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Molecular mechanism of peptide selection by MHC molecule
No full textMajor histocompatibility complex (MHC) class I and II proteins are intracellular receptors that bind peptides derived from endogenous and exogenous proteins, resp., and display them on the cell surface for surveillance by T cells of the immune system. The presented peptides help the T cells to discriminate between self and non-self and to eliminate the pathogen infected or abnormal cells. After their synthesis, both class I and II molecules first bind suboptimal low-affinity ligand peptides and only later exchange them for high-affinity ones. For this exchange process, most class I and II molecules need the assistance of specific helper chaperones (tapasin and HLA-DM, resp.), the exact role of which is not well understood. In my thesis work, I have studied the molecular mechanism of peptide binding to MHC molecules with biochemical and computational methods, with a special emphasis on the mechanism of action of the helper chaperones. A comprehensive understanding of this process promises important clinical applications, for example in the development of new vaccines against viruses and in the suppression of autoimmune disorders
Automated Theory Interpretation
No full textThis thesis presents novel methods from automated reasoning to find reusable knowledge and knowledge overlaps in large formalized knowledge bases. The focus is on formalized mathematics, but the methods are applicable on any kind of formalized content as long as the application of classical logic inference rules on this content is admissible.
Formalized as well as traditional mathematics is advantageously organized in theories as its biggest knowledge units. As history of mathematics has shown, appearently unrelated theories happen to share a common core (i.e. knowledge overlap) once the concepts of each theories are translated appropriately. If all valid sentences of a theory A also hold in another theory B with an appropriate translation T, then A is said to be included in B -- or A can be interpreted in B. Since all sentences of a theory are derivable from a few of it, namely from its axioms, we know that A is included in B as soon as we have shown that the axioms of A hold in B. In this case all derivable sentences in A automatically hold in B too, i.e.the knowledge from A can be reused in B.
In this thesis an algorithm for automated theory interpretation search is presented. It is based on semantic formula matching by means of normalization taken from term rewriting and a novel standardization technique for associative and commutative terms. Moreover, a practical notion of theory intersection is introduced and an algorithm for the construction of such intersections is presented.
Both algorithms are implemented in a prototype system and experiments are conducted on the largest library of formalized mathematics -- the Mizar Mathematical Library -- which demonstrates the scalability of the algorithms and also reveal thousands of theory interpretations
Spatial Positioning with Wireless Chirp Spread Spectrum Ranging
No full textEuclidean distance ratios between networked nodes can be represented by the weight values of a subset of multidimensional graph edges. Through acquiring the real world data measures, our approach aims to accurately realize the spatial relationship of such layout elements. In particular, this solution is tremendously useful for mobile robotics relative localization, geo-location dynamic data management platforms, wireless sensor networking, smart routing, and so forth. In this research, we employ chirp spread spectrum modulation enabled radio transceivers for proximity measurement of the network nodes as the bidirectional weight information of the graph edges. Physical link experiments confirm that this recent technology is adequately reliable against environmental distortions when employed for asynchronous round trip time of flight measurements. In order to achieve the best affordable accuracy and reach a high level of robustness against the estimation noise, the multidimensional scaling method is utilized. Implementation phase's outcome is a cooperative and proprioceptive self-constructive infrastructure, for a flexible any-time localization application
Applications of advanced sampling methods for enhanced conformational sampling of biomolecules
No full textThe application of Classical Molecular Dynamics (MD) for the structure prediction of biomolecules is limited by the accuracy of current force fields and the simulation time scale. Biomolecules can adopt several locally stable conformations separated by high energy barriers. Conformational transitions between these stable states can therefore be rare events even on the time scale of tens to hundreds of nanoseconds. Out of the various methods Replica Exchange Molecular Dynamics (Rex MD) is the most successful method to enhance the conformational sampling of biomolecules. But this is limited to only small systems, as the number of replicas required for Rex MD increases with increasing system size. Therefore, during my PhD, I have developed an alternative "Hamiltonian" replica-exchange method that focuses on the biomolecule backbone flexibility by employing a specific biasing potential to promote backbone transitions as a replica coordinate. The aim of this biasing potential is to reduce the energy barriers associated with peptide backbone dihedral transitions. The level of biasing gradually changes along the replicas such that frequent transitions are possible at high levels of biasing and thus the system can escape from getting trapped in local energy minima. This thesis discusses the development of this Biasing Potential Replica Exchange Molecular Dynamics (BP-Rex MD) method in detail. Application of the method to study the conformational sampling of peptides, folding of a mini protein and also for refinement and loop modeling of homology modeled proteins in explicit solvent shows much better sampling of conformational space as compared to the standard MD simulations. One of the main advantages of this BP-Rex MD simulation is that only the biasing potential energy term enters into the exchange probability, meaning that the number of required replicas is expected to scale approximately linearly with the number of included backbone dihedral angles
