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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 role of normally silenced transposable elements (TEs) in tumorigenesis remains unclear. Here, the authors show that increased expression of TEs in both patients and mice with colitis or by DNA hypomethylating drugs elicits a viral mimicry response that suppresses tumorigenesis. This viral mimicry response inhibits the stemness of cancer initiating cells in a cell autonomous manner.

Single strontium atoms are trapped in optical tweezer arrays generated via holographic metasurfaces, overcoming a critical barrier to realizing scalable neutral-atom quantum technologies.

The authors present DNA-Diffusion, a generative AI framework that designs synthetic regulatory elements with tunable cell-type specificity. Experimental validation demonstrates their ability to reactivate AXIN2 expression, a leukemia-protective gene, in its native genomic context.

A complementary analysis of DESI DR2 distance measurements along with supernova and CMB data shows consistent, moderate evidence that dark energy changes over time rather than behaving as a simple cosmological constant.

The Southern Annular Mode (SAM) has shifted towards its positive phase owing to ozone depletion and increasing greenhouse gas concentrations. This Review discusses the dynamics, trends and projections of the SAM and how these will affect southern high-latitude climate, including Southern Ocean circulation, carbon cycling and the Antarctic cryosphere.

A consensus cell type atlas for the fly brain provides both an intellectual framework and open-source toolchains for brain-scale comparative connectomics.

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.

Genome-wide analyses in over one million self-reported cases and controls identify genetic variants associated with stuttering and find genetic correlations with autism, depression and impaired musical rhythm, supporting a potential neurological basis for stuttering.

CENcyclopedia reveals the dynamic architecture of kinetochore proteins throughout the cell cycle, providing a foundational framework for understanding accurate chromosome partitioning during cell division.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

The authors collate literature on the responses of bird assemblages to forest loss and show that locations with a more variable natural environment and a longer history of agricultural land use have bird assemblages that are more tolerant to forest loss.

In a quantum simulation of a (2+1)D lattice gauge theory using a superconducting quantum processor, the dynamics of strings reveal the transition from deconfined to confined excitations as the effective electric field is increased.

Coordinating protein translation with energy supply is a significant challenge faced by cells. Here, the authors found that the protein quality control network may provide a link between the two.

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Actin in migrating cells adopt distinct geometries depending on the migration mode. Using a probe to highlight membrane-bound actin, the authors reveal that fly macrophages require coordination of lamellar and cortical actin networks during motility.

Microneedle patches that can actively address individual needles are challenging to realize. Here, the authors introduce a spatiotemporal on-demand patch for precise and personalized drug delivery, utilizing electrically triggered control with drug-loaded microneedles and biocompatible metallic membranes.

Duncan and colleagues link specific human brain cell types to schizophrenia and other complex brain phenotypes, providing mechanistic insights and a cellular taxonomy for psychiatric disorders.

FlyWire presents a neuronal wiring diagram of the whole fly brain with annotations for cell types, classes, nerves, hemilineages and predicted neurotransmitters, with data products and an open ecosystem to facilitate exploration and browsing.

Using a battery of statistical tools, Alagöz et al. examine the genetic overlap between dyslexia and rhythm impairment and shed light on how the genome influences the neural bases of human language and musicality.

Multi-ancestry genome-wide association analyses identify new risk loci for Parkinson’s disease, and fine-mapping and co-localization analyses implicate candidate genes whose expression is associated with disease susceptibility.

REM-sleep behavior disorder often precedes Parkinson’s disease or dementia. Here, the authors perform a genome-wide association study for REM-sleep behavior disorder, and discover how it potentially affects gene expression in the brain.

The measurement of the total cross-section of proton–proton collisions is of fundamental importance for particle physics. Here, the first measurement of the inelastic cross-section is presented for proton–proton collisions at an energy of 7 teraelectronvolts using the ATLAS detector at the Large Hadron Collider.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Omicron subvariants may differ in their replicative fitness and their potential to cause more severe disease. In this study, the authors characterized Omicron BA.2.75 in a hamster model and found that it replicates more efficiently in the lungs than BA.2 and BA.5.

Xiao et al. show that, in monkeys freely viewing natural images, visual neurons from V1 to the inferior temporal cortex encode feature information in the gaze-centered space with limited predictive remapping and develop a neural network model to map the receptive fields.

Post-international travel quarantine has been widely implemented to mitigate SARS-CoV-2 transmission, but the impacts of such policies are unclear. Here, the authors used linked genomic and contact tracing data to assess the impacts of a 14-day quarantine on return to England in summer 2020.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

Genome-wide analysis of self-reported dyslexia identifies 42 associated loci, including 27 not previously associated with cognitive traits. Dyslexia shows genetic correlation with ambidexterity but not neuroanatomical measures of language-related circuitry.

Huang et al. report upregulation of GABA synthesis and activation of β-catenin after rewiring of glutamine metabolism, which suppresses T-cell infiltration, enhances tumour growth and can be targeted to overcome resistance to immune checkpoint blockade.

Genetic and testing data from England show that the SARS-CoV-2 variant of concern B.1.1.7 has a transmission advantage over other lineages.

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common skin cancers and have genetic overlap. Here, the authors use a multi-trait genetic and phenotypic analysis to reveal susceptibility loci for BCC and SCC, and report an optimised polygenic risk score for risk stratification.

The spectroscopic and photometric observations of a high-mass, transiting warm Jupiter, TIC 241249530 b, with an orbital eccentricity of 0.94, provide evidence that hot Jupiters may have formed by means of a high-eccentricity tidal-migration pathway.

The growth of colorectal cancer is reduced by ketogenic diet consumption, the properties of which are mediated by the ketone body β-hydroxybutyrate.

M⁶A RNA modifications mediate RNA processing and stability. Ceramides are lipid metabolites containing an amino acid-based backbone, which promote metabolic dysfunction. Wang et al. describe a novel m⁶A-dependent regulatory node that tunes ceramide-generating enzymes.

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.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

A genome-wide association study performed in 1,126,563 individuals identifies seven new loci associated with Alzheimer’s disease and implicates microglia and immune cells in late-onset disease.

Understanding T cell behaviour in cancers is vital for improving immunotherapies. Here, the authors present spatially resolved T cell receptor sequencing (SPTCR-seq), a technology that annotates T cell receptors within the tumour ecosystem.

Mixed-halide perovskites are of interest for photovoltaic devices, but light-induced halide segregation obstructs bandgap tuning and is not fully understood. Here the authors study the effects of strain and iodide/bromide ratio on light-induced halide segregation in mixed-halide perovskites.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

The immune receptor Transmembrane and immunoglobulin domain containing 2 (TMIGD2) mediates T-cell and nature killer cells co-stimulation upon B7-family HHLA2 engagement. Here, the authors show that TMIGD2 is expressed in Acute Myeloid Leukaemia stem cells regulating self-renewal and differentiation to facilitate leukemogenesis.

The effects of genetic variation on DNA methylation patterns are poorly understood. Here, Shi et al.systematically map methylation-quantitative trait loci in lung, breast and kidney tissue to reveal the impact of inherited variation on the human methylome, which also affects cancer risk.

Neuropeptide Y signalling in the periphery contributes to the regulation of metabolic and energy homeostasis. Here the authors show that blocking Y1R signalling in peripheral tissues using the selective antagonist BIBO3304 ameliorates diet-induced obesity and improves whole-body glucose metabolism.