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Streptococcus pneumoniae (the pneumococcus) is a harmless resident of the human nasopharyngeal cavity, and, in general, every individual is likely to be colonized asymptomatically at least once during life. However, under certain conditions, the bacterium can spread to other tissues and organs causing local, non-invasive infections but also lifethreatening, invasive diseases. Pneumococcal carriage and infection is a highly regulated interplay between pathogen- and host-specific factors and the intimate contact of S. pneumoniae with the surface of the nasopharynx is the crucial step in pneumococcal pathogenesis. Pneumococcal adherence to the respiratory epithelium is mediated by surface-exposed adhesins. These adhesins engage host cell receptors either directly or indirectly by recognizing glycoproteins of the extracellular matrix (ECM) including structural components, such as collagens, laminins, and fibronectins, as well as plasma-derived ECM modulators, like vitronectin and Factor H. Pneumococcal surface protein C (PspC) is a surface-exposed protein and important virulence factor of S. pneumoniae. The multifunctional PspC protein promotes pneumococcal adherence to host cells by interacting with the secretory component of the human polymeric Immunoglobulin receptor of respiratory cells. In addition, PspC facilitates pneumococcal immune evasion by recruiting the complement inhibitor proteins C4b-binding protein (C4BP) and Factor H. Moreover, Factor H bound to the pneumococcal surface promotes bacterial adhesion to human epithelial and endothelial cells. S. pneumoniae also interacts with the human glycoprotein vitronectin. In plasma, monomeric vitronectin regulates thrombosis, fibrinolysis and the terminal complement cascade, while it additionally mediates cell-matrix interactions, cell adhesion and migration in the ECM. It was shown that multimeric, ECM-associated vitronectin facilitates pneumococcal adherence to respiratory epithelial cells. In addition, the interaction of pneumococci with vitronectin promotes their uptake by mucosal epithelial cells via the engagement of the integrin αvβ3 receptor and activation of intracellular signaling pathways culminating in cytoskeletal rearrangements. This study aims to identify and characterize the surface-exposed protein(s) that mediate binding of pneumococci to vitronectin and to elucidate the impact of vitronectin on pneumococcal pathogenesis beyond its function as molecular bridge between pneumococcus and host. Flow cytometric, immunosorbent and surface plasmon resonance experiments revealed that PspC is a vitronectin-binding protein of S. pneumoniae. The specificity of the interaction with vitronectin was confirmed using recombinant PspC proteins and Lactococcus lactis heterologously expressing PspC on their surface. Factor H did not hinder vitronectinbinding to PspC indicating that vitronectin recognizes the central part of PspC. Secretory IgA inhibited but not completely prevented vitronectin-binding to PspC, strongly suggesting that vitronectin binds near, but not directly to, the SC-binding region within the R domain(s) of PspC. In addition, PspC proteins comprising two R domains bound with higher affinity to vitronectin than PspC containing only one R domain, indicating that two interconnected R domains are required for efficient vitronectin-binding. Despite the sequential and structural differences to classical PspC, the PspC-like protein Hic specifically interacted with vitronectin with similar affinity than PspC containing two linked R domains. Binding studies confirmed that Factor H interacts with the very N-terminal region of Hic showing high sequence homology to classical PspC proteins, while vitronectin recognizes an adjacent region in the N-terminal region of Hic. The studied PspC proteins bound to both soluble and immobilized vitronectin, and the C-terminal heparin-binding domain (HBD3) was identified as PspC-binding motif in soluble vitronectin. However, in its immobilized form, vitronectin likely exposes additional binding sites for PspC since a region N-terminally to the identified HBD3 conferred binding of PspC. Vitronectin inhibits the terminal complement pathway, thereby preventing proinflammatory immune reactions and tissue damage. In general, pneumococci are protected from opsonization and MAC-dependent lysis by their capsule. However, pneumococci in close contact to human cells can become susceptible to complement attack due to reduced amounts of capsule. In addition, they can be severely affected by TCC-induced inflammatory responses. Vitronectin bound to PspC significantly inhibited the formation of terminal complement complexes. Thus, the interaction of PspC with vitronectin might aid in immune evasion of S. pneumoniae by inhibiting complement-mediated lysis and/or suppressing proinflammatory events. In conclusion, the results revealed the multifunctional PspC and Hic as vitronectin-binding proteins and proposed a novel role for the specific interaction of S. pneumoniae with vitronectin in regulating the complement cascade, beside its function as molecular bridge to the respiratory epithelium.
