Transcription factor GATA4 and apoptotic TRAIL pathway in granulosa cell function and tumors

Normal growth and development require the precise control of gene expression. Transcription factors are proteins that regulate gene expression by binding specific sequences of DNA. Abnormalities in transcription are implicated in a variety of human diseases, including cancer, endocrine disorders and birth defects. Transcription factor GATA4 has emerged as an important regulator of normal development and function in a variety of endoderm- and mesoderm- derived tissues, including gut, heart and several endocrine organs, such as gonads. Mice harboring a null mutation of Gata4 gene die during embryogenesis due to failure in heart formation, complicating the study of functional role of GATA4 in other organs. However, the expression pattern of GATA4 suggests it may play a role in the regulation of ovarian granulosa cell development, function and apoptosis. This premise is supported by in vitro studies showing that GATA4 regulates several steroidogenic enzymes as well as auto-, para- and endocrine signaling molecules important for granulosa cell function. This study assessed the in vivo role of GATA4 for granulosa cell function by utilizing two genetically modified mouse strains. The findings in the GATA4 deficient mice included delayed puberty, impaired fertility and signs of diminished estrogen production. At the molecular level, the GATA4 deficiency leads to attenuated expression of central steroidogenic genes, Steroidogenic acute regulatory protein (StAR), Side-chain cleavage (SCC), and aromatase as a response to stimulations with exogenous gonadotropins. Taken together, these suggest GATA4 is necessary for the normal ovarian function and female fertility. Programmed cell death, apoptosis, is a crucial part of normal ovarian development and function. In addition, disturbances in apoptosis have been implicated to pathogenesis of human granulosa cell tumors (GCTs). Apoptosis is controlled by extrinsic and intrinsic pathways. The intrinsic pathway is regulated by members of Bcl-2 family, and its founding member, the anti-apoptotic Bcl-2, is known to be important for granulosa cell survival. This study showed that the expression levels of GATA4 and Bcl-2 correlate in the human GCTs and that GATA4 regulates Bcl-2 expression, presumably by directly binding to its promoter. In addition, disturbing GATA4 function was sufficient to induce apoptosis in cultured GCT- derived cell line. Taken together, these results suggest GATA4 functions as an anti-apoptotic factor in GCTs. The extrinsic apoptotic pathway is controlled by the members of tumor necrosis factor (TNF) superfamily. An interesting ligand of this family is TNF-related apoptosis-inducing ligand (TRAIL), possessing a unique ability to selectively induce apoptosis in malignant cells. This study characterized the previously unknown expression of TRAIL and its receptors in both developing and adult human ovary, as well as in malignant granulosa cell tumors. TRAIL pathway was shown to be active in GCTs suggesting it may be a useful tool in treating these malignancies. However, more studies are required to assess the function of TRAIL pathway in normal ovaries. In addition to its ability to induce apoptosis in GCTs, this study revealed that GATA4 protects these malignancies from TRAIL-induced apoptosis. GATA4 presumably exerts this effect by regulating the expression of anti-apoptotic Bcl-2. This is of particular interest as high expression of GATA4 is known to correlate to aggressive GCT behavior. Thus, GATA4 seems to protect GCTs from endogenous TRAIL by upregulating anti-apoptotic factors such as Bcl-2.

Sterol-binding proteins in late endosomes : Regulation of endosome motility and lipid metabolism

