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- Die molekulare Pathogenese von Präeklampsie : Charakterisierung und Analyse der wichtigen Regulatoren Survivin und B-Zell-Lymphom-6 (2014)
- Die vorliegende Dissertation hatte das Ziel molekulare Mechanismen der Präeklampsieerkrankung aufzuklären. Bei PE handelt es sich um eine schwangerschaftsassoziierte Krankheit, die in 3 bis 5 % aller Schwangerschaften auftritt und eine der Hauptursachen für maternale und fetale Mortalität und Morbidität ist. Zudem haben PE-Patientinnen und ihre Kinder im späteren Leben ein erhöhtes Risiko für die Ausbildung kardiovaskulärer und hypertensiver Erkrankungen. Trotz langer und intensiver Forschung konnte die komplexe Pathogenese von PE noch nicht aufgeklärt werden. Im Rahmen der Promotion sollten neue Gene in der präeklamptischen Plazenta identifiziert und ihre Funktionen im Pathogeneseprozess der Krankheit untersucht werden. Dabei war es wichtig die Zusammenhänge der gestörten Prozesse zu verstehen um Mutter und Kind vor schwerwiegenden und langfristigen Folgeerscheinungen von PE zu schützen. Mit dem durchgeführten Gen-Array konnte gezeigt werden, dass bei PE die Expression einiger Gene der Angiogenese-, der Invasions- sowie der Migrationsregulation verändert waren. Zudem konnten anhand von Deregulationen bei der SURVIVIN und BCL6 Expression zwei weitere Gene identifiziert werden, deren Funktionen in der präeklamptischen Plazenta bislang unbekannt waren. Bei PE kam es im Vergleich zur gesunden Kontrolle zu einer verringerten Genexpression von SURVIVIN. Eine Veränderung des Proteinlevels konnte jedoch nicht festgestellt werden. Die Analyse der Survivin Funktionen zeigte, dass die Zellen der präeklamptischen Plazenta, die konstantem zellulärem Stress ausgesetzt sind, versuchen durch Aktivierung aller Überlebensmechanismen, wie einer Stabilisierung des anti-apoptotischen Proteins Survivin, ihr Überleben zu sichern und somit die Funktionalität des ganzen Organs zu gewährleisten. Als multifunktionelles Protein ist Survivin bislang vor allem als Apoptose-Inhibitor sowie als Partner des CPC mit Funktionen bei der Zellteilung bekannt. Die Untersuchungen ergaben, dass Survivin auch in Trophoblastenzellen für den einwandfreien Ablauf der Mitose verantwortlich ist, da es bei einer Depletion zu einem G2/M Arrest der Zellen sowie einer erhöhten Rate an Centrosomen Abberationen und congression Fehlern kam. Die vorliegende Arbeit zeigt zum ersten Mal, dass die Stabilisierung von Survivin bei Präeklampsie der Kompensation der gestörten Trophoblastenfunktionen dient indem die vermehrte Apoptose der Zellen verhindert und die Proliferation der Trophoblasten präzise gesteuert wird. Im Rahmen der Dissertation wurden zudem die Funktionen von BCL6 bei Präeklampsie untersucht. BCL6 ist vorrangig durch seine Rolle bei der B-Zell Reifung und der T-Zell Regulation sowie als Onkogen bei B-Zell Lymphomen und auch bei Mammakarzinomen bekannt. Es konnte gezeigt werden, dass sowohl die Gen-, wie auch Proteinexpression von BCL6 in der präeklamptischen Plazenta erhöht sind. Bei einer Depletion von BCL6 kam es zu verminderter Proliferation der Trophoblasten mit G2/M Arrest und vermehrter Apoptose sowie reduzierter Invasions- und Migrationsfähigkeit. Eine erhöhte BCL6 Expression führte zu einer verminderten Expression der Fusionsregulatoren Syncytin 2, β-hCG und GCM1, woraus eine gestörte, reduzierte Fusionsfähigkeit der Trophoblasten resultierte. Dies bedeutet, dass die Expression von BCL6 präzise reguliert werden muss um die Trophoblasten zu Beginn der Schwangerschaft vor Apoptose und Zellzyklusarrest zu schützen und somit die Invasion und Plazentation zu ermöglichen. Kommt es im weiteren Verlauf zu einer Deregulation mit erhöhter BCL6 Expression, so resultiert daraus eine verminderte Trophoblastenfusion und Präeklampsie. Zusammenfassend belegt die Arbeit, dass mit Survivin und BCL6 zwei weitere Regulatoren der PE-Pathogenese identifiziert und charakterisiert wurden. Im Rahmen der Promotion konnten die Funktionen bei der Regulation von Zellzyklus, Apoptose sowie Trophoblastenfusion und –invasion dargestellt werden. Weitere Untersuchungen sind jedoch notwendig um die Rolle von Survivin und BCL6 im ersten Schwangerschaftstrimester aufzuklären. Aufgrund ihrer wichtigen Rolle bei PE stellen Survivin und BCL6 neue Möglichkeiten zur Entwicklung von Therapieansätzen sowie zur Identifizierung prognostischer Marker für die Präeklampsieerkrankung dar.

