Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (leaves 75-91).

The binding energies and momentum profiles for each of the valence orbitals of CO and H₂S have been measured by high momentum resolution electron momentum spectroscopy. The experimental momentum profiles are compared on a quantitative basis within the Target Hartree-Fock Approximation to theoretical calculations using SCF wavefunctions ranging in quality from minimal basis to Hartree-Fock limit. Calculated momentum distributions for the 5σ orbital of CO are shown to be very basis set dependant while calculated momentum distributions of the CO 3σ, 4σ and 1π orbitals change very little with improvements in the wavefunction beyond the double-zeta level. The CO 1π orbital is not very well described in the low momentum region even at the Hartree-Fock limit with basis set saturation including diffuse functions. While the 4a₁, and 2b₂ momentum profiles of H₂S are well described using even minimal basis calculations, diffuse functions must be included in the basis set to describe the 2b₁, and 5a₁, momentum profiles. The experimental momentum profiles of H₂S are also compared with full ion-neutral overlap calculations incorporating correlation in the ground state and correlation and relaxation in the final ion state. These calculations are very similar to the Hartree-Fock level momentum distributions, indicating that correlation is not very important in describing the momentum profiles of H₂S. The binding energy spectra and momentum profiles of the inner valence region of both CO and H₂S are studied in detail. Peaks in the CO binding energy spectrum at 24.1 and 28.3 eV are assigned as satellites 4σ and 1π main lines respectively while the structure above 30 eV is shown to be predominantly due to satellites of the 3σ orbital. The intense structure in the inner valence region of H₂S is found to arise predominantly from the 4a₁, orbital. The assignments of the inner valence spectra of both molecules is confirmed within experimental uncertainties by the spectroscopic sum rule. / Science, Faculty of / Chemistry, Department of / Graduate

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Hydrogen sulfide (H2S) has emerged as an important mediator of host function. In the gastrointestinal tract H2S is enzymatically produced and plays a vital role in cytoprotection, inflammation, and tissue repair. During a bout of colitis, the ability of the colon to produce H2S is markedly increased and drives the resolution of colitis. However, little is known about how the production of H2S is regulated in the colon and how dysregulated production can affect the course of colitis in vivo. Additionally, the mechanisms through which H2S can promote the resolution of colitis remain to be fully investigated. In Chapter 3 of this dissertation, the regulation of H2S production in the colon was explored by examining the contributions of three enzymatic pathways to colonic H2S synthesis. The largest source of the H2S synthesis was from a pathway previously unrecognized in the GI tract involving the enzyme 3-mercaptopyruvate sulfurtransferase (3MST). Additionally we found that the upregulation of H2S production during colitis occurred specifically at sites of mucosal ulceration. At the same time H2S inactivation via the enzyme sulfide quinone reductase (SQR) was significantly reduced at these sites. We propose that the site-specific alterations in H2S production and inactivation during colitis promote the resolution of inflammation and injury. Chapter 4 examined whether the ability of hyperhomocysteinemia (Hhcy) to exacerbate colonic inflammation occurred through impaired H2S synthesis. Hyperhomocysteinemia is often reported in patients with inflammatory bowel disease and is a consequence of decreased vitamin B intake. In all three models tested, diet-induced Hhcy significantly exacerbated colitis. Being dependent on vitamin B6 as a co-factor, the increased H2S production normally observed during colitis was abolished during Hhcy. Administration of an H2S donor to Hhcy rats significantly decreased the severity of colitis. These results also uncovered a novel role for IL-10 in promoting H2S production and homocysteine metabolism, which may have therapeutic value in conditions characterized by Hhcy. Finally, in Chapter 5 we looked for a mechanism through which H2S can promote resolution of colitis. Using CSE-deficient mice we found that H2S production was required to maintain HIF-1α signaling in the colon. Additionally, proper HIF-1α signaling was required for H2S-donating molecules to promote the resolution of colitis. These results suggest that HIF-1α signaling is a critical event through which H2S promotes resolution of colitis. Collectively, these chapters further highlight the importance of H2S production in colon during inflammation and injury and offer insight into new therapeutic targets mediated through H2S. / Dissertation / Doctor of Philosophy (PhD)

