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A comprehensive atlas platform integrating transcriptional and epigenetic data enables more precise engineering of T cell states, accelerating the rational design of more effective cellular immunotherapies.

Understanding of the immune microenvironment in pediatric acute T cell lymphoblastic leukemia is limited. By analyzing single-cell transcriptome, surface protein expression and immune repertoire data, the authors here identify non-malignant CD4^-CD8^- TCRαβ T cells that are present in a subset of patients with Rap1 signaling in leukemia cells and are associated with adverse clinical outcome in patients with low minimal residual disease.

Drosophila Microproteins Simba1/2 act in neural stem cells and blood-brain-barrier glia to promote reactivation of neural stem cells via activating WNT/Wingless signaling, while human ortholog ZNF706 is found to have a conserved role in activating WNT pathway.

Genomic and transcriptomic analysis of 393 non-small cell lung cancer patients treated with checkpoint inhibitors identifies molecular features associated with response.

Brastianos and colleagues report interim trial results on the intracranial clinical benefit of palbociclib for patients with progressive metastatic brain cancer carrying cyclin-dependent kinase pathway alterations.

Dual cyclin A/B RxL inhibitors selectively kill small cell lung cancer cells and other cancer cells with high E2F activity.

A screening approach finds VH-domain antibodies that bind the SARS-CoV-2 Spike protein receptor-binding domain at its interface with host ACE2. Bi-paratopic and multivalent binders have high affinity and potency.

Immune checkpoint inhibitors with or without chemotherapy are now standard of care for non-small cell lung cancer. However, the benefits of combination vs sequential therapy have not been fully explored. Here, the authors analysed 1,133 patient records and show combination therapy showed increased protection against early progression, but similar overall survival.

Metabolic enzymes of the tricarboxylic acid cycle, such as 2-oxoglutarate dehydrogenase, are differentially expressed in absorptive and secretory lineages, guiding cell fate establishment and offering insights for targeted regenerative therapies.

Systematic base-editing and computational screens identify specific cysteine residues on VPS35 in the retromer complex as key sensors that decrease mitochondrial translation in response to reactive oxygen species signals.

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.

The molecular characteristics of myocarditis associated with immune checkpoint inhibitors are described and potential biomarkers of onset and severity are identified.

Genome-wide CRISPR screens, biochemical studies and animal models show that RASA2 has a key role in regulating T cell function and has potential as a genetic target for enhancing anti-tumour immunity.

Immunotherapy is used to treat melanoma, however patient responses vary widely highlighting the need for factors that can predict therapeutic success. Here, the authors show that MHC-II molecules expressed by tumour cells are positively correlated with a good response to therapy and overall patient survival.

The dTAG system pairs potent heterobifunctional degraders and extensible tagging strategies to achieve immediate and reversible degradation of divergent proteins, facilitating biological investigation and drug target validation in cells and in mice.

Concatenating Original Duplex for Error Correction (CODEC) is a method that concatenates both strands of each DNA duplex to enable highly sensitive mutation detection in a range of analytes with fewer reads and lower error rates than current methods.

 Prophage lysogeny-to-lysis transitions are controlled by regulatory modules consisting of transcription factors and partner small proteins that are activated through DNA-damage-independent pathways, including by quorum sensing, and these modules determine inter-prophage competition outcomes.

TET mediated RNA-hydroxymethylation (5hmC) has been detected in mammals, but its physiological role remains unclear. Here the authors map 5hmC during embryonic stem cell (ESC) differentiation and find that Tet-mediated RNA hydroxymethylation reduces the stability of crucial pluripotency related transcripts.

In an analysis of adult patients with hematologic malignancies who received anti-CD19 chimeric antigen receptor T cell therapy, baseline gut microbiome composition was correlated with clinical response and treatment with broad-spectrum antibiotics in the four weeks prior to infusion was associated with worse survival and increased neurotoxicity.

Lim et al. show that OSBP and VAPA and VAPB deliver cholesterol across ER–lysosome contacts to activate mTORC1. OSBP-mediated cholesterol trafficking activates mTORC1 in a disease model caused by loss of Niemann–Pick C1.

Chandarlapaty and colleagues use longitudinal ctDNA samples to identify genomic alterations in PTEN and ESR1 associated with resistance in a phase I/II trial of a PI3K inhibitor and aromatase inhibition for hormone receptor–positive metastatic breast cancer.

Novel protein-coding genes can arise either from pre-existing genes or de novo; here it is shown that functional genes emerge de novo through transitory proto-genes generated by widespread translational activity in non-genic sequences.

Pancreatic ductal adenocarcinoma in mice induces loss of adipose tissue through altered function of the exocrine pancreas, and supplementing pancreatic enzymes attenuates the wasting of peripheral tissues induced by pancreatic cancer.

Distinct transcription factors influence cell fate, including the generation of effector or memory CD8⁺ T cells. Goldrath, Wang and colleagues have developed a Page-Rank analysis that shows that the transcription factors YY1 and Nr3c1, which are expressed constitutively, promote the differentiation of effector cells or memory cells, respectively.

Circulating tumor DNA is detected with high sensitivity and specificity using molecular barcoding and in silico error correction.

If deprived of exogenous glutamine, naive mouse embryonic stem cells are shown to be capable of generating the amino acid from other sources to enable their proliferation; the stem cells use glutamine and glucose catabolism to maintain a high level of intracellular α-ketoglutarate and promote demethylation of chromatin and ensure sufficient expression of pluripotency-associated genes.

ENL, identified in a genome-scale loss-of-function screen as a crucial requirement for proliferation of acute leukaemia, is required for leukaemic gene expression, and its YEATS chromatin-reader domain is essential for leukaemic growth.

In mice, provision of butyrate—a short-chain fatty acid produced by commensal microorganisms during starch fermentation—facilitates extrathymic generation and differentiation of Foxp3⁺ regulatory T cells, demonstrating that metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells.

The E3 ubiquitin ligase TRAIP governs the choice between the NEIL3 or the Fanconi anaemia pathway for the repair of DNA interstrand crosslinks.

Fusion proteins in cancers with low mutational burden represent functional neoantigens that elicit T cell activation and mediate responses to immunotherapy.

Jens Lykke-Andersen, Frank Baas, Joseph Gleeson and colleagues report that mutations in the 3′ exonuclease TOE1 cause pontocerebellar hypoplasia type 7. They further show that these mutations result in the accumulation of incompletely processed small nuclear RNAs, leading to severe, early-onset neurodegeneration.

Protein–protein interactions in cells are rapidly identified with improved proximity labeling methods.

Leukemias bearing heterozygous mutations in the SRSF2 splicing-factor-encoding gene can be therapeutically targeted by pharmacologic inhibition of residual spliceosome function.

The hypothesis that cancer is driven by tumour-initiating cells — popularly known as cancer stem cells — has recently attracted considerable attention, owing to the promise of a novel cellular target for the treatment of haematopoietic and solid malignancies. This Review considers recent advances in the cancer stem cell field, focusing on the challenges and opportunities for anticancer drug discovery.

Brian Brown et al. report the results of the Zurquí All Diptera Biodiversity Inventory project, one of the largest efforts to date to directly assess species richness of a megadiverse order of insects. The authors identified 41,001 flies to 4332 species, including 73 of the world's 160 Diptera families.