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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.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Olfactory deficits occur early in Alzheimer’s disease (AD). Here, the authors identify that loss of locus coeruleus axons in the olfactory bulb underlies impaired olfaction in an AD mouse model and provide translational evidence for similar deficits in humans.

MoDL, a deep learning algorithm, is developed to link mitochondrial morphology and function. Trained on extensive mitochondrial image and biochemical data, MoDL delivers high segmentation accuracy and accurate function prediction.

Clinically significant genetic variation in Asian populations is under-characterized. Here, the authors show the diversity in prevalence and spectrum of human disease and pharmacogenetic variants in a multi-ethnic Asian population.

The authors observe that the atomic reconstruction in MoS₂/WSe₂ heterobilayers with large lattice mismatch results in the most significant periodic strain distribution, contributing to the effective localisation of excitons within moiré potential traps at room temperature.

Hydrous silicate melts atop the 410 km discontinuity have ultra-low viscosities, enabling rapid segregation. These melts form paired layers through continuous dehydration melting, which can merge under specific conditions, explaining seismically observed deep melt structures.

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.

Examining drivers of the latitudinal biodiversity gradient in a global database of local tree species richness, the authors show that co-limitation by multiple environmental and anthropogenic factors causes steeper increases in richness with latitude in tropical versus temperate and boreal zones.

An analysis of tree survival data from forest sites worldwide shows that in the tropics, rare tree species experience stronger stabilizing density dependence than common species, wheras no correlation of stabilizing density dependence and abundance exists in the temperate zone.

Heme is an abundant cofactor required by nearly all known organisms. Here, authors discover a cyanobacterial protein with a distinct Zn-mirror heme site, which may function to sense heme and regulate energy metabolism.

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.

As presented at the 2025 ASCO Annual Meeting, intracerebroventricular infusion of bivalent CAR T cells targeting EGFR and IL-13Rα2 in patients with multifocal, recurrent glioblastoma was feasible and well tolerated, with the maximum tolerated dose identified, one patient with a partial response and one patient with durable stable disease.

Structural variations (SV) contribute to inter-individual variability. Here, the authors describe a first-generation multi-ancestry Asian SV catalogue containing 73,035 SVs from 8392 Singaporeans to provide insights into Asian SV diversity.

Ultra-high-energy gamma-ray emission from the microquasar V4641 Sagittarii is reported, suggesting that large-scale jets from microquasars could be more common than previously thought and also could be a notable source of galactic cosmic rays.

Variants of the 3′−5′ exonuclease TREX1 can cause retinal vasculopathy with cerebral leukoencephalopathy (RVCL). Here, the authors show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and render cells more vulnerable to DNA damage inducing agents.

The authors demonstrate that cells that are deficient in H3K9 trimethylation display more compact mitotic chromosomes decorated with aberrantly high H3S10 phosphorylation and H3K27 trimethylation. By quantitative proteomics, they show that H3K9 trimethylation is essential for mitotic bookmarking by Esrrb and thus for the maintenance of epigenetic memory during cell division.

Exploring the molecular mechanisms by which the blood-borne factor osteocalcin promotes cognitive resilience, Rivagorda, Romeo-Guitart et al. identify a primary cilia axis through which osteocalcin promotes autophagy in neurons.

It is unclear if the molecular profiles of pancreatic ductal adenocarcinoma (PDAC) preclinical models remain stable during propagation. Here, the authors characterise clonal evolution throughout propagation in PDAC cell lines and a patient-derived organoid using single-cell genomics, transcriptomics and epigenomics.

Historical dynamics show that no country has achieved minimum social thresholds within biophysical boundaries between 1992 and 2015, and a projection indicates that no country is on the path to achieve them.

A technique for threading long protein strands through a nanopore by electrophoresis and back using a protein unfoldase motor, ClpX, enables single protein molecules to be analyzed multiple times with single-amino-acid sensitivity.

Bacteria have evolved proteinaceous microcompartments (BMCs) to control the passage of metabolites and facilitate catabolism in a micro-environment. Here, Yang et al. apply fluorescence microscopy to characterize the protein-protein interaction and assembly involved in the de novo biogenesis of propanediol-utilization (Pdu) metabolosomes and show that Pdu BMCs undergo a combination of ‘Shell first’ and ‘Cargo first’ assembly.

The relationships that control seed production in trees are key to understand evolutionary pressures that have shaped forests. A global synthesis of fecundity data reveals that while seed production is not constrained by a strict size-number trade-off, it is influenced by taxonomy and nutrient allocation.

The clinical detection of fluorescent protoporphyrin IX during glioma-resection surgery can be improved via a microscope that pairs stimulated Raman histology and two-photon excitation fluorescence microscopy.

