👤 Mathew T Pletcher

We aimed to examine how coronary artery calcium (CAC) and its progression relate to cognitive function in midlife, an important time for cognitive aging. We studied participants enrolled in the prospective CARDIA (Coronary Artery Risk Development in Young Adults) study, a longitudinal cohort of Black and White adults aged 18 to 30 years at baseline, who completed CAC measurements using computed tomography at year 15 (2000-2001; our baseline), had at least 1 follow-up CAC measurement at years 20 (2005-2006) or 25 (2010-2011), and completed cognitive assessments with a battery of 5 tests at years 30 (2015-2016) or 35 (2020-2022). CAC progression was defined as: (1) CAC >0 at follow-up among participants with baseline CAC=0; (2) an annualized change of ≥10 units at follow-up among those with 00) and CAC progression. Among the 2341 participants (mean baseline age 40.3±3.6 years; 56% female), baseline CAC >0 (9%) was associated with lower processing speed, verbal memory, and global cognition, whereas CAC progression (26%) was associated with lower processing speed and global cognition after adjusting for demographics, education, physical activity, depressive symptoms, APOE ε4 allele, and baseline CAC score. The standardized cognitive differences (95% CI) for CAC progression versus no progression were -0.14 (95% CI, -0.23 to -0.06) for the Digit Symbol Substitution Test and -0.09 (95% CI, -0.17 to -0.01) for the Montreal Cognitive Assessment. CAC progression was associated with worse midlife processing speed and global cognition, independent of baseline CAC score and established risk factors. Repeated CAC assessments may offer clinical value for identifying individuals at increased risk for midlife cognitive decline. Show less

Isoniazid (INH), the mainstay therapeutic for tuberculosis infection, has been associated with rare but serious hepatotoxicity in the clinic. However, the mechanisms underlying inter-individual variability in the response to this drug have remained elusive. A genetically diverse mouse population model in combination with a systems biology approach was utilized to identify transcriptional changes, INH-responsive metabolites, and gene variants that contribute to the liver response in genetically sensitive individuals. Sensitive mouse strains developed severe microvesicular steatosis compared with corresponding vehicle control mice following 3 days of oral treatment with INH. Genes involved in mitochondrial dysfunction were enriched among liver transcripts altered with INH treatment. Those associated with INH treatment and susceptibility to INH-induced steatosis in the liver included apolipoprotein A-IV, lysosomal-associated membrane protein 1, and choline phosphotransferase 1. These alterations were accompanied by metabolomic changes including reduced levels of glutathione and the choline metabolites betaine and phosphocholine, suggesting that oxidative stress and reduced lipid export may additionally contribute to INH-induced steatosis. Finally, genome-wide association mapping revealed that polymorphisms in perilipin 2 were linked to increased triglyceride levels following INH treatment, implicating a role for inter-individual differences in lipid packaging in the susceptibility to INH-induced steatosis. Taken together, our data suggest that INH-induced steatosis is caused by not one, but multiple events involving lipid retention in the livers of genetically sensitive individuals. This work also highlights the value of using a mouse diversity panel to investigate drug-induced responses across a diverse population. Show less

We report the identification and characterization of a five-carbon protein posttranslational modification (PTM) called lysine glutarylation (Kglu). This protein modification was detected by immunoblot and mass spectrometry (MS), and then comprehensively validated by chemical and biochemical methods. We demonstrated that the previously annotated deacetylase, sirtuin 5 (SIRT5), is a lysine deglutarylase. Proteome-wide analysis identified 683 Kglu sites in 191 proteins and showed that Kglu is highly enriched on metabolic enzymes and mitochondrial proteins. We validated carbamoyl phosphate synthase 1 (CPS1), the rate-limiting enzyme in urea cycle, as a glutarylated protein and demonstrated that CPS1 is targeted by SIRT5 for deglutarylation. We further showed that glutarylation suppresses CPS1 enzymatic activity in cell lines, mice, and a model of glutaric acidemia type I disease, the last of which has elevated glutaric acid and glutaryl-CoA. This study expands the landscape of lysine acyl modifications and increases our understanding of the deacylase SIRT5. Show less

Cardiotoxicity is one of the leading causes of drug attrition. Current in vitro models insufficiently predict cardiotoxicity, and there is a need for alternative physiologically relevant models. Here we describe the gene expression profile of human-induced pluripotent stem cell-derived cardiocytes (iCC) postthaw over a period of 42 days in culture and compare this profile to human fetal and adult as well as adult cynomolgus nonhuman primate (NHP, Macaca fascicularis) heart tissue. Our results indicate that iCC express relevant cardiac markers such as ion channels (SCN5A, KCNJ2, CACNA1C, KCNQ1, and KCNH2), tissue-specific structural markers (MYH6, MYLPF, MYBPC3, DES, TNNT2, and TNNI3), and transcription factors (NKX2.5, GATA4, and GATA6) and lack the expression of stem cell markers (FOXD3, GBX2, NANOG, POU5F1, SOX2, and ZFP42). Furthermore, we performed a functional evaluation of contractility of the iCC and showed functional and pharmacological correlations with myocytes isolated from adult NHP hearts. These results suggest that stem cell-derived cardiocytes may represent a novel in vitro model to study human cardiac toxicity with potential ex vivo and in vivo translation. Show less