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Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most ERVs by generating a repressive environment that prevents their expression (heterochromatin), little is known about mechanisms silencing ERVs residing in open regions of the genome (euchromatin). This is particularly important during embryonic development, where induction and repression of distinct classes of ERVs occur in short temporal windows. Here, we demonstrate that transcription-associated RNA degradation by the nuclear RNA exosome and Integrator is a regulatory mechanism that controls the productive transcription of most genes and many ERVs involved in preimplantation development. Disrupting nuclear RNA catabolism promotes dedifferentiation to a totipotent-like state characterized by defects in RNAPII elongation and decreased expression of long genes (gene-length asymmetry). Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards RNAPII activity, ERV expression, cell identity, and developmental potency.

Emerging evidence indicates that transfer RNA (tRNA)‐derived small RNAs (tsRNAs), originated from tRNA with high abundance RNA modifications, play an important role in many complex physiological and pathological processes. However, the biological functions and regulatory mechanisms of modified tsRNAs in cancer remain poorly understood. Here, it is screened for and confirmed the presence of a novel m7G‐modified tsRNA, m7G‐3′‐tiRNA LysTTT (mtiRL), in a variety of chemical carcinogenesis models by combining small RNA sequencing with an m7G small RNA‐modified chip. Moreover, it is found that mtiRL, catalyzed by the tRNA m7G‐modifying enzyme mettl1, promotes bladder cancer (BC) malignancy in vitro and in vivo. Mechanistically, mtiRL is found to specifically bind the oncoprotein Annexin A2 (ANXA2) to promote its Tyr24 phosphorylation by enhancing the interactions between ANXA2 and Yes proto‐oncogene 1 (Yes1), leading to ANXA2 activation and increased p‐ANXA2‐Y24 nuclear localization in BC cells. Together, these findings define a critical role for mtiRL and suggest that targeting this novel m7G‐modified tsRNA can be an efficient way for to treat BC. [ABSTRACT FROM AUTHOR]

Fatty liver disease is a common metabolic disease in chickens. This disease can lead to a decrease in egg production and increase the risk of death in chickens. Long non‐coding RNAs (lncRNAs) are involved in fatty liver formation by directly targeting genes or regulating gene expression by competitively binding microRNAs. However, a large proportion of competing endogenous RNA (ceRNA) networks in fatty liver diseases are still unclear. The total of 300 Jingxing‐Huang chickens were used for fatty liver model construction. Then, differentially expressed (DE) genes (DEGs) identified through whole‐transcriptome sequencing from four chickens with fatty liver and four chickens without fatty liver were chosen from the F1 generation. A total of 953 DEGs were identified between the fatty liver group and the control group, including 26 DE micro (mi)RNAs and 56 DE lncRNAs. Differential expression heatmaps and volcano plots were obtained after clustering expression analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that these DEGs were involved in many biological processes and signaling pathways related to fatty acid metabolism and lipid synthesis. Furthermore, cytoscape was used to construct a ceRNA network of the DE miRNAs, DE mRNAs, and DE lncRNAs. Eleven DE lncRNAs, seven DE miRNAs, and 13 DE mRNAs were found to be associated with the pathogenesis of fatty liver disease. An lncRNA–miRNA–mRNA ceRNA network was constructed to elucidate the mechanisms of fatty liver diseases, and the ENSGALT00000079786‐miR‐140/miR‐143/miR‐1a/miR‐22/miR‐375 network was identified. These results provide a valuable resource for further elucidating the posttranscriptional regulatory mechanisms of chicken liver and adipose fat development or deposition. [ABSTRACT FROM AUTHOR]

SUMMARY Alternative transcription start sites (TSS) are widespread in eukaryotes and can alter the 5′ UTR length and coding potential of transcripts. Here we show that inorganic phosphate (Pi) availability regulates the usage of several alternative TSS in Arabidopsis (Arabidopsis thaliana). In comparison to phytohormone treatment, Pi had a pronounced and specific effect on the usage of many alternative TSS. By combining short‐read RNA sequencing with long‐read sequencing of full‐length mRNAs, we identified a set of 45 genes showing alternative TSS under Pi deficiency. Alternative TSS affected several processes, such as translation via the exclusion of upstream open reading frames present in the 5′ UTR of RETICULAN LIKE PROTEIN B1 mRNA, and subcellular localization via removal of the plastid transit peptide coding region from the mRNAs of HEME OXYGENASE 1 and SULFOQUINOVOSYLDIACYLGLYCEROL 2. Several alternative TSS also generated shorter transcripts lacking the coding potential for important domains. For example, the EVOLUTIONARILY CONSERVED C‐TERMINAL REGION 4 (ECT4) locus, which encodes an N6‐methyladenosine (m6A) reader, strongly expressed under Pi deficiency a short noncoding transcript (named ALTECT4) ~550 nt long with a TSS in the penultimate intron. The specific and robust induction of ALTECT4 production by Pi deficiency led to the identification of a role for m6A readers in primary root growth in response to low phosphate that is dependent on iron and is involved in modulating cell division in the root meristem. Our results identify alternative TSS usage as an important process in the plant response to Pi deficiency. [ABSTRACT FROM AUTHOR]

Endometriosis is a complex gynecologic disorder characterized primarily by symptoms of pelvic pain, infertility, and altered quality of life. National and international guidelines highlight the diagnostic difficulties and lack of conclusive diagnostic tools for endometriosis. Furthermore, guidelines are becoming questionable at an increasingly rapid rate as new diagnostic techniques emerge. This work aims to provide a knowledge synthesis of the relevance of various diagnostic tools and to assess areas of improvement of conventional algorithms. MEDLINE and Cochrane Library databases were searched from January 2021 to December 2023 using relevant key words. Articles evaluating the diagnostic relevance and performance of various tools were included and independently reviewed by the authors for eligibility. Included studies were assessed using the GRADE and QUADAS‐2 tools. Of the 4204 retrieved articles, 26 were included. While anamnesis and clinical examination do contribute to diagnostic accuracy, their level of evidence and impact on the diagnostic process remains limited. Although imaging techniques are recommended to investigate endometriosis, ultrasonography remains highly operator dependent. Magnetic resonance imaging appears to exhibit higher sensitivities than ultrasound. However, concerns persist with regards to the terminology, anatomical definition of lesions, and accuracies of both ultrasound and magnetic resonance imaging. Recently, several biological markers have been studied and cumulative evidence supports the contribution of noncoding RNAs to the diagnosis of endometriosis. Marginal improvements have been suggested for anamnesis, clinical examination, and imaging examinations. Conversely, some biomarkers, including the saliva microRNA signature for endometriosis, have emerged as diagnostic tools which inspire reflection on the revision of conventional diagnostic algorithms. [ABSTRACT FROM AUTHOR]

Objective: The main pathological change of myocarditis is an inflammatory injury of cardiomyocytes. Long noncoding RNAs (lncRNAs) are closely related to inflammation, and our previous study showed that differential expression of lncRNAs is associated with myocarditis. This study aimed to investigate the impact of lncRNAs on the onset of myocarditis. Methods: RNA expression was measured by quantitative reverse-transcription polymerase chain reaction (RT-qPCR). Lipopolysaccharide (LPS) was used to induce inflammation in human cardiomyocytes (HCMs). The expression of inflammatory cytokines and myocardial injury markers was detected by enzyme-linked immunosorbent assay (ELISA) and RT-qPCR. Cell viability and apoptosis were measured by the cell counting kit-8 assay and flow cytometry. The binding force between lncRNA NONHSAT122636.2 and microRNA miRNA-2110 was detected using the dual-luciferase assay. Results: NONHSAT122636.2 was dynamically expressed in patients with myocarditis and negatively correlated with inflammation severity. The overexpression of NONHSAT122636.2 improved inflammatory injury in LPS-stimulated HCMs. The study observed that there was a weak binding force between NONHSAT122636.2 and miR-2110. Conclusion: NONHSAT122636.2 attenuates myocardial inflammation and apoptosis in myocarditis. Additionally, its expression decreases in the peripheral blood of children suffering from myocarditis and in patients who are diagnosed for the first time showing higher diagnostic sensitivity and specificity. This decrease is negatively correlated with the degree of inflammation. Overall, the study suggests that NONHSAT122636.2 can be exploited as a potential diagnostic biomarker for pediatric myocarditis. [ABSTRACT FROM AUTHOR]