Despite its bad reputation in the mass media, cholesterol is an indispensable constituent of cellular membranes and vertebrate life. It is, however, also potentially lethal as it may accumulate in the arterial intima causing atherosclerosis or elsewhere in the body due to inherited conditions. Studying cholesterol in cells, and research on how the cell biology of cholesterol affects on system level is essential for a better understanding of the disease states associated with cholesterol and for the development of new therapies for these conditions. On its way to the cell, exogenous cholesterol traverses through endosomes, transport vesicles involved in internalizing material to cells, and needs to be transported out of this compartment. This endosomal pool of cholesterol is important for understanding both the common disorders of metabolism and the more rare hereditary disorders of cholesterol metabolism. The study of cholesterol in cells has been hampered by the lack of bright fluorescent sterol analogs that would resemble cholesterol enough to be used in cellular studies. In the first study of my thesis, we present a new sterol analog, Boron-Dipyrromethene (BODIPY)-cholesterol for visualizing sterols in living cells and organism. This fluorescent cholesterol derivative is shown to behave similarly to cholesterol both by atomic scale computer simulations and biochemical experiments. We characterize its localization inside different types of living cells and show that it can be used to study sterol trafficking in living organisms. Two sterol binding proteins associated with the endosomal membrane; the Niemann-Pick type C disease protein 1 (NPC1) and the Oxysterol Binding Protein Related Protein 1 (ORP1) are the subjects of the rest of this study. Sensing cholesterol on endosomes, transporting lipids away from this compartment and the effects these lipids play on cellular metabolism are considered. In the second study we characterize how the NPC1 protein affects lipid metabolism. We show that this cholesterol binding protein affects synthesis of triglycerides and that genetic polymorphisms or a genetic defect in the NPC1 gene affect triglyceride on the whole body level. These effects take place via regulation of carbon fluxes to different lipid classes in cells. In the third part we characterize the effects of another endosomal sterol binding protein, ORP1L on the function and motility of endosomes. Specifically we elucidate how a mutation in the ability of ORP1L to bind sterols affects its behavior in cells, and how a change in ORP1L levels in cells affects the localization, degradative capacity and motility of endosomes. In addition we show that ORP1L manipulations affect cholesterol balance also in macrophages, a cell type important for the development of atherosclerosis.

Ammatillisten opettajien tieto- ja viestintätekniikan opetuskäytön intentionaalisuutta selittävät tekijät

Intention-based models have been one of the main theoretical orientations in the research on the implementation of information and communication technology (ICT). According to these models, actual behavior can be predicted from the intention towards the behavior. If the level of intention to use technology is high, the probability of actual usage of ICT increases. The purpose of this study was to find out which factors explain vocational teachers intention to use ICT in their teaching. In addition, teachers of media and information sciences and teachers of welfare and health were compared. The study also explored how regularly ICT was applied by teachers and how strong their intention to apply the technology was. This Master s thesis is a quantitative study and the data was collected using an Email survey and Eform. The instruments were based on a decomposed theory of planned behavior. The research group consisted of 22 schools of media and information sciences and 20 schools of welfare and health. The data consisted of 231 vocational teachers: 57 teachers worked with media and information sciences and 174 with welfare and health. The data was analyzed using Mann-Whitney U-test, factor analysis and regression analysis. In addition, categorized results were compared with previous study. In this study, the intention to use ICT in teaching was explained by the teachers attitudes and skills and the attitudes of their work community. However, the environment in which ICT was used, i.e., the technical environment, economical resources and time, did not explain the intention. The results did not directly support any of the intention-based models, but they could be interpreted as congruent with the technology acceptance model. The majority of the teachers used ICT at least weekly. They had a strong intention to continue to do that in the future. The study also revealed that there were more teachers who had a critical attitude towards ICT among the teachers of welfare and health. According to the results of this study, it is not possible to state that ICT would not suit any one profession because in every group with teachers with a critical attitude towards ICT there were also teachers with a positive attitude.

Synthesis, aggregation behavior and cholesterol solubilization studies of 16-epi-pythocholic acid (3 alpha,12 alpha,16 beta-trihydroxy-5 beta-cholan-24-oic acid)

