New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

The SEQC2 epigenomics quality control (EpiQC) study

BACKGROUND: Cytosine modifications in DNA such as 5-methylcytosine (5mC) underlie a broad range of developmental processes, maintain cellular lineage specification, and can define or stratify types of cancer and other diseases. However, the wide variety of approaches available to interrogate these modifications has created a need for harmonized materials, methods, and rigorous benchmarking to improve genome-wide methylome sequencing applications in clinical and basic research. Here, we present a multi-platform assessment and cross-validated resource for epigenetics research from the FDA's Epigenomics Quality Control Group. RESULTS: Each sample is processed in multiple replicates by three whole-genome bisulfite sequencing (WGBS) protocols (TruSeq DNA methylation, Accel-NGS MethylSeq, and SPLAT), oxidative bisulfite sequencing (TrueMethyl), enzymatic deamination method (EMSeq), targeted methylation sequencing (Illumina Methyl Capture EPIC), single-molecule long-read nanopore sequencing from Oxford Nanopore Technologies, and 850k Illumina methylation arrays. After rigorous quality assessment and comparison to Illumina EPIC methylation microarrays and testing on a range of algorithms (Bismark, BitmapperBS, bwa-meth, and BitMapperBS), we find overall high concordance between assays, but also differences in efficiency of read mapping, CpG capture, coverage, and platform performance, and variable performance across 26 microarray normalization algorithms. CONCLUSIONS: The data provided herein can guide the use of these DNA reference materials in epigenomics research, as well as provide best practices for experimental design in future studies. By leveraging seven human cell lines that are designated as publicly available reference materials, these data can be used as a baseline to advance epigenomics research

Co-limitation towards lower latitudes shapes global forest diversity gradients

The latitudinal diversity gradient (LDG) is one of the most recognized global patterns of species richness exhibited across a wide range of taxa. Numerous hypotheses have been proposed in the past two centuries to explain LDG, but rigorous tests of the drivers of LDGs have been limited by a lack of high-quality global species richness data. Here we produce a high-resolution (0.025° × 0.025°) map of local tree species richness using a global forest inventory database with individual tree information and local biophysical characteristics from ~1.3 million sample plots. We then quantify drivers of local tree species richness patterns across latitudes. Generally, annual mean temperature was a dominant predictor of tree species richness, which is most consistent with the metabolic theory of biodiversity (MTB). However, MTB underestimated LDG in the tropics, where high species richness was also moderated by topographic, soil and anthropogenic factors operating at local scales. Given that local landscape variables operate synergistically with bioclimatic factors in shaping the global LDG pattern, we suggest that MTB be extended to account for co-limitation by subordinate drivers

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

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)

Search for single production of vector-like T quarks decaying into Ht or Zt in pp collisions at s√ = 13 TeV with the ATLAS detector

This paper describes a search for the single production of an up-type vector-like quark (T) decaying as T → Ht or T → Zt. The search utilises a dataset of pp collisions at s√ = 13 TeV collected with the ATLAS detector during the 2015–2018 data-taking period of the Large Hadron Collider, corresponding to an integrated luminosity of 139 fb−1. Data are analysed in final states containing a single lepton with multiple jets and b-jets. The presence of boosted heavy resonances in the event is exploited to discriminate the signal from the Standard Model background. No significant excess above the Standard Model expectation is observed, and 95% CL upper limits are set on the production cross section of T quarks in different decay channels. The results are interpreted in several benchmark scenarios to set limits on the mass and universal coupling strength (κ) of the vector-like quark. For singlet T quarks, κ values above 0.53 are excluded for all masses below 2.3 TeV. At a mass of 1.6 TeV, κ values as low as 0.35 are excluded. For T quarks in the doublet scenario, where the production cross section is much lower, κ values above 0.72 are excluded for all masses below 1.7 TeV, and this exclusion is extended to κ above 0.55 for low masses around 1.0 TeV

Search for excited τ-leptons and leptoquarks in the final state with τ-leptons and jets in pp collisions at s√ = 13 TeV with the ATLAS detector

A search is reported for excited τ-leptons and leptoquarks in events with two hadronically decaying τ-leptons and two or more jets. The search uses proton-proton (pp) collision data at s√ = 13 TeV recorded by the ATLAS experiment during the Run 2 of the Large Hadron Collider in 2015–2018. The total integrated luminosity is 139 fb−1. The excited τ-lepton is assumed to be produced and to decay via a four-fermion contact interaction into an ordinary τ-lepton and a quark-antiquark pair. The leptoquarks are assumed to be produced in pairs via the strong interaction, and each leptoquark is assumed to couple to a charm or lighter quark and a τ-lepton. No excess over the background prediction is observed. Excited τ-leptons with masses below 2.8 TeV are excluded at 95% CL in scenarios with the contact interaction scale Λ set to 10 TeV. At the extreme limit of model validity where Λ is set equal to the excited τ-lepton mass, excited τ-leptons with masses below 4.6 TeV are excluded. Leptoquarks with masses below 1.3 TeV are excluded at 95% CL if their branching ratio to a charm quark and a τ-lepton equals 1. The analysis does not exploit flavour-tagging in the signal region