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With the advent of highthroughput sequencing (HTS), profiling immunoglobulin (IG) repertoires has become an essential part of immunological research. The dissection of IG repertoires promises to transform our understanding of the adaptive immune system dynamics. Advances in sequencing technology now also allow the use of the Ion Torrent Personal Genome Machine (PGM) to cover the full length of IG mRNA transcripts. The applications of this benchtop scale HTS platform range from identification of new therapeutic antibodies to the deconvolution of malignant B cell tumors. In the context of this thesis, the usability of the PGM is assessed to investigate the IG heavy chain (IGH) repertoires of animal models. First, an innovate bioinformatics approach is presented to identify antigendriven IGH sequences from bulk sequenced bone marrow samples of transgenic humanized rats, expressing a human IG repertoire (OmniRatTM). We show, that these rats mount a convergent IGH CDR3 response towards measles virus hemagglutinin protein and tetanus toxoid, with high similarity to human counterparts. In the future, databases could contain all IGH CDR3 sequences with known specificity to mine IG repertoire datasets for past antigen exposures, ultimately reconstructing the immunological history of an individual. Second, a unique molecular identifier (UID) based HTS approach and network property analysis is used to characterize the CLLlike CD5+ B cell expansion of A20BKO mice overexpressing a natural short splice variant of the CYLD gene (A20BKOsCYLDBOE). We could determine, that in these mice, overexpression of sCYLD leads to unmutated subvariant of CLL (UCLL). Furthermore, we found that this short splice variant is also seen in human CLL patients highlighting it as important target for future investigations. Third, the UID based HTS approach is improved by adapting it to the PGM sequencing technology and applying a custommade data processing pipeline including the ImMunoGeneTics (IMGT) database error detection. Like this, we were able to obtain correct IGH sequences with over 99.5% confidence and correct CDR3 sequences with over 99.9% confidence. Taken together, the results, protocols and sample processing strategies described in this thesis will improve the usability of animal models and the Ion Torrent PGM HTS platform in the field if IG repertoire research.
Numerous RCTs demonstrate that cognitive behavioral therapy (CBT) for depression is effective. However, these findings are not necessarily representative of CBT under routine care conditions. Routine care studies are not usually subjected to comparable standardizations, e.g. often therapists may not follow treatment manuals and patients are less homogeneous with regard to their diagnoses and sociodemographic variables. Results on the transferability of findings from clinical trials to routine care are sparse and point in different directions. As RCT samples are selective due to a stringent application of inclusion/exclusion criteria, comparisons between routine care and clinical trials must be based on a consistent analytic strategy. The present work demonstrates the merits of propensity score matching (PSM), which offers solutions to reduce bias by balancing two samples based on a range of pretreatment differences. The objective of this dissertation is the investigation of the transferability of findings from RCTs to routine care settings.
Interaction between the Hypothalamic-Pituitary-Adrenal Axis and the Circadian Clock System in Humans
(2017)
Rotation of the Earth creates day and night cycles of 24 h. The endogenous circadian clocks sense these light/dark rhythms and the master pacemaker situated in the suprachiasmatic nucleus of the hypothalamus entrains the physical activities according to this information. The circadian machinery is built from the transcriptional/translational feedback loops generating the oscillations in all nucleated cells of the body. In addition, unexpected environmental changes, called stressors, also challenge living systems. A response to these stimuli is provided immediately via the autonomic-nervous system and slowly via the hypothalamus"pituitary"adrenal (HPA) axis. When the HPA axis is activated, circulating glucocorticoids are elevated and regulate organ activities in order to maintain survival of the organism. Both the clock and the stress systems are essential for continuity and interact with each other to keep internal homeostasis. The physiological interactions between the HPA axis and the circadian clock system are mainly addressed in animal studies, which focus on the effects of stress and circadian disturbances on cardiovascular, psychiatric and metabolic disorders. Although these studies give opportunity to test in whole body, apply unwelcome techniques, control and manipulate the parameters at the high level, generalization of the results to humans is still a debate. On the other hand, studies established with cell lines cannot really reflect the conditions occurring in a living organism. Thus, human studies are absolutely necessary to investigate mechanisms involved in stress and circadian responses. The studies presented in this thesis were intended to determine the effects of cortisol as an end-product of the HPA axis on PERIOD (PER1, PER2 and PER3) transcripts as circadian clock genes in healthy humans. The expression levels of PERIOD genes were measured under baseline conditions and after stress in whole blood. The results demonstrated here have given better understanding of transcriptional programming regulated by pulsatile cortisol at standard conditions and short-term effects of cortisol increase on circadian clocks after acute stress. These findings also draw attention to inter-individual variations in stress response as well as non-circadian functions of PERIOD genes in the periphery, which need to be examined in details in the future.
