BACKGROUND & AIMS: :mRNA expression dynamics promote and maintain the identity of somatic tissues in living organisms; however, their impact in post-transcriptional gene regulation in these processes is not fully understood. Here, we applied the PAT-Seq approach to systematically isolate, sequence, and map tissue-specific mRNA from five highly studied Caenorhabditis elegans somatic tissues: GABAergic and NMDA neurons, arcade and intestinal valve cells, seam cells, and hypodermal tissues, and studied their mRNA expression dynamics. The integration of these datasets with previously profiled transcriptomes of intestine, pharynx, and body muscle tissues, precisely assigns tissue-specific expression dynamics for 60% of all annotated C. elegans protein-coding genes, providing an important resource for the scientific community. The mapping of 15,956 unique high-quality tissue-specific polyA sites in all eight somatic tissues reveals extensive tissue-specific 3'untranslated region (3'UTR) isoform switching through alternative polyadenylation (APA) . Almost all ubiquitously transcribed genes use APA and harbor miRNA targets in their 3'UTRs, which are commonly lost in a tissue-specific manner, suggesting widespread usage of post-transcriptional gene regulation modulated through APA to fine tune tissue-specific protein expression. Within this pool, the human disease gene C. elegans orthologs rack-1 and tct-1 use APA to switch to shorter 3'UTR isoforms in order to evade miRNA regulation in the body muscle tissue, resulting in increased protein expression needed for proper body muscle function. Our results highlight a major positive regulatory role for APA, allowing genes to counteract miRNA regulation on a tissue-specific basis.

背景与目标： : mRNA表达动力学促进并维持活生物体中体细胞组织的身份; 但是，它们在这些过程中对转录后基因调控的影响尚未完全了解。在这里，我们应用PAT-Seq方法从五个高度研究的秀丽隐杆线虫体细胞组织中系统地分离、测序和定位组织特异性mRNA: gaba能和NMDA神经元、拱廊和肠瓣细胞、接缝细胞和皮下组织，并研究了它们的mRNA表达动力学。将这些数据集与先前描述的肠，咽和身体肌肉组织的转录组进行整合，精确地为所有注释的秀丽隐杆线虫蛋白质编码基因的60% 分配了组织特异性表达动力学，为科学界提供了重要的资源。在所有八个体细胞组织中15,956独特的高质量组织特异性polyA位点的作图揭示了通过替代多腺苷酸化 (APA) 进行广泛的组织特异性3' 非翻译区 (3'UTR) 同工型转换。几乎所有普遍转录的基因都使用APA，并在其3'utr中携带miRNA靶标，这些靶标通常以组织特异性方式丢失，这表明广泛使用通过APA调节的转录后基因调控来微调组织特异性蛋白表达。在该池中，人类疾病基因C. elegans直系同源物rack-1和tct-1使用APA切换到较短的3'UTR同工型，以逃避身体肌肉组织中的miRNA调节，导致适当的身体肌肉功能所需的蛋白质表达增加。我们的结果强调了APA的主要积极调节作用，允许基因在组织特异性的基础上抵消miRNA的调节。

BACKGROUND & AIMS: :MicroRNAs play an important role in tumor development and progression. Tumor growth is closely associated with glucose metabolism. Specifically, tumor cells produce energy (ATP) under aerobic and anaerobic conditions through glycolysis and metabolites, such as lactic acid and ATP, as a result of the Warburg effect. However, the transport of glucose into cells depends on protein transporters in the cell membrane. Therefore, this area has recently become a topic of interest for research on targeted cancer therapy. We found that miRNA-451 inhibits the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway to modify the biological behavior of glioma cells. Inhibiting the PI3K/Akt pathway may prevent glucose-addicted cancer cells from performing glycolysis. Akt directly affects glycolysis by regulating the localization of the glucose transporter 1 (GLUT1). However, how miRNA-451 regulates glucose transporters on the cell membrane and affects the regulatory mechanisms of glucose metabolism in glioma cells remains unclear. Consequently, we predict and verify related gene protein interactions. By targeting CAB 39, miRNA-451 likely triggers the LKB1/AMPK/PI3K/AKT pathway, which regulates GLUT1, to inhibit the glucose metabolism of, reduce the energy supply to, and inhibit the proliferation and invasion of glioma cells. Our results suggest a new direction for the treatment of glioma.