To be or not to be at risk: Reactions to blood pressure and cholesterol feedback in a South Korean sample
No full textReactions to cholesterol and blood pressure feedback were explored in a South Korean sample. The prevailing researcher-oriented approach towards studying reactions is contrasted with a more recipient-oriented one in which spontaneous reactions are assessed through thought listing tasks. In Study 1, a coding system was developed to explore array and base rates of reactions. Reactions related to emotions, risk feedback valence, feedback expectedness and future lifestyle were found most frequently, across different threat levels. Importantly, three of those reaction types are underrepresented in previous research. Consideration of feedback valence, expectedness, and future lifestyle point towards the adaptivity of reactions. In Study 2 thought-listing data were used to explore array, base rates, and co-occurrences of spontaneous reactions on a more specific level, applying a network perspective. Emotions, risk feedback valence, feedback expectedness, and future lifestyle form large and well-connected nodes in a network of reactions. The network highlights previously neglected relevant reactions and provides a group-level background against which individual reactions can be evaluated. When reaction patterns of varying adaptivity were explored, patterns in accordance with feedback valence were predominant after positive but also negative feedback. Study 3 explored hindsight bias following health risk feedback, using questionnaire data. Overall, hindsight bias was found, with higher levels of bias and marginally lower levels of resultant surprise after unexpected positive compared with unexpected negative feedback. Those who displayed the bias reported lower levels of resultant surprise than those whose hindsight estimates were accurate. Thus, hindsight bias can occur in Eastern samples after self-relevant outcomes, and feedback valence and surprise appear to play similar roles as in Western samples. The thesis is part of the project Risk Appraisal Consequences in Korea
Family biographies and retirement processes : a comparative analysis of West Germany and the United Kingdom
No full textOver the past decades population aging put retirement policies at the center of political debate and academic research. Women are at a higher risk of poverty in retirement across advanced societies and therefore a key target group for social policy. Yet, retirement research has largely concentrated on how employment histories determine labor market exit of men. In a comparison of West Germany and the United Kingdom this thesis addresses how gender inequality in old age emerges over the life course and which role institutions play in this process. Two main arguments are put forward. To advance our understanding of gender inequality in retirement it is necessary to (1) develop alternative retirement measures beyond labor force exit, and (2) include family events over the life course as predictors of retirement outcomes. Based on the conceptual foundation of differential life course sociology alternative measures of retirement are proposed and empirically explored with recent advances in sequence analysis. Divorce and child care periods are included as determinants of retirement outcomes in event history analysis. Based on household panel data, results from both methodological approaches underline the power of pension institutions in shaping retirement processes and pension consequences of family events. The thesis concludes that changing family arrangements call for a shift in the design of pension systems to compensate not only full employment histories of male breadwinners, but diversified work life histories of men and women.Das Thema Verrentung ist mit fortschreitender Bevölkerungsalterung immer mehr in das Zentrum politischer und akademischer Debatten gerückt. Frauen sind in praktisch allen fortgeschrittenen Gesellschaften einem höheren Armutsrisiko im Alter ausgesetzt und deshalb eine zentrale Zielgruppe für die Sozialpolitik. Dennoch beschränken sich wissenschaftliche Analysen zur Rententhematik bisher überwiegend darauf, wie Berufsverläufe den Arbeitsmarktaustritt von Männern beeinflussen. Die vorliegende Dissertation untersucht im Vergleich von Westdeutschland und Grossbritanien, wie Ungleichheit zwischen den Geschlechtern im Alter über den Lebenslauf entsteht und welche Rolle Wohlfahrtsstaatsinstitutionen dabei spielen. Die Untersuchung basiert auf zwei zentralen Argumenten: Um geschlechtsspezifische Ungleichheit im Alter besser zu verstehen, ist es notwendig: (1) über das Kriterium des Arbeitsmarktaustritts hinaus neue Konzepte der Verrentung zu entwickeln und (2) Familienereignisse über den Lebenslauf als Determinanten der Verrentung mit einzubeziehen.
