Topological set theories and hyperuniverses

We give a new set theoretic system of axioms motivated by a topological intuition: The set of subsets of any set is a topology on that set. On the one hand, this system is a common weakening of Zermelo-Fraenkel set theory ZF, the positive set theory GPK and the theory of hyperuniverses. On the other hand, it retains most of the expressiveness of these theories and has the same consistency strength as ZF. We single out the additional axiom of the universal set as the one that increases the consistency strength to that of GPK and explore several other axioms and interrelations between those theories. Hyperuniverses are a natural class of models for theories with a universal set. The Aleph_0- and Aleph_1-dimensional Cantor cubes are examples of hyperuniverses with additivity Aleph_0, because they are homeomorphic to their hyperspace. We prove that in the realm of spaces with uncountable additivity, none of the generalized Cantor cubes has that property. Finally, we give two complementary constructions of hyperuniverses which generalize many of the constructions found in the literature and produce initial and terminal hyperuniverses

Orientation in space using the sense of smell

Several studies reported that respiration interacts with olfactory perception. Therefore, in the pilot study of this experiment series human breathing was investigated during an olfactory experiment. Breathing parameters (respiratory minute volume, respiratory amplitude, and breathing rate) were quantified in response to odor stimulation and olfactory imagery. We provide evidence that respiration changed during smelling and during olfactory imagery in comparison to the baseline condition. In conclusion, olfactory perception and olfactory imagery both have an impact on the human respiratory profile, which is hypothesized to be based on a common underlying mechanism named sniffing. Our findings underline that for certain aspects of olfactory research it may be necessary to control and/or monitor respiration during olfactory stimulation. The human ability to localize odors has been investigated in a limited number of studies, but the findings are contradictory. We hypothesized that this was mainly due to differential effects of olfactory and trigeminal stimulation. Only few substances excite selectively the olfactory system. One of them is hydrogen sulphide (H2S). In contrast, most odorants stimulate both olfactory and trigeminal receptors of the nasal mucosa. The main goal of this study was to test the human ability to localize substances, which excite the olfactory system selectively. For this purpose we performed localization experiment using low and high concentrations of the pure odorant H2S, the olfactory-trigeminal substance isoamyl acetate (IAA), and the trigeminal substance carbon dioxide (CO2). In preparation for the localization study a detection experiment was carried out to ensure that subjects perceived the applied stimuli consciously. The aim of the detection study was to quantify the human sensitivity in response to stimulation with H2S, IAA, and CO2. We tested healthy subjects using an event-related experimental design. The olfactory stimulation was performed using an olfactometer. The results showed that humans are able to detect H2S in low concentration (2 ppm) with moderate sensitivity, and possess a high sensitivity in response to stimulation with 8ppm H2S, 50% v/v CO2, and 17.5% v/v IAA. The localization experiment revealed that subjects can localize H2S neither in low nor in high concentrations. In contrast to that, subjects possess an ability to localize both IAA and CO2 stimuli. These results clearly demonstrate that humans are able to localize odorants which excite the trigeminal system, but they are not able to localize odors that stimulate the olfactory system exclusively, in spite of consciously perceiving the stimuli

Studies on the release of neutrophil extracellular traps and IFN-γ as part of the innate immune response to Aspergillus fumigatus and on the fungal stress response via the hybrid sensor kinase TcsC

Aspergillus fumigatus is a saprophytic mold that naturally inhabits the soil. Asexual reproduction yields hardy conidia that circulate in the air and are inhaled daily by humans. The fungus seems not to have evolved distinct mechanisms of pathogenicity, but is capable of responding to many stressful environmental cues present in its naturally harsh niche. The robust conidia present no problem to a fully functioning immune system, but if the innate immune system is compromised, the conidia can become activated and differentiate within the lung tissue to form invasive and disseminating hyphae. The resulting disease is called aspergillosis and is difficult to detect and to treat. To date, scientists have yet to find the factor(s) missing during immunosuppression that allow a healthy patient to easily dispose of A. fumigatus. We explored two possibilities: the production of neutrophil extracellular traps (NETs) and the release of IFN-γ by natural killer (NK) cells. We report here that NETs alone cannot kill the fungus, but do inhibit polar growth. Elongation of hyphal tips is abrogated due to zinc starvation, likely a consequence of the zinc-chelating, NETs-associated protein calprotectin. NK cells alone are also incapable of fungicidal activity, but their release of IFN-γ upon contact with A. fumigatus abrogates hyphal growth by a yet unknown mechanism. In vitro studies of the innate immune response, though helpful, are far from representative of the in vivo response. Neither NETs nor IFN-γ alone can manage Aspergillus infection, but in combination, these and other immune assaults certainly can. The difficulty lies in identifying the precise combination of immune cells and cytokine milieu that in a healthy individual prevent infection. Additionally, we explored mechanisms by which the fungus responds to stress, namely the HOG MAPK pathway, historically involved in osmotic stress response. In filamentous fungi, certain stress signals are sensed by a cytoplasmic hybrid histidine kinase sensor and then passed through the HOG system via phosphorylation. We identified the putative hybrid sensor kinase in A. fumigatus, and generated a corresponding knockout mutant. The ΔtcsC mutant was indeed sensitive to osmotic stress, and resistant to the phenolpyrrole fungicide fludioxonil. In the wild type the addition of either osmotic stress or fludioxonil resulted in SakA phosphorylation and translocation to the nucleus. SakA, the Hog1 homolog in A. fumigatus, is located at the end of the HOG pathway, confirming the role of TcsC as the cytoplasmic sensor upstream of SakA. In hypoxia, on farnesol, and in high concentrations of divalent cations the ΔtcsC mutant exhibited a striking “fluffy” phenotype characterized by the production of tremendous aerial hyphae and little or no differentiation, i.e., no conidiation. Though the ΔtcsC mutant showed no change in virulence compared to wild type, components of the TcsC signalling pathway remain promising targets for antifungal agents

