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A dataset of coding variation, derived from exome sequencing of nearly one million individuals from a range of ancestries, provides insight into rare variants and could accelerate the discovery of disease-associated genes and advance precision medicine efforts.

Benjamin et al. construct polygenic indexes (DNA-based predictors) for 47 phenotypes and make them available to researchers in 11 datasets. They also present a theoretical framework and estimator to help interpret analyses using polygenic indexes.

Engineering of a high-affinity Delta-like variant, named Delta^MAX, potently activates Notch signaling when provided in a bead-bound or cellular format, while administration as a soluble decoy inhibits signaling.

Heavy pnictogen-based compounds are promising nontoxic and stable alternatives to lead-halide perovskites, but are limited by carrier localization. Here, by investigating CuSbSe₂, the authors identify how this limitation could be avoided.

Better analytical methods are needed to extract biological meaning from genome-wide association studies (GWAS) of psychiatric disorders. Here the authors take GWAS data from over 60,000 subjects, including patients with schizophrenia, bipolar disorder and major depression, and identify common etiological pathways shared amongst them.

T cell development involves extensive proliferation of developing thymocytes. Here, the authors demonstrate that the transcription factor Zfp335 regulates the survival post-β-selection thymocytes via the cGAS/STING pathway.

Unprecedented floods and droughts bring new challenges for risk reduction, as is clear from this analysis of the drivers of changing impacts in many cases worldwide, with implications for efficient governance and investment in integrated management.

A Lyst knockout mouse model of Chediak-Higashi Syndrome recapitulates human neurological disease, providing new insights into its neuropathophysiology and a robust platform for therapeutic development.

Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.

OligoFISSEQ combines Oligopaints with fluorescence in situ sequencing to enable the 3D mapping of many regions across the genome in human cells to interrogate genome organization at improved genomic resolution. OligoFISSEQ is compatible with immunochemistry and OligoSTORM for super-resolution imaging.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

Protein tethers can bridge the actin cytoskeleton with cellular membranes. Here, the authors show that two members of the NETWORKED family, NET4A and NET4B, tether actin filaments and the tonoplast through interaction with RABG3b and are essential for actin reorganization during stomatal closure in plant immunity.

CB₂ receptor agonists are developed as potential analgesics or immune-modulatory compounds. Here, the authors characterize the pharmacological properties of widely used CB₂ receptor agonists and antagonists, recommending three that appear most suitable for in vitro and in vivostudies.

Ten years after the discovery of the Higgs boson, the ATLAS  experiment at CERN probes its kinematic properties with a significantly larger dataset from 2015–2018 and provides further insights on its interaction with other known particles.

Niemann-Pick type C1 is a lysosomal storage disease caused by mutations in the NPC1 gene. The authors show that NPC1 regulates calcium levels in the lysosome, and calcium dysregulation could be the proximal event in inducing the accumulation of lipids that characterizes the disease.

Family-based study designs have been applied to resolve confounding by population stratification, dynastic effects and assortative mating in genetic association analyses. Here, Brumpton et al. describe theory and simulations for overcoming such biases in Mendelian randomization through within-family studies.

A continuously evolved adenine base editor is compatible with various Cas proteins and mediates efficient A•T-to-G•C base conversions at a wide variety of PAM sites.

A randomized trial in patients hospitalized with COVID-19 showed no benefit and potentially increased harm associated with the use of convalescent plasma, with subgroup analyses suggesting that the antibody profile in donor plasma is critical in determining clinical outcomes.

Idiopathic pulmonary arterial hypertension is a rare and fatal disease with a heterogeneous treatment response. Here the authors show that unsupervised machine learning of whole blood transcriptomes from 359 patients with idiopathic pulmonary arterial hypertension identifies 3 subgroups (endophenotypes) that improve risk stratification and provide new molecular insights.

Prior to its implantation into the uterus, the mammalian embryo stores substantial lipids. Here the authors unveil how lipid storage and morphogenesis of pluripotent stem cells are fundamentally connected during peri-implantation development.

Genomic structural equation modeling of genome-wide association data for educational attainment and cognitive test performance is used to estimate the genetic component of variation in educational attainment that is independent of cognitive ability. The study finds that noncognitive skills account for 57% of genetic variation in educational attainment.

The ATLAS Collaboration reports the observation of the electroweak production of two jets and a Z-boson pair. This process is related to vector-boson scattering and allows the nature of electroweak symmetry breaking to be probed.

Substantial risk for schizophrenia is conferred by large copy number variants at a number of genomic loci. Here, a significant association between duplications on chromosome 7 and schizophrenia is reported. Importantly, microduplication analysis narrowed down the region to a region just upstream of a gene encoding vasoactive intestinal peptide receptor (VIPR2). Increased expression of VIPR2 in patients with schizophrenia implicates VIP signalling as a molecular mechanism underlying schizophrenia.

RNA-sequencing analysis of cells in the human cortex enabled identification of diverse cell types, revealing well-conserved architecture and homologous cell types as well as extensive differences when compared with datasets covering the analogous region of the mouse brain.

This paper identified >500 genetic loci associated with behaviors and disorders related to self-regulation, including addiction and child behavior problems. The resulting genetic risk scores predict several behavioral, medical and social outcomes.

The ATLAS Collaboration reports a measurement of the ratio of the decay rates of W bosons to τ leptons and muons, in agreement with universal lepton couplings as postulated in the standard model of particle physics.

The ATLAS experiment at the Large Hadron Collider reports a search for charged-lepton-flavour violation in decays of Z bosons into a τ lepton and an electron or muon of opposite charge.

Plasma levels of neurological proteins have the potential to serve as biomarkers for neurological conditions. Here, Hillary et al. perform genome- and epigenome-wide association studies for 92 neurological proteins and identify 41 genomic loci for 33 proteins and 26 CpG sites for 9 proteins.

Cells with mitochondrial defects are shown to be eliminated by cell competition in the early mouse embryo, thus suggesting that cell competition acts as a purifying selection that optimizes mitochondrial performance during development.

Cell shape provides a structural signature for the classification and investigation of the jamming of bronchial epithelial layers in asthma.

Quantum electrodynamics predicts a rare process in which light is scattered by light. The ATLAS Collaboration reports signs of this elusive effect in the collisions of ultra-relativistic lead ions.

DNA metabarcoding is used to survey the spatial and temporal distribution of airborne grass pollen genera over the summer grass pollen season across Great Britain.

Doping 2D materials is an effective way to engineer a wide range of properties of interest from catalysis to quantum bits. Here, the authors investigate Br-doped 2H-MoTe₂ using electron spin resonance and scanning tunneling spectroscopy, demonstrating that the dopant-orbitals hybridise to the Q-valleys of the conduction band and produce long-lived spin states protected by spin-valley locking.

Phytase is a high molecular weight acid phosphatase. The structure has an α/β-domain similar to that of rat acid phosphatase and an α-domain with a new fold.

The microstructure of organic semiconductors affects their transport properties, but directly probing this relationship is challenging. He et al. show that step edges act as electron traps on the surfaces of n-type single crystals, resulting in a field effect transistor mobility that depends on step density.

As phase 1 of the Earth Microbiome Project, analysis of 16S ribosomal RNA sequences from more than 27,000 environmental samples delivers a global picture of the basic structure and drivers of microbial distribution.

Gene-editing technology and large-scale proteomics are used to provide insights into the modular assembly of the human mitochondrial respiratory chain complex I, as well as identifying new assembly factors.