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Institute
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Investigation of the TCA cycle and glycolytic metabolons and their physiological impacts in plants
(2016)
Recently, due to an increasing demand on functionality and flexibility, beforehand isolated systems have become interconnected to gain powerful adaptive Systems of Systems (SoS) solutions with an overall robust, flexible and emergent behavior. The adaptive SoS comprises a variety of different system types ranging from small embedded to adaptive cyber-physical systems. On the one hand, each system is independent, follows a local strategy and optimizes its behavior to reach its goals. On the other hand, systems must cooperate with each other to enrich the overall functionality to jointly perform on the SoS level reaching global goals, which cannot be satisfied by one system alone. Due to difficulties of local and global behavior optimizations conflicts may arise between systems that have to be solved by the adaptive SoS.
This thesis proposes a modeling language that facilitates the description of an adaptive SoS by considering the adaptation capabilities in form of feedback loops as first class entities. Moreover, this thesis adopts the Models@runtime approach to integrate the available knowledge in the systems as runtime models into the modeled adaptation logic. Furthermore, the modeling language focuses on the description of system interactions within the adaptive SoS to reason about individual system functionality and how it emerges via collaborations to an overall joint SoS behavior. Therefore, the modeling language approach enables the specification of local adaptive system behavior, the integration of knowledge in form of runtime models and the joint interactions via collaboration to place the available adaptive behavior in an overall layered, adaptive SoS architecture.
Beside the modeling language, this thesis proposes analysis rules to investigate the modeled adaptive SoS, which enables the detection of architectural patterns as well as design flaws and pinpoints to possible system threats. Moreover, a simulation framework is presented, which allows the direct execution of the modeled SoS architecture. Therefore, the analysis rules and the simulation framework can be used to verify the interplay between systems as well as the modeled adaptation effects within the SoS. This thesis realizes the proposed concepts of the modeling language by mapping them to a state of the art standard from the automotive domain and thus, showing their applicability to actual systems. Finally, the modeling language approach is evaluated by remodeling up to date research scenarios from different domains, which demonstrates that the modeling language concepts are powerful enough to cope with a broad range of existing research problems.
The horse is a fascinating animal symbolizing power, beauty, strength and grace. Among all the animal species domesticated the horse had the largest impact on the course of human history due to its importance for warfare and transportation. Studying the process of horse domestication contributes to the knowledge about the history of horses and even of our own species.
Research based on molecular methods has increasingly focused on the genetic basis of horse domestication. Mitochondrial DNA (mtDNA) analyses of modern and ancient horses detected immense maternal diversity, probably due to many mares that contributed to the domestic population. However, mtDNA does not provide an informative phylogeographic structure. In contrast, Y chromosome analyses displayed almost complete uniformity in modern stallions but relatively high diversity in a few ancient horses. Further molecular markers that seem to be well suited to infer the domestication history of horses or genetic and phenotypic changes during this process are loci associated with phenotypic traits.
This doctoral thesis consists of three different parts for which I analyzed various single nucleotide polymorphisms (SNPs) associated with coat color, locomotion or Y chromosomal variation of horses. These SNPs were genotyped in 350 ancient horses from the Chalcolithic (5,000 BC) to the Middle Ages (11th century). The distribution of the samples ranges from China to the Iberian Peninsula and Iceland. By applying multiplexed next-generation sequencing (NGS) I sequenced short amplicons covering the relevant positions: i) eight coat-color-associated mutations in six genes to deduce the coat color phenotype; ii) the so-called ’Gait-keeper’ SNP in the DMRT3 gene to screen for the ability to amble; iii) 16 SNPs previously detected in ancient horses to infer the corresponding haplotype. Based on these data I investigated the occurrence and frequencies of alleles underlying the respective phenotypes as well as Y chromosome haplotypes at different times and regions. Also, selection coefficients for several Y chromosome lineages or phenotypes were estimated.
Concerning coat color differences in ancient horses my work constitutes the most comprehensive study to date. I detected an increase of chestnut horses in the Middle Ages as well as differential selection for spotted and solid phenotypes over time which reflects changing human preferences.
With regard to ambling horses, the corresponding allele was present in medieval English and Icelandic horses. Based on these results I argue that Norse settlers, who frequently invaded parts of Britain, brought ambling individuals to Iceland from the British Isles which can be regarded the origin of this trait. Moreover, these settlers appear to have selected for ambling in Icelandic horses.
Relating to the third trait, the paternal diversity, these findings represent the largest ancient dataset of Y chromosome variation in non-humans. I proved the existence of several Y chromosome haplotypes in early domestic horses. The decline of Y chromosome variation coincides with the movement of nomadic peoples from the Eurasian steppes and later with different breeding practices in the Roman period.
In conclusion, positive selection was estimated for several phenotypes/lineages
in different regions or times which indicates that these were preferred by humans. Furthermore, I could successfully infer the distribution and dispersal of horses in association with human movements and actions. Thereby, a better understanding of the influence of people on the changing appearance and genetic diversity of domestic horses could be gained. My results also emphasize the close relationship of ancient genetics and archeology or history and that only in combination well-founded conclusions can be reached.
