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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.

A cavity-array microscope is realized using intra-cavity lenses to create a two-dimensional array of over 40 modes, each coupled to a single atom in free-space.

A platform using matched patient-derived lung tumouroids and healthy lung organoids enables accurate examination of patient responses to CAR T therapy and offers a faithful framework for improved CAR T design.

Krisai et al. compare brain structure and cognitive function in elderly patients with and without atrial fibrillation using brain MRI and cognitive testing. They find that atrial fibrillation is associated with more brain lesions and lower cognitive function, but the cognitive impairment occurs primarily through direct effects of the arrhythmia rather than through brain damage.

Aligning foundation models with human judgments enables them to more accurately approximate human behaviour and uncertainty across various levels of visual abstraction, while additionally improving their generalization performance.

The rapid expansion of agricultural irrigation raises concerns about exacerbating water scarcity, but land–atmosphere interactions are often overlooked. This study isolates irrigation impacts from other drivers using a multi-model framework to reveal that historical irrigation expansion substantially reduces net atmospheric water influx, intensifying drying trends and accelerating terrestrial water storage depletion, urging immediate mitigation strategies.

By unifying data from engineered β-barrel nanopores and supported by modelling, it is demonstrated that the lumen charge in a β-barrel nanopore governs rectification and voltage-driven gating, with applications in computing using nanofluidic synapses.

A doped quantum antiferromagnet is obtained by using a Rydberg tweezer array comprising three levels encoding spins and holes to implement a tunable model that allows the study of previously inaccessible parameter regimes.

Risk stratification in non-small cell lung cancer (NSCLC) remains challenging. By combining multiplex immunofluorescence, H&E histology, and AI, the study identifies spatial “cell-niche” patterns that enhance survival prediction beyond UICC8 staging. These patterns reclassify many stage I patients as high risk, revealing potentially undertreated cases and establishing spatial tumor microenvironment features as clinically actionable biomarkers.

Single-cell RNA sequencing efforts have made large amounts of data available for transcriptomics research. Simon and colleagues develop a neural network embedding approach that avoids batch effects, such that it can rapidly and efficiently integrate large datasets from different studies.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Spinal cord injury leads to lasting motor and sensory loss, with limited treatment options. Here, the authors show that subdural electric field stimulation delivered across the injury via an ultra-thin implant improves functional recovery in rats.

A scalable solution involving direct wafer-bonding of high-quality, epitaxially grown gallium phosphide to low-index substrates is introduced. The promise of this platform for integrated nonlinear photonics is demonstrated with low-threshold frequency comb generation, frequency-doubled combs and Raman lasing.

Second-generation oxidation boosts the production of anthropogenic organic aerosol, according to an analysis of urban haze in an experimental chamber.

Human influence on the climate and terrestrial systems is increasingly altering global river flow. This Review discusses past and projected changes in global river flow, with an emphasis on annual volumes, seasonal dynamics and sudden changes in flow dynamics.

Natural products have historically made a major contribution to pharmacotherapy, but also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization. This Review discusses recent technological developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — that are enabling a revitalization of natural product-based drug discovery.

Substrate-specific proteases have an enormous potential in the life sciences, but tailoring their specificity remains challenging. Here, the authors describe a data-driven approach combining DNA recording and epistasis-aware deep learning to augment protease specificity engineering at large scale.

Feuerer and colleagues use multiomic analyses to identify DNA methylation, chromatin accessibility and gene expression programs that govern the tissue adaptation of human skin T_reg cells.

This work highlights the technical issues in previous approaches and introduces a preprocessing approach along with a software package, MethSCAn, for single-cell bisulfite sequencing data analysis.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

A phase 1 clinical trial provides evidence that a vaccine against mutant IDH1 is safe and produces a T helper immune response in patients with glioma.

The authors provide cryo-EM reconstructions of human transfer RNA splicing endonuclease during substrate recognition, rationalizing disease-relevant mutations.

Climate models, impact models and demographic data are used to estimate the number of people projected to experience unprecedented lifetime exposure to extreme climate events across multiple dimensions, including birth year, warming scenario and vulnerability.

EU wine geographical indications are bound to a strict regulatory system, limiting their potential to adapt to climate change. In this study, analysis of social, environmental and economic characteristics of over 1000 EU wine regions suggests that innovation and flexibility are key to increase the resilience of European viticulture.

53BP1 is marker of double-strand breaks and accumulates in nuclear foci. These foci are shown to accumulate in G1 at lesions generated by replication stress and may shield lesions from erosion.

