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Crucial biological processes are often dictated by the action of proteins, including cell growth, intercellular communication and apoptosis. The behaviour and function of proteins, and other important bio-macromolecules, is inherently linked to the 3D con-formation of the polypeptide and the range of dynamics within the structure. The rapidly developing tool, solid-state NMR, is uniquely placed to structurally probe large, non-crystalline macromolecules, such as proteins, and provide data at atomic-level resolution. Amyloid diseases, such as Alzheimer's disease and Parkinson's disease, are linked to neuronal damage caused by toxic species which occur through misfolding and aggregation of naturally expressed proteins. Aggregation of the 36-43 residue protein amyloid-beta (A ) is thought to be involved in the pathology of Alzheimer's disease. In this thesis, solid-state NMR is used to obtain 1 H,15 N and 13 C chemical shifts for U-[13 C,15 N] A 1-40 aggregates formed in the presence of copper, a metal found in abnormally high concentrations in amyloidogenic plaques in Alzheimer's-disease-afflicted patients' brains via post-mortem examination. A suite of 2D13 C-13 C DARR and15 N-13 C DCP experiments alongside 2D and 3D X-1 H,15 N-1 H-1 H and13 C-15 N-1 H. Inverse Detection experiments employed at 100 kHz MAS frequency is employed to obtain chemical shift values. TALOS-N provides torsion angle restraints and secondary chemical shift analysis is performed to identify turn and -sheet regions. The results are compared to previously published models, and indicate the sample is similar to a brain-derived fibrillar structure. 2D13 C-13 C DARR experiments are also performed on selectively labelled samples of A 1-42 with cysteine replacements at locations A21 and A30. This cross-linking mechanism between C21 and C30 has been shown to stabilise an oligomeric form, thought to be the most toxic, on the aggregatory pathway to fibrils. The labels allow detailed characterisation of the turn region between residues 22 and 29. The incorporation of the oligomers into lipid membranes was studied by 1D31 P NMR, specifically to investigate the effect of the oligomers on the stability of the membranes and the effect of cholesterol and curcumin, a potentially therapeutic compound currently of high interest, on this de-stabilisation. Work with collaborators has enabled the oligomeric form to be modelled and the results indicate these toxic oligomers form a hexamer barrel structure, with the hydrophobic sidechains contained within the barrel. The secondary structure of the oligomer is shown to contain 3 or 4 -sheets; with an extended -sheet region between K16-V24, 1 or 2 -sheets between N27 and V36, and then a short -sheet between V39 and A42. A method for inter-molecular –sheet interaction in the hexamer is postulated. A method for further aggregation from this oligomeric form to a protofibrillar form has also been suggested, thus enabling a claim to be made for an on-pathway nature for this oligomeric form.

A large number of animal studies have investigated the effects of hypoxia on the pulmonary vasculature and hypoxic pulmonary vasoconstriction (HPV) is now established as an important homeostatic mechanism for perfusion-ventilation matching in the lung. However, there is a conspicuous lack of studies investigating HPV in human pulmonary vascular preparations. In comparison to the pulmonary vasculature only a limited number of studies have previously investigated the effects of acute hypoxia on the airways. In this thesis the effects of hypoxia on the human pulmonary vasculature and airways was investigated in a number of ex vivo human lung models. In isolated human pulmonary arteries and veins and in ex vivo perfused and ventilated human lungs it was found that hypoxia caused a vasodilation. This finding is at variance with a large body of published literature and it is suggested that a neuronal mechanism could play an important role in the regulation of pulmonary vascular tone under hypoxic conditions in vivo which is not present in the ex vivo models used in this thesis. In exploring the effects of hypoxia on the pulmonary vasculature it was identified that the pulmonary veins could play a more significant role in the regulation of pulmonary vascular resistance than was previously believed. It was also found that exposure of the pulmonary veins to hypoxia precipitated a phasic activity which was suggestive of an automaticity and that the isolated human pulmonary vein model could therefore be used to investigate arrhythmic activity and the efficacy of new antiarrhythmic agents. Exposure of ex vivo perfused and ventilated human lungs to hypoxia caused a reduction in the rate of oedema formation and it is hypothesised that this effect could be mediated by an inhibition of pulmonary vascular endothelial cell contraction and an increase in endothelial barrier function. In isolated human bronchi and ex vivo human lungs hypoxia caused a robust and reversible bronchodilation. The mechanism of hypoxic bronchodilation (HBD) was investigated and it was found that HBD could be mediated by a reversal of the calcium sensitisation mechanism. This mechanism represents a significant therapeutic target for the future development of effective bronchodilator therapies which are not subject to the limitations of GPCR agonists (desensitisation). Studies investigating the effects of changing oxygen concentrations on bronchial tone identified that oxygen concentrations above ambient levels (21%) caused a robust contraction of human airways which could have significant implications for the clinical use of oxygen therapy in constrictive airway disease. In investigating the putative role of hydrogen sulphide (H₂S) as an oxygen sensor it was found that H₂S is an effective vasodilator and bronchodilator in the human lung and could have significant therapeutic potential in the treatment of human pulmonary disease. Further studies have been planned to build on the significant findings in this thesis.

