This research presents a multi-scalar work on the effects of human disturbance on high Andean forests in Colombia. It focuses on the analysis of vegetation composition and structure and on the dynamics of forest cover change and connectivity through time in selected localities around Bogotá. Additionally, a distribution model exercise is carried out to further the understanding of the environmental constraints driving the present distribution of a distinctive Andean treeline species and to examine its response to climate change in the future. High Andean forests are a unique and highly biodiverse ecosystem, located at high elevations in one of the world’s biodiversity hotspots, the Tropical Andes. Unfortunately, these forests are extremely fragmented and particularly vulnerable to climate change. Despite the fact that they provide essential ecosystem services to neighboring high Andean cities, such as the capital of Colombia, Bogotá, overall, high Andean forests have been poorly studied. Their fragility and their great value in terms of environmental services, together with their outstanding diversity, make them ecosystems with high priority for conservation. Nevertheless, especially around Bogotá, the vegetation studies carried out often have been rather circumscribed, rarely incorporating more complex parameters such as landscape fragmentation and anthropic disturbance metrics nor assessing functional and phylogenetic diversity attributes and ecosystem services. Also, there is a lack of studies that consider multiple vegetation strata at once and that address long-term changes in the extent and structure of high Andean forests, pairing plot-based work with forest cover change analysis. Lastly, few efforts have been made so far to model the response to climate change of high Andean forests and their species. Investigating these aspects could provide meaningful insights into species’ responses to anthropic influences and community assembly mechanisms, broadening our understanding of high Andean forests and strengthening strategies to conserve them. The aim of the present study is to explore the relationship between human disturbance and the condition of high Andean forest in the surroundings of Bogotá, the growing capital city of Colombia. Therefore, three parallel approaches were developed and implemented. On one hand, permanent plots establishment and plot-based fieldwork was carried out in several localities in the surroundings of Bogotá. Here, tree viii layer and understory vegetation were assessed and analyzed in terms of their taxonomic, functional and phylogenetic diversity, but also as to their structure and above-ground biomass production. A broad array of environmental factors and anthropic disturbance-related indicators was compiled and subsequently used to characterize the tree layer and understory plant communities using a cluster analysis in combination with ordination techniques (Non-metric Multidimensional Scaling and partial Redundancy Analysis). Finally, environmental and disturbance predictors were related to tree and understory diversity metrics and above-ground biomass by means of Generalized Linear Models (GLMs). As a result, a noticeable effect of anthropic related predictors on both tree and understory layer community composition and also a direct negative effect on tree layer diversity and above-ground biomass production have been documented. On the other hand, a thorough analysis of aerial pictures from the studied localities of the first study has been conducted, covering the period between the 1940s to early 2000s, in order to deepen the understanding of the history of forest fragmentation in the area. The images were classified into three land cover classes (Forest, Grasslands and Bare ground), utilizing texture analysis and object-based image segmentation. Then, the extent of forested areas was assessed through time. Additionally, forest connectivity metrics were calculated by performing a Morphological Spatial Pattern Analysis (MSPA) and correlated with the forest cover dynamics over the same period. For the period 1940-2000, in all except one of the studied localities a general restoration of forest cover and connectivity was determined. The highlighted forest cover and connectivity trends were related to the individual history of each locality in terms of population displacement and urban expansion. Lastly, to further expand the geographical and temporal coverage of this study, species distribution models were performed for Weinmannia fagaroides (Cunoniaceae), a tree species that was found to be distinctive of the higher elevation forest fragments that were studied in this project. This species is found throughout the Central and Northern Andes, and is a typical component of high elevation treelines, ecotonal zones that are believed to be highly vulnerable to climate change impacts. The main aim was to understand which are the focal drivers of the current distribution of W. fagaroides, and to hypothesize its response to climate change in the future. At the same time, a comparison of the efficacy of environmental predictors pertaining to three different climate datasets (Chelsa 1.2, Worldclim 1.4 and Worldclim 2) and of ix three different modelling algorithms (GLMs, Random Forests - RF, MaxEnt) was carried out for predicting the current distribution of W. fagaroides. The current species distribution was found to be