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Proteomic data from natural isolates of Saccharomyces cerevisiae provide insight into how these cells tolerate aneuploidy (an imbalance in the number of chromosomes), and reveal differences between lab-engineered aneuploids and diverse natural yeasts.

The mechanical stability of proteins affects their import into the nucleus. Now it is shown that protein transport in and out of the nucleus depends on the local mechanostability of the protein cargo.

Viral ribonucleoprotein–viral protein networks form pre-replication centres that nucleate viral factories and drive respiratory syncytial virus replication.

INSTALL overcomes fundamental challenges for DNA delivery and integration methods by synergizing immune-stealth nucleic acids with recombinases to enable kilobase-scale integration strategies without viral vectors.

Using single-cell tissue imaging and spatial proteomics to study mitochondria–lipid droplet coupling in hepatocytes, PLIN5 phosphorylation is identified as a mediator of lipid flux and nutrient stress responses.

In targeted protein degradation, a degrader molecule brings a neosubstrate protein proximal to a hijacked E3 ligase for its ubiquitination. Here, pseudo-natural products derived from (−)-myrtanol—iDegs—are identified to inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs prime apo-IDO1 ubiquitination and subsequent degradation using its native proteolytic pathway.

Massively parallel reporter assays promise rapid in vivo characterization of enhancer AAVs. Here, through systematic testing, authors uncover pervasive technical and biological noise, including chimeric AAV species, that exposes fundamental limitations in pooled enhancer screening.

GLP-1–GIP–lanifibranor, a single-molecule agonist of GLP-1R, GIPR, PPARα, PPARγ and PPARδ, shows promising therapeutic efficacy against obesity-linked metabolic dysfunction in vitro and in mouse models via synergistic incretin and PPAR activity.

Age-related microbiome changes increase medium-chain fatty acid-producing bacteria, driving GPR84-mediated myeloid inflammation, impaired vagal signalling and hippocampal dysfunction; targeting this gut–brain pathway restores memory in aged mice.

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.

This study reveals that the immune system has a role in driving ALS. These findings link blood immune changes to spinal cord damage and suggest personalized treatments targeting specific immune pathways.

Torres et al. present ApexGO, a generative approach capable of redesigning peptide antibiotics to better kill drug-resistant bacteria. They validated candidates in laboratory tests and mouse infections and matching or outperforming standard antibiotics.

Inhibitor-induced kinase degradation is a common event that positions supercharging of endogenous degradation circuits as an alternative to classical proximity-inducing degraders.

A spatial and single-cell transcriptomics study across multiple mammalian species identifies epidermal BMP signalling as a functional requirement for rete ridge formation, providing insight into mechanisms underlying hair density loss and wound healing.

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.

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.

Here the authors compare genetic testing strategies in rare movement disorders, improve diagnostic yield with genome analysis, and establish CD99L2 as an X-linked spastic ataxia gene, showing that CD99L2–CAPN1 signaling disruption likely drives neurodegeneration.

Insulin signaling plays a crucial role in coordinating skeletal development with whole‑body energy metabolism. Here, the authors use phosphoproteomics to show insulin-signaling rewiring in aged, insulin-resistant bone and identify defective phosphorylation of AFF4 as a key mechanism for regulating gene-specific transcriptional activation.

A tissue-engineered esophageal segment is functional in minipigs.

Genome-wide analysis coupled with long-read sequencing identifies a repeat expansion in GOLGA8A associated with high risk for atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions.

HIV-transcribing cells in people living with HIV are difficult to study with conventional single-cell RNA-seq. Here the authors develop a technique to increase detection of HIV RNA during scRNA-seq and, comparing the transcriptomes of HIV RNA+ blood cells obtained pre- and post-antiretroviral therapy, provide insights into the persistence of the HIV RNA+ reservoir.

l-lactate is a key metabolite supporting neuronal activity, but methods to monitor l-lactate dynamics alongside neuronal activity in vivo have been limited. Here, authors report R-eLACCO2.1, a red fluorescent extracellular l-lactate biosensor enabling simultaneous, multiplexed imaging in awake mice.

Mutations in the PBAF chromatin-remodeling complex cause various neurodevelopmental disorders. This study shows that PBAF shapes distinct motor neuron identities, revealing how its disruption impairs movement and offering insight into neurodevelopmental disorders caused by PBAF mutations.

The RNA methyltransferase activity of SPOUT1/CENP-32 is crucial for accurate mitotic spindle organization. Here, the authors describe a neurodevelopmental disorder caused by bi-allelic pathogenic SPOUT1 variants with reduced activity and compromised function in spindle organization.

C-COMPASS is an open-source software designed to predict the spatial cellular distribution of proteins and lipids from cellular organelle profiling using a neural network-based regression model.

Pocock et al. reveal that transient activation of 5′ AMP-activated protein kinase and estrogen-related receptor drives robust maturation of multicellular human cardiac organoids, enabling modeling of desmoplakin cardiomyopathy dysfunction, which could be rescued using the bromodomain and extra-terminal inhibitor INCB054329.

Using the single-cell Deep Visual Proteomics technique, the authors develop a resource providing spatially resolved proteomic analysis of individual cells in human liver tissue.

Characterizing molecular aging features is crucial for understanding systemic and local factors contributing to the aging process. Here Costa, Chen et al. performed RNA sequencing on 13 tissues across six ages in male and female African turquoise killifish. This sex-balanced killifish aging atlas provides a comprehensive resource for studying aging dynamics across tissues in the killifish—a powerful, short-lived vertebrate model of aging.

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.

Robust protein synthesis by the ribosome is required for rapid cancer growth. Here authors present interdictors, small molecule inhibitors of protein synthesis with context-dependent activity that inhibit MYC-driven cancer cell growth in a mouse model.

Donahue et al. show that ageing is associated with changes in ER morphology. ER-phagy drives age-associated ER remodelling through tissue-specific factors.

The contribution of ether lipid species in cancer cell fate has not been fully understood yet. Here the authors show that malignant cancer cells employ ether lipids to modulate membrane biophysical properties, enhancing iron endocytosis and ferroptosis susceptibility.

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.

The success of allogeneic hematopoietic stem cell transplantation for the treatment of haematological cancers is limited by the morbidity and mortality associated with graft-versus-host disease (GVHD). Here the authors show that the microbial metabolite desaminotyrosine contributes to graft-versus-leukemia responses while protecting against GVHD and promoting mTORC1 and STING-dependent intestinal regeneration.

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.

This study detects Chlamydia pneumoniae in human retina and brain, increasing with AD severity. Retinal pathogen load with Aβ₄₂ may predict AD stage. In models, infection drives Aβ deposition and NLRP3 activation, worsening pathology and cognition.

Analysis of a placebo-controlled trial of a BCMA-targeting CAR-T cell therapy in patients with myasthenia gravis shows that CAR-T cell infusion selectively remodels the systemic immune environment, with elimination of BCMA-high plasma cells and activated plasmacytoid dendritic cells and changes in the autoreactive B cell repertoire.

17β-oestradiol establishes an anti-ferroptotic state in female kidney tubules.

MYC-driven medulloblastoma is an aggressive pediatric tumor with limited treatment options. Here, the authors show that CDK8 regulates ribosome biogenesis and that combined inhibition of CDK8 and mTOR demonstrates therapeutic efficacy in mouse models of this cancer.

Klingelhuber, Frendo-Cumbo et al. develop a proteomic atlas elucidating the intracellular spatiotemporal changes in protein levels and localizations during human adipogenesis.

This study provides insights into the chromatin-looping-dependent and chromatin-looping-independent roles of cohesin and CTCF in controlling gene regulation.

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

Familial Parkinsonism can arise from many genes. Here, the authors show that 24 genetically controlled Drosophila Parkinsonism models cluster into two molecular groups that converge on mitochondrial function or vesicle trafficking and autophagy.

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.

FLiP–MS uses a library of protein–protein interaction markers to understand protein complex dynamics.

Precise profiling of dendritic RNA regulation reveals how neuronal depolarization leads to ribosome switching onto short upstream open reading frames and new coding sequences to acutely modulate local protein synthesis.

Longitudinal metatranscriptomics in a prospective cohort of 1,164 adults hospitalized for COVID-19 reveals that azithromycin offered no apparent anti-inflammatory benefit but enriched the respiratory microbiome with potential pathogens and antimicrobial resistance genes.

Inhibition of a cardiac stroma-enriched mechanosensor, SRC—in concert with suppression of the TGFβ pathway—potentiates the reversal of fibroblast activation and alleviates contractile dysfunction in fibrotic hearts.

The authors analyze rare coding variants in 1990 individuals with congenital kidney anomalies, finding diagnostic variants in 14.1% of cases. They identify two new causal genes, ARID3A and NR6A1, along with 38 candidate genes, providing evidence for shared genetics with other developmental disorders.