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Microsporidia are a group of parasites that infect a wide range of species, many of which play important roles in agriculture and human disease. At least 14 microsporidian species have been confirmed to cause potentially lifethreatening infectious diseases in both immunocompromised and immunocompetent humans. Approximately 1,400 species of microsporidia have been described. Depending on their host and habitat they are classified into three groups, the aquasporidia, the terresporidia and the marinosporidia.
Microsporidia were originally classified as fungi by Naegeli (1857). However, their lack of typical eukaryotic components – such as mitochondria, Golgi bodies or peroxisomes – suggested to place the microsporidia together with other amitochondriate protists within the Archezoa kingdom. This "microsporidia-early" hypothesis was further supported by molecular phylogenies inferred from individual genes. Despite this evidence, the placement of microsporidia as an early branching eukaryote remained a topic for debate. The phylogeny of microsporidia is prone to suffer from biases in their reconstruction. The high evolutionary rate of microsporidian proteins tends to place these proteins together with other fast evolving lineages, a phenomenon known as long-branch attraction. In 1996, the first molecular phylogenetic studies placed the microsporidia inside the fungi.
Subsequently, several further studies located the microsporidia at different positions inside the fungal clade. Since then, microsporidia have been considered as members of the Ascomycota, Zygomycota, Cryptomycota, or as a sister group to the Ascomycota and Basidiomycota, or even as the sister group of all fungi.
The difficulties in determining the evolutionary origin of microsporidia are not only caused by their lack of several cellular components but also by their reduced genomes and metabolism. Being obligate intracellular parasites, microsporidia successfully reduced their genome sizes, down to the range of bacteria. As the smallest eukaryotic genome described so far, the genome of Encephalitozoon intestinalis is just 2.3 Mbp, about half the size of the one of Escherichia coli. Due to their low number of protein coding genes (less than 4,000), microsporidia are thought to retain only genes essential for their survival and development. Furthermore, several key metabolic pathways are missing in the microsporidia, such as the citric acid cycle, oxidative phosphorylation, or the de novo biosynthesis of nucleotides. As a result they are in an obligatory dependence on many primary metabolites from the hosts. However, the presence of hsp70 protein suggests a more complex genome of the microsporidian ancestor. Consequently, the small microsporidian genomes and the reduced metabolism would be consequences of a secondary loss process that molded the contemporary microsporidia from a functionally more complex ancestral species. However, it remains unclear whether the last common ancestor (LCA) of the microsporidia was already reduced, or whether the genome compaction was lineage-specific and started from a more complex LCA.
We investigated the evolutionary history of the contemporary microsporidia through the reconstruction and analysis of their LCA. As a first step in our analysis, we have developed and implemented a software facilitating an intuitive data analysis of the large presence absence-patterns resulting from the tracing of microsporidian proteins in gene sets of many different species. These so called phylogenetic profiles can now be dynamically visualized and explored with PhyloProfile. The software allows the integration of other additional information layers into the phylogenetic profile, such as the similarity of feature architecture (FAS) between the protein under study and its orthologs. The FAS score can be displayed along the presence-absence pattern, which can help to identify orthologs that have likely diverged in function. PhyloProfile closes the methodological gap that existed between tools to generate large phylogenetic profiles to delineate the evolutionary history and the contemporary distribution of large – and ultimately complete – gene sets, and the more function-oriented analysis of individual protein. In the next step we tackled the problem of how to transfer functional annotation from one protein to another. We have developed HamFAS that integrates a targeted ortholog search based on the HaMStR algorithm with a weighted assessment of feature architecture similarities (FAS) between orthologs. In brief, for a seed protein we identify orthologs in reference species in which proteins have been functionally annotated based on manually curated assignments to KEGG Ortholog (KO) groups. The FAS scores between the orthologs and seed proteins are calculated. Subsequently, we compute pairwise FAS scores for all reference proteins within a KO group. A group's mean FAS score serves then as cutoff that must be exceeded to warrant transfer of its KO identifier to the seed. A benchmark using a manually curated yeast protein set showed that HamFAS yields the best precision (98.5%) when compared with two state-of-the-art annotation tools, KAAS and BlastKOALA. Furthermore, HamFAS achieves a higher sensitivity. On average HamFAS annotates almost 50% more proteins than KAAS or BlastKOALA.