driven mostly by one temperature, one precipitation and one soil-related variables. In regards to the performance of the three different climate datasets no significant difference was found, although Chelsa 1.2 retrieved slightly higher model evaluation scores. As to the algorithms, RF and MaxEnt retrieved the highest model evaluation scores. Moreover, the modeled distribution of W. fagaroides was predicted to decrease by 38% and to shift towards higher elevations in the period 2060-2080 for a high CO2 emission scenario. Considering that at present only around 22% of the modeled species distribution is situated in protected areas, an adaptation of currently implemented conservation efforts is strongly recommended to protect this and other fragile high Andean treeline species. Overall, this study contributes to the characterization of forest fragments in the vicinity of Bogotá and is an important addition for a better understanding of the effects of anthropic disturbances on high Andean forests and their species. Also, several methodological approaches are provided that may serve as a basis to better understand the situation of other species and ecosystems in similar regions.View less
Superconductivity and magnetism are two phenomena which seem to be incompatible on macropscopic view. Microscopically, this can be traced back to the different spin-orders of both phases: Spin-singlet Cooper pairs versus ferromagnetic spin order. In this thesis we investigate magnetic Fe atoms on the quasi-2D superconductor 2H-NbSe2 by means of combined scanning tunneling microscopy and spectroscopy. The magnetic moment of the Fe atoms locally interacts with the Cooper pair condensate and gives rise to in-gap quasiparticle states - the so-called Yu-Shiba-Rusinov (YSR) states. The peculiar properties of NbSe2 manifest in versatile features of the YSR states which we explore in detail. Capable of atomic manipulation we assemble customized structures - atomic dimers and extended chains - and investigate the hybridization within these structures.
We start by characterizing the pure substrate which exhibits an incommensurate charge-density wave (CDW) that coexists with superconductivity at low temperatures. Both correlated phases are driven by electron-phonon coupling yielding a highly anisotropic superconducting order parameter which appears as a peculiar quasiparticle peak distribution in differential conductance spectra around the superconducting gap.
Fe atoms adsorbed on the surface exhibit multiple YSR resonances with extended wave functions due to the quasi-2D nature of the substrate. The CDW wave induces local variations of the density of states which affect the energy and symmetry of the YSR states. Hence, apart from the two different crystalline hollow sites, the incommensurate CDW creates a multitude of inequivalent sites for Fe atoms. The influence of the CDW on the YSR states was systematically investigated and could be qualitatively modeled in collaboration with theorists.
We study the influence of the CDW on the hybridization between the long-ranged YSR states within the versatile energetic landscape arising from the incommensurate CDW. We assemble various dimers and show that equal positions relative to the CDW are a prerequisite for substantial hybridization. Further, we detect signatures of the quantum spin nature in the coupling of atomic dimers.
We go beyond dimers and stepwise assemble a dilute chain where the coupling between adjacent atoms is entirely mediated via the substrate. We track the formation of YSR bands which are identified by tunneling into their van Hove singularities. In longer chains, the incommensurate CDW induces band bending of the YSR bands. As a last step we investigate chains consisting of densely packed Fe atoms in which direct exchange between d orbitals drives the formation of Fe2 molecules on the surface.View less
Posttraumatic stress disorder (PTSD) and borderline personality disorder (BPD) are highly comorbid. Patients with both disorders report the highest likelihood of lifetime suicide attempts and the lowest mental health related quality of life. Given the high likelihood of comorbid PTSD and BPD and the great burden on those affected, mutual biological and behavioural characteristics of both disorders and their causes seem worthwhile investigating. The current dissertation project aims at further describing overlapping and distinct alterations in stress-regulating systems, stress-relevant brain regions and their interplay in patients with PTSD and BPD, to better explain the evolvement of clinical symptoms, such as affect dysregulation and dissociation that characterize both disorders. As a secondary aim, the current project focusses on the role of childhood trauma (CT), as a mutual environmental factor and possible cause of overlapping symptoms and characteristics in PTSD and BPD. Both disorders are associated with exposure to traumatic events. Traumatic events, such as physical and sexual childhood abuse, in the early phase of development especially increase the risk of developing a psychiatric disorder, among them PTSD and BPD. The organism is especially sensitive to environmental influences in the early period of ontogeny, and changes of stress-regulating systems and stress-relevant brain regions occur in response to stressful environments. Therefore, research has focused on stress-regulating systems and stress-relevant