Soluble CTLA-4 regulates immune homeostasis and promotes resolution of inflammation by suppressing type 1 but allowing type 2 immunity

Immunity, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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miR-142 deficit in T cells during blast crisis promotes chronic myeloid leukemia immune escape

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 1, 2025

We reported that an acquired miR-142 deficit transforms chronic phase (CP) myeloid leukemia (CML) leukemic stem cells (LSCs) into blast crisis (BC) LSCs. Given the role of in development and activity immune system, we postulated this also promotes LSC escape. Herein, report on IL-6-driven occurring T during BC transformation. In CML murine models, impairs thymic differentiation lymphoid-primed multipotent progenitors (LMPP) prevents cells' metabolic reprogramming, thereby leading to loss Correcting with a mimic compound (M-miR-142), alone or combination checkpoint antibodies, restores cell number activity, elimination prolonged survival patient-derived xenograft models. These observations may open new therapeutic opportunities for other malignancies.

Language: Английский

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Identification of Genomic Instability-Associated LncRNAs as Potential Therapeutic Targets in Lung Adenocarcinoma

Cancers, Journal Year: 2025, Volume and Issue: 17(6), P. 996 - 996

Published: March 15, 2025

Background/Objectives: Non-small cell lung cancer (NSCLC) is the most common type of cancer, with adenocarcinoma (LUAD) as predominant subtype. Despite advancements in targeted therapies, many NSCLC patients still experience poor outcomes due to treatment resistance and disease progression. Genomic instability (GI), a hallmark defined increased tendency DNA mutations alterations, closely linked initiation, progression, therapy. Emerging evidence suggests that long non-coding RNAs (lncRNAs)—molecules longer than 200 nucleotides do not encode proteins but regulate gene expression—play critical roles biology are associated GI. However, relationship between GI lncRNA expression LUAD remains poorly understood. Methods: In this study, we analyzed transcript profiles lncRNAs mRNAs from samples The Cancer Genome Atlas (TCGA) database classified them based on their Homologous Recombination Deficiency (HRD) score. HRD score an unweighted sum three independent DNA-based measures genomic instability: loss heterozygosity, telomeric allelic imbalance, large-scale transitions. We then performed differential analysis identify were either upregulated or downregulated high scores compared those low scores. Following this, conducted correlation assess significance association both mRNAs. Results: identified 30 differentially expressed instability. Using RNA interactome sequencing experiments, found interactions GI-associated (GI-lncRNAs) (GI-mRNAs). Further investigation showed some GI-lncRNAs play regulatory functional other diseases. also have potential prognostic biomarkers, particularly when integrated stratification. specific was primary therapy response immune infiltration LUAD. Additionally, existing drugs could modulate GI-lncRNAs, offering therapeutic strategies address Conclusions: Our findings suggest serve valuable biomarkers for prognosis response. Furthermore, modulating these presents avenues

Language: Английский

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MCL‑1 safeguards activated hair follicle stem cells to enable adult hair regeneration

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 22, 2025

Abstract Hair follicles cycle through expansion, regression and quiescence. To investigate the role of MCL‑1, a BCL‑2 family protein with anti‑apoptotic apoptosis‑unrelated functions, we delete Mcl‑1 within skin epithelium using constitutive inducible systems. Constitutive deletion does not impair hair follicle organogenesis but leads to gradual loss elimination stem cells. Acute rapidly depletes activated cells completely blocks depilation‑induced regeneration in adult mice, while quiescent remain unaffected. Single‑cell RNA‑seq profiling reveals engagement P53 DNA mismatch repair signaling upon activation. Trp53 rescues defects caused by acute deletion, highlighting critical interplay between MCL‑1 balancing proliferation death. The ERBB pathway plays central sustaining survival promoting expression. Remarkably, single Bak allele, pro‑apoptotic Bcl‑2 effector gene, deletion‑induced both mammary glands. These findings demonstrate pivotal inhibiting stress‑induced apoptosis when activate fuel tissue regeneration.

Language: Английский

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The potential role of miR-450a-1-3p in chromium-associated heart rate variability reduction

Environmental Pollution, Journal Year: 2025, Volume and Issue: unknown, P. 126117 - 126117

Published: March 1, 2025

Language: Английский

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MicroRNAs as Sensitizers of Tyrosine Kinase Inhibitor Resistance in Cancer: Small Molecule Partnerships

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(4), P. 492 - 492

Published: March 28, 2025

Tyrosine kinase inhibitors (TKIs) have revolutionized cancer treatments by being less toxic and improving the survival of patients. The greatest challenge to their success is resistance exhibited However, potential microRNAs (miRNAs) for sensitizing molecules TKIs has been well recognized, with several reports publishing promising results. Nonetheless, this therapeutic window faces challenges often-overlooked limitations. One most fundamental selecting optimal miRNA candidates clinical trials, as miRNAs are promiscuous regulate hundreds targets. In review, we describe how enhance sensitivity across various types cancer. We highlight limitations in achieving a successful collaboration between small (TKIs–miRNAs). Our focus on proposing workflow select suitable candidate, recommending available bioinformatics tools develop partnership miRNAs. hope that initial proposal will provide valuable support future research.

