Insulin resistance is the major metabolic defect in obesity and Type 2 diabetes. Increased lipid accumulation is strongly associated with insulin resistance. A significant component of insulin resistance is thought to be a reduced ability of insulin to activate the cascade of phosphorylation events that lead to the metabolic effects of this hormone. The broad aims of this thesis were to examine the effect of high-fat diets containing different fat subtypes on in vivo insulin signalling, under conditions normally used to detect whole body insulin resistance, and to compare the effects of acute and chronic lipid oversupply on insulin signalling in vivo. Time-course and dose-response effects of insulin stimulation on site-specific phosphorylation of key signalling proteins were studied in rat tissues in vivo, to establish an appropriate experimental system to examine the onset of activation of the insulin signalling pathway. It was determined that short insulin infusions with concurrent glucose infusion, similar to the beginning of a euglycaemic-hyperinsulinaemic clamp, significantly increased the phosphorylation of major intermediates of the insulin signalling pathway in important tissues of insulin action (skeletal muscle [RQ], liver [LIV] and white adipose tissue [EPI]). These experiments provided a platform to study insulin signalling under the same conditions used to study lipid-induced insulin resistance. The provision of diets enriched in polyunsaturated or saturated fatty acids (FA) resulted in the corresponding enrichment of these fat subtypes in rat plasma and tissues. However, the effects on insulin signalling were essentially the same. Both fat diets induced defects in sitespecific phosphorylation of insulin receptor substrate (IRS)-1 and protein kinase B (PKB) in RQ and LIV, but not EPI. This suggests that the amount of fat in the diet, rather than enrichment in a particular fat subtype, had a greater impact on the development of signalling defects and that the response to high-fat feeding was tissue-specific. A 3hr elevation of circulating FA (using a lipid/heparin infusion), to a level that is relevant in clinical Type 2 diabetes, impaired insulin-stimulated PKB phosphorylation with no significant effect on IRS-1 phosphorylation. This suggests that there may be differences in the way acute and chronic exposure to increased FA impair insulin signalling. The phosphorylation defects observed in both chronic and acute studies did not seem to be associated with activation of major stress signalling pathways (JNK and NFkB), which have been suggested to have a role in lipidinduced insulin resistance. In conclusion, these studies demonstrate that impaired IRS-1 and PKB phosphorylation do have a role in the reduced insulin action observed with lipid oversupply in vivo, because the changes were detected under similar conditions as those used to determine whole body insulin resistance.

"August 2002." / Bibliography: p. 157-169. / xi, 169 p. : ill. (some col.), plates (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Analysis of the expression of Drosophilia cyclin EII through development show that it was present during larval development and oogenesis, implying a role for DmcycEII outside of early embyogenesis. Ectopic expression analyses using full-length DmcycE proteins as well as N- and C-terminal deletions of DmcycEI, revealed that DmcycEII and N-terminal deletions were able to drive all G1 cells within the morphogenetic furrow of the eye imaginal disc into S phase, while a C-terminal deletion of DmcycEI could not. These results show the DmcycEII is more potent than DmcycEI in driving cells into S phase and that the N-terminal region of DmcycEI contains a negative regulatory domean., suggesting that an inhibitor is present in the posterior morphogenetic furrow that binds to DmcycEI N-terminus and inhibits DmcycEI function. To identify the DmcycEI specific inhibitor, genetic interaction and yeast-2 hybrid screens were undertaken, and an enhancer CG7394, encoding a MAGUK homologue was identified for further study. / Thesis (Ph.D.)--University of Adelaide, Dept. of Molecular Biosciences, 2002

