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Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Cosgun et al. show that, in B cell leukemia, β-catenin expression is maintained at low levels through glycogen synthase kinase 3B (GSK3β)-mediated phosphorylation. Inhibition of GSK3β results in β-catenin–Ikaros–NuRD complex formation, leading to B-ALL cell death through MYC repression.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

This study found E. coli phylogenetic background shapes TEM-1 beta-lactamase expression and co-amoxiclav resistance. Phylogeny alone shifted isolates from susceptible to resistant, stressing a need for lineage-sensitive genotype-phenotype prediction.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Polyamines produced by gut bacteria have been proposed to contribute to inflammatory bowel diseases. Here, Nauta et al. show that bacteria can produce a noncanonical polyamine intermediate that functions similarly to deoxyhypusine synthase inhibitors, activates mitochondrial stress responses, and inhibits nematode development and mouse macrophage differentiation.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

Mass-wasting deposits that accumulated against mid-ocean ridge faults have high porosity in which calcium carbonate precipitated, storing seawater carbon dioxide, as revealed by cores of a 61-million-year-old seafloor talus deposit.

Limited diagnostic capacity for asymptomatic individuals hinders malaria elimination efforts in Africa. Here, the authors present a near point-of-care method based on colorimetric LAMP detection that outperforms expert microscopy and commercial rapid diagnostic tests for Plasmodium detection in asymptomatic and submicroscopic individuals.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Phylogenomic analysis of 7,923 angiosperm species using a standardized set of 353 nuclear genes produced an angiosperm tree of life dated with 200 fossil calibrations, providing key insights into evolutionary relationships and diversification.

Metagenomic and biochemical analyses of soil samples from Antarctic desert regions provides evidence that bacteria in these soils derive carbon and energy from atmospheric CO, H₂ and CO₂.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Assigning inter-individual similarities to genetic and non-genetic factors is central to quantitative genetics. Here, the authors look at phenotypic covariance among pairs of individuals for 32 traits across the UK Biobank, from nominally unrelated pairs through to monozygotic twins.

Megaraptoran theropod dinosaur anatomy and evolution is unclear due to the fragmentary nature of most available fossils. Here the authors report a well-preserved, late surviving megaraptoran from Argentina that clarifies our understanding of the morphology of this group and potentially provides insights into its diet and feeding strategies.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

This Consensus Statement presents the standards for technical reporting in environmental and host-associated microbiome studies (STREAMS) guidelines.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Genetic and testing data from England show that the SARS-CoV-2 variant of concern B.1.1.7 has a transmission advantage over other lineages.

Genome-wide association analysis of gout and urate identifies 148 new loci, implicating biological pathways and prioritizing candidate genes involved in inflammatory processes.

Post-international travel quarantine has been widely implemented to mitigate SARS-CoV-2 transmission, but the impacts of such policies are unclear. Here, the authors used linked genomic and contact tracing data to assess the impacts of a 14-day quarantine on return to England in summer 2020.

This study shows that epigenetic gene body DNA methylation regulates transcription and accounts for much of its variance in the Arabidopsis population, efficiently identifies genes regulating diverse traits and may facilitate local adaptation.

Reconstructing bacterial diversity dynamics from phylogenies, the authors estimate that there are about 1.4–1.9 million extant bacterial lineages and that diversity has been continuously increasing over the past 1 billion years, although most lineages to have inhabited Earth are now extinct.

Brook trout are at risk from climate change, making it crucial to understand how they adapt to warming temperatures. This study identifies genomic variation linked with response to heat stress, revealing population differences in vulnerability and the potential for assisted gene flow to improve climate resilience.

Here, the authors show that post-translational molecular signatures of human skeletal muscle in response to acute or chronic aerobic and resistance exercise are distinct, potentially dictating the differential physiologic adaptations to different exercise modes.

Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

A century after being predicted by theory, the authors detect and quantify the genomic signature of assortative mating in ~400,000 contemporary human genomes, and report new genetic evidence for assortative mating on height and educational attainment.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Trees come in all shapes and size, but what drives this incredible variation in tree form remains poorly understood. Using a global dataset, the authors show that a combination of climate, competition, disturbance and evolutionary history shape the crown architecture of the world’s trees and thereby constrain the 3D structure of woody ecosystems.

Genetic variation in phenotypic plasticity suggests local adaptation is possible. A multi-site, multi-trait experiment shows such adaptation driven by predation in Daphnia pulex.

Linking epigenetic marks to clinical outcomes promises insight into the underlying processes. Here, the authors introduce a statistical approach to estimate associations between a phenotype and all epigenetic probes jointly, and to estimate the proportion of variation captured by epigenetic effects.

A wireless device for measuring bioimpedance during breastfeeding allows accurate quantification of the volume of expressed milk in 12 new mothers in a neonatal intensive care unit and in home settings.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

Mutations in the Wnt co-receptor, LRP5, lead to skeletal diseases in humans. Matthew Warman and his colleagues have now developed mutant mice with tissue-specific alterations of Lrp5 expression and found that these mice phenocopy the human skeletal diseases. They also found that Lrp5 acts locally to affect bone homeostasis. Their data suggest that increasing LRP5 signaling in mature bone cells may be a strategy to treat osteoporosis.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.