Febrile seizure incidence and age at first occurrence are associated with changes in placental normalized gene expression: the '3D' pregnancy cohort study.

Self-reported maternal prenatal stress (MPS) has been associated with earlier febrile seizure (FS) age of onset in offspring. Studies are needed to understand how the biological systems associated with exposure to psychological MPS are linked to seizure disorders in children. The present study aimed to investigate whether placental markers of MPS are linked to FS incidence and age at first occurrence. A subsample of children with FS (n = 28) and matched controls (n = 84), were drawn from the longitudinal 3D pregnancy cohort (N = 2366 mother-child dyads). Expression of placental genes associated with glucocorticoids, serotonin and fetal/placental growth were analysed from placental tissues, compared between groups and associated with age at first FS. Overall placental normalized gene expression was statistically different (p < .001). Children with FS showed overexpression of the serotonin transporter (mean difference = 0.61, 95% confidence interval [CI] = 0.9-1.13), connexin 43 (mean difference = 0.69, 95% CI = 0.30-1.09), zonula occludens-1 (mean difference = 0.84, 95% CI = 0.42-1.26) and underexpression of glucocorticoid receptor ß (mean difference = 0.84, 95% CI = -1.49 to 0.19) and serotonin receptor 2B (mean difference = 1.57, 95% CI = -2.35 to 0.78) compared to controls. Increased expression of the serotonin transporter predicted 37.2% in variation of age at first FS. The correlation matrix showed pregnancy-specific anxiety during the second trimester was moderately associated with age at first FS (r = -0.38) but was not a significant predictor in the regression model. Although our current results do not display a significant effect of self-reported MPS on FS, the present study is the first to show that placental gene biomarkers usually known to be associated with MPS display different expressions in children with FS. Specifically, our results suggest that placental genes associated with the glucocorticoid, serotonergic and fetal/placental growth systems may be candidate mechanisms leading to increased vulnerability offspring in FS. Because self-reported MPS was not found as a significant predictor in our statistical models, future studies are needed to investigate the mechanisms causing the observed changes in placental genes and their association with seizure disorders.

Network-Based Integration of Multi-Omics Data Identifies the Determinants of miR-491-5p Effects.

The identification of miRNAs' targets and associated regulatory networks might allow the definition of new strategies using drugs whose association mimics a given miRNA's effects. Based on this assumption we devised a multi-omics approach to precisely characterize miRNAs' effects. We combined miR-491-5p target affinity purification, RNA microarray, and mass spectrometry to perform an integrated analysis in ovarian cancer cell lines. We thus constructed an interaction network that highlighted highly connected hubs being either direct or indirect targets of miR-491-5p effects: the already known EGFR and BCL2L1 but also EP300, CTNNB1 and several small-GTPases. By using different combinations of specific inhibitors of these hubs, we could greatly enhance their respective cytotoxicity and mimic the miR-491-5p-induced phenotype. Our methodology thus constitutes an interesting strategy to comprehensively study the effects of a given miRNA. Moreover, we identified targets for which pharmacological inhibitors are already available for a clinical use or in clinical trials. This study might thus enable innovative therapeutic options for ovarian cancer, which remains the leading cause of death from gynecological malignancies in developed countries.