Background: Animal studies and data from a single-center study suggest that tobacco smoke exposure may be a risk factor for precapillary pulmonary hypertension (PH). Objective: We aimed to survey tobacco smoke exposure in a large PH collective and to compare it with epidemiological data from healthy subjects. Methods: This is an international, multicenter, case-control study including patients with pulmonary arterial and chronic thromboembolic PH. All patients were asked specific questions about tobacco smoke exposure. Healthy controls were retrieved from the Swiss Health Survey (n = 18,747). Results: Overall (n = 472), 49% of PH patients were smokers and there was a clear sex difference (women 37%, men 71%). Significantly more PH men were smokers compared with healthy controls, whereas less PH women were ever active smokers. However, 50% of the non-smoking PH women were exposed to secondhand smoke, leading to a significantly higher number of tobacco smoke-exposed individuals compared to healthy controls. PH smokers were significantly younger compared to those not exposed. Conclusion: Active and environmental tobacco smoke exposure is common in PH. The higher prevalence of male PH smokers, the higher exposure to environmental tobacco smoke in PH women compared to healthy controls and the lower age at PH diagnosis in smokers may indicate a pathogenic role of tobacco smoke exposure in PH.
A novel method for time-resolved tuned diode laser absorption spectroscopy has been developed. In this paper, we describe in detail developed electronic module that controls time-resolution of laser absorption spectroscopy system. The TTL signal triggering plasma pulse is used for generation of two signals: the first one triggers the fine tuning of laser wavelength and second one controls time-defined signal sampling from absorption detector. The described method and electronic system enable us to investigate temporal evolution of sputtered particles in technological low-temperature plasma systems. The pulsed DC planar magnetron sputtering system has been used to verify this method. The 2" in diameter titanium target was sputtered in pure argon atmosphere. The working pressure was held at 2 Pa. All the experiments were carried out for pulse ON time fixed at 100 (is. When changing OFF time the discharge has operated between High Power Impulse Magnetron Sputtering regime and pulsed DC magnetron regime. The effect of duty cycle variation results in decrease of titanium atom density during ON time while length of OFF time elongates. We believe that observed effect is connected with higher degree of ionization of sputtered particles. As previously reported by Bohlmark et al., the measured optical emission spectra in HiPIMS systems were dominated by emission from titanium ions [1].
The UNESCO Man and the Biosphere Programme has been active in South Africa for almost 20 years. The country currently has six designated biosphere reserves with a few sites in various stages of the nomination process. Within the South African context, agencies are using a series of seemingly different instruments to practice landscape-scale management. The UNESCO biosphere reserve concept sometimes finds it difficult to obtain prominence amongst these different landscape initiatives. Biosphere reserves are special sites wherein sustainable development is promoted. For this reason, the biosphere reserve concept has much to offer towards long-term sustainable socialecological land management. In our modern age of population growth, dwindling natural resources and a general disconnectedness of humans from nature due to large scale urbanization, there is an urgent need for innovative ways in which to showcase sustainable living practices. South Africa has limited natural, economic and social resources and therefore needs to prioritize where these resources could best be allocated. This dissertation comprises the history of the MAB Programme in South Africa, as well as a multicase study on five existing biosphere reserves. Results from this study indicated that not all biosphere reserves are equally effective in their implementation of the three functions of biosphere reserves and that all biosphere reserves in South Africa face an uncertain future due to pressing challenges. Collective results of the multicase study as well as literature reviews were used to inform options for the future effective implementation of the MAB Programme in South Africa. Options that could contribute towards effective biosphere reserves include more sustainable funding support, and community-based demonstration projects. In addition a new suite of criteria to inform the selection of future biosphere reserves was developed. Biosphere reserves need to be optimally located in order to secure long-term efficiency and effectiveness. These sites need to be representative of biodiversity, efficiently managed and persistent in the long run. Presently in South Africa, new sites for biosphere reserves are nominated in an ad hoc manner. Should their locations be selected discerningly, they offer many benefits to the South African social and environmental landscape that should be recognized and utilized. The final suite of selection criteria are structured according to four subsections, namely a general section that addresses national matters of general concern to the MAB Programme, and three sections covering the three biosphere reserve functions of conservation, sustainable development and logistic support. This suite of biosphere reserve selection criteria for South Africa is being put forward for deliberation and discussion at local, provincial and national level. It has the potential to be of valuable assistance in selection processes for future effective and efficient biosphere reserves that will proudly earn their place in the South African landscape as “special places for people and nature”.
The Role of Pregnancy-Associated Hormones in the Development and Function of Regulatory B Cells
(2014)
During mammalian pregnancy, highly specialized mechanisms of immune tolerance are triggered in order to allow the semi-allogeneic fetus to grow within the maternal uterus in harmony with the maternal immune system. Among other mechanisms, changes in the endocrine status have been proposed to be at least part of the machinery responsible for the induction of immune tolerance during pregnancy. Indeed, pregnancy-associated hormones, estradiol, progesterone, and human chorionic gonadotropin are known to confer immune suppressive capacity to innate as well as adaptive immune cells. Regulatory B cells, a subpopulation of B lymphocytes with strong immunosuppressive functions, were shown to expand during pregnancy. Furthermore, it is well-known that some women suffering from multiple sclerosis, significantly improve their symptoms during pregnancy and this was attributed to the effect of female sex hormones. Accordingly, estradiol protects mice from developing experimental autoimmune encephalomyelitis by triggering the expansion and activation of regulatory B cells. In this review, we discuss different mechanisms associated with the development, activation, and function of regulatory B cells with a special focus on those involving pregnancy-associated hormones.
