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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.

Results from the randomized ProfiLER-02 trial, which compared two gene panels in guiding molecular-based treatment in patients with solid tumors, show that a broader gene panel led to more molecular-based recommended therapies compared to a more limited gene panel.

A survey of the entire human genome has found that five genetic loci contribute a large fraction of disease risk in type 2 diabetes.

Single-agent maintenance PARP inhibition may represent an effective strategy for advanced/metastatic endometrial cancer treatment. Here this randomized phase IIb UTOLA trial evaluates the efficacy and safety of orally administered olaparib in female patients (n = 145) without progression following front-line platinum-based chemotherapy for advanced/metastatic endometrial cancer.

A randomized trial in patients hospitalized with COVID-19 showed no benefit and potentially increased harm associated with the use of convalescent plasma, with subgroup analyses suggesting that the antibody profile in donor plasma is critical in determining clinical outcomes.

Fossil data shed light on a debate about when vertebrate dental tissues arose by assigning an early sensory structure to arthropods rather than to vertebrates.

The use of electric fields to control the magnetization of ferromagnetic materials could enable more efficient electronics. Lei et al.show that by applying lateral strain to a magnetostrictive nanowire with a piezoelectric, voltage-controlled gating of magnetic domain wall motion in the wire can be achieved.

Switches made up of single molecules form the basis for the concept of molecular electronics. Miyamachiet al.demonstrate that an iron-based spin crossover molecule can be switched between different spin states, provided it is decoupled from a metallic substrate by a thin insulating layer.

Ruth Loos and colleagues report results of a large genome-wide association study for body mass index. They identify 18 new loci associated with this trait, some of which map near key hypothalamic regulators of energy balance.

Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth.

Partitioning clustering based on clinical variables applied to multiple patient cohorts identifies two subtypes of metabolic dysfunction-associated steatotic liver disease with different associations to hepatic and cardiovascular outcomes.

Sepsis induces a period of immunosuppression which can be problematic in the face of subsequent infectious challenge. Here the authors show the presence of PD-L1 expressing regulatory plasma cells that can inhibit T cells in a murine model and in patients with sepsis.

Deregulation of the Phosphoinositide 3-kinase (PI3K) pathway is associated with metabolic flexibility leading to cancer poor prognosis. Here, the authors show that targeting both glutamine degradation and mTOR inhibition effectively kills PI3K-altered cancer cells in pre-clinical and clinical settings for T-cell acute lymphoblastic leukemia and solid cancer.

Meta-analyses in up to 1.3 million individuals identify 87 rare-variant associations with blood pressure traits. On average, rare variants exhibit effects ~8 times larger than the mean effects of common variants and implicate candidate causal genes at associated regions.

Analysis of snRNA genes in individuals with rare disorders identifies de novo and recurrent variants in RNU5B-1 and RNU5A-1, in addition to previously unreported cases with pathogenic or likely pathogenic variants in RNU4-2.

Here, the authors use smFRET to assess the structural dynamics of metabotropic glutamate receptor mGlu2 and show that a positive allosteric modulator or the Gi protein stabilize mGlu2 in the glutamate-induced active state, leading to the full activation of the receptor.

Cao et al. show that SPIN90 enhances formation of Arp2/3-mediated unbranched filaments and promotes a formin-based cortex by recruiting mDia1 or forming a ternary SPIN90–Arp2/3–mDia1 complex.

Multiancestry genome-wide association analyses identify new risk loci for stroke and stroke subtypes. Fine mapping and bioinformatics analyses of these risk loci point to mechanisms not previously implicated in stroke pathophysiology.

Cytokinesis — the final step of mitosis in which the two daughter cells separate — requires accumulation of specific proteins and lipids at the connecting bridge to ensure cleavage by abscission. Phosphatidylinositol-3-phosphate (PtdIns(3)P), an endosomal phosphoinositide, and FYVE-CENT, a PtdIns3P-binding protein, are found in the bridge, where they contribute to the mechanism of abscission.

Philippe Froguel, Ralf Jockers and colleagues report the functional characterization of 40 rare protein-coding variants of the MTNR1B gene (encoding melatonin receptor 1B, also known as MT₂). They find that functionally impaired MT₂ melatonin receptors confer higher risk to type 2 diabetes in Europeans.

Timothy Frayling, Joel Hirschhorn, Peter Visscher and colleagues report a meta-analysis of genome-wide association studies for adult height in 253,288 individuals. They identify 697 variants in 423 loci significantly associated with adult height and find that these variants cluster in pathways involved in growth and together explain one-fifth of the heritability for this trait.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Antimicrobial resistance is a major global health threat and its development is promoted by antibiotic misuse. Here, the authors present an offline smartphone application for automated and standardized antibiotic susceptibility testing, to be deployed in resource-limited settings.

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.

Current approaches studying the collection of extracellular fluid to monitor neurological disorders have temporal resolution limitations. Here the authors show functional in vivo validation of a droplet collection system included at the tip of a neural probe.

Cecilia Lindgren and colleagues report results of a large-scale genome-wide association study for waist-to-hip ratio, a measure of body fat distribution. They identify 13 new loci associated with this trait, several of which show stronger effects in women than in men.

Plant primary microRNA (miRNA) transcripts (pri-miRNAs) are not just a source of miRNAs but can also encode regulatory peptides (miPEPs) that enhance the accumulation, and so the effect, of the corresponding mature miRNAs—an observation that may have agronomical applications.

Philippe Froguel and colleagues report an analysis of large chromosomal clonal mosaic events in individuals with type 2 diabetes. They find a significant association between CME occurrence and T2D with vascular complications.

The molecular mechanisms involved in the development of SMARCB1-deficient renal medullary carcinomas (RMCs) remain to be characterised. Here, the authors integrated RMC omics data to show that ferroptosis resistance contributes to transformation of renal thick ascending limb cells into several RMC cell states.

Super-enhancers (SEs) drive specific gene expression programmes underlying different cancer cell states offering opportunities for therapeutic targeting. Here, the authors suggest targeting SE-dependent genes with synthetic ecteinascidins in tumors with heterogeneous transcriptional landscapes.

Pacific oyster mortality syndrome is a poorly understood cause of mortality in commercially important oyster species. Here, the authors use multiple infection experiments to show that the syndrome is caused by sequential infection by herpesvirus and opportunistic bacteria.

In eukaryotic cells, a subset of microtubules undergoes acetylation, resulting in stabilization: here, clathrin-coated pits are shown to control microtubule acetylation through a direct interaction between the α-tubulin acetyltransferase αTAT1 and the clathrin adaptor AP2, promoting directional cell migration.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

Steve Brown and colleagues report an analysis of 20 phenotyping tests, including 413 data parameters, across 449 mutant mouse alleles. They identify widespread pleiotropy and assign putative functions to genes that lacked previous phenotypic annotation.