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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.

Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.

A prospective nationwide genomic screening pilot for ten genes in young adults in Australia detected pathogenic variants in 2% of the population, most of whom were ineligible for government-funded genomic testing.

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.

HDAC6 is a tau deacetylase and acetylation of tau inhibits its function and promotes aggregation. Here the authors show that HDAC6 protects against tau accumulation in a mouse model of tauopathy.

Earth’s inner core has both changed its relative rotation rate and deformed in the past few decades, according to an analysis of seismic waves recorded when the inner core occupied the same relative location owing to its changing rotation rate.

Microglial states throughout remyelination are incompletely understood. Here, the authors show that microglia form several states during the early stages of remyelination that coalesce into a partially resolved state that is dysregulated with age.

SARS-CoV-2 viruses are known to hijack human proteins in order to facilitate their own virulence and replication. In this study, Liu and colleagues present structural analysis of how this phenomenon occurs between SARS-CoV-2 viral envelope protein and human PALS1. The findings provide insights in to viral-host recognition.

During SARS-CoV-2 infection caspase-8 fuels harmful inflammation independent of apoptosis. Genetic loss of caspase-8 reduces cytokine levels, lowers viral load and mitigates disease severity, revealing non-apoptotic caspase-8 as a key driver of severe COVID-19.

Parity induces an accumulation of CD8⁺ T cells, including cells with a tissue-resident-memory-like phenotype within human normal breast tissue, offering long-term protection against triple-negative breast cancer.

Geospatial estimates of the prevalence of anemia in women of reproductive age across 82 low-income and middle-income countries reveals considerable heterogeneity and inequality at national and subnational levels, with few countries on track to meet the WHO Global Nutrition Targets by 2030.

A high-resolution, global atlas of mortality of children under five years of age between 2000 and 2017 highlights subnational geographical inequalities in the distribution, rates and absolute counts of child deaths by age.

Phosphorylation of the microtubule-associated protein tau is associated with disease, but other post-translational modifications of tau are not well studied. Here, Cohenet al. study the acetylation of tau and suggest that this form of the protein may be associated with tauopathies.

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.

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.

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.

Severe sepsis has a high mortality rate. Here, the authors provide genomic, transcriptomic, proteomic and metabolomic data across four sepsis-causing pathogens and identify a signature of global increase in fatty acid and lipid biosynthesis as well as cholesterol acquisition.

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.

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.

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.

Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth.

Enhanced recovery after surgery (ERAS) pathways are increasingly used for patients undergoing radical cystectomy, but data on their benefits are still sparse. A new paper charts improvements in patient outcomes during a 10-year period. An optimized, defined ERAS protocol is certainly important, but the ERAS culture of consistency, performance measurement, and continual adoption of best practice are also crucial.

Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities.

Although progress in the coverage of routine measles vaccination in children in low- and middle-income countries was made during 2000–2019, many countries remain far from the goal of 80% coverage in all districts by 2019.

Electron-beam lithography is often used for patterning of asymmetric metal electrodes for nanoscale devices, but suffers from several limitations. Here, the authors report a new adhesion lithography process, which allows for high-throughput and simple fabrication of nanogap metal electrodes.

Analysis of pre- and post-chemotherapy samples collected from 22 patients with high-risk neuroblastoma using single-nucleus RNA and ATAC sequencing and spatial omics characterizes therapy-related changes in cell composition and the tumor microenvironment.

Zinc uptake and regulation are vital in all life forms. Here, authors describe a dimer of a ZIP-family zinc transporter in an inward-facing, inhibited conformation. A built-in zinc sensor is proposed to sense the intracellular zinc content to autoregulate zinc uptake across membranes.

Roots bend towards water. The root cortex in the elongation zone is the site of perception during hydrotropism but also the site of differential root growth, which is different from gravitropism.

Be careful what you think out loud...

Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index. Gene-based meta-analysis and functional studies implicate 13 genes, eight of which are novel, and neuronal pathways as factors in human obesity.

The impact of breakage fusion bridge (BFB) cycles on tumour heterogeneity and clinical outcomes remains poorly understood. Here, the authors develop OM2BFB, an algorithm to detect and reconstruct BFB amplifications using optical genome maps and use it to study BFB events across 2557 primary tumours and cancer cell lines.

The nuclear protein TDP-43 is implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Here, Cohen et al. discover lysine acetylation as a modification that regulates TDP-43 function, providing a mechanism that could be implicated in the pathogenesis of TDP-43 proteinopathies.

Bhattacharjee and Schaeffer et al. map exclusive breastfeeding (EBF) in 94 low- and middle-income countries (LMICs), finding increased EBF practice and reduced subnational variation across the majority of LMICs from 2000 to 2018. However, only six LMICs will meet WHO’s target of ≥70% EBF by 2030 nationally, and only three will achieve this in all districts.