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Nitrogen-containing bisphophonates (N-BPs) are a blockbuster class of drugs for the treatment of common metabolic bone diseases.  Recently, N-BPs have been shown to inhibit FPP synthase and/or isopentenyl diphosphate (IPP) isomerase (both enzymes in the mevalonate pathway), thereby preventing the synthesis of the isoprenoid lipids farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), which are vital substrates for protein prenylation.  By preventing the synthesis of FPP and GGPP, N-BPs prevent the prenylation of small GTPases and inhibit osteoclast function. This study demonstrates conclusively that the major pharmacological target of N-BPs is FPP synthase.  Furthermore, minor structural modifications to the N-BPs that govern <i>n vivo </i>potency have a marked effect on potency for inhibition of FPP synthase <i>in vitro.  </i>Non-N-BPs, such as clodronate and etidronate, did not inhibit FPP synthase, consistent with other studies suggesting that the non-N-BPs and N-BPs act by different molecular mechanisms. Clinically, N-BPs have been shown to exhibit marked differences in efficacy between patients and may lie resident in the skeleton for many years.  J774 macrophage-like cells resistant to the effects of N-BP (J774-RES) were generated to study the possible cellular mechanisms underlying clinical resistance to treatment.  The J774-RES cells accumulated N-BP to a lesser extent than parental cells and also exhibited increased expression of the MCSF receptor, although further studies are required to clarify the exact mechanism of the resistance of J774-RES cells. Finally, N-BPs have been shown to induce the proliferation of the major subset (V<span style='font-family:Symbol'>g9V<span style='font-family:Symbol'>d2) of <span style='font-family:Symbol'>g,<span style='font-family:Symbol'>d-T cells in humans, attributed to an agnostic effect on the <span style='font-family:Symbol'>g,<span style='font-family:Symbol'>d-T cell receptor (TCR).  The findings of this study indicate that the N-BPs act indirectly, by inhibiting FPP synthase and causing the accumulation of IPP, a known agonist of the <span style='font-family:Symbol'>g,<span style='font-family:Symbol'>d-TCR.  Furthermore, this proliferative effect of N-BPs could be abrogated by statins, possibly indicating a means of preventing the acute-phase response, the major side effect to intravenously-administrated N-BPs.

Increasing concern over the adverse environmental impact of intensive agriculture has led to pressure to develop more sustainable, integrated farming systems which have the potential to minimise the loss of nitrogen to the environment whilst maintaining productivity. Alternative systems include pluricompartmental systems, which combine more than one enterprise or species in a formalised design, such as a crop rotation or spatial arrangement e.g. agroforestry. Three approaches to nitrogen budgeting were developed and their ability to quantitatively describe nitrogen cycling in pluricompartmental systems tested. Budgets ranged in complexity from the EIO Budget, which accounted simply for purchases and sales of nitrogen over the farmgate, through the BIO Budget which included estimation of biological nitrogen fixation and attempted to partition losses into leaching and gaseous forms, to the TRIO Budget which also accounted for key soil processes. Unaccounted for N was attributed to leaching, however it is recognised that this is a predictor of leaching potential rather than actual loss. These approaches were tested in a range of systems; a mixed organic farm, a silvopastoral agroforestry system, organically and conventionally managed beef systems and a series of ley/arable rotations containing different proportions of ley. A simple model for predicting nitrogen fixation from yield was also developed and tested. The success of the different approaches was strongly dependent on the precise objective; whilst all the approaches were able to predict N use efficiency in economic terms, the TRIO Budget was likely to give the best estimate of potential N loss by leaching. The TRIO Budget was the only approach which quantified intercompartmental N fluxes, and it is suggested that this parameter may be a useful indicator of sustainability. Intercompartmental fluxes were particularly difficult to quantify in spatially pluricompartmental systems due to the importance of belowground processes in these systems.

Chapter 1 is a general and historical introduction to the field of atomic nitrogen research. Specific mention is made of the methods by which atomic nitrogen has been generated and detected, and examples of its reactions with (predominantly organic) substrates are included. The overall aim of the thesis, the generation of atomic nitrogen in solution by mild thermolysis or photolysis, is stated. This concerns bond breaking, mainly in nitrogen heterocycles. In Chapter 2, 1,2,4-dioxazolidines are investigated and discussed according to the overall aim. Competing 0-0 and N-X (X = nitrogen substituent) scissions are compared by selective derivatisation. The thermal and photochemical fragmentation of these dioxazolidines is described, and evidence for atomic nitrogen and nitrene formation is adduced. Chapter 3 considers the use of heteroaromatic <i>N</i>-imines as a means to the proposed goal. Attention is centred on benzo[c]cinnoline <i>N</i>-imine, and its selective derivatisation. Radicals produced during photochemical decomposition of benzo[c]cinnoline <i>N</i>-imine derivatives are detected both directly and indirectly by e.s.r. spectroscopy, and evidence for the spin-trapping of atomic nitrogen is presented. In Chapter 4, the <i>in situ</i> oxidation of urazoles is investigated by e.s.r. spectroscopy, and <i>in situ</i> cycloadditions of these oxidised species are performed. 7-Azabenzonorbornadienes and 7-azanorbornadienes are applied as potential sources of atomic nitrogen in Chapter 5. The generation of the corresponding radicals is investigated by e.s.r. spectroscopy.