With this extended bioinformatics toolbox at hand, we aimed at reconstructing the evolutionary history of the microsporidia. We generated a robust phylogeny of microsporidia using a phylogenomics approach. As a data basis, we identified a set of microsporidian proteins encoded by 80 core genes with one-to-one orthologs. A maximum likelihood analysis of this data
with 48 fungi and additionally in 13 species from more distantly related such as animals and plants combined in a supermatrix strongly supported the hypothesis that microsporidia form the sister group of the fungi. We confirmed that the data explains this microsporidia-fungi relationship significantly better than any other of the previously proposed phylogenetic hypotheses.
On the basis of this phylogeny, and of the phylogenetic profiles of microsporidian proteins, we then focused on reconstructing the dynamics microsporidian genome evolution. Between 2% of the proteins in the compact microsporidia Encephalitozoon intestinalis and up to 49% of the proteins of Edhazardia aedis are private for individual microsporidian species. A comparison of the sequence characteristics of these proteins to that of proteins with orthologs in other microsporidian species revealed individual differences. Yet, without further evidences it remains unclear whether these private genes are indeed lineage-specific innovations contributing to the adaptation of each microsporidium to its host, or whether these are artifacts introduced in the process of gene annotation. A total of 14,410 microsporidian proteins could then be grouped into 1605 orthologous groups that can be traced back to the last common ancestor of the microsporidia (LCA set). We found that 94% of the microsporidian LCA proteins could be tracked back to the last eukaryotic common ancestor. The high evolutionary age of these proteins, together with the resistance against gene loss in the microsporidia suggests that the corresponding functions are essential for eukaryotic life. Further 3% of the LCA proteins could be dated to the common ancestor microsporidia share with the fungi. Only 3% of the LCA proteins appear as microsporidia specific inventions. These proteins are potentially of importance for the evolutionary of the obligate parasitic lifestyle nowadays shared by all microsporidia.
The functional annotation and metabolic pathway analysis of the microsporidian LCA protein set gave us more insight into the adaptation of the microsporidia to their parasitic lifestyle and the origin of the microsporidian genome reduction. The presence of E1 and E3 components of the pyruvate dehydrogenase complex and the mitochondrial hsp70 protein support an ancestral presence of mitochondria in the ancestral microsporidia. In addition, several ancient proteins that complement gapped metabolic pathways were found in the microsporidian LCA. They suggested a more complex genome and metabolism in the LCA. However, our reconstruction of the metabolic network of the microsporidian LCA still lacks many main pathways. For example, the TCA cycle for effective energy production, and key enzymes that are required for in vivo synthesis of critical metabolites like purines and pyrimidines appear absent. We therefore find that the parasitic lifestyle and the genome reduction already occurred in the microsporidian LCA. This ancestral state was followed by further losses and gains during the evolution of each individual microsporidian lineage.
This thesis presents the first measurement of the proton capture reaction on the isotope 124Xe performed in inverse kinematics. The experiment was carried out in June 2016 at the Experimental Storage Ring (ESR) at the GSI Helmholtz Centre for Heavy Ion Research in Darmstadt, Germany.
124Xe is one of about 35 p-nuclei that cannot be produced via neutron-induced nucleo- synthesis as the vast majority of heavy elements. Its production and destruction provide important information about the nucleosynthesis of the p-nuclei. Measuring the 124Xe(p,g)125Cs reaction also gives strong constraints for its reverse 125Cs(g,p)124Xe reaction.
Fully stripped 124Xe ions repeatedly passed a H2 gas jet target at five different energies between 5.5 MeV/u and 8 MeV/u. An electron cooler compensated for the energy loss in the target and reduced the beam momentum spread. The reaction product 125Cs55+ has a smaller magnetic rigidity than 124Xe54+. Therefore 125Cs55+ was deflected towards smaller radii in the first dipole after the target area and thereby separated from 124Xe54+. It was detected with a position-sensitive Double-Sided Silicon Strip Detector (DSSSD). The novelty of this experiment was the installation of the DSSSD inside the ultra-high vacuum of the storage ring using a newly designed manipulator.
Three High-Purity Germanium X-ray detectors were used to measure the X-rays following the Radiative Electron Capture (REC) events into 124Xe53+. The REC cross sections are well-known and were used to determine the luminosity.
