Thesis (Ph. D.)--University of Chicago, Dept of Chemistry, August 2003. / Includes bibliographical references. Also available on the Internet.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2002. / Restricted until October 2003. Includes bibliographical references.

This dissertation focuses on two areas of garnet porphyroblast crystallization that have until now remained largely uninvestigated: epitaxial nucleation of garnet porphyroblasts and yttrium and rare earth (Y+REE) uptake in metamorphic garnet. The mechanism of epitaxial nucleation is explored as a step towards determining which aspects of interfaces are significant to interfacial energies and nucleation rates. Garnet from the aureole of the Vedrette di Ries tonalite, Eastern Alps, shows a clear case of epitaxial nucleation in which garnet nucleated on biotite with (110)grt / (001)bt with [100]grt / [100]bt. The occurrence is remarkable for the clear genetic relationships revealed by the microstructures and for its preservation of the mica substrate, which allows unambiguous determination of the coincident lattice planes and directions involved in the epitaxy. Not all epitaxial nucleation is conspicuous; to increase the ability to document epitaxial relationships between garnet and micas, I develop and apply a method for determining whether evidence for epitaxial nucleation of garnet is present in porphyroblasts containing an included fabric. Although the magnitude of uncertainties in orientation measurements for garnets from Passo del Sole (Switzerland), the Nevado Filabride Complex (Spain), and Harpswell Neck (USA) preclude definitive identification of epitaxial relationships, the method has potential to become a viable technique for creating an inventory of instances and orientations of epitaxial nucleation with appropriate sample selection. Using lattice-dynamics simulations, I explore the most commonly documented epitaxial relationship, (110)grt / (001)ms. The range of interfacial energies resulting from variations in the intracrystalline layer within garnet at the interface, the initial atomic arrangement at the interface, and the rotational orientation of the garnet structure relative to the muscovite structure shows that the intracrystalline layer within garnet has the greatest effect on interfacial energy. A complete understanding of the role of intergranular diffusion for yttrium and rare-earth-element uptake in porphyroblastic garnet is critical because the complexities of Y+REE zoning in garnets and the mechanisms of Y+REE uptake have implications for petrologic interpretations and garnet-based geochronology. Y+REE distributions in garnets from the Picuris Mountains (USA), Passo del Sole (USA), and the Franciscan Complex (USA) imply diverse origins linked to differing degrees of mobility of these elements through the intergranular medium during garnet growth. / text