- Dynamics of mantle circulation and convection : the signatures in the satellite derived gravity fields (2013)
- Mantle convection is the process by which heat from the Earth’s core is transferred upwards to the surface and it is accepted to explain the dynamics of the Earth’s interior. On geological time-scales, mantle material flows like a viscous fluid as a consequence of the buoyancy forces arising from thermal expansion. Indeed, mantel convection provides a framework which links together the major disciplines, such as seismology, mineral physics, geochemistry tectonic and geology. The numerical model has been applied to understand the dynamic, structure and evaluation of the Earth, and other terrestrial planets and the investigations continue to explore, different aspects of the mantle convection. In fact, to model this phenomenon, two complementary approaches are possible. On the one hand, one can solve self-consistently the equations of thermal convection, including parameters and employing physical relationships derived from mineral physics. Our understanding of mantle convection depends ultimately upon the success of such fully self-consistent dynamic models in explaining observable features of the flow. Although, these models presently unable to predict the actual convection pattern of the Earth, they are extremely useful to investigate general characteristics of given physical systems. On the other hand, to permit comparison with specific observables associated with the flow, one can consider a more restricted problem. Instead of focusing on the time evolution of mantle flow, if we know a priori the temperature - and hence presumably the density - anomalies that drive the convection, we can try to build a snapshot of the present-day flow pattern, consistent with those anomalies, that can successfully predict the observables. As matter of fact, the aim of this study is to investigate both approaches in comparison with the main geophysical constraints on mantle structure. These constraints include the geoid anomalies, the dynamic surface and core-mantle boundary topography and tectonic plate motions. The most appropriate mathematical basis functions for describing a bounded and continuous function on a spherical surface are spherical harmonics. We may therefore expand the geodynamic observables in terms of spherical harmonics. We have investigated two methods of the global spherical harmonic analysis by specific attention to the dynamic geoid computation of the geodynamic models. The first method is the quadrature method in which the loss of the orthogonality of the Legendre functions in transition from continues to discrete case is the major drawback to the method. Particularly, we showed that in the absence of the tesseral harmonics, quadrature formulation leads to obtain inaccurate results. The second method is the least-squares which can be considered as the best linear unbiased estimator that provides the exact results. We showed that even with a low resolution grid data it is possible to reconstruct the data and achieve an accurate result by using this method, which is extremely remarkable in three-dimensional global convection studies. However, special care has to be taken since there is some source of errors that might influence the efficiency of this method. In general, to better understanding of the properties of the mantle, it is useful to assess observable characteristics of plumes in the mantle, including geoid, topography and heat flow anomalies. However, only few studies exist on geoid and topography for axi-symmetric convection and their models were restricted to isoviscous (or stratified) mantle and low Rayleigh numbers. We studied fully coupled depth and temperature dependent Arrhenius type of viscosity in axi-symmetric spherical shell geometry in order to investigate the shape of geoid anomalies and dynamic topography above a plume. Indeed, the topography and geoid anomalies produced from plumes are sensitive to rheology of the mantle and rheology of the plume; both have effects on shape and amplitude of the geoid anomalies. As results we are able to define different classes of plumes by their geoid signals. Mainly depth-dependent viscosity models show a geoid with negative sign above the plume which can turn to the positive sign by decrease the viscosity contrast. This