RCAN1 knockout and overexpression recapitulate an ensemble of rest-activity and circadian disruptions characteristic of Down syndrome, Alzheimer's disease, and normative aging

Regulator of calcineurin 1 (RCAN1) is overexpressed in Down syndrome (DS), but RCAN1 levels are also increased in Alzheimer&rsquo;s disease (AD) and normal aging. AD is highly comorbid among individuals with DS and is characterized in part by progressive neurodegeneration that resembles accelerated aging. Importantly, abnormal RCAN1 levels have been demonstrated to promote memory deficits and pathophysiology that appear symptomatic of DS, AD, and aging. Anomalous diurnal rest-activity patterns and circadian rhythm disruptions are also common in DS, AD, and aging and have been implicated in facilitating age-related cognitive decline and AD progression. However, no prior studies have assessed whether RCAN1 dysregulation may also promote the age-associated alteration of rest-activity profiles and circadian rhythms, which could in turn contribute to neurodegeneration in DS, AD, and aging. &nbsp;</p

Leptin Stimulates Cellular Glycolysis Through a STAT3 Dependent Mechanism in Tilapia

We assessed if leptin, a cytokine hormone known to enhance energy expenditure by promoting lipid and carbohydrate catabolism in response to physiologic stress, might directly regulate cellular glycolysis. A transcriptomic analysis of prolactin cells in the tilapia (Oreochromis mossambicus) pituitary rostral pars distalis (RPD) revealed that recombinant leptin (rtLep) differentially regulates 1,995 genes, in vitro. Machine learning algorithms and clustering analyses show leptin influences numerous cellular gene networks including metabolism; protein processing, transport, and metabolism; cell cycle and the hypoxia response. Leptin stimulates transcript abundance of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (gapdh) in a covariate manner to the hypoxic stress gene network. Orthogonal tests confirm that rtLepA dose-dependently increases gapdh gene expression in the RPD along with transcript abundance of 6-phosphofructo-1-kinase (pfk1), the rate limiting glycolytic enzyme. Functional testing demonstrated that leptin stimulates PFK activity and glycolytic output, while Stattic (a STAT3 blocker) was sufficient to suppress these responses, indicating leptin stimulates glycolysis through a STAT3-dependent mechanism. Leptin also stimulated pfk1 gene expression and lactate production in primary hepatocyte incubations in a similar manner to those shown for the pituitary RPD. This work characterizes a critical metabolic action of leptin to directly stimulate glycolysis across tissue types in a teleost model system, and suggest that leptin may promote energy expenditure, in part, by stimulating glycolysis. These data in a teleost fish, suggest that one of leptin's ancient, highly-conserved functions among vertebrates may be stimulation of glycolysis to facilitate the energetic needs associated with various stressors

Gender Separation Increases Somatic Growth in Females but Does Not Affect Lifespan in Nothobranchius furzeri

According to life history theory, physiological and ecological traits and parameters influence an individual's life history and thus, ultimately, its lifespan. Mating and reproduction are costly activities, and in a variety of model organisms, a negative correlation of longevity and reproductive effort has been demonstrated. We are employing the annual killifish Nothobranchius furzeri as a vertebrate model for ageing. N. furzeri is the vertebrate displaying the shortest known lifespan in captivity with particular strains living only three to four months under optimal laboratory conditions. The animals show explosive growth, early sexual maturation and age-dependent physiological and behavioural decline. Here, we have used N. furzeri to investigate a potential reproduction-longevity trade-off in both sexes by means of gender separation. Though female reproductive effort and offspring investment were significantly reduced after separation, as investigated by analysis of clutch size, eggs in the ovaries and ovary mass, the energetic surplus was not reallocated towards somatic maintenance. In fact, a significant extension of lifespan could not be observed in either sex. This is despite the fact that separated females, but not males, grew significantly larger and heavier than the respective controls. Therefore, it remains elusive whether lifespan of an annual species evolved in periodically vanishing habitats can be prolonged on the cost of reproduction at all

The triterpene echinocystic acid and its 3-O-glucoside derivative are revealed as potent and selective glucocorticoid receptor agonists