Targeted novel treatment approaches for GBM using 4-amino cyanine and miRNA inhibitors. [Display omitted] • Developing novel therapeutic strategies is a promising approach for GBM. • ncRNAs play important roles in GBM pathogenesis, proliferation, and metastasis. • This review highlights the roles of miRNAs in GBM pathogenesis. • GBM treatment by combining 4-amino cyanine, and miRNAs-related Inhibitors. • Highlights the key challenges in miRNA therapy that need to be overcome. Glioblastoma (GBM) poses a formidable challenge in oncology due to its aggressive nature and dismal prognosis, with average survival rates around 15 months despite conventional treatments. This review proposes a novel therapeutic strategy for GBM by integrating microRNA (miRNA) therapy with 4-amino cyanine molecules possessing near-infrared (NIR) properties. miRNA holds promise in regulating gene expression, particularly in GBM, making it an attractive therapeutic target. 4-amino cyanine molecules, especially those with NIR properties, have shown efficacy in targeted tumor cell degradation. The combined approach addresses gene expression regulation and precise tumor cell degradation, offering a breakthrough in GBM treatment. Additionally, the review explores noncoding RNAs classification and characteristics, highlighting their role in GBM pathogenesis. Advanced technologies such as antisense oligonucleotides (ASOs), locked nucleic acids (LNAs), and peptide nucleic acids (PNAs) show potential in targeting noncoding RNAs therapeutically, paving the way for precision medicine in GBM. This synergistic combination presents an innovative approach with the potential to advance cancer therapy in the challenging landscape of GBM. [ABSTRACT FROM AUTHOR]

Introduction: The activation of cerebral endothelial cells (CECs) has recently been reported to be the earliest acute neuroinflammation event in the CNS during sepsis-associated encephalopathy (SAE). Importantly, adenosine-toinosine (A-to-I) RNA editing mediated by ADARs has been associated with SAE, yet its role in acute neuroinflammation in SAE remains unclear. Methods: Our current study systematically analyzed A-to-I RNA editing in cerebral vessels, cerebral endothelial cells (CECs), and microglia sampled during acute neuroinflammation after treatment in a lipopolysaccharide (LPS)-induced SAE mouse model. Results: Our results showed dynamic A-to-I RNA editing activity changes in cerebral vessels during acute neuroinflammation. Differential A-to-I RNA editing (DRE) associated with acute neuroinflammation were identified in these tissue or cells, especially missense editing events such as S367G in antizyme inhibitor 1 (Azin1) and editing events in lincRNAs such as maternally expressed gene 3 (Meg3), AW112010, and macrophage M2 polarization regulator (Mm2pr). Importantly, geranylgeranyl diphosphate synthase 1 (Ggps1) and another three genes were differentially edited across cerebral vessels, CECs, and microglia. Notably, Spearman correlation analysis also revealed dramatic time-dependent DRE during acute neuroinflammation, especially in GTP cyclohydrolase1 (Gch1) and non-coding RNA activated by DNA damage (Norad), both with the editing level positively correlated with both post-LPS treatment time and edited gene expression in cerebral vessels and CECs. Discussion: The findings in our current study demonstrate substantial A-to-I RNA editing changes during acute neuroinflammation in SAE, underlining its potential role in the disease. [ABSTRACT FROM AUTHOR]

This study aimed to develop a prognostic risk model based on immune-related long non-coding RNAs (lncRNAs). By analyzing the expression profiles of specific long non-coding RNAs, the objective was to construct a predictive model to accurately assess the survival prognosis of breast cancer (BC) patients. This effort seeks to provide personalized treatment strategies for patients and improve clinical outcomes. Based on the median risk value, 300 samples of triple-negative BC (TNBC) patients were rolled into a high-risk group (HR group, n = 140) and a low-risk group (LR group, n = 160). Multivariate Cox (MVC) analysis was performed by combining the patient risk score and clinical information to evaluate the prognostic value of the prognostic risk (PR) model. A total of 371 immune-related lncRNAs associated with the prognosis of TNBC were obtained from 300 TNBC samples. Nine associated with prognosis were obtained by univariate Cox (UVC) analysis, and 3 (AC090181.2, LINC01235, and LINC01943) were selected by MVC analysis for the construction of TNBC PR model. Survival analysis showed a great difference in TNBC patients in different groups (P < 0.001). The receiver operator characteristic (ROC) curve showed the model possessed a good area under ROC curve (AUC), which was 0.928. The patient RS jointing with clinical information as well as the MVC analysis revealed that RS was an independent risk factor (IRF) for prognosis of TNBC (P < 0.05, HR = 1.033286). Therefore, the lncRNAs associated with TNBC immunity can be screened by bioinformatics analysis, and the established PR model of TNBC could better predict the prognosis of patients with TNBC, exhibiting a high application value in clinic. [ABSTRACT FROM AUTHOR]

Background: The activity and number of immune cells in the tumor microenvironment are closely related to the overall survival of patients with hepatocellular carcinoma (HCC). The sex-determining region Y-box 4 (SOX4) gene is abnormally expressed in various tumor tissues and is critical for tumor development. However, the correlation between SOX4 expression in HCC and tumor immunity is unclear. Methods: SOX4 expression was explored using data from The Cancer Genome Atlas, and UALCAN databases. Real-time reverse transcription quantitative and western blotting were used to analyze SOX4 expression in several liver cancer cell lines. Additionally, correlations among SOX4 expression, cancer immune characteristics, and infiltrated immune cell gene marker sets in patients with HCC were analyzed using data from the Tumor Immune Estimation Resource, Gene Expression Profiling Interactive Analysis, and Tumor-Immune System Interactions databases. Moreover, we evaluated SOX4 expression in HCC tissues and the correlation of SOX4 expression with survival rate. Subsequently, noncoding RNAs (ncRNAs) responsible for SOX4 overexpression were identified using expression, correlation, and survival analyses. Results: SOX4 expression was significantly upregulated in HCC and correlated with a poor prognosis. Additionally, SOX4 upregulation in HCC positively correlated with immune cell infiltration, several biomarkers of immune cells, and immune checkpoint expression. Finally, the MCM3AP-AS1/hsa-miR-204-5p axis was identified as the most likely upstream ncRNA-related pathway for SOX4 in HCC. These results indicated that ncRNA-mediated upregulation of SOX4 correlated with the immune infiltration level and poor prognosis in HCC. Our findings provide new directions for the development of novel immunotherapeutic targets for HCC. [ABSTRACT FROM AUTHOR]

The emergent role of nucleic acid-based biomarkers—microRNAs(miRNAs), long non-coding RNAs(lncRNAs), and messenger RNAs(mRNAs), is becoming increasingly prominent in disease diagnostics and risk assessment. qRT-PCR is the primary analytical method for quantitative measurement of biomarkers. Yet, the relative infancy of non-coding RNAs recognition as biomarkers poses a challenge due to the absence of a consensus on a universally accepted normalizer gene, an absolute requirement for accurate quantification. Current tools normalizer selection are fraught with statistical limitations and suboptimal graphical user interface for data visualisation. These deficiencies underscore the necessity for a balanced tool tailored to handle qRT-PCR datasets. Addressing the identified challenges, we have developed 'gQuant' tool crafted to address these limitations. We employed voting classifiers that combine predictions from multiple statistical methods. Tool's efficacy was validated through different available and in house data derived from urinary exosomal miRNAs datasets. Comparative analysis with existing tools revealed that their integrated methodologies could skew the ranking of normalizer genes, whereas 'gQuant' consistently yielded rankings characterised by lower standard-deviation, reduced covariance, and enhanced kernel density estimation values. Given 'gQuant's' promising performance, normalizer gene identification will be greatly improved, improving precision of gene expression quantification in a variety of research scenarios. The gQuant tool developed for this study is available for public use and can be accessed at [https://github.com/ABHAYHBB/gQuant-Tool]." [ABSTRACT FROM AUTHOR]

Red swamp crayfish, Procambarus clarkii, is the most cultured freshwater crayfish species. It attracts significant research attention due to its considerable economic importance. However, the limited availability of genome information has impeded further genetic studies and breeding programs. By utilizing Illumina, PacBio, and Hi-C sequencing technologies, we present a more comprehensive and continuous chromosome-level assembly for P. clarkii than the published one. The final genome size is 4.03 Gb, consisting of 2,358 scaffolds with a N50 of 42.87 Mb. Notably, 3.68 Gb, corresponding to 91.42% of the genome, was anchored to 94 chromosomes. The assembly comprises 70.64% repetitive sequences, including 5.21% tandem repeats and 65.40% transposable elements. Additionally, a total of 4,456 non-coding RNAs and 28,852 protein-coding genes were predicted in the P. clarkii genome, with 96.26% of the genes were annotated. This high-quality genome assembly not only represents a significant improvement for the genome of P. clarkii and provides insights into the unique genome evolution, but also offers valuable information for developing freshwater aquaculture and accelerating genetic breeding. [ABSTRACT FROM AUTHOR]