背景与目标： : microrna在肿瘤的发展和进展中起重要作用。肿瘤生长与葡萄糖代谢密切相关。具体来说，由于Warburg效应，肿瘤细胞在有氧和厌氧条件下通过糖酵解和代谢产物 (例如乳酸和ATP) 产生能量 (ATP)。然而，葡萄糖向细胞的转运取决于细胞膜中的蛋白质转运蛋白。因此，该领域最近成为靶向癌症治疗研究的兴趣话题。我们发现miRNA-451抑制phosphatidylinositol-3激酶 (PI3K)/Akt信号通路来改变神经胶质瘤细胞的生物学行为。抑制PI3K/Akt途径可能会阻止葡萄糖成瘾的癌细胞进行糖酵解。Akt通过调节葡萄糖转运蛋白1 (GLUT1) 的定位直接影响糖酵解。然而，miRNA-451如何调节细胞膜上的葡萄糖转运蛋白并影响神经胶质瘤细胞中葡萄糖代谢的调节机制仍不清楚。因此，我们预测并验证了相关的基因蛋白相互作用。通过靶向CAB 39，miRNA-451可能会触发LKB1/AMPK/PI3K/AKT途径，该途径调节GLUT1，以抑制其葡萄糖代谢，减少能量供应并抑制神经胶质瘤细胞的增殖和侵袭。我们的结果为神经胶质瘤的治疗提供了新的方向。

BACKGROUND & AIMS: :miRNAs are key regulators that bind to target genes to suppress their gene expression level. The relations between miRNA-target genes enable users to derive co-expressed genes that may be involved in similar biological processes and functions in cells. We hypothesize that target genes of miRNAs are co-expressed, when they are regulated by multiple miRNAs. With the usage of these co-expressed genes, we can theoretically construct co-expression networks (GCNs) related to 152 diseases. In this study, we introduce ARNetMiT that utilize a hash based association rule algorithm in a novel way to infer the GCNs on miRNA-target genes data. We also present R package of ARNetMiT, which infers and visualizes GCNs of diseases that are selected by users. Our approach assumes miRNAs as transactions and target genes as their items. Support and confidence values are used to prune association rules on miRNA-target genes data to construct support based GCNs (sGCNs) along with support and confidence based GCNs (scGCNs). We use overlap analysis and the topological features for the performance analysis of GCNs. We also infer GCNs with popular GNI algorithms for comparison with the GCNs of ARNetMiT. Overlap analysis results show that ARNetMiT outperforms the compared GNI algorithms. We see that using high confidence values in scGCNs increase the ratio of the overlapped gene-gene interactions between the compared methods. According to the evaluation of the topological features of ARNetMiT based GCNs, the degrees of nodes have power-law distribution. The hub genes discovered by ARNetMiT based GCNs are consistent with the literature.

背景与目标： : mirna是与靶基因结合以抑制其基因表达水平的关键调节因子。miRNA-靶基因之间的关系使用户能够获得可能参与细胞中类似生物学过程和功能的共表达基因。我们假设mirna的靶基因被多个mirna调控时是共表达的。通过使用这些共表达基因，我们可以从理论上构建与152疾病相关的共表达网络 (GCNs)。在这项研究中，我们介绍了ARNetMiT，它以一种新颖的方式利用基于哈希的关联规则算法来推断miRNA靶基因数据上的GCNs。我们还介绍了ARNetMiT的R软件包，该软件包推断并可视化了用户选择的疾病的GCNs。我们的方法假设mirna作为交易，目标基因作为它们的项目。支持和置信度值用于修剪miRNA靶基因数据上的关联规则，以构建基于支持的GCNs (sGCNs) 以及基于支持和置信度的GCNs (scGCNs)。我们使用重叠分析和拓扑特征进行GCNs的性能分析。我们还使用流行的GNI算法推断GCNs，以与ARNetMiT的GCNs进行比较。重叠分析结果表明，ARNetMiT优于比较的GNI算法。我们看到，在scGCNs中使用高置信度值会增加比较方法之间重叠的基因-基因相互作用的比率。根据对基于ARNetMiT的GCNs的拓扑特征的评估，节点的度具有幂律分布。基于ARNetMiT的GCNs发现的hub基因与文献一致。

BACKGROUND & AIMS: :Osteosarcoma is the most common human primary malignant bone tumor in children and young adults. Sensitive and non-invasive biomarkers that can facilitate disease detection at early stage are highly desirable to improve survival rate and help to determine optimized treatment for osteosarcoma. The small non-coding RNAs, microRNAs (miRNAs), have recently been identified as critical regulators for various diseases including cancer and may represent a novel class of cancer biomarkers. In this study, we aimed to detect the potential of circulating miRNAs as biomarkers for osteosarcoma. Levels of six candidate miRNAs (miR-21, miR-199a-3p, miR-143, miR-34, miR-140, and miR-132) that were previously demonstrated to be regulated in osteosarcoma were examined in plasma of 40 osteosarcoma patients and 40 matched healthy controls by quantitative reverse-transcription polymerase chain reaction assays. The results showed that circulating levels of miR-21 were significantly higher in osteosarcoma patients than controls, while miR-199a-3p and miR-143 were decreased in osteosarcoma patients. We replicated the findings in an independent study of 40 osteosarcoma patients and 40 matched controls and confirmed the results. Receiver operating characteristics curve analysis of the combined populations demonstrated that the three-miRNA signature could discriminate cases from controls with an area under the curve of 0.953 (95 % CI 0.924-0.984). In addition, circulating miR-21 and miR-143 were correlated with both metastasis status and histological subtype of the patients, while miR-199a-3p only correlated with histological subtype. Our data suggest that altered levels of circulating miRNAs might have great potential to serve as novel, non-invasive biomarkers for osteosarcoma.

