Conditional deletion of miR-204 and miR-211 in murine retinal pigment epithelium results in retinal degeneration.

MicroRNAs (miRs) are short, evolutionarily conserved noncoding RNAs that canonically downregulate expression of target genes. The miR family composed of miR-204 and miR-211 is among the most highly expressed miRs in the retinal pigment epithelium (RPE) in both mouse and human and also retains high sequence identity. To assess the role of this miR family in the developed mouse eye, we generated two floxed conditional KO mouse lines crossed to the RPE65-ERT2-Cre driver mouse line to perform an RPE-specific conditional KO of this miR family in adult mice. After Cre-mediated deletion, we observed retinal structural changes by optical coherence tomography; dysfunction and loss of photoreceptors by retinal imaging; and retinal inflammation marked by subretinal infiltration of immune cells by imaging and immunostaining. Single-cell RNA sequencing of diseased RPE and retinas showed potential miR-regulated target genes, as well as changes in noncoding RNAs in the RPE, rod photoreceptors, and Müller glia. This work thus highlights the role of miR-204 and miR-211 in maintaining RPE function and how the loss of miRs in the RPE exerts effects on the neural retina, leading to inflammation and retinal degeneration.

Tissue-specific transcriptional programming of macrophages controls the microRNA transcriptome targeting multiple functional pathways.

Recent interest in the biology and function of peritoneal tissue resident macrophages (pMΦ) has led to a better understanding of their cellular origin, programming, and renewal. The programming of pMΦ is dependent on microenvironmental cues and tissue-specific transcription factors, including GATA6. However, the contribution of microRNAs remains poorly defined. We conducted a detailed analysis of the impact of GATA6 deficiency on microRNA expression in mouse pMΦ. Our data suggest that for many of the pMΦ, microRNA composition may be established during tissue specialization and that the effect of GATA6 knockout is largely unable to be rescued in the adult by exogenous GATA6. The data are consistent with GATA6 modulating the expression pattern of specific microRNAs, directly or indirectly, and including miR-146a, miR-223, and miR-203 established by the lineage-determining transcription factor PU.1, to achieve a differentiated pMΦ phenotype. Lastly, we showed a significant dysregulation of miR-708 in pMΦ in the absence of GATA6 during homeostasis and in response to LPS/IFN-γ stimulation. Overexpression of miR-708 in mouse pMΦ in vivo altered 167 mRNA species demonstrating functional downregulation of predicted targets, including cell immune responses and cell cycle regulation. In conclusion, we demonstrate dependence of the microRNA transcriptome on tissue-specific programming of tissue macrophages as exemplified by the role of GATA6 in pMΦ specialization.

Regulatory effects of microRNAs on monocytic HLA-DR surface expression.

Decreased monocytic HLA-DR expression is the most studied biomarker of immune competency in critically ill and autoimmune disease patients. However, the underlying regulatory mechanisms remain largely unknown. One probable HLA-DR dysregulation is through microRNAs. The aim of this study was to investigate the effects of specific microRNAs on HLA-DR expression in human monocytic cells. Four up- and four down-HLA-DR-regulating microRNAs were identified, with hsa-miR-let-7f-2-3p showing the most significant upregulation and hsa-miR-567 and hsa-miR-3972 downregulation. Anti-inflammatory glucocorticoid medication Dexamethasone-decreased HLA-DR was significantly restored by hsa-miR-let-7f-2-3p and hsa-miR-5693. Contrarily, proinflammatory cytokines IFN-γ and TNF-α-increased HLA-DR were significantly reversed by hsa-miR-567. Clinically, paired plasma samples from patients before and one day after cardiac surgery revealed up-regulated expression of hsa-miR-5693, hsa-miR-567, and hsa-miR-3972, following the major surgical trauma. In silico approaches were applied for functional microRNA-mRNA interaction prediction and candidate target genes were confirmed by qPCR analysis. In conclusion, novel monocytic HLA-DR microRNA modulators were identified and validated in vitro. Moreover, both the interaction between the microRNAs and anti- and proinflammatory molecules and the up-regulated microRNAs identified in cardiac surgery highlight the potential clinical relevance of our findings.

