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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.

Understanding of the immune microenvironment in pediatric acute T cell lymphoblastic leukemia is limited. By analyzing single-cell transcriptome, surface protein expression and immune repertoire data, the authors here identify non-malignant CD4^-CD8^- TCRαβ T cells that are present in a subset of patients with Rap1 signaling in leukemia cells and are associated with adverse clinical outcome in patients with low minimal residual disease.

Arsenic contamination of groundwater threatens the health of millions of people in southeast Asia. Measurements in an arsenic-contaminated aquifer in Vietnam point to sediment age as a key determinant of groundwater arsenic concentrations.

Multi-strain pathogens, such as influenza, present challenges for interpretation of seroprevalence data as estimates may vary by strain. Here, the authors develop a method for estimating age-specific seroprevalence based on principal components analysis and apply it to influenza data from Vietnam.

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.

The geographic distribution of dengue has been expanding in recent decades, and Vietnam is one of the most severely affected countries. In this study, the authors use Bayesian hierarchical modelling to investigate the socio-environmental and climatic drivers of dengue incidence in Vietnam and how they vary across the country.

Dominic Kwiatkowski and colleagues report analysis of genetic variation in 826 Plasmodium falciparum samples collected from 10 locations in West Africa and southeast Asia. They characterize the population structure of this parasite in Cambodia and find evidence for multiple distinct subpopulations showing high levels of genetic differentiation and artemisinin resistance.

Recent prior influenza A infection is associated with elevated hemagglutinin-inhibiting antibody responses and greater breadth of reactivity to influenza strains following vaccination, suggesting that infection history boosts vaccine responses.

Tran et al. show that environmental glutamine restriction promotes Wnt signaling and intestinal tumorigenesis, whereas supplementation of the metabolite α-ketoglutarate has the reverse effect, reducing tumor growth and extending survival.

An overall downregulation of RNA editing was observed in postmortem brains from people with autism, which was consistent across brain regions and genetic disorder subtypes. These changes were regulated by the RNA-binding proteins FMRP and FXR1P.

While EGFR tyrosine kinase inhibitors (TKIs) are often effective in EGFR mutant lung cancer, resistance often occurs. Here, the authors identify intratumoural heterogeneity of EGFR expression and find that EGFR-low cells are more tolerant to EGFR-TKI, promoting resistance.

Mota et al. show that poor response to immune checkpoint blockade in mouse models of ALK-rearranged NSCLC can be overcome by vaccination with an immunogenic ALK peptide and identify immunogenic human ALK peptides for future translational study.

Analysis of HbA1c and FPG levels across 117 population-based studies demonstrates regional variation in prevalence of previously undiagnosed screen-detected diabetes using one or both measures and suggests that use of elevated FPG alone could underestimate diabetes prevalence in low- and middle-income countries.

From 1980 to 2018, the levels of total and non-high-density lipoprotein cholesterol increased in low- and middle-income countries, especially in east and southeast Asia, and decreased in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe.

Pancreatic ductal adenocarcinoma must adapt to a nutrient-poor microenvironment. Here, the authors show that miR-135 accumulates in response to glutamine deprivation and inhibits aerobic glycolysis by targeting phosphofructokinase-1, thereby redirecting glucose carbon to the TCA cycle and allowing pancreatic cancer cells survival.

The availability of nutrients within the tumour microenvironment can influence tumour growth. Here, the authors find that, in a melanoma mouse model, mice fed a high glutamine diet have reduced tumour growth, increased sensitivity to Braf inhibitors and elevated a-ketoglutarate levels.

In Alzheimer’s disease (AD) tau and neurodegeneration have complex regional relationships. Here, the authors show neuronal hypometabolism discordant with tau burden defines functional resilience or susceptibility to Alzheimer’s pathology via limbic/cortical axes. Susceptible groups have faster cognitive decline and evidence of non-Alzheimer’s pathologies.

Coherent transfer of an optical photon polarization state to a single nuclear spin in a nitrogen–vacancy defect centre in diamond is demonstrated without a high-finesse cavity. A storage time of 10 s is achieved with a transfer fidelity of 98%.

Based on a CMOS-compatible growth process, researchers successfully demonstrate the bottom-up integration of InGaAs nanopillar lasers onto silicon chips. The resulting nanolaser offers tiny footprints and scalability, making it particularly suited to high-density optoelectronics.

The integration of photonic components on silicon chips creates the challenge of achieving a uniform and efficient architecture. Here, the authors demonstrate on-chip light-emitters, photodetectors, photovoltaic power supply and optical data link, all based on InGaAs nanoresonators grown on silicon.

Pan et al. find that regional glutamine deficiency in melanoma tumours induces tumour cell dedifferentiation and confers therapeutic resistance through histone methylation changes.

Four genome-wide associated loci are currently known for malaria susceptibility. Here, the authors expand on earlier work by combining data from 11 malaria-endemic countries and additional population sequencing informing an African-enriched imputation reference panel, with findings including a previously unreported association on chromosome 6.

Contrary to the view that urbanization is a major driver of the global rise in obesity, the global increase in body-mass index is shown to be mostly due to increases in the body-mass indexes of rural populations.