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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.

Stable adipocytes resist lipolysis in healthy states but are highly susceptible to a catecholamine-independent, neurosystemic pathway-driven catabolic state.

Engineering of local Anopheles gambiae under containment enables the generation of a transgenic strain equipped with non-autonomous gene drive capabilities that robustly inhibits genetically diverse Plasmodium falciparum isolates obtained from naturally infected children.

Kukreja, Jeon et al. leverage spatial transcriptomics to map immune gene expression in the developing mouse brain, identifying key sex-specific changes in the context of maternal gut−immune perturbations.

Genome editing tools can precisely introduce a specified lesion into the DNA, but ultimately rely on the cell’s DNA repair machinery to determine the editing outcome. Here, authors demonstrate how neurons’ unique DNA repair pathways impact the safety, efficiency, and precision of CRISPR edits.

Koina is an open-source, online platform that simplifies access to machine learning models in proteomics, enabling easier integration into analysis tools and helping researchers adopt and reuse ML models more efficiently.

Resistance signaling in the tumor microenvironment limits CAR T cell therapy in solid tumors. This study introduces a multiplex engineered CAR T cell strategy using six gene edits to overcome multiple inhibitory barriers.

Down Syndrome is a common genetic cause of intellectual disability and is associated with altered fetal neurodevelopment. Here, the authors identify altered expression dynamics of lineage commitment genes and de-repression of transposable elements in DS neural progenitor cells.

Genome editing in plants typically requires the expression of Cas9 and guide RNA from stably transformed plasmid DNA. Here, the authors show that successful editing can be achieved after delivery of the Cas9-guide RNA complex as a ribonucleoprotein to maize embryos via biolistics.

Pressure overload in the heart, such as from aortic stenosis, triggers early molecular changes before visible damage occurs. Here, the authors show that combining proteomics, transcriptomics, and genetic data reveals key drivers of heart failure, highlighting potential targets for treatment.

This paper presents TDAC-seq, a targeted chromatin-accessibility-profiling method using cytidine deaminases and long-read sequencing, to resolve the effects of CRISPR edits on single chromatin fibers.

Our basic understanding of neuromodulation in the claustrum remains limited. Here Madden et al., identify a key mechanism by which serotonin and the psychedelic psilocybin modulate cortical signalling through the claustrum, a brain region involved in regulating cognition and brain network states.

NextBrain is an open source, probabilistic atlas of the entire human brain, assembled using artificial-intelligence-enabled registration and segmentation methods to reconstruct the multimodal serial histology of five human half brains, and which can be used to automatically segment brain MRI scans into 333 regions.

Artificial intelligence and international scientists are some of the big winners in the country’s spending plan this year.

The affected cellular populations during Alzheimer’s disease progression remain understudied. Here the authors use a cohort of 84 donors, quantitative neuropathology and multimodal datasets from the BRAIN Initiative. Their pseudoprogression analysis revealed two disease phases.

CORAL can infer the occurrence of rare species based on common species, using DNA metabarcoding data or other high-dimensional biodiversity data. The approach is illustrated on a large-scale biodiversity survey from Madagascar.

A study in eastern Canada finds that forest-management strategies that lead to simplified forest structure and composition have resulted in loss of breeding habitat and associated population losses for many bird species.

LYMTACs are heterobifunctional small molecules that take advantage of lysosomal membrane proteins to degrade membrane targets via relocalization and lysosomal degradation, offering a modular approach to drug otherwise intractable membrane proteins.

Hominin fossils from the Ledi-Geraru Research Project area, Ethiopia, suggest that early Homo and Australopithecus species co-existed in the region more than 2.5 million years ago.

Hollow-core fibre technologies provide an exceptional platform for applications in sensing, communications and higher-power pulse delivery, yet these fibres suffer from uncontrolled coupling of polarization modes. Here Fini et al. fabricate a single-moded, polarization-maintaining hollow-core fibre.

Pleiotropy is the effect of a single locus on multiple traits, which can lead to undesirable outcomes during crop improvement. Here, the authors reveal regulatory variation controlling pleiotropy between maize leaf angle and tassel branching, two important agronomic traits.

Fluid shear stress plays a role in medulloblastoma metastasis through a PIEZO2-actomyosin-GLUT1 signalling cascade.

In the lungs, recently identified epithelial structures known as hillocks can act as injury-resistant reservoirs of stem cells.

The country’s output in quality health research is going from strength to strength, but can it overcome questions about the integrity of its publishing practices?

We find that leptin-target neurons expressing basonuclin 2 in the arcuate nucleus that acutely suppress appetite by directly inhibiting agouti-related protein neurons are a key component of the neural circuit that maintains energy balance.

JWST data reveal a multi-galaxy merger 800 Myr after the Big Bang, likely a progenitor of massive quiescent galaxies seen at later times. Its extended [O iii] halo offers direct evidence of early metal enrichment via tidal stripping.

Electron-spin resonance spectroscopy can detect radical species in live cells, but the method suffers from limitations of spin-label stability and selectivity. Here, flavoproteins are employed as genetically encoded spin probes to reveal structural features of bacterial chemotaxis proteins in cell.

Ibanez et al. introduce multimodal diversity, a synergistic framework integrating multimodal brain metrics, whole-body health, and exposomic data through neurosyndemic computational modeling to advance context-sensitive precision brain health across global settings.

Gene-edited waxy corn lines have higher yields in field trials than hybrids produced by traditional trait introgression.

This study reconstructs the evolution of leaf venation networks, describing the transition from fewer, corrugated veins to high vein density and smoother loops. It also suggests herbivory as a potential driver of venation architectural changes.

Mucosal melanoma (MM) is a cancer with poor prognosis derived from mucosal melanocytes. Here, the authors implement a combination of genetic changes that occur in MM patients in a zebrafish model, revealing the potential MM cell of origin and showing that patient and zebrafish MMs share a gene signature that is more metastatic and immune-evasive.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

Combinations of single-stranded DNA repair templates and small molecules markedly enhance genome editing.

The structure of the GLP-1 receptor complexed with its ligand offers insight into the mechanism of class B G-protein-coupled receptor activation.

Fracture behaviours in multilayer h-BN, involving interlayer-friction toughening and edge-reconstruction embrittlement, are identified through in situ experiments and theoretical analyses.

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).

Here, the authors computationally designed and produced small protein antagonists to target IL-6 and IL-1β signaling to develop modulators of CRS.

Studies on the essentiality of Ku in human cells reveal that Ku interacts with diverse double-stranded RNA molecules, including antisense Alu, and enables tolerance of Alu sequence expansion in primates.

GPCR dynamics are critical for signal transmission into the cell. Here, the authors probe receptor plasticity using molecular dynamics simulations, enabling the detection of allosteric sites and drug entry gateways for a broad range of GPCR types.