Confined animal feeding operations (CAFOs) relating to swine and their resulting odors continues to be an issue of concern. The primary sources of odors from a CAFO include general ventilation of the confinement house, the anaerobic lagoon, and the land application of lagoon sludge. This paper focuses on lagoon wastewaters, but the results therein could have influence on the other two aforementioned areas. An advanced upflow anaerobic/aerobic reactor system was developed to determine its impact on microbial activities that ultimately result in offensive odors. The microbial activity of SRB (sulfate-reducing bacteria) and hydrogen-sulfide production was monitored closely in each ?zone?, as well as other parameters such as dissolved oxygen and BOD. The results indicated a microbial physiology conducive to offensive odor production in the anaerobic zone of the pilot reactor and an aerobic microbial population in the upper zone of the pilot reactor. This aerobic zone was found to be effective in oxidizing the odorous gases created in the anaerobic zone. The overall microflora was consistent with an average magnitude of 108 CFU/mL. From the analysis performed, it was concluded that the microbiotic flora development and related substrate decomposition was the result of different metabolic pathways employed by the microflora rather than changes in the microbial population. In addition, the rise in pH throughout the experiment indicated the impact of the protein metabolic pathways (ammonification) over the carbohydrate metabolic pathways. Overall, the upflow anaerobic/aerobic pilot reactor proved to be an effective method for ?zoning? of the microbiotic flora, and a positive impact on the modifying the compounds related to offensive odor production.

No description available.

Peptide amphiphiles (PAs), peptides that self-assemble into hydrogels with a nanofibrous network, are interesting biomaterials due to their biocompatibility and biodegradability. Self-assembling peptide-based materials include a wide range of peptide motifs that form one-dimensional nanostructures in aqueous solution. Two different PAs are considered in this M.S. thesis work: lipidated peptides, and gas-releasing peptides (GRPs). These biomaterials have been developed to function as potential therapeutics that promote the growth of new blood vessels. The analyses conducted on the lipidated peptides, which were designed to include a peptide sequence that promotes angiogenesis, include cytotoxicity, viability, and tube formation assays. The GRPs were designed to release H2S, which is also capable of promoting angiogenesis. Several characteristic properties of the GRPs were analyzed, including morphology, mechanics, self-assembly, and gas release rates. Furthermore, cytotoxicity assays were conducted followed by the demonstration of gas uptake in endothelial cells. / Master of Science