This work describes the recent scientific and technical achievements obtained at the high-precision Penning trap mass spectrometer SHIPTRAP. The scientific focus of the SHIPTRAP experiment are mass measurements of short-lived nuclides with proton number larger than 100. The masses of these isotopes are usually determined via extrapolations, systematic trends, predictions based on theoretical models or alpha-decay spectroscopy. In several experiments the masses of the isotopes 252-255No and 255,256Lr have been measured directly. With the obtained results the region of enhanced nuclear stability at the deformed shell closure at the neutron number 152 was investigated. Furthermore, the masses have been used to benchmark theoretical mass models. The measured masses were compared selected mass models which revealed differences between few keV/c² up to several MeV/c² depending on the investigated nuclide and model. In order to perform mass measurements on superheavy nuclei with lower production rates, the efficiency of the SHIPTRAP setup needs to be increased. Currently, the efficiency is 2% and mainly limited by the stopping- and extraction efficiency of the buffer gas cell. The stopping and extraction efficiency of the current buffer gas cell is 12%. To this end, a modified version of the buffer gas cell was developed and characterized with 223Ra ion source. Besides a larger stopping volume and a coaxial injection the new buffer gas cell is operated at a temperature of 40K. The operation at cryogenic temperatures increases the cleanliness of the buffer gas. From extraction measurements and simulations an overall efficiency of 62(3)% was determined which results in an increase by a factor of 5 in comparison to the current buffer gas cell. Aside from high-precision mass measurements of heavy radionuclides the mass differences of metastable isobars was measured to identify candidates for the neutrinoless double-electron capture. Neutrinoless double-electron capture can only occur if the neutrino is its own antiparticle and a physics beyond the standard model exists since the neutrinoless double-electron capture violates the conservation of the lepton number. Due to its expected long half-life this decay has not yet been observed. However, the decay rate is resonantly enhanced if mother and daughter nuclide are degenerate in energy. Suitable candidates for the search of the neutrinoless double-electron capture have been identified with mass difference measurements uncertainties of about 100eV/c². In this work the results of the mass difference measurements of 12 possible candidates are presented.
The globally threatened Aquatic Warbler (Acrocephalus paludicola) is the rarest migratory songbird in Europe. Before the population declined dramatically after 1960, the Aquatic Warbler was a common species in European mires and river flood¬plains. Today, the global population is estimated to count 27 600 individuals, of which approx. 90 % are concentrated in only three countries during the breeding season: Belarus, Poland and Ukraine. Despite numerous conservation efforts mainly under¬taken in European countries, the population decline has not been stopped. Although the Aquatic Warbler is considered a “European” bird species because of the location of its breeding grounds, it spends up to six months on migration and on the wintering grounds on the African continent. A comprehensive species conservation strategy must therefore include the preservation of African resting and wintering grounds. This study analyses the ecol¬ogy of Aquatic Warbler in its wintering grounds using the example of the Djoudj National Park area in north-western Senegal. The study aims, first, to close knowledge gaps regarding the behaviour and the habitat requirements of Aquatic Warblers during their stay on the wintering grounds to provide a scientific base for long-term species conservation management; second, to assess the importance of the wintering site in the Djoudj area is in a global perspec¬tive; and third, to identify threats to the Djoudj area as a suitable Aquatic Warbler habitat. In a fourth step, science-based management recommendations are formu¬lated to support the ongoing practical conservation work of the Djoudj National Park administration with regard to the Aquatic Warbler. The main outcomes of the study are the following: (I) We confirmed the presence of Aquatic Warblers in the Djoudj area between mid-December and the end of March. (II) The connection between the wintering ground “Djoudj National Park area” and the breeding ground “Biebrza valley” (eastern Poland) was confirmed by the resighting of a ringed Aquatic Warbler individual. (III) The remiges moult of the species was observed under natural conditions for the first time. We confirmed that the Aquatic Warbler undergoes a complete moult on its wintering grounds, following the typical sequence of passerine moult. (IV) Aquatic Warblers occur in shallowly inundated vegetation with dominant stands of Oryza longistaminata, Eleocharis mutata, Scirpus maritimus, Scirpus litto¬ralis and Sporobulus robustus interspersed with small (1–2 m²) areas of open water. The afore mentioned herbaceous species form a homogenous wetland vegetation of approximately 0.6–1.5 m height, with a coverage of 80 % to 100 %. Wild rice (Oryza longistaminata) may provide the most suitable habitat conditions as suggested by the very high density of Aquatic Warblers at sites dominated by this species. Preferential habitat may include a few solitary trees, but open woodland or scrublands are unsuit-able for Aquatic Warbler. Pure stands of cattail (Typha australis) are avoided. The water level in the habitat areas varies between 0 (humid soil) and 40 cm above the ground. Constant inundation seems to be essential, as Aquatic Warblers were never encountered in dry parts of the study area. All known Aquatic Warbler habitats in the study area are influenced by brackish or salty water. (V) During winter Aquatic Warblers use a home range of 3.9 ha (± 1.9) in aver¬age, which is shared with other individuals and species. No territorial behaviour was observed in the winter quarters. (VI) The vegetation and land cover map prepared distinguishes six classes of her¬baceous vegetation and five general land cover classes. (VII) There are 4 729 ha of potential Aquatic Warbler habitat within the study area. (VIII) We estimate the density of the Aquatic Warbler population in the study area to range between 0 and 2.26 individuals per hectare with a total population size of 776 individuals, or 260–4 057 individuals in a 95 % credibility interval. Hence we conclude that 1.1–3.8 % (0.37–19.8 % within the 95 % credibility interval) of the global Aquatic Warbler wintering population are found in the Djoudj area. (VIII) The Aquatic Warbler habitats in the Djoudj area are affected by the inun¬dation regime, water circulation, changes in salinity, grazing, the spread of cattail (Typha australis), the encrustation of vegetation, the protection status of passerine migrator habitats and the expansion of rice cultivation a. Our management proposals for the preservation of existing and the development of new Aquatic Warbler habitats were formulated and incorporated into the Management Plan of the Djoudj National Park 2014–2018.
