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ResearcherID
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- N-3741-2015 (1)
In the present thesis the MBE growth and sample characterization of HgTe structures is investigated
and discussed. Due to the first experimental discovery of the quantum Spin Hall effect
(QSHE) in HgTe quantum wells, this material system attains a huge interest in the spintronics
society. Because of the long history of growing Hg-based heterostructures here at the Experimentelle
Physik III in Würzburg, there are very good requirements to analyze this material
system more precisely and in new directions. Since in former days only doped HgTe quantum
wells were grown, this thesis deals with the MBE growth in the (001) direction of undoped
HgTe quantum wells, surface located quantum wells and three dimensional bulk layers. All
Hg-based layers were grown on CdTe substrates which generate strain in the layer stack and
provide therefore new physical effects. In the same time, the (001) CdTe growth was investigated
on n-doped (001) GaAs:Si because the Japanese supplier of CdTe substrates had a
supply bottleneck due to the Tohoku earthquake and its aftermath in 2011.
After a short introduction of the material system, the experimental techniques were demonstrated
and explained explicitly. After that, the experimental part of this thesis is displayed.
So, the investigation of the (001) CdTe growth on (001) GaAs:Si is discussed in chapter 4.
Firstly, the surface preparation of GaAs:Si by oxide desorption is explored and analyzed.
Here, rapid thermal desorption of the GaAs oxide with following cool down in Zn atmosphere
provides the best results for the CdTe due to small holes at the surface, while e.g. an atomic
flat GaAs buffer deteriorates the CdTe growth quality. The following ZnTe layer supplies the
(001) growth direction of the CdTe and exhibits best end results of the CdTe for 30 seconds
growth time at a flux ratio of Zn/Te ~ 1/1.2. Without this ZnTe layer, CdTe will grow in the
(111) direction. However, the main investigation is here the optimization of the MBE growth
of CdTe. The substrate temperature, Cd/Te flux ratio and the growth time has to be adjusted
systematically. Therefore, a complex growth process is developed and established. This optimized
CdTe growth process results in a RMS roughness of around 2.5 nm and a FWHM value
of the HRXRD w-scan of 150 arcsec. Compared to the literature, there is no lower FWHM
value traceable for this growth direction. Furthermore, etch pit density measurements show
that the surface crystallinity is matchable with the commercial CdTe substrates (around 1x10^4
cm^(-2)). However, this whole process is not completely perfect and offers still room for improvements.
The growth of undoped HgTe quantum wells was also a new direction in research in contrast
to the previous n-doped grown HgTe quantum wells. Here in chapter 5, the goal of very low
carrier densities was achieved and therefore it is now possible to do transport experiments in
the n - and p - region by tuning the gate voltage. To achieve this high sample quality, very precise
growth of symmetric HgTe QWs and their HRXRD characterization is examined. Here,
the quantum well thickness can now determined accurate to under 0.3 nm. Furthermore, the transport analysis of different quantum well thicknesses shows that the carrier density and
mobility increase with rising HgTe layer thickness. However, it is found out that the band
gap of the HgTe QW closes indirectly at a thickness of 11.6 nm. This is caused by the tensile
strained growth on CdTe substrates. Moreover, surface quantum wells are studied. These
quantum wells exhibit no or a very thin HgCdTe cap. Though, oxidization and contamination
of the surface reduces here the carrier mobility immensely and a HgCdTe layer of around 5 nm
provides the pleasing results for transport experiments with superconductors connected to the
topological insulator [119]. A completely new achievement is the realization of MBE growth
of HgTe quantum wells on CdTe/GaAs:Si substrates. This is attended by the optimization of
the CdTe growth on GaAs:Si. It exposes that HgTe quantum wells grown in-situ on optimized
CdTe/GaAs:Si show very nice transport data with clear Hall plateaus, SdH oscillations, low
carrier densities and carrier mobilities up to 500 000 cm^2/Vs. Furthermore, a new oxide etching
process is developed and analyzed which should serve as an alternative to the standard
HCl process which generates volcano defects at some time. However, during the testing time
the result does not differ in Nomarski, HRXRD, AFM and transport measurements. Here,
long-time tests or etching and mounting in nitrogen atmosphere may provide new elaborate
results.
The main focus of this thesis is on the MBE growth and standard characterization of HgTe bulk
layers and is discussed in chapter 6. Due to the tensile strained growth on lattice mismatched
CdTe, HgTe bulk opens up a band gap of around 22 meV at the G-point and exhibits therefore
its topological surface states. The analysis of surface condition, roughness, crystalline quality,
carrier density and mobility via Nomarski, AFM, XPS, HRXRD and transport measurements
is therefore included in this work. Layer thickness dependence of carrier density and mobility
is identified for bulk layer grown directly on CdTe substrates. So, there is no clear correlation
visible between HgTe layer thickness and carrier density or mobility. So, the carrier density is
almost constant around 1x10^11 cm^(-2) at 0 V gate voltage. The carrier mobility of these bulk
samples however scatters between 5 000 and 60 000 cm^2/Vs almost randomly. Further experiments
should be made for a clearer understanding and therefore the avoidance of unusable
bad samples.But, other topological insulator materials show much higher carrier densities and
lower mobility values. For example, Bi2Se3 exhibits just density values around 1019 cm^(-2)
and mobility values clearly below 5000 cm2/Vs. The carrier density however depends much
on lithography and surface treatment after growth. Furthermore, the relaxation behavior and
critical thickness of HgTe grown on CdTe is determined and is in very good agreement with
theoretical prediction (d_c = 155 nm). The embedding of the HgTe bulk layer between HgCdTe
layers created a further huge improvement. Similar to the quantum well structures the carrier
mobility increases immensely while the carrier density levels at around 1x10^11 cm^(-2) at 0
V gate voltage as well. Additionally, the relaxation behavior and critical thickness of these
barrier layers has to be determined. HgCdTe grown on commercial CdTe shows a behavior as
predicted except the critical thickness which is slightly higher than expected (d_c = 850 nm).
Otherwise, the relaxation of HgCdTe grown on CdTe/GaAs:Si occurs in two parts. The layer
is fully strained up to 250 nm. Between 250 nm and 725 nm the HgCdTe film starts to relax
randomly up to 10 %. The relaxation behavior for thicknesses larger than 725 nm occurs than
linearly to the inverse layer thickness. A explanation is given due to rough interface conditions
and crystalline defects of the CdTe/GaAs:Si compared to the commercial CdTe substrate. HRXRD and AFM data support this statement. Another point is that the HgCdTe barriers protect the active HgTe layer and because of the high carrier mobilities the Hall measurements provide new transport data which have to be interpreted more in detail in the future. In addition, HgTe bulk samples show very interesting transport data by gating the sample from the top and the back. It is now possible to manipulate the carrier densities of the top and bottom surface states almost separately. The back gate consisting of the n-doped GaAs substrate and the thick insulating CdTe buffer can tune the carrier density for Delta(n) ~ 3x10^11 cm^(-2). This is sufficient to tune the Fermi energy from the p-type into the n-type region [138].
In this thesis it is shown that strained HgTe bulk layers exhibit superior transport data by embedding between HgCdTe barrier layers. The n-doped GaAs can here serve as a back gate.
Furthermore, MBE growth of high crystalline, undoped HgTe quantum wells shows also new
and extended transport output. Finally, it is notable that due to the investigated CdTe growth
on GaAs the Hg-based heterostructure MBE growth is partially independent from commercial
suppliers.
In this work, Emilio de’ Cavalieri’s musical sources will serve as a platform in an attempt to overcome the lack of explicit original guidance and guidelines of performance practice of early basso continuo. It will offer a methodology that will allow the unraveling of implicit theory and practice hidden in the music sources themselves. The methodology of this work is based on the fact that Cavalieri’s Rappresentatione di Anima e di Corpo (Rome, 1600) is printed using a unique continuo notation, which is detailed, precise, and coherent—more so than any other contemporaneous printed source. Through thorough investigation of this continuo notation, it will be possible to enrich our practical as well as theoretical knowledge of the early basso continuo. A wide range of evidences will emerge, covering a wide spectrum, from general questions of instrumentation up to the very notes that should be played. Using a special notation for illustration, I will demonstrate how Cavalieri’s basso continuo figuration, when combined with the known rules of counterpoint, is at times equivalent to written-out realizations.
