Recoding: reprogrammed genetic decoding.
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Reprogramming of the transcriptional machinery in Xenopus oocytes by injection of mouse poly(A)+ RNA.
We have devised an assay for species-specific transcription factors for the mouse rRNA gene by exploiting the ability of Xenopus oocytes to transcribe injected DNA and translate mRNAs. When mouse rRNA genes are microinjected into Xenopus oocytes, they are not transcribed. We show here that transcription of mouse rRNA genes is supported when mouse mRNAs are injected before the transcription template is injected, indicating that the necessary transcription factors are translated in the oocyte and are available to transcribe an appropriate template. The use of this assay in cloning genes for transcription factors is discussed.
Animals↗
Ascites reprograms innate lymphoid immune cells in ovarian cancer by promoting ILC2 enrichment and dysfunctional NK-cell states.
BACKGROUND: High-grade serous ovarian cancer (HGSOC) is commonly accompanied by malignant ascites, a clinically relevant tumor niche that promotes immune evasion, metastasis, and treatment resistance. Although natural killer (NK)-cell dysfunction has been described in ovarian cancer, the broader innate lymphoid landscape of ascites and the mechanisms linking ascites-derived signals to innate immune suppression remain insufficiently resolved. METHODS: We performed single-cell RNA sequencing of NK/innate lymphoid cells from ovarian cancer ascites to define cellular heterogeneity and differentiation states. Functional assays assessed NK-cell cytotoxicity, degranulation, and receptor expression following exposure to patient-derived ascites, with or without transforming growth factor-β (TGF-β) receptor inhibition. Proteomic profiling was used to characterize the soluble ascites milieu, and clinical associations were examined for innate lymphoid subsets. RESULTS: Single-cell analysis identified eight transcriptionally distinct NK/innate lymphoid states, including cytotoxic, precursor, early-like, tolerant/immunoregulatory, regulatory, proinflammatory, and innate lymphoid populations. Ovarian cancer ascites was characterized by depletion of cytotoxic and precursor NK-cell states together with enrichment of early-like, tolerant, regulatory, pro-inflammatory, and innate lymphoid cell (ILC) populations. Trajectory analysis indicated impaired maturation toward terminally differentiated cytotoxic NK cells. Notably, ascites contained an expanded population of programmed cell death protein 1 (PD-1)+ ILC2s, which were more abundant in patients with shorter progression-free survival. In functional assays, short-term exposure of healthy donor NK cells to ascites suppressed degranulation and tumor-cell killing, reduced expression of activating receptors including NKp30 and DNAM-1, increased inhibitory receptor expression, and shifted NK cells toward a CD56highCD16low phenotype. Proteomic profiling supported a soluble milieu consistent with type 2 immune skewing and NK-cell suppression. Importantly, TGF-β receptor inhibition partially restored NK-cell activation and function in the presence of ascites. CONCLUSIONS: HGSOC ascites establishes a type 2-skewed immunoregulatory niche that coordinately drives NK cell dysfunction and PD-1+ ILC2 accumulation. The findings identify TGF-β-linked suppression and ascites-associated immune regulators as candidate immunotherapeutic vulnerabilities for restoring antitumor immunity in ovarian cancer.
Humans↗
The Novel Hypomethylating Agent NTX-301 Reprograms Epigenetic and Hippo Signaling Pathways and Exhibits Preclinical Activity in Venetoclax-Resistant and TP53-Mutant AML.
PURPOSE: Hypomethylating agent (HMA) and the BCL-2 inhibitor venetoclax (VEN) combinations have evolved into first-line therapies for patients with acute myeloid leukemia (AML), yielding high response rates. However, most patients ultimately relapse, particularly those with TP53 mutations. We investigated mechanisms of action and therapeutic efficacy of NTX-301, a next-generation HMA. EXPERIMENTAL DESIGN: Methods used include flow cytometry-based cell viability assays, Western blotting, reverse-phase protein arrays, RNA sequencing, Cytometry by Time-Of-Flight single-cell mass cytometry, and methylation profiling in various therapy-resistant AML models. RESULTS: We demonstrate that NTX-301 exhibits superior efficacy compared with 5-azacytidine (5-AZA) in 5-AZA- or VEN-resistant AML. It synergizes with VEN in VEN- or VEN/HMA-resistant and TP53-mutant AML blasts and stem/progenitor cells (combination index <1). NTX-301 inhibits DNA methyltransferase 1 (DNMT1) and increases p73 and caspase 8 (CASP8)/activated CASP8 levels in TP53 wild-type and TP53-mutant AML and activates p53 signaling. It extends survival (≥45%) in both xenograft and patient-derived xenograft models. Methylation profiling revealed that NTX-301 is a more targeted HMA compared with 5-AZA, enabling suppression of functionally enriched genes/pathways. Pathway analysis of 954 commonly hypomethylated genes showed profoundly greater enrichment of Hippo signaling in NTX-301-treated compared with 5-AZA-treated cells and enrichment of insulin signaling, VEGF pathway, and cell cycle selectively in NTX-301- but not in 5-AZA-treated cells. NTX-301-mediated Hippo signaling was validated at protein levels. CONCLUSIONS: Data suggest that NTX-301 exerts potent antileukemic activities superior to 5-AZA and synergizes with VEN in VEN-resistant and TP53-mutant AML, in part by suppressing DNMT1, inducing DNA damage responses and apoptosis through p53 signaling, and demethylating LATS1/2, thereby activating Hippo signaling.
