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Over the past decades, natural hazards, many of which are aggravated by climate change and reveal an increasing trend in frequency and intensity, have caused significant human and economic losses and pose a considerable obstacle to sustainable development. Hence, dedicated action toward disaster risk reduction is needed to understand the underlying drivers and create efficient risk mitigation plans. Such action is requested by the Sendai Framework for Disaster Risk Reduction 2015-2030 (SFDRR), a global agreement launched in 2015 that establishes stating priorities for action, e.g. an improved understanding of disaster risk. Turkey is one of the SFDRR contracting countries and has been severely affected by many natural hazards, in particular earthquakes and floods. However, disproportionately little is known about flood hazards and risks in Turkey. Therefore, this thesis aims to carry out a comprehensive analysis of flood hazards for the first time in Turkey from triggering drivers to impacts. It is intended to contribute to a better understanding of flood risks, improvements of flood risk mitigation and the facilitated monitoring of progress and achievements while implementing the SFDRR.
In order to investigate the occurrence and severity of flooding in comparison to other natural hazards in Turkey and provide an overview of the temporal and spatial distribution of flood losses, the Turkey Disaster Database (TABB) was examined for the years 1960-2014. The TABB database was reviewed through comparison with the Emergency Events Database (EM-DAT), the Dartmouth Flood Observatory database, the scientific literature and news archives. In addition, data on the most severe flood events between 1960 and 2014 were retrieved. These served as a basis for analyzing triggering mechanisms (i.e. atmospheric circulation and precipitation amounts) and aggravating pathways (i.e. topographic features, catchment size, land use types and soil properties). For this, a new approach was developed and the events were classified using hierarchical cluster analyses to identify the main influencing factor per event and provide additional information about the dominant flood pathways for severe floods. The main idea of the study was to start with the event impacts based on a bottom-up approach and identify the causes that created damaging events, instead of applying a model chain with long-term series as input and searching for potentially impacting events as model outcomes. However, within the frequency analysis of the flood-triggering circulation pattern types, it was discovered that events in terms of heavy precipitation were not included in the list of most severe floods, i.e. their impacts were not recorded in national and international loss databases but were mentioned in news archives and reported by the Turkish State Meteorological Service. This finding challenges bottom-up modelling approaches and underlines the urgent need for consistent event and loss documentation. Therefore, as a next step, the aim was to enhance the flood loss documentation by calibrating, validating and applying the United Nations Office for Disaster Risk Reduction (UNDRR) loss estimation method for the recent severe flood events (2015-2020). This provided, a consistent flood loss estimation model for Turkey, allowing governments to estimate losses as quickly as possible after events, e.g. to better coordinate financial aid.
This thesis reveals that, after earthquakes, floods have the second most destructive effects in Turkey in terms of human and economic impacts, with over 800 fatalities and US$ 885.7 million in economic losses between 1960 and 2020, and that more attention should be paid on the national scale. The clustering results of the dominant flood-producing mechanisms (e.g. circulation pattern types, extreme rainfall, sudden snowmelt) present crucial information regarding the source and pathway identification, which can be used as base information for hazard identification in the preliminary risk assessment process. The implementation of the UNDRR loss estimation model shows that the model with country-specific parameters, calibrated damage ratios and sufficient event documentation (i.e. physically damaged units) can be recommended in order to provide first estimates of the magnitude of direct economic losses, even shortly after events have occurred, since it performed well when estimates were compared to documented losses.
The presented results can contribute to improving the national disaster loss database in Turkey and thus enable a better monitoring of the national progress and achievements with regard to the targets stated by the SFDRR. In addition, the outcomes can be used to better characterize and classify flood events. Information on the main underlying factors and aggravating flood pathways further supports the selection of suitable risk reduction policies.
All input variables used in this thesis were obtained from publicly available data. The results are openly accessible and can be used for further research.
As an overall conclusion, it can be stated that consistent loss data collection and better event documentation should gain more attention for a reliable monitoring of the implementation of the SFDRR. Better event documentation should be established according to a globally accepted standard for disaster classification and loss estimation in Turkey. Ultimately, this enables stakeholders to create better risk mitigation actions based on clear hazard definitions, flood event classification and consistent loss estimations.
With the downscaling of CMOS technologies, the radiation-induced Single Event Transient (SET) effects in combinational logic have become a critical reliability issue for modern integrated circuits (ICs) intended for operation under harsh radiation conditions. The SET pulses generated in combinational logic may propagate through the circuit and eventually result in soft errors. It has thus become an imperative to address the SET effects in the early phases of the radiation-hard IC design. In general, the soft error mitigation solutions should accommodate both static and dynamic measures to ensure the optimal utilization of available resources. An efficient soft-error-aware design should address synergistically three main aspects: (i) characterization and modeling of soft errors, (ii) multi-level soft error mitigation, and (iii) online soft error monitoring. Although significant results have been achieved, the effectiveness of SET characterization methods, accuracy of predictive SET models, and efficiency of SET mitigation measures are still critical issues. Therefore, this work addresses the following topics: (i) Characterization and modeling of SET effects in standard combinational cells, (ii) Static mitigation of SET effects in standard combinational cells, and (iii) Online particle detection, as a support for dynamic soft error mitigation.
Since the standard digital libraries are widely used in the design of radiation-hard ICs, the characterization of SET effects in standard cells and the availability of accurate SET models for the Soft Error Rate (SER) evaluation are the main prerequisites for efficient radiation-hard design. This work introduces an approach for the SPICE-based standard cell characterization with the reduced number of simulations, improved SET models and optimized SET sensitivity database. It has been shown that the inherent similarities in the SET response of logic cells for different input levels can be utilized to reduce the number of required simulations. Based on characterization results, the fitting models for the SET sensitivity metrics (critical charge, generated SET pulse width and propagated SET pulse width) have been developed. The proposed models are based on the principle of superposition, and they express explicitly the dependence of the SET sensitivity of individual combinational cells on design, operating and irradiation parameters. In contrast to the state-of-the-art characterization methodologies which employ extensive look-up tables (LUTs) for storing the simulation results, this work proposes the use of LUTs for storing the fitting coefficients of the SET sensitivity models derived from the characterization results. In that way the amount of characterization data in the SET sensitivity database is reduced significantly.
The initial step in enhancing the robustness of combinational logic is the application of gate-level mitigation techniques. As a result, significant improvement of the overall SER can be achieved with minimum area, delay and power overheads. For the SET mitigation in standard cells, it is essential to employ the techniques that do not require modifying the cell structure. This work introduces the use of decoupling cells for improving the robustness of standard combinational cells. By insertion of two decoupling cells at the output of a target cell, the critical charge of the cell’s output node is increased and the attenuation of short SETs is enhanced. In comparison to the most common gate-level techniques (gate upsizing and gate duplication), the proposed approach provides better SET filtering. However, as there is no single gate-level mitigation technique with optimal performance, a combination of multiple techniques is required. This work introduces a comprehensive characterization of gate-level mitigation techniques aimed to quantify their impact on the SET robustness improvement, as well as introduced area, delay and power overhead per gate. By characterizing the gate-level mitigation techniques together with the standard cells, the required effort in subsequent SER analysis of a target design can be reduced. The characterization database of the hardened standard cells can be utilized as a guideline for selection of the most appropriate mitigation solution for a given design.
As a support for dynamic soft error mitigation techniques, it is important to enable the online detection of energetic particles causing the soft errors. This allows activating the power-greedy fault-tolerant configurations based on N-modular redundancy only at the high radiation levels. To enable such a functionality, it is necessary to monitor both the particle flux and the variation of particle LET, as these two parameters contribute significantly to the system SER. In this work, a particle detection approach based on custom-sized pulse stretching inverters is proposed. Employing the pulse stretching inverters connected in parallel enables to measure the particle flux in terms of the number of detected SETs, while the particle LET variations can be estimated from the distribution of SET pulse widths. This approach requires a purely digital processing logic, in contrast to the standard detectors which require complex mixed-signal processing. Besides the possibility of LET monitoring, additional advantages of the proposed particle detector are low detection latency and power consumption, and immunity to error accumulation.
The results achieved in this thesis can serve as a basis for establishment of an overall soft-error-aware database for a given digital library, and a comprehensive multi-level radiation-hard design flow that can be implemented with the standard IC design tools. The following step will be to evaluate the achieved results with the irradiation experiments.
This thesis focuses on the study of marked Gibbs point processes, in particular presenting some results on their existence and uniqueness, with ideas and techniques drawn from different areas of statistical mechanics: the entropy method from large deviations theory, cluster expansion and the Kirkwood--Salsburg equations, the Dobrushin contraction principle and disagreement percolation.
We first present an existence result for infinite-volume marked Gibbs point processes. More precisely, we use the so-called entropy method (and large-deviation tools) to construct marked Gibbs point processes in R^d under quite general assumptions. In particular, the random marks belong to a general normed space S and are not bounded. Moreover, we allow for interaction functionals that may be unbounded and whose range is finite but random. The entropy method relies on showing that a family of finite-volume Gibbs point processes belongs to sequentially compact entropy level sets, and is therefore tight.
We then present infinite-dimensional Langevin diffusions, that we put in interaction via a Gibbsian description. In this setting, we are able to adapt the general result above to show the existence of the associated infinite-volume measure. We also study its correlation functions via cluster expansion techniques, and obtain the uniqueness of the Gibbs process for all inverse temperatures β and activities z below a certain threshold. This method relies in first showing that the correlation functions of the process satisfy a so-called Ruelle bound, and then using it to solve a fixed point problem in an appropriate Banach space. The uniqueness domain we obtain consists then of the model parameters z and β for which such a problem has exactly one solution.
Finally, we explore further the question of uniqueness of infinite-volume Gibbs point processes on R^d, in the unmarked setting. We present, in the context of repulsive interactions with a hard-core component, a novel approach to uniqueness by applying the discrete Dobrushin criterion to the continuum framework. We first fix a discretisation parameter a>0 and then study the behaviour of the uniqueness domain as a goes to 0. With this technique we are able to obtain explicit thresholds for the parameters z and β, which we then compare to existing results coming from the different methods of cluster expansion and disagreement percolation.
Throughout this thesis, we illustrate our theoretical results with various examples both from classical statistical mechanics and stochastic geometry.
The spread of shrubs in Namibian savannas raises questions about the resilience of these ecosystems to global change. This makes it necessary to understand the past dynamics of the vegetation, since there is no consensus on whether shrub encroachment is a new phenomenon, nor on its main drivers. However, a lack of long-term vegetation datasets for the region and the scarcity of suitable palaeoecological archives, makes reconstructing past vegetation and land cover of the savannas a challenge.
To help meet this challenge, this study addresses three main research questions: 1) is pollen analysis a suitable tool to reflect the vegetation change associated with shrub encroachment in savanna environments? 2) Does the current encroached landscape correspond to an alternative stable state of savanna vegetation? 3) To what extent do pollen-based quantitative vegetation reconstructions reflect changes in past land cover?
The research focuses on north-central Namibia, where despite being the region most affected by shrub invasion, particularly since the 21st century, little is known about the dynamics of this phenomenon.
Field-based vegetation data were compared with modern pollen data to assess their correspondence in terms of composition and diversity along precipitation and grazing intensity gradients. In addition, two sediment cores from Lake Otjikoto were analysed to reveal changes in vegetation composition that have occurred in the region over the past 170 years and their possible drivers. For this, a multiproxy approach (fossil pollen, sedimentary ancient DNA (sedaDNA), biomarkers, compound specific carbon (δ13C) and deuterium (δD) isotopes, bulk carbon isotopes (δ13Corg), grain size, geochemical properties) was applied at high taxonomic and temporal resolution. REVEALS modelling of the fossil pollen record from Lake Otjikoto was run to quantitatively reconstruct past vegetation cover. For this, we first made pollen productivity estimates (PPE) of the most relevant savanna taxa in the region using the extended R-value model and two pollen dispersal options (Gaussian plume model and Lagrangian stochastic model). The REVEALS-based vegetation reconstruction was then validated using remote sensing-based regional vegetation data.
The results show that modern pollen reflects the composition of the vegetation well, but diversity less well. Interestingly, precipitation and grazing explain a significant amount of the compositional change in the pollen and vegetation spectra. The multiproxy record shows that a state change from open Combretum woodland to encroached Terminalia shrubland can occur over a century, and that the transition between states spans around 80 years and is characterized by a unique vegetation composition. This transition is supported by gradual environmental changes induced by management (i.e. broad-scale logging for the mining industry, selective grazing and reduced fire activity associated with intensified farming) and related land-use change. Derived environmental changes (i.e. reduced soil moisture, reduced grass cover, changes in species composition and competitiveness, reduced fire intensity) may have affected the resilience of Combretum open woodlands, making them more susceptible to change to an encroached state by stochastic events such as consecutive years of precipitation and drought, and by high concentrations of pCO2. We assume that the resulting encroached state was further stabilized by feedback mechanisms that favour the establishment and competitiveness of woody vegetation.
The REVEALS-based quantitative estimates of plant taxa indicate the predominance of a semi-open landscape throughout the 20th century and a reduction in grass cover below 50% since the 21st century associated with the spread of encroacher woody taxa. Cover estimates show a close match with regional vegetation data, providing support for the vegetation dynamics inferred from multiproxy analyses. Reasonable PPEs were made for all woody taxa, but not for Poaceae.
In conclusion, pollen analysis is a suitable tool to reconstruct past vegetation dynamics in savannas. However, because pollen cannot identify grasses beyond family level, a multiproxy approach, particularly the use of sedaDNA, is required. I was able to separate stable encroached states from mere woodland phases, and could identify drivers and speculate about related feedbacks. In addition, the REVEALS-based quantitative vegetation reconstruction clearly reflects the magnitude of the changes in the vegetation cover that occurred during the last 130 years, despite the limitations of some PPEs.
This research provides new insights into pollen-vegetation relationships in savannas and highlights the importance of multiproxy approaches when reconstructing past vegetation dynamics in semi-arid environments. It also provides the first time series with sufficient taxonomic resolution to show changes in vegetation composition during shrub encroachment, as well as the first quantitative reconstruction of past land cover in the region. These results help to identify the different stages in savanna dynamics and can be used to calibrate predictive models of vegetation change, which are highly relevant to land management.
In Systems Medicine, in addition to high-throughput molecular data (*omics), the wealth of clinical characterization plays a major role in the overall understanding of a disease. Unique problems and challenges arise from the heterogeneity of data and require new solutions to software and analysis methods. The SMART and EurValve studies establish a Systems Medicine approach to valvular heart disease -- the primary cause of subsequent heart failure.
With the aim to ascertain a holistic understanding, different *omics as well as the clinical picture of patients with aortic stenosis (AS) and mitral regurgitation (MR) are collected. Our task within the SMART consortium was to develop an IT platform for Systems Medicine as a basis for data storage, processing, and analysis as a prerequisite for collaborative research. Based on this platform, this thesis deals on the one hand with the transfer of the used Systems Biology methods to their use in the Systems Medicine context and on the other hand with the clinical and biomolecular differences of the two heart valve diseases. To advance differential expression/abundance (DE/DA) analysis software for use in Systems Medicine, we state 21 general software requirements and features of automated DE/DA software, including a novel concept for the simple formulation of experimental designs that can represent complex hypotheses, such as comparison of multiple experimental groups, and demonstrate our handling of the wealth of clinical data in two research applications DEAME and Eatomics. In user interviews, we show that novice users are empowered to formulate and test their multiple DE hypotheses based on clinical phenotype. Furthermore, we describe insights into users' general impression and expectation of the software's performance and show their intention to continue using the software for their work in the future. Both research applications cover most of the features of existing tools or even extend them, especially with respect to complex experimental designs. Eatomics is freely available to the research community as a user-friendly R Shiny application.
Eatomics continued to help drive the collaborative analysis and interpretation of the proteomic profile of 75 human left myocardial tissue samples from the SMART and EurValve studies. Here, we investigate molecular changes within the two most common types of valvular heart disease: aortic valve stenosis (AS) and mitral valve regurgitation (MR). Through DE/DA analyses, we explore shared and disease-specific protein alterations, particularly signatures that could only be found in the sex-stratified analysis. In addition, we relate changes in the myocardial proteome to parameters from clinical imaging. We find comparable cardiac hypertrophy but differences in ventricular size, the extent of fibrosis, and cardiac function. We find that AS and MR show many shared remodeling effects, the most prominent of which is an increase in the extracellular matrix and a decrease in metabolism. Both effects are stronger in AS. In muscle and cytoskeletal adaptations, we see a greater increase in mechanotransduction in AS and an increase in cortical cytoskeleton in MR. The decrease in proteostasis proteins is mainly attributable to the signature of female patients with AS. We also find relevant therapeutic targets.
In addition to the new findings, our work confirms several concepts from animal and heart failure studies by providing the largest collection of human tissue from in vivo collected biopsies to date. Our dataset contributing a resource for isoform-specific protein expression in two of the most common valvular heart diseases. Apart from the general proteomic landscape, we demonstrate the added value of the dataset by showing proteomic and transcriptomic evidence for increased expression of the SARS-CoV-2- receptor at pressure load but not at volume load in the left ventricle and also provide the basis of a newly developed metabolic model of the heart.
Iron-sulfur clusters are essential enzyme cofactors. The most common and stable clusters are [2Fe-2S] and [4Fe-4S] that are found in nature. They are involved in crucial biological processes like respiration, gene regulation, protein translation, replication and DNA repair in prokaryotes and eukaryotes. In Escherichia coli, Fe-S clusters are essential for molybdenum cofactor (Moco) biosynthesis, which is a ubiquitous and highly conserved pathway. The first step of Moco biosynthesis is catalyzed by the MoaA protein to produce cyclic pyranopterin monophosphate (cPMP) from 5’GTP. MoaA is a [4Fe-4S] cluster containing radical S-adenosyl-L-methionine (SAM) enzyme. The focus of this study was to investigate Fe-S cluster insertion into MoaA under nitrate and TMAO respiratory conditions using E. coli as a model organism. Nitrate and TMAO respiration usually occur under anaerobic conditions, where oxygen is depleted. Under these conditions, E. coli uses nitrate and TMAO as terminal electron. Previous studies revealed that Fe-S cluster insertion is performed by Fe-S cluster carrier proteins. In E. coli, these proteins are known as A-type carrier proteins (ATC) by phylogenomic and genetic studies. So far, three of them have been characterized in detail in E. coli, namely IscA, SufA, and ErpA. This study shows that ErpA and IscA are involved in Fe-S cluster insertion into MoaA under nitrate and TMAO respiratory conditions. ErpA and IscA can partially replace each other in their role to provide [4Fe-4S] clusters for MoaA. SufA is not able to replace the functions of IscA or ErpA under nitrate respiratory conditions.
Nitrate reductase is a molybdoenzyme that coordinates Moco and Fe-S clusters. Under nitrate respiratory conditions, the expression of nitrate reductase is significantly increased in E. coli. Nitrate reductase is encoded in narGHJI genes, the expression of which is regulated by the transcriptional regulator, fumarate and nitrate reduction (FNR). The activation of FNR under conditions of nitrate respiration requires one [4Fe-4S] cluster. In this part of the study, we analyzed the insertion of Fe-S cluster into FNR for the expression of narGHJI genes in E. coli. The results indicate that ErpA is essential for the FNR-dependent expression of the narGHJI genes, a role that can be replaced partially by IscA and SufA when they are produced sufficiently under the conditions tested. This observation suggests that ErpA is indirectly regulating nitrate reductase expression via inserting Fe-S clusters into FNR.
Most molybdoenzymes are complex multi-subunit and multi-cofactor-containing enzymes that coordinate Fe-S clusters, which are functioning as electron transfer chains for catalysis. In E. coli, periplasmic aldehyde oxidoreductase (PaoAC) is a heterotrimeric molybdoenzyme that
consists of flavin, two [2Fe-2S], one [4Fe-4S] cluster and Moco. In the last part of this study, we investigated the insertion of Fe-S clusters into E. coli periplasmic aldehyde oxidoreductase (PaoAC). The results show that SufA and ErpA are involved in inserting [4Fe-4S] and [2Fe-2S] clusters into PaoABC, respectively under aerobic respiratory conditions.