As part of this study, different models of contrapuntal phenomena will be analyzed, mainly in the context of cadences but also in the context of other progressions that deserve to be recognized as formulas. Their theoretical structure will be uncovered as well as their actual application in music and their manner of execution. The prevalence of each phenomenon will be examined in order to distinguish common and recurrent phenomena from rarely-used formulas. In order to do this, and due to problematic historical terminology, it will be necessary to create a set of new terms inspired by Cavalieri’s notation. Those terms will not be solely relevant to Cavalieri’s music; the models were made flexible so that they may prove useful for future discussions or studies of early continuo in general.
Out of the known early basso continuo sources, a “mini-compendium” of practical implications will be extracted in order to exhaust the practical knowledge implicit in them. This endeavor will be concluded with a list of rules and general advice drawn from the sources, but it will also reveal some problematic aspects of these sources.
This endeavor will make it possible to compare the “new” implicit practical information deduced in this study with the explicit known continuo sources, and assess to what extant Cavalieri’s continuo practices illuminate and complement the known knowledge from previously-studied yet opaque sources of basso continuo.
The focus of this dissertation is on Cavalieri’s music, but the findings proposed here will be traced so as to illuminate the broader realm of the early Baroque and the 17th century musical style at large. Finally, this new research about Cavalieri’s music and continuo, along reevaluating of its place among the common continuo sources, calls for redistribution of source materials on the traditional “shelf” of early basso continuo sources.
Aspergillus fumigatus is the most common cause for invasive fungal infections, a disease associated with high mortality in immune-compromised patients. CD1d-restricted invariant Natural Killer T (iNKT) cells compose a small subset of T cells known to impact the immune response towards various infectious pathogens. To investigate the role of human iNKT cells during A. fumigatus infection, we studied their activation as determined by CD69 expression and cytokine production in response to distinct fungal morphotypes in the presence of different CD1d⁺ antigen presenting cells using flow cytometry and multiplex ELISA. Among CD1d⁺ subpopulations, CD1d⁺CD1c⁺ mDCs showed the highest potential to activate iNKT cells on a per cell basis. The presence of A. fumigatus decreased this effect of CD1d⁺CD1c⁺ mDCs on iNKT cells and led to reduced secretion of TNF-α, G-CSF and RANTES. Production of other Th1 and Th2 cytokines was not affected by the fungus, suggesting an immune-modulating function for human iNKT cells during A. fumigatus infection.
The controlled shaping of ultrashort laser pulses is a powerful technology and applied in many laser laboratories today. Most of the used pulse shapers are only able to produce linearly polarized pulses shaped in amplitude and phase. Some devices are also capable of producing limited time-varying polarization profiles, but they are not able to control the amplitude. However, for some state-of-the-art non-linear time-resolved methods, such as polarization-enhanced two-dimensional spectroscopy, the possibility of controlling the amplitude and the polarization simultaneously is desirable.
Over the last years, different concepts have been developed to overcome these restrictions and to manipulate the complete vector-field of an ultrashort laser pulse with independent control over all four degrees of freedom - phase, amplitude, orientation, and ellipticity. The aim of this work was to build such a vector-field shaper. While the basic concept used for our setup is based on previous designs reported in the literature, the goal was to develop an optimized optical design that minimizes artifacts, allowing for the generation of predefined polarization pulse sequences with the highest achievable accuracy.
In Chapter 3, different approaches reported in the literature for extended and unrestricted vector-field control were examined and compared in detail. Based on this analysis, we decided to follow the approach of modulating the spectral phase and amplitude of two perpendicularly polarized pulses independently from each other in two arms of an interferometer and recombining them to a single laser pulse to gain control over the complete vector field.
As described in Chapter 4, the setup consists of three functional groups: i) an optical component to generate and recombine the two polarized beams, ii) a 4f setup, and iii) a refracting telescope to direct the two beams under two different angles of incidence onto the grating of the 4f setup in a common-path geometry. This geometry was chosen to overcome potential phase instabilities of an interferometric vector-field shaper. Manipulating the two perpendicularly polarized pulses simultaneously within one 4f setup and using adjacent pixel groups of the same liquid-crystal spatial light modulator (LC SLM) for the two polarizations has the advantages that only a single dual-layer LC SLM is required and that a robust and compact setup was achieved. The shaping capabilities of the presented design were optimized by finding the best parameters for the setup through numerical calculations to adjust the frequency distributions for a broad spectrum of 740 – 880 nm. Instead of using a Wollaston prism as in previous designs, a thin-film polarizer (TFP) is utilized to generate and recombine the two orthogonally polarized beams. Artifacts such as angular dispersion and phase distortions along the beam profile which arise when a Wollaston prism is used were discussed. Furthermore, it was shown by ray-tracing simulations that in combination with a telescope and the 4f setup, a significant deformation of the beam profile would be present when using a Wollaston prism since a separation of the incoming and outgoing beam in height is needed. The ray-tracing simulations also showed that most optical aberrations of the setup are canceled out when the incoming and outgoing beams propagate in the exact same plane by inverting the beam paths. This was realized by employing a TFP in the so-called crossed-polarizer arrangement which has also the advantage that the polarization-dependent efficiencies of the TFP and the other optics are automatically compensated and that a high extinction ratio in the order of 15000:1 is reached. Chromatic aberrations are, however, not compensated by the crossed-polarizer arrangement. The ray-tracing simulations confirmed that these chromatic aberrations are mainly caused by the telescope and not by the cylindrical lens of the 4f setup. Nevertheless, in the experimentally used wavelength range of 780 – 816 nm, only minor distortions of the beam profile were observed, which were thus considered to be negligible in the presented setup.
The software implementation of the pulse shaper was reviewed in Chapter 5 of this thesis. In order to perform various experiments, five different parameterizations, accounting for the extended shaping capabilities of a vector-field shaper, were developed. The Pixel Basis, the Spectral Basis, and the Spectral Taylor Basis can generally be used in combination with an optimization algorithm and are therefore well suited for quantum control experiments. For multidimensional spectroscopy, the Polarized Four-Pulse Basis was established. With this parameterization pulse sequences with up to four subpulses can be created. The polarization state of each subpulse can be specified and the relative intensity, phase, and temporal delay between consecutive subpulses can be controlled. In addition, different software programs were introduced in Chapter 5 which are required to perform the experiments conducted in this work.
The experimental results were presented in Chapter 6. The frequency distribution across the LC SLM was measured proving that the optimal frequency distribution was realized experimentally. Furthermore, the excellent performance of the TFP was verified. In general, satellite pulses are emitted from the TFP due to multiple internal reflections. Various measurements demonstrated that these pulses are temporally separated by at least 4.05 ps from the main pulse and that they have vanishing intensity. The phase stability between the two arms of the presented common-path setup σ = 28.3 mrad (λ/222) over 60 minutes. To further improve this stability over very long measurement times, an on-the-fly phase reduction and stabilization (OPRAS) routine utilizing the pulse shaper itself was developed. This routine automatically produces a compressed pulse with a minimized relative phase between the two polarization components. A phase stability of σ = 31.9 mrad (λ/197) over nearly 24 hours was measured by employing OPRAS. Various pulse sequences exceeding the capabilities of conventional pulse shapers were generated and characterized. The experimental results proved that shaped pulses with arbitrary phase, amplitude, and polarization states can be created. In all cases very high agreement between the target parameters and the experimental data was achieved.
For the future use of the setup also possible modifications were suggested. These are not strictly required, but all of them could further improve the performance and flexibility of the setup. Firstly, it was illustrated how a “dual-output” of the setup can be realized. With this modification it would be possible to use the main intensity of the shaped pulse for an experiment while using a small fraction to characterize the pulse or to perform OPRAS simultaneously. Secondly, the basic idea of replacing the telescope by focusing mirrors in order to eliminate the chromatic aberrations was presented. Regarding the different parameterizations for vector-field shaping, some modifications increasing the flexibility of the implemented bases and the realization of a von Neumann Basis for the presented setup were proposed. In future experiments, the vector-field shaper will be used in conjunction with a photoemission electron microscope (PEEM). This approach combines the temporal resolution provided by ultrashort laser pulses with the high spatial resolution gained by electron microscopy in order to perform two-dimensional spectroscopy and coherent control on nanostructures with polarization-shaped femtosecond laser pulses. In combination with other chiral-sensitive experimental setups implemented earlier in our group, the vector-field shaper opens up new perspectives for chiral femtochemistry and chiral control.
