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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.

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.

Here, as part of the Sherlock-Lung study, the authors profile the microbiomes of 940 lung cancers in never smokers finding no significant associations with demographic and clinical features, suggesting lung bacteria are unlikely to have a sizable role in lung cancer.

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

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

This study used fine-mapping to analyze genetic regions associated with bipolar disorder, identifying specific risk genes and providing new insights into the biology of the condition that may guide future research and treatment approaches.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Leishmania use large (5–10 kb) transcriptional start regions, where the chromatin is highly enriched for acetylated histones, to drive the expression of polycistronic gene arrays. Here the authors show bromodomain-containing protein BDF5 is enriched at transcriptional start sites and its depletion leads to cell death in vitro and in murine infections, and they identify its interactors.

An analysis of data from the Sherlock-Lung study provides insight into the mutational processes that contribute to lung cancer in never smokers, and looks at the possible role of factors such as air pollution and passive smoking.

Fluorinated poly(aryl thioethers), unlike their poly(aryl ethers) counterparts, have received little attention despite excellent physical properties displayed by many polysulfides. Here the authors show a highly efficient route to fluorinated poly(aryl thioethers) via an organocatalyzed nucleophilic aromatic substitution of silyl-protected dithiols.

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.

It remains unclear why some paediatric tumours appear to have such a low mutation burden. Here, the authors shed light on this paradox by analysing Wilms tumours using high resolution and high depth sequencing approaches, finding that - due to an unusual clonal architecture - standard methods significantly underestimate the mutation burden at the cellular level.

This multisite study detects a link between brain dynamic functional network connectivity and current and future post-traumatic stress symptom severity with a stronger effect in the female group.

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.

Recently, a pipeline for the design of protein-binding proteins using only the structure of the target protein was reported. Here, the authors report that the incorporation of deep learning methods into the original pipeline increases experimental success rate by ten-fold.

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.

Global geospatial datasets and a regression discontinuity design enable the country-level effects, such as agricultural policies, on crop yields and nitrogen pollution to be quantified. The influences of countries were much larger on nitrogen pollution than on crop yields.

A design pipeline is presented whereby binding proteins can be designed de novo without the need for prior information on binding hotspots or fragments from structures of complexes with binding partners.

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.

The authors report data from the emergency department AURORA study to characterize resilience in more detail than the absence of psychopathology after trauma.

Reninomas are very rare kidney tumours of juxtaglomerular cells. Here, the authors analyse reninomas using whole-genome and transcriptome sequencing, and reveal the presence and functional effects of NOTCH1 rearrangements.

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.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Whole-genome sequencing of 962 clear cell renal cell carcinomas from 11 countries shows geographic variations in somatic mutation profiles, including a mutational signature of unknown cause in 70% of cases from Japan.

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.

Reanalysis of bipedal trackways from Laetoli site A in Tanzania suggest that the footprints were made by a hominin that coexisted with at least one other hominin species.

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.

There are many open questions about biogeochemical function in peatlands. Here, the authors investigate the nitrogen cycle of tropical peatlands, finding that a surprisingly high fraction of nitrous oxide production is abiotic and that denitrification is a coupled abiotic-biotic process.

Allele-preferential transcription factor binding can influence pancreatic ductal adenocarcinoma risk loci function. Here, the authors show allele-specific JunB and JunD binding at chr1p36.33 and propose a role for KLHL17 in protein homeostasis by mitigating inflammation.

Susan Slager and colleagues report a meta-analysis of genome-wide association studies for chronic lymphocytic leukemia (CLL). They identify nine loci newly associated with CLL.

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.

Yin et al. show that motor learning is delayed in mice with 16p11.2 deletion, associated with abnormal ensemble activity and delayed spine remodeling in motor cortex and reduced activity of of locus coeruleus noradrenergic neurons. The motor-related abnormalities were rescued by activation of ocus coeruleus noradrenergic neurons.

Studying how the ligand design influences the bonding of f-block complexes is crucial to control their properties. Here, the authors report the preparation of Bk(III) and Ce(III) complexes featuring a terpyridyl ligand; structural, spectroscopic, electrochemical, and theoretical analysis reveal that the ligand induces unusual bonding by creating a plane of enhanced bond covalency.

The parasite Toxoplasma gondii secretes a virulence factor, the kinase ROP17 that modulates Rho–ROCK signalling in the infected host cell, enhancing monocyte motility on the surface of endothelial cells and inhibiting transmigration across endothelial barriers.

Ewing sarcoma (EWS) is a rare pediatric bone cancer typically involving the EWSR1-FLI1 fusion. Here the authors perform a genome-wide association study and report three new EWS risk loci that reside near GGAA repeat sequences, and identify candidate genes (RREB1 and KIZ) from eQTL analysis.

Activation of the non-canonical NF-κB signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of antiretroviral-therapy-treated humanized mice and rhesus macaques.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

Endomucin is expressed by endothelial cells that line postcapillary venules—the site of leukocyte recruitment during inflammation. Zahr et al.show that endomucin is an anti-adhesive molecule that is downregulated by the cytokine TNF-a and thereby helps in the transition from a quiescent to a pro-adhesive inflamed endothelium.

An international consortium reports the genomic sequence for ten Drosophila species, and compares them to two other previously published Drosophila species. These data are invaluable for drawing evolutionary conclusions across an entire phylogeny of species at once.