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Institute
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- Fachbereich 4 (50)
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- Fachbereich 1 (19)
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- Fachbereich 2 (7)
- Fachbereich 6 (7)
As a target for condemnation, the thematic prevalence of racism in African American novels of satire is not surprising. In order to confront this vice in its shifting manifestations, however, the African American satirist has to employ special techniques. This thesis examines some of these devices as they occur in George Schuyler- Black No More, Charles Wright- The Wig, and Percival Everett- Erasure. Given the reciprocity of target and technique in the satiric context, close attention is paid to how the authors under study locate and interrogate racism in their narratives. In this respect, the significance of anti-essentialist Marxist criticism in Schuyler- Black No More and the author- portrayal of the society of his time as capitalist machinery is examined. While Schuyler is concerned with exposing the general socioeconomic workings of the 1920s from a Marxist perspective, Wright offers the reader perspective into how this oppressive machinery psychologically manipulates and corrupts the individual in the historic context of Lyndon B. Johnson- political vision of the Great Society. Everett then elaborates on the epistemological concern which is traceable in Wright- work and addresses the role media representation plays in manufacturing images and rigid categories that shape systematic racism. As such, the present study not only highlights the versatility of satire as a rhetorical secret weapon and thus ventures toward the idiosyncrasies of the African American novel of satire, it also makes an effort to trace the ever-changing face of racial discrimination.
There is ample evidence that the personality trait of extraversion is associated with frequent experiences of positive affect whereas introversion is associated with less frequent experiences of positive affect. According to a theory of Watson et al. (1997), these findings demonstrate that positive affect forms the conceptual core of extraversion. In contrast, several other researchers consider sociability - and not positive affect - as the core of extraversion. The aim of the present work is to examine the relation between extraversion and dispositional positive affect on the neurobiological level. In 38 participants resting cerebral blood flow was measured with continuous arterial spin labeling (CASL). Each participant was scanned on two measurement occasions separated by seven weeks. In addition, questionnaire measures of extraversion and dispositional positive affect were collected. To employ CASL for investigating the biological basis of personality traits, the psychometric properties of CASL blood flow measurements were examined in two studies. The first study was conducted to validate the CASL technique. Using a visual stimulation paradigm, the expected pattern of activity was found, i.e. there were specific differences in blood flow in the primary and secondary visual areas. Moreover, the results in the first measurement occasion could be reproduced in the second. Thus, these results suggest that CASL blood flow measurements have a high degree of validity. The aim of the second psychometric study was to examine whether resting blood flow measurements are characterized by a sufficient trait stability to be used as a marker for personality traits. Employing the latent state-trait theory developed by Steyer and colleagues, it was shown that about 70 % of the variance of regional blood flow could be explained by individual differences in a latent trait. This suggests that blood flow measurements have sufficient trait stability for investigating the biological basis of personality traits. In the third study, the relation between extraversion and dispositional positive affect was investigated on the neurobiological level. Voxel-based analyses showed that dispositional positive affect was correlated with resting blood flow in the ventral striatum, i.e. a brain structure that is associated with approach behavior and reward processing. This biological basis was also found for extraversion. In addition, when extraversion was statistically controlled, the association between dispositional positive affect and blood flow in the ventral striatum was still present. However, when dispositional positive affect was statistically controlled, the relation between extraversion and the ventral striatum disappeared. Taken together, these results suggest that positive affect forms a core of extraversion on the neurobiological level. The present findings thus add psychophysiological evidence to the theory of Watson et al. (1997), which suggests that positive affect forms the conceptual core of extraversion.
Memory consists of multiple anatomically and functionally distinct systems. Animal studies suggest that stress modulates multiple memory systems in a manner that favors nucleus caudatus-based stimulus-response learning at the expense of hippocampus-based spatial learning. The present work aimed (i) to translate these findings to humans, (ii) to determine the involvement of the stress hormone cortisol in this effect, and (iii) to assess whether the use of stimulus-response and spatial strategies is a long lasting person characteristic. To address these issues we developed a new paradigm that differentiates the use of spatial and stimulus-response learning in humans. Our findings indicate that (i) psychosocial stress (Trier Social Stress Test) modulates the use of spatial and stimulus-response learning in humans, (ii) cortisol plays a key role in this modulatory effect of stress, and (iii) the use of spatial and stimulus-response learning is affected by situational rather than long lasting person factors.
Tropospheric ozone (O3) is known to have various detrimental effects on plants, such as visible leaf injury, reduced growth and premature senescence. Flux models offer the determination of the harmful ozone dose entering the plant through the stomata. This dose can then be related to phytotoxic effects mentioned above to obtain dose-response relationships, which are a helpful tool for the formulation of abatement strategies of ozone precursors. rnOzone flux models are dependant on the correct estimation of stomatal conductance (gs). Based on measurements of gs, an ozone flux model for two white clover clones (Trifolium repens L. cv Regal; NC-S (ozone-sensitive) and NC-R (ozone-resistant)) differing in their sensitivity to ozone was developed with the help of artificial neural networks (ANNs). White clover is an important species of various European grassland communities. The clover plants were exposed to ambient air at three sites in the Trier region (West Germany) during five consecutive growing seasons (1997 to 2001). The response parameters visible leaf injury and biomass ratio of NC-S/NC-R clone were regularly assessed. gs-measurements of both clones functioned as output of the ANN-based gs model, while corresponding climate parameters (i.e. temperature, vapour pressure deficit (VPD) and photosynthetic active radiation (PAR)) and various ozone concentration indices were inputs. The development of the model was documented in detail and various model evaluation techniques (e.g. sensitivity analysis) were applied. The resulting gs model was used as a basis for ozone flux calculations, which were related to above mentioned response parameters. rnThe results showed that the ANNs were capable of revealing and learning the complex relationship between gs and key meteorological parameters and ozone concentration indices. The dose-response relationships between ozone fluxes and visible leaf injury were reasonably strong, while those between ozone fluxes and NC-S/NC-R biomass ratio were fairly weak. The results were discussed in detail with respect to the suitability of the chosen experimental methods and model type.
In this thesis, we investigate the quantization problem of Gaussian measures on Banach spaces by means of constructive methods. That is, for a random variable X and a natural number N, we are searching for those N elements in the underlying Banach space which give the best approximation to X in the average sense. We particularly focus on centered Gaussians on the space of continuous functions on [0,1] equipped with the supremum-norm, since in that case all known methods failed to achieve the optimal quantization rate for important Gauss-processes. In fact, by means of Spline-approximations and a scheme based on the Best-Approximations in the sense of the Kolmogorov n-width we were able to attain the optimal rate of convergence to zero for these quantization problems. Moreover, we established a new upper bound for the quantization error, which is based on a very simple criterion, the modulus of smoothness of the covariance function. Finally, we explicitly constructed those quantizers numerically.
The aim of the thesis was to investigate the role of the immune system in fibromyalgia (FM), as part of a dynamic co-regulation between different bodily systems. FM is a chronic musculoskeletal disorder characterized by widespread pain and specific tender points, combined with other symptoms including fatigue, sleep disturbances, morning stiffness and anxiety. The main goal of the work was to identify possible dysregulation of peripheral immune and endocrine parameters in patients with FM compared to matched healthy controls. Moreover, the possible relation between symptom complaints and the specific parameters measured was also evaluated. A first approach was to investigate possible differences between FM patients and controls in the expression of cytokines, as they have been implicated in the occurrence of several of the symptoms associated with FM. Furthermore, adhesion molecules which are involved in cell-to-cell communication and immune cell trafficking were also studied. The latter are known to be regulated by both cytokines and glucocorticoids (GCs) and their expression is often found altered in patients with immune dysregulation. It was expected that subjects with FM would have an increased production of proinflammatory cytokines and/or a reduced antiinflammatory cytokine production and that certain cytokines and/or adhesion molecules would be differently regulated by dexamethasone (DEX). Unstimulated blood was used in the analysis of adhesion molecule expression by flow cytometry while stimulated whole blood cell cultures were used in cytokine flow cytometry assays. Peripheral blood mononuclear cells (PBMCs) were also cultured and the supernatants collected to determine the concentration of cytokines by biochip protein array. In addition, serum samples were used in enzyme-linked immunosorbent assays (ELISA) for quantification of soluble adhesion molecules. L-selectin was found elevated on monocytes and neutrophils of FM patients. A bias toward lower IL-4 levels was observed in FM patients. Based on studies showing differences in glucocorticoid receptor (GR) affinity and disturbances associated with loss of hypothalamic-pituitary-adrenal (HPA) axis resiliency in FM, it was hypothesized whether FM would be associated with abnormalities in glucocorticoid sensitivity. Total plasma cortisol and salivary free cortisol were quantified by ELISA and time-resolved fluorescence immunoassay, respectively. GR sensitivity through DEX inhibition of IL-6, in stimulated whole blood, was evaluated after cytokine quantification by ELISA. The corticosteroid receptors, GR alpha and mineralocorticoid receptor (MR), as well as the glucocorticoid-induced leucine zipper (GILZ) and the FK506 binding protein 5 mRNA expression were assessed in PBMCs by real-time reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, sequencing of RT-PCR products and/or genomic DNA was used for mutational analysis of the corticosteroid receptors. We observed lower basal plasma cortisol levels (borderline statistical significance) and a lower expression of corticosteroid receptors and GILZ in FM patients when compared to healthy controls. The minor allele of the MR single nucleotide polymorphism (SNP) rs5522 was found more often in FM patients than in controls. In addition, female carriers of this SNP seemed to have reduced salivary cortisol responses to a strong psychological stressor (Trier Social Stress Test) compared to non-carriers. FM patient carriers of an MR intronic SNP (rs17484245), before exon 3, were associated with significantly higher scores of depression symptoms compared to patient non-carriers. The thesis includes also a comprehensive analysis of the complexity of GR regulation and the role of alternative mRNA splicing. It focuses on the differential expression of the untranslated GR first exons, their high sequence homology among different species and how genetic determinants, without apparent relevance, may have implications in health and disease. In FM patients, GR exon 1-C expression was found lower and a significant difference was observed when comparing GR 1-C expression between antidepressant-free and patients who had taken antidepressants until two weeks before sample collection. In summary, the study shows a slight disturbance of some components of the innate immune system of FM patients and suggests an enhanced adhesion and possible recruitment of leukocytes to inflammatory sites. The reduced expression of corticosteroid receptors and possibly the reduced MR function may be associated with an impaired function of the HPA axis in these patients. A hyporesponsiveness of the HPA axis under stress or disturbances of the stress response could make these patients more vulnerable to cytokines and inflammation which, compounded by lower antiinflammatory mediators, may sustain some of the symptoms that contribute to the clinical picture of FM.
During the last decade, anatomic and physiological neuroscience research has yielded extensive information on the physiological regulators of short-term satiety, visceral and interoceptive sensation. Distinct neural circuits regulate the elements of food ingestion physiologically. The general aim of the current studies is to elucidate the peripheral neural pathways to the brain in healthy subjects to establish the groundwork for the study of the pathophysiology of bulimia nervosa (BN). We aimed to define the central activation pattern during non-nutritive gastric distension in humans, and aimed to define the cognitive responses to this mechanical gastric distension. We estimated regional cerebral blood flow with 15O-water positron emission tomography during intragastric balloon inflation and deflation in 18 healthy young women of normal weight. The contrast between inflated minus deflated in the exploratory analysis revealed activation in more than 20 brain regions. The analysis confirmed several well known areas in the central nervous system that contribute to visceral processing: the inferior frontal cortex, representing a zone of convergence for food related stimuli; the insula and operculum referred to as "visceral cortex"; the anterior cingulate gyrus (and insula), processing affective information; and the brainstem, a site of vagal relay for visceral afferent stimuli. Brain activation in the left ventrolateral prefrontal cortex was reproducible. This area is well known for higher cognitive processing, especially reward-related stimuli. The ventrolateral prefrontal cortex with the insular regions may provide a link between the affective and rewarding components of eating and disordered eating as observed in BN and binge-eating obesity. Gastric distension caused a significant rapid, reversible, and reproducible increase in the feelings of fullness, sleepiness, and gastric discomfort as well as a significant rapid, reversible, and reproducible decrease in the feeling of hunger. We showed that mechanical activation of the neurocircuitry involved in meal termination led to the described phenomena. The current brain activation studies of non-painful, proximal gastric distension could provide groundwork in the field of abnormal eating behavior by suggesting a link between visceral sensation and abnormal eating patterns. A potential treatment for disordered eating and obesity could alter the conscious and unconscious perception and interoceptive awareness of gastric distension contributing to meal termination.
