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

Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

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

Analysis of shared heritability in common disorders of the brain

Paroxysmal Cerebral Disorder

Measurement of the top-quark mass using a leptonic invariant mass in pp collisions at s√ = 13 TeV with the ATLAS detector

A measurement of the top-quark mass (mt) in the tt¯ → lepton + jets channel is presented, with an experimental technique which exploits semileptonic decays of b-hadrons produced in the top-quark decay chain. The distribution of the invariant mass mℓμ of the lepton, ℓ (with ℓ = e, μ), from the W-boson decay and the muon, μ, originating from the b-hadron decay is reconstructed, and a binned-template profile likelihood fit is performed to extract mt. The measurement is based on data corresponding to an integrated luminosity of 36.1 fb−1 of s√ = 13 TeV pp collisions provided by the Large Hadron Collider and recorded by the ATLAS detector. The measured value of the top-quark mass is mt = 174.41 ± 0.39 (stat.) ± 0.66 (syst.) ± 0.25 (recoil) GeV, where the third uncertainty arises from changing the PYTHIA8 parton shower gluon-recoil scheme, used in top-quark decays, to a recently developed setup

Search for resonances decaying into photon pairs in 139 fb−1 of pp collisions at √s = 13 TeV with the ATLAS detector

Searches for new resonances in the diphoton final state, with spin 0 as predicted by theories with an extended Higgs sector and with spin 2 using a warped extra-dimension benchmark model, are presented using 139 fb−1 of √s = 13 TeV pp collision data collected by the ATLAS experiment at the LHC. No significant deviation from the Standard Model is observed and upper limits are placed on the production cross-section times branching ratio to two photons as a function of the resonance mass

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

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

Constraints on spin-0 dark matter mediators and invisible Higgs decays using ATLAS 13 TeV pp collision data with two top quarks and missing transverse momentum in the final state

This paper presents a statistical combination of searches targeting final states with two top quarks and invisible particles, characterised by the presence of zero, one or two leptons, at least one jet originating from a b-quark and missing transverse momentum. The analyses are searches for phenomena beyond the Standard Model consistent with the direct production of dark matter in pp collisions at the LHC, using 139 fb−1 of data collected with the ATLAS detector at a centre-of-mass energy of 13 TeV. The results are interpreted in terms of simplified dark matter models with a spin-0 scalar or pseudoscalar mediator particle. In addition, the results are interpreted in terms of upper limits on the Higgs boson invisible branching ratio, where the Higgs boson is produced according to the Standard Model in association with a pair of top quarks. For scalar (pseudoscalar) dark matter models, with all couplings set to unity, the statistical combination extends the mass range excluded by the best of the individual channels by 50 (25) GeV, excluding mediator masses up to 370 GeV. In addition, the statistical combination improves the expected coupling exclusion reach by 14% (24%), assuming a scalar (pseudoscalar) mediator mass of 10 GeV. An upper limit on the Higgs boson invisible branching ratio of 0.38 (0.30+0.13−0.09) is observed (expected) at 95% confidence level

Search for doubly charged Higgs boson production in multi-lepton final states using 139 fb−1 of proton–proton collisions at s√ = 13 TeV with the ATLAS detector

A search for pair production of doubly charged Higgs bosons (H±± ), each decaying into a pair of prompt, isolated, and highly energetic leptons with the same electric charge, is presented. The search uses a proton–proton collision data sample at a centre-of-mass energy of 13 TeV corresponding to an integrated luminosity of 139 fb−1 recorded by the ATLAS detector during Run 2 of the Large Hadron Collider (LHC). This analysis focuses on same-charge leptonic decays, H±±→ℓ±ℓ′± where ℓ,ℓ′=e,μ,τ, in two-, three-, and four-lepton channels, but only considers final states which include electrons or muons. No evidence of a signal is observed. Corresponding upper limits on the production cross-section of a doubly charged Higgs boson are derived, as a function of its mass m(H±±), at 95% confidence level. Assuming that the branching ratios to each of the possible leptonic final states are equal, B(H±±→e±e±)=B(H±±→e±μ±)=B(H±±→μ±μ±)=B(H±±→e±τ±)=B(H±±→μ±τ±)=B(H±±→τ±τ±)=1/6, the observed (expected) lower limit on the mass of a doubly charged Higgs boson is 1080 GeV (1065 GeV) within the left-right symmetric type-II seesaw model, which is the strongest limit to date produced by the ATLAS Collaboration. Additionally, this paper provides the first direct test of the Zee–Babu neutrino mass model at the LHC, yielding an observed (expected) lower limit of m(H±±) = 900 GeV (880 GeV)