Experimental demonstration of a W-band gyroklystron amplifier

The experimental demonstration of a four cavity W-band (93 GHz) gyroklystron amplifier is reported. The gyroklystron has produced 67 kW peak output power and 28% efficiency in the TE011 mode using a 55 kV, 4.3 A electron beam. The full width at half maximum instantaneous bandwidth is greater than 460 MHz, a significant increase over the bandwidth demonstrated in previous W-band gyroklystron amplifier experiments. The amplifier is unconditionally stable at this operating point. Experimental results are in good agreement with theoretical predictions

It takes two to tango: NAD+ and sirtuins in aging/longevity control

The coupling of nicotinamide adenine dinucleotide (NAD⁺) breakdown and protein deacylation is a unique feature of the family of proteins called ‘sirtuins.’ This intimate connection between NAD⁺ and sirtuins has an ancient origin and provides a mechanistic foundation that translates the regulation of energy metabolism into aging and longevity control in diverse organisms. Although the field of sirtuin research went through intensive controversies, an increasing number of recent studies have put those controversies to rest and fully established the significance of sirtuins as an evolutionarily conserved aging/longevity regulator. The tight connection between NAD⁺ and sirtuins is regulated at several different levels, adding further complexity to their coordination in metabolic and aging/longevity control. Interestingly, it has been demonstrated that NAD⁺ availability decreases over age, reducing sirtuin activities and affecting the communication between the nucleus and mitochondria at a cellular level and also between the hypothalamus and adipose tissue at a systemic level. These dynamic cellular and systemic processes likely contribute to the development of age-associated functional decline and the pathogenesis of diseases of aging. To mitigate these age-associated problems, supplementation of key NAD⁺ intermediates is currently drawing significant attention. In this review article, we will summarize these important aspects of the intimate connection between NAD⁺ and sirtuins in aging/longevity control.National Institute on Aging (Grant AG037457)National Institute on Aging (Grant AG047902

Forecasting the seasonal timing of Maine's lobster fishery

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Frontiers in Marine Science 4 (2017): 337, doi:10.3389/fmars.2017.00337.The fishery for American lobster is currently the highest-valued commercial fishery in the United States, worth over US$620 million in dockside value in 2015. During a marine heat wave in 2012, the fishery was disrupted by the early warming of spring ocean temperatures and subsequent influx of lobster landings. This situation resulted in a price collapse, as the supply chain was not prepared for the early and abundant landings of lobsters. Motivated by this series of events, we have developed a forecast of when the Maine (USA) lobster fishery will shift into its high volume summer landings period. The forecast uses a regression approach to relate spring ocean temperatures derived from four NERACOOS buoys along the coast of Maine to the start day of the high landings period of the fishery. Tested against conditions in past years, the forecast is able to predict the start day to within 1 week of the actual start, and the forecast can be issued 3–4 months prior to the onset of the high-landings period, providing valuable lead-time for the fishery and its associated supply chain to prepare for the upcoming season. Forecast results are conveyed in a probabilistic manner and are updated weekly over a 6-week forecasting period so that users can assess the certainty and consistency of the forecast and factor the uncertainty into their use of the information in a given year. By focusing on the timing of events, this type of seasonal forecast provides climate-relevant information to users at time scales that are meaningful for operational decisions. As climate change alters seasonal phenology and reduces the reliability of past experience as a guide for future expectations, this type of forecast can enable fishing industry participants to better adjust to and prepare for operating in the context of climate change.This forecast was initiated with support from NSF Coastal SEES (OCE 1325484) and was developed with funds from NASA EPSCoR through Maine Space Grant Consortium (EP-15-03)

Small-Molecule Allosteric Activators of Sirtuins

The mammalian sirtuins (SIRT1–7) are NAD[superscript +]-dependent lysine deacylases that play central roles in cell survival, inflammation, energy metabolism, and aging. Members of this family of enzymes are considered promising pharmaceutical targets for the treatment of age-related diseases including cancer, type 2 diabetes, inflammatory disorders, and Alzheimer's disease. SIRT1-activating compounds (STACs), which have been identified from a variety of chemical classes, provide health benefits in animal disease models. Recent data point to a common mechanism of allosteric activation by natural and synthetic STACs that involves the binding of STACs to a conserved N-terminal domain in SIRT1. Compared with polyphenols such as resveratrol, the synthetic STACs show greater potency, solubility, and target selectivity. Although considerable progress has been made regarding SIRT1 allosteric activation, key questions remain, including how the molecular contacts facilitate SIRT1 activation, whether other sirtuin family members will be amenable to activation, and whether STACs will ultimately prove safe and efficacious in humans.Glenn Foundation for Medical ResearchNational Institute on Agin

The relation between productivity and species diversity in temperate-arctic marine ecosystems

Energy variables, such as evapotranspiration, temperature, and productivity explain significant variation in the diversity of many groups of terrestrial plants and animals at local to global scales. Although the ocean represents the largest continuous habitat on earth with a vast spectrum of primary productivity and species richness, little is known about how productivity influences species diversity in marine systems. To search for general relationships between productivity and species richness in the ocean, we analyzed data from three different benthic marine ecosystems (epifaunal communities on subtidal rock walls, on navigation buoys in the Gulf of St. Lawrence, and Canadian Arctic macrobenthos) across local to continental spatial scales (1000 km) using a standardized proxy for productivity, satellite-derived chlorophyll a. Theoretically, the form of the function between productivity and species richness is either monotonically increasing or decreasing, or curvilinear (hump- or U-shaped). We found three negative linear and three hump-shaped relationships between chlorophyll a and species richness out of 10 independent comparisons. Scale dependence was suggested by more prevalent diversity-productivity relationships at smaller (local, landscape) than larger (regional, continental) spatial scales. Differences in the form of the functions were more closely allied with community type than with scale, as negative linear functions were restricted to sessile epifauna while hump-shaped functions occurred in Arctic macrobenthos (mixed epifauna, infauna). In two of the data sets, (St. Lawrence epifauna and Arctic macrobenthos) significant effects of chlorophyll a co-varied with the effects of salinity, suggesting that environmental stress as well as productivity influences diversity in these marine systems. The co-varying effect of salinity may commonly arise in broad-scale studies of productivity and diversity in marine ecosystems when attempting to sample the largest range of productivity, often encompassing a coastal-oceanic gradient

Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy

SIRT1 is a metabolic sensor and regulator in various mammalian tissues and functions to counteract metabolic and age-related diseases. Here we generated and analyzed mice that express SIRT1 at high levels specifically in skeletal muscle. We show that SIRT1 transgenic muscle exhibits a fiber shift from fast-to-slow twitch, increased levels of PGC-1α, markers of oxidative metabolism and mitochondrial biogenesis, and decreased expression of the atrophy gene program. To examine whether increased activity of SIRT1 protects from muscular dystrophy, a muscle degenerative disease, we crossed SIRT1 muscle transgenic mice to mdx mice, a genetic model of Duchenne muscular dystrophy. SIRT1 overexpression in muscle reverses the phenotype of mdx mice, as determined by histology, creatine kinase release into the blood, and endurance in treadmill exercise. In addition, SIRT1 overexpression also results in increased levels of utrophin, a functional analogue of dystrophin, as well as increased expression of PGC-1α targets and neuromuscular junction genes. Based on these findings, we suggest that pharmacological interventions that activate SIRT1 in skeletal muscle might offer a new approach for treating muscle diseases.American Heart Association (Postdoctoral Fellowship)National Institutes of Health (U.S.)Glenn Foundation for Medical Researc

Caloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway

Machado–Joseph disease (MJD) is a neurodegenerative disorder characterized by an abnormal expansion of the CAG triplet in the ATXN3 gene, translating into a polyglutamine tract within the ataxin-3 protein. The available treatments only ameliorate symptomatology and do not block disease progression. In this study we find that caloric restriction dramatically rescues the motor incoordination, imbalance and the associated neuropathology in transgenic MJD mice. We further show that caloric restriction rescues SIRT1 levels in transgenic MJD mice, whereas silencing SIRT1 is sufficient to prevent the beneficial effects on MJD pathology. In addition, the re-establishment of SIRT1 levels in MJD mouse model, through the gene delivery approach, significantly ameliorates neuropathology, reducing neuroinflammation and activating autophagy. Furthermore, the pharmacological activation of SIRT1 with resveratrol significantly reduces motor incoordination of MJD mice. The pharmacological SIRT1 activation could provide important benefits to treat MJD patients.Fonds Europeen de Developpement Economique et Regional. Competitive Factors Operational Program (CENTRO-07-ST24-FEDER-002002)Fundação para a Ciência e a Tecnologia (Portugal) (Strategic Project UID/NEU/04539/2013, E-Rare4/0003/2012)French Muscular Dystrophy Association (AFM-Téléthon)National Ataxia FoundationRichard Chin and Lily Lock Machado-Joseph Disease Research Fun

Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study

NRPT is a combination of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD⁺) precursor vitamin found in milk, and pterostilbene (PT), a polyphenol found in blueberries. Here, we report this first-in-humans clinical trial designed to assess the safety and efficacy of a repeat dose of NRPT (commercially known as Basis). NRPT was evaluated in a randomized, double-blind, and placebo-controlled study in a population of 120 healthy adults between the ages of 60 and 80 years. The study consisted of three treatment arms: placebo, recommended dose of NRPT (NRPT 1X), and double dose of NRPT (NRPT 2X). All subjects took their blinded supplement daily for eight weeks. Analysis of NAD⁺ in whole blood demonstrated that NRPT significantly increases the concentration of NAD⁺ in a dose-dependent manner. NAD⁺ levels increased by approximately 40% in the NRPT 1X group and approximately 90% in the NRPT 2X group after 4 weeks as compared to placebo and baseline. Furthermore, this significant increase in NAD⁺ levels was sustained throughout the entire 8-week trial. NAD⁺ levels did not increase for the placebo group during the trial. No serious adverse events were reported in this study. This study shows that a repeat dose of NRPT is a safe and effective way to increase NAD⁺ levels sustainably

SIRT1 is a positive regulator of in vivo bone mass and a therapeutic target for osteoporosis

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Overexpression or pharmacological activation of SIRT1 has been shown to extend the lifespan of mice and protect against aging-related diseases. Here we show that pharmacological activation of SIRT1 protects in two models of osteoporosis. Ovariectomized female mice and aged male mice, models for post-menopausal and aging-related osteoporosis, respectively, show significant improvements in bone mass upon treatment with SIRT1 agonist, SRT1720. Further, we find that calorie restriction (CR) results in a two-fold upregulation of sirt1 mRNA expression in bone tissue that is associated with increased bone mass in CR mice. Reciprocally, SIRT1 whole-body knockout (KO) mice, as well as osteoblast and osteoclast specific KOs, show a low bone mass phenotype; though double knockout mice (containing SIRT1 deleted in both osteoblasts and osteoclasts) do not show a more severe phenotype. Altogether, these findings provide strong evidence that SIRT1 is a positive regulator of bone mass and a promising target for the development of novel therapeutics for osteoporosis