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Seit einigen Jahrzehnten ist Lysozym eines der am meisten erforschten Proteine in der Literatur und wird hauptsächlich als Modell Protein zur Aufklärung der Faltungs- und Entfaltungsprozesse genutzt. Da die Frage nach Fehlfaltung und deren Verknüpfung mit neurodegenerativen Krankheiten bis zum heutigen Tag nicht vollständig geklärt ist, besteht hier ein großer Spielraum für weitere Forschungsansätze. In der vorliegenden Arbeit wurden daher zwei Modellsysteme verwendet, Hühereiweiß-Lysozym und menschliches Lysozym, jeweils in ihrem nicht-nativen ungefalteten Zustand. Diese ungefalteten Ensembles wurden mit Hilfe NMR spektroskopischer Methoden untersucht und ergaben sehr detaillierte, zum Teil auch überraschende neue Einblicke in Struktur und Dynamik der beiden Proteine und liefern somit wichtige Erkenntnisse zu Faltungs- und Aggregationsprozessen. ...
The miniaturization of electronics is reaching its limits. Structures necessary to build integrated circuits from semiconductors are shrinking and could reach the size of only a few atoms within the next few years. It will be at the latest at this point in time that the physics of nanostructures gains importance in our every day life. This thesis deals with the physics of quantum impurity models. All models of this class exhibit an identical structure: the simple and small impurity only has few degrees of freedom. It can be built out of a small number of atoms or a single molecule, for example. In the simplest case it can be described by a single spin degree of freedom, in many quantum impurity models, it can be treated exactly. The complexity of the description arises from its coupling to a large number of fermionic or bosonic degrees of freedom (large meaning that we have to deal with particle numbers of the order of 10^{23}). An exact treatment thus remains impossible. At the same time, physical effects which arise in quantum impurity systems often cannot be described within a perturbative theory, since multiple energy scales may play an important role. One example for such an effect is the Kondo effect, where the free magnetic moment of the impurity is screened by a "cloud" of fermionic particles of the quantum bath.
The Kondo effect is only one example for the rich physics stemming from correlation effects in many body systems. Quantum impurity models, and the oftentimes related Kondo effect, have regained the attention of experimental and theoretical physicists since the advent of quantum dots, which are sometimes also referred to as as artificial atoms. Quantum dots offer a unprecedented control and tunability of many system parameters. Hence, they constitute a nice "playground" for fundamental research, while being promising candidates for building blocks of future technological devices as well.
Recently Loss' and DiVincenzo's p roposal of a quantum computing scheme based on spins in quantum dots, increased the efforts of experimentalists to coherently manipulate and read out the spins of quantum dots one by one. In this context two topics are of paramount importance for future quantum information processing: since decoherence times have to be large enough to allow for good error correction schemes, understanding the loss of phase coherence in quantum impurity systems is a prerequisite for quantum computation in these systems. Nonequilibrium phenomena in quantum impurity systems also have to be understood, before one may gain control of manipulating quantum bits.
As a first step towards more complicated nonequilibrium situations, the reaction of a system to a quantum quench, i.e. a sudden change of external fields or other parameters of the system can be investigated. We give an introduction to a powerful numerical method used in this field of research, the numerical renormalization group method, and apply this method and its recent enhancements to various quantum impurity systems.
The main part of this thesis may be structured in the following way:
- Ferromagnetic Kondo Model,
- Spin-Dynamics in the Anisotropic Kondo and the Spin-Boson Model,
- Two Ising-coupled Spins in a Bosonic Bath,
- Decoherence in an Aharanov-Bohm Interferometer.
Recent data indicate that reactive oxygen species (ROS) are produced in the nociceptive system during persistent pain and contribute to pain sensitization. Aim of this study was to investigate potential antinociceptive effects of ROS scavengers in different animal models of pain. Intrathecal injection of ROS scavengers 1-Oxyl-2,2,6,6-tetramethyl -4-hydroxypiperidine (TEMPOL) or Phenyl-N-tert-butylnitrone (PBN) significantly inhibited formalin-induced nociceptive behavior in mice, suggesting that ROS released in the spinal cord are involved in nociceptive processing. Formalin-induced nociceptive behavior was also inhibited by intraperitoneal injection of a combination of vitamin C and vitamin E, but not of vitamin C or vitamin E alone. Moreover, the combination of vitamin C and E dose-dependently attenuated mechanical allodynia in the spared nerve injury (SNI) model of neuropathic pain. The SNI-induced mechanical allodynia was also reduced after intrathecal injection of the combination of vitamin C and E, and western blot analyses revealed that vitamin C and E treatment can ameliorate the activation of p38 MAPK in the spinal cord and in DRGs. These data suggest that a combination of vitamin C and E can inhibit the nociceptive behavior in animal models of pain, and points to a role of the spinal cord as an important area of ROS production during nociceptive processing.