The human brain is characterised by two apparently symmetrical cerebral hemispheres. However, the functions attributed to each half of the brain are very distinct with a relative specialisation of the left hemisphere for language processing. Most laterality research has been performed on a behavioural level, using techniques such as visual half-field presentation. The visual half-field technique involves the presentation of stimuli in the left or right visual field for a very short time (about 200 ms). During the presentation of lateralized stimuli, the gaze of the participants is fixated on a centrally presented fixation cross. This technique takes advantage of the anatomy of the visual pathway as the temporal hemiretinae project ipsilateral, while the nasal hemiretinae project contralateral. Thus, stimuli presented in the left or right visual field are initially processed in the contralateral hemisphere. Language organisation can also be directly investigated using functional magnetic resonance imaging (fMRI). Both behavioural and neuroimaging studies showed that about 95% of right-handed men have a left hemispheric specialisation for language. In contrast, data on language organisation in women are ambiguous. It is supposed that this ambivalent picture might be associated with changes in gonadal steroid levels in blood during the menstrual cycle. However, gonadal steroid effects are complex and their role in functional cerebral lateralization is still open to discussion. The aim of this PhD project was to investigate, using fMRI: (1) the processing of linguistic information initially received in the specialised, non-specialised or both hemispheres; (2) linking the associated brain activation pattern with progesterone levels during the menstrual cycle. Firstly, brain activation was measured in 16 right-handed, healthy males during processing of different components of language (orthography, phonology and semantics) after reception in the left, right or both hemispheres. Secondly, to investigate changes in language organisation during the menstrual cycle, we conducted an event-related fMRI study during semantic and phonological processing also using visual half-field and central presentation of linguistic stimuli. Our results revealed higher BOLD signal intensity change in the visual cortex contralateral to the visual field of stimulus presentation compared to the ipsilateral visual cortex reflecting the crossing of visual pathways. We also found support for the hypothesis that the superiority of word recognition in the left VWFA is the result of a reduced activity in the right VWFA under left hemispheric control. Further, linguistic information received in the subdominant RH, is interhemispheric transferred to the left hemisphere for phonological processing. Semantic processing in contrast occurs in the specialised and in the non-specialised hemisphere. For the group of women, data analysis revealed that during semantic processing, salivary progesterone levels correlated positively with brain activity of the left superior frontal gyrus, left middle and inferior occipital gyri and bilateral fusiform gyrus. In contrast, the brain activation pattern for phonological processing did not change significantly across the menstrual cycle. In conclusion, the effect of serum progesterone levels on brain activity is task and region specific.
The glucocorticoid (GC) cortisol, main mediator of the hypothalamic-pituitary-adrenal axis, has many implications in metabolism, stress response and the immune system. GC function is mediated mainly via the glucocorticoid receptor (GR) which binds as a transcription factor to glucocorticoid response elements (GREs). GCs are strong immunosuppressants and used to treat inflammatory and autoimmune diseases. Long-term usage can lead to several irreversible side effects which make improved understanding indispensable and warrant the adaptation of current drugs. Several large scale gene expression studies have been performed to gain insight into GC signalling. Nevertheless, studies at the proteomic level have not yet been made. The effects of cortisol on monocytes and macrophages were studied in the THP-1 cell line using 2D fluorescence difference gel electrophoresis (2D DIGE) combined with MALDI-TOF mass spectrometry. More than 50 cortisol-modulated proteins were identified which belonged to five functional groups: cytoskeleton, chaperones, immune response, metabolism, and transcription/translation. Multiple GREs were found in the promoters of their corresponding genes (+10 kb/-0.2 kb promoter regions including all alternative promoters available within the Database for Transcription Start Sites (DBTSS)). High quality GREs were observed mainly in cortisol modulated genes, corroborating the proteomics results. Differential regulation of selected immune response related proteins were confirmed by qPCR and immuno-blotting. All immune response related proteins (MX1, IFIT3, SYWC, STAT3, PMSE2, PRS7) which were induced by LPS were suppressed by cortisol and belong mainly to classical interferon target genes. Mx1 has been selected for detailed expression analysis since new isoforms have been identified by proteomics. FKBP51, known to be induced by cortisol, was identified as the strongest differentially expressed protein and contained the highest number of strict GREs. Genomic analysis of five alternative FKBP5 promoter regions suggested GC inducibility of all transcripts. 2D DIGE combined with 2D immunoblotting revealed the existence of several previously unknown FKBP51 isoforms, possibly resulting from these transcripts. Additionally multiple post-translational modifications were found, which could lead to different subcellular localization in monocytes and macrophages as seen by confocal microscopy. Similar results were obtained for the different cellular subsets of human peripheral blood mononuclear cells (PBMCs). FKBP51 was found to be constitutively phosphorylated with up to 8 phosphosites in CD19+ B lymphocytes. Differential Co-immunoprecipitation for cytoplasm and nucleus allowed us to identify new potential interaction partners. Nuclear FKBP51 was found to interact with myosin 9, whereas cytosolic FKBP51 with TRIM21 (synonym: Ro52, Sjögren`s syndrome antigen). The GR has been found to interact with THOC4 and YB1, two proteins implicated in mRNA processing and transcriptional regulation. We also applied proteomics to study rapid non-genomic effects of acute stress in a rat model. The nuclear proteome of the thymus was investigated after 15 min restraint stress and compared to the non-stressed control. Most of the identified proteins were transcriptional regulators found to be enriched in the nucleus probably to assist gene expression in an appropriate manner. The proteomic approach allowed us to further understand the cortisol mediated response in monocytes/macrophages. We identified several new target proteins, but we also found new protein variants and post-translational modifications which need further investigation. Detailed study of FKBP51 and GR indicated a complex regulation network which opened a new field of research. We identified new variants of the anti-viral response protein MX1, displaying differential expression and phosphorylation in the cellular compartments. Further, proteomics allowed us to follow the very early effects of acute stress, which happen prior to gene expression. The nuclear thymocyte proteome of restraint stressed rats revealed an active preparation for subsequent gene expression. Proteomics was successfully applied to study differential protein expression, to identify new protein variants and phosphorylation events as well as to follow translocation. New aspects for future research in the field of cortisol-mediated immune modulation have been added.
In this psycho-neuro-endocrine study the molecular basis of different variants of steroid receptors as well as highly conserved non steroidal receptors was investigated. These nuclear receptors (NRs) are important key regulators of a wide variety of different physiological and pathophysiological challenges ranging from inflammation and stress to complex behaviour and disease. NRs control gene transcription in a ligand dependent manner and are embedded in the huge interaction network of the neuroendocrine and immune system. Two receptors, the glucocorticoid receptor (GR) and the chicken ovalbumin upstream promoter-transcription factorII (Coup-TFII), both expressed in the immune and nervous system, were investigated regarding possible splice variants and their implication in the control of gene transcription. Both NRs are known to interact and modulate each other- target gene regulation. This study could be shown that both NRs have different splice variants that are expressed in a tissue specific manner. The different 5-´alternative transcript variants of the human GR were in silico identified in other species and evidence for a highly conserved and tightly controlled function was provided. Investigations of the N-terminal transactivation domain of the GR showed a deletion suggesting an altered glucocorticoid-dependent transactivation profile. The newly identified alternative transcript variant of Coup-TFII leads to a DNA binding deficient Coup-TFII isoform that is highly expressed in the brain. This Coup-TFII isoform alters Coup-TFII target gene expression and is suggested to interact with GR via its ligand binding domain resulting in an impaired GR target gene regulation in the nervous system. In this thesis it was demonstrated that NR variants are important for the understanding of the enormous regulatory potential of this receptor family and have to be taken into account for the development of therapeutic strategies for complex diseases such as stress related and neurodegenerative disorders.
Considering the numerical simulation of mathematical models it is necessary to have efficient methods for computing special functions. We will focus our considerations in particular on the classes of Mittag-Leffler and confluent hypergeometric functions. The PhD Thesis can be structured in three parts. In the first part, entire functions are considered. If we look at the partial sums of the Taylor series with respect to the origin we find that they typically only provide a reasonable approximation of the function in a small neighborhood of the origin. The main disadvantages of these partial sums are the cancellation errors which occur when computing in fixed precision arithmetic outside this neighborhood. Therefore, our aim is to quantify and then to reduce this cancellation effect. In the next part we consider the Mittag-Leffler and the confluent hypergeometric functions in detail. Using the method we developed in the first part, we can reduce the cancellation problems by "modifying" the functions for several parts of the complex plane. Finally, in in the last part two other approaches to compute Mittag-Leffler type and confluent hypergeometric functions are discussed. If we want to evaluate such functions on unbounded intervals or sectors in the complex plane, we have to consider methods like asymptotic expansions or continued fractions for large arguments z in modulus.
International private equity development is highly volatile with increasing global diversification. This thesis examines the transaction patterns of cross-border private equity investment with a particular focus on the affinity of country pairs. Analysis is based on a comprehensive dataset of 99 countries over 25 years. A three-dimensional gravity model analysis covering source and host country over time exposes the effects of the country determinants: economic mass, economic distance, banking system, corporate endowment, as well as legal, political, and institutional system on the transactions. A new method is developed to examine countries in their dual roles as investor and target. This approach verifies their global importance as source and host, and also makes possible an analysis of overall private equity investment. For private equity-specific multi-investor deals, a scheme is designed to measure cross-border activity with more precision by participation, proportional deal participation, and deal flow. The analysis identifies intense level of affinity between country pairs and reveals that no single country is ideal for private equity activity. Instead, the findings show that the specific push and pull factors within each country constellation define the optimal country as trading partner. The results verify a correlation between cross-border deals and economic masses and reduced economic distance of countries. Geographic distance and cultural similarities, such as language and legal system, intensify the likelihood of initiating transactions. International trade-oriented countries with a high level of development lower the entrance barriers and increase the chances of deal success. A well-funded financial system for the investor and an efficient and competitive banking system of target countries enhance the probability of investment between countries. Also relevant for the likelihood of starting cross-border deals are low corporate tax burdens and advanced scientific competitiveness, and a well-developed stock market in the investor country. Fundamental to frequency and likelihood of success are well-established, high standards of a country- social, political, and legal systems with widespread confidence in the rules of society. In particular, the reliability of contract enforcement, with proven quality of regulations that promote private sector development, proves to be crucial for deal success.
In this study, candidate loci for periodic catatonia (SCZD10, OMIM #605419) on chromosome 15q15 and 22q13.33 have been fine mapped and investigated. Previously, several studies found evidences for a major susceptibility locus on chromosome 15q15 and a further potential locus on 22q13.33 pointing to genetic heterogeneity. Fine mapping was done in our multiplex families through linkage and mutational analysis using genomic markers selected from public databases. Positional candidate genes like SPRED1 and BRD1, and ultra-conserved elements were investigated by direct sequencing in these families. The results narrow down the susceptibility locus on chromosome 15q14-15q15.1 to a region between markers D15S1042 and D15S968, as well as exclusion of SPRED1 and ultra-conserved elements as susceptibility candidates. Fine mapping for two chromosome 23q13.33-linked families showed that the recombination events would place the disease-causing gene to a telomeric ~577 Kb interval and SNP rs138880 investigation revealed an A-allele in the affected person, therefore excludes BRD1 as well as confirmed MLC1 to be the candidate gene for periodic catatonia.
