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Background: Increasing exposure to engineered inorganic nanoparticles takes actually place in both terrestric and aquatic ecosystems worldwide. Although we already know harmful effects of AgNP on the soil bacterial community, information about the impact of the factors functionalization, concentration, exposure time, and soil texture on the AgNP effect expression are still rare. Hence, in this study, three soils of different grain size were exposed for up to 90 days to bare and functionalized AgNP in concentrations ranging from 0.01 to 1.00 mg/kg soil dry weight. Effects on soil microbial community were quantified by various biological parameters, including 16S rRNA gene, photometric, and fluorescence analyses.
Results: Multivariate data analysis revealed significant effects of AgNP exposure for all factors and factor combinations investigated. Analysis of individual factors (silver species, concentration, exposure time, soil texture) in the unifactorial ANOVA explained the largest part of the variance compared to the error variance. In depth analysis of factor combinations revealed even better explanation of variance. For the biological parameters assessed in this study, the matching of soil texture and silver species, and the matching of soil texture and exposure time were the two most relevant factor combinations. The factor AgNP concentration contributed to a lower extent to the effect expression compared to silver species, exposure time and physico–chemical composition of soil.
Conclusions: The factors functionalization, concentration, exposure time, and soil texture significantly impacted the effect expression of AgNP on the soil microbial community. Especially long-term exposure scenarios are strongly needed for the reliable environmental impact assessment of AgNP exposure in various soil types.
In this thesis, three studies investigating the impact of stress on the protective startle eye blink reflex are reported. In the first study a decrease in prepulse inhibition of the startle reflex was observed after intravenous low dose cortisol application. In the second study a decrease in reflex magnitude of the startle reflex was observed after pharmacological suppression of endogenous cortisol production. In the third study, a higher reflex magnitude of the startle reflex was observed at reduced arterial and central venous blood pressure. These results can be interpreted in terms of an adaption to hostile environments.
Early life adversity (ELA) poses a high risk for developing major health problems in adulthood including cardiovascular and infectious diseases and mental illness. However, the fact that ELA-associated disorders first become manifest many years after exposure raises questions about the mechanisms underlying their etiology. This thesis focuses on the impact of ELA on startle reflexivity, physiological stress reactivity and immunology in adulthood.
The first experiment investigated the impact of parental divorce on affective processing. A special block design of the affective startle modulation paradigm revealed blunted startle responsiveness during presentation of aversive stimuli in participants with experience of parental divorce. Nurture context potentiated startle in these participants suggesting that visual cues of childhood-related content activates protective behavioral responses. The findings provide evidence for the view that parental divorce leads to altered processing of affective context information in early adulthood.
A second investigation was conducted to examine the link between aging of the immune system and long-term consequences of ELA. In a cohort of healthy young adults, who were institutionalized early in life and subsequently adopted, higher levels of T cell senescence were observed compared to parent-reared controls. Furthermore, the results suggest that ELA increases the risk of cytomegalovirus infection in early childhood, thereby mediating the effect of ELA on T cell-specific immunosenescence.
The third study addresses the effect of ELA on stress reactivity. An extended version of the Cold Pressor Test combined with a cognitive challenging task revealed blunted endocrine response in adults with a history of adoption while cardiovascular stress reactivity was similar to control participants. This pattern of response separation may best be explained by selective enhancement of central feedback-sensitivity to glucocorticoids resulting from ELA, in spite of preserved cardiovascular/autonomic stress reactivity.
