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Liver-derived apolipoprotein B-100 (ApoB100) is an autoantigen that is recognized by atherogenic CD4We identified ApoB100-specific T cells in blood from healthy controls, nonalcoholic fatty liver disease (NAFLD) patients, and CVD patients by activation-induced marker expression and analyzed their differentiation pattern in correlation to the lipid profile and liver damage parameters in a cross-sectional study. To assess the induction of extrahepatic ApoB100-specific T cells upon transient liver damage in vivo, we performed hydrodynamic tail vein injections with diphtheria toxin A (DTA)-encoding plasmid in human ApoB100-transgenic mice.Utilizing immunodominant ApoB100-derived peptides, we found increased ApoB100-specific T-cell populations in NAFLD and CVD patients compared to healthy controls. In a peptide-specific manner, ApoB100 reactivity in healthy controls was accompanied by expression of the regulatory T (Treg)-cell transcription factor FOXP3. In contrast, FOXP3 expression decreased, whereas expression of pro-inflammatory cytokine interleukin (IL)-17A increased in ApoB100-specific T cells from NAFLD and CVD patients. Dyslipidemia and liver damage parameters in blood correlated with reduced FOXP3 expression and elevated IL-17A production in ApoB100-specific T-cell populations, respectively. Moreover, DTA-mediated transient liver damage in human ApoB100-transgenic mice accumulated IL-17a-expressing ApoB100-specific T cells in the periphery.Our results show that liver damage promotes pro-inflammatory ApoB100-specific T-cell populations, thereby providing a cellular mechanism for the increased CVD risk in liver disease patients.

There is mounting evidence that Alzheimer's disease progression and severity are linked to neuronal membrane damage caused by aggregates of the amyloid- β (A β ) peptide. However, the detailed mechanism behind the membrane damage is not well understood yet. Recently, the lipid-chaperone hypothesis has been put forward, based on which the formation of complexes between A β and free lipids enables an easy insertion of A β into membranes. In order to test this hypothesis, we performed numerous all-atom molecular dynamics simulations. We studied the complex formation between individual lipids, considering both POPC and DPPC, and A β and examined whether the resulting complexes would be able to insert into lipid membranes. Complex formation at a one-to-one ratio was readily observed, yet with minimal effects on A β 's characteristics. Most importantly, the peptide remains largely disordered in 1:1 complexes, and the complex does not insert into the membrane; instead, it is adsorbed to the membrane surface. The results change considerably once A β forms a complex with a POPC cluster composed of three lipid molecules. The hydrophobic interactions between A β and the lipid tails cause the peptide to fold into either a helical or a β -sheet structure. These observations provide atomic insight into the disorder-to-order transition that is needed for membrane insertion or amyloid aggregation to proceed.

Intelligent transportation systems (ITS) require the extension of the systems engineering approach to a higher system level. Up to now, vehicles could be considered as closed systems while in future they have to be seen as components of an open system with ad hoc interfaces. Since ITS influence the series development and production of single vehicles, standards and procedures of process quality, systems engineering and functional safety apply for this higher level as well. The paper discusses the impact of those standards to the design of ITS and the role of model-based software and service oriented architectures (SOA) as means for process quality and functional safety assurance. It emphasizes on the mutual synergies between process capability standards, functional safety, model-based development and design for variability. Finally, it shows an approach for the design of ad hoc and distributed systems proposed by the authors.

Surrey Archaeological Collections, 55, 41-64

Intelligent transportation systems (ITS) require the extension of the systems engineering approach to a higher abstraction level. Up to now, vehicles could be considered as closed systems while in future they have to be seen as components of an open system with ad hoc interfaces. Since ITS have reached the series development and production of single vehicles, standards of process quality and functional safety apply for this higher level as well. The paper discusses the impact of those standards to the design of ITS and the role of model-based software as a means for process quality and functional safety assurance. It emphasizes on the mutual synergies between process capability standards, functional safety, model-based development and design for variability.