The search for relevant determinants of knowledge acquisition has a long tradition in educational research, with systematic analyses having started over a century ago. To date, a variety of relevant environmental and learner-related characteristics have been identified, providing a wide body of empirical evidence. However, there are still some gaps in the literature, which are highlighted in the current dissertation. The dissertation includes two meta-analyses summarizing the evidence on the effectiveness of electrical brain stimulation and the effects of prior knowledge on later learning outcomes and one empirical study employing latent profile transition analysis to investigate the changes in conceptual knowledge over time. The results from the three studies demonstrate how learning outcomes can be advanced by input from the environment and that they are highly related to the students" level of prior knowledge. It is concluded that the effects of environmental and learner-related variables impact both the biological and cognitive processes underlying knowledge acquisition. Based on the findings from the three studies, methodological and practical implications are provided, followed by an outline of four recommendations for future research on knowledge acquisition.
The first part of this thesis offers a theoretical foundation for the analysis of Tolkien- texts. Each of the three fields of interest, nostalgia, utopia, and the pastoral tradition, are introduced in separate chapters. Special attention is given to the interrelations of the three fields. Their history, meaning, and functions are shortly elaborated and definitions applicable to their occurrences in fantasy texts are reached. In doing so, new categories and terms are proposed that enable a detailed analysis of the nostalgic, pastoral, and utopian properties of Tolkien- works. As nostalgia and utopia are important ingredients of pastoral writing, they are each introduced first and are finally related to a definition of the pastoral. The main part of this thesis applies the definitions and insights reached in the theoretical chapters to Tolkien- The Lord of the Rings and The Hobbit. This part is divided into three main sections. Again, the order of the chapters follows the line of argumentation. The first section contains the analysis of pastoral depictions in the two texts. Given the separation of the pastoral into different categories, which were outlined in the theoretical part, the chapters examine bucolic and georgic pastoral creatures and landscapes before turning to non-pastoral depictions, which are sub-divided into the antipastoral and the unpastoral. A separate chapter looks at the bucolic and georgic pastoral- positions and functions in the primary texts. This analysis is followed by a chapter on men- special position in Tolkien- mythology, as their depiction reveals their potential to be both pastoral and antipastoral. The second section of the analytical part is concerned with the role of nostalgia within pastoral culture. The focus is laid on the meaning and function of the different kinds of nostalgia, which were defined in the theoretical part, detectable in bucolic and georgic pastoral cultures. Finally, the analysis turns to the utopian potential of Tolkien- mythology. Again, the focus lies on the pastoral and non-pastoral creatures. Their utopian and dystopian visions are presented and contrasted. This way, different kinds of utopian vision are detected and set in relation to the overall dystopian fate of Tolkien- fictional universe. Drawing on the results of this thesis and on Terry Gifford- ecocritical work, the final chapter argues that Tolkien- texts can be defined as modern pastorals. The connection between Tolkien- work and pastoral literature made explicit in the analysis is thus cemented in generic terms. The conclusion presents a summary of the central findings of this thesis and introduces questions for further study.
