Thesis (Ph.D.)--Drexel University, 2010. / Includes abstract and vita. Includes bibliographical references (leaves 115-126).

Thesis (PH.D.)--Syracuse University, 2003. / "Publication number AAT 3099736."

Thesis (Ph. D.)--University of Oregon, 2005. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 113-131). Also available for download via the World Wide Web; free to University of Oregon users.

Although the X chromosome is usually similar to the autosomes in size, gene density and cytogenetic appearance, theoretical models predict that its hemizygosity in males may cause unusual patterns of evolution. The sequencing of several genomes has indeed revealed differences between the X chromosome and the autosomes in the rates of gene divergence, patterns of gene expression and rates of gene movement between chromosomes. In this thesis, I have attempted to investigate some of these patterns and their possible causes. The first two chapters consist of theoretical and empirical work intended to analyse the rates of evolution of coding sequences of X-linked and autosomal loci, with particular emphasis on faster-X evolution, the theory that more effective selection on the X can lead to higher rates of adaptive evolution on this chromosome. By analyzing X-linked and autosomal coding sequence in several species of Drosophila, we found some evidence for more effective selection on the X, particularly evident in the higher levels of codon usage bias detected at X-linked loci. We argue that this could be due to higher levels of recombination on the X chromosome increasing its effective population size (NeX) relative to the autosomal effective population size (NeA). To further investigate this hypothesis, we have modeled the effect of increased NeX/NeA on rates of evolution and confirmed that this can contribute to faster-X evolution. The last two chapters deal with the evolution of sex-biased genes and the possible causes for their differential accumulation on the X. We used EST data to create expression profiles for D. melanogaster male-, female- and unbiased genes. Our results suggest that the expression levels of sex-biased genes are incompatible with the accepted iii model of sex-biased gene evolution. We also show that the deficit of testis-expressed genes that is observed in Drosophila seems to be stronger for highly expressed genes. In fact, for very lowly expressed genes, we observe a small excess of testis-expressed genes on the X. We attempt to discuss this pattern in view of what is currently known about the evolution of sex-biased gene expression.

Thesis (Ph. D.)--University of Notre Dame, 2004. / Thesis directed by Kristin S. Shrader-Frechette for the Program in History and Philosophy of Science. "April 2004." Includes bibliographical references (leaves 385-406).

Prions are infectious proteins that form transmissible, self-propagating amyloids that convert protein from its normal state into the prion state. The accumulation of amyloid is the causative agent of several neurodegenerative diseases, for instance, Huntington’s disease, which is caused by a polyglutamine expansion in the huntingtin (Htt) protein. In this study, a yeast-based Huntington’s disease model was created to investigate the mechanism of amyloid toxicity and how nuclear genes modulate this toxicity. The model amyloid used was Rnq1, a transferable epigenetic modifier which is able to form a prion known as [PIN+]. [PIN+] is known to enhance the formation of polyglutamine aggregates in yeast. In this study, a series of cellular assays were employed to determine the mechanism of Rnq1-mediated cytotoxicity and compared with polyglutamine-rich-protein-mediated cytotoxicity dependent upon the [PIN+] prion. In [PIN+] cells RNQ1 overexpression leads to a significant increase in the production of reactive oxygen species (ROS). Furthermore, overexpression of RNQ1 resulted in a nuclear migration defect in [PIN+] cells. Upf1 (Up-frameshift protein 1), a highly conserved protein that plays an important role in nonsense-mediated mRNA decay, was found to modify amyloid toxicity. In a upf1Δ deletion strain, both Rnq1 and polyglutamine-rich-protein-mediated cytotoxicity were suppressed in a [PIN+] background. To further study the novel role of Upf1 in amyloid toxicity, a combination of cell biological and genetic approaches were being employed.