Language: Английский

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Foxf1 -mediated co-regulation of miR-495 and let-7c modulates epicardial cell migration and myocardial specification

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Background The heart is the first functional organ to develop in vertebrate embryos. In mice, primitive tubular begins beating at embryonic day (E) 8.0-E.8.5 and undergoes rightward looping form atrial ventricular chambers. proepicardium, a transient cell cluster sinus venous-lateral plate mesenchyme junction migrates onto gives rise epicardium, squamous epithelium that plays key role cardiac development. Despite advances understanding epicardial lineage contributions, molecular mechanisms governing these processes remain poorly understood. Methods To characterize transcriptional post-transcriptional regulation of development, we performed RNA sequencing two critical timepoints, proepicardium formation epicardium establishment. We analysed differentially expressed coding non-coding RNAs, focusing on microRNAs their potential regulatory interactions. Results identified complex network involving mRNAs, lncRNAs between epicardium. Notably, with miR-495 let-7c emerged as regulators migration, an essential process for proper epicardial-derived migration. Our findings also reveal not only regulate target gene expression but modulate other microRNAs, suggesting novel mechanism Additionally, Foxf1 inhibition modulates let-7c, promoting cardiogenic markers cells. Conclusion study highlights regulating miR-495 which turn migration myocardial specification. These finding provide new insights into intricate interplay transcription factors cardiogenesis.

Language: Английский

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Prognostic Assessment and Analysis of Underlying Biological Mechanisms of Prostate Cancer Based on Estrogen-Related Genes

Hormone and Metabolic Research, Journal Year: 2025, Volume and Issue: 57(04), P. 273 - 285

Published: April 1, 2025

Abstract Prostate cancer (PCa) ranks among the most prevalent cancers in men, noted for its high mortality rate and unfavorable prognosis. Estrogen-related genes (ERGs) are significantly associated with progression of PCa. This investigation aims to comprehensively assess prognosis PCa based on ERGs explore underlying biological mechanisms. Univariate, multivariate, Least Absolute Shrinkage Selection Operator (LASSO) regression analyses were conducted identify prognostic signature build a model. The model’s predictive performance was assessed using Receiver Operating Characteristic (ROC) curve analysis. Gene Set Enrichment Analysis (GSEA), Ontology (GO), Kyoto Encyclopedia Genes Genomes (KEGG) enrichment employed investigate molecular mechanisms Antitumor drugs sensitivity predicted CellMiner database pRRophitic package. Additionally, miRNAs targeting identified miRNet database. study six as biomarkers PCa: POU4F1, BMP2, PGF, GAS1, GNAZ, FGF11. findings indicated that individuals low-risk category exhibited improved results. Notably, may be closely linked cell adhesion molecule pathway epigenetic regulation. hsa-let-7a-5p hsa-miR-34a-5p potential therapeutic regulators treatment. In conclusion, this research offers novel perspectives into PCa, providing robust scientific support development personalized treatment strategies patients.

Language: Английский

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Automation of RNA-Seq Sample Preparation and Miniaturized Parallel Bioreactors Enable High-Throughput Differential Gene Expression Studies

Microorganisms, Journal Year: 2025, Volume and Issue: 13(4), P. 849 - 849

Published: April 8, 2025

A powerful strategy to accelerate bioprocess development is complement parallel bioreactor systems with an automated approach, often achieved using liquid handling stations. The benefit of such high-throughput experiments determined by the employed monitoring procedures. To gain a molecular understanding microbial production strains in miniaturized single-use bioreactors, we extended at-line procedures transcriptome analysis approach RNA-Seq. perform RNA-Seq experiments, developed sample preparation workflow consisting cell disruption enzymatic lysis, total RNA extraction, nucleic acid concentration normalization, and Nanopore cDNA Library preparation. pH-controlled aerobic batch growth Saccharomyces cerevisiae was studied six different carbon sources (glucose, pyruvate, fructose, galactose, sucrose, mannose) on 11 mL scale 24 stirred tank bioreactors integrated into station while performing for same deck. With four biological replicates per condition, libraries were prepared over 11.5 h. Off-line sequencing yielded 20.97 M classified reads Q-score > 9. Differential gene expression revealed significant differences transcriptomic profiles when comparing glucose (exponential growth) pyruvate (stress conditions), allowing identification 674 downregulated 709 upregulated genes. Insignificant changes patterns measured yielding only 64 differentially expressed expected cellular responses identified this study show promising profiling cultures, providing valuable insights level fashion.

Language: Английский

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PAF1C-mediated activation of CDK12/13 kinase activity is critical for CTD phosphorylation and transcript elongation

Molecular Cell, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

The transcription cycle is regulated by dynamic changes in RNA polymerase II (RNAPII) C-terminal domain (CTD) phosphorylation, which are crucial for gene expression. However, the mechanisms regulating transcription-specific cyclin-dependent kinases (CDKs) during remain poorly understood. Here, we show that human CDK12 co-phosphorylates CTD Serine2 and Serine5. This di-phosphorylated Serine2-Serine5 mark may then act as a precursor mono-phosphorylated through Serine5 de-phosphorylation. Notably, specifically association with elongation-specific factor PAF1 complex (PAF1C), CDC73 subunit contains metazoan-specific peptide motif, capable of allosteric CDK12/cyclin K activation. motif essential cell proliferation required normal levels phosphorylation chromatin, transcript elongation, particularly across long genes. Together, these findings provide insight into governing RNAPII phospho-CTD dynamics ensure progression cycle.

Language: Английский

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