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PubMed1988

Reprogrammed expression of subunit 9 of the mitochondrial ATPase complex of Saccharomyces cerevisiae. Expression in vitro from a chemically synthesized gene and import into isolated mitochondria.

A synthetic gene has been designed and constructed by total chemical synthesis as a first step in the functional relocation from the mitochondrion to the nucleus of a gene encoding subunit 9 of the yeast mitochondrial ATPase complex. This gene (NAP9) incorporates codons frequently used in nuclear genes of Saccharomyces cerevisiae and additionally includes a series of unique restriction enzyme cleavage sites to facilitate future systematic manipulations of the gene and its protein product. Following the expression of the NAP9 gene by transcription and translation in vitro, a radiolabelled protein was produced which displayed a gel electrophoretic mobility and solubility in chloroform/methanol characteristic of the authentic subunit 9 proteolipid encoded in vivo by the mitochondrial oli1 gene. In order to achieve import into mitochondria of yeast subunit 9, a fusion was made between the NAP9 gene and DNA encoding the cleavable presequence of the nuclearly encoded precursor to subunit 9 from Neurospora crassa. Following expression in vitro, the resultant fusion protein was imported and appropriately processed by isolated yeast mitochondria. The import of yeast subunit 9 was less efficient than that observed in parallel import experiments with yeast subunit 8 attached to the same presequence or with the naturally occurring intact N. crassa subunit 9 precursor. Yeast subunit 9 lacking a leader sequence is not imported into mitochondria but, unlike subunit 8, it does not embed itself into the outer membrane, in spite of its highly hydrophobic character.

Base Sequence↗
PubMed1991

The role of passive stretch and repetitive electrical stimulation in preventing skeletal muscle atrophy while reprogramming gene expression to improve fatigue resistance.

The effects of mechanical stimuli on preserving muscle mass while transforming them into slow, fatigue resistant muscles have been studied in the rabbit. When combined, stretching and electrical stimulation (10 Hz) induce rapid and marked growth of muscles. This procedure also more rapidly activates the transformation process(es) than when either stretching or electrical stimulation (10 Hz) are used alone. Stretch by itself is also anabolic causing useful lengthening of muscles and preventing collagen accumulation. In contrast, muscle inactivity leads to rapid atrophy, fiber shortening and reduced muscle compliance. We believe these findings have important implications to cardiomyoplasty.

Animals↗
PubMed2025

Synthetic allopolyploidy unveils hybridization-driven transcriptional reprogramming underlying thermal adaptation in Cucumis.

Both heterosis (hybrid vigor) resulting from hybridization and genetic plasticity conferred by whole-genome duplication (WGD) are recognized as drivers of evolutionary success and ecological adaptation in plants. Allopolyploids, which combine both hybridization and WGD, are widespread in both natural and agricultural settings and often exhibit superior performance. However, the relative contributions of these two elements to the success of allopolyploids remain poorly understood. Here, we employed an experimentally reconstructed allotetraploid Cucumis species (C. × hytivus, 2n = 4x = 38) and its diploid interspecific hybrid progenitor (allodiploid, 2n = 2x = 19) to decouple and investigate the distinct and combined contributions of hybridization and whole-genome doubling to immediate genetic and phenotypic consequences of allopolyploid formation under environmental stress. Both C. × hytivus and the allodiploid exhibited superior heat tolerance compared with the parental species with significantly higher semi-lethal temperature and enhanced physiological acclimation capacity. While the allodiploid and allotetraploid retain transcriptomic features where differences persist (e.g., WGCNA modules), comparative analysis of the 15,680 homoeologous gene pairs in the allodiploid and allotetraploid under heat stress (45°C) versus control conditions (28°C) revealed conserved heat-responsive transcriptional plasticity, suggesting that enhanced thermotolerance in C. × hytivus is presented as consequences arising dominantly after interspecific hybridization. This study provides mechanistic insights into allopolyploid adaptation through experimental reconstruction of allopolyploid genomes, demonstrating that hybridization initiates key transcriptional and physiological advantages under stress, subsequent WGD stabilizes these adaptations and contributes to the full phenotypic realization. This work decouples the roles of interspecific hybridization and WGD and proposes a synthetic biology approach for developing climate-resilient crops.

Hybridization, Genetic↗
PubMed1990

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↗
PubMed2026

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↗
PubMed2026

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 (&#x2265;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↗
PubMed2024

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↗
PubMed2026

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&#x207a; 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↗
PubMed2026

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↗
PubMed2026

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↗
PubMedDate not supplied

[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↗
PubMed1978

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↗