Correction for founder effects in host-viral association studies via principal components

Viruses such as HIV and Hepatitis C (HCV) replicate rapidly and with high transcription error rates, which may facilitate their escape from immune detection through the encoding of mutations at key positions within human leukocyte antigen (HLA)-specific peptides, thus impeding T-cell recognition. Large-scale population-based host-viral association studies are conducted as hypothesis-generating analyses which aim to determine the positions within the viral sequence at which host HLA immune pressure may have led to these viral escape mutations. When transmission of the virus to the host is HLA-associated, however, standard tests of association can be confounded by the viral relatedness of contemporarily circulating viral sequences, as viral sequences descended from a common ancestor may share inherited patterns of polymorphisms, termed 'founder effects'. Recognizing the correspondence between this problem and the confounding of case-control genome-wide association studies by population stratification, we adapt methods taken from that field to the analysis of host-viral associations. In particular, we consider methods based on principal components analysis within a logistic regression framework motivated by alternative formulations in the Frisch-Waugh-Lovell Theorem. We demonstrate via simulation their utility in detecting true host-viral associations whilst minimizing confounding by associations generated by founder effects. The proposed methods incorporate relatively robust, standard statistical procedures which can be easily implemented using widely available software, and provide alternatives to the more complex computer intensive methods often implemented in this area

An Altered Immune Response, but Not Individual Cationic Antimicrobial Peptides, Is Associated with the Oral Attenuation of Ara4N-Deficient Salmonella enterica Serovar Typhimurium in Mice

Salmonella enterica serovar Typhimurium (S. Typhimurium) uses two-component regulatory systems (TCRS) to respond to stimuli in the local microenvironment. Upon infection, the Salmonella TCRSs PhoP-PhoQ (PhoPQ) and PmrA-PmrB (PmrAB) are activated by environmental signals in the intestinal lumen and within host cells. TCRS-mediated gene expression results in lipopolysaccharide (LPS) modification and cationic antimicrobial peptide resistance. The PmrA-regulated pmrHFIJKLM operon mediates 4-amino-4-deoxy-L-arabinose (Ara4N) production and attachment to the lipid A of LPS. A ΔpmrF S. Typhimurium strain cannot produce Ara4N, exhibits increased sensitivity to cationic antimicrobial peptide (CAMP)-mediated killing, and attenuated virulence in mice upon oral infection. CAMPs are predicted to play a role in elimination of Salmonella, and may activate PhoPQ and PmrAB in vivo, which could increase bacterial resistance to host defenses. Competition experiments between wild type (WT) and ΔpmrF mutant strains of S. Typhimurium indicated that selection against this mutant first occurs within the intestinal lumen early during infection. However, CRAMP and active cryptdins alone are not responsible for elimination of Ara4N-deficient bacteria in vivo. Investigation into the early immune response to ΔpmrF showed that it differed slightly from the early immune response to WT S. Typhimurium. Further investigation into the early immune response to infection of Peyer's patches suggests a role for IL-13 in the attenution of the ΔpmrF mutant strain. Thus, prominent CAMPs present in the mouse intestine are not responsible for the selection against the ΔpmrF strain in this location, but limited alterations in innate immune induction were observed that affect bacterial survival and virulence

Automated Coronal Hole Detection using Local Intensity Thresholding Techniques

We identify coronal holes using a histogram-based intensity thresholding technique and compare their properties to fast solar wind streams at three different points in the heliosphere. The thresholding technique was tested on EUV and X-ray images obtained using instruments onboard STEREO, SOHO and Hinode. The full-disk images were transformed into Lambert equal-area projection maps and partitioned into a series of overlapping sub-images from which local histograms were extracted. The histograms were used to determine the threshold for the low intensity regions, which were then classified as coronal holes or filaments using magnetograms from the SOHO/MDI. For all three instruments, the local thresholding algorithm was found to successfully determine coronal hole boundaries in a consistent manner. Coronal hole properties extracted using the segmentation algorithm were then compared with in situ measurements of the solar wind at 1 AU from ACE and STEREO. Our results indicate that flux tubes rooted in coronal holes expand super-radially within 1 AU and that larger (smaller) coronal holes result in longer (shorter) duration high-speed solar wind streams

