Includes bibliographical references (leaves 291-311)

Normal tissue homeostasis and appropriate responses to injury and infection are dependent on cellular communication mediated by cell surface receptors that respond to extrinsic stimuli. The GM-CSF receptor was the major focus of this project. This receptor shares a common signalling subunit, β [subscript c], with the IL-3 and IL-5 receptors. The unique GM-CSF receptor α-subunit ( GMRα ) confers ligand binding specificity to the complex and is essential for GM-CSF receptor signalling, although the full complement of signalling events mediated by GMRα remains elusive. Through cloning of candidate interacting proteins, expression and co-immunoprecipitation studies, we have confirmed interactions for two proteins previously reported to interact with the GMRα, p85 and IKKβ. Additionally, we identified the Src family kinase, Lyn, as a novel direct interacting partner of GMRα and provide insights into possible roles of this kinase in initiating signalling from the GM-CSF receptor. In addition to GMRα associated events we aimed to further characterise the role of the common β [subscript c] subunit in GM-CSF mediated signalling. We utilised two classes of consitutively active β [subscript c] mutants ( extracellular or transmembrane ) which transform the bi-potential myeloid FDB1 cell line to either factor-independent growth and survival, or granulocyte-macrophage differentiation, respectively. Here we report a comprehensive biochemical analysis of signalling by these two classes of mutants in this cell line. The two activated GMR mutants displayed distinct and non-overlapping signalling capacity. In particular, expression of a mutant with a substitution in the transmembrane domain ( V449E ) selectively activated JAK / STAT5 and MAPK pathways resulting in a high level of sensitivity to JAK and MEK inhibitors. In contrast, expression of a mutant with a 37 amino acid duplication in its extracellular domain ( FI Δ ) selectively activates the PI3K / AKT and IKKβ / NFkB pathways. Cells responding to this mutant display a relative high level of sensitivity to two independent PI3K inhibitors and relative resistance to inhibition of MEK and JAK2. The non-overlapping nature of signalling by these two activated mutants suggests that there are alternative modes of receptor activation that differentially dependent on JAK2 and that act synergistically in the mature liganded cytokine receptor complex. Further detailed analysis of these mutants will facilitate the dissection of the signalling pathways involved in the GM-CSF response that mediate proliferation, survival and differentiation. / Thesis (Ph.D.)--School of Medicine, 2007.

Includes bibliographical references (leaves 291-311) / xxiii, 313 leaves : ill. (chiefy col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Molecular Biosciences, 2002

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on December 17, 2007) Vita. Includes bibliographical references.

Includes bibliographical references (43 leaves) This study shows that when LR3IGF-I is administered to animals in pharmacologically active doses, it may be present in either the free form or bound to IGF-binding protein(s) in the circulation. Age and nutrition which are factors that regulate synthesis of endogenous IGF-I and IGF-binding proteins, affect the in vivo formation of complexes between the analog and IGFBP(s). This study also suggests that IGFBP-1 inhibits the pharmacological activity of circulating LR3IGF-I on thymus whereas it appears to stimulate the pharmacological activity of LR3IGF-I in kidneys.

No description available.

In vivo analyses of the Von Willebrand Factor (VWF) promoter previously demonstrated that a fragment spanning sequences -487 to +247 targets promoter activation to brain vascular endothelial cells. This fragment is active in all embryonic vessels of transgenic mice but in adult mice its activity is restricted to brain vascular endothelial cells, while endogenous VWF gene is expressed in vasculature of all major organs. In this study we demonstrate that a DNase I hypersensitive (HSS) sequences in intron 51 of the VWF gene contain cis-acting elements that are necessary for the VWF gene transcription in a subset of lung endothelial cells in vivo. Our results demonstrated that Nuclear Factor 1 (NF1) and Nuclear transcription Factor Y (NFY) repressors contribute to VWF organ-specific regulation. Mutation of the NF1 binding site resulted in promoter activation in lung and heart, while mutation of the repressor corresponding to a novel binding site for NFY resulted in promoter activation in kidney vasculature. / Experimental Medicine

This research aims at evaluating a new ventilation concept: personal displacement ventilation (PDV) for improving indoor air quality. The new ventilation method combines room displacement ventilation with task ventilation, the latter being directed at controlling air quality and comfort in the microenvironment where the building occupant is working, with the premise that such directed ventilation will maintain air quality where it matters. This approach could lead to improved ventilation system design that could even provide individual control of indoor microclimate. The effectiveness of PDV was studied by using computational fluid dynamics (CFD) modeling and rigorous validation experiments. First, a small office setup was built in a controlled environmental chamber. Three PDV cases with different locations of contaminant source and one general displacement ventilation (DV) case were investigated. Spatial distributions of airflow, temperature, and hypothetical pollutant distributions were measured. The measured data were then used to evaluate the performance of PDV against defined indoor air quality and thermal comfort criteria, and to validate the CFD model. The validated CFD program was further used to study PDV under various conditions. This study found that basic equipped PDV acts no different from DV from airflow pattern?s point of view. Due to the lack of heat generation around occupant?s legs, local buoyancy effect is not strong enough to attract supply air, which is generated from diffuser nearby, to join in the plume around occupant. However, auxiliary activities adjusting the direction of supply air and adding high panels around person can improve the fraction of supply air to join the plume around person or decrease the average contaminant concentration in breathing zone.

This research has three parts. Part 1: The Policy on Geometric Design of Highways and Street provides 5 methods of superelevation (e) distribution. Many states use methods 2 and 5 for low speed, urban and rural high-speed facilities. Method 5 aims to address speed variations; but is complicated, computationally intractable and may violate design consistency. Design recommendation by NCHRP439 accounts for speed variation, tractable; but is cumbersome along with irregular/step-wise design curves. New reliability based e distribution method is developed that addresses the speed variation; which is simple in determining and evaluating acceptable required e rates. At 95% level of reliability, the e rate obtained is lower than that from current practice resulting in cost savings. Part 2: Current practice/research does not address safety issue of the left-turn-bay at high degree of saturation (x). Left-Turn-Bay distance has three components: clearance, breaking to a stop and queue. The variation in the queue length reduces clearance and breaking distance resulting in unsafe breaking. Failure = clearance plus breaking distance < demand. The reliability of the left-turn-bay defined as the availability of the three components for left-turning vehicles to complete clearance and breaking maneuver safely; measured as increase in the deceleration rate over limit of 11.2ft/s2, safety index and probability of failure. Results show that at 95% reliability, current design practice fails when x exceeds 50%. Part 3: Current practice uses mean traffic volumes (Vd) as input for traffic signal control at roadway intersections. Variations in traffic flows affect the performance of intersection measured by the delay per vehicle traversing the intersection in seconds. Peak hour factor (PHF), the hourly volume divided by the peak 15-min flow rate within the peak hour is adopted by Highway Capacity Manual (HCM) to control surge. HCM suggests PHF design value of 0.92 for urban and 0.88 for rural areas. Fixed PHF may lead to increase in delay. Effects of variation of peak hour volumes on intersection signal delays are examined with large data. A new model is developed for PHF and Vd and used in signal timing to minimize intersection delay. The results show that the assumption of Poisson distribution for Vd is not reliable; delay reduction of 6.2 seconds per vehicle is achieved. Annual savings in travel time, fuel consumption and emissions cost is estimated in billions of dollars.