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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.

The PCRCR complex of Plasmodium spp. binds basigin on the erythrocyte surface. While Rh5 of the complex is restricted to P. falciparum, PTRAMP, CSS and Ripr orthologs are present across the genus, for which the authors report common features.

Biomolecular phase separation arises from collective molecular interactions and is emerging as a key theme for biological function. Here the authors propose a broadly applicable method to quantify these interactions based on compositional and energetic parameters.

Pacific salmon transport of nutrients and contaminants to freshwaters increased by 30% and 20%, respectively, between 1976 and 2015, an increase dominated by pink salmon, which had the highest nutrient-to-contaminant ratios.

Here, the authors sample air and surfaces in hospital rooms of COVID-19 patients, detect SARS-CoV-2 RNA in air samples of two of three tested airborne infection isolation rooms, and find surface contamination in 66.7% of tested rooms during the first week of illness and 20% beyond the first week of illness.

Dysregulation of ribonucleoprotein complex granules, previously implicated in neuromuscular disease, can drive pathogenesis in a genetic form of dilated cardiomyopathy, as shown in gene-edited pigs and patient-derived cardiomyocytes.

As presented at the ESMO Congress 2025: Results of the phase 2/3 AGITG DYNAMIC-III trial show that de-escalated chemotherapy based on ctDNA-negative status in patients with stage III colon cancer did not meet non-inferiority for 3-year recurrence-free survival when compared to standard of care, although it enables better informed treatment decisions.

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).

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.

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.

Epithelial organoids are grown without Matrigel using a single-chain antibody.

Previously, OLIG2-expressing stems cells have been identified as having a role in medulloblastoma recurrence. Here, the authors investigate the effects of targeting this OLIG2+ stem cell population in Sonic Hedgehog (SHH) medulloblastoma using CT-179, an OLIG2 inhibitor.

Filamin C is a key actin-binding protein involved in cardiomyopathies and musculoskeletal disorders. Here, Wang et al reveal that it interacts with the heat shock protein HSPB7 under biomechanical stress, forming a stable hetero-dimer which is regulated by phosphorylation.

Here, the authors develop hydrocarbon-stapled paxillin-mimetic peptides that act as selective and potent focal adhesion kinase (FAK) scaffold inhibitors to displace FAK from focal adhesions. Treatment shows reduced cancer cell survival in vitro and reduced tumor burden in vivo.

Hospital treatment for children with severe malnutrition may facilitate antibiotic resistance. Here, using rectal swabs from 1,371 children receiving treatment for severe acute malnutrition in Niger, the authors identify high rates of bacteria carrying carbapenemase genes, highlighting the urgent need to prioritize infection control.

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 transcriptomic cell-type atlas of the whole adult mouse brain with ~5,300 clusters built from single-cell and spatial transcriptomic datasets with more than eight million cells reveals remarkable cell type diversity across the brain and unique cell type characteristics of different brain regions. 

Cryo-EM faces a problem of sample damage at the air-water interface. In this work, the authors show that stress-response proteins from dehydration-tolerant organisms can be used as a simple sample additive to mitigate the sample damage problem.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Behavior is the result of a Bayesian computation that weights past experience and current sensory information by their reliabilities. Here single-neuron activity in eye movement cortex exemplifies how the brain implements a Bayesian computation.

The authors investigate functional connectivity before and after transcranial magnetic stimulation in veterans with treatment-resistant depression stratified by cognitive biotype, demonstrating associated brain connectivity-mediated improvement in cognitive behavioral task performance.

Bayesian models explain how context biases perceptual behavior toward expected categories, but sensory neurons do not reflect this bias. Instead, expectation sharpens sensory acuity, independent of downstream decision making.

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.

The FANTOM4 study identified transcriptional start sites active during proliferation arrest and differentiation of the human monocytic cell line THP-1. Systematic knockdown of 52 transcription factors provide support for their model in which a complex transcriptional network regulates the differentiation process.

A 50 microRNA-based dynamic risk score for stratifying individuals with and without type 1 diabetes was developed using samples obtained from multicenter and multiethnic cohorts.

Making Bohmian mechanics fully compatible with special relativity is still an ongoing challenge. Here, the authors make a further step in this direction by providing a way of constructing the relativistic Bohmian-type velocity field of single photons which is operationally based on weak measurements.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

Using integrative multi-omics and CRISPR knock-out of all ~1,900 transcription factors, the authors identify essential transcription factors required for Neurogenin-driven differentiation of human cortical neurons.

Integrins come in subtypes that bind distinct ligands. This work reveals and quantifies subtype-specific mechanical force transmission and assembly of cytoskeleton architectures.

T cell responses can be generated to either pathogen infection or from priming with a vaccine. Here the authors compare T cell generation, phenotype and single cell transcriptome of participants vaccinated with a mpox vaccine or infected with the virus showing that the virus induced T cells showed more effective function and phenotype.

The contribution of genetic factors to the tumour immune microenvironment (TIME) remains to be investigated. Here, the authors suggest the role of TIME eQTLs for target genes involved in reversing immune suppressive features.

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.

A comparison of the three dimensional structures of neurotoxic peptides reveals distinct electrostatic topographies that help define surfaces important for binding and kinetic properties.

We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M⁺ diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG.

Patients with Williams syndrome have defects in visuo-spatial cognition (a failure to integrate parts into a whole) that are linked to deletion of the gene that encodes LIM kinase-1 (LIMK-1). The reasons for this are becoming clearer with the identification of a molecular target for LIMK-1. It turns out that this enzyme phosphorylates cofilin, which is essential for the turnover of actin filaments. Such turnover may be implicated in axon guidance, and could explain why high levels of LIMK-1 are found in neurons.

Human pathogenic-like Th17 cells express the chemokine receptor CCR6, but how CCR6, together with other chemokine receptors, modulate Th17 functions is still unclear. Here the authors show that CCR2 is coexpressed with CCR6 on these cells, and specifically mediates transendothelial migration, while CCR6 and other chemokine receptors induce T cell arrest on activated endothelial cells.

SPI1 fusion genes in T-cell acute lymphoblastic leukemia (T-ALL) are commonly found with co-occurring NRAS mutations. Here, the authors show that the combination of these oncogenes is necessary to drive T-ALL in a murine model and that the oncogenic activity of the SPI1 fusion is dependent on β-catenin.

A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

This study reveals an important chondrocytic progenitor population for maintenance of adult articular cartilage marked by Gremlin 1. Loss of these progenitors causes osteoarthritis and suggests methods to sustain them may be effective future targets for management of osteoarthritis.

On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.