Transgenic Rescue of the LARGEmyd Mouse: A LARGE Therapeutic Window?

LARGE is a glycosyltransferase involved in glycosylation of α-dystroglycan (α-DG). Absence of this protein in the LARGEmyd mouse results in α-DG hypoglycosylation, and is associated with central nervous system abnormalities and progressive muscular dystrophy. Up-regulation of LARGE has previously been proposed as a therapy for the secondary dystroglycanopathies: overexpression in cells compensates for defects in multiple dystroglycanopathy genes. Counterintuitively, LARGE overexpression in an FKRP-deficient mouse exacerbates pathology, suggesting that modulation of α-DG glycosylation requires further investigation. Here we demonstrate that transgenic expression of human LARGE (LARGE-LV5) in the LARGEmyd mouse restores α-DG glycosylation (with marked hyperglycosylation in muscle) and that this corrects both the muscle pathology and brain architecture. By quantitative analyses of LARGE transcripts we also here show that levels of transgenic and endogenous LARGE in the brains of transgenic animals are comparable, but that the transgene is markedly overexpressed in heart and particularly skeletal muscle (20–100 fold over endogenous). Our data suggest LARGE overexpression may only be deleterious under a forced regenerative context, such as that resulting from a reduction in FKRP: in the absence of such a defect we show that systemic expression of LARGE can indeed act therapeutically, and that even dramatic LARGE overexpression is well-tolerated in heart and skeletal muscle. Moreover, correction of LARGEmyd brain pathology with only moderate, near-physiological LARGE expression suggests a generous therapeutic window

Effects of infection-induced migration delays on the epidemiology of avian influenza in wild mallard populations

Wild waterfowl populations form a natural reservoir of Avian Influenza (AI) virus, and fears exist that these birds may contribute to an AI pandemic by spreading the virus along their migratory flyways. Observational studies suggest that individuals infected with AI virus may delay departure from migratory staging sites. Here, we explore the epidemiological dynamics of avian influenza virus in a migrating mallard (Anas platyrhynchos) population with a specific view to understanding the role of infection-induced migration delays on the spread of virus strains of differing transmissibility. We develop a host-pathogen model that combines the transmission dynamics of influenza with the migration, reproduction and mortality of the host bird species. Our modeling predicts that delayed migration of individuals influences both the timing and size of outbreaks of AI virus. We find that (1) delayed migration leads to a lower total number of cases of infection each year than in the absence of migration delay, (2) when the transmission rate of a strain is high, the outbreak starts at the staging sites at which birds arrive in the early part of the fall migration, (3) when the transmission rate is low, infection predominantly occurs later in the season, which is further delayed when there is a migration delay. As such, the rise of more virulent AI strains in waterfowl could lead to a higher prevalence of infection later in the year, which could change the exposure risk for farmed poultry. A sensitivity analysis shows the importance of generation time and loss of immunity for the effect of migration delays. Thus, we demonstrate, in contrast to many current transmission risk models solely using empirical information on bird movements to assess the potential for transmission, that a consideration of infection-induced delays is critical to understanding the dynamics of AI infection along the entire flyway.<br /

Measurements of integrated and differential cross sections for isolated photon pair production in pp collisions at √s=8 TeV with the ATLAS detector

A measurement of the production cross section for two isolated photons in proton-proton collisions at a center-of-mass energy of √s=8 TeV is presented. The results are based on an integrated luminosity of 20.2 fb−1 recorded by the ATLAS detector at the Large Hadron Collider. The measurement considers photons with pseudorapidities satisfying |ηγ|40GeV and EγT,2>30 GeV for the two leading photons ordered in transverse energy produced in the interaction. The background due to hadronic jets and electrons is subtracted using data-driven techniques. The fiducial cross sections are corrected for detector effects and measured differentially as a function of six kinematic observables. The measured cross section integrated within the fiducial volume is 16.8 ± 0.8  pb . The data are compared to fixed-order QCD calculations at next-to-leading-order and next-to-next-to-leading-order accuracy as well as next-to-leading-order computations including resummation of initial-state gluon radiation at next-to-next-to-leading logarithm or matched to a parton shower, with relative uncertainties varying from 5% to 20%

Search for the direct production of charginos and neutralinos in final states with tau leptons in √s=13 TeV collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with at least two hadronically decaying tau leptons is presented. The analysis uses a dataset of pp collisions corresponding to an integrated luminosity of 36.1 fb−1, recorded with the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 13TeV.Nosignificant deviation from the expected Standard Model background is observed. Limits are derived in scenarios of ˜χ+1 ˜χ−1 pair production and of ˜χ±1 ˜χ02 and ˜χ+1 ˜χ−1 production in simplified models where the neutralinos and charginos decay solely via intermediate left-handed staus and tau sneutrinos, and the mass of the ˜ τL state is set to be halfway between the masses of the ˜χ±1 and the ˜χ01. Chargino masses up to 630 GeV are excluded at 95% confidence level in the scenario of direct production of ˜χ+1 ˜χ−1 for a massless ˜χ01. Common ˜χ±1 and ˜χ02 masses up to 760 GeV are excluded in the case of production of ˜χ±1 ˜χ02 and ˜χ+1 ˜χ−1 assuming a massless ˜χ01. Exclusion limits for additional benchmark scenarios with large and small mass-splitting between the ˜χ±1 and the ˜χ01 are also studied by varying the ˜ τL mass between the masses of the ˜χ±1 and the ˜χ01