Flexibility and spatial mobility of labour are central characteristics of modern societies which contribute not only to higher overall economic growth but also to a reduction of interregional employment disparities. For these reasons, there is the political will in many countries to expand labour market areas, resulting especially in an overall increase in commuting. The picture of the various, unintended long-term consequences of commuting on individuals is, however, relatively unclear. Therefore, in recent years, the journey to work has gained high attention especially in the study of health and well-being. Empirical analyses based on longitudinal as well as European data on how commuting may affect health and well-being are nevertheless rare. The principle aim of this thesis is, thus, to address this question with regard to Germany using data from the Socio-Economic Panel. Chapter 2 empirically investigates the causal impact of commuting on absence from work due to sickness-related reasons. Whereas an exogenous change in commuting distance does not affect the number of absence days of those individuals who commute short distances to work, it increases the number of absence days of those employees who commute middle (25 " 49 kilometres) or long distances (50 kilometres and more). Moreover, our results highlight that commuting may deteriorate an individual- health. However, this effect is not sufficient to explain the observed impact of commuting on absence from work. Chapter 3 explores the relationship between commuting distance and height-adjusted weight and sheds some light on the mechanisms through which commuting might affect individual body weight. We find no evidence that commuting leads to excess weight. Compensating health behaviour of commuters, especially healthy dietary habits, could explain the non-relationship of commuting and height-adjusted weight. In Chapter 4, a multivariate probit approach is used to estimate recursive systems of equations for commuting and health-related behaviours. Controlling for potential endogeneity of commuting, the results show that long distance commutes significantly decrease the propensity to engage in health-related activities. Furthermore, unobservable individual heterogeneity can influence both the decision to commute and healthy lifestyle choices. Chapter 5 investigates the relationship between commuting and several cognitive and affective components of subjective well-being. The results suggest that commuting is related to lower levels of satisfaction with family life and leisure time which can largely be ascribed to changes in daily time use patterns, influenced by the work commute.
Entrepreneurship is a process of discovering and exploiting opportunities, during which two crucial milestones emerge: in the very beginning when entrepreneurs start their businesses, and in the end when they determine the future of the business. This dissertation examines the establishment and exit of newly created as well as of acquired firms, in particular the behavior and performance of entrepreneurs at these two important stages of entrepreneurship. The first part of the dissertation investigates the impact of characteristics at the individual and at the firm level on an entrepreneur- selection of entry modes across new venture start-up and business takeover. The second part of the dissertation compares firm performance across different entrepreneurship entry modes and then examines management succession issues that family firm owners have to confront. This study has four main findings. First, previous work experience in small firms, same sector experience, and management experience affect an entrepreneur- choice of entry modes. Second, the choice of entry mode for hybrid entrepreneurs is associated with their characteristics, such as occupational experience, level of education, and gender, as well as with the characteristics of their firms, such as location. Third, business takeovers survive longer than new venture start-ups, and both entry modes have different survival determinants. Fourth, the family firm- decision of recruiting a family or a nonfamily manager is not only determined by a manager- abilities, but also by the relationship between the firm- economic and non-economic goals and the measurability of these goals. The findings of this study extend our knowledge on entrepreneurship entry modes by showing that new venture start-ups and business takeovers are two distinct entrepreneurship entry modes in terms of their founders" profiles, their survival rates and survival determinants. Moreover, this study contributes to the literature on top management hiring in family firms: it establishes family firm- non-economic goals as another factor that impacts the family firm- hiring decision between a family and a nonfamily manager.
Why do some people become entrepreneurs while others stay in paid employment? Searching for a distinctive set of entrepreneurial skills that matches the profile of the entrepreneurial task, Lazear introduced a theoretical model featuring skill variety for entrepreneurs. He argues that because entrepreneurs perform many different tasks, they should be multi-skilled in various areas. First, this dissertation provides the reader with an overview of previous relevant research results on skill variety with regard to entrepreneurship. The majority of the studies discussed focus on the effects of skill variety. Most studies come to the conclusion that skill variety mainly affects the decision to become self-employed. Skill variety also favors entrepreneurial intentions. Less clear are the results with regard to the influence of skill variety on the entrepreneurial success. Measured on the basis of income and survival of the company, a negative or U-shaped correlation is shown. Within the empirical part of this dissertation three research goals are tackled. First, this dissertation investigates whether a variety of early interests and activities in adolescence predicts subsequent variety in skills and knowledge. Second, the determinants of skill variety and variety of early interests and activities are investigated. Third, skill variety is tested as a mediator of the gender gap in entrepreneurial intentions. This dissertation employs structural equation modeling (SEM) using longitudinal data collected over ten years from Finnish secondary school students aged 16 to 26. As indicator for skill variety the number of functional areas in which the participant had prior educational or work experience is used. The results of the study suggest that a variety of early interests and activities lead to skill variety, which in turn leads to entrepreneurial intentions. Furthermore, the study shows that an early variety is predicted by openness and an entrepreneurial personality profile. Skill variety is also encouraged by an entrepreneurial personality profile. From a gender perspective, there is indeed a gap in entrepreneurial intentions. While a positive correlation has been found between the early variety of subjects and being female, there are negative correlations between the other two variables, education and work related Skill variety, and being female. The negative effect of work-related skill variety is the strongest. The results of this dissertation are relevant for research, politics, educational institutions and special entrepreneurship education programs. The results are also important for self-employed parents that plan the succession of the family business. Educational programs promoting entrepreneurship can be optimized on the basis of the results of this dissertation by making the transmission of a variety of skills a central goal. A focus on teenagers could also increase the success as well as a preselection based on the personality profile of the participants. Regarding the gender gap, state policies should aim to provide women with more incentives to acquire skill variety. For this purpose, education programs can be tailored specifically to women and self-employment can be presented as an attractive alternative to dependent employment.
