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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.

Here they show that HDAC6 inhibition regulates fumarate hydratase (FH), disrupts mitochondria, increases fumarate, and causes cancer cell death. This suggests that HDAC6 inhibition could be a strategy to target tumour metabolism indirectly.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

John Perry and colleagues report the results of a large genome-wide association study meta-analysis to identify variants influencing age at natural menopause. They identify 54 independent signals and find enrichment near genes involved in delayed puberty and DNA damage response.

The tuberculosis pandemic requires new methods for diagnosing and containing infections prior to active disease. Here, the authors performed a multi-site observational study within sub-Saharan Africa and present serum and plasma metabolic signatures that can predict the onset of active TB with a high degree of sensitivity and specificity.

In this Stage 2 Registered Report, Buchanan et al. show evidence confirming the phenomenon of semantic priming across speakers of 19 diverse languages.

Peptidoglycan released by neighbouring kin or non-kin cell lysis induces physiological changes that protect from a range of stresses, including phage predation.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

Kathryn Lunetta and colleagues report a meta-analysis of 22 genome-wide association studies for age at menopause. They identify 13 loci newly associated with age at natural menopause, including several candidate genes with roles in DNA repair and immune function.

Senegal has initiated a national sentinel surveillance program for malaria parasite genetics. Here, the authors report data from the first year of the program and use it to investigate local malaria incidence, patterns of transmission, and genetic loci under selection.

Structural determination and analysis of HLA-I that presents an HIV-derived peptide to an NK cell receptor reveal that N-terminal extended epitope conformations contribute to immune recognition and mechanisms of HIV immune escape.

Flexomagnetism refers to the modification of the magnetic properties of a material due to inhomogeneous strain, and offers a promising pathway to the control and manipulation of magnetism. Here, Makushko et al. explore flexomagnetism in antiferromagnetic thin films of Cr₂O₃, demonstrating a gradient of the Néel temperature as a result of an inhomogeneous strain.

FAM72A differentially controls mutation rates by regulating uracil processing at different stages of the cell cycle, thereby regulating somatic hypermutation and class-switch recombination in B cells.

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

Stabilization of DNA quadruplex structures (G4) is lethal for cells with a compromised DNA repair pathway. Here, the authors show that CX-5461, a small molecule in clinical trials as RNA polymerase inhibitor, has G4-stablization properties and can be repurposed to target DNA repair-defective cancers cells.

A multi-omic atlas of breast cancers, integrating single-cell RNA sequencing, spatial transcriptomics and immunophenotyping, identifies nine ecotypes associated with cellular heterogeneity and prognosis.

Mammalian genomes are scattered with repetitive sequences, but their biology remains largely elusive. Here, the authors show that transcription can initiate from short tandem repetitive sequences, and that genetic variants linked to human diseases are preferentially found at repeats with high transcription initiation level.

Direct RNA sequencing using nanopore platform can be used to detect N6-methyladenosine (m6A) modifications on mRNAs. Here the authors systematically compare tools used for m6A detection from nanopore direct sequencing.

An optical sensing technique reveals an abundance of correlated insulating states at fractional fillings of moiré superlattices that are proposed to arise from a series of charge-ordered states.

Hong Kong experienced a severe wave of SARS-CoV-2 in early 2022. Here, the authors use genomic and serosurveillance data and show that this wave was dominated by the Omicron BA.2 sublineage, and that low protective immunity, particularly in older age groups, contributed to its severity.

Results of the TRACERx study shed new light into the association between body composition and body weight with survival in individuals with non-small cell lung cancer, and delineate potential biological processes and mediators contributing to the development of cancer-associated cachexia.

A consortium reports the tripling of the number of genetic markers in Phase II of the International HapMap Project. This map of human genetic variation will continue to revolutionize discovery of susceptibility loci in common genetic diseases, and study of genes under selection in humans.

A two-fold rotational symmetry is observed in the superconducting state of NbSe₂. This is strikingly different from the three-fold symmetry of the lattice, and suggests that a mixed conventional and unconventional order parameter exists in this material.

Until today effective antivirals for COVID-19 treatment are not widely available. Here, Zhao et al. characterize a dual-functional cross-linking peptide, 8P9R, that can inhibit SARS-CoV-2 virus entry in vitro and suppresses viral replication in vivo in golden Syrian hamster.

Transposon based screens carried out in mice can identify genes critical for tumourigensis. Here, the authors describe transposon screens in mouse models of breast cancer and highlight a large group of tumour suppressors that could underlie selection for common chromosome arm losses in cancer.

A computational approach to generate reference-free protein families from the sequence space in metagenomes reveals an enormously diverse functional space.

The protein DJ-1 is known to have antioxidant effects in cells. Here, the authors reveal that DJ-1 has a role in coupling mitochondrial respiration in skeletal muscles of mice, and show that absence of DJ-1 increases energy expenditure and protects mice from diet-induced obesity.

Gui et al. report that tumor-cell-derived factors induce p38a activation in lung fibroblasts, leading to inactivation of type I interferon signaling, matrix remodeling and neutrophil infiltration, thereby generating a metastasis-permissive niche.

Structural variants in more than 17,000 human genomes are mapped and characterized using whole-genome sequencing, showing how this type of variation contributes to rare deleterious coding and noncoding alleles.

Condensation of interlayer excitons at temperatures above 100 kelvin is demonstrated in a van der Waals heterostructure consisting of two-dimensional atomic double layers of transition metal chalcogenides.

Although checkpoint inhibitor blockade has been extremely successful in certain types of cancer, harnessing the immune system for immunosurveillance has met with numerous failures. In this Review, Mak and colleagues discuss the lessons learned from these failures, and how to incorporate the growing understanding of immuno-oncology into potential therapies, including combinations with existing checkpoint inhibitors.

A new study by Minna Woo and colleagues shows that a neuronal relay from the brain to the adipose tissue regulates whole-body insulin sensitivity by affecting macrophage function, and thus inflammation, in the periphery. These results suggest that a centrally mediated anti-inflammatory reflex exists to regulate metabolic health.

Expression of the transporter SLC43A2 by tumour cells allows them to outcompete T cells for methionine and thereby disrupt the survival and function of tumour-infiltrating T cells.

Remote-sensing estimates of fires and the estimated geographic ranges of thousands of plant and vertebrate species in the Amazon Basin reveal that fires have impacted the ranges of 77–85% of threatened species over the past two decades.