RESUMO
Cognitive dysfunctions are core-enduring symptoms of schizophrenia, with important sex-related differences. Genetic variants of the DTBPN1 gene associated with reduced dysbindin-1 protein (Dys) expression negatively impact cognitive functions in schizophrenia through a functional epistatic interaction with Catechol-O-methyltransferase (COMT). Dys is involved in the trafficking of dopaminergic receptors, crucial for prefrontal cortex (PFC) signaling regulation. Moreover, dopamine signaling is modulated by estrogens via inhibition of COMT expression. We hypothesized a sex dimorphism in Dys-related cognitive functions dependent on COMT and estrogen levels. Our multidisciplinary approach combined behavioral-molecular findings on genetically modified mice, human postmortem Dys expression data, and in vivo fMRI during a working memory task performance. We found cognitive impairments in male mice related to genetic variants characterized by reduced Dys protein expression (pBonferroni = 0.0001), as well as in male humans through a COMT/Dys functional epistatic interaction involving PFC brain activity during working memory (t(23) = -3.21; pFDR = 0.004). Dorsolateral PFC activity was associated with lower working memory performance in males only (p = 0.04). Also, male humans showed decreased Dys expression in dorsolateral PFC during adulthood (pFDR = 0.05). Female Dys mice showed preserved cognitive performances with deficits only with a lack of estrogen tested in an ovariectomy model (pBonferroni = 0.0001), suggesting that genetic variants reducing Dys protein expression could probably become functional in females when the protective effect of estrogens is attenuated, i.e., during menopause. Overall, our results show the differential impact of functional variants of the DTBPN1 gene interacting with COMT on cognitive functions across sexes in mice and humans, underlying the importance of considering sex as a target for patient stratification and precision medicine in schizophrenia.
RESUMO
OBJECTIVE: The aim of this study was to investigate the influence of the shape of 3 different artificial canals on the trajectory followed by different nickel-titanium rotary instruments. STUDY DESIGN: Ten ProFile and Mtwo instruments, tip sizes 20 and 25, taper .06, were tested in 3 simulated root canals with an angle of curvature of 60 degrees and radius of curvature of 5 mm but with different shapes. Geometric analysis of the trajectory that each instrument followed inside the 3 different artificial canals was performed on digital images, determining 3 parameters: angle and radius of the curvature and the position of the center of the curvature. Mean values were then calculated for each instrument size in all of the artificial canals. Data were analysed using 1-way analysis of variance, Holm t test, and Student t test to determine any statistical difference (P < .05). RESULTS: In all instrument sizes, a statistically significant difference was noted among the artificial canals for the radius and angle of curvature. No statistically significant difference was noted between instruments of the same size for the radius and angle of curvature and the position of the center of the curve when measured in the canal constructed on the dimension of the instruments. CONCLUSIONS: Different instruments follow different trajectories in artificial canals constructed with the same parameters of curvature but different shapes, depending on their different bending properties. All of the instruments respected the established parameters of curvature only when the artificial canal is designed on the dimension of the instruments.