背景与目标： 骨肉瘤是儿童和年轻人中最常见的人类原发性恶性骨肿瘤。可以促进早期疾病检测的敏感和非侵入性生物标志物非常需要提高生存率并有助于确定骨肉瘤的最佳治疗方法。小的非编码rna，microrna (mirna)，最近已被确定为包括癌症在内的各种疾病的关键调节剂，并且可能代表一类新的癌症生物标志物。在这项研究中，我们旨在检测循环mirna作为骨肉瘤生物标志物的潜力。通过定量逆转录聚合酶链反应测定，在40名骨肉瘤患者和40名匹配的健康对照的血浆中检查了先前被证明在骨肉瘤中调控的六个候选mirna (miR-21，miR-199a-3p，miR-143，miR-34，miR-140和miR-132) 的水平。结果表明，骨肉瘤患者的miR-21循环水平明显高于对照组，而骨肉瘤患者的miR-199a-3p和miR-143水平降低。我们在一项针对40名骨肉瘤患者和40名匹配对照的独立研究中重复了这一发现，并证实了这一结果。组合种群的接收器工作特征曲线分析表明，三miRNA签名可以将病例与具有0.953曲线下面积的对照区分开 (95% CI 0.924-0.984)。此外，循环miR-21和miR-143与患者的转移状态和组织学亚型相关，而miR-199a-3p仅与组织学亚型相关。我们的数据表明，循环mirna水平的改变可能具有作为骨肉瘤的新型，非侵入性生物标志物的巨大潜力。

BACKGROUND & AIMS: :Although previous results showed that exogenous hydrogen (H2) alleviated aluminum (Al) toxicity, the detailed mechanism remains unclear. Here, we reported that the exposure of germinating rice seeds to Al triggered H2 production, followed by a decrease of GA/ABA ratio and seed germination inhibition. Compared to inert gas (argon), H2 pretreatment not only strengthened H2 production and alleviated Al-induced germination inhibition, but also partially reestablished the balance between GA and ABA. By contrast, a GA biosynthesis inhibitor paclobutrazol (PAC) could block the H2-alleviated germination inhibition. The expression of GA biosynthesis genes (GA20ox1 and GA20ox2) and ABA catabolism genes (ABA8ox1 and ABA8ox2), was also induced by H2. Above results indicated that GA/ABA might be partially involved in H2 responses. Subsequent results revealed that compared with Al alone, transcripts of miR398a and miR159a were decreased by H2, and expression levels of their target genes OsSOD2 and OsGAMYB were up-regulated. Whereas, miR528 and miR160a transcripts were increased differentially, and contrasting tendencies were observed in the changes of their target genes (OsAO and OsARF10). The transcripts of Al-tolerant gene OsSTAR1/OsSTAR2 and OsFRDL4 were up-regulated. Above results were consistent with the anti-oxidant defense, decreased Al accumulation, and enhanced citrate efflux. Together, our results provided insight into the mechanism underlying H2-triggered Al tolerance in plants.

背景与目标： : 尽管先前的结果表明外源氢 (H2) 减轻了铝 (Al) 的毒性，但详细的机理尚不清楚。在这里，我们报告了发芽的水稻种子暴露于Al会触发H2的产生，随后降低了GA/ABA比率并抑制了种子发芽。与惰性气体 (氩气) 相比，H2预处理不仅增强了H2的产生并减轻了Al诱导的发芽抑制，而且还部分恢复了GA和ABA之间的平衡。相比之下，GA生物合成抑制剂多效唑 (PAC) 可以阻断H2-alleviated发芽抑制。GA生物合成基因 (GA20ox1和GA20ox2) 和ABA分解代谢基因 (ABA8ox1和ABA8ox2) 的表达也被h2诱导。上述结果表明GA/ABA可能部分参与H2反应。随后的结果表明，与单独的Al相比，H2降低了miR398a和miR159a的转录本，并且其靶基因OsSOD2和OsGAMYB的表达水平上调。而miR528和miR160a转录本差异增加，并且在其靶基因 (OsAO和osaf10) 的变化中观察到相反的趋势。耐铝基因ossate1/ossate2和ossrdl4的转录本上调。上述结果与抗氧化防御，减少Al积累和增加柠檬酸盐外排一致。总之，我们的结果提供了对植物H2-triggered铝耐受性的潜在机制的见解。