Synthesis, aggregation behavior and in vitro cholesterol solubilization studies of 16-epi-pythocholic acid (3 alpha,12 alpha,16 beta-trihydroxy-5 beta-cholan-24-oic acid, EPCA) are reported. The synthesis of this unnatural epimer of pythocholic acid (3 alpha,12 alpha,16 alpha-trihydroxy-5 beta-cholan-24-oic acid, PCA) involves a series of simple and selective chemical transformations with an overall yield of 21% starting from readily available cholic acid (CA). The critical micellar concentration (CMC) of 16-epi-pythocholate in aqueous media was determined using pyrene as a fluorescent probe. In vitro cholesterol solubilization ability was evaluated using anhydrous cholesterol and results were compared with those of other natural di-and trihydroxy bile acids. These studies showed that 16-epi-pythocholic acid (16 beta-hydroxy-deoxycholic acid) behaves similar to cholic acid (CA) and avicholic acid (3 alpha,7 alpha,16 alpha-trihydroxy-5 beta-cholan-24-oic acid, ACA) in its aggregation behavior and cholesterol dissolution properties. (C) 2010 Elsevier Inc. All rights reserved.

Energy landscape view of phase transitions and slow dynamics in thermotropic liquid crystals

Thermotropic liquid crystals are known to display rich phase behavior on temperature variation. Although the nematic phase is orientationally ordered but translationally disordered, a smectic phase is characterized by the appearance of a partial translational order in addition to a further increase in orientational order. In an attempt to understand the interplay between orientational and translational order in the mesophases that thermotropic liquid crystals typically exhibit upon cooling from the high-temperature isotropic phase, we investigate the potential energy landscapes of a family of model liquid crystalline systems. The configurations of the system corresponding to the local potential energy minima, known as the inherent structures, are determined from computer simulations across the mesophases. We find that the depth of the potential energy minima explored by the system along an isochor grows through the nematic phase as temperature drops in contrast to its insensitivity to temperature in the isotropic and smectic phases. The onset of the growth of the orientational order in the parent phase is found to induce a translational order, resulting in a smectic-like layer in the underlying inherent structures; the inherent structures, surprisingly, never seem to sustain orientational order alone if the parent nematic phase is sandwiched between the high-temperature isotropic phase and the low-temperature smectic phase. The Arrhenius temperature dependence of the orientational relaxation time breaks down near the isotropic-nematic transition. We find that this breakdown occurs at a temperature below which the system explores increasingly deeper potential energy minima.

Enhanced Ion Anisotropy by Nonconventional Coordination Geometry: Single-Chain Magnet Behavior for a [{(FeL)-L-II}(2){Nb-IV(CN)(8)}] Helical Chain Compound Designed with Heptacoordinate Fe-II

Nonconventional heptacoordination in combination with efficient magnetic exchange coupling is shown to yield a 1-D heteronuclear {(FeNbIV)-Nb-II} compound with remarkable magnetic features when compared to other Fe(II)-based single chain magnets (SCM). Cyano-bridged heterometallic {3d-4d} and {3d-5d} chains are formed upon assembling Fe(II) bearing a pentadentate macrocycle as the blocking ligand with octacyano metallates, [M(CN)(8)](4-) (M = Nb-IV, Mo-IV, W-IV.) X-ray diffraction (single-crystal and powder) measurements reveal that the [{(H2O)Fe(L-1)}{M(CN)(8)}{Fe(L-1)}](infinity) architectures consist of isomorphous 1-D polymeric structures based on the alternation of {Fe(L-1)}(2+) and {M(CN)(8)}(4-) units (L-1 stands for the pentadentate macrocycle). Analysis of the magnetic susceptibility behavior revealed cyano-bridged {Fe-Nb} exchange interaction to be antiferromagnetic with J = -20 cm(-1) deduced from fitting an Ising model taking into account the noncollinear spin arrangement. For this ferrimagnetic chain a slow relaxation of its magnetization is observed at low temperature revealing a SCM behavior with Delta/k(B) = 74 K and tau(0) = 4.6 x 10(-11) s. The M versus H behavior exhibits a hysteresis loop with a coercive field of 4 kOe at 1 K and reveals at 380 mK magnetic avalanche processes, i.e., abrupt reversals in magnetization as H is varied. The origin of these characteristics is attributed to the combination of efficient {Fe-Nb} exchange interaction and significant anisotropy of the {Fe(L-1)) unit. High field EPR and magnetization experiments have revealed for the parent compound [Fe(L-1)(H2O)(2)]Cl-2 a negative zero field splitting parameter of D approximate to -17 cm(-1). The crystal structure, magnetic behavior, and Mossbauer data for [Fe(L-1)(H2O)(2)]Cl-2 are also reported.

