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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.

Yan et al. use cryo-EM to obtain structures that reveal how DNMT3A2 and DNMT3L cooperate to read histone signals and bind chromatin, illustrating a mechanism that controls DNA methylation and shapes epigenetic regulation.

Candida auris is a fungal pathogen notorious for persistent skin colonization and transmission in healthcare settings. Here, Zhao et al. explore the mechanisms driving pathogen’s adherence to skin, involving a conserved adhesin, as well as the potential of collagen coatings as a strategy to reduce C. auris adherence to abiotic surfaces.

Structural variants (SVs) in human genomes contribute diversity and diseases. Here, the authors use a multi-platform strategy to generate haplotype-resolved SVs for three human parent–child trios.

The authors show PTEN mutations, which can cause both congenital hydrocephalus and autism spectrum disorder, disrupt CSF homeostasis and brain connectivity in mice. Reducing mTORC1 activation ameliorates ventricular enlargement and neuronal deficits.

Analyses of imputed ancient genomes and of samples from the UK Biobank indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans.

Jayavelu, Samaha et al., apply machine learning models on hospital admission data, including antibody titers and viral load, to identify patients at high risk for Long COVID. Low antibody levels, high viral loads, chronic diseases, and female sex are key predictors, supporting early, targeted interventions.

Using sequencing and haplotype-resolved assembly of 65 diverse human genomes, complex regions including the major histocompatibility complex and centromeres are analysed.

A technique using barcoded beads for DNA sequencing within tissue sections enables spatial resolution of tumour clonal heterogeneity and can be multiplexed with other analytical techniques for analysis of complex cellular phenotypes.

Whether multimorbidity accelerates brain Aβ deposition in humans remains largely unknown. Here, the authors demonstrate that higher self-reported multimorbidity burden predicts increased brain Aβ accumulation rates in the ADNI cohort.

Complete sequences of chromosomes telomere-to-telomere from chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan and siamang provide a comprehensive and valuable resource for future evolutionary comparisons.

An analysis involving the shotgun sequencing of more than 300 ancient genomes from Eurasia reveals a deep east–west genetic divide from the Black Sea to the Baltic, and provides insight into the distinct effects of the Neolithic transition on either side of this boundary.

Catenanes can exhibit chirality even when their component rings are achiral. Here an isostructural desymmetrization strategy is developed, demonstrating that two achiral rings, each featuring two mirror planes and a two-fold axis of symmetry, can form a catenane with tuneable mechanical chirality.

This manuscript evaluates forecasts of laboratory-confirmed influenza hospital admissions, a new target for influenza forecasting in the United States. Across two influenza seasons, the FluSight ensemble is robust compared to submitted models.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

The translation of transgenes is regulated using RNA sensors.

Aqueous organic redox flow batteries offer a safe and inexpensive solution to the problem of storing electricity produced from intermittent renewables. However, decomposition of the redox-active organic molecules that they rely on limits their lifetimes, preventing commercialization. Now it has been shown that these redox molecules can be electro-recomposed in situ, rejuvenating their function.

The ability to reversibly control monobody binding affinity would find use in biotechnology and research applications. Here the authors fuse the light-sensitive AsLOV2 domain to a monobody against the Abl SH2 domain to obtain a light dependent monobody and apply it in vitro and in mammalian cells.

The ability to regulate nanobody affinity with light would expand the applications toolbox for these reagents. Here the authors insert an optimised photoswitchable AsLOV2 domain into multiple nanobodies and demonstrate photoswitchable binding to fluorescent proteins and endogenous proteins in cells.

Vein of Galen malformations (VOGMs) are severe congenital brain arteriovenous malformations. Here the authors work to elucidate the pathogenesis of VOGMs by performing an integrated analysis of 310 VOGM proband family exomes and 336,326 human cerebrovasculature single-cell transcriptomes to identify mutations of key signaling regulators.

The authors demonstrate a graphene/CrSBr heterostructure exhibiting anisotropic surface plasmon polariton (SPP) propagation in the mid-infrared and terahertz range. Charge transfer at the interface directs SPPs along the quasi-1D chains that compose each CrSBr layer, with propagation lengths varying by an order of magnitude between the two in-plane crystallographic axes.

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.

C-SIDE facilitates accurate cell type-specific differential expression analysis for multiple spatially resolved transcriptomics technologies by cell type mixture modeling.

Comparative genomic analysis of human and primate relatives can reveal important biological and evolutionary insights. Here, the authors present a long-read assembly of the Chinese rhesus macaque genome and identify ape-specific structural variants.