Reducing nitrous oxide emissions by changing N fertiliser use from calcium ammonium nitrate (CAN) to urea based formulations

This research was financially supported under the National Development Plan, through the Research Stimulus Fund, administered by the Department of Agriculture, Food and the Marine (Grant numbers RSF10-/RD/SC/716 and RSF11S138) and from the Department of Agriculture and Rural Development (Ref: DARD Evidence and Innovation project 13/04/06) for Northern Ireland. The first author gratefully acknowledges funding received from the Teagasc Walsh Fellowship Scheme (Ref: 2012005).peer-reviewedThe accelerating use of synthetic nitrogen (N) fertilisers, to meet the world's growing food demand, is the primary driver for increased atmospheric concentrations of nitrous oxide (N2O). The IPCC default emission factor (EF) for N2O from soils is 1% of the N applied, irrespective of its form. However, N2O emissions tend to be higher from nitrate-containing fertilisers e.g. calcium ammonium nitrate (CAN) compared to urea, particularly in regions, which have mild, wet climates and high organic matter soils. Urea can be an inefficient N source due to NH3 volatilisation, but nitrogen stabilisers (urease and nitrification inhibitors) can improve its efficacy. This study evaluated the impact of switching fertiliser formulation from calcium ammonium nitrate (CAN) to urea-based products, as a potential mitigation strategy to reduce N2O emissions at six temperate grassland sites on the island of Ireland. The surface applied formulations included CAN, urea and urea with the urease inhibitor N-(n-butyl) thiophosphoric triamide (NBPT) and/or the nitrification inhibitor dicyandiamide (DCD). Results showed that N2O emissions were significantly affected by fertiliser formulation, soil type and climatic conditions. The direct N2O emission factor (EF) from CAN averaged 1.49% overall sites, but was highly variable, ranging from 0.58% to 3.81. Amending urea with NBPT, to reduce ammonia volatilisation, resulted in an average EF of 0.40% (ranging from 0.21 to 0.69%)-compared to an average EF of 0.25% for urea (ranging from 0.1 to 0.49%), with both fertilisers significantly lower and less variable than CAN. Cumulative N2O emissions from urea amended with both NBPT and DCD were not significantly different from background levels. Switching from CAN to stabilised urea formulations was found to be an effective strategy to reduce N2O emissions, particularly in wet, temperate grassland.Department of Agriculture and Rural Development for Northern IrelandTeagasc Walsh Fellowship ProgrammeDepartment of Agriculture, Food and the Marin

Origins of the Ambient Solar Wind: Implications for Space Weather

The Sun's outer atmosphere is heated to temperatures of millions of degrees, and solar plasma flows out into interplanetary space at supersonic speeds. This paper reviews our current understanding of these interrelated problems: coronal heating and the acceleration of the ambient solar wind. We also discuss where the community stands in its ability to forecast how variations in the solar wind (i.e., fast and slow wind streams) impact the Earth. Although the last few decades have seen significant progress in observations and modeling, we still do not have a complete understanding of the relevant physical processes, nor do we have a quantitatively precise census of which coronal structures contribute to specific types of solar wind. Fast streams are known to be connected to the central regions of large coronal holes. Slow streams, however, appear to come from a wide range of sources, including streamers, pseudostreamers, coronal loops, active regions, and coronal hole boundaries. Complicating our understanding even more is the fact that processes such as turbulence, stream-stream interactions, and Coulomb collisions can make it difficult to unambiguously map a parcel measured at 1 AU back down to its coronal source. We also review recent progress -- in theoretical modeling, observational data analysis, and forecasting techniques that sit at the interface between data and theory -- that gives us hope that the above problems are indeed solvable.Comment: Accepted for publication in Space Science Reviews. Special issue connected with a 2016 ISSI workshop on "The Scientific Foundations of Space Weather." 44 pages, 9 figure