Gravitational-wave (GW) astrophysics is a field in full blossom. Since the landmark detection of GWs from a binary black hole on September 14th 2015, fifty-two compact-object binaries have been reported by the LIGO-Virgo collaboration. Such events carry astrophysical and cosmological information ranging from an understanding of how black holes and neutron stars are formed, what neutron stars are composed of, how the Universe expands, and allow testing general relativity in the highly-dynamical strong-field regime. It is the goal of GW astrophysics to extract such information as accurately as possible. Yet, this is only possible if the tools and technology used to detect and analyze GWs are advanced enough. A key aspect of GW searches are waveform models, which encapsulate our best predictions for the gravitational radiation under a certain set of parameters, and that need to be cross-correlated with data to extract GW signals. Waveforms must be very accurate to avoid missing important physics in the data, which might be the key to answer the fundamental questions of GW astrophysics. The continuous improvements of the current LIGO-Virgo detectors, the development of next-generation ground-based detectors such as the Einstein Telescope or the Cosmic Explorer, as well as the development of the Laser Interferometer Space Antenna (LISA), demand accurate waveform models. While available models are enough to capture the low spins, comparable-mass binaries routinely detected in LIGO-Virgo searches, those for sources from both current and next-generation ground-based and spaceborne detectors must be accurate enough to detect binaries with large spins and asymmetry in the masses. Moreover, the thousands of sources that we expect to detect with future detectors demand accurate waveforms to mitigate biases in the estimation of signals’ parameters due to the presence of a foreground of many sources that overlap in the frequency band. This is recognized as one of the biggest challenges for the analysis of future-detectors’ data, since biases might hinder the extraction of important astrophysical and cosmological information from future detectors’ data. In the first part of this thesis, we discuss how to improve waveform models for binaries with high spins and asymmetry in the masses. In the second, we present the first generic metrics that have been proposed to predict biases in the presence of a foreground of many overlapping signals in GW data.
For the first task, we will focus on several classes of analytical techniques. Current models for LIGO and Virgo studies are based on the post-Newtonian (PN, weak-field, small velocities) approximation that is most natural for the bound orbits that are routinely detected in GW searches. However, two other approximations have risen in prominence, the post-Minkowskian (PM, weak- field only) approximation natural for unbound (scattering) orbits and the small-mass-ratio (SMR) approximation typical of binaries in which the mass of one body is much bigger than the other. These are most appropriate to binaries with high asymmetry in the masses that challenge current waveform models. Moreover, they allow one to “cover” regions of the parameter space of coalescing binaries, thereby improving the interpolation (and faithfulness) of waveform models. The analytical approximations to the relativistic two-body problem can synergically be included within the effective-one-body (EOB) formalism, in which the two-body information from each approximation can be recast into an effective problem of a mass orbiting a deformed Schwarzschild (or Kerr) black hole. The hope is that the resultant models can cover both the low-spin comparable-mass binaries that are routinely detected, and the ones that challenge current models. The first part of this thesis is dedicated to a study about how to best incorporate information from the PN, PM, SMR and EOB approaches in a synergistic way. We also discuss how accurate the resulting waveforms are, as compared against numerical-relativity (NR) simulations. We begin by comparing PM models, whether alone or recast in the EOB framework, against PN models and NR simulations. We will show that PM information has the potential to improve currently-employed models for LIGO and Virgo, especially if recast within the EOB formalism. This is very important, as the PM approximation comes with a host of new computational techniques from particle physics to exploit. Then, we show how a combination of PM and SMR approximations can be employed to access previously-unknown PN orders, deriving the third subleading PN dynamics for spin-orbit and (aligned) spin1-spin2 couplings. Such new results can then be included in the EOB models currently used in GW searches and parameter estimation studies, thereby improving them when the binaries have high spins. Finally, we build an EOB model for quasi-circular nonspinning binaries based on the SMR approximation (rather than the PN one as usually done). We show how this is done in detail without incurring in the divergences that had affected previous attempts, and compare the resultant model against NR simulations. We find that the SMR approximation is an excellent approximation for all (quasi-circular nonspinning) binaries, including both the equal-mass binaries that are routinely detected in GW searches and the ones with highly asymmetric masses. In particular, the SMR-based models compare much better than the PN models, suggesting that SMR-informed EOB models might be the key to model binaries in the future. In the second task of this thesis, we work within the linear-signal ap- proximation and describe generic metrics to predict inference biases on the parameters of a GW source of interest in the presence of confusion noise from unfitted foregrounds and from residuals of other signals that have been incorrectly fitted out. We illustrate the formalism with simple (yet realistic) LISA sources, and demonstrate its validity against Monte-Carlo simulations. The metrics we describe pave the way for more realistic studies to quantify the biases with future ground-based and spaceborne detectors.
Magmatic continental rifts often constitute the earliest stage of nascent plate boundaries. These extensional tectonic provinces are characterized by ubiquitous normal faulting and volcanic activity; the spatial pattern, the geometry, and the age of these normal faults can help to unravel the spatiotemporal relationships between extensional deformation, magmatism, and long-wavelength crustal deformation of continental rift provinces. This study focuses on the active faulting in the Kenya Rift of the Cenozoic East African Rift System (EARS) with a focus on the mid-Pleistocene to the present-day.
To examine the early stages of continental break-up in the EARS, this thesis presents a time-averaged minimum extension rate for the inner graben of the Northern Kenya Rift (NKR) for the last 0.5 m.y. Using the TanDEM-X digital elevation model, fault-scarp geometries and associated throws are determined across the volcano-tectonic axis of the inner graben of the NKR. By integrating existing geochronology of faulted units with new ⁴⁰Ar/³⁹Ar radioisotopic dates, time-averaged extension rates are calculated. This study reveals that in the inner graben of the NKR, the long-term extension rate based on mid-Pleistocene to recent brittle deformation has minimum values of 1.0 to 1.6 mm yr⁻¹, locally with values up to 2.0 mm yr⁻¹. In light of virtually inactive border faults of the NKR, we show that extension is focused in the region of the active volcano-tectonic axis in the inner graben, thus highlighting the maturing of continental rifting in the NKR.
The phenomenon of focused extension is further investigated with a structural analysis of the youngest volcanic manifestations of the Kenya Rift, their relationship with extensional structures, and their overprint by Holocene faulting. In this context I analyzed the fault characteristics at the ~36 ka old Menengai Caldera and adjacent areas in the Central Kenya Rift using detailed field mapping and a structure-from-motion-based DEM generated from UAV data. In general, the Holocene intra-rift normal faults are dip-slip faults which strike NNE and thus reflect the present-day tectonic stress field; however, inside Menengai caldera persistent magmatic activity and magmatic resurgence overprints these young structures significantly. The caldera is located at the center of an actively extending rift segment and this and the other volcanic edifices of the Kenya Rift may constitute nucleation points of faulting an magmatic extensional processes that ultimately lead into a future stage of magma-assisted rifting.
When viewed at the scale of the entire Kenya Rift the protracted normal faulting in this region compartmentalizes the larger rift depressions, and influences the sedimentology and the hydrology of the intra-rift basins at a scale of less than 100 km. In the present day, most of the fault-bounded sub-basins of the Kenya Rift are hydrologically isolated due to this combination of faulting and magmatic activity that has generated efficient hydrological barriers that maintain these basins as semi-independent geomorphic entities. This isolation, however, was overcome during wetter climatic conditions during the past when the basins were transiently connected. I therefore also investigated the hydrological connectivity of the rift basins during the African Humid Period of the early Holocene, when climate was wetter. With the help of DEM analysis, lake-highstand indicators, radiocarbon dating, and a review of the fossil record, two lake-river-cascades could be identified: one directed southward, and one directed northward. Both cascades connected presently isolated rift basins during the early Holocene via spillovers of lakes and incised river gorges. This hydrological connection fostered the dispersal of aquatic faunas along the rift, and in addition, the water divide between the two river systems represented the only terrestrial dispersal corridor across the Kenya Rift. The reconstruction explains isolated distributions of Nilotic fish species in Kenya Rift lakes and of Guineo-Congolian mammal species in forests east of the Kenya Rift. On longer timescales, repeated episodes of connectivity and isolation must have occurred. To address this problem I participated in research to analyze a sediment drill core from the Koora basin of the Southern Kenya Rift, which provides a paleo-environmental record of the last 1 Ma. Based on this record it can be concluded that at ~400 ka relatively stable environmental conditions were disrupted by tectonic, hydrological, and ecological changes, resulting in increasingly large and frequent fluctuations in water availability, grassland communities, and woody plant cover. The major environmental shifts reflected in the drill core data coincide with phases where volcano-tectonic activity affected the basin. This thesis therefore shows how protracted extensional tectonic processes and the resulting geomorphologic conditions can affect the hydrology, the paleo-environment and the biodiversity of extensional zones in Kenya and elsewhere.
In the last decades, there was a notable progress in solving the well-known Boolean satisfiability (Sat) problem, which can be witnessed by powerful Sat solvers. One of the reasons why these solvers are so fast are structural properties of instances that are utilized by the solver’s interna. This thesis deals with the well-studied structural property treewidth, which measures the closeness of an instance to being a tree. In fact, there are many problems parameterized by treewidth that are solvable in polynomial time in the instance size when parameterized by treewidth.
In this work, we study advanced treewidth-based methods and tools for problems in knowledge representation and reasoning (KR). Thereby, we provide means to establish precise runtime results (upper bounds) for canonical problems relevant to KR. Then, we present a new type of problem reduction, which we call decomposition-guided (DG) that
allows us to precisely monitor the treewidth when reducing from one problem to another problem. This new reduction type will be the basis for a long-open lower bound result for quantified Boolean formulas and allows us to design a new methodology for establishing runtime lower bounds for problems parameterized by treewidth.
Finally, despite these lower bounds, we provide an efficient implementation of algorithms that adhere to treewidth. Our approach finds suitable abstractions of instances, which are subsequently refined in a recursive fashion, and it uses Sat solvers for solving subproblems. It turns out that our resulting solver is quite competitive for two canonical counting problems related to Sat.
Precipitation forecasting has an important place in everyday life – during the day we may have tens of small talks discussing the likelihood that it will rain this evening or weekend. Should you take an umbrella for a walk? Or should you invite your friends for a barbecue? It will certainly depend on what your weather application shows.
While for years people were guided by the precipitation forecasts issued for a particular region or city several times a day, the widespread availability of weather radars allowed us to obtain forecasts at much higher spatiotemporal resolution of minutes in time and hundreds of meters in space. Hence, radar-based precipitation nowcasting, that is, very-short-range forecasting (typically up to 1–3 h), has become an essential technique, also in various professional application contexts, e.g., early warning, sewage control, or agriculture.
There are two major components comprising a system for precipitation nowcasting: radar-based precipitation estimates, and models to extrapolate that precipitation to the imminent future. While acknowledging the fundamental importance of radar-based precipitation retrieval for precipitation nowcasts, this thesis focuses only on the model development: the establishment of open and competitive benchmark models, the investigation of the potential of deep learning, and the development of procedures for nowcast errors diagnosis and isolation that can guide model development.
The present landscape of computational models for precipitation nowcasting still struggles with the availability of open software implementations that could serve as benchmarks for measuring progress. Focusing on this gap, we have developed and extensively benchmarked a stack of models based on different optical flow algorithms for the tracking step and a set of parsimonious extrapolation procedures based on image warping and advection. We demonstrate that these models provide skillful predictions comparable with or even superior to state-of-the-art operational software. We distribute the corresponding set of models as a software library, rainymotion, which is written in the Python programming language and openly available at GitHub (https://github.com/hydrogo/rainymotion). That way, the library acts as a tool for providing fast, open, and transparent solutions that could serve as a benchmark for further model development and hypothesis testing.
One of the promising directions for model development is to challenge the potential of deep learning – a subfield of machine learning that refers to artificial neural networks with deep architectures, which may consist of many computational layers. Deep learning showed promising results in many fields of computer science, such as image and speech recognition, or natural language processing, where it started to dramatically outperform reference methods.
The high benefit of using "big data" for training is among the main reasons for that. Hence, the emerging interest in deep learning in atmospheric sciences is also caused and concerted with the increasing availability of data – both observational and model-based. The large archives of weather radar data provide a solid basis for investigation of deep learning potential in precipitation nowcasting: one year of national 5-min composites for Germany comprises around 85 billion data points.
To this aim, we present RainNet, a deep convolutional neural network for radar-based precipitation nowcasting. RainNet was trained to predict continuous precipitation intensities at a lead time of 5 min, using several years of quality-controlled weather radar composites provided by the German Weather Service (DWD). That data set covers Germany with a spatial domain of 900 km x 900 km and has a resolution of 1 km in space and 5 min in time. Independent verification experiments were carried out on 11 summer precipitation events from 2016 to 2017. In these experiments, RainNet was applied recursively in order to achieve lead times of up to 1 h. In the verification experiments, trivial Eulerian persistence and a conventional model based on optical flow served as benchmarks. The latter is available in the previously developed rainymotion library.
RainNet significantly outperformed the benchmark models at all lead times up to 60 min for the routine verification metrics mean absolute error (MAE) and critical success index (CSI) at intensity thresholds of 0.125, 1, and 5 mm/h. However, rainymotion turned out to be superior in predicting the exceedance of higher intensity thresholds (here 10 and 15 mm/h). The limited ability of RainNet to predict high rainfall intensities is an undesirable property which we attribute to a high level of spatial smoothing introduced by the model. At a lead time of 5 min, an analysis of power spectral density confirmed a significant loss of spectral power at length scales of 16 km and below.
Obviously, RainNet had learned an optimal level of smoothing to produce a nowcast at 5 min lead time. In that sense, the loss of spectral power at small scales is informative, too, as it reflects the limits of predictability as a function of spatial scale. Beyond the lead time of 5 min, however, the increasing level of smoothing is a mere artifact – an analogue to numerical diffusion – that is not a property of RainNet itself but of its recursive application. In the context of early warning, the smoothing is particularly unfavorable since pronounced features of intense precipitation tend to get lost over longer lead times. Hence, we propose several options to address this issue in prospective research on model development for precipitation nowcasting, including an adjustment of the loss function for model training, model training for longer lead times, and the prediction of threshold exceedance.
The model development together with the verification experiments for both conventional and deep learning model predictions also revealed the need to better understand the source of forecast errors. Understanding the dominant sources of error in specific situations should help in guiding further model improvement. The total error of a precipitation nowcast consists of an error in the predicted location of a precipitation feature and an error in the change of precipitation intensity over lead time. So far, verification measures did not allow to isolate the location error, making it difficult to specifically improve nowcast models with regard to location prediction.
To fill this gap, we introduced a framework to directly quantify the location error. To that end, we detect and track scale-invariant precipitation features (corners) in radar images. We then consider these observed tracks as the true reference in order to evaluate the performance (or, inversely, the error) of any model that aims to predict the future location of a precipitation feature. Hence, the location error of a forecast at any lead time ahead of the forecast time corresponds to the Euclidean distance between the observed and the predicted feature location at the corresponding lead time.
Based on this framework, we carried out a benchmarking case study using one year worth of weather radar composites of the DWD. We evaluated the performance of four extrapolation models, two of which are based on the linear extrapolation of corner motion; and the remaining two are based on the Dense Inverse Search (DIS) method: motion vectors obtained from DIS are used to predict feature locations by linear and Semi-Lagrangian extrapolation.
For all competing models, the mean location error exceeds a distance of 5 km after 60 min, and 10 km after 110 min. At least 25% of all forecasts exceed an error of 5 km after 50 min, and of 10 km after 90 min. Even for the best models in our experiment, at least 5 percent of the forecasts will have a location error of more than 10 km after 45 min. When we relate such errors to application scenarios that are typically suggested for precipitation nowcasting, e.g., early warning, it becomes obvious that location errors matter: the order of magnitude of these errors is about the same as the typical extent of a convective cell. Hence, the uncertainty of precipitation nowcasts at such length scales – just as a result of locational errors – can be substantial already at lead times of less than 1 h. Being able to quantify the location error should hence guide any model development that is targeted towards its minimization. To that aim, we also consider the high potential of using deep learning architectures specific to the assimilation of sequential (track) data.
Last but not least, the thesis demonstrates the benefits of a general movement towards open science for model development in the field of precipitation nowcasting. All the presented models and frameworks are distributed as open repositories, thus enhancing transparency and reproducibility of the methodological approach. Furthermore, they are readily available to be used for further research studies, as well as for practical applications.
Media artists have been struggling for financial survival ever since media art came into being. The non-material value of the artwork, a provocative attitude towards the traditional arts world and originally anti-capitalist mindset of the movement makes it particularly difficult to provide a constructive solution. However, a cultural entrepreneurial approach can be used to build a framework in order to find a balance between culture and business while ensuring that the cultural mission remains the top priority.
Fluids in the Earth's crust can move by creating and flowing through fractures, in a process called `hydraulic fracturing’. The tip-line of such fluid-filled fractures grows at locations where stress is larger than the strength of the rock. Where the tip stress vanishes, the fracture closes and the fluid-front retreats. If stress gradients exist on the fracture's walls, induced by fluid/rock density contrasts or topographic stresses, this results in an asymmetric shape and growth of the fracture, allowing for the contained batch of fluid to propagate through the crust.
The state-of-the-art analytical and numerical methods to simulate fluid-filled fracture propagation are two-dimensional (2D). In this work I extend these to three dimensions (3D). In my analytical method, I approximate the propagating 3D fracture as a penny-shaped crack that is influenced by both an internal pressure and stress gradients. In addition, I develop a numerical method to model propagation where curved fractures can be simulated as a mesh of triangular dislocations, with the displacement of faces computed using the displacement discontinuity method. I devise a rapid technique to approximate stress intensity and use this to calculate the advance of the tip-line. My 3D models can be applied to arbitrary stresses, topographic and crack shapes, whilst retaining short computation times.
I cross-validate my analytical and numerical methods and apply them to various natural and man-made settings, to gain additional insights into the movements of hydraulic fractures such as magmatic dikes and fluid injections in rock. In particular, I calculate the `volumetric tipping point’, which once exceeded allows a fluid-filled fracture to propagate in a `self-sustaining’ manner. I discuss implications this has for hydro-fracturing in industrial operations. I also present two studies combining physical models that define fluid-filled fracture trajectories and Bayesian statistical techniques. In these studies I show that the stress history of the volcanic edifice defines the location of eruptive vents at volcanoes. Retrieval of the ratio between topographic to remote stresses allows for forecasting of probable future vent locations. Finally, I address the mechanics of 3D propagating dykes and sills in volcanic regions. I focus on Sierra Negra volcano in the Gal\'apagos islands, where in 2018, a large sill propagated with an extremely curved trajectory. Using a 3D analysis, I find that shallow horizontal intrusions are highly sensitive to topographic and buoyancy stress gradients, as well as the effects of the free surface.
3D point clouds are a universal and discrete digital representation of three-dimensional objects and environments. For geospatial applications, 3D point clouds have become a fundamental type of raw data acquired and generated using various methods and techniques. In particular, 3D point clouds serve as raw data for creating digital twins of the built environment.
This thesis concentrates on the research and development of concepts, methods, and techniques for preprocessing, semantically enriching, analyzing, and visualizing 3D point clouds for applications around transport infrastructure. It introduces a collection of preprocessing techniques that aim to harmonize raw 3D point cloud data, such as point density reduction and scan profile detection. Metrics such as, e.g., local density, verticality, and planarity are calculated for later use. One of the key contributions tackles the problem of analyzing and deriving semantic information in 3D point clouds. Three different approaches are investigated: a geometric analysis, a machine learning approach operating on synthetically generated 2D images, and a machine learning approach operating on 3D point clouds without intermediate representation.
