Nicotine Dependence and Smoking Behaviour : A genetic and epidemiological study

The worldwide health burden caused by the tobacco epidemic highlights the importance of study-ing determinants of smoking behaviour and key factors sustaining nicotine dependence. Despite vast-ranging preventive efforts, smoking remains one of the most deleterious health behaviours, and its genetic and environmental factors warrant continuous investigation. The heritability of smoking behaviour and nicotine dependence has been suggested to be relatively high. Earlier smoking behaviour, nicotine dependence, socio-economic position and demographic factors have all been shown to be associated with smoking cessation. This thesis aimed to examine various aspects of smoking behaviour and nicotine dependence from an epidemiological and genetic per-spective. Data for Studies I and IV were obtained from the Older Finnish Twin Cohort, a postal health sur-vey conducted in 1975, 1981 and 1990 on same-sexed pairs and in 1996-1997 on male-female adult pairs. The number of ever-smoking participants was 8941 in Study I and 3069 in Study IV. Data for Studies II and III came from the Family Study of Cigarette Smoking - Vulnerability to Nicotine Addiction. This study is linked to the Older Finnish Twin Cohort with new data collec-tion during 2001-2006 that focused on smoking twin pairs and their family members. The meas-ures included intensive telephone interviews, blood samples and additional postal questionnaires. The numbers of ever-smoking participants was 1370 in Study II and 529 in Study III. Study I examined whether a genetic component underlies smoking behaviour among Finnish adults. Genetic factors were important in the amount smoked and smoking cessation, with about half of the phenotypic differences explained by genetic variance. A novel finding was that genetic influences on amount smoked and smoking cessation were largely independent of genetic influ-ences on age at initiation. This result has implications for defining phenotypes in the search for genes underlying smoking behaviour. Furthermore, even if smoking initiation is postponed to a later age, potential vulnerability to subsequent nicotine dependence cannot be completely inhib-ited. Study II investigated the effect of genetic and environmental factors on nicotine dependence, as measured by the novel multidimensional Nicotine Dependence Syndrome Scale (NDSS). This scale was validated in the Finnish data. The NDSS correlated highly with other established nico-tine dependence scales (FTND and DSM-IV), suggesting that this new scale would be a feasible and valid measure for identifying nicotine-dependent smokers among the ever-smoking popula-tion. About one-third of the phenotypic variation in nicotine dependence in this sample was ex-plained by genetic influences. Study III aimed at identifying chromosomal regions harbouring genes that influence smoking be-haviour and nicotine dependence. Linkage analysis of family data revealed that for smoker and nicotine dependence phenotypes as well as for co-morbidity between nicotine dependence and alcohol use signals on specific chromosome regions (chromosomes 2q33, 5q12, 5q34 7q21, 7q31, 10q25, 11p15, 20p13) exist. Results further support the hypothesis that smoking behaviour phe-notypes have a genetic background. Study IV examined associations of smoking behaviour, socio-economic position and transition of marital status with smoking cessation. Indicators of socio-economic position were important pre-dictors of smoking cessation even when adjusted for previous smoking behaviour. Getting married was associated with an increased probability of cessation in men, a finding confirmed among dis-cordant twin pairs. Thus, having a partner appears to have a positive impact on smoking cessation. In conclusion, nicotine dependence and smoking behaviour demonstrate significant genetic liabil-ity, but also substantial environmental influences among Finnish adults. Smoking initiation should be prevented or at least postponed to a later age. Although genetic factors are important in nicotine dependence and smoking behaviour, societal actions still have a primary role in tobacco control and smoking prevalence. Future studies should examine the complex interactions between genetic and environmental factors in nicotine dependence.

Regulation of Growth by Drosophila FoxO Transcription Factor

Forkhead box class O (FoxO) transcription factors are members of the forkhead box transcription factor superfamily, with orthologues in various species such as human, worm and fly. FoxO proteins are key regulators of growth, metabolism, stress resistance and, consequently, life span. FoxOs integrate signals from different pathways, e.g. the growth controlling Insulin-TOR signaling pathway and the stress induced JNK and Hippo signaling pathways. FoxO proteins have evolved to guide the cellular response to varying energy and stress conditions by inducing the expression of genes involved in the regulation of growth and metabolism. This work has aimed to deepen the understanding of how FoxO executes its biological functions. A particular emphasis has been laid to its role in growth control. Specifically, evidence is presented indicating that FoxO restricts tissue growth in a situation when TOR signaling is high. This finding can have implications in a human condition called Tuberous sclerosis, manifested by multiple benign tumors. Further, it is shown that FoxO directly binds to the promoter and regulates the expression of a Drosophila Adenylate cyclase gene, ac76e, which in turn modulates the fly s development and growth systemically. These results strengthen FoxOs position among central size regulators as it is able to operate at the level of individual cells as well as in the whole organism. Finally, an attempt to reveal the regulatory network upstream of FoxO has been carried out. Several putative FoxO activity regulators were identified in an RNAi screen of Drosophila kinases and phosphatases. The results underscore that FoxO is regulated through an elaborate network, ensuring the correct execution of key cellular processes in metabolism and response to stress. Overall, the evidence provided in this study strengthens our view of FoxO as a key integrator of growth and stress signals.

