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Recently, we demonstrated that the anti-bacterial agent tigecycline preferentially induces death in leukemia cells through the inhibition of mitochondrial protein synthesis. To better understand the mechanisms of sensitivity and resistance to mitochondrial translation inhibition, we treated TEX leukemia cells with increasing concentrations of tigecycline over 4 months, and selected a population of cells resistant to tigecycline (RTEX+TIG). Compared to their wild type counterparts, the resistant RTEX+TIG cells had an altered metabolic profile with diminished oxidative phosphorylation and a greater reliance on glycolysis. Upon removal of tigecycline from RTEX+TIG cells, the cells re-established aerobic metabolism and oxidative phosphorylation to wild type levels. At the molecular level, these cells had increased levels of HIF1a. Strikingly, tigecycline-resistant cells had decreased expression of CD34 and CD117, clonogenic growth potential and engraftment capabilities in vivo. Thus, chronic inhibition of mitochondrial translation leads to the establishment of rho-zero-like metabolic phenotype, and is associated with differentiation of leukemia cells.

The roles of vitamin C and the effects of supplementation have been under investigation for many years. The purpose of this study was to use high performance liquid chromatography to assess the presence of vitamin C in human sweat, to evaluate sweat as a possible excretory route for vitamin C and to note any effects of vitamin C supplementation. Vitamin C in sweat was determined in samples from 10 active men and women prior to supplementation and weekly for 4 consecutive weeks as the vitamin C supplements were with a reverse-phase liquid chromatograph (Model ALC-202) equipped with a solvent delivery system (Model 6000, Waters Association).The presence of vitamin C in sweat samples was indicated by comparing peaks to those seen with vitamin C observed in sweat samples. Vitamin C was observed in sweat at the end of the first week of supplementation. The pres C.However, 4 and 5 when standards. During the first week of the study, when subjects' diets were not supplemented, vitamin C was not observed in sweat samples. Vitamin C was observed in sweat at the end of the first week o supplementation. The presence of vitamin C in sweat diminished during weeks 4 and 5 when intakes were supplemented with 750 mg and 1000 mg, respectively. It appeared that supplementation affected the presence of vitamin C in human sweat until plasma or tissues were saturated, at which point absorption may have decreased and other means of excretion may have been enhanced.

Hybridization between species has the potential to exert pleiotropic effects on metabolism. Reduced fitness in hybrids may arise through incompatibilities between nuclear- and mitochondrial-encoded subunits of the enzyme complexes of oxidative phosphorylation. In my thesis, I examined metabolic properties and hypoxia tolerance of bluegill (Lepomis macrochirus), pumpkinseed (L. gibbosus), and their unidirectional F1 hybrids (male bluegill x female pumpkinseed). Electron transport system (ETS) complex activities were examined in isolated mitochondria of bluegill, pumpkinseed and hybrids. The specific activities (units per mg mitochondrial protein) of complexes I, II, and V were indistinguishable between groups; however, both complex III and IV showed indications of depressed activities in hybrid mitochondria. The nature of sequence differences in complex IV catalytic subunits (CO1, CO2, CO3) were minor, however the mtDNA-encoded subunit of complex III (cytochrome b) showed 8 differences between bluegill and pumpkinseed, several of which could have structural consequences to the multimeric enzyme and contribute to the depressed complex III catalytic activity in hybrids. I next examined hypoxia tolerance in bluegill, pumpkinseed and hybrids to see if metabolic disruption in hybrids would lead to a reduced ability to cope with this stress. Though no difference in critical oxygen concentration (Pcrit) was noted, the time to loss of equilibrium (LOE) in 0.8 mg O2 /ml suggests that hybrids and bluegills have a lower hypoxia tolerance than pumpkinseeds. Hybrids showed a unique independence between size and LOE time. Analysis of tissue metabolite levels during normoxia, after LOE, and after a short-term hypoxia exposure suggest that differences in hypoxia tolerance are not due to differences in starting metabolite levels or differential metabolite use during hypoxia exposure. / Thesis (Master, Biology) -- Queen's University, 2013-08-30 15:08:45.779

The intent of this investigation was to determine the effects of contractile velocity on muscle glycogen depletion patterns during maximal isokinetic contractions.Three physically active male subjects performed maximal knee extensions and flexions using the Cybex II. Work was performed with one leg at a contractile volecity of 60 degs./sec. (1.05 rads./sec.) and the other at 300 degs./sec. (5.23 rads./sec.). Histochemical data was collected from muscle samples taken from the vastus lateralis m. of each leg. Gylcogen depletion patterns were later observed from a periodic-acid Schiffs stain (PAS) on the muscle sections. Additional muscle samples were freeze-dried for single fiber evaluation, of glycogen content. Both fast twitch (FT) and slow twitch (ST) muscle fibers were depleted of glycogen equally during each of the contractile velocities. Observations from FAS staining suggest that most of the FT fibers were depleted before the ST fibers. The results of this study indicate that the glycogen depletion pattern is independent of the velocity of contraction. This study also supports previous investigations in suggesting that the intensity of muscular contraction is one of the major determinants of the glycogen depletion pattern.

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