The skin is continuously challenged by environmental antigens that may penetrate and elicit a skin sensitization, which can develop into allergic contact dermatitis. Medical treatment for allergic contact dermatitis is limited - in fact only acute symptoms can be cured and for secondary prevention of the disease a lifelong avoidance of the allergen(s) is necessary. Therefore, the screening of the sensitization potential of substance used in commercially available products is indispensable to prevent such diseases. Hence, risk assessment is deduced from data obtained by murine local lymph node assay predominantly, but there exists a need to develop methods capable of providing the same information that do not require the use of animals in view of legislative initiatives such as REACH (registration, evaluation, authorization of chemicals) as well as the 7th Amendment to the Cosmetics Directive (2003/15/EC). Therefore, a number of promising in silico and in vitro approaches are being developed to address this need. In vitro test systems using the response of dendritic cells, which are the key player in the elicitation process of contact dermatitis, are established, but, although these novel methods for hazard identification might find application in the context of screening, it is not clear whether these approaches are useful for the purposes of risk assessment and risk management to predict allergic potency. Therefore, it was investigated whether on the one hand in vitro generated dendritic cells from primary blood monocytes (MoDC) and on the other hand a continuous monocytic cell line, the THP-1 cells, suggested as dendritic cell surrogate, react to a presumably weak allergen. Ascaridol, predicted as one of the possible causes for tea tree oil contact dermatitis, was studied and its effects in these two in vitro skin sensitization models were explored. Thus, the surface expression of CD86, HLADR, CD54, and CD40, which are known as activation markers in both in vitro models, were measured via flow cytometry. For MoDC, an augmented CD86 and HLADR surface expression in comparison to untreated cells were determined after 24 h exposure with ascaridol. An increased CD54 and CD40 surface expression were found only in some donors. After long term incubation of 96 h, ascaridol-treated MoDC still up-regulated CD86 and additionally an augmented CD40 expression was measured in all studied donors. An enhanced CD54 expression was determined for 50 percentage of all investigated donors. Furthermore, CD80, CD83 and CD209 protein expression were up-regulated in MoDC after 96 h of ascaridol incubation. In addition, it was determined that after 24 h ascaridol-treated MoDC showed an increased capacity to uptake antigens, whereas after 96 h this capacity got lost and antigen-capturing devices were reduced in comparison to non-treated MoDC. Moreover, the cytokine release of ascaridol-treated MoDC were measured after 24 h. Tumor necrosis factor (TNF)alpha, interleukin (IL)-1beta and IL 6 secretion were determined in some donors. Furthermore, IL-8 release was clearly increased after 24 h ascaridol treatment. By the same token, THP-1 cells were analyzed after ascaridol treatment for several activation markers. We found a similar response pattern as measured in MoDC. Ascaridol induced CD86 expression as well as CD54 after 24 h incubation. Additionally, the impact of ascaridol on phosphorylation of p38 mitogen-activated protein kinase, which had been shown to be involved in increased expression of activation markers like CD86 by others, were studied via Western blot analysis. A phosphorylation of p38 was determined after 15 min of ascaridol stimulation. Moreover, an augmented CD40 and HLADR surface expression were measured in a dose-response manner after 24 h ascaridol treatment. Also similar to MoDC an enhanced IL-8 secretion after ascaridol stimulation was observed in THP-1 cells. Hence, for the first time it was shown that ascaridol has immuno-modulating effects. The obtained data from both in vitro systems, MoDC and THP-1 cells, identified ascaridol as a sensitizer. Although for both systems there remain significant challenges to overcome for potency assessment, ascaridol is presumed to be a weak sensitizer probably. Interestingly, ascaridol treatment of THP-1 cells resulted also in an increased augmentation of CD184 and CCR2, two chemokine receptors expressed on monocyte. Therefore, these data encouraged the exploration of chemokine receptors as tools in skin sensitization prediction. Consequently, the combination of chemical assays with in vitro techniques may provide a useful surrogate to animal testing for skin sensitization. Due to the continuously changing environmental conditions, it is necessary to regularly monitor and update the spectrum of sensitizers that elicit contact dermatitis. Therefore, both debated in vitro test systems will become indispensable tools.
As an interface between an individual and its environment, the skin is a major site of direct exposure to exogenous substances. Once absorbed, these substances may interact with different biomolecules within the skin. The aryl hydrocarbon receptor (AhR) signaling pathway is one mechanism whereby the skin responds to exposures, predominantly through the induction or upregulation of metabolizing enzymes. One known physiological role of the AhR in many tissues is its involvement in the control of cell cycle progression. In skin, almost nothing is known about this physiological function. Moreover, the question whether frequently used naturally occurring phenolic derivatives like eugenol and isoeugenol impact on the AhR within the skin has rarely been studied so far. Eugenol and isoeugenol are due to their odour referred to as fragrances. The ubiquitous distribution of eugenol and isoeugenol results in an almost unavoidable contact with these substances in our daily lives. Despite this fact, their molecular mechanisms of action in skin are poorly understood. There is evidence supporting the hypothesis that these substances may impact on the AhR. On the one hand, eugenol is shown to induce cytochrome P450 1A1 (CYP1A1), a well-known target gene of the AhR. On the other hand, their known anti-proliferative properties might also be mediated by the AhR, based on its physiological function. In order to proof this hypothesis, it was investigated whether eugenol and isoeugenol impact on the AhR signaling pathway in skin cells. Results revealed that eugenol as well as isoeugenol impact on the AhR signaling pathway in skin cells. Both substances caused the translocation of the AhR into the nucleus, induced the expression of the well-known AhR target genes CYP1A1 and AhR repressor (AhRR) and exhibited impact on cell cycle progression. Both substances caused an AhR-dependent cell cycle arrest in skin cells, modulated protein levels of several cell cycle regulatory proteins, inhibited DNA synthesis and thereby reduced cell numbers. The comparison of wildtype cells to AhR knockdown cells revealed an influence of the AhR on cell cycle progression in skin cells in the absence of exogenous ligands. AhR knockdown cells exhibited a slower progression through the cell cycle caused by an accumulation of cells in the G0/G1 phase of the cell cycle and a decreased DNA synthesis rate. Modulation of cell cycle regulatory proteins involved in the transition from the G0/G1 to the S phase of the cell cycle was altered in AhR knockdown cells as well. To conclude, eugenol as well as isoeugenol were able to impact on the AhR signaling pathway in skin cells. Their molecular mechanisms of action are similar to those of classical AhR ligands, although their structural characteristics strongly differ from that of these ligands. In the absence of exogenous ligands the AhR promotes cell cycle progression in many tissues and this knowledge could be expanded on skin-derived cells within the scope of this thesis.
This thesis presents a study of the visual change detection mechanism. This mechanism is thought to be responsible for the detection of sudden and unexpected changes in our visual environment. As the brain is a capacity limited system and has to deal with a continuous stream of information from its surroundings only a part of the vast amount of information can be completely processed and be brought to conscious awareness. This information, which passes through attentional filters, is used for goal-directed behaviour. Therefore, the change detection mechanism is a very useful aid to cope with important information which is outside the focus of our attention. rnIt is thought that a neural memory trace of repetitive visual information is stored. Each new information input is compared to this existing memory trace by a so-called change or mismatch detection system. Following a sudden change, the comparison process leads to a mismatch and the detection system elicits a warning signal, to which an orienting response can follow. This involves a change in the focus of attention towards this sudden environmental change which can then be evaluated for potential danger and allows for a behavioural adaptation to the new situation. rnTo this purpose a paradigm was developed combining a 2-choice response time task with in the background a mismatch detection task of which the subjects were not aware. This paradigm was implemented in an ERP and an fMRI study and was used to study the the change detection mechanism and its relationship with impulsivity.rnIn previous studies a change detection system for auditory information had already been established. As the brain is a very efficient system it was thought to be unlikely that this change detection system is only available for the processing of auditory information. rnIndeed, a modality specific mismatch response at the sensory specific occipital cortex and a more general response at the frontocentral midline, both resembling the components shown in auditory research, were found in the ERP study.rnAdditionally, magnetic resonance imaging revealed a possible functional network of regions, which responded specifically to the processing of a deviant. These regions included the occipital gyrus, premotor cortex, inferior frontal cortex, thalamas, insula, and parts of the cingular cortex. rnThe relationship between impulsivity measures and visual change detection was established in an additional study. More impulsive subjects showed less detection of deviant stimuli, which was most likely due to too fast and imprecise information processing.rnIn summary it can be said, that the work presented in this thesis demonstrates that visual mismatch negativity was established, a number of regions could be associated with change detection and additionally the relevance of change detection in information processing was shown.rn
The visualization of relational data is at the heart of information visualization. The prevalence of visual representations for this kind of data is based on many real world examples spread over many application domains: protein-protein interaction networks in the field of bioinformatics, hyperlinked documents in the World Wide Web, call graphs in software systems, or co-author networks are just four instances of a rich source of relational datasets. The most common visual metaphor for this kind of data is definitely the node-link approach, which typically suffers from visual clutter caused by many edge crossings. Many sophisticated algorithms have been developed to layout a graph efficiently and with respect to a list of aesthetic graph drawing criteria. Relations between objects normally change over time. Visualizing the dynamics means an additional challenge for graph visualization researchers. Applying the same layout algorithms for static graphs to intermediate states of dynamic graphs may also be a strategy to compute layouts for an animated graph sequence that shows the dynamics. The major drawback of this approach is the high cognitive effort for a viewer of the animation to preserve his mental map. To tackle this problem, a sophisticated layout algorithm has to inspect the whole graph sequence and compute a layout with as little changes as possible between subsequent graphs. The main contribution and ultimate goal of this thesis is the visualization of dynamic compound weighted multi directed graphs as a static image that targets at visual clutter reduction and at mental map preservation. To achieve this goal, we use a radial space-filling visual metaphor to represent the dynamics in relational data. As a side effect the obtained pictures are very aesthetically appealing. In this thesis we firstly describe static graph visualizations for rule sets obtained by extracting knowledge from software archives under version control. In a different work we apply animated node-link diagrams to code-developer relationships to show the dynamics in software systems. An underestimated visualization paradigm is the radial representation of data. Though this kind of data has a long history back to centuries-old statistical graphics, only little efforts have been done to fully explore the benefits of this paradigm. We evaluated a Cartesian and a radial counterpart of a visualization technique for visually encoding transaction sequences and dynamic compound digraphs with both an eyetracking and an online study. We found some interesting phenomena apart from the fact that also laymen in graph theory can understand the novel approach in a short time and apply it to datasets. The thesis is concluded by an aesthetic dimensions framework for dynamic graph drawing, future work, and currently open issues.
Although it has been demonstrated that nociceptive processing can be modulated by heterotopically and concurrently applied noxious stimuli, the nature of brain processes involved in this percept modulation in healthy subjects remains elusive. Using functional magnetic resonance imaging (fMRI) we investigated the effect of noxious counter-stimulation on pain processing. FMRI scans (1.5 T; block-design) were performed in 34 healthy subjects (median age: 23.5 years; range: 20-31 yrs.) during combined and single application (duration: 15 s; ISI=36 s incl. 6 s rating time) of noxious interdigital-web pinching (intensity range: 6-15 N) and contact-heat (45-49 -°C) presented in pseudo-randomized order during two runs separated by approx. 15 min with individually adjusted equi-intense stimuli. In order to control for attention artifacts, subjects were instructed to maintain their focus either on the mechanical or on the thermal pain stimulus. Changes in subjective pain intensity were computed as percent differences (∆%) in pain ratings between single and heterotopic stimulation for both fMRI runs, resulting in two subgroups showing a relative pain increase (subgroup P-IN, N=10) vs. decrease (subgroup P-DE, N=12). Second level and Region of Interest analysis conducted for both subgroups separately revealed that during heterotopic noxious counter-stimulation, subjects with relative pain decrease showed stronger and more widespread brain activations compared to subjects with relative pain increase in pain processing regions as well as a fronto-parietal network. Median-split regression analyses revealed a modulatory effect of prefrontal activation on connectivity between the thalamus and midbrain/pons, supporting the proposed involvement of prefrontal cortex regions in pain modulation. Furthermore, the mid-sagittal size of the total corpus callosum and five of its subareas were measured from the in vivo magnetic resonance imaging (MRI) recordings. A significantly larger relative truncus size (P=.04) was identified in participants reporting a relative decrease of subjective pain intensity during counter-stimulation, when compared to subjects experiencing a relative pain increase. The above subgroup differences observed in functional and structural imaging data are discussed with consideration of potential differences in cognitive and emotional aspects of pain modulation.
In Beloved, Jazz and Paradise, Toni Morrison negotiates ways of individual and collective identity formation through figurations of space and trauma. In geographical spaces that are public and private, open and closed, inclusive and exclusive, space of the past and spaces of the present, Morrison writes discursive spaces in which to create individual and communal African American history and identity, based on the traumatic hi-stories at the core of the Black American experience: the Middle Passage, slavery, Jim Crow and the Civil Rights Movement, just to name a few. In the three novels, Toni Morrison subscribes to a postmodern notion of space and place, presenting it as relative to the individual- frame of mind. Places are used as metonymies for the protagonists" traumatized minds and their different ways of dealing with trauma. Trauma that is not worked through and transcended is presented by Morrison as impacting the protagonists- ability to fashion a home out of a vast and often hostile space. The physical and mental space of Morrison- protagonists is occupied by historical traumata that disables the protagonists to find a place in the present without revisiting the places of their troubled past. While this burdens their lives, it also opens up a historical and metahistorical discourse that allows the revision of mainstream historiography to include minority histories of oppression and trauma. Morrison reconfigures the American historical landscape by emphasizing the subjectivity of any history and offering alternatives to historical grand narratives through her historiographic metafiction. All three novels explore the possibility of reconciliation between past trauma and present life. Doing so requires Morrison to send her protagonists on strenuous journeys through time and space in order to visit the past trauma that keeps them from making a home in the here and now. The protagonists venture back to the primal scenes that bear major significance for their lives but have been suppressed for being too painful to remember. Their pain thus awakens anew, but out of it grow the possibility of a life in the present and the hope for a future. The pasts Morrison thus digs up serve as anchors to situate the African American place in the American historical landscape. Those primal places have a geographical as well as a historical and psychological quality, as places in Morrison- novels are often used as metonymies for the protagonists" traumatized minds, containing the memory of the traumatic past. By spatializing time, Morrison makes history accessible to a communal working through, thus countering the modernist impulse to treat memory as a private faculty embedded in the individual- psyche. This makes it difficult, for African Americans with individual recollections of slavery and racist oppression for example, to use traumatic memory as the basis for a common sense of identity. Morrison uses spatialized time as a forum to discover this basis, to allow for the establishment of a common historical bond. At the same time, she warns against instrumentalizing a common history to exclude those who do not share it. Any history, for Morrison, should be open and flexible enough to accommodate different perspectives. Essentially, Morrison suggests that western historiography is a discursive construct. By allowing, in all three novels, a polyphonic weaving of different equal histories to destablize a single, authoritative, hegemonic historiography, Morrison gives African Americans the power to construct her own past, her own present, and thereby claim back her identity. Moreover, Morrison destabilizes the duality of private space and public space that has long served to distinguish subjective individual memory from objective communal history and thus to legitimize certain accounts of history at the expense of others. The gendered as well as the racial other, by virtue of being excluded from the public sphere, have been excluded from their own historicization. By opening up the private sphere of personal trauma and loss, Morrison spatializes personal memory in a way that it forms a parallel public sphere in which African Americans may negotiate their historicity, move out of the timelessness of the private into the historicized public. By opening up the traditionally private sphere of the home to the public and turning it into a deeply political place, Morrison redefines home in a way that it does not necessarily conform to the classic view of a closed-off shelter but rather a transient place with flexible boundaries that allows for the formation of liberated individual and communal identities out of (hi)stories of pain and trauma.
