Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants

The electron transport chain (ETC) is a well-studied and highly conserved metabolic pathway that produces ATP through generation of a proton gradient across the inner mitochondrial membrane coupled to oxidative phosphorylation. ETC mutations are associated with a wide array of human disease conditions and to aging-related phenotypes in a number of different organisms. In this study, we sought to better understand the role of the ETC in aging using a yeast model. A panel of ETC mutant strains that fail to survive starvation was used to isolate suppressor mutants that survive. These suppressors tend to fall into major nutrient sensing and signaling pathways, suggesting that the ETC is involved in proper starvation signaling to these pathways in yeast. These suppressors also partially restore ETC-associated gene expression and pH homeostasis defects, though it remains unclear whether these phenotypes directly cause the suppression or are simply effects. This work further highlights the complex cellular network connections between metabolic pathways and signaling events in the cell and their potential roles in aging and age-related diseases.     

Inter-species variation in yolk steroid levels and a cowbird-host comparison

We examined variability in yolk hormone levels among songbird species and the role of yolk steroids as a mechanism for enhanced exploitation of hosts by the parasitic brown-headed cowbird Molothrus ater . Within-clutch variation in yolk steroids has been found in several avian species in single species studies, but few comparisons have been made among species. We found a large range of differences in yolk testosterone among the seven passerine species examined, with significant differences between those at the high end (song sparrow Melospiza melodia , red-winged blackbird Agelaius phoeniceus , and house sparrow, Passer domesticus ) and those at the low end (eastern phoebe Sayornis phoebe , and house finch Carpodacus mexicanus ). We also found that the testosterone level in cowbird eggs was intermediate in relation to host species levels and was significantly lower than that in three common cowbird hosts (song sparrow, red-winged blackbird, and house sparrow), but not significantly different from three others. Geographical comparisons of yolk testosterone levels in all cowbird subspecies and populations from several regions showed no significant differences, though a trend that deserves further exploration was the pattern of lowest level in the ancestral population of cowbirds in the central prairies and of highest level in the northwestern population where range invasion occurred approximately 40 years ago. The levels of 17 beta-estradiol were similar in the seven songbird species examined, which is consistent with current hypotheses that this hormone plays a role in embryonic sexual differentiation. Further investigation is needed to determine whether the large differences observed among species in absolute level of yolk testosterone are the relevant focal point or whether target tissue sensitivity differences mediate the effects of this yolk steroid, particularly between parasitic and non-parasitic species.     

Species distribution and <Emphasis Type="Italic">in vitro</Emphasis> antifungal susceptibility of oral yeast isolates from Tanzanian HIV-infected patients with primary and recurrent oropharyngeal candidiasis

Background  

In Tanzania, little is known on the species distribution and antifungal susceptibility profiles of yeast isolates from HIV-infected patients with primary and recurrent oropharyngeal candidiasis.     

Effects of risk, cost, and their interaction on optimal escape by nonrefuging Bonaire whiptail lizards, Cnemidophorus murinus

Optimal escape theory seeks to explain variation in the distanceto an approaching predator at which the prey initiates escape(flight initiation distance). Flight initiation distance increaseswhen predators pose a greater threat and decreases when escapecosts increase. Although optimal escape theory has been highlysuccessful, its predictions have been tested primarily for speciesthat escape to discrete refuges, and most studies have focusedon single risk or cost factors. We present data from two experimentsin which two risks or a risk and a cost varied in Bonaire whiptaillizards (Cnemidophorus murinus) that escaped without enteringrefuges. Our data verify several predictions about optimal escapefor nonrefuging lizard prey. Two risk factors, speed and directnessof approach by the predator, interacted. Directly approachedlizards had greater flight initiation distances than did indirectlyapproached lizards when approached rapidly, but shorter flightinitiation distances when approached slowly. Flight initiationdistance was shorter in the presence of food and during slowversus rapid approaches, but contrary to expectation, food presenceand approach speed did not interact. This would be explainedif cost curves are nonlinear or if they are parallel ratherthan intersecting when the predator reaches the prey. More empiricalwork is needed to determine which risk and cost factors actadditively and which act synergistically. The absence of interactionbetween the risk and cost factors suggests that cost curveswere nonlinear.     

Exploiting flavour preferences of common marmosets to increase palatability of a dry pellet diet

Although commercially available complete diets exist for common marmosets, the animals’ consumption of these diets (available in dry pellet form) is typically very low. Increasing consumption of the pellet diet could have positive consequences for the welfare of the marmosets as the pellets are designed specifically to meet their full nutritional requirements, and therefore an increase in intake should help to ensure that they take in an appropriate balance of nutrients. We carried out a series of studies targeted towards improving the palatability, and hence increasing the intake, of a complete dry pellet diet for marmosets. In Study 1 we attempted to determine which of a wide range of flavours appeared to be preferred by the marmosets. In Study 2 we tested the marmosets’ preferences for a smaller number of highly preferred flavours (as determined in Study 1) when actually added to the dry pellet diet in a series of paired preference tests. Finally, in Study 3 we tested whether adding the most highly preferred flavours (as determined in Study 2) to the dry pellet diet would in fact increase consumption of these pellets in comparison with unflavoured pellets. Despite finding strong and consistent preferences for particular flavours amongst the marmosets, we found that adding these to the pellets did not significantly increase consumption. Reasons for this are discussed, along with other potential modifications which might prove more successful in increasing consumption of pellet diets for marmosets.     

The discovery of tropane derivatives as nociceptin receptor ligands for the management of cough and anxiety

The discovery of 1 as a high-affinity ligand for the nociceptin receptor has led to the synthesis of a series of tropane (8-methyl-8-azabicyclo[3.2.1]octane) derivatives as optimized ligands. These compounds exhibit high affinity for the nociceptin receptor, moderate to excellent selectivity over the opioid μ receptor, and behave as full agonists. In this Letter, we present the synthesis and highlight the structure–activity relationship of tropane derivatives culminating in the identification of 24 and 32 as potent and orally active antitussive and anxiolytic agents. The in vitro and in vivo activities, pharmacokinetic profile, and the hPXR activity, which predicts the potential 3A4 induction in human, are disclosed.     

Synthesis and structure–activity relationships of N-substituted spiropiperidines as nociceptin receptor ligands: Part 2

A series of N-8 substituted analogs based upon the spiropiperidine core of the original lead compound 1 was synthesized. This lead has been elaborated to compounds to give compounds 2 and 3 (R = H) that exhibited high NOP binding affinity as well as selectivity against other known opioid receptors. These two series have been further functionalized at the amido nitrogen. The synthesis and structure–activity relationship (SAR) of these and related compounds are discussed.