A general strategy has been developed to synthesize biologically monodisperse polypeptides with the major repeat unit 1. These polymers are derivatives of poly($\alpha$,L-glutamic acid) (PLGA).$$- \rm Glu\sb{17}Asp-\qquad{\bf 1}$$ Such polymers should adopt an $\alpha$-helical structure when the side chain carboxylate groups are protonated, since Glu has the highest helix forming propensity (P$\sb\alpha$ = 1.59) of all twenty natural amino acids. Polymer 2 was synthesized as a fusion protein with glutathione S-transferase (GST) in a bacterial host, and was liberated from the GST fragment by CNBr cleavage.$$\rm GluAsp(Glu\sb{17}Asp)\sb4GluGlu\qquad{\bf 2}$$ DNA sequencing and amino acid analysis confirmed the composition of 2. Polymer 2 undergoes a conformational transition in aqueous solution from a random coil to an $\alpha$-helix as indicated by circular dichroism measurements. The $\alpha$-helical structure persists when the solvent is removed as demonstrated by Fourier transform infrared (FTIR) spectroscopy. Electrophoresis shows that polymer 2 is much more homogeneous in terms of molecular weight than chemically synthesized PLGAs of comparable molecular weight. A method was adopted to make the monodisperse rodlike molecule 3, a derivative of poly($\gamma$-benzyl $\alpha$,L-glutamate) (PBLG), by reacting 2 with phenyl diazomethane. Quantitative conversion was indicated by nuclear magnetic resonance spectroscopy. In helicogenic solvents for PBLG, 3 also assumes an $\alpha$-helical structure and transforms into a random coil when trifluoroacetic acid is added to the solution. Polymer 3 self-assembles into $\alpha$-helical structure when cast as a film from tetrahydrofuran solution. Gel permeation chromatography shows that 3 has a much narrower molecular weight distribution than chemically synthesized PBLG of comparable molecular weight.$$\eqalign{\rm Glu(OBzl)Asp(OBzl)&\{\lbrack(\rm Glu(OBzl)\rbrack\sb{17} Asp\cr&\qquad(\rm OBzl)\}\sb4Glu(OBzl)Glu(OBzl)\qquad{\bf 3}\cr}$$where OBzl denotes a benzyl ester. High molecular weight PLGA was chemically synthesized from $\gamma$-benzyl $\alpha$,L-glutamate N-carboxy anhydride. This polymer was modified with 8 mol % or 15 mol % hexylamine. The modified polymers can disrupt dilauroylphosphatidylcholine multilamellar vesicles and egg yolk phosphatidylcholine small unilamellar vesicles in a manner which is dependent on the solution pH. Fluorescent probes, specifically pyrene and S-anilino-naphthalene-1-sulfonic acid, ammonium salt, indicate that the modified polymers associate in a pH-dependent fashion and provide hydrophobic domains to solubilize lipid membrane vesicles.

Skeletal muscle contains a number of endogenous antioxidants that aid in protecting the muscle from oxidative damage. Antioxidant systems are comprised of water and lipid soluble compounds. The histidine containing dipeptides, anserine and carnosine, and α-tocopherol represent water and lipid soluble antioxidants which protect the muscle from oxidative damage. Raw and cooked turkey thigh and breast muscle were oxidatively challenged in order to understand the role of water and lipid soluble antioxidants in protecting the muscle from oxidative damage. The data suggest both water soluble and lipid soluble antioxidants affect the oxidative stability of turkey muscle. Conjugated linoleic acid (CLA) was supplemented in the diets of rats in order to ascertain the antioxidant capacity of rat liver microsomes and muscle homogenates after up to 48 hr oxidation. CLA was shown to alter the fatty acid profile but was not shown to be as effective as α-tocopherol. Trained and untrained muscle biopsies were oxidatively stressed for 3 hrs. Trained muscle homogenates exhibited lower hexanal formation and reduced α-tocopherol loss. Supplementation of untrained subjects failed to improve the oxidative stability of the muscle.

In Part I, we study the effects of random fluctuations included in microscopic models for phase transitions, to macroscopic interface flows. We first derive asymptotically a stochastic mean curvature evolution law from the stochastic Ginzburg-Landau model and develop a corresponding level set formulation. Secondly we demonstrate numerically, using stochastic Ginzburg-Landau and Ising algorithms, that microscopic random perturbations resolve geometric and numerical instabilities in the event of non-uniqueness in the corresponding deterministic flow. In Part II, we analyze the effects of random local linker length variability on the global morphology of a very long, linear, homogeneous chromatin fiber that is modelled as a diffusion process which is parametrized by arclength under a suitable spatial re-scaling. We obtain a Fokker-Planck equation for the process whose solution, a probability density function describes the folding.

Optic nerve section (ONS) is an experimental model for damage of the optic nerve associated with diseases such as glaucoma and optic neuritis. Damage to the optic nerve causes loss of retinal ganglion cells that are attached, once the cells are damaged, they are not typically replaced. Recently, Fischer and Reh (2003) found that Müller glia have the potential to adopt phenotypes and functional capabilities similar to those of retinal progenitors, a potential source of retinal regeneration. In the chick, when the specific retinal cells are targeted for damage by chemotoxins, there is widespread apoptosis but also mitotically active cells that label with retinal progenitor markers. Fischer and Reh (2002) also discovered that the combination of growth factors FGF2 and insulin is capable of stimulating the regenerative response of the Müller glia to retinal progenitor cells in chick eyes. This study was conducted to analyse damage to the ganglion cells by optic nerve section in chicks to determine the effect of age on the cell death timeline, the proliferative qualities of the retina and to see if injections of growth factors had the ability to increase the proliferation. Histological methods were used to analyse cellular changes and ultrasound to monitor eye growth. Apoptotic activity preceded retinal thinning and ganglion cell loss, indicating that ONS-related cell death is mediated at least in part by apoptotic mechanisms and age did not affect the time course, although, age did affect the eye growth changes, which may be attributed to the plasticity of the younger eyes. ONS damage elicited proliferative activity in the retina as did growth factor injections alone. The combination of ONS damage and growth factor injections increased the proliferative activity and the overall total number of cells in the ganglion cell layer. These findings can potentially lead to the development of therapeutic strategies for the preservation or restoration of retinal cells in diseased eyes.