The designed vector-field shaper meets all requirements to generate high-precision polarization-shaped multipulse sequences. These can be used to perform numerous polarization-sensitive experiments. Employing the OPRAS routine, a quasi-infinitely long phase stability is achieved and complex and elaborated long-term measurements can be carried out. The fact that OPRAS demands no additional hardware and that only a single dual-layer LC SLM and inexpensive optics are required allows the building of a vector-field shaper at comparatively low costs. We hope that with the detailed insights into the optical design process as well as into the software implementation given in this thesis, vector-field shaping will become a standard technique just as conventional pulse shaping in the upcoming years.
Following the early experiences in aviation, medical simulation has rapidly
evolved into one of the most novel educational tools of the last three decades. In addition to its
use in training individuals or teams in crisis resource management, simulation has been studied as
a tool to evaluate technical and non-technical skills of individuals as well as, more recently,
entire medical teams.
It is usually fairly difficult to obtain clinical reference data from critical events to refute
claims that the management of actual events fell below what could reasonably be expected and we
demonstrated the use of rank order statistics to calculate quantiles with confidence limits for
management times of critical obstetrical events using data from realistic simulation. This approach
could be used to describe the distribution of treatment times in order to assist in deciding what
performance may constitute an outlier. It can also identify particular challenges of clinical
practice and allow the development of educational curricula. While the information derived from
simulation has to be interpreted with a high degree of caution for a clinical context, it may
represent a further ‘added value’ or important step in establishing simulation as a training tool
and to provide information that could be used in an appropriate clinical context for adverse
events. Large amounts of data (such as from a simulation registry) would allow the calculation of
acceptable confidence intervals for the required
outcome parameters as well as actual tolerance limits.
In this work, Emilio de’ Cavalieri’s musical sources will serve as a platform in an attempt to overcome the lack of explicit original guidance and guidelines of performance practice of early basso continuo. It will offer a methodology that will allow the unraveling of implicit theory and practice hidden in the music sources themselves. The methodology of this work is based on the fact that Cavalieri’s Rappresentatione di Anima e di Corpo (Rome, 1600) is printed using a unique continuo notation, which is detailed, precise, and coherent—more so than any other contemporaneous printed source. Through thorough investigation of this continuo notation, it will be possible to enrich our practical as well as theoretical knowledge of the early basso continuo. A wide range of evidences will emerge, covering a wide spectrum, from general questions of instrumentation up to the very notes that should be played. Using a special notation for illustration, I will demonstrate how Cavalieri’s basso continuo figuration, when combined with the known rules of counterpoint, is at times equivalent to written-out realizations.
As part of this study, different models of contrapuntal phenomena will be analyzed, mainly in the context of cadences but also in the context of other progressions that deserve to be recognized as formulas. Their theoretical structure will be uncovered as well as their actual application in music and their manner of execution. The prevalence of each phenomenon will be examined in order to distinguish common and recurrent phenomena from rarely-used formulas. In order to do this, and due to problematic historical terminology, it will be necessary to create a set of new terms inspired by Cavalieri’s notation. Those terms will not be solely relevant to Cavalieri’s music; the models were made flexible so that they may prove useful for future discussions or studies of early continuo in general.
Out of the known early basso continuo sources, a “mini-compendium” of practical implications will be extracted in order to exhaust the practical knowledge implicit in them. This endeavor will be concluded with a list of rules and general advice drawn from the sources, but it will also reveal some problematic aspects of these sources.
This endeavor will make it possible to compare the “new” implicit practical information deduced in this study with the explicit known continuo sources, and assess to what extant Cavalieri’s continuo practices illuminate and complement the known knowledge from previously-studied yet opaque sources of basso continuo.
The focus of this dissertation is on Cavalieri’s music, but the findings proposed here will be traced so as to illuminate the broader realm of the early Baroque and the 17th century musical style at large. Finally, this new research about Cavalieri’s music and continuo, along reevaluating of its place among the common continuo sources, calls for redistribution of source materials on the traditional “shelf” of early basso continuo sources.
Environmental interlinked problems such as human-induced land cover change, water scarcity, loss in soil fertility, and anthropogenic climate change are expected to affect the viability of agriculture and increase food insecurity in many developing countries. Climate change is certainly the most serious of these challenges for the twenty-first century. The poorest regions of the world – tropical West Africa included – are the most vulnerable due to their high dependence on climate and weather sensitive activities such as agriculture, and the widespread poverty that limits the institutional and economic capacities to adapt to the new stresses brought about by climate change. Climate change is already acting negatively on the poor smallholders of tropical West Africa whose livelihoods dependent mainly on rain-fed agriculture that remains the cornerstone of the economy in the region. Adaptation of the agricultural systems to climate change effects is, therefore, crucial to secure the livelihoods of these rural communities. Since information is a key for decision-making, it is important to provide well-founded information on the magnitude of the impacts in order to design appropriate and sustainable adaptation strategies.
Considering the case of agricultural production in the Republic of Benin, this study aims at using large-scale climatic predictors to assess the potential impacts of past and future climate change on agricultural productivity at a country scale in West Africa. Climate signals from large-scale circulation were used because state-of-the art regional climate models (RCM) still do not perfectly resolve synoptic and mesoscale convective processes. It was hypothesised that in rain-fed systems with low investments in agricultural inputs, yield variations are widely governed by climatic factors. Starting with pineapple, a perennial fruit crops, the study further considered some annual crops such as cotton in the group of fibre crops, maize, sorghum and rice in the group of cereals, cowpeas and groundnuts belonging to the legume crops, and cassava and yams which are root and tuber crops. Thus the selected crops represented the three known groups of photosynthetic pathways (i.e. CAM, C3, and C4 plants).
In the study, use was made of the historical agricultural yield statistics for the Republic of Benin, observed precipitation and mean near-surface air temperature data from the Climatic Research Unit (CRU TS 3.1) and the corresponding variables simulated by the regional climate model (RCM) REMO. REMO RCM was driven at its boundaries by the global climate model ECHAM 5. Simulations with different greenhouse gas concentrations (SRES-A1B and B1 emission scenarios) and transient land cover change scenarios for present-day and future conditions were considered. The CRU data were submitted to empirical orthogonal functions analysis over the north hemispheric part of Africa to obtain large-scale observed climate predictors and associated consistent variability modes. REMO RCM data for the same region were projected on the derived climate patterns to get simulated climate predictors. By means of cross-validated Model Output Statistics (MOS) approach combined with Bayesian model averaging (BMA) techniques, the observed climate predictors and the crop predictand were further on used to derive robust statistical relationships. The robust statistical crop models perform well with high goodness-of-fit coefficients (e.g. for all combined crop models: 0.49 ≤ R2 ≤ 0.99; 0.28 ≤ Brier-Skill-Score ≤ 0.90).
Provided that REMO RCM captures the main features of the real African climate system and thus is able to reproduce its inter-annual variability, the time-independent statistical transfer functions were then used to translate future climate change signal from the simulated climate predictors into attainable crop yields/crop yield changes. The results confirm that precipitation and air temperature governed agricultural production in Benin in general, and particularly, pineapple yield variations are mainly influenced by temperature. Furthermore, the projected yield changes under future anthropogenic climate change during the first-half of the 21st century amount up to -12.5% for both maize and groundnuts, and -11%, -29%, -33% for pineapple, cassava, and cowpeas respectively. Meanwhile yield gain of up to +10% for sorghum and yams, +24% for cotton, and +39% for rice are expected. Over the time period 2001 – 2050, on average the future yield changes range between -3% and -13% under REMO SRES–B1 (GHG)+LCC, -2% and -11% under REMO SRES–A1B (GHG only),and -3% and -14% under REMO SRES–A1B (GHG)+LCC for pineapple, maize, sorghum, groundnuts, cowpeas and cassava. In the meantime for yams, cotton and rice, the average yield gains lie in interval of about +2% to +7% under REMO SRES–B1 (GHG)+LCC, +0.1% and +12% under REMO SRES–A1B (GHG only), and +3% and +10% under REMO SRES–A1B (GHG)+LCC. For sorghum, although the long-term average future yield depicts a reduction there are tendencies towards increasing yields in the future. The results also reveal that the increases in mean air temperature more than the changes in precipitation patterns are responsible for the projected yield changes. As well the results suggest that the reductions in pineapple yields cannot be attributed to the land cover/land use changes across sub-Saharan Africa. The production of groundnuts and in particular yams and cotton will profit from the on-going land use/land cover changes while the other crops will face detrimental effects.
