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SummaryThe mouse is often the model of choice for genetic analysis of neurological disorders, but the introduction of pathogenic mutations into a single inbred strain sometimes fails to yield phenotypes relevant to human disease. Interrogating genetically diverse panels of mice can identify better models of human sensitivity and resistance to candidate disease variants. We developed anin vitromethodology for modeling multiple stages of central nervous system development using a panel of genetically diverse mouse embryonic stem cell lines. Chemical knockdown of the neurodevelopmental geneDyrk1ademonstrated profound strain differences in the cellular response to the ablation of DYRK1A activity throughout developmentin vitro. Responsive strains showedin vitrodevelopmental defects consistent with those observedin vivoinDyrk1aknockout mice, and mirrored the phenotype seen in neural progenitors derived fromDYRK1Aknockout human pluripotent cells. Transcriptomic analysis of differentiated cells from sensitive and resistant cell strain backgrounds successfully identified key molecular pathways in neural development known to be associated withDyrk1ahaploinsufficiencyin vivo. Thus, comparative phenotypic analysis of differentiated cells from human and genetically diverse mouse pluripotent stem cells bearing disease mutations provides a facile route to identification of optimal mouse strains for precision disease modelingin vivo.

Previous research has consistently demonstrated that regular exercise promotes antioxidant production and decreases the expression of inflammation markers. However, there is very little research examining the effects of intermittent fasting (IF) on oxidative stress and inflammation. The present study investigated the hypothesis that a combination of IF and physical activity will reduce the need for glutathione (GSH) production by decreasing oxidative stress. In addition, it was hypothesized that a combination of IF and physical activity will significantly reduce inflammation, as indicated by a decrease in interleukin-1β (IL-1β) concentration. For three months, subjects practicing IF (n=7) ate only during an eight-hour window each day and fasted for the next 16 hours. A standard diet control group (n=18) maintained a normal, balanced diet spread out over the course of 14–18 hours each day. Based on data obtained from fitness-tracking devices, subjects were placed into one of three activity level groups: minimum, moderate, and maximum physical activity. Subjects provided fasting saliva samples monthly. The samples were subjected to a glutathione microplate assay and an interleukin ELISA test to determine salivary concentrations of GSH and IL-1β, respectively. For GSH concentration, there were no significant differences between the diets at any physical activity level. However, moderate to maximum physical activity, in conjunction with fasting, led to significant decreases in IL-1β concentration. In summary, results suggest that a combination of moderate physical activity and intermittent fasting promotes the maintenance of antioxidant function while inhibiting the inflammatory process.