Im Rahmen einer differentiellen Lebenslaufsoziologie entwickelt die vorliegende Arbeit ein alternatives Konzept von Verrentung als Prozess, welches empirisch mittels neuer Entwicklungen der Sequenzanalyse untersucht wird. Scheidung und Kindererziehungszeiten als Determinanten der Verrentung werden mittels Ereignisdatenanalyse untersucht. Die Ergebnisse beider methodischer Ansätze unterstreichen den Einfluss von Wohlfahrtsstaatsinstitutionen auf die Beziehung zwischen Familienbiographien und Verrentungsprozessen. Als Schlussfolgerung ergibt sich, dass veränderte Familienstrukturen neue Renteninstitutionen erfordern, die nicht nur kontinuierliche Erwerbsverläufe von Männern, sondern diverse Erwerbs- und Familienbiographien von Frauen und Männern absichern
Advancing the Synthosome system towards industrial application : introduction of trigger systems and enzyme quantification
No full textSynthosomes are copolymer vesicles which harbour a transmembrane channel in the polymer membrane and are functionalised in the interior of the vesicle, for example by encapsulating an enzyme. Protein engineering can introduce trigger systems to channel or encapsulated enzyme, making the system highly specific for the desired task. The aim of the work was to advance the synthosome system towards industrial applications by introducing trigger systems and investigating encapsulation efficiencies. For efficient characterisation of synthosomes, we aimed at developing a method for quantifying the encapsulated enzyme. The principle was based on a fusion protein and a reporter oligonucleotide, both of which were optimised and shown to be fully functional. Although the single steps were successfully completed, final proof of principle could not be shown due to encapsulation efficiencies below the detection limit. In the second part of the work, pH triggers for a channel protein (OmpF) and a protease (Subtilisin E) are described. Protease activation only after pH change could be used to overcome low stability of the enzyme in liquid detergents. Subtilisin variants with a narrowed pH activity profile were therefore generated by Directed Evolution. The mutations contributing to the altered characteristics can be found in the prosequence, on the protease surface and close to the catalytic triad. Furthermore, we report for the first time a reversible pH-controlled release system based on OmpF. Six histidine mutations were introduced to the channel constriction site. By varying the pH (5 to 7), it was possible to monitor the pH dependent release of the fluorophore acridine orange through the engineered OmpF His. Molecular modelling studies suggest that the principle of pH-switchability is based on a combination of changes in channel diameter and electrostatics. Since the changes occur near physiological pH, the system is especially interesting for drug delivery
Functional characterization of the outer membrane protein ToIC in the fire blight pathogen Erwinia amylovora
No full textAcrAB-TolC is the major multidrug efflux system in Enterobacteriaceae recognizing various structurally diverse molecules. The outer membrane protein, TolC, of Escherichia coli is involved in export of proteins beside it role in efflux of bile salts and antibiotics. In Erwinia amylovora, AcrAB was shown to be essential for phytoalexin resistance. The E. amylovora TolC might mediate phytoalexin resistance through its interaction with the AcrAB multidrug efflux pump. To prove this, mutational analyses of tolC and an acrB/tolC double mutant were conducted. Minimal inhibitory concentrations of diverse antimicrobials and phytoalexins, in planta survival, and virulence assays on apple plants were determined for all mutants and compared with wild type. The results showed that TolC plays an important role as a virulence and fitness factor of E. amylovora by mediating resistance towards phytoalexins through its exclusive interaction with AcrAB. Furthermore, exchange analysis of AcrAB-TolC was conducted by complementing generated mutants of both, E. coli and E. amylovora, defective in acrB or tolC with alleles from either species. Results of this study