The result is combined with the previous measurement performed by the ATLAS Collaboration in the multilepton final state. The combined four-top-quark production cross section is measured to be 24+7−6 fb, with a corresponding observed (expected) signal significance of 4.7 (2.6) standard deviations over the background-only predictions. It is consistent within 2.0 standard deviations with the Standard Model expectation of 12.0 ± 2.4 fb

Measurements of Higgs bosons decaying to bottom quarks from vector boson fusion production with the ATLAS experiment at √=13TeV

The paper presents a measurement of the Standard Model Higgs Boson decaying to b-quark pairs in the vector boson fusion (VBF) production mode. A sample corresponding to 126 fb−1 of s√=13TeV proton–proton collision data, collected with the ATLAS experiment at the Large Hadron Collider, is analyzed utilizing an adversarial neural network for event classification. The signal strength, defined as the ratio of the measured signal yield to that predicted by the Standard Model for VBF Higgs production, is measured to be 0.95+0.38−0.36 , corresponding to an observed (expected) significance of 2.6 (2.8) standard deviations from the background only hypothesis. The results are additionally combined with an analysis of Higgs bosons decaying to b-quarks, produced via VBF in association with a photon

Muon reconstruction and identification efficiency in ATLAS using the full Run 2 pp collision data set at \sqrt{s}=13 TeV

This article documents the muon reconstruction and identification efficiency obtained by the ATLAS experiment for 139 \hbox {fb}^{-1} of pp collision data at \sqrt{s}=13 TeV collected between 2015 and 2018 during Run 2 of the LHC. The increased instantaneous luminosity delivered by the LHC over this period required a reoptimisation of the criteria for the identification of prompt muons. Improved and newly developed algorithms were deployed to preserve high muon identification efficiency with a low misidentification rate and good momentum resolution. The availability of large samples of Z\rightarrow \mu \mu and J/\psi \rightarrow \mu \mu decays, and the minimisation of systematic uncertainties, allows the efficiencies of criteria for muon identification, primary vertex association, and isolation to be measured with an accuracy at the per-mille level in the bulk of the phase space, and up to the percent level in complex kinematic configurations. Excellent performance is achieved over a range of transverse momenta from 3 GeV to several hundred GeV, and across the full muon detector acceptance of |\eta |<2.7

Measurements of W+W−+ ≥ 1 jet production cross-sections in pp collisions at s \sqrt{s} = 13 TeV with the ATLAS detector

Fiducial and differential cross-section measurements of W+W− production in association with at least one hadronic jet are presented. These measurements are sensitive to the properties of electroweak-boson self-interactions and provide a test of perturbative quantum chromodynamics and the electroweak theory. The analysis is performed using proton-proton collision data collected at p s = 13TeV with the ATLAS experiment, corresponding to an integrated luminosity of 139 fb−1. Events are selected with exactly one oppositely charged electron-muon pair and at least one hadronic jet with a transverse momentum of pT > 30 GeV and a pseudorapidity of |�| < 4.5. After subtracting the background contributions and correcting for detector effects, the jet-inclusive W+W−+ � 1 jet fiducial cross-section and W+W−+ jets differential cross-sections with respect to several kinematic variables are measured. These measurements include leptonic quantities, such as the lepton transverse momenta and the transverse mass of the W+W− system, as well as jet-related observables such as the leading jet transverse momentum and the jet multiplicity. Limits on anomalous triple-gauge-boson couplings are obtained in a phase space where interference between the Standard Model amplitude and the anomalous amplitude is enhanced

Search for bottom-squark pair production in pp collision events at √s=13 TeV with hadronically decaying τ-leptons, b-jets, and missing transverse momentum using the ATLAS detector

A search for pair production of bottom squarks in events with hadronically decaying τ -leptons, b -tagged jets, and large missing transverse momentum is presented. The analyzed dataset is based on proton-proton collisions at √ s = 13     TeV delivered by the Large Hadron Collider and recorded by the ATLAS detector from 2015 to 2018, and corresponds to an integrated luminosity of 139     fb − 1 . The observed data are compatible with the expected Standard Model background. Results are interpreted in a simplified model where each bottom squark is assumed to decay into the second-lightest neutralino ˜ χ 0 2 and a bottom quark, with ˜ χ 0 2 decaying into a Higgs boson and the lightest neutralino ˜ χ 0 1 . The search focuses on final states where at least one Higgs boson decays into a pair of hadronically decaying τ -leptons. This allows the acceptance and thus the sensitivity to be significantly improved relative to the previous results at low masses of the ˜ χ 0 2 , where bottom-squark masses up to 850 GeV are excluded at the 95% confidence level, assuming a mass difference of 130 GeV between ˜ χ 0 2 and ˜ χ 0 1 . Model-independent upper limits are also set on the cross section of processes beyond the Standard Model