Extraction of microRNA-target interaction sentences from biomedical literature by deep learning approach.

MicroRNA (miRNA)-target interaction (MTI) plays a substantial role in various cell activities, molecular regulations and physiological processes. Published biomedical literature is the carrier of high-confidence MTI knowledge. However, digging out this knowledge in an efficient manner from large-scale published articles remains challenging. To address this issue, we were motivated to construct a deep learning-based model. We applied the pre-trained language models to biomedical text to obtain the representation, and subsequently fed them into a deep neural network with gate mechanism layers and a fully connected layer for the extraction of MTI information sentences. Performances of the proposed models were evaluated using two datasets constructed on the basis of text data obtained from miRTarBase. The validation and test results revealed that incorporating both PubMedBERT and SciBERT for sentence level encoding with the long short-term memory (LSTM)-based deep neural network can yield an outstanding performance, with both F1 and accuracy being higher than 80% on validation data and test data. Additionally, the proposed deep learning method outperformed the following machine learning methods: random forest, support vector machine, logistic regression and bidirectional LSTM. This work would greatly facilitate studies on MTI analysis and regulations. It is anticipated that this work can assist in large-scale screening of miRNAs, thereby revealing their functional roles in various diseases, which is important for the development of highly specific drugs with fewer side effects. Source code and corpus are publicly available at https://github.com/qi29.

Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity.

Directly reprogramming fibroblasts into cardiomyocytes improves cardiac function in the infarcted heart. However, the low efficacy of this approach hinders clinical applications. Unlike the adult mammalian heart, the neonatal heart has an intrinsic regenerative capacity. Consequently, we hypothesized that birth imposes fundamental changes in cardiac fibroblasts which limit their regenerative capabilities. In support, we found that reprogramming efficacy in vitro was markedly lower with fibroblasts derived from adult mice versus those derived from neonatal mice. Notably, fibroblasts derived from adult mice expressed significantly higher levels of pro-angiogenic genes. Moreover, under conditions that promote angiogenesis, only fibroblasts derived from adult mice differentiated into tube-like structures. Targeted knockdown screening studies suggested a possible role for the transcription factor Epas1. Epas1 expression was higher in fibroblasts derived from adult mice, and Epas1 knockdown improved reprogramming efficacy in cultured adult cardiac fibroblasts. Promoter activity assays indicated that Epas1 functions as both a transcription repressor and an activator, inhibiting cardiomyocyte genes while activating angiogenic genes. Finally, the addition of an Epas1 targeting siRNA to the reprogramming cocktail markedly improved reprogramming efficacy in vivo with both the number of reprogramming events and cardiac function being markedly improved. Collectively, our results highlight differences between neonatal and adult cardiac fibroblasts and the dual transcriptional activities of Epas1 related to reprogramming efficacy.

A decade of dinoflagellate genomics illuminating an enigmatic eukaryote cell.