suggested that AcrAB and TolC of both species could interact. These protein-protein interactions did not yield in altered functions despite the divergent ecological niches, to which E. coli and E. amylovora have adopted phylogenetically. Comparison of extra-cellular protein profiles produced by E. amylovora wild type and its tolC mutant in vitro revealed absence of a ̃55-kDa protein in the supernatant of the tolC mutant. This protein was identified as HsvB (Hrp systemic virulence); a proposed effector protein secreted by the Hrp type III secretion system. Incubation of E. amylovora with sub-lethal concentrations of the antibiotics, phloretin and novobiocin, respectively, revealed that under survival stress TolC is preferentially recruited for its antibiotics efflux activity and secreted significantly less of the HsvB protein
Link scheduling and power control for OFDMA uplink systems
No full textThis thesis aims at tackling the problem of optimum joint power allocation and resource scheduling while maintaining certain QoS constraints. In particular, the uplink of an OFDMA (orthogonal frequency division multiple access) system is investigated for which a detailed model for the signal-to-interference-plus-noise (SINR) is developed. This model includes multiple access interference (MAI) due to frequency synchronization errors and Doppler shifts as well as CCI due to the reuse of radio frequency resources in neighboring cells. The developed SINR model serves as the basis for the optimization problem which makes use of a heuristic relaxation to simplify the NP hard problem of the joint power and user scheduling optimization. The chosen power controlled random access (PCRA) problem formulation incorporates the power v/s delay dilemma prevalent in wireless multiple access networks. The PCRA problem is transformed into a convex optimization problem through the technique of geometric programming. The final contribution of this thesis is the improvement of an existing link scheduling algorithm for non-perfect channel estimation information at the transmitter
Age Climate : age stereotypes in organizations and older workers
No full textAge climate describes how favorably older employees are perceived within a given organization. It integrates research on organizational (and psychological) climates and research on age stereotypes in the workplace. The main goals of this dissertation were (1) to develop the construct of age climate and present an instrument for its measurement, (2) to investigate relationships of individual (psychological) age climate perceptions with work-related outcomes at the individual level, including interindividual differences in these relationships, and (3) to assess the consensual validity of the developed scale as well as to explore relationships of the shared organizational age climate perceptions with organizational level outcomes. Study 1 demonstrates the usefulness of the Psychological Age Climate Scale (PACS). In a sample of 302 older employees (age 40+) from 8 companies, the PACS showed a high reliability and clear single factor structure. A fixed-effects approach to clustering revealed significant associations between psychological age climate (PAC) and older employees’ organizational commitment. In Study 2, analysis of a sample of 273 older workers (age 40-63) from different occupations revealed that the perception of a less favorable age climate was related to lower work ability. This relationship was stronger at higher ages. At higher ages Selection, Optimization, and Compensation strategy use buffered the detrimental effect of an unfavorable PAC on work ability. Study 3 introduces the concept of organizational age climate (OAC), defined as employees’ shared perceptions of how favorable older workers are perceived within their organization. Analysis of data from n = 204 employees age 45+ from 8 companies confirmed the consensual validity of OAC. Moreover, companies have significantly different OACs. Analysis of a sub-sample of three companies provides first evidence that companies’ OAC is related to their personnel, knowledge, and health management practices