The present work comprises different projects within the scope of public health. In detail, they all aim at combating the high-burden diseases HIV/AIDS, malaria and tuberculosis more effectively. Since there was, and still is, no harmonization between the existing biowaiver guidelines, the biowaiver dissolution test conditions by WHO and FDA were compared against each other using drug products, which had already demonstrated BE to the comparator in vivo. Thereby it could be shown that the dissolution conditions proposed by the WHO are more appropriate for granting biowaivers than those of the FDA. Further, the applicability of the WHO dissolution test conditions was investigated using the APIs ethambutol, isoniazid and pyrazinamide (all BCS Class III) as model compounds. These investigations demonstrated that the concept of the biowaiver proved to work properly, i.e. leading to no false positive BE decision and an acceptable incidence of false negative BE decisions. In addition, four new biowaiver monographs were published addressing important APIs in the treatment of HIV/AIDS and malaria. Before these efforts, there were only a very few biowaiver monographs available for antiviral or antimalarial APIs, i.e. the database of biowaiver monographs has been clearly improved. The last part of the present work dealt with the extension of the biowaiver concept to related areas such as the WHO Prequalification of Medicines Programme. Investigations revealed that the biowaiver tools are generally eligible for prequalification of drug products containing ethambutol, isoniazid, pyrazinamide, or lamivudine to prove BE between an appropriate comparator and the test candidate. By contrast, some APIs are excluded from the biowaiver procedure. In conclusion, the implementation of the biowaiver tools for prequalification of biowaivable APIs is, along with BCS-based biowaiver approval of new generics, an important step towards making essential, high-quality drug products more cost-effective and, as a consequence, more accessible for a larger percentage of the population. In that way, the treatment conditions for those in need living in the developing countries can be improved enormously, so that those who are poor do not have to receive poor treatment. The quality standard of essential medicines will increase worldwide, thereby helping to combat the high-burden diseases better and, in turn, lead to an improvement of the global health status.
Visual perception has increasingly grown important during the last decades in the robotics domain. Mobile robots have to localize themselves in known environments and carry out complex navigation tasks. This thesis presents an appearance-based or view-based approach to robot self-localization and robot navigation using holistic, spherical views obtained by cameras with large fields of view. For view-based methods, it is crucial to have a compressed image representation where different views can be stored and compared efficiently. Our approach relies on the spherical Fourier transform, which transforms a signal defined on the sphere to a small set of coefficients, approximating the original signal by a weighted sum of orthonormal basis functions, the so-called spherical harmonics. The truncated low order expansion of the image signal allows to compare input images efficiently, and the mathematical properties of spherical harmonics also allow for estimating rotation between two views, even in 3D. Since no geometrical measurements need to be done, modest quality of the vision system is sufficient. All experiments shown in this thesis are purely based on visual information to show the applicability of the approach. The research presented on robot self localization was focused on demonstrating the usability of the compressed spherical harmonics representation to solve the well-known kidnapped robot problem. To address this problem, the basic idea is to compare the current view to a set of images from a known environment to obtain a likelihood of robot positions. To localize the robot, one could choose the most probable position from the likelihood map; however, it is more beneficial to apply standard methods to integrate information over time while the robot moves, that is, particle or Kalman filters. The first step was to design a fast expansion method to obtain coefficient vectors directly in image space. This was achieved by back-projecting basis functions on the input image. The next steps were to develop a dissimilarity measure, an estimator for rotations between coefficient vectors, and a rotation-invariant dissimilarity measure, all of them purely based on the compact signal representation. With all these techniques at hand, generating likelihood maps is straightforward, but first experiments indicated strong dependence on illumination conditions. This is obviously a challenge for all holistic methods, in particular for a spherical harmonics approach, since local changes usually affect each single element of the coefficient vector. To cope with illumination changes, we investigated preprocessing steps leading to feature images (e.g. edge images, depth images), which bring together our holistic approach and classical feature-based methods. Furthermore, we concentrated on building a statistical model for typical changes of the coefficient vectors in presence of changes in illumination. This task is more demanding but leads to even better results. The second major topic of this thesis is appearance-based robot navigation. I present a view-based approach called Optical Rails (ORails), which leads a robot along a prerecorded track. The robot navigates in a network of known locations which are denoted as waypoints. At each waypoint, we store a compressed view representation. A visual servoing method is used to reach a current target waypoint based on the appearance and the current camera image. Navigating in a network of views is achieved by reaching a sequence of stopover locations, one after another. The main contribution of this work is a model which allows to deduce the best driving direction of the robot based purely on the coefficient vectors of the current and the target image. It is based on image registration as the classical method by Lucas-Kanade, but has been transferred to the spectral domain, which allows for great speedup. ORails also includes a waypoint selection strategy and a module for steering our nonholonomic robot. As for our self-localization algorithm, dependance on illumination changes is also problematic in ORails. Furthermore, occlusions have to be handled for ORails to work properly. I present a solution based on the optimal expansion, which is able to deal with incomplete image signals. To handle dynamic occlusions, i.e. objects appearing in an arbitrary region of the image, we use the linearity of the expansion process and cut the image into segments. These segments can be treated separately, and finally we merge the results. At this point, we can decide to disregard certain segments. Slicing the view allows for local illumination compensation, which is inherently non-robust if applied to the whole view. In conclusion, this approach allows to handle the most important criticism to holistic view-based approaches, that is, occlusions and illumination changes, and consequently improves the performance of Optical Rails.
