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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 examine the mechanisms behind cheatgrass’s successful invasion of North American ecosystems. Their genetic analyses and common garden experiments demonstrate that multiple introductions and migrations facilitated cheatgrass local adaptation.

Detection of hot intracluster gas in SPT2349−56 with the Atacama Large Millimeter/submillimeter Array provides new insights into early cluster formation.

Pulmonary type 2 inflammation is associated with type 2 innate lymphoid cells. Here the authors use the Collaborative Cross mouse panel to show that ILC2 abundance during type 2 lung inflammation is different across the panel and identify free-fatty acid receptor 3 (Ffar3) as a gene responsible and show cytokine and ILC2 functional changes.

The origin of the nematic state in the kagome metal CsTi₃Bi₅ remains unclear. Here, using polarization-dependent angle-resolved photoelectron spectroscopy and ab initio based field theoretical methods, the authors propose a d-wave nematic order driven by electronic correlations via an orbital-selective mechanism.

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.

Tree longevity is thought to increase in harsh environments, but global evidence of drivers is lacking. Here, the authors find two different pathways for tree longevity: slow growth in resource limited environments and increasing tree stature and/or slow growth in competitive environments.

Elhan et al. show that ATG2A acts with DGAT2, the enzyme producing triacylglycerol (TAG), in lipid droplet growth. By delivering diacylglycerol to lipid droplets, ATG2A not only fuels TAG production but also promotes the recruitment of DGAT2 to droplet surfaces.

The heteromeric insect TRPV channel, Nanchung-Inactive, is a previously structurally uncharacterized insecticide target. Here, Fedor et al. provide insights into how an insecticide and a natural agonist modulate channel behavior, paving the way for future insecticide development.

Vinyl acetate is an important polymer building block, but the mechanisms governing its catalytic production are not well understood. This study shows that dynamic palladium-acetate clusters determine catalyst efficiency and selectivity in vinyl acetate synthesis.

Tissue-resident macrophages (TRM) are important mediators of local immunity. Here the authors show that the deficiency or inhibition of a kinase, WNK1, unlinks macrophage colony-stimulating factor signaling and resulted macropinocytosis with the downstream, potentially IRF8-mediated genetic program to bias progenitor differentiation to neutrophil instead of TRM.

Early high-resolution images of two 2021 novae reveal eruptions unfolding in multiple stages with colliding outflows that produce shocks and gamma rays, reshaping our understanding of stellar explosions.

Here Jaster et al., show a single psilocybin dose produce sex-specific post-acute changes in opioid reward and withdrawal via 5-HT2A receptors in frontal cortex-to–nucleus accumbens circuits, with epigenetic and synaptic changes shaping therapeutic potential.

Despite often being poorly immunogenic, some subsets of patients with hormone receptor-positive, HER2-negative (HR + /HER2-) breast cancer benefit from immunotherapy. Here, the authors present a randomised pilot clinical trial comparing a neoadjuvant run-in of either nab-paclitaxel or pembrolizumab (anti-PD-1) monotherapy, followed by the combination, in patients with stage II-III HR + /HER2- breast cancer.

A method termed ac⁴C-seq is introduced for the transcriptome-wide mapping of the RNA modification N⁴-acetylcytidine, revealing widespread temperature-dependent acetylation that facilitates thermoadaptation in hyperthermophilic archaea.

Dysregulated protein levels can cause disease. The authors present a scalable platform capable of identifying small molecules that alter disease-linked target protein levels, and report >40 that increase SynGAP protein abundance, with SR1815 restoring neuronal function in Syngap1 deficient neurons.

Gold has a vital role in human society and the global economy, but its production currently causes high levels of environmental pollution. This work reports an approach that can effectively produce gold from both primary and secondary resources without the use of toxic substances such as mercury or cyanide.

Mass-wasting deposits that accumulated against mid-ocean ridge faults have high porosity in which calcium carbonate precipitated, storing seawater carbon dioxide, as revealed by cores of a 61-million-year-old seafloor talus deposit.

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.

Fragile X syndrome is a neurodevelopmental disorder caused by inactivating the RNA-binding protein FMRP. Here, the authors show that FMRP acutely regulates structural plasticity in mature adult pacemaker neurons in the Drosophila central brain.

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.

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.

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).

The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.

Pulmonary large cell neuroendocrine carcinoma is an aggressive subtype of lung cancer. Here, the authors identify distinct subtypes based on genomic alterations and transcriptomic alterations.

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.

The electronic band structure in silicon optical fibres can be engineered by continuous laser irradiation during the crystallization of the fibres. A reduction of the bandgap down to 0.59 eV is demonstrated.

The first experimental demonstration of saturable absorption in core-electron transitions in aluminium paves the way for investigating warm dense matter, which potentially has an important role in planetary science and the realization of inertial confinement fusion.

Although the number of participants is important for phenotypic prediction accuracy in brain-wide association studies using functional MRI, scanning for at least 30 min offers the greatest cost effectiveness.

Authors report MagNet, a plasma extracellular vesicle (EV) enrichment strategy using magnetic beads. Proteomic interrogation of this plasma EV fraction enables the detection of proteins that are beyond the dynamic range of mass spectrometry of unfractionated plasma.

Quantum computers may help to solve classically intractable problems, such as simulating non-equilibrium dissipative quantum systems. The critical dynamics of a dissipative quantum model has now been probed on a trapped-ion quantum computer.

Spin dynamics in magnetic materials can be driven by ultrafast light pulses, resulting in transient magnetization changes on femtosecond timescales. Rudolphet al. find that in magnetic trilayers the magnetization of one layer can be enhanced by superdiffusive spin currents from adjacent layers.

This study examines the outcomes of dietary shifts across intrinsic and instrumental conservation perspectives, finding that most conservation benefits already come from a partial shift to healthier, more plant-based diets, whereas greater benefits depend on more targeted conservation action.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease group with CAR T cells offering therapeutic success in otherwise hard-to-treat cases. Here, authors study the in vivo expansion and persistence of CAR T cells in the peripheral blood of successfully treated DLBCL patients, demonstrating that two different CD8+ precursor phenotypes in the initial cell product give rise to two independent waves of clonally expanded CAR T cells with distinct phenotypes in peripheral blood.

Synthetic routes to aminoglycosides are often long and rely upon the coupling of semisynthetically produced fragments. Now, an enantioselective, copper-catalysed hydroamination of benzene has been developed to enable access to the aminoglycoside antibiotic ribostamycin. This bottom-up strategy provides modular and expedient entry into the aminocyclitol class.

Machine-learning algorithms trained on 25,000 geolocated soil samples are used to create high-resolution global maps of mycorrhizal fungi, revealing that less than 10% of their biodiversity hotspots are in protected areas.

Basal cells, rather than neuroendocrine cells, have been identified as the probable origin of small cell lung cancer and other neuroendocrine–tuft cancers, explaining neuroendocrine–tuft heterogeneity and offering new perspectives for targeting lineage plasticity.

Cryo-electron and atomic force microscopy shed light on how fibrils of the protein tau, which accumulate in the brain of people with Alzheimer’s disease, can be disassembled by short peptides, providing a possible route towards developing treatments.

Despite evidence for an ice-rich outer shell, little water ice has been observed on the surface of Ceres. Lobate morphologies observed on Ceres that are increasingly prevalent towards the dwarf planet’s poles are consistent with ice-rich flows.