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Symbiotic associations between animals and microbes are widespread in nature, yet the factors controlling the abundance and distributions of particular symbionts are mostly unknown. Vertically transmitted (VT) symbionts can invade host populations by providing net benefits to hosts. While most beneficial symbiotic interactions that have been characterized are nutritional, other major pathways likely exist that facilitate symbiont transmission within host populations. Natural enemies, for example, are important selective forces in shaping the life history of many invertebrates and hosts may benefit from collaborations with microbes to aid in their defense.In this dissertation I have addressed the role of VT, facultative (= secondary) symbionts (SS) of Acyrthosiphon pisum in mediating interactions with an important natural enemy, the parasitic wasp, Aphidius ervi. I found that, in a common genetic background, two A. pisum SS (R- and T-type SS) confer resistance to A. ervi, by causing mortality to developing wasp larvae. Defensive mutualisms with microbes provide a mechanism for the spread and persistence of VT symbionts.A. pisum superinfected with both R- and T-type SS were found to be more resistant to parasitism that those singly infected with either SS. Despite this added benefit to resistance, R + T-type superinfections were rare in a survey of A. pisum symbionts, likely attributable to severe fecundity costs. R-type densities increased dramatically in superinfected hosts and over-proliferation of SS may result in poor aphid performance. Thus, interactions among the symbionts themselves also likely play a critical role in determining the distributions of symbionts in nature.I also found that four T-type isolates from A. pisum, and one from another aphid species, all conferred resistance to parasitism in the same A. pisum host background. The levels of resistance varied greatly among isolates, including one that conferred nearly complete resistance. A single T-type isolate was also found to confer similar levels of resistance in five A. pisum backgrounds. These results indicate that SS-mediated resistance is a general phenomenon in A. pisum and that the SS isolate is more important in determining the level of resistance than is the aphid genotype or interaction between isolate and aphid genotype.

Most neonates and infants acquire HIV-1 infection as a result of mother-to-infant (vertical) transmission and are infected with the minor genotype with macrophage-tropic (R5) phenotype of the mother. Several studies suggest that infected infants have a higher viral load and develop AIDS more rapidly than infected adults, but the mechanisms of this differential HIV-1 infection are not known. The hypothesis of my dissertation is that viral determinants and differential cellular gene expression profiles influence differential HIV-1 replication and disease progression seen in neonates vs. adults. This work includes characterization of viral determinants, including reverse transcriptase (RT) and envelope gp120, and host determinants, including cellular transcription factors and cytokines that may be associated with differential HIV-1 replication in infants and adults. The characterization of HIV-1 RT gene from five mother-infant pairs following vertical transmission revealed a low degree of viral heterogeneity and a high conservation of intact open reading frames comprising functional domains and CTL epitopes. Biological characterization of HIV-1 subtype C envelope gp120 from infected patients from India was performed by constructing chimeras with HIV-1 subtype B. Infection of cell lines and primary cells with chimeric subtype C/B virus showed that the subtype C env gp120 from patients contributed to an increased rate of virus entry, which correlated with higher replication efficiencies and virus production in subtype C env chimeras compared with subtype B env chimeras and subtype B primary isolates. Higher level of viremia with subtype C infection compared with subtype B may be responsible for its rapid disease progression and spread. The mechanisms of HIV-1 replication in neonatal and adult cells was determined and found that differential HIV-1 replication in neonatal and adult cells is influenced at the level of HIV-1 gene expression. Evaluation of cellular gene expression profile of neonatal and adult mononuclear cells performed by microarray analysis identified several factors, including transcription factors, cytokines and matrix metalloproteinases that may be associated with increased HIV-1 gene expression and replication in neonates and infants. Taken together, these results provide new insights into the understanding of mecahnsims of HIV-1 vertical transmission, pathogenesis and disease progression in infected neonates and infants.