The main objective of the present thesis was to investigate whether antibody effects observed in earlier in vitro studies can translate into the protection against chemical carcinogenesis in vivo as the basis of an immunoprophylactic approach against carcinogens. As model for chemical carcinogenesis, we selected B[a]P the prototype polycyclic aromatic hydrocarbon (PAH), an environmental pollutant emanating from both natural and anthropogenic sources. Many in vivo models conveniently use high doses of carcinogens mostly given as single bolus, which provides simple surrogate readouts, but poorly reflects chronic exposure to the low concentrations found in the environment. In addition, these concentrations cannot be matched with equimolar antibody concentrations obtained by immunisation. However, low B[a]P concentrations do not permit to directly measure chemical carcinogenesis. Therefore, in the present thesis, the pharmacokinetic, metabolism and B[a]P mediated immunotoxicity were chosen as experimental read-outs. B[a]P conjugate vaccines based on ovalbumin, tetanus toxoid and diphtheria toxoid (DT) as carrier proteins were developed to actively immunise mice against B[a]P. B[a]P-DT conjugate induced the most robust immune response. The antibodies reacted not only with B[a]P but also with the proximate carcinogen 7,8-diol-B[a]P. Antibodies modulated the bioavailability of B[a]P and its metabolic activation in a dose-dependent manner by sequestration in the blood. In order to further improve the vaccination, we replaced the protein carrier by promiscuous T-helper cell epitopes to induce higher antibody titer with increased specificity for the B[a]P hapten. We hypothesised that a reduction of B cell binding sites on the carrier, compared to whole protein carrier, should favour the activation of B cells recognising the hapten instead of the carrier protein. An internal processing of the carrier and cleavage of the B[a]P-BA and subsequent presentation of the carrier peptide by MHC II molecules to T cell receptor should induce a B cell dependent immune response by activating B cells capable to recognise B[a]P. We demonstrated that a vaccination against B[a]P using promiscuous T-helper cell epitopes as a carrier is feasible and some tested peptide conjugates were more immunogenic as whole protein conjugates with increased specificity. We showed that vaccination against B[a]P reduces immunotoxicity. B[a]P suppressed the proliferative response of both T and B cells after a sub-acute administration, an effect that was completely reversed by vaccination. In immunized mice the immunotoxic effect of B[a]P on IFN-γ, Il-12, TNF-ï¡ production and B cell activation was restored. In addition, specific antibodies inhibited the induction of Cyp1a1 by B[a]P in lymphocytes and Cyp1b1 in the liver, enzymes that are known to convert the procarcinogen B[a]P to the ultimate DNA-adduct forming metabolite, a major risk factor of chemical carcinogenesis. In order to replace Freund adjuvant and to improve the immunisation strategy in terms of antibody quantity and quality, several adjuvants that are potentially compatible with their use in humans were tested. In combination with Freund adjuvant, the conjugate-vaccine induced high levels of B[a]P-specific antibodies. We showed that all adjuvants tested induced specific antibodies against B[a]P and 7,8-diol-B[a]P, its carcinogenic metabolite. The highest antibody levels were obtained with Quil A, MF-59 and Alum. Biological activity in terms of enhanced retention of B[a]P was confirmed in mice immunised with Quil A, Montanide, Alum and MF-59. Our findings demonstrate that a vaccination against B[a]P is feasible in combination with adjuvants licensed in humans. Based on these results and with the current understanding of the mechanisms of chemical carcinogenesis of the ubiquitous carcinogen B[a]P and of the effects of specific antibodies, an immunoprophylactic approach against chemical carcinogenesis is absolutely warranted. Nevertheless, the direct effects of B[a]P-specific antibodies on the different stages of carcinogenesis (e.g. adduct formation) and whether these effects may translate into long-term protective effect against tumourigenesis needs to be proven in further experiments.
Legalisation cannot be fully explained by interest politics. If that were the case, the attitudes towards legalisation would be expected to be based on objective interests and actual policies in France and Germany would be expected to be more similar. Nor can it be explained by institutional agency, because there are no hints that states struggle with different normative traditions. Rather, political actors seek to make use of the structures that already exist to guar-antee legitimacy for their actions. If the main concern of governmental actors really is to accumulate legitimacy, as stated in the introduction, then politicians have a good starting position in the case of legalisation of illegal foreigners. Citizens" negative attitudes towards legalisation cannot be explained by imagined labour market competition; income effects play only a secondary role. The most important explanatory factor is the educational level of each individual. Objective interests do not trigger attitudes towards legalisation, but rather a basic men-tal predisposition for or against illegal immigrants who are eligible for legalisation. Politics concerning amnesties are thus not tied to an objectively given structure like the socio-economic composition of the electorate, but are open for political discretion. Attitudes on legalising illegal immigrants can be regarded as being mediated by beliefs and perceptions, which can be used by political agents or altered by political developments. However, politicians must adhere to a national frame of legitimating strategies that cannot be neglected without consequences. It was evident in the cross-country comparison of political debates that there are national systems of reference that provide patterns of interpretation. Legalisation is seen and incorporated into immigration policy in a very specific way that differs from one country to the next. In both countries investigated in this study, there are fundamental debates about which basic principles apply to legalisation and which of these should be held in higher esteem: a legal system able to work, humanitarian rights, practical considerations, etc. The results suggest that legalisation is "technicized" in France by describing it as an unusual but possible pragmatic instrument for the adjustment of the inefficient rule of law. In Germany, however, legalisation is discussed at a more normative level. Proponents of conservative immigration policies regard it as a substantial infringement