Hypervirulent Klebsiella pneumoniae (HvKP) is an emerging bacterial pathogen causing invasive infection in immune-competent humans. The hypervirulence is strongly linked to the overproduction of hypermucoviscous capsule, but the underlying regulatory mechanisms of hypermucoviscosity (HMV) have been elusive, especially at the post-transcriptional level mediated by small noncoding RNAs (sRNAs). Using a recently developed RNA interactome profiling approach iRIL-seq, we interrogate the Hfq-associated sRNA regulatory network and establish an intracellular RNA-RNA interactome in HvKP. Our data reveal numerous interactions between sRNAs and HMV-related mRNAs, and identify a plethora of sRNAs that repress or promote HMV. One of the strongest HMV repressors is ArcZ, which is activated by the catabolite regulator CRP and targets many HMV-related genes including mlaA and fbp. We discover that MlaA and its function in phospholipid transport is crucial for capsule retention and HMV, inactivation of which abolishes Klebsiella virulence in mice. ArcZ overexpression drastically reduces bacterial burden in mice and reduces HMV in multiple hypervirulent and carbapenem-resistant clinical isolates, indicating ArcZ is a potent RNA inhibitor of bacterial pneumonia with therapeutic potential. Our work unravels a novel CRP-ArcZ-MlaA regulatory circuit of HMV and provides mechanistic insights into the posttranscriptional virulence control in a superbug of global concern. By performing a global RNA-RNA interactome analysis in hypervirulent Klebsiella pneumoniae, the authors identify the small RNA ArcZ targets many capsule genes and a key virulence factor MlaA, inhibiting Klebsiella infection and pathogenesis in mice. [ABSTRACT FROM AUTHOR]

Introduction: Acinetobacter baumannii (AB) is rising as a human pathogen of critical priority worldwide as it is the leading cause of opportunistic infections in healthcare settings and carbapenem-resistant AB is listed as a "super bacterium" or "priority pathogen for drug resistance" by the World Health Organization. Methods: Clinical isolates of A. baumannii were collected and tested for antimicrobial susceptibility. Among them, carbapenem-resistant and carbapenem-sensitive A. baumannii were subjected to prokaryotic transcriptome sequencing. The change of sRNA and mRNA expression was analyzed by bioinformatics and validated by quantitative reverse transcription-PCR. Results: A total of 687 clinical isolates were collected, of which 336 strains of A. baumannii were resistant to carbapenem. Five hundred and six differentially expressed genes and nineteen differentially expressed sRNA candidates were discovered through transcriptomic profile analysis between carbapenemresistant isolates and carbapenem-sensitive isolates. Possible binding sites were predicted through software for sRNA21 and adeK, sRNA27 and pgaC, sRNA29 and adeB, sRNA36 and katG, indicating a possible targeting relationship. A negative correlation was shown between sRNA21 and adeK (r = -0.581, P = 0.007), sRNA27 and pgaC (r = -0.612, P = 0.004), sRNA29 and adeB (r = -0.516, P = 0.020). Discussion: This study preliminarily screened differentially expressed mRNA and sRNA in carbapenem-resistant A. baumannii, and explored possible targeting relationships, which will help further reveal the resistance mechanism and provide a theoretical basis for the development of drugs targeting sRNA for the prevention and treatment of carbapenem-resistant A. baumannii infection. [ABSTRACT FROM AUTHOR]

The epigenetic layer of regulation has become increasingly relevant in the research focused on tumor suppressors. KLF4 is a well-described zinc-finger transcription factor, mainly known for its role in the acquisition of cell pluripotency. Here we report and describe the most relevant epigenetic regulation mechanisms that affect KLF4 expression in tumors. CpG island methylation emerges as the most common mechanism in several tumors including lung adenocarcinoma, hepatocellular carcinoma, non-Hodgkin lymphomas, among others. Further layers of regulation represented by histone methylation and acetylation and by non-coding RNAs are described. Overall, KLF4 emerges as a crucial target in the fight against cancer. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs characterized by their lack of 5′ caps and 3′ poly(A) tails. These molecules have garnered substantial attention from the scientific community. A wide range of circRNA types has been found to be expressed in various tissues of the human body, exhibiting unique characteristics such as high abundance, remarkable stability, and tissue-specific expression patterns. These attributes, along with their detectability in liquid biopsy samples such as plasma, position circRNAs an ideal choice as cancer diagnostic and prognostic biomarkers. Additionally, several studies have reported that the functions of circRNAs are associated with tumor proliferation, metastasis, and drug resistance. They achieve this through various mechanisms, including modulation of parental gene expression, regulation of gene transcription, acting as microRNA (miRNA) sponges, and encoding functional proteins. In recent years, a large number of studies have focused on synthesizing circRNAs in vitro and delivering them to tumor tissue to exert its effects in inhibit tumor progression. Herein, we briefly discuss the biogenesis, characteristics, functions, and detection of circRNAs, emphasizing their clinical potential as biomarkers for cancer diagnosis and prognosis. We also provide an overview the recent techniques for synthesizing circRNAs and delivery strategies, and outline the application of engineered circRNAs in clinical cancer therapy. [ABSTRACT FROM AUTHOR]

Circular RNA (CircRNA)–microRNA (miRNA) interaction (CMI) is an important model for the regulation of biological processes by non-coding RNA (ncRNA), which provides a new perspective for the study of human complex diseases. However, the existing CMI prediction models mainly rely on the nearest neighbor structure in the biological network, ignoring the molecular network topology, so it is difficult to improve the prediction performance. In this paper, we proposed a new CMI prediction method, BEROLECMI, which uses molecular sequence attributes, molecular self-similarity, and biological network topology to define the specific role feature representation for molecules to infer the new CMI. BEROLECMI effectively makes up for the lack of network topology in the CMI prediction model and achieves the highest prediction performance in three commonly used data sets. In the case study, 14 of the 15 pairs of unknown CMIs were correctly predicted. [ABSTRACT FROM AUTHOR]

Programmed cell death (PCD) is a process that eliminates infected, damaged, or possibly neoplastic cells to sustain homeostatic multicellular organisms. Although long noncoding RNAs (lncRNAs) are involved in various types of PCD and regulate tumor growth, invasion, and migration, the role of PCD-related lncRNAs in bladder cancer still lacks systematic exploration. In this research, we integrated multiple types of PCD as pan-PCD and identified eight pan-PCD-related lncRNAs (LINC00174, HCP5, HCG27, UCA1, SNHG15, GHRLOS, CYB561D2, and AGAP11). Then, we generated a pan-PCD-related lncRNA prognostic signature (PPlncPS) with excellent predictive power and reliability, which performed equally well in the E-MTAB-4321 cohort. In comparison with the low-PPlncPS score group, the high-PPlncPS score group had remarkably higher levels of angiogenesis, matrix, cancer-associated fibroblasts, myeloid cell traffic, and protumor cytokine signatures. In addition, the low-PPlncPS score group was positively correlated with relatively abundant immune cell infiltration, upregulated expression levels of immune checkpoints, and high tumor mutation burden (TMB). Immunogenomic profiles revealed that patients with both low PPlncPS scores and high TMB had the best prognosis and may benefit from immune checkpoint inhibitors. Furthermore, for patients with high PPlncPS scores, docetaxel, staurosporine, and luminespib were screened as potential therapeutic candidates. In conclusion, we generated a pan-PCD-related lncRNA signature, providing precise and individualized prediction for clinical prognosis and some new insights into chemotherapy and immune checkpoint inhibitor therapy for bladder cancer. [ABSTRACT FROM AUTHOR]