In the first application case, 2D image classification is applied and evaluated for mobile mapping data focusing on road networks to derive road marking vector data. The second application case investigates how 3D point clouds can be merged with ground-penetrating radar data for a combined visualization and to automatically identify atypical areas in the data. For example, the approach detects pavement regions with developing potholes. The third application case explores the combination of a 3D environment based on 3D point clouds with panoramic imagery to improve visual representation and the detection of 3D objects such as traffic signs.
The presented methods were implemented and tested based on software frameworks for 3D point clouds and 3D visualization. In particular, modules for metric computation, classification procedures, and visualization techniques were integrated into a modular pipeline-based C++ research framework for geospatial data processing, extended by Python machine learning scripts. All visualization and analysis techniques scale to large real-world datasets such as road networks of entire cities or railroad networks.
The thesis shows that some use cases allow taking advantage of established image vision methods to analyze images rendered from mobile mapping data efficiently. The two presented semantic classification methods working directly on 3D point clouds are use case independent and show similar overall accuracy when compared to each other. While the geometry-based method requires less computation time, the machine learning-based method supports arbitrary semantic classes but requires training the network with ground truth data. Both methods can be used in combination to gradually build this ground truth with manual corrections via a respective annotation tool.
This thesis contributes results for IT system engineering of applications, systems, and services that require spatial digital twins of transport infrastructure such as road networks and railroad networks based on 3D point clouds as raw data. It demonstrates the feasibility of fully automated data flows that map captured 3D point clouds to semantically classified models. This provides a key component for seamlessly integrated spatial digital twins in IT solutions that require up-to-date, object-based, and semantically enriched information about the built environment.
Anerkennung und Macht
(2021)
In der vorliegenden Untersuchung habe ich das Ziel verfolgt, einen sachlich-eigenständigen Beitrag für eine Debatte gegen Honneths kritische Gesellschaftstheorie zu leisten. In dieser Debatte wird Honneth dahingehend kritisiert, dass es ihm mit seiner kritischen Gesellschaftstheorie entgegen seiner eigenen systematischen Zielsetzung nicht gelingt, in modernen liberaldemokratischen Gesellschaften sämtliche Phänomene von sozialer Herrschaft kritisch zu hinterfragen. Denn soziale Anerkennung, die Honneth als Schlüsselbegriff für diese kritische Hinterfragung behandelt, bei der soziale Herrschaft in Verbindung mit sozialer Missachtung (als mangelnde soziale Anerkennung) steht, kann laut der Kritik faktisch selbst ein Medium für die Stiftung von sozialer Unterwerfung sein. Dies geschieht in Prozessen von Identitätsentwicklung, in denen soziale Anerkennung für Individuen als Anerkannte bestimmte Identitätsmöglichkeiten einräumt und auf diese Weise gleichzeitig andere Identitätsmöglichkeiten ausschließt, womit sie auf diese Identität einschränkend und insofern herrschend wirkt. Es handelt sich um eine Form von sozialer Herrschaft, die durch soziale Anerkennung gestiftet wird. Honneth zieht dem Vorwurf zufolge nicht in Erwägung, dass soziale Anerkennung bei Individuen als Anerkannte einen solchen negativen Effekt erzielen kann. Hieraus ergeben sich die Fragen, ob soziale Anerkennung in Prozessen von Identitätsentwicklung jeweils mit sozialer Herrschaft einhergeht und wie dieser Typus von sozialer Herrschaft kritisiert werden kann. Diese Fragen hat Honneth zuletzt in einem persönlichen Gespräch mit Allen und Cooke (als zwei Teilnehmerinnen der Debatte gegen Honneth) beantwortet. An dieser Stelle vertritt er mit beiden Gesprächsteilnehmerinnen die Auffassung, dass die Operation der Einschränkung von Identitätsmöglichkeiten an sich keine Operation darstellt, welche, wie sonst in der Debatte gegen seine kritische Gesellschaftstheorie behauptet wird, auf soziale Herrschaft zurückführt. Diese Auffassung beruht auf der Idee, wonach soziale Anerkennung sich in jenem praktischen Kontext nur unter der Bedingung als herrschaftsstiftend erweist, dass sie immanente Prinzipien verletzt, die substanziell kritische Maßstäbe definieren.
Mein Beitrag zu dieser Debatte gegen Honneth besteht auf der einen Seite in der Erklärung, dass sowohl jene Auffassung als auch jene Idee argumentativ mangelhaft sind, und auf der anderen Seite in der Ausführung des Vorhabens, diesen argumentativen Mangel selbst zu beheben. Gegen jene Auffassung behaupte ich, dass die drei Autoren in ihrem Gespräch nicht erläutern, inwiefern soziale Anerkennung nicht herrschend wirkt, wenn sie die Identitätsmöglichkeiten von Individuen als Anerkannte einschränkt, denn mit dieser Einschränkung wird vielmehr faktisch über diese Individuen geherrscht – die Debatte gegen Honneth, so zur Unterstützung dieser Ansicht, baut hauptsächlich auf ebendiesem Faktum auf. Gegen jene Idee habe ich fünf problematische Fragen gestellt und beantwortet, die Bezug eigentlich nicht allein auf diese Idee selbst, sondern überdies auf weitere, naheliegende Ideen nehmen, welche die drei Autoren angesprochen haben.
This project describes the nominal, verbal and ‘truncation’ systems of Awing and explains the syntactic and semantic functions of the multifunctional l<-><-> (LE) morpheme in copular and wh-focused constructions. Awing is a Bantu Grassfields language spoken in the North West region of Cameroon. The work begins with morphological processes viz. deverbals, compounding, reduplication, borrowing and a thorough presentation of the pronominal system and takes on verbal categories viz. tense, aspect, mood, verbal extensions, negation, adverbs and triggers of a homorganic N(asal)-prefix that attaches to the verb and other verbal categories. Awing grammar also has a very unusual phenomenon whereby nouns and verbs take long and short forms. A chapter entitled truncation is dedicated to the phenomenon. It is observed that the truncation process does not apply to bare singular NPs, proper names and nouns derived via morphological processes. On the other hand, with the exception of the 1st person non-emphatic possessive determiner and the class 7 noun prefix, nouns generally take the truncated form with modifiers (i.e., articles, demonstratives and other possessives). It is concluded that nominal truncation depicts movement within the DP system (Abney 1987). Truncation of the verb occurs in three contexts: a mass/plurality conspiracy (or lattice structuring in terms of Link 1983) between the verb and its internal argument (i.e., direct object); a means to align (exhaustive) focus (in terms of Fery’s 2013), and a means to form polar questions.
The second part of the work focuses on the role of the LE morpheme in copular and wh-focused clauses. Firstly, the syntax of the Awing copular clause is presented and it is shown that copular clauses in Awing have ‘subject-focus’ vs ‘topic-focus’ partitions and that the LE morpheme indirectly relates such functions. Semantically, it is shown that LE does not express contrast or exhaustivity in copular clauses. Turning to wh-constructions, the work adheres to Hamblin’s (1973) idea that the meaning of a question is the set of its possible answers and based on Rooth’s (1985) underspecified semantic notion of alternative focus, concludes that the LE morpheme is not a Focus Marker (FM) in Awing: LE does not generate or indicate the presence of alternatives (Krifka 2007); The LE morpheme can associate with wh-elements as a focus-sensitive operator with semantic import that operates on the focus alternatives by presupposing an exhaustive answer, among other notions. With focalized categories, the project further substantiates the claim in Fominyam & Šimík (2017), namely that exhaustivity is part of the semantics of the LE morpheme and not derived via contextual implicature, via a number of diagnostics. Hence, unlike in copular clauses, the LE morpheme with wh-focused categories is analysed as a morphological exponent of a functional head Exh corresponding to Horvath's (2010) EI (Exhaustive Identification). The work ends with the syntax of verb focus and negation and modifies the idea in Fominyam & Šimík (2017), namely that the focalized verb that associates with the exhaustive (LE) particle is a lower copy of the finite verb that has been moved to Agr. It is argued that the LE-focused verb ‘cluster’ is an instantiation of adjunction. The conclusion is that verb doubling with verb focus in Awing is neither a realization of two copies of one and the same verb (Fominyam and Šimík 2017), nor a result of a copy triggered by a focus marker (Aboh and Dyakonova 2009). Rather, the focalized copy is said to be merged directly as the complement of LE forming a type of adjoining cluster.
Die stetige Weiterentwicklung von VR-Systemen bietet neue Möglichkeiten der Interaktion mit virtuellen Objekten im dreidimensionalen Raum, stellt Entwickelnde von VRAnwendungen aber auch vor neue Herausforderungen. Selektions- und Manipulationstechniken müssen unter Berücksichtigung des Anwendungsszenarios, der Zielgruppe und der zur Verfügung stehenden Ein- und Ausgabegeräte ausgewählt werden. Diese Arbeit leistet einen Beitrag dazu, die Auswahl von passenden Interaktionstechniken zu unterstützen. Hierfür wurde eine repräsentative Menge von Selektions- und Manipulationstechniken untersucht und, unter Berücksichtigung existierender Klassifikationssysteme, eine Taxonomie entwickelt, die die Analyse der Techniken hinsichtlich interaktionsrelevanter Eigenschaften ermöglicht. Auf Basis dieser Taxonomie wurden Techniken ausgewählt, die in einer explorativen Studie verglichen wurden, um Rückschlüsse auf die Dimensionen der Taxonomie zu ziehen und neue Indizien für Vor- und Nachteile der Techniken in spezifischen Anwendungsszenarien zu generieren. Die Ergebnisse der Arbeit münden in eine Webanwendung, die Entwickelnde von VR-Anwendungen gezielt dabei unterstützt, passende Selektions- und Manipulationstechniken für ein Anwendungsszenario auszuwählen, indem Techniken auf Basis der Taxonomie gefiltert und unter Verwendung der Resultate aus der Studie sortiert werden können.
While patients are known to respond differently to drug therapies, current clinical practice often still follows a standardized dosage regimen for all patients. For drugs with a narrow range of both effective and safe concentrations, this approach may lead to a high incidence of adverse events or subtherapeutic dosing in the presence of high patient variability. Model-informedprecision dosing (MIPD) is a quantitative approach towards dose individualization based on mathematical modeling of dose-response relationships integrating therapeutic drug/biomarker monitoring (TDM) data. MIPD may considerably improve the efficacy and safety of many drug therapies. Current MIPD approaches, however, rely either on pre-calculated dosing tables or on simple point predictions of the therapy outcome. These
approaches lack a quantification of uncertainties and the ability to account for effects that are delayed. In addition, the underlying models are not improved while applied to patient data. Therefore, current approaches are not well suited for informed clinical decision-making based on a differentiated understanding of the individually predicted therapy outcome.
The objective of this thesis is to develop mathematical approaches for MIPD, which (i) provide efficient fully Bayesian forecasting of the individual therapy outcome including associated uncertainties, (ii) integrate Markov decision processes via reinforcement learning (RL) for a comprehensive decision framework for dose individualization, (iii) allow for continuous learning across patients and hospitals. Cytotoxic anticancer chemotherapy with its major dose-limiting toxicity, neutropenia, serves as a therapeutically relevant application example.
For more comprehensive therapy forecasting, we apply Bayesian data assimilation (DA) approaches, integrating patient-specific TDM data into mathematical models of chemotherapy-induced neutropenia that build on prior population analyses. The value of uncertainty quantification is demonstrated as it allows reliable computation of the patient-specific probabilities of relevant clinical quantities, e.g., the neutropenia grade. In view of novel home monitoring devices that increase the amount of TDM data available, the data processing of
sequential DA methods proves to be more efficient and facilitates handling of the variability between dosing events.
By transferring concepts from DA and RL we develop novel approaches for MIPD. While DA-guided dosing integrates individualized uncertainties into dose selection, RL-guided dosing provides a framework to consider delayed effects of dose selections. The combined
DA-RL approach takes into account both aspects simultaneously and thus represents a holistic approach towards MIPD. Additionally, we show that RL can be used to gain insights into important patient characteristics for dose selection. The novel dosing strategies substantially reduce the occurrence of both subtherapeutic and life-threatening neutropenia grades in a simulation study based on a recent clinical study (CEPAC-TDM trial) compared to currently used MIPD approaches.
If MIPD is to be implemented in routine clinical practice, a certain model bias with respect to the underlying model is inevitable, as the models are typically based on data from comparably small clinical trials that reflect only to a limited extent the diversity in real-world patient populations. We propose a sequential hierarchical Bayesian inference framework that enables continuous cross-patient learning to learn the underlying model parameters of the target patient population. It is important to note that the approach only requires summary information of the individual patient data to update the model. This separation of the individual inference from population inference enables implementation across different centers of care.
The proposed approaches substantially improve current MIPD approaches, taking into account new trends in health care and aspects of practical applicability. They enable progress towards more informed clinical decision-making, ultimately increasing patient benefits beyond the current practice.
The presented study investigated the influence of microbial and biogeochemical processes on the physical transport related properties and the fate of microplastics in freshwater reservoirs. The overarching goal was to elucidate the mechanisms leading to sedimentation and deposition of microplastics in such environments. This is of importance, as large amounts of initially buoyant microplastics are found in reservoir sediments worldwide. However, the transport processes which lead to microplastics accumulation in sediments, were up to now understudied.
The impact of biofilm formation on the density and subsequent sedimentation of microplastics was investigated in the eutrophic Bautzen reservoirs (Chapter 2). Biofilms are complex microbial communities fixed to submerged surfaces through a slimy organic film. The mineral calcite was detected in the biofilms, which led to the
sinking of the overgrown microplastic particles. The calcite was of biogenic origin, most likely precipitated by sessile cyanobacteria within the biofilms.
Biofilm formation was also studied in the mesotrophic Malter reservoir. Unlike in Bautzen reservoir, biofilm formation did not govern the sedimentation of different microplastics in Malter reservoir (Chapter 3). Instead autumnal lake mixing led to
the formation of sinking aggregates of microplastics and iron colloids. Such colloids form when anoxic, iron-rich water from the hypolimnion mixes with the oxygenated epilimnetic waters. The colloids bind organic material from the lake water, which leads to the formation of large and sinking iron-organo flocs.
Hence, iron-organo floc formation and their influence on the buoyancy or burial of microplastics into sediments of Bautzen reservoir was studied in laboratory experiments (Chapter 4). Microplastics of different shapes (fiber, fragment, sphere) and sizes were readily incorporated into sinking iron-organo flocs. By this initially buoyant polyethylene microplastics were transported on top of sediments from Bautzen reservoir. Shortly after deposition, the microplastic bearing flocs started to subside and transported the pollutants into deeper sediment layers. The microplastics were not released from the sediments within two months of laboratory incubation.
The stability of floc microplastic deposition was further investigated employing experiments with the iron reducing model organism Shewanella oneidensis (Chapter 5). It was shown, that reduction or re-mineralization of the iron minerals did not affect the integrity of the iron-organo flocs. The organic matrix was stable under iron reducing conditions. Hence, no incorporated microplastics were released from the flocs. As similar processes are likely to take place in natural sediments, this might explain the previous described low microplastic release from the sediments.
This thesis introduced different mechanisms leading to the sedimentation of initially buoyant microplastics and to their subsequent deposition in freshwater reservoirs. Novel processes such as the aggregation with iron-organo flocs were identified and the understudied issue of biofilm densification through biogenic mineral formation was further investigated. The findings might have implications for the fate of microplastics within the river-reservoir system and outline the role of freshwater reservoirs as important accumulation zone for microplastics. Microplastics deposited in the sediments of reservoirs might not be transported further by through flowing river. Hence the study might contribute to better risk assessment and transport balances of these anthropogenic contaminants.
Die herausragenden mechanischen Eigenschaften natürlicher anorganisch-organischer Kompositmaterialien wie Knochen oder Muschelschalen entspringen ihrer hierarchischen Struktur, die von der nano- bis hinauf zur makroskopischen Ebene reicht, und einer kontrollierten Verbindung entlang der Grenzflächen der anorganischen und organischen Komponenten.
Ausgehend von diesen Schlüsselprinzipien des biologischen Materialdesigns wurden in dieser Arbeit zwei Konzepte für die bioinspirierte Strukturbildung von Kompositen untersucht, die auf dem Verkleben von Nano- oder Mesokristallen mit funktionalisierten Poly(2-oxazolin)-Blockcopolymeren beruhen sowie deren Potenzial zur Herstellung bioinspirierter selbstorganisierter hierarchischer anorganisch-organischer Verbundstrukturen ohne äußere Kräfte beleuchtet. Die Konzepte unterschieden sich in den verwendeten anorganischen Partikeln und in der Art der Strukturbildung.
Über einen modularen Ansatz aus Polymersynthese und polymeranaloger Thiol-En-Funktionalisierung wurde erfolgreich eine Bibliothek von Poly(2-oxazolin)en mit unterschiedlichen Funktionalitäten erstellt. Die Blockcopolymere bestehen aus einem kurzen partikelaffinen "Klebeblock", der aus Thiol-En-funktionalisiertem Poly(2-(3-butenyl)-2-oxazolin) besteht, und einem langen wasserlöslichen, strukturbildenden Block, der aus thermoresponsivem und kristallisierbarem Poly(2-isopropyl-2-oxazolin) besteht und hierarchische Morphologien ausbildet. Verschiedene analytische Untersuchungen wie Turbidimetrie, DLS, DSC, SEM oder XRD machten das thermoresponsive bzw. das Kristallisationsverhalten der Blockcopolymere in Abhängigkeit vom eingeführten Klebeblock zugänglich. Es zeigte sich, dass diese Polymere ein komplexes temperatur- und pH-abhängiges Trübungsverhalten aufweisen. Hinsichtlich der Kristallisation änderte der Klebeblock nicht die nanoskopische Kristallstruktur; er beeinflusste jedoch die Kristallisationszeit, den Kristallisationsgrad und die hierarchische Morphologie. Dieses Ergebnis wurde auf das unterschiedliche Aggregationsverhalten der Polymere in Wasser zurückgeführt.
Für die Herstellung von Kompositen nutzte Konzept 1 mikrometergroße Kupferoxalat-Mesokristalle, die eine innere Nanostruktur aufweisen. Die Strukturbildung über den anorganischen Teil wurde durch das Verkleben und Anordnen dieser Partikel erstrebt. Konzept 1 ermöglichte homogene freistehende stabile Kompositfilme mit einem hohen anorganischen Anteil. Die Partikel-Polymer-Kombination vereinte jedoch ungünstige Eigenschaften in sich, d. h. ihre Längenskalen waren zu unterschiedlich, was die Selbstassemblierung der Partikel verhinderte. Aufgrund des geringen Aspektverhältnisses von Kupferoxalat blieb auch die gegenseitige Ausrichtung durch äußere Kräfte erfolglos. Im Ergebnis eignet sich das Kupferoxalat-Poly(2-oxazolin)-Modellsystem nicht für die Herstellung hierarchischer Kompositstrukturen.