Dinoflagellates are a remarkable group of protists, not only for their association with harmful algal blooms and coral reefs but also for their numerous characteristics deviating from the rules of eukaryotic biology. Genome research on dinoflagellates has lagged due to their immense genome sizes in most species (~ 1-250 Gbp). Nevertheless, the last decade marked a fruitful era of dinoflagellate genomics, with 27 genomes sequenced and many insights attained. This review aims to synthesize information from these genomes, along with other omic data, to reflect on where we are now in understanding dinoflagellates and where we are heading in the future. The most notable insights from the decade-long genomics work include: (1) dinoflagellate genomes have been expanded in multiple times independently, probably by a combination of rampant retroposition, accumulation of repetitive DNA, and genome duplication; (2) Symbiodiniacean genomes are highly divergent, but share about 3,445 core unigenes concentrated in 219 KEGG pathways; (3) Most dinoflagellate genes are encoded unidirectionally and are not intron-poor; (4) The dinoflagellate nucleus has undergone extreme evolutionary changes, including complete or nearly complete loss of nucleosome and histone H1, and acquisition of dinoflagellate viral nuclear protein (DVNP); (5) Major basic nuclear protein (MBNP), histone-like protein (HLP), and bacterial HU-like protein (HCc) belong to the same protein family, and MBNP can be the unifying name; (6) Dinoflagellate gene expression is regulated by poorly understood mechanisms, but microRNA and other epigenetic mechanisms are likely important; (7) Over 50% of dinoflagellate genes are "dark" and their functions remain to be deciphered using functional genetics; (8) Initial insights into the genomic basis of parasitism and mutualism have emerged. The review then highlights functionally unique and interesting genes. Future research needs to obtain a finished genome, tackle large genomes, characterize the unknown genes, and develop a quantitative molecular ecological model for addressing ecological questions.

Integrated analysis of microRNA and messenger RNA expression profiles reveals functional microRNA in infectious bovine rhinotracheitis virus-induced mitochondrial damage in Madin-Darby bovine kidney cells.

BACKGROUND: Studies have confirmed that Infectious bovine rhinotracheitis virus (IBRV) infection induces mitochondrial damage. MicroRNAs (miRNAs) are a class of noncoding RNA molecules, which are involved in various biological processes and pathological changes associated with mitochondrial damage. It is currently unclear whether miRNAs participate in IBRV-induced mitochondrial damage in Madin-Darby bovine kidney (MDBK) cells. RESULTS: In the present study, we used high-throughput sequencing technology, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to screen for mitochondria-related miRNAs and messenger RNAs (mRNAs). In total, 279 differentially expressed miRNAs and 832 differentially expressed mRNAs were identified in 6 hours (IBRV1) versus 24 hours (IBRV2) after IBRV infection in MDBK cells. GO and KEGG enrichment analysis revealed that 42 differentially expressed mRNAs and 348 target genes of differentially expressed miRNAs were correlated with mitochondrial damage, and the miRNA-mitochondria-related target genes regulatory network was constructed to elucidate their potential regulatory relationships. Among the 10 differentially expressed miRNAs, 8 showed expression patterns consistent with the high-throughput sequencing results. Functional validation results showed that overexpression of miR-10a and miR-182 aggravated mitochondrial damage, while inhibition of miR-10a and miR-182 alleviated mitochondrial damage. CONCLUSIONS: This study not only revealed the expression changes of miRNAs and mRNAs in IBRV-infected MDBK cells, but also revealed possible biological regulatory relationship between them. MiR-10a and miR-182 may have the potential to be developed as biomarkers for the diagnosis and treatment of IBRV. Together, Together, these data and analyses provide additional insights into the roles of miRNA and mRNA in IBRV-induced mitochondria damage.

Perturbation of periodic spot-generation balance leads to diversified pigmentation patterning of harlequin Phalaenopsis orchids: in silico prediction.