The senescence of bone marrow mesenchymal stem cells (BMSCs) contributes to the development of degenerative skeletal conditions. To date, the molecular mechanism resulting in BMSC senescence has not been fully understood. In this study, we identified a small non‐coding RNA, miR‐203‐3p, the expression of which was elevated in BMSCs from aged mice. On the other hand, overexpression of miR‐203‐3p in BMSCs from young mice reduced cell growth and enhanced their senescence. Mechanistically, PDZ‐linked kinase (PBK) is predicted to be the target of miR‐203‐3p. The binding of miR‐203‐3p to Pbk mRNA could decrease its expression, which in turn inhibited the ubiquitination‐mediated degradation of p53. Furthermore, the intravitreal injection of miR‐203‐3p‐inhibitor into the bone marrow cavity of aged mice attenuated BMSC senescence and osteoporosis in aged mice. Collectively, these findings suggest that targeting miR‐203‐3p to delay BMSC senescence could be a potential therapeutic strategy to alleviate age‐related osteoporosis. [ABSTRACT FROM AUTHOR]

piRNAs are crucial for transposon silencing, germ cell maturation, and fertility in male mice. Here, we report on the genetic landscape of piRNA dysfunction in humans and present 39 infertile men carrying biallelic variants in 14 different piRNA pathway genes, including PIWIL1, GTSF1, GPAT2, MAEL, TDRD1, and DDX4. In some affected men, the testicular phenotypes differ from those of the respective knockout mice and range from complete germ cell loss to the production of a few morphologically abnormal sperm. A reduced number of pachytene piRNAs was detected in the testicular tissue of variant carriers, demonstrating impaired piRNA biogenesis. Furthermore, LINE1 expression in spermatogonia links impaired piRNA biogenesis to transposon de-silencing and serves to classify variants as functionally relevant. These results establish the disrupted piRNA pathway as a major cause of human spermatogenic failure and provide insights into transposon silencing in human male germ cells. piRNAs are small RNA molecules found primarily in the testes of mice and men. Stallmeyer et al. demonstrate that variants in specific genes can disrupt the formation of piRNAs, impairing spermatogenesis and causing human male infertility. [ABSTRACT FROM AUTHOR]

Cancer remains a global health challenge, necessitating continuous advancements in diagnostic and treatment strategies. This review focuses on the utility of non-invasive biomarkers in cancer diagnosis and treatment, their role in early detection, disease monitoring, and personalized therapeutic interventions. Through a systematic review of the literature, we identified 45 relevant studies that highlight the potential of these biomarkers across various cancer types, such as breast, prostate, lung, and colorectal cancers. The noninvasive biomarkers discussed include liquid biopsies, epigenetic markers, noncoding RNAs, exosomal cargo, and metabolites. Notably, liquid biopsies, particularly those based on circulating tumour DNA (ctDNA), have emerged as the most promising method for early, non-invasive cancer detection due to their ability to provide comprehensive genetic and epigenetic information from easily accessible blood samples. This review demonstrates how non-invasive biomarkers can facilitate early cancer detection, accurate subtyping, and tailored treatment strategies, thereby improving patient outcomes. It underscores the transformative potential of non-invasive biomarkers in oncology, highlighting their application for enhancing early detection, survival rates, and treatment precision in cancer care. [ABSTRACT FROM AUTHOR]

Small nucleolar RNAs (snoRNAs) were previously regarded as a class of functionally conserved housekeeping genes, primarily involved in the regulation of ribosome biogenesis by ribosomal RNA (rRNA) modification. However, some of them are involved in several biological processes via complex molecular mechanisms. DNA damage response (DDR) is a conserved mechanism for maintaining genomic stability to prevent the occurrence of various human diseases. It has recently been revealed that snoRNAs are involved in DDR at multiple levels, indicating their relevant theoretical and clinical significance in this field. The present review systematically addresses four main points, including the biosynthesis and classification of snoRNAs, the mechanisms through which snoRNAs regulate target molecules, snoRNAs in the process of DDR, and the significance of snoRNA in disease diagnosis and treatment. It focuses on the potential functions of snoRNAs in DDR to help in the discovery of the roles of snoRNAs in maintaining genome stability and pathological processes. [ABSTRACT FROM AUTHOR]

Midbrain dopamine (mDA) neurons play an essential role in cognitive and motor behaviours and are linked to different brain disorders. However, the molecular mechanisms underlying their development, and in particular the role of non-coding RNAs (ncRNAs), remain incompletely understood. Here, we establish the transcriptomic landscape and alternative splicing patterns of circular RNAs (circRNAs) at key developmental timepoints in mouse mDA neurons in vivo using fluorescence-activated cell sorting followed by short- and long-read RNA sequencing. In situ hybridisation shows expression of several circRNAs during early mDA neuron development and post-transcriptional silencing unveils roles for different circRNAs in regulating mDA neuron morphology. Finally, in utero electroporation and time-lapse imaging implicate circRmst, a circRNA with widespread morphological effects, in the migration of developing mDA neurons in vivo. Together, these data for the first time suggest a functional role for circRNAs in developing mDA neurons and characterise poorly defined aspects of mDA neuron development. The function of circular RNAs in the brain remains poorly understood. Here the authors identify a role for circular RNAs in the control of neuron morphology and migration in the developing midbrain dopamine system. [ABSTRACT FROM AUTHOR]

Small non-coding RNAs (sncRNAs) derived from tRNAs are known as tRNA-derived small RNAs (tsRNAs). These tsRNAs are further categorized into tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs), which play significant roles in the various molecular mechanisms underlying certain human diseases. However, the generation of tsRNAs and their potential roles during Dengue virus (DENV) infection is not yet known. Here, we performed small RNA sequencing to identify the generation and alterations in tsRNAs expression profiles of DENV-infected Huh7 cells. Upon DENV infection, tRNA fragmentation was found to be increased. We identified a significant number of differentially expressed tsRNAs during DENV infection. Interestingly, the 3′tRF population showed upregulation, while the i-tRF population exhibited downregulation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed to analyze the impact of differentially expressed tsRNAs on DENV pathogenesis. Our results suggest that differentially expressed tsRNAs are involved in transcriptional regulation via RNA polymerase II promoter and metabolic pathways. Overall, our study contributes significantly to our understanding of the roles played by tsRNAs in the complex dynamics of DENV infection. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer (PaCa) is one of the most intractable and fatal malignancies and is associated with the dysregulation of long noncoding RNAs (lncRNAs), which are a large class of noncoding RNAs larger than 200 nt that act as competing endogenous RNAs or sponges for miRNAs to induce tumour biological behaviours. However, their clinical value in treating pancreatic cancer has been poorly explained, but they are essential for improving the prognosis of PaCa patients. Methods: We analysed the plasma-derived exosomal lncRNA profiles of PaCa patients by using whole-transcriptome sequencing analysis and identified significantly differentially expressed lncRNAs, including LINC01268, LINC02802, AC124854.1, and AL132657.1. In the current study, the expression levels of four plasma-derived exosomal lncRNAs in PaCa plasma were validated via quantitative real-time polymerase chain reaction (qRT‒PCR). The relationship between the expression of the four lncRNAs and the clinicopathological features of patients with PaCa was also evaluated. Results: We demonstrated that exosomal LINC01268, LINC02802, AC124854.1 and AL132657.1 were highly expressed in PaCa plasma compared with those in normal controls; moreover, they were positively correlated with the serum expression of carbohydrate antigen 19–9 (CA19-9). The receiver operating characteristic curves (AUCs) of the four lncRNAs were 0.8421, 0.6544, 0.7190, and 0.6321, and the AUC value of the combination of the four exosomal lncRNAs increased to 0.8476, with a sensitivity of 0.72 and specificity of 0.89. These results suggested that the plasma-derived exosomal genes LINC01268, LINC02802, AC124854.1, and AL132657.1 may be novel diagnostic markers for PaCa. Conclusions: Our research demonstrated that the plasma-derived exosomal lncRNAs of PaCa patients are novel blood-based biomarkers of disease. [ABSTRACT FROM AUTHOR]

During the course of disease progression, changes in nucleic acid and non-nucleic acid marker contents can serve as indicators for disease diagnosis. The clustered regularly spaced short palindromic repeat (CRISPR)/Cas12a system, as a natural amplifier, has been widely exploited to construct amplified detection platforms for the detection of various analytes owing to its advantages of simplicity, high activity, and strong specificity. Nowadays, most of the focus is on the use of nucleic acid chains as response elements to activate Cas12a. Consequently, the development of switchable crRNA-based detection methods is urgently needed to expand such a switch's application in the quantification of non-nucleic acid analytes. A powerful and universal fluorescent sensing platform for the detection of non-nucleic acid analytes based on programmable switching of CRISPR/Cas12 activity via modulating crRNA conformation is proposed. In this system, two states, one in which the crRNA sequence is partially caged with a specially designed blocker DNA ("locked state") and the other where native crRNA is regained after the blocker DNA gets lost ("unlocked state"), are modulated through target recognition. When a target is present, the function of the CRISPR/Cas12a system can be rapidly reinstated by switching locking to unlocking to cleave fluorescent reporters for signal output. As a proof-of-concept example, it was demonstrated that this platform could detect three analytes, namely adenosine triphosphate (ATP), glutathione (GSH), and formamidopyrimidine-DNA glycosylase (Fpg), with high specificity and good sensitivity (LODATP = 0.046 μM, LODGSH = 0.1 μM, and LODFpg = 0.2 U mL−1). Moreover, by importing a programmable module, a set of CRISPR/Cas12 system-based logic gates was successfully constructed. Our constructed switchable crRNA-based sensing platform is universal, in which the target binding event is converted into the tunable trans-cleavage of ssDNA reporters via Cas12a, and thus, this platform could be expanded for detecting a wide spectrum of analytes by redesigning the corresponding sequence for target recognition. With its properties of universality, robustness, convenience, and programmability, the present platform indeed provides a useful and practical tool for molecular diagnosis and biomedicine research. [ABSTRACT FROM AUTHOR]