Henceforth, policymakers should take effective measures to limit the on-going land degradation processes and all other anthropogenic actions responsible for temperature increase. Biotechnological improvement of the cultivated crop varieties towards development of set of seed varieties adapted to hotter and dry conditions should be included in the breeding pipeline programs. Amongst other solutions, application of appropriate climate-smart agricultural practices and conservation agriculture are also required to offset the negative impacts of climate change in agriculture.
Kinetic assessment by in vitro approaches - A contribution to reduce animals in toxicity testing
(2015)
The adoption of directives and regulations by the EU requires the development of alternative testing strategies as opposed to animal testing for risk assessment of xenobiotics. Additionally, high attrition rates of drugs late in the discovery phase demand improvement of current test batteries applied in the preclinical phase within the pharmaceutical area. These issues were taken up by the EU founded 7th Framework Program “Predict-IV”; with the overall goal to improve the predictability of safety of an investigational product, after repeated exposure, by integration of “omics” technologies applied on well established in vitro approaches. Three major target organs for drug-induced toxicity were in focus: liver, kidney and central nervous system. To relate obtained dynamic data with the in vivo situation, kinetics of the test compounds have to be evaluated and extrapolated by physiologically based pharmacokinetic modeling.
This thesis assessed in vitro kinetics of the selected test compounds (cyclosporine A, adefovir dipivoxil and cisplatinum) regarding their reliability and relevance to respective in vivo pharmacokinetics. Cells were exposed daily or every other day to the test compounds at two concentration levels (toxic and non-toxic) for up to 14 days. Concentrations of the test compounds or their major biotransformation products were determined by LC-MS/MS or ICP-MS in vehicle, media, cells and plastic adsorption samples generated at five different time-points on the first and the last treatment day.
Cyclosporine A bioaccumulation was evident in primary rat hepatocytes (PRH) at the high concentration, while efficient biotransformation mediated by CYP3A4 and CYP3A5 was determined in primary human hepatocytes (PHH) and HepaRG cells. The lower biotransformation in PRH is in accordance with observation made in vivo with the rat being a poor model for CYP3A biotransformation. Further, inter-assay variability was noticed in PHH caused by biological variability in CYP3A4 and CYP3A5 activity in human donors. The inter-assay variability observed for PRH and HepaRG cells was a result of differences between vehicles regarding their cyclosporine A content. Cyclosporine A biotransformation was more prominent in HepaRG cells due to stable and high CYP3A4 and CYP3A5 activity. In addition, in vitro clearances were calculated and scaled to in vivo. All scaled in vitro clearances were overestimated (PRH: 10-fold, PHH: 2-fold, HepaRG cells: 2-fold). These results should be proven by physiologically-based pharmacokinetic modeling and additional experiments, in order to verify that these overestimations are constant for each system and subsequently can be diminished by implementation of further scaling factors.
Brain cell cultures, primary neuronal culture of mouse cortex cells and primary aggregating rat brain cells, revealed fast achieved steady state levels of cyclosporine A. This indicates a chemical distribution of cyclosporine A between the aqueous and organic phases and only minor involvement of biological processes such as active transport and biotransformation. Hence, cyclosporine A uptake into cells is presumably transport mediated, supported by findings of transporter experiments performed on a parallel artificial membrane and Caco-2 cells. Plastic adsorption of cyclosporine A was significant, but different for each model, and should be considered by physiologically based pharmacokinetic modeling.
Kinetics of adefovir dipivoxil highlights the limits of in vitro approaches. Active transporters are required for adefovir uptake, but were not functional in RPTECT/TERT1. Therefore, adefovir uptake was limited to passive diffusion of adefovir dipivoxil, which itself degrades time-dependently under culture conditions.
Cisplatinum kinetics, studied in RPTEC/TERT1 cells, indicated intracellular enrichment of platinum, while significant bioaccumulation was not noted. This could be due to cisplatinum not reaching steady state levels within 14 days repeated exposure. As shown in vivo, active transport occurred from the basolateral to apical side, but with lower velocity. Hence, obtained data need to be modeled to estimate cellular processes, which can be scaled and compared to in vivo.
Repeated daily exposure to two different drug concentrations makes it possible to account for bioaccumulation at toxic concentrations or biotransformation/extrusion at non-toxic concentrations. Potential errors leading to misinterpretation of data were reduced by analyses of the vehicles as the applied drug concentrations do not necessarily correspond to the nominal concentrations. Finally, analyses of separate compartments (medium, cells, plastic) give insights into a compound’s distribution, reduce misprediction of cellular processes, e.g. biotransformation, and help to interpret kinetic data. On the other hand, the limits of in vitro approaches have also been pointed out. For correct extrapolation to in vivo, it is essential that the studied in vitro system exhibits the functionality of proteins, which play a key role in the specific drug induced toxicity. Considering the benefits and limitations, it is worth to validate this long-term treatment experimental set-up and expand it on co-culture systems and on organs-on-chips with regard to alternative toxicity testing strategies for repeated dose toxicity studies.
The purpose of confidence and prediction intervals is to provide an interval estimation for an unknown distribution parameter or the future value of a phenomenon. In many applications, prior knowledge about the distribution parameter is available, but rarely made use of, unless in a Bayesian framework. This thesis provides exact frequentist confidence intervals of minimal volume exploiting prior information. The scheme is applied to distribution parameters of the binomial and the Poisson distribution. The Bayesian approach to obtain intervals on a distribution parameter in form of credibility intervals is considered, with particular emphasis on the binomial distribution. An application of interval estimation is found in auditing, where two-sided intervals of Stringer type are meant to contain the mean of a zero-inflated population. In the context of time series analysis, covariates are supposed to improve the prediction of future values. Exponential smoothing with covariates as an extension of the popular forecasting method exponential smoothing is considered in this thesis. A double-seasonality version of it is applied to forecast hourly electricity load under the use of meteorological covariates. Different kinds of prediction intervals for exponential smoothing with covariates are formulated.
The main objective of this thesis was the design and synthesis of perylene bisimide dyes with sufficient water-solubility for the construction of self-assembled architectures in aqueous solutions. Beside these tasks another goal of this project was the control over the self-assembly process in terms of aggregate size and helicity, respectively. Within this thesis an appropriate synthesis for spermine-functionalized perylene bisimide dyes was developed and conducted successfully. The characterization of these building blocks and their course of self-assembly were investigated by NMR, UV/Vis and fluorescence spectroscopy as well as by atomic force and transmission electron microscopy. For the better understanding of the experimental results theoretical calculations were performed.
Although many researchers refer to organizational culture as the key to explain employees' organizational corruption (= corruption on behalf of the organization), literature lacks systematic empirical evidence. Through a mixed-method approach this research tries to shed some first lights on this issue with the questions: what characteristics describe an organizational culture that promotes employees' corruption? Does a certain type of organizational culture shape a positive attitude towards organizational corruption? Does organizational culture differ in its impact on different types of corruption? Does organizational culture interact with employees’ sex to promote employees’ corruption? And, is there a main effect of sex on corruption?
A qualitative study investigates the characteristics of a corrupt organizational culture in both general and in particular for managers and employees (Study 1). 14 experts of different occupations were asked about underlying assumptions, values, and norms of a corrupt organizational culture coding the frequency and relationship of their answers. The results showed specific underlying assumptions, values, and norms that were shared by the interviewees and provide first insights into their interrelatedness.
In addition, the quantitative field survey (Study 2) analyzed if a corrupt organizational culture shapes a positive attitude towards organizational corruption and if both tangible rewards and lax control mechanism mediate this impact. 131 participants answered questionnaires about their perceived competition in their industry, tangible rewards, lax control mechanism, and their attitude towards both gifting and bribery. Results showed that lax control mechanism (and for gifting also tangible rewards) mediated the positive impact of a corrupt organizational culture on organizational corruption. In addition, men and women did not differ in their attitude towards organizational corruption in a corrupt organizational culture.
