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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.

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.

Using multi-ancestry genome-wide association study and fine-mapping, 298 loci and 36 credible genes are identified in the aetiology of bipolar disorder.

Extrachromosomal circular DNAs (ecDNAs) are prevalent in human cancers and are thought to drive tumor evolution and drug resistance by amplifying oncogenes. Here, authors develop ec3D to reconstruct three-dimensional ecDNA structures, revealing how their spatial organization rewires regulatory circuits.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

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.

Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.

The potential for enhanced sediment delivery to the Ganges-Brahmaputra delta exists, but it alone is insufficient to sustain the system. The delta may be resilient to climate change, but only in the absence of dam construction and water diversions.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

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.

Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

The archaeological site Shinfa-Metema 1 in the lowlands of northwest Ethiopia provides early evidence of intensive riverine-based foraging aided by the likely adoption of the bow and arrow.

Analysis of soundscape data from 139 globally distributed sites reveals that sounds of biological origin exhibit predictable rhythms depending on location and season, whereas sounds of anthropogenic origin are less predictable. Comparisons between paired urban–rural sites show that urban green spaces are noisier and dominated by sounds of technological origin.

Long-distance migration and dispersion is a common characteristic of nearly all classes of telencephalic GABAergic neurons, which diversify extensively after birth in the cortex and striatum, but show limited postnatal changes in the septum, preoptic area and pallidum.

This study incorporates local ancestry into the Genome Aggregation Database (gnomAD) to improve allele frequency estimates for admixed populations, enhancing variant interpretation and enabling more accurate and equitable genomic research and clinical care.

Foragers hunted small game locally and procured most large prey in riparian habitats and Afromontane grasslands to the southeast of the Kasitu Valley of northern Malawi, suggesting that migratory behavior in large grazers was absent, according to strontium isotopic analysis.

The authors defined a roadmap for investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders. Their proof-of-concept study using the largest available common variant data sets for schizophrenia and volumes of several (mainly subcortical) brain structures did not find evidence of genetic overlap.

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.

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.

Study shows PTSD predisposition shares distinct genes and genomic regions with several cardiovascular conditions. Here the findings reveal neuronal, immune, and metabolic pathways, and repurposed drug targets that further the understanding of the comorbidity.

A genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

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.

The prognostic and diagnostic roles of DNA methylation in acute myeloid leukemia remains to be explored. Here, the authors develop DNA methylation-based models for the prediction of five-year survival and clinical molecular subtypes in both pediatric and adult test cohorts.

The heart is formed from several spatiotemporally distinct progenitor pools during development. Here they show that modulation of retinoic acid signaling can instruct human pluripotent stems cells into heart progenitors that are useful for studying human development and disease.

An expert-elicitation process identifies current methodological barriers for monitoring terrestrial biodiversity, and how technological and procedural development of robotic and autonomous systems may contribute to overcoming these challenges.

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.

In patients with advanced cancer, the development of brain metastasis (BM) often signals a worsening prognosis with limited therapeutic options. Here, the authors assemble a large, open-source neuroimaging dataset of BM and perform spatial and morphological analysis which they use to develop a framework for function-sparing brain radiotherapy design.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

DNA analysis of 6 individuals from eastern and south-central Africa spanning the past approximately 18,000 years, and of 28 previously published ancient individuals, provides genetic evidence supporting hypotheses of increasing regionalization at the end of the Pleistocene.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

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.

A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.

Tan and colleagues conducted a single-cell multiomic analysis of T cell acute lymphoblastic leukemia and identified a treatment-resistant subpopulation of bone marrow progenitor-like blasts associated with poor outcomes.

Genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2 identify mucins as key host factors restricting viral infection.

A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.

Metastatic prostate cancer can be difficult to biopsy and characterise. Here, the authors use cell-free DNA methylation analysis to illustrate changes in hypermethylation in metastatic disease.

Seronegative healthcare workers with an innate signature of infection preferentially expand pre-existing T cells targeting the conserved replication transcription complex of SARS-CoV-2 in abortive infection.

A soft mesh microelectrode array can seamlessly integrate in developing brains, enabling long-term, stable mapping of how single-neuron activity and population dynamics emerge and evolve during brain development.

Different functional variants in ADH1B (and elsewhere) in Europeans and Africans strongly affect risk for alcohol dependence. Dependence only partly genetically correlates with consumption, with strong correlations to other psychiatric disorders.

Does self-administered mindfulness effectively reduce stress? In a study across 37 sites involving 2,239 participants, four mindfulness exercises significantly reduced short-term, self-reported stress.

Genome-wide analysis identifies 30 loci associated with bipolar disorder, allowing for comparisons of shared genes and pathways with other psychiatric disorders, including schizophrenia and depression.

Recent reviewers suggest good books to refresh your mind this summer — from a cultural history of piracy to a scientific tour of the boulevards of Paris.

A genome-wide association study and Metabochip meta-analysis of body mass index (BMI) detects 97 BMI-associated loci, of which 56 were novel, and many loci have effects on other metabolic phenotypes; pathway analyses implicate the central nervous system in obesity susceptibility and new pathways such as those related to synaptic function, energy metabolism, lipid biology and adipogenesis.

Independent of antigen presentation, migratory CCR7⁺ dendritic cells orchestrate the influx, proliferation and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges.

A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.

A novel variant annotation metric that quantifies the level of expression of genetic variants across tissues is validated in the Genome Aggregation Database (gnomAD) and is shown to improve rare variant interpretation.