BACKGROUND: A retrotransposon HORT1 in the promoter of the anthocyanin activator gene PeMYB11, microRNA858 (miR858) that targets PeMYB11, and a repressor PeMYBx have been implicated in pigmentation patterning diversity of harlequin Phalaenopsis orchids. However, the interrelationship among them remains to be elucidated. RESULTS: To understand how these factors interact to generate anthocyanin spots in Phalaenopsis, we successfully developed a mathematical model based on the known reaction-diffusion system to simulate their interplay and refined the conceptual biological model. Intriguingly, the expression of both PeMYBx and PeMYB11 were in phase for purple spot formation, even though they showed adverse effects on anthocyanin accumulations. An increase in the self-activation rate of PeMYB11 resulted in the increased size of purple spots, but no effects on spot fusion. Decreased degradation rate of miR858 in the purple regions, led to disruption of the formation of spotted pigmentation patterning and a full-red pigmentation pattern. Significantly, the reduced miR858 level promotes the fusion of large dark purple dots induced by the solo-LTR of HORT1, eventually generating the purple patches. In addition, the spatially heterogeneous insertion of HORT1 caused by the remnant solo-LTR of HORT1 derived from random homologous unequal recombination of HORT1 in individual cells of floral organs could explain the diverse pigmentation patterning of harlequin Phalaenopsis. CONCLUSIONS: This devised model explains how HORT1 and miR858 regulate the formation of the pigmentation patterning and holds great promise for developing efficient and innovative approaches to breeding harlequin Phalaenopsis orchids.

Target recycle initiated entropy driven assembly strategy for sensitive, enzyme-free, and portable miRNA detection.

MicroRNA (miRNA) is a pivotal biomarker in the diagnosis of various cancers, including bladder cancer (BCa). Despite their significance, the low abundance of miRNA presents a substantial challenge for sensitive and reliable detection. We introduce an innovative, highly sensitive assay for miRNA expression quantification that is both enzyme-free and portable. This method leverages the synergy of target recycling and entropy-driven assembly (EDA) for enhanced sensitivity and specificity. The proposed method possesses several advantages, including i) dual signal amplification through target recycling and EDA, which significantly boosts sensitivity with a lower limit of detection of 2.54 fM; ii) elimination of enzyme requirements, resulting in a cost-effective and stable signal amplification process; and iii) utilization of a personal glucose meter (PGM) for signal recording, rendering the method portable and adaptable to diverse settings. In summary, this PGM-based approach holds promising potential for clinical molecular diagnostics, offering a practical and efficient solution for miRNA analysis in cancer detection.

MicroRNA sequencing analysis reveals immune responses in hepatopancreas of Fenneropenaeus penicillatus under white spot syndrome virus infection.

White Spot Disease is one of the most harmful diseases of the red tail shrimp, which can cause devastating economic losses due to the highest mortality up to 100% within a few days. MicroRNAs (miRNAs) are large class of small noncoding RNAs with the ability to post-transcriptionally repress the translation of target mRNAs. MiRNAs are considered to have a significant role in the innate immune response of crustaceans, particularly in relation to antiviral defense mechanisms. Numerous crustacean miRNAs have been verified to be required in host immune defense against viral infection, however, till present, the miRNAs functions of F. penicillatus defense WSSV infection have not been studied yet. Here in this study, for the first time, miRNAs involved in the F. penicillatus immune defense against WSSV infection were identified using high-throughput sequencing platform. A total of 432 miRNAs were obtained including 402 conserved miRNAs and 30 novel predicted miRNAs. Comparative analysis between the WSSV-challenged group and the control group revealed differential expression of 159 microRNAs in response to WSSV infection. Among these, 48 were up-regulated and 111 were down-regulated. Ten candidate MicroRNAs associated with immune activities were randomly selected for qRT-PCR analysis, which confirming the expression profiling observed in the MicroRNA sequencing data. As a result, most differentially expressed miRNAs were down-regulated lead to increase the expression of various target genes that mediated immune reaction defense WSSV infection, including genes related to signal transduction, Complement and coagulation cascade, Phagocytosis, and Apoptosis. Furthermore, the genes expression of the key members in Toll and Imd signaling pathways and apoptotic signaling were mediated by microRNAs to activate host immune responses including apoptosis against WSSV infection. These results will help to understand molecular defense mechanism against WSSV infection in F. penicillatus and to develop an effective WSSV defensive strategy in shrimp farming.

Clinical implications of miRNAs in erythropoiesis, anemia, and other hematological disorders.