A phenomenon of recent decades is that digital marketplaces on the Internet are establishing themselves for a wide variety of products and services. Recently, it has become possible for private individuals to invest in young and innovative companies (so-called "start-ups"). Via Internet portals, potential investors can examine various start-ups and then directly invest in their chosen start-up. In return, investors receive a share in the firm- profit, while companies can use the raised capital to finance their projects. This new way of financing is called "Equity Crowdfunding" (ECF) or "Crowdinvesting". The aim of this dissertation is to provide empirical findings about the characteristics of ECF. In particular, the question of whether ECF is able to overcome geographic barriers, the interdependence of ECF and capital structure, and the risk of failure for funded start-ups and their chances of receiving follow-up funding by venture capitalists or business angels will be analyzed. The results of the first part of this dissertation show that investors in ECF prefer local companies. In particular, investors who invest larger amounts have a stronger tendency to invest in local start-ups. The second part of the dissertation provides first indications of the interdependencies between capital structure and ECF. The analysis makes clear that the capital structure is not a determinant for undertaking an ECF campaign. The third part of the dissertation analyzes the success of companies financed by ECF in a country comparison. The results show that after a successful ECF campaign German companies have a higher chance of receiving follow-up funding by venture capitalists compared to British companies. The probability of survival, however, is slightly lower for German companies. The results provide relevant implications for theory and practice. The existing literature in the area of entrepreneurial finance will be extended by insights into investor behavior, additions to the capital structure theory and a country comparison in ECF. In addition, implications are provided for various actors in practice.
This dissertation looked at both design-based and model-based estimation for rare and clustered populations using the idea of the ACS design. The ACS design (Thompson, 2012, p. 319) starts with an initial sample that is selected by a probability sampling method. If any of the selected units meets a pre-specified condition, its neighboring units are added to the sample and observed. If any of the added units meets the pre-specified condition, its neighboring units are further added to the sample and observed. The procedure continues until there are no more units that meet the pre-specified condition. In this dissertation, the pre-specified condition is the detection of at least one animal in a selected unit. In the design-based estimation, three estimators were proposed under three specific design setting. The first design was stratified strip ACS design that is suitable for aerial or ship surveys. This was a case study in estimating population totals of African elephants. In this case, units/quadrant were observed only once during an aerial survey. The Des Raj estimator (Raj, 1956) was modified to obtain an unbiased estimate of the population total. The design was evaluated using simulated data with different levels of rarity and clusteredness. The design was also evaluated on real data of African elephants that was obtained from an aerial census conducted in parts of Kenya and Tanzania in October (dry season) 2013. In this study, the order in which the samples were observed was maintained. Re-ordering the samples by making use of the Murthy's estimator (Murthy, 1957) can produce more efficient estimates. Hence a possible extension of this study. The computation cost resulting from the n! permutations in the Murthy's estimator however, needs to be put into consideration. The second setting was when there exists an auxiliary variable that is negatively correlated with the study variable. The Murthy's estimator (Murthy, 1964) was modified. Situations when the modified estimator is preferable was given both in theory and simulations using simulated and two real data sets. The study variable for the real data sets was the distribution and counts of oryx and wildbeest. This was obtained from an aerial census that was conducted in parts of Kenya and Tanzania in October (dry season) 2013. Temperature was the auxiliary variable for two study variables. Temperature data was obtained from R package raster. The modified estimator provided more efficient estimates with lower bias compared to the original Murthy's estimator (Murthy, 1964). The modified estimator was also more efficient compared to the modified HH and the modified HT estimators of (Thompson, 2012, p. 319). In this study, one auxiliary variable is considered. A fruitful area for future