The 124Xe(p,g)125Cs cross sections at ion beam energies between 5.5 MeV/u and 8 MeV/u were determined relatively to the K-REC cross sections and finally compared to the theoretically predicted cross sections. While theoretical predictions of the TENDL database are lower than the measured ones by a factor of up to seven, the NON-SMOKER data are higher by a factor of up to two, except of the cross section at 7 MeV/u, where NON-SMOKER data are slightly lower than the experimental value.
For the first time, a proton capture cross section could be measured in inverse kinematics close to the astrophysically relevant Gamow window. This allows the direct determination of the (p,g) cross section of isotopes with half-lives down to several minutes, which is not possible with any other technique.
In this thesis we work on the theoretical description of relativistic heavy-ion collisions, focussing on electromagnetic probes. We present mainly four topics: electric conductivity and diffusion properties of the hot plasma and hadronic matter, response of the quark-gluon plasma to external magnetic fields, direct photon production in the quark-gluon plasma and a study about initial and final state effects in small systems. The latter topic aims, i.a., at a better understanding of the initial state, which is crucial for electromagnetic probes. In all research areas we make use of the Boltzmann transport equation, whereby the presented methods provide analytical and numerical solutions. We pay particular attention to the construction of complete leading order photon production processes in numerical transport simulations of the quark-gluon plasma.
To begin with, our findings are the complete conserved charge diffusion matrix and electric conductivity. Those properties are important ingredients, e.g., for future simulations of baryon rich collisions. Next, we find that the influence of external magnetic fields to the QGP dynamics is not quantifiable in observables.
We present results for a variety of direct photon observables and we can partly explain experimental data. We emphasize the importance of the chemical composition and non-equilibrium nature of the medium to the direct photon puzzle. Lastly, we observe the interesting dynamic behavior of azimuthal correlations in small systems and identify signatures of the initial state in final observables. This will also be of interest for more precise simulations of electromagnetic probes and allows for various future studies.
Whereas many writers across all times and cultures have written about the potential aesthetic effects of music experiences which could be labeled as absorption, only limited empirical research has been done on the state aspects of this fascinating aspect of human involvement. What is more, there are still few tested models which explain how people can be absorbed by a piece of music as well as continue to be third-person observers monitoring and even reflecting on that same musical experience.
Adopting a dual process approach – in which human thinking, emotion, and routes to appraisal are defined in terms of an interplay between two distinct systems of psychological processing – this thesis aimed to examine a) the cognitive mechanisms underlying the paradox of losing oneself in the music on the one hand, and meta-awareness on the other, b) its corresponding psychophenomenological profile(s) when listening intentionally to self-chosen music, and c) the different potential of state and trait aspects of absorption and meta-awareness in predicting three indicators of the aesthetic response to music: enjoyment, lasting impression, and behavioral intention.
To this end, a quantitative empirical research method (state and trait questionnaires) was employed in a series of online surveys, using self-selected music as well as pre-determined music by the researcher as stimulus, together approaching a naturalistic listening setting.Aesthetic absorption was confirmed to be structured– in terms of dual process terminology – by intuitive type I and reflective type II processing. Two forms of music absorption were empirically
identified and labeled as zoning in and tuning in. These experience profiles distinguished themselves significantly in terms of the degree in which a music listener maintained his or her meta-awareness, assessed via volitional control, rationality, self-awareness, and memory of the previous event. The overall pattern of consciousness parameters of both types of absorbed listening are suggestive of a unique interchanging between brain networks for intuitive processing and areas related to self-reference, -awareness and -control. The distinction between zoning in and tuning in was further found to be strongly related to the quality of affective state.
These emotions modulate the experiential intensity of absorption, suggesting this experience to be an affect-biased type of attention. Based on the feelings-as-information theory, postulating that positive emotions are differently processed than negatively-tinted types of emotions, it was
concluded that music-induced rumination ‘competes’ with higher-order functions relevant to meta-awareness. From this perspective, the two found absorption types match conceptually with the positively-tinged self-reflection and negatively-tinged self-rumination as two different types of self-focused introspection. It was also shown that being absorbed by music is a continuous phenomenon; a matter of ‘more-or-less’ involvement rather than a ‘unique state of mind’. Consequently, determining ‘music absorbers’ is a matter of imprecise estimation rather than being marked by a clear observable onset. Finally, as expected, an absorbed state of mind - operationalized here as a multidimensional bifactor model – completely mediated the effect of trait absorption, and was a good predictor for enjoyment, lasting impression, and behavioral intention.