Table of Contents – Cumulative Dissertation Thesis German Summary Summary of Analysis Results for German-Speaking Readers Introductory Paper Introduction and Overview of the Dissertation Paper 1 Vykoukal, Jens / Wolf, Martin / Beck, Roman (2009) Services Grids in Industry: On-Demand Provisioning and Allocation of Grid-based Business Services In: Business & Information Systems Engineering (BISE), 1(2), 177-184 Paper 2 Vykoukal, Jens / Setzer, Michael / Beck, Roman (2008) Grid Architecture for Risk Management: A Case Study in a Financial Institution In: Proceedings of the 12th Pacific Asia Conference on Information Systems (PACIS), Suzhou, China Paper 3 Vykoukal, Jens / Pahlke, Immanuel / Beck, Roman (2011) Impact of Grid Assimilation on Operational Agility in Turbulent Environments: An Empirical Investigation in the Financial Services Industry In: Proceedings of the 19th European Conference on Information Systems (ECIS), Helsinki, Finland Paper 4 Vykoukal, Jens / Wolf, Martin / Beck, Roman (2009) Does Green IT Matter? Analysis of the Relationship between Green IT and Grid Technology from a Resource-based View Perspective In: Proceedings of the 13th Pacific Asia Conference on Information Systems (PACIS), Hyderabad, India Paper 5 Vykoukal, Jens (2010) Grid Technology as Green IT Strategy? Empirical Results from the Financial Services Industry In: Proceedings of the 18th European Conference on Information Systems (ECIS), Pretoria, South Africa Paper 6 Vykoukal, Jens / Beck, Roman / Wolf, Martin (2010) Impact of Pressure for Environmental Sustainability on Grid Assimilation: Empirical Results from the Financial Services Industry In: Australasian Journal of Information Systems (AJIS), 17(1), 83-106 Appendix: Publications, Curriculum Vitae
The canonical Wnt/β-catenin and the Shh pathway as well as the Notch signaling cascade
are key regulators in stem cell biology and are independently associated with the development
of cancer. Despite the knowledge of a balanced signaling for cellular maintenance, the
fundamental biochemical mechanisms of crosstalk are still poorly understood. This study
demonstrates that the outcome of interaction between Wnt and Shh is cell type specific. A
combined inhibitory mechanism of the Shh and Notch2/Jagged2 pathways on dominant
active β-catenin signaling in the adult tongue epithelium keeps Wnt/β-catenin signaling
restricted to physiological tolerable levels. In the opposite crosstalk the activation of
Wnt/β-catenin signaling in medulloblastoma (MB) of the Shh subtype, in turn inhibits the Hh
pathway.
The inhibitory mechanism of Shh and Notch2/Jagged2 on Wnt/β-catenin signaling is
independent of the degradation complex of β-catenin and takes place inside the nucleus.
Furthermore, the negative feedback on Wnt/β-catenin signaling by the Shh pathway relies
on transcriptional activity of Gli1/2A. Inhibition of Gli1/2A with the specific inhibitor GANT61
abrogated the negative impact of Shh on β-catenin signaling in vitro. Although the negative
feedback loop of Shh is still functional in human SCC25 cells, the inhibitory effect of
Notch2/Jagged2 is lost and contributes to the cancerogenic phenotype of these cells. In the
inverse situation, the activation of β−catenin signaling has a negative feedback on
constantly active Shh signaling and significantly inhibits the Hh pathway. This was shown in
Ptch+/- and Math1-Cre:SmoM2Fl/+ MB tumor spheres in vitro, in which inhibition of sphere
formation and growth was observed and Hh target gene transcription was down-regulated.