Recently, much interest has been raised for the characterization of signaling molecules carried by extracellular vesicles (EVs), which are particularly enriched in milk (mEVs). Such interest is linked to the capability of EVs to cross biological barriers, resist acidification in the gastric environment, and exert modulation of the immune system, mainly through their microRNA (miRNA) content. We characterized the small-RNA cargo of colostrum EVs (colosEVs) and mEVs from Italian Mediterranean buffalo through next generation sequencing. Colostrum (first milking after birth) and milk (day 50 of lactation) were sampled from seven subjects from five farms. ColosEVs and mEVs were subjected to morphological characterization, followed by high-depth sequencing of small RNA libraries produced from total RNA. The main difference was the amount of EV in the two samples, with colostrum showing 10 to 100-fold higher content than milk. For both matrices, miRNA was the most abundant RNA species (95% for colosEVs and 96% for mEVs) and three lists were identified: colosEV-specific, mEV-specific and shared most expressed. Gene ontology (GO) enrichment analysis on miRNA targets highlighted many terms related to the epigenetic, transcriptional and translational regulations across the three lists, with a higher number of enriched terms for colosEV-specific miRNAs. Terms specific to colosEVs were related to "cell differentiation" and "microvillus assembly", while for mEV "cardiac and blood vessel development" and "mitochondria" emergerd. Immune modulation terms were found for both sample-specific miRNAs. Overall, both matrices carry a similar molecular message in terms of biological processes potentially modulated into receiving cells, but there is significant difference in the abundance, with colostrum containing much more EVs than milk. Moreover, colosEVs carry molecules involved in signal transduction, cell cycle and immune response, as for mEVs and EVs of other previously characterized species, but with a special enrichment for miRNAs with epigenetic regulation capacities. These beneficial characteristics of colosEVs and mEVs are essential for the calf and could also be exploited for the therapeutic purposes in humans, although further studies are necessary to measure the sanitization treatment impact on EV conservation, especially in buffalo where milk is consumed almost exclusively after processing. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs), particles enriched in bioactive molecules like proteins, nucleic acids, and lipids, are crucial mediators of intercellular communication and play key roles in various physiological and pathological processes. EVs have been shown to be involved in ovarian follicular function and to be altered in two prevalent gynecological disorders; polycystic ovarian syndrome (PCOS) and endometriosis. Ovarian follicles are complex microenvironments where folliculogenesis takes place with well-orchestrated interactions between granulosa cells, oocytes, and their surrounding stromal cells. Recent research unveiled the presence of EVs, including exosomes and microvesicles, in the follicular fluid (FFEVs), which constitutes part of the developing oocyte's microenvironment. In the context of PCOS, a multifaceted endocrine, reproductive, and metabolic disorder, studies have explored the dysregulation of these FFEVs and their cargo. Nine PCOS studies were included in this review and two miRNAs were commonly reported in two different studies, miR-379 and miR-200, both known to play a role in female reproduction. Studies have also demonstrated the potential use of EVs as diagnostic tools and treatment options. Endometriosis, another prevalent gynecological disorder characterized by ectopic growth of endometrial-like tissue, has also been linked to aberrant EV signaling. EVs in the peritoneal fluid of women with endometriosis carry molecules that modulate the immune response and promote the establishment and maintenance of endometriosis lesions. EVs derived from endometriosis lesions, serum and peritoneal fluid obtained from patients with endometriosis showed no commonly reported biomolecules between the eleven reviewed studies. Importantly, circulating EVs have been shown to be potential biomarkers, also reflecting the severity of the pathology. Understanding the interplay of EVs within human ovarian follicles may provide valuable insights into the pathophysiology of both PCOS and endometriosis. Targeting EV-mediated communication may open avenues for novel diagnostic and therapeutic approaches for these common gynecological disorders. More research is essential to unravel the mechanisms underlying EV involvement in folliculogenesis and its dysregulation in PCOS and endometriosis, ultimately leading to more effective and personalized interventions. [ABSTRACT FROM AUTHOR]

Depression is a prevalent and intricate mental disorder. The involvement of small RNA molecules, such as microRNAs in the pathogenesis and neuronal mechanisms underlying the depression have been documented. Previous studies have demonstrated the involvement of microRNA-143-3p (miR-143-3p) in the process of fear memory and pathogenesis of ischemia; however, the relationship between miR-143-3p and depression remains poorly understood. Here we utilized two kinds of mouse models to investigate the role of miR-143-3p in the pathogenesis of depression. Our findings reveal that the expression of miR-143-3p is upregulated in the ventral hippocampus (VH) of mice subjected to chronic restraint stress (CRS) or acute Lipopolysaccharide (LPS) treatment. Inhibiting the expression of miR-143-3p in the VH effectively alleviates depressive-like behaviors in CRS and LPS-treated mice. Furthermore, we identify Lasp1 as one of the downstream target genes regulated by miR-143-3p. The miR-143-3p/Lasp1 axis primarily affects the occurrence of depressive-like behaviors in mice by modulating synapse numbers in the VH. Finally, miR-143-3p/Lasp1-induced F-actin change is responsible for the synaptic number variations in the VH. In conclusion, this study enhances our understanding of microRNA-mediated depression pathogenesis and provides novel prospects for developing therapeutic approaches for this intractable mood disorder. This study links miR-143-3p's role in the ventral hippocampus to depressive-like behaviors in mice, identifying Lasp1 as a target gene influencing synapses, hinting at a new axis for depression therapy. [ABSTRACT FROM AUTHOR]

The transition of fibroblasts to myofibroblasts (FMT) represents a pivotal process in wound healing, tissue repair, and fibrotic diseases. This intricate transformation involves dynamic changes in cellular morphology, gene expression, and extracellular matrix remodeling. While extensively studied at the molecular level, recent research has illuminated the regulatory roles of non-coding RNAs (ncRNAs) in orchestrating FMT. This review explores the emerging roles of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in regulating this intricate process. NcRNAs interface with key signaling pathways, transcription factors, and epigenetic mechanisms to fine-tune gene expression during FMT. Their functions are critical in maintaining tissue homeostasis, and disruptions in these regulatory networks have been linked to pathological fibrosis across various tissues. Understanding the dynamic roles of ncRNAs in FMT bears therapeutic promise. Targeting specific ncRNAs holds potential to mitigate exaggerated myofibroblast activation and tissue fibrosis. However, challenges in delivery and specificity of ncRNA-based therapies remain. In summary, ncRNAs emerge as integral regulators in the symphony of FMT, orchestrating the balance between quiescent fibroblasts and activated myofibroblasts. As research advances, these ncRNAs appear to be prospects for innovative therapeutic strategies, offering hope in taming the complexities of fibrosis and restoring tissue equilibrium. [ABSTRACT FROM AUTHOR]

The three most common kinds of urologic malignancies are prostate, bladder, and kidney cancer, which typically cause substantial morbidity and mortality. Early detection and effective treatment are essential due to their high fatality rates. As a result, there is an urgent need for innovative research to improve the clinical management of patients with urologic cancers. A type of small noncoding RNAs of 22 nucleotides, microRNAs (miRNAs) are well-known for their important roles in a variety of developmental processes. Among these, microRNA-21 (miR-21) stands out as a commonly studied miRNA with implications in tumorigenesis and cancer development, particularly in urological tumors. Recent research has shed light on the dysregulation of miR-21 in urological tumors, offering insights into its potential as a prognostic, diagnostic, and therapeutic tool. This review delves into the pathogenesis of miR-21 in prostate, bladder, and renal cancers, its utility as a cancer biomarker, and the therapeutic possibilities of targeting miR-21. [ABSTRACT FROM AUTHOR]

