Thesis (Ph. D.)--University of Missouri-Columbia, 2000. / Typescript. Vita. Includes bibliographical references. Also available on the Internet.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 106-115).

Thesis (M.S. in Systems Engineering)--Naval Postgraduate School, September 2003. / Thesis advisor(s): Gurminder Singh, Perry McDowell. Includes bibliographical references (p. 55-56). Also available online.

Thesis (M.S.)--Massachusetts Institute of Technology, 2002. / Includes bibliographical references (p. 51.52). Also available online.

Precancerous lesions from a variety of human tissues display markers of DNA damage suggesting that genetic instability occurs early during the process of carcinogenesis. Consistent with this, several oncogenes can activate ATM and other components of the DNA damage response pathway when expressed in cultured cells. Here we demonstrate that preneoplastic epithelial tissues from four different transgenic mouse models expressing the oncogenes c-myc, SV40 T antigen, human papilloma virus (HPV) E7, or E2F3a display [gamma]-H2AX foci and other markers of DNA damage. Moreover, transgenic expression of these oncogenes leads to increased levels of damaged DNA as measured by the comet assay. In at least the Myc transgenic model, the formation of [gamma]-H2AX foci is dependent on functional ATM. Inactivation of Atm also impairs p53 activation and reduces the level of apoptosis observed in transgenic tissue overexpressing Myc. This correlates with accelerated tumor development in Myc transgenic mice lacking ATM. To understand the mechanism by which oncogenes induce DNA damage, we employed an adenoviral overexpression system. Under conditions in which Myc or E2F3a induced replication is inhibited, we see a reduction in the DNA damage induced by these oncogenes both by comet assay and levels of [gamma]-H2AX. Moreover, Myc and E2F3a induced increased levels of the Cdt1 protein, a replication origin- licensing factor implicated in aberrant DNA replication. Taken together, these findings suggest that deregulated oncogenes induce unscheduled DNA replication leading to DNA damage and activation of the ATM DNA damage response pathway, which is important for the activation of p53, induction of apoptosis and the suppression of tumorigenesis. / text

Lead zirconate titantate (PZT) is an electroceramic material with many important technological applications in sensing and computer memory. Some of these applications require the PZT based devices to operate in radiation fields where they will be exposed to a high flux of energetic, heavy and light, charged and uncharged particles. The risk to any device exposed to ionizing radiation is the accumulation of displacement and ionization damage. Significant damage accumulation over time can lead to property drifts and, in some cases, failure of the device to perform properly. The goal of the undertaking recounted in this dissertation was to study changes in the ferroelectric properties of PZT exposed to the neutron field of a research nuclear reactor and to help develop an understanding for the type of radiation induced defects that play a dominant role in the degradation process. Thin film PZT capacitors were prepared using a wet chemical technique. The capacitors were then irradiated in a 1 MW TRIGA research nuclear reactor at the University of Texas at Austin up to a maximum 1 MeV equivalent neutron flux of 5.2 x 10¹⁵ cm⁻². Following irradiation, electronic characterization of polarization-electric field hysteresis loops, first order reversal curves, and small-signal permittivity were performed to ascertain tendencies between irradiation dose and ferroelectric properties. The measurements indicate a drop in remanent polarization, a loss of domain wall mobility, shifts in local switching fields and the formation of dipolar defects. These effects are all attributed to the introduction of defects into the material through displacement damage cascades. Numerical models of the damage cascades were performed to determine the displacement concentration. Comparison of those values and the primary recoil spectrum with typical survival rates found in the literature suggest that both free point defects as well as defect clusters are produced in comparable if not larger concentrations. It is proposed that defect clusters play a more significant role in ferroelectric property change than previously believed. / text

We evaluated the efficacy of treating eccentric muscle damage with IGF-1 PEGylated to a fibrin biomatrix. With one injection, delivered one hour after the induction of eccentric muscle damage we saw an attenuation of force loss early in recovery, maintenance of muscle weight, and progression to the repair/regeneration of the damaged fibers at a greater speed and magnitude in the first week of recovery. As opposed to introducing an unbound bolus of IGF-1, we believe the ability of the PEGylated-fibrin to stabilize and sustain delivery of the molecule results in significantly better recovery. Coupling IGF-1, which has multiple beneficial effects in tissue repair, with this system of delivery provides a simple and easy to administer treatment for eccentric muscle damage. With this form of damage being the most prevalent of all skeletal muscle damage types, since it is underlies all muscle strain, a simple and effective treatment is important for increasing functional recovery after injury. / text

The purpose of this study was to investigate the effects of 6 weeks of hydroxytyrosol (HT) supplementation on markers of muscle damage in healthy, recreationally active men before and throughout acute aerobic exercise bouts. Using a randomized, double-blind, repeated-measures, placebo-controlled design, sixty-one (n = 61) subjects (21.46 ± 0.22 yrs, 179.46 ± 0.79 cm, 78.91 ± 1.19 kg) consumed either a high dose (HI) HT supplement (150 mg HT), a low dose (LO) HT supplement (50 mg HT), or a placebo (PLA) every day for 6 weeks. Throughout the course of the study, the subjects performed four time trial rides (TT1-TT4) on a cycle ergometer. TT1 occurred before supplementation, TT2 halfway through the supplementation period, and TT3 and TT4 occurred in the sixth week and final two days of supplementation. Blood was drawn prior to (pre) and just before termination (end) of each time trial to measure markers of muscle damage during exercise. We observed that endurance exercise increased indicators of muscle damage, CPK and myoglobin, but an association between HT treatment and reduced muscle damage indicators during exercise were not demonstrated. However, the HT supplementation for 6 weeks in recreationally-active males improved time trial performance in the HT treatment groups over the course of the study and this improvement was accompanied by a lower increase in myoglobin concentration in blood in the HI treatment group than in the LO treatment group. Also, performance was improved after 6 weeks in the PLA group. This improvement was associated with an increase in rating of perceived exertion (RPE). RPE was not increased in either the LO and HI treatment groups, although time trial performance was significantly improved. It is possible that HT can improve performance by altering perception of effort. We conclude that chronic and acute HT supplementation did not reduce markers of muscle damage in this population at rest, during, or following exercise, but improved aerobic performance. / text

abstract / Biochemistry / Master / Master of Philosophy

The "DNA Damage Hypothesis" pertaining to the evolution of sex was tested using Hydra littoralis. DNA damage was produced by irradiating whole live hydra with ultraviolet light. A curve of uv light dosage vs. survival was constructed. Estimations of threshold fluence and LD50 were made from the survival curve. In four separate experiments, using various combinations of environmental temperatures, uv doses, and number of doses, frequencies of asexual and sexual reproduction were observed and compared. The hydra that received uv treatments did not show an increase in the consequent amount of sexual reproduction, and actually showed a decrease. An increase in the amount of sexual reproduction following DNA damage is predicted by the DNA damage hypothesis, therefore these results do not support this theory. The data was also used to make contradictory observations regarding the "stress hypothesis" for the occurrence of sexual reproduction in hydra.