can be considered as a transition between the strongly depth dependent and the constant viscosity case. Our results basically support the idea by Morgan [1965] and McKenzie [1977]. They have shown the magnitude and even the sign of the total gravity anomaly depend on the spatial variation in effective viscosity. In addition, Hager [1984] has concluded that the total gravity field is depend on the radial distribution of effective viscosity, and a small change in viscosity contrast leads to varying sign of the response function. In the case of temperature-dependent viscosity, the formation of an immobile lithosphere is a natural result, and the flow as well as the total geoid becomes strongly time dependent. When we increase the activation energy, all geoids associated with the first arriving plumes look like bell shaped whereas for typical plumes, after reaching a statistical steady state, bell-shaped geoids with decreasing amplitude as well as linear flank shaped geoids are observed. It is surprising that in spite of large differences in lateral and depth varying viscosities, the shapes of the geoid anomalies remained rather similar. We also identified different behaviors in the combined model with temperature-and pressure-dependent viscosity. In fact, in spite of the strongly different rheology, the geoid anomalies in all cases were surprisingly similar. Furthermore, we proposed a scaling law for the geoid which makes our results directly applicable to other planets. Moreover, we can apply the results of our calculation to find relations between different rheology and sub-lid temperature, since we know that the mantle temperature can change significantly with variation in pressure-temperature dependent viscosity. It is also possible to define a range of stagnant lid thickness related to the amplitude of the geoid which can be reasonable for study of the lid thickness in Venus or Mars. Nevertheless, in these series of models, we simplified a number of complexities within the Earth. One of the most important of such simplification is the Boussinesq approximation. This approximation is valid if the temperature scale height (i.e. the depth over which temperature increases by a factor of “ ” due to adiabatic compression) is much greater than the convection depth. However, a temperature scale height in the Earth’s mantle is at best only slightly greater than the mantle depth. Hence, the Boussinesq approximation could mask some very important stratification and compressibility effects that influence both the spatial and temporal structure of the convection. Therefore, in more advance models we considered compressibility in our mantle convection models, assuming that density vary both radially and laterally, being determined as a function of pressure and temperature through an appropriate equation of the state. Moreover, thermodynamic properties assumed to be a function of depth. We examined the details of the structure of the spherical axi-symmetric Anelastic Liquid Approximation model (ALA) with special attention to the Arrhenius rheology, and compare it to the cases of compressible convection without depth dependent thermodynamical properties, and to cases of the extended Boussinesq approximation. At the same time, the effects of the interaction between temperature and pressure-dependent viscosity and thermodynamic parameters in the compressible mantle convection on the geoid and topography have been studied. We showed that assuming compressible convection with depth-dependent thermodynamic properties strongly influence the geoid undulations. Using compressible convection with constant thermodynamic properties is physically inconsistent and may lead to spurious results for the geoid and convection pattern. Indeed, by a systematic study of different approaches of compressibility in the spherical shell convection for different Arrhenius viscosity laws we proved that only in the unrealistic case of zero activation energy the different compressibility modes result in comparable convection and geoid patterns. In all other rheological cases, large differences have been obtained, that stressing the important role of consistent compressible thermodynamic properties for mantle convection. In addition, we examine the impact of compressibility as well as different rheologies on the power law relation that connects