research would be to incorporate multi-auxiliary information at the estimation phase of an ACS design. This could, in principle, be done by using for instance a multivariate extension of the product estimator (Singh, 1967) or by using the generalized regression estimator (Särndal et al., 1992). The third case under design-based estimation, studied the conjoint use of the stopping rule (Gattone and Di Battista, 2011) and the use of the without replacement of clusters (Dryver and Thompson, 2007). Each of these two methods was proposed to reduce the sampling cost though the use of the stopping rule results in biased estimates. Despite this bias, the new estimator resulted in higher efficiency gain in comparison to the without replacement of cluster design. It was also more efficient compared to the stratified design which is known to reduce final sample size when networks are truncated at stratum boundaries. The above evaluation was based on simulated and real data. The real data was the distribution and counts of hartebeest, elephants and oryx obtained in the same census as above. The bias attributed by the stopping rule has not been evaluated analytically. This may not be direct since the truncated network formed depends on the initial unit sampled (Gattone et al., 2016a). This and the order of the bias however, deserves further investigation as it may help in understanding the effect of the increase in the initial sample size together with the population characteristics on the efficiency of the proposed estimator. Chapter four modeled data that was obtained using the stratified strip ACS (as described in sub-section (3.1)). This was an extension of the model of Rapley and Welsh (2008) by modeling data that was obtained from a different design, the introduction of an auxiliary variable and the use of the without replacement of clusters mechanism. Ideally, model-based estimation does not depend on the design or rather how the sample was obtained. This is however, not the case if the design is informative; such as the ACS design. In this case, the procedure that was used to obtain the sample was incorporated in the model. Both model-based and design-based simulations were conducted using artificial and real data. The study and the auxiliary variable for the real data was the distribution and counts of elephants collected during an aerial census in parts of Kenya and Tanzania in October (dry season) and April (wet season) 2013 respectively. Areas of possible future research include predicting the population total of African elephants in all parks in Kenya. This can be achieved in an economical and reliable way by using the theory of SAE. Chapter five compared the different proposed strategies using the elephant data. Again the study variable was the elephant data from October (dry season) 2013 and the auxiliary variable was the elephant data from April (wet season) 2013. The results show that the choice of particular strategy to use depends on the characteristic of the population under study and the level and the direction of the correlation between the study and the auxiliary variable (if present). One general area of the ACS design that is still behind, is the implementation of the design in the field especially on animal populations. This is partly attributed by the challenges associated with the field implementation, some of which were discussed in section 2.3. Green et al. (2010) however, provides new insights in undertaking the ACS design during an aerial survey such as how the aircraft should turn while surveying neighboring units. A key point throughout the dissertation is the reduction of cost during a survey which can be seen by the reduction in the number of units in the final sample (through the use of stopping rule, use of stratification and truncating networks at stratum boundaries) and ensuring that units are observed only once (by using the without replacement of cluster sampling technique). The cost of surveying an edge unit(s) is assumed to be low in which case the efficiency of the ACS design relative to the non-adaptive design is achieved (Thompson and Collins, 2002). This is however not the case in aerial surveys as the aircraft flies at constant speed and height (Norton-Griffiths, 1978). Hence the cost of surveying an edge unit is the same as the cost of surveying a unit that meets the condition of interest. The without replacement of cluster technique plays a greater role of reducing the cost of sampling in such surveys. Other key points that motivated the sections in the dissertation include gains in efficiency (in all sections) and practicability of the designs in the specific setting. Even though the dissertation focused on animal populations, the methods can as well be implemented in any population that is rare and clustered such as in the study of forestry, plants, pollution, minerals and so on.