Finally a web-based experiment investigates if organizational culture shapes employees' corruption (Study 3). In addition this approach also covers if the impact of organizational culture on corruption depends on the type of corruption (organizational corruption vs. counterproductive), and if employees’ sex influence corruption and if there is an interaction of organizational culture and sex on employees’ corruption. 563 participants had to decide whether they engage in corruption. Although a corrupt organizational culture raises both types of corruption, there was neither a notable main effect of sex nor a high impact interaction effect of both on both types of corruption. Thus, aspects of a corrupt organizational culture seem to influence employees' corruption.
Early life stress, including exposure to prenatal stress (PS), has been shown to affect the developing brain and induce severe effects on emotional health in later life, concomitant with an increased risk for psychopathology. However, some individuals are more vulnerable to early-life stress, while others adapt successfully, i.e. they are resilient and do not succumb to adversity. The molecular substrates promoting resilience in some individuals and vulnerability in other individuals are as yet poorly investigated. A polymorphism in the serotonin transporter gene (5HTT/SLC6A4) has been suggested to play a modulatory role in mediating the effects of early-life adversity on psychopathology, thereby rendering carriers of the lower-expressing short (s)-allele more vulnerable to developmental adversity, while long (l)-allele carriers are relatively resilient. The molecular mechanisms underlying this gene x environment interaction (GxE) are not well understood, however, epigenetic mechanisms such as DNA methylation and histone modifications have been discussed to contribute as they are at the interface of environment and the genome. Moreover, developmental epigenetic programming has also been postulated to underlie differential vulnerability/resilience independent of genetic variation.
The present work comprises two projects investigating the effects of prenatal maternal restraint stress in 5-HTT deficient mice. In the first study, we examined to which extent previously observed changes in behavior and hippocampal gene expression of female 5-Htt+/- prenatally stressed (PS) offspring were associated with changes in DNA methylation patterns. Additionally, we investigated the expression of genes involved in myelination in hippocampus and amygdala of those animals using RT-qPCR. The genome-wide hippocampal DNA methylation screening was performed using methylated-DNA immunoprecipitation (MeDIP) on Affymetrix GeneChip® Mouse Promoter 1.0R arrays. In order to correlate individual gene-specific DNA methylation, mRNA expression and behavior, we used hippocampal DNA from the same mice as assessed before. 5-Htt genotype, PS and their interaction differentially affected the DNA methylation signature of numerous genes, a part of which were also differentially expressed. More specifically, we identified a differentially methylated region in the Myelin basic protein (Mbp) gene, which was associated with Mbp expression in a 5-Htt-, PS- and 5-Htt x PS-dependent manner. Subsequent fine-mapping linked the methylation status of two specific CpG sites in this region to Mbp expression and anxiety-related behavior. We furthermore found that not only the expression of Mbp but of large gene set associated with myelination was affected by a 5-Htt x PS interaction in a brain-region specific manner. In conclusion, hippocampal DNA methylation patterns and expression profiles of female PS 5-Htt+/- mice suggest that distinct molecular mechanisms, some of which are associated with changes in gene promoter methylation, and processes associated with myelination contribute to the behavioral effects of the 5-Htt genotype, PS exposure, and their interaction.
In the second study, we aimed at investing the molecular substrates underlying resilience to PS. For this purpose, we exposed 5-Htt+/+ dams to the same restraint stress paradigm and investigated the effects of PS on depression- and anxiety-like behavior and corticosterone (CORT) secretion at baseline and after acute restraint stress in female 5-Htt+/+ and 5-Htt+/- offspring. We found that PS affected the offspring’s social behavior in a negative manner. When specifically examining those PS animals, we grouped the PS offspring of each genotype into a social, resilient and an unsocial, vulnerable group. While anxiety-like behavior in the EPM was reduced in unsocial, but not social, PS 5-Htt+/+ animals when compared to controls, this pattern could not be found in animals of the other genotype, indicating that social anxiety and state anxiety in the EPM were independent of each other. We then assessed genome-wide hippocampal gene expression profiles using mRNA sequencing in order to identify pathways and gene ontology (GO) terms enriched due to 5-Htt genotype (G), PS exposure (E) and their interaction (GxE) as well as enriched in social, but not unsocial, PS offspring, and vice versa. Numerous genes were affected by 5-Htt genotype, PS and most of all a GxE-interaction. Enrichment analysis using enrichr identified that the genotype affected mitochondrial respiration, while GxE-interaction-affected processes associated primarily with myelination and chromatin remodeling. We furthermore found that 5-Htt+/- mice showed profound expression changes of numerous genes in a genomic region located 10 mio kb upstream of the 5 Htt locus on the same chromosome. When looking at social vs. unsocial mice, we found that a much higher number of genes was regulated in 5 Htt+/- animals than in 5-Htt+/+ animals, reflecting the impact of GxE-interaction. Double the number of genes was regulated in social PS vs. control mice when compared to unsocial PS vs. control in both genotypes, suggesting that the successful adaption to PS might have required more active processes from the social group than the reaction to PS from the unsocial group. This notion is supported by the up-regulation of mitochondrial respiration in social, but not in unsocial, PS 5-Htt+/- mice when compared to controls, as those animals might have been able to raise energy resources the unsocial group was not. Next to this, processes associated with myelination seemed to be down-regulated in social 5-Htt+/- mice, but not in unsocial animals, when compared to controls. Taken together, PS exposure affected sociability and anxiety-like behavior dependent on the 5-Htt genotype in female offspring. Processes associated with myelination and epigenetic mechanisms involved in chromatin remodeling seemed be affected in a GxE-dependent manner in the hippocampus of these offspring. Our transcriptome data furthermore suggest that mitochondrial respiration and, with this, energy metabolism might be altered in 5-Htt+/- offspring when compared to 5-Htt+/+ offspring. Moreover, myelination and mitochondrial respiration might contribute to resilience towards PS exposure in 5-Htt+/- offspring, possibly by affecting brain connectivity and energy capabilities.
Since its discovery as a small signaling molecule in the human body, researchers have tried to utilize the beneficial cytoprotective properties of carbon monoxide in therapeutic applications. Initial work focused on the controlled direct application of CO gas. However, to circumvent the disadvantages of this method such as requirement for special equipment, hospitalization of the patient and the risk of overdosing, metal-carbonyl complexes were developed as CO-releasing molecules (CORMs) which are able to deliver CO in a tissue-specific manner. However, upon the release of CO from the metal coordination sphere, complex fragments termed inactivated CORMs (iCORMs) with free coordination sites remain which can undergo nonspecific follow-up reactions under physiological conditions.
Thus, the first aim of the present thesis was the coordination of tetradentate ligands such as tris(2-pyridylmethyl)amine (tpa), bis(2-pyridylmethyl)(2-quinolylmethyl)amine (bpqa), bis(2-quinolylmethyl)(2-pyridylmethyl)amine (bqpa) and tris(2-quinolylmethyl) amine (tmqa) in a tridentate facial manner to a fac-Mn(CO)3 moiety previously established as a photoactivatable CO-releasing molecule (PhotoCORM). The desired coordination of the pedant donor group upon photolytic CO release at 365 nm was demonstrated by UV/Vis-, IR- und 1H NMR experiments and verified by DFT calculations. All complexes of the series showed long-term dark stability in phosphate-buffered saline (PBS), but released between two and three equivalents of carbon monoxide with half-lives of around 5-10 minutes upon illumination at 365 nm. Although the photolytic properties of the complexes were quite similar besides the differences in type of hetereoaromatic ligands, the determination of the logP values showed an increase of lipophilicity with the number of quinoline groups, which might enable tissue-specific uptake. A significant cellular manganese uptake as well as the binding of CO released upon photolysis to the cytochrome c oxidases in E. coli cells was demonstrated for [Mn(CO)3(tpa)]+. Furthermore, this complex exhibited photoinduced bactericidal activity when the cells were grown in succinate-containing medium and thus unable to change their metabolism to mixed acid fermentation.