Erythropoiesis is regulated by the differential expression of many genes. Besides being transcriptionally regulated, these genes are also with the oath of epigenetic regulation by the microRNAs (miRNAs), in particular. Various miRNAs appear to be very important for the normal process of erythropoiesis and various hematological abnormalities in humans. Therefore, the review aims to summarize the significance of miRNAs in erythropoiesis and different hematological diseases with clinical importance. Our analysis indicates that specific miRNAs regulate erythropoiesis in a stage-specific manner from hematopoietic stem cells to differentiated erythrocytes. Further, many miRNAs have been reported to be linked with various hematological diseases. The importance of miRNAs as biomarkers or therapeutic drug targets for various hematological disorders like anemia, ß-thalassemia, and leukemia has been revealed through various clinical studies and clinical trials. The miR-34a mimic and miR-155 inhibitor demonstrate promising therapeutic effects in various hematological malignancies. Additionally, miR-34a, miR-538e, miR-193e, and miR-198 exhibit diagnostic potential in acute myeloid leukemia, while miR-451, miR-151-5p, and miR-1290 show diagnostic potential in B-cell acute lymphoblastic leukemia. Thus, this review encompasses the latest observations and implications of specific miRNAs in erythropoiesis and various hematological disorders. However, challenges persist in developing safe and efficient delivery strategies to target miRNAs specifically, minimizing off-target effects and enhancing therapeutic outcomes. Future mechanistic pre-clinical and clinical research would contribute to overcoming these challenges.

miR-30a-5p attenuates hypoxia/reoxygenation-induced cardiomyocyte apoptosis by regulating PTEN protein expression and activating PI3K/Akt signaling pathway.

BACKGROUND: This study was designed to investigate the mechanism by which miR-30a-5p mediates cardiomyocyte apoptosis after acute myocardial infarction (AMI) induced by hypoxia/reoxygenation (H/R). METHODS: Differentially expressed miRNAs were analyzed by RNA high-throughput sequencing in acute myocardial infarction (ST-elevation myocardial infarction) patients versus healthy individuals (controls). The H/R model was used to assess the regulatory mechanism of miRNAs in AMI. Lentivirus-associated vectors were used to overexpress or knock down miR-30a-5p in cellular models. The pathological mechanisms of miR-30a-5p regulating the development of acute myocardial infarction were serially explored by qPCR, bioinformatics, target gene prediction, dual luciferase, enzyme-linked immunosorbent assays (ELISAs) and Western blotting. RESULTS: The results showed that the expression of miR-30a-5p was significantly increased in AMI patients and H9C2 cells. Hypoxia decreased cardiomyocyte survival over time, and reoxygenation further reduced cell survival. Bax and Phosphatase and tensin homolog (PTEN)were suppressed, while Bcl-2 was upregulated. Additionally, miR-30a-5p specifically targeted the PTEN gene. According to the GO and KEGG analyses, miR-30a-5p may participate in apoptosis by interacting with PTEN. The miR-30a-5p mimic decreased the expression of apoptosis-related proteins and the levels of the proinflammatory markers IL-1ß, IL-6, and TNF-α by activating the PTEN/PI3K/Akt signaling pathway. Conversely, anti-miR-30a-5p treatment attenuated these effects. Additionally, silencing PTEN and anti-miR-30a-5p had opposite effects on H/R-induced cell apoptosis. CONCLUSIONS: miR-30a-5p plays a crucial role in cardiomyocyte apoptosis after hypoxia-induced acute myocardial infarction. Our findings provide translational evidence that miR-30a-5p is a novel potential therapeutic target for AMI.

MiRNA research-The potential for understanding the multiple facets of anorexia nervosa.