Whereas absorption and enjoyment were found to have a mutual positive effect on each other, absorption and meta-awareness were found to be unrelated to each other. Also, meta-awareness contributed little to aesthetic appreciation. The results confirm the need for a dynamic approach to the relationship between state absorption and enjoyment; the one-directional approach common in many research reports does not seem to fully capture the relationship between them. Taken together, this dissertation shows the potential of including the interplay between the trait and state constructs of absorption and meta-awareness in order to better understand the mechanisms underlying aesthetic experiences with music. The present work demonstrated that these two constructs should not be conflated. Moreover, this thesis underlined the power of absorption not only to evoke short-lived pleasurable experiences, but also to stimulate longlasting impressions. Knowing more about absorbed listening and its potential effects, learning to consciously recognize it as it happens, and perhaps regulate and maintain its positive consequences (i.e., savoring), could further improve the way we engage ourselves with music or other aesthetic objects. Only then could we engage in behavior that we’re sure would make us happy rather than seeking out experiences which we hope would make us happy.
In conclusion, I described for the first time the in vivo functions of PAK2 during cardiac development and its requirement for heart contractility
AIM1 – Characterization of Pak2a and Pak2b functions during cardiovascular system development: description of the phenotype triggered by the loss of expression of pak2b in the pak2a mutant Firstly, in addition to the confirmation of the published data regarding the pak2a mutant and morphant phenotype, I showed that pak2bbns159 mutant does not exhibit morphological defects, neither in the ISV formation nor in the brain vascular patterning. More importantly, I analyzed in more details the phenotypic consequences of pak2a and pak2b loss of expression in the trunk and brain vasculatures. Indeed, the lack of blood flow in the embryos, was associated with central arteries migration defects and reduced lumen in these central arteries and the ISVs. Moreover, pak2a and pak2b loss of expression resulted in cardiac failure.
AIM2 – Role of Pak2 on cardiac contractility From 40 -46 hpf, I found a weaker heart contractility in the pak2ami149/mi149;pak2bbns159/bns159. Although, the PAK proteins have been shown to impact the actin cytoskeleton organization, the heart morphological defects associated with the altered contractility, were not associated with acto-myosin filament reorganization. However, by analyzing in more details the structure of the sarcomeres, I was able to demonstrate that the proteins constituting the sarcomeres were strongly affected and showed an altered spatial organization. Then, I also described the effects of the loss of expression of both paralogs on the junctional protein localization. I demonstrated the loss of Pak2 function resulted in junction protein rearrangement in the cardiomyocytes in the pak2ami149/mi149;pak2bbns159/bns159 mutants at 40 and 46 hpf.
Thus, I was able for the first time to demonstrate in vivo PAK2 functions during cardiac development and its requirement for proper cardiac contractility activity.
AIM3 – Decipher mechanism of Pak2 signaling cascade involved during cardiac development Both pak2a and pak2b WT mRNAs were able to rescue the pak2ami149/mi149;pak2bbns159/bns159 mutant heart defects and the results indicated that these paralogs share overlapping function during cardiac development. Moreover, although I was not able to examine the control transgenic lines, myocardial and endothelial specific pak2a overexpression did not ameliorate the mutant cardiac deficiency. Thus,the absence of rescue by reactivating pak2a in cardiomyocytes indicates a non-cell autonomous function of Pak2a on cardiomyocytes.
For the first time, this study allowed to follow PAK2 in vivo functions during cardiovascular development. More importantly, its role on heart contractility regulation would enable further investigations to generate new tools for the treatment of cardiomyopathies.
Die vorliegende Untersuchung wurde mit dem Ziel durchgeführt, fördernde und hemmende Einflussfaktoren auf die Entstehung und Durchführung von translationaler Forschung näher bestimmen zu können. Dazu wurden im Verlauf der Forschung sechs Gruppen von möglichen Einflussfaktoren untersucht. Diese waren 1) externe politische, 2) institutsbezogene, 3) soziale (auf soziale Rollen und sozialen Status bezogene), 4) epistemische, 5) forschungskulturelle und 6) individuelle Faktoren.