BACKGROUND & AIMS: :Visceral leishmaniasis is characterized by mixed production of Th1/2 cytokines and the disease is established by an enhanced level of Th2 cytokine. CD4+ T cells are main cell type which produces Th1/2 cytokine in the host upon Leishmania infection. However, the regulatory mechanism for Th1/2 production is not well understood. In this study, we co-cultured mice CD4+ T cells with Leishmania donovani infected and uninfected macrophage for the identification of dysregulated miRNAs in CD4+ T cells by next-generation sequencing. Here, we identified 604 and 613 known miRNAs in CD4+ T cells in control and infected samples respectively and a total of only 503 miRNAs were common in both groups. The expression analysis revealed that 112 miRNAs were up and 96 were down-regulated in infected groups, compared to uninfected control. Nineteen up-regulated and 17 down-regulated miRNAs were statistically significant (p < 0.05), which were validated by qPCR. Further, using insilco approach, we identified the gene targets of significant miRNAs on the basis of CD4+ T cell biology. Eleven up-regulated miRNAs and 9 down-regulated miRNAs were associated with the cellular immune responses and Th1/2 dichotomy upon Leishmania donovani infection. The up-regulated miRNAs targeted transcription factors that promote differentiation of CD4+ T cells towards Th1 phenotype. While down-regulated miRNAs targeted the transcription factors that facilitate differentiation of CD4+ T cells towards Th2 populations. The GO and pathway enrichment analysis also showed that the identified miRNAs target the pathway and genes related to CD4+ T cell biology which plays important role in Leishmania donovani infection.

背景与目标： : 内脏利什曼病的特征是混合产生Th1/2细胞因子，并且该疾病是由Th2细胞因子水平升高引起的。CD4 + T细胞是利什曼原虫感染后在宿主中产生Th1/2细胞因子的主要细胞类型。然而，Th1/2生产的调节机制还没有很好的理解。在这项研究中，我们将小鼠CD4 T细胞与利什曼原虫多诺瓦尼感染和未感染的巨噬细胞共培养，以通过下一代测序鉴定CD4 T细胞中失调的mirna。在这里，我们分别在对照和感染样品中确定了CD4 + T细胞中的604和613已知的mirna，并且在两组中总共只有503个mirna是常见的。表达分析显示，与未感染对照组相比，感染组中有112个mirna升高，96个下调。19个上调和17个下调的mirna差异有统计学意义 (p  <  0.05)，qPCR验证。此外，使用insilco方法，我们基于CD4 T细胞生物学鉴定了重要mirna的基因靶标。11个上调的mirna和9个下调的mirna与利什曼原虫感染后的细胞免疫反应和Th1/2二分法相关。上调的miRNAs靶向转录因子，促进CD4 + T细胞向Th1表型分化。而下调的mirna靶向促进CD4 + T细胞向Th2群体分化的转录因子。GO和途径富集分析还表明，所鉴定的mirna靶向CD4 + T细胞生物学相关的途径和基因，在利什曼原虫感染中发挥重要作用。

BACKGROUND & AIMS: :RNA silencing refers to a series of nuclear and cytoplasmatic processes involved in the post-transcriptional regulation of gene expression or post-transcriptional gene silencing (PTGS), either by sequence-specific mRNA degradation or by translational arrest. The best characterized small RNAs are microRNAs (miRNAs), which predominantly perform gene silencing through post-transcriptional mechanisms. In this work we used bioinformatic approaches to identify the parasitic trematode Schistosoma mansoni sequences that are similar to enzymes involved in the post-transcriptional gene silencing mediated by miRNA pathway. We used amino acid sequences of well-known proteins involved in the miRNA pathway against S. mansoni genome and transcriptome databases identifying a total of 13 putative proteins in the parasite. In addition, the transcript levels of SmDicer1 and SmAgo2/3/4 were identified by qRT-PCR using cercariae, adult worms, eggs and in vitro cultivated schistosomula. Our results showed that the SmDicer1 and SmAgo2/3/4 are differentially expressed during schistosomula development, suggesting that the miRNA pathway is regulated at the transcript level and therefore may control gene expression during the life cycle of S. mansoni.