One mechanism underlying the acquisition of interpersonal attitudes is the formation of an association between a valenced unconditioned stimulus (US) and an affectively neutral conditioned stimulus (CS). However, a stimulus (e.g., a person) is not always and necessarily perceived to be unambiguously positive or negative. An individual can be negative regarding abstract (trait) information but at the same time display a positive (concrete) behavior. The present research deals with the question of whether the valence of abstract or concrete information about a US is encoded and subsequently transferred to an associated CS. The central assumptions are that the valence of the concrete information is more important for the evaluation of the US, whereas the abstract information is more important for the evaluation of the CS. The rationale behind these assumptions is that the US is a psychologically proximal stimulus because it elicits a more direct affective reaction. The CS, however, is psychologically more distal because it is merely associated with the US and is therefore only experienced indirectly. It is postulated that the associative relation between US and CS constitutes a dimension of psychological distance. In four studies, the valence of abstract and concrete information about a number of USs was manipulated. Within an evaluative learning paradigm, these stimuli were associated with affectively neutral CSs. As predicted, ambivalent USs were evaluated according to the valence of the concrete information. The evaluation of CSs, however, was influenced more strongly by the valence of the abstract information. Moreover, in a subsequent lexical decision task, participants were faster to categorize abstract (vs. concrete) stimuli when the stimuli were preceded by a CS prime as compared to a US prime. The results provide first evidence that perceived psychological distance influences the evaluations of US and CS in an associative evaluative learning paradigm.
Interoception - the perception of bodily processes - plays a crucial role in the subjective experience of emotion, consciousness and symptom genesis. As an alternative to interoceptive paradigms that depend on the participants" active cooperation, five studies are presented to show that startle methodology may be employed to study visceral afferent processing. Study 1 (38 volunteers) showed that startle responses to acoustic stimuli of 105 dB(A) intensity were smaller when elicited during the cardiac systole (R-wave +230 ms) as compared to the diastole (R +530 ms). In Study 2, 31 diabetic patients were divided into two groups with normal or diminished (< 6 ms/mmHg) baroreflex sensitivity (BRS) of heart rate control. Patients with normal BRS showed a startle inhibition during the cardiac systole as was found for healthy volunteers. Diabetic patients with diminished BRS did not show this pattern. Because diminished BRS is an indicator of impaired baro-afferent signal transmission, we concluded that cardiac modulation of startle is associated with intact arterial baro-afferent feedback. Thus, pre-attentive startle methodology is feasible to study visceral afferent processing. rnVisceral- and baro-afferent information has been found to be mainly processed in the right hemisphere. To explore whether cardiac modulation of startle eye blink is lateralized as well, in Study 3, 37 healthy volunteers received 160 unilateral acoustic startle stimuli presented to both ears, one at a time (R +0, 100, 230, 530 ms). Startle response magnitude was only diminished at R +230 ms and for left-ear presentation. This lateralization effect in the cardiac modulation of startle eye blink may reflect the previously described advantages of right-hemispheric brain structures in relaying viscero- and baro-afferent signal transmission. rnThis lateralization effect implies that higher cognitive processes may also play a role in the cardiac modulation of startle. To address this question, in Study 4, 25 volunteers responded first by 'fast as possible' button pushes (reaction time, RT), and second, rated perceived intensity of 60 acoustic startle stimuli (85, 95, or 105 dB; R +230, 530 ms). RT was divided into evaluation and motor response time. Increasing stimulus intensity enhanced startle eye blink, intensity ratings, and RT components. Eye blinks and intensity judgments were lower when startle was elicited at a latency of R +230 ms, but RT components were differentially affected. It is concluded that the cardiac cycle affects the attentive processing of acoustic startle stimuli. rnBeside the arterial baroreceptors, the cardiopulmonary baroreceptors represent another important system of cardiovascular perception that may have similar effects on startle responsiveness. To clarify this issue, in Study 5, Lower Body Negative Pressure at gradients of 0, -10, -20, and -30 mmHg was applied to unload cardiopulmonary baroreceptors in 12 healthy males, while acoustic startle stimuli were presented (R +230, 530 ms). Unloading of cardiopulmonary baroreceptors increased startle eye blink responsiveness. Furthermore, the effect of relative loading/unloading of arterial baroreceptors on startle eye blink responsiveness was replicated. These results demonstrate that the loading status of cardiopulmonary baroreceptors also has an impact on brainstem-based CNS processes. rnThus, the cardiac modulation of acoustic startle is feasible to reflect baro-afferent signal transmission of multiple neural sources, it represents a pre-attentive method that is independent of active cooperation, but its modulatory effects also reach higher cognitive, attentive processes.rn
The thesis studies the question how universal behavior is inherited by the Hadamard product. The type of universality that is considered here is universality by overconvergence; a definition will be given in chapter five. The situation can be described as follows: Let f be a universal function, and let g be a given function. Is the Hadamard product of f and g universal again? This question will be studied in chapter six. Starting with the Hadamard product for power series, a definition for a more general context must be provided. For plane open sets both containing the origin this has already been done. But in order to answer the above question, it becomes necessary to have a Hadamard product for functions that are not holomorphic at the origin. The elaboration of such a Hadamard product and its properties are the second central part of this thesis; chapter three will be concerned with them. The idea of the definition of such a Hadamard product will follow the case already known: The Hadamard product will be defined by a parameter integral. Crucial for this definition is the choice of appropriate integration curves; these will be introduced in chapter two. By means of the Hadamard product- properties it is possible to prove the Hadamard multiplication theorem and the Borel-Okada theorem. A generalization of these theorems will be presented in chapter four.
The catechol-O-methyltransferase gene (COMT) plays a crucial role in the metabolism of catecholamines in the frontal cortex. A single nucleotide polymorphism (Val158Met SNP, rs4680) leads to either methionine (Met) or valine (Val) at codon 158, resulting in a three- to fourfold reduction in COMT activity. The aim of the present study was to assess the COMT Val158Met SNP as a risk factor for attention-deficit/hyperactivity disorder (ADHD), ADHD symptom severity and co-morbid conduct disorder (CD) in 166 children with ADHD. The main finding of the present study is that the Met allele of the COMT Val158Met SNP was associated with ADHD and increased ADHD symptom severity. No association with co-morbid CD was observed. In addition, ADHD symptom severity and early adverse familial environment were positive predictors of lifetime CD. These findings support previous results implicating COMT in ADHD symptom severity and early adverse familial environment as risk factors for co-morbid CD, emphasizing the need for early intervention to prevent aggressive and maladaptive behavior progressing into CD, reducing the overall severity of the disease burden in children with ADHD.
The reduction of information contained in model time series through the use of aggregating statistical performance measures is very high compared to the amount of information that one would like to draw from it for model identification and calibration purposes. It is readily known that this loss imposes important limitations on model identification and -diagnostics and thus constitutes an element of the overall model uncertainty as essentially different model realizations with almost identical performance measures (e.g. r-² or RMSE) can be generated. In three consecutive studies the present work proposes an alternative approach towards hydrological model evaluation based on the application of Self-Organizing Maps (SOM; Kohonen, 2001). The Self-Organizing Map is a type of artificial neural network and unsupervised learning algorithm that is used for clustering, visualization and abstraction of multidimensional data. It maps vectorial input data items with similar patterns onto contiguous locations of a discrete low-dimensional grid of neurons. The iterative training of the SOM causes the neurons to form a discrete, data-compressed representation of the high-dimensional input data. Using appropriate visualization techniques, information on distributions, patterns and relationships in complex data sets can be extracted. Irrespective of their potential, SOM applications have earned very little attention in hydrological modelling compared to other artificial neural network techniques. Therefore, the aim of the present work is to demonstrate that the application of Self-Organizing Maps has very high potential to address fundamental issues of model evaluation: It is shown that the clustering and classification of model time series by means of SOM can provide useful insights into model behaviour. In combination with the diagnostic properties of Signature Indices (Gupta et al., 2008; Yilmaz et al., 2008) SOM provides a novel tool for interpreting the model parameters in the hydrological context and identifying parameter sets that simultaneously meet multiple objectives, even if the corresponding model realizations belong to different models. Moreover, the presented studies and reviews also encourage further studies on the application of SOM in hydrological modelling.
This thesis presents a study of tsunami deposits created by the 2004 Indian Ocean tsunami at the Thai Andaman coast. The outcomes of a study are the characteristics of tsunami deposit for paleo-tsunami database, the identification of major sediment layers in tsunami deposit and the reconstructing tsunami run-ups from the characteristics of tsunami deposit for a coastal development program. The investigations of tsunami deposit are made almost 3 years after the event. Field investigations characterize the tsunami deposit as a distinct sediment layer variable in thickness of gray sand deposited with an erosional basis on a pre-existing soil. The best location for the observation of recent tsunami deposit is the area located about 50-200 m inland from the coastline. In most cases, the deposit layer is normally graded. In some cases, the deposit contains rip-up clasts of muddy soils and/or organic matters. The tsunami deposits are compared with three deposits from coastal sub-environments. The mean grain-size and standard deviation of deposits show that the shoreface deposits are fine to very fine sand, poorly to moderately well sorted; the swash zone deposits are coarse to fine sand, poorly to well sorted; the berm/dune deposits are medium to fine sand, poorly to well sorted; and the tsunami deposits are coarse to very fine sand, poorly to moderately well sorted. The plots of deposit mean grain-size versus sorting indicate that the tsunami deposits are composed of shoreface deposits, swash zone deposits and berm/dune deposits as well. The vertical variation of the texture of tsunami deposit shows that the mean grain-size fines upward and fining landward. The analysis and interpretation of the run-up numbers from the characteristics of tsunami deposits get three run-ups for the 2004 Indian Ocean tsunami at the Thai Andaman coast. It corresponds to field observations from the eye-witness reports and local people- affirmations. The total deposition is a major transportation pattern of onshore tsunami sediments. The sediments must fine in the direction of transport. In general, the major origins of the sediment are the swash zone and berm/dune zone where coarse to medium sand is a significant material, the minor origin of tsunami sediment is a shoreface where a significant material is fine to very fine sand. Only at an area with flat slope shorface, the major origin of tsunami sediment is the shoreface. The thicknesses, the mean grain-sizes, and the standard deviations of tsunami deposits are used to evaluate the influences of coastal morphology on the sediment characteristics. The evaluations show that the tsunami affected areas were attacked by the variable energy waves. Wave energies at the direct tsunami wave affected areas are higher than at the indirect tsunami wave affected areas. Tsunami wave energy is highly dissipated at an area with steep slope shoreface. In the same way, tsunami run-up energy is highly dissipated at an area with steep slope onshore. A channel paralleled to the coastline decreases the run-up velocity, slightly dissipates run-up energy. The road and pond highly influence the characteristics of tsunami deposit and tsunami run-up. A road obstructs the run-up velocity, dissipates run-up energy. A pond decreases run-up velocity, dissipates run-up energy. The characteristics of tsunami deposit can be interpreted for reconstructing the characteristics of tsunami run-up such as a run-up height and a flow velocity. Soulsby et al.(2007)- model is applied for reconstructing tsunami run-up at the study areas. The input parameters are sediment grain-size and sediment inundation distance. Ao Kheuy beach and Khuk Khak beach, Phang Nga province, Thailand are the areas listed for reconstructing tsunami run-up. The evaluated run-up heights are 4.2-4.9 m at Ao Kheuy beach, and 5.4-9.4 m at Khuk Khak beach. The evaluated run-up velocities are 12.8-19.2 m/s (maximum) and 0.2-1.9 m/s (mean) at the coastline and onshore, respectively. Hence, a reasonably good agreement between the evaluated and observed run-up is found. Tsunami run-up height and velocity can be used for coastal development and risk management in the tsunami affected areas. The case studies from the Thai Andaman coast suggest that in the area from coastline to about 70-140 m inland was flooded by the high velocity (high energy) run-ups, and those run-up energies were dissipated there. That area ought to be a non-residential area or a physical protection construction area (flood barrier, forest planting, etc.).
