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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.

Combining multiomic datasets from adolescent and middle-aged-to-older population cohorts with a purposefully devised analytical framework, we revealed substantial heterogeneity in brain-chronotype-behavior patterns and their complex interactions with everyday life.

The authors present DNA-Diffusion, a generative AI framework that designs synthetic regulatory elements with tunable cell-type specificity. Experimental validation demonstrates their ability to reactivate AXIN2 expression, a leukemia-protective gene, in its native genomic context.

An understanding of nuclear magnetic resonance (NMR) in terms of magnetic susceptibility is still lacking. Here, Chenet al. numerically study the temperature and doping dependent Knight shift and spin relaxation time in NMR response, providing insight to understand the pseudogap in cuprates.

This study presents a scalable reinforcement learning framework that accelerates the discovery of bioactive peptides by efficiently screening vast peptide libraries with demonstrated activity towards breast cancer.

Gonzalez-Gallego et al. developed a fully iPS-cell-based human three-dimensional blood–brain barrier (BBB) model and used it to study roles of the stroke risk gene FOXF2 in BBB dysregulation, demonstrating its applicability for mechanistic research and drug development.

Kazemian et al. report that untrained convolutional networks with wide layers predict primate visual cortex responses nearly as well as task-optimized networks, revealing how architectural constraints shape brain-like representations in deep networks.

EDI048 is a gastrointestinal-targeted Cryptosporidium PI(4)K inhibitor that undergoes a predictable metabolism and limits systemic exposure without compromising its anti-parasitic activity.

Human papillomavirus (HPV) DNA testing is the preferred method for cervical cancer screening, but existing tests are inaccessible for resource-limited settings. Here, authors develop a low-cost, simple HPV DNA assay suitable for bedside testing and demonstrate strong performance in Mozambique.

Intermediate-coverage long-read sequencing in 1,019 diverse humans from the 1000 Genomes Project, representing 26 populations, enables the generation of comprehensive population-scale structural variant catalogues comprising common and rare alleles.

Although the number of participants is important for phenotypic prediction accuracy in brain-wide association studies using functional MRI, scanning for at least 30 min offers the greatest cost effectiveness.

The simplicity of particle suspension reactors and the precise synthetic control afforded by silicon nanowire growth are used to develop a system that can produce hydrogen fuel by splitting water with sunlight.

Processing is crucial to ensure material quality and stability in perovskite solar cells. Here, Poolet al. develop a scalable infrared annealing method and use in situXRD to map the processing phase space relative to the device efficiency. This provides a tool to determine processing requirements.

Little sulfur from the 2022 Hunga submarine eruption reached the atmosphere due to seawater–magma interactions, indicating that the climate impact of this type of eruption may be underestimated, according to analysis of ash collected throughout the event.

The establishment of a drug-discovery screening pipeline for cryptosporidiosis, and identification of pyrazolopyridines as selective ATP-competitive inhibitors of the Cryptosporidium lipid kinase PI(4)K.

UNAGI deciphers cellular dynamics from human disease time-series single-cell data and facilitates in silico drug perturbations to discover drugs potentially active against complex human diseases.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Naturally occurring single crystals can exhibit various intricate porous morphologies. Here, the authors are able to grow nanoporous single crystals of gold following solidification of a eutectic composition melt that forms as a result of the dewetting of nanometric thin films.

Horses have lived in Iberia since the Ice Age. Using ancient genomes to study their history, Lira Garrido et al. reveal a local wild lineage lasting until Late Iron Age, and highlight the far-reaching influence of Iberian bloodlines across Europe and north Africa during the Iron Age and beyond.

Capitalizing on multimodel data from the UK Biobank, Bzdok and colleagues delineate the deep phenotyping and brain basis of early risers and night owls at a population scale, showing links to habit formation, reward function and emotional regulation.

In a cohort of 87 individuals with COVID-19, the memory B cell response at 6.2 months after the onset of disease evolves in a manner that is consistent with the persistence of SARS-CoV-2 antigen.

Coventry et al. show that spatial demonstratives—such as ‘this’ and ‘that’ in English—are selected on the basis of whether the speaker is able to reach the object or not, across 29 diverse languages.

SrCu2(BO3)2 is a 2D quantum antiferromagnet on a particular frustrated lattice showing multiple magnetization plateaus and quantum phase transitions under high pressure. Here the authors uncover novel magnetic phases in this material under combined effects of extreme magnetic field and pressure.

Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.

A dataset of the genomes of 363 species from the Bird 10,000 Genomes Project shows increased power to detect shared and lineage-specific variation, demonstrating the importance of phylogenetically diverse taxon sampling in whole-genome sequencing.

Analyses of 475 ancient horse genomes show modern horses emerged around 2200 bce, coinciding with sudden expansion across Eurasia, refuting the narrative of large horse herds accompanying earlier migrations of steppe peoples across Europe.

Autophagy is essential to endothelial cell homeostasis. Here the authors show that lipophagy in LEC supports fatty acid oxidation to sustain a mitochondrial-Prox1 gene expression circuit and promote response of LEC to lymphangiogenic mediators.

Angiogenesis requires dynamic endothelial rearrangements and relative position changes within the vascular tubes. Here the authors show that a PI3K/NUAK1/MYPT1/MLCP pathway regulates actomyosin contractility in endothelial cells and cellular rearrangement during vascular patterning.

Combined analysis of new genomic data from 116 ancient hunter-gatherer individuals together with previously published data provides insights into the genetic structure and demographic shifts of west Eurasian forager populations over a period of 30,000 years.

The pressure dependence and magnetic field dependence of the specific heat of a quantum magnet, SrCu₂(BO₃)₂, demonstrate that its phase diagram contains a line of first-order transitions terminating at a critical point, in analogy with water.

Here, the authors use data from the Adolescent Brain Cognitive Development study to show how individual variation in cognition, personality and mental health can be predicted by shared and unique brain network features.

Genetic variants at multiple loci of chr5p15.33 have been associated with susceptibility to numerous cancers. Here the authors show that the association of one of these loci may be explained by a variant, rs36115365, influencing telomerase reverse transcriptase (TERT) expression via ZNF148.

Asymmetry is a key organising principle of the brain. Here the authors leveraged rare genetic mutations to revisit structural brain asymmetry showing the planum temporale is susceptible to deletions & duplications of specific gene sets.

Analysis of 273 ancient horse genomes reveals that modern domestic horses originated in the Western Eurasian steppes, especially the lower Volga-Don region.

Disease signatures in high-dimensional biomedical data are detected with a visualization algorithm.

Across 21 societies, people alter their speech and song when interacting with infants. These infant-directed vocalizations are recognized by listeners. This suggests that forms of human vocalizations may be shaped by their functions.

Ageing increases the risk of many diseases. Here the authors compare blood cell transcriptomes of over 14,000 individuals and identify a set of about 1,500 genes that are differently expressed with age, shedding light on transcriptional programs linked to the ageing process and age-associated diseases.

Methodological shortcomings have constrained studies describing the complex dynamics of interpersonal coordination, which is essential to human sociality. In this Perspective, Chidichimo et al. advance the case for the formal introduction of information-theoretic quantities and methods to overcome existing limitations in studies of naturalistic human interactions.