Chintan Patel

Following synaptic vesicle fusion, vacated release sites are replenished immediately by new vesicles for subsequent neurotransmission. These replacement vesicles are assumed to be located near release sites and used by chance. Here we find in mouse hippocampal excitatory synapses that replacement vesicles are clustered near the active zone where release sites reside by intersectin-1. Specifically, intersectin-1 forms dynamic molecular condensates with endophilin A1 and sequesters vesicles around this region. In the absence of intersectin-1, fewer vesicles cluster within 20 nm of the plasma membrane, and consequently vacated sites cannot be replenished rapidly, leading to synaptic depression. Mutations in intersectin-1 that disrupt endophilin A1 binding result in similar phenotypes. In the absence of endophilin A1, intersectin-1 is mislocalized, and this replacement pool of vesicles cannot be accessed, suggesting that endophilin A1 is needed to mobilize these vesicles. Thus, our work describes the replacement zone within a synapse, where replacement vesicles are stored for replenishment of the release site.

Di-(2-ethylhexyl) phthalate (DEHP) is a chemical that is widely used as a plasticizer. Exposure to DEHP has been shown to alter ovarian function in humans. Additionally, foods high in fat content, regularly found in the western diet, have been shown to be another potential disruptor of fetal ovarian function. Due to DEHP’s lipophilicity, high-fat foods can be easily contaminated. Therefore, exposure to DEHP and a high-fat diet are both health concerns, especially in pregnant women, and the effects of these exposures on fetal oocyte quality and quantity should be elucidated. In this study, our goal was to determine if there are synergistic effects of DEHP exposure at an environmentally relevant level (20 μg/kg body weight/day) and high-fat diet on oogenesis and folliculogenesis. Dams were fed with a high-fat diet (45 kcal% fat) or a control diet (10 kcal% fat) 1 week before mating and during pregnancy and lactation. The pregnant mice were dosed with DEHP (20 μg/kg body weight/day) or vehicle control from E10.5 to litter birth. We found that treatment with an environmentally relevant dosage of DEHP and consumption of high-fat diet significantly increases synapsis defects in meiosis and affects folliculogenesis in the F1 generation.

Although conventional biomedical research has largely focused on mechanisms of weight loss and genetic aspects of obesity, most medical solutions are plagued by side-effects and fraught with complex questions. As a consequence, consumers are seriously considering herbal products, nutraceuticals and functional foods as alternatives to conventional medications. This is evidently driven by a growing consumer understanding of diet/disease links, aging-related consequences, rising health care costs, and advances in food technology and nutrition. This study investigated the effects of up to 12 months exposure to a multinutrient and botanical extract supplement (Metabolic Nutrition System Orange (MNSO) - sold by AdvoCare, Carrollton, TX, USA) at five dietary concentrations on serum biochemistry and target organ histopathology of the hearts of B6C3F1 mice. The MNSO is a unique combination of vitamins, minerals, omega-3 fatty acids and herbal extracts designed to provide a strong foundation of nutritional support, and to enhance thermogenesis and perception of energy. The MNSO contain extracts of citrus, ephedra, guarana, gingko, green tea and Ocimum. In this study, female B6C3F1 mice were fed control (−MNSO) or MNSO (one time to ten times, one time = daily human dose) diets. Animals were sacrificed after 4, 8 and 12 months’, at which time blood was collected for serum chemistry analysis, and hearts were prepared for histopathology and tissue biochemistry. Food consumption and body weight changes were also monitored throughout the study. The MNSO exposure did not significantly affect any of the cardiosensitive enzymes [including creatine kinase (CK), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST)] and normal histopathological architecture of the heart was observed. Although animals given the MNSO diet consumed more food, they were relatively leaner and more active compared to controls. The results indicate that ingestion of ephedra and caffeine for one year in the doses used as part of a comprehensive metabolic nutrition system does not significantly alter normal serum chemistry or induce any irreversible histological changes in the mouse heart, since this study employed up to ten times the normal human consumption dose of ephedra and the metabolic nutrition system.