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Antigen presentation in skull bone marrow by hematopoietic stem and progenitor cells induces myelopoiesis and generates CD4⁺ regulatory T cells in a mouse model of ependymoma, promoting immune tolerance. Treatment with anti-GM-CSF antibody has antitumor effects that are augmented by immunotherapy.

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.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

Using infant fMRI, the authors show that, by 2 months of age, representations in high-level visual cortex encode visual categories that align with deep neural networks, and lateral object-selective regions are later to develop.

De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

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.

Disease course and pathology an infection may cause can change owing to the structural and functional physiological changes that accumulate with age, but therapy can be tailored accordingly; disease tolerance genes show antagonistic pleiotropy.

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).

Here the authors show DNGR-1 expressed by cDC1s promotes CD8⁺ T cell priming to cytoskeletal neoantigens from dying tumor cells, thereby shaping cancer immune visibility and tumor evolution through immunoediting.

McGrail and colleagues report that high intratumoral bacteria abundance is associated with an immunosuppressive microenvironment and resistance to immune checkpoint blockade in head and neck squamous cell carcinoma.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Using viral barcode tracing to detect interactions between glioblastoma cells and non-malignant astrocytes in patient samples, investigators discovered a pathway that reduces tumour-specific immunity and identified potential therapeutic targets.

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.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

Here, the authors perform metagenomic analysis of Ecuadorian mothers and children showing that improved WASH and reduced animal exposure can lower antimicrobial resistance in the gut but may reduce gut microbial diversity, with the strongest effects observed in mothers.

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.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

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

Jayavelu, Samaha et al., apply machine learning models on hospital admission data, including antibody titers and viral load, to identify patients at high risk for Long COVID. Low antibody levels, high viral loads, chronic diseases, and female sex are key predictors, supporting early, targeted interventions.

A high-resolution transcriptomic and epigenomic cell-type atlas of the developing mouse visual cortex from embryonic to postnatal development is presented, providing a real-time dynamic molecular map associated with individual cell types and specific developmental events.

Pilcher et al. present a single-cell transcriptomics-based immune atlas of participants with newly diagnosed multiple myeloma, reporting on the association of cell types, gene expression and intercellular interactions with disease progression phenotypes.

Long-distance migration and dispersion is a common characteristic of nearly all classes of telencephalic GABAergic neurons, which diversify extensively after birth in the cortex and striatum, but show limited postnatal changes in the septum, preoptic area and pallidum.

Using multi-ancestry genome-wide association study and fine-mapping, 298 loci and 36 credible genes are identified in the aetiology of bipolar disorder.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

Lee et al. use an aggregation-prone CLN4 mutant that causes lysosomal damage in neurons and show that in non-neurons, the ubiquitin ligase CHIP prevents CLN4-dependent lysotoxicity via microautophagy.

In this work, researchers address a key question for maternal group B Streptococcus (GBS) vaccine assessment: What newborn antibody concentrations protect against invasive infant GBS disease? They present serologic thresholds by age at onset and serotype based on a large U.S. case-control study.

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.

Using a mouse model enabling an inducible ‘switch’, Golden et al. show that an astrocyte-specific replacement of the Alzheimer’s risk gene APOE4 with protective APOE2 alters metabolism and gene expression, reducing amyloid pathology and gliosis.

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.

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.

Genomic deletions in poxviruses are not well understood, the authors found large deletions in >2% of Mpox virus genomes during routine surveillance, highlighting their role in poxvirus evolution and potential impact on diagnostics and therapeutics.

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 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.

Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.

CNS toxicity was unexpectedly observed for anti-miR-17 RGLS4326 in nonclinical studies. Here, authors identify AMPA receptor inhibition as the likely culprit. Replacement of 3’-terminus guanine to adenine leads to discovery of farabursen (RGLS8429) that is devoid of CNS toxicity.

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 population of TRAIL-positive astrocytes in glioblastoma contributes to an immunosuppressive tumour microenvironment and this mechanism can be targeted with an engineered oncolytic virus to improve outcomes.

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.

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.

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.

Here, the authors find that relative abundances of stress-sensitive gastrointestinal microbes at age 2 years predicts internalizing symptoms in middle childhood through altered emotion-related brain network connectivity.

Here, the authors report recent updates to the ENCODE data portal including a redesigned home page, an improved search interface, custom-designed pages highlighting biologically related datasets and an enhanced cart interface for data visualisation plus user-friendly data download options.

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.

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.