I have studied syntectonic veins from shales and coarse calcareous sands of the Ordovician Womble Shale, Benton uplift, Arkansas. All veins are composed of calcite with minor quartz and trace feldspar and dolomite or high-Mg calcite in the coarser veins. All host lithologies have a pressure-solution cleavage, more closely spaced in the fine-grained shale beds. The vein internal fabrics are coarsely to finely fibered, with a strong host-rock grain size control on fiber width. The finest fibers are in veins with shale host and the coarsest in the coarse-grained calcareous sandstone. Fiber aspect ratio is inversely proportional to host grain size; more equant vein grains are found in the veins hosted in the coarse host fraction. Within one outcrop, the δ13C and δ18O compositions of the host lithologies range from 1.5 to -3.0 per mil and 7.5 to -14.0 per mil (VPDB), respectively. By contrast, the δ18O composition of the veins is remarkably constant (-13.5 per mil) among veins of starkly different fabrics. This composition is identical to that of the coarse calcareous sandstone lithology in the outcrop. No cathodoluminescence or stable isotope zoning was observed in the veins. In addition, there were no gradients in Ca or Si in the vicinity of the veins, suggesting either that the host did not contribute these elements or that diffusion was not the rate-limiting step to vein formation. In any case, the wide variety of veins was probably formed from meter-scale migration of fluid derived from local calcite-rich layers in calcareous sandstone.

Poly(methacrylic acid -co- methyl methacrylate) beads were previously shown to have a therapeutic effect on wound closure through the promotion of angiogenesis. However, it was unclear how this polymer elicited its beneficial properties. The goal of this thesis was to characterize the host response to MAA beads by identifying molecules of interest involved in MAA-mediated angiogenesis (in comparison to poly(methyl methacrylate) beads, PMMA). Using a model of diabetic wound healing and a macrophage-like cell line (dTHP-1), eight molecules of interest were identified in the host response to MAA beads. Gene and/or protein expression analysis showed that MAA beads increased the expression of Shh, IL-1β, IL-6, TNF-α and Spry2, but decreased the expression of CXCL10 and CXCL12, compared to PMMA and no beads. MAA beads also appeared to modulate the expression of OPN. In vivo, the global gene expression of OPN was increased in wounds treated with MAA beads, compared to PMMA and no beads. In contrast, dTHP-1 decreased OPN gene expression compared to PMMA and no beads, but expressed the same amount of secreted OPN, suggesting that the cells decreased the expression of the intracellular isoform of OPN. Interestingly, MAA beads had no effect on the expression of pro-angiogenic growth factors VEGF, bFGF and PDGF-B in vivo or in vitro, suggesting that MAA beads do not induce angiogenesis by simply increasing the expression of pro-angiogenic factors, but use more subtle mechanisms. It was hypothesized that these mechanisms may involve modulation of toll-like receptor signaling in macrophages interacting with the protein layer adsorbed on to MAA beads, in a manner distinct from PMMA beads and no beads. Taken together, the results suggest that MAA beads promote angiogenesis through increased expression of Shh, decreased expression of CXCL10 and modulation of the expression of OPN, but not through increased expression of typical pro-angiogenic growth factors. The resulting vessel-rich “alternative foreign body reaction” has exciting clinical implications as the polymer itself was found to exert a therapeutic effect in the absence of bioactive components or transplanted cells. Understanding the mechanism could lead to new applications for this material and others designed on similar principles.