In the second part of the project, the hexadentate ligand 1,4,7-tris(2-pyridylmethyl)-1,4,7-triazacyclononane (py3tacn) was coordinated to a facial Mn(CO)3 moiety. The resulting [Mn(CO)3(py3tacn-3N)]+ complex has one pedant donor group per labile carbonyl ligand and thus is a significant improvement over the 1st generation tpa-complexes. The metal-coligand inactivated CORM (iCORM) fragment expected to be generated upon complete photolytic CO release, [Mn(py3tacn-6N)]2+, was synthesized independently and will serve as a well-defined negative control in upcoming biological tests. The corresponding CORM has long-term dark stability in pure dimethylsulfoxide or phosphate-buffered myoglobin solution, with three equivalents of CO released with a half-life of 22 minutes upon illumination at 412 nm. The photolysis was also followed by IR spectroscopy and the intermediates, in line with a stepwise release of carbon monoxide, and occupation of vacated sites by the pedant pyridine group were verified by DFT calculations.
Due to possible tissue damage by energy-rich light and the inverse correlation of tissue penetration depth and illumination wavelength, the absorption maxima of PhotoCORMs should ideally be in the phototherapeutic window between 600 and 1200 nm. Thus, in the third part of this work, a series of heterobinuclear Mn(CO)3/Ru(bpy)2 PhotoCORMs was prepared to shift the absorption of these compounds into the red region of the UV/Vis spectrum. For the synthesis of such Mn(I)/Ru(II) complexes, the bridging ligands 2,3-di(2-pyridyl)quinoxaline (dpx) and 3-(pyridin-2-yl)-1,2,4-triazine[5,6-f]-1,10-phenanthroline (pytp) were prepared and the two binding pockets subsequently filled with a Ru(bpy)2 and a fac-Mn(CO)3 moiety. The resulting two heterobinuclear metal complexes [Ru(bpy)2(dpx)MnBr(CO)3]2+ and [Ru(bpy)2(pytp)MnBr(CO)3]2+ as well as [Ru(etx)(tbx)MnBr(CO)3]2+ with etx = ethyl(2,2':6',2''-terpyridine)-4'-carboxylate and tbx = N-((2,2’:6’,2’’-terpyridin)-4’-yl)2,2’-bipyridine-5-carboxamide which was prepared by a metal precursor provided by the group of Prof. Dr. Katja Heinze showed a significant shift of the main absorption bands to higher wavelengths as well as two times higher extinction coefficients than the analogous mononuclear Mn(I) compounds. However, both the Mn(I)/Ru(II) and Mn(I) complexes had a reduced stability in phosphate-buffered myoglobin solution even in the absence of light. The efficiency of the CO-release from [Ru(etx)(tbx)MnBr(CO)3]2+ and [Ru(bpy)2(dpx)MnBr(CO)3]2+ could be controlled by proper choice of the excitation wavelength. A change from 468 to 525 nm or even 660 nm led to a decrease of the number of CO equivalents released from two to one and an elongation of the half-lives.
Finally, since nitric oxide also serves as a small messenger molecule in the human body with its signaling pathways interacting with those of CO, a mixed-ligand CO/NO metal complex was sought. [Mo(CO)2(NO)(iPr3tacn)]+ with iPr3tacn = 1,4,7-triisopropyl-1,4,7-triazacyclonane was selected from the literature and its molecular structure determined by single crystal diffraction, demonstrating the presence of an NO+ ligand in the coordination sphere as indicated by a MO-N-O angle close to 180°. Photolysis of [Mo(CO)2(NO)(iPr3tacn)]+ required high-energy UV light, which prevented a quantification of the CO release due to photolytic decomposition of the myoglobin. However, solution IR experiments showed that the complex lost the two carbon monoxide ligands upon illumination at 254 nm while the NO remained tightly bound to the metal. The structures observed of the intermediates were also verified by DFT calculations.
In conclusion, in this project, four different classes of novel transition metal-based photoactivatable CO-releasing molecules (PhotoCORMs) were prepared and studied. The first group incorporated one additional free donor group per LMn(CO)3 moiety but varied in the number of coordinated pyridyl and quinolinyl groups which allows the control of the lipophilicity of these compounds. As an extension of this concept, the second series incorporated one free donor group per labile carbonyl ligand which gives rise to well-defined photolysis products that can be independently prepared and assayed. The third class was based on a Ru(II) photosensitizer unit connected to a MnBr(CO)3 PhotoCORM moiety. This shifts the absorption maximum from 500 nm to about 585 nm in [Ru(bpy)2(dpx)MnBr(CO)3]2+. Finally, a first mixed-ligand CO/NO carrier molecule was evaluated for its photolytic behavior. However, while the carbonyl ligands were photolabile at low excitation wavelengths, release of the NO ligand was not observed under the conditions studied.
In a next step, detailed studies on the bioactivity of the different classes of PhotoCORMs need to be carried out with partner groups from biochemistry to fully explore their biomedical potential.
The Corona® charged aerosol detector (CAD) is an aerosol-based detector first de-scribed by Dixon and Peterson in 2002. It is capable of detecting compounds inde-pendent from their physico-chemical properties presumed the analyte is sufficiently non-volatile. Consequently, the CAD is often applied to the analysis of substances that do not possess a suitable UV chromophore. Major drawbacks are however, the detector signal is non-linear and depending on the content of organic solvent in the mobile phase.
This thesis tried to explore possible applications of the CAD for pharmaceutical analysis. Therefore, several substances from different compound classes were in-vestigated. Newly developed or existing methods were validated. Thus the perfor-mance of the CAD could be examined. Both assay and impurity determination were evaluated for their compliance with ICH Q2(R1) “Validation of Analytical Proce-dures” and the “Technical Guide for the Elaboration of Monographs”.
In the course of the establishment of reference substances at the EDQM, a generic screening method for the identification of organic and inorganic pharmaceutical counterions was needed. An HPLC-CAD method developed by Zhang et al. was therefore investigated for its suitability for pharmacopoeial purpose. Method valida-tion was performed. It was found that 23 ions could be separated and detected. Iden-tification was achieved via retention time of an authentic standard of the corre-sponding ions. Alternatively, peak assignment was performed by determination of the exact mass using TOF-MS. Ions could be quantified as impurities or for stoichi-ometric purpose.
For the impurity control in topiramate, the performance characterstics of the CAD were compared to that of an ELSD. CAD was superior to ELSD in terms of repeata-bility, sensitivity and linearity. However, impurities could be quantified with satisfac-tory accuracy with both detectors. The application of the ELSD was not feasible due to non-reproducible spike peaks eluting after the principle peak in the chromatogram of the test solution. One of the impurities, topiramate impurity A (diacetonide), gave no or a vastly diminished signal in the ELSD and the CAD, respectively. It is evapo-rated during the detection process due to its relatively high vapor pressure. The re-sponse could be enhanced by a factor of nine via post-column addition of acetoni-trile and a lower nebulizer temperature. As the response of topiramate impurity A was still about thousand-fold lower than the response of all other impurities, its quantification was not feasible. Additionally, the HPLC-CAD was successfully vali-dated as an assay procedure for topiramate.
There seems to be a great potential in the application of the CAD to the analysis of excipients as most compounds do not possess a suitable UV chromophore. Here, a simple and rapid HPLC-CAD method for the determination of polidocanol (PD) was developed. The method was successfully validated as a potential assay procedure for the Ph. Eur. as none is described in either of the two PD monographs. The same method was applied to the determination of the PD release from a pharmaceutical polymer matrix.
A method for the determination of the fatty acid (FA) composition of polysorbate 80 (PS80) was developed and validated. Using the CAD and mass spectrometry, we were able to identify two new FAs in 16 batches from four manufacturers. All batch-es complied with pharmacopoeial specification. Furthermore, the overall composi-tion of the different PS80 species (“fingerprinting”) and the peroxide content were determined. In addition to the chemical characterization, functionality related charac-teristics (FRCs) were determined. Correlations between chemical composition and FRCs were found.
The validation data of the above mentioned methods suggests that the CAD repre-sents a viable detection technique for pharmaceutical analysis. The CAD was suffi-ciently sensitive for non-volatile analytes. Impurity control down to concentrations of 0.05 or 0.03%, as demanded by ICH Q3A (R2), is achievable. However, the response of semi-volatile compounds may be drastically diminished. It could be confirmed that the response of the CAD is linear when the range does not exceed two orders of magnitude. Exceptions may be observed depending on the actual method setup. When the measuring range is sufficiently narrow, quantification can be done using single-point calibration which is common practice in pharmaceutical anlysis. Impuri-ties may also be quantified against a single calibration solution. However, correction factors may be needed and the accuracy is considerably lower compared to an as-say method. If a compound is to be quantified over a large concentration range, log-log transformation of the calibration curve is needed and a decreased accuracy has to be accepted.