Four Essays on Technological and Organizational Change in Health Care

This thesis contains four essays on technological and organizational change in health care. Although each chapter can be read independently, there is a central thread resumed in each chapter. The interaction of patient, physician and insurer in the health care market is analysed in different contexts. Chapter 2 studies the physician's decision to adopt new technologies in a situation where patients have control over the amount of health care consumed. This setup of ex-post moral hazard is complemented in chapter 3 by an analysis of supplier-induced demand. Providers' technology choice and adoption of innovations here depend on the profitability of treatment and patients' willingness to consent. A conclusion which may be drawn from these sections is a call for a more integrated provision of health care in the form of managed care. Chapter 4 contains an analysis which explains why physicians, particularly in Germany, are often very much opposed to such new organizational forms of provision of care. In chapter 5, it is shown that patients may not always want to make use of the opportunities offered by technological progress. Information on one's health status which may be acquired, for instance, by genetic tests, may be declined by individuals who fear a breakdown of will. This finding has important implications for the disclosure of information by physicians and for the information acquisition policy of insurers

Characterisation of components and mechanisms involved in redox-regulation of protein import into chloroplasts

The vast majority of chloroplast proteins is encoded in the nucleus and thus has to be posttranslationally imported into the organelle, a process that is facilitated by two multimeric protein machineries, the Toc and Tic complexes (translocon at the outer/inner envelope of chloroplasts). Regulation of protein import, e.g. by redox signals, is a crucial step to adapt the protein content to the biochemical requirements of the organelle. In particular, one subunit of the Tic complex, Tic62, has been proposed as a redox sensor, whose possible function is to regulate protein import by sensing and reacting to the redox state of the organelle. To elucidate a potential redox regulation of protein import, structural features, redox-dependent properties and the evolutional origin of Tic62 were investigated. The results show that Tic62 consists of two very different modules: the N-terminal part was found to be mainly -helical and possesses dehydrogenase activity in vitro. It is furthermore an evolutionary ancient domain, as it is highly conserved in all photosynthetic organisms from flowering plants to cyanobacteria and even green sulfur bacteria. In contrast to this, the C-terminus is largely disordered and interacts specifically with ferredoxin-NADP+ oxidoreductase (FNR), a key enzyme in photosynthetic electron transfer reactions. Moreover, this domain was found to exist only in flowering plants, and thus the full-length Tic62 protein seems to be one of the evolutionary youngest Tic components. The results of this study make also clear that Tic62 is a target of redox regulation itself, as its localization and interaction properties depend on the metabolic redox state: oxidized conditions lead to fast membrane binding and interaction with the Tic complex, whereas reduced conditions cause solubilization of Tic62 into the stroma and increased interaction with FNR. This novel shuttling behaviour indicates a dynamic composition of the Tic complex. The NADP+/NADPH ratio was furthermore found to be able to influence the import efficiency of many precursor proteins. Interestingly, the import of not all preproteins depends on the stromal redox state. Hence it was proposed that not a single stable Tic translocon exists, but several Tic subcomplexes with different subunit compositions, which might mediate the import of different precursor groups in a redox-dependent or -independent fashion. Another redox signal that was analyzed in regard to an impact on protein import is the reversible reduction of disulfide bridges, which was found to affect the channel and receptor proteins of the Toc complex. The import of all proteins that use the Toc translocon for entering the chloroplast was shown to be influenced by disulfide bridge formation. Thus it can be concluded that a variety of redox signals, acting both on the Toc and Tic complexes, are able to influence chloroplast protein import