During and after application, pesticides enter the atmosphere by volatilisation and by wind erosion of particles on which the pesticide is sorbed. Measurements at application sites revealed that sometimes more than half of the amount applied is lost into the atmosphere within a few days. The atmosphere is an important part of the hydrologic cycle that can transport pesticides from their point of application and deposit them into aquatic and terrestrial ecosystems far from their point of use. In the region of Trier pesticides are widely used. In order to protect crops from pests and increase crop yields in the viniculture, six to eight pesticide applications take place between May and August. The impact that these applications have on the environmental pollution of the region is not yet well understood. The present study was developed to characterize the atmospheric presence, temporal patterns, transport and deposition of a variety of pesticides in the atmosphere of the area of Trier. To this purpose, rain samples were weekly collected at eight sites during the growing seasons 2000, 2001 and 2002, and air samples (gas and particle phases) were collected during the growing season 2002. Multiresidue analysis methods were developed to determine multiple classes of pesticides in rain water, particle- and gas-phase samples. Altogether 24 active ingredients and 3 metabolites were chosen as representative substances, focussing mainly on fungicides. Twenty-four of the 27 measured pesticides were detected in the rain samples; seventeen pesticides were detected in the air samples. The most frequently detected pesticides and at the highest concentrations, both in rain and air, were compounds belonging to the class of fungicides. The insecticide methyl parathion was also detected in several rain samples as well as two substances that are banned in Germany, such as the herbicides atrazine and simazine. Concentration levels varied during the growing season with the highest concentrations being measured in the late spring and summer months, coinciding with application times and warmer months. Concentration levels measured in the rain samples were, generally, in the order of rnng l-1. Though average concentrations for single substances were less than 100 ng l-1, total concentrations were considerable and in some instances well above the EU drinking water quality standard of 500 ng l-1 for total pesticides. Compared to the amounts applied for pest control, the amounts deposited by rain resulted between 0,004% and 0,10% of the maximum application rates. These low pesticide inputs from precipitation to surface-water bodies is not of concern in vinicultural areas where the impact of other sources, such as superficial runoff inputs from the treated areas and cleaning of field crop sprayers, is more important. However, the potential impacts of these aerial pesticide inputs to non-target sites, such as organic crops, and sensitive ecosystems are as yet not known. Concentration levels in the air samples were in the order of ng m-3 at sites close to the fields were pesticides were applied, while lower values, in the order of pg m-3, were detected at the site located further away from fields where applications were performed. The measured air concentration levels found in this study do not represent a concern for human health in terms of acute risk. Inhalation toxicity studies have shown that an acute potential risk only arises at air concentrations in the range of g m-3. Finally, it must be kept in mind that only a small number of chemicals that were applied in the area were analysed for in this study. In order to gain a better evaluation of the local atmospheric load of pesticides, a wider spectrum of applied substances (including metabolites) needs to be investigated.
For the first time, the German Census 2011 will be conducted via a new method the register based census. In contrast to a traditional census, where all inhabitants are surveyed, the German government will mainly attempt to count individuals using population registers of administrative authorities, such as the municipalities and the Federal Employment Agency. Census data that cannot be collected from the registers, such as information on education, training, and occupation, will be collected by an interview-based sample survey. Moreover, the new method reduces citizens' obligations to provide information and helps reduce costs significantly. The use of sample surveys is limited if results with a detailed regional or subject-matter breakdown have to be prepared. Classical estimation methods are sometimes criticized, since estimation is often problematic for small samples. Fortunately, model based small area estimators serve as an alternative. These methods help to increase the information, and hence the effective sample size. In the German Census 2011 it is possible to embed areas on a map in a geographical context. This may offer additional information, such as neighborhood relations or spatial interactions. Standard small area models, like Fay-Herriot or Battese-Harter-Fuller, do not account for such interactions explicitly. The aim of our work is to extend the classical models by integrating the spatial information explicitly into the model. In addition, the possible gain in efficiency will be analyzed.
Stress and pain are common experiences in human lives. Both, the stress and the pain system have adaptive functions and try to protect the organism in case of harm and danger. However, stress and pain are two of the most challenging problems for the society and the health system. Chronic stress, as often seen in modern societies, has much impact on health and can lead to chronic stress disorders. These disorders also include a number of chronic pain syndromes. However, pain can also be regarded as a stressor itself, especially when we consider how much patients suffer from long-lasting pain and the impact of pain on life quality. In this way, the effects of stress on pain can be fostered. For the generation and manifestation of chronic pain symptoms also learning processes such as classical conditioning play an important role. Processes of classical conditioning can also be influenced by stress. These facts illustrate the complex and various interactions between the pain and the stress systems. Both systems communicate permanently with each other and help to protect the organism and to keep a homeostatic state. They have various ways of communication, for example mechanisms related to endogenous opioids, immune parameters, glucocorticoids and baroreflexes. But an overactivation of the systems, for example caused by ongoing stress, can lead to severe health problems. Therefore, it is of great importance to understand these interactions and their underlying mechanisms. The present work deals with the relationship of stress and pain. A special focus is put on stress related hypocortisolism and pain processing, stress induced hypoalgesia via baroreceptor related mechanisms and stress related cortisol effects on aversive conditioning (as a model of pain learning). This work is a contribution to the wide field of research that tries to understand the complex interactions of stress and pain. To demonstrate the variety, the selected studies highlight different aspects of these interactions. In the first chapter I will give a short introduction on the pain and the stress systems and their ways of interaction. Furthermore, I will give a short summary of the studies presented in Chapter II to V and their background. The results and their meaning for future research will be discussed in the last part of the first chapter. Chronic pain syndromes have been associated with chronic stress and alterations of the HPA axis resulting in chronic hypocortisolism. But if these alterations may play a causal role in the pathophysiology of chronic pain remains unclear. Thus, the study described in Chapter II investigated the effects of pharmacological induced hypocortisolism on pain perception. Both, the stress and the pain system are related to the cardiovascular system. Increase of blood pressure is part of the stress reaction and leads to reduced pain perception. Therefore, it is important for the usage of pain tests to keep in mind potential interferences from activation of the cardiovascular system, especially when pain inhibitory processes are investigated. For this reason we compared two commonly and interchangeably used pain tests with regard to the triggered autonomic reactions. This study is described in chapter III. Chapter IV and V deal with the role of learning processes in pain and related influences of stress. Processes of classical conditioning play an important role for symptom generation and manifestation. In both studies aversive eyeblink conditioning was used as a model for pain learning. In the study described in Chapter IV we compared classical eyeblink conditioning in healthy volunteers to patients suffering from fibromyalgia, a chronic pain disorder. Also, differences of the HPA axis, as part of the stress system, were taken in account. The study of Chapter V investigated effects of the very first stress reaction, particularly rapid non-genomic cortisol effects. Healthy volunteers received an intravenous cortisol administration immediately before the eyeblink conditioning. Rapid effects have only been demonstrated on a cellular level and on animal behavior so far. In general, the studies presented in this work may give an impression of the broad variety of possible interactions between the pain and the stress system. Furthermore, they contribute to our knowledge about theses interactions. However, more research is needed to complete the picture.
The subject of this thesis is a homological approach to the splitting theory of PLS-spaces, i.e. to the question for which topologically exact short sequences 0->X->Y->Z->0 of PLS-spaces X,Y,Z the right-hand map admits a right inverse. We show that the category (PLS) of PLS-spaces and continuous linear maps is an additive category in which every morphism admits a kernel and a cokernel, i.e. it is pre-abelian. However, we also show that it is neither quasi-abelian nor semi-abelian. As a foundation for our homological constructions we show the more general result that every pre-abelian category admits a largest exact structure in the sense of Quillen. In the pre-abelian category (PLS) this exact structure consists precisely of the topologically exact short sequences of PLS-spaces. Using a construction of Ext-functors due to Yoneda, we show that one can define for each PLS-space A and every natural number k the k-th abelian-group valued covariant and contravariant Ext-functors acting on the category (PLS) of PLS-spaces, which induce for every topologically exact short sequence of PLS-spaces a long exact sequence of abelian groups and group morphisms. These functors are studied in detail and we establish a connection between the Ext-functors of PLS-spaces and the Ext-functors for LS-spaces. Through this connection we arrive at an analogue of a result for Fréchet spaces which connects the first derived functor of the projective limit with the first Ext-functor and also gives sufficient conditions for the vanishing of the higher Ext-functors. Finally, we show that Ext^k(E,F) = 0 for a k greater or equal than 1, whenever E is a closed subspace and F is a Hausdorff-quotient of the space of distributions, which generalizes a result of Wengenroth that is itself a generalization of results due to Domanski and Vogt.
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.
This thesis introduces a calibration problem for financial market models based on a Monte Carlo approximation of the option payoff and a discretization of the underlying stochastic differential equation. It is desirable to benefit from fast deterministic optimization methods to solve this problem. To be able to achieve this goal, possible non-differentiabilities are smoothed out with an appropriately chosen twice continuously differentiable polynomial. On the basis of this so derived calibration problem, this work is essentially concerned about two issues. First, the question occurs, if a computed solution of the approximating problem, derived by applying Monte Carlo, discretizing the SDE and preserving differentiability is an approximation of a solution of the true problem. Unfortunately, this does not hold in general but is linked to certain assumptions. It will turn out, that a uniform convergence of the approximated objective function and its gradient to the true objective and gradient can be shown under typical assumptions, for instance the Lipschitz continuity of the SDE coefficients. This uniform convergence then allows to show convergence of the solutions in the sense of a first order critical point. Furthermore, an order of this convergence in relation to the number of simulations, the step size for the SDE discretization and the parameter controlling the smooth approximation of non-differentiabilites will be shown. Additionally the uniqueness of a solution of the stochastic differential equation will be analyzed in detail. Secondly, the Monte Carlo method provides only a very slow convergence. The numerical results in this thesis will show, that the Monte Carlo based calibration indeed is feasible if one is concerned about the calculated solution, but the required calculation time is too long for practical applications. Thus, techniques to speed up the calibration are strongly desired. As already mentioned above, the gradient of the objective is a starting point to improve efficiency. Due to its simplicity, finite differences is a frequently chosen method to calculate the required derivatives. However, finite differences is well known to be very slow and furthermore, it will turn out, that there may also occur severe instabilities during optimization which may lead to the break down of the algorithm before convergence has been reached. In this manner a sensitivity equation is certainly an improvement but suffers unfortunately from the same computational effort as the finite difference method. Thus, an adjoint based gradient calculation will be the method of choice as it combines the exactness of the derivative with a reduced computational effort. Furthermore, several other techniques will be introduced throughout this thesis, that enhance the efficiency of the calibration algorithm. A multi-layer method will be very effective in the case, that the chosen initial value is not already close to the solution. Variance reduction techniques are helpful to increase accuracy of the Monte Carlo estimator and thus allow for fewer simulations. Storing instead of regenerating the random numbers required for the Brownian increments in the SDE will be efficient, as deterministic optimization methods anyway require to employ the identical random sequence in each function evaluation. Finally, Monte Carlo is very well suited for a parallelization, which will be done on several central processing units (CPUs).
Stress is a common phenomenon for animals living in the wild, but also for humans in modern societies. Originally, the body's stress response is an adaptive reaction to a possibly life-threatening situation, and it has been shown to impact on energy distribution and metabolism, thereby increasing the chance of survival. However, stress has also been shown to impact on mating behaviour and reproductive strategies in animals and humans. This work deals with the effect of stress on reproductive behavior. Up to now, research has only focused on the effects of stress on reproduction in general. The effects of stress on reproduction may be looked at from two points of view. First, stress affects reproductive functioning by endocrine (e.g. glucocorticoid) actions on the reproductive system. However, stress can also influence reproductive behavior, i.e. mate choice and mating preferences. Animals and humans do not mate randomly, but exhibit preferences towards mating partners. One factor by which animals and humans choose their mating partners is similarity vs. dissimilarity: Similar mates usually carry more of one's own genes and the cooperation between similar mates is, at least theoretically, less hampered by expressing diverse behaviors. By mating with dissimilar mates on the other hand one may acquire new qualities for oneself, but also for one's offspring, useful to cope with environmental challenge. In humans we usually find a preference for similar mates. Due to the high costs of breeding, variables like cooperation and life-long partnerships may play a greater role than the acquaintance of new qualities.The present work focuses on stress effects on mating preferences of humans and will give a first answer to the question whether stress may affect our preference for similar mates. Stress and mating preferences are at the centre of this work. Thus, in the first Chapter I will give an introduction on stress and mating preferences and link these topics to each other. Furthermore, I will give a short summary of the studies described in Chapter II - Chapter IV and close the chapter with a general discussion of the findings and directions for further research on stress and mating preferences. Human mating behavior is complex, and many aspects of it may not relate to biology but social conventions and education. This work will not focus on those aspects but rather on cognitive and affective processing of erotic and sexually-relevant stimuli, since we assume that these aspects of mating behaviour are likely related to psychobiological stress mechanisms. Therefore, a paradigm is needed that measures such aspects of mating preferences in humans. The studies presented in Chapter II and Chapter III were performed in order to develop such a paradigm. In these studies we show that affective startle modulation may be used to indicate differences in sexual approach motivation to potential mating partners with different similarity levels to the participant. In Chapter IV, I will describe a study that aimed to investigate the effects of stress on human mating preferences. We showed that stress reverses human mating preferences: While unstressed individuals show a preference for similar mates, stressed individuals seem to prefer dissimilar mates. Overall, the studies presented in this work showed that affective startle modulation can be employed to measure mating preferences in humans and that these mating preferences are influenced by stress.
