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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.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

Hiʻiaka is the largest moon of the distant dwarf planet Haumea. Here, the authors report the first multi-chord stellar occultations of Hiʻiaka, revealing its size, shape, and density, suggesting an origin from Haumea’s icy mantle.

Optical neural network processors offering benefits in bandwidth and energy consumption but problems in scaling and parallelism. The author presenting a novel optical tensor processor capable of optically performing large-scale, high-speed matrix-matrix multiplication in a single step.

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.

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.

A detailed spatiotemporal roadmap of the human female and male reproductive tracts during key periods of sexual differentiation provides new cellular and molecular insights into how early axial gradients lead to specific cell lineages and tissue structures.

Typical quantum error correcting codes assign fixed roles to the underlying physical qubits. Now the performance benefits of alternative, dynamic error correction schemes have been demonstrated on a superconducting quantum processor.

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.

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).

Experimental measurements of high-order out-of-time-order correlators on a superconducting quantum processor show that these correlators remain highly sensitive to the quantum many-body dynamics in quantum computers at long timescales.

A multi-institute, multi-platform initiative generates standard metrics and best practices for spatial transcriptomics analysis.

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.

Inherited mitochondrial DNA mutations can result in diverse clinical phenotypes. Here, the authors characterise a heteroplasmic tRNA^Ala mutation (m.5019A>G) in mice and demonstrate that macrophages carrying this mutation display altered function and metabolism in vitro, along with increased type I IFN release following LPS challenge in vivo.

Here, the authors report that combining Army Liposome Formulation with QS21 saponin (ALFQ) and Alum to formulate the ΔV1gp120 boost decreases the risk of simian immunodeficiency virus (SIV) mac251 acquisition in female macaques.

A consensus cell type atlas for the fly brain provides both an intellectual framework and open-source toolchains for brain-scale comparative connectomics.

The authors demonstrate deeply subwavelength light confinement in the terahertz spectral range by exploiting the strong light–matter coupling and hyperbolicity of phonon polaritons in hafnium-based dichalcogenides.

Decoded quantum interferometry is a quantum algorithm that uses the quantum Fourier transform to reduce optimization problems to decoding problems.

A flexible micro-electrocorticography brain–computer interface that integrates a 256 × 256 array of electrodes, signal processing, data telemetry and wireless powering on a single complementary metal–oxide–semiconductor substrate can provide stable, chronic in vivo recordings.

Although 30% of streams in the contiguous United States have some protection status, only 5% of stream diversity is represented and as little as 9% of streams are effectively protected from human disturbances, according to a nationwide assessment.

Pathogenic variants in UNC13A underlie a novel neurodevelopmental syndrome, with three subtypes defined by distinct genotypes with varying clinical and functional impacts characterized in cellular and animal models.

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.

Cooperative paramagnetism refers to a strongly correlated state without long range magnetic order that occurs in frustrated magnetic systems between the Neel temperature and Curie-Weiss temperature. Here, using resonant elastic magnetic and inelastic x-ray scattering, Terilli et al find a spectrally sharp gapped magnetic excitations that persists above the Neel temperature in Y₂Ir₂O₇, implying a cooperative paramagnetic phase.

Controlling nanoscale interfaces is key for ensuring stable plasmonic and catalytic function yet remains difficult to achieve under operando conditions. Now it has been shown that transient Au–Cl adlayers function as redox-active Au(I) intermediates, modulating interfacial electrostatics. This modulation stabilizes gold nanogaps and directs ligand rebinding, thereby enabling reproducible regeneration of subnanometre architectures.

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

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.

Chronic Kidney Disease affects 1 in 10 people worldwide with prevalence continuing to rise, thus there is a need to identify novel biomarkers that can add value to existing clinical and biochemical risk predictors. Here the authors identify miR190a-5p as potential indicator of kidney health and disease progression in patients with chronic kidney disease.

Over 20 species of geographically and phylogenetically diverse bird species produce convergent whining vocalizations towards their respective brood parasites. Model presentation and playback experiments across multiple continents suggest that these learned calls provoke an innate response even among allopatric species.

Response to inflammatory stimuli such as endotoxin is coordinated at many levels. Here, the authors show that two microRNAs known to regulate inflammatory response inside the cell are secreted by dendritic cells and modulate inflammatory signalling in the neighbouring cells.

A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.

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.

The prevalence of propargylic fluorides in bioactive molecules necessitates development of synthetic methods towards this connectivity. Here, the authors present a protocol to construct propargylic fluorides from allenes via I(I)/I(III) catalysis, delivering the products in high regioselectivity.

The authors report a meta-analysis of methylome-wide association studies, identifying 15 significant CpG sites linked to major depression, revealing associations with inflammatory markers and suggesting potential causal relationships through Mendelian randomization analysis.

Hypervalent iodine catalysis remains a powerful method to enable geminal difluoromethylenation of alkenes. However, the scope is mainly limited to styrene derivatives. Now, enynes have been validated as competent substrates where a formal 1,2-shift of the alkyne occurs, thereby enabling highly versatile homopropargylic difluorides to be generated.

FlyWire presents a neuronal wiring diagram of the whole fly brain with annotations for cell types, classes, nerves, hemilineages and predicted neurotransmitters, with data products and an open ecosystem to facilitate exploration and browsing.

Studies using human pluripotent stem cells and a mouse model of Down syndrome identify HMGN1 as a key contributor to congenital heart defects in individuals with Down syndrome.

Nanobody-based immune checkpoint inhibitors conjugated to an immunoglobulin kappa light chain-binding nanobody showed antitumour efficacy in colorectal carcinoma and melanoma models.

The relationship between pathogenic germline variation, clonal hematopoiesis (CH) and risk of hematologic malignancy is explored in 731,835 individuals across 6 cohorts. Carriers of variants in certain genes show distinct patterns of CH and increased risk of CH progression to malignancy.

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.

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.

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.

Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.

Optical frequency combs in the mid-infrared are required for molecular gas detection applications but their realization in compact microresonator-based platforms is challenging. Here, Griffith et al. demonstrate on-chip broadband comb generation on a silicon microresonator spanning from 2.1 to 3.5 μm.

A study reports whole-genome sequences for 490,640 participants from the UK Biobank and combines these data with phenotypic data to provide new insights into the relationship between human variation and sequence variation.

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

An RNA-binding protein on leukemia cells provides an effective target in mouse models.