on the rule of law, so that even defenders of a humanitarian solution for illegal immigrants are not able to challenge this view without significant political harm. But the arguments brought to bear in the debate on legalisation are not necessarily sound because they are not irrefutable facts, but instruments to generate legitimacy, and there are enough possibilities for arguing and persuading because socio-economic factors play a minor role. One of the most important arguments, the alleged pull effect of legalisation, has been subjected to an empirical investigation. In the political debate, it does not make any dif-ference whether this is true or not, insofar as it is not contested by incontrovertible findings. In reality, the results suggest that amnesties indeed exert a small attracting influence on illegal immigration, which has been contested by immigration friendly politicians in the French par-liament. The effect, however, is not large; therefore, some conservative politicians may put too much stress on this argument. Moreover, one can see legalisation as an instrument to restore legitimacy that has slipped away from immigration politics because of a high number of illegally residing foreigners. This aspect explains some of the peculiarities in the French debate on legalisation, e.g. the idea that the coherence of the law is secured by creating exceptional rules for legalising illegal immigrants. It has become clear that the politics of legalisation are susceptible to manipulation by introducing certain interpretations into the political debate, which become predominant and supersede other views. In this study, there are no signs of a systematic misuse of this constellation by any certain actor. However, the history of immigration policy is full of examples of symbolic politics in which a certain measure has been initiated while the actors are totally aware of its lack of effect. Legalisation has escaped this fate so far because it is a specific instrument that is the result of neglecting populist mechanisms rather than an ex-ample of a superficial measure. This result does not apply to policies concerning illegal immi-gration in general, both with regard to concealing a lack of control and flexing the state- muscles.
In recent decades, Border Studies have gained importance and have seen a noticeable increase in development. This manifests itself in an increased institutionalization, a differentiation of the areas of research interest and a conceptual reorientation that is interested in examining processes. So far, however, little attention has been paid to questions about (inter)disciplinary self-perception and methodological foundations of Border Studies and the associated consequences for research activities. This thematic issue addresses these desiderata and brings together articles that deal with their (inter)disciplinary foundations as well as method(olog)ical and practical research questions. The authors also provide sound insights into a disparate field of work, disclose practical research strategies, and present methodologically sophisticated systematizations.
The dissertation includes three published articles on which the development of a theoretical model of motivational and self-regulatory determinants of the intention to comprehensively search for health information is based. The first article focuses on building a solid theoretical foundation as to the nature of a comprehensive search for health information and enabling its integration into a broader conceptual framework. Based on subjective source perceptions, a taxonomy of health information sources was developed. The aim of this taxonomy was to identify most fundamental source characteristics to provide a point of reference when it comes to relating to the target objects of a comprehensive search. Three basic source characteristics were identified: expertise, interaction and accessibility. The second article reports on the development and evaluation of an instrument measuring the goals individuals have when seeking health information: the ‘Goals Associated with Health Information Seeking’ (GAINS) questionnaire. Two goal categories (coping focus and regulatory focus) were theoretically derived, based on which four goals (understanding, action planning, hope and reassurance) were classified. The final version of the questionnaire comprised four scales representing the goals, with four items per scale (sixteen items in total). The psychometric properties of the GAINS were analyzed in three independent samples, and the questionnaire was found to be reliable and sufficiently valid as well as suitable for a patient sample. It was concluded that the GAINS makes it possible to evaluate goals of health information seeking (HIS) which are likely to inform the intention building on how to organize the search for health information. The third article describes the final development and a first empirical evaluation of a model of motivational and self-regulatory determinants of an intentionally comprehensive search for health information. Based on the insights and implications of the previous two articles and an additional rigorous theoretical investigation, the model included approach and avoidance motivation, emotion regulation, HIS self-efficacy, problem and emotion focused coping goals and the intention to seek comprehensively (as outcome variable). The model was analyzed via structural equation modeling in a sample of university students. Model fit was good and hypotheses with regard to specific direct and indirect effects were confirmed. Last, the findings of all three articles are synthesized, the final model is presented and discussed with regard to its strengths and weaknesses, and implications for further research are determined.
Computer simulation has become established in a two-fold way: As a tool for planning, analyzing, and optimizing complex systems but also as a method for the scientific instigation of theories and thus for the generation of knowledge. Generated results often serve as a basis for investment decisions, e.g., road construction and factory planning, or provide evidence for scientific theory-building processes. To ensure the generation of credible and reproducible results, it is indispensable to conduct systematic and methodologically sound simulation studies. A variety of procedure models exist that structure and predetermine the process of a study. As a result, experimenters are often required to repetitively but thoroughly carry out a large number of experiments. Moreover, the process is not sufficiently specified and many important design decisions still have to be made by the experimenter, which might result in an unintentional bias of the results.