Enhanced Ion Anisotropy by Nonconventional Coordination Geometry: Single-Chain Magnet Behavior for a [{(FeL)-L-II}(2){Nb-IV(CN)(8)}] Helical Chain Compound Designed with Heptacoordinate Fe-II

Nonconventional heptacoordination in combination with efficient magnetic exchange coupling is shown to yield a 1-D heteronuclear {(FeNbIV)-Nb-II} compound with remarkable magnetic features when compared to other Fe(II)-based single chain magnets (SCM). Cyano-bridged heterometallic {3d-4d} and {3d-5d} chains are formed upon assembling Fe(II) bearing a pentadentate macrocycle as the blocking ligand with octacyano metallates, [M(CN)(8)](4-) (M = Nb-IV, Mo-IV, W-IV.) X-ray diffraction (single-crystal and powder) measurements reveal that the [{(H2O)Fe(L-1)}{M(CN)(8)}{Fe(L-1)}](infinity) architectures consist of isomorphous 1-D polymeric structures based on the alternation of {Fe(L-1)}(2+) and {M(CN)(8)}(4-) units (L-1 stands for the pentadentate macrocycle). Analysis of the magnetic susceptibility behavior revealed cyano-bridged {Fe-Nb} exchange interaction to be antiferromagnetic with J = -20 cm(-1) deduced from fitting an Ising model taking into account the noncollinear spin arrangement. For this ferrimagnetic chain a slow relaxation of its magnetization is observed at low temperature revealing a SCM behavior with Delta/k(B) = 74 K and tau(0) = 4.6 x 10(-11) s. The M versus H behavior exhibits a hysteresis loop with a coercive field of 4 kOe at 1 K and reveals at 380 mK magnetic avalanche processes, i.e., abrupt reversals in magnetization as H is varied. The origin of these characteristics is attributed to the combination of efficient {Fe-Nb} exchange interaction and significant anisotropy of the {Fe(L-1)) unit. High field EPR and magnetization experiments have revealed for the parent compound [Fe(L-1)(H2O)(2)]Cl-2 a negative zero field splitting parameter of D approximate to -17 cm(-1). The crystal structure, magnetic behavior, and Mossbauer data for [Fe(L-1)(H2O)(2)]Cl-2 are also reported.

Fracture behavior of concrete–concrete interface using acoustic emission technique

The fracture behavior of concrete–concrete interface is characterized using acoustic emission (AE). Beams of different sizes having jointed interface between two different strengths of concrete are tested. The results of load, displacement, CMOD, AE-events and AE-energy are analyzed. The width of fracture process zone and damage zone are computed using AE-data and are found to be independent of size. It is observed that, as the difference in compressive strength of concrete on either side of interface increases, the load carrying capacity, number of AE-events, AE-energy, width of fracture process zone and damage zone decreases.

Determinants and Consequences of Information Sharing with Key Suppliers

As companies become more efficient with respect to their internal processes, they begin to shift the focus beyond their corporate boundaries. Thus, the recent years have witnessed an increased interest by practitioners and researchers in interorganizational collaboration, which promises better firm performance through more effective supply chain management. It is no coincidence that this interest comes in parallel with the recent advancements in Information and Communication Technologies, which offer many new collaboration possibilities for companies. However, collaboration, or any other type of supply chain integration effort, relies heavily on information sharing. Hence, this study focuses on information sharing, in particular on the factors that determine it and on its value. The empirical evidence from Finnish and Swedish companies suggests that uncertainty (both demand and environmental) and dependency in terms of switching costs and asset specific investments are significant determinants of information sharing. Results also indicate that information sharing improves company performance regarding resource usage, output, and flexibility. However, companies share information more intensely at the operational rather than the strategic level. The use of supply chain practices and technologies is substantial but varies across the two countries. This study sheds light on a common trend in supply chains today. Whereas the results confirm the value of information sharing, the contingent factors help to explain why the intensity of information shared across companies differ. In the future, competitive pressures and uncertainty are likely to intensify. Therefore, companies may want to continue with their integration efforts by focusing on the determinants discussed in this study. However, at the same time, the possibility of opportunistic behavior by the exchange partner cannot be disregarded.

