Assessment of systemic AAV-microdystrophin gene therapy in the GRMD model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by the DMD gene. Although mouse models of DMD provide insight into the potential of a corrective therapy, data from genetically homologous large animals, such as the dystrophin-deficient golden retriever muscular dystrophy (GRMD) model, may more readily translate to humans. To evaluate the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)–microdystrophin (μDys5) construct, we performed a blinded, placebo-controlled study in which 12 GRMD dogs were divided among four dose groups [control, 1 × 1013 vector genomes per kilogram (vg/kg), 1 × 1014 vg/kg, and 2 × 1014 vg/kg; n = 3 each], treated intravenously at 3 months of age with a canine codon-optimized microdystrophin construct, rAAV9-CK8e-c-μDys5, and followed for 90 days after dosing. All dogs received prednisone (1 milligram/kilogram) for a total of 5 weeks from day-7 through day 28. We observed dose-dependent increases in tissue vector genome copy numbers; μDys5 protein in multiple appendicular muscles, the diaphragm, and heart; limb and respiratory muscle functional improvement; and reduction of histopathologic lesions. As expected, given that a truncated dystrophin protein was generated, phenotypic test results and histopathologic lesions did not fully normalize. All administrations were well tolerated, and adverse events were not seen. These data suggest that systemically administered AAV-microdystrophin may be dosed safely and could provide therapeutic benefit for patients with DMD

Search for flavour-changing neutral currents in processes with one top quark and a photon using 81 fb⁻¹ of pp collisions at \sqrts = 13 TeV with the ATLAS experiment

A search for flavour-changing neutral current (FCNC) events via the coupling of a top quark, a photon, and an up or charm quark is presented using 81 fb−1 of proton–proton collision data taken at a centre-of-mass energy of 13 TeV with the ATLAS detector at the LHC. Events with a photon, an electron or muon, a b-tagged jet, and missing transverse momentum are selected. A neural network based on kinematic variables differentiates between events from signal and background processes. The data are consistent with the background-only hypothesis, and limits are set on the strength of the tqγ coupling in an effective field theory. These are also interpreted as 95% CL upper limits on the cross section for FCNC tγ production via a left-handed (right-handed) tuγ coupling of 36 fb (78 fb) and on the branching ratio for t→γu of 2.8×10−5 (6.1×10−5). In addition, they are interpreted as 95% CL upper limits on the cross section for FCNC tγ production via a left-handed (right-handed) tcγ coupling of 40 fb (33 fb) and on the branching ratio for t→γc of 22×10−5 (18×10−5). © 2019 The Author(s

Genetic insights into biological mechanisms governing human ovarian ageing

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause in approximately 200,000 women of European ancestry. These common alleles were associated with clinical extremes of age at natural menopause; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the lifecourse to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease

Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease

Search for single vector-like B quark production and decay via B → bH(b¯b) in pp collisions at √s = 13 TeV with the ATLAS detector

A search is presented for single production of a vector-like B quark decaying into a Standard Model b-quark and a Standard Model Higgs boson, which decays into a b¯b pair. The search is carried out in 139 fb−1 of √s = 13 TeV proton-proton collision data collected by the ATLAS detector at the LHC between 2015 and 2018. No significant deviation from the Standard Model background prediction is observed, and mass-dependent exclusion limits at the 95% confidence level are set on the resonance production cross-section in several theoretical scenarios determined by the couplings cW, cZ and cH between the B quark and the Standard Model W, Z and Higgs bosons, respectively. For a vector-like B occurring as an isospin singlet, the search excludes values of cW greater than 0.45 for a B resonance mass (mB) between 1.0 and 1.2 TeV. For 1.2 TeV < mB < 2.0 TeV, cW values larger than 0.50–0.65 are excluded. If the B occurs as part of a (B, Y) doublet, the smallest excluded cZ coupling values range between 0.3 and 0.5 across the investigated resonance mass range 1.0 TeV < mB < 2.0 TeV

Search for boosted diphoton resonances in the 10 to 70 GeV mass range using 138 fb−1 of 13 TeV pp collisions with the ATLAS detector

