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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.

Here, the authors combine bioinformatic, mass spectrometric, and sequencing-based mapping tools to identify previously undescribed phosphorothioate epigenetic systems widespread in the human gut microbiome.

Estimates from the Global Burden of Disease study reveal declines in chronic respiratory disease mortality between 1990 and 2023—especially during the COVID-19 pandemic—but the burdens on people affected remain substantial.

Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.

Engineered mucus-tethering bispecific nanobodies neutralize and entrap viruses to enhance mucosal immunity, preventing influenza infection and limiting SARS-CoV-2 transmission.

Cells depend on early protein modifications for proper function. Here, the authors show that when Src-family signaling kinases lack their typical myristoylation, an alternative acetylated start is detected by DCAF10, directing them to degradation.

TEAD transcription factors are critical effectors and druggable sites of the Hippo pathway in cancer, however, the development of small molecule inhibitors and degraders remains underexplored. Here, the authors identify and characterize bifunctional IAP-based degraders targeting TEAD1 via a lipid pocket and recruit different members of the inhibitor of apoptosis proteins (IAPs) family, offering a comprehensive toolkit for structural, biophysical and cellular profiling.

Here, the authors show that brain dynamics mature from childhood to adulthood with increased hierarchical propagation and reduced visual-somatomotor dynamics. Top-down hierarchical flow strengthens throughout this developmental period.

Sources of chiral mid-infrared light are difficult to obtain. Here, the authors demonstrate that twisted bilayers of anisotropic α-MoO₃ van der Waals crystals can emit mid-infrared thermal chiral radiation without any lithographic processes.

Researchers have developed a fullerene-decorated PdCo nano-resistor network sensor that achieves fast hydrogen detection time of 0.40 seconds at 0.1% H₂ and a detection limit of 40 ppb at room temperature.

Grosjean et al. present a network-aware, self-supervised learning approach for screening neuronal activity dynamics. They demonstrate its applicability across a range of neural interventions.

Combining high-resolution mapping of foliar and herbivore faecal sodium concentrations across Africa, the authors show that plant-derived sodium availability constrains megaherbivore densities at a continental scale.

The authors previously pinpointed OLAH (oleoyl-ACP-hydrolase) as a driver of life-threatening viral diseases. Here, the authors identify increased IL-18Rα expression on CD8⁺ T cells, which acquire a reduced cytotoxic signature, correlates with severe respiratory viral infection of influenza A virus, RSV and COVID-19.

The study combines bulk, single-cell, and spatial transcriptomics of human carotid plaques. It identifies immune– stromal cell diversity, spatial macrophage gradients, smooth muscle cell heterogeneity, and morphology-defined plaque subtypes.

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.

Coufal and colleagues generated microglia from human iPS cells to examine mechanistic roles of the transcription factor MEF2C and how these roles might relate to the autism phenotype seen following the loss of MEF2C in human microglia.

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.

The tolerogenic activity of type 1 conventional dendritic cells (cDC1s) is determined by EPOR, which is preferentially expressed in cDC1s and induces antigen-specific FOXP3-expressing regulatory T cells.

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 high-resolution transcriptomic and epigenomic cell-type atlas of the developing mouse visual cortex from embryonic to postnatal development is presented, providing a real-time dynamic molecular map associated with individual cell types and specific developmental events.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

Somatic mutations in blood cells (CHIP) are linked to diseases like heart disease, but the mechanisms are unclear. Here, the authors show that different CHIP driver genes alter unique sets of plasma proteins, some of which are validated in mouse models.

RNA molecules aggregate in certain conditions, but how and why remains unclear. Here the authors develop a model that quantitatively explains the conditions and mechanism of RNA aggregation, and predicts a surprising non-monotonicity in the transition.

The BioDIGS project is a nationwide initiative involving students, researchers and educators across more than 40 research and teaching institutions. Participants lead sample collection, computational analysis and results interpretation to understand the relationships between the soil microbiome, environment and health.