Loss of let-7, a key microRNA, causes lung alveolar stem cells to grow abnormally and dieprematurely, leading to scarring and lung damage. Here the study links let-7 loss to cancer-like signals and epigenomic gene changes, revealing new treatment paths for lung fibrosis.

The need for redox balancing limits the array of fermentable substrate-product combinations in anaerobic microbe-based bioproduction. Here, the authors design and engineer an E. coli strain with new-to-nature aerobic fermentative metabolism that allows tightly controlled re-balanced fermentations.

The spatial architecture of multiple myeloma remains to be explored. Here, the authors perform bulk and single cell sequencing for samples from newly diagnosed patients and reveal gene signatures associated with focal lesions and spatial heterogeneity in the tumour microenvironment.

An antibody–drug conjugate that targets the pan-haematopoietic marker CD45 combined with transplanted stem cells engineered to be shielded from it can eradicate leukaemic cells while preserving haematopoiesis.

Single-cell analysis of the transcriptome, chromatin accessibility and methylome of adult neural stem cells and astrocytes demonstrates that stemness is driven by methylation profiles distinct from those of astrocytes.

The human endoderm-derived organoid cell atlas (HEOCA) presents an integrative analysis of single-cell transcriptomes across different conditions, sources and protocols. It compares cell types and states between models, and harmonizes cell annotations through mapping to primary tissues.

I-Motifs (iM) are non-canonical DNA structures potentially forming in the accessible, single stranded, cytosine-rich genomic region, but the specific contributions of several factors involved in their formation are unknown. Using in-cell NMR, the authors examined DNA i-motif formation in human cells at body temperature, suggesting i-M occur in a small portion (<1%) of genomic sites predisposed to its formation.

Hofer et al. show that fasting promotes the synthesis of spermidine, which stimulates eIF5A hypusination to induce autophagy and increase lifespan in various species in a conserved manner.

Rinnerthaler et al. perform a randomized phase 2 trial of neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin in patients with early HER2-positive breast cancer and report positively on efficacy and safety.

Zeiser and colleagues show that CAR T cell therapy results in upregulation of the TGFβ-activated kinase-1 (TAK1)–NF-κB–p38 MAPK pathway in microglia, causing neurocognitive defects, and find that TAK1 inhibition can reduce immune effector cell-associated neurotoxicity syndrome.

Development of the secondary palate is a complex process. Here, the authors profile mouse palatogenesis through single-cell multiome sequencing, revealing dynamic gene regulation across embryonic days (E) 12.5, E13.5, E14.0, and E14.5.

Single-cell RNA sequencing is a powerful method to study gene expression, but noise in the data can obstruct analysis. Here the authors develop a denoising method based on a deep count autoencoder network that scales linearly with the number of cells, and therefore is compatible with large data sets.

Assessing person-level human brain maps across 18 fMRI studies, the authors identify separable representations of pain, cognitive control, and negative emotion in the medial frontal cortex that generalize across different studies and tasks.

HERC2 regulates the retention of repair proteins 53BP1, RAP80 and BRCA1 on damaged chromosomes in response to ionizing radiation by forming a complex with the ubiquitin ligases RNF8 and RNF168. Hecr2 deficiency leads to radiosensitivity.

Phosphatidic acid constitutes less than 1% of total lipids, but does not play a minor role. It serves as a lipid precursor, affects membrane curvature and regulates signalling transduction. Now, by employing a new powerful PAleon biosensor, the researchers visualized PA dynamics in different pH conditions corresponding to salt stress responses in Arabidopsis.

A direct imaging study demonstrates the existence of a giant planet in a wide orbit around the high-mass b Centauri binary system, and uses measurements of the orbital properties to discuss its formation mechanism.

Due to various structural and sequence complexities, the human Y chromosome is challenging to sequence and characterize. Here, the authors develop a strategy to sequence native, unamplified flow sorted Y chromosomes with a nanopore sequencing platform, and report the first assembly of a human Y chromosome of African origin.

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

Aging impacts lung functionality and makes it more susceptible to chronic diseases. Combining proteomics and single cell transcriptomics, the authors chart molecular and cellular changes in the aging mouse lung, discover aging hallmarks, and predict the cellular sources of regulated proteins.

This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual.

The epigenetic modifier EZH2 is highly expressed in melanoma but its role in cancer initiation and progression is still unclear. Here the authors use mouse models and human cell lines to show that EZH2 has an essential role in melanoma progression and metastasis, thus highlighting its potential as a therapeutic target.