Anorexia nervosa (AN) has a multifaceted and complex pathology, yet major gaps remain in our understanding of factors involved in AN pathology. MicroRNAs (miRNAs) play a regulatory role in translating genes into proteins and help understand and treat diseases. An extensive literature review on miRNAs with AN and comorbidities has uncovered a significant lack in miRNA research. To demonstrate the importance of understanding miRNA deregulation, we surveyed the literature on depression and obesity providing examples of relevant miRNAs. For AN, no miRNA sequencing or array studies have been found, unlike other psychiatric disorders. For depression and obesity, screenings and mechanistic studies were conducted, leading to clinical studies to improve understanding of their regulatory influences. MiRNAs are promising targets for studying AN due to their role as signaling molecules, involvement in psychiatric-metabolic axes, and potential as biomarkers. These characteristics offer valuable insights into the disease's etiology and potential new treatment options. The first miRNA-based treatment for rare metabolic disorders has been approved by the FDA and it is expected that these advancements will increase in the next decade. MiRNA research in AN is essential to examine its role in the development, manifestation, and progression of the disease. PUBLIC SIGNIFICANCE: The current understanding of the development and treatment of AN is insufficient. miRNAs are short regulatory sequences that influence the translation of genes into proteins. They are the subject of research in various diseases, including both metabolic and psychiatric disorders. Studying miRNAs in AN may elucidate their causal and regulatory role, uncover potential biomarkers, and allow for future targeted treatments.

A Machine Learning Approach to Identify Potential miRNA-Gene Regulatory Network Contributing to the Pathogenesis of SARS-CoV-2 Infection.

Worldwide, many lives have been lost in the recent outbreak of coronavirus disease. The pathogen responsible for this disease takes advantage of the host machinery to replicate itself and, in turn, causes pathogenesis in humans. Human miRNAs are seen to have a major role in the pathogenesis and progression of viral diseases. Hence, an in-silico approach has been used in this study to uncover the role of miRNAs and their target genes in coronavirus disease pathogenesis. This study attempts to perform the miRNA seq data analysis to identify the potential differentially expressed miRNAs. Considering only the experimentally proven interaction databases TarBase, miRTarBase, and miRecords, the target genes of the miRNAs have been identified from the mirNET analytics platform. The identified hub genes were subjected to gene ontology and pathway enrichment analysis using EnrichR. It is found that a total of 9 miRNAs are deregulated, out of which 2 were upregulated (hsa-mir-3614-5p and hsa-mir-3614-3p) and 7 were downregulated (hsa-mir-17-5p, hsa-mir-106a-5p, hsa-mir-17-3p, hsa-mir-181d-5p, hsa-mir-93-3p, hsa-mir-28-5p, and hsa-mir-100-5p). These miRNAs help us to classify the diseased and healthy control patients accurately. Moreover, it is also found that crucial target genes (UBC and UBB) of 4 signature miRNAs interact with viral replicase polyprotein 1ab of SARS-Coronavirus. As a result, it is noted that the virus hijacks key immune pathways like various cancer and virus infection pathways and molecular functions such as ubiquitin ligase binding and transcription corepressor and coregulator binding.

Non-Coding Ribonucleic Acids as Diagnostic and Therapeutic Targets in Cardiac Fibrosis.

PURPOSE OF REVIEW: Cardiac fibrosis is a crucial juncture following cardiac injury and a precursor for many clinical heart disease manifestations. Epigenetic modulators, particularly non-coding RNAs (ncRNAs), are gaining prominence as diagnostic and therapeutic tools. RECENT FINDINGS: miRNAs are short linear RNA molecules involved in post-transcriptional regulation; lncRNAs and circRNAs are RNA sequences greater than 200 nucleotides that also play roles in regulating gene expression through a variety of mechanisms including miRNA sponging, direct interaction with mRNA, providing protein scaffolding, and encoding their own products. NcRNAs have the capacity to regulate one another and form sophisticated regulatory networks. The individual roles and disease relevance of miRNAs, lncRNAs, and circRNAs to cardiac fibrosis have been increasingly well described, though the complexity of their interrelationships, regulatory dynamics, and context-specific roles needs further elucidation. This review provides an overview of select ncRNAs relevant in cardiac fibrosis as a surrogate for many cardiac disease states with a focus on crosstalk and regulatory networks, variable actions among different disease states, and the clinical implications thereof. Further, the clinical feasibility of diagnostic and therapeutic applications as well as the strategies underway to advance ncRNA theranostics is explored.