Translationale Forschung wurde als Spezialform interdisziplinärer Forschung konzeptualisiert. Auch bei dieser wird Wissen aus mehr als einer wissenschaftlichen Disziplin herangezogen, um ein disziplinübergreifendes Problem zu lösen. Das Besondere an der translationalen Forschung ist jedoch, dass zusätzlich mindestens eine der beteiligten Disziplinen grundlagenorientiert und eine andere anwendungsorientiert ist. Der Vorteil besteht darin, dass fortan der Wissensbestand beider Disziplinen kombiniert werden kann. Ein Nachteil ergibt sich daraus, dass die Wissensbestände untereinander nicht ohne Weiteres anschlussfähig sind und eine „Übersetzung“ durch die unterschiedlichen Praxisbezüge der beteiligten Disziplinen erschwert wird. Die translationalen Forschung muss neben dieser noch einer weiteren Herausforderung begegnen: Denn sie gewinnt ihre Erkenntnisse unter Laborbedingungen, wo Umweltfaktoren praktisch keine Rolle spielen. Dadurch lassen sich ihre Ergebnisse nicht unbedingt in die klinische Praxis transferieren. Kurz gesagt: Was im Labor eine bestimmte Wirkung erzielt hat, entfaltet diese Wirkung nicht automatisch am Patienten.
Im Rahmen der Dissertation wurden sechs translationale Forschungsprojekte aus Berlin-Buch aus der Zeit zwischen 1959 und 1989 untersucht. Aufgrund der in der DDR etablierten, staatlichen Überführungspolitik konnte insbesondere der Einfluss externen politischen Drucks auf diese Forschungsprojekte untersucht werden. Als Quellen dienten archivierte Akten, graue Literatur, zur damaligen Zeit publizierte Fachliteratur und Interviews mit Forschern, die damals an diesen Projekten beteiligt waren. Da es an soziologischer Literatur spezifisch zu translationaler Forschung bisher mangelt, wurden mehrere Einzelstudien aus der soziologischen und wissenschaftshistorischen Forschung herangezogen. Die Untersuchungsergebnisse erweitern den Forschungsstand zur interdisziplinären Forschung und zu Praxisbezügen von Forschung.
Die untersuchten Fallstudien zeigen exemplarisch, dass es die von der Staatsführung der DDR gewollten anwendungsorientierten medizinischen Forschungsprojekte auch in Berlin-Buch gegeben hat. Entgegen der Erwartung zeigen sie aber auch, dass translationale Forschung nicht speziell gefördert (mit Ressourcen oder einem besonderen Commitment) wurde und es somit oft vom Zufall abhängig war, ob diese (vorzeitig) beendet wurde oder nicht. Darüber hinaus konnten Anhaltspunkte dafür gefunden werden, dass translationale Forschung im Wesentlichen auf epistemischen (fachlichen) Schnittstellen beruht, die von anwendungsorientierten Biomedizinern meist aus persönlichem Interesse aufgegriffen werden, wenn sie als solche erkannt werden und wenn entsprechende Ressourcen zur Forschung zur Verfügung stehen.
Somit konnte widerlegt werden, dass das so genante „Translationsproblem“ darauf zurückzuführen ist, dass Kliniker und Forscher kein Interesse haben, miteinander zu kommunizieren oder zu forschen. Ein Problem stellt lediglich dar, dass epistemische Schnittstellen meist zufällig (oft als Nebenprodukte von disziplinärer Forschung) sichtbar werden und es an kurzfristig verfügbaren Ressourcen fehlen kann, um diesen nachzugehen. Hinzu kommt der erhöhte Aufwand, der sich durch das Einbeziehen von Forschern aus anderen Disziplinen ergibt und das vergleichsweise hohe Risiko, dass medizinische Anwendungen, die auf translationaler Forschung aufbauen, unter komplexen Umweltbedingungen (am Patienten) nicht mehr die gewünschte Wirkung entfalten. Die untersuchten Fallstudien haben jedoch auch gezeigt, dass translationale Infrastrukturen und regelmäßiges Peer Review Forschern dabei helfen können, Ergebnisse translationaler Forschung auf ihre Tauglichkeit in der Klinik zu prüfen. Das Risiko des Scheiterns lässt sich jedoch nicht vollständig ausschließen.