Glucocorticoids are steroid hormones widely used to control many inflammatory conditions. These effects are primarily attributed to glucocorticoid receptor transrepressional activities but with concomitant receptor transactivation associated with considerable side effects. Accordingly, there is an immediate need for selective glucocorticoid receptor agonists able to dissociate transactivation from transrepression. Triterpenoids have structural similarities with glucocorticoids and exhibit anti-inflammatory and apoptotic activities via mechanisms that are not well-defined. In this study, we examined whether echinocystic acid and its 3-O-glucoside derivative act, at least in part, through the regulation of glucocorticoid receptor and whether they can constitute selective receptor activators. We showed that echinocystic acid and its glucoside induced glucocorticoid receptor nuclear translocation by 75% and 55%. They suppressed the nuclear factor-kappa beta transcriptional activity by 20% and 70%, respectively, whereas they have no glucocorticoid receptor transactivation capability and stimulatory effect on the expression of the phosphoenolopyruvate carboxykinase target gene in HeLa cells. Interestingly, their suppressive effect is diminished in glucocorticoid receptor low level COS-7 cells, verifying the receptor involvement in this process. Induced fit docking calculations predicted favorable binding in the ligand binding domain and structural characteristics which can be considered consistent with the experimental observations. Further, glucocorticoids exert apoptotic activities; we have demonstrated here that the echinocystic acids in combination with the synthetic glucocorticoid, dexamethasone, induce apoptosis. Taken together, our results indicate that echinocystic acids are potent glucocorticoid receptor regulators with selective transrepressional activities (dissociated from transactivation), highlighting the potential of echinocystic acid derivatives as more promising treatments for inflammatory conditions

Congressional Record Tribute: Burd, James E.

Commander Burd received his Masters Degree in Aeronautical Engineering from the Naval Postgraduate School. He also attended the Defense Systems Management College.Mr. BORSKI. Mr. Speaker, I would like to extend my deepest congratulations to Commander James E. Burd, the Commanding Officer of the Naval Air Technical Services Facility, on his retirement. Commander Burd was born in Harrisburg and raised in Pittsburgh, Pennsylvania. In 1975 he graduated from the United States Naval Academy and he obtained of his pilot wings a year later. He was initially assigned to a Helicopter Combat Squadron and flew an H–46D helicopter aboard the USS White Plains (AFS–4), USS Midway (CV–41), and USS Niagara Falls (AFS–3) in the Pacific and Indian Oceans. In 1980, Commander Burd received his Masters Degree in Aeronautical Engineering from the Naval Postgraduate School. He also attended the Defense Systems Management College where he issued over 2,200 individual engineering safety clearances for almost every aircraft and aviation weapon system in the Navy and Marine Corps inventory, in addition to the prototype and classified systems successfully employed during Desert Storm. While aboard the USS Shasta (AE–33), he demonstrated true heroism by helping to save an aircraft from a ditching situation. By 1984, he was appointed as an Aeronautical Engineering Duty Officer, yet he still found the time to volunteer as a Detachment Officer in Charge of a helicopter deployment aboard USS Flint (AE–32).Approved for public release; distribution is unlimited

Congressional Record Tribute: Burd, James E.

Commander Burd received his Masters Degree in Aeronautical Engineering from the Naval Postgraduate School. He also attended the Defense Systems Management College.Mr. BORSKI. Mr. Speaker, I would like to extend my deepest congratulations to Commander James E. Burd, the Commanding Officer of the Naval Air Technical Services Facility, on his retirement. Commander Burd was born in Harrisburg and raised in Pittsburgh, Pennsylvania. In 1975 he graduated from the United States Naval Academy and he obtained of his pilot wings a year later. He was initially assigned to a Helicopter Combat Squadron and flew an H–46D helicopter aboard the USS White Plains (AFS–4), USS Midway (CV–41), and USS Niagara Falls (AFS–3) in the Pacific and Indian Oceans. In 1980, Commander Burd received his Masters Degree in Aeronautical Engineering from the Naval Postgraduate School. He also attended the Defense Systems Management College where he issued over 2,200 individual engineering safety clearances for almost every aircraft and aviation weapon system in the Navy and Marine Corps inventory, in addition to the prototype and classified systems successfully employed during Desert Storm. While aboard the USS Shasta (AE–33), he demonstrated true heroism by helping to save an aircraft from a ditching situation. By 1984, he was appointed as an Aeronautical Engineering Duty Officer, yet he still found the time to volunteer as a Detachment Officer in Charge of a helicopter deployment aboard USS Flint (AE–32).Approved for public release; distribution is unlimited