Morphology-Dependent Interactions between α-Synuclein Monomers and Fibrils

Amyloid fibrils may adopt different morphologies depending on the solution conditions and the protein sequence. Here, we show that two chemically identical but morphologically distinct α-synuclein fibrils can form under identical conditions. This was observed by nuclear magnetic resonance (NMR), circular dichroism (CD), and fluorescence spectroscopy, as well as by cryo-transmission electron microscopy (cryo-TEM). The results show different surface properties of the two morphologies, A and B. NMR measurements show that monomers interact differently with the different fibril surfaces. Only a small part of the N-terminus of the monomer interacts with the fibril surface of morphology A, compared to a larger part of the monomer for morphology B. Differences in ThT binding seen by fluorescence titrations, and mesoscopic structures seen by cryo-TEM, support the conclusion of the two morphologies having different surface properties. Fibrils of morphology B were found to have lower solubility than A. This indicates that fibrils of morphology B are thermodynamically more stable, implying a chemical potential of fibrils of morphology B that is lower than that of morphology A. Consequently, at prolonged incubation time, fibrils of morphology B remained B, while an initially monomorphic sample of morphology A gradually transformed to B

X-linked cataract and Nance-Horan syndrome are allelic disorders

Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication–triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes

BACKGROUND: Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition plays a more substantial role in this group.OBJECTIVE: To identify the spectrum of rare and novel variation in known IBD susceptibility genes using exome sequencing analysis in eight individual cases of childhood onset severe disease.DESIGN: DNA samples from the eight patients underwent targeted exome capture and sequencing. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, and identify and annotate variants where patient sequence differed from the reference sequence. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued.RESULTS: Across the panel of 169 known IBD susceptibility genes, approximately 300 variants in 104 genes were found. Excluding splicing and HLA-class variants, 58 variants across 39 of these genes were classified as rare, with an alternative allele frequency of <5%, of which 17 were novel. Only two patients with early onset Crohn's disease exhibited rare deleterious variations within NOD2: the previously described R702W variant was the sole NOD2 variant in one patient, while the second patient also carried the L1007 frameshift insertion. Both patients harboured other potentially damaging mutations in the GSDMB, ERAP2 and SEC16A genes. The two patients severely affected with ulcerative colitis exhibited a distinct profile: both carried potentially detrimental variation in the BACH2 and IL10 genes not seen in other patients.CONCLUSION: For each of the eight individuals studied, all non-synonymous, truncating and frameshift mutations across all known IBD genes were identified. A unique profile of rare and potentially damaging variants was evident for each patient with this complex disease

When signalling goes wrong: pathogenic variants in structural and signalling proteins causing cardiomyopathies

Cardiomyopathies are a diverse group of cardiac disorders with distinct phenotypes, depending on the proteins and pathways affected. A substantial proportion of cardiomyopathies are inherited and those will be the focus of this review article. With the wide application of high-throughput sequencing in the practice of clinical genetics, the roles of novel genes in cardiomyopathies are recognised. Here, we focus on a subgroup of cardiomyopathy genes [TTN, FHL1, CSRP3, FLNC and PLN, coding for Titin, Four and a Half LIM domain 1, Muscle LIM Protein, Filamin C and Phospholamban, respectively], which, despite their diverse biological functions, all have important signalling functions in the heart, suggesting that disturbances in signalling networks can contribute to cardiomyopathies.</p

Searches for the ZγZ\gamma decay mode of the Higgs boson and for new high-mass resonances in pppp collisions at s=13\sqrt{s} = 13 TeV with the ATLAS detector

International audienceThis article presents searches for the Zγ decay of the Higgs boson and for narrow high-mass resonances decaying to Zγ, exploiting Z boson decays to pairs of electrons or muons. The data analysis uses 36.1 fb$^{−1}$ of pp collisions at $\sqrt{s}=13$ recorded by the ATLAS detector at the CERN Large Hadron Collider. The data are found to be consistent with the expected Standard Model background. The observed (expected — assuming Standard Model pp → H → Zγ production and decay) upper limit on the production cross section times the branching ratio for pp → H → Zγ is 6.6. (5.2) times the Standard Model prediction at the 95% confidence level for a Higgs boson mass of 125.09 GeV. In addition, upper limits are set on the production cross section times the branching ratio as a function of the mass of a narrow resonance between 250 GeV and 2.4 TeV, assuming spin-0 resonances produced via gluon-gluon fusion, and spin-2 resonances produced via gluon-gluon or quark-antiquark initial states. For high-mass spin-0 resonances, the observed (expected) limits vary between 88 fb (61 fb) and 2.8 fb (2.7 fb) for the mass range from 250 GeV to 2.4 TeV at the 95% confidence level

Search for direct top squark pair production in final states with two leptons in s=13\sqrt{s} = 13 TeV pppp collisions with the ATLAS detector

International audienceThe results of a search for direct pair production of top squarks in events with two opposite-charge leptons (electrons or muons) are reported, using $36.1~\hbox {fb}^{-1}$ of integrated luminosity from proton–proton collisions at $\sqrt{s}=13$ TeV collected by the ATLAS detector at the Large Hadron Collider. To cover a range of mass differences between the top squark $\tilde{t}$ and lighter supersymmetric particles, four possible decay modes of the top squark are targeted with dedicated selections: the decay $\tilde{t} \rightarrow b \tilde{\chi }_{1}^{\pm }$ into a b-quark and the lightest chargino with $\tilde{\chi }_{1}^{\pm } \rightarrow W \tilde{\chi }_{1}^{0}$ , the decay $\tilde{t} \rightarrow t \tilde{\chi }_{1}^{0}$ into an on-shell top quark and the lightest neutralino, the three-body decay $\tilde{t} \rightarrow b W \tilde{\chi }_{1}^{0}$ and the four-body decay $\tilde{t} \rightarrow b \ell \nu \tilde{\chi }_{1}^{0}$ . No significant excess of events is observed above the Standard Model background for any selection, and limits on top squarks are set as a function of the $\tilde{t}$ and $\tilde{\chi }_{1}^{0}$ masses. The results exclude at 95% confidence level $\tilde{t}$ masses up to about 720 GeV, extending the exclusion region of supersymmetric parameter space covered by previous searches

Measurements of ttˉt\bar{t} differential cross-sections of highly boosted top quarks decaying to all-hadronic final states in pppp collisions at s=13 \sqrt{s}=13\, TeV using the ATLAS detector

Measurements are made of differential cross-sections of highly boosted pair-produced top quarks as a function of top-quark and $t\bar{t}$ system kinematic observables using proton--proton collisions at a center-of-mass energy of $\sqrt{s} = 13$ TeV. The data set corresponds to an integrated luminosity of $36.1$ fb$^{-1}$, recorded in 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. Events with two large-radius jets in the final state, one with transverse momentum $p_{\rm T} > 500$ GeV and a second with $p_{\rm T}>350$ GeV, are used for the measurement. The top-quark candidates are separated from the multijet background using jet substructure information and association with a $b$-tagged jet. The measured spectra are corrected for detector effects to a particle-level fiducial phase space and a parton-level limited phase space, and are compared to several Monte Carlo simulations by means of calculated $\chi^2$ values. The cross-section for $t\bar{t}$ production in the fiducial phase-space region is $292 \pm 7 \ \rm{(stat)} \pm 76 \rm{(syst)}$ fb, to be compared to the theoretical prediction of $384 \pm 36$ fb