A search for diphoton resonances in the mass range between 10 and 70 GeV with the ATLAS experiment at the Large Hadron Collider (LHC) is presented. The analysis is based on pp collision data corresponding to an integrated luminosity of 138 fb−1 at a centre-of-mass energy of 13 TeV recorded from 2015 to 2018. Previous searches for diphoton resonances at the LHC have explored masses down to 65 GeV, finding no evidence of new particles. This search exploits the particular kinematics of events with pairs of closely spaced photons reconstructed in the detector, allowing examination of invariant masses down to 10 GeV. The presented strategy covers a region previously unexplored at hadron colliders because of the experimental challenges of recording low-energy photons and estimating the backgrounds. No significant excess is observed and the reported limits provide the strongest bound on promptly decaying axion-like particles coupling to gluons and photons for masses between 10 and 70 GeV

Evidence for the charge asymmetry in pp → tt¯ production at s√ = 13 TeV with the ATLAS detector

Inclusive and differential measurements of the top–antitop (tt¯) charge asymmetry Att¯C and the leptonic asymmetry Aℓℓ¯C are presented in proton–proton collisions at s√ = 13 TeV recorded by the ATLAS experiment at the CERN Large Hadron Collider. The measurement uses the complete Run 2 dataset, corresponding to an integrated luminosity of 139 fb−1, combines data in the single-lepton and dilepton channels, and employs reconstruction techniques adapted to both the resolved and boosted topologies. A Bayesian unfolding procedure is performed to correct for detector resolution and acceptance effects. The combined inclusive tt¯ charge asymmetry is measured to be Att¯C = 0.0068 ± 0.0015, which differs from zero by 4.7 standard deviations. Differential measurements are performed as a function of the invariant mass, transverse momentum and longitudinal boost of the tt¯ system. Both the inclusive and differential measurements are found to be compatible with the Standard Model predictions, at next-to-next-to-leading order in quantum chromodynamics perturbation theory with next-to-leading-order electroweak corrections. The measurements are interpreted in the framework of the Standard Model effective field theory, placing competitive bounds on several Wilson coefficients

Study of Z → llγ decays at √s = 8 TeV with the ATLAS detector

This paper presents a study of Z → llγ decays with the ATLAS detector at the Large Hadron Collider. The analysis uses a proton–proton data sample corresponding to an integrated luminosity of 20.2 fb−1 collected at a centre-ofmass energy √s = 8 TeV. Integrated fiducial cross-sections together with normalised differential fiducial cross-sections, sensitive to the kinematics of final-state QED radiation, are obtained. The results are found to be in agreement with stateof-the-art predictions for final-state QED radiation. First measurements of Z → llγ γ decays are also reported

Search for third-generation vector-like leptons in pp collisions at s√ = 13 TeV with the ATLAS detector

A search for vector-like leptons in multilepton (two, three, or four-or-more electrons plus muons) final states with zero or more hadronic τ-lepton decays is presented. The search is performed using a dataset corresponding to an integrated luminosity of 139 fb−1 of proton-proton collisions at a centre-of-mass energy of 13 TeV recorded by the ATLAS detector at the LHC. To maximize the separation of signal and background, a machine-learning classifier is used. No excess of events is observed beyond the Standard Model expectation. Using a doublet vector-like lepton model, vector-like leptons coupling to third-generation Standard Model leptons are excluded in the mass range from 130 GeV to 900 GeV at the 95% confidence level, while the highest excluded mass is expected to be 970 GeV

Search for leptoquark pair production decaying into te−te¯ + or tμ−t¯μ+ in multi-lepton final states in pp collisions at √s = 13 TeV with the ATLAS detector

A search for leptoquark pair production decaying into te−te¯ + or tμ−t¯μ+ in final states with multiple leptons is presented. The search is based on a dataset of pp collisions at √s = 13 TeV recorded with the ATLAS detector during Run 2 of the Large Hadron Collider, corresponding to an integrated luminosity of 139 fb−1. Four signal regions, with the requirement of at least three light leptons (electron or muon) and at least two jets out of which at least one jet is identified as coming from a b-hadron, are considered based on the number of leptons of a given flavour. The main background processes are estimated using dedicated control regions in a simultaneous fit with the signal regions to data. No excess above the Standard Model background prediction is observed and 95% confidence level limits on the production cross section times branching ratio are derived as a function of the leptoquark mass. Under the assumption of exclusive decays into te− (tμ−), the corresponding lower limit on the scalar mixed-generation leptoquark mass mLQd mix is at 1.58 (1.59) TeV and on the vector leptoquark mass mU˜1 at 1.67 (1.67) TeV in the minimal coupling scenario and at 1.95 (1.95) TeV in the Yang–Mills scenario