Master Regulators of Causal Networks in Intestinal- and Diffuse-Type Gastric Cancer and the Relation to the RNA Virus Infection Pathway.

Causal networks are important for understanding disease signaling alterations. To reveal the network pathways affected in the epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs), which are related to the poor prognosis of cancer, the molecular networks and gene expression in diffuse- and intestinal-type gastric cancer (GC) were analyzed. The network pathways in GC were analyzed using Ingenuity Pathway Analysis (IPA). The analysis of the probe sets in which the gene expression had significant differences between diffuse- and intestinal-type GC in RNA sequencing of the publicly available data identified 1099 causal networks in diffuse- and intestinal-type GC. Master regulators of the causal networks included lenvatinib, pyrotinib, histone deacetylase 1 (HDAC1), mir-196, and erb-b2 receptor tyrosine kinase 2 (ERBB2). The analysis of the HDAC1-interacting network identified the involvement of EMT regulation via the growth factors pathway, the coronavirus pathogenesis pathway, and vorinostat. The network had RNA-RNA interactions with microRNAs such as mir-10, mir-15, mir-17, mir-19, mir-21, mir-223, mir-25, mir-27, mir-29, and mir-34. The molecular networks revealed in the study may lead to identifying drug targets for GC.

Serum microRNA Profiles and Pathways in Hepatitis B-Associated Hepatocellular Carcinoma: A South African Study.

The incidence and mortality of hepatocellular carcinoma (HCC) in Sub-Saharan Africa is projected to increase sharply by 2040 against a backdrop of limited diagnostic and therapeutic options. Two large South African-based case control studies have developed a serum-based miRNome for Hepatitis B-associated hepatocellular carcinoma (HBV-HCC), as well as identifying their gene targets and pathways. Using a combination of RNA sequencing, differential analysis and filters including a unique molecular index count (UMI) ≥ 10 and log fold change (LFC) range > 2: <-0.5 (p < 0.05), 91 dysregulated miRNAs were characterized including 30 that were upregulated and 61 were downregulated. KEGG analysis, a literature review and other bioinformatic tools identified the targeted genes and HBV-HCC pathways of the top 10 most dysregulated miRNAs. The results, which are based on differentiating miRNA expression of cases versus controls, also develop a serum-based miRNA diagnostic panel that indicates 95.9% sensitivity, 91.0% specificity and a Youden Index of 0.869. In conclusion, the results develop a comprehensive African HBV-HCC miRNome that potentially can contribute to RNA-based diagnostic and therapeutic options.

Differential Transcription Profiling Reveals the MicroRNAs Involved in Alleviating Damage to Photosynthesis under Drought Stress during the Grain Filling Stage in Wheat.

