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Native top-down proteomics reveals epidermal growth factor receptor–estrogen receptor-alpha (EGFR–ER) signaling crosstalk in breast cancer cells and dissociation of nuclear transport factor 2 (NUTF2) dimers to modulate ER signaling and cell growth.

Viruses generally have compact genomes, resulting in many viral mRNAs with short 5’ untranslated regions. An antiviral complex exploits this feature of viral mRNAs to selectively inhibit viral protein synthesis and repress viral replication.

Endosomal sequestration of lipid-based nanoparticles is a barrier to delivery of nucleic acids. Here the authors test an array of cholesterol variants and perform in-depth investigation of nanoparticle shape, internal structure and intracellular trafficking.

Lin, Geng and colleagues identify a non-canonical AHR pathway that is activated by canonical AHR inhibitors, promoting the proliferation of quiescent endothelial cells with potential applications in cell therapy.

The broad activity windows of current base editors pose a major challenge to their therapeutic application. Here, the authors established a generalizable re-engineering framework to narrow the activity windows of diverse base editors, streamlining the development of therapeutic base editing.

Acetyl-CoA synthetases have been proposed as targets for development of new antimicrobial drugs. Here, Jezewski et al. identify isoxazole-based compounds with activity against the pathogenic fungus Cryptococcus neoformans, and describe their mechanism of action as inhibitors of fungal acetyl-CoA synthetases.

Li, Burgos-Bravo and colleagues report that NDF phase separation regulates FACT condensation, which enhances transcription by generating a localized biochemical environment that promotes nucleosome disassembly while preserving chromatin integrity by retaining histones.

Capillary-associated macrophages are selectively lost over time, contributing to impaired vascular repair and reduced tissue perfusion in older mice.

Self-assembled multidomain supramolecular peptide hydrogels that engage in dynamic covalent bonding with small-molecule drugs and biologics are shown to offer sustained release, extend the activity, and maintain safe and potent drug levels in vivo.

The use of antimicrobial agents can exacerbate the proliferation of antimicrobial resistance genes, which can put public health at risk; evaluating this risk requires proper monitoring. An extensive investigation of Australian wastewater reveals a distinct correlation between the type of antimicrobial used and the socioeconomic status of the population.

Glioblastoma—the deadliest form of brain cancer—alters the calvarial bone and its marrow components, pushing it toward producing more myeloid cells and contributing to an immunosuppressive environment.

Mutation of conserved prolines enhances correct pairing of light and heavy chains for bispecific IgG-like antibody production.

Understanding the growth dynamics of GBMs can help expand therapeutic options. Here, authors use a cross-species computational approach to compare GBM cells to healthy neural stem cells, identifying predictors and modulators of tumour growth, including the Wnt antagonist, SFRP1, which stalls growth in preclinical xenograft models.

African ancestry is a known risk factor for prostate cancer development, but the genetic determinants of this are incompletely understood. Here, the authors identify 172 potentially pathogenic variants which are enriched in an African population.

The causative agent of sea star wasting disease has been elusive. This study used genetic datasets and experimental exposures to demonstrate that a strain of the bacterium Vibrio pectenicida caused disease and mortality in sea stars.

It is important to know how the recent COVID-19 pandemic shaped the immune memory against the causal SARS-CoV-2 virus. Here authors show that long years following mild disease at primary infection, SARSCoV-2 spike-specific CD4 + T cells with distinct phenotypes and T cell receptor clonotypes, associated with viral suppression persist.

The enzyme ABHD18 is shown to have a key role in cardiolipin metabolism in mitochondria, offering a potential route for a small-molecule treatment of the rare genetic disease Barth syndrome.

Phaeocystales are ecologically significant nanoplankton whose evolutionary history and functional diversity remain incompletely characterized. Here, the authors integrate genomic and transcriptomic data to reveal their lineage diversification, metabolic plasticity, and adaptation to polar and temperate regimes.

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.

This study shows that Galectin-3 promotes wound healing by binding to and undergoing phase separation with integrin α5β1, a process disrupted by AGEs in pre-clinical models of diabetes. Topical Galectin-3 restored healing in synergy with insulin.

The chromatin-remodelling enzyme ATRX and the transcription factor HNF4A are identified as pivotal regulators of colonic epithelial identity, with roles in metastasis in colorectal cancer.

Many SARS-CoV-2 infections may go undetected through conventional PCR or lateral flow tests. Here, the authors analyse the utility of analysing longitudinal nucleocapsid antibody trajectories to improve identification of prior SARS-CoV-2 infections using surveillance data from the UK.

Dysregulated CD4 T cells that recognize gut commensal antigens are able to infiltrate the central nervous systems and are re-stimulated by host proteins, resulting in neuroinflammation.

This study used multiplex serology to monitor multiple diseases simultaneously from a single serosurvey. Seroprevalence estimates were performed for five disease categories in Zambezia Province, Mozambique.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

PSC can be differentiated into blood cells in vitro. In this report, Sun and Motazedian et al describe a differentiation method that generates blood-forming endothelial cells that push newly emerging blood cells to become lymphocytes.