Proteins are amphiphilic and adsorb at liquid interfaces. Therefore, they can be efficient stabilizers of foams and emulsions. β-lactoglobulin (BLG) is one of the most widely studied proteins due to its major industrial applications, in particular in food technology.
In the present work, the influence of different bulk concentration, solution pH and ionic strength on the dynamic and equilibrium pressures of BLG adsorbed layers at the solution/tetradecane (W/TD) interface has been investigated. Dynamic interfacial pressure (Π) and interfacial dilational elastic modulus (E’) of BLG solutions for various concentrations at three different pH values of 3, 5 and 7 at a fixed ionic strength of 10 mM and for a selected fixed concentration at three different ionic strengths of 1 mM, 10 mM and 100 mM are measured by Profile Analysis Tensiometer PAT-1 (SINTERFACE Technologies, Germany). A quantitative data analysis requires additional consideration of depletion due to BLG adsorption at the interface at low protein bulk concentrations. This fact makes experiments more efficient when oil drops are studied in the aqueous protein solutions rather than solution drops formed in oil. On the basis of obtained experimental data, concentration dependencies and the effect of solution pH on the protein surface activity was qualitatively analysed. In the presence of 10 mM buffer, we observed that generally the adsorbed amount is increasing with increasing BLG bulk concentration for all three pH values. The adsorption kinetics at pH 5 result in the highest Π values at any time of adsorption while it exhibits a less active behaviour at pH 3.
Since the experimental data have not been in a good agreement with the classical diffusion controlled model due to the conformational changes which occur when the protein molecules get in contact with the hydrophobic oil phase in order to adapt to the interfacial environment, a new theoretical model is proposed here. The adsorption kinetics data were analysed with the newly proposed model, which is the classical diffusion model but modified by assuming an additional change in the surface activity of BLG molecules when adsorbing at the interface. This effect can be expressed through the adsorption activity constant in the corresponding equation of state. The dilational visco-elasticity of the BLG adsorbed interfacial layers is determined from measured dynamic interfacial tensions during sinusoidal drop area variations. The interfacial tension responses to these harmonic drop oscillations are interpreted with the same thermodynamic model which is used for the corresponding adsorption isotherm.
At a selected BLG concentration of 2×10-6 mol/l, the influence of the ionic strength using different buffer concentration of 1, 10 and 100 mM on the interfacial pressure was studied. It is affected weakly at pH 5, whereas it has a strong impact by increasing buffer concentration at pH 3 and 7. In conclusion, the structure formation of BLG adsorbed layer in the early stage of adsorption at the W/TD interface is similar to those of the solution/air (W/A) surface. However, the equation of state at the W/TD interface provides an adsorption activity constant which is almost two orders of magnitude higher than that for the solution/air surface.
At the end of this work, a new experimental tool called Drop and Bubble Micro Manipulator DBMM (SINTERFACE Technologies, Germany) has been introduced to study the stability of protein covered bubbles against coalescence. Among the available protocols the lifetime between the moment of contact and coalescence of two contacting bubble is determined for different BLG concentrations. The adsorbed amount of BLG is determined as a function of time and concentration and correlates with the observed coalescence behaviour of the contacting bubbles.
This dissertation uses a common grammatical phenomenon, light verb constructions (LVCs) in English and German, to investigate how syntax-semantics mapping defaults influence the relationships between language processing, representation and conceptualization. LVCs are analyzed as a phenomenon of mismatch in the argument structure. The processing implication of this mismatch are experimentally investigated, using ERPs and a dual task. Data from these experiments point to an increase in working memory. Representational questions are investigated using structural priming. Data from this study suggest that while the syntax of LVCs is not different from other structures’, the semantics and mapping are represented differently. This hypothesis is tested with a new categorization paradigm, which reveals that the conceptual structure that LVC evoke differ in interesting, and predictable, ways from non-mismatching structures’.
This book provides for an extensive legal analysis of the international drug control system in light of the growing challenges and criticism that this system faces. In the current debate on global drug policy, the central pillars of the international drug control system – the UN Drug Conventions as well as its institutions – are portrayed as outdated, suppressive and seen as an obstacle to necessary changes. The book’s objective is to provide an in-depth and positivist insight into drug control’s present legal framework and thus provide for a better understanding of the normative assumptions upon which drug control is currently based. This is attained by clarifying the objectives of the international drug control system and the premises by which these objectives are to be achieved.
The objective of the current global framework of international drug control is the limitation of drugs to medical and scientific purposes. The meaning of this objective and its concrete implications for States’ parties as well as its problems from the perspective of other regimes of international law, most notably international human rights law, are extensively analysed. Additionally, the book focuses on how the international drug control system attempts to reach the objective of confining drugs to medical and scientific purposes, i.e. by setting up a universal system that exercises a rigid control on drug supply. The consequences of this heavy focus on the reduction of drug supply are outlined, and the book concludes by making suggestions on how the international drug control system could be reformed in the near future in order to better meet the existing challenges.
The analysis occurs from a general international law perspective. It aims to map the international drug control system within a wider context of international law and to understand whether the problems that the international drug control system faces are exemplary for the difficulties that institutionalized systems of global scope face in the twenty-first century.