We are living in a connected world, surrounded by interwoven technical systems. Since they pervade more and more aspects of our everyday lives, a thorough understanding of the structure and dynamics of these systems is becoming increasingly important. However - rather than being blueprinted and constructed at the drawing board - many technical infrastructures like for example the Internet's global router network, the World Wide Web, large scale Peer-to-Peer systems or the power grid - evolve in a distributed fashion, beyond the control of a central instance and influenced by various surrounding conditions and interdependencies. Hence, due to this increase in complexity, making statements about the structure and behavior of tomorrow's networked systems is becoming increasingly complicated. A number of failures has shown that complex structures can emerge unintentionally that resemble those which can be observed in biological, physical and social systems. In this dissertation, we investigate how such complex phenomena can be controlled and actively used. For this, we review methodologies stemming from the field of random and complex networks, which are being used for the study of natural, social and technical systems, thus delivering insights into their structure and dynamics. A particularly interesting finding is the fact that the efficiency, dependability and adaptivity of natural systems can be related to rather simple local interactions between a large number of elements. We review a number of interesting findings about the formation of complex structures and collective dynamics and investigate how these are applicable in the design and operation of large scale networked computing systems. A particular focus of this dissertation are applications of principles and methods stemming from the study of complex networks in distributed computing systems that are based on overlay networks. Here we argue how the fact that the (virtual) connectivity in such systems is alterable and widely independent from physical limitations facilitates a design that is based on analogies between complex network structures and phenomena studied in statistical physics. Based on results about the properties of scale-free networks, we present a simple membership protocol by which scale-free overlay networks with adjustable degree distribution exponent can be created in a distributed fashion. With this protocol we further exemplify how phase transition phenomena - as occurring frequently in the domain of statistical physics - can actively be used to quickly adapt macroscopic statistical network parameters which are known to massively influence the stability and performance of networked systems. In the case considered in this dissertation, the adaptation of the degree distribution exponent of a random, scale-free overlay allows - within critical regions - a change of relevant structural and dynamical properties. As such, the proposed scheme allows to make sound statements about the relation between the local behavior of individual nodes and large scale properties of the resulting complex network structures. For systems in which the degree distribution exponent cannot easily be derived for example from local protocol parameters, we further present a distributed, probabilistic mechanism which can be used to monitor a network's degree distribution exponent and thus to reason about important structural qualities. Finally, the dissertation shifts its focus towards the study of complex, non-linear dynamics in networked systems. We consider a message-based protocol which - based on the Kuramoto model for coupled oscillators - achieves a stable, global synchronization of periodic heartbeat events. The protocol's performance and stability is evaluated in different network topologies. We further argue that - based on existing findings about the interrelation between spectral network properties and the dynamics of coupled oscillators - the proposed protocol allows to monitor structural properties of networked computing systems. An important aspect of this dissertation is its interdisciplinary approach towards a sensible and constructive handling of complex structures and collective dynamics in networked systems. The associated investigation of distributed systems from the perspective of non-linear dynamics and statistical physics highlights interesting parallels both to biological and physical systems. This foreshadows systems whose structures and dynamics can be analyzed and understood in the conceptual frameworks of statistical physics and complex systems.
Aggression is one of the most researched topics in psychology. This is understandable, since aggression behavior does a lot of harm to individuals and groups. A lot is known already about the biology of aggression, but one system that seems to be of vital importance in animals has largely been overlooked: the hypothalamic-pituitary-adrenal (HPA) axis. Menno Kruk and Jószef Haller and their research teams developed rodent models of adaptive, normal, and abnormal aggressive behavior. They found the acute HPA axis (re)activity, but also chronic basal levels to be causally relevant in the elicitation and escalation of aggressive behavior. As a mediating variable, changes in the processing of relevant social information is proposed, although this could not be tested in animals. In humans, not a lot of research has been done, but there is evidence for both the association between acute and basal cortisol levels in (abnormal) aggression. However, not many of these studies have been experimental of nature. rnrnOur aim was to add to the understanding of both basal chronic levels of HPA axis activity, as well as acute levels in the formation of aggressive behavior. Therefore, we did two experiments, both with healthy student samples. In both studies we induced aggression with a well validated paradigm from social psychology: the Taylor Aggression Paradigm. Half of the subjects, however, only went through a non-provoking control condition. We measured trait basal levels of HPA axis activity on three days prior. We took several cortisol samples before, during, and after the task. After the induction of aggression, we measured the behavioral and electrophysiological brain response to relevant social stimuli, i.e., emotional facial expressions embedded in an emotional Stroop task. In the second study, we pharmacologically manipulated cortisol levels 60min before the beginning of the experiment. To do that, half of the subjects were administered 20mg of hydrocortisone, which elevates circulating cortisol levels (cortisol group), the other half was administered a placebo (placebo group). Results showed that acute HPA axis activity is indeed relevant for aggressive behavior. We found in Study 1 a difference in cortisol levels after the aggression induction in the provoked group compared to the non-provoked group (i.e., a heightened reactivity of the HPA axis). However, this could not be replicated in Study 2. Furthermore, the pharmacological elevation of cortisol levels led to an increase in aggressive behavior in women compared to the placebo group. There were no effects in men, so that while men were significantly more aggressive than women in the placebo group, they were equally aggressive in the cortisol group. Furthermore, there was an interaction of cortisol treatment with block of the Taylor Aggression Paradigm, in that the cortisol group was significantly more aggressive in the third block of the task. Concerning basal HPA axis activity, we found an effect on aggressive behavior in both studies, albeit more consistently in women and in the provoked and non-provoked groups. However, the effect was not apparent in the cortisol group. After the aggressive encounter, information processing patterns were changed in the provoked compared to the non-provoked group for all facial expressions, especially anger. These results indicate that the HPA axis plays an important role in the formation of aggressive behavior in humans, as well. Importantly, different changes within the system, be it basal or acute, are associated with the same outcome in this task. More studies are needed, however, to better understand the role that each plays in different kinds of aggressive behavior, and the role information processing plays as a possible mediating variable. This extensive knowledge is necessary for better behavioral interventions.
Recently, optimization has become an integral part of the aerodynamic design process chain. However, because of uncertainties with respect to the flight conditions and geometrical uncertainties, a design optimized by a traditional design optimization method seeking only optimality may not achieve its expected performance. Robust optimization deals with optimal designs, which are robust with respect to small (or even large) perturbations of the optimization setpoint conditions. The resulting optimization tasks become much more complex than the usual single setpoint case, so that efficient and fast algorithms need to be developed in order to identify, quantize and include the uncertainties in the overall optimization procedure. In this thesis, a novel approach towards stochastic distributed aleatory uncertainties for the specific application of optimal aerodynamic design under uncertainties is presented. In order to include the uncertainties in the optimization, robust formulations of the general aerodynamic design optimization problem based on probabilistic models of the uncertainties are discussed. Three classes of formulations, the worst-case, the chance-constrained and the semi-infinite formulation, of the aerodynamic shape optimization problem are identified. Since the worst-case formulation may lead to overly conservative designs, the focus of this thesis is on the chance-constrained and semi-infinite formulation. A key issue is then to propagate the input uncertainties through the systems to obtain statistics of quantities of interest, which are used as a measure of robustness in both robust counterparts of the deterministic optimization problem. Due to the highly nonlinear underlying design problem, uncertainty quantification methods are used in order to approximate and consequently simplify the problem to a solvable optimization task. Computationally demanding evaluations of high dimensional integrals resulting from the direct approximation of statistics as well as from uncertainty quantification approximations arise. To overcome the curse of dimensionality, sparse grid methods in combination with adaptive refinement strategies are applied. The reduction of the number of discretization points is an important issue in the context of robust design, since the computational effort of the numerical quadrature comes up in every iteration of the optimization algorithm. In order to efficiently solve the resulting optimization problems, algorithmic approaches based on multiple-setpoint ideas in combination with one-shot methods are presented. A parallelization approach is provided to overcome the amount of additional computational effort involved by multiple-setpoint optimization problems. Finally, the developed methods are applied to 2D and 3D Euler and Navier-Stokes test cases verifying their industrial usability and reliability. Numerical results of robust aerodynamic shape optimization under uncertain flight conditions as well as geometrical uncertainties are presented. Further, uncertainty quantification methods are used to investigate the influence of geometrical uncertainties on quantities of interest in a 3D test case. The results demonstrate the significant effect of uncertainties in the context of aerodynamic design and thus the need for robust design to ensure a good performance in real life conditions. The thesis proposes a general framework for robust aerodynamic design attacking the additional computational complexity of the treatment of uncertainties, thus making robust design in this sense possible.
Large scale non-parametric applied shape optimization for computational fluid dynamics is considered. Treating a shape optimization problem as a standard optimal control problem by means of a parameterization, the Lagrangian usually requires knowledge of the partial derivative of the shape parameterization and deformation chain with respect to input parameters. For a variety of reasons, this mesh sensitivity Jacobian is usually quite problematic. For a sufficiently smooth boundary, the Hadamard theorem provides a gradient expression that exists on the surface alone, completely bypassing the mesh sensitivity Jacobian. Building upon this, the gradient computation becomes independent of the number of design parameters and all surface mesh nodes are used as design unknown in this work, effectively allowing a free morphing of shapes during optimization. Contrary to a parameterized shape optimization problem, where a smooth surface is usually created independently of the input parameters by construction, regularity is not preserved automatically in the non-parametric case. As part of this work, the shape Hessian is used in an approximative Newton method, also known as Sobolev method or gradient smoothing, to ensure a certain regularity of the updates, and thus a smooth shape is preserved while at the same time the one-shot optimization method is also accelerated considerably. For PDE constrained shape optimization, the Hessian usually is a pseudo-differential operator. Fourier analysis is used to identify the operator symbol both analytically and discretely. Preconditioning the one-shot optimization by an appropriate Hessian symbol is shown to greatly accelerate the optimization. As the correct discretization of the Hadamard form usually requires evaluating certain surface quantities such as tangential divergence and curvature, special attention is also given to discrete differential geometry on triangulated surfaces for evaluating shape gradients and Hessians. The Hadamard formula and Hessian approximations are applied to a variety of flow situations. In addition to shape optimization of internal and external flows, major focus lies on aerodynamic design such as optimizing two dimensional airfoils and three dimensional wings. Shock waves form when the local speed of sound is reached, and the gradient must be evaluated correctly at discontinuous states. To ensure proper shock resolution, an adaptive multi-level optimization of the Onera M6 wing is conducted using more than 36, 000 shape unknowns on a standard office workstation, demonstrating the applicability of the shape-one-shot method to industry size problems.
This work addresses the algorithmic tractability of hard combinatorial problems. Basically, we are considering \NP-hard problems. For those problems we can not find a polynomial time algorithm. Several algorithmic approaches already exist which deal with this dilemma. Among them we find (randomized) approximation algorithms and heuristics. Even though in practice they often work in reasonable time they usually do not return an optimal solution. If we constrain optimality then there are only two methods which suffice for this purpose: exponential time algorithms and parameterized algorithms. In the first approach we seek to design algorithms consuming exponentially many steps who are more clever than some trivial algorithm (who simply enumerates all solution candidates). Typically, the naive enumerative approach yields an algorithm with run time $\Oh^*(2^n)$. So, the general task is to construct algorithms obeying a run time of the form $\Oh^*(c^n)$ where $c<2$. The second approach considers an additional parameter $k$ besides the input size $n$. This parameter should provide more information about the problem and cover a typical characteristic. The standard parameterization is to see $k$ as an upper (lower, resp.) bound on the solution size in case of a minimization (maximization, resp.) problem. Then a parameterized algorithm should solve the problem in time $f(k)\cdot n^\beta$ where $\beta$ is a constant and $f$ is independent of $n$. In principle this method aims to restrict the combinatorial difficulty of the problem to the parameter $k$ (if possible). The basic hypothesis is that $k$ is small with respect to the overall input size. In both fields a frequent standard technique is the design of branching algorithms. These algorithms solve the problem by traversing the solution space in a clever way. They frequently select an entity of the input and create two new subproblems, one where this entity is considered as part of the future solution and another one where it is excluded from it. Then in both cases by fixing this entity possibly other entities will be fixed. If so then the traversed number of possible solution is smaller than the whole solution space. The visited solutions can be arranged like a search tree. To estimate the run time of such algorithms there is need for a method to obtain tight upper bounds on the size of the search trees. In the field of exponential time algorithms a powerful technique called Measure&Conquer has been developed for this purpose. It has been applied successfully to many problems, especially to problems where other algorithmic attacks could not break the trivial run time upper bound. On the other hand in the field of parameterized algorithms Measure&Conquer is almost not known. This piece of work will present examples where this technique can be used in this field. It also will point out what differences have to be made in order to successfully apply the technique. Further, exponential time algorithms for hard problems where Measure&Conquer is applied are presented. Another aspect is that a formalization (and generalization) of the notion of a search tree is given. It is shown that for certain problems such a formalization is extremely useful.
