👤 Meerarani Purushothaman

Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Here, combining differential expression and gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across six brain regions. We overlap our human profiles with those from a mouse model, chronic variable stress, and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Our results show a major rearrangement of transcriptional patterns in MDD, with limited overlap between males and females, an effect seen in both depressed humans and stressed mice. We identify key regulators of sex-specific gene networks underlying MDD and confirm their sex-specific impact as mediators of stress susceptibility. For example, downregulation of the female-specific hub gene Dusp6 in mouse prefrontal cortex mimicked stress susceptibility in females, but not males, by increasing ERK signaling and pyramidal neuron excitability. Such Dusp6 downregulation also recapitulated the transcriptional remodeling that occurs in prefrontal cortex of depressed females. Together our findings reveal marked sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder. Show less

Despite extensive evidence demonstrating the beneficial effects of statins on clinical outcomes, the mechanisms underlying these effects remain elusive. This study assessed changes in plaque morphology using intravascular imaging, with a comprehensive evaluation of cholesterol efflux capacity (CEC) and peripheral blood mononuclear cell (PBMC) transcriptomics in patients receiving high-dose statin therapy. In a prospective study, 85 patients with stable coronary artery disease underwent percutaneous coronary intervention for a culprit lesion, followed by intracoronary multimodality imaging, including optical coherence tomography (OCT) of an obstructive nonculprit lesion. All subjects received 40 mg of rosuvastatin daily for 8 to 12 weeks, when the nonculprit lesion was reimaged and intervention performed. Blood samples were drawn at both times to assess CEC and transcriptomic profile in PBMC. Baseline OCT minimal fibrous cap thickness (FCT) was 100.9 ± 41.7 μm, which increased to 108.6 ± 39.6 μm at follow-up, and baseline CEC was 0.81 ± 0.14, which increased at follow-up to 0.84 ± 0.14 (p = 0.003). Thin-cap fibroatheroma prevalence decreased from 20.0% to 7.1% (p = 0.003). Changes in FCT were independently associated with CEC increase by multivariate analysis (β: 0.30; p = 0.01). PBMC microarray analysis detected 117 genes that were differentially expressed at follow-up compared to baseline, including genes playing key roles in cholesterol synthesis (SQLE), regulation of fatty acids unsaturation (FADS1), cellular cholesterol uptake (LDLR), efflux (ABCA1 and ABCG1), and inflammation (DHCR24). Weighted coexpression network analysis revealed unique clusters of genes associated with favorable FCT and CEC changes. The study demonstrated an independent association between fibrous cap thickening and improved CEC that may contribute to morphological changes suggesting plaque stabilization among patients taking intensive statin therapy. Furthermore, the significant perturbations in PBMC transcriptome may help determine the beneficial effects of statin on plaque stabilization. (Reduction in Coronary Yellow Plaque, Lipids and Vascular Inflammation by Aggressive Lipid Lowering [YELLOW II]; NCT01837823). Show less