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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.

Hair is a skin component that functions as a physical barrier and thermal regulator. Nagao and colleagues show that hair follicles recruit Langerhans cells to the epidermis via the secretion of various chemokines.

cfDNA fragmentomics is a potential clinically applicable method for identifying cancer. Here, the authors assess fragmentomics analysis methods and their application to commercial targeted sequencing panels.

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.

Available wheat genomes are annotated by projecting Chinese Spring gene models across the new assemblies. Here, the authors generate de novo gene annotations for the 9 wheat genomes, identify core and dispensable transcriptome, and reveal conservation and divergence of gene expression balance across homoeologous subgenomes.

Agrobacterium-mediated transformation of plants and fungi is enhanced by plasmid copy number variants.

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

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.

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.

Pre-malignant cells harbouring oncogenic mutations can populate and spread throughout a tissue. Here, using a rainbow mouse system, the authors explore how clonal expansion in the mouse intestine might explain high levels of intra-tumoural heterogeneity observed in the disease.

Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.

A neural circuit activated by the male pheromone, darcin, mediates a complex and variable array of innate and reinforced behaviours that may promote mate encounters and mate selection.

A multiomic approach profiles the three-dimensional, epigenetic and mutational landscapes of 80 metastatic prostate cancer biopsies. Hi-C experiments identify an extrachromosomal circular DNA at the AR locus associated with therapy resistance.

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.

Imiquimod exacerbates IL-23-induced skin inflammation and models psoriasis in mice. Here the authors show that this pathology is not dependent on resident dendritic cells, but on CCR6-induced immigration of monocyte-derived cells.

Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

The auditory striatum, the tail portion of dorsal striatum, is implicated in decision-making. This study uncovers a phasic mechanism within the nigrostriatal system that regulates auditory decisions by modulating ongoing auditory perception.

Activating mutations of BRAF alone are inadequate to drive melanoma formation. Here the authors show that activation of Hippo signalling by oncogenic BRAF represents an additional safeguard to limit BRAF-dependent human melanocyte growth and melanoma formation.

NEIL2, a mammalian DNA repair enzyme, has been reported to suppress infection induced inflammation. Here, the authors characterize its role in modulating the severity of SARS-CoV-2 infection.

eQTL analysis of human brain RNA-seq data targeted to genes within the 10q24.32 schizophrenia-associated locus reveals that the risk SNP in this region is selectively associated with expression of BORCS7 and a human-specific isoform of AS3MT across multiple independent samples. Expression of only the associated AS3MT isoform is higher in tissue from humans with schizophrenia than in healthy controls.

Whole-genome bisulfite sequencing along with whole-genome and transcriptome sequencing of 100 prostate cancer metastases identifies genomic regions that are differentially methylated during disease progression and a novel epigenomic subtype.

The authors developed a patient-specific microphysiological system using the LumeNEXT microfluidic platform to more accurately recreate the prostate cancer metastatic bone tumor microenvironment.

In placental malaria, interactions between parasite protein VAR2CSA and human glycosaminoglycan chondroitin sulfate A (CS) sequesters infected red blood cells in the placenta. Here, the authors provide cryo-EM structures of VAR2CSA and placental CS, identifying molecular interactions that could guide design of placental malaria vaccines.

Rare-earth nickelates undergo a metal-to-insulator transition accompanied by the formation of ordered lattice distortions, but the role of the lattice in the metallic phase remains unclear. Here the authors provide evidence that the metal is a polaronic liquid that freezes into the insulating state.

Resistance to first line treatment is a major hurdle in cancer treatment, that can be overcome with drug combinations. Here, the authors provide a large drug combination screen across cancer cell lines to benchmark crowdsourced methods and to computationally predict drug synergies.

A ChIP–exo method is used to define the genome-wide positional organization of proteins associated with gene transcription, DNA replication, centromeres, subtelomeres and transposons, revealing distinct protein assemblies for constitutive and inducible gene expression.

Through the direct immunization of a nurse shark, we identified a suite of VNAR domains that were effective at targeting FAP.

Cataloging microbial genomes from Earth’s environments expands the known phylogenetic diversity of bacteria and archaea.

Catalyst development in academia focuses on performance metrics, giving only secondary attention to costs despite their relevance for commercialization. Here, the authors analyse the properties of a handy and free cost estimation tool that can inform the early stages of catalysis research.

Precision oncology is important for patient treatment. Here the authors review the current applications of microfluidic systems to cancer precision medicine, and discuss the issues that must be addressed prior to getting these technologies into the clinic.

Human scientists make unrepresentative chemical reagent and reaction condition choices, and machine-learning algorithms trained on human-selected experiments are less capable of successfully predicting reaction outcomes than those trained on randomly generated experiments.

Mutations in isocitrate dehydrogenases IDH1 and IDH2 are common in human gliomas and acute myeloid leukaemias; here, mice that carry the IDH1(R132H) mutation are described, in a new model that should help in investigating the links between mutant IDH1 and leukaemia.

Complex heritable traits — such as human height and many human diseases — are caused by multiple genetic loci, each with small effects. It is hard to identify such loci, however, because of a lack of statistical power. Now, a method has been developed to overcome this problem. The method has been applied to chemical resistance traits and mitochondrial function in yeast, and has identified loci for each of these phenotypes.

ATLAS is a pair of AI Tumor Lineage and Site-of-origin machine learning models, that can accurately classify both primary and metastatic tumors using high-throughput RNA expression data and can identify de-differentiated anaplastic tumors.

Loss of HLA-I gene expression in prostate cancer is associated with repressive chromatin states, which can be reversed by pharmacological DNMT and HDAC inhibition leading to increased activation of co-cultured tumor-specific CD8+ T-cells.