Im Gegensatz dazu verwendet Konzept 2 scheibenförmige Laponit®-Nanopartikel und kristallisierbare Blockcopolymere zur Strukturbildung über die organische Komponente durch polymervermittelte Selbstassemblierung. Komplementäre Analysemethoden (Zeta-Potenzial, DLS, SEM, XRD, DSC, TEM) zeigten sowohl eine kontrollierte Wechselwirkung zwischen den Komponenten in wässriger Umgebung als auch eine kontrollierte Strukturbildung, die in selbstassemblierten Nanokompositen resultiert, deren Struktur sich über mehrere Längenskalen erstreckt. Es wurde gezeigt, dass die negativ geladenen Klebeblöcke spezifisch und selektiv an den positiv geladenen Rändern der Laponit®-Partikel binden und so Polymer-Laponit®-Nanohybridpartikel entstehen, die als Grundbausteine für die Kompositbildung dienen. Die Hybridpartikel sind bei Raumtemperatur elektrosterisch stabilisiert - sterisch durch ihre langen, mit Wasser wechselwirkenden Poly(2-isopropyl-2-oxazolin)-Blöcke und elektrostatisch über die negativ geladenen Laponit®-Flächen. Im Ergebnis ließ sich Konzept 2 und damit die Strukturbildung über die organische Komponente erfolgreich umsetzten. Das Laponit®-Poly(2-oxazolin)-Modellsystem eröffnete den Weg zu selbstassemblierten geschichteten quasi-hierarchischen Nanokompositstrukturen mit hohem anorganischen Anteil. Abhängig von der frei verfügbaren Polymerkonzentration bei der Kompositbildung entstanden zwei unterschiedliche Komposit-Typen. Darüber hinaus entwarf die Arbeit einen Erklärungsansatz für den polymervermittelten Bildungsprozess der Komposit-Strukturen.
Insgesamt legt diese Arbeit Struktur-Prozess-Eigenschafts-Beziehungen offen, um selbstassemblierte bioinspirierte Kompositstrukturen zu bilden und liefert neue Einsichten zu einer geeigneten Kombination an Komponenten und Herstellungsbedingungen, die eine kontrollierte selbstassemblierte Strukturbildung mithilfe funktionalisierter Poly(2-oxazolin)-Blockcopolymere erlauben.
Boon and bane
(2021)
Semi-natural habitats (SNHs) in agricultural landscapes represent important refugia for biodiversity including organisms providing ecosystem services. Their spill-over into agricultural fields may lead to the provision of regulating ecosystem services such as biological pest control ultimately affecting agricultural yield. Still, it remains largely unexplored, how different habitat types and their distributions in the surrounding landscape shape this provision of ecosystem services within arable fields. Hence, in this thesis I investigated the effect of SNHs on biodiversity-driven ecosystem services and disservices affecting wheat production with an emphasis on the role and interplay of habitat type, distance to the habitat and landscape complexity.
I established transects from the field border into the wheat field, starting either from a field-to-field border, a hedgerow, or a kettle hole, and assessed beneficial and detrimental organisms and their ecosystem functions as well as wheat yield at several in-field distances. Using this study design, I conducted three studies where I aimed to relate the impacts of SNHs at the field and at the landscape scale on ecosystem service providers to crop production.
In the first study, I observed yield losses close to SNHs for all transect types. Woody habitats, such as hedgerows, reduced yields stronger than kettle holes, most likely due to shading from the tall vegetation structure. In order to find the biotic drivers of these yield losses close to SNHs, I measured pest infestation by selected wheat pests as potential ecosystem disservices to crop production in the second study. Besides relating their damage rates to wheat yield of experimental plots, I studied the effect of SNHs on these pest rates at the field and at the landscape scale. Only weed cover could be associated to yield losses, having their strongest impact on wheat yield close to the SNH. While fungal seed infection rates did not respond to SNHs, fungal leaf infection and herbivory rates of cereal leaf beetle larvae were positively influenced by kettle holes. The latter even increased at kettle holes with increasing landscape complexity suggesting a release of natural enemies at isolated habitats within the field interior.
In the third study, I found that also ecosystem service providers benefit from the presence of kettle holes. The distance to a SNH decreased species richness of ecosystem service providers, whereby the spatial range depended on species mobility, i.e. arable weeds diminished rapidly while carabids were less affected by the distance to a SNH. Contrarily, weed seed predation increased with distance suggesting that a higher food availability at field borders might have diluted the predation on experimental seeds. Intriguingly, responses to landscape complexity were rather mixed: While weed species richness was generally elevated with increasing landscape complexity, carabids followed a hump-shaped curve with highest species numbers and activity-density in simple landscapes. The latter might give a hint that carabids profit from a minimum endowment of SNHs, while a further increase impedes their mobility. Weed seed predation was affected differently by landscape complexity depending on weed species displayed. However, in habitat-rich landscapes seed predation of the different weed species converged to similar rates, emphasising that landscape complexity can stabilize the provision of ecosystem services. Lastly, I could relate a higher weed seed predation to an increase in wheat yield even though seed predation did not diminish weed cover. The exact mechanisms of the provision of weed control to crop production remain to be investigated in future studies.
In conclusion, I found habitat-specific responses of ecosystem (dis)service providers and their functions emphasizing the need to evaluate the effect of different habitat types on the provision of ecosystem services not only at the field scale, but also at the landscape scale. My findings confirm that besides identifying species richness of ecosystem (dis)service providers the assessment of their functions is indispensable to relate the actual delivery of ecosystem (dis)services to crop production.
Noise is ubiquitous in nature and usually results in rich dynamics in stochastic systems such as oscillatory systems, which exist in such various fields as physics, biology and complex networks. The correlation and synchronization of two or many oscillators are widely studied topics in recent years.
In this thesis, we mainly investigate two problems, i.e., the stochastic bursting phenomenon in noisy excitable systems and synchronization in a three-dimensional Kuramoto model with noise. Stochastic bursting here refers to a sequence of coherent spike train, where each spike has random number of followers due to the combined effects of both time delay and noise. Synchronization, as a universal phenomenon in nonlinear dynamical systems, is well illustrated in the Kuramoto model, a prominent model in the description of collective motion.
In the first part of this thesis, an idealized point process, valid if the characteristic timescales in the problem are well separated, is used to describe statistical properties such as the power spectral density and the interspike interval distribution. We show how the main parameters of the point process, the spontaneous excitation rate, and the probability to induce a spike during the delay action can be calculated from the solutions of a stationary and a forced Fokker-Planck equation. We extend it to the delay-coupled case and derive analytically the statistics of the spikes in each neuron, the pairwise correlations between any two neurons, and the spectrum of the total output from the network.
In the second part, we investigate the three-dimensional noisy Kuramoto model, which can be used to describe the synchronization in a swarming model with helical trajectory. In the case without natural frequency, the Kuramoto model can be connected with the Vicsek model, which is widely studied in collective motion and swarming of active matter. We analyze the linear stability of the incoherent state and derive the critical coupling strength above which the incoherent state loses stability. In the limit of no natural frequency, an exact self-consistent equation of the mean field is derived and extended straightforward to any high-dimensional case.
Many children struggle with reading for comprehension. Reading is a complex cognitive task depending on various sub-tasks, such as word decoding and building connections across sentences. The task of connecting sentences is guided by referential expressions. References, such as anaphoric noun phrases (Minky/the cat) or pronouns (Minky/she), signal to the reader how the protagonists of adjacent sentences are connected. Readers construct a coherent mental model of the text by resolving these references. Personal pronouns (he/she) in particular need to be resolved towards an appropriate antecedent before they can be fully understood. Pronoun resolution therefore is vital for successful text comprehension. The present thesis investigated children’s resolution of personal pronouns during natural reading as a possible source of reading comprehension difficulty. Three eye tracking studies investigated whether children aged 8-9 (Grade 3-4) resolve pronouns online during reading and how the varying information around the pronoun region influences children’s eye movement behavior.
The first study investigated whether children prefer a pronoun over a noun phrase when the antecedent is highly accessible. Children read three-sentence stories that introduced a protagonist (Mia) in the first sentence and a reference to this protagonist in one of the following sentences using either a repeated name (Mia) or a pronoun (she). For proficient readers, it was repeatedly shown that there is a preference for a pronoun over the name in these contexts, i.e., when the antecedent is salient. The first study tested the repeated name penalty effect in children using eye tracking. It was hypothesized that in contrast to proficient readers, the fluency of children’s reading processing profits from an overlapping word form (i.e., the repeated noun phrase) compared to a pronoun. This is because overlapping word forms allow for direct mapping, whereas pronouns have to be resolved towards their antecedent first.
The second study investigated children’s online processing of pronominal gender in a mismatch paradigm. Children read sentences in which the pronoun either was a gender-match to the antecedent or a gender-mismatch. Reading skill and reading fluency were also tested and related to children’s ability to detect a mismatching pronoun during reading.
The third study investigated the online processing of gender information on the pronoun and whether disambiguating gender information improves the accuracy of pronoun comprehension. Offline comprehension accuracy, that is the comprehension of the pronoun, was related to children’s online eye movement behavior. This study was conducted in a semi-longitudinal paradigm: 70 children were tested in Grade 3 (age 8) and again in Grade 4 (age 9) to investigate effects of age and reading skill on pronoun processing and comprehension.
The results of this thesis clearly show that children aged 8-9, when they are in the second half of primary school, struggle with the comprehension of pronouns in reading tasks. The responses to pronoun comprehension questions revealed that children have difficulties with the comprehension of a pronoun in the absence of a disambiguating gender cue, that is when they have to apply context information. When there is a gender cue to disambiguate the pronoun, children’s accuracy improves significantly. This is true for children in Grade 3, but also in Grade 4, albeit their overall resolution accuracy slightly improves with age.
The results from the analyses of eye movements suggest that the discourse accessibility of an antecedent does play a role in children’s processing of pronouns and repeated names. The repetition of a name does not facilitate children’s reading processing like it was anticipated. Similar to adults, children showed a penalty effect for the repeated name where a pronoun is expected. However, this does not mean that children’s processing of pronouns is always adult-like. The results from eye movement analyses in the pronoun region during sentence reading revealed significant individual differences related to children’s individual reading skill and reading fluency.
The results from the mismatch study revealed that reading fluency is associated with children’s detection of incongruent pronouns. All children had longer gaze durations at mismatching than matching pronouns, but only fluent readers among the children followed this up with a regression out of the pronoun region. This was interpreted as an attempt to gain processing time and “repair” the inconsistency. Reading fluency was therefore associated with detection of the mismatch, while less fluent readers did not see any mismatch between pronoun and antecedent. The eye movement pattern of the “detectors” is more adult-like and was interpreted as reflecting successful monitoring and attempted pronoun resolution.
Children differ considerably in their reading comprehension skill. The results of this thesis show that only skilled readers among the children use gender information online for pronoun resolution. They took more time to read the pronoun when there was disambiguating gender information that was useful to resolve the pronoun, in contrast to the less skilled readers. Age was a less important factor in pronoun resolution processes and comprehension than were reading skill and reading fluency. Taken together, this suggests that the good readers direct cognitive resources towards pronoun resolution when the pronoun can be resolved, which is a successful comprehension strategy. Moreover, there was evidence that reading skill is a relevant factor in this task but not age.
The contribution of the present thesis is a depiction of the specific eye movement patterns that are related to successful and unsuccessful attempts at pronoun resolution in children. Eye movement behavior in the pronoun area is related to children’s reading skill and fluency. The results of this thesis suggest that many children do not resolve pronouns spontaneously during sentence reading, which is likely detrimental to their reading comprehension in more complex reading materials. The present thesis informs our understanding of the challenge that pronoun resolution poses for beginning readers, and gives new impulses for the study of higher-order reading processes in children’s natural reading.
Active Galactic Nuclei (AGN) are considered to be the main powering source of active galaxies, where central Super Massive Black Holes (SMBHs), with masses between 106 and 109 M⊙ gravitationally pull the surrounding material via accre- tion. AGN phenomenon expands over a very wide range of luminosities, from the most luminous high-redshift quasars (QSOs), to the local Low-Luminosity AGN (LLAGN), with significantly weaker luminosities. While "typical" luminous AGNs distinguish themselves by their characteristical blue featureless continuum, the Broad Emission Lines (BELs) with Full Widths at Half Maximum (FWHM) in order of few thousands km s1, arising from the so-called Broad Line Region (BLR), and strong radio and/or X-ray emission, detection of LLAGNs on the other hand is quite chal- lenging due to their extremely weak emission lines, and absence of the power-law continuum. In order to fully understand AGN evolution and their duty-cycles across cosmic history, we need a proper knowledge of AGN phenomenon at all luminosi- ties and redshifts, as well as perspectives from different wavelength bands.
In this thesis I present a search for AGN signatures in central spectra of 542 local (0.005 < z < 0.03) galaxies from the Calar Alto Legacy Integral Field Area (CALIFA) survey. The adopted aperture of 3′′ × 3′′ corresponds to central ∼ 100 − 500 pc for the redshift range of CALIFA. Using the standard emission-line ratio diagnostic diagrams, we initially classified all CALIFA emission-line galaxies (526) into star- forming, LINER-like, Seyfert 2 and intermediates. We further detected signatures of the broad Hα component in 89 spectra from the sample, of which more than 60% are present in the central spectra of LINER-like galaxies. These BELs are very weak, with luminosities in range 1038 − 1041 erg s−1, but with FWHMs between 1000 km s−1 and 6000 km s−1, comparable to those of luminous high-z AGN. This result implies that type 1 AGN are in fact quite frequent in the local Universe. We also identified additional 29 Seyfert 2 galaxies using the emission-line ratio diagnostic diagrams.
Using the MBH − σ∗ correlation, we estimated black hole masses of 55 type 1 AGN from CALIFA, a sample for which we had estimates of bulge stellar velocity dispersions σ∗. We compared these masses to the ones that we estimated from the virial method and found large discrepancies. We analyzed the validity of both meth- ods for black hole mass estimation of local LLAGN, and concluded that most likely virial scaling relations can no longer be applied as a valid MBH estimator in such low-luminosity regime. These black holes accrete at very low rate, having Edding- ton ratios in range 4.1 × 10−5 − 2.4 × 10−3. Detection of BELs with such low lumi- nosities and at such low Eddington rates implies that these LLAGN are still able to form the BLR, although with probably modified structure of the central engine.
In order to obtain full picture of black hole growth across cosmic time, it is es- sential that we study them in different stages of their activity. For that purpose, we estimated the broad AGN Luminosity Function (AGNLF) of our entire type 1 AGN sample using the 1/Vmax method. The shape of AGNLF indicates an apparent flattening below luminosities LHα ∼ 1039 erg s−1. Correspondingly we estimated ac- tive Black Hole Mass Function (BHMF) and Eddington Ration Distribution Function (ERDF) for a sub-sample of type 1 AGN for which we have MBH and λ estimates. The flattening is also present in both BHMF and ERDF, around log(MBH) ∼ 7.7 and log(λ) < 3, respectively. We estimated the fraction of active SMBHs in CALIFA by comparing our active BHMF to the one of the local quiescent SMBHs. The shape of
the active fraction which decreases with increasing MBH, as well as the flattening of AGNLF, BHMF and ERDF is consistent with scenario of AGN cosmic downsizing.
To complete AGN census in the CALIFA galaxy sample, it is necessary to search for them in various wavelength bands. For the purpose of completing the census we performed cross-correlations between all 542 CALIFA galaxies and multiwavelength surveys, Swift – BAT 105 month catalogue (in hard 15 - 195 keV X-ray band), and NRAO VLA Sky Survey (NVSS, in 1.4 GHz radio domain). This added 1 new AGN candidate in X-ray, and 7 in radio wavelength band to our local LLAGN count.
It is possible to detect AGN emission signatures within 10 – 20 kpc outside of the central galactic regions. This may happen when the central AGN has recently switched off and the photoionized material is spread across the galaxy within the light-travel-time, or the photoionized material is blown away from the nucleus by outflows. In order to detect these extended AGN regions we constructed spatially resolved emission-line ratio diagnostic diagrams of all emission-line galaxies from the CALIFA, and found 1 new object that was previously not identified as AGN.
Obtaining the complete AGN census in CALIFA, with five different AGN types, showed that LLAGN contribute a significant fraction of 24% of the emission-line galaxies in the CALIFA sample. This result implies that AGN are quite common in the local Universe, and although being in very low activity stage, they contribute to large fraction of all local SMBHs. Within this thesis we approached the upper limit of AGN fraction in the local Universe and gained some deeper understanding of the LLAGN phenomenon.
One third of the world's population lives in areas where earthquakes causing at least slight damage are frequently expected. Thus, the development and testing of global seismicity models is essential to improving seismic hazard estimates and earthquake-preparedness protocols for effective disaster-risk mitigation. Currently, the availability and quality of geodetic data along plate-boundary regions provides the opportunity to construct global models of plate motion and strain rate, which can be translated into global maps of forecasted seismicity. Moreover, the broad coverage of existing earthquake catalogs facilitates in present-day the calibration and testing of global seismicity models. As a result, modern global seismicity models can integrate two independent factors necessary for physics-based, long-term earthquake forecasting, namely interseismic crustal strain accumulation and sudden lithospheric stress release.
In this dissertation, I present the construction of and testing results for two global ensemble seismicity models, aimed at providing mean rates of shallow (0-70 km) earthquake activity for seismic hazard assessment. These models depend on the Subduction Megathrust Earthquake Rate Forecast (SMERF2), a stationary seismicity approach for subduction zones, based on the conservation of moment principle and the use of regional "geodesy-to-seismicity" parameters, such as corner magnitudes, seismogenic thicknesses and subduction dip angles. Specifically, this interface-earthquake model combines geodetic strain rates with instrumentally-recorded seismicity to compute long-term rates of seismic and geodetic moment. Based on this, I derive analytical solutions for seismic coupling and earthquake activity, which provide this earthquake model with the initial abilities to properly forecast interface seismicity. Then, I integrate SMERF2 interface-seismicity estimates with earthquake computations in non-subduction zones provided by the Seismic Hazard Inferred From Tectonics based on the second iteration of the Global Strain Rate Map seismicity approach to construct the global Tectonic Earthquake Activity Model (TEAM). Thus, TEAM is designed to reduce number, and potentially spatial, earthquake inconsistencies of its predecessor tectonic earthquake model during the 2015-2017 period. Also, I combine this new geodetic-based earthquake approach with a global smoothed-seismicity model to create the World Hybrid Earthquake Estimates based on Likelihood scores (WHEEL) model. This updated hybrid model serves as an alternative earthquake-rate approach to the Global Earthquake Activity Rate model for forecasting long-term rates of shallow seismicity everywhere on Earth.
Global seismicity models provide scientific hypotheses about when and where earthquakes may occur, and how big they might be. Nonetheless, the veracity of these hypotheses can only be either confirmed or rejected after prospective forecast evaluation. Therefore, I finally test the consistency and relative performance of these global seismicity models with independent observations recorded during the 2014-2019 pseudo-prospective evaluation period. As a result, hybrid earthquake models based on both geodesy and seismicity are the most informative seismicity models during the testing time frame, as they obtain higher information scores than their constituent model components. These results support the combination of interseismic strain measurements with earthquake-catalog data for improved seismicity modeling. However, further prospective evaluations are required to more accurately describe the capacities of these global ensemble seismicity models to forecast longer-term earthquake activity.
In my doctoral thesis, I examine continuous gravity measurements for monitoring of the geothermal site at Þeistareykir in North Iceland. With the help of high-precision superconducting gravity meters (iGravs), I investigate underground mass changes that are caused by operation of the geothermal power plant (i.e. by extraction of hot water and reinjection of cold water). The overall goal of this research project is to make a statement about the sustainable use of the geothermal reservoir, from which also the Icelandic energy supplier and power plant operator Landsvirkjun should benefit.
As a first step, for investigating the performance and measurement stability of the gravity meters, in summer 2017, I performed comparative measurements at the gravimetric observatory J9 in Strasbourg. From the three-month gravity time series, I examined calibration, noise and drift behaviour of the iGravs in comparison to stable long-term time series of the observatory superconducting gravity meters. After preparatory work in Iceland (setup of gravity stations, additional measuring equipment and infrastructure, discussions with Landsvirkjun and meetings with the Icelandic partner institute ISOR), gravity monitoring at Þeistareykir was started in December 2017. With the help of the iGrav records of the initial 18 months after start of measurements, I carried out the same investigations (on calibration, noise and drift behaviour) as in J9 to understand how the transport of the superconducting gravity meters to Iceland may influence instrumental parameters.