Many ethicists consider the rule of nonmaleficence – Do no harm! – to be the most fundamental ethical rule and key to ethics. This rule is taken as the foundation of the present work. I argue that any entity, that can be harmed, ought to be morally considered. Only those entities can be harmed that are inherently goal-directed or striving – in other words, that possess a telos. The reason is that by constantly acting in ways to preserve their being and to prevent their own not-being, goal-directed entities express that they value their own good. To harm such a goal-directed entity therefore means to act against the values and the good of it. The argument so far supports ethical biocentrism, that is, the view that all living, goal-directed beings are harmable, possess interests, and are, thus, morally considerable, while non-living beings are not. Yet, I digress from classical biocentrism since I conclude, based on analysis of evolutionary and biological findings, that the locus of goal-directedness and potential harm is also, if not foremost, situated in genes. Within many species, individual organisms sacrifice themselves for the betterment of their descendants like in praying mantises where males sacrifice themselves and are eaten by the female during copulation. This shows that it is not necessarily the organism as an individual which follows its own interests and goals. Individual organisms are – to a high degree – “directed” by their genes. Even in highly developed animals, genes play a significant role in the goal-directedness of the individuals. An adult human organism, for example, consists of trillions of individual cells. However, all these cells are derived from a single cell – the fertilized egg. Each of our lives begins with a single cell that contains almost all information to finally form our functioning body. Where do all the instructions, the goal-directedness come from to finally form an adult organism if not from the genes contained in this first cell, the zygote? It is the genes of each zygote that contain a set of information for making the appropriate adult. Organisms are largely programmed to do everything necessary to stay in existence, to survive, and finally to pass on their genes successfully – either by reproducing or by helping close relatives that carry a similar set of genes. The main interests of genes lie in their continued existence. This necessitates reproduction since the gene-carrying organisms will inevitably die. Single genes, though, are difficult to morally consider directly since they perform entirely in and through individual organisms. Without the individual organisms, genes cannot survive. The good news for ethics is that the interests of genes and organism usually converge: individual organisms try to survive – as do their genes. In practice, it thus makes much more sense to give moral attention to entire organisms instead of single genes. An advantage of the gene-centric ethical theory proposed here is that the moral relevance of future generations and species can be “directly” justified: Since genes have an interest in their continued existence (in the form of identical copies), they would be harmed if future generations were doomed to inexistence. Within a species with many individuals, each gene is likely to be represented in many organisms. The smaller the gene pool of a species gets, the less likely is the existence of the same gene and, therefore, the less likely is the fulfillment of its fundamental interests. Hence, saving one of the last individuals of an endangered species would be ethically preferable to saving an individual of a populous species. Unfortunately, moral conflicts are abundant – not only concerning biodiversity conservation. We often have to choose between harming either entity A or entity B – for example in the daily questions of food and eating. In such cases, a strictly egalitarian theory (especially an egalitarian biocentric one) would be no real help and without any guiding power. Therefore, on a second level of morality, we have to include additional criteria that help to minimize the overall harm. For these criteria to be objective, universalizable, and thus moral ones, I apply a number of widely accepted ethical principles like the principle of proportionality, impartiality, self-defense, and universalizability. By recurring to these principles, I identify a set of morally relevant criteria for a fair resolution of moral conflict situations which help to minimize the overall harm done. The identified criteria are: (phylogenetic) nearness, endangerment, r- or K-selected species, evolutionary distinctiveness, ability to regrow and to regenerate, pain-susceptibility, and ecosystematic role. In sum, my gene-centric environmental ethical theory provides numerous reasons and arguments for biodiversity conservation – for protecting genes, organisms, species, and ecosystems alike – without neglecting the needs of humans.