背景与目标： : RNA沉默是指通过序列特异性mRNA降解或通过翻译阻滞，参与基因表达的转录后调控或转录后基因沉默 (PTGS) 的一系列核和细胞质过程。表征最好的小rna是microRNAs (miRNAs)，它们主要通过转录后机制进行基因沉默。在这项工作中，我们使用生物信息学方法来鉴定曼氏血吸虫的寄生吸虫序列，这些序列与miRNA途径介导的转录后基因沉默中涉及的酶相似。我们使用了涉及针对曼氏链球菌基因组的miRNA途径的众所周知的蛋白质的氨基酸序列和转录组数据库，鉴定了该寄生虫中总共13种假定的蛋白质。此外，使用尾蚴，成虫，卵和体外培养的血吸虫，通过qRT-PCR鉴定SmDicer1和SmAgo2/3/4的转录水平。我们的结果表明SmDicer1和SmAgo2/3/4在血吸虫发育过程中差异表达，这表明miRNA途径在转录水平上受到调节，因此可能在曼氏链球菌的生命周期中控制基因表达。

BACKGROUND & AIMS: BACKGROUND:Since the proposal of Brachypodium distachyon as a model for the grasses, over 500 Bdi-miRNAs have been annotated in miRBase making Brachypodium second in number only to rice. Other monocots, such as switchgrass, are completely absent from the miRBase database. While a significant number of miRNAs have been identified which are highly conserved across plants, little research has been done with respect to the conservation of miRNA targets. Plant responses to abiotic stresses are regulated by diverse pathways many of which involve miRNAs; however, it can be difficult to identify miRNA guided gene regulation when the miRNA is not the primary regulator of the target mRNA. RESULTS:To investigate miRNA target conservation and stress response involvement, a set of PARE (Parallel Analysis of RNA Ends) libraries totaling over two billion reads was constructed and sequenced from Brachypodium, switchgrass, and sorghum representing the first report of RNA degradome data from the latter two species. Analysis of this data provided not only PARE evidence for miRNA guided cleavage of over 7000 predicted target mRNAs in Brachypodium, but also evidence for miRNA guided cleavage of over 1000 homologous transcripts in sorghum and switchgrass. A pipeline was constructed to compare RNA-seq and PARE data made from Brachypodium plants exposed to various abiotic stress conditions. This resulted in the identification of 44 miRNA targets which exhibit stress regulated cleavage. Time course experiments were performed to reveal the relationship between miR393ab, miR169a, miR394ab, and their respective targets throughout the first 36 h of the cold stress response in Brachypodium. CONCLUSIONS:Knowledge gained from this study provides considerable insight into the RNA degradomes and the breadth of miRNA target conservation among these three species. Additionally, associations of a number of miRNAs and target mRNAs with the stress responses have been revealed which could aid in the development of stress tolerant transgenic crops.

背景与目标：

BACKGROUND & AIMS: :A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

背景与目标： : 对本文的更正已发布，并链接到本文的HTML和PDF版本。该错误尚未在论文中修复。

BACKGROUND & AIMS: :Circulating miRNAs (c-miRNAs) are promising biomarkers for HF diagnosis and prognosis. There are no studies on HF pediatric patients undergoing VAD-implantation. Aims of this study were: to examine the c-miRNAs profile in HF children; to evaluate the effects of VAD on c-miRNAs levels; to in vitro validate putative c-miRNA targets. c-miRNA profile was determined in serum of HF children by NGS before and one month after VAD-implant. The c-miRNA differentially expressed were analyzed by real time-PCR, before and at 4 hrs,1,3,7,14,30 days after VAD-implant. A miRNA mimic transfection study in HepG2 cells was performed to validate putative miRNA targets selected through miRWalk database. Thirteen c-miRNAs were modified at 30 days after VAD-implant compared to pre-VAD at NSG, and, among them, six c-miRNAs were confirmed by Real-TimePCR. Putative targets of the validated c-miRNAs are involved in the hemostatic process. The in vitro study confirmed a down-regulatory effect of hsa-miR-409-3p towards coagulation factor 7 (F7) and F2. Of note, all patients had thrombotic events requiring pump change. In conclusion, in HF children, the level of six c-miRNAs involved in the regulation of hemostatic events changed after 30 days of VAD-treatment. In particular, the lowering of c-miR-409-3p regulating both F7 and F2 could reflect a pro-thrombotic state after VAD-implant.

背景与目标： : 循环mirna (c-mirna) 是有前途的HF诊断和预后的生物标志物。尚无关于接受VAD植入的HF儿科患者的研究。这项研究的目的是: 检查HF儿童中的c-miRNAs谱; 评估VAD对c-miRNAs水平的影响; 在体外验证推定的c-miRNA靶标。在VAD植入前和植入后一个月，通过NGS测定HF儿童血清中的c-miRNA谱。在VAD植入之前和之后4小时、1,3、7、14、30天，通过real time-PCR分析差异表达的c-miRNA。在HepG2细胞中进行了miRNA模拟转染研究，以验证通过miRWalk数据库选择的推定miRNA靶标。与NSG的VAD前相比，在VAD植入后30天对13个c-mirna进行了修饰，其中，通过实时pcr确认了6个c-mirna。经验证的c-mirna的推定靶标参与止血过程。体外研究证实了hsa-miR-409-3p对凝血因子7 (F7) 和f2的下调作用。值得注意的是，所有患者都有需要更换泵的血栓事件。总之，在HF儿童中，VAD治疗30天后，参与止血事件调节的6个c-mirna的水平发生了变化。特别地，调节F7和F2的c-miR-409-3p的降低可以反映VAD植入后的血栓前状态。

