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Induction of CD11b-positive regulatory B cells and low expression of CD40 in melanoma cells have been associated with resistance to agonist CD40 (aCD40) and immune checkpoint blockade (ICB). Here the authors show that the addition of RAS/MEK/PI3K inhibitors to aCD40 abrogates these effects and reverses ICB resistance in preclinical melanoma models.

Mantle cell lymphoma (MCL) is a form of B-cell non-Hodgkin lymphoma with a high degree of genetic and clinical heterogeneity. Here, using a multi-omics approach, the authors investigate genetic alterations in association with the tumour microenvironment to identify potential therapeutic vulnerabilities.

CAR-T cells have been found to be less effective as treatment for solid tumours. Here the authors, utilising B7H3 as an antigen, consider how changes in B7H3 binders lead to functional changes of CAR-T cells and differences in tumour outcomes in humanised mouse tumour models.

How landscapes are arranged affects soil pathogenic fungi worldwide. The authors reveal the global pattern and pronounced scale-dependency of landscape complexity and land-cover quantity on soil pathogenic fungal diversity.

A structure-guided fragment screen identified a compound, which interacts with a ligand-binding site of unknown function in eukaryotic initiation factor 4E (eIF4E). X-ray crystallography was used to characterise binding and target engagment was shown in cells.

Drug combination discovery remains slow and challenging. Here, the authors introduce Combocat, an open-source framework that combines acoustic liquid handling protocols with machine learning to achieve ultrahigh-throughput drug combination screening; as proof of concept, they use Combocat to screen 9,045 drug combinations in a neuroblastoma cell line.

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.

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.

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

The Taiwan Precision Medicine Initiative recruited and genotyped more than half a million Taiwanese participants, almost all of Han Chinese ancestry, and performed comprehensive genomic analyses and developed polygenic risk score prediction models for numerous health conditions.

The thymus is sensitive to acute insults including infection, as well as to injury from chemotherapy and myeloablative conditioning before hematopoietic cell transplantation. Here, Granadier et al. describe a role for IL-18 in limiting thymic regeneration by stimulating NK cells, which then target thymic epithelial cells.

Gut microbiota contribute to the pathogenesis of ulcerative colitis (UC), but the molecular mechanisms are still unclear. Here the authors show that colonic fluid from patients with UC is enriched for bacteria extracellular vesicles (BEV) coated with host IgA, and that these IgA-coated BEV may activate CD89⁺ immune cells to aggravate inflammation and colitis in mouse models.

Inborn errors of the alternative NF-κB pathway in humans impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases

Cancer cells rely on mitochondria for energy and macromolecule synthesis. Here, the authors show that RNA G-quadruplex dynamics, driven by oncogenic signals, regulate the translation of nuclear-encoded mitochondrial mRNAs, affecting mitochondrial function and promoting cancer cell growth.

Characterization of DCAF16-based BRD4 molecular glue degraders revealed a trans-labeling mechanism termed ‘template-assisted covalent modification’, which opens a new path for proximity-driven pharmacology.

Bournonville et al. identify key proteins of the centriole’s A-C linker and reveals their essential roles in maintaining centriole structure and enabling duplication during cell division.

Modifying the polyethylene glycol lipid ratio and phospholipids in the lipid nanoparticle component of nucleoside-modified mRNA–lipid nanoparticle vaccines is shown to have an impact on the elicited cellular and humoral immune responses.

Immune evasion mechanisms of initial HIV infection are incompletely understood. Here, the authors show that HIV rewires the glycosylation machinery of infected myeloid cells, forming a glycan shield that engages glyco-immune checkpoints and inhibits cell function, and thus targeted killing of infected cells.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Here the authors use a range of approaches to examine the interplay between genetic variants linked to risk for polygenic skin diseases and transcription factors (TFs) important for skin homeostasis. The findings implicate dysregulated binding of specific TF families in risk for diverse skin diseases.

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.

This study reveals how the pathogen Staphylococcus aureus adapts to the lung microenvironment, rich in host metabolites fumarate and itaconate, by using a key enzyme, FumC, to support its metabolic fitness, survival, and persistence.

Silencing of transgenes such as Cas9 limits gene editing and CRISPRa applications. Here, the authors show that adding intronic sequences reduces silencing and boosts transgene expression, enabling improved CRISPRa-mediated gene activation and more stable expression of the transgene over time.

Loss-of-function mutations in TECPR2 result in a form of hereditary sensory and autonomic neuropathy. Here, the authors report that TECPR2 is a Rab5 effector that mediates actin-dependent endocytic cargo recycling from early endosomes to the cell surface.