Background: Abdominal surgery is frequently followed by immune dysfunction usually lasting for several days. This is especially important in cases with tumour diseases as an intact immune function is essential in this situation. Therefore, we analysed the outcome of tumour-bearing mice in a mouse model of surgically induced immune dysfunction (SID). Methods: In male C57BL/6 mice, a pancreatic tumour was implanted orthotopically. Following tumour implantation, the model of SID was applied. The control groups were either laparotomised or underwent no surgical procedure. The survival rate was determined by observation for >60 days. The tumour growth progress was imaged by a 7-tesla small animal MRI. Results: On day 60 after tumour implantation, the survival rate in SID mice was reduced to 41%. In the laparotomised group, 81% of mice survived, while the control group had a survival rate of 75%. These differences were significant (SID vs. control: p < 0.02, and SID vs. laparotomy: p < 0.002). The tumour volume was not influenced by the degree of surgical trauma. Conclusion: In pancreatic cancer, the SID model is ideally suited to investigate the influence of SID on this tumour entity.
Simulations of Short Model Peptides and Practically Relevant Modeled Titanium Implant Surfaces
(2014)
One of the aims of this work was to generate a non restrained force field model including carbon contamination to make the adsorption simulations more realistic and comparable with experimental data. Another purpose was to find out how the special recognition of small linker proteins on titanium dioxide is working. During this work a fixed and a non restrained rutile (100) model was used and critical properties were observed which are not only related to the surface. The rigid water layers on top of the oxide are very important for the protein and peptide adsorption. Therefore the first discussing object were the properties of the water layers and how they can be influenced. The charge distribution on the surface was found to have a big effect on them. Depending on the charges of the surface atoms or the functional groups, resulting out of the hydroxylation equilibrium, precisely the first water layer gets more rigid or smother. This has a big effect on biomolecule adsorption. The peptides need to penetrate these water layers to generate direct interaction points. The correct description of the surface in molecular dynamic simulations therefore has a high influence on the results. The better the model is the better the findings are comparable with experimental ones. Additionally carbon contamination was mimicked by using a monolayer of pentanol molecules. This fits very good with experimental data (e.g. contact angle) and make the oxide model more hydrophobic. Interaction of proteins and peptides in experiments or in medical use are often observed under normal air conditions, which means that the scaffold is i) hydroxylated by water and ii) carbon contaminated in a short period of time. Therefore investigations were done to find out how the contamination influences the adsorption of a formally know good or bad binding peptide (TiOBP1; TiOBP2). It was found that the TiOBP1 is able to bind the different surface modifications very well which coincides with observations made in experiments. The way of adsorption (direct or indirect) depends on the water layers properties. The first layer on high charged surface models is that rigid, that the peptide is not able to adsorb in a direct way. On the carbon contaminated oxide model the adsorption is possible by reducing the flexibility of the secondary structure motive. In the case of TiOBP2 adsorption on the clean surface model results in only weak binding or even in no interaction. Whereas on the carbon contaminated dioxide the once know bad binder is able to interact with the Pentanol monolayer. No direct adsorption is observed but the hydrophobic side chains have the possibility to orient themselves according to the hydrophobic layer without changing significantly in the secondary structure motive. An additional test peptide (minTBP) adsorbs without being affected by the contamination. This raises the question if the distribution of hydrophobic to hydrophilic amino acids has influence on the adsorption ability according to clean and contaminated surface. For experimental application it could be of interest to generated peptides (GEPI´s) which bind both surface types without changing the secondary structure motives then as we know functionality is based on these structures. In the case of the PHMB polymer adsorption was observed depending on the hydroxylation ratio and therefore on the charge density of the rutile (100) surface. After analysis of the simulations takeaways from experiments could be substantiated. The PHMB interacts with the negative charged surface via the first water layer as a film. So the new force field model describing the rutile (100) titanium dioxide surface with additional carbon contamination model of one monolayer pentanol fits the experimental data very well. The adsorption studied on this surfaces indicates that the contamination as expected makes the surface more hydrophobic and influences the adsorption behavior of the tested peptides especially the secondary structure of TiOBP1. This indeed enhances experimental investigations. Peptides which e.g. link organic and inorganic parts should be good adsorbing on clean and contaminated surfaces by keeping their functionality. Furthermore experimental data can be substantiated by using atomistic simulations like in the case of PHMB adsorption.
