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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.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

This study uses single-nucleus RNA sequencing to analyze lung tissue from 141 individuals with chronic obstructive pulmonary disease. Distinct patterns of spatially resolved changes in cell composition and cell states that correlate with clinical features are highlighted.

A randomized controlled trial found that eliminating opioids after minimally invasive gynecologic surgery did not compromise pain control at postoperative day 1, with similar pain scores and recovery outcomes between opioid-free and restrictive opioid groups up to day 7.

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.

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.

Bennu samples have abundant supernova stardust and clasts that are richer in presolar silicates and organics than other chondritic samples, suggesting that the protolith sampled material with a unique mixture of primordial components before undergoing heterogeneous aqueous alteration.

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.

A genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

The immune response to SARS-CoV-2 infection is variable but has been linked to prognosis and the development of severe immunopathology. Here the authors assess a range of immune parameters in both peripheral blood and respiratory samples, providing a comparative assessment of the immune response between these compartments and their potential impact on immune-pathogenesis.

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.

Authors perform an analysis of the patient data and risk factors to evaluate unfavorable outcomes and adverse events in adults with pulmonary tuberculosis treated with a 4-month rifapentine based regimen. Low rifapentine exposure was the most clinically significant risk factor for treatment failure and tuberculosis relapse.

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.

Metagenomic next-generation sequencing has the potential to support diagnosis of unknown infections as it can identify all potential pathogens without requiring a prior suspected cause. Here, the authors develop and clinically validate a metagenomics-based assay for common and novel respiratory viral pathogens.

Protein/protein interaction (PPI) interfaces have emerged as drug targets to develop medications with less side effects. Here, Dvorak et al. show that small molecule targeting of PPIs in the brain is an approach for psychiatric drug discovery.

RNAtracker is a computational pipeline that distinguishes variants associated with allele-specific RNA stability from those associated with allele-specific RNA transcription. Variants affecting RNA stability are enriched in immune-related genes and contribute to disease risk.

Here, the authors identify distinct gut microbiome and metabolome signatures in microscopic colitis, a condition causing chronic diarrhea, highlighting pro-inflammatory species and metabolites as potential non-invasive biomarkers and therapeutic targets.

The prognostic and diagnostic roles of DNA methylation in acute myeloid leukemia remains to be explored. Here, the authors develop DNA methylation-based models for the prediction of five-year survival and clinical molecular subtypes in both pediatric and adult test cohorts.

Lipophilic siRNA conjugates exert therapeutic activity in the mouse CNS.

Fine-scale geospatial mapping of overweight and wasting (two components of the double burden of malnutrition) in 105 LMICs shows that overweight has increased from 5.2% in 2000 to 6.0% in children under 5 in 2017. Although overall wasting decreased over the same period, most countries are not on track to meet the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025.

An integrated dataset combining genetics, epigenomics, transcriptomics, proteomics and metabolomics from 1,342 people living with HIV illuminates molecular pathways driving immune responses and comorbidities in this population.

A study of dependencies associated with cancer-causing mutations has identified a small molecule that binds to SHOC2 and inhibits RAS signalling in cells carrying NRAS Q61 mutations, a common oncogenic driver in melanoma.

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.

Long-term expression of AAV transgenes in macaque liver is traced to integrated vectors.

Here the authors reveal that a neomorphic mutation in chromatin protein SMCHD1 enhances SMCHD1-mediated gene silencing, including at the FSHD disease-relevant locus, while depleting SMCHD1-mediated chromatin interactions, suggesting these SMCHD1 functions are unlinked.

In an updated report on 70 laboratory-confirmed highly pathogenic avian influenza A H5N1 cases in the USA between March 2024 and May 2025, the absence of human-to-human transmission to date was confirmed, with no known mutations of resistance to neuroaminidase inhibitors.