Humans↗
Loss of Gst1 enhances resistance to MMS by reprogramming the transcription of DNA damage response genes in a Rad53-dependent manner in Candida albicans.
The DNA damage response is a highly conserved protective mechanism that enables cells to cope with various lesions in the genome. Extensive studies across different eukaryotic cells have identified the crucial roles played by components required for response to DNA damage. When compared to the essential signal transducers and repair factors in the DNA damage response circuitry, the negative regulators and underlying mechanisms of this circuitry have been relatively under-examined. In this study, we investigated Gst1, a putative glutathione transferase in the fungal pathogen Candida albicans. We found that under stress caused by the DNA damage agent MMS, GST1 expression was significantly upregulated, and this upregulation was further enhanced by the loss of the checkpoint kinases and DNA repair factors. Somewhat counterintuitively, deletion of GST1 conferred increased resistance to MMS, potentially via enhancing the phosphorylation of Rad53. Furthermore, overexpression of RAD53 or deletion of GST1 resulted in upregulated transcription of DNA damage repair genes, including CAS1, RAD7, and RAD30, while repression of RAD7 transcription in the GST1 deletion reversed the strain's heightened resistance to MMS. Finally, Gst1 physically interacted with Rad53, and their interaction weakened in response to MMS-induced stress. Overall, our findings suggest a negative regulatory role for GST1 in DNA damage response in C. albicans, and position Gst1 within the Rad53-mediated signaling pathway. These findings hold significant implications for understanding the mechanisms underlying the DNA damage response in this fungal pathogen and supply new potential targets for therapeutic intervention.
Candida albicans↗
A pan-cancer single-cell atlas uncovers the role of sex hormones and chromosomes in sex-divergent reprogramming of the tumor microenvironment.
BACKGROUND: Sex bias is pervasive in tumors; however, how sex chromosomes and hormone-responsive signaling shape the tumor microenvironment (TME) remains insufficiently characterized. Considering the critical impact of the TME on tumor progression and response to immunotherapy, a pan-cancer investigation of sex-specific and cancer-context-dependent TME features is warranted. METHOD: Based on stringent inclusion criteria, we constructed a high-resolution pan-cancer single-cell sequencing atlas by integrating 31 publicly available single-cell RNA-seq datasets, comprising a total of 1,831,436 cells by integrating 468 samples from eight types of non-sex-specific solid tumors (282 males and 186 females). After correcting for batch effects, we identified major and minor cellular subsets. Multiple computational approaches were applied to investigate sex-associated differences in cellular composition, gene expression, pathway activity, malignant cell states and intercellular communication. RESULTS: We systematically compared sex-specific TME features across eight common solid malignancies. Male-biased CD8+ T cell exhaustion emerged as a recurrent but non-uniform feature, with its magnitude varying across cancer types and being modified by tissue-specific contexts. This pattern was associated with androgen-response signature scores and expression-based loss of the Y chromosome (LOY) scores. M2-like macrophage polarization showed a more cancer-type-dependent pattern; although female-biased enrichment was observed in selected malignancies, it did not represent a uniform pan-cancer feature. Expression-based X chromosome inactivation (XCI)/XCI escape-related programs, estrogen-response signature scores and stromal components, including fibroblasts and endothelial cells, were associated with macrophage and immune-regulatory states in specific tumor contexts. Tumor cells of male origin displayed higher genomic instability and more aggressive phenotypes, with androgen-response signatures and LOY contributing to the development of a male biased malignant state. Furthermore, expression-based LOY scores in malignant cells were associated with CD8+ T cell exhaustion based on transcriptomic proxies. CONCLUSION: Our study uncovers extensive but heterogeneous sex-specific differences in the TME across multiple cancer types. We propose a regulatory framework linking sex chromosomes, hormone-responsive signaling and TME interactions, which is consistent with recurrent male-biased CD8⁺ T cell exhaustion and context-dependent M2-like macrophage polarization. Importantly, the magnitude and, in some cancers, the direction of these sex-biased features are modified by tissue-specific contexts. These findings underscore the need to include sex chromosome and hormone status as essential biological variables in studies of the tumor microenvironment and the design of immunotherapies.