BACKGROUND & AIMS: :In recent years, scientists have found evidence confirming the aberrant expression of miRNAs in cancer patients compared to healthy individuals. The growing interest in the identification of non-invasive and specific diagnostic and prognostic molecular markers has identified microRNAs as potential candidates in cancer diagnosis, prognosis and treatment response. In the present study, we have analyzed the expression profile of circulating miR-21, -191 and -421 in peripheral blood of head and neck cancer patients (HNC) to investigate a possible modulation of mRNA levels by radiation and to identify the role of mRNA as biomarkers of cancer prognosis. Results showed a modulation of the microRNA expression at different time points after radiotherapy, suggesting that treatment may influence the release of circulating miRNAs depending also on the time interval elapsed since radiotherapy. The expression levels of miR-21, -191 and -421 were higher in blood of patients treated with radiotherapy alone after 6 months from the end of therapy and high levels of them seemed to correlate with the remission of the disease. The trends shown in this study confirmed that miRNAs could be useful prognosis markers and could provide preliminary data for further evaluation in predicting patients' response to radiotherapy by developing miRNA-based treatments to improve the sensitivity of cancer cells to radiotherapy.

背景与目标： : 近年来，科学家发现了证据，证实了与健康个体相比，癌症患者中mirna的异常表达。对鉴定非侵入性和特异性诊断和预后分子标志物的兴趣日益浓厚，已将microRNAs确定为癌症诊断，预后和治疗反应的潜在候选者。在本研究中，我们分析了头颈癌患者 (HNC) 外周血中循环miR-21，-191和-421的表达谱，以研究辐射对mRNA水平的可能调节，并确定mRNA作为癌症预后生物标志物的作用。结果显示放疗后不同时间点microRNA表达的调节，表明治疗可能会影响循环mirna的释放，这也取决于放疗后经过的时间间隔。从治疗结束后的6个月后，单独接受放射治疗的患者血液中miR-21，-191和-421的表达水平较高，并且高水平似乎与疾病的缓解相关。本研究显示的趋势证实，miRNA可能是有用的预后标志物，并可以通过开发基于miRNA的治疗方法来提高癌细胞对放射治疗的敏感性，为进一步评估患者对放射治疗的反应提供初步数据。

BACKGROUND & AIMS: :Multiple myeloma remains incurable due to the persistence of a minor population of multiple myeloma cells that exhibit drug resistance, which leads to relapsed and/or refractory multiple myeloma. Elucidating the mechanism underlying drug resistance and developing an effective treatment are critical for clinical management of multiple myeloma. Here we showed that promoting expression of the gene for polycomb-like protein 3 (PHF19) induced multiple myeloma cell growth and multidrug resistance in vitro and in vivo. PHF19 was overexpressed in high-risk and drug-resistant primary cells from patients. High levels of PHF19 were correlated with inferior survival of patients with multiple myeloma, in the Total Therapy 2 cohort and in the Intergroup Francophone du Myeloma (IFM) cohort. Enhancing PHF19 expression levels increased Bcl-xL, Mcl-1, and HIF-1a expression in multiple myeloma cells. PHF19 also bound directly with EZH2 and promoted the phosphorylation of EZH2 through PDK1/AKT signaling. miR-15a is a small noncoding RNA that targeted the 3'UTR of PHF19. We found that downregulation of miR-15a led to high levels of PHF19 in multiple myeloma cells. These findings revealed that PHF19 served a crucial role in multiple myeloma proliferation and drug resistance and suggested that the miR-15a/PHF19/EZH2 pathway made a pivotal contribution to multiple myeloma pathogenesis, offering a promising approach to multiple myeloma treatment. IMPLICATIONS: Our findings identify that PHF19 mediates EZH2 phosphorylation as a mechanism of myeloma cell drug resistance, providing a rationale to explore therapeutic potential of targeting PHF19 in relapsed or refractory patients with multiple myeloma.