To facilitate the conducting of simulation studies and to improve both replicability and reproducibility of the generated results, this thesis proposes a procedure model for carrying out Hypothesis-Driven Simulation Studies, an approach that assists the experimenter during the design, execution, and analysis of simulation experiments. In contrast to existing approaches, a formally specified hypothesis becomes the key element of the study so that each step of the study can be adapted and executed to directly contribute to the verification of the hypothesis. To this end, the FITS language is presented, which enables the specification of hypotheses as assumptions regarding the influence specific input values have on the observable behavior of the model. The proposed procedure model systematically designs relevant simulation experiments, runs, and iterations that must be executed to provide evidence for the verification of the hypothesis. Generated outputs are then aggregated for each defined performance measure to allow for the application of statistical hypothesis testing approaches. Hence, the proposed assistance only requires the experimenter to provide an executable simulation model and a corresponding hypothesis to conduct a sound simulation study. With respect to the implementation of the proposed assistance system, this thesis presents an abstract architecture and provides formal specifications of all required services.
To evaluate the concept of Hypothesis-Driven Simulation Studies, two case studies are presented from the manufacturing domain. The introduced approach is applied to a NetLogo simulation model of a four-tiered supply chain. Two scenarios as well as corresponding assumptions about the model behavior are presented to investigate conditions for the occurrence of the bullwhip effect. Starting from the formal specification of the hypothesis, each step of a Hypothesis-Driven Simulation Study is presented in detail, with specific design decisions outlined, and generated inter- mediate data as well as final results illustrated. With respect to the comparability of the results, a conventional simulation study is conducted which serves as reference data. The approach that is proposed in this thesis is beneficial for both practitioners and scientists. The presented assistance system allows for a more effortless and simplified execution of simulation experiments while the efficient generation of credible results is ensured.
Hypothalamic-pituitary-adrenal (HPA) axis-related genetic variants influence the stress response
(2019)
The physiological stress system includes the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary system (SAM). Parameters representing these systems such as cortisol, blood pressure or heart rate define the physiological reaction in response to a stressor. The main objective of the studies described in this thesis was to understand the role of the HPA-related genetic factors in these two systems. Genetic factors represent one of the components causing individual variations in physiological stress parameters. Five genes involved in the functioning of the HPA axis regarding stress responses are examined in this thesis. They are: corticotropin-releasing hormone (CRH), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), the 5-hydroxytryptamine-transporter-linked polymorphic region (5-HTTLPR) in the serotonin transporter (5-HTT) and the brain-derived neurotrophic factor (BDNF) gene. Two hundred thirty-two healthy participants were genotyped. The influence of genetic factors on physiological parameters, such as post-awakening cortisol and blood pressure was assessed, as well as the influence of genetic factors on stress reactivity in response to a socially evaluated cold pressor test (SeCPT). Three studies tested the HPA-related genes each on three different levels. The first study examined the influences of genotypes and haplotypes of these five genes on physiological as well as psychological stress indicators (Chapter 2). The second study examined the effects of GR variants (genotypes and haplotypes) and promoter methylation level on both the SAM system and the HPA axis stress reactivity (Chapter 3). The third study comprised the characterization of CRH promoter haplotypes in an in-vitro study and the association of the CRH promoter with stress indicators in vivo (Chapter 4).
The subject of this thesis is hypercyclic, mixing, and chaotic C0-semigroups on Banach spaces. After introducing the relevant notions and giving some examples the so called hypercyclicity criterion and its relation with weak mixing is treated. Some new equivalent formulations of the criterion are given which are used to derive a very short proof of the well-known fact that a C0-semigroup is weakly mixing if and only if each of its operators is. Moreover, it is proved that under some "regularity conditions" each hypercyclic C0-semigroup is weakly mixing. Furthermore, it is shown that for a hypercyclic C0-semigroup there is always a dense set of hypercyclic vectors having infinitely differentiable trajectories. Chaotic C0-semigroups are also considered. It is proved that they are always weakly mixing and that in certain cases chaoticity is already implied by the existence of a single periodic point. Moreover, it is shown that strongly elliptic differential operators on bounded C^1-domains never generate chaotic C0-semigroups. A thorough investigation of transitivity, weak mixing, and mixing of weighted compositioin operators follows and complete characterisations of these properties are derived. These results are then used to completely characterise hypercyclicity, weak mixing, and mixing of C0-semigroups generated by first order partial differential operators. Moreover, a characterisation of chaos for these C0-semigroups is attained. All these results are achieved on spaces of p-integrable functions as well as on spaces of continuous functions and illustrated by various concrete examples.