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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.

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.

Yang et al. apply high-throughput structure probing approaches to characterize the secondary structure throughout the SARS-CoV-2 WT and VOC genomes, uncovering an ultra-long-range RNA-RNA interaction that directly binds ADAR1 to promote viral fitness.

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.

Clinically significant genetic variation in Asian populations is under-characterized. Here, the authors show the diversity in prevalence and spectrum of human disease and pharmacogenetic variants in a multi-ethnic Asian population.

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.

Tailored to provide diabetes management recommendations from large training and validation datasets, an artificial intelligence system integrating language and computer vision capabilities is shown to improve self-management of patients in a prospective implementation study.

Structural variations (SV) contribute to inter-individual variability. Here, the authors describe a first-generation multi-ancestry Asian SV catalogue containing 73,035 SVs from 8392 Singaporeans to provide insights into Asian SV diversity.

Cell type labelling in single-cell datasets remains a major bottleneck. Here, the authors present AnnDictionary, an open-source toolkit that enables atlas-scale analysis and provides the first benchmark of LLMs for de novo cell type annotation from marker genes, showing high accuracy at low cost.

The molecular organization of exocytic vesicles regulates their transport and fusion. Prasai, Taraska, and colleagues use correlative light and electron microscopy, along with 3D tomography and gold labeling, to directly map proteins on single exocytic organelles at the plasma membrane.

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).

In cancer, the impact on cellular fitness of copy-number gains affecting collaterally-amplified genes remains poorly understood compared to oncogenes. Here, the authors integrate genomic data from tumours and cell lines and identify a class of ‘Amplification-Related Gain Of Sensitivity’ (ARGOS) genes, with potential therapeutic applications.

A ‘mouse atlas’, comprising single-cell transcriptomic data from more than 100,000 cells from 20 organs and tissues, has been created as a resource for cell biology.

Dräger et al. establish a rapid, scalable platform for iPSC-derived microglia. CRISPRi/a screens uncover roles of disease-associated genes in phagocytosis, and regulators of disease-relevant microglial states that can be targeted pharmacologically.

8-oxoG is a common single-base DNA lesion caused by oxidative stress. Here, authors characterize the mutational signature of potassium bromate (KBrO₃) exposure, the chromatin structural determinants of 8-oxoG-induced mutation and the mechanisms involved in the repair of KBrO₃-induced 8-oxoG.

Ian Blair and colleagues use genome-wide linkage analysis and whole exome sequencing to identify mutations in the CCNF gene in large cohorts of amyotrophic lateral sclerosis and frontotemporal dementia patients. In addition to validating the mutations in international cohorts, the authors also show that mutant CCNFgene product affects ubiquitination and protein degradation in cultured cells.

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.

Estimates from the Global Dietary Database indicated that 2.2 million new type 2 diabetes and 1.2 million new cardiovascular disease cases were attributable to sugar-sweetened beverages worldwide in 2020, with the highest burdens in sub-Saharan Africa, Latin America and the Caribbean.

Mathematical tools can be used to help identify pathological features from images of diseased lungs. Here, the authors used mathematical tools combined with high resolution multiplex imaging mass cytometry to show an association between immature neutrophils, CD8 T cells and proliferating alveolar epithelial cells in areas of maximal alveolar damage in COVID-19 lungs.

Recent estimates of sugar-sweetened beverages (SSBs) intake are generally unavailable. Here the authors show a global SSBs intake of 2.7 servings/week in 2018 in adults (range: 0.7 South Asia, 7.8 Latin America/Caribbean); intakes were higher among males, younger, more educated, and urban adults.

A nanoscale polymer layer formed by mucins at the surface of tumour cells protects them against immune cell attack. This shield can be circumvented through immune cell engineering, using chimeric antigen receptors to stimulate natural killer and T cells or by tethering glycocalyx-editing enzymes to immune cells.

A single-cell transcriptomic analysis of 63 patients with colorectal cancer classifies tumor cells into two epithelial subtypes. An improved tumor classification based on epithelial subtype, microsatellite stability and fibrosis reveals differences in pathway activation and metastasis.