Plasmid-mediated conjugation is a common mechanism for most bacteria to transfer antibiotic resistance genes (ARGs). The conjugative transfer of ARGs is emerging as a major threat to human beings. Although several transfer-related factors are known to regulate this process, small RNAs (sRNAs)-based regulatory roles remain to be clarified. Here, the Hfq-binding sRNA GadY in donor strain Escherichia coli (E. coli) SM10lp was identified as a new regulator for bacterial conjugation. Two conjugation models established in our previous studies were used, which SM10λπ carrying a chromosomally integrated IncP-1α plasmid RP4 and a mobilizable plasmid pUCP24T served as donor cells, and P. aeruginosa PAO1 or E. coli EC600 as the recipients. GadY was found to promote SM10λπ-PAO1 conjugation by base-pairing with its target mRNA SdiA, an orphan LuxRtype receptor that responds to exogenous N-acylated homoserine lactones (AHLs). However, SM10λπ-EC600 conjugation was not affected due to EC600 lacking AHLs synthase. It indicates that the effects of GadY on conjugation depended on AHLs-SdiA signalling. Further study found GadY bound SdiA to negatively regulate the global RP4 repressors KorA and KorB. When under ciprofloxacin or levofloxacin treatment, GadY expression in donor strain was enhanced, and it positively regulated quinolone-induced SM10λπ-PAO1 conjugation. Thus, our study provides a novel role for sRNA GadY in regulating plasmid-mediated conjugation, which helps us better understand bacterial conjugation to counter antibiotic resistance. [ABSTRACT FROM AUTHOR]

microRNAs (miRNAs), tiny, non-coding RNA molecules, fine-tune the expression of target genes through interacting with mRNAs. These miRNAs are involved in a wide range of biological processes, encompassing cell division, death, blood cell production, and tumor development. When these miRNAs become dysfunctional, they can promote the invasion and spread of cancer cells in various human malignancies, including leukemia. Acute lymphoblastic leukemia (ALL), the preeminent malignancy affecting children, is a blood cancer marked by the uncontrollable growth of immature lymphoid cells that displace healthy blood precursors in the bone marrow. Despite a decline in ALL mortality rates over the past two decades, a significant proportion of deaths still results from a lack of effective diagnostic and prognostic markers that can guide treatment decisions and overcome drug resistance. The analysis of miRNA expression patterns in ALL could lead to more precise disease classification, earlier diagnosis, and better prognostic outcomes in the near future. The connection between miRNA dysfunction and the biology of ALL suggests that these molecules could represent promising therapeutic targets. Therefore, this review delves into the regulatory mechanisms of miRNAs in pediatric ALL, exploring how miRNA-based diagnostic, prognostic, and therapeutic strategies offer unique advantages and hold promise for clinical applications. [ABSTRACT FROM AUTHOR]

Introduction: Fusarium oxysporum is a significant soil-borne fungal pathogen that affects over 100 plant species, including crucial crops like tomatoes, bananas, cotton, cucumbers, and watermelons, leading to wilting, yellowing, growth inhibition, and ultimately plant death. The root rot disease of A. macrocephala, caused by F. oxysporum, is one of the most serious diseases in continuous cropping, which seriously affects its sustainable development. Methods: In this study, we explored the interaction between A. macrocephala and F. oxysporum through integrated small RNA (sRNA) and degradome sequencing to uncover the microRNA (miRNA)-mediated defense mechanisms. Results: We identified colonization of F. oxysporum in A. macrocephala roots on day 6. Nine sRNA samples were sequenced to examine the dynamic changes in miRNA expression in A. macrocephala infected by F. oxysporum at 0, 6, and 12 days after inoculation. Furthermore, we using degradome sequencing and quantitative real-time PCR (qRT-PCR), validated four miRNA/target regulatory units involved in A. macrocephala-F. oxysporum interactions. Discussion: This study provides new insights into the molecular mechanisms underlying A. macrocephala's early defense against F. oxysporum infection, suggesting directions for enhancing resistance against this pathogen. [ABSTRACT FROM AUTHOR]

T-box riboswitches are noncoding RNA elements involved in genetic regulation of most Gram-positive bacteria. They regulate amino acid metabolism by assessing the aminoacylation status of tRNA, subsequently affecting the transcription or translation of downstream amino acid metabolism-related genes. Here we present single-molecule FRET studies of the Mycobacterium tuberculosis IleS T-box riboswitch, a paradigmatic translational T-box. Results support a two-step binding model, where the tRNA anticodon is recognized first, followed by interactions with the NCCA sequence. Furthermore, after anticodon recognition, tRNA can transiently dock into the discriminator domain even in the absence of the tRNA NCCA-discriminator interactions. Establishment of the NCCA-discriminator interactions significantly stabilizes the fully bound state. Collectively, the data suggest high conformational flexibility in translational T-box riboswitches; and supports a conformational selection model for NCCA recognition. These findings provide a kinetic framework to understand how specific RNA elements underpin the binding affinity and specificity required for gene regulation. smFRET studies of the M. tuberculosis IleS translational T-box riboswitch support a two-step tRNA binding mechanism and the use of conformational selection for tRNA 3' end recognition, which is distinct from the one used by transcriptional T-boxes. [ABSTRACT FROM AUTHOR]

The development of flowers in soybean (Glycine max) is essential for determining the yield potential of the plant. Gene silencing pathways are involved in modulating flower development, but their full elucidation is still incomplete. Here, we conducted a forward genetic screen and identified an abnormal flower mutant, deformed floral bud1‐1 (Gmdfb1‐1), in soybean. We mapped and identified the causal gene, which encodes a member of the armadillo (ARM)‐repeat superfamily. Using small RNA sequencing (sRNA‐seq), we found an abnormal accumulation of small interfering RNAs (siRNAs) and microRNA (miRNAs) in the Gmdfb1 mutants. We further demonstrated that GmDFB1 interacts with the RNA exosome cofactor SUPER KILLER7 (GmSKI7). Additionally, GmDFB1 interacts with the PIWI domain of ARGONAUTE 1 (GmAGO1) to inhibit the cleavage efficiency on the target genes of sRNAs. The enhanced gene silencing mediated by siRNA and miRNA in the Gmdfb1 mutants leads to the downregulation of their target genes associated with flower development. This study revealed the crucial role of GmDFB1 in regulating floral organ identity in soybean probably by participating in two distinct gene silencing pathways. [ABSTRACT FROM AUTHOR]

The Sapindaceae family, encompassing a wide range of plant forms such as herbs, vines, shrubs, and trees, is widely distributed across tropical and subtropical regions. This family includes economically important crops like litchi, longan, rambutan, and ackee. With the wide application of genomic technologies in recent years, several Sapindaceae plant genomes have been decoded, leading to an accumulation of substantial omics data in this field. This surge in data highlights the pressing need for a unified genomic data center capable of storing, sharing, and analyzing these data. Here, we introduced SapBase, that is, the Sapindaceae Genome Database. SapBase houses seven published plant genomes alongside their corresponding gene structure and functional annotations, small RNA annotations, gene expression profiles, gene pathways, and synteny block information. It offers user‐friendly features for gene information mining, co‐expression analysis, and inter‐species comparative genomic analysis. Furthermore, we showcased SapBase's extensive capacities through a detailed bioinformatic analysis of a MYB gene in litchi. Thus, SapBase could serve as an integrative genomic resource and analysis platform for the scientific exploration of Sapinaceae species and their comparative studies with other plants. [ABSTRACT FROM AUTHOR]

Noncoding RNA (NcRNA)-protein interactions (NPIs) play fundamentally important roles in carrying out cellular activities. Although various predictors based on molecular features and graphs have been published to boost the identification of NPIs, most of them often ignore the information between known NPIs or exhibit insufficient learning ability from graphs, posing a significant challenge in effectively identifying NPIs. To develop a more reliable and accurate predictor for NPIs, in this article, we propose NPI-DCGNN, an end-to-end NPI predictor based on a dual-channel graph neural network (DCGNN). NPI-DCGNN initially treats the known NPIs as an ncRNA-protein bipartite graph. Subsequently, for each ncRNA-protein pair, NPI-DCGNN extracts two local subgraphs centered around the ncRNA and protein, respectively, from the bipartite graph. After that, it utilizes a dual-channel graph representation learning layer based on GNN to generate high-level feature representations for the ncRNA-protein pair. Finally, it employs a fully connected network and output layer to predict whether an interaction exists between the pair of ncRNA and protein. Experimental results on four experimentally validated datasets demonstrate that NPI-DCGNN outperforms several state-of-the-art NPI predictors. Our case studies on the NPInter database further demonstrate the prediction power of NPI-DCGNN in predicting NPIs. With the availability of the source codes (https://github.com/zhangxin11111/NPI-DCGNN), we anticipate that NPI-DCGNN could facilitate the studies of ncRNA interactome by providing highly reliable NPI candidates for further experimental validation. [ABSTRACT FROM AUTHOR]