In many statistical applications, the aim is to model the relationship between covariates and some outcomes. A choice of the appropriate model depends on the outcome and the research objectives, such as linear models for continuous outcomes, logistic models for binary outcomes and the Cox model for time-to-event data. In epidemiological, medical, biological, societal and economic studies, the logistic regression is widely used to describe the relationship between a response variable as binary outcome and explanatory variables as a set of covariates. However, epidemiologic cohort studies are quite expensive regarding data management since following up a large number of individuals takes long time. Therefore, the case-cohort design is applied to reduce cost and time for data collection. The case-cohort sampling collects a small random sample from the entire cohort, which is called subcohort. The advantage of this design is that the covariate and follow-up data are recorded only on the subcohort and all cases (all members of the cohort who develop the event of interest during the follow-up process).
In this thesis, we investigate the estimation in the logistic model for case-cohort design. First, a model with a binary response and a binary covariate is considered. The maximum likelihood estimator (MLE) is described and its asymptotic properties are established. An estimator for the asymptotic variance of the estimator based on the maximum likelihood approach is proposed; this estimator differs slightly from the estimator introduced by Prentice (1986). Simulation results for several proportions of the subcohort show that the proposed estimator gives lower empirical bias and empirical variance than Prentice's estimator.
Then the MLE in the logistic regression with discrete covariate under case-cohort design is studied. Here the approach of the binary covariate model is extended. Proving asymptotic normality of estimators, standard errors for the estimators can be derived. The simulation study demonstrates the estimation procedure of the logistic regression model with a one-dimensional discrete covariate. Simulation results for several proportions of the subcohort and different choices of the underlying parameters indicate that the estimator developed here performs reasonably well. Moreover, the comparison between theoretical values and simulation results of the asymptotic variance of estimator is presented.
Clearly, the logistic regression is sufficient for the binary outcome refers to be available for all subjects and for a fixed time interval. Nevertheless, in practice, the observations in clinical trials are frequently collected for different time periods and subjects may drop out or relapse from other causes during follow-up. Hence, the logistic regression is not appropriate for incomplete follow-up data; for example, an individual drops out of the study before the end of data collection or an individual has not occurred the event of interest for the duration of the study. These observations are called censored observations. The survival analysis is necessary to solve these problems. Moreover, the time to the occurence of the event of interest is taken into account. The Cox model has been widely used in survival analysis, which can effectively handle the censored data. Cox (1972) proposed the model which is focused on the hazard function. The Cox model is assumed to be
λ(t|x) = λ0(t) exp(β^Tx)
where λ0(t) is an unspecified baseline hazard at time t and X is the vector of covariates, β is a p-dimensional vector of coefficient.
In this thesis, the Cox model is considered under the view point of experimental design. The estimability of the parameter β0 in the Cox model, where β0 denotes the true value of β, and the choice of optimal covariates are investigated. We give new representations of the observed information matrix In(β) and extend results for the Cox model of Andersen and Gill (1982). In this way conditions for the estimability of β0 are formulated. Under some regularity conditions, ∑ is the inverse of the asymptotic variance matrix of the MPLE of β0 in the Cox model and then some properties of the asymptotic variance matrix of the MPLE are highlighted. Based on the results of asymptotic estimability, the calculation of local optimal covariates is considered and shown in examples. In a sensitivity analysis, the efficiency of given covariates is calculated. For neighborhoods of the exponential models, the efficiencies have then been found. It is appeared that for fixed parameters β0, the efficiencies do not change very much for different baseline hazard functions. Some proposals for applicable optimal covariates and a calculation procedure for finding optimal covariates are discussed.
Furthermore, the extension of the Cox model where time-dependent coefficient are allowed, is investigated. In this situation, the maximum local partial likelihood estimator for estimating the coefficient function β(·) is described. Based on this estimator, we formulate a new test procedure for testing, whether a one-dimensional coefficient function β(·) has a prespecified parametric form, say β(·; ϑ). The score function derived from the local constant partial likelihood function at d distinct grid points is considered. It is shown that the distribution of the properly standardized quadratic form of this d-dimensional vector under the null hypothesis tends to a Chi-squared distribution. Moreover, the limit statement remains true when replacing the unknown ϑ0 by the MPLE in the hypothetical model and an asymptotic α-test is given by the quantiles or p-values of the limiting Chi-squared distribution. Finally, we propose a bootstrap version of this test. The bootstrap test is only defined for the special case of testing whether the coefficient function is constant. A simulation study illustrates the behavior of the bootstrap test under the null hypothesis and a special alternative. It gives quite good results for the chosen underlying model.
References
P. K. Andersen and R. D. Gill. Cox's regression model for counting processes: a large samplestudy. Ann. Statist., 10(4):1100{1120, 1982.
D. R. Cox. Regression models and life-tables. J. Roy. Statist. Soc. Ser. B, 34:187{220, 1972.
R. L. Prentice. A case-cohort design for epidemiologic cohort studies and disease prevention trials. Biometrika, 73(1):1{11, 1986.