Search for High-Mass Resonances Decaying to τν in pp Collisions at √s=13 TeV with the ATLAS Detector

A search for high-mass resonances decaying to τν using proton-proton collisions at √s=13 TeV produced by the Large Hadron Collider is presented. Only τ-lepton decays with hadrons in the final state are considered. The data were recorded with the ATLAS detector and correspond to an integrated luminosity of 36.1 fb−1. No statistically significant excess above the standard model expectation is observed; model-independent upper limits are set on the visible τν production cross section. Heavy W′ bosons with masses less than 3.7 TeV in the sequential standard model and masses less than 2.2–3.8 TeV depending on the coupling in the nonuniversal G(221) model are excluded at the 95% credibility level

Measurement of the inelastic proton-proton cross section at √s=13 TeV with the ATLAS detector at the LHC

This Letter presents a measurement of the inelastic proton-proton cross section using 60  μb −1 of pp collisions at a center-of-mass energy √s of 13 TeV with the ATLAS detector at the LHC. Inelastic interactions are selected using rings of plastic scintillators in the forward region (2.0710 −6 , where M X is the larger invariant mass of the two hadronic systems separated by the largest rapidity gap in the event. In this ξ range the scintillators are highly efficient. For diffractive events this corresponds to cases where at least one proton dissociates to a system with M X >13  GeV . The measured cross section is compared with a range of theoretical predictions. When extrapolated to the full phase space, a cross section of 78.1±2.9  mb is measured, consistent with the inelastic cross section increasing with center-of-mass energy

Measurement of the cross section for inclusive isolated-photon production in pp collisions at √s=13TeV using the ATLAS detector

Inclusive isolated-photon production in pp collisions at a centre-of-mass energy of 13TeVis studied with the ATLAS detector at the LHC using a data set with an integrated luminosity of 3.2fb−1. The cross section is measured as a function of the photon transverse energy above 125GeVin different regions of photon pseudorapidity. Next-to-leading-order perturbative QCD and Monte Carlo event-generator predictions are compared to the cross-section measurements and provide an adequate description of the data

Performance of missing transverse momentum reconstruction with the ATLAS detector using proton–proton collisions at √s = 13 TeV

The performance of the missing transverse momentum (EmissT) reconstruction with the ATLAS detector is evaluated using data collected in proton–proton collisions at the LHC at a centre-of-mass energy of 13 TeV in 2015. To reconstruct EmissT, fully calibrated electrons, muons, photons, hadronically decaying τ -leptons, and jets reconstructed from calorimeter energy deposits and charged-particle tracks are used. These are combined with the soft hadronic activity measured by reconstructed charged-particle tracks not associated with the hard objects. Possible double counting of contributions from reconstructed charged-particle tracks from the inner detector, energy deposits in the calorimeter, and reconstructed muons from the muon spectrometer is avoided by applying a signal ambiguity resolution procedure which rejects already used signals when combining the various EmissT contributions. The individual terms as well as the overall reconstructed EmissT are evaluated with various performance metrics for scale (linearity), resolution, and sensitivity to the data-taking conditions. The method developed to determine the systematic uncertainties of the EmissT scale and resolution is discussed. Results are shown based on the full 2015 data sample corresponding to an integrated luminosity of 3.2 fb−1

Search for dark matter at √s=13 TeV in final states containing an energetic photon and large missing transverse momentum with the ATLAS detector

Results of a search for physics beyond the Standard Model in events containing an energetic photon and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. As the number of events observed in data, corresponding to an integrated luminosity of 36.1 fb−1 of proton–proton collisions at a centre-of-mass energy of 13 TeV, is in agreement with the Standard Model expectations, model-independent limits are set on the fiducial cross section for the production of events in this final state. Exclusion limits are also placed in models where dark-matter candidates are pair-produced. For dark-matter production via an axial-vector or a vector mediator in the s-channel, this search excludes mediator masses below 750–1200 GeV for dark-matter candidate masses below 230–480 GeV at 95% confidence level, depending on the couplings. In an effective theory of dark-matter production, the limits restrict the value of the suppression scale M∗ to be above 790 GeV at 95% confidence level. A limit is also reported on the production of a high-mass scalar resonance by processes beyond the Standard Model, in which the resonance decays to Zγ and the Z boson subsequently decays into neutrinos

Heritable symbionts in a world of varying temperature

Heritable microbes represent an important component of the biology, ecology and evolution of many plants, animals and fungi, acting as both parasites and partners. In this review, we examine how heritable symbiont–host interactions may alter host thermal tolerance, and how the dynamics of these interactions may more generally be altered by thermal environment. Obligate symbionts, those required by their host, are considered to represent a thermally sensitive weak point for their host, associated with accumulation of deleterious mutations. As such, these symbionts may represent an important determinant of host thermal envelope and spatial distribution. We then examine the varied relationship between thermal environment and the frequency of facultative symbionts that provide ecologically contingent benefits or act as parasites. We note that some facultative symbionts directly alter host thermotolerance. We outline how thermal environment will alter the benefits/costs of infection more widely, and additionally modulate vertical transmission efficiency. Multiple patterns are observed, with symbionts being cold sensitive in some species and heat sensitive in others, with varying and non-coincident thresholds at which phenotype and transmission are ablated. Nevertheless, it is clear that studies aiming to predict ecological and evolutionary dynamics of symbiont–host interactions need to examine the interaction across a range of thermal environments. Finally, we discuss the importance of thermal sensitivity in predicting the success/failure of symbionts to spread into novel species following natural/engineered introduction