In the further course of this work, I focus on modelling and reduction of local gravity contributions at Þeistareykir. These comprise additional mass changes due to rain, snowfall and vertical surface displacements that superimpose onto the geothermal signal of the gravity measurements. For this purpose, I used data sets from additional monitoring sensors that are installed at each gravity station and adapted scripts for hydro-gravitational modelling. The third part of my thesis targets geothermal signals in the gravity measurements.
Together with my PhD colleague Nolwenn Portier from France, I carried out additional gravity measurements with a Scintrex CG5 gravity meter at 26 measuring points within the geothermal field in the summers of 2017, 2018 and 2019. These annual time-lapse gravity measurements are intended to increase the spatial coverage of gravity data from the three continuous monitoring stations to the entire geothermal field. The combination of CG5 and iGrav observations, as well as annual reference measurements with an FG5 absolute gravity meter represent the hybrid gravimetric monitoring method for Þeistareykir. Comparison of the gravimetric data to local borehole measurements (of groundwater levels, geothermal extraction and injection rates) is used to relate the observed gravity changes to the actually extracted (and reinjected) geothermal fluids. An approach to explain the observed gravity signals by means of forward modelling of the geothermal production rate is presented at the end of the third (hybrid gravimetric) study. Further modelling with the help of the processed gravity data is planned by Landsvirkjun. In addition, the experience from time-lapse and continuous gravity monitoring will be used for future gravity measurements at the Krafla geothermal field 22 km south-east of Þeistareykir.
The development and optimization of carbonaceous materials is of great interest for several applications including gas sorption, electrochemical storage and conversion, or heterogeneous catalysis. In this thesis, the exploration and optimization of nitrogen containing carbonaceous materials by direct condensation of smart chosen, molecular precursors will be presented. As suggested with the concept of noble carbons, the choice of a stable, nitrogen-containing precursor will lead to an even more stable, nitrogen doped carbonaceous material with a controlled structure and electronic properties. Molecules fulfilling this requirement are for example nucleobases. The direct condensation of nucleobases leads to highly nitrogen containing carbonaceous materials without any further post or pretreatment. By using salt melt templating, pore structure adjustment is possible without the use of hazardous or toxic reagents and the template can be reused.
Using these simple tools, the synergetic effect of the pore structure and nitrogen content of the materials can be explored. Within this thesis, the influence of the condensation parameters will be correlated to the structure and performance of the materials. First, the influence of the condensation temperature to the porosity and nitrogen content of guanine will be discussed and the exploration of highly CO2 selective structural pores in C1N1 materials will be shown. Further tuning the pore structure of the materials by salt melt templating will be then explored, the potential of the prepared materials as heterogeneous catalysts and their basic catalytic strength will be correlated to their nitrogen content and pore morphology. A similar approach is used to explore the water sorption behavior of uric acid derived carbonaceous materials as potential sorbents for heat transformation applications. Changes in maximum water uptake and hydrophilicity of the prepared materials will be correlated to the nitrogen content and pore architecture. Due to the high thermal stability, porosity, and nitrogen content of ionic liquid derived nitrogen doped carbonaceous materials, a simple impregnation and calcination route can be conducted to obtain copper nano cluster decorated nitrogen-doped carbonaceous materials. The activity as catalyst for the oxygen reduction reaction of the obtained materials will be shown and structure performance relations are discussed.
In conclusion, the versatility of nitrogen doped carbonaceous materials with a nitrogen to carbon ratio of up to one will be shown. The possibility to tune the pore structure as well as the nitrogen content by using a simple procedure including salt melt templating as well as the use of molecular precursors and their effect on the performance will be discussed.
Das Fachwissen von Lehrkräften weist für die Ausprägung fachdidaktischer Expertise eine hohe Bedeutung auf. Welche Merkmale universitäre Lehrveranstaltungen aufweisen sollten, um Lehramtsstudierenden ein berufsspezifisches Fachwissen zu vermitteln, ist jedoch überwiegend noch unklar.
Innerhalb des Projekts PSI-Potsdam wurde auf theoretischer Grundlage das fachübergreifende Modell des erweiterten Fachwissens für den schulischen Kontext entwickelt. Als Ansatz zur Verbesserung des Biologie-Lehramtsstudiums diente dieses Modell als Konzeptionsgrundlage für eine additive Lehrveranstaltung. Hierbei werden Lerngelegenheiten geboten, um das universitär erworbene Fachwissen über zellbiologische Inhalte auf schulische Kontexte anzuwenden, z.B. durch die Dekonstruktion und anschließende Rekonstruktion von schulischen Lerntexten. Die Wirkung des Seminars wurde in mehreren Zyklen im Forschungsformat der Fachdidaktischen Entwicklungsforschung beforscht. Eine der zentralen Forschungsfragen lautet dabei: Wie kann eine Lerngelegenheit für Lehramtsstudierende der Biologie gestaltet sein, um ein erweitertes Fachwissen für den schulischen Kontext für den zellbiologischen Themenbereich „Struktur und Funktion der Biomembran“ zu fördern?
Anhand fallübergreifender Analysen (n = 29) wird im empirischen Teil aufgezeigt, welche Einstellungen zum Lehramtsstudium in der Stichprobe bestehen. Als ein wichtiges Ergebnis kann hierbei herausgestellt werden, dass sich das Fachinteresse hinsichtlich schulisch und universitär vermittelter Inhalte bei den untersuchten Studierenden auffallend unterscheidet, wobei dem Schulwissen ein deutlich höheres Interesse entgegengebracht wird. Die Berufsrelevanz fachlicher Inhalte wird seitens der Studierenden häufig am Schulwissen festgemacht.
Innerhalb konkreter Einzelfallanalysen (n = 6) wird anhand von Lernpfaden dargestellt, wie sich über mehrere Design-Experimente hinweg fachliche Konzepte entwickelt haben. Bei der Beschreibung wird vor allem auf Schlüsselstellen und Hürden im Lernprozess fokussiert. Aus diesen Ergebnissen folgend werden vorgenommene Iterationen für die einzelnen Zyklen beschrieben, die ebenfalls anhand der iterativen Entwicklung der Design-Prinzipien dargelegt werden.
Es konnte gezeigt werden, dass die Schlüsselstellen sehr individuell aufgrund der subjektiv fokussierten Inhalte zu Tage treten. Meist treten sie jedoch im Zusammenhang mit der Verknüpfung verschiedener fachlicher Konzepte oder durch kooperative Aufschlüsselungen von Konzepten auf. Fachliche Hürden konnten hingegen in Form von fachlich unangemessenen Vorstellungen fallübergreifend identifiziert werden. Dies betrifft unter anderem die Vorstellung der Biomembran als Wand, die mit den Vorstellungen einer Schutzfunktion und einer formgebenden Funktion der Biomembran einhergeht.
Weiterhin wird beleuchtet, wie das erweiterte Fachwissen für den schulischen Kontext zur Bearbeitung der Lernaufgaben angewendet wurde. Es hat sich gezeigt, dass sich bestimmte Lerngelegenheiten eigenen, um bestimmte Facetten des erweiterten Fachwissens zu fördern.
Insgesamt scheint das Modell des erweiterten Fachwissens für den schulischen Kontext äußerst geeignet zu sein, um anhand der Facetten und deren Beschreibungen Lerngelegenheiten oder Gestaltungsprinzipien für diese zu konzipieren. Für das untersuchte Lehr-Lernarrangement haben sich kleinere Adaptationen des Modells als sinnvoll erwiesen. Hinsichtlich der Methodologie konnten Ableitungen für die Anwendung der fachdidaktischen Entwicklungsforschung für additive fachliche Lehrveranstaltungen dieser Art herausgestellt werden.
Um den Professionsbezug der fachwissenschaftlichen Anteile im Lehramtsstudium zu verbessern, ist der weitere Einbezug des erweiterten Fachwissens für den schulischen Kontext in die fachwissenschaftlichen Studienanteile überaus wünschenswert.
Die Geschichtsschreibung terminiert das Ende des deutschen Zionismus bisher mit dem NS-Verbot der Zionistischen Vereinigung für Deutschland im Zuge des Novemberpogroms 1938. Zu diesem Zeitpunkt hatte er aber von seinem geographischen Kontext entgrenzt, in Erez Israel bereits neue Wurzeln geschlagen. Zionisten aus Deutschland schickten sich nun an, mit ihrem spezifischen Erfahrungshorizont und Wertemaßstab und mitgebrachtem ideologischen Rüstzeug die Entwicklung des jüdischen Nationalheims mitzugestalten und einer umfassenden ökonomischen, kulturellen und politischen Akkulturation der deutschen Alijah den Weg zu bahnen. Entgegen aller zionistischen Theorie gründeten sie auf landsmannschaftlicher Basis im Jahr 1932 die Selbsthilfeorganisation Hitachduth Olej Germania und während des Weltkrieges die Partei Alija Chadascha.
Die Dissertation beinhaltet die Gesamtschau des deutschen Zionismus in seiner letzten Phase in den Jahren 1932 bis 1948; zugleich beleuchtet sie die Geschichte der etwa 60.000 in Palästina eingewanderten Juden aus Deutschland in der für diese Abhandlung relevanten Zeitperiode. Im ersten Teil wird in chronologischer Folge die 1932 beginnende letztmalige Sammlung und Neuformierung des deutschen Zionismus in seiner neu-alten Heimat dargestellt. Wenn man so will, die formativen Jahre im personellen, organisatorischen und ideologisch-politischen Sinne, die schließlich nach dem fast gänzlichen Scheitern der politischen Integration der deutschen Alijah mit der – in der Rückschau – fast zwangsläufig erscheinenden Begründung der Alija Chadascha ihren Abschluss fanden. Im zweiten Teil werden die Positionen der deutschen Zionisten zu den existenziellen Fragen der jüdischen Gemeinschaft in Palästina, hebräisch Jischuw genannt, in der im Fokus stehenden Zeitperiode dargestellt. Im Einzelnen handelt es sich erstens um die Einwanderungsfrage, die untrennbar verbunden war mit der in der zionistischen Theorie unabdingbaren Forderung nach der Erlangung einer jüdischen Majorität in Palästina; zweitens um die der staatlichen Ausgestaltung des zukünftigen jüdischen Gemeinwesens und drittens um die Frage der adäquaten Reaktion des Jischuw auf die Schoah. In diese jeweils in separaten Kapiteln behandelten Themenkomplexe wird die Frage nach dem anzustrebenden Verhältnis zur britischen Mandatsmacht mit einfließen. Hieran mussten die deutschen Zionisten ihr mitgebrachtes geistig-ideologisches Rüstzeug einem Praxistest unterziehen und nach realpolitischen Antworten suchen.
Dem kometenhaften Aufstieg der weiterhin landsmannschaftlich geprägten Alija Chadascha folgte dann in den ersten Nachkriegsjahren ein ebenso rapider Zerfall. Einige Monate nach der Staatsgründung Israels löste sie sich dann sang- und klanglos auf und das Gros ihrer Aktivisten integrierte sich in das Parteiengefüge des neuen Staates. Der deutsche Zionismus als politische Bewegung kam nun wirklich an sein Ende. Diese Abhandlung wird somit zum einen den Kampf der deutschen Alijah um gesellschaftliche Anerkennung und politische Partizipation im Jischuw nachzeichnen und zum anderen eine geistig-ideologische Verortung des deutschen Zionismus in seiner letzten Phase vollziehen und Tendenzen der ideologischen Neuausrichtung offenlegen. Darüber hinaus werden in der Historiographie vorhandene Allgemeinplätze wie die fast allseits anerkannte These vom Scheitern der deutschen Zionisten in der neuen Heimat einer Überprüfung unterzogen. Die letzte vorhandene Leerstelle im wissenschaftlichen Kanon zur mehr als 50-jährigen Geschichte des deutschen Zionismus wird somit geschlossen.
Anthropogenic climate change alters the hydrological cycle. While certain areas experience more intense precipitation events, others will experience droughts and increased evaporation, affecting water storage in long-term reservoirs, groundwater, snow, and glaciers. High elevation environments are especially vulnerable to climate change, which will impact the water supply for people living downstream. The Himalaya has been identified as a particularly vulnerable system, with nearly one billion people depending on the runoff in this system as their main water resource. As such, a more refined understanding of spatial and temporal changes in the water cycle in high altitude systems is essential to assess variations in water budgets under different climate change scenarios.
However, not only anthropogenic influences have an impact on the hydrological cycle, but changes to the hydrological cycle can occur over geological timescales, which are connected to the interplay between orogenic uplift and climate change. However, their temporal evolution and causes are often difficult to constrain. Using proxies that reflect hydrological changes with an increase in elevation, we can unravel the history of orogenic uplift in mountain ranges and its effect on the climate.
In this thesis, stable isotope ratios (expressed as δ2H and δ18O values) of meteoric waters and organic material are combined as tracers of atmospheric and hydrologic processes with remote sensing products to better understand water sources in the Himalayas. In addition, the record of modern climatological conditions based on the compound specific stable isotopes of leaf waxes (δ2Hwax) and brGDGTs (branched Glycerol dialkyl glycerol tetraethers) in modern soils in four Himalayan river catchments was assessed as proxies of the paleoclimate and (paleo-) elevation. Ultimately, hydrological variations over geological timescales were examined using δ13C and δ18O values of soil carbonates and bulk organic matter originating from sedimentological sections from the pre-Siwalik and Siwalik groups to track the response of vegetation and monsoon intensity and seasonality on a timescale of 20 Myr.
I find that Rayleigh distillation, with an ISM moisture source, mainly controls the isotopic composition of surface waters in the studied Himalayan catchments. An increase in d-excess in the spring, verified by remote sensing data products, shows the significant impact of runoff from snow-covered and glaciated areas on the surface water isotopic values in the timeseries.
In addition, I show that biomarker records such as brGDGTs and δ2Hwax have the potential to record (paleo-) elevation by yielding a significant correlation with the temperature and surface water δ2H values, respectively, as well as with elevation. Comparing the elevation inferred from both brGDGT and δ2Hwax, large differences were found in arid sections of the elevation transects due to an additional effect of evapotranspiration on δ2Hwax. A combined study of these proxies can improve paleoelevation estimates and provide recommendations based on the results found in this study.
Ultimately, I infer that the expansion of C4 vegetation between 20 and 1 Myr was not solely dependent on atmospheric pCO2, but also on regional changes in aridity and seasonality from to the stable isotopic signature of the two sedimentary sections in the Himalaya (east and west).
This thesis shows that the stable isotope chemistry of surface waters can be applied as a tool to monitor the changing Himalayan water budget under projected increasing temperatures. Minimizing the uncertainties associated with the paleo-elevation reconstructions were assessed by the combination of organic proxies (δ2Hwax and brGDGTs) in Himalayan soil. Stable isotope ratios in bulk soil and soil carbonates showed the evolution of vegetation influenced by the monsoon during the late Miocene, proving that these proxies can be used to record monsoon intensity, seasonality, and the response of vegetation. In conclusion, the use of organic proxies and stable isotope chemistry in the Himalayas has proven to successfully record changes in climate with increasing elevation. The combination of δ2Hwax and brGDGTs as a new proxy provides a more refined understanding of (paleo-)elevation and the influence of climate.
The controlled dosage of substances from a device to its environment, such as a tissue or an organ in medical applications or a reactor, room, machinery or ecosystem in technical, should ideally match the requirements of the applications, e.g. in terms of the time point at which the cargo is released. On-demand dosage systems may enable such a desired release pattern, if the device contain suitable features that can translate external signals into a release function. This study is motivated by the opportunities arising from microsystems capable of an on-demand release and the contributions that geometrical design may have in realizing such features. The goals of this work included the design, fabrication, characterization and experimental proof-of-concept of geometry-assisted triggerable dosing effect (a) with a sequential dosing release and (b) in a self-sufficient dosage system. Structure-function relationships were addressed on the molecular, morphological and, with a particular attention, the device design level, which is on the micrometer scale. Models and/or computational tools were used to screen the parameter space and provide guidance for experiments.
Botulinum neurotoxin (BoNT) is produced by the anaerobic bacterium Clostridium botulinum. It is one of the most potent toxins found in nature and can enter motor neurons (MN) to cleave proteins necessary for neurotransmission, resulting in flaccid paralysis. The toxin has applications in both traditional and esthetic medicine. Since BoNT activity varies between batches despite identical protein concentrations, the activity of each lot must be assessed. The gold standard method is the mouse lethality assay, in which mice are injected with a BoNT dilution series to determine the dose at which half of the animals suffer death from peripheral asphyxia. Ethical concerns surrounding the use of animals in toxicity testing necessitate the creation of alternative model systems to measure the potency of BoNT.
Prerequisites of a successful model are that it is human specific; it monitors the complete toxic pathway of BoNT; and it is highly sensitive, at least in the range of the mouse lethality assay. One model system was developed by our group, in which human SIMA neuroblastoma cells were genetically modified to express a reporter protein (GLuc), which is packaged into neurosecretory vesicles, and which, upon cellular depolarization, can be released – or inhibited by BoNT – simultaneously with neurotransmitters. This assay has great potential, but includes the inherent disadvantages that the GLuc sequence was randomly inserted into the genome and the tumor cells only have limited sensitivity and specificity to BoNT. This project aims to improve these deficits, whereby induced pluripotent stem cells (iPSCs) were genetically modified by the CRISPR/Cas9 method to insert the GLuc sequence into the AAVS1 genomic safe harbor locus, precluding genetic disruption through non-specific integrations. Furthermore, GLuc was modified to associate with signal peptides that direct to the lumen of both large dense core vesicles (LDCV), which transport neuropeptides, and synaptic vesicles (SV), which package neurotransmitters. Finally, the modified iPSCs were differentiated into motor neurons (MNs), the true physiological target of BoNT, and hypothetically the most sensitive and specific cells available for the MoN-Light BoNT assay.
iPSCs were transfected to incorporate one of three constructs to direct GLuc into LDCVs, one construct to direct GLuc into SVs, and one “no tag” GLuc control construct. The LDCV constructs fused GLuc with the signal peptides for proopiomelanocortin (hPOMC-GLuc), chromogranin-A (CgA-GLuc), and secretogranin II (SgII-GLuc), which are all proteins found in the LDCV lumen. The SV construct comprises a VAMP2-GLuc fusion sequence, exploiting the SV membrane-associated protein synaptobrevin (VAMP2). The no tag GLuc expresses GLuc non-specifically throughout the cell and was created to compare the localization of vesicle-directed GLuc.
The clones were characterized to ensure that the GLuc sequence was only incorporated into the AAVS1 safe harbor locus and that the signal peptides directed GLuc to the correct vesicles. The accurate insertion of GLuc was confirmed by PCR with primers flanking the AAVS1 safe harbor locus, capable of simultaneously amplifying wildtype and modified alleles. The PCR amplicons, along with an insert-specific amplicon from candidate clones were Sanger sequenced to confirm the correct genomic region and sequence of the inserted DNA. Off-target integrations were analyzed with the newly developed dc-qcnPCR method, whereby the insert DNA was quantified by qPCR against autosomal and sex-chromosome encoded genes. While the majority of clones had off-target inserts, at least one on-target clone was identified for each construct.
Finally, immunofluorescence was utilized to localize GLuc in the selected clones. In iPSCs, the vesicle-directed GLuc should travel through the Golgi apparatus along the neurosecretory pathway, while the no tag GLuc should not follow this pathway. Initial analyses excluded the CgA-GLuc and SgII-GLuc clones due to poor quality protein visualization. The colocalization of GLuc with the Golgi was analyzed by confocal microscopy and quantified. GLuc was strongly colocalized with the Golgi in the hPOMC-GLuc clone (r = 0.85±0.09), moderately in the VAMP2-GLuc clone (r = 0.65±0.01), and, as expected, only weakly in the no tag GLuc clone (r = 0.44±0.10). Confocal microscopy of differentiated MNs was used to analyze the colocalization of GLuc with proteins associated with LDCVs and SVs, SgII in the hPOMC-GLuc clone (r = 0.85±0.08) and synaptophysin in the VAMP2-GLuc clone (r = 0.65±0.07). GLuc was also expressed in the same cells as the MN-associated protein, Islet1.