IL-2 has multiple functions in T cell-mediated adaptive immunity. The stringent control of its expression is important for T cell activation, proliferation and the subsequent T cell clone contraction. Our lab has recently shown that the transcriptional repressor Blimp-1 is part of a negative feedback loop which controls IL-2 gene expression in mice. Understanding the molecular mechanisms of this signaling loop in T cells might help us to better understand the regulation as well as the role of IL-2 in T cell immunity. The human ortholog to murine Blimp-1 is termed PRDI-BF1 (each encoded by the respective Prdm1 gene). Both genes contain five zinc finger regions, whereby the first two zinc fingers are dispensable for DNA binding. In case of the human protein they are instead required to recruit the G9?Ñ methyltransferase to the gene promotor. We found that the human wild-type PRDI-BF1 protein suppressed IL-2 production in murine T cells, while deletion of the first two zinc fingers abolished this ability. Thus, a similar Blimp-1-mediated methylation mechanism might exist in IL-2 gene silencing. IL-2/IL-2R signaling is indispensable for Blimp-1 induction. PI-3Kinase and Stat5 are downstream of the IL-2 receptor complex and are known to contribute to IL-2 inhibition in T cells from C57BL/6 mice. However, activating only these two pathways are still not sufficient to induce Blimp-1 or suppress IL-2 expression in in IL-2R beta-/- mice. The Blimp-1-dependent IL-2 self regulatory loop is not functional in IL-2R beta-/-mice. In order to conveniently study this dysregulation we crossed these mice with a GFP transgenic strain in which the GFP transgene is under the control of IL-2 promoter sequence. In IL-2R beta-/-IL-2p-GFP mice about five times as many spleenic CD4+ T cells transcribe IL-2pGFP, compared to the littermate IL-2R beta+/-IL-2p-GFP control animals. And most of the GFP cells demonstrate activated phenotype (CD44HighCD62Llow). Blimp-1 is known as a master regulator of B cell terminal differentiation. Since a recent report indicated that IL-2 signaling via STAT5 constrains Th17 Cell differentiation, we speculated that Blimp-1 might play a similar role in effector T cell differentiation. In order to evaluate this possibility, activated CD4+ T cells from C57BL/6 mice were transduced with Blimp-1 and cultured under Th17 polarizing conditions. Blimp-1 overexpression in did not change the profile of IL-17 production.

People in the oil and gas industry sometimes do not consider pressure-dependent permeability in reservoir performance calculations. It basically happens due to lack of lab data to determine level of dependency. This thesis attempts to evaluate the error introduced in calculations when a constant permeability is assumed in tight gas reservoir. It is desired to determine how accurate are conventional pressure analysis calculations when the reservoir has a strong pressure-dependent permeability. The analysis considers the error due to effects of permeability and skin factor. Also included is the error associated when calculating Original Gas in Place in the reservoir. The mathematical model considers analytical and numerical solutions of radial and linear flow of gas through porous media. The model includes both the conventional method, which assumes a constant permeability (pressure-independent), and a numerical method that incorporates a pressure-dependent permeability. Analysis focuses on different levels of pressure draw down in a well located in the center of a homogeneous reservoir considering two types of flow field geometries: radial and linear. Two different producing control modes for the producer well are considered: constant rate and constant bottom hole pressure. Methodology consists of simulated tight gas well production with k(p) included. Then, we analyze results as though k(p) effects were ignored and finally, observe errors in determining permeability (k) and skin factor (s). Additionally, we calculate pore volume and OGIP in the reservoir. Analysis demonstrates that incorporation of pressure-dependence of permeability k(p) is critical in order to avoid inference of erroneous values of permeability, skin factor and OGIP from well test analysis of tight gas reservoirs. Estimation of these parameters depends on draw down in the reservoir. The great impact of permeability, skin factor and OGIP calculations are useful in business decisions and profitability for the oil company. Miscalculation of permeability and skin factor can lead to wrong decisions regarding well stimulation, which reduces well profitability. In most cases the OGIP calculated is underestimated. Calculated values are lower than the correct value. It can be taken as an advantage if we consider that additional gas wells and reserves would be incorporated in the exploitation plan.

Often in statistics it is of interest to investigate whether or not a trend is significant. Methods for testing such a trend depend on the assumptions of the error terms such as whether the distribution is known and also if the error terms are independent. Likelihood ratio tests may be used if the distribution is known but in some instances one may not want to make such assumptions. In a time series, these errors will not always be independent. In this case, the error terms are often modelled by an autoregressive or moving average process. There are resampling techniques for testing the hypothesis of interest when the error terms are dependent, such as, modelbased bootstrapping and the wild bootstrap, but the error terms need to be whitened. In this dissertation, a bootstrap procedure is used to test the hypothesis of no trend for variable stars when the error structure assumes a particular form. In some cases, the bootstrap to be implemented is preferred over large sample tests in terms of the level of the test. The bootstrap procedure is able to correctly identify the underlying distribution which may not be χ2.

No description available.