Tumor Microenvironment↗
Reprogramming SynchroMed pumps: unanticipated inaccuracy.
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Antineoplastic Combined Chemotherapy Protocols↗
Cyclin-dependent kinase 4 and 6 inhibitors and the breast cancer immune ecosystem: immune remodeling, resistance, and therapeutic reprogramming.
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) combined with endocrine therapy have become a therapeutic backbone for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, yet durable disease control is frequently limited by intrinsic and acquired resistance. Canonical tumor-cell mechanisms, including retinoblastoma-pathway escape, cyclin E-cyclin-dependent kinase 2 (CDK2) activation, endocrine adaptation, and phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) signaling, explain only part of this failure because they do not fully capture dynamic immune and stromal remodeling. Preclinical and translational studies indicate that early CDK4/6 inhibition can enhance antigen presentation, activate interferon-related programs, restrain regulatory T cells, and promote a T-cell-inflamed state. These effects are conditional and may not persist during prolonged treatment. Sustained therapy can instead drive heterogeneous resistant niches characterized by stromal remodeling, myeloid recruitment, checkpoint adaptation, and T-cell dysfunction. This immune-state dependence provides a rationale for immune checkpoint blockade, although clinical combinations have shown mixed efficacy and clinically relevant hepatic, pulmonary, and hematologic toxicities. Sequential or lead-in strategies therefore warrant prospective evaluation. Oxidative phosphorylation (OXPHOS) and redox adaptation may sustain selected resistant states and expose context-dependent ferroptotic vulnerabilities. Ferroptosis may connect tumor-cell killing with immune regulation, whereas nanomedicine may improve tumor-selective delivery. Both strategies remain largely preclinical and require further evaluation of pharmacokinetics, biodistribution, toxicity, manufacturability, and immune-cell safety. This Review distinguishes intrinsic from acquired resistance across interpatient, intratumoral, spatial, and temporal dimensions. It integrates tumor-cell escape with cytokine, immune, stromal, vascular, and metabolic remodeling and summarizes emerging therapeutic strategies. We further propose a candidate biomarker-informed framework that integrates genomic profiling, spatial immune architecture, circulating biomarkers, T-cell receptor (TCR) dynamics, transcriptomic and single-cell analyses, artificial intelligence (AI)-assisted multimodal integration, and longitudinal sampling. This framework is intended to support biomarker development and prospective trial design rather than current clinical decision-making, providing a translational basis for testing state-informed and sequence-aware therapeutic strategies.
Humans↗
Multi-omics analysis to uncover constitutive priming and dynamic metabolic reprogramming conferring white rust resistance in Brassica juncea.
White rust, caused by Albugo candida, is one of the most devastating diseases of Indian mustard (Brassica juncea), causing yield losses of up to 90%. Durable resistance sources within cultivated Brassica germplasm remain limited. In this study, near-isogenic lines (NILs) of B. juncea cv. Varuna harbouring resistance from an East European source (Donskaja-IV, possessing a single CC-NB-LRR protein-coding R gene) was used to investigate the molecular basis of resistance through integrated transcriptomic and metabolomic analyses at 48 and 96 hours post-inoculation (hpi). Transcriptomic profiling revealed that the resistant Varuna_WRR line exhibited significantly higher unique transcript expression (18.76%) compared to the susceptible parent (8.41%) during the progression of infection. Principal component analysis showed clear separation between genotypes based on infection status, time, and genetic background. In the resistant line, upregulated genes were enriched in ethylene-activated signaling, protein phosphorylation, endoplasmic reticulum stress response, pectin biosynthesis, and hypersensitive response at 48 hpi, shifting toward programmed cell death, protein ubiquitination, abscisic acid metabolism, and starch biosynthesis at 96 hpi. Conversely, the susceptible line displayed broad downregulation of primary metabolic processes, indicating metabolic exhaustion. Metabolomic analysis demonstrated that the resistant genotype accumulated higher levels of defense-related amino acids (proline, glutamine, glutamic acid, serine, threonine, glycine), carbohydrates, organic acids, and polyamines, supporting enhanced nitrogen assimilation, energy reserves, membrane stability, and signaling. Together, these findings indicate that constitutive priming and dynamic activation of defense signaling, protein turnover, and osmoprotectant accumulation underpin the enhanced resistance in Varuna_WRR against Albugo candida. This integrated multi-omics approach provides valuable insights for breeding durable white rust resistance in Brassica juncea.
