Thesis--University of Denver. / Bibliography: leaves [107]-119.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1981. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 87-89).

Thesis (M.S.)--Miami University, Dept. of Zoology, 2006. / Title from first page of PDF document. Includes bibliographical references (p. 25-30).

Thesis (M.D.)--Boston University

The central fatigue hypothesis suggests that during prolonged exercise, the increased plasma free-tryptophan (f-Trp) concentration may lead to an increased rate of synthesis of brain serotonin (5-HT). This may impair central nervous system function and cause increased perceptions of fatigue and deteriorate exercise performance. Two-fold increases in plasma concentrations of f-Trp have resulted in a 20% and 53% increase in brain Trp and forebrain Trp respectively. In addition, it has been suggested that 5-HT is involved in the stimulation of PRL release. The aim of the present thesis was to examine the relationship between the main peripheral markers of central fatigue, namely venous concentrations of f-Trp and prolactin (PRL), under three different experimental conditions. It was hypothesised that the changes in venous concentrations of f-Trp and PRL would exhibit similar patterns. Plasma f-Trp concentration increased by 110% after 2 h of cycling in normobaric hypoxia at a workload corresponding to 55% of FO2max determined in normobaric normoxia (P < 0.05). Serum PRL concentration did not differ between trials but the mean concentration increased at 30 min post exercise (P < 0.05). Following highintensity exercise for 30 s, plasma f-Trp concentration decreased by 23.5% (P < 0.05), whereas serum PRL concentration did not change (P > 0.05). Oral administration of L-Trp was followed by an increased plasma f-Trp concentration of 920%, however, plasma PRL concentrations decreased by 32.6% at the same time-point (P < 0.05). Analysis of functional magnetic resonance imaging of the brain demonstrated a different pattern of brain activation while subjects performed the interference task of the counting Stroop test following L-Trp ingestion. From these results it can be proposed that central fatigue is likely not to play any part during high-intensity exercise lasting 30s. However, the 110% and 920% increase in plasma f-Trp concentration during prolonged exercise in normobaric hypoxia and following oral administration of L-Trp respectively may have led to an increased rate of brain 5-HT synthesis, although venous concentrations of PRL were not in support of this increase. There may be many reasons for the lack of relationship between the two peripheral markers of central fatigue, including an effect of the catecholamines on inhibiting PRL secretion. During oral ingestion of L-Trp, the increased plasma f-Trp concentration may also have caused the increased brain activation in the areas known to house 5-HT neurones, and for the unique pattern of brain activation when performing a cognitive task. It remains to be established whether the increased f-Trp concentration, and unique brain activation pattern is evidence of fatigue originating within the brain.

The finding that NAD+ plays a role in a variety of signalling pathways, including gene expression, Ca2+ signalling and DNA repair mechanisms, has sparked interest in the proteins involved in these pathways as potential pharmacological targets for drug development. Recently, FK866, a potent inhibitor of nicotinamide phosphoribosyltransferase (Nampt) an important enzyme in the NAD+ rescue pathway, has been evaluated in clinical trials against cancer. The aim of this study is to further investigate the mechanisms and therapeutic characteristics of FK866 in different cancer cell lines and to determine if decreasing intracellular NAD+ levels can be used as a co-therapy strategy to improve the efficacy of current and new chemotherapy treatments. Experiments measuring cell vitality showed that FK866 dose-dependently decreased cell vitality. To investigate NAD+ consumption during Nampt inhibition, NAD+ levels were measured in cells treated with FK866 and inhibition of each of the main NAD+ consuming enzymes (PARP, sirtuins or CD38). This revealed differential NAD+ consumption rates by the different NAD+ consuming enzymes in MDA-MB-231 cells, with sirtuins being the major NAD+ consuming enzyme. The glycolytic effects of Nampt inhibition was measured using SEAHORSE assays; which measured the oxygen consumption and extracellular acidification rates as well as measuring NAD+/ NADH ratios. In the MCF-7 and MDA-MB-231 cell lines, FK866 had no effect on the oxygen consumption rates; however there was a general decrease in extracellular acidification rates indicating an effect on glycolytic activity. When measuring the NAD+/NADH ratio however, there was only a decrease in the MDA -MB-231 cells but no change in the MCF-7 cell line. Cell vitality and NAD+ levels were measured after treatment with FK866 in addition to NAD+ consuming enzyme inhibitors or the alkylating agent, Temozolomide to see if combination therapy would have more cytotoxic potential. This co-treatment indicated that there was no real positive effect on either the MCF-7 or MDA-MB-231 cells in either the cell vitality or NAD+ levels. Finally the effects of FK866 and the oral PARP inhibitor, Olaparib, were investigated using 3D cell culture (spheroids) and compared with 2D monolayer cultures. The effects of FK866 showed little difference in spheroid or monolayer culture. However, when treating with Olaparib there was higher level of cell viability and NAD+ levels with the cells grown in spheroid culture in comparison to cells grown in monolayer. In conclusion, this study has shown that FK866, as a single treatment decreases cell vitality, NAD+ levels and glycolytic activity. However as a co -therapy with PARP or Sirtuin inhibitors there is an increase in the cell vitality and NAD+ levels. Although similarities have been seen between spheroid culture and monolayers as a single treatment, FK866 does not seem to have the beneficial effects as a therapeutic.

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Previous work on tensile and compressive failure of both monofibre and hybrid unidirectional composites is reviewed, together with a summary of some of the more important works on the variation of elastic modulus.

As a reliable, convenient, and advantageous tool in the theoretical investigations of bioorganic, inorganic, and organometallic chemistry, density functional theory (DFT) computations have provided chemists with numerous significant insights. The understanding of mechanisms of chemical reactions, and the design and development of catalysts have been greatly promoted by the employment of DFT. In this dissertation, the applications of DFT computations in the catalytic bioorganic, inorganic, and organometallic systems were studied. Phosphoramidate hydrolysis catalyzed by human histidine triad nucleotide binding protein 1 (hHint1) was investigated using a cluster-model DFT approach, and the key involvement of the histidine triad as a proton shuttle was discussed in the proposed mechanism. The IEFPCM-Bondi-B3LYP/BS1 methodology was demonstrated as a reliable, and time-saving model in computing the reduction potentials of transition metal complexes. Moderate accuracy (MAD = 0.233 V, mean absolute deviation) and good linear correlation (R2 = 0.93) between computed and experimental reduction potentials of the 49 studied species are osberved. The fluxionality of cyclohexenyl manganese tricarbonyl [(C6H9)Mn(CO)3] was investigated using DFT computations, which uncovered a previously uncharacterized “closed” Cs agostomer. The intramolecular oxidative amination of an alkene catalyzed by the extreme π-loading N-heterocyclic carbene pincer Tantalum(V) bis(imido) complex was also computationally analyzed, and the mechanisms of the formation of oxidative amination product, reduction product, and hydroamination product were investigated. The computational results are consistent with the experimentally observed product ratios and selectivity.