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Anaerobic ammonium oxidation (anammox) is a pathway that has been known for almost 2 decades, but few studies have investigated its importance in natural groundwaters. This thesis investigated the presence of anammox cells and the groundwater geochemistry of 2 sites (Elmira and Putnam) in southwestern Ontario where groundwaters are contaminated with high levels of nitrate and ammonium. Fluorescence in situ hybridization (FISH) was used to quantify the relative abundance of anammox cells in these waters. Our results showed that anammox cells could be detected in many wells at both sites and that their relative abundance varied between 0.45 and 4.81 % at the Putnam site, whereas it ranged between 0.8 to 8.4 % at the Elmira site. These values are within the same range as those obtained for marine and freshwater environments where anammox cells have been detected. In addition, indirect observations point to the fact that N cycling at the 2 sites might be linked to Fe and Mn reduction, but additional experiments are needed. In summary, our results corroborate the findings of N-labeled microcosm experiments which demonstrated that anammox was an important pathway of N cycling in those groundwaters and molecular analyses that detected important anammox organisms at the same sites.

The nitrogen uptake of organically selected and conventional spring wheat cultivars was assessed throughout the growing season. High protein yielding advanced lines were selected from the Agriculture and Agri-Food Canada and the University of Manitoba’s joint organic breeding program. The organic breeding lines were compared with conventional check cultivars. The organic lines were found to have higher average yield, grain N yield, kernel density, HI, and NHI while the check cultivars were found to have higher average grain protein. No significant differences were observed between organic lines and the check cultivars for biomass and N biomass accumulation. The strong performance of the organic breeding lines compared to their conventional counterparts for several key parameters is a positive indication of the benefits of specialized breeding programs. The higher yield of the organic lines indicated that they were better able to cope with the environmental stresses associated with organic growing conditions.

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The provision of high quality analytical data is an essential prerequisite for understanding the biogeochemical cycling of nutrients in the aquatic environment. Due to the instability of samples collected for nutrient determinations however, in situ analysis is preferred. This approach also allows for high temporal and spatial resolution of the data and alteration of the sampling frequency to meet local environmental needs. Chapter One describes the role of nitrogen species, particularly ammonia and nitrate, in the aquatic environment, their sources, and possible environmental effects and summarises analytical techniques for their determination. Solid state miniaturised detectors and their suitability for in situ monitoring are also discussed. The characterisation and evaluation of a miniature Ocean Optics PSD - 1000 spectrometer and its suitability for field deployment is described in Chapter Two. Parameters investigated were optical resolution, wavelength repeatability, photometric linearity and instrumental noise and drift. The incorporation of the Ocean Optics PSD - 1000 miniature spectrometer into a gas diffusion Flow Injection (Fl) manifold for the determination of ammonia in natural waters is detailed in Chapter Three. Optimisation of the Fl parameters and analytical performance are discussed in detail. The development of an immobilised pH indicator and adaptation to a laminar Fl manifold is also considered. Chapter Four describes the use of the miniature spectrometer in a Fl manifold for the determination of nitrate and nitrite, with analytical figures of merit detailed. The increased information potential of the spectrometer (i.e. full spectral acquisition) facilitated the removal of the refractive index problem using dual wavelength correction. Miniaturisation and automation of the optimised nitrate manifold using micro-solenoid pumps and LabView™ graphical programming is described in Chapter Five. Field deployment of the automated system was assessed during a six week British Schools Exploring Society Expedition to Lesotho, S. Africa (in which an intensive biogeochemical survey of the Sehlabathebe National Park was conducted) and a three day campaign on the River Frome, Dorset, U.K. Chapter Six details the ion chromatographic analysis of major anions and cations (including ammonium and nitrate) in precipitation samples. Two sampling campaigns were conducted. One was at an urban site (Plymouth City Centre) from 27/01/98 - 11/05/98, and the influence of aerosol source on the chemical composition of Plymouth precipitation is discussed. The other involved the Austrian precipitation network and wet deposition trends for nitrate, ammonium and sulphate are discussed. The multivariate analysis technique of PCA was applied to both environmental datasets and the interpretation and merits of this statistical approach are considered.

No description available.