The focus of this thesis is the synthesis of organometallic complexes incorporating the η8-permethylpentalene titanium moiety (η8-Pn*Ti), their characterisation, and their reactivity with small molecules. Chapter One summarises the chemistry of the pentalene molecule, from its instability in the free state to the incorporation of the hydrocarbon into organometallic complexes. The chapter continues with a review of the coordination modes available to Pn and concludes with a brief discussion on the effects of permethylation of hydrocarbon ligands and the advent of permethylpentalene (Pn*). Chapter Two documents the improved synthesis of [Pn*TiCl(μ-Cl)]2 utilising isomeric control imparted on the Pn* synthon, Pn*(SnMe3)2. This protocol permits access to a variety of methylated compounds through metathesis chemistry, of which five have been crystallographically elucidated, revealing the fold angle to be reliant on an interplay between steric and electronic factors. Mono-, bi- and trimetallic {Pn*TiMe2, [Pn*TiMe(μ-Cl)]2 and [Pn*Ti(μ-Me)]2(μ-CH2), and [Pn*TiMe(μ-Me)2]2Mg respectively} species were synthesised dependent on the methylating agent employed and they displayed varying thermal stabilities, with the dimeric nature of [Pn*TiMe(μ-Cl)]2 proving crucial in the formation of [Pn*Ti(μ-Cl)]2(μ-CH2). Chapter Three describes the incorporation of classical organometallic ligands into the Pn*Ti moiety, including the first examples of benzyl, alkyl, aryl, allyl and η1-Cp bound to a PnTi fragment. Seven complexes have been structurally characterised including the first ever crystal structure of a π-hydrocarbon bound Ti species bearing two CH2tBu groups, Pn*Ti(CH2tBu)2, and the fluxional mixed hapticity complex Pn*Ti(η5-Cp)(η1-Cp), whose η1-Cp rearranges via a 1,2-sigmatropic shift. Chapter Four investigates the reactivity of the monomeric dialkyls, Pn*TiR2 (R = Me, CH2Ph, CH2SiMe3 and CH2tBu) with CO2, CO and H2. All four compounds demonstrate “normal” insertion of the CO2 moiety into both Ti-R bonds, revealing a symmetrical bidentate coordination of the RCO2 units. Computational studies have highlighted two competing pathways for their reaction with CO, dependent on the concentration of CO and size of R, which results either in formation of an enediolate or a titanoxirane. The reaction with H2 yields the fascinating trimeric mixed valence, [Pn*Ti(μ2-H)]3(μ3-H), the first structurally characterised example of a trimeric Ti-H species and the first to include a Ti-(μ3-H) moiety. (Pn*TiCl)2(μ-O) is formed by the action of adventitious H2O and possesses a linear Ti-O-Ti bridge with a degree of Ti-O double bond character, supported by crystallographic data and DFT calculations. Chapter Five discusses ethylene polymerisation studies on the monomeric dialkyl complexes Pn*TiR2 (R = Me, CH2Ph, CH2SiMe3 and CH2tBu) using the activators [Ph3C][B(C6F5)4], [PhNMe2H][B(C6F5)4], AliBu3 and H2. Chapter Six presents full experimental procedures for all of the syntheses and reactions outlined in Chapters Two to Five. Chapter Seven details characterising data for all novel compounds, and crystallographic data in the form of CIF files may be found in the electronic version.

The following study examined the perceived developmental influence of the university supervisor-student teacher relationship during the student teaching phase of teacher preparation. Since the supervisor is viewed as the gatekeeper to eventual teacher certification and acts as an evaluator, mentor, and instructor (Borko & Mayfield, 1995; Zimpher, deVoss, & Nott, 1980), findings presented in this study may inform future supervisory practice and shed light on the valuable developmental aspects of this relationship. By utilizing a qualitative case study design, this investigation answered the following central research question: How do the roles of supervisory faculty influence the development of pre-service teachers during the student teaching phase of teacher preparation programs? Data were collected through participant interview, questionnaire, and document collection and analyzed by dividing collected data into overarching codes and themes. The results of this research study hope to inform future practice with respect to university settings in the Commonwealth of Pennsylvania and assist in reviewing and revising, as necessary, the supervisory role and function of the university supervisor-student teacher relationship in the development of pre-service teacher candidates. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

Understanding the turnover and storage of C and N in soils is central to the wider studyof biogeochemical cycles. The loss of C and N to the atmosphere can be monitored usingsimple analytical techniques both in the field and under laboratory conditions, with the loss of C (soil respiration) being one of the most studied components of terrestrial biogeochemistry. The sensitivity of these processes to climate change,and the general driving by edaphic, vegetation and climatic conditions are variable and still poorly understood. This thesis considers three issues in contemporary biogeochemistry; 1. How do warming and throughfall reduction (i.e. climate change) alter soil respiration in an upland heathland. 2. What are the drivers of gaseous losses of C (and N) over spatial scales. 3. What controls the turnover of long residence-time soil C on a national scale. Reduction in summer throughfall had a significant effect on soil respiration when monitored over a three year period. Passive night time warming also had a significant effect on soil respiration, and both treatments increased the temperature sensitivity of soil respiration. There was a strong seasonal element thoughwhich suggests a greater temporal resolution is needed to further understand the nature of these fluxes. Assessment of C fluxes on across a nationalscale suggested that the quantity (and possible quality)of Soil Organic Matter (SOM) was a major factor alongside vegetation type when explaining large-scale soil respiration rates under controlled conditions. Using radiocarbon to model the turnover of SOM on a national scale suggested a fundamental difference between vegetation types with regard to the storage of SOM on decadal or millennial timescales. These results reinforce the sensitivity of shorter-term processes,such as soil respiration,to fluctuations in prevailing climatic conditions, but suggest that vegetation type (and therefore litter inputquantity and quality) may be more important when considering the longer-residence time SOM stored in GB soils. Linking concepts across scales is therefore deemed the way forward in an attempt to integrate model predictions of the resilience of different pools of SOM to perturbations such as climate and land-use change.