Seit einigen Jahren ist bekannt, dass Sphingolipide nicht nur eine strukturgebende Funktion in der Plasmamembran aufweisen, sondern ebenfalls als Botenstoffe intra- und extrazellulär aktiv sind. Sphingosin-1-Phosphat (S1P) bildet dabei einen Schlüssel-Metaboliten, da es verschiedene Zellfunktionen wie Wachstum und Zelltod beeinflusst. Es wird durch zwei Isoformen der Sphingosinkinasen, SK1 und SK2, gebildet. Die SK1 wurde bereits gut untersucht und es konnte gezeigt werden, dass sie eine wichtige Rolle beim Zellwachstum einnimmt und einen entscheidender Regulator bei inflammatorischen Erkrankungen und Krebs darstellt. Über die SK2 ist soweit wenig bekannt und die Ergebnisse sind zum Teil kontrovers. Sowohl pro-proliferative als auch anti-proliferative Funktionen der SK2 wurden beschrieben. Andererseits handelt meine Arbeit von Nierenfibrose, da beschrieben wurde, dass Sphingolipide einen wichtigen Einfluss auf die Entwicklung chronischer Nierenerkrankungen nehmen. Nierenfibrose stellt das Endstadium chronischer Nierenerkrankungen dar und führt zu einer Akkumulation der Extrazellulärmatrix, Organvernarbung und zum Verlust der Nierenfunktion. Die SK1 spielt dabei eine protektive Rolle bei der Entstehung von Nierenfibrose. Deshalb sollte in dieser Arbeit die Rolle der Sk2 bei der Entstehung von Nierenfibrose untersucht werden.
Im ersten Teil meiner Arbeit wurde das Mausmodell der unilateralen Ureterobstruktion (UUO) verwendet, welches zur Entwicklung einer tubulointerstitiellen Nephritits und nachfolgender Fibrose führt. Es konnte dabei gezeigt werden, dass sowohl die Protein-Expression als auch die Aktivität der SK2 im fibrotischen Nierengewebe gesteigert wurden. Allgemein wiesen die SK2-/--Mäuse eine verminderte Fibrose in Folge des UUO auf im Vergleich zu den Wildtyp-Mäusen. Dies wurde bestätigt durch eine reduzierte Kollagenakkumulation, sowie eine verminderte Protein-Expression von Fibronektin-1, Kollagen-1, α-smooth muscle actin, connective tissue growth factor (CTGF) und Plasminogen-Aktivator-Inhibitor1 (PAI-1). Diese Effekte gingen einher mit einer gesteigerten Protein-Expression des inhibitorischen Smad7 und erhöhten Sphingosin-Spiegeln in SK2-/--UUO-Nieren. Auf mechanistischer Ebene vermindern die erhöhten Sphingosin-Spiegel die durch transforming growth factor-β (TGFβ) induzierte Kollagenakkumulation, die PAI-1- und CTGF-Expression, aber induzieren die Smad7-Expression in primären Nierenfibroblasten. In einem komplementären Versuch mit hSK2 tg-Mäusen wurde eine verstärkte Entstehung von Nierenfibrose mit erhöhter Kollagenakkumulation, sowie erhöhte Protein-Expressionen von Fibronektin-1, Kollagen-1, α-smooth muscle actin, CTGF und PAI-1 festgestellt. Die Smad7-Expression dagegen war vermindert.
Im zweiten Teil meiner Arbeit stand der glomeruläre Teil der Niere im Fokus und es wurde untersucht, ob die Überexpression der SK2 zu einer phänotypischen Veränderung der glomerulären Mesangiumzellen führt. Mesangiumzellen wurden dazu aus den hSK2 tg-Mäuse isoliert und charakterisiert. Es konnte gezeigt werden, dass hSK2 und mSK2 in den transgenen Zellen hauptsächlich in der zytosolischen Fraktion lokalisiert sind, während S1P ausschließlich im Kern akkumulierte. Weiterhin konnte eine verminderte Proliferation unter normalen Wachstumsbedingungen der hSK2 tg-Zellen im Vergleich zu den Kontrollzellen beobachtet werden. Die Zellen reagierten auch sensitiver auf Stress-induzierte Apoptose. Auf molekularer Ebene konnte dies durch eine reduzierte ERK- und Akt/PKB-Aktivierung erklärt werden. Nach Staurosporin-Behandlung wurde Apoptose durch den intrinsischen, mitochondrialen Apoptosesignalweg induziert. Dabei konnte eine reduzierte anti-apoptotische Bcl-xL-Expression und vermehrte Prozessierung von Caspase-9 und Caspase-3 und PARP beobachtet werden.