Daytime radiative cooling materials typically require high filler loading or porosity. Here, authors introduce rheology–optics coupling to control particle dispersion, enabling printable low-filler PDMS–ZrO₂ composites for scalable and durable radiative coolers with versatile architectures.

Cell state plasticity of neuroblastoma cells is linked to therapy resistance. Here, the authors develop a transcriptomic and epigenetic map of indisulam (RBM39 degrader) resistant neuroblastoma, demonstrating bidirectional cell state switching accompanied by increased NK cell activity, which they therapeutically enhance by the addition of an anti-GD2 antibody.

The safety and efficacy of ribonucleoproteins for genome editing can be enhanced by formulations of lipid nanoparticles optimized for enhanced stability, delivery efficiency and editing potency of the protein complexes.

Matrix viscoelasticity regulates cell behavior in a stiffness-dependent manner. Here, the authors reveal that the mechanosensitive channel Piezo1 transduces soft matrix viscoelastic cues, through a coordinated interaction with molecular clutch mechanisms.

Vallentgoed et al. integrate clinical and multiomic data from persons with matched initial and recurrent IDH-mutant astrocytomas to identify progression-associated mechanisms and report a DNA methylation-based signature associated with survival.

Three BRAF inhibitors are used to treat melanoma and colorectal cancer. Here, the authors demonstrate that these drugs bind and activate the protein kinase GCN2, a previously unappreciated off-target effect that may modulate tumour cell responses.

A UCP1-independent mechanism of thermogenesis involving ATP-consuming metabolism of monomethyl branched-chain fatty acids in peroxisomes is described and a previously unrecognized role for peroxisomes in adipose tissue thermogenesis is identified.

This study discusses polygenic, omnigenic and stratagenic models developed to explain multigenic disease risk. It proposes means to test their validity, which has implications for research, drug development and precision medicine.

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

CD103⁺ T cells are associated with control over tumors but how this is mediated is unclear. Here the authors show that CD61 colocalizes and functionally combines with CD103 in the T cell synaptic response to promote antitumor T cell responses.

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.

Examining human brain organoids and ex vivo neonatal murine cortical slices demonstrates that structured neuronal sequences emerge independently of sensory input, highlighting the potential of brain organoids as a model for neuronal circuit assembly.

Here the authors use a genome-wide approach to identify genetic variants associated with RNA isoform variation, uncovering new links between transcriptional regulation and complex traits. The findings can advance understanding of disease mechanisms.

Here the authors report single-cell and spatial transcriptomics of young and aged male fibrotic mouse lungs. Age-related alterations in capillary sub-populations are associated with a proangiogenic phenotype linked to regeneration of the alveolar niche.

TIRTL-seq is a high-throughput method for paired T cell receptor sequencing at the cohort scale.

The taurine–taurine transporter axis is a critical dependency of aggressive myeloid leukaemias.

Oligodendrocytes are vulnerable to chemical toxicity during development. However, few environmental chemicals have been identified as potential hazards. Here, the authors discover chemicals in common household products as harmful to oligodendrocyte development.

Astrocytes have important roles in disease. However, modulation of their reactive state is challenging. Here the authors present a phenotypic in vitro screening platform they can leverage to identify chemical compounds able to modulate astrocyte reactivity in vitro and in vivo.

Mechanical forces at the immunological synapse are believed to influence antigen recognition by the T cell receptor (TCR). Here the authors analyse these forces at single-molecule resolution to show that the ligand-engaged TCR of CD4+ T-cells create a stable environment with only a small fraction of TCR:pMHC complexes experiencing mechanistic forces at any given time during antigen surveillance and upon T-cell activation.

Posfai, Schell, Janiszewski et al. assess candidate totipotent stem cells with in vitro and in vivo assays of increasing stringency to evaluate their developmental potential and lineage contributions.

Opposing forces generated by exopolysaccharide trail binding versus type IV pilus retraction generate a high cyclic diGMP–high cyclic AMP state in Pseudomonas aeruginosa that promotes social motility.

The long-range genomic interactions present in different inbreeds and their hybrid offspring have not been assessed in maize. Here, the authors report conservation and variability of long-range interactions in structurally diverse maize genomes.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but seems to be largely redundant physiologically.

Loss-of-function CRISPR-based screens have identified several genes associated with cancer resistance to T cell-induced cytotoxicity. Here the authors perform a genome-scale, gain-of-function CRISPR screen and identify candidate genes, including the poly-N-acetyllactosamine synthase B3GNT2, whose overexpression confers tumor cell resistance to T cell cytotoxicity