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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.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

Superlubric arrays of double-bilayer graphene enable elastically coupled switching between Bernal and rhombohedral graphene polytypes under shear forces below 1 nN with an estimated energy cost of less than 1 fJ per switching event.

Analysis combining multiple global tree databases reveals that whether a location is invaded by non-native tree species depends on anthropogenic factors, but the severity of the invasion depends on the native species diversity.

Latent catalysis in olefin metathesis has seen great progress over the years, leading to key advances in the properties of polymers and 3D printing technologies. Now it is shown that the latency mechanism can be extended to the monomer through quadricyclane–norbornadiene interconversion, expanding the tools available to this field.

Identifying jets originating from heavy quarks plays a fundamental role in hadronic collider experiments. In this work, the ATLAS Collaboration describes and tests a transformer-based neural network architecture for jet flavour tagging based on low-level input and physics-inspired constraints.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

Climate change can alter when and how animals grow, breed, and migrate, but it is unclear whether this allows populations to persist. This global study shows that shifts in seasonal timing are key to helping vertebrate species maintain population growth under global warming.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

This study associates p53 loss and brain metastasis in breast cancer. Mechanistically, p53-null tumors recruit astrocytes that provide substrates for enhanced fatty acid synthesis via upregulated SCD1 expression, representing a targetable axis in the disease.

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.

T cells can recognise lipid antigen in the context of CD1d molecules. Here, the authors show that γδ T cell activation in response to CD1d differs from that of αβ T cells and determine the structure of a γδ T cell receptor that binds to CD1d independently of the presented lipid.

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).

Using synthesized experimental and observational data, Cen et al. revealed that anthropogenic nitrogen deposition has increased global forest soil CO₂ emissions by ~5%, despite considerable spatial variation in the effects of nitrogen deposition.

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.

The ankylosaurian dinosaur Spicomellus afer possessed a tail weapon and uniquely elaborate dermal armour.

Lung adenocarcinomas bearing the ID2 mutational signature display increased LINE-1 retrotransposon activity, which contributes to their fast evolutionary dynamics and aggressive phenotype.

Species’ traits and environmental conditions determine the abundance of tree species across the globe. Here, the authors find that dominant tree species are taller and have softer wood compared to rare species and that these trait differences are more strongly associated with temperature than water availability.

Here, the authors examine the mechanisms behind cheatgrass’s successful invasion of North American ecosystems. Their genetic analyses and common garden experiments demonstrate that multiple introductions and migrations facilitated cheatgrass local adaptation.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

The authors identify pathogenic variants in the SMARCA1 gene as the cause of a variable neurodevelopmental disorder. Mouse studies suggest diverse genetic mechanisms related to NURF complex composition mediate the phenotype.

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.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

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.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Little is known about the diets of early modern humans as they dispersed into Australia. Here, Florin et al. study charred plant remains from Madjedbebe rockshelter, which show that 65–53 thousand years ago, early modern humans in northern Australia already had a broad diet of plants.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Data from questionnaires distributed to hunters and wild meat vendors in Nigeria suggest that most captured pangolins are not specifically targeted and that the animals are primarily captured for their meat, which is mostly consumed by hunters’ households, rather than for their scales.

The authors combine fossil occurrence data, phylogenies and climatic niche modelling to explore the palaeobiogeography of early pterosaurs and their non-flying close relatives, the lagerpetids.

Dysfunction of mitochondrial complex I in mice is sufficient to cause progressive parkinsonism in which the loss of nigral dopamine release critically contributes to motor dysfunction.

The number of individuals in a given space influences animal interactions and network dynamics. Here the authors identify general rules underlying density dependence in animal networks and reveal some fundamental differences between spatial and social dynamics.

A global research network monitoring the Amazon for 30 years reports in this study that tree size increased by 3% each decade.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

In this genomic analysis of peripheral blood samples of the phase 3 CheckMate-067 trial of ipilimumab (IPI) versus nivolumab (NIVO) versus ipilimumab and nivolumab (IPI-NIVO) in melanoma, the status of certain mitochondrial haplogroups in patients was associated therapeutic resistance to NIVO or IPI-NIVO, a finding validated in an independent cohort.

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.

How cells adapt to glucose starvation is still elusive. Here, Levy et al. show that the mTOR substrate 4EBP1 protects human, mouse, and yeast cells from glucose starvation and is exploited by cancer cells to promote tumorigenesis.

Wood density is an important plant trait. Data from 1.1 million forest inventory plots and 10,703 tree species show a latitudinal gradient in wood density, with temperature and soil moisture explaining variation at the global scale and disturbance also having a role at the local level.