Growth and Convergence: The case of China

Growth and Convergence: The Case of China Since the initiation of economic reforms in 1978, China has become one of the world’s fast-growing economies. The rapid growth, however, has not been shared equally across the different regions in China. The prominent feature of substantial differences in incomes and growth rates across the different Chinese regions has attracted the attention of many researchers. This book focuses on issues related to economic growth and convergence across the Chinese regions over the past three decades. The book has eight chapters. Apart from an introduction chapter and a concluding chapter, all the other chapters each deal with some certain aspects of the central issue of regional growth and convergence across China over the past three decades. The whole book is organized as follows. Chapter 1 provides an introduction to the basic issues involved in this book. Chapter 2 tests economic growth and convergence across 31 Chinese provinces during 1981-2005, based on the theoretical framework of the Solow growth model. Chapter 3 investigates the relationship between openness to foreign economic activities, such as foreign trade and foreign direct investment, and the regional economic growth in the case of China during 1981-2005. Chapter 4, based on data of 31 Chinese provinces over the period 1980-2004, presents new evidence on the effects of structural shocks and structural transformation on growth and convergence among the Chinese regions. Chapter 5, by building up an empirical model that takes account of different potential effects of foreign direct investment, focuses on the impacts of foreign direct investment on China’s regional economic performance and growth. Chapter 6 reconsiders the growth and convergence problem of the Chinese regions in an alternative theoretical framework with endogenous saving behavior and capital mobility across regions. Chapter 7, by building up a theoretical model concerning comparative advantage and transaction efficiency, focuses on one of the potential mechanisms through which China achieves its fast economic growth over the past few decades. Chapter 8 concludes the book by summarizing the results from the previous chapters and suggesting directions for further studies.

Essays on Stock Market Reactions to New Information

A functioning stock market is an essential component of a competitive economy, since it provides a mechanism for allocating the economy’s capital stock. In an ideal situation, the stock market will steer capital in a manner that maximizes the total utility of the economy. As prices of traded stocks depend on and vary with information available to investors, it is apparent that information plays a crucial role in a functioning stock market. However, even though information indisputably matters, several issues regarding how stock markets process and react to new information still remain unanswered. The purpose of this thesis is to explore the link between new information and stock market reactions. The first essay utilizes new methodological tools in order to investigate the average reaction of investors to new financial statement information. The second essay explores the behavior of different types of investors when new financial statement information is disclosed to the market. The third essay looks into the interrelation between investor size, behavior and overconfidence. The fourth essay approaches the puzzle of negative skewness in stock returns from an altogether different angle than previous studies. The first essay presents evidence of the second derivatives of some financial statement signals containing more information than the first derivatives. Further, empirical evidence also indicates that some of the investigated signals proxy risk while others contain information priced with a delay. The second essay documents different categories of investors demonstrating systematical differences in their behavior when new financial statement information arrives to the market. In addition, a theoretical model building on differences in investor overconfidence is put forward in order to explain the observed behavior. The third essay shows that investor size describes investor behavior very well. This finding is predicted by the model proposed in the second essay, and hence strengthens the model. The behavioral differences between investors of different size furthermore have significant economic implications. Finally, the fourth essay finds strong evidence of management news disclosure practices causing negative skewness in stock returns.

