RESUMEN
Progressive ventricular enlargement, a key feature of several neurologic and psychiatric diseases, is mediated by unknown mechanisms. Here, using murine models of 22q11-deletion syndrome (22q11DS), which is associated with schizophrenia in humans, we found progressive enlargement of lateral and third ventricles and deceleration of ciliary beating on ependymal cells lining the ventricular walls. The cilia-beating deficit observed in brain slices and in vivo is caused by elevated levels of dopamine receptors (Drd1), which are expressed in motile cilia. Haploinsufficiency of the microRNA-processing gene Dgcr8 results in Drd1 elevation, which is brought about by a reduction in Drd1-targeting microRNAs miR-382-3p and miR-674-3p. Replenishing either microRNA in 22q11DS mice normalizes ciliary beating and ventricular size. Knocking down the microRNAs or deleting their seed sites on Drd1 mimicked the cilia-beating and ventricular deficits. These results suggest that the Dgcr8-miR-382-3p/miR-674-3p-Drd1 mechanism contributes to deceleration of ciliary motility and age-dependent ventricular enlargement in 22q11DS.
Asunto(s)
Ventrículos Cerebrales/metabolismo , Cilios/fisiología , MicroARNs/genética , Esquizofrenia/genética , Animales , Deleción Cromosómica , Cilios/genética , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologíaRESUMEN
The iMachine is a spring-loaded turntable used to measure inertial properties of irregularly shaped rigid bodies, specifically manual wheelchairs. We used a Newton-Euler approach to calculate wheelchair mass and center of mass (CM) location from static force measurements using load cells. We determined the moment of inertia about the vertical axis from the natural frequency of the system in simple harmonic motion. The device was calibrated to eliminate the effects of platform components on measurement error. For objects with known inertial properties, the average relative error of the mass and the CM coordinates (x and y) were 0.76%, 0.89%, and 1.99%, respectively. The resolution of the moment of inertia calculation depends on the ratio of test piece inertia to system inertia, such that the higher the ratio, the more accurate the measurements. We conducted a Gage Repeatability and Reproducibility (Gage R&R) test using three manual wheelchairs measured three times by three operators; the results showed that over 90% of the variance in inertia was caused by differences in the wheelchairs being measured. Gage R&R analysis indicated that measurement system operation was acceptable using criteria from the Automobile Industry Action Group for both inertia and mass measurements.
