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Low oxidation state aluminium complexes have gained wide recognition as discrete and versatile 2-electron reductants, but neutral trimeric structures remain elusive. Here the authors report the synthesis and characterization of two neutral Al(I) trimers whose trimeric structure is retained in solution.

Natural rubber is a widely used biopolymer and further improving its resistance to crack growth will extend its service life. Here the authors show a strategy to amplify the resistance to crack growth in natural rubber by forming a tanglemer.

Muscularis macrophages, housekeepers of enteric nervous system integrity and intestinal homeostasis, modulate α-synuclein pathology and neurodegeneration in models of Parkinson’s disease, and understanding the accompanying mechanisms could pave the way for early-stage biomarkers.

CDK4/6 inhibitors are promising treatments for ER+ breast cancer, however resistance remains a challenge. Here, the authors analyse the NeoPalANA cohort and indicate that a 33 gene signature was predictive of response to neoadjuvant anastrozole and palbociclib.

Here the authors present NCATS-SM0225, a small molecule that inhibits ERAD and selectively kills cancer cells by binding VDACs, disrupting calcium homeostasis, and triggering the PERK-STIM1 pathway to degrade ERAD regulators.

Transcriptomic and clinical data analyses from multiple cohorts of patients with cancer receiving immunotherapy find that PD-1 blockade potentiates tumor-specific IgG1 plasma cell responses that complement cellular immunity and contribute to clinical benefit.

An in-depth analysis of tissue biopsies from patients with multiple myeloma and CAR T cell therapy-associated immune-related adverse events (CirAEs) after treatment with commercial BCMA-targeted CAR T cell therapy shows that CD4⁺ CAR T cells mediate off-tumor toxicities and that high CD4:CD8 ratio at apheresis, robust early CAR T cell expansion, ICANS and ciltacabtagene autoleuce treatment are independently associated with the development of CirAEs.

The endoplasmic-reticulum (ER) transmembrane protein IRE1 mitigates ER stress through kinase-ribonuclease and scaffolding activities. However, a significant nonenzymatic IRE1 dependency has been shown in cancer. Here, the authors design a proteolysis-targeting chimera (PROTAC) to fully disrupt cellular IRE1 protein, selectively blocking growth of IRE1-dependent cancer 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.

DBiTplus represents an integrated experimental and computational workflow that unifies sequencing-based and imaging-based spatial omics, demonstrated by combining transcriptomic profiling and multiplexed protein imaging on the same tissue section.

Elevated levels of IL-33 induce the production of autoantibodies through an unknown mechanism. Here, the authors show that IL-33 disrupts splenic architecture and germinal center organization, causing an expansion of antibody-secreting plasmablasts and plasma cells. In multiple mouse models of inflammation, administration of IL-33 exacerbates the pathology, increasing the production of autoantibodies, whereas IL-33 blockade reverses autoantibody production in a model of lung inflammation.

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.

Allogeneic T cell therapies could be used in therapeutic applications because of their potential for ‘off-the-shelf’ access and standardised production. Here the authors have developed a multidimensional workflow profiling platform for EBV-specific T cell therapy and show that correlative biomarkers of T cell potency and effector function are associated with therapeutic effectiveness in xenogeneic mouse EBV-LCL models.

Structural, genetic, functional and biochemical analyses of the complex flagellar motor of Campylobacter jejuni reveal structural adaptations with an ancient origin also found more widely across bacterial species, including elements exapted from the type IV pilus machinery.

H5N1 avian influenza viruses caused an outbreak in dairy cattle. We show that the potential for avian viruses to replicate in cow cells varies across H5N1 evolution, suggesting that the risk of spillover into mammals differs between variants.

Here the authors show that persistent antigen stimulation drives the generation of CD8⁺ tissue-resident exhausted T cells with distinct developmental origins, function and therapeutic responsiveness when compared to CD8⁺ tissue-resident memory T cells.

PU.1^low CD28-expressing microglia may act as suppressive cells in Alzheimer’s disease, mitigating its progression by reducing neuroinflammation and amyloid plaque load, indicating potential immunotherapeutic approaches for treatment.

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.

Mu opioid receptor agonists with a preference for the non-GTP-bound state of the G protein promote GTP release, thereby potentiating antinociceptive effects of drugs such as morphine and fentanyl without also increasing their respiratory or cardiac effects.

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.

An exploratory analysis of the phase 3 ECOSPOR III trial shows that a higher dosage of the oral microbiome therapeutic VOWST led to enhanced pharmacokinetics, increased species engraftment and altered microbiome and metabolite profiles, providing mechanistic insights into how it may prevent Clostridioides difficile infection recurrence.

The authors developed a screen to find compounds that modulate intracellular Staphylococcus aureus metabolism and discovered KL1, which sensitizes persisters to antibiotics by reversing host-induced tolerance.

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.

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.

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.

Covalent KRAS inhibitors show initial responses but resistance limits durability. Here drug-induced hapten peptides are identified and characterized, enabling production of high affinity, cross-HLA T cell engagers that stabilize low density hapten peptide MHCs to drive tumor-specific killing.