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.

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.

It is known that exercise influences many human traits, but not which tissues and genes are most important. This study connects transcriptome data collected across 15 tissues during exercise training in rats as part of the Molecular Transducers of Physical Activity Consortium with human data to identify traits with similar tissue specific gene expression signatures to exercise.

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.

Songlin Chen and colleagues sequenced the whole genomes of a male (ZZ) and a female (ZW) Chinese half-smooth tongue sole, Cynoglossus semilaevis. Their analysis provides insights into the structure and evolution of the sex chromosomes and adaptation to the benthic lifestyle of this flatfish.

Temporal multi-omic analysis of tissues from rats undergoing up to eight weeks of endurance exercise training reveals widespread shared, tissue-specific and sex-specific changes, including immune, metabolic, stress response and mitochondrial pathways.

NK cells control SIV infection in secondary lymphoid tissues in the natural host that typically doesn’t progress toward disease. Here the authors show that this control is associated with terminal NK cell differentiation and improved MHC-E-dependent activity lacking in pathogenic SIV infection.

The measurement of the total cross-section of proton–proton collisions is of fundamental importance for particle physics. Here, the first measurement of the inelastic cross-section is presented for proton–proton collisions at an energy of 7 teraelectronvolts using the ATLAS detector at the Large Hadron Collider.

Hydrogel actuators have been widely developed to be osmotic-driven but many are in fact only capable of producing low forces. Here, the authors developed high speed and high force hydrogel actuators capable of camouflage optically and sonically with low fatigue over multiple cycles.

One of the problems of water-treatment membranes based on two-dimensional materials is that they tend to swell once in operation in water. A new strategy is presented for the preparation of non-swelling, covalently functionalized molybdenum disulfide membranes with tunable interlayer space and cohesion energy of the laminates.

Moigneu, Abdellaoui and colleagues show that GDF11 attenuates depression-like behavior and improves memory in aged mice through neuronal autophagy and mTOR. Serum levels of GDF11 are inversely associated with depression in patients.

This study characterizes a subset of clock neurons known as large lateral-ventral neurons and their dopaminergic/octopaminergic input circuitry in balancing light-mediated wakefulness in Drosophila.

Mutations in LRRK2 are linked to Parkinson’s Disease. Here, the authors identify WSB1 as a LRRK2 interacting protein and find that it promotes LRRK2 aggregation in primary neurons and drosophila models via ubiquitin K27 and K29 linkages.

Nitrate stimulates seed germination in many plant species. Here, Yan et al. show that the Arabidopsistranscription factor NIN-like protein 8 is required to stimulate germination in response to nitrate and induces expression of an enzyme involved in ABA catabolism.

Increased levels of the Yap oncoprotein stimulate liver growth and promote hepatocarcinogenesis. Here the authors show that hepatocyte-specific loss of Atg7 in mice leads to decreased autophagic degradation of Yap and liver overgrowth, and further establish this association in human liver cancer tissues.

Beyond its canonical role in translation, lysyl-tRNA synthetase (KRS) stabilizes the prometastatic 67-kDa laminin receptor (67LR) in the plasma membrane. A small-molecule inhibitor of the KRS-67LR interaction modulates the KRS-promoted metastatic potential of 67LR without disrupting the normal function of each protein.

Observations of teraelectronvolt γ-rays accelerated by the jets of the miniature quasar SS 433 are reported.

 Malignant evolution enabled by p53 inactivation in mice proceeds through an ordered and predictable pattern of Trp53 loss of heterozygosity, accumulation of deletions, genome doubling and the emergence of gains and amplifications.

This Perspective article discusses Singapore’s efforts to implement a National Precision Medicine Strategy through the integration of genomic, clinical and lifestyle data of up to one million Singaporean individuals.

A study from the FANTOM consortium using single-molecule cDNA sequencing of transcription start sites and their usage in human and mouse primary cells, cell lines and tissues reveals insights into the specificity and diversity of transcription patterns across different mammalian cell types.

Following HAWC observations of the Cygnus Cocoon, massive star-forming regions can now be considered to be sources of very-high-energy (TeV to PeV) Galactic cosmic rays.

7.7 million non-redundant genes have been documented in the pig gut microbiome gene catalogue, revealing a 96% similarity in functional pathways to the human catalogue and influences from sex, age, host genetics and antibiotic treatments.

In an inter-laboratory study, the authors compare the accuracy and performance of three optical density calibration protocols (colloidal silica, serial dilution of silica microspheres, and colony-forming unit (CFU) assay). They demonstrate that serial dilution of silica microspheres is the best of these tested protocols, allowing precise and robust calibration that is easily assessed for quality control and can also evaluate the effective linear range of an instrument.