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Moral-Sanz, Fernández-Carrasco and colleagues identify senolytic properties of sea anemone-derived pore-forming toxins, with selectivity mediated by senescence-associated lipid profiles. An optimized senotoxin improves the efficacy of chemotherapy in mouse models.

One of three back-to-back papers to show that dosage of BACH2 can modulate T cell differentiation and function and how we might apply this to enhance CAR T cell therapies for cancer.

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.

Zhang, Lahry, Cipurko et al. show that the microbial metabolites queuine and preQ₁ modify the same host tRNA. PreQ₁-tRNA reduces cell proliferation, slows tumour growth, decreases the translation of ribosomal proteins and is cleaved by IRE1 on the ER ribosome.

Bohlen and colleagues report that the E3 ubiquitin ligase CBL is necessary for the development, tolerance and activation of B cells in humans, unlike in mice where CBL deficiency results in loss of T cells.

Intelectin-2 defends mucosal interfaces by crosslinking mucus and blocking microbial growth. This study reveals that mouse and human intelectin-2 recognizes galactose-rich glycans to bind and target diverse bacteria—uncovering a potent, dual-action lectin that shapes host–microbe balance.

This study uses single-cell DNA sequencing to analyze genomic evolution in pancreatic cancer using a cohort of multiregionally and longitudinally sampled patients’ tissues across various clinical contexts.

Murphy et al. reveal a unifying pathogenetic mechanism according to which diverse mutations in the muscle-specific ribosomal protein RPL3L cause severe neonatal dilated cardiomyopathy, establishing a framework for interpreting the growing spectrum of RPL3L variants.

The choroid plexus is a vital brain ventricular organ that produces cerebrospinal fluid. This study shows how developmental origins and local niches shape the specialization of choroid plexus macrophages, a key first line of immune defense for the brain.

Mitochondrial respiration provides reducing power to the electron transport chain (ETC), driving proton pumping and ATP synthesis required for T cell activation and differentiation. Here, the authors use alternative oxidase (AOX) as a mechanistic probe to bypass cytochrome c oxidase deficiency and thereby isolate the role of respiration and demonstrate that intact mitochondrial respiration is important for T cell proliferation, effector function, memory formation, and regulation of apoptotic and metabolic signaling pathways.

The cell states and lineage connections underlying the progression from Barrett’s esophagus to esophageal adenocarcinoma remain unresolved. Here, the authors use single-cell lineage tracing and transcriptomics to analyse patient samples from the gastroesophageal junction and identify cellular relationships in the progression of Barrett’s esophagus to cancer.

Alström syndrome (AöS) is a rare genetic disorder characterized by metabolic problems. Here, the authors show that in AöS models, defects in cilia and autophagy lead to ACBP accumulation, which drives obesity. An anti-ACBP antibody reduces weight gain and metabolic dysfunction, highlighting ACBP as a therapeutic target for this ciliopathy.

Ulcerative colitis (UC) is associated with epithelial metabolic derangements which exacerbate gut inflammation. Here the authors report that colonoids from children with ulcerative colitis exhibit hypermetabolism and cellular stress primarily driven by lipid dysregulation. Pharmacological inhibition of PPAR-a, a transcriptional regulator of lipid metabolism, alleviates epithelial stress and inflammation.

cAMP export by ABCC4 is critical for localized signaling. Here, the authors revealed that PKA activation drives ABCC4 to the plasma membrane and organizes a PDZ-dependent protein network with actin cytoskeleton and scaffolds, like SCRIB, that stabilize the transporter and optimize cAMP efflux. Furthermore, the authors show that the potent ABCC4 inhibitor Ceefourin 2 disrupts this network, revealing a non-canonical mechanism of ABCC4 inhibition.

A mass spectrometry-based approach globally identifies protein regulators of metabolism and reveals the role of LRRC58 in controlling cysteine catabolism.