This demonstrates for the first time that the activation of canonical Wnt/β-catenin signaling
in primary MB cells with a Hh pathway over-activation has a negative effect on the growth of
these cells in vitro.
In summary the results show that crosstalk of Wnt/β-catenin and Shh signaling has context
specific outcome on pathway activity. Elucidation of the molecular interactions will improve
our understanding of Wnt and Hh associated tumors and contribute to the development of
new therapeutic strategies.
In this thesis, laboratory investigations have been conducted to investigate several processes occurring during the melt segregation (crystal settling and compaction processes), as well as during emplacement of plutons. With the help of three different sets of centrifuge experiments rates of these three magmatic processes have been evaluated. In the first series of the centrifuge experiments, the diapiric ascent of buoyant material from two source layers at different depths was studied. Through five models, the hypothesis of ascending diapirs was tested and it was demonstrated whether a rising diapir ascends straight upward or if its ascent might be deviated by another buoyant, softer – and consequently easier to travel through – layer which is located within the overburden strata. We were interested under which conditions they can be formed. For this purpose we placed perturbations on top of both the buoyant layers; either with a set-off of both the protrusions (for three of these experiments), or with both protrusion sitting directly on top of each other (for one of the experiments). In the first experiment, we omitted the perturbations, to test which pathways diapirs take which grow from natural Rayleigh-Taylor instabilities. Three others experiments differed in the viscosity contrast between the overburden and the buoyant material. Through the experimental runs, the effects of different overburden viscosities and perturbation positions on the number of the diapirs were observed. The modeling results show that two diapirs rising from the offset perturbations do not take the same pathway through the overburden layer. Rather, each diapir takes a different pathway, with the deeper diapir piercing through its overburden while rising, regardless if it was a buoyant layer or denser overburden layers. However, when the two perturbations were situated directly above each other in the different PDMS layers, this resulted in the formation of one big diapir rather than several smaller ones, and the overburden layer was less deformed than with offset perturbations. Diapiric structures as those derived from the models without perturbation and where the perturbation are offset occur within Great Kavir Basin (Iran), where numerous salt diapirs grew from several salt horizons, which show a similar spatial distribution. The resulting structure observed in the model where the two perturbations situated directly above each other, is close to what is observed in composite batholiths such as the Flasergranitoid Zone within the Bergsträßer Odenwald Crystalline Complex (Germany). The second series of models were aimed to study crystal settling within a magma. For this purpose experiments with an artificial magma of 30 vol% olivine in 70 vol% basaltic melt were conducted to elucidate the formation mechanisms and time scales of gravitational cumulates. Through the experiments, two physical processes have been observed: (i) purely mechanical compaction, and (ii) chemical compaction induced by dissolution and re-precipitation of settled crystals. The results reveals that the mechanical settling of the dense olivine suspension occurs at about 1/6 the speed of simple Stokes settling, and a sedimentation exponent n of 4.1 is found. Evidences of chemical compaction induced by dissolution and re-precipitation of settled crystals have been highlighted by a detailed analysis of the fine structure of olivine grain boundaries. This last has revealed (1) the presence of Ca, which is characteristic only for MORB-melt, at the interface of two adjacent Ol-grains even when no melt is present; (2) a not fully crystallized boundary layer between two adjacent olivine grains. The crystal size distribution curves and the grain size growth exponent n ~3.6 indicate that diffusion controlled Ostwald ripening is the dominant crystal growth mechanism in concentrated magmatic suspensions. Finally, the formation times in natural olivine adcumulates have been calculated. The last series of centrifuge experiments deals with the crystal-melt settling-floating mechanism in a system composed of natural two pyroxene gabbro. The results have revealed a vertical evolution of the major and trace elements in the melt phase. Then, a numerical modelling of the sedimentation process of the crystals has been made in order to describe the compaction evolution with time. In comparing the numerical simulation with the centrifuge modelling, the stratification of the compacted layer in the runs is reproduced in numerical models. Moreover, on the base of the numerical and centrifuge modelling, a sedimentation exponent describing a deviation of settling in concentrated suspensions from Stokes sedimentation has been evaluated. Finally, the numerical simulation is applied to the Muskox intrusion to estimate the formation time and the melt fraction evolution in using the hindered sedimentation model calculations.