the Nusselt number to the Rayleigh number. We have discovered that the power law index of the relationship is controlled by the rheology, independent of which approximation is used. Instead, the bound of this relation is controlled by a combination of different approximation and rheology. Next, instead of focusing on the time evolution of mantle flow, we have carried out three-dimensional spherical shell models of mantle circulation to investigate the effects of joint radial and lateral viscosity variations on the Earth’s non-hydrostatic geoid, surface and core-mantle boundary topographies. These models include realistic lateral viscosity variations (LVV) in the lithosphere, upper mantle and lower mantle in combination with different stratified viscosity structures. We have demonstrated that the contradictory results concerning the effects of LVV can be clarified by the most straight-forward problem in geoid modeling; namely, rather poorly known stratified viscosity structure. We explored three classes of dynamic geoid models due to lateral viscosity variations. In the first class, the LVV strongly improved the fit to the observed geoid. Indeed, when the viscosity contrast between lower and upper mantles is not large enough to produce a good fit to geoid the LVVs are able to perform this action by adjusting amplitudes, so that it becomes comparable with observation. In the second class, inducing the LVV moderately improved the fit. Actually, when the geoid induced by a stratified viscosity structure already has a good correlation with observation, then the LVV causes its amplitude to further improve. In the last class, if the viscosity contrast between upper and lower mantle would be high enough, inducing LVV deteriorate the fit to the observed geoid.. Indeed, depending on the stratified viscosity, inducing the LVV may take place in one of these categories. We also quantified the effects of LVV in the mantle and lithosphere individually. We found that the presence of LVV in the mantle (upper and lower) improves the fit to the observed geoid regardless of stratified viscosity. While LVV in the lithosphere is a crucial parameter, and dependent of the stratified viscosity, may increase or decrease the geoid fit. In fact, when the lower mantle considers being viscous enough, it would support the negative buoyancy of subducting slabs. Thus, it transmits some of the stress back to the top boundary and causes a weak coupling between slab and surface. Therefore, by including the low viscous plate boundaries in this model, the slabs and overriding plates decouples and the fit to the observed geoid degrades. In contrast, when the lower mantle viscosity is not sufficiently stiff, the presence of the low viscous plate boundaries assists to weaken the strong mechanical coupling between slab and surface. Hence, a better fit achieved.

- Training der Emotionsregulation bei Schizophrenie : Entwicklung und Evaluation einer kognitiv-verhaltenstherapeutischen Gruppentherapie (2012)
- Die Schizophrenie stellt eine sehr vielfältige und schwere psychische Erkrankung dar, die fundamentale Bereiche, wie Denken, Fühlen, Wahrnehmen, Willensbildung und Handeln beeinträchtigt (Kircher & Gauggel, 2008). Neben der Störung der Kognition und der Wahrnehmung sind es die Störungen der Emotionen, die das Krankheitsbild der Schizophrenie prägen. Eine Emotion ist Grundlage eines informativen Bedeutungssystems einer Person. Sie informiert über die Relevanz einer Situation sowie über Wohlbefinden, Wünsche und Bedürfnisse. Sie ermöglicht eine bedürfnis- und situationsgerechte Auswahl von Ver-haltensweisen, beeinflusst kognitive Prozesse, prägt die Entscheidungsfindung und Problemlösung. Durch den mimischen Ausdruck, der aus einer Emotion resultiert, bekommt sie eine kommunikative bzw. interpersonelle Funktion. Damit stellen Emotionen zentrale Phänomene des alltäglichen Lebens dar, die einen großen Einfluss auf Ver-halten, Lernen, Wahrnehmung und Gedächtnis haben. Nicht immer ist es sinnvoll und funktional, Emotionen auszuagieren. Um adäquat mit Emotionen umgehen zu können, bedarf es der Emotionsregulation. Hierbei handelt es sich um einen Prozess, bei dem beeinflusst wird, welche Emotionen wann und wie erlebt und ausgedrückt werden (Gross, 1998), um flexibel auf Umwelteinflüsse und den sozialen Kontext eingehen zu können (Thompson, 1994)...

