The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition.

For nearly a century developmental biologists have recognized that cells from embryos can differ in their potential to differentiate into distinct cell types. Recently, it has been recognized that embryonic stem cells derived from both mice and humans exhibit two stable yet epigenetically distinct states of pluripotency: naive and primed. We now show that nicotinamide N-methyltransferase (NNMT) and the metabolic state regulate pluripotency in human embryonic stem cells (hESCs).  Specifically, in naive hESCs, NNMT and its enzymatic product 1-methylnicotinamide are highly upregulated, and NNMT is required for low S-adenosyl methionine (SAM) levels and the H3K27me3 repressive state. NNMT consumes SAM in naive cells, making it unavailable for histone methylation that represses Wnt and activates the HIF pathway in primed hESCs. These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development

The Saturn Ring Skimmer Mission Concept: The next step to explore Saturn's rings, atmosphere, interior, and inner magnetosphere

The innovative Saturn Ring Skimmer mission concept enables a wide range of investigations that address fundamental questions about Saturn and its rings, as well as giant planets and astrophysical disk systems in general. This mission would provide new insights into the dynamical processes that operate in astrophysical disk systems by observing individual particles in Saturn's rings for the first time. The Ring Skimmer would also constrain the origin, history, and fate of Saturn's rings by determining their compositional evolution and material transport rates. In addition, the Ring Skimmer would reveal how the rings, magnetosphere, and planet operate as an inter-connected system by making direct measurements of the ring's atmosphere, Saturn's inner magnetosphere and the material owing from the rings into the planet. At the same time, this mission would clarify the dynamical processes operating in the planet's visible atmosphere and deep interior by making extensive high-resolution observations of cloud features and repeated measurements of the planet's extremely dynamic gravitational field. Given the scientific potential of this basic mission concept, we advocate that it be studied in depth as a potential option for the New Frontiers program.Comment: White paper submitted to the Planetary Science and Astrobiology Decadal Survey (submission #420

The Saturn Ring Skimmer Mission Concept: The next step to explore Saturn's rings, atmosphere, interior and inner magnetosphere

The innovative Saturn Ring Skimmer mission concept enables a wide range of investigations that address fundamental questions about Saturn and its rings, as well as giant planets and astrophysical disk systems in general. This mission would provide new insights into the dynamical processes that operate in astrophysical disk systems by observing individual particles in Saturn's rings for the first time. The Ring Skimmer would also constrain the origin, history, and fate of Saturn's rings by determining their compositional evolution and material transport rates. In addition, the Ring Skimmer would reveal how the rings, magnetosphere, and planet operate as an inter-connected system by making direct measurements of the ring's atmosphere, Saturn's inner magnetosphere and the material owing from the rings into the planet. At the same time, this mission would clarify the dynamical processes operating in the planet's visible atmosphere and deep interior by making extensive high-resolution observations of cloud features and repeated measurements of the planet's extremely dynamic gravitational field. Given the scientific potential of this basic mission concept, we advocate that it be studied in depth as a potential option for the New Frontiers program

Gallbladder and Small Intestinal Regulation of Biliary Lipid Secretion during Intraduodenal Infusion of Standard Stimuli

The gallbladder and small intestine are reservoirs for the bile acid pool during its enterohepatic circulation and, as such, may regulate biliary secretion of bile acid. During studies of biliary bile acid secretion, a stimulus to gallbladder contraction is continuously infused into the duodenum. Under these conditions, it is assumed that the gallbladder is tonically contracted and that the rate of bile acid secretion into the duodenum equals the hepatic bile acid secretion rate. However, secretion rates vary by as much as 100%, depending upon which of two standard stimuli is used. Therefore, we studied the role of gallbladder emptying and small intestinal transit in determining biliary lipid secretion rate and composition during infusion of these stimuli in five healthy subjects. Each subject was studied with a liquid formula containing 40% of calories as fat, and with an amino acid solution for 10 h. Bile acid, phospholipid, cholesterol, and markers were measured in duodenal bile and hourly secretion rates were calculated by marker dilution technique. Real-time gallbladder sonographs and serum pancreatic polypeptide levels were obtained every 30 min. Small bowel transit time was estimated levels were obtained every 30 min. Small bowel transit time was estimated by the breath hydrogen response after giving lactulose intraduodenally. During liquid formula infusion, gallbladder emptying was more complete, small intestinal transit was faster, and pancreatic polypeptide levels were higher. Secretion rates of all lipids were greater and molar percent cholesterol was lower. For the combined data from both infusions, the secretory relationships of cholesterol to bile acid, cholesterol to phospholipid, and phospholipid to bile acid were curvilinear. We conclude that more complete gallbladder emptying and faster intestinal transit increase the enterohepatic cycling of bile acids and lower the molar percent cholesterol of bile. Some of the fluctuation observed in biliary lipid secretion rates, especially during amino acid infusion, is due to gallbladder refilling and emptying