A pilot study of experiencing racial microaggressions, obsessive-compulsive symptoms, and the role of psychological flexibility.

BACKGROUND: Experiencing racial microaggressions has clear effects on physical and psychological health, including obsessive-compulsive disorder symptoms (OCS). More research is needed to examine this link. Psychological flexibility is an important process to examine in this work. AIMS: This study aimed to examine if, while controlling for depression and anxiety, experiences of microaggressions and psychological flexibility helped explain OCD symptoms within a university-affiliated sample (undergraduate, graduate and law students). This was a pilot exploration of the relationships across themes. METHOD: Initial baseline data from a longitudinal study of psychological flexibility, OCD symptoms, depression, anxiety and experience of microaggressions was utilized. Correlations and regressions were utilized to examine which OCD symptom dimensions were associated with experiencing racial microaggressions in addition to anxiety and depression, and the added role of psychological flexibility was examined. RESULTS: OCD symptoms, experiences of microaggressions and psychological flexibility were correlated. Experiences of racial microaggressions explained responsibility for harm and contamination OCD symptoms above and beyond psychological distress. Exploratory results support the relevance of psychological flexibility. CONCLUSION: Results support other work that experiences of racial microaggressions help explain OCS and they add some support for psychological flexibility as a relevant risk or protective factor for mental health in marginalized populations. These topics should be studied longitudinally with continued consideration of all OCD themes, larger sample sizes, intersecting identities, clinical samples, and continued exploration of psychological flexibility and mindfulness and values-based treatments.

Ketogenic and anaplerotic dietary modifications ameliorate seizure activity in Drosophila models of mitochondrial encephalomyopathy and glycolytic enzymopathy.

Seizures are a feature not only of the many forms of epilepsy, but also of global metabolic diseases such as mitochondrial encephalomyopathy (ME) and glycolytic enzymopathy (GE). Modern anti-epileptic drugs (AEDs) are successful in many cases, but some patients are refractory to existing AEDs, which has led to a surge in interest in clinically managed dietary therapy such as the ketogenic diet (KD). This high-fat, low-carbohydrate diet causes a cellular switch from glycolysis to fatty acid oxidation and ketone body generation, with a wide array of downstream effects at the genetic, protein, and metabolite level that may mediate seizure protection. We have recently shown that a Drosophila model of human ME (ATP61) responds robustly to the KD; here, we have investigated the mechanistic importance of the major metabolic consequences of the KD in the context of this bioenergetics disease: ketogenesis, reduction of glycolysis, and anaplerosis. We have found that reduction of glycolysis does not confer seizure protection, but that dietary supplementation with ketone bodies or the anaplerotic lipid triheptanoin, which directly replenishes the citric acid cycle, can mimic the success of the ketogenic diet even in the presence of standard carbohydrate levels. We have also shown that the proper functioning of the citric acid cycle is crucial to the success of the KD in the context of ME. Furthermore, our data reveal that multiple seizure models, in addition to ATP61, are treatable with the ketogenic diet. Importantly, one of these mutants is TPIsugarkill, which models human glycolytic enzymopathy, an incurable metabolic disorder with severe neurological consequences. Overall, these studies reveal widespread success of the KD in Drosophila, further cementing its status as an excellent model for studies of KD treatment and mechanism, and reveal key insights into the therapeutic potential of dietary therapy against neuronal hyperexcitability in epilepsy and metabolic disease.

Cardiac natriuretic peptide deficiency sensitizes the heart to stress-induced ventricular arrhythmias via impaired CREB signalling.

AIMS: The cardiac natriuretic peptides [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)] are important regulators of cardiovascular physiology, with reduced natriuretic peptide (NP) activity linked to multiple human cardiovascular diseases. We hypothesized that deficiency of either ANP or BNP would lead to similar changes in left ventricular structure and function given their shared receptor affinities. METHODS AND RESULTS: We directly compared murine models deficient of ANP or BNP in the same genetic backgrounds (C57BL6/J) and environments. We evaluated control, ANP-deficient (Nppa-/-) or BNP-deficient (Nppb-/-) mice under unstressed conditions and multiple forms of pathological myocardial stress. Survival, myocardial structure, function and electrophysiology, tissue histology, and biochemical analyses were evaluated in the groups. In vitro validation of our findings was performed using human-derived induced pluripotent stem cell cardiomyocytes (iPS-CMs). In the unstressed state, both ANP- and BNP-deficient mice displayed mild ventricular hypertrophy which did not increase up to 1 year of life. NP-deficient mice exposed to acute myocardial stress secondary to thoracic aortic constriction (TAC) had similar pathological myocardial remodelling but a significant increase in sudden death. We discovered that the NP-deficient mice are more susceptible to stress-induced ventricular arrhythmias using both in vivo and ex vivo models. Mechanistically, deficiency of either ANP or BNP led to reduced myocardial cGMP levels and reduced phosphorylation of the cAMP response element-binding protein (CREBS133) transcriptional regulator. Selective CREB inhibition sensitized wild-type hearts to stress-induced ventricular arrhythmias. ANP and BNP regulate cardiomyocyte CREBS133 phosphorylation through a cGMP-dependent protein kinase 1 (PKG1) and p38 mitogen-activated protein kinase (p38 MAPK) signalling cascade. CONCLUSIONS: Our data show that ANP and BNP act in a non-redundant fashion to maintain myocardial cGMP levels to regulate cardiomyocyte p38 MAPK and CREB activity. Cardiac natriuretic peptide deficiency leads to a reduction in CREB signalling which sensitizes the heart to stress-induced ventricular arrhythmias.

Replication Stress Response Modifies Sarcomeric Cardiomyopathy Remodeling.

Background Sarcomere gene mutations lead to cardiomyocyte hypertrophy and pathological myocardial remodeling. However, there is considerable phenotypic heterogeneity at both the cellular and the organ level, suggesting modifiers regulate the effects of these mutations. We hypothesized that sarcomere dysfunction leads to cardiomyocyte genotoxic stress, and this modifies pathological ventricular remodeling. Methods and Results Using a murine model deficient in the sarcomere protein, Mybpc3-/- (cardiac myosin-binding protein 3), we discovered that there was a surge in cardiomyocyte nuclear DNA damage during the earliest stages of cardiomyopathy. This was accompanied by a selective increase in ataxia telangiectasia and rad3-related phosphorylation and increased p53 protein accumulation. The cause of the DNA damage and DNA damage pathway activation was dysregulated cardiomyocyte DNA synthesis, leading to replication stress. We discovered that selective inhibition of ataxia telangiectasia and rad3 related or cardiomyocyte deletion of p53 reduced pathological left ventricular remodeling and cardiomyocyte hypertrophy in Mybpc3-/- animals. Mice and humans harboring other types of sarcomere gene mutations also had evidence of activation of the replication stress response, and this was associated with cardiomyocyte aneuploidy in all models studied. Conclusions Collectively, our results show that sarcomere mutations lead to activation of the cardiomyocyte replication stress response, which modifies pathological myocardial remodeling in sarcomeric cardiomyopathy.