Rate Control State-of-the-art Survey

The majority of Internet traffic use Transmission Control Protocol (TCP) as the transport level protocol. It provides a reliable ordered byte stream for the applications. However, applications such as live video streaming place an emphasis on timeliness over reliability. Also a smooth sending rate can be desirable over sharp changes in the sending rate. For these applications TCP is not necessarily suitable. Rate control attempts to address the demands of these applications. An important design feature in all rate control mechanisms is TCP friendliness. We should not negatively impact TCP performance since it is still the dominant protocol. Rate Control mechanisms are classified into two different mechanisms: window-based mechanisms and rate-based mechanisms. Window-based mechanisms increase their sending rate after a successful transfer of a window of packets similar to TCP. They typically decrease their sending rate sharply after a packet loss. Rate-based solutions control their sending rate in some other way. A large subset of rate-based solutions are called equation-based solutions. Equation-based solutions have a control equation which provides an allowed sending rate. Typically these rate-based solutions react slower to both packet losses and increases in available bandwidth making their sending rate smoother than that of window-based solutions. This report contains a survey of rate control mechanisms and a discussion of their relative strengths and weaknesses. A section is dedicated to a discussion on the enhancements in wireless environments. Another topic in the report is bandwidth estimation. Bandwidth estimation is divided into capacity estimation and available bandwidth estimation. We describe techniques that enable the calculation of a fair sending rate that can be used to create novel rate control mechanisms.

Specifying Reuse Interfaces for Task-Oriented Framework Specialization

Reuse of existing carefully designed and tested software improves the quality of new software systems and reduces their development costs. Object-oriented frameworks provide an established means for software reuse on the levels of both architectural design and concrete implementation. Unfortunately, due to frame-works complexity that typically results from their flexibility and overall abstract nature, there are severe problems in using frameworks. Patterns are generally accepted as a convenient way of documenting frameworks and their reuse interfaces. In this thesis it is argued, however, that mere static documentation is not enough to solve the problems related to framework usage. Instead, proper interactive assistance tools are needed in order to enable system-atic framework-based software production. This thesis shows how patterns that document a framework s reuse interface can be represented as dependency graphs, and how dynamic lists of programming tasks can be generated from those graphs to assist the process of using a framework to build an application. This approach to framework specialization combines the ideas of framework cookbooks and task-oriented user interfaces. Tasks provide assistance in (1) cre-ating new code that complies with the framework reuse interface specification, (2) assuring the consistency between existing code and the specification, and (3) adjusting existing code to meet the terms of the specification. Besides illustrating how task-orientation can be applied in the context of using frameworks, this thesis describes a systematic methodology for modeling any framework reuse interface in terms of software patterns based on dependency graphs. The methodology shows how framework-specific reuse interface specifi-cations can be derived from a library of existing reusable pattern hierarchies. Since the methodology focuses on reusing patterns, it also alleviates the recog-nized problem of framework reuse interface specification becoming complicated and unmanageable for frameworks of realistic size. The ideas and methods proposed in this thesis have been tested through imple-menting a framework specialization tool called JavaFrames. JavaFrames uses role-based patterns that specify a reuse interface of a framework to guide frame-work specialization in a task-oriented manner. This thesis reports the results of cases studies in which JavaFrames and the hierarchical framework reuse inter-face modeling methodology were applied to the Struts web application frame-work and the JHotDraw drawing editor framework.

Factors Affecting Knowledge Sharing in Strategic Alliances: The Role of Knowledge Sharing as Strategic Control Behavior among Multinational Enterprises

International strategic alliances (ISAs) have become increasingly important for the stability, growth, and long-term viability of modern business organizations. Alliance partnerships as inter-firm cooperative ventures represent an influential mechanism for asserting corporate strategic control among autonomous multinational enterprises. These different cooperative arrangements are made of equity investments or contractually-based partnerships. Different alliance forms represent different approaches that partner firms adopt to control their mutual dependence on the alliance and on other partners. Earlier research shows that the partner characteristics could provide an explanation for alliance strategic behavior and see alliances as alternative forms to markets or hierarchies for addressing specific strategic needs linked to partners’ characteristics and their subsequent strategic motives. These characteristics of the partners’ and subsequent strategic motives are analyzed as knowledge sharing factors and how these influence inter-firm control in alliances within the context of the focal-firm STMicroelectronics and its alliance partners Nokia, Ericsson and IBM. This study underline that as contracts are incomplete, they are therefore required to maintain mutual dependence based control mechanisms in addition to a contract. For example, mutual dependence based control mechanisms could be joint financial investments and the building of an ownership structure between the parties (e.g., JVs). However, the present study clarifies that subsequent inter-firm control is also exercised through inter-firm knowledge sharing. The present study contributes by presenting a dynamic interplay between competitive and cooperative rent seeking behavior. Such coopetition behavior describes the firm's strategic orientation to achieve a dynamic balance between competitive and cooperative strategies. This balance is seen in knowledge sharing based cooperation and competition behavior. Thus this study clarifies coopetition strategies by introducing the role of inter-firm cooperation and the competitive nature of knowledge sharing. Simultaneous cooperative and competitive behavior is also seen as synergetic rent-seeking behavior. Therefore, this study extends the perspective of previous studies on competitive and cooperative seeking behavior.