During SARS-CoV-2 infection caspase-8 fuels harmful inflammation independent of apoptosis. Genetic loss of caspase-8 reduces cytokine levels, lowers viral load and mitigates disease severity, revealing non-apoptotic caspase-8 as a key driver of severe COVID-19.

How DNA Polymerase Epsilon accomplishes continuous leading strand synthesis during DNA replication is not understood. Here, the authors describe a two tiers mechanism required to sustain Pol Epsilon processivity: CHTF18-dependent loading of PCNA at leading strand and dsDNA binding by its POLE3-POLE4 subunits.

Equitable and accessible education in life sciences, bioengineering, and synthetic biology is crucial for training the next generation of scientists. Here the authors present the CRISPRkit, a cost-effective educational tool that enables high school students to perform CRISPR experiments affordably and safely without prior experience, using smartphone-based quantification and an automated algorithm for data analysis.

Deaminases of the APOBEC3 family contribute to the mutagenesis of various cancers, including urothelial carcinoma (UC) of the bladder. Here, the authors use functional studies and transcriptomics to demonstrate that APOBEC3 promotes tumour progression and squamous trans-differentiation in UC through IL-1α and downstream activation of the AP-1 transcription factor.

Clear cell renal cell carcinoma (ccRCC) bears the hallmark loss of VHL but remains incurable. Here, the authors identify the SLC1A1 dicarboxylic amino acid transporter as an actionable, oncogenic, HIF-independent, metabolic dependency in VHL-deficient ccRCCs.

Pulmonary type 2 inflammation is associated with type 2 innate lymphoid cells. Here the authors use the Collaborative Cross mouse panel to show that ILC2 abundance during type 2 lung inflammation is different across the panel and identify free-fatty acid receptor 3 (Ffar3) as a gene responsible and show cytokine and ILC2 functional changes.

An NNMT inhibitor reduces tumour burden and metastasis in multiple mouse cancer models and restores immune checkpoint blockade efficacy by decreasing cancer-associated-fibroblast-mediated recruitment of myeloid-derived suppressor cells and reinvigorating CD8⁺ T cell activation.

Gene regulation varies across cell types and states. Here, the authors present airqtl, a scalable method for single-cell eQTL mapping that enables efficient causal gene regulatory network inference, revealing the genetic drivers of cell state-specific regulation.

Previous work has shown that natural cardiac rhythms modulate the perception and reaction to sensory cues through changes in associated neural signals. Here, the authors show that sensitivity to prediction errors during reward learning is related to the phase of the cardiac cycle.

Allogenic mesenchymal stem cells are engineered with three mRNAs to bind to multiple myeloma B cells while activating T cells for cancer therapy.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Intrinsic capacity (IC) was introduced by the World Health Organization to promote healthy aging. Here, using data from the Longitudinal Ageing Study in India, the authors develop an IC measure for older Indian adults. Their analysis shows that higher IC scores are associated with better health and functioning and reveals regional and sociodemographic variations.

This research developed and compared firearm-specific and method-agnostic machine-learning models using data from 800,579 Army veterans, revealing that model choice and intervention thresholds impact predictive accuracy and fairness, guiding tailored suicide prevention efforts.

This study found E. coli phylogenetic background shapes TEM-1 beta-lactamase expression and co-amoxiclav resistance. Phylogeny alone shifted isolates from susceptible to resistant, stressing a need for lineage-sensitive genotype-phenotype prediction.

Here, using samples from ~1,100 individuals, the authors define the nasal microbiome linked to Staphylococcus aureus colonization, identifying seven communities- either S. aureus-dominated or dominated by other bacteria.

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.

Approaches making virtual and experimental screening more resource-efficient are vital for identifying effective inhibitors from a vast pool of potential drugs but remain elusive. Here, the authors address this issue by developing an active learning framework leveraging high-throughput molecular dynamics simulations to identify potential inhibitors for therapeutic applications.

Conventional ammonia synthesis is energy intensive. Here the authors explore the mechanism of light-driven ammonia synthesis through in situ spectroscopy and modelling, and demonstrate that certain AuRu plasmonic alloys are promising catalysts for this potentially more sustainable process.

Using multi-omic analyses, the authors reveal how aging, sex, and trisomy 21 shape human biology across the lifespan, showing that age- and sex-specific changes peak during puberty and adulthood, while trisomy 21 exerts differential effects over time.

cfDNA fragmentomics is a potential clinically applicable method for identifying cancer. Here, the authors assess fragmentomics analysis methods and their application to commercial targeted sequencing panels.

Eosinophils exist as a functionally heterogeneous population. Whether the heterogeneity is driven by cell-intrinsic or extrinsic factors is underexplored. Here, by leveraging single-cell transcriptomic data and epigenomic analysis, the authors propose that local environmental cues define the gene expression program of murine esophageal eosinophils and identify AP-1 family members, including ATF3, as key regulators of gene expression.