Brassica juncea↗
[Morphogenetic reactions of cells and the reprogramming of their syntheses].
Several groups of experimental findings concerning the influence of alteration of cell shape on cell proliferation and differentiation are reviewed. Analysis of the data suggests that interactions between cells and extracellular matrix may control the programming of intracellular synthesis. The pathways of this control remain obscure. It is stressed that this control mechanism plays essential role in development.
Animals↗
Reprogramming the social environment of an autistic child.
The effects of a token reinforcement and response cost procedure on the social skills, and academic and problem behaviours of a nine-year-old autistic child were assessed using a token economy treatment programme. The treatment was carried out in the child's home environment with his parents acting as therapists. It was found that the child's learning was enhanced and his problem behaviours were brought under parental control. These results seem particularly significant because it demonstrates the feasibility of using a token economy treatment programme with autistic children.
Autistic Disorder↗
Stage-specific reprogramming of globin gene expression.
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Animals↗
DDD pacing mode survival in patients with a dual-chamber pacemaker.
Dual-chamber (DDD) pacing mode survival was assessed by reviewing 486 consecutive initial transvenous DDD pacemaker implantations between December 1981 and December 1988 inclusive, with a mean follow-up time of 33 months. The patients' mean age was 71.4 years and 55% were male; 38% had dominant sinoatrial and 62% had dominant atrioventricular (AV) node disease. Nineteen patients (4%) underwent secondary operative intervention for lead dislodgement (n = 11), lead or pulse generator malfunction (n = 6) or infection (n = 2). During follow-up, 87 patients (18%) had their device permanently reprogrammed out of the DDD mode and 10 others (2%) required temporary reprogramming out of this mode; 12 patients who required device reprogramming were managed in other dual-chamber or atrial pacing modes. Reasons for reprogramming included atrial fibrillation (n = 48; 10%); loss of atrial sensing (n = 26; 5%); recurrent "endless loop" tachycardia (n = 5; 1%); lead dislodgement without repositioning (n = 4; 1%); pulse generator malfunction (n = 1; 1%) and other (n = 5; 1%). The occurrence of atrial fibrillation was associated with dominant sinoatrial disease and a prior history of atrial fibrillation; 19% of atrial sensing loss was attributable to early or faulty pacemaker technology. The DDD mode survival rate at 1, 2, 3, 4 and 5 years was, respectively, 90%, 88%, 84%, 79% and 78%.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Clinical experience with a new multiprogrammable dual chamber pacemaker.
We evaluated the clinical performance of a new dual chamber pacemaker, ELA Chorus, in 35 patients. This device incorporates linear rate adaptive AV delay (AVDR), rate smoothing, fallback, impedance telemetry, pacemaker mediated tachycardia (PMT) recognition and reprogramming software, intracardiac electrogram displays, autothreshold testing, diagnostic data, battery depletion curves, and laptop computer programming. Mean patient age was 68 years; 18 patients had AV block, six had sinus node dysfunction (one with AV block), nine had carotid sinus hypersensitivity (three with AV block), and two had vagally mediated syncope. At hospital discharge, programming was DDD with a mean low rate of 60 (50-70) beats/min, mean high rate of 126 (120-154) beats/min; AVDR was ON in 21 patients, rate smoothing ON in six patients, fallback ON in six patients, and PMT reprogramming algorithm ON in 27 patients. Pacemaker follow-up involved 500 clinic visits over 14.3 months (1-36). Three patients developed atrial fibrillation, reprogrammed to DDI mode (two patients) or fallback (one patient). Fallback was used 617 times. PMT occurred 427 times in six patients; the PMT algorithm reprogrammed AV delay and postventricular atrial refractory period (PVARP) automatically, a function unique to the Chorus. Intracardiac electrograms and autothreshold testing improved follow-up efficiency. This new dual chamber pacemaker enhances programming flexibility and improves diagnostic accuracy at follow-up.
Aged↗
Cloning of embryos.