Two-dimensional polyaramid polymers are synthesized to form nanofilms that exhibit the lowest gas permeability of any polymer by orders of magnitude, despite lacking crystallinity, enabling molecular-scale nanomechanical resonators and barrier materials.

Geospatial estimates of the prevalence of anemia in women of reproductive age across 82 low-income and middle-income countries reveals considerable heterogeneity and inequality at national and subnational levels, with few countries on track to meet the WHO Global Nutrition Targets by 2030.

Silencing of transgenes such as Cas9 limits gene editing and CRISPRa applications. Here, the authors show that adding intronic sequences reduces silencing and boosts transgene expression, enabling improved CRISPRa-mediated gene activation and more stable expression of the transgene over time.

Fewer than 100 wild Cat Ba langurs survive in Vietnam. Here, the authors use whole genome sequencing to demonstrate potential adaptations to saltwater consumption as well as maintenance of adaptive potential despite low levels of genetic diversity and high levels of inbreeding.

The low-density lipoprotein receptor family members LRP1, LRP4 and VLDLR are entry receptors for yellow fever virus.

Myocardial infarction disrupts cardiac repair mechanisms, limiting regeneration. Here, the authors show that extracellular matrix therapies activate spatial and cell-specific pro reparative programs, revealed through spatial transcriptomics and snRNA-seq.

Here the authors map the dynamics of human NK cell residency and recirculation, showing that CD56^bright NK cells transiently occupy tissues and recirculate via lymphatics, whereas CD56^dim NK cells remain vascular except during inflammation.

Systematic analysis from the Global Burden of Disease study reported that, despite global improvements from 1990 to 2021, dietary iron deficiency-associated disease burden remains high in women, children and residents in low socio-demographic index countries.

Synthetic cells have huge potential in model systems. Here, the authors engineer synthetic–living hybrid tumoroids that replicate tumour-immune interactions in 3D, study synthetic cells integration, and demonstrate systematic studies of immune evasion and T cell engager therapies.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

In this Expert Recommendation, a working group integrating diverse perspectives presents a comprehensive overview of the clinical relevance and applicability of the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the rationale for its use as an outcome measure in clinical trials, addressing a long-standing roadblock in the development of new drugs for CLE.

A high-resolution, global atlas of mortality of children under five years of age between 2000 and 2017 highlights subnational geographical inequalities in the distribution, rates and absolute counts of child deaths by age.

This study identifies long-lived closed and pre-open states of GORK K+ channel through structural and functional analysis, suggesting semi-independent conformational transitions underlying channel activity and promising sites for stomata engineering.

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.

Williams et al. report a growth arrest mechanism in residual cancer persister cells through targeted therapy-induced upregulation of type I interferon signalling, which is negatively regulated by apoptotic DNA endonuclease DFFB to allow tumour relapse.

Despite exhibiting ferroelectric features, SrTiO₃ fails to display long-range polar order at low temperatures due to quantum fluctuations. An ultrafast X-ray diffraction experiment now probes polar dynamics of this material at the nanometre scale.

Cell type labelling in single-cell datasets remains a major bottleneck. Here, the authors present AnnDictionary, an open-source toolkit that enables atlas-scale analysis and provides the first benchmark of LLMs for de novo cell type annotation from marker genes, showing high accuracy at low cost.

Massively parallel reporter assay in primary human CD4⁺ T cells and bulk and single-cell CRISPR-interference screens identify candidate causal variants linked to autoimmune disease risk that modulate T cell gene expression and proliferation.

This work integrates duplex sequencing with cost-effective Ultima sequencing to enhance the accuracy of whole-genome circulating cell-free DNA profiling.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

The role of IgG glycosylation in the immune response has been studied, but less is known about IgM glycosylation. Here the authors characterize glycosylation of SARS-CoV-2 spike specific IgM and show that it correlates with COVID-19 severity and affects complement deposition.