An efficient and accurate computational framework for solving control problems governed by quantum spin systems is presented. Spin systems are extremely important in modern quantum technologies such as nuclear magnetic resonance spectroscopy, quantum imaging and quantum computing. In these applications, two classes of quantum control problems arise: optimal control problems and exact-controllability problems, with a bilinear con- trol structure. These models correspond to the Schrödinger-Pauli equation, describing the time evolution of a spinor, and the Liouville-von Neumann master equation, describing the time evolution of a spinor and a density operator. This thesis focuses on quantum control problems governed by these models. An appropriate definition of the optimiza- tion objectives and of the admissible set of control functions allows to construct controls with specific properties. These properties are in general required by the physics and the technologies involved in quantum control applications. A main purpose of this work is to address non-differentiable quantum control problems. For this reason, a computational framework is developed to address optimal-control prob- lems, with possibly L1 -penalization term in the cost-functional, and exact-controllability problems. In both cases the set of admissible control functions is a subset of a Hilbert space. The bilinear control structure of the quantum model, the L1 -penalization term and the control constraints generate high non-linearities that make difficult to solve and analyse the corresponding control problems. The first part of this thesis focuses on the physical description of the spin of particles and of the magnetic resonance phenomenon. Afterwards, the controlled Schrödinger- Pauli equation and the Liouville-von Neumann master equation are discussed. These equations, like many other controlled quantum models, can be represented by dynamical systems with a bilinear control structure. In the second part of this thesis, theoretical investigations of optimal control problems, with a possible L1 -penalization term in the objective and control constraints, are consid- ered. In particular, existence of solutions, optimality conditions, and regularity properties of the optimal controls are discussed. In order to solve these optimal control problems, semi-smooth Newton methods are developed and proved to be superlinear convergent. The main difficulty in the implementation of a Newton method for optimal control prob- lems comes from the dimension of the Jacobian operator. In a discrete form, the Jacobian is a very large matrix, and this fact makes its construction infeasible from a practical point of view. For this reason, the focus of this work is on inexact Krylov-Newton methods, that combine the Newton method with Krylov iterative solvers for linear systems, and allows to avoid the construction of the discrete Jacobian. In the third part of this thesis, two methodologies for the exact-controllability of quan- tum spin systems are presented. The first method consists of a continuation technique, while the second method is based on a particular reformulation of the exact-control prob- lem. Both these methodologies address minimum L2 -norm exact-controllability problems. In the fourth part, the thesis focuses on the numerical analysis of quantum con- trol problems. In particular, the modified Crank-Nicolson scheme as an adequate time discretization of the Schrödinger equation is discussed, the first-discretize-then-optimize strategy is used to obtain a discrete reduced gradient formula for the differentiable part of the optimization objective, and implementation details and globalization strategies to guarantee an adequate numerical behaviour of semi-smooth Newton methods are treated. In the last part of this work, several numerical experiments are performed to vali- date the theoretical results and demonstrate the ability of the proposed computational framework to solve quantum spin control problems.
In the thesis discrete moments of the Riemann zeta-function and allied Dirichlet series are studied.
In the first part the asymptotic value-distribution of zeta-functions is studied where the samples are taken from a Cauchy random walk on a vertical line inside the critical strip. Building on techniques by Lifshits and Weber analogous results for the Hurwitz zeta-function are derived. Using Atkinson’s dissection this is even generalized to Dirichlet L-functions associated with a primitive character. Both results indicate that the expectation value equals one which shows that the values of these
zeta-function are small on average.
The second part deals with the logarithmic derivative of the Riemann zeta-function on vertical lines and here the samples are with respect to an explicit ergodic transformation. Extending work of Steuding, discrete moments are evaluated and an equivalent formulation for the Riemann Hypothesis in terms of ergodic theory is obtained.
In the third and last part of the thesis, the phenomenon of universality with respect
to stochastic processes is studied. It is shown that certain random shifts of the zeta-function can approximate non-vanishing analytic target functions as good as we please. This result relies on Voronin's universality theorem.
Staphylococcus aureus is a facultative Gram-positive human pathogen which can cause different severe infections. Staphylococci are phagocytosed by professional and non-professional phagocytes; they are strongly cytotoxic against eukaryotic cells and have been proposed to play a role in immune evasion by spreading within migrating phagocytes. This study investigated the post invasive events upon S. aureus infection. Strains which are able to escape the phagosome were identified and the responsible toxins were determined. Thereby innovative insights into host pathogen interaction were obtained.
A novel class of small amphipathic peptides with strong surfactant-like properties, the phenol soluble modulins, particularly PSMα as well as the leukocidin LukAB, are involved in phagosomal escape of the clinical S. aureus strains LAC, MW2 and 6850 in non-professional and professional phagocytes. Whereas, PSMβ, δ-toxin, α-toxin, β-toxin or phosphatidyl inositol-dependent phospholipase C did not affect phagosomal escape. By blocking the bacterial DNA-dependent RNA polymerase with rifampicin phagosomal escape is determined to start approximately 2.5 hours post infection. Phagosomal escape further was required for intracellular replication of S. aureus. Strains which are not able to escape cannot replicate in the acidic vacuole, whereas, the host cytoplasm offers a rich milieu for bacterial replication. Additionally, phagosomal escape, with intracellular bacterial replication induces the subsequent host cell death. This could be confirmed by an infection assay including S. aureus knockout mutants in psmα or lukAB which were significantly less cytotoxic, compared with those infected with escape-positive wild type strains.
Further, this study showed that phagosomal escape is not only mediated by bacterial toxins. Since, the phagocyte-specific cognate receptors for both escape relevant toxins, FPR2 (PSMα receptor) and CD11b (LukAB receptor) are produced in epithelial and endothelial cells only after infection with S. aureus in a calcium dependent fashion. The knockdown of both receptors using siRNA prevents S. aureus to escape the phagosome. Furthermore, blocking intracellular calcium release with the inositol trisphosphate receptor (IP3R) inhibitor 2-APB prohibits upregulation of fpr2 and cd11b and subsequently phagosomal escape of S. aureus.
To conclude, the current study clarifies that phagosomal escape and host cell death are interplay of both, bacterial toxins and host cell factors.
Staphylococcus aureus ist ein fakultativ Gram-positives Humanpathogen, dass verschiedene schwerwiegende Infektionen verursachen kann. Staphylokokken werden von professionellen und nicht-professionellen Phagozyten (Fresszellen) zu gleich aufgenommen. Desweitern sind sie stark zytotoxisch für eukaryotische Zellen. Außerdem wird vermutet, dass sie sich mittels migrierender Phagozyten dem angeborenen Immunsystem entziehen können. In dieser Studie werden die post-invasiven Ereignisse während einer Staphylokokken Infektion untersucht. Im Detail wurden Stämme identifiziert die aus den Phagosomen entkommen können und die dafür verantwortlichen Toxine. Im Zuge dessen wurden neue Erkenntnisse der Interaktion zwischen Bakterien und Wirtszellen gewonnen.