背景与目标： : 多发性骨髓瘤仍然无法治愈，这是由于少数多发性骨髓瘤细胞的持续存在，这些细胞表现出耐药性，从而导致复发和/或难治性多发性骨髓瘤。阐明耐药机制和开发有效的治疗方法对于多发性骨髓瘤的临床治疗至关重要。在这里，我们表明促进多梳样蛋白3 (PHF19) 基因的表达在体内外诱导多发性骨髓瘤细胞生长和多药耐药性。PHF19在患者的高风险和耐药原代细胞中过表达。在总治疗2队列和组间法语du骨髓瘤 (IFM) 队列中，高水平的PHF19与多发性骨髓瘤患者的生存率较低相关。增强PHF19表达水平增加了多发性骨髓瘤细胞中Bcl-xL、Mcl-1和HIF-1a的表达。PHF19还与EZH2直接结合，并通过PDK1/AKT信号传导促进EZH2的磷酸化。miR-15a是一种小的非编码RNA，靶向phf19的3'UTR。我们发现miR-15a的下调导致多发性骨髓瘤细胞中PHF19的高水平。这些发现表明，PHF19在多发性骨髓瘤的增殖和耐药性中起着至关重要的作用，并表明miR-15a/PHF19/EZH2通路对多发性骨髓瘤的发病机理做出了关键贡献，为多发性骨髓瘤的治疗提供了一种有希望的方法。含义: 我们的发现表明，PHF19介导EZH2磷酸化是骨髓瘤细胞耐药性的一种机制，为探索在复发或难治性多发性骨髓瘤患者中靶向PHF19的治疗潜力提供了理论依据。

BACKGROUND & AIMS: :Neuropsychiatric disorders, including autism spectrum disorders (ASD) and anxiety disorders are characterized by a complex range of symptoms, including social behaviour and cognitive deficits, depression and repetitive behaviours. Although the mechanisms driving pathophysiology are complex and remain largely unknown, advances in the understanding of gene association and gene networks are providing significant clues to their aetiology. In recent years, small noncoding RNA molecules known as microRNA (miRNA) have emerged as a new gene regulatory layer in the pathophysiology of mental illness. These small RNAs can bind to the 3'-UTR of mRNA thereby negatively regulating gene expression at the post-transcriptional level. Their ability to regulate hundreds of target mRNAs simultaneously predestines them to control the activity of entire cellular pathways, with obvious implications for the regulation of complex processes such as animal behaviour. There is growing evidence to suggest that numerous miRNAs are dysregulated in pathophysiology of neuropsychiatric disorders, and there is strong genetic support for the association of miRNA genes and their targets with several of these conditions. This review attempts to cover the most relevant microRNAs for which an important contribution to the control of social and anxiety-related behaviour has been demonstrated by functional studies in animal models. In addition, it provides an overview of recent expression profiling and genetic association studies in human patient-derived samples in an attempt to highlight the most promising candidates for biomarker discovery and therapeutic intervention.

背景与目标： : 神经精神疾病，包括自闭症谱系障碍 (ASD) 和焦虑症，其特征是一系列复杂的症状，包括社交行为和认知缺陷，抑郁和重复行为。尽管驱动病理生理学的机制很复杂并且仍然未知，但对基因关联和基因网络的理解的进步为其病因学提供了重要线索。近年来，称为microRNA (miRNA) 的非编码小RNA分子已成为精神疾病病理生理中的新基因调控层。这些小rna可以与mRNA的3 '-UTR结合，从而在转录后水平上负调节基因表达。它们调节数百个靶mrna的能力同时决定了它们控制整个细胞途径的活性，对调节复杂过程 (例如动物行为) 具有明显的意义。越来越多的证据表明，许多miRNA在神经精神疾病的病理生理学中失调，并且有强大的遗传支持miRNA基因及其靶标与其中几种疾病的关联。这篇综述试图涵盖最相关的microrna，动物模型中的功能研究已证明对控制社交和焦虑相关行为做出了重要贡献。此外，它还概述了人类患者衍生样本中最近的表达谱分析和遗传关联研究，以强调生物标志物发现和治疗干预的最有希望的候选者。

BACKGROUND & AIMS: :Novel therapeutic strategies are urgently required for the clinical management of chemoresistant ovarian carcinoma, which is the most lethal of the gynecologic malignancies. miRNAs hold promise because they play a critical role in determining the cell phenotype by regulating several hundreds of targets, which could constitute vulnerabilities of cancer cells. A combination of gain-of-function miRNA screening and real-time continuous cell monitoring allows the identification of miRNAs with robust cytotoxic effects in chemoresistant ovarian cancer cells. Focusing on miR-3622b-5p, we show that it induces apoptosis in several ovarian cancer cell lines by both directly targeting Bcl-xL and EGFR-mediating BIM upregulation. miR-3622b-5p also sensitizes cells to cisplatin by inhibiting Bcl-xL in ovarian cancer cell lines escaping BIM induction. miR-3622b-5p also exerts antimigratory capacities by targeting both LIMK1 and NOTCH1. These wide-ranging antitumor properties of miR-3622b-5p in ovarian cancer cells are mimicked by the associations of pharmacologic inhibitors targeting these proteins. The combination of an EGFR inhibitor together with a BH3-mimetic molecule induced a large decrease in cell viability in a panel of ovarian cancer cell lines and several ovarian patient-derived tumor organoids, suggesting the value of pursuing such a combination therapy in ovarian carcinoma. Altogether, our work highlights the potential of phenotype-based miRNA screening approaches to identify lethal interactions which might lead to new drug combinations and clinically applicable strategies.