The specifics of the pediatric immune response that gives rise to antibodies capable of neutralising diverse HIV-1 strains is not fully understood. Here the authors characterise the immune environment of Simian-HIV infected paediatric macaques and link to antibody neutralisation induction.

Pattern recognition receptors (PRR) critically modulate innate immunity. Here the authors show in cancer cells that interferon responses and anti-tumor immunity activated by dsRNA-induced PRR signaling is enhanced by palbociclib-induced ER stress, with epigenetic changes and altered antigen presentation potentially contributing to this effect.

Bond et al. show that inducible PolG mutation in muscle causes mtDNA damage and muscle wasting. This is driven by the integrated stress response (ISR) and reduction in folate intermediates, linking impaired folate metabolism with ISR/disease induction.

Polluted plants from constructed wetlands are considered unusable waste. Here, authors present a cost-effective, sustainable, scalable, nature-based method that eliminates micropollutants and transforms this waste into phytoprotective and biostimulant liquid fertilizers for agriculture.

Exogenous addition of glucosylsphingosine affects cellular energy metabolism in SH-Sy5y cell line via changes in mitochondrial function and glycolysis. It also induces an increase in protein ubiquitination with tubulin species affected the most.

This study explores the relationship between telomere length and clonal hematopoiesis. Splicing factor and PPM1D gene mutations are more frequent in people with genetically predicted shorter telomere lengths, suggesting that these mutations protect against the consequences of telomere attrition.

Dietary n-6 PUFAs enhance adipose tissue expandability through the PPARγ–LPCAT3 membrane remodelling axis.

Enfortumab vedotin (EV) is the current standard treatment for advanced bladder cancer, but resistance typically develops within a year, highlighting the need for new therapies. This study demonstrates that NECTIN4-targeting CAR T cells are effective against bladder cancer, including EV-resistant cells, and their potency can be further enhanced by using rosiglitazone to boost NECTIN4 expression.

Permafrost locks away the largest reservoir of mercury on the planet, but climate warming threatens to thaw these systems. Here the authors use models to show that unconstrained fossil fuel burning will dramatically increase the amount of mercury released into future ecosystems.

Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Here, Faust et al. find that healthy human synovial fibroblasts under the influence of adjacent adipocytes have altered lipid metabolism driven by cortisol signaling. Both adipocytes and these characteristics are lost in inflammatory arthritis.

Arctic marine ecosystems have experienced significant change through the Holocene. Here, the authors used sedaDNA from Northern Greenland to reconstruct marine mammal occurrence, demonstrating the impact of air temperature and sea ice cover over the past 12000 years.

tRNA modifications are essential for function, yet their timing relative to processing is unclear. Here, the authors show that queuosine and derivative modifications occur before splicing of pre-tRNA^Tyr, with cryo-EM confirming direct recognition by the QTRT1/2 complex.

Oncolytic virus holds potential as a cancer therapy, but further optimization is desirable. Here the authors screen existing drug to find talazoparib, a PARP inhibitor, synergizing with reovirus type 3 Dearing (RT3D) to induce cancer cell apoptosis, anti-tumor immunity, as well as control of primary and rechallenge tumor in mouse models.

A human ascending somatosensory assembloid model was developed, which integrates multiple organoids to simulate the spinothalamic pathway, demonstrating functional connectivity and responsiveness to stimuli and revealing insights into pain-related genetic mutations.

Here the authors dissect the developmental and functional relationship between tumor-responsive cytotoxic T cells in the tumor versus the tumor-draining lymph nodes (tdLNs), finding that stem-like T_PEX cells dependent on MYB in the tdLNs are required for CD8⁺ T cell tumor infiltration and ICB responses.

In interstitial lung disease, aberrant KRT8+ basaloid cells impair alveolar repair mechanisms. Here they show that Interleukin-11 expression in KRT8+ cells potentiates their pathological properties and causes lung scarring, which can be prevented by anti-IL11 therapy.

This study, together with a companion manuscript, shows that in mice, weight loss as a result of GIP receptor antagonism requires and potentiates functional GLP-1 receptor signalling in the brain, explaining how both GIP receptor agonists and antagonists trigger weight loss through different mechanisms.

The efficacy of CAR-T cells against solid tumors is still limited by immunosuppressive factors. Here, the authors show that engineering of CAR T cells with A1R enhances their efficacy against solid tumors in vitro and in vivo.

The influence of mRNA splicing on colon cancer development and progression is unclear. In this study, the authors demonstrate that the SRSF1 splicing factor is essential to sustain the stem cell phenotype of WNT-activated colorectal cancers.

Most people who are infected with SARS-CoV-2 seroconvert within a few weeks, but the determinants and duration of the antibody response are not known. Here, the authors characterise these features of the immune response using data from a large representative community sample of the UK population.