Within the present work, photodissociation reactions on 100Mo, 93Mo and 92Mo isotopes were studied by means of the Coulomb dissociation method at the LAND setup at GSI. Experimental data on these isotopes are important to explain the problem of the underproduction of the lighter p-nuclei - 92; 94Mo - within the models of the p-process nucleosynthesis. The reaction rates used in the nucleosynthesis calculations are usually obtained within the framework of the statistical model. In order to verify the model predictions and reduce the uncertainties, experimental measurements of the reaction cross sections are required. In particular, the data on (γ,n) reactions are of interest, since these reactions were shown to dominate the p-process flow in the molybdenum mass region.
As a result of the analysis of the present experiment, integrated Coulomb excitation cross sections of the 100Mo(γ,n), 100Mo(γ,2n), 93Mo(γ,n) and 92Mo(γ,n) reactions were determined. The measurement of the 93Mo isotope is particularly important, since this nucleus is unstable, and the corresponding cross section has not been measured before.
It should be emphasized that Coulomb dissociation is a unique tool to study photoninduced reactions on unstable nuclei, which is especially relevant in the context of nucleosynthesis network calculations. However, because of to the complexity of the data analysis procedure and a number of model assumptions that are required in order to extract the Coulomb excitation cross section from the data, one of the main aspects of this thesis was to verify the method by comparing the results with the previously published data obtained with real photon beams. Integrated cross sections of the 100Mo(γ,n) and 100Mo(γ,2n) reactions were directly compared to the data by Beil et al., obtained at Saclay with photons from positron annihilation, while an indirect comparison could be performed with a recent photoactivation measurement by Erhard and co-workers. A reasonable agreement was observed for the 1n channel: a scaling factor of 0.8 ± 0.1 between our result and Beil et al. data is consistent with the scaling factor of 0.89±0.09 reported by Erhard et al. between their data and Beil et al. data. Both results are in agreement with the scaling factor of 0.85 ± 0.03 recommended by Berman et al. for the data measured at Saclay on nuclei in the respective mass region. A somewhat lower factor of 0.61 ± 0.09 between the present data and Beil et al. data was obtained for the 2n channel. The discrepancy might be explained by both the substantial efficiency correction that has to be applied to the LAND data in the two-neutron case, as well as by an insufficiently accurate assumption that the Saclay neutron detector efficiency is energy- and multiplicity- independent.
A second important topic of the present thesis is the investigation of the efficiency of the CsI gamma detector. The calorimetric information that it delivers is essential to reconstruct the energy-differential cross section from the present measurement. The data taken with the gamma calibration sources shortly after the experiment were used for the investigation. In addition, a test experiment in refined conditions was conducted within the framework of this thesis. Numerous GEANT3 simulations of the detector were performed in order to understand various aspects of its performance. As a result, the efficiency of the detector was determined to be approximately a factor of 2 lower than the efficiency expected from the simulation. This result is consistent with several independent investigations, which were performed using different methods. At the same time, a remarkable agreement between the simulated and experimental data was achieved under assumption that the inefficiency of the detector is explained by the loss of data from a number of crystals, which are randomly chosen in each event according to their averaged performance ratio (the ”on-off” effect). The reasons for the observed malfunction are yet not fully clear. Regardless of the exact reason, in the present conditions a deconvolution of the measured data from the CsI response is not possible. Consequently, within the framework of this thesis, the results are presented in terms of integrated cross sections. A search for alternative methods of data interpretation, allowing to extract energy-differential information out of the available data, in currently ongoing.
In the more recent experiments at the LAND setup, where the Crystal Ball gamma detector was used as a calorimeter, the reconstruction of the energy-differential cross section with a reasonable resolution was already shown to be feasible. It means that, even considering the uncertainties of the present experiment of the order of 10%, the uncertainties of the statistical model predictions, which are on average estimated to be within a factor of 1.5-2, can already be constrained.
The analysis of the present experiment is still in progress. As a next step, Coulomb excitation cross section for 94Mo will be obtained. The 94Mo(γ,n) reaction cannot be studied by photoactivation, since the life time of the daughter nucleus is too long (4000 y). At the same time, this reaction plays a key role in the p-process nucleosynthesis.
The future of the LAND setup - the R3B setup1 at FAIR2 - will take advantage of a three orders of magnitude higher intensity of the radioactive beams [85], as well as of a completely new detector system. High-resolution measurements of the energy-differential cross sections will be possible for exotic nuclei, which were never accessible in the laboratory before. Such measurements will open great opportunities for nuclear astrophysics, allowing to obtain high-quality experimental data even for regions of the nuclear chart where the statistical model calculations are not applicable.
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.