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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.

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.

Fresh basaltic glass preserved in a sample of volcanic breccia record a single eruptive event at the Alpha Ridge around 90 Ma, suggesting that parts of the ridge were emergent during the final stages of magmatism in the High Arctic Large Igneous Province, according to geochemical and geochronological analysis of the sample.

Interactive climate and ice sheet simulations project substantial East Antarctic ice loss under high emissions, amplified regional sea level rise in the Pacific, and enhanced northern latitude warming despite dampened global mean temperature rise.

Microscopy has undoubtedly advanced biomedical research, but novel hypotheses are often lost to a lack of analytical tools. Here authors propose iCLOTS, a freely-available software that allows researchers to apply image processing and artificial intelligence algorithms to their own data.

This multisite study detects a link between brain dynamic functional network connectivity and current and future post-traumatic stress symptom severity with a stronger effect in the female group.

This study describes a novel population of cholinergic neurons in the adult subependymal zone (SEZ) of mouse that modulates neural progenitor proliferation. These ChAT⁺ neurons in the SEZ display neuronal activity-dependent release of acetylcholine locally and stimulate neurogenesis accordingly.

A COVID-19 test implemented in an automated microfluidic device and leveraging isothermal RNA amplification followed by T7 transcription and Cas13-mediated cleavage of a quenched fluorophore rapidly detects SARS-CoV-2 RNA in saliva samples.

The authors report data from the emergency department AURORA study to characterize resilience in more detail than the absence of psychopathology after trauma.

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.

Genome assembly of durum wheat cultivar Svevo enables genome-wide genetic diversity analyses highlighting modifications imposed by thousands of years of empirical selection and breeding.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

Preclinical studies indicate that myeloproliferative neoplasms (MPN) may be sensitive to the estrogen receptor modulator, tamoxifen. Here, the authors present a phase II clinical trial reporting the efficacy of tamoxifen in MPN and analysis of peripheral haematopoietic stem cells to identify potential predictive signatures of responders.

Matthew Meyerson and colleagues report whole-exome and whole-genome sequencing of 55 small intestine neuroendocrine tumors. They identify recurrent somatic mutations in CDKN1B, implicating cell cycle dysregulation in the pathogenesis of these tumors.

Longitudinal genomic and transcriptomic profiling of 1,143 patients with multiple myeloma by the Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study yields an improved copy number and gene expression subtype scheme, most notably a high-risk proliferative subtype associated with complete loss of RB1 or MAX.

Michael Talkowski and colleagues analyze balanced chromosomal abnormalities in 273 individuals by whole-genome sequencing. Their findings suggest that sequence-level resolution improves prediction of clinical outcomes for balanced rearrangements and provides insight into pathogenic mechanisms such as altered gene regulation due to changes in chromosome topology.

Melinda Mills, Nicola Barban, Harold Snieder, Marcel den Hoed and colleagues perform a meta-analysis of data from over 300,000 individuals for age at first birth and number of children ever born. They identify 12 significant loci that associate with these traits, providing insights into the genetic basis of human reproductive behavior.

Analysis of antibody responses to COVID-19 vaccines encoding variant-specific spike, with or without ancestral spike, suggests no loss of neutralization of the ancestral virus with variant-only vaccines, which may simplify future vaccine updates.

Here, Frisbee et al. show that hypervirulent Clostridium difficile induces IL-33 expression in the gut and IL-33 reduces mortality and morbidity via group 2 innate lymphoid cells. Furthermore, serum levels of the soluble IL-33 decoy receptor, sST2, are associated with enhanced disease severity in human C. difficile patients.

The Human Microbiome Project Consortium has established a population-scale framework to study a variety of microbial communities that exist throughout the human body, enabling the generation of a range of quality-controlled data as well as community resources.

Autosomal dominant polycystic kidney disease (ADPKD) is a progressive inherited disorder in which renal tissue is gradually replaced with fluid-filled cysts. Interestingly, improved understanding of the signalling and pathological derangements characteristic of ADPKD has revealed marked similarities to those of solid tumours. Here, the authors examine the pathological features and signalling pathways common to both ADPKD and cancer. Their analysis highlights potential avenues for further research and therapeutic potential in both diseases.

Deploying two unrelated CRISPR nucleases in tandem, with multiplexed CRISPR RNAs and a chemically stabilized activator, creates a simple, one-step assay that can rapidly detect attomolar concentrations of RNA without needing target amplification.

This genome-wide study of age at first sexual intercourse and first birth identifies 371 signals driven by reproductive biology, externalising behaviour and environmental effects, with later onset associated with lower incidence of some diseases.

Including participants from 45 countries, Bago et al. find that the situational factors that affect moral reasoning are shared across countries, with diminished observed cultural variation.

The Human Microbiome Project Consortium reports the first results of their analysis of microbial communities from distinct, clinically relevant body habitats in a human cohort; the insights into the microbial communities of a healthy population lay foundations for future exploration of the epidemiology, ecology and translational applications of the human microbiome.

Mass cytometry can measure up to 34 markers on cells, but samples cannot be multiplexed. Bodenmiller et al. use metal ion tags to facilitate multiplexed mass cytometry analysis of human blood cell samples treated with 27 kinase inhibitors and 12 stimuli across a range of dosages and time points.

An analysis of the finished sequence of human chromosome 12 representing 4.5% of the human genome determines that chromosome 12 hosts a number of genes mutated in specific cancers, as well as movement disorders and potentially Alzheimer's disease.

Rusca et al. propose the plural climate storylines framework to build on the narrative element of physical climate storylines with methods that emphasize power asymmetries, decoloniality, co-production and desired futures. The goal of pluralizing climate storylines is to promote just, equitable development interventions.

Heparin analogs can serve as potent anticoagulants, but heterogeneous structures in some preparations and lack of antidote for others can complicate treatments. A chemoenzymatic method that prevents reversible epimerization now enables reversible application of defined constructs in cells and mice.

A genetically encoded fluorescent voltage indicator, SomArchon, is used to image changes in membrane voltage from many neurons simultaneously in multiple brain regions of awake, behaving mice.