- Quantification and analysis of neuropil transcriptome in the central nervous system (2014)
- Local protein synthesis has re-defined our ideas on the basic cellular mechanisms that underlie synaptic plasticity and memory formation. The population of messenger RNAs that are localised to dendrites, however, remains sparsely identified. Furthermore, neuronal morphological complexity and spatial compartmentalisation require efficient mechanisms for messenger RNA localisation and control over translational efficiency or transcript stability. 3’ untranslated regions, downstream from stop codons, are recognised for providing binding platforms for many regulatory units, thus encoding the processing of the above processes. The hippocampus, a part of the brain involved in the formation, organisation and storage of memories, provides a natural platform to investigate patterns of RNA localisation. The hippocampus comprises tissue layers, which naturally separate the principle neuronal cell bodies from their processes (axons and dendrites). Identifying the full-complement of localised transcripts and associated 3’UTR isoforms is of great importance to understand both basic neuronal functions and principles of synaptic plasticity. These findings can be used to study the properties of neuronal networks as well as to understand how these networks malfunction in neuronal diseases. Here, deep sequencing is used to identify the mRNAs resident in the synaptic neuropil in the hippocampus. Analysis of a neuropil data set yields a list of 8,379 transcripts of which 2,550 are localised in dendrites and/or axons. Using a fluorescent barcode strategy to label individual mRNAs shows that the relative abundance of different mRNAs in the neuropil varies over 5 orders of magnitude. High-resolution in situ hybridisation validated the presence of mRNAs in both cultured neurons and hippocampal slices. Among the many mRNAs identified, a large fraction of known synaptic proteins including signaling molecules, scaffolds and receptors is discovered. These results reveal a previously unappreciated enormous potential for the local protein synthesis machinery to supply, maintain and modify the dendritic and synaptic proteome. Using advances in library preparation for next generation sequencing experiments, the diversity of 3’UTR isoforms present in localised transcripts from the rat hippocampus is examined. The obtained results indicate that there is an increase in 3’UTR heterogeneity and 3’UTR length in neuronal tissue. The evolutionary importance of the 3’UTR diversity and correlation with changes in species,tissue and cell complexity is investigated. The conducted analysis reveals the population of 3’UTR isoforms required for transcript localisation in overall neuronal transcriptome as well as the regulatory elements and binding sites specific for neuronal compartments. The configuration of poly(A) signals is correlated with gene function and can be further exploit to determine similar mechanisms for alternative polyadenylation. Usage of custom specified methods for next-generation sequencing as well as novel approaches for RNA quantification and visualisation necessitate the development and implementation of new downstream analytic methods. Library methods for data-mining transcripts annotation, expression and ontology relations is provided. Usage of a specialised search engine targeting key features of previous experiments is proposed. A processing pipeline for NanoString technology, defining experimental quality and exploiting methods for data normalisation is developed. High-resolution in situ images are analysed by custom application, showing a correlation between RNA quantity and spatial distribution. The vast variety of bioinformatic methods included in this work indicates the importance of downstream analysis to reach biological conclusions. Maintaining the integrability and modularity of our implementations is of great priority, as the dynamic nature of many experimental techniques requires constant improvement in computational analysis.

- In vitro investigation of genes identified by genome-wide association studies of Parkinson's disease (2014)

- The multidrug efflux, secondary metabolite and protein secretion network of the cyanobacterium Anabaena sp. PCC 7120 (2013)
- The TolC protein of E. coli is a versatile OMF which is involved in secretion of antibiotics, heavy metal ions, secondary metabolites and proteins. These individual tasks are accomplished by a dynamic formation of different secretion complexes which comprising a plasma membrane transporter, a Membrane Fusion Protein and TolC as the outer membrane channel-tunnel. The TolC-like protein HgdD of the cyanobacterium Anabaena sp. PCC 7120 was previously described as an indispensable OMF involved in formation of the heterocyst-specific glycolipid layer which is needed to sustain the microoxic environment that allows nitrogen fixation in heterocysts of filamentous cyanobacteria. Here I show that HgdD is involved in macrolide antibiotic resistance and ethidium efflux, which is used as a model substrate for cytotoxic compounds and secondary metabolites. It can be shown that ethidium uptake is a passive and porin-dependent process, while multidrug efflux is performed together with the RND efflux pump All3143 (and the MFP All3144). In contrast to HgdD, All3143 can complement the function of its homologue AcrB in E. coli and was suggested to be named anaAcrB. Multidrug efflux is assisted by SmsA and SchE, two secondary transporters of the MFS-type, which facilitate the transport of cytoplasmatic ethidium to the periplasmic space prior to the All3143- and HgdD-dependent efflux. Moreover, it can be demonstrated that SchE and HgdD are involved in secretion of the metal ion-chelating siderophore schizokinin, which functions in iron(III) acquisition. However, a physical interaction of SchE and HgdD is unlikely since SchE does not possess an OMF interacting domain. In addition, both RND efflux pumps All3143 and Alr1656 are needed for the homeostasis of the photosystems during diazotrophic growth. Although a direct involvement in heterocyst development or metabolism cannot be discounted at this stage, it is speculated that both RND transporters are involved in detoxification of reactive nitrogen species, similar to the function of MexF and MdtF of P. aeruginosa and E. coli respectively. In addition to its function in multidrug efflux, HgdD has been shown to be involved in protein secretion. By comparative analysis of the Anabaena sp. wild type and hgdD mutant secretome it was possible to identify eight putative HgdD protein substrates. The localization of four proteins was exemplary demonstrated by secretome isolation and cell fractionation of hemagglutinin-tagged mutant strains. The absence of detectable protein in the hgdD mutant strain suggests a highly efficient secretion system which is quality controlled by proteolysis of mislocalized proteins.