brain regions in both disorders. Especially, the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system (SNS), fronto-limbic networks and the influences of glucocorticoids on memory retrieval and its neural activity have been investigated. Results suggest that some common features in patients with PTSD and BPD may be related to CT, in addition to distinct features that are related to e.g. genetics or single-event trauma. However, there has been little systematic investigation of distinct and overlapping features in PTSD and BPD, or of how CT is related to features that are present in both patient groups. To further characterize distinct and overlapping features in PTSD and BPD, and the role of CT, the following research questions are examined: 1. How do female patients with PTSD differ in their physiological and subjectively perceived stress response to an acute psychosocial stressor, compared with healthy women, and how do these differences relate to CT? 2. How does amygdala and hippocampus resting state functional connectivity (RSFC) differ between female patients with PTSD and BPD and healthy women, in a placebo condition and after hydrocortisone administration, and how does amygdala or hippocampus RSFC in the placebo or hydrocortisone condition relate to CT? 3. How do female patients with PTSD and BPD differ from healthy women in their neural activity during autobiographical memory (AM) retrieval after hydrocortisone administration compared with a placebo condition, and how do these differences relate to CT? To investigate the psychosocial stress response, we used the Trier Social Stress Test, a well-established psychosocial stressor. To examine the effect of hydrocortisone on RSFC and on neural activity during AM retrieval, we used a standardized resting state scan and an autobiographical memory task adapted for functional magnet resonance imaging. The main results of this dissertation are as follows. First, female patients with PTSD are characterized by a blunted cortisol response to a psychosocial stressor compared with healthy women. Measure of cortisol changes over time in response to a psychosocial stressor correlated negatively with severity of CT. We found no evidence for increased SNS reactivity in female patients with PTSD. Secondly, hippocampus dorsomedial prefrontal cortex (dmPFC) RSFC is reduced in female patients with PTSD and BPD. Hippocampus dmPFC RSFC correlated negatively with severity of CT and clinical symptoms. There were no differences between female patients and healthy women in amygdala RSFC. In addition, there was no influence of hydrocortisone on either amygdala or hippocampus RSFC, nor an interaction of hydrocortisone with group. Thirdly, female PTSD and BPD patients and healthy women did not differ in their neural activity during AM retrieval, neither in the placebo condition nor after hydrocortisone administration. Severity of CT correlated with a hydrocortisone induced pattern of neural activity. To conclude, the conducted studies extend findings on the physiological stress response and fronto-limbic network functioning and on the influence of glucocorticoids on memory retrieval and neural activity in patients with PTSD and BPD. Particularly, the revealed association of CT with a blunted cortisol stress response, decreased hippocampus dmPFC RSFC and a hydrocortisone induced neural activity pattern during AM retrieval, suggest an influence of CT on overlapping features in PTSD and BPD. This dissertation project condenses the current findings into a model that describes how CT might induce changes that partially account for overlapping features in PTSD and BPD. The model focusses on glucocorticoid receptor (GR) functioning and its consequences on HPA axis, SNS and fronto-limbic network functioning, and on the influence of glucocorticoids on memory retrieval and its associated neural activity. The current dissertation project yields important new insights into how CT as a common environmental factor in both disorders results in changes in stress-regulating systems and stress-relevant brain regions, and how these explain overlapping symptoms in both disorders.View less
It has long been known that the injection of fluids into the earth’s subsurface can cause seismic activity. Usually, magnitudes of this anthropogenic seismicity are too small to be felt at the surface, but several cases of large-magnitude earthquakes related to fluid operations are known. A deeper understanding of the physical mechanisms and controlling parameters of this anthropogenic seismicity is therefore of interest for science as well as for society.
This thesis aims to improve the characterization of source mechanisms of fracturing-induced seismicity. For this, I develop a framework that takes the effect of seismic anisotropy on the source process into account. Microseismic events induced by hydraulic fracturing are typically located in shales, that can exhibit high degrees of anisotropy. This can affect the radiation pattern of events and thus can lead to a misinterpretation of source deformation if not accounted for correctly. In this thesis, I describe a methodology that considers adequately the anisotropy both in the source region and along the propagation path. I examine the influence of various anisotropy parameters on different seismic sources and propose a visualization that directly represents the strain caused by a microseismic source.
