Competition in the chemostat with an undesirable lethal competitor.

In this study, we compare the effects of competitors in a chemostat when one of the competitors is lethal to the other. The first competitor ("the mutant") is the desired organism because it provides a benefit, such as a substance that is harvested. However, when the mutant undergoes cell division the result may return to the original ("wild type") organism that produces a substance ("toxin") that is lethal to the mutant.

Left ventricle transcriptomic analysis reveals connective tissue accumulation associates with initial age-dependent decline in V̇o2peak from its lifetime apex.

Peak oxygen consumption (V̇o) strongly predicts morbidity and mortality better than other established risk factors, yet mechanisms associated with its age-associated decline are unknown. Our laboratory has shown that V̇o first begins to decrease at the same age of 19-20 wk in both sedentary and wheel-running, female Wistar rats (Toedebusch et al., Physiol Genomics 48: 101-115, 2016).

AMPK agonist AICAR delays the initial decline in lifetime-apex V̇o2 peak, while voluntary wheel running fails to delay its initial decline in female rats.

There has never been an outcome measure for human health more important than peak oxygen consumption (V̇o2 peak), yet little is known regarding the molecular triggers for its lifetime decline with aging. We examined the ability of physical activity or 5 wk of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) administration to delay the initial aging-induced decline in lifetime-apex V̇o2 peak and potential underlying molecular mechanisms. Experiment 1 consisted of female rats with (RUN) and without (NO RUN) running wheels, while experiment 2 consisted of female nonrunning rats getting the AMPK agonist AICAR (0.

Reduced metabolic disease risk profile by voluntary wheel running accompanying juvenile Western diet in rats bred for high and low voluntary exercise.

Metabolic disease risk is influenced by genetics and modifiable factors, such as physical activity and diet. Beginning at 6 weeks of age, rats selectively bred for high (HVR) versus low voluntary running distance (LVR) behaviors were housed in a complex design with or without voluntary running wheels being fed either a standard or Western (WD, 42% kcal from fat and added sucrose) diet for 8 weeks. Upon intervention completion, percent body fat, leptin, insulin, and mediobasal hypothalamic mRNAs related to appetite control were assessed.

2-aryloxy-4-alkylaminopyridines: discovery of novel corticotropin-releasing factor 1 antagonists.

An orally active clinical candidate of corticotropin-releasing factor 1 (CRF 1) antagonist 1 showed a significant positive food effect in dog and human after oral administration. Efforts to address the food effect issue led us to explore and discover compounds in series 2 as orally active CRF 1 receptor antagonists, in which some compounds showed improved physicochemical properties while retaining desired pharmacological properties. Compound 3a (CP-376395) was selected for further development, due not only to its reduced food effects but also its greater efficacy in CNS models.