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.
Mechanical and Biological Treatment (MBT) generally aims to reduce the amount of solid waste and emissions in landfills and enhance the recoveries. MBT technology has been studied in various countries in Europe and Asia. Techniques of solid waste treatment are distinctly different in the study areas. A better understanding of MBT waste characteristics can lead to an optimization of the MBT technology. For a sustainable waste management, it is essential to determine the characteristics of the final MBT waste, the effectiveness of the treatment system as well as the potential application of the final material regarding future utilization. This study aims to define and compare the characteristics of the final MBT materials in the following countries: Luxembourg (using a high degree technology), Fridhaff in Diekirch/Erpeldange, Germany (using a well regulated technology), Singhofen in Rhein-Lahn district, Thailand (using a low cost technology): Phitsanulok in Phitsanulok province. The three countries were chosen for this comparative study due to their unique performance in the MBT implementation. The samples were taken from the composting heaps of the final treatment process prior to sending them to landfills, using a random sampling standard strategy from August 2008 onwards. The size of the sample was reduced to manageable sizes before characterization. The size reduction was achieved by the quartering method. The samples were first analyzed for the size fraction on the day of collection. They were screened into three fractions by the method of dry sieving: small size with a diameter of <10 mm, medium size with a diameter of 10-40 mm and large size with a diameter of >40 mm. These fractions were further analyzed for their physical and chemical parameters such as particle size distribution (total into 12 size fractions), particle shape, porosity, composition, water content, water retention capacity and respiratory activity. The extracted eluate was analyzed for pH-value, heavy metals (lead, cadmium and arsenic), chemical oxygen demand, ammonium, sulfate and chloride. In order to describe and evaluate the potential application of the small size material as a final cover of landfills, the fraction of small size samples were tested for the geotechnical properties as well. The geotechnical parameters were the compaction test, permeability test and shear strength test. The detailed description of the treatment facilities and methods of the study areas were included in the results. The samples from the three countries are visibly smaller than waste without pretreatment. Maximum particle size is found to be less than 100 mm. The samples are found to consist of dust to coarse fractions. The small size with a diameter of <10 mm was highest in the sample from Germany (average 60% by weight), secondly in the sample from Luxembourg (average 43% by weight) and lowest in the sample from Thailand (average 15% by weight). The content of biodegradable material generally increased with decreasing particle sizes. Primary components are organic, plastics, fibrous materials and inert materials (glass and ceramics). The percentage of each components greatly depends on the MBT process of each country. Other important characteristics are significantly reduced water content, reduced total organic carbon and reduced potential heavy metals. The geotechnical results show that the small fraction is highly compact, has a low permeability and lot of water adsorbed material. The utilization of MBT material in this study shows a good trend as it proved to be a safe material which contained very low amounts of loadings and concentrations of chemical oxygen demand, ammonium, and heavy metals. The organic part can be developed to be a soil conditioner. It is also suitably utilized as a bio-filter layer in the final cover of landfill or as a temporary cover during the MBT process. This study showed how to identify the most appropriate technology for municipal solid waste disposal through the study of waste characterization.
N-acetylation by N-acetyltransferase 1 (NAT1) is an important biotransformation pathway of the human skin and it is involved in the deactivation of the arylamine and well-known contact allergen para-phenylenediamine (PPD). Here, NAT1 expression and activity were analyzed in antigen presenting cells (monocyte-derived dendritic cells, MoDCs, a model for epidermal Langerhans cells) and human keratinocytes. The latter were used to study exogenous and endogenous NAT1 activity modulations. Within this thesis, MoDCs were found to express metabolically active NAT1. Activities were between 23.4 and 26.6 nmol/mg/min and thus comparable to peripheral blood mononuclear cells. These data suggest that epidermal Langerhans cells contribute to the cutaneous N-acetylation capacity. Keratinocytes, which are known for their efficient N-acetylation, were analyzed in a comparative study using primary keratinocytes (NHEK) and different shipments of the immortalized keratinocyte cell line HaCaT, in order to investigate the ability of the cell line to model epidermal biotransformation. N-acetylation of the substrate para-aminobenzoic acid (PABA) was 3.4-fold higher in HaCaT compared to NHEK and varied between the HaCaT shipments (range 12.0"44.5 nmol/mg/min). Since B[a]P induced cytochrome p450 1 (CYP1) activities were also higher in HaCaT compared to NHEK, the cell line can be considered as an in vitro tool to qualitatively model epidermal metabolism, regarding NAT1 and CYP1. The HaCaT shipment with the highest NAT1 activity showed only minimal reduction of cell viability after treatment with PPD and was subsequently used to study interactions between NAT1 and PPD in keratinocytes. Treatment with PPD induced expression of cyclooxygenases (COX) in HaCaT, but in parallel, PPD N-acetylation was found to saturate with increasing PPD concentration. This saturation explains the presence of the PPD induced COX induction despite the high N-acetylation capacities. A detailed analysis of the effect of PPD on NAT1 revealed that the saturation of PPD N-acetylation was caused by a PPD-induced decrease of NAT1 activity. This inhibition was found in HaCaT as well as in primary keratinocytes after treatment with PPD and PABA. Regarding the mechanism, reduced NAT1 protein level and unaffected NAT1 mRNA expression after PPD treatment adduced clear evidences for substrate-dependent NAT1 downregulation. These results expand the existing knowledge about substrate-dependent NAT1 downregulation to human epithelial skin cells and demonstrate that NAT1 activity in keratinocytes can be modulated by exogenous factors. Further analysis of HaCaT cells from different shipments revealed an accelerated progression through the cell cycle in HaCaT cells with high NAT1 activities. These findings suggest an association between NAT1 and proliferation in keratinocytes as it has been proposed earlier for tumor cells. In conclusion, N-acetylation capacity of MoDCs as well as keratinocytes contribute to the overall N-acetylation capacity of human skin. NAT1 activity of keratinocytes and consequently the detoxification capacities of human skin can be modulated by the presence of exogenous NAT1 substrates and endogenous by the cell proliferation status of keratinocytes.
The overall objective of this thesis was to gain a deeper understanding of the antecedents, processes, and manifestations of uniqueness-driven consumer behavior. To achieve this goal, five studies have been conducted in Germany and Switzerland with a total of 1048 participants across different demographic and socio-economic backgrounds. Two concepts were employed in all studies: Consumer need for uniqueness (CNFU) and general uniqueness perception (GUP). CNFU (Tian, Bearden, & Hunter, 2001), a mainly US"based consumer research concept, measures the individual need, and thus the motivation to acquire, use, and dispose consumer goods in order to develop a unique image. GUP, adapted from the two-component theory of individuality (Kampmeier, 2001), represents a global and direct measure of self-ascribed uniqueness. Study #1 looked at the interrelation of the uniqueness-driven concepts. Therefore, GUP and CNFU were employed in the study as potential psychological factors that influence and predict uniqueness-driven consumer behavior. Different behavioral measures were used: The newly developed possession of individualized products (POIP), the newly developed products for uniqueness display (PFUD), and the already established uniqueness-enhancing behaviors (UEB). Analyses showed that CNFU mediates the relationship between GUP and the behavioral measures in a German speaking setting. Thus, GUP (representing self-perception) was identified as the driver behind CNFU (representing motivation) and the actual consumer behavior. Study #2 examined further manifestations of uniqueness-driven consumer behavior. For this purpose, an extreme form of uniqueness-increasing behavior was researched: Tattooing. The influence of GUP and CNFU on tattooing behavior was investigated using a sample derived from a tattoo exhibition. To do so, a newly developed measure to determine the percentage of the body covered by tattoos was employed. It was revealed that individuals with higher GUP and CNFU levels indeed have a higher tattooing degree. Study #3 further explored the predictive possibilities and limitations of the GUP and CNFU concepts. On the one hand, study #3 specifically looked at the consumption of customized apparel products as mass customization is said to become the standard of the century (Piller & Müller, 2004). It was shown that individuals with higher CNFU levels not only purchased more customized apparel products in the last six months, but also spend more money on them. On the other hand, uniqueness-enhancing activities (UEA), such as travel to exotic places or extreme sports, were investigated by using a newly developed 30-item scale. It was revealed that CNFU partly mediates the GUP and UEA relationship, proving that CNFU indeed predicts a broad range of consumer behaviors and that GUP is the driver behind the need and the behavior. Study #4, entered a new terrain. In contrast to the previous three studies, it explored the so termed "passive" side of uniqueness-seeking in the consumer context. Individuals might feel unique because business companies treat them in a special way. Such a unique customer treatment (UCT) involves activities like customer service or customer relationship management. Study #4 investigated if individuals differ in their need for such a treatment. Hence, with the need for unique customer treatment (NFUCT) a new uniqueness-driven consumer need was introduced and its impact on customer loyalty examined. Analyses, for example, revealed that individuals with high NFUCT levels receiving a high unique customer treatment (UCT) showed the highest customer loyalty, whereas the lowest customer loyalty was found among those individuals with high NFUCT levels receiving a low unique customer treatment (UCT). Study #5 mainly examined the processes behind uniqueness-driven consumer behavior. Here, not only the psychological influences, but also situational influences were examined. This study investigated the impact of a non-personal "indirect" uniqueness manipulation on the consumption of customized apparel products by simultaneously controlling for the influence of GUP and CNFU. Therefore, two equal experimental groups were created. Afterwards, these groups either received an e-mail with a "pro-individualism" campaign or a "pro-collectivism" campaign especially developed for study #5. The conducted experiment revealed that, individuals receiving a "pro-individualism" poster campaign telling the participants that uniqueness is socially appropriate and desired were willing to spend more money on customization options compared to individuals receiving a "pro-collectivism" poster campaign. Hence, not only psychological antecedents such as GUP and CNFU influence uniqueness-driven consumer behavior, but also situational factors.
Extension of inexact Kleinman-Newton methods to a general monotonicity preserving convergence theory
(2011)
The thesis at hand considers inexact Newton methods in combination with algebraic Riccati equation. A monotone convergence behaviour is proven, which enables a non-local convergence. Above relation is transferred to a general convergence theory for inexact Newton methods securing the monotonicity of the iterates for convex or concave mappings. Several application prove the pratical benefits of the new developed theory.
Variational inequality problems constitute a common basis to investigate the theory and algorithms for many problems in mathematical physics, in economy as well as in natural and technical sciences. They appear in a variety of mathematical applications like convex programming, game theory and economic equilibrium problems, but also in fluid mechanics, physics of solid bodies and others. Many variational inequalities arising from applications are ill-posed. This means, for example, that the solution is not unique, or that small deviations in the data can cause large deviations in the solution. In such a situation, standard solution methods converge very slowly or even fail. In this case, so-called regularization methods are the methods of choice. They have the advantage that an ill-posed original problem is replaced by a sequence of well-posed auxiliary problems, which have better properties (like, e.g., a unique solution and a better conditionality). Moreover, a suitable choice of the regularization term can lead to unconstrained auxiliary problems that are even equivalent to optimization problems. The development and improvement of such methods are a focus of current research, in which we take part with this thesis. We suggest and investigate a logarithmic-quadratic proximal auxiliary problem (LQPAP) method that combines the advantages of the well-known proximal-point algorithm and the so-called auxiliary problem principle. Its exploration and convergence analysis is one of the main results in this work. The LQPAP method continues the recent developments of regularization methods. It includes different techniques presented in literature to improve the numerical stability: The logarithmic-quadratic distance function constitutes an interior point effect which allows to treat the auxiliary problems as unconstrained ones. Furthermore, outer operator approximations are considered. This simplifies the numerical solution of variational inequalities with multi-valued operators since, for example, bundle-techniques can be applied. With respect to the numerical practicability, inexact solutions of the auxiliary problems are allowed using a summable-error criterion that is easy to implement. As a further advantage of the logarithmic-quadratic distance we verify that it is self-concordant (in the sense of Nesterov/Nemirovskii). This motivates to apply the Newton method for the solution of the auxiliary problems. In the numerical part of the thesis the LQPAP method is applied to linearly constrained, differentiable and nondifferentiable convex optimization problems, as well as to nonsymmetric variational inequalities with co-coercive operators. It can often be observed that the sequence of iterates reaches the boundary of the feasible set before being close to an optimal solution. Against this background, we present the strategy of under-relaxation, which robustifies the LQPAP method. Furthermore, we compare the results with an appropriate method based on Bregman distances (BrPAP method). For differentiable, convex optimization problems we describe the implementation of the Newton method to solve the auxiliary problems and carry out different numerical experiments. For example, an adaptive choice of the initial regularization parameter and a combination of an Armijo and a self-concordance step size are evaluated. Test examples for nonsymmetric variational inequalities are hardly available in literature. Therefore, we present a geometric and an analytic approach to generate test examples with known solution(s). To solve the auxiliary problems in the case of nondifferentiable, convex optimization problems we apply the well-known bundle technique. The implementation is described in detail and the involved functions and sequences of parameters are discussed. As far as possible, our analysis is substantiated by new theoretical results. Furthermore, it is explained in detail how the bundle auxiliary problems are solved with a primal-dual interior point method. Such investigations have by now only been published for Bregman distances. The LQPAP bundle method is again applied to several test examples from literature. Thus, this thesis builds a bridge between theoretical and numerical investigations of solution methods for variational inequalities.