Type 2 diabetes mellitus is one of the most challenging health problems for the next decades. The impact of type 2 diabetes mellitus on health care systems is largely driven by the increasing prevalence, the management of the disease and subsequent comorbidities, even in people with prediabetes or undiagnosed type 2 diabetes mellitus. An early detection of high risk groups is necessary to identify and modify risk factors such as obesity, physical inactivity or cigarette smoking which showed regional disparities in their distribution within a country. This leads to the assumption that there might be regional disparities regarding the prevalence and incidence of type 2 diabetes mellitus as well. For Germany as for other countries, comparable data on possible regional disparities in the prevalence and incidence of type 2 diabetes mellitus are missing. The aim of the present dissertation is to estimate the prevalence and incidence of type 2 diabetes mellitus on regional level within Germany, and to estimate the smoking prevalence as a modifiable risk factor in individuals with type 2 diabetes mellitus using data from the Diabetes Collaborative Research of Epidemiologic Studies consortium (DIAB CORE) within the Competence Net Diabetes in Germany. Well comparable data of five regional studies and one nationwide reference study are included: the Study of Health in Pomerania (SHIP); the Cardiovascular Disease, Living and Ageing in Halle Study (CARLA); the Dortmund Health Study (DHS); the Heinz Nixdorf Recall Study (HNR); the Cooperative Health Research in the Region of Augsburg Study (KORA); and the German National Health Interview and Examination Survey 1998 (GNHIES 98). First, the prevalence of type 2 diabetes mellitus was estimated. Data from five regional population-based studies and one nationwide study conducted between 1997 and 2006 with participants aged 45 to 74 years were analyzed. Type 2 diabetes mellitus prevalence estimates based on self-reports (standardized to the German population for the regional studies, reference date 2007/12/31) were compared. Of 11,688 participants of the regional studies, 1,008 had a known type 2 diabetes mellitus, corresponding to a prevalence of 8.6% (95% confidence interval [CI] 8.1% 9.1%). The standardized prevalence was highest in the East with 12.0% (95% CI 10.3% 13.7%) and lowest in the South of Germany with 5.8% (95% CI 4.9% 6.7%).Second, the incidence of type 2 diabetes mellitus was estimated. Data from participants (baseline age 45 to 74 years) from five regional population-based studies were included. The incidence rates per 1,000 person-years (95% CI) and the cumulative incidence (95% CI) from regional studies were directly standardized to the German population (reference date 2007/12/31) and weighted by inverse probability weights for losses to follow-up. Of 8,787 participants, 521 (5.9%) developed type 2 diabetes mellitus corresponding to an incidence rate of 11.8 per 1,000 person-years (95% CI 10.8 12.9). The incidence of known type 2 diabetes mellitus showed regional disparities within Germany. The incidence was highest in the East and lowest in the South of Germany with 16.9 (95% CI 13.3 21.8) vs. 9.0 (95% CI 7.4 11.1) per 1,000 person-years, respectively. Third, the smoking prevalence in participants aged 20 to 79 years with type 2 diabetes mellitus in the regional SHIP and the nationwide GNHIES 98 was estimated. Prevalence estimates of cigarette smoking were calculated using weights reflecting the European adult population (reference date 2005/12/31). The overall prevalence of current smoking was lower among participants with type 2 diabetes mellitus than among participants without type 2 diabetes mellitus (17.3% vs. 38.0% in SHIP and 24.7% vs. 32.1% in GNHIES 98). In both studies, the prevalence of current smoking was highest in men aged 20 to 39 years, in particular among men with type 2 diabetes mellitus. To conclude, considerable disparities in prevalence and incidence of type 2 diabetes mellitus indicate the need for interventions on the regional level within Germany. Former smoking was more prevalent among both men and women with type 2 diabetes mellitus in comparison to current and non-smoking. This finding probably reflects behavioural changes secondary to the disease onset and medical counselling. The finding that men aged 20 to 39 years with type 2 diabetes mellitus were more often current smokers than men without type 2 diabetes mellitus underpins the importance of smoking as one of the main modifiable risk factors for type 2 diabetes mellitus.
Modern cavity QED and cavity optomechanical systems realize the interaction of light with mesoscopic devices, which exhibit discrete (atom-like) energy spectra or perform micromechanical motion. In this thesis we have studied the crossover from the quantum regime to the classical limit of two prototypical models, the Dicke model and the generic optomechanical model. The physical problems considered in this approach range from a ground state phase transition, its dynamical response to general nonequilibrium dynamics including Hamiltonian and driven dissipative chaotic motion. The classical limit of these models follows from the classical limit of at least one of its subsystems. The classical equations of motion result from the respective quantum equations through the application of the semiclassical approximation, i.e., the neglect of quantum correlations. The approach of the results from quantum mechanics to the prediction of the classical equations can be obtained by subsequently decreasing the respective scaling parameter. In order to obtain exact results we have utilized advanced numerical methods, e.g., the Lanczos diagonalization method for ground state calculations, the Kernel Polynomial Method for dynamical response functions, Chebyshev recursion for time propagation, and quantum state diffusion for open system dynamics. We have studied the quantum phase transition of the Dicke model in the classical oscillator limit. Our work shows that in this limit the transition occurs already for finite spin length but with the same critical behavior as in the classical spin limit. We have derived an effective model for the oscillator degrees of freedom and have discussed the differences of both classical limits with respect to quantum fluctuations around the mean-field ground state and spin-oscillator entanglement. In this thesis we have proposed a variational ansatz for the Dicke model which extends the mean-field description through the inclusion of spin-oscillator correlations. The ansatz becomes correct in the limit of large oscillator frequency and in the limit of a large spin. For the latter it captures the leading quantum corrections to the classical limit exactly including the spin-oscillator