Mapping and characterization of structural variation in 17,795 human genomes

A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline1 to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0–11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing

Search for heavy resonances decaying into a Z or W boson and a Higgs boson in final states with leptons and b-jets in 139 fb−1 of pp collisions at s√ = 13 TeV with the ATLAS detector

This article presents a search for new resonances decaying into a Z or W boson and a 125 GeV Higgs boson h, and it targets the νν¯¯¯bb¯¯, ℓ+ℓ−bb¯¯, or ℓ±νbb¯¯ final states, where ℓ = e or μ, in proton-proton collisions at s√ = 13 TeV. The data used correspond to a total integrated luminosity of 139 fb−1 collected by the ATLAS detector during Run 2 of the LHC at CERN. The search is conducted by examining the reconstructed invariant or transverse mass distributions of Zh or Wh candidates for evidence of a localised excess in the mass range from 220 GeV to 5 TeV. No significant excess is observed and 95% confidence-level upper limits between 1.3 pb and 0.3 fb are placed on the production cross section times branching fraction of neutral and charged spin-1 resonances and CP-odd scalar bosons. These limits are converted into constraints on the parameter space of the Heavy Vector Triplet model and the two-Higgs-doublet model

The ATLAS trigger system for LHC Run 3 and trigger performance in 2022

The ATLAS trigger system is a crucial component of the ATLAS experiment at the LHC. It is responsible for selecting events in line with the ATLAS physics programme. This paper presents an overview of the changes to the trigger and data acquisition system during the second long shutdown of the LHC, and shows the performance of the trigger system and its components in the proton-proton collisions during the 2022 commissioning period as well as its expected performance in proton-proton and heavy-ion collisions for the remainder of the third LHC data-taking period (2022–2025)

Inclusive-photon production and its dependence on photon isolation in pp collisions at s√ = 13 TeV using 139 fb−1 of ATLAS data

Measurements of differential cross sections are presented for inclusive isolated-photon production in pp collisions at a centre-of-mass energy of 13 TeV provided by the LHC and using 139 fb−1 of data recorded by the ATLAS experiment. The cross sections are measured as functions of the photon transverse energy in different regions of photon pseudorapidity. The photons are required to be isolated by means of a fixed-cone method with two different cone radii. The dependence of the inclusive-photon production on the photon isolation is investigated by measuring the fiducial cross sections as functions of the isolation-cone radius and the ratios of the differential cross sections with different radii in different regions of photon pseudorapidity. The results presented in this paper constitute an improvement with respect to those published by ATLAS earlier: the measurements are provided for different isolation radii and with a more granular segmentation in photon pseudorapidity that can be exploited in improving the determination of the proton parton distribution functions. These improvements provide a more in-depth test of the theoretical predictions. Next-to-leading-order QCD predictions from JETPHOX and SHERPA and next-to-next-to-leading-order QCD predictions from NNLOJET are compared to the measurements, using several parameterisations of the proton parton distribution functions. The measured cross sections are well described by the fixed-order QCD predictions within the experimental and theoretical uncertainties in most of the investigated phase-space region

Measurements of Zγ+jets differential cross sections in pp collisions at s√ = 13 TeV with the ATLAS detector

Differential cross-section measurements of Zγ production in association with hadronic jets are presented, using the full 139 fb−1 dataset of s√ = 13 TeV proton–proton collisions collected by the ATLAS detector during Run 2 of the LHC. Distributions are measured using events in which the Z boson decays leptonically and the photon is usually radiated from an initial-state quark. Measurements are made in both one and two observables, including those sensitive to the hard scattering in the event and others which probe additional soft and collinear radiation. Different Standard Model predictions, from both parton-shower Monte Carlo simulation and fixed-order QCD calculations, are compared with the measurements. In general, good agreement is observed between data and predictions from MATRIX and MiNNLOPS, as well as next-to-leading-order predictions from MADGRAPH5_AMC@NLO and SHERPA