Zusammenfassend konnte in dieser Arbeit gezeigt werden, dass eine verminderte tubulointerstitielle Fibrose-Entstehung durch die Deletion der SK2, sowie anti-proliferative und Apoptose-induzierende Effekte durch die SK2 in Mesangiumzellen nachgewiesen werden konnten. Somit könnten SK2-Inhibitoren die Entstehung tubulointerstitieller Fibrose und mit Proliferation assoziierte Erkrankungen wie mesangioproliferative Glomerulonephritis positiv beeinflussen.
The purpose of this thesis is to achieve two highly interconnected yet distinct tasks. On the one hand, the thesis explains how foreign investment insurance works by focusing on the law governing the relationships between involved actors. On the other hand, it provides a critique of the operation of foreign investment insurance as an investment protection instrument by mainly drawing on critical studies of the investment protection regime.
The main question this thesis attempts to answer is how foreign investment insurance works. I construe foreign investment insurance as a typical insurance product and focus on the operation of insurance arrangements from a legal perspective. Ideas about how insurance should be deployed in any given social, political or economic context are instrumental in the development of insurers, insurance products and insurance techniques. The thesis examines investment insurers, the products they offer and their techniques to identify and deal with so-called political risks.
Another important question concerns the notion of political risk. What are considered political risks in the context of investment insurance and how are they conceptualized by investment insurance providers? Investment insurers have largely adopted a business-oriented political risk definition which denotes governmental intervention in foreign investment as political risk without regard to the objectives of government actions. Descriptive studies explain political risk by replicating investment insurers’ categorization of basic coverages that include expropriation, currency inconvertibility and remittance transfer restrictions, political violence and breach of contract. Yet recent studies have increasingly provided in-depth analyses on the notion of political risk as well as on the specific categories of political risk, particularly expropriation. The thesis draws on these studies to critically discuss the concept of political risk as it is used by investment insurance providers.
I focus on foreign investment insurance provided by OPIC and MIGA due to their mandate to promote economic development in the capital-importing countries and for their historical role as the major providers of investment insurance. While focus is on MIGA and OPIC, the thesis offers a general account of the operation of foreign investment insurance by incorporating the available information on investment insurance industry and the international governance of investment insurance. The central issues explored in this thesis such as the principle of subrogation and the notion of political risk help me generalize the study as these issues are characterized similarly with respect to each public investment insurance provider.
The case studies and most examples in this thesis are based on expropriation risk insurance.
Precise timing of spikes between different neurons has been found to convey reliable information beyond the spike count. In contrast, the role of small phase delays with high temporal variability, as reported for example in oscillatory activity in the visual cortex, remains largely unclear. This issue becomes particularly important considering the high speed of neuronal information processing, which is assumed to be based on only a few milliseconds, or oscillation cycles within each processing step.
We investigate the role of small and imprecise phase delays with a stochastic spiking model that is strongly motivated by experimental observations. Within individual oscillation cycles the model contains only two signal parameters describing directly the rate and the phase. We specifically investigate two quantities, the probability of correct stimulus detection and the probability of correct change point detection, as a function of these signal parameters and within short periods of time such as individual oscillation cycles.
Optimal combinations of the signal parameters are derived that maximize these probabilities and enable comparison of pure rate, pure phase and combined codes. In particular, the gain in detection probability when adding imprecise phases to pure rate coding increases with the number of stimuli. More interestingly, imprecise phase delays can considerably improve the process of detecting changes in the stimulus, while also decreasing the probability of false alarms and thus, increasing robustness and speed of change point detection.
The results are applied to parameters extracted from empirical spike train recordings of neurons in the visual cortex in response to a number of visual stimuli. The results suggest that near-optimal combinations of rate and phase parameters can be implemented in the brain, and that phase parameters could particularly increase the quality of change point detection in cases of highly similar stimuli.
Systemerkrankungen der arteriellen Gefäße stellen eine häufige Todesursache in Deutschland und der westlichen Welt dar. Hierbei sind vor allem die auf Grundlage von Arteriosklerose entstehende Koronare Herzerkrankung sowie der Myokardinfarkt zu nennen. Ursache des Myokardinfarktes ist eine Minderperfusion und damit bedingte Ischämie des Myokardgewebes. Ziel einer jeden Minderperfusion ist die therapeutisch schnellstmögliche Reperfusion. Ischämie- und Hypoxie-bedingt entstehen hierbei durch inflammatorische Prozesse, Ansammlung toxischer Metabolite, veränderter Protein-Expressionsmuster sowie durch das reperfundierende Blut der sogenannte Ischämie-Reperfusionsschaden. Dieser komplexe Effekt lässt sich über dem hinaus auch bei Organtransplantationen beobachten.