entanglement entropy. We have studied the dynamics of spin and oscillator coherent states in the nonresonant Dicke model at weak coupling. In this regime periodic collapses and revivals of Rabi oscillations occur, which are accompanied by the buildup and decay of atom-field entanglement. The spin-oscillator wave function evolves into a superposition of multiple field coherent states that are correlated with the spin configuration. In our work we provide a description of the underlying dynamical mechanism based on perturbation theory. Our analysis shows that collapse and revival at nonresonance is distinguished from the resonant case treated within the rotating wave approximation by the appearance of two time scales instead of one. We have extended our study of the Dicke dynamics to the case of increasing spin length, as the system approaches the classical spin limit. We described the emergence of collective excitations above the ground state that converge to the coupled spin-oscillator oscillations observed in the classical limit. With increased spin length the corresponding Green functions thus reveal quantum dynamical signatures of the quantum phase transition. For the dynamics at larger coupling and energy, classical phase space drift and quantum diffusion hinders the direct comparison of quantum and classical observables. As we show in our work, signatures of classical quasiperiodic orbits can be identified in the Husimi phase-space functions of the propagated wave function and individual eigenstates with energies close to that of the quasiperiodic orbits. The analysis of the generic optomechanical system complements our study of cavity QED systems by a quantum dissipative system. In this thesis we have shown for the first time, how the route to chaos in the classical optomechanical system takes place, given as a sequence of consecutive period doubling bifurcations of self-induced cantilever oscillations. In addition to the semiclassical dynamics we have analyzed the possibility of chaotic motion in the quantum regime. Our results showed that quantum mechanics protects the optomechanical system against irregular dynamics. In sufficient distance to the semiclassical limit simple periodic orbits reappear and replace the classically chaotic motion. In this way direct observation of the dynamical properties of an optomechanical system makes it possible to pin down the crossover from quantum to classical mechanics.
Staphylococcus aureus is a commensal that colonizes the skin and mucosa of 20-30% of the human population without leading to symptoms of diseases. However, it is also the most important cause of nosocomial infections. Those range from minor skin infections to life-threatening diseases such as pneumonia, endocarditis or septicaemia. Development of strains with resistance against many antibiotics complicates the situation further. The variety of strains with their various properties is one reason why no successful vaccine has been introduced to the market, yet. Therefore, efficient strategies for prevention and therapy of these dangerous infections are urgently needed. To accomplish these goals, the understanding of molecular interactions between host and pathogen is indispensable. Within this dissertation, several internalization experiments were performed aiming to investigate the interaction of S. aureus HG001 and human cell lines upon infection on the protein level. In order to obtain sufficient amounts of proteins for comprehensive physiological interpretations, it is necessary to enrich bacteria, secreted bacterial proteins or infected host cells upon internalization. In the framework of this thesis, bacteria which continuously produce green fluorescent protein (GFP) were employed. With that it was possible to sort bacteria from lysed host cells by flow cytometry or to separate host cells carrying bacteria after contact from those which did not. Subsequently, the proteins were proteolytically digested and peptides were analyzed by mass spectrometry in a gel-free proteomics approach. To allow such analyses also for staphylococci which do not produce GFP, such as clinical isolates, an additional protocol was developed. Prior to the infection, bacteria were labeled with fluorescent or para-magnetic nanoparticles. Afterwards bacteria could be separated from host cell debris by fluorescence-based cell sorting or with the help of a strong magnet. In order to cover also important secreted virulence factors of S. aureus HG001, phagosomes and engulfed bacteria and secreted proteins were isolated from infected host cells. Further steps of protocol optimization included improved bacterial cell counting by fluorescence-based flow cytometry, enhanced data analysis by combination of different search algorithms, and comprehensive functional annotation of proteins of the applied strain by sequence comparison with other strains and organisms. First, the proteome adaptation of internalized S. aureus HG001 and the infected A549 host cells was investigated during the first hours of infection. It became clear, that the bacteria replicate inside the host during the first 6.5 h. After internalization the levels of bacterial enzymes involved in protein biosynthesis decreased. Furthermore, bacteria adapted their proteome to the harsh intracellular conditions such as oxygen limitation, cell wall stress, host defense in terms of oxidative stress, and nutrient limitation. After contact to S. aureus HG001, A549 cells produced increased amounts of cytokines (e.g. IL-8, IFN-γ) in comparison to non-treated A549 cells. In addition, activation of the immunoproteasome and hints of early apoptosis activity were observed. Afterwards, the response of S. aureus HG001 to internalization by A549, S9 or HEK 293 cells was compared on the proteome level. It was obvious, that the adaptation to stress and the reduced protein synthesis are conserved mechanisms. Host dependent differences were detected especially in the energy metabolism and the synthesis of some amino acids. Additionally, bacteria showed different intracellular replication patterns depending on the host cell line. A higher percentage of extracellular bacterial proteins was found in isolated phagosomes compared to the sorted samples. Selected low abundant virulence factors could be quantified at two points in time after infection with the help of the sensitive single reaction monitoring (SRM) method. Further, a heterogeneous mixture of several phagosomal maturation steps was present during the first 6.5 h after infection. Finally, the gel-free proteome analyses could be applied to investigate Bordetella pertussis, the cause of whooping cough, during iron limitation and after internalization, and the results were compared to the S. aureus HG001 data.