- Jet fragmentation properties in proton-proton and Pb-Pb collisions with ALICE at the LHC (2012)
- According to the standard model of particle physics, the most fundamental building blocks of the known matter are quarks and leptons, while the interactions between these fundamental objects is mediated through bosons. On one hand the leptons can exist in nature as individual particles, while on the other hand quarks appear always as bound states called hadrons. The knowledge that hadrons are built from more fundamental particles dates back to the second half of the 20th century when the work by Gell-Mann and Zweig led to the development of the quark model. The experimental proof that the hadrons are bound objects composed of more elementary particles was done through the study of deep inelastic scattering of electrons off protons. These experiments were done in a similar fashion to the studies of the atomic model led by Rutherford at the beginning of the 20th century. Further experimental analysis led to the conclusion that a large fraction of the proton momentum is not carried alone by the quarks, but by the bosons that mediate the strong interaction called gluons. The cleanest experimental signature for the existence of the gluons came from electron-positron annihilation experiments, where a quark-antiquark pair is created and one of the quarks radiates a hard gluon. Due to confinement neither the quarks nor the gluon can be observed directly, but are measured experimentally as three collimated showers of particles named jets. Since the ground breaking experiments performed at DESY, jets have provided a tool to study the properties of quarks and gluons...

- Design and optimization of the lattice of the superconducting synchrotron SIS300 for slow extraction (2011)
- The superconducting synchrotron SIS300 is planned to be built at the new Facility for Antiproton and Ion Research (FAIR), at GSI-Darmstadt [1]. SIS300 will be a versatile machine, which by means of a low-energy stretcher-mode or a high-energy ramped-mode will provide slowly extracted heavy ion beams towards the experimental areas. To reach the required maximum field of 4.5 T, cos(θ) magnets are necessary. Thus, SIS300 will become the first superconducting synchrotron worldwide with cos(θ) magnets providing resonant slow extraction. Since SIS300 will be installed in the same tunnel as the SIS100 synchrotron, the dipole layout of SIS300 cannot be freely chosen. Thus, a standard lattice cannot be applied. A redesign of the SIS300 lattice accepting compromises concerning the positions and phase advances between the optical elements has been proposed. Using the analytical model of the slow extraction, firstly proposed by Kobayashi, and the analytical description of the resonance driving modes, a multiobjective optimization algorithm has been developed for the optimization of the lattice under the given boundary conditions. The final goal of the lattice optimization is a higher efficiency of the slow extraction. The results are evaluated by means of tracking simulations performed with the code Elegant. The field quality in superconducting cos(θ) magnets is determined by the positions of the superconducting cable and the static and time-dependent effects of the current in the cable. Furthermore, the fast ramp rates of 1 T/s in the dipoles, which are fifty times faster than in any other superconducting cos(θ) magnet, together with the fact that the aperture is smaller than in conventional accelerator magnets, makes it extremely difficult to obtain a high-quality magnetic field. The unavoidable field errors affect the beam dynamics and worsen the slow extraction efficiency. Therefore, the field errors in the SIS300 dipoles have been estimated, and their effects have been taken into account in the optimization algorithm. As a result a compensation scheme has been proposed, in which time-dependent gradients in the sextupoles counteract the decay of the sextupole field errors in the dipole magnets during the slow extraction. For the limits where the compensation was no longer possible, tolerances to the magnet field errors have been determined.