Extranuclear localization of long noncoding RNAs (lncRNAs) is poorly understood. Based on machine learning evaluations, we propose a lncRNA-mitochondrial interaction pathway where polynucleotide phosphorylase (PNPase), through domains that provide specificity for primary sequence and secondary structure, binds nuclear-encoded lncRNAs to facilitate mitochondrial import. Using FVB/NJ mouse and human cardiac tissues, RNA from isolated subcellular compartments (cytoplasmic and mitochondrial) and cross-linked immunoprecipitate (CLIP) with PNPase within the mitochondrion were sequenced on the Illumina HiSeq and MiSeq, respectively. lncRNA sequence and structure were evaluated through supervised [classification and regression trees (CART) and support vector machines (SVM)] machine learning algorithms. In HL-1 cells, quantitative PCR of PNPase CLIP knockout mutants (KH and S1) was performed. In vitro fluorescence assays assessed PNPase RNA binding capacity and verified with PNPase CLIP. One hundred twelve (mouse) and 1,548 (human) lncRNAs were identified in the mitochondrion with Malat1 being the most abundant. Most noncoding RNAs binding PNPase were lncRNAs, including Malat1. lncRNA fragments bound to PNPase compared against randomly generated sequences of similar length showed stratification with SVM and CART algorithms. The lncRNAs bound to PNPase were used to create a criterion for binding, with experimental validation revealing increased binding affinity of RNA designed to bind PNPase compared to control RNA. The binding of lncRNAs to PNPase was decreased through the knockout of RNA binding domains KH and S1. In conclusion, sequence and secondary structural features identified by machine learning enhance the likelihood of nuclear-encoded lncRNAs binding to PNPase and undergoing import into the mitochondrion. NEW & NOTEWORTHY: Long noncoding RNAs (lncRNAs) are relatively novel RNAs with increasingly prominent roles in regulating genetic expression, mainly in the nucleus but more recently in regions such as the mitochondrion. This study explores how lncRNAs interact with polynucleotide phosphorylase (PNPase), a protein that regulates RNA import into the mitochondrion. Machine learning identified several RNA structural features that improved lncRNA binding to PNPase, which may be useful in targeting RNA therapeutics to the mitochondrion. [ABSTRACT FROM AUTHOR]

The tumor suppressor p14/19ARF regulates ribosomal RNA (rRNA) synthesis by controlling the nucleolar localization of Transcription Termination Factor 1 (TTF1). However, the role played by TTF1 in regulating the rRNA genes and in potentially controlling growth has remained unclear. We now show that TTF1 expression regulates cell growth by determining the cellular complement of ribosomes. Unexpectedly, it achieves this by acting as a "roadblock" to synthesis of the noncoding LncRNA and pRNA that we show are generated from the "Spacer Promoter" duplications present upstream of the 47S pre‐rRNA promoter on the mouse and human ribosomal RNA genes. Unexpectedly, the endogenous generation of these noncoding RNAs does not induce CpG methylation or gene silencing. Rather, it acts in cis to suppress 47S preinitiation complex formation and hence de novo pre‐rRNA synthesis by a mechanism reminiscent of promoter interference or occlusion. Taken together, our data delineate a pathway from p19ARF to cell growth suppression via the regulation of ribosome biogenesis by noncoding RNAs and validate a key cellular growth law in mammalian cells. [ABSTRACT FROM AUTHOR]

Objective: Kidney renal clear cell carcinoma (KIRC, ccRCC) is the most common type of renal cancer with high recurrence and mortality. It has long been recognized that Antizyme inhibitor 1 (AZIN1) serves as a pro‐oncogenic molecule in multiple cancers. However, the clinicopathological features of AZIN1 in KIRC remain unexplored. Materials and Methods: The Cancer Genome Atlas (TCGA, TIMER, and GEPIA) were employed for pan‐cancer expression and survival analysis of AZIN1, indicating the unique anti‐tumor role of AZIN1 in KIRC. The expression and clinical characteristics of AZIN1 in KIRC were further proven via Human Protein Atlas and TCGA. single‐sample GSEA was employed to investigate the immune infiltration of AZIN1. Then the downstream pathways were illustrated via the LinkedOmics, Metascape, and Cytoscape databases. The possible upper regulating noncoding RNAs (ncRNAs) were analyzed from five programs‐TargetScan, StarBase, miRanda, PITA, and miRmap. Results: AZIN1 is downregulated in KIRC patients. Lower levels of AZIN1 were linked with unfavorable outcomes in KIRC patients. The AZIN1 expression was positively related to immune cell infiltration in KIRC. We also elucidated a possible upstream regulatory ncRNA of AZIN1 in KIRC namely STK4‐AS1/AC068338.2‐miR‐106b‐5p‐AZIN1 axis as well as the downstream signaling pathways. Conclusion: This study illustrated the unique anti‐tumor role of AZIN1 in KIRC and provided potential value for guiding immunotherapy and targeted therapy. [ABSTRACT FROM AUTHOR]

Nonagenarians and centenarians serve as successful examples of aging and extended longevity, showcasing robust regulation of biological mechanisms and homeostasis. Given that human longevity is a complex field of study that navigates molecular and biological mechanisms influencing aging, we hypothesized that microRNAs, a class of small noncoding RNAs implicated in regulating gene expression at the post‐transcriptional level, are differentially regulated in the circulatory system of young, middle‐aged, and nonagenarian individuals. We sequenced circulating microRNAs in Okinawan males and females <40, 50–80, and >90 years of age accounting for FOXO3 genetic variations of single nucleotide polymorphism (SNP) rs2802292 (TT ‐ common vs. GT ‐ longevity) and validated the findings through RT‐qPCR. We report five microRNAs exclusively upregulated in both male and female nonagenarians with the longevity genotype, play predictive functional roles in TGF‐β, FoxO, AMPK, Pi3K‐Akt, and MAPK signaling pathways. Our findings suggest that these microRNAs upregulated in nonagenarians may provide novel insight into enhanced lifespan and health span. This discovery warrants further exploration into their roles in human aging and longevity. [ABSTRACT FROM AUTHOR]

Non-coding RNA has many types which has rich functions and plays an important role in the study of basic molecular mechanisms. Many non-coding RNA have important implications for pluripotent stem cells and embryonic stem cells. It has been found to affect the self-renewal and osteogenesis of many types of stem cells. They have also been found to regulate stem cell proliferation and induct bone differentiation. Periodontal ligament stem cells are essential for the regeneration of periodontal tissue. In recent years, in the field of stomatology, studies have found that many non-coding RNA also have significant regulatory effects on the proliferation and differentiation of periodontal stem cells and may become potential therapeutic targets for many common periodontal diseases such as periodontitis, bone/tooth/soft tissue loss and orthodontic treatment. Therefore, we summarized the current research status of non-coding RNA in the field of molecular mechanism of periodontal ligament stem cells and prospected its future progress. [ABSTRACT FROM AUTHOR]

The post-transcriptional control of gene expression is a complex and evolving field in adipocyte biology, with the premise that the delivery of microRNA (miRNA) species to the obese adipose tissue may facilitate weight loss. Cells shed extracellular vesicles (EVs) that may deliver miRNAs as intercellular messengers. However, we know little about the miRNA profile of EVs secreted by adipocytes during postnatal development. Here, we defined the miRNA cargo of EVs secreted by mouse adipocytes in two distinct phases of development: on postnatal day 6, when adipocytes are lipolytic and thermogenic, and on postnatal day 56, when adipocytes have active lipogenesis. EVs were collected from cell culture supernatants, and their miRNA profile was defined by small RNA sequencing. The most abundant miRNA of mouse adipocyte-derived EVs was mmu-miR-148a-3p. Adipocyte EVs on postnatal day 6 were hallmarked with mmu-miR-98-5p, and some miRNAs were specific to this developmental stage, such as mmu-miR-466i-5p and 12 novel miRNAs. Adipocytes on postnatal day 56 secreted mmu-miR-365-3p, and 16 miRNAs were specific to this developmental stage. The miRNA cargo of adipocyte EVs targeted gene networks of cell proliferation, insulin signaling, interferon response, thermogenesis, and lipogenesis. We provided here a database of miRNAs secreted by developing mouse adipocytes, which may be a tool for further studies on the regulation of gene networks that control mouse adipocyte development. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer-related death worldwide. Due to the high mortality rate in HCC patients, discovering and developing novel systemic treatment options for HCC is a vital unmet medical need. Among the numerous molecular alterations in HCCs, microRNAs (miRNAs) have been increasingly recognised to play critical roles in hepatocarcinogenesis. We and others have recently revealed that members of the microRNA-181 (miR-181) family were up-regulated in some, though not all, human cirrhotic and HCC tissues—this up-regulation induced epithelial–mesenchymal transition (EMT) in hepatocytes and tumour cells, promoting HCC progression. MiR-181s play crucial roles in governing the fate and function of various cells, such as endothelial cells, immune cells, and tumour cells. Previous reviews have extensively covered these aspects in detail. This review aims to give some insights into miR-181s, their targets and roles in modulating signal transduction pathways, factors regulating miR-181 expression and function, and their roles in HCC. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small, non-coding RNAs that play a crucial role in regulating gene expression. Dysfunction in miRNAs can lead to various diseases, including cancers, neurological disorders, and cardiovascular conditions. To date, approximately 2000 miRNAs have been identified in humans. These small molecules have shown promise as disease biomarkers and potential therapeutic targets. Therefore, identifying miRNA biomarkers for diseases and developing effective miRNA drug delivery systems are essential. Nanotechnology offers promising new approaches to addressing scientific and medical challenges. Traditional miRNA detection methods include next-generation sequencing, microarrays, Northern blotting, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Nanotechnology can serve as an effective alternative to Northern blotting and RT-qPCR for miRNA detection. Moreover, nanomaterials exhibit unique properties that differ from larger counterparts, enabling miRNA therapeutics to more effectively enter target cells, reduce degradation in the bloodstream, and be released in specific tissues or cells. This paper reviews the application of nanotechnology in miRNA detection and drug delivery systems. Given that miRNA therapeutics are still in the developing stages, nanotechnology holds great promise for accelerating miRNA therapeutics development. [ABSTRACT FROM AUTHOR]

