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Iridoids are terpenoid metabolites found in thousands of plants. Using single-cell transcriptomics, the authors discovered an unexpected enzyme that has been neofunctionalized to catalyse the cyclization required to form the iridoid scaffold.

Rubio-Navarro et al. identify a subset of pancreatic beta cells marked by high CD63 levels with enhanced glucose-stimulated insulin secretion. CD63-high beta cells are diminished in mouse models of and in humans with type 2 diabetes.

Branched organoids embedded in collagen gels can recapitulate the phenotypic landscape and pronounced molecular and morphological heterogeneity of pancreatic ductal adenocarcinoma.

A minimal effector subset enables Salmonella Typhimurium to overcome bottlenecks regulated by the early innate immune response and establish infection within a CD62L⁺ monocyte niche in the spleen.

Machine-learning-augmented single-nucleus transcriptomic analysis compared molecular landscapes of immature neurons in the mammalian hippocampus across species, highlighting human-specific gene expression but convergent biological processes.

Therapeutic T cells engineered to recognize tumour antigens are frequently short-lived and acquire unfavourable phenotypes in tumours. Here authors show that a tandem approach using autologous T cells targeted against the tumour antigen NY-ESO-1, followed by transfer of hematopoietic stem cells with the same specificity in the clinical trial NCT03240861, provides a safe and promising therapeutic option.

Tumour endothelial cell macropinocytosis is the dominant mechanism for nanoparticle entry into the tumour. Enhanced nanoparticle tumour accumulation may be due to upregulated macropinocytosis membrane ruffling compared with most healthy tissues.

How lung epithelial and endothelial cells develop into alveoli is a major knowledge gap, with implications for lung repair in preterm infants. Here, the authors establish a transcriptomic atlas of human neonatal lung disease, identifying semaphorins as pivotal mediators of organogenesis and injury.

Astrocytes are important players in brain development, homeostasis, and disease. Here, the authors compare the transcriptional profiles of human and mouse astrocytes. They report species-specific susceptibility to oxidative stress and response to hypoxic and inflammatory conditions.

Subcutaneously injected biomaterial scaffolds mimicking key features of physiological T-cell activation enhance the antitumour activity of intravenously pre-administered CAR-T cells.

Influenza virus infection causes injury to the lung. Here, Pervizaj-Oruqaj et al. show that Plet1 expressed by lung macrophages promotes epithelial repair by boosting epithelial cell proliferation and barrier function.

Large genes require dual adeno-associated viral (AAV) vectors for in vivo delivery/expression, but current methods have limitations. Here the authors develop and functionally evaluate REVeRT, an efficient and flexible dual AAV vector technology based on reconstitution via mRNA trans-splicing.

Understanding the tumor microenviroment is important before it can be exploited therapeutically. Here, the authors use single cell sequencing to study stromal cells in mouse tumors and identify a subset of interferon-licensed cancer associated fibroblasts that appear after anti-TGFβ treatment.

Zinc finger protein transcription factors are developed for the selective silencing of the mutant huntingtin gene in human neurons in vitro and multiple animal models of Huntington’s disease in vivo while preserving expression of the wild-type allele.

This paper presents a label-free chemoproteomics platform using data-independent acquisition to profile covalent fragment binding across the human proteome. The platform offers high reproducibility and data completeness, identifying >400 protein-ligand interactions for probe development.

Dual cyclin A/B RxL inhibitors selectively kill small cell lung cancer cells and other cancer cells with high E2F activity.

Heterochronic parabiosis ameliorates age-related diseases in mice, but how it affects epigenetic aging and long-term health was not known. Here, the authors show that in mice exposure to young circulation leads to reduced epigenetic aging, an effect that persists for several months after removing the youthful circulation.

Brown adipose tissue (BAT) is key for metabolic balance. Here, the authors show that RAP250 deficiency enhances BAT activity. Under these conditions, BAT-derived neuritin-1 regulates thermogenesis and fat metabolism, showing therapeutic promise for obesity and metabolic disorders.

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.

Using brain organoids models, Prigione and colleagues uncovered the impact of Huntington’s disease on human brain developmental and identified early dysregulation of CHCHD2, which disrupted mitochondria and might serve as a therapeutic target.

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 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.

Gene regulation in oocytes relies heavily on poly(A) tail-length changes. Here, the authors develop PAL-AI, a neural network model that predicts tail-length changes, identifies regulatory motifs, and links disruptive genetic variants to negative selection in humans, implicating tail-length control in female fertility.