Gut microbiota composition is altered in patients with alcohol use disorder, and fecal microbiota transplant reduced alcohol craving in patients with alcohol use disorder and liver cirrhosis in a phase 1 clinical trial. Here the authors used stool samples collected in the trial to report that this phenotype is transmissible via microbial transfer to germ free mice, as assessed by reduced ethanol acceptance, intake and preference.

An analysis based on data from the Global Dietary Database shows mean animal-sourced food intakes among children and adolescents increased modestly from 1990 to two portions per day in 2018, but remain low in sub-Saharan Africa, India and Bangladesh.

Liquid glycan arrays (LiGAs), presented on M13 bacteriophage surface proteins through bioorthogonal chemistry, link surface glycans to genetic barcodes in phage DNA, enabling lectin–glycan interaction profiling by DNA sequencing.

Machine learning has now been shown to enable the de novo design of abiotic nuclear-targeting miniproteins. To achieve this, high-throughput experimentation was combined with a directed evolution-inspired deep-learning approach in which the molecular structures of natural and unnatural residues are represented as topological fingerprints. The designed miniproteins, called Mach proteins, are non-toxic and can efficiently deliver antisense cargo in mice.

Crohn’s disease (CD) is a complex disease associated with immune dysregulation. Here the authors use multimodal data to identify and characterize an epithelial cell population, termed ‘LND’ cells, in both terminal ileum and ascending colon, with LND interacting locally with immune cells and potentially contributing to CD pathology.

Dietary quality is reported at the global, regional and national level across 185 countries. Though diet quality increased modestly since 1990 at the global level, in South Asia and Sub-Saharan Africa it did not improve. In some regions, children’s dietary quality is lower than that of adults.

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.

Modeling analysis from the Global Dietary Database estimated that 70% of new global cases of type 2 diabetes are attributable to suboptimal intake of 11 dietary factors, with substantial differences in dietary risks across world regions and nations.

Forkhead box transcription factor, FOXQ1 is reported to promote epithelial-mesenchymal transition (EMT) and cancer metastasis. Here the authors show that FOXQ1 recruits the KMT2/MLL histone methyltransferase complex as a transcriptional coactivator to activate EMT programme in breast cancer.

Emmanuel Mignot and colleagues report that variants in the T-cell receptor alpha (TRA@) locus are strongly associated with narcolepsy. This is the first documented involvement of the TCR locus in human disease and will shed light on how HLA-TCR interactions contribute to organ-specific autoimmune targeting.

Rational design of live-attenuated RNA viruses with potential as vaccines is enabled by identification of sequence rules for zinc finger antiviral protein.

H3K27me3 binding to the EED pocket of the Polycomb repressive complex 2 (PRC2) is required to activate PRC2. An allosteric small-molecule inhibitor of PRC2 was identified that binds to the EED pocket and blocks PRC2 methyltransferase activity in cells.

A single-cell transcriptomic atlas across the lifespan of the mouse, denoted Tabula Muris Senis, provides molecular information about the hallmarks of ageing in a range of tissues and cell types.

Massively parallel DNA sequencing allows entire genomes to be screened for genetic changes associated with tumour progression. Here, the genomes of four DNA samples from a 44-year-old African-American patient with basal-like breast cancer were analysed. The samples came from peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The findings indicate that cells with a distinct subset of the primary tumour mutation might be selected during metastasis and xenografting.

A transcriptomics study demonstrates cell-type-specific responses to differentially aged blood and shows young blood to have restorative and rejuvenating effects that may be invoked through enhanced mitochondrial function.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies.

Bulk RNA sequencing of organs and plasma proteomics at different ages across the mouse lifespan is integrated with data from the Tabula Muris Senis, a transcriptomic atlas of ageing mouse tissues, to describe organ-specific changes in gene expression during ageing.

MEK inhibition in breast cancer is associated with increased tumour infiltrating lymphocytes (TILs), however, MAPK activity is required for T cells function. Here the authors show that TILs activity following MEK inhibition can be enhanced by agonist immunotherapy resulting in synergic therapeutic effects.

A fraction of the intestinal microbiota as precise as a single bacterial species confers infection resistance by synthesizing Clostridium difficile-inhibiting metabolites from host-derived bile salts.

This Perspective article discusses Singapore’s efforts to implement a National Precision Medicine Strategy through the integration of genomic, clinical and lifestyle data of up to one million Singaporean individuals.