The Somatic Mosaicism across Human Tissues Network aims to create a reference catalogue of somatic mosaicism across different tissues and cells within individuals.

This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual.

Solid organ transplant recipients are at increased risk of infectious disease and have unique molecular pathophysiology. Here the authors use host-microbe profiling to assess SARS-CoV-2 infection and immunity in solid organ transplant recipients, showing enhanced viral abundance, impaired clearance, and increased expression of innate immunity genes.

The role of IgG glycosylation in the immune response has been studied, but less is known about IgM glycosylation. Here the authors characterize glycosylation of SARS-CoV-2 spike specific IgM and show that it correlates with COVID-19 severity and affects complement deposition.

Association analyses in over 1 million individuals identify 535 new loci influencing blood pressure traits. The results provide new insights into blood pressure regulation and highlight shared genetic architecture between blood pressure and lifestyle exposures.

Studies on the µ-opioid receptor using fluorescent labelling of intracellular residues and energy transfer experiments in the presence of different ligands with or without G-protein binding reveals conformational changes that correlate to ligand efficacy.

Single-cell RNA sequencing of testes from young and old male Drosophila, together with genomic sequencing of somatic tissues of the same flies, shows distinct mutational biases in old and young flies and suggests late spermatogenesis as a source of evolutionary innovation.

Neurodevelopmental disorders (NDDs) are a heterogeneous group of diseases for which the genetic basis is still unknown in more than half of the cases. Here, the authors report a NDD associated with disruptive variants in the TANC2 gene and show that rols, the TANC2 homolog in flies, is required for synapse growth and function.

Jun Zhao, Evan S. Krystofiak, and colleagues identified a new cis interface (Cis-1) essential for the formation of normal tight junctions. This study suggests that Cis-1 contributes to maintaining structural flexibility of tight junction strands for proper ion balance and hearing.

An integrated data and sample repository for clinical, cellular and multi-omics research from diverse spaceflight missions known as Space Omics and Medical Atlas (SOMA) is presented.

Aqueous organic redox-flow batteries are known to suffer capacity loss via degradation of the redox-active species. Here, the authors use in situ methods to study the electrolyte flavin mononucleotide, identifying a redox mediator mechanism that mitigates capacity loss and a route to prevent its degradation.

The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

In a phase 1b/2a trial, the combination of the oral PI3K inhibitor duvelisib and romidepsin had limited toxicity and exhibited encouraging clinical activity in patients with relapsed or refractory T cell lymphoma, suggesting an approach whereby PI3K inhibitors can be safely used in this patient population.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

In the US, the cropland and non-cropland conversion from existing uses to cellulosic feedstocks for sustainable aviation fuels reduces the net greenhouse gas emissions intensity, according to a framework that combines economic, biochemical, and feedstock-specific process engineering models.

Genome-wide association analyses of blood glucose measurements under nonstandardized conditions provide insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

Roy et al. quantify the impact of a high-fat diet across genetically diverse strains of mice, revealing a generally negative effect on lifespan but also a wide variability.

Sperm motility and male fertility requires function of the CatSper calcium channels. Here, using cryo-electron tomography, authors visualize the native in-cell 3D structure and higher-order organization of the CatSper as long zigzag rows along the sperm tail.

Post-acute sequelae of SARS-CoV-2 (PASC) is still not well understood. Here the authors provide patient reported outcomes from 590 hospitalized COVID-19 patients and show association of PASC with higher respiratory SARS-CoV-2 load and circulating antibody titers, and in some an elevation in circulating fibroblast growth factor 21.

A comparison of two complete sets of human centromeres reveals that the centromeres show at least a 4.1-fold increase in single-nucleotide variation compared with their unique flanks, and up to 3-fold variation in size, resulting from an accelerated mutation rate.

Longitudinal multi-omics reveals shifts to the human microbiome across multiple body sites and the associated immune responses during short-term spaceflight.

The redox behaviour of pyridinium electrolytes under representative flow battery conditions is investigated, offering insights into air tolerance of batteries containing these electrolytes while providing a universal physico-chemical descriptor of their reversibility.

Optogenetically controlling the assembly of enzyme clusters enhances product formation and specificity during deoxyviolacein biosynthesis by decreasing concentrations of intermediate metabolites and reducing flux through competing pathways.

Understanding charge-compensating interactions and ionic dynamics in organic mixed conductors can be challenging. Operando NMR spectroscopy is now used to quantify cation and water movement during doping/dedoping in mixed conductor films.