Neuronal SIRT1 regulates metabolic and reproductive function and the response to caloric restriction

Sirt1 is a NAD-dependent class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism. In this study we generated mice expressing an enzymatically inactive form (NMUT) or wild-type SIRT1 (N-OX) in mature neurons. Both N-OX male and female mice showed impaired glucose tolerance, and N-MUT female, but not male, mice showed improvedglucose tolerance compared to WT littermates. Furthermore, all mice showed improved glucose tolerance with caloric restriction (CR), but the N-OX mice showed the greatest change and now showed better glucose tolerance than their littermates. At the reproductive level, N-OX females showed impaired estrous cycles, with increased cycle length and more time in estrus. LH andprogesterone surges were absent on the evening of proestrus in the N-OX mice suggesting a defect in spontaneous ovulation, which was confirmed by the ovarian histology with a reduced number of corpora lutea. Despite this defect, the mice were still fertile when mated to wild-type mice on the day of pro-estrus indicating that the mice can respond to normal pheromonal or environmental cues. When subjected to CR, the N-OX mice went into diestrus arrest earlier than their littermates. Together, these results suggested that the overexpression of SIRT1 rendered the mice more sensitive to the metabolic improvements and suppression of reproductive cycles by CR, which was independent of circadian rhythms.Fil: Rickert, Emily. University of California at San Diego; Estados Unidos. VA San Diego Healthcare System; Estados UnidosFil: Fernandez, Marina Olga. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. University of California at San Diego; Estados UnidosFil: Gorman, Michael. University of California at San Diego; Estados UnidosFil: Olefsky, Jerrold M.. University of California at San Diego; Estados UnidosFil: Webster, Nicholas J.G.. Va San Diego Healthcare System; Estados Unidos. University of California at San Diego; Estados Unido

Rapid Development of an Integrated Network Infrastructure to Conduct Phase 3 COVID-19 Vaccine Trials

Importance: The COVID-19 pandemic has caused millions of infections and deaths and resulted in unprecedented international public health social and economic crises. As SARS-CoV-2 spread across the globe and its impact became evident, the development of safe and effective vaccines became a priority. Outlining the processes used to establish and support the conduct of the phase 3 randomized clinical trials that led to the rapid emergency use authorization and approval of several COVID-19 vaccines is of major significance for current and future pandemic response efforts. Observations: To support the rapid development of vaccines for the US population and the rest of the world, the National Institute of Allergy and Infectious Diseases established the COVID-19 Prevention Network (CoVPN) to assist in the coordination and implementation of phase 3 efficacy trials for COVID-19 vaccine candidates and monoclonal antibodies. By bringing together multiple networks, CoVPN was able to draw on existing clinical and laboratory infrastructure, community partnerships, and research expertise to quickly pivot clinical trial sites to conduct COVID-19 vaccine trials as soon as the investigational products were ready for phase 3 testing. The mission of CoVPN was to operationalize phase 3 vaccine trials using harmonized protocols, laboratory assays, and a single data and safety monitoring board to oversee the various studies. These trials, while staggered in time of initiation, overlapped in time and course of conduct and ultimately led to the successful completion of multiple studies and US Food and Drug Administration-licensed or -authorized vaccines, the first of which was available to the public less than 1 year from the discovery of the virus. Conclusions and Relevance: This Special Communication describes the design, geographic distribution, and underlying principles of conduct of these efficacy trials and summarizes data from 136 382 prospectively followed-up participants, including more than 2500 with documented COVID-19. These successful efforts can be replicated for other important research initiatives and point to the importance of investments in clinical trial infrastructure integral to pandemic preparedness

EXTINCTION OF A VACUUM ARC BY APPLICATION OF A TRANSVERSE MAGNETIC FIELD

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