Jayavelu, Samaha et al., apply machine learning models on hospital admission data, including antibody titers and viral load, to identify patients at high risk for Long COVID. Low antibody levels, high viral loads, chronic diseases, and female sex are key predictors, supporting early, targeted interventions.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

 A transcriptomic cell-type atlas of the whole adult mouse brain with ~5,300 clusters built from single-cell and spatial transcriptomic datasets with more than eight million cells reveals remarkable cell type diversity across the brain and unique cell type characteristics of different brain regions. 

Analyses of epigenomic datasets spanning transitions from normal prostate epithelium to localized prostate cancer to metastases show that latent developmental programs are reactivated in metastatic disease and that prostate lineage-specific regulatory elements are strongly enriched for prostate cancer risk heritability.

Senescent melanocytes of skin nevi drive hyperactivation of hair growth through the signalling factor SPP1.

Wolbachia infection in mosquitoes reduces dengue virus spread under specific lab conditions, prompting its use in disease control. Here, King et al. show that Wolbachia increases mean and variance in mosquito susceptibility and explain how this affects Wolbachia invasion and dengue transmission.

A CRISPR-based screening platform was used to identify previously uncharacterized genes that regulate the regulatory T cell-specific master transcription factor Foxp3, indicating that this screening method may be broadly applicable for the discovery of other genes involved in autoimmunity and immune responses to cancer.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

Infection of African green monkeys with simian immunodeficiency virus is a potential model for HIV vaccine development. Here, Zhang et al. catalogue the immunoglobulin loci present in the genome of these animals, and experimentally study their B-cell response to the viral envelope protein.

Together with a companion paper, the generation of a transcriptomic atlas for the mouse lemur and analyses of example cell types establish this animal as a molecularly tractable primate model organism.

Analysis of gene expression and open chromatin regions in up to 32 immune cell populations under resting and stimulated conditions identifies widespread chromatin remodeling and shared response elements between stimulated B and T cells.

Nursing homes are high-risk settings for transmission of infections, but risks associated with specific activities are not well understood. Here, the authors investigate transmission dynamics of multi-resistant organisms in nursing homes in the United States with a focus on out-of-room, interactive visits.

A risk score based on a 34-gene signature for outcome prediction in meningioma was developed and validated in large multi-institutional cohorts and showed better performance in discriminating postoperative menignioma outcomes compared with existing meningioma classification systems.

Solid organ transplant recipients are at increased risk of infectious disease and have unique molecular pathophysiology. Here the authors use host-microbe profiling to assess SARS-CoV-2 infection and immunity in solid organ transplant recipients, showing enhanced viral abundance, impaired clearance, and increased expression of innate immunity genes.

Rocks and dust from the asteroid Bennu contain some of the molecular building blocks of life on Earth, such as amino acids and nucleobases. They also carry ammonia that formed billions of years ago in cold, distant regions of our Solar System.

The Human Breast Cell Atlas identifies 12 major breast cell types and 58 biological cell states, revealing abundant pericyte, endothelial and immune cell populations, and highly diverse luminal epithelial cell states.

Transfer hydrogenation is challenging to apply to aryl halide reductive cross-couplings because of competing hydrogenolysis. Now aryl halide cross-couplings mediated by sodium formate have been developed. These processes display orthogonality to Suzuki and Buchwald–Hartwig couplings as pinacol boronates and anilines are tolerated and, owing to chelated intermediates, effective for challenging 2-pyridyl systems.

Replacing the extracellular domains of heterodimeric cytokine receptors in chimeric antigen receptor T cells with two leucine zipper motifs leads to optimal JAK/STAT signalling and augments the effector function of the T cells.

Different gut bacteria have been shown to promote colorectal cancer (CRC) progression. The authors identify formate as an oncometabolite derived from Fusobacterium nucleatum, which promotes CRC formation by increasing cancer stemness.

Dystrophic Epidermolysis Bullosa is an uncurable monogenetic skin disease. Here, Neumayer et al. develop a cGMP-compatible CRISPR- and iPS cell-based approach that produces gene-corrected, autologous skin composite grafts for definitive treatment.

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.

The GREGoR consortium provides foundational resources and substrates for the future of rare disease genomics.