Discovery of anti-cancer cisplatin was a great success in anti-cancer chemotherapy. Numerous analogues of cisplatin such as carboplatin and oxaliplatin, were developed to improve the clinical effectiveness. Nevertheless, the clinical uses of these platinum-based drugs are limited by the occurrence of drug-resistance, narrow range of susceptible cancer types and severe toxicity. These drawbacks have stimulated the development of other metal-based compounds with distinct mechanisms of anti-cancer action. In this study, a series of ytterbium(III) porphyrin and iron(II) polypyridyl complexes were synthesized. Their anti-cancer activities were examined. With the aid of gene expression profiling and bioinformatics analysis, the mechanisms of these anti-cancer active complexes have been examined. A series of ytterbium(III) porphyrin complexes have been prepared and structurally characterized. An ytterbium(III) octaethylporphyrin complex (1) was found to exhibit potent anti-cancer activities with cytotoxic IC50 values down to sub-micromolar range. Complex (1) was shown to exist as a dimeric hydroxyl-bridged complex [Yb2(OEP)2(μ-OH)2] (where H2OEP = octylethylporphyrin) in CH2Cl2 and in solid state, and as monomeric [Yb(OEP)(DMSO)(OH)(OH2)] in DMSO/aqueous solution. Unlike various anti-cancer lanthanide complexes which are commonly proposed to target cellular DNA, our transcriptomics data, bioinformatics connectivity map analysis and cellular experiments altogether indicate that (1) exerts its anticancer effect through apoptosis which is highly associated with endoplasmic reticulum stress pathway. Two iron(II) polypyridyl complexes [Fe(qpy)(CH3CN)2](ClO4)2 (Fe-1a) (qpy =2,2’:6’,2”:6”,2’”:6”’,2””-quinquepyridine) and [Fe(Py5-OH)(CH3CN)](ClO4)2 (Fe-2a) (Py5-OH = 2,6-bis[hydroxybis(2-pyridyl)methyl]pyridine) were found to display selective cytotoxicity towards cancer cell lines over a normal lung fibroblast cell line. Affymetrix oligonucleotide microarray and bioinformatics analysis suggested that the anti-cancer mechanisms of Fe-1a and Fe-2a involve apoptosis, cell cycle arrest, activation of p53 and mitogen activated protein kinase (MAPK). Complex Fe-1a induced the formation of reactive oxygen species (ROS) in a concentration-dependent manner. Both iron complexes could cleave supercoiled plasmid DNA. The cellular DNA damage induced by both complexes was confirmed by comet assay and phospho-histone protein ( -H2AX) immunofluorescence assay. Cell cycle progression analysis revealed that Fe-1a induced both S- and G2/M-phase cell cycle arrests, whereas Fe-2a induced a G0/G1-phase arrest. Apoptosis induced by both complexes was confirmed by annexin-V/SYTOX green flow cytometry analysis and western blotting. Moreover, p53 and MAPK activation were found to be associated with the induced apoptosis. By employing the cationic porphyrin ligand, 5-(p-N-methylpyridyl)triphenylporphyrin [H2(5-MePyTPP)]+, a series of cationic metalloporphyrin complexes formulated as [M(porphyrinato)]n+ (where M = PtII, RuII, CoII or AuIII, n = 1 or 2) were prepared. The cytotoxicities of these complexes were examined. The platinum(II) and ruthenium(II) complexes were relatively non-cytotoxic towards the examined cancer cell lines with IC50 >24 μM. [CoII(5-MePyTPP)]Cl displayed a more pronounced anti-cancer activity with IC50 values between 7.48 – 17.7 μM. However, this Co(II) complex displayed poor selectivity towards the cancer cell lines compared to the normal cell line. The gold(III) porphyrin complex [AuIII(5-MePyTPP)]Cl2 showed a much higher potency (IC50 =3.01 -10.7μM) than the other [M(5-MePyTPP)]n+ prepared. By means of flow cytometry and fluorescence microscopy, [AuIII(5-MePyTPP)]Cl2 was found to induce G2/M-phase cell cycle arrest and necrotic cell death in HeLa cells. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

This dissertation aims at investigating the association between genotypes and phenotypes in human. Both common and rare regulatory variants have been studied. The phenotypes include disease risk, clinical traits and gene expression levels. This dissertation describes three different types of association study. The first study investigated the relationship between common variants and three sub-clinical traits as well as three complex diseases in the Center for Health Discovery and Well Being study (CHDWB). The second study is GWAS analysis of TNF-α and BMI/CRP conducted as a contribution to meta-GWAS analyses of these traits with investigators at the University of Groningen in the Netherlands, and the 1000 Genomes Consortium. The third study was the most original contribution of my thesis as it assessed the association between rare regulatory variants in promoter regions and gene expression levels. The results clearly show an enrichment of rare variants at both extremes of gene expression. This dissertation provides insight into how common and rare variants associate with broadly-defined quantitative phenotypes. The demonstration that rare regulatory variants make a substantial contribution to gene expression variation has important implications for personalized medicine as it implies that de novo and other rare alleles need to be considered as candidate effectors of rare disease risk.

Studies of large families with inherited single gene disorders identified a role of rare genetic variation as a cause of disease and enabled gene-based diagnosis. The increasing availability of population-scale genomic sequencing implies the potential to extend gene-based diagnosis from individuals with monogenic disease to the prediction of disease risk in the general population. Cardiovascular disease (CVD), as a highly heritable condition with significant public health burden, represents an excellent place to consider the promise and limitations of extending our understanding of rare variation in single gene disorders to the general population.