Prostate volume estimation in MR images for epidemiological and clinical studies – new methods
(2014)
Benign prostatic hyperplasia (BPH) is one of the most widespread diseases among men older than 50 years. The literature provides various cut-off values for pathological enlargement of the prostate. Prostate volume (PV) measurement in large population-based studies would allow deriving more objective reference values and a more valid early BPH diagnosis. A fully automated method is therefore required. In the clinical context, the measurement of the PV is important for treatment response monitoring in the clinical applications for BPH management research, and an accurate method for PV is essential. Magnetic Resonance Imaging was used for PV estimation. Two methods based on the Support Vector Machines (SVM) were developed: the binary Support Vector Machines (C SVM)-based method for epidemiological studies and the single-class Support Vector Machines (S SVM)-based method for clinical studies. The second method was additionally compared to the ellipsoid formula for PV estimation, which is widespread in the clinic. The comparison between volume measurement of the C SVM-based method and manual delineation of observers A and B yielded a strong correlation (Spearmans rank correlation coefficients ñ of 0.936 [p < 0.001] and 0.859 [p < 0.001], respectively). Comparing the C SVM-based method and the two manual delineations by observers A and B shows an agreement with a mean difference of 3.0 ml (95% confidence interval of -3.1 to +9.2 ml) and 1.9 ml (95% confidence interval of −7.1 to +10.8 ml), respectively. The S SVM-based method and the reference PV (manual delineation of observer A) show excellent correlation (Spearmans rank correlation coefficient ñ = 0.965, p < 0.001), while the ellipsoid formula is less well correlated with the reference PV (Spearmans rank correlation coefficient ñ = 0.873, p < 0.001). The mean difference between S SVM and the reference PV was −0.05 ml (95% confidence interval of −3.8 to +3.7 ml); on the other hand, the mean difference between the ellipsoid formula and the reference PV was much greater, with 8.6 ml (95% confidence interval of +1 to +16.2 ml). The C SVM-based method has considerable potential for integration in epidemiological studies. The prostate volumes obtained by the S SVM-based method agreed excellently with the reference and would be clinically useful for urologists in prostate volumetric analysis.
Abstract
The presented experimental system is a barrier discharge system with plane parallel electrodes. The lateral surface charge distribution being deposited on the dielectric layer during each breakdown is observed optically using the well known electro-optic effect (Pockels effect). The temporal resolution of the surface charge measurement has been increased to 200 ns, and so for the first time it is possible to resolve the charge transfer to the dielectric surface in a single breakdown. In the present measurements, a patterned glow-like barrier discharge is investigated. It is found that the charge reversal in a single discharge spot (microdischarge) starts in the centre and then grows outwards. These experimental findings verify previously unconfirmed predictions from earlier numerical calculations and thereby contribute to a better understanding of the interaction between the plasma and the electrical charge on the electrodes.
Abstract
Experimental studies on dusty plasmas containing systems of (super-)paramagnetic dust particles are presented. In our experiments, external (homogeneous as well as inhomogeneous) magnetic fields in the mT range are applied to study the effect on single particles or few-particle systems that are trapped inside the sheath region. The behavior of the paramagnetic dust particles is considerably different than that of dielectric plastic particles, which are widely used in dusty plasmas. It is revealed that especially non-magnetic contributions play an important role in the interaction between superparamagnetic particles.
Inflammation is part of the body's immune response in order to remove harmful stimuli—like pathogens, irritants or damaged cells—and start the healing process. Recurrent or chronic inflammation on the other side seems a predisposing factor for carcinogenesis and has been found associated with cancer development. In chronic pancreatitis mutations of the cationic trypsinogen (PRSS1) gene have been identified as risk factors of the disease. Hereditary pancreatitis (HP) is a rare cause of chronic pancreatic inflammation with an early onset, mostly during childhood. HP often starts with recurrent episodes of acute pancreatitis and the clinical phenotype is not very much different from other etiologies of the disease. The long-lasting inflammation however generates a tumor promoting environment and represents a major risk factor for tumor development This review will reflect our knowledge concerning the specific risk of HP patients to develop pancreatic cancer.
The Atomic Force Microscope (AFM) has become an important tool for probing the mechanical properties of cells and microparticles by force-indentation experiments. In this thesis optimized AFM approaches for these experiments are developed and applied to three types of living human cells in order to answer biologically relevant questions about their mechanics. These microscopic investigations are then interpreted with respect to nanoscopic and macroscopic biologic parameters, such as the function of cell surface receptors or the size of human heart ventricles. This thesis comprises two physical/technical chapters and three medical/biological chapters. The physical/technical chapters discuss the measurement process itself, aiming for its improvement with respect to a proper data analysis and contact model (for spherical cells). The medical/biological chapters investigate the elasticity of cells by the use of optimized AFM approaches, with respect to the used data analysis.