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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.

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

Reduced sulfate aerosols due to ship fuel regulation may increase shortwave radiation on the Great Barrier Reef, exacerbating the impact of marine heatwaves on coral bleaching, according to model analysis of ship emission impacts on aerosols, clouds and solar radiation.

Streptococcus thermophilus phages circumvent host CRISPR defences via AcrIIIA2, which complexes with enolase, a highly abundant glycolysis enzyme, to block phage RNA binding.

Energy demand and intensive computation limit the use of machine learning on-device for wearables. Here, the authors deploy edge AI in a wearable form factor to provide clinical-grade gait-based frailty assessment over weeks with no interaction required from the wearer at any point.

From lectures by avatars to entire qualifications, higher education centred around AI is just around the corner.

This study introduces P3T-Net, a pseudo-3D deep learning model that enables accurate and efficient cross-domain transfer of large 3D material images, improving image quality and ensuring image consistency across diverse imaging conditions.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

Selective alkyne transformations via precise orbital activation remain challenging. Here, O-bridged Cu catalytic pairs boost acetylene hydrochlorination by tailored orbital coupling, shifting reaction pathways and lowering energy barriers.

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).

The pachycephalosaurian Zavacephale rinpoche, from the Early Cretaceous of Mongolia, provides crucial insights into the early evolution of dome-headed dinosaurs, including the development of the frontoparietal dome and decoupling of sociosexual and somatic maturity.

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.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

High-density multimodal soft bioelectronic fibres provide a platform for minimally invasive implantable electronics, where diverse sensing and stimulation functionalities can be effectively integrated.

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.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

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.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

Myocardial contractile force and intracardiac hemodynamic shear stress coordinate the initiation of trabeculation in heart development. Here, the authors report that radially aligned myocardial strain activates snai1b⁺/Notch⁻ cardiomyocytes, initiating delamination for trabeculation.

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.

Glycans regulate cells via glycosylation, and aberrant glycosylation is linked to disease initiation and progression. Here, the authors present GlycanDIA, a DIA-based workflow enabling sensitive, precise glycan analysis, revealing low-abundant modifications and profiling distinct RNA glycan patterns with biological relevance.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

A sequencing chemistry that separates nucleotide identification from nucleotide incorporation achieves high accuracy.

A simple and versatile strategy is established to facilitate molecular recognition by extending electron catalysis for use in supramolecular non-covalent chemistry.

GIANT, a genetically informed brain atlas, integrates genetic heritability with neuroanatomy. It shows strong neuroanatomical validity and surpasses traditional atlases in discovery power for brain imaging genomics.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

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.

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.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

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.

The pilot phase of PigGTEx, re-analyzing 5,457 published RNA-seq samples, presents a pan-tissue catalog of molecular quantitative trait loci. Cross-species comparisons identify traits with shared genetic regulation in humans.

This study characterizes the three-dimensional (3D) genome architecture of 15 primary human cancer types from The Cancer Genome Atlas. The analyses identify different archetypes of enhancer usage and enhancer rewiring events due to different classes of mutations and structural variants.

Methods for ancestral sequence reconstruction are currently tested with computer simulations, since true biological phylogenies are unknown. Here, Randall et al.build an experimental phylogeny to benchmark the performance of alternate ancestral sequence reconstruction algorithms in inferring ancestral genotypes and phenotypes.

Analysis of whole-genome sequences of 25,465 individuals of European ancestry shows that rare variants contribute substantially to the heritability of height and body mass index.

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

A study shows that clonal haematopoiesis of indeterminate potential is associated with an increased risk of chronic liver disease specifically through the promotion of liver inflammation and injury.

Spatially resolved images of M87 obtained at a wavelength of 3.5 mm in 2018 show a ring-like accretion structure, the inner (outer) edge of which connects the black hole (jet).

The molecular mechanisms underlying the function of different cellular states in glioblastoma stem cells (GSCs) remain poorly understood. Here, the authors perform integrated single cell and bulk analysis of GSCs and identify potential therapeutic targets.

Accurate liquid water modelling is challenging. Here the authors use X-ray micro-computed tomography, deep learned super-resolution, multi-label segmentation, and direct multiphase simulation to simulate fuel cell and guide fuel cell design.

Here, the authors perform a rare-variant analysis of whole-genome sequence data that takes advantage of three global biobanks. They identify 29 novel rare variants associated with human height, and demonstrate an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data.

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.

TG2 functions as an eraser and exchanger of H3 monoaminylations, including histaminylation of Gln5 of histone H3.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Mesenchymal stromal cells are key components of hematopoietic stem cell (HSC) niches in the bone marrow. Two studies now show that hematopoietic-derived megakaryocytes also contribute to the HSC niche, regulating HSC quiescence and function.

Pooling participant-level genetic data into a single analysis can result in variance stratification, reducing statistical performance. Here, the authors develop variant-specific inflation factors to assess variance stratification and apply this to pooled individual-level data from whole genome sequencing.

The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.