Die vorliegende Arbeit beschreibt den Versuch den Ischämie-Reperfusionsschaden durch den Einfluss von mTOR-Inhibition im humanen Gefäßmodel zu quantifizieren. Hierbei wurden die mTOR-Inhibitoren Sirolimus und Everolimus verwendet. Beide Immunsuppressiva finden aktuell unter anderem klinische Anwendung nach Organtransplantationen. Bereits in einigen Studien konnten positive Effekte von Sirolimus als auch Everolimus auf den Ischämie-Reperfusionsschaden nachgewiesen werden. Dieser Versuch sollte nun weitere zielführende Erkenntnisse hinsichtlich mTOR-Inhibition und proinflammatorischer Prozesse sowie der Expression von Zell-Adhäsionsmolekülen im humanen Gefäßmodell liefern. Ebenso sollte die Qualität des Bioreaktors als adäquates Humangefäß-Perfusionsmodell evaluiert werden.
Als Versuchsgrundlage wurde hierbei eine Ischämiezeit der Gefäße von vier bis fünf Stunden festgelegt. Die verwendeten Gefäße wurden in der Folge nach standardisierten Kriterien (Präoxygenierung, Heparinisierung, 37° Grad Celsius Temperatur, Blutgruppe AB Rhesusfaktor negativ, Hämatokritwert 30%) zwei Stunden lang mittels Vollblut im Bioreaktormodel reperfundiert. Unterschieden wurde hierbei eine Gefäßkontrollgruppe (n=7), von einer Sirolimus-Gruppe (n=6, standardisierte Blutkonzentration 10ng/ml) und einer Everolimus-Gruppe (n=7, standardisierte Blutkonzentration 5 ng/ml). Nach standardisierten Zeitpunkten der Reperfusion (0 Minuten, 15 Minuten, 30 Minuten, 60 Minuten und 120 Minuten) wurden jeweils Blutproben dem simulierten Kreislauf entnommen. Mittels Blutgasanalyse wurde über die Bestimmung des Sauerstoffpartialdrucks, des Kohlendioxidpartialdrucks sowie des pH-Wertes eine qualitative Evaluierung des Bioreaktors als humanes Gefäßmodel vorgenommen. Des Weiteren dienten die Blutproben zur Erfassung der proinflammatorischer Marker Interleukin-6, TNF-α, sowie VEGF während der unterschiedlichen Zeitpunkte der Blutentnahme. Nach Beendigung der Reperfusion wurden Gefäßproben mittels immunhistochemischen Verfahren auf die Expression der Zell-Adhäsionsmoleküle CD31 sowie CD11b hin untersucht.
Aufgrund durchgeführter Versuche konnte gezeigt werden, dass in der Kontrollgruppe die Interleukin-6- sowie VEGF-Spiegel signifikant im Zuge der Reperfusion anstiegen. Sirolimus als auch Everolimus konnten demgegenüber einen signifikanten Anstieg dieser proinflammatorischen Signalmoleküle verhindern. Im Vergleich des proinflammatorischen TNF-α konnte allerdings ein signifikanter Einfluss der mTOR-Inhibitoren nicht bestätigt werden. Hinsichtlich des Expressionsmusters konnte Sirolimus als auch Everolimus eine signifikante Reduktion von sowohl CD31-positiven als auch CD11b-positiven Zellen im Vergleich zur Kontrollgruppe aufzeigen.
In der Zusammenschau lässt sich aus den erhobenen Daten schlussfolgern, dass der Bioreaktor als humanes Gefäßmodell ein suffizientes Perfusionssystem darstellt. Sirolimus als auch Everolimus können über ihren Wirkungsmechanismus der mTOR-Inhibition einen Anstieg proinflammatorischen Moleküle zum Teil verhindern. Den größten Einfluss auf den Ischämie-Reperfusionsschaden nehmen Sirolimus als auch Everolimus hierbei mittels der Suppression von Zell-Adhäsionsmolekülen CD31 und CD11b.