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Talin has been believed to be indispensable for integrin activation. Here, the authors show that the curvature-sensing protein FCHo2, not talin, enables inside-out activation of integrin ɑvβ5 in curved adhesions formed at curved membranes.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

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.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

This study reports that de novo germline missense variants in SF3B1, distinct from the somatic variants frequently observed in cancer, cause a neurodevelopmental disorder and disrupt global RNA splicing.

Resistance to BRAF/MEK inhibitors is a major impediment to long-term survival for patients with BRAF-mutant melanomas. Here, the authors show that ABL kinases drive resistance by promoting MEK/ERK reactivation and the FDA-approved ABL kinase inhibitor nilotinib prevents and overcomes resistance.

The clinical adaptation of CRISPR assays is constrained by complexity and the absence of quality control. Here, authors report a thermally regulated asynchronous CRISPR-enhanced assay enabling direct, highly sensitive one-step detection of monkeypox virus and a human gene in clinical samples.

The clinical outcomes and treatment responses of acute myeloid leukemia (AML) patients are heterogeneous. Here, the authors use bulk and single-cell sequencing approaches and identify two transcriptomic subtypes within NPM1-mutated AML with distinct immune evasion properties and responses to hematopoietic stem cell transplantation.

Autonomous delivery of exogenous cargo into plant tissues is achieved by a nanocarrier system harnessing amino acid transporters, enabling force-free, species-independent uptake and ultra-low dose drought resistance in crops like soybean and maize.

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.

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

Enhanced polyamine depletion in neuroblastoma models decreases translation of mRNA codons with adenosine in the third position, reprogramming the tumour proteome away from cell cycle progression and towards differentiation.

Pretrained using 335,645 whole-slide images, a foundation model is developed to provide representations for slide- and patient-level tasks. It is capable of performing clinical tasks and generating reports even in data-scarce scenarios, such as rare cancer diagnosis and survival prediction, without requiring further fine-tuning.

GeneAgent is a language agent using large language models and self-verification to improve gene-set function annotation.

In this phase 1 trial, patients with heavily pretreated and refractory CD30⁺ lymphoma were safely treated with donor-cord-blood-derived NK cells that were precomplexed with the anti-CD30 and anti-CD16A bispecific antibody AFM13, showing encouraging preliminary clinical response rates.

A focused-ultrasound-mediated mechanogenetics approach enables the genetic modification of cancer cells near solid tumours to activate chimeric antigen receptor T cell response and achieve tumour suppression at distinct sites.

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.

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.

Sandén et al. report that the ligand signaling lymphocyte activation molecule family member 6 protects acute myeloid leukemia cancer cells from T cell-mediated killing, leading to immune escape, and show that this can be targeted by a blocking antibody.

Structural studies of a homodimeric arrangement of hepatitis C virus envelope E1/E2 heterodimers reveals the molecular basis of intracomplex interactions and  provides mechanistic insights into neutralizing antibody evasion and membrane fusion with host cells.

Embryonic stem cells for chicken and seven other avian species are derived.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

Long-range cis-regulatory elements play important roles in regulating agronomic traits, but they are largely uncharacterized in crops. This study provides genetic, epigenomic and functional molecular evidence to support their widespread existence in the maize genome.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

Eberhard et al. show that SEMA3A regulates liver sinusoidal endothelial cell fenestrations by signaling through NRP1 and LIMK1, revealing a pathway that connects hyperlipidemia to the development of steatotic liver disease.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

Malignant pleural effusion (MPE) is the terminal stage of cancer and the current standard of care for MPE is largely palliative. Here the authors design a liposomal nanoparticle loaded with cyclic dinucleotide for targeted activation of STING signalling in macrophages and dendritic cells and show that, on intrapleural administration, the nanoparticle effectively mitigates the immune cold MPE and significantly augments the checkpoint blockade immunotherapy in a mouse MPE model and clinical patients’ samples.

Metagenomic next-generation sequencing has the potential to support diagnosis of unknown infections as it can identify all potential pathogens without requiring a prior suspected cause. Here, the authors develop and clinically validate a metagenomics-based assay for common and novel respiratory viral pathogens.

A retrospective analysis using PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing finds an association between adeno-associated virus type 2 and paediatric hepatitis of unknown cause.

Triple-negative breast cancers are aggressive tumours, but their prognosis is critically determined by the immune cell activity within the microenvironment, with the more inflamed, hot milieu predicting better prognosis. Here authors show that the tumour draining lymph nodes, even if not invaded by the tumours, reflect the difference between the cold and hot tumours via differential Th2 polarization.