Person:

McManus, Michael

MicroRNAs (miRNAs) post-transcriptionally regulate the expression of thousands of distinct mRNAs. While some regulatory interactions help to maintain basal cellular functions, others are likely relevant in more specific settings, such as response to stress. Here we describe such a role for the mir-290-295 cluster, the dominant miRNA cluster in mouse embryonic stem cells (mESCs). Examination of a target list generated from bioinformatic prediction, as well as expression data following miRNA loss, revealed strong enrichment for apoptotic regulators, two of which we validated directly: Caspase 2, the most highly conserved mammalian caspase, and Ei24, a p53 transcriptional target. Consistent with these predictions, mESCs lacking miRNAs were more likely to initiate apoptosis following genotoxic exposure to gamma irradiation or doxorubicin. Knockdown of either candidate partially rescued this pro-apoptotic phenotype, as did transfection of members of the mir-290-295 cluster. These findings were recapitulated in a specific mir-290-295 deletion line, confirming that they reflect miRNA functions at physiological levels. In contrast to the basal regulatory roles previously identified, the pro-survival phenotype shown here may be most relevant to stressful gestations, where pro-oxidant metabolic states induce DNA damage. Similarly, this cluster may mediate chemotherapeutic resistance in a neoplastic context, making it a useful clinical target.

Background: Postpartum depression carries adverse consequences for mothers and children, so widespread screening during primary care visits is recommended. However, the rates, timing, and factors associated with significant depressive episodes are incompletely understood. Methods and findings We examined the Healthcare Cost and Utilization Project (HCUP) State Inpatient, Emergency Department, and Ambulatory Surgery and Services Databases from California (2005–2011) and Florida (2005–2012). Within 203 million records, we identified 3,213,111 births and all mothers who had hospital encounters for severe depression within 40 weeks following delivery. We identified 15,806 episodes of postpartum depression after 11,103 deliveries among 10,883 unique women, and calculated an overall rate of 36.7 depression- associated hospital visits per 10,000 deliveries. Upward trends were observed in both states, with combined five-year increases of 34%. First depressive events were most common within 30 days of delivery, but continued for the entire observation period. About half (1,661/3,325) of PPD first episodes occurred within 34 days of delivery, 70% (2,329/3,325) by the end of the second month, and 87% (2,893/3,325) before four-months of the delivery. Women with private insurance were less likely to have hospital encounters for depression than women with public insurance and women with depression were much more likely to have had some kind of hospital encounter at some time during their pregnancies. Rates of depression increased with the number of prenatal hospital encounters in a “dose-dependent” fashion: the rate of depression was 17.2/10,000 for women with no prenatal hospital visits, doubling for women with at least one encounter (34.9/10,000), and increasing 7-fold to 126/10,000 for women with three or more encounters during their pregnancies. Conclusions: Our findings suggest that (1) hospital encounters for post-partum depression are increasing, (2) screening should begin very early and continue for the first year after delivery, and (3) added attention should be given to women who had hospital encounters during their pregnancies.