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Correction of an knock-in mouse model of acrodysostosis with gene therapy utilizing a rAAV9-CAG-human PRKAR1A vector.
Previously, we demonstrated that global knockout (KO) of the gene encoding myelin protein zero-like 3 (Mpzl3) results in reduced body weight and adiposity, increased energy expenditure, and reduced hepatic lipid synthesis in mice. These mice also exhibit cyclic and progressive alopecia which may contribute to the observed hypermetabolic phenotype. The goal of the current study was to determine if acute and peripherally restricted knockdown of Mpzl3 could ameliorate the negative metabolic effects of exposure to a high-fat and sucrose, energy-dense (HED) diet similar to what was observed in global Mpzl3 KO mice in the absence of a skin phenotype. Mpzl3 antisense oligonucleotide (ASO) administration dose-dependently decreased fat mass and circulating lipids in HED-fed C57BL/6N mice. These changes were accompanied by a decrease in respiratory exchange ratio, a reduction in energy expenditure and food intake, a decrease in expression of genes regulating de novo lipogenesis in white adipose tissue, and an upregulation of genes associated with steroid hormone biosynthesis in liver, thermogenesis in brown adipose tissue and fatty acid transport in skeletal muscle. These data demonstrate that resistance to the negative metabolic effects of HED is a direct effect of Mpzl3 knockdown, rather than compensatory changes that could be associated with deletion of Mpzl3 during development in global KO mice. Inhibiting MPZL3 could be a potential therapeutic approach for the treatment of obesity and associated dyslipidemia.The purpose of this study was to determine whether smooth pursuit eye movements affect visual motion prediction using a time-to-contact task where observers anticipate the exact instant that a partially occluded target would coincide with a stationary object. Moreover, we attempted to clarify the influence of second-order motion on visual motion prediction during smooth pursuit. One target object moved to another stationary object (6 deg apart) at constant velocity of 3, 4, and 5 deg/s, and then the two objects disappeared 500 ms after the onset of target motion. The observers estimated the moment the moving object would overlap the stationary object and pressed a button. For the pursuit condition, both a Gaussian window and a random dots texture moved in the same direction at the same speed for the first-order motion, whereas a Gaussian window moved over a static background composed of random dots texture for the second-order motion. The results showed that the constant error of the time-to-contact shifted to a later response for the pursuit condition compared to the fixation condition, regardless of the object velocity. In addition, during smooth pursuit, the constant error for the second-order motion shifted to an earlier response compared to the first-order motion when the object velocity was 3 deg/s, whereas no significant difference was found at 4 and 5 deg/s. Therefore, our results suggest that visual motion prediction using a time-to-contact task is affected by both eye movements and motion configuration such as second-order motion.Mechanistic target of rapamycin complex 1 (mTORC1) plays a central role in muscle protein synthesis and repeated bouts of resistance exercise (RE) blunt mTORC1 activation. However, the changes in the proteolytic signaling when recurrent RE bouts attenuate mTORC1 activation are unclear. MK-5108 Using a RE model of electrically stimulated rat skeletal muscle, this study aimed to clarify the effect of repeated RE bouts on acute proteolytic signaling, particularly the calpain, autophagy-lysosome, and ubiquitin-proteasome pathway. p70S6K and rpS6 phosphorylation, indicators of mTORC1 activity, were attenuated by repeated RE bouts. Calpain 3 protein was decreased at 6 h post-RE in all exercised groups regardless of the bout number. Microtubule-associated protein 1 light chain 3 beta-II, an indicator of autophagosome formation, was increased at 3 h and repeated RE bouts increased at 6 h, post-RE. Ubiquitinated proteins were increased following RE, but these increases were independent of the number of RE bouts. These results suggest that the magnitude of autophagosome formation was increased following RE when mTORC1 activity was attenuated with repeated bouts of RE.Sojourners to high altitude often experience poor sleep quality due to sleep-disordered breathing. Additionally, multiple aspects of cognitive function are impaired at high altitude. However, the impact of acclimatization on sleep-disordered breathing and whether poor sleep is a major contributor to cognitive impairments at high altitude remains uncertain. We conducted nocturnal actigraphy and polygraphy, as well as daytime cognitive function tests, in 15 participants (33% women) at sea level and over 3 days of partial acclimatization to high altitude (3800 m). Our goal was to determine if sleep-disordered breathing improved over time and if sleep-disordered breathing was associated with cognitive function. The apnea-hypopnea index and oxygen desaturation index increased on night 1 (adj. p = 0.026 and adj. p = 0.026, respectively), but both improved over the subsequent 2 nights. These measures were matched by poorer self-reported sleep quality on the Stanford Sleepiness Scale and PROMIS questionnaires following 1 night at high altitude (adj. p = 0.027 and adj. p = 0.022, respectively). The reaction time on the psychomotor vigilance task was slower at high altitude and did not improve (SL 199 ± 27, ALT1 224 ± 33, ALT2 216 ± 41, ALT3 212 ± 27 ms). The reaction times on the balloon analog risk task decreased at high altitude (SL 474 ± 235, ALT1 375 ± 159, ALT2 291 ± 102, ALT3 267 ± 90 ms), perhaps indicating increased risk-taking behavior. Finally, multiple cognitive function measures were associated with sleep-disordered breathing and measures of subjective sleep quality, rather than low daytime arterial oxygen saturation. These data indicate that sleep-disordered breathing at moderately high altitude improves with partial acclimatization and that some aspects of cognitive performance in unacclimatized sojourners may be impacted by poor sleep rather than hypoxemia alone.
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