published_or_final_version / Physics / Master / Master of Philosophy

published_or_final_version / Physics / Master / Master of Philosophy

Cancer currently represents one of the greatest burdens on human health in the world, claiming in excess of 7 million lives a year worldwide. Advances in both our understanding of the disease as well as our ability to diagnose it before it has had a chance to metastasize will lead to a reduction in its burden on society. To these ends, optical imaging techniques are particularly attractive. The ability to resolve cellular details noninvasively is paramount to improved cancer detection and to research on diseased tissue and cells. Lanthanoid nanoparticles, a group of photoluminescent contrast agents developed within the last two to three decades, have numerous unique optical properties that enable their use in improved and novel optical techniques. They possess large Stokes and anti-Stokes shifts, sharp electronic transitions, long luminescence lifetimes, and exceptional photostability. For these reasons, they are a good choice for biomedical applications that benefit from low background fluorescence or long illumination times. The major goal of the research presented in this dissertation was to synthesize functional lanthanoid nanoparticles for optical imaging modalities, and to explore their potential uses in a variety of biomedical applications. To this end, the research can be broken up into three specific aims. The first aim was to successfully and reproducibly synthesize downconverting and upconverting lanthanoid nanoparticles, and to functionalize these nanoparticles for use in optical techniques that would aid in the research and diagnosis of cancer. The second aim was to conduct a thorough investigation of the optical properties of these nanoparticles, and the third aim was to explore the utility of these nanoparticles in a variety of biomedical applications. First, both downconverting and upconverting lanthanoid nanoparticles were synthesized using several different methods, resulting in nanoparticles of varying size and surface functionality. Novel methods were employed to improve the utility of these nanoparticles for specific applications, including the incorporation of a mixed surface ligand population in downconverting lanthanoid nanoparticles and the use of a biomimetic surface coating to render upconverting nanoparticles water dispersible. These coated particles were further functionalized by the addition of folic acid and an antibody for epidermal growth factor receptor, both of which bind to cell surface receptors overexpressed in a number of cancers. Second, the spectral properties of lanthanoid nanoparticles were explored in detail, with special attention paid to many of the unique optical properties of upconverting lanthanoid nanoparticles. This included the discovery of one such unique property, the excitation frequency dependent emission of NaYF₄ nanocrystals codoped with Yb³⁺ and Er³⁺. Third, lanthanoid nanoparticles were used as contrast agents in a number of biomedical applications, including the development of a homogenous assay based on diffusion enhanced luminescence resonance energy transfer, a wide-field luminescence lifetime microscope, and a super resolution microscope based on the aforementioned excitation frequency dependent emission of NaYF₄:Yb³⁺,Er³⁺ nanoparticles. Specific binding of functionalized upconverting lanthanoid nanoparticles was investigated with laser scanning multiphoton microscopy, and an image processing technique was developed to overcome the challenge of working with long lived luminescent contrast agents using this imaging modality.

In this dissertation we present theoretical and experimental investigation of the performance quality of fiber optical communication systems, and find new and inexpansive ways of increasing the rate of theinformation transmission.The first part of this work discuss the two major factors limiting the quality of information channels in the fiber optical communication systems. Using methods of large deviation theory from statisticalphysics, we carry out analytical and numerical study of error statistics in optical communication systems in the presence of the temporal noise from optical amplifiers and the structural disorder of optical fibers. In the slowly varying envelope approximation light propagation through optical fiber is described by Schr\{o}dinger's equation. Signal transmission is impeded by the additive (amplifiers) and multiplicative (birefringence) noise This results in signal distortion that may lead to erroneous interpretation of the signal. System performance is characterized by the probability of error occurrence. Fluctuation of spacial disorder due to changing external factors (temperature, vibrations, etc) leads to fluctuations of error rates. Commonly the distribution of error rates is assumed to be Gaussian. Using the optimal fluctuation method we show that this distribution is in fact lognormal. Sucha distribution has ""fat"" tails implying that the likelihood of system outages is much higher than itwould be in the Gaussian approximation. We present experimental results that provide excellent confirmation of our theoretical predictions.In the second part of this dissertation we present some published work on bisolitons in the dispersion managed systems. Modern communication systems use light pulses to transmit tremendous amounts of information. These systems can be modeled using variations of the Nonlinear Shrodinger Equation where chromatic dispersion and nonlinear effects in the glass fiber are taken into account. The best system performance to date is achieved using dispersion management. We will see how the dispersion management works and how it can be modeled. As you pack information more tightly the interaction between the pulsesbecomes increasingly important. In Fall 2005, experiments in Germany showed that bound pairs of pulses (bisolitons) could propagate significant distances. Through numerical investigation we found parametric bifurcation of bisolitonic solutions, and developed a new iterative method with polynomial correction for the calculation of these solutions. Using these solutions in the signal transmission could increase the transmission rates.