Gasotransmitters are endogenous small molecule gases that are freely permeable to membranes and possess biological signaling functions. The three recognized gasotransmitters are carbon monoxide (CO), nitric oxide (NO), and hydrogen sulfide (H2S). H2S is featured in this work, as well as persulfides (RSSH), which also have similar functions to H2S (e.g., angiogenesis) and are the presumed signaling products of H2S but are less studied. Other compounds that are considered potential gasotransmitters include methane, sulfur dioxide, hydrogen cyanide, and nitroxyl (HNO). This dissertation covers compounds that release HNO, which possesses similar functions to NO (cardioprotection and vasodilation) but has been studied much less. While HNO, H2S, and RSSH have vital biological functions, they also have short half-lives in vivo (seconds to minutes), thus necessitating the development of prodrugs, also called donor compounds, that can release these reactive species over a biologically relevant time scale. While donor compounds extend the release rate of such small molecule gases, they do not have the ability to release drugs as slowly and continuously as endogenous gasotransmitter-generating enzymes do. As such, polymeric delivery systems have been developed to extend the release of drugs, and in the case of gasotransmitters this more closely mimics in vivo production of HNO/H2S/RSSH. Polymeric systems have been employed to modulate gasotransmitter delivery to control drug release rate, location, and longevity precisely. H2S has been employed in numerous polymeric systems, as discussed in Chapter 2, but there is a significant gap in the literature focusing on polymeric donors for HNO/RSSH. Researchers need to develop novel materials that demonstrate an extended release of these small molecules to better understand the effects of long-term exogenous delivery of HNO/RSSH/H2S which exist fleetingly in vivo. Therefore, materials that release a continuous, well characterized amount of gasotransmitters are vital for biologists to understand long-term effects of such short-lived gasses. The aim of this dissertation, in part, is to hopefully inspire the development of novel HNO/RSSH/H2S releasing systems. In Chapter 3 we discuss an HNO-donating polymer. Here we demonstrate a simple system derived from polyethylene glycol (PEG) and sulfonated polystyrene (PSS). We synthesized a polymeric version of Piloty's acid — a well-known HNO donor — by converting the PSS into a Piloty's acid motif in a two-step process. We found that by simply changing the block ratio of PEG and PSS, we were able to vary the release rate of HNO over an order of magnitude. In Chapter 4 we focus on the development of depolymerizable H2S donors encapsulated within polymer micelles. We report the synthesis of two classes of monomers, one derived from norbornene and one from acrylates. We anticipate that the results from this study will further direct and impact the study of exogenous H2S-releasing materials. In Chapter 5 we discuss electrospun polymer films made of poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) with embedded RSSH donors. We found that the RSSH donors can rescue cells from H2O2 exposure and do not interfere with angiogenesis in HMVECs. We report the fabrication, characterization, and drug release studies of the polymer fiber mats. Lastly, the appendix included at the end of this dissertation briefly discusses the synthesis of a novel depolymerizable poly(thiourethane) derived from a pyrrole monomer. / Doctor of Philosophy / Polymers, long chains of repeating units, are found everywhere. From biological polymers such as starch or cellulose to commercial plastics that come from crude oil sources, applications of natural and synthetic polymers have grown exponentially over the last century. While most people associate polymers with plastic water bottles or shopping bags, researchers have developed ways to harness the power of these long-chain molecules for drug delivery. Common examples of polymer drug delivery systems include nicotine patches and controlled-release drug capsules such as Allegra D. As scientists push the limits of drug delivery and more advanced materials are developed, the quality of human life could improve drastically. The potential for this industry can be seen by the sheer magnitude of money that has been put toward drug delivery devices – the market is expected to reach $2.2 trillion within the next two years. In this dissertation we highlight three separate projects focusing on the delivery of gasotransmitters from polymer systems. Gasotransmitters are small gases that are produced in the cells of bacteria, plants, fungi, and animals. To be considered a gasotransmitter, the gas has to be able to enter or exit cells freely and also have specific biological functions. There are three currently accepted gasotransmitters: nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). The first chapter of this work briefly discusses the biological importance of these gases. Each of the aforementioned gasotransmitters possesses key biological functions such as anti-inflammatory properties, protection of the cardiovascular system from injury, and encouraging the growth of new blood cells. Despite their helpful effects, gasotransmitters exist fleetingly in the body, existing for only seconds to minutes before being converted into a different molecule. Therefore, if researchers want to exploit the therapeutic potential of these gases, we must develop small molecules donors of these gasotransmitters, termed prodrugs. A prodrug is a compound that is administered in an inactive form, but upon a triggering event, e.g., a change in pH, or through the body's metabolism of the compound, an active therapeutic is released. Numerous research groups, including ours, have developed and examined the biological effects of gasotransmitter-releasing prodrugs. To push the efficacy of these prodrugs even further, we can incorporate them within polymer drug delivery systems, as is discussed throughout this dissertation. When a drug or a prodrug is used in a drug delivery system, the release rate and location, circulation time, and other critical properties are carefully tuned. In the case of the work reported here, we set out to develop different delivery systems to control the release of H2S (Chapter 4), persulfides (RSSH, Chapter 5), and nitroxyl (HNO, Chapter 3); while not officially recognized as part of the gasotransmitter family, RSSH and HNO are closely related to H2S and NO respectively. Both RSSH and HNO are significantly less studied than the gasotransmitters and developing systems that can help biologists elucidate the effects of RSSH/HNO from H2S/NO could provide a better understanding of how to treat different disease states.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 185-195).

No description available.