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Nitric oxide (NO) is a small, gaseous molecule that is toxic to life at high doses but serves a crucial role in biological processes at lower concentrations, including: cell signaling, immune response, and more recently, as a synthon in the biosynthesis of natural products in bacteria. Metalloenzymes are incredibly versatile catalysts that enable chemistry that often, still has no comparable laboratory reaction. TxtE, a cytochrome P450 (CYP), utilizes NO as a co-substrate along with dioxygen (O2) to catalyze the regioselective nitration of L-tryptophan (Trp) to produce 4-NO2-Trp. Work in this dissertation established that the TxtE ferric-superoxo intermediate is resistant to reduction, which facilitates its reaction with diffusible NO en route to an , as yet,-uncharacterized nitrating species. Furthermore, it is shown that an outer-sphere protein residue influences the nitration chemistry of TxtE. A Thr250Ala mutant version of TxtE characterized and found to lack all nitration ability despite maintaining cofactor incorporation and retaining competence for formation of the ferric-superoxo intermediate. Separately, experiments performed with wild-type TxtE demonstrate that analogs of Trp affect the lifetime of the ferric-superoxo intermediate and enable substrate hydroxylation. Additionally, a non-heme, diiron enzyme from Mycobacterium kansasii (MkaHLP) was previously established to possess NO peroxidase activity. In this dissertation, a Tyr54Phe mutant form of MkaHLP was characterized and found to have greatly diminished NO peroxidase activity due to the removal of the characteristic tyrosine ligand to the diiron site. Implications of this change in activity are discussed in the relevant section.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2004. / I publikationen felaktig serie: Linköping studies in health sciences. Härtill 4 uppsatser.

This thesis discusses findings gained through work with the NOx abatement system at Radford Facility and Army Ammunition Plant (RFAAP). Removal of harmful substances from flue-gas emissions has garnered increased priority in the chemical industry in preceding decades, as governmental restrictions on these substances become more stringent and as national awareness concerning environmental quality and resource utilization continues to grow. These reasons make the study of NOx abatement an important and challenging endeavor. This work concerns itself specifically with reduction of NOx in flue-gas emissions from stationary sources. First we present an overview of current technology and approaches to controlling NOx for stationary sources. Next, we focus in on one particular approach to control of NOx within the context of a case study of the technology used at the Radford Facility and Army Ammunition Plant. RFAAP employs a scrubber/absorber tower followed in series by a selective catalytic reduction (SCR) reaction vessel in their NOx abatement system. We use as the method of study computer simulations within ASPEN Plus, a process simulation software package for chemical plants. We develop three different models with which to characterize NOx abatement at RFAAP, a conversion model, an equilibrium model and a kinetic model. The conversion-reaction model approximates the absorption and SCR reactions with constant percentage extent-of-reaction values. Though useful for initial investigation and mass balance information, we find the conversion model's insensitivity to process changes to be unacceptable for in-depth study of the case of NOx absorption and SCR. The equilibrium-reaction model works on the assumption that all the reactions reach chemical equilibrium. For the conditions studied here, we find the equilibrium model accurately simulates NOx absorption but fails in the case of SCR. Therefore, we introduce a kinetic-reaction model to handle the SCR. The SCR reactions prove to be highly rate-dependant and the kinetic approach performs well. The final evolution of the ASPEN Plus simulation uses an equilibrium model for the absorption operation and a kinetic model for the SCR. We explore retrofit options using this combined model and propose process improvements. We end this work with observations of the entire project in the form of conclusions and recommendations for improving the operation of the NOx abatement system through process-parameter optimization and equipment-retrofit schemes. By leading the reader through the process by which we arrived at a successful and highly informative computer model for NOx absorption and SCR, we hope to educate the reader on the subtleties of NOx abatement by absorption and SCR. We attempt to break down the numerous complex processes to present a less daunting prospect to the engineer challenged with the application of current NOx removal technology. In addition, we introduce the reader to the power and usefulness of computer modeling in instances of such complexity. The model teaches us about the details of the process and helps us develop concrete information for its optimization. Ideally, the reader could use a similar approach in tackling related operations and not confine the usefulness of this thesis to NOx absorption and SCR. The audiences that we think would benefit from exposure to this thesis are the following: • Environmental engineers with a NOx problem; • Process engineers interested in optimization tools; • Design engineers exploring flue-gas treatment options; • Combustion engineer desiring to learn about SCR; • Chemists and mathematicians intrigued by the complexities of NOx absorption chemistry. / Master of Science

published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Molecular Biology / Doctoral / Doctor of Philosophy

The objective of this research is to investigate both mathematically and numerically the effects of vascular geometry upon the cellular dynamics in the endothelium and its consequence in the localisation of atherosclerosis. It is widely accepted that the formation of atherosclerotic plaques preferentially occurs at specific locations in the vasculature, such as arterial branches and bends. It has also been observed that, at the sites of plaque formation, the physiological functions of the vascular endothelium are impaired due to a defect in the production mechanisms of or diminished activities of endothelial nitric oxide (NO). From these observations, a correlation between the vascular geometry, which is effected via local haemodynamic forces, and local bioavailability of endothelial NO has been postulated. The research areas that have been involved in the investigation of atherosclerosis's localisation in the past, haemodynamics, medicine, calcium dynamics, NO kinetics and endothelial cell biology, have been studied individually, and there appears to be no integrated model to date that allows investigation of coupled haemodynamic and cellular mechanism applied in physiologically realistic model geometries. An integrated numerical model that includes these mechanisms will be developed in this research, which will lead to a further, more comprehensive understanding of the pathogenesis of atherosclerosis.

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