New treatments are needed for muscle invasive bladder cancers. Here, the authors show that combined Pparg activation and MEK inhibition using FDA approved drugs shrinks tumor volume and induces a Basal/Squamous-to-Luminal shift in the urothelium as well as in invading tumors.

Functional integration limits the potential for morphological differences to evolve. Here, the authors show an association between changes in skull morphology and evolutionary integration with feeding behaviour in eels.

The largest harmonized proteomic dataset of plasma, serum and cerebrospinal fluid samples across major neurodegenerative diseases reveals both disease-specific and transdiagnostic proteomic signatures, including a robust plasma profile associated with the APOEε4 genotype.

Heterozygous mutations in the mechanoenzyme dynamin (DNM2) manifest as either a myopathy or a peripheral neuropathy. Here, the authors show antagonistic effects of these mutations and combining them, in mice, mitigates the phenotypic manifestations observed in individual mutants.

Partitioning of FtsN and the septal peptidoglycan synthesis complex between an active synthesis track and an inactive denuded glycan track coordinates opposing peptidoglycan synthesis and degradation activities in E. coli.

Tasnim et al. show that ASD-associated genes act in different compartments of somatosensory circuits and that differences in developmental timing of ASD gene function and circuit maturation contribute to phenotypic heterogeneity across ASD models.

A synthetic receptor platform that enables mammalian cells to respond to soluble factors allows specific signalling networks to be precisely controlled, with a variety of therapeutic applications.

Tumor-associated neutrophils exhibit heterogeneity in breast cancer. Here, the authors identify a distinct precursor population (PreNeu) in estrogen receptor-positive tumors. PreNeu suppress homologous recombination in cancer cells, promoting error-prone DNA repair and enhancing sensitivity to PARP inhibitors.

CD40 is typically understood as a costimulatory molecule. Here, the authors show CD4⁺ T cell-induced CD40 signaling in conventional type 1 dendritic cells results in complicated gene expression that can enhance CD8⁺ T cell priming by various underappreciated and independent mechanisms.

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 quark structure of the f₀(980) hadron is still unknown after 50 years of its discovery. Here, the CMS Collaboration reports a measurement of the elliptic flow of the f₀(980) state in proton-lead collisions at a nucleon-nucleon centre-of-mass energy of 8.16 TeV, providing strong evidence that the state is an ordinary meson.

In this work, through a comprehensive proteomics approach, the authors identified host plasma protein biosignatures that could distinguish tuberculosis (TB) disease in children.

Hydroazidation of alkenes provides a direct entry to alkyl azides which are prevalent structural motifs in medicine development and chemical biology probes. Here the authors report a photocatalytic anti-Markovnikov hydroazidation of alkenes enabled by cooperative ligand-to-metal charge transfer and hydrogen atom transfer.

Multiple types of cell elongation have been described in bacteria, but little is known about how these strategies vary across species. Here, the authors use fluorescent D-amino acids to track the spatiotemporal dynamics of bacterial cell elongation, revealing unsuspected diversity of elongation modes among closely related species of the family Caulobacteraceae.

Hildreth et al. show that during diet-induced obesity, conventional type 1 dendritic cells (cDC1s) in white adipose tissue (WAT) take up DNA-containing apoptotic bodies from adipocytes, which triggers STING-dependent interleukin-12 production from cDC1s, contributing to WAT inflammation in mice.

The authors identify a specific histone variant as a memory-suppressor that is initially reduced in expression within the hippocampus during memory formation; as a memory is consolidated to the cortex, reduced histone association with specific plasticity genes is observed, promoting stabilization of the memory.

Targeting extracellular matrix (ECM) remodelling is a feasible avenue to prevent cancer aggressiveness and metastasis. In this study, Kay et al. show that metabolic flux in cancer-associated fibroblasts is coupled to enhanced proline synthesis by PYCR1 to support elevated production of collagen-rich ECM, thus contributing to cancer spreading.

A mathematical framework to estimate the fitness of cancer driver mutations by integrating mutational bias, oncogenicity and immunogenicity finds fundamental trade-offs in cancer evolution.

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.

The heart’s tolerance to ischemia–reperfusion injury varies according to a day–night cycle. Vinod et al. show that a timed low dose of cardiac glycosides, such as digoxin, is protective against heart ischemia–reperfusion injury by promoting the proteasomal degradation of the molecular-clock component and transrepressive nuclear receptor REV-ERBα.

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.

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.

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

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.