Until this day, e-learning scenarios have not been able to meet the great expectations that have been put on them. From a psychological point of view, one of the reasons for previously disappointing results is the high degree of freedom that e-learning scenarios confront individuals with. The concept of self-regulated learning (SRL) provides a framework for improving the quality of learning in environments of high self-determination. Following the assumption that the deployment of SRL processes during learning is an indicator for a learning process of high quality, which in turn entails a learning outcome of high quality, scientists have created a variety of SRL interventions. In line with this research, the main goal of this dissertation was to improve the quality of e-learning, applying learning on the World Wide Web (WWW) as a specific scenario, by enhancing individuals’ deployment of SRL processes. As a first study, synthesizing past SRL research, a meta-analysis was conducted to evaluate the relevance of SRL for the quality of learning, and to quantify the impact of SRL interventions on academic achievement. Another aim was to provide guidance for future SRL research by identifying features of SRL interventions that have proven to be effective as well as features that have lacked effectiveness and escaped attention in the past. Putting special effort into identifying unpublished dissertations in order to avoid a publication bias, a pool of 39 studies that reported 44 independent treatments was established. Applying a random effects model, a weighted mean effect of SRL interventions on academic performance of ΔˉGlass = .45 was determined. One-way moderator analyses identified peer-review status, research design, instance of delivery, and age of participants as influential variables. In further analyses, when combining heterogeneous categories of moderators to establish homogeneous subgroups, it was found that treatments focusing on the metacognitive and cognitive layers, strategy instructions, and interventions within a mathematical domain were most effective for young learners between the ages of 9 and 14. With regard to computer-based interventions, nonsignificant effects on performance were revealed. Aiming to improve the quality of e-learning, the author simultaneously developed a concept for providing SRL support. Following an indirect approach of assistance, the core of the concept was to optimize the learning environment by providing learners with scaffolds that served as tools that could be used to complete a learning task and that simultaneously induced the deployment of six metacognitive processes in the three cyclical phases of learning. Aiming to provide learners with more intensive guidance, an extended concept also included administering additional prompts. The sketched scaffolding concept was realized by implementing the Firefox extension E-Learning knoWledge Management System (ELWMS). The second study of this dissertation served to evaluate whether working with ELWMS enhanced the quality of the learning process and the learning outcome. Randomly assigned to four conditions, N = 64 participants learned on Wikipedia about Classical Antiquity for 45 min. The two experimental groups were equipped with the standard version of ELWMS, and were either free to apply the scaffolds of their own accord or received two additional prompts, whereas the two control groups worked with the standard version of Firefox. The quality of the learning process was evaluated by a self-developed context-specific SRL self-report questionnaire. In addition, participants’ overt actions were assessed by generating log data and by conducting qualitative analyses of screen recordings. The quality of the learning outcome was evaluated by a self-developed achievement test, applied as a pretest and a posttest, and by determining the quality of the created structure. Results revealed positive effects of the scaffolding concept on the quality of the learning process, and ambiguous effects of additional prompting. The third study of this dissertation served to provide further insight into the effectiveness of the sketched scaffolding concept with an elaborated study design. Equipped with the second generation of ELWMS, learners of experimental groups were either free to apply the scaffolds of their own accord or received additional intensive prompting of six processes that were considered to enhance achievement. To be able to generate comparable log data for all conditions, the control group worked with a downgraded version of ELWMS that did not provide metacognitive support. Before learning on Wikipedia about Classical Antiquity for 45 min, all N = 108 participants had to complete a web-based training on ELWMS. The quality of the learning process was evaluated by applying a revised context-specific SRL self-report questionnaire that was synchronized with an advanced and optimized method of collecting log data. In further qualitative analyses, logged overt actions were assigned a rating of relevance. The quality of the learning outcome was evaluated by a revised achievement test, applied as a pretest and a posttest, and by determining the quality of the created structure. In line with the second study, results revealed positive effects of the scaffolding concept on the quality of the learning process. This effect was enhanced by additional intensive prompting. In whole, this dissertation presents evidence that enhancing SRL improves the quality of learning and provides a path for creating effective SRL interventions. By applying a complex multimethod approach, it further proposes a promising concept for inducing SRL processes in e-learning.