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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.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

Antimicrobial resistance genes that have been mobilized between bacterial species represent a subset of the naturally occurring resistome. Here, the authors compare the abundance, diversity and geographical patterns of acquired resistance genes with latent resistance genes in global sewage metagenomes.

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.

Genome-wide association analyses comprising 14,256 cases and 1,199,156 controls and incorporating correlated cardiac magnetic resonance imaging traits provide insights into the molecular etiology of dilated cardiomyopathy.

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

Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.

Genome-wide association analyses identify new risk loci for heart failure and its subtypes, extending understanding of the underlying biological pathways and disease mechanisms.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

Central Anatolia harbored some of the earliest farming societies outside the Fertile Crescent of the Near East. Here, the authors report and analyze genome-wide data from a 15,000-year-old Anatolian hunter-gatherer and from seven Anatolian and Levantine early farmers, and suggest high genetic continuity between the hunter-gatherers and early farmers of Anatolia.

Understanding the emergence, evolution, and transmission of antibiotic resistance genes (ARGs) is essential to combat antimicrobial resistance. Here, Munk et al. analyse ARGs in hundreds of sewage samples from 101 countries and describe regional patterns, diverse genetic environments of common ARGs, and ARG-specific transmission patterns.

Substitutions in SARS-CoV-2 spike protein present in the B.1.351 variant first detected in South Africa, when expressed in pseudoviruses, mediate escape from neutralization by monoclonal antibodies under clinical development and by plasma from individuals previously infected with SARS-CoV-2, but do not prevent binding of convalescent plasma to recombinant spike protein containing B.1.351 lineage substitutions.

Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.

Sexual dimorphism in genetic vulnerability to schizophrenia, systemic lupus erythematosus and Sjögren’s syndrome is linked to differential protein abundance from alleles of complement component 4.

Analysis of 1.32 billion records of medication data from England, Scotland and Wales reveals that the COVID-19 pandemic led to substantial declines in dispensing of antihypertensive and lipid-lowering medications, leading to increased risks for future cardiovascular disease.

The leg-enriched sensory appendage protein, SAP2, confers pyrethroid resistance to Anopheles gambiae, through high-affinity binding of pyrethroid insecticides; an observed selective sweep in field mosquitoes mirrors the increasing resistance reported in Africa.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

Obtaining data on antimicrobial resistance (AMR) from healthy human populations is difficult. Here, Hendriksen et al. use metagenomic analysis to obtain AMR data from untreated sewage from 79 sites in 60 countries, finding correlations with socio-economic, health and environmental factors.

The authors test whether spatial scale (plot, local and landscape) affects the supply of various ecosystem services in grasslands, finding that some services are predicted by plot-level properties while others depend more on landscape-level management.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

Two doses of the coronavirus disease 2019 vaccine ChAdOx1 nCoV-19 boost antibody responses and functions in phase 1/2 trial participants.

Genome-wide analysis identifies 30 loci associated with bipolar disorder, allowing for comparisons of shared genes and pathways with other psychiatric disorders, including schizophrenia and depression.

Linking epigenetic marks to clinical outcomes promises insight into the underlying processes. Here, the authors introduce a statistical approach to estimate associations between a phenotype and all epigenetic probes jointly, and to estimate the proportion of variation captured by epigenetic effects.

The liver is an important regulator of glucose homeostasis. Here, the authors provide insight into the molecular signalling pathways controlling hepatic gluconeogenesis by showing that SIK protein kinases suppress gluconeogenesis, and that glucagon—but not insulin—regulates phosphorylation of SIK2.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong ethnic and gender bias. In a transancestral genetic association study, Langefeldet al. identify 24 novel regions associated with risk to lupus and propose a cumulative hits hypothesis for loci conferring risk to SLE.

The proteasome is a large proteolytic machine that degrades ubiquitin-tagged proteins. Substrates are recognized and unfolded by the regulatory particle (RP) and translocated into a central proteolytic chamber, called the core particle (CP), where degradation takes place. Here, and in a complimentary study, the pathway of RP assembly is elucidated, demonstrating that RP assembly is a highly orchestrated process.

Here Ramanan and colleagues provide an analysis of mammary T cells during late pregnancy and lactation. This revealed an increase in intraepithelial lymphocytes in the lactating mammary gland, which was driven by thymic and intestinal inputs and was sensitive to changes in the microbiota

This study uses gene expression predictors for the dorsolateral prefrontal cortex and other brain regions to perform a transcriptomic imputation analysis of schizophrenia, identifying 413 genic associations across 13 brain regions and 36 significantly enriched pathways.

Better analytical methods are needed to extract biological meaning from genome-wide association studies (GWAS) of psychiatric disorders. Here the authors take GWAS data from over 60,000 subjects, including patients with schizophrenia, bipolar disorder and major depression, and identify common etiological pathways shared amongst them.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

Gunn Hildrestrand, Veslemøy Rolseth, and Nicolas Kunath et al. examine mice lacking the NEIL1 and NEIL2 DNA glycosylases involved in base excision repair. Their results suggest that loss of both NEIL1 and NEIL2 dysregulates genes relevant to synaptic function and modulates behavior in mice.

Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.

Schizophrenia is a highly heritable genetic disorder, however, identification of specific genetic risk variants has proven difficult because of its complex polygenic nature—a large multi-stage genome-wide association study identifies 128 independent associations in over 100 loci (83 of which are new); key findings include identification of genes involved in glutamergic neurotransmission and support for a link between the immune system and schizophrenia.

Description of a novel function for autophagy in regulating lipid metabolism, called 'macrolipophagy', in which lipid droplets and autophagic components associate during starvation and inhibition of autophagy increases lipid storage in lipid droplets. A critical role of autophagy in regulating lipid metabolism is identified, and may provide a new approach to prevent lipid accumulation in disease.

Dysfunctional or aggregated proteins in cells are degraded by autophagy. Wong et al.study aggregates of the protein synphilin-1 and show that ubiquitination alters their dynamic properties, which determines whether the aggregates are degraded via basal or inducible forms of autophagy.