Interactions between DNA and ligands are important in the rational design of drugs and in research into DNA function. In particular, the interaction of DMZ with DNA structures named “G-quadruplexes” was considered. G-quadruplexes are structures present in telomeres and several oncogenes. The main purpose of this project was to provide a computational tool to study DNA ligand interactions using a variety of molecular modeling techniques that include molecular docking, molecular dynamics simulations (MD) and MM/PBSA (Molecular Mechanics/Poisson Boltzmann Surface Area). We investigated the binding modes and binding affinities of DMZ with c-MYC G-quadruplexes (G4s). We found that the conformation and structural design of the quadruplex can dramatically influence the binding profiles of the ligand. The binding free energies for each site were estimated by the MM/PBSA method. The binding of small molecules to DNA can result in the disruption of oncogene transcription, making it an effective anticancer strategy.

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<p> The effectiveness of vitamin C in treatment of cancer and heart disease is a matter of debate. While some studies show that vitamin C intake is correlated with improved clinical outcome in cancer patients and is associated with better cardiovascular health, others did not. In this thesis, we examine the biochemical and pharmacological properties of this vitamin in the hope that they will be conducive to resolving this controversy. </p> <p>In Chapter 1 of this thesis, we present a compilation of three publications reviewing the current knowledge about this nutrient, including its chemical and biological properties, with focus placed on its therapeutic potentials. From these literatures, we arrived at the hypothesis that vitamin C, at pharmacological concentrations in the serum, may have mitigative effect on cancer and cardiovascular disease. </p> <p> In Chapter 2 of this thesis, we examine the effectiveness of an alternative vitamin C delivery method using gene therapeutic vectors in a humanized transgenic mouse model. These mice have been rendered defective in endogenous vitamin C production by genetic knockout of gulonolactone oxidase ( GULO -/- encoding gene ( Gulo ), which is responsible for catalyzing ascorbic acid biosynthesis. In an earlier study, we constructed gene therapeutic helper-dependent adenoviral vectors (HDAd) carrying the coding sequence for Gulo under either human phosphoenolpyruvate carboxykinase (PEPCK) promoter (HDAd-PEPCK-Gulo) or munne cytomegalovirus(mCMV) immediate-early promoter (HDAd-mCMV-Gulo ). In this study, we sought to examine the ability of these vectors to mediate the expression of GULO and the production of ascorbic acid in human hepatocellular carcinoma (HEPG-2) and Gulo-knockout (Gulo -/-) mice. We found that HEPG-2 infected with HDAd-mCMV-Gulo expressed GULO, which can be readily detected in cells infected at a multiplicity of infection (MOl) of 10 viral particles per cell (vp/cell) using immuno-based blot. Immunoblot also showed that GULO expression occurred at 18 h post-infection in cells treated with HDAd-mCMV-Gulo at a MOl of 500 vp/cell. Vitamin C production was observed in HEPG-2 treated with HDAdmCMV- Gulo as measured by HPLC-electrochemical detection (HPLC-ECD). We showed that vitamin C production is dependent on the substrate, gulonolactone, concentrations. Gu/a-knockout mice treated with 2X1011 vp expressed GULO in the liver. Using HPLCECD, we showed that the serum vitamin C concentrations of these mice were elevated to levels comparable to those of the wild type mice (60 J.LM) after 4 days of infection and were maintained at 30 J.LM for the duration of the experiment (23 days and ongoing). Similar elevation was observed in urine and tissue vitamin C concentrations in vectortreated animals. In conclusion, we demonstrated here that gene therapeutic HDAdmCMV- Gulo vectors are able to mediate the expression of GULO and endogenous production of vitamin C in human cells and in Gulo -/- transgenic mice. Taken together, these findings support the feasibility of gene therapy as a novel vitamin C delivery method to achieve supra-physiological concentrations of vitamin C in the blood. </p> / Thesis / Master of Science (MSc)

Though he is generally known as one of the key voices in conservative Christianity, this thesis demonstrates that C. S. Lewis was in fact far more liberal in his view of salvation than many would expect. Lewis argued for a universalist interpretation of salvation, in which the death of Christ opened up the possibility of salvation for all of humanity, not merely those people who could be identified as Christians. Lewis did believe that people could and did choose Hell over Heaven, however, and still saw evangelism as the duty of every Christian. All of Lewis's writings are in a sense evangelistic, and all attempt to effect the conversion of the reader in the same manner in which Lewis himself was first drawn to Christianity: by baptizing the imagination in the hope that the reason will follow. / Master of Arts