A significant portion of GLuc was found in the correct cell type and compartment. However, in the MoN-Light BoNT assay, the hPOMC-GLuc clone could not be provoked to reliably release GLuc upon cellular depolarization. The depolarization protocol for hPOMC-GLuc must be further optimized to produce reliable and specific release of GLuc upon exposure to a stimulus. On the other hand, the VAMP2-GLuc clone could be provoked to release GLuc upon exposure to the muscarinic and nicotinic agonist carbachol. Furthermore, upon simultaneous exposure to the calcium chelator EGTA, the carbachol-provoked release of GLuc could be significantly repressed, indicating the detection of GLuc was likely associated with vesicular fusion at the presynaptic terminal. The application of the VAMP2-GLuc clone in the MoN-Light BoNT assay must still be verified, but the results thus far indicate that this clone could be appropriate for the application of BoNT toxicity assessment.
Der Verfasser beschäftigt sich mit der Frage des Glaubensübertritts in einem Asylverfahren. Dabei nimmt er Zeitpunkt, Art und Umstände des Religionswechsels in den Blick. Ferner untersucht er, wie die sogenannte Konversion von den zuständigen Behörden und Gerichten zu behandeln und zu bewerten ist. Einführend gibt er einen Überblick zum völkerrechtlichen Schutz der Religions- und Weltanschauungsfreiheit sowie typischen Gefährdungslagen. Überdies befasst er sich mit den Rechtsgrundlagen des Asyl- und Flüchtlingsschutzrechts und stellt Verbindungen zum Flucht- und Verfolgungsgrund der Religion her.
Schwerpunkt bildet die Untersuchung der Verfahrensstadien, in denen die Konversion relevant wird. Dabei berücksichtigt der Verfasser die nationale und europäische Rechtsprechung. Von besonderer Bedeutung sind die Ausführungen zum Zusammenspiel von staatlichen Ermittlungspflichten und Mitwirkungsgeboten von Asylantragstellenden, wobei den Besonderheiten des grund- und menschenrechtlichen Mehrebenensystems Rechnung getragen wird.
Zentral sind ferner die Ausführungen zum Umgang mit Taufurkunden und sonstigen Bescheinigungen über die religiöse Überzeugung. Besonderes Gewicht liegt auf der verfassungsrechtlichen Stellung der Religionsgemeinschaften und der Frage, ob die Entscheidung einer Religionsgemeinschaft, ein neues Mitglied aufzunehmen, die Behörde im Asylverfahren bindet. Diesem Problem widmet sich der Verfasser unter Heranziehung der relevanten Literaturstimmen und einschlägigen Rechtsprechung.
Der rechtswissenschaftliche Beitrag bietet den beteiligten Akteuren nicht nur eine Einführung in das Themengebiet des Glaubensübertritts im Asylverfahren, sondern gibt den Lesenden auch eine praxistaugliche Handlungsunterstützung rund um die wichtigsten Fragen einer Konversion im Asylverfahren an die Hand. Praktische Bezüge entstehen beispielsweise dadurch, dass wichtige Impulse und Empfehlungen für eine gleichermaßen moderne, rechtsstaatliche und grundrechtsorientierte Verfahrensführung entwickelt werden.
Die vorliegende Studie beschreitet im religionswissenschaftlichen Kontext einen Weg zur Erforschung der Modifikation und Neuausrichtung eines einzelnen christlichen Bildmotivs, dessen Bildformel sich bis in die Gegenwart durchgesetzt hat.
Das Bildmotiv der Pietà wird in der Gegenwartskunst verstärkt als innovative Bildformel in politischen oder sozialen Kontexten verwendet, um existenzielle Lebenserfahrungen oder gesellschaftskritische, sowie politische Anklagen zu formulieren. Es erlebt einen Relaunch in der Medienberichterstattung, der Kunst, in Filmen oder der Alltagskultur. Künstler_innen und Fotojournalist_innen geben ihren Objekten vermehrt den Titel Pietà oder er wird ihnen von außen zuge-schrieben. Die Semantik dieses spezifischen Bildmotivs rührt offenbar an und kann bei Betrachtenden eine emotionale Gestimmtheit evozieren. Für diese Stu-die ist das Norm- und Wertesystem mit dem dahinter liegenden Tradierungs- und Transformationsprozess von Interesse. Bisher fehlt eine Monografie, in der die Zusammenhänge der Wiederbelebung eines primär christlichen Bildmotivs und der gegenwärtigen Bezüge zu Gewalt, Tod, Angst, Vergänglichkeit, dem Altern oder des Verlustes analysiert werden.
Im Vordergrund steht die Frage nach einer Modifikation bzw. Neuinterpretation dieser Ikonik. Das Aufzeigen eines möglichen dynamischen Entwicklungspro-zesses des Bildmotivs soll klären, welche veränderten Funktionen dem Pietà-Motiv in der Gegenwartskunst zugeschrieben werden. Über ein Set international renomierter, zeitgenössischer Künstler_innen werden eventuelle Veränderun-gen und ein damit verbundener gesellschaftlicher Bedeutungswandel seit dem 21. Jahrhundert analysiert.
Vor diesem Hintergrund ist die Frage nach einer religionsübergreifenden Wirk-mächtigkeit ikonischer Präsenz eines religiösen Bildmotivs in der Kunst und den Bildmedien von aktueller Relevanz. Diese Studie leistet einen exemplarischen Beitrag für die Affektforschung, die sich in den vergangenen Jahren vermehrt mit der Emotionsdarstellung und der Emotionsvermittlung in den audiovisuellen Medien befasst.
Die Arbeit untersucht die historische Entwicklung der Prätorianerpräfektur im 3. Jh. und bewertet die Funktion im Rahmen der kaiserlichen Herrschaftsordnung. Aufgrund der militärischen und politischen Krisen des 3. Jh. und der daran angepassten Herrschaftsstrategien erhielten die Prätorianerpräfekten umfassende Aufgaben. Die disparate Quellen- und Forschungslage beschreibt den Machtzuwachs und die Funktionsaufwertung der Prätorianerpräfekten in dieser wichtigen Phase aber sehr unterschiedlich. Ausgehend von den spätantiken Berichten geht die mehrheitliche Forschung zudem von einem Machtverlust der Prätorianerpräfekten unter Konstantin aus, dem eine Reformierung der Prätorianerpräfektur zugesprochen wird. Dieser Machtverlust lässt sich zeitlich und funktional jedoch nicht sicher bestimmen. In der Forschung wird dieser funktionale Abstieg oft mit der konstantinischen Demilitarisierung und Regionalisierung der Prätorianerpräfektur begründet. Bisher fehlte eine aktuelle Gesamtdarstellung, die die Prätorianerpräfektur in der Herrschaftsordnung des 3. Jh. bewertet und kategorisiert, um eine funktionale Abgrenzung zur klassischen Prätorianerpräfektur und zur Regionalpräfektur im 4. Jh. vorzunehmen.
Für diese funktionale Abgrenzung wurden in dieser Arbeit die Funktionsmerkmale und historischen Zusammenhänge der Prätorianerpräfektur im 3. Jh. abstrahiert und hieraus der Idealtypus einer „Kaiserlichen Magistratur“ gebildet. Die Ergebnisse dieser Abstrahierung zeigen die Prätorianerpräfektur im 3. Jh. als eine kommunikative Schnittstelle zwischen dem Kaiser und den leitenden Stellen der Zentral- und Provinzadministration. Die Prätorianerpräfektur übernahm hierbei eine leitende Stabsfunktion, die im Zusammenhang mit der höchsten inappellablen Gerichtsbarkeit die zweite Funktionsträgerebene nach dem Kaiser bildete. Diese Funktion übten die Prätorianerpräfekten ohne territoriale Bindung bis zum Ende der Tetrarchie bzw. bis zur frühen Herrschaft Konstantins aus.
Digital inclusion
(2021)
In this thesis, we tackle two social disruptions: recent refugee waves in Germany and the COVID-19 pandemic. We focus on the use of information and communication technology (ICT) as a key means of alleviating these disruptions and promoting social inclusion. As social disruptions typically lead to frustration and fragmentation, it is essential to ensure the social inclusion of individuals and societies during such times.
In the context of the social inclusion of refugees, we focus on the Syrian refugees who arrived in Germany as of 2015, as they form a large and coherent refugee community. In particular, we address the role of ICTs in refugees’ social inclusion and investigate how different ICTs (especially smartphones and social networks) can foster refugees’ integration and social inclusion. In the context of the COVID-19 pandemic, we focus on the widespread unconventional working model of work from home (WFH). Our research here centers on the main constructs of WFH and the key differences in WFH experiences based on personal characteristics such as gender and parental status.
We reveal novel insights through four well-established research methods: literature review, mixed methods, qualitative method, and quantitative method. The results of our research have been published in the form of eight articles in major information systems venues and journals. Key results from the refugee research stream include the following: Smartphones represent a central component of refugee ICT use; refugees view ICT as a source of information and power; the social connectedness of refugees is strongly correlated with their Internet use; refugees are not relying solely on traditional methods to learn the German language or pursue further education; the ability to use smartphones anytime and anywhere gives refugees an empowering feeling of global connectedness; and ICTs empower refugees on three levels (community participation, sense of control, and self-efficacy).
Key insights from the COVID-19 WFH stream include: Gender and the presence of children under the age of 18 affect workers’ control over their time, technology usefulness, and WFH conflicts, while not affecting their WFH attitudes; and both personal and technology-related factors affect an individual’s attitude toward WFH and their productivity. Further insights are being gathered at the time of submitting this thesis.
This thesis contributes to the discussion within the information systems community regarding how to use different ICT solutions to promote the social inclusion of refugees in their new communities and foster an inclusive society. It also adds to the growing body of research on COVID-19, in particular on the sudden workplace transformation to WFH. The insights gathered in this thesis reveal theoretical implications and future opportunities for research in the field of information systems, practical implications for relevant stakeholders, and social implications related to the refugee crisis and the COVID-19 pandemic that must be addressed.
One of the key challenges in modern Facility Management (FM) is to digitally reflect the current state of the built environment, referred to as-is or as-built versus as-designed representation. While the use of Building Information Modeling (BIM) can address the issue of digital representation, the generation and maintenance of BIM data requires a considerable amount of manual work and domain expertise. Another key challenge is being able to monitor the current state of the built environment, which is used to provide feedback and enhance decision making. The need for an integrated solution for all data associated with the operational life cycle of a building is becoming more pronounced as practices from Industry 4.0 are currently being evaluated and adopted for FM use. This research presents an approach for digital representation of indoor environments in their current state within the life cycle of a given building. Such an approach requires the fusion of various sources of digital data. The key to solving such a complex issue of digital data integration, processing and representation is with the use of a Digital Twin (DT). A DT is a digital duplicate of the physical environment, states, and processes. A DT fuses as-designed and as-built digital representations of built environment with as-is data, typically in the form of floorplans, point clouds and BIMs, with additional information layers pertaining to the current and predicted states of an indoor environment or a complete building (e.g., sensor data). The design, implementation and initial testing of prototypical DT software services for indoor environments is presented and described. These DT software services are implemented within a service-oriented paradigm, and their feasibility is presented through functioning and tested key software components within prototypical Service-Oriented System (SOS) implementations. The main outcome of this research shows that key data related to the built environment can be semantically enriched and combined to enable digital representations of indoor environments, based on the concept of a DT. Furthermore, the outcomes of this research show that digital data, related to FM and Architecture, Construction, Engineering, Owner and Occupant (AECOO) activity, can be combined, analyzed and visualized in real-time using a service-oriented approach. This has great potential to benefit decision making related to Operation and Maintenance (O&M) procedures within the scope of the post-construction life cycle stages of typical office buildings.
Selfsustained oscillations are some of the most commonly observed phenomena in biological systems. They emanate from non-linear systems in a heterogeneous environment and can be described by the theory of dynamical systems. Part of this theory considers reduced models of the oscillator dynamics by means of amplitudes and a phase variable. Such variables are highly attractive for theoretical and experimental studies. Theoretically these variables correspond to an integrable linearization of the generally non-linear system. Experimentally, there exist well established approaches to extract phases from oscillator signals. Notably, one can define phase models also for networks of oscillators. One highly active field examines effects of non-local coupling among oscillators, which is thought to play a key role in networks with strong coupling. The dissertation introduces and expands the knowledge about high-order phase coupling in networks of oscillators. Mathematical calculations consider the Stuart-Landau oscillator. A novel phase estimation scheme for direct observations of an oscillator dynamics is introduced based on numerics. A numerical study of high-order phase coupling applies a Fourier fit for the Stuart-Landau and for the van-der-Pol oscillator. The numerical approach is finally tested on observation-based phase estimates of the Morris-Lecar neuron. A popular approach for the construction of phases from signals is based on phase demodulation by means of the Hilbert transform. Generally, observations of oscillations contain a small and generic variation of their amplitude. The work presents a way to quantify how much the variations of signal amplitude spoil a phase demodulation procedure. For the ideal case of phase modulated signals, amplitude modulations vanish. However, the Hilbert transform produces artificial variations of the reconstructed amplitude even in this case. The work proposes a novel procedure called Iterative Hilbert Transform Embedding to obtain an optimal demodulation of signals. The text presents numerous examples and tests of application for the method, covering multicomponent signals, observables of highly stable limit cycle oscillations and noisy phase dynamics. The numerical results are supported by a spectral theory of convergence for weak phase modulations.
Eukaryotic cells can be regarded as complex microreactors capable of performing various biochemical reactions in parallel which are necessary to sustain life. An essential prerequisite for these complex metabolic reactions to occur is the evolution of lipid membrane-bound organelles enabling compartmental- ization of reactions and biomolecules. This allows for a spatiotemporal control over the metabolic reactions within the cellular system. Intracellular organi- zation arising due to compartmentalization is a key feature of all living cells and has inspired synthetic biologists to engineer such systems with bottom-up approaches.
Artificial cells provide an ideal platform to isolate and study specific re- actions without the interference from the complex network of biomolecules present in biological cells. To mimic the hierarchical architecture of eukaryotic cells, multi-compartment assemblies with nested liposomal structures also re- ferred to as multi-vesicular vesicles (MVVs) have been widely adopted. Most of the previously reported multi-compartment systems adopt bulk method- ologies which suffer from low yield and poor control over size. Microfluidic strategies help circumvent these issues and facilitate a high-throughput and robust technique to assemble MVVs of uniform size distribution.
In this thesis, firstly, the bulk methodologies are explored to build MVVs and implement a synthetic signalling cascade. Next, a polydimethylsiloxane (PDMS)-based microfluidic platform is introduced to build MVVs and the significance of PEGylated lipids for the successful encapsulation of inner com- partments to generate stable multi-compartment systems is highlighted.
Next, a novel two-inlet channel PDMS-based microfluidic device to create MVVs encompassing a three-step enzymatic reaction cascade is presented. A directed reaction pathway comprising of the enzymes α-glucosidase (α-Glc), glucose oxidase (GOx), and horseradish peroxidase (HRP) spanning across three compartments via reconstitution of size-selective membrane proteins is described. Furthermore, owing to the monodispersity of our MVVs due to microfluidic strategies, this platform is employed to study the effect of com- partmentalization on reaction kinetics.
Further integration of cell-free expression module into the MVVs would allow for gene-mediated signal transduction within artificial eukaryotic cells. Therefore, the chemically inducible cell-free expression of a membrane protein alpha-hemolysin and its further reconstitution into liposomes is carried out.
In conclusion, the present thesis aims to build artificial eukaryotic cells to achieve size-selective chemical communication that also show potential for applications as micro reactors and as vehicles for drug delivery.
Generative adversarial networks (GANs) have been broadly applied to a wide range of application domains since their proposal. In this thesis, we propose several methods that aim to tackle different existing problems in GANs. Particularly, even though GANs are generally able to generate high-quality samples, the diversity of the generated set is often sub-optimal. Moreover, the common increase of the number of models in the original GANs framework, as well as their architectural sizes, introduces additional costs. Additionally, even though challenging, the proper evaluation of a generated set is an important direction to ultimately improve the generation process in GANs. We start by introducing two diversification methods that extend the original GANs framework to multiple adversaries to stimulate sample diversity in a generated set. Then, we introduce a new post-training compression method based on Monte Carlo methods and importance sampling to quantize and prune the weights and activations of pre-trained neural networks without any additional training. The previous method may be used to reduce the memory and computational costs introduced by increasing the number of models in the original GANs framework. Moreover, we use a similar procedure to quantize and prune gradients during training, which also reduces the communication costs between different workers in a distributed training setting. We introduce several topology-based evaluation methods to assess data generation in different settings, namely image generation and language generation. Our methods retrieve both single-valued and double-valued metrics, which, given a real set, may be used to broadly assess a generated set or separately evaluate sample quality and sample diversity, respectively. Moreover, two of our metrics use locality-sensitive hashing to accurately assess the generated sets of highly compressed GANs. The analysis of the compression effects in GANs paves the way for their efficient employment in real-world applications. Given their general applicability, the methods proposed in this thesis may be extended beyond the context of GANs. Hence, they may be generally applied to enhance existing neural networks and, in particular, generative frameworks.
There is a general consensus that diverse ecological communities are better equipped to adapt to changes in their environment, but our understanding of the mechanisms by which they do so remains incomplete. Accurately predicting how the global biodiversity crisis affects the functioning of ecosystems, and the services they provide, requires extensive knowledge about these mechanisms.
Mathematical models of food webs have been successful in uncovering many aspects of the link between diversity and ecosystem functioning in small food web modules, containing at most two adaptive trophic levels. Meaningful extrapolation of this understanding to the functioning of natural food webs remains difficult, due to the presence of complex interactions that are not always accurately captured by bitrophic descriptions of food webs. In this dissertation, we expand this approach to tritrophic food web models by including the third trophic level. Using a functional trait approach, coexistence of all species is ensured using fitness-balancing trade-offs. For example, the defense-growth trade-off implies that species may be defended against predation, but this defense comes at the cost of a lower maximal growth rate. In these food webs, the functional diversity on a given trophic level can be varied by modifying the trait differences between the species on that level.
In the first project, we find that functional diversity promotes high biomass on the top level, which, in turn, leads to a reduction in the temporal variability due to compensatory dynamical patterns governed by the top level. Next, these results are generalized by investigating the average behavior of tritrophic food webs, for wide intervals of all parameters describing species interactions in the food web. We find that the diversity on the top level is most important for determining the biomass and temporal variability of all other trophic levels, and show how biomass is only transferred efficiently to the top level when diversity is high everywhere in the food web. In the third project, we compare the response of a simple food chain against a nutrient pulse perturbation, to that of a food web with diversity on every trophic level. By joint consideration of the resistance, resilience, and elasticity, we uncover that the response is efficiently buffered when biomass on the top level is high, which is facilitated by functional diversity on every trophic level in the food web. Finally, in the fourth project, we show that even in a simple consumer-resource model without any diversity, top-down control on the intermediate level frequently causes the phase difference between the intermediate and basal level to deviate from the quarter-cycle lag rule. By adding a top predator, we show that these deviations become even more likely, and anti-phase cycles are often observed.
The combined results of these projects show how the properties of the top trophic level, including its functional diversity, have a decisive influence on the functioning of tritrophic food webs from a mechanistic perspective. Because top species are often among the most vulnerable to extinction, our results emphasize the importance of their conservation in ecosystem management and restoration strategies.
Kenya and Uganda are amongst the countries that, for different historical, political, and economic reasons, have embarked on law reform processes as regards to citizenship. In 2009, Uganda made provisions in its laws to allow citizens to have dual citizenship while Kenya’s 2010 constitution similarly introduced it, and at the same time, a general prohibition on dual citizenship was lifted, that is, a ban on state officers, including the President and Deputy President, being dual nationals (Manby, 2018).