Functional differential equations with delay have long been studied due to their practical applications. For the delay term is not a constant number, many researches study the case when this deviating argument depends on the state variable. So we deal with the differential and functional equations involving with the compositions of the unknown function, i.e. the iterative functional differential equations (IFDEs) and iterative functional equations (IFEs) without derivative. The main purpose of this dissertation is to investigate the solutions of such equations, including their analytic solutions, numerical solutions and qualitative behaviors. First, we survey some well known differential equations of this type which possess analytic solutions. Then the classical method of undetermined coefficients is used to compute these power series solutions for the first order IFDEs in Chapter 1, the second order IFDEs in Chapter 2 and FDEs in Chapter 3. Taylor series method is also used to get these analytic solutions in Chapter 4. Systematical method is found to locate the fixed point in generalized sense, so we can use these methods to calculate the coefficients of their analytic solutions. Furthermore, we also establish the existence and uniqueness theorem for analytic solution in Chapter 5. Second, we survey the known existence and uniqueness theorems of solutions for these IFDEs and FDEs in Chapter 6. Then we apply Schauder fixed point theorem to establish new existence theorems of local solutions for general IFDEs. Under certain conditions, these local solutions can be extended to global solutions. Chapter 7 deals with the simplest IFDEs the Eder's equation. We extend the qualitative properties of this case and find its solution is not unique. In Chapter 8, we use Euler method to get the numerical solution of IFDEs. Under some conditions, we have the error analysis on these equations. In Chapter 9, we employ the method of undetermined coefficients, Taylor series, Picard's iteration and Si's methods to get their analytic solutions. Their comparisons, the advantage and disadvantage of these methods are also discussed.

none

People in the oil and gas industry sometimes do not consider pressure-dependent permeability in reservoir performance calculations. It basically happens due to lack of lab data to determine level of dependency. This thesis attempts to evaluate the error introduced in calculations when a constant permeability is assumed in tight gas reservoir. It is desired to determine how accurate are conventional pressure analysis calculations when the reservoir has a strong pressure-dependent permeability. The analysis considers the error due to effects of permeability and skin factor. Also included is the error associated when calculating Original Gas in Place in the reservoir. The mathematical model considers analytical and numerical solutions of radial and linear flow of gas through porous media. The model includes both the conventional method, which assumes a constant permeability (pressure-independent), and a numerical method that incorporates a pressure-dependent permeability. Analysis focuses on different levels of pressure draw down in a well located in the center of a homogeneous reservoir considering two types of flow field geometries: radial and linear. Two different producing control modes for the producer well are considered: constant rate and constant bottom hole pressure. Methodology consists of simulated tight gas well production with k(p) included. Then, we analyze results as though k(p) effects were ignored and finally, observe errors in determining permeability (k) and skin factor (s). Additionally, we calculate pore volume and OGIP in the reservoir. Analysis demonstrates that incorporation of pressure-dependence of permeability k(p) is critical in order to avoid inference of erroneous values of permeability, skin factor and OGIP from well test analysis of tight gas reservoirs. Estimation of these parameters depends on draw down in the reservoir. The great impact of permeability, skin factor and OGIP calculations are useful in business decisions and profitability for the oil company. Miscalculation of permeability and skin factor can lead to wrong decisions regarding well stimulation, which reduces well profitability. In most cases the OGIP calculated is underestimated. Calculated values are lower than the correct value. It can be taken as an advantage if we consider that additional gas wells and reserves would be incorporated in the exploitation plan.

Often in statistics it is of interest to investigate whether or not a trend is significant. Methods for testing such a trend depend on the assumptions of the error terms such as whether the distribution is known and also if the error terms are independent. Likelihood ratio tests may be used if the distribution is known but in some instances one may not want to make such assumptions. In a time series, these errors will not always be independent. In this case, the error terms are often modelled by an autoregressive or moving average process. There are resampling techniques for testing the hypothesis of interest when the error terms are dependent, such as, modelbased bootstrapping and the wild bootstrap, but the error terms need to be whitened. In this dissertation, a bootstrap procedure is used to test the hypothesis of no trend for variable stars when the error structure assumes a particular form. In some cases, the bootstrap to be implemented is preferred over large sample tests in terms of the level of the test. The bootstrap procedure is able to correctly identify the underlying distribution which may not be χ2.