To explore the possible novel microRNA (miRNA) regulatory pathways in Zhengmai 1860, a newly cultivated drought-tolerant wheat (Triticum aestivum L.) cultivar, miRNA transcriptome sequencing of the flag leaves of Zhengmai 1860, drought-sensitive variety Zhoumai 18, and drought-resistant variety Bainong 207 was performed during the grain filling stage. We also observed changes in the chloroplast ultrastructure, phytohormone levels, and antioxidant- and photosynthesis-related physiological indicators in three wheat varieties. The results showed that the flag leaves of the drought-tolerant variety Zhengmai 1860 had higher chlorophyll contents and net photosynthetic rates than those of Zhoumai 18 under drought stress during the grain filling stage; in addition, the chloroplast structure was more complete. However, there was no significant difference between Zhengmai 1860 and Bainong 207. MiRNA transcriptome analysis revealed that the differential expression of the miRNAs and mRNAs exhibited variable specificity. The KEGG pathway enrichment results indicated that most of the genes were enriched in the MAPK signaling pathway, plant hormone signal transduction, photosynthetic antennae protein, and amino acid and carbohydrate metabolism. In the drought-tolerant cultivar Zhengmai 1860, tae-miR408 was targeted to regulate the allene oxide synthase (AOS) gene, inhibit its expression, reduce the AOS content, and decrease the synthesis of jasmonic acid (JA) and abscisic acid (ABA). The results of this study suggest that Zhengmai 1860 could improve the photosynthetic performance of flag leaves by inhibiting the expression of genes involved in the JA pathway through miRNAs under drought conditions. Moreover, multiple miRNAs may target chlorophyll, antioxidant enzymes, phytohormone signal transduction, and other related pathways; thus, it is possible to provide a more theoretical basis for wheat molecular breeding.

Multiple knockout mouse and embryonic stem cell models reveal the role of miR-124a in neuronal maturation.

MicroRNA-124a (miR-124a) is one of the most abundantly expressed microRNAs in the central nervous system and is encoded in mammals by the three genomic loci miR-124a-1/2/3; however, its in vivo roles in neuronal development and function remain ambiguous. In the present study, we investigated the effect of miR-124a loss on neuronal differentiation in mice and in embryonic stem (ES) cells. Since miR-124a-3 exhibits only background expression levels in the brain and we were unable to obtain miR-124a-1/2/3 triple knockout (TKO) mice by mating, we generated and analyzed miR-124a-1/2 double knockout (DKO) mice. We found that these DKO mice exhibit perinatal lethality. RNA-seq analysis demonstrated that the expression levels of proneural and neuronal marker genes were almost unchanged between the control and miR-124a-1/2 DKO brains; however, genes related to neuronal synaptic formation and function were enriched among downregulated genes in the miR-124a-1/2 DKO brain. In addition, we found the transcription regulator Tardbp/TDP-43, loss of which leads to defects in neuronal maturation and function, was inactivated in the miR-124a-1/2 DKO brain. Furthermore, Tardbp knockdown suppressed neurite extension in cultured neuronal cells. We also generated miR-124a-1/2/3 TKO ES cells using CRISPR-Cas9 as an alternative to TKO mice. Phase-contrast microscopic, immunocytochemical, and gene expression analyses showed that miR-124a-1/2/3 TKO ES cell lines were able to differentiate into neurons. Collectively, these results suggest that miR-124a plays a role in neuronal maturation rather than neurogenesis in vivo and advance our understanding of the functional roles of microRNAs in central nervous system development.

miRNA in Parkinson's disease: From pathogenesis to theranostic approaches.

Parkinson's disease (PD) is an age associated neurological disorder which is specified by cardinal motor symptoms such as tremor, stiffness, bradykinesia, postural instability, and non-motor symptoms. Dopaminergic neurons degradation in substantia nigra region and aggregation of αSyn are the classic signs of molecular defects noticed in PD pathogenesis. The discovery of microRNAs (miRNA) predicted to have a pivotal part in various processes regarding regularizing the cellular functions. Studies on dysregulation of miRNA in PD pathogenesis has recently gained the concern where our review unravels the role of miRNA expression in PD and its necessity in clinical validation for therapeutic development in PD. Here, we discussed how miRNA associated with ageing process in PD through molecular mechanistic approach of miRNAs on sirtuins, tumor necrosis factor-alpha and interleukin-6, dopamine loss, oxidative stress and autophagic dysregulation. Further we have also conferred the expression of miRNAs affected by SNCA gene expression, neuronal differentiation and its therapeutic potential with PD. In conclusion, we suggest more rigorous studies should be conducted on understanding the mechanisms and functions of miRNA in PD which will eventually lead to discovery of novel and promising therapeutics for PD.