This thesis centers on formal tree languages and on their learnability by algorithmic methods in abstractions of several learning settings. After a general introduction, we present a survey of relevant definitions for the formal tree concept as well as special cases (strings) and refinements (multi-dimensional trees) thereof. In Chapter 3 we discuss the theoretical foundations of algorithmic learning in a specific type of setting of particular interest in the area of Grammatical Inference where the task consists in deriving a correct formal description for an unknown target language from various information sources (queries and/or finite samples) in a polynomial number of steps. We develop a parameterized meta-algorithm that incorporates several prominent learning algorithms from the literature in order to highlight the basic routines which regardless of the nature of the information sources have to be run through by all those algorithms alike. In this framework, the intended target descriptions are deterministic finite-state tree automata. We discuss the limited transferability of this approach to another class of descriptions, residual finite-state tree automata, for which we propose several learning algorithms as well. The learnable class by these techniques corresponds to the class of regular tree languages. In Chapter 4we outline a recent range of attempts in Grammatical Inference to extend the learnable language classes beyond regularity and even beyond context-freeness by techniques based on syntactic observations which can be subsumed under the term 'distributional learning', and we describe learning algorithms in several settings for the tree case taking this approach. We conclude with some general reflections on the notion of learning from structural information.
This dissertation focuses on the link between labour market institutions and precautionary savings. It is evaluated whether private households react to changes in social insurance provision such as the income replacement in case of unemployment by increased savings for precautionary reasons. The dissertation consists of three self-contained chapters, each focusing on slightly different aspects of the topic. The first chapter titled "Precautionary saving and the (in)stability of subjective earnings uncertainty" empirically looks at the influence of future income uncertainty on household saving behavior. Numerous cross-section studies on precautionary saving use subjective expectations regarding the income variance one year ahead as a proxy for income uncertainty. Using such proxies observed only at one point in time, however, may give rise to biased estimates for precautionary wealth if expectations are not stable over time. Survey data from the Dutch DNB Household Survey suggest that subjective future income distributions are not stable over the mid-term. Moreover, in this study I contrast estimates of precautionary wealth using the variation coefficient observed at one point in time with those using a simple mid-term average. Estimates of precautionary wealth based on the average are about 40% to 80% higher than the estimates using the variation coefficient observed only once. In addition to that, wealth accumulation for precautionary reasons is estimated for different parts of the income distribution. The share of precautionary wealth is highest for households at the center of the income distribution. By linking saving behaviour with unemployment insurance, the following chapters then shed some light on an issue that has largely been neglected in the literature on labour market institutions so far. Whereas the third chapter models the relevance of unemployment insurance for income uncertainty and intertemporal decision making during institutional reform processes, chapter 4 seeks to establish empirically a relationship between saving behavior and unemployment insurance. Social insurance, especially unemployment insurance, provides agents with income insurance against not marketable income risks. Since the early 1990s, reform measures like more activating policies as suggested by the OECD Jobs Study in 1994 have been observed in Europe. In the third chapter it is argued that such changes in unemployment insurance reduce public insurance and increase income uncertainty. Moreover, a simple three period model is discussed which shows a link between a welfare state reform and agents' saving decisions as one possible reaction of agents to self-insure against income risk. Two sources of uncertainty seem to be important in this context: (1) uncertain results of the reform process concerning the replacement rate, and (2) uncertainty regarding the timing of information about the content of the reform. It can be shown that the precautionary motive for saving explains an increased accumulation of capital in times of reform activities. In addition to that, early information about the expected replacement rate increases agents' utility and reduces under and oversaving. Following the argument of the previous chapters, that an important feature of labour market institutions in modern welfare states is to provide cash transfers as income replacement in case of unemployment, it is hypothesised that unemployment benefits reduce the motive to save for precautionary reasons. Based on consumer sentiment data from the European Commission's Consumer Survey, chapter four finally provides some evidence that aggregate saving intentions are significantly influenced by unemployment benefits. It can be shown that higher benefits lower the intention to save.
Stress represents a significant problem for Western societies inducing costs as high as 3-4 % of the European gross national products, a burden that is continually increasing (WHO Briefing, EUR/04/5047810/B6). The classical stress response system is the hypothalamic-pituitary-adrenal (HPA) axis which acts to restore homeostasis after disturbances. Two major components within the HPA axis system are the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Cortisol, released from the adrenal glands at the end of the HPA axis, binds to MRs and with a 10 fold lower affinity to GRs. Both, impairment of the HPA axis and an imbalance in the MR/GR ratio enhances the risk for infection, inflammation and stress related psychiatric disorders. Major depressive disorder (MDD) is characterised by a variety of symptoms, however, one of the most consistent findings is the hyperactivity of the HPA axis. This may be the result of lower numbers or reduced activity of GRs and MRs. The GR gene consists of multiple alternative first exons resulting in different GR mRNA transcripts whereas for the MR only two first exons are known to date. Both, the human GR promoter 1F and the homologue rat Gr promoter 1.7 seem to be susceptible to methylation during stressful early life events resulting in lower 1F/1.7 transcript levels. It was proposed that this is due to methylation of a NGFI-A binding site in both, the rat promoter 1.7 and the human promoter 1F. The research presented in this thesis was undertaken to determine the differential expression and methylation patterns of GR and MR variants in multiple areas of the limbic brain system in the healthy and depressed human brain. Furthermore, the transcriptional control of the GR transcript 1F was investigated as expression changes of this transcript were associated with MDD, childhood abuse and early life stress. The role of NGFI-A and several other transcription factors on 1F regulation was studied in vitro and the effect of Ngfi-a overexpression on the rat Gr promoter 1.7 in vivo. The susceptibility to epigenetic programming of several GR promoters was investigated in MDD. In addition, changes in methylation levels have been determined in response to a single acute stressor in rodents. Our results showed that GR and MR first exon transcripts are differentially expressed in the human brain, but this is not due to epigenetic programming. We showed that NGFI-A has no effect on endogenous 1F/1.7 expression in vitro and in vivo. We provide evidence that the transcription factor E2F1 is a major element in the transcriptional complex necessary to drive the expression of GR 1F transcripts. In rats, highly individual methylation patterns in the paraventricular nucleus of the hypothalamus (PVN) suggest that this is not related to the stressor but can rather be interpreted as pre-existing differences. In contrast, the hippocampus showed a much more uniform epigenetic status, but still is susceptible to epigenetic modification even after a single acute stress suggesting a differential "state‟ versus "trait‟ regulation of the GR gene in different brain regions. The results of this thesis have given further insight in the complex transcriptional regulation of GR and MR first exons in health and disease. Epigenetic programming of GR promoters seems to be involved in early life stress and acute stress in adult rats; however, the susceptibility to methylation in response to stress seems to vary between brain regions.
The brain is the central coordinator of the human stress reaction. At the same time, peripheral endocrine and neural stress signals act on the brain modulating brain function. Here, three experimental studies are presented demonstrating this dual role of the brain in stress. Study I shows that centrally acting insulin, an important regulator of energy homeostasis, attenuates the stress related cortisol secretion. Studies II and III show that specific components of the stress reaction modulate learning and memory retrieval, two important aspects of higher-order brain function.
During pregnancy every eighth woman is treated with glucocorticoids. Glucocorticoids inhibit cell division but are assumed to accelerate the differentiation of cells. In this review animal models for the development of the human fetal and neonatal hypothalamic-pituitary-adrenal (HPA) axis are investigated. It is possible to show that during pregnancy in humans, as in most of the here-investigated animal models, a stress hyporesponsive period (SHRP) is present. In this period, the fetus is facing reduced glucocorticoid concentrations, by low or absent fetal glucocorticoid synthesis and by reduced exposure to maternal glucocorticoids. During that phase, sensitive maturational processes in the brain are assumed, which could be inhibited by high glucocorticoid concentrations. In the SHRP, species-specific maximal brain growth spurt and neurogenesis of the somatosensory cortex take place. The latter is critical for the development of social and communication skills and the secure attachment of mother and child. Glucocorticoid treatment during pregnancy needs to be further investigated especially during this vulnerable SHRP. The hypothalamus and the pituitary stimulate the adrenal glucocorticoid production. On the other hand, glucocorticoids can inhibit the synthesis of corticotropin-releasing hormone (CRH) in the hypothalamus and of adrenocorticotropic hormone (ACTH) in the pituitary. Alterations in this negative feedback are assumed among others in the development of fibromyalgia, diabetes and factors of the metabolic syndrome. In this work it is shown that the fetal cortisol surge at the end of gestation is at least partially due to reduced glucocorticoid negative feedback. It is also assumed that androgens are involved in the control of fetal glucocorticoid synthesis. Glucocorticoids seem to prevent masculinization of the female fetus by androgens during the sexual gonadal development. In this work a negative interaction of glucocorticoids and androgens is detectable.
Cortisol is a stress hormone that acts on the central nervous system in order to support adaptation and time-adjusted coping processes. Whereas previous research has focused on slow emerging, genomic effects of cortisol likely mediated by protein synthesis, there is only limited knowledge about rapid, non-genomic cortisol effects on in vivo neuronal cell activity in humans. Three independent placebo-controlled studies in healthy men were conducted to test effects of 4 mg cortisol on central nervous system activity, occurring within 15 minutes after intravenous administration. Two of the studies (N = 26; N = 9) used continuous arterial spin labeling as a magnetic resonance imaging sequence, and found rapid bilateral thalamic perfusion decrements. The third study (N = 14) revealed rapid cortisol-induced changes in global signal strength and map complexity of the electroencephalogram. The observed changes in neuronal functioning suggest that cortisol may act on the thalamic relay of non-relevant background as well as on task specific sensory information in order to facilitate the adaptation to stress challenges. In conclusion, these results are the first to coherently suggest that a physiologically plausible amount of cortisol profoundly affects functioning and perfusion of the human CNS in vivo by a rapid, non-genomic mechanism.
By rodent studies it has been shown that the mineralocorticoid receptor (MR) is a candidate gene for the investigation of cognitive functions comparable to human executive function. The present work addresses the question if polymorphisms in the MR gene can act as a "probe" to explain a part of the interindividual variance of human executive functions. For this purpose, 72 healthy young participants were assigned to four equally sized groups, concerning their particular MR genotype for two common MR polymorphisms. They were investigated in an electroencephalogram (EEG) test session, accomplishing two cognitive tests while delivering saliva samples for subsequent cortisol measures. The two tests chosen for the assessment of executive functions were the Attention Network Task (ANT) and a modified version of the Wisconsin Card Sorting Test (WCST).Chapter 1 of the present work reports of the rational bases for the empirical approach, which were built up on a broad theoretical background presented in Chapter 2. In the third chapter, the investigation and results of the statistical analysis for behavioral data (i.e. reaction times, accuracy/error rates) are presented. No association with MR polymorphisms was found for the reaction times of both tests. For the accuracy rate, differences between genotype groups were found for ANT and WCST, indicating an association of MR polymorphisms and accuracy in the Alertness and Executive Control network of the ANT and during the detection of an intradimensional shift in the WCST. Data acquisition and the results for EEG data analyses are presented in Chapter 4. The results show that groups differing for MR genotype show different activity over prefrontal motor areas during the process of answering to the ANT. Those group differences again were prominent for the Alertness and Executive Control network. A tendency for further significant group differences was found for activity on frontopolar positions in extradimensional rule switching. Chapter 5 summarizes the findings for the analysis of salivary free cortisol, showing a tendency for an association between MR polymorphisms and a mildly stimulated Hypothalamus-pituitary-adrenal (HPA) axis during the test situation. The results of the different measures are integrated and discussed in Chapter 6 within the scope of novel findings in investigating the functionality of the chosen MR polymorphisms. Finally, Chapter 7 gives an outlook on the methodology and constraints of future research strategies to further describe the role of the MR in human cognitive function.