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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.

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.

Available methods for deeper super-resolution imaging in plants require specialized hardware or fluorescent reagents. Here, the authors report a dynamic, deep-tissue single-molecule bioimaging technology and show its application in tracking two vernalization-specific proteins with which Arabidopsis forms memory of winter cold.

Using multi-ancestry genome-wide association study and fine-mapping, 298 loci and 36 credible genes are identified in the aetiology of bipolar disorder.

Transancestral GWAS meta-analysis in 160,420 individuals identifies 139 loci associated with refractive error, including myopia. Newly identified genes implicate pathways involved in eye growth and light signaling cascades.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

Meta-analyses in up to 1.3 million individuals identify 87 rare-variant associations with blood pressure traits. On average, rare variants exhibit effects ~8 times larger than the mean effects of common variants and implicate candidate causal genes at associated regions.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

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 mechanism by which Mars lost its early dense and carbon dioxide-rich atmosphere remains relatively unknown. Here, via mineralogical analysis of the Lafayette Martian meteorite, Tomkinson et al. infer that carbonation was an effective carbon dioxide sequestration mechanism on an early, water-rich Mars.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

Here, the authors used electronic healthcare records to analyse the genetic basis of variation in 42 routinely-acquired quantitative blood tests among up to 40,000 British South Asian volunteers from the Genes and Health study. By combining their results with genetic findings from UK Biobank, they explore similarities and differences between ancestries in the genetic basis of these traits.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

El Niño–Southern Oscillation (ENSO) profoundly affects Australian weather, climate, ecosystems and socio-economic sectors. This Review presents the progress made in understanding ENSO teleconnections to Australian weather over the past 40 years, describing the atmospheric dynamics, complexities and impacts of this climate phenomenon.

A randomized trial in patients hospitalized with COVID-19 showed no benefit and potentially increased harm associated with the use of convalescent plasma, with subgroup analyses suggesting that the antibody profile in donor plasma is critical in determining clinical outcomes.

A SARS-CoV-2-human protein contactome map uncovers an inhibitor of viral replication.

Biodistribution analysis of two patients with spinal muscular atrophy shows widespread onasemnogene abeparvovec DNA, mRNA and SMN protein throughout the central nervous system and peripheral organs following intravenous gene therapy administration.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

Digital twins are virtual representations that evolve over time with new data inputs. In this Comment, Asghar and Chung describe cancer applications of digital twins that include the integration of molecular information and individual drug responses of patients, and explain how they can inform individualized treatment, accelerate drug development through clinical trial simulation and enable the exploration of multiscale relationships in the entire human body to drive new therapeutic discoveries.

Constantinides et al., perform a recall study from a British South Asian genetic cohort to explore the genetic and phenotypic risk of cholestatic liver disease. 55.6% of participants with rare heterozygous ABCB4/ABCB11 variants or a history of intrahepatic cholestasis of pregnancy showed evidence of liver involvement, highlighting the utility of genetic screening and monitoring.

A multi-ancestry genome-wide gene–smoking interaction study identifies 13 new loci associated with serum lipids.

Studies on the essentiality of Ku in human cells reveal that Ku interacts with diverse double-stranded RNA molecules, including antisense Alu, and enables tolerance of Alu sequence expansion in primates.

Using cryo-EM, Chung et al. investigate conformational states of mammalian respiratory complex I to reveal an ubiquinone-10 molecule occupying the full length of the Q-binding channel. Molecular dynamics simulations suggest how the charge states of key residues influence the substrate binding pose.

Stig Bojesen, Georgia Chenevix-Trench, Alison Dunning and colleagues report common variants at the TERT-CLPTM1L locus associated with mean telomere length measured in whole blood. They also identify associations at this locus to breast or ovarian cancer susceptibility and report functional studies in breast and ovarian cancer tissue and cell lines.

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.

Here, the authors perform a rare-variant analysis of whole-genome sequence data that takes advantage of three global biobanks. They identify 29 novel rare variants associated with human height, and demonstrate an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data.

Allele-preferential transcription factor binding can influence pancreatic ductal adenocarcinoma risk loci function. Here, the authors show allele-specific JunB and JunD binding at chr1p36.33 and propose a role for KLHL17 in protein homeostasis by mitigating inflammation.

An E. coli and K. pneumoniae phenotype resistant to piperacillin/tazobactam has recently emerged. Here, the authors show that hyperproduction of the β-lactamase driving this resistance occurs due to excision and reinsertion of a translocatable unit containing bla_TEM-1B, creating a tandem array.

Deconvolution methods infer levels of immune infiltration from bulk expression of tumour samples. Here, authors assess 6 published and 22 community-contributed methods via a DREAM Challenge using in vitro and in silico transcriptional profiles of admixed cancer and healthy immune cells.

Machine learning can be used to identify subtypes of psychiatric disease. Here the authors identified two neurostructural subgroups in schizophrenia, each showing reproducibility and generalizability across different collection locations and illness stages, using the SuStain algorithm.

Current guidelines recommend stereotactic radiosurgery for brain metastasis measuring less than 3 cm but there is significant variability in outcomes following treatment. This study shows that in treatment naïve brain metastasis less than 3 cm, intrinsic biological differences across multiple histologies may influence response to stereotactic radiosurgery.

Predicting recurrence risk in non small cell lung cancer can help to guide treatment decisions. Here, the authors use CT and PET imaging to develop predictive imaging subtypes, which can be integrated with existing ctDNA methods to predict recurrence.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases such as chronic kidney disease (CKD). Here, the authors perform a sex-stratified, cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits, with results including identification of four novel loci associated with the CKD-defining trait eGFR.

Semantic heterogeneity exists regarding terminology for active surveillance (AS) for prostate cancer. A panel of leading specialists in prostate cancer and AS involved in the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) consortium participated in a consensus-forming project to reach international consensus on definitions of terms related to this management option. This standard terminology could support multidisciplinary communication, reduce the extent of variations in clinical practice and optimize clinical decision making.

Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.

This Brain Somatic Mosaicism Network analysis of 283 cases of malformations of cortical development identifies 69 candidate and known genes in 76 patients. Single-nucleus RNA sequencing and mouse modeling implicate radial glia and daughter excitatory neurons.

Analysis of blood pressure data from the Million Veteran Program trans-ethnic cohort identifies common and rare variants, and genetically predicted gene expression across multiple tissues associated with systolic, diastolic and pulse pressure in over 775,000 individuals.

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.

In this study, Uldrich and colleagues describe the crystal structure of the Vγ9Vδ2 T cell antigen receptor (TCR) interacting with BTN2A1 and demonstrate the existence of a second ligand that co-binds to a distinct epitope on Vγ9Vδ2 TCR. Using these data, the authors suggest a model of Vγ9Vδ2 TCR activation in which BTN2A1 and BTN3A1 are tethered to each other at the steady state, and must disengage to allow TCR binding.

Trans-ancestry meta-analysis of estimated glomerular filtration rate (eGFR) from 1,046,070 individuals identifies 264 associated loci, providing a resource of molecular targets for translational research of chronic kidney disease.

A neurocomputational model of social forward thinking shows that smokers under-estimate the influence of their actions on future interactions, a cognitive deficit associated with aberrant prefrontal and midbrain activities.

The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke.