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Affinity-proteomics platforms often yield poorly correlated measurements. Here, the authors show that protein-altering variants drive a portion of inter-platform inconsistency and that accounting for genetic variants can improve concordance of protein measures and phenotypic associations across ancestries.

PARM is a deep-learning model trained on data from massively parallel reporter assays to help predict promoter activity in different human cell types, design synthetic promoters and identify key features of regulatory promoter grammar.

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.

METALoci, a new three-dimensional genome computational tool, reveals a major rewiring of regulatory interactions during sex determination. By combining this method with transgenic models, the authors identify a noncoding regulatory region at the Fgf9 locus and reveal that Meis genes are key regulators of sexual differentiation.

Analysis of the somatic and transcriptomic profile of 123 acral melanoma samples from Mexican patients helps understand tumour origins and prognosis, and highlights the importance of including samples from diverse ancestries in cancer genomics studies.

Post-transcriptional regulation of mRNA translation was explored using Ribo-STAMP and single-cell RNA sequencing to reveal cell-type-specific and isoform-specific translation patterns across hippocampal neuronal and non-neuronal cell types, highlighting functional differences between CA1 and CA3.

Here the authors perturb genes linked to schizophrenia risk in human neurons. They find that single perturbations share common downstream effects on gene networks, while joint perturbations result in downstream effects being saturated.

Hepatic glycogenolysis is essential for protein glycosylation and rhythmic secretion by the liver. Disruptions to hepatic glycogenolysis, caused by congenital diseases or physiological factors such as obesity, caloric restriction and changes to meal timing, alter hepatic protein secretion.

Here they demonstrate a therapeutic intervention elevating levels of CYP450-derived lipids to control the expansion of intermediate monocytes in tissue and peripheral blood, presenting a first in class therapeutic approach for treating chronic inflammatory disease.

Mucosal administration of a multivalent, adjuvanted vaccine against Clostridioides difficile promoted bacterial clearance and protected against morbidity, mortality, tissue damage and recurrence in mice.

A follow-up analysis of a clinical trial that evaluated anti-PD-1 therapy in patients with cancer who are living with HIV provides mechanistic insights into transcriptomic, cellular and cytokine changes related to immune checkpoint inhibitor treatment and identifies a signature associated with clinical response.

This study shows that TE, an inferotemporal (IT) cortex subregion, displays stronger neural plasticity than TEO, another IT subregion, during learning of a challenging visual categorization task in primates, to which both areas contribute.

Neville, Ferguson et al. show that non-canonical Polycomb repressive complex 1.1-mediated gene silencing is antagonized by DOT1L and is required for the therapeutic efficacy of Menin and DOT1L inhibitors in mixed-lineage leukaemia.

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

In this article, the authors characterise genetic variation in CARTaGENE, a population-based cohort from Quebec, Canada. This genomic resource enables population and disease genetic studies in a founder population and other under-represented groups.

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.

Genetic models for psychiatric disorders often overlook ancestry diversity. Here, the authors use PsychENCODE and GWAS data to build ancestry-specific GReX models, improving TWAS and revealing novel genes and pathways linked to brain development and psychiatric risk.

In mice, a SPOCD1–TPR-dependent ‘nowhere-to-hide’ mechanism is required for complete non-stochastic piRNA-directed LINE1 DNA methylation by preventing transposons from escaping surveillance within heterochromatin.

How the complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth is explored.

Extrachromosomal circular DNAs (ecDNAs) are prevalent in human cancers and are thought to drive tumor evolution and drug resistance by amplifying oncogenes. Here, authors develop ec3D to reconstruct three-dimensional ecDNA structures, revealing how their spatial organization rewires regulatory circuits.

Understanding the mechanisms underlying the survival of drug tolerant persister cells following chemotherapy remains elusive. Here, multi-omics analysis and experimental approaches show that the germ-cell-specific H3K4 methyltransferase PRDM9 promotes metabolic rewiring in glioblastoma stem cells.

The impact of variants of uncertain significance (VUS) on protein function and cancer risk remain unclear. Here, the authors focus on the functional impact of VUS of the PALB2 gene and identify defects in DNA damage repair by homologous recombination associated with increased risk of breast cancer.

The therapeutic relevance of telomere maintenance mechanisms in cancer, remains to be explored. Here, the authors integrate multi-omic data and functional readouts, generate a resource of telomere biology metrics and identify potential molecular vulnerabilities.

The 4D Nucleome Project demonstrates the use of genomic assays and computational methods to measure genome folding and then predict genomic structure from DNA sequence, facilitating the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.

The potential of mammogram-based biological age predictors remains to be fully explored. Here this group introduces a deep learning model to estimate the biological age of the breast using healthy mammograms.

A covariate-aware analysis reveals that microbiome changes in the gut of patients with chronic kidney disease are better explained by intestinal transit time than by kidney function.

The identification of cellular targets for natural products that potently inhibit the growth of cancer cell lines implicates oxysterol-binding proteins in the growth of cancer cells. These natural products, termed ORPphilins, also affect sphingomyelin biosynthesis.

Type 2 diabetes and hypertension often co-occur, suggesting shared biological mechanisms. Here, Pascat et al. use partitioned polygenic scores to show distinct biological processes link both conditions and improve risk prediction.

Establishment and maintenance of appropriate cell size is a prerequisite for cells to function efficiently. Here, Kiriakopulos et al. reveal that the lncRNA CISTR-ACT maintains cell size across cell types in humans and mice by regulating cell morphogenesis genes in trans via guidance of the transcription factor FOSL2.

Limited-size object microscopy (LSOM) enables label-free super-resolution imaging of isolated nano-objects with a resolution as low as λ/8 under the sole assumption of the limited size of the imaged object.

The distinct architecture of the Escherichia coli membrane transporter LetA mediates lipid trafficking across the bacterial envelope in partnership with the tunnel-like complex LetB.

Glioblastoma is characterised by high levels of intratumoural heterogeneity and plasticity, hindering treatment. Here, the authors develop an analytical framework, scFOCAL, to predict the sensitivity of glioblastoma cell subpopulations to therapies based on reversal of disease transcriptional signatures to identify synergistic therapeutic combinations.

Adipose CoA handling is critical for lipid metabolism and homeostasis. Here, the authors identify TMEM120A as an ER-resident CoA binding protein enriched in adipocytes that promotes fatty acid recycling to support energy metabolism and limit lipotoxic stress, while its loss leads to adipose inflammation and metabolic dysfunction under high-fat diet conditions.

Phosphorylation-dephosphorylation and ubiquitination tune TCR signaling to avoid self-reactivity. Kim and colleagues show that acetylation also modulates TCR signaling.

It has been proposed that language meaning is represented throughout the cerebral cortex in a distributed ‘semantic system’, but little is known about the details of this network; here, voxel-wise modelling of functional MRI data collected while subjects listened to natural stories is used to create a detailed atlas that maps representations of word meaning in the human brain.

Npm1 promotes tumor formation via attenuating the integrated stress response and p53 activation in mouse WNT-driven intestinal and liver tumorigenesis.

Creative experiences such as dance, music, drawing, and strategy video games might preserve brain health. The authors show that regular practice or short training in these activities is linked to brains that look younger and work more efficiently.

Non-invasive strategies to detect and track activated myeloid cells will facilitate disease diagnosis and monitoring in patients affected by neuroinflammatory disorders. Here, the authors present 18F-FMD, a dendrimer-based PET tracer that detects and monitors activated myeloid cells at different stages (presymptomatic and symptomatic) of Experimental Autoimmune Encephalomyelitis (EAE) in mice and in response to disease-modifying therapies.

The impact of tumour heterogeneity on metastatic potential in prostate cancer remains poorly understood. Here, the analysis of single nuclei RNA sequencing and whole-genome sequencing from samples from five patients suggests an interplay between clonal evolution and cellular plasticity driving metastatic seeding.

The Integrative Genome Modeling platform is a tool for population-based three-dimensional genome structure modeling and analysis by integrating various experimental data sources.

Mepolizumab (anti-IL-5 therapy) has been shown to reduce type 2 inflammation in asthma. Here the authors use bulk transcriptomics from nasal samples before and after mepolizumab treatment to assess the changes and associations with treatment outcomes.

Risk stratification in non-small cell lung cancer (NSCLC) remains challenging. By combining multiplex immunofluorescence, H&E histology, and AI, the study identifies spatial “cell-niche” patterns that enhance survival prediction beyond UICC8 staging. These patterns reclassify many stage I patients as high risk, revealing potentially undertreated cases and establishing spatial tumor microenvironment features as clinically actionable biomarkers.

The authors analytically determine how neuronal correlations and geometry collectively determine readout generalization across tasks and show how these geometric features follow distinct trajectories over the course of learning.

In vitro propagation of the pathogenic bacterium Coxiella burnetii, the causative agent of Q fever, leads to attenuated virulence and lipopolysaccharide (LPS) truncation. Here, Long et al. show that a strain considered to be avirulent (NMII) can be recovered from infected animals, and these isolates display increased virulence and an elongated LPS due to reversion of a 3-bp mutation in a gene.

Five-year survival data and biomarker analysis of the PRADO extension cohort of the phase 2 OpACIN-neo trial, in which patients with high-risk stage III melanoma received neoadjuvant ipilimumab and nivolumab and underwent pathologic response-directed surgery and adjuvant therapy, show 71% event-free survival and 88% overall survival, with tumor mutational burden, IFNγ signature and PD-L1 expression associated with favorable outcomes.

Even when neocortical neurons form in abnormal locations, they retain their identity and function, revealing that brain circuit formation can be guided by intrinsic developmental programs rather than physical position.

Climate change can alter when and how animals grow, breed, and migrate, but it is unclear whether this allows populations to persist. This global study shows that shifts in seasonal timing are key to helping vertebrate species maintain population growth under global warming.

Omnivores like bears can switch between plant and animal diets, potentially helping them respond to changing conditions. By combining modern and fossil data, this study shows that bears shift toward carnivory in harsher climates and toward herbivory in more productive environments.