Eine neue Klasse von kleinen amphiphatischen Peptiden mit starken grenzflächenaktiven Eigenschaften (Surfactant), die sogenannten Phenol soluble modulins (PSMs) im Besonderen PSMα sowie das Leukozidin LukAB, sind am phagosomalen Ausbruch der klinisch relevanten S. aureus Stämmen LAC, MW2 und 6850 in nicht professionellen und professionellen Phagozyten involviert. Hingegen, sind PSMβ, δ-toxin, α-toxin, β-toxin oder Phosphatidylinositol abhängige Phospholipase C nicht am phagosomalen Ausbruch beteiligt. Durch die Hemmung der bakteriellen DNA-abhängigen RNA Polymerase mit Rifampicin wurde der Zeitpunkt für den Ausbruch auf etwa 2,5 Stunden nach der Infektion eingegrenzt. Der phagosomale Ausbruch ist weiterhin für die intrazelluläre Replikation von S. aureus notwendig. Während Stämme, die nicht ausbrechen können in der angesäuerten Vakuole nicht replizieren können, bietet das Zytoplasma ein reichhaltiges Milieu für die Vermehrung. Zudem wird der Pathogen induzierte Zelltod erst nach dem phagosomalen Ausbruch und mit anschließender Vermehrung ermöglicht. Nachgewiesen wurde dies mittels psmα und lukAB defizienten Mutanten welche signifikant weniger zytotoxisch waren als der Wildtyp Stamm. Diese Studie zeigt darüber hinaus, dass der phagosomale Ausbruch nicht nur durch bakterielle Toxine vermittelt wird. Sondern, dass die Phagozyten-spezifischen Rezeptoren für beide relevanten Toxine, FPR2 (PSMα Rezeptor) und CD11b (LukAB Rezeptor), in Epithel- und Endothelzellen nach Infektion mit S. aureus calciumabhängig produziert werden und für den Ausbruch notwendig sind. Der knockdown beider Rezeptoren mittels siRNA verhindert den Ausbruch. Wird der intrazelluläre Calciumstrom mittels des Inositoltrisphosphat Rezeptor (IP3R) Inhibitor 2-APB blockiert können die Gene fpr2 und cd11b nicht hochreguliert werden und der Ausbruch wird ebenfalls verhindert.
Folglich zeigt diese Studie, dass der phagosomale Ausbruch und Pathogen induzierte Zelltod sowohl durch bakterielle Toxine als auch Wirtsfaktoren vermittelt wird.
Exploring the transport properties of the three-dimensional topological insulator material HgTe
(2015)
In the present thesis the transport properties of strained bulk HgTe devices are investigated. Strained HgTe forms a 3D TI and is of special interest for studying topological surface states, since it can be grown by MBE in high crystal quality. The low defect density leads to considerable mobility values, well above the mobilities of other TI materials. However, strained HgTe has a small band gap of ca. 20 meV. With respect to possible applications the question is important, under which conditions the surface transport occurs. To answer this question, the HgTe devices are investigated at dilution refrigerator temperatures (T<100 mK) in high magnetic fields of different orientation. The influence of top and back gate electrodes as well as surface protecting layers is discussed.
On the basis of an analysis of the quantum Hall behaviour it is shown that transport is dominated by the topological surface states in a surprisingly large parameter range. A dependence on the applied top gate voltage is presented for the topological surface states. It enables the first demonstration of an odd integer QHE sequence from the surfaces perpendicular to the magnetic field. Furthermore, the p-type QHE from the surface states is observed for the first time in any 3D TI. This is achieved in samples of high surface quality. It is concluded from the gate response that the screening behaviour in 3D TI devices is non-trivial. The transport data are qualitatively analysed by means of intuitive theoretical models.
Fulminant myocarditis is rare but a potentially life-threatening disease. Acute or mild myocarditis following acute ischemia is generally associated with a profound activation of the host’s immune system. On one hand this is mandatory to protect the host’s heart by fighting the invading agents (i.e., bacteria, viruses or other microbial agents) and/or to induce healing and repair processes in the damaged myocardium. On other hand, uncontrolled activation of the immune system may result in the generation of auto-reactive (not always beneficial) immune cells.
Myocarditis or inflammatory cardiomyopathy is characterized by focal or diffuse infiltrates, myocyte necrosis and/or apoptosis and subsequent fibrotic replacement of the heart muscle. In humans, about 30% of the myocarditis-patients develop dilated cardiomyopathy. As the clinical picture of myocarditis is multifaceted, it is difficult to diagnose the disease. Therefore, the main goal of the present work was to test and further develop novel non-invasive methods for the detection of myocardial inflammation by employing both contrast enhanced MRI techniques as well as novel nuclear tracers that are suitable for in vivo PET/ SPECT imaging.
As a part of this thesis, a pre-clinical animal model was successfully established by immunizing female Lewis rats with whole-porcine cardiac myosin (CM). Induction of Experimental Autoimmune Myocarditis (EAM) is considered successful when anti-myosin antibody titers are increased more than 100-fold over control animals and pericardial effusion develops. In addition, cardiac tissues from EAM-rats versus controls were analyzed for the expression of various pro-inflammatory and fibrosis markers. To further exploit non-invasive MRI techniques for the detection of myocarditis, our EAM-rats were injected either with (1) ultra-small Paramagnetic iron oxide particles (USPIO’s; Feraheme®), allowing for in vivo imaging , (2) micron sized paramagnetic iron oxide particles (MPIO) for ex vivo inflammatory cell-tracking by cMRI, or (3) with different radioactive nuclear tracers (67gallium citrate, 68gallium-labeled somatostatin analogue, and 68gallium-labeled cyclic RGD-peptide) which in the present work have been employed for autoradiographic imaging, but in principle are also suitable for in vivo nuclear imaging (PET/SPECT). In order to compare imaging results with histology, consecutive heart sections were stained with hematoxylin & eosin (HE, for cell infiltrates) and Masson Goldner trichrome (MGT, for fibrosis); in addition, immuno-stainings were performed with anti-CD68 (macrophages), anti-SSRT2A (somatostatin receptor type 2A), anti-CD61 (β3-integrins) and anti-CD31 (platelet endothelial cell adhesion molecule 1).
Sera from immunized rats strongly reacted with cardiac myosin. In immunized rats, echocardiography and subsequent MRI revealed huge amounts of pericardial effusion (days 18-21). Analysis of the kinetics of myocardial infiltrates revealed maximal macrophage invasion between days 14 and 28. Disappearance of macrophages resulted in replacement-fibrosis in formerly cell-infiltrated myocardial areas. This finding was confirmed by the time-dependent differential expression of corresponding cytokines in the myocardium. Immunized animals reacted either with an early or a late pattern of post-inflammation fibrosis. Areas with massive cellular infiltrates were easily detectible in autoradiograms showing a high focal uptake of 67gallium-citrate and 68gallium labeled somatostatin analogues (68Ga DOTA-TATE). Myocardium with a loss of cardiomyocytes presented a high uptake of 68gallium labeled cyclic RGD-peptide (68Ga NOTA-RGD). MRI cell tracking experiments with Feraheme® as the contrast-agent were inconclusive; however, strikingly better results were obtained when MPIOs were used as a contrast-agent: histological findings correlated well with in vivo and ex vivo MPIO-enhanced MRI images.
Imaging of myocardial inflammatory processes including the kinetics of macrophage invasion after microbial or ischemic damage is still a major challenge in, both animal models and in human patients. By applying a broad panel of biochemical, histological, molecular and imaging methods, we show here that different patterns of reactivity may occur upon induction of myocarditis using one and the same rat strain. In particular, immunized Lewis rats may react either with an early or a late pattern of macrophage invasion and subsequent post-inflammation fibrosis. Imaging results achieved in the acute inflammatory phase of the myocarditis with MPIOs, 67gallium citrate and 68gallium linked to somatostatin will stimulate further development of contrast agents and radioactive-nuclear tracers for the non-invasive detection of acute myocarditis and in the near future perhaps even in human patients.
Genome wide association studies (GWAS) have identified Clec16a as disease suscepti-bility gene for numerous auto-immune disorders in particular type 1 diabetes. In spite of this strong genetic link, the role of Clec16a for immune regulation continues to be largely unknown. To study the function of Clec16a in an environment susceptible to autoimmune diseases a Clec16a deficient non obese diabetic (NOD) mouse strain was generated by means of lentiviral RNA interference. Clec16a knock down (KD) mice prove to be strongly protected against developing type 1 diabetes, an effect that is mediated by hyporeactive T effector cells. T cell hyporeactivity seems to result from an impairment of proximal TCR signalling and its cause is likely to be external to T cells. Given evidence on the involvement of the Clec16a Drosophila ortholog ema in endo- and autophagosomal processes, alterations in peripheral and/or central antigen presenting cells appeared to be potential reasons for the observed T cell hyporeactivity. While we are not able to identify any changes in quantity and quality of peripheral antigen presenting cells due to Clec16a silencing activation status of thymic epithelial cells in Clec16a KD mice deviates from NOD WT. The findings presented here suggest that thymic T cell development is affected by Clec16a variation. Such a relationship could explain the genetic association between Clec16a variations in humans and susceptibility to immune-mediated diseases, yet further investigations are needed to confirm this notion.