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Lineage tracing in mice identifies a subpopulation of basal cells that express Tmprss2 and Nkx3 as the origin of ERG-driven prostate cancer. Upon expansion, these cells show an enrichment for STAT3 chromatin binding and elevated expression of KMT2A and DOT1L as dependencies for ERG oncogenicity.

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.

PFAS are “forever chemicals” that build up in living things and can move through food webs. This study shows their levels roughly double with each step up the food chain, highlighting widespread chemical magnification in nature.

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.

Analysis of wild orangutan calls demonstrates that different degrees of sociality across populations are associated with different ‘vocal personalities’.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Bacteria evolving within humans employ strategies to overcome trade-offs. Here, the authors report that the cystic fibrosis-associated pathogen Burkholderia dolosa alternates phenotypes in vivo by accumulating successive de novo mutations.

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.

A key component of quantum error correction is the decoding algorithm, which needs to be accurate but also with a computational overhead that doesn’t lead to backlogs and allows fast logical clock rates. Here, the authors show an FPGA-driven decoder featuring a coarse-grained parallel architecture and on-the-fly error model updates, allowing both high accuracy and real-time operation.

Using data from 142,238 Mass General Brigham Biobank participants, researchers explored population history and social and genetic risk factors for disease in Greater Boston. The study links genetics and context to guide equitable precision health.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

The authors present a scalable mass spectral search tool that identifies both known molecules and structural variants by estimating match significance. The method revealed biosynthetic pathways in Streptomyces, expanding the scope of metabolite discovery.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

FOS has been linked to bone tumour pathogenesis, and viral homologue v-fos causes osteosarcoma in mice. Here, the authors report rearrangement of FOS and its paralogue FOSB in osteoblastoma and osteoid osteoma, revealing human bone tumours that are defined by mutations of FOS and FOSB.

Brain-wide recordings in mice reveal that prior expectations are distributed through recurrent loops across all levels of cortical and subcortical processing.

A comprehensive analysis of the cell-specific molecular regulatory mechanisms underlying post-traumatic stress disorder in the human prefrontal cortex.

Polyamines produced by gut bacteria have been proposed to contribute to inflammatory bowel diseases. Here, Nauta et al. show that bacteria can produce a noncanonical polyamine intermediate that functions similarly to deoxyhypusine synthase inhibitors, activates mitochondrial stress responses, and inhibits nematode development and mouse macrophage differentiation.

Kraft, Murphy, Jones et al. identify extrachromosomal DNA (ecDNA)-interacting elements (EIEs) enriched for transposable elements within ecDNA in colorectal cancer cells. They show that EIE 14 integrated within ecDNA acts as an enhancer to promote cancer fitness.

Quantum simulations of the phase diagram of quantum chromodynamics faces hard challenges, such as having to prepare mixed states and enforcing the non-Abelian gauge symmetry constraints. Here, the authors show how to solve the two above problems in a trapped-ion device using motional ancillae and charge-singlet measurements.

Roles of of viruses in ocean subsurface oxygen maxima are unclear. Here, the authors analyse Bermuda Atlantic Time Series data to show that viruses may drive SOM in stratified oceans by boosting nutrient recycling and phytoplankton productivity linking virus activity to oxygen buildup and a stronger microbial loop.

In this study, the authors generated iPSC lines from more than 100 sporadic ALS cases, which recapitulated key disease phenotypes and enabled large-scale drug screening, identifying a promising combination therapy of baricitinib, memantine and riluzole.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

A combination of high-resolution spatial imaging, spatial proteomics and transcriptional data reveals sparse and heterogeneous bacterial signals in gliomas and brain metastases.

Here, Bottery et al show that resistance to next generation antifungals is more likely to occur within azole resistant Aspergillus fumigatus due to the close linkage between a globally distributed azole resistance allele and a DNA repair variant which elevates mutation rates.

The human superior temporal gyrus processes acoustic–phonetic properties of speech regardless of whether the language is familiar to the listener, but only encodes word boundaries and language-specific sound sequences if the language is known.

A systematic statistical genetics approach discovers CES drivers as hotspots of human de novo mutation and shows that clonal expansions in germline may both modulate the prevalence of disorders and lead to false-positive disease associations.

Williams et al. report a growth arrest mechanism in residual cancer persister cells through targeted therapy-induced upregulation of type I interferon signalling, which is negatively regulated by apoptotic DNA endonuclease DFFB to allow tumour relapse.

Pressure overload in the heart, such as from aortic stenosis, triggers early molecular changes before visible damage occurs. Here, the authors show that combining proteomics, transcriptomics, and genetic data reveals key drivers of heart failure, highlighting potential targets for treatment.

PARP inhibitors, either alone or in combination with bevacizumab, have regulatory approval as maintenance therapy following response to first-line platinum-based chemotherapy. Here this group reports SOLACE2 trial investigating whether combining olaparib with low dose cyclophosphamide treatment improves progression-free survival, comparing to olaparib monotherapy alone, in platinum-sensitive recurrent ovarian cancer.

The placenta plays vital roles in supporting fetal development. Here, Richards et al. develop a high-throughput bioprinted trophoblast organoid model to recapitulate the microenvironment of the early placenta, enabling investigation of placenta development and evaluation of therapeutics for placenta dysfunction disorders.

Drug-induced liver injury is a major cause of patient harm, trial failures, and drug withdrawals. Here, the authors show that a toxicogenomics resource of 300 drugs enables the prediction of liver injury with 88% sensitivity at 100% specificity and reveals mechanisms for safer drug development.

Disparities in risk and outcomes of pediatric acute lymphoblastic leukemia (ALL) are apparent between different ancestries. Here the authors identify genetic variants with African ancestry-specific risks for developing pediatric B-cell ALL that are also linked to greater 5-year mortality risk.

In a prospective study enrolling 1,222 patients from 22 emergency departments, a device using a machine-learning-based signature of blood mRNAs demonstrated clinically acceptable performance to diagnose bacterial and viral infections and to predict the all-cause need for critical care interventions within 7 days, with benchmark to established biomarkers and risk scores.

In a prospective study involving 579,583 women in multiple sites across the USA, a multistage AI-driven workflow for digital breast tomosynthesis mammograms assisted radiologists in identifying 21.6% more cancers with respect to historical data, showing no significant variation across socio-demographic and breast density subgroups.

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.

This Review compares predictive genomics across humans, animals and plants, and outlines shared statistical foundations and key differences in phenotype structure, as well as opportunities for biologically grounded, generalizable artificial intelligence models.

Mismatch repair pathway is frequently dysregulated across cancer types, commonly represented by loss of MLH1 or MSH2 gene expression. Here the authors model MLH1 missense mutations from patients to study how cytoplasmic localization of MLH1, promotes resistance to endocrine therapy but predicts response to cell cycle inhibitors in breast cancer.

The regulatory landscape controlling Hoxd gene expression in tetrapod digit development was probably co-opted from a pre-existing cloacal regulatory mechanism, as evidenced by the effects of genetic deletion experiments in zebrafish fin, cloaca and mouse urogenital development.

An analysis of data from the Sherlock-Lung study provides insight into the mutational processes that contribute to lung cancer in never smokers, and looks at the possible role of factors such as air pollution and passive smoking.

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 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.