Nuclear transfer for the study of differentiation in amphibians has been used since the 1950s, but not until recently have the same procedures been applied successfully to some mammals. Nuclear transfer, as developed for the amphibian, is successful in sheep, cattle, rabbit, and pig, but not mouse embryos. This fact is discussed in relation to the species-specific timing of the activation of the zygotic genome. Nuclear transfer to an oocyte presumably results in a genomic reprogramming of the transferred nucleus. The limits of differentiation that can be reprogrammed have yet to be determined. Since the cells of early embryos are thought to have identical nuclear genomes, early embryos can be used as a source of donor nuclei; and, when combined with serial nuclear transfer, can theoretically produce an unlimited number of identical offspring. Cloning by splitting does not result in a reprogramming of the genome and is limited in the number of identical offspring that can result. Here we discuss some of the factors to consider concerning micromanipulation and nuclear reprogramming and how they relate to other embryo technologies.
Animals↗
Fetal-like reversion in the regenerating intestine is regulated by mesenchymal asporin.
Mesenchymal cells and the extracellular matrix (ECM) support epithelium during homeostasis and regeneration. However, the role of the mesenchyme in epithelial conversion into a fetal-like regenerative state after damage is not known. We modeled epithelial regeneration by culturing intestinal epithelium on decellularized small intestinal scaffolds (iECM) and identify asporin (Aspn), an ECM-bound proteoglycan, as a critical mediator of epithelial fetal-like reprogramming. After damage, transient increase in Aspn expression by the pericryptal fibroblasts induces epithelial transforming growth factor β (TGF-β)-signaling via CD44 and promotes timely epithelial reprogramming. Temporal control of Aspn is lost in old mice, and after damage, the persistently high level of Aspn stagnates epithelium in the regenerative state. Increase in Wnt signaling can resolve the stagnated regenerative program of the old epithelium, promoting restoration of tissue function. In summary, we establish a platform for modeling epithelial injury responses ex vivo and show that the mesenchymal Aspn-producing niche modulates tissue repair by regulating epithelial fetal-like reprogramming.
Animals↗
Transcription regulation of cell fate plasticity - from embryonic development to tissue regeneration.
Cell fate plasticity refers to the capacity of cells sharing the same genome to alter, reverse, or reconfigure their identity under physiological, pathological, or experimental conditions. This property underlies embryonic development, cellular reprogramming, and tissue regeneration, but becomes progressively restricted as lineage identity is stabilized. Embryonic development represents an intrinsic process of fate transitions, whereas reprogramming and regeneration reveal how differentiated cells can dedifferentiate or transdifferentiate under specific conditions. Across these contexts, plasticity is governed by multilayered regulatory networks involving transcription factors, epigenetic regulators, cofactors, and the core transcription machinery. Robust regulatory programs stabilize cell identity, whereas stochastic fluctuations in gene expression and chromatin state can prime cells for fate transitions, adding a tunable dimension to plasticity control. In this review, we synthesize recent advances in the regulation of cell fate plasticity across development, reprogramming, and regeneration, highlighting how transcription factors, epigenetic modifications, transcriptional cofactors, and core transcription machinery cooperate to control cell fate decisions and plasticity.
Animals↗
Crosstalk between S-nitrosylation and glycation defines a metabolic vulnerability in liver and renal cancers.
Metabolic reprogramming is a defining feature of cancer; however, how it contributes to therapeutic resistance remains incompletely understood. Here we show that loss of aldo-ketoreductase 1A1 (AKR1A1) in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) disrupts terminal glycolytic flux and lactate production through S-nitrosylation-mediated inhibition of pyruvate kinase, resulting in the accumulation of methylglyoxal (MGO). In multiple AKR1A1-deficient models, but not in those endogenously expressing the C423/424 A mutant of pyruvate kinase M2, elevated MGO triggers autophagic degradation of Kelch-like ECH-associated protein 1, leading to Nuclear factor erythroid 2-Related Factor 2 (NRF2) activation and transcriptional reprogramming. This NRF2-driven response enhances chemoresistance and promotes tumor cell migration, two hallmarks of aggressive cancer. Therapeutically, we demonstrate that pharmacological inhibition of the glyoxalase system-the major pathway for MGO detoxification-restores drug sensitivity in patient-derived cells and xenograft models, revealing a context-dependent metabolic vulnerability in AKR1A1 loss conditions. These findings identify AKR1A1 as a metabolic tumor suppressor and uncover crosstalk between S-nitrosylation and glycation as a key regulatory axis linking metabolic reprogramming to NRF2-driven therapy resistance, offering glyoxalase inhibition as a potential precision treatment strategy for RCC and HCC.
Humans↗