miR-15b-5p promotes expression of proinflammatory cytokines in human placenta by inhibiting Apelin signaling pathway.

INTRODUCTION: The timing of parturition at end of human gestation may be controlled by fetal signals. The signaling molecules contributing to activation of human labor may be mediated by fetal exosomes. In this study, we focused on investigation of the role of microRNAs (miRNAs) derived from fetal exosomes in the regulation of human placental gene expression. METHODS: Using immunofluorescent labeling, array-based miRNA profiling assay, target prediction analysis, and conducting a variety of biochemical approaches including miRNA mimics, dual-luciferase, siRNA-mediated gene silencing, and immunohistochemical staining assay in primary trophoblast culture and formalin-fixed paraffin-embedded placental tissues, we examined whether fetal exosomal miRNAs can stimulate expression of proinflammatory mediators in human placenta. RESULTS: We showed placental uptake of exosomes derived from the umbilical artery, and found that 9 fetal exosomal miRNAs: let-7i-5p, miR-185-5p, miR-15b-5p, miR-376c-3p, miR-548d-5p, miR-92b-3p, miR-16-5p, and miR-1301-3p were significantly increased in placentas of women delivering following term labor compared to those delivering by Cesarean section in the late preterm period. Target prediction analysis identified miR-15b-5p of particular interest, because one of its predicted targets is Apelin, a potent inhibitor of proinflammatory mediators. We further found that miR-15b-5p repressed Apelin protein levels and activated pro-labor hormones and cytokines including IL-1, IL-6, IL-8, and TNF-α. DISCUSSION: These data suggest a potential fetal-to-placental signal that could play a role in the length of human gestation and onset of human labor.

Whole exome sequencing for prenatal diagnosis in cases with fetal anomalies: Criteria to improve diagnostic yield.

Whole exome sequencing (WES) for prenatal diagnosis has a reported diagnostic yield of 6.2%-57%. Our aim was to identify patients with a high likelihood of genetic diagnosis using WES in cases with fetal ultrasound anomalies. This is a series of five selected cases for prenatal WES at our institution. Pregnant couples were initially identified due to fetal ultrasound anomalies. Candidates for WES for fetal diagnosis had a normal fetal karyotype and negative microarray with at least one of the following: parental consanguinity, large regions of homozygosity on fetal microarray, or high likelihood of single gene disorder based on ultrasound findings. All trios underwent sequencing of parental and fetal samples. WES was diagnostic in four of the five cases (80%). We identified two recessive conditions and two de novo mutations. Four couples consented to secondary findings and in one case, the father was found to have an MSH2 mutation associated with Lynch syndrome. The use of specific selection criteria for WES increased diagnostic yield to 80%. This is higher than previously reported. Wide application of our criteria can help identify those who may benefit most from this testing in prenatal diagnosis.

Top-cited articles in the Journal: a bibliometric analysis.

BACKGROUND: The Journal has had a profound influence in nearly 150 years of publishing. A bibliometric analysis, which uses citation analyses to evaluate the impact of articles, can be used to identify the most impactful papers in the Journal's history. OBJECTIVE: The objective was to identify and characterize the top-cited articles published in the Journal since 1920. STUDY DESIGN: We used the Web of Science and Scopus databases to identify the most frequently cited articles of the Journal from 1920 through 2018. The top 100 articles from each database were included in our analysis. Articles were evaluated for several characteristics including year of publication, article type, topic, open access, and country of origin. Using the Scopus data, we performed an unadjusted categorical analysis to characterize the articles and a 2 time point analysis to compare articles before and after 1995, the median year of publication from each database list. RESULTS: The top 100 articles from each database were included in the analysis. This included 120 total articles: 80 articles listed in both and 20 unique in each database. More than half (52%) were observational studies, 9% were RCTs, and 75% were from US authors. When the post-1995 studies were compared with the articles published before 1995, articles were more frequently cited (median 27 vs 13 citations per year, P < .001), more likely to be randomized (14.0% vs 4.8%, P = .009), and more likely to originate from international authors (33.3% vs 17.5%, P = .045). CONCLUSION: Slightly more than half of the top-cited papers in the Journal since 1920 were observational studies and three quarters of all papers were from US authors. Compared with top-cited papers before 1995, the Journal's top-cited papers after 1995 were more likely to be randomized and to originate from international authors.

Vitamin D stimulates multiple microRNAs to inhibit CRH and other pro-labor genes in human placenta.

Maternal vitamin D deficiency is linked to adverse pregnancy outcomes including spontaneous preterm birth (SPB). Placental corticotropin-releasing hormone (CRH) has been proposed to be part of a clock that governs the length of gestation in humans, with elevated maternal serum levels predicting early delivery. In this study, we test the hypothesis that vitamin D could contribute to the prevention of preterm labor by inhibiting CRH and other pro-labor mediators. The biological activity of vitamin D occurs via two pathways: non-genomic and genomic responses, both of which involve binding of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D binding to the vitamin D receptor (VDR). By using chromatin immunoprecipitation followed by sequencing (ChIP-seq), we found that 1,25(OH)2D stimulates association of VDR with a number of miRNA genes including MIR181B2 and MIR26B, and their mature products miR-181b-5p and miR-26b-5p are predicted to target CRH and cyclooxygenase-2 (COX-2) mRNA at 3'-untranslated region (UTR), respectively. We performed RT-qPCR analysis to validate that expression of mature miR-181b-5p and miR-26b-5p in term human syncytiotrophoblast increased in response to treatment with 1,25(OH)2D. miR-181b-5p- or miR-26b-5p-mediated inhibition of CRH or COX-2 was further assessed by the use of miRNA mimics/inhibitors and a luciferase reporter assay. Taken together, this study has identified novel mechanisms by which vitamin D downregulates pro-labor genes and could lower the risk of preterm delivery.