Intraday Dynamics of International Equity Markets

The increased availability of high frequency data sets have led to important new insights in understanding of financial markets. The use of high frequency data is interesting and persuasive, since it can reveal new information that cannot be seen in lower data aggregation. This dissertation explores some of the many important issues connected with the use, analysis and application of high frequency data. These include the effects of intraday seasonal, the behaviour of time varying volatility, the information content of various market data, and the issue of inter market linkages utilizing high frequency 5 minute observations from major European and the U.S stock indices, namely DAX30 of Germany, CAC40 of France, SMI of Switzerland, FTSE100 of the UK and SP500 of the U.S. The first essay in the dissertation shows that there are remarkable similarities in the intraday behaviour of conditional volatility across European equity markets. Moreover, the U.S macroeconomic news announcements have significant cross border effect on both, European equity returns and volatilities. The second essay reports substantial intraday return and volatility linkages across European stock indices of the UK and Germany. This relationship appears virtually unchanged by the presence or absence of the U.S stock market. However, the return correlation among the U.K and German markets rises significantly following the U.S stock market opening, which could largely be described as a contemporaneous effect. The third essay sheds light on market microstructure issues in which traders and market makers learn from watching market data, and it is this learning process that leads to price adjustments. This study concludes that trading volume plays an important role in explaining international return and volatility transmissions. The examination concerning asymmetry reveals that the impact of the positive volume changes is larger on foreign stock market volatility than the negative changes. The fourth and the final essay documents number of regularities in the pattern of intraday return volatility, trading volume and bid-ask spreads. This study also reports a contemporaneous and positive relationship between the intraday return volatility, bid ask spread and unexpected trading volume. These results verify the role of trading volume and bid ask quotes as proxies for information arrival in producing contemporaneous and subsequent intraday return volatility. Moreover, asymmetric effect of trading volume on conditional volatility is also confirmed. Overall, this dissertation explores the role of information in explaining the intraday return and volatility dynamics in international stock markets. The process through which the information is incorporated in stock prices is central to all information-based models. The intraday data facilitates the investigation that how information gets incorporated into security prices as a result of the trading behavior of informed and uninformed traders. Thus high frequency data appears critical in enhancing our understanding of intraday behavior of various stock markets’ variables as it has important implications for market participants, regulators and academic researchers.

Essays on Stock Options, Incentives, and Managerial Action

Executive compensation and managerial behavior have received an increasing amount of attention in the financial economics literature since the mid 1970s. The purpose of this thesis is to extend our understanding of managerial compensation, especially how stock option compensation is linked to the actions undertaken by the management. Furthermore, managerial compensation is continuously and heatedly debated in the media and an emerging consensus from this discussion seems to be that there still exists gaps in our knowledge of optimal contracting. In Finland, the first executive stock options were introduced in the 1980s and throughout the last 15 years it has become increasingly popular for Finnish listed firms to use this type of managerial compensation. The empirical work in the thesis is conducted using data from Finland, in contrast to most previous studies that predominantly use U.S. data. Using Finnish data provides insight of how market conditions affect compensation and managerial action and provides an opportunity to explore what parts of the U.S. evidence can be generalized to other markets. The thesis consists of four essays. The first essay investigates the exercise policy of the executive stock option holders in Finland. In summary, Essay 1 contributes to our understanding of the exercise policies by examining both the determinants of the exercise decision and the markets reaction to the actual exercises. The second essay analyzes the factors driving stock option grants using data for Finnish publicly listed firms. Several agency theory based variables are found to have have explanatory power on the likelihood of a stock option grant. Essay 2 also contributes to our understanding of behavioral factors, such as prior stock return, as determinants of stock option compensation. The third essay investigates the tax and stock option motives for share repurchases and dividend distributions. We document strong support for the tax motive for share repurchases. Furthermore, we also analyze the dividend distribution decision in companies with stock options and find a significant difference between companies with and without dividend protected options. We thus document that the cutting of dividends found in previous U.S. studies can be avoided by dividend protection. In the fourth essay we approach the puzzle of negative skewness in stock returns from an altogether different angle than in previous studies. We suggest that negative skewness in stock returns is generated by management disclosure practices and find proof for this. More specifically, we find that negative skewness in daily returns is induced by returns for days when non-scheduled firm specific news is disclosed.