Components of the glycocalyx have been shown to impair immune cell functions, including of CAR-T cells. Here the authors show that CAR-T cell mediated cytotoxicity in pancreatic cancer models can be enhanced by incorporating non-signalling binding domains that target the glycocalyx.

ATP synthase powers cells by converting proton translocation into energy. Here, authors reveal distinct structural features of the P. aeruginosa ATP synthase that regulate activity and may serve as targets for new antimicrobial therapies.

Rhine et al. find that neuronal aging leads to widespread dysregulation of RNA biology, including mislocalization of splicing proteins like TDP-43, chronic cellular stress and reduced resiliency.

Synthetic fibril strain 1B is a pathogen that is capable of self-replication and inducing glial cytoplasmic inclusions in vivo in mice, and the structural features of 1B may underlie the pathology of individuals with multiple-system atrophy.

UM171 promotes corepressor degradation by acting as a molecular glue to induce KBTBD4–HDAC1/2 interactions with the help of inositol hexakisphosphate.

In a phase 1 trial, intramuscular injection of synthetic plasmid DNA encoding monoclonal antibodies against SARS-CoV-2 was safe and well tolerated and did not elicit antidrug antibodies.

Despite improving therapeutic options, the prognosis for patients with metastatic castration-resistance prostate cancer (mCRPC) remains poor. Here, the authors identify MCL1 copy number alterations as a prognostic and predictive biomarker, demonstrating its therapeutic potential as a drug target, either alone or in combination, in patients with mCRPC.

In this phase 1 trial, treatment of patients with fibrolamellar hepatocellular carcinoma with a therapeutic peptide vaccine targeting the fusion kinase DNAJB1–PRKACA, which is the driver of the disease, together with nivolumab and ipilimumab, was safe and led to encouraging preliminary clinical responses, and translational analysis showed activation of immune responses.

Results of an early-phase breast cancer prevention trial demonstrate the potential for breast cancer prevention in premenopausal women with anti-progestin therapy by inducing epithelial–stromal remodelling and suppression of luminal progenitors.

LSFM imaging revealed 3D islet maps: GADA+ cases mirrored controls, while short-duration T1D showed loss of small INS + GCG– islets but preserved larger mixed INS + GCG+ ones, highlighting islet size- and composition-dependent vulnerability

There are currently no licensed vaccines to prevent Group A Streptococcus (GAS) infections. In this study, the authors evaluate the immune response and preclinical efficacy of a multicomponent mRNA lipid-nanoparticle vaccine against GAS.

Extracellular vesicles have been implicated in the transmission of pathogens from the arthropod to the human host. Here the authors show that tick-derived extracellular vesicles play a role in feeding and modulate the outcome of bacterial infection.

High-content protein arrays were used to identify cysteine dioxygenase (CDO1) as a small-molecule glue target for the von Hippel–Lindau (VHL) E3 ubiquitin ligase and induces VHL-dependent proteasomal degradation of CDO1 in cells.

Quantifying ecosystem dynamics is critical in the face of rapid environmental change. This study uses airborne eDNA to quantify changes in organism abundances across the tree of life and reveal a regional decline in biodiversity over three decades.

Analyses of clinical and genomic data from a cohort of 2,336 patients with pancreatic adenocarcinoma find that KRAS dosage gains are a hallmark of disease progression and are predictive of poor outcomes across different disease stages.

The relevance of mitochondrial cysteine metabolism to ferroptosis is unknown. Here, Ward et al. show that mitochondrial Fe-S cluster synthesis persists under cysteine limitation via the catabolism of glutathione and at the expense of cell viability.

Here, the authors examine the mechanisms behind cheatgrass’s successful invasion of North American ecosystems. Their genetic analyses and common garden experiments demonstrate that multiple introductions and migrations facilitated cheatgrass local adaptation.

Mycobacterium tuberculosis protein Ku is involved in DNA repair and a potential drug target. Here, using cryo-EM and complementary approaches, the authors obtain insights into Ku oligomerization and mechanisms of function in DNA synapsis.