Against this background, I analysed the reasons for which these countries that previously held stringent laws and policies against dual citizenship, made a shift in a close time proximity. Given their geo-political roles, location, regional, continental, and international obligations, I conducted a comparative study on the processes, actors, impact, and effect. A specific period of 2000 to 2010 was researched, that is, from when the debates for law reforms emerged, to the processes being implemented, the actors, and the implications.
According to Rubenstein (2000, p. 520), citizenship is observed in terms of “political institutions” that are free to act according to the will of, in the interests of, or with authority over, their citizenry. Institutions are emergent national or international, higher-order factors above the individual spectrum, having the interests and political involvement of their actors without requiring recurring collective mobilisation or imposing intervention to realise these regularities. Transnational institutions are organisations with authority beyond single governments. Given their International obligations, I analysed the role of the UN, AU, and EAC in influencing the citizenship debates and reforms in Kenya and Uganda. Further, non-state actors, such as civil society, were considered.
Veblen, (1899) describes institutions as a set of settled habits of thought common to the generality of men. Institutions function only because the rules involved are rooted in shared habits of thought and behaviour although there is some ambiguity in the definition of the term “habit”. Whereas abstracts and definitions depend on different analytical procedures, institutions restrain some forms of action and facilitate others. Transnational institutions both restrict and aid behaviour. The famous “invisible hand” is nothing else but transnational institutions. Transnational theories, as applied to politics, posit two distinct forms that are of influence over policy and political action (Veblen, 1899). This influence and durability of institutions is “a function of the degree to which they are instilled in political actors at the individual or organisational level, and the extent to which they thereby “tie up” material resources and networks. Against this background, transitional networks with connection to Kenya and Uganda were considered alongside the diaspora from these two countries and their role in the debate and reforms on Dual citizenship.
Sterian (2013, p. 310) notes that Nation states may be vulnerable to institutional influence and this vulnerability can pose a threat to a nation’s autonomy, political legitimacy, and to the democratic public law. Transnational institutions sometimes “collide with the sovereignty of the state when they create new structures for regulating cross-border relationships”. However, Griffin (2003) disagrees that transnational institutional behaviour is premised on the principles of neutrality, impartiality, and independence. Transnational institutions have become the main target of the lobby groups and civil society, consequently leading to excessive politicisation. Kenya and Uganda are member states not only of the broader African union but also of the E.A.C which has adopted elements of socio-economic uniformity. Therefore, in the comparative analysis, I examine the role of the East African Community and its partners in the dual citizenship debate on the two countries.
I argue in the analysis that it is not only important to be a citizen within Kenya or Uganda but also important to discover how the issue of dual citizenship is legally interpreted within the borders of each individual nation-state. In light of this discussion, I agree with Mamdani’s definition of the nation-state as a unique form of power introduced in Africa by colonial powers between 1880 and 1940 whose outcomes can be viewed as “debris of a modernist postcolonial project, an attempt to create a centralised modern state as the bearer of Westphalia sovereignty against the background of indirect rule” (Mamdani, 1996, p. xxii). I argue that this project has impacted the citizenship debate through the adopted legal framework of post colonialism, built partly on a class system, ethnic definitions, and political affiliation. I, however, insist that the nation-state should still be a vital custodian of the citizenship debate, not in any way denying the individual the rights to identity and belonging. The question then that arises is which type of nation-state? Mamdani (1996, p. 298) asserts that the core agenda that African states faced at independence was threefold: deracialising civil society; detribalising the native authority; and developing the economy in the context of unequal international relations. Post-independence governments grappled with overcoming the citizen and subject dichotomy through either preserving the customary in the name of “defending tradition against alien encroachment or abolishing it in the name of overcoming backwardness and embracing triumphant modernism”. Kenya and Uganda are among countries that have reformed their citizenship laws attesting to Mamdani’s latter assertion.
Mamdani’s (1996) assertions on how African states continue to deal with the issue of citizenship through either the defence of tradition against subjects or abolishing it in the name of overcoming backwardness and acceptance of triumphant modernism are based on the colonial legal theory and the citizen-subject dichotomy within Africa communities. To further create a wider perspective on legal theory, I argue that those assertions above, point to the historical divergence between the republican model of citizenship, which places emphasis on political agency as envisioned in Rousseau´s social contract, as opposed to the liberal model of citizenship, which stresses the legal status and protection (Pocock, 1995).
I, therefore, compare the contexts of both Kenya and Uganda, the actors, the implications of transnationalism and post-nationalism, on the citizens, the nation-state and the region. I conclude by highlighting the shortcomings in the law reforms that allowed for dual citizenship, further demonstrating an urgent need to address issues, such as child statelessness, gender nationality laws, and the rights of dual citizens. Ethnicity, a weak nation state, and inconsistent citizenship legal reforms are closely linked to the historical factors of both countries. I further indicate the economic and political incentives that influenced the reform.
Keywords: Citizenship, dual citizenship, nation state, republicanism, liberalism, transnationalism, post-nationalism
Compound values are not universally supported in virtual machine (VM)-based programming systems and languages. However, providing data structures with value characteristics can be beneficial. On one hand, programming systems and languages can adequately represent physical quantities with compound values and avoid inconsistencies, for example, in representation of large numbers. On the other hand, just-in-time (JIT) compilers, which are often found in VMs, can rely on the fact that compound values are immutable, which is an important property in optimizing programs. Considering this, compound values have an optimization potential that can be put to use by implementing them in VMs in a way that is efficient in memory usage and execution time. Yet, optimized compound values in VMs face certain challenges: to maintain consistency, it should not be observable by the program whether compound values are represented in an optimized way by a VM; an optimization should take into account, that the usage of compound values can exhibit certain patterns at run-time; and that necessary value-incompatible properties due to implementation restrictions should be reduced.
We propose a technique to detect and compress common patterns of compound value usage at run-time to improve memory usage and execution speed. Our approach identifies patterns of frequent compound value references and introduces abbreviated forms for them. Thus, it is possible to store multiple inter-referenced compound values in an inlined memory representation, reducing the overhead of metadata and object references. We extend our approach by a notion of limited mutability, using cells that act as barriers for our approach and provide a location for shared, mutable access with the possibility of type specialization. We devise an extension to our approach that allows us to express automatic unboxing of boxed primitive data types in terms of our initial technique. We show that our approach is versatile enough to express another optimization technique that relies on values, such as Booleans, that are unique throughout a programming system. Furthermore, we demonstrate how to re-use learned usage patterns and optimizations across program runs, thus reducing the performance impact of pattern recognition.
We show in a best-case prototype that the implementation of our approach is feasible and can also be applied to general purpose programming systems, namely implementations of the Racket language and Squeak/Smalltalk. In several micro-benchmarks, we found that our approach can effectively reduce memory consumption and improve execution speed.
Die Dissertation legt ihren Schwerpunkt auf die synchronische und diachronische Variation im Gebrauch der französischen Kausalkonjunktion parce que sowie auf die Interaktion mit den außersprachlichen Variablen Alter und sozioprofessionelle Kategorie. Basierend auf vorausgehenden makrodiachronischen Studien, die Anhaltspunkte dafür liefern, dass die Konjunktion einen Prozess der Pragmatikalisierung durchlaufen hat und weiterhin durchläuft, wurde ein Untersuchungskorpus von 56 Interviews aus den diachronisch distinkten Korpora ESLO1, ESLO2 und LangAge extrahiert. Dieses Untersuchungskorpus diente als Grundlage für Panelstudien und Trendstudien, die darauf ausgerichtet waren, die Pragmatikalisierung von parce que aus einem mikrodiachronischen Gesichtspunkt zu verifizieren. Zusätzlich zu der diachronischen Perspektive wurde eine synchronische Perspektive eingenommen, um die Variation im Gebrauch der Konjunktion so einem diachronischen Phänomen wie dem age grading oder der apparent time zuordnen zu können. Ausgehend von der Theorie der Konstruktionsgrammatik wurden parce que enthaltende Konstruktionen bottom-up annotiert und in fünf Pragmatikalitätsgrade kategorisiert (pra0–pra4). Diese wurden anschließend quantifiziert und in Abhängigkeit des Geburtsjahres und der sozioprofessionellen Kategorie der (männlichen) Sprecher mithilfe mehrerer R-Modelle wie ctrees, trees, lm, hclust und kmeans analysiert.
Die Frequenzentwicklung der Pragmatikalitätsgrade bestätigte die Pragmatikalisierungshypothese in einem mikrodiachronischen Rahmen. Zudem konnte ein quantitativer Rückgang im Gebrauch der Konstruktionen am nicht- oder weniger pragmatikalisierten (pra0, pra1) Pol festgestellt werden, während Verwendungsweisen höherer Pragmatikalisierungsgrade (pra2–pra4) über 40 Jahre vergleichsweise stabil blieben.
Obwohl für pra2 kein signifikanter Wandel hervortrat, wies dessen Entwicklung bei den Sprechern im mittleren Lebensalter sowie das synchronische Muster in Abhängigkeit von Alter (oder Geburtsjahr) und von sozioprofessioneller Kategorie dennoch in Richtung einer zugrundeliegenden diachronischen Variation. Diese könnte als ein durch die sozialen Transformationen der 1960er und 1970er Jahre katalysiertes Phänomen des age grading interpretiert werden. Für die näher am pragmatischen Pol situierten Gebrauchsweisen (pra3 und pra4) konnte keine klare Tendenz ermittelt werden.
Die Ergebnisse fordern diachronische Konzepte wie age grading und apparent time heraus, indem sie die Simplizität der zugrundeliegenden Mechanismen sowie die gängigen Methoden, diese zu identifizieren, infrage stellen.
To achieve a sustainable energy economy, it is necessary to turn back on the combustion of fossil fuels as a means of energy production and switch to renewable sources. However, their temporal availability does not match societal consumption needs, meaning that renewably generated energy must be stored in its main generation times and allocated during peak consumption periods. Electrochemical energy storage (EES) in general is well suited due to its infrastructural independence and scalability. The lithium ion battery (LIB) takes a special place, among EES systems due to its energy density and efficiency, but the scarcity and uneven geological occurrence of minerals and ores vital for many cell components, and hence the high and fluctuating costs will decelerate its further distribution.
The sodium ion battery (SIB) is a promising successor to LIB technology, as the fundamental setup and cell chemistry is similar in the two systems. Yet, the most widespread negative electrode material in LIBs, graphite, cannot be used in SIBs, as it cannot store sufficient amounts of sodium at reasonable potentials. Hence, another carbon allotrope, non-graphitizing or hard carbon (HC) is used in SIBs. This material consists of turbostratically disordered, curved graphene layers, forming regions of graphitic stacking and zones of deviating layers, so-called internal or closed pores.
The structural features of HC have a substantial impact of the charge-potential curve exhibited by the carbon when it is used as the negative electrode in an SIB. At defects and edges an adsorption-like mechanism of sodium storage is prevalent, causing a sloping voltage curve, ill-suited for the practical application in SIBs, whereas a constant voltage plateau of relatively high capacities is found immediately after the sloping region, which recent research attributed to the deposition of quasimetallic sodium into the closed pores of HC.
Literature on the general mechanism of sodium storage in HCs and especially the role of the closed pore is abundant, but the influence of the pore geometry and chemical nature of the HC on the low-potential sodium deposition is yet in an early stage. Therefore, the scope of this thesis is to investigate these relationships using suitable synthetic and characterization methods. Materials of precisely known morphology, porosity, and chemical structure are prepared in clear distinction to commonly obtained ones and their impact on the sodium storage characteristics is observed. Electrochemical impedance spectroscopy in combination with distribution of relaxation times analysis is further established as a technique to study the sodium storage process, in addition to classical direct current techniques, and an equivalent circuit model is proposed to qualitatively describe the HC sodiation mechanism, based on the recorded data. The obtained knowledge is used to develop a method for the preparation of closed porous and non-porous materials from open porous ones, proving not only the necessity of closed pores for efficient sodium storage, but also providing a method for effective pore closure and hence the increase of the sodium storage capacity and efficiency of carbon materials.
The insights obtained and methods developed within this work hence not only contribute to the better understanding of the sodium storage mechanism in carbon materials of SIBs, but can also serve as guidance for the design of efficient electrode materials.
Elucidating the molecular basis of enhanced growth in the Arabidopsis thaliana accession Bur-0
(2021)
The life cycle of flowering plants is a dynamic process that involves successful passing through several developmental phases and tremendous progress has been made to reveal cellular and molecular regulatory mechanisms underlying these phases, morphogenesis, and growth. Although several key regulators of plant growth or developmental phase transitions have been identified in Arabidopsis, little is known about factors that become active during embryogenesis, seed development and also during further postembryonic growth. Much less is known about accession-specific factors that determine plant architecture and organ size. Bur-0 has been reported as a natural Arabidopsis thaliana accession with exceptionally big seeds and a large rosette; its phenotype makes it an interesting candidate to study growth and developmental aspects in plants, however, the molecular basis underlying this big phenotype remains to be elucidated. Thus, the general aim of this PhD project was to investigate and unravel the molecular mechanisms underlying the big phenotype in Bur-0.
Several natural Arabidopsis accessions and late flowering mutant lines were analysed in this study, including Bur-0. Phenotypes were characterized by determining rosette size, seed size, flowering time, SAM size and growth in different photoperiods, during embryonic and postembryonic development. Our results demonstrate that Bur-0 stands out as an interesting accession with simultaneously larger rosettes, larger SAM, later flowering phenotype and larger seeds, but also larger embryos. Interestingly, inter-accession crosses (F1) resulted in bigger seeds than the parental self-crossed accessions, particularly when Bur-0 was used as the female parental genotype, suggesting parental effects on seed size that might be maternally controlled. Furthermore, developmental stage-based comparisons revealed that the large embryo size of Bur-0 is achieved during late embryogenesis and the large rosette size is achieved during late postembryonic growth. Interestingly, developmental phase progression analyses revealed that from germination onwards, the length of developmental phases during postembryonic growth is delayed in Bur-0, suggesting that in general, the mechanisms that regulate developmental phase progression are shared across developmental phases.
On the other hand, a detailed physiological characterization in different tissues at different developmental stages revealed accession-specific physiological and metabolic traits that underlie accession-specific phenotypes and in particular, more carbon resources during embryonic and postembryonic development were found in Bur-0, suggesting an important role of carbohydrates in determination of the bigger Bur-0 phenotype. Additionally, differences in the cellular organization, nuclei DNA content, as well as ploidy level were analyzed in different tissues/cell types and we found that the large organ size in Bur-0 can be mainly attributed to its larger cells and also to higher cell proliferation in the SAM, but not to a different ploidy level.
Furthermore, RNA-seq analysis of embryos at torpedo and mature stage, as well as SAMs at vegetative and floral transition stage from Bur-0 and Col-0 was conducted to identify accession-specific genetic determinants of plant phenotypes, shared across tissues and developmental stages during embryonic and postembryonic growth. Potential candidate genes were identified and further validation of transcriptome data by expression analyses of candidate genes as well as known key regulators of organ size and growth during embryonic and postembryonic development confirmed that the high confidence transcriptome datasets generated in this study are reliable for elucidation of molecular mechanisms regulating plant growth and accession-specific phenotypes in Arabidopsis.
Taken together, this PhD project contributes to the plant development research field providing a detailed analysis of mechanisms underlying plant growth and development at different levels of biological organization, focusing on Arabidopsis accessions with remarkable phenotypical differences. For this, the natural accession Bur-0 was an ideal outlier candidate and different mechanisms at organ and tissue level, cell level, metabolism, transcript and gene expression level were identified, providing a better understanding of different factors involved in plant growth regulation and mechanisms underlying different growth patterns in nature.
Ground-based astronomy is set to employ next-generation telescopes with apertures larger than 25 m in diameter before this decade is out. Such giant telescopes observe their targets through a larger patch of turbulent atmosphere, demanding that most of the instruments behind them must also grow larger to make full use of the collected stellar flux. This linear scaling in size greatly complicates the design of astronomical instrumentation, inflating their cost quadratically. Adaptive optics (AO) is one approach to circumvent this scaling law, but it can only be done to an extent before the cost of the corrective system itself overwhelms that of the instrument or even that of the telescope. One promising technique for miniaturizing the instruments and thus driving down their cost is to replace some, or all, of the free space bulk optics in the optical train with integrated photonic components.
Photonic devices, however, do their work primarily in single-mode waveguides, and the atmospherically-distorted starlight must first be efficiently coupled into them if they are to outperform their bulk optic counterparts. This is doable by two means: AO systems can again help control the angular size and motion of seeing disks to the point where they will couple efficiently into astrophotonic components, but this is only feasible for the brightest of objects and over limited fields of view. Alternatively, tapered fiber devices known as photonic lanterns — with their ability to convert multimode into single-mode optical fields — can be used to feed speckle patterns into single-mode integrated optics. They, nonetheless, must conserve the degrees of freedom, and the number of output waveguides will quickly grow out of control for uncorrected large telescopes. An AO-assisted photonic lantern fed by a partially corrected wavefront presents a compromise that can have a manageable size if the trade-off between the two methods is chosen carefully. This requires end-to-end simulations that take into account all the subsystems upstream of the astrophotonic instrument, i.e., the atmospheric layers, the telescope, the AO system, and the photonic lantern, before a decision can be made on sizing the multiplexed integrated instrument.
The numerical models that simulate atmospheric turbulence and AO correction are presented in this work. The physics and models for optical fibers, arrays of waveguides, and photonic lanterns are also provided. The models are on their own useful in understanding the behavior of the individual subsystems involved and are also used together to compute the optimum sizing of photonic lanterns for feeding astrophotonic instruments. Additionally, since photonic lanterns are a relatively new concept, two novel applications are discussed for them later in this thesis: the use of mode-selective photonic lanterns (MSPLs) to reduce the multiplicity of multiplexed integrated instruments and the combination of photonic lanterns with discrete beam combiners (DBCs) to retrieve the modal content in an optical waveguide.
Smart contracts promise to reform the legal domain by automating clerical and procedural work, and minimizing the risk of fraud and manipulation. Their core idea is to draft contract documents in a way which allows machines to process them, to grasp the operational and non-operational parts of the underlying legal agreements, and to use tamper-proof code execution alongside established judicial systems to enforce their terms. The implementation of smart contracts has been largely limited by the lack of an adequate technological foundation which does not place an undue amount of trust in any contract party or external entity. Only recently did the emergence of Decentralized Applications (DApps) change this: Stored and executed via transactions on novel distributed ledger and blockchain networks, powered by complex integrity and consensus protocols, DApps grant secure computation and immutable data storage while at the same time eliminating virtually all assumptions of trust.
However, research on how to effectively capture, deploy, and most of all enforce smart contracts with DApps in mind is still in its infancy. Starting from the initial expression of a smart contract's intent and logic, to the operation of concrete instances in practical environments, to the limits of automatic enforcement---many challenges remain to be solved before a widespread use and acceptance of smart contracts can be achieved.
This thesis proposes a model-driven smart contract management approach to tackle some of these issues. A metamodel and semantics of smart contracts are presented, containing concepts such as legal relations, autonomous and non-autonomous actions, and their interplay. Guided by the metamodel, the notion and a system architecture of a Smart Contract Management System (SCMS) is introduced, which facilitates smart contracts in all phases of their lifecycle. Relying on DApps in heterogeneous multi-chain environments, the SCMS approach is evaluated by a proof-of-concept implementation showing both its feasibility and its limitations.
Further, two specific enforceability issues are explored in detail: The performance of fully autonomous tamper-proof behavior with external off-chain dependencies and the evaluation of temporal constraints within DApps, both of which are essential for smart contracts but challenging to support in the restricted transaction-driven and closed environment of blockchain networks. Various strategies of implementing or emulating these capabilities, which are ultimately applicable to all kinds of DApp projects independent of smart contracts, are presented and evaluated.
