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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.

Large informal settlements reflect inequalities in Latin America, where transport interventions can build social capital. TransMiCable increased the probability of individuals transitioning to bridging social capital networks, suggesting an increase in trust among neighbors and an improvement in bridging community networks.

Vassy, Dornisch and colleagues developed a genomics-based prostate cancer risk model to support a randomized clinical trial of precision screening in a national healthcare system.

Polyamines prevent the action of kinases on acidic phosphorylatable motifs in spliceosomal proteins, thus providing a mechanism for metabolite-mediated regulation of alternative splicing in cells.

Alström syndrome (AöS) is a rare genetic disorder characterized by metabolic problems. Here, the authors show that in AöS models, defects in cilia and autophagy lead to ACBP accumulation, which drives obesity. An anti-ACBP antibody reduces weight gain and metabolic dysfunction, highlighting ACBP as a therapeutic target for this ciliopathy.

The intestinal microbiome is shaped by genetics and environment. Here, the authors show in rats that host genetic effects, including indirect social effects, influence microbiome composition, identify replicated loci, and reveal mechanisms contributing to microbiome heritability.

The existing ENCODE registry of candidate human and mouse cis-regulatory elements is expanded with the addition of new ENCODE data, integrating new functional data as well as new cell and tissue types.

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.

Actin is crucial for nervous system function yet the role of microexons in its modulation is unclear. Here, the authors show that a microexon in DAAM1 has a role in actin dynamics, neuronal function and memory formation in mice.

The signaling-specific inhibitor AEF0117 selectively inhibits CB₁ activation by THC and reduces self-administration and subjective effects of cannabis in clinical trials, making it a potential treatment for cannabis use disorder.

Here, the authors generated and analyzed run-on sequencing data to observe transcription in species across the tree of life to uncover the origins of the promoter-proximal pause.

Chaperone-mediated autophagy declines with age in skeletal muscle of humans and mice, leading to muscle dysfunction characterized by impaired calcium homoeostasis and mitochondrial function.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 role of the complement system (CS) - part of the immune system - in pancreatic ductal adenocarcinoma (PDAC) remains underexplored. Here, the authors evaluate the association of genetic variants in CS-related genes with PDAC risk, and explore their potential role in prognosis and immune infiltration.

A previously unsampled deep lineage in central Argentina was discovered that had distinctive genetic drift by 8,500 bp and persisted as the main Native American ancestry component in the region up to the present day.

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.

Castells-Nobau et al. provide insight into how bacteriophages in the gut microbiome contribute to regulating food addiction by modulating tryptophan and tyrosine metabolism in the host.

An optimized 3D culture system enabled a stem cell-derived monkey blastoid to develop to day 25, recapitulating key events of primate late gastrula and demonstrating notable similarity to natural embryos.

The balance between cell proliferation and cell cycle arrest is essential for liver regeneration. Here the authors report the emergence of partially reprogrammed hepatocytes persisting in plastic states during liver tissue injury, which are resistant to proliferation thereby limiting overgrowth and tumorigenesis.

popEVE is a proteome-wide deep generative model to identify and predict pathogenicity of missense mutations causing genetic disorders.

Long-read sequencing in 18 unicellular eukaryotes reveals that 6mA is widespread across eukaryotes and is enriched at transcriptionally permissive regions, which are also marked by H3K4me3.

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.

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

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.

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.

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.

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.

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.

Koina is an open-source, online platform that simplifies access to machine learning models in proteomics, enabling easier integration into analysis tools and helping researchers adopt and reuse ML models more efficiently.

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.

Thirteen pharmaceutical companies have shared and integrated preclinical and clinical data for creating computational resources that enhance translational drug safety assessment.

Over 20 species of geographically and phylogenetically diverse bird species produce convergent whining vocalizations towards their respective brood parasites. Model presentation and playback experiments across multiple continents suggest that these learned calls provoke an innate response even among allopatric species.

This Consensus Statement presents the standards for technical reporting in environmental and host-associated microbiome studies (STREAMS) guidelines.

Genomic sequencing of the thermotolerant coral species Oculina patagonica, single-cell transcriptomic analyses of symbiotic and non-symbiotic specimens and comparisons with obligate symbiotic coral species reveal adaptations that provide resilience to coral bleaching.