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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.

This multicenter study demonstrates use of dried and capillary blood as a minimally invasive, scalable approach for Alzheimer’s biomarker testing in research, with potential as a widely scalable population-based research approach, especially in resource-limited settings.

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.

Specific pain-sensing nociceptors and chemosensory tuft cells form a circuit to promote type 2 immune responses in the intestine.

It remains unclear whether rRNA modifications can be naturally altered in response to antibiotics in bacteria. Here, the authors analyzed direct RNA nanopore sequencing data with an analytical pipeline Nanoconsensus, to investigate whether bacterial rRNA modifications are modulated upon exposure to various antibiotics.

Pretrained on SpatialCorpus-110M, a curated resource of vast and diverse transcriptomes of dissociated and spatially resolved cells from both human and mouse, Nicheformer advances toward building foundation models for spatial single-cell analysis.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

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.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Extensive oxidative potential measurements from across Europe analysed with the two most common assays, dithiothreitol and ascorbic acid, using a standardized protocol show the strong influence of site type and suggest pathways for mitigation strategies.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

Modelling the tumour immune microenvironment in vitro is a valuable tool to test immunotherapy efficiency but capturing its complexity is challenging. Here authors present a fully humanised in vitro platform representing tumour/stroma interface and demonstrate how modulation by IL2 may allow immune cells to overcome stromal barriers.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Phylogenomic analysis of 7,923 angiosperm species using a standardized set of 353 nuclear genes produced an angiosperm tree of life dated with 200 fossil calibrations, providing key insights into evolutionary relationships and diversification.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

The molecular mechanisms of how small changes in the degree of inclusion of a neuron-specific microexon in CPEB4 lead to dominant-negative effects in the expression of genes associated with autism spectrum disorder are identified.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

The percentage of national populations infected during the first stages of the COVID-19 pandemic are unclear owing to limited early testing. Here the authors provide a nation-wide prevalence study of SARS-CoV-2 antibodies in France from the first wave of COVID-19 in 2020, including stratification based on age, sex and region.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Quantitative flow virometry assay to measure the shape of viral particles under various conditions reveals that influenza virus infections dynamically tune shape distribution of progeny particles depending on viral efficiency.

A histology-informed, diffusion Magnetic Resonance Imaging simulation framework improves the non-invasive assessment of cancer biology in solid tumours in vivo

Hawkey et al. provide insights into the spatio-temporal distribution and genetic diversity of Salmonella Paratyphi B — the agent of paratyphoid B fever — and report a genotyping scheme facilitating the international surveillance of this pathogen.

An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.

Grussu et al. use co-localised MRI and histology data to design a practical MRI technique for cell size and density measurement in liver tumours in vivo. The method provides non-invasive proxies of histological properties that are associated to cell proliferation, that explain tumour volume and that distinguish liver tumour types.

Yellow fever is a public health threat in the Americas but has not recently been reported in the Caribbean despite presence of the mosquito vector Aedes aegypti. Here, the authors show through experimental infection that populations of Aedes aegypti from the Caribbean and surrounding areas are competent of yellow fever transmission.

AAV vectors are a promising gene delivery vehicle but have a limited DNA packaging capacity. Here, the authors identify cellular restriction factors whose temporary inhibition significantly enhances transduction efficiency of oversized transgenes split into dual AAV vectors.

A patterned neural tube and somites in an embryonic context are generated in vitro.

An apparent redundant role with EZH2 has rendered EZH1 as a secondary player in PRC2-mediated homeostasis regulation. Here, the authors report that gain- and loss-of-function variants in EZH1 cause neurodevelopmental disorders, highlighting its functional relevance.

Little is known about the diets of early modern humans as they dispersed into Australia. Here, Florin et al. study charred plant remains from Madjedbebe rockshelter, which show that 65–53 thousand years ago, early modern humans in northern Australia already had a broad diet of plants.

Interactions with the extracellular matrix (ECM) control tumor proliferation, invasion and metastasis. Here, authors provide spatial information on ECM organization and how it influences tumor cell invasive and metastasis properties through induction of cytoskeletal and transcriptional memory.