Das Professionswissen einer Lehrkraft gilt als Voraussetzung für erfolgreichen Unterricht. Trotz großer Unterschiede der Professionswissensmodelle ist die Forschung sich aus theoretischer Sicht weitestgehend einig darüber, dass das fachliche und fachdidaktische Wissen wichtige Bestandteile des Professionswissens und damit bedeutsam für Unterrichtserfolg sind. Zurecht gibt es daher die Forderung, dass Lehrkräfte unter anderem ein ausgeprägtes fachliches Wissen benötigen, das sie in den verschiedensten Situationen ihres Berufslebens, wie z.B. dem Erklären von Konzepten und dem Planen von Unterricht einsetzen. Die Forschung untersucht aus diesem Grund schon seit über 30 Jahren die Bedeutung des Fachwissens einer Lehrkraft. Dabei werden die Betrachtungen des Fachwissens immer differenzierter. So hat sich in vielen Forschungsansätzen der Physikdidaktik eine Dreiteilung des Fachwissens in schulisches Wissen, vertieftes Schulwissen und universitäres Wissen durchgesetzt. Während das Schulwissen als jenes Wissen verstanden wird, das in der Schule gelehrt und gelernt wird, beschreibt die Facette des universitären Wissens die stark akademisch geprägte Wissensform, die zukünftige Physiklehrkräfte in den Fachveranstaltungen an der Universität erwerben sollen. Das vertiefte Schulwissen ist hingegen eine spezielle Form des fachlichen Wissens, die aus Forschungssicht als besonders wichtig für Lehrkräfte angenommen wird. Zusammengenommen sollen angehende Physiklehrkräfte alle genannten Facetten des Fachwissens, also Schulwissen, vertieftes Schulwissen und universitäres Wissen, während des Lehramtsstudiums Physik erwerben. Neben dem fachlichen Wissen benötigt eine Lehrkraft als wichtigen Bestandteil des Professionswissens auch noch fachdidaktisches Wissen, welches ebenfalls während des Studiums erworben werden soll. Gleichzeitig geht man in der Forschung davon aus, dass für die Entwicklung des fachdidaktischen Wissens fachliches Wissen eine Grundvoraussetzung ist. Es ist jedoch empirisch nahezu ungeklärt, wie sich das beschriebene Fachwissen und das fachdidaktische Wissen im Verlauf des Lehramtsstudiums Physik entwickeln oder wie sich diese Wissensformen gegenseitig beeinflussen. Darüber hinaus ist unklar, welche Herausforderungen sich aus der Leistungsheterogenität der Studienanfänger:innen ergeben. Bisherige Untersuchungen aus der Studienerfolgsforschung legen nahe, dass besonders das Vorwissen prognostisch für Studienerfolg ist. Die vorliegende Arbeit untersucht daher zunächst, wie sich das fachliche Wissen (Schulwissen, vertieftes Schulwissen, universitäres Wissen) von Lehrkräften im Verlauf des Bachelor- und Masterstudiums entwickelt. In einem nächsten Schritt wurde untersucht, wie sich Studierende mit einem geringen, mittleren bzw. hohen Fachwissen zum Beginn des Studiums über das Bachelorstudium entwickeln. Darüber hinaus wurde die Entwicklung des fachdidaktischen Wissens betrachtet und Zusammenhänge zum fachlichen Wissen in den Blick genommen. Durchgeführt wurde die vorliegende Studie im Längsschnitt im Verlauf von drei Jahren an 11 Hochschulen mit 145 Bachelorstudierenden und 73 Masterstudierenden. Die Bachelorstudierenden haben jährlich an einer Testung des fachlichen und fachdidaktischen Wissens teilgenommen. Die Masterstudierenden nahmen jeweils vor und nach einem einsemestrigen Schulpraktikum an den Erhebungen teil. Zur Testung wurde jeweils ein schriftliches Testinstrument verwendet. Das weiterentwickelte Fachwissensinstrument wurde zusätzlich ausführlichen Validierungsuntersuchungen unterzogen. Die Ergebnisse zeigen, dass sich das Schulwissen, das vertiefte Schulwissen und das universitäre Wissen sowohl im Bachelor- als auch Masterstudium signifikant weiterentwickeln. Auch für das fachdidaktische Wissen können signifikante Zuwächse über das Bachelor- und Masterstudium berichtet werden. Interessant ist dabei, dass eine starke Korrelation zwischen dem fachlichen Wissen zu Beginn des Studiums und dem Zuwachs des fachdidaktischen Wissens vom ersten zum dritten Semester erkennbar ist. Es liegen also erste Hinweise dafür vor, dass – wie in der Forschung vermutet – das fachliche Wissen eine Voraussetzung für die Entwicklung von fachdidaktischem Wissen ist. Die angesprochene Leistungsheterogenität zu Beginn des Studiums stellt dabei jedoch ein Hindernis für die Entwicklung des fachlichen Wissens dar. So holt die Gruppe der zu Beginn schwächeren Studierenden nicht einmal das Mittelfeld im Lauf des Studiums ein. Gleichzeitig ist zu beobachten, dass die Gruppe der stärksten Studierenden im Vergleich zu den übrigen Studierenden vom ersten zum dritten Semester überproportional dazulernt. Insgesamt bleibt das heterogene Leistungsbild im Verlauf des Studiums erhalten, was die Forderung nach Unterstützung für leistungsschwächere Studierende gerade zu Beginn des Studiums betont. Wie sich innerhalb der vorliegenden Untersuchung zeigte, könnte insbesondere ein ausgeprägtes mathematisches Vorwissen hilfreich sein, um fachliches Wissen zu entwickeln. Die bisher angebotenen Vorkurse scheinen dem Bedarf nicht gerecht zu werden und so könnte es lohnenswert sein, zusätzliche Veranstaltungen auch in Bezug auf fachliches Wissen in der gesamten Studieneingangsphase anzubieten. Forschungsergebnisse deuten darauf hin, dass insbesondere schwächere Studierende von einer klaren Strukturierung innerhalb dieser zusätzlichen Kurse profitieren könnten. Auch ein allgemeines Vorstudium könnte helfen, die Vorkenntnisse anzugleichen.
Einleitung
Ältere Patienten mit Herzklappenerkrankungen werden zunehmend häufig mit der kathetergestützten Aortenklappenimplantation (Transcatheter Aortic Valve Implantation, TAVI) oder dem MitraClip®-Verfahren behandelt. In der kardiologischen Rehabilitation nimmt infolgedessen die Patientenpopulation der Hochbetagten stetig zu. Die funktionale Gesundheit dieser Patienten wird durch häufig auftretende, sogenannte geriatrische Syndrome wie Multimorbidität, Mangelernährung, Gebrechlichkeit oder Sturzereignisse beeinflusst. Insbesondere die eingeschränkte Mobilität und Mangelernährung sind wichtige Prädiktoren für die Prognose der Patienten nach TAVI.
Etablierte Verfahren, um die körperliche Leistungsfähigkeit von kardiologischen Rehabilitanden zu beurteilen, sind die Belastungsergometrie und der 6-Minuten-Gehtest. Allerdings ist nahezu die Hälfte der hochbetagten Patienten nicht in der Lage, eine Belastungsergometrie durchzuführen. Bislang erfolgt in der kardiologischen Rehabilitation keine differenzierte Erfassung des funktionellen Status hinsichtlich Mobilität, Kraft und Gleichgewicht, um die geriatrischen Syndrome individuell zu beurteilen. Darüber hinaus werden keine Assessments zur Erfassung des Ernährungsstatus eingesetzt.
Daher war es das Ziel der vorliegenden Arbeit, die Ausprägung des funktionellen und nutritiven Status älterer Patienten anhand geeigneter Assessments in der kardiologischen Rehabilitation zu ermitteln.
Methode
Zwischen Oktober 2018 und Juni 2019 nahmen Patienten im Alter von 75 Jahren oder älter nach TAVI, atrioventrikulärer Intervention mittels MitraClip®-Verfahren (AVI) oder perkutaner Koronarintervention (PCI) an der Studie teil. Zu Beginn der kardiologischen Rehabilitation wurden soziodemografische Daten, echokardiografische Parameter (z. B. links und rechtsventrikuläre Ejektionsfraktion, Herzrhythmus) und Komorbiditäten (z. B. Diabetes mellitus, Niereninsuffizienz, orthopädische Erkrankungen) erhoben, um die Patientenpopulation zu beschreiben. Zusätzlich wurde die Gebrechlichkeit der Rehabilitanden mit dem Index von Stortecky et al., bestehend aus den Komponenten Kognition, Mobilität, Ernährung und Aktivitäten des täglichen Lebens, beurteilt.
Der 6-Minuten-Gehtest diente zur Ermittlung der körperlichen Leistungsfähigkeit der Patienten. Die Mobilität wurde mit Hilfe des Timed-Up-and-Go-Tests, die Ganggeschwindigkeit mit dem Gait Speed Test und die Handkraft mit dem Hand Grip Test erfasst.
Für die Objektivierung des Gleichgewichts wurde eine Kraftmessplatte (uni- und bipedaler Stand mit geöffneten und geschlossenen Augen) erprobt, die bislang bei älteren Rehabilitanden noch nicht eingesetzt wurde.
Der Ernährungsstatus wurde mit dem Mini Nutritional Assessment-Short Form und den ernährungsbezogenen Laborparametern (Hämoglobin, Serumalbumin, Eiweißkonzentration) erfasst.
Die Eignung der Assessments bewerteten wir anhand folgender Kriterien: Durchführbarkeit (bei ≥ 95 % der Patienten durchführbar), Sicherheit (< 95 % Stürze oder andere unerwünschte Ereignisse) und der Pearson-Korrelationen zwischen den funktionellen Tests und dem Goldstandard 6-Minuten-Gehtest sowie den Laborparametern und dem Mini Nutritional Assessment-Short Form.
Ergebnisse
Es wurden 124 Patienten (82 ± 4 Jahre, 48 % Frauen, 5 ± 2 Komorbiditäten, 9 ± 3 Medikamente) nach TAVI (n = 59), AVI (n = 21) und PCI (n = 44) konsekutiv in die Studie eingeschlossen.
Etwa zwei Drittel aller Patienten der Gesamtpopulation waren als gebrechlich zu klassifizieren, bei einer mittleren Punktzahl von 2,9 ± 1,4. Annähernd die Hälfte der Patienten zeigte eine eingeschränkte körperliche Leistungsfähigkeit aufgrund einer reduzierten 6-Minuten-Gehstrecke (48 % < 350 m) sowie eine eingeschränkte Mobilität im Timed-Up-and-Go-Test (55 % > 10 s). Es wurden eine mittlere Gehstrecke von 339 ± 131 m und eine durchschnittliche Zeit im Timed-Up-and-Go-Test von 11,4 ± 6,3 s erzielt. Darüber hinaus wies ein Viertel der Patienten eine eingeschränkte Ganggeschwindigkeit (< 0,8 m/s) auf und etwa 35 % von Ihnen zeigten eine reduzierte Handkraft (Frauen/Männer < 16/27 kg). Im Mittel wurde eine Geschwindigkeit von 1,0 ± 0,2 m/s im Gait Speed Test sowie eine Handkraft von 24 ± 9 kg im Hand Grip Test erreicht. Ein Risiko einer Mangelernährung konnte bei 38 % (< 12 Punkte) der Patienten nachgewiesen werden bei einer mittleren Punktzahl von 11,8 ± 2,2 im Mini Nutritional Assessment-Short Form.
Im Vergleich zwischen den einzelnen Subpopulationen bestanden keine statistisch signifikanten Unterschiede in den Ergebnissen der funktionellen Assessments. Bezüglich des Ernährungsstatus wiesen allerdings die Patienten nach AVI einen statistisch signifikant niedrigeren Punktewert im Mini Nutritional Assessment-Short Form (10,3 ± 3,0 Punkte) auf als die Patienten nach TAVI (12,0 ± 1,8 Punkte) und PCI (12,1 ± 2,1 Punkte), wobei etwa 57 % der Patienten nach AVI, 38 % nach TAVI und 50 % nach PCI ein Risiko einer Mangelernährung zeigten.
Mit Ausnahme der Tests auf der Kraftmessplatte waren alle Assessments durchführbar und sicher. Während 86 % der Patienten den bipedalen Stand mit geschlossenen Augen auf der Kraftmessplatte durchführen konnten und damit nahezu den Grenzwert von 95 % erreichten, war der unipedale Stand mit 12 % an durchführbaren Messungen weit von diesem entfernt.
Der Gait Speed Test (r = 0,79), Timed-Up-and-Go-Test (r = 0,68) und Hand Grip Test (r = 0,33) korrelierten signifikant mit dem 6-Minuten-Gehtest, Hämoglobin (r = 0,20) und Albumin (r = 0,24) korrelierten mit dem Mini Nutritional Assessment-Short Form.
Schlussfolgerung
Über die bestehende Multimorbidität und Multimedikation hinaus wiesen die untersuchten Patienten vor allem eine eingeschränkte Mobilität und ein Risiko einer Mangelernährung auf, wobei die Subpopulation nach AVI besonders betroffen war.
Um den Bedürfnissen hochbetagter Rehabilitanden nach kathetergestützer Intervention gerecht zu werden, ist eine individuelle Behandlung der einzelnen Defizite erforderlich, mit besonderer Berücksichtigung der Komorbiditäten sowie der geriatrischen Kofaktoren. Aufgrund des multidisziplinären Ansatzes erfüllt die kardiologische Rehabilitation bereits die Voraussetzung, hochbetagte Patienten bedarfsgerecht zu behandeln, jedoch mangelt es an Assessments, um die individuellen Defizite der Patienten zu identifizieren
Der Gait Speed Test, der Timed-Up-and-Go-Test und der Hand Grip Test sollten daher in den klinischen Alltag der kardiologischen Rehabilitation implementiert werden, um die körperliche Funktion und Leistungsfähigkeit älterer Patienten detailliert zu beurteilen. In Kombination dieser Assessments mit dem Mini Nutritional Assessment-Short Form können die individuellen funktionellen und nutritiven Bedürfnisse der Patienten während der Rehabilitation erkannt und mit geeigneten Maßnahmen die weitere Ausbildung geriatrischer Syndrome gemindert werden.
Monoklonale Antikörper sind essenzielle Werkzeuge in der modernen Laboranalytik sowie in der medizinischen Therapie und Diagnostik. Die Herstellung monoklonaler Antikörper ist ein zeit- und arbeitsintensiver Prozess. Herkömmliche Methoden beruhen auf der Immunisierung von Labortieren, die mitunter mehrere Monate in Anspruch nimmt. Anschließend werden die Antikörper-produzierenden B-Lymphozyten bzw. deren Antikörpergene isoliert und in Screening-Verfahren untersucht, um geeignete Binder zu identifizieren.
Der Transfer der humoralen Immunantwort in eine in vitro Umgebung erlaubt eine Verkürzung des Prozesses und umgeht die Notwendigkeit der in vivo Immunisierung. Das komplexe Zusammenspiel aller involvierten Immunzellen in vitro abzubilden, stellt sich allerdings als schwierig dar. Der Schwerpunkt dieser Arbeit war deshalb die Realisierung einer vereinfachten In vitro Immunisierung, die sich auf die Protagonisten der Antikörper-Produktion konzentriert: die B-Lymphozyten. Darüber hinaus sollte eine permanente Zelllinie etabliert werden, die zur Antikörper-Herstellung eingesetzt werden und die Verwendung von Primärzellen ersetzen würde.
Im ersten Teil der Arbeit wurde ein Protokoll zur In vitro Immunisierung muriner BLymphozyten etabliert. In Vorversuchen wurden die optimalen Konditionen für die Antigenspezifische Aktivierung gereinigter Milz-B-Lymphozyten aus nicht-immunisierten Mäusen
determiniert. Dazu wurde der Einfluss verschiedener Stimuli auf die Produktion unspezifischer und spezifischer Antikörper untersucht. Eine Kombination aus dem Modellantigen VP1 (Hamster Polyomavirus Hüllprotein 1), einem Anti-CD40-Antikörper, Interleukin 4 (IL 4) und Lipopolysaccharid (LPS) oder IL 7 induzierte nachweislich eine Antigen-spezifische Antikörper-Antwort in vitro. Als Indikatoren einer erfolgreichen Aktivierung der B-Lymphozyten infolge der in vitro Stimulation wurden die rapide Proliferation und die Expression charakteristischer Aktivierungsmarker auf der Zelloberfläche nachgewiesen. In einer Zeitreihe über zehn Tage wurde am zehnten Tag der In vitro Immunisierung die verhältnismäßig höchste Konzentration Antigen-spezifischer IgG-Antikörper im Kulturüberstand der stimulierten Zellen nachgewiesen.
Als nächster Schritt sollte eine permanente Zelllinie hergestellt werden, die statt primärer BLymphozyten für die zuvor etablierte In vitro Immunisierung eingesetzt werden könnte. Zu diesem Zweck wurden retrovirale Vektoren hergestellt, die durch den Transfer verschiedener Onkogene in murine B-Lymphozyten bzw. deren Vorläuferzellen das Proliferationsverhalten der Zellen manipulieren sollen. Es wurden Retroviren mit Doxycyclin-induzierbaren Expressionskassetten mit den Onkogenen cmyc, Bcl2, BclxL und dem Fusionsgen NUP98HOXB4 generiert. Eine Testzelllinie wurde erfolgreich mit den hergestellten Retroviren transduziert und die Funktionalität der hergestellten Viren anhand verschiedener Assays belegt. Die transferierten Gene konnten in der Testzelllinie auf DNAEbene nachgewiesen oder die Überexpression der entsprechenden Proteine im Western Blot detektiert werden. Es wurden schließlich B-Lymphozyten bzw. unreife Vorläuferzellen derselben mit den generierten Retroviren transduziert und mit Knochenmark-ähnlichen Stromazellen co-kultiviert. Aus keinem der transduzierten Ansätze konnte bisher eine Zelllinie oder eine Langzeit-Kultur etabliert werden.
Im letzten Teil der Arbeit wurde die Effektivität und Übertragbarkeit des zuvor etablierten Protokolls zur In vitro Immunisierung muriner B-Lymphozyten anhand verschiedener Antigene gezeigt. Es konnten in vitro spezifische IgG-Antworten gegen VP1, Legionella pneumophila und das Protein Mip, von dem ein Peptid in das zur Immunisierung eingesetzte VP1 integriert wurde, induziert werden. Die stimulierten B-Lymphozyten wurden durch Fusion mit Myelomzellen in permanente Antikörper-produzierende Zelllinien transformiert.
Dabei konnten mehrere Hybridomzelllinien generiert werden, die spezifische IgGAntikörper gegen VP1 oder Mip produzieren. Die generierten Antikörper konnten sowohl im Western Blot als auch im ELISA (Enzyme-Linked Immunosorbent Assay) das entsprechende Antigen spezifisch binden.
Die hier etablierte In vitro Immunisierung bietet eine effektive Alternative zu bisherigen Verfahren zur Herstellung spezifischer Antikörper. Sie ersetzt die Immunisierung von Versuchstieren und reduziert den Zeitaufwand erheblich. In Kombination mit der Hybridomtechnologie können die in vitro immunisierten Zellen, wie hier demonstriert, zur Generation von Hybridomzelllinien und zur Herstellung monoklonaler Antikörper genutzt werden. Um die Verwendung von Versuchstieren in dieser Methode durch eine adäquate permanente Zelllinie zu ersetzen, muss die genetische Veränderung von B-Lymphozyten und unreifen hämatopoetischen Zellen optimiert werden. Die Ergebnisse bieten eine Basis für eine universelle, Spezies-unabhängige Methodik zur Antikörperherstellung und für die
Etablierung einer idealen, tierfreien In vitro Immunisierung.