Peripheral artery disease (PAD), a significant health burden worldwide, affects lower extremities due to atherosclerosis in peripheral vessels. Although the mechanisms of PAD have been well studied, the molecular milieu of the plaques localized within peripheral arteries are not well understood. Thus, to identify PAD-lesion-specific gene expression profiles precluding genetic, environmental, and dietary biases, we studied the transcriptomic profile of nine plaque tissues normalized to non-plaque tissues from the same donors. A total of 296 upregulated genes, 274 downregulated genes, and 186 non-coding RNAs were identified. STAG1, SPCC3, FOXQ1, and E2F3 were key downregulated genes, and CD93 was the top upregulated gene. Autophagosome assembly, cellular response to UV, cytoskeletal organization, TCR signaling, and phosphatase activity were the key dysregulated pathways identified. Telomerase regulation and autophagy were identified as novel interacting pathways using network analysis. The plaque tissue was predominantly composed of immune cells and dedifferentiated cell populations indicated by cell-specific marker-imputed gene expression analysis. This study identifies novel genes, non-coding RNAs, associated regulatory pathways, and the cell composition of the plaque tissue in PAD patients. The autophagy and immunoregulatory genes may drive novel mechanisms, resulting in atheroma. These novel interacting networks and genes have potential for PAD-specific therapeutic applications. [ABSTRACT FROM AUTHOR]

Simple Summary: In our study, we aimed to understand the role of non-coding RNA in egg production by analyzing the transcriptome of chickens. We collected tissues from both low-yielding and high-yielding Bian chickens, focusing on the hypothalamus, pituitary, and ovaries, which are key to reproduction. Using advanced sequencing technology, we identified circular RNAs that differed between high and low egg producers. Our results revealed that these circRNAs are involved in crucial processes like cell development, nervous system function, and protein regulation. We also discovered networks of RNA interactions that may influence egg production. These findings enhance our understanding of the genetic factors that control egg production, potentially leading to improved breeding strategies for better poultry production and health, benefiting farmers and consumers alike. The hypothalamic–pituitary–ovarian (HPO) axis plays a pivotal role in the regulation of egg production in chickens. In addition to the traditional understanding of the HPO axis, emerging research highlights the significant role of circRNAs in modulating the functions of this axis. In the study, we collected hypothalamus, pituitary, and ovarian tissues from low-yielding and high-yielding Bian chickens for transcriptome sequencing. We identified 339, 339, and 287 differentially expressed (DE) circRNAs with p_value < 0.05 and |log2 (fold change)| ≥ 1 in hypothalamus, pituitary, and ovarian tissues. The Gene Ontology (GO) enrichment analysis for the source genes of DE circRNAs has yielded multiple biological process (BP) entries related to cell development, the nervous system, and proteins, including cellular component morphogenesis, cell morphogenesis, nervous system development, neurogenesis, protein modification process, and protein metabolic process. In the top 30 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we observed the enrichment of the GnRH signaling pathway in both the hypothalamus and the pituitary, solely identified the GnRH secretion pathway in the pituitary, and discovered the pathway of oocyte meiosis in the ovary. Furthermore, given that circRNA primarily functions through the ceRNA mechanism, we constructed ceRNA regulatory networks with DE circRNAs originating from the GnRH signaling pathway, GnRH secretion, ovarian steroidogenesis, steroid hormone biosynthesis, and the estrogen signaling pathway. Finally, several important ceRNA regulatory networks related to reproduction were discovered, such as novel_circ_003662-gga-let-7b/miR-148a-3p/miR-146a-5p/miR-146b-5p and novel_circ_003538-gga-miR-7464-3p-SLC19A1. This study will contribute to advancements in understanding the involvement of circRNAs in the HPO axis, potentially leading to innovations in improving egg production and poultry health. [ABSTRACT FROM AUTHOR]

Simple Summary: Skeletal muscle fibers, the smallest functional unit of skeletal muscle, directly affect the normal growth and development of animal muscles and the quality of carcass muscle after slaughter. Individual characteristics, feeding, and genetic factors influence the heterogeneity of muscle fibers in livestock. Notably, genetic factors rapidly and efficiently improve the proportion and conversion of animal muscle fibers with the development of omics technology and sequencing technology. Therefore, only a global approach including all parameters seems to be pertinent to understand the relationships among the characteristics of myofibers, growth performance, and meat quality. The type of muscle fiber plays a crucial role in the growth, development, and dynamic plasticity of animals' skeletal muscle. Additionally, it is a primary determinant of the quality of both fresh and processed meat. Therefore, understanding the regulatory factors that contribute to muscle fibers' heterogeneity is of paramount importance. Recent advances in sequencing and omics technologies have enabled comprehensive cross-verification of research on the factors affecting the types of muscle fiber across multiple levels, including the genome, transcriptome, proteome, and metabolome. These advancements have facilitated deeper exploration into the related biological questions. This review focused on the impact of individual characteristics, feeding patterns, and genetic regulation on the proportion and interconversion of different muscle fibers. The findings indicated that individual characteristics and feeding patterns significantly influence the type of muscle fiber, which can effectively enhance the type and distribution of muscle fibers in livestock. Furthermore, non-coding RNA, genes and signaling pathways between complicated regulatory mechanisms and interactions have a certain degree of impact on muscle fibers' heterogeneity. This, in turn, changes muscle fiber profile in living animals through genetic selection or environmental factors, and has the potential to modulate the quality of fresh meat. Collectively, we briefly reviewed the structure of skeletal muscle tissue and then attempted to review the inevitable connection between the quality of fresh meat and the type of muscle fiber, with particular attention to potential events involved in regulating muscle fibers' heterogeneity. [ABSTRACT FROM AUTHOR]

Summary: Multiple myeloma (MM) is an incurable plasma cell cancer in the bone marrow. Immunomodulatory drugs, such as lenalidomide (LEN) and pomalidomide, are backbone agents in MM treatment, and LEN resistance is commonly seen in the MM clinic. In this study, we presented that heterogeneous nuclear ribonucleoprotein U (hnRNPU) affected MM resistance to LEN via the regulation of target mRNA translation. hnRNPULow MM cells exhibited upregulated CRBN and IKZF1 proteins, stringent IKZF1/3 protein degradation upon LEN addition and increased sensitivity to LEN. RNA pulldown assays and RNA electrophoretic mobility shift assays revealed that hnRNPU bound to the 3′‐untranslated region of CRBN and IKZF1 mRNA. A sucrose gradient assay suggested that hnRNPU specifically regulated CRBN and IKZF1 mRNA translation. The competition of hnRNPU binding to its target mRNAs by small RNAs with hnRNPU‐binding sites restored MM sensitivity to LEN. hnRNPU function in vivo was confirmed in an immunocompetent MM mouse model constructed by the inoculation of Crbn‐humanized murine 5TGM1 cells into CrbnI391V/+ mice. Overall, this study suggests a novel mechanism of LEN sensitivity in which hnRNPU represses CRBN and IKZF1 mRNA translation. [ABSTRACT FROM AUTHOR]