背景与目标： : 迫切需要新的治疗策略来治疗化学耐药性卵巢癌，这是最致命的妇科恶性肿瘤。Mirna之所以有希望，是因为它们通过调节数百个可能构成癌细胞脆弱性的靶标，在确定细胞表型方面发挥关键作用。功能获得miRNA筛选和实时连续细胞监测相结合，可以鉴定在化学抗性卵巢癌细胞中具有强大细胞毒性作用的miRNA。着眼于miR-3622b-5p，我们表明它通过直接靶向Bcl-xL和EGFR介导的BIM上调诱导了几种卵巢癌细胞系的凋亡。miR-3622b-5p还通过抑制逃避BIM诱导的卵巢癌细胞系中的Bcl-xL使细胞对顺铂敏感。miR-3622b-5p还通过同时针对LIMK1和notch1来发挥抗igr能力。卵巢癌细胞中miR-3622b-5p的这些广泛抗肿瘤特性被靶向这些蛋白质的药物抑制剂的关联所模仿。EGFR抑制剂与BH3-mimetic分子的组合在一组卵巢癌细胞系和几种卵巢患者衍生的肿瘤类器官中诱导了细胞活力的大幅降低，这表明在卵巢癌中寻求这种联合疗法的价值。总之，我们的工作强调了基于表型的miRNA筛选方法识别致死相互作用的潜力，这可能导致新的药物组合和临床适用的策略。

BACKGROUND & AIMS: :In the present study, the role of microRNA-663b (miR-663b) in cardiomyocyte injury was examined. Reverse transcription-quantitative PCR (RT-qPCR) was performed to detect miR-663b expression in hypoxia-induced H9c2 cells. The results revealed that miR-663b expression was significantly upregulated in hypoxia-induced H9c2 cells compared with control cells. TargetScan analysis and dual-luciferase reporter assays demonstrated that miR-663b directly targeted the B-cell lymphoma 2 like 1 (BCL2L1) gene. RT-qPCR and western blotting data indicated that BCL2L1 expression was significantly downregulated in hypoxia-induced H9c2 cells compared with control cells. Under hypoxic conditions, H9c2 cells were transfected with miR-663b inhibitor, inhibitor control, miR-663b inhibitor + control small interfering (si)RNA or miR-663b inhibitor + BCL2L1-siRNA for 48 h. ELISA against creatine kinase-muscle/brain (CK-MB) and cardiac troponin 1 (cTnI) demonstrated that the miR-663b inhibitor reduced CK-MD and cTnI release and increased mitochondrial viability when compared with hypoxia-treated cells. Additionally, the miR-663b inhibitor significantly increased H9c2 cell viability and decreased cell apoptosis under hypoxic conditions. The results of ELISA further revealed that the miR-663b inhibitor decreased the release of various inflammatory factors, including tumour necrosis factor α, interleukin (IL) 1β and IL-6 in H9c2 cells under hypoxic conditions. These changes were reversed following BCL2L1 knockdown. In conclusion, miR-663b inhibition protected cardiomyocytes against hypoxia-induced injury by targeting BCL2L1 and may potentially be a novel target for the treatment of patients with myocardial infarction.

背景与目标： : 在本研究中，研究了microRNA-663b (miR-663b) 在心肌细胞损伤中的作用。进行逆转录-定量PCR (rt-qpcr) 以检测缺氧诱导的H9c2细胞中的miR-663b表达。结果表明，与对照细胞相比，低氧诱导的H9c2细胞中miR-663b表达显着上调。Targetsca分析和双荧光素酶报告基因分析表明，miR-663b直接靶向b细胞淋巴瘤2样1 (BCL2L1) 基因。Rt-qpcr和western印迹数据表明，与对照细胞相比，低氧诱导的H9c2细胞中BCL2L1表达显着下调。在低氧条件下，用miR-663b抑制剂转染H9c2细胞，miR-663b抑制剂 + 对照小干扰 (si)RNA或miR-663b抑制剂 + BCL2L1-siRNA 48小时针对肌酸激酶-肌肉/脑 (ck-mb) 和心肌肌钙蛋白1 (cTnI) 的酶联免疫吸附试验表明，与缺氧相比，miR-663b抑制剂减少ck-md和cTnI的释放并增加线粒体活力-处理过的细胞。此外，在低氧条件下，miR-663b抑制剂可显著提高H9c2细胞活力并减少细胞凋亡。ELISA的结果进一步表明，miR-663b抑制剂可降低各种炎症因子的释放，包括肿瘤坏死因子 α，缺氧条件下H9c2细胞中的白细胞介素 (IL) 1β 和IL-6。这些变化在BCL2L1敲低后被逆转。总之，miR-663b抑制通过靶向BCL2L1保护心肌细胞免受缺氧诱导的损伤，并可能成为治疗心肌梗死患者的新靶标。