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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.
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 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.
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.
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.
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.
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.
The midcingulate cortex has become the focus of scientific interest as it has been associated with a wide range of attentional phenomena. This survey found evidence indicating the relevance of gender and handedness for measures of regional cortical morphology. Although gender was associated with structural variations concerning the neuroanatomy of the midcingulum bundle as well, handedness did not emerge in the analyses of white matter characteristics as significant factor. Hemispheric differences were found at the level of both gray and white matter. Turning to the functional implications of neuroanatomical variations and comparing subjects with a pronounced and a low degree of midcingulate folding, which indicates differential expansions of cytoarchitectural areas, behavioral and electrophysiological differences in the processing of interference became evident. A high degree of leftward midcingulate fissurization was associated with better behavioral performance, presumably caused by a more effective conflict-monitoring system triggering fast and automatic attentional filtering mechanisms. Subjects exhibiting a lower degree of midcingulate fissurization rather seem to rely on more effortful control processes. These results carry implications not only concerning neuronal representations of individual differences in attentional processes, but might also be of relevance for the refinement of models for mental disorders.
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.