Molecular glue degraders eliminate cellular proteins by promoting their interaction with E3 ubiquitin ligases. Here, the authors identify molecular glue degraders targeting the E3 ligase TRIM21 and synthesize a heterobifunctional degrader that recruits TRIM21 to degrade an engineered protein aggregate.

In vivo loss-of-function CRISPR screens were performed to identify genes influencing CAR T cell persistence and function in human multiple myeloma, highlighting CDKN1B as a promising target.

ENTRAP-seq systematically links protein sequence to transcriptional output in a native plant context.

In mice, prolonged consumption of a high-fat diet decreases interest in calorie-rich foods as a result of reduced neurotensin expression and signalling, which uncouples hedonic feeding behaviour linked to neurons projecting from lateral nucleus accumbens to ventral tegmental area.

Successful skeletal muscle regeneration involves a complex and finely tuned inter-cellular response. Here, by using spatial transcriptomics, the authors identify an intercellular communication axis between fibro-adipogenic progenitors and macrophages to enhance macrophage-mediated tissue repair.

RNA-binding protein TDP-43 contains a region forming a dynamic α-helical multimer that accounts for its functional role, evolutionary conservation, and disruption in amyotrophic lateral sclerosis, making for a possible therapeutic target.

Injectable biomaterial vaccines designed to magnetically capture pathogen-associated molecular patterns protect mice and pigs against septic shock from lethal bacterial infections.

A pangenome of oat, assembled from 33 wild and domesticated oat lines, sheds light on the evolution and genetic diversity of this cereal crop and will aid genomics-assisted breeding to improve productivity and sustainability.

A microglial state, featuring lipid droplets and secretion of neurotoxic factors, is shown to be most prominent in people with Alzheimer’s disease who have the APOE4 genotype.

Here, the authors show that high alpha diversity, differences in beta diversity, and a high abundance of Bacteroides in the gut microbiome are associated with positive vaccine take and stool shedding following administration of RV3-BB vaccine in the neonatal schedule, but not in the infant schedule or placebo groups, suggesting that the early-life gut microbiome provides a gut environment that optimizes the potential for a positive vaccine response.

Transplantation of allogeneic hematopoietic stem cells (HSCs) is the only reported cure of HIV-1. Here, authors describe an autologous HSC transplant therapy with cells engineered for multilayered resistance to HIV-1 through CCR5 knockout and secretion of HIV inhibiting antibodies by B cell progeny.

Mulholland et al. identify progenitor exhausted T cells, expressing intermediate levels of PD-1 (PD-1^int), as a prominent source of pro-inflammatory cytokines in the murine atherosclerotic aorta and potential cellular targets driving checkpoint inhibition-elicited pro-atherosclerotic immune responses. They further demonstrate elevated levels of circulating PD-1-expressing T cells in individuals with subclinical cardiovascular disease.

Chan and colleagues report that tumor ecosystem and microbiome features are associated with response to anti-PD-L1 avelumab plus chemoradiotherapy in patients with locally advanced head and neck cancer.

CD4⁺ T cells promote immunity to tuberculosis infection via macrophages. Here the authors show upregulation of SLAMF1/CD150 on infected macrophages after interaction with CD4⁺ T cells and that the presence of SLAMF1 promotes ROS production by macrophages and the absence of Slamf1 in macrophages results in higher mycobacterial loads in infected mice.

Drug resistance remains a major challenge in cancer treatment. Here, the authors identify Connexin43 as target that enhances BRAF/MEKi efficacy by interfering with DNA repair pathways, overcoming drug resistance. They develop an mRNA therapy that improves efficacy and sensitizes resistant cells.

Aminoadamantane compounds, delivered to cells via binding to viroporin channels, induce S-nitrosylation of the ACE2 protein, inhibiting binding to SARS-CoV-2 spike protein and viral infection.