No description available.

No description available.

No description available.

Aberrant phenotypes of airway smooth muscle cells are central to the pathophysiology of asthma. The hypercontractile nature of these cells and hypertrophy are the key reasons for the excessive narrowing of the airways observed in allergic asthma. Although previous studies have indicated a role of enhanced content of smMLCK in modulating the contractile reactivity, as well as an indication of hypertrophy of HASM cells in asthmatic conditions, the effect of IgE on the expression of smMLCK in HASM cells is not fully understood. In this study, we demonstrate that IgE augments the expression of smMLCK at the mRNA and protein level. Inhibition of IgE binding with anti-FcεRI blocking antibody, Syk silencing, pharmacological inhibitors to MAPK (ERK1/2, p38, and JNK) and PI3K significantly diminished the IgE-mediated smMLCK expression in HASM cells. Finally, we found that IgE, similar to metacholine induces the contraction of HASM cells grown on collagen gel matrix. Our data suggest that IgE stimulates the phosphorylation of ERK, P38, STAT3 and induces the dephosphorylation of smMLCK to phosphorylate myosin regulatory light chain in HASM cells. Taken together, our data suggest a modulatory role of IgE in regulating the contractile machinery and hypertrophic phenotype of HASM cells.

No description available.

No description available.

During the last few years nonlinear models have been a very active area of econometric research: new models have been introduced and existing ones generalized. To a large extent, these developments have concerned models in which the conditional moments are regime-dependent. In such models, the different regimes are usually linear and the change between them is governed by an observable or unobservable variable. These specifications can be useful in situations in which it is suspected that the behaviour of the dependent variable may vary between regimes. A classical example can be found the business cycle literature where it is argued that contractions in the economy are not only more violent but also short-lived than expansions. Unemployment, which tends to rise faster during recessions than decline during booms, constitutes another example. Two of the most popular regime-dependent models are the smooth transition and the threshold model. In both models cases the transition variable is observable but the specification of the way in which the model changes from one regime to the other is different. Particularly, in the smooth transition model the change is a continuous whereas in the threshold model it is abrupt. One of the factors that has influenced the development of nonlinear models are improvements in computer technology. They have not only permitted an introduction of more complex models but have also allowed the use of computer-intensive methods in hypothesis testing. This is particularly important in nonlinear models because there these methods have proved to be practical in testing statistical hypothesis such as linearity and parameter constancy. In general, these testing situation are not trivial and their solution often requires computer-intensive methods. In particular, bootstrapping and Monte Carlo testing are now commonly used. In this thesis the smooth transition model is used in different ways. In the first chapter, a vector smooth transition model is used as a device for deriving a test for parameter constancy in stationary vector autoregressive models. In the second chapter we introduce a panel model whose parameters can change in a smooth fashion between regimes as a function of an exogenous variable. The method is used to investigate whether financial constraints affect firms' \ investment decisions. The third chapter is concern with linearity testing in smooth transition models. New tests are introduced and Monte Carlo testing techniques are shown to be useful in achieving control over the size of the test. Finally, the last chapter is devoted to the Smooth Permanent Surge model. This is a nonlinear moving average model in which a shock can have transitory or permanent effects depending on its sign and magnitude. Test for linearity and random walk hypothesis are introduced. / Diss. Stockholm : Handelshögsk., 2004

Neointimal proliferation is a key process underlying many cardiovascular diseases such as atherosclerosis and angioplasty-induced restenosis. Vascular smooth muscle cells (SMC) are significant contributors to the development and stability of the neointimal lesion. This is due, in part, to their capacity to be phenotypically modulated, facilitating SMC proliferation in response to mechanical injury, their subsequent migration, and deposition of extracellular matrix. The aim of this thesis was to characterize the function of two genes identified in our laboratory to be upregulated shortly after mechanical injury of vascular SMC and their exposure to fibroblast growth factor (FGF)-2, an injury-induced cytokine. The first is activation transcription factor (ATF) 4, which is upregulated by FGF-2 and mechanical injury in vascular SMC in vitro, and by balloon-injury in the artery wall. The induction of ATF4 by FGF-2 was shown to be mediated through the PI3K pathway, and preceded by phoshorylation of eIF2alpha, a known upstream effector of ATF4 activation. Knock-down of ATF4 expression inhibited balloon-injury induced neointimal hyperplasia, suggesting that ATF4 is a key player in the SMC response to injury. Furthermore, microarray analysis identified several genes whose transcription in response to FGF-2 may be regulated by ATF4. In particular, this work demonstrates that ATF4 is necessary for VEGF-A upregulation in SMC in response to FGF-2 and mechanical injury in vitro and in the artery wall following balloon-injury. The second is a translation factor, YrdC203. Using confocal fluorescence microscopy, YrdC203 was found to localize partially to the ER, and with RPL12, a component of the 60S ribosomal subunit. Immunoprecipitation studies demonstrate that YrdC203 also interacts with an initiation factor, eIF5B. Mutation of an initiation factor’s signature on the exterior of YrdC203 perturbed its interaction with RPL12 and eIF5B, and inhibited the increase in protein synthesis observed with overexpression of YrdC203. This implicates YrdC203 as a translation factor responsible for ensuring protein synthesis in vascular SMC in response to injury. The present work provides evidence for new molecular mechanisms, transcriptional and translational, regulating the response of vascular SMC to injury. This would provide leads for future therapeutic targets.

Thesis (Ph. D.)--University of Nevada, Reno, 2006. / "August, 2006." Includes bibliographical references (leaves 111-128). Online version available on the World Wide Web.

Thesis (Ph. D.)--University of Nevada, Reno, 2007. / "December, 2007." Includes bibliographical references (leaves 76-109). Online version available on the World Wide Web.