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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.

Using chemical photoswitchable reagents to exert purely wavelength-dependent control over biological systems in deep tissue and in vivo requires a concentration-independent design paradigm. Here, such photoswitchable ligands are realized by ensuring that E/Z isomers have opposing efficacies yet similarly high affinity, allowing them to probe transient receptor potential C4 and C5 channel functions up to the tissue level.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

Membrane ion channels can be responsive to a variety of stimuli such as pressure, temperature, or pH. Here, the authors show that simply shining 365 nm light activates a native potassium channel in rodent pain-sensing neurons, delivering powerful analgesia without drugs or genetic manipulations.

The extreme hot and dry conditions of 2023 reduced soil respiration and enhanced net forest carbon sequestration in Canada, offsetting wildfire emissions, according to satellite-based and in situ observations of CO₂ fluxes.

Extreme sea level rises are a threat to coastal communities, but their cause, in terms of seasonal or interannual time scales, has received little attention. Here, the authors combine observational and model data to show that one such rise in 2009–10 was caused by a 30% downturn in the Atlantic overturning circulation.

Radiation reaction (RR) on particles in strong fields is the subject of intense experimental research, but previous efforts lacked statistical significance due to the extreme regimes required. Here, the authors report a 5σ observation of RR and obtain strong, quantitative evidence favouring quantum models over classical, using an all-optical setup where electrons are accelerated by a laser in a gas jet before colliding with a second, intense pulse.

Lorentz invariance, tested more than a century ago by Michelson and Morley, is a foundational property of modern physics within the standard model and general relativity. Here, the authors report the most precise terrestrial test to date, bounding the lack of violations of Lorentz symmetry in photons to 10^–18.

Schuermans et al. discovered that genetic predisposition to thromboembolism is associated with a greater risk of post-acute sequelae after SARS-CoV-2 infection, including long COVID, and downstream analyses implicated PAR-1 as a potential contributor to long COVID.

Across 13 longitudinal studies (3,737 adults), the authors show that brain atrophy parallels memory loss, with a stronger coupling in later life. APOE ε4 increases decline, yet genetic risk does not modify the brain–memory relationship.

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.

During filamentous growth in the human fungal pathogen Candida albicans, a reduction in ribosome concentration leads to a decrease in macromolecular crowding. Inhibition of ribosome biogenesis can trigger filamentous growth in this pathogen.

Evolutionary and ecological insights into marine SAR11 bacteria require whole genome data. Here, the authors expand the number of complete SAR11 isolate genomes by 81 new strains from the tropical Pacific Ocean, combining their sequence analysis with metagenomics to further resolve SAR11 evolution.

Incorporation of the far-red light adaptation of cyanobacteria into crops has been suggested as a potential strategy to increase photosynthesis and yields, but the magnitude of this benefits has not been estimated. Here, via 3D canopy model of soybean, the authors show that it could increase CO₂ assimilation up to 26%.

This research investigates the neurobiological factors influencing weight gain, using brain scans from diverse cohorts to develop a predictive model. The findings indicate that BMIgap correlates with psychiatric conditions, suggesting its potential for identifying at-risk individuals and guiding personalized interventions.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

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.

A liquid flow can cross a solid wall, at odds with classical hydrodynamics, thanks to couplings between the liquid’s fluctuations and the electronic excitations of the solid inducing a momentum tunnelling.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Chaotic dynamics can arise in quantum systems as well as classical ones, leading to its own interesting phenomena. Using an all-optical approach, Lemos et al. study the quantum-kicked harmonic oscillator and its nonlinear dynamics, controlling and mapping the transition into quantum chaotic behaviour.

Individuals with symptoms of anxiety and depression exhibit persistent underconfidence. Here, the authors show that distortions in learning from local metacognition can explain how underconfidence is maintained in the face of intact performance.

Several multi-cancer GWAS loci within the region encoding telomerase reverse transcriptase (TERT) have been identified. Here, the authors explore the locus within TERT intron 4, link it with a variable number tandem repeat (VNTR), and investigate its biological significance and role in cancer.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Dietary protein influences metabolic health and ageing. Here Solon-Biet et al. show that, rather than having a direct toxic effect, dietary branched-chain amino acids (BCAAs) appear to induce hyperphagia, owing to an imbalance between BCAAs and other amino acids, which reduces lifespan as a consequence of obesity.

A re-assessment of the global carbon budget shows the natural land sink is substantially smaller than previously estimated, indicating emerging impacts of climate change on the evolution of the carbon sinks.

Kallies and colleagues examine the role of the chromatin regulator SATB1 in CD8⁺ T cell differentiation during viral infection and cancer. They show that SATB1 is a negative regulator of exhausted CD8⁺ T cell expansion and effector differentiation.

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.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

The ENIGMA-ORIGINs group presents a large and globally diverse pediatric neuroimaging dataset from birth to age 6. They use this resource to study the effects of sociodemographics and adverse birth outcomes on trajectories of brain volumes and cognition.

The accretion geometry of X-ray binary Cygnus X-3 is determined here from IXPE observations. X-ray polarization reveals a narrow funnel with reflecting walls, which focuses emission, making Cyg X-3 appear as an ultraluminous X-ray source.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

Dynamic nanodomains in lead halide perovskites, dictated by A-site cations, crucially affect the optoelectronic properties by modulating electronic disorder and consequently enabling better solar cells and optoelectronic devices.