Poly(methacrylic acid -co- methyl methacrylate) beads were previously shown to have a therapeutic effect on wound closure through the promotion of angiogenesis. However, it was unclear how this polymer elicited its beneficial properties. The goal of this thesis was to characterize the host response to MAA beads by identifying molecules of interest involved in MAA-mediated angiogenesis (in comparison to poly(methyl methacrylate) beads, PMMA). Using a model of diabetic wound healing and a macrophage-like cell line (dTHP-1), eight molecules of interest were identified in the host response to MAA beads. Gene and/or protein expression analysis showed that MAA beads increased the expression of Shh, IL-1β, IL-6, TNF-α and Spry2, but decreased the expression of CXCL10 and CXCL12, compared to PMMA and no beads. MAA beads also appeared to modulate the expression of OPN. In vivo, the global gene expression of OPN was increased in wounds treated with MAA beads, compared to PMMA and no beads. In contrast, dTHP-1 decreased OPN gene expression compared to PMMA and no beads, but expressed the same amount of secreted OPN, suggesting that the cells decreased the expression of the intracellular isoform of OPN. Interestingly, MAA beads had no effect on the expression of pro-angiogenic growth factors VEGF, bFGF and PDGF-B in vivo or in vitro, suggesting that MAA beads do not induce angiogenesis by simply increasing the expression of pro-angiogenic factors, but use more subtle mechanisms. It was hypothesized that these mechanisms may involve modulation of toll-like receptor signaling in macrophages interacting with the protein layer adsorbed on to MAA beads, in a manner distinct from PMMA beads and no beads. Taken together, the results suggest that MAA beads promote angiogenesis through increased expression of Shh, decreased expression of CXCL10 and modulation of the expression of OPN, but not through increased expression of typical pro-angiogenic growth factors. The resulting vessel-rich “alternative foreign body reaction” has exciting clinical implications as the polymer itself was found to exert a therapeutic effect in the absence of bioactive components or transplanted cells. Understanding the mechanism could lead to new applications for this material and others designed on similar principles.

This thesis deals primarily with supramolecular chemistry based on cucurbit[n]uril (CB[n], n = 7 and 8) host molecules. The research has been focused on the synthesis and characterization of host-guest complexes CB[n] with aromatic guest molecules, and the study of the effects of the host-guest complexation on the chemical reactivity and spectroscopic properties of the included guests, such as their photoreactivity and their UV-visible absorption and emission properties, in aqueous solution. The [4+4] photodimerization of protonated 2-aminopyridine (APH+) occurs stereoselectively to give the anti-trans product as the result of a preferred orientation of two APH+ guests in the cavity of CB[7]. The CB[7] host inhibits photohydration in the course of the photoisomerizations of protonated trans-1,2-bis(4-pyridyl)ethylene and trans-1,2-bis(1-methyl-4-pyridinium)ethylene by including the (4-pyridyl)ethylene portion of the guest, while this is not observed with trans-1,2-bis(1-hexyl-4-pyridinium)ethylene, as preferential inclusion of the hexyl groups leaves the vinyl group vulnerable to photohydration. Very strong CB[7] complexation of (E)-1-ferrocenyl-2-(1-methyl-4-pyridinium)ethylene completely inhibits the (E)→(Z) photoisomerization process. The H/D exchange rates and acidities of the C(2)-proton of cationic imidazolium and thiazolium (including thiamine and thiamine phosphates) carbon acids are decreased upon their complexation with CB[7]. Inclusion of protonated aromatic amines (and aromatic alcohols) in the cavity CB[7] significantly decreases their ground and excited state acidities, such that the emission is switched from the neutral amine to the protonated amine excited state, resulting in changes in the color of fluorescence. The fluorescence of acridizinium cations can be switched off by the formation of 2:1 complexes with CB[8] and then switched back on again by the addition of CB[7] or a competing guest molecule. The stabilization of the deep blue color of the 4,4’-bis(dimethylamino)diphenyl carbonium ion, upon complexation of the corresponding carbinol with CB[7], results from a complexation-induced shift in the carbinol/carbonium ion equilibrium. A dramatic purple to blue color change in pinacyanol chloride upon addition of CB[7] is due to a partial breakup of dye aggregates, upon the interactions of the dye with the host molecule. The CB[n] complexation-induced emission and/or absorption color switch have the potential to be employed in molecular switches and in chemical sensing. / Thesis (Ph.D, Chemistry) -- Queen's University, 2007-08-07 09:21:06.553

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