The source process of most earthquakes can be approximated by double-couple faulting, that is the rupture occurs as shear on a fault plane and does not contain opening or closing components. For such sources, I propose a decomposition that can be used to analyze different source orientations. Additionally, I suggest a new visualization tool to evaluate the diversity of many mechanisms at the same time. This could be applied to potentially distinguish between natural and induced seismicity. The new decomposition and the source type plot are particularly beneficial for the analysis of fracturing-induced seismicity as it explicitly incorporates the half-moon faulting type, which is typical in this environment.
Subsequently, I use these two theoretical tools to invert and analyze source mechanisms of hydraulic fracturing-induced seismicity. I show that anisotropy has a notable effect on the determined mechanisms and that accounting for this effect correctly, creates a more coherent distribution of mechanisms. The decomposition shows two main types of faulting, (1) strike-slip faulting and (2) dip-slip faulting on nearly vertical fault planes. Strike-slip faulting is characteristic for the tectonic seismicity of the region, the second mechanism type, frequently called half-moon faulting, is a typical source mechanism for hydraulic fracturing.
Half-moon events are observed hardly anywhere in natural seismicity but are typically observed during hydraulic fracturing stimulations. Therefore, this event type seems to be directly related to the fracturing process. I provide an explanation for the occurrence of these events, by using geomechanical modeling. This involves the quantification of fracturing-induced changes of the local stress field which triggers these earthquakes. I elaborate that half-moon events require special stress conditions in the subsurface, for instance, local rotations of the principal stresses. 2D geomechanical modeling shows that these conditions are created in the vicinity of the tips of hydraulic fractures and at layer boundaries that are crossed by the fracture. This model can be used to study hydraulic fracturing under normal-faulting conditions. I complement the modeling with a 3D model that is also capable of modeling hydraulic fracturing under general strike-slip conditions. I compare this model to the studied dataset and show that several field characteristics can be reproduced and explained. The study demonstrates the importance of the integration of data analysis and numerical modeling to accurately capture the physical processes in the source.
Altogether, this thesis provides two new theoretical tools that can be applied to any microseismic dataset in order to achieve more accurate and more consistent results. It further provides new insights into the long-standing discussion on the physical conditions responsible for the occurrence of half-moon events. Consequently, this thesis yields an important contribution to the general physical understanding of fluid-induced seismicity.View less
Carbohydrates are the most abundant biomolecules on earth and play pivotal roles in biological events. These carbohydrates exist as polymers, and as glycoconjugates, are connected to proteins, peptides, and lipids. Consequently, tremendous efforts to understand functions of carbohydrates have been made. Automated solid-phase oligosaccharide synthesis showed possibilities to make synthetic routes straightforward and streamlined for even non- specialists as a general and robust instrument like DNA and peptide synthesizer. Tremendous efforts were made over the past decades to advance automated systems and to produce various structures of oligosaccharides. In the extension of these investigations, the ultimate goal of this thesis is to show the possibility to establish the logic of automated glycan assembly (AGA) by developing new methods for automated glycan assembly to prepare different classes of glycans. Therefore, various oligosaccharides using generalized protocols have been procured and conjugation-ready carbohydrates serve as molecular tools. After a comprehensive introduction into automated oligosaccharide synthesis in Chapter 1, Chapter 2 describes the automated glycan assembly of oligo-N-acetyllactosamine (oligo-LacNAc) and keratin sulfates using building blocks bearing three temporary protecting groups. Following purification protocols using HPLC allowed for access to a small library of linear and branched LacNAc structures including sulfated KSs. Additionally, glycan microarray screening performed using seven LacNAc structures and fluorescence-labeled recombinant AAV particles revealed that one specific virus, AAV 10 identified disulfated tetrasaccharide LacNAc as a relevant epitope. Automated synthesis of oligosaccharides containing challenging 1,2-cis-glycosidic linkages or disarmed building blocks is demonstrated in Chapter 3. Assembly of Lc4 and nLc4 core structures containing only 1,2-trans-glycosidic linkages was executed with building blocks employing a participating group at C2. The stereoselective installation of α-(12)- fucosidic linkage was achieved with the corresponding fucose building blocks depending on the sequence of the core structure, Lc4 or nLc4 in order to synthesize H-type I and II. For the synthesis of three α-Gal epitopes, the last glycosylation reaction formed α-(13)-galactosidic linkage. The stereoselectivity was found to be affected by the sequence of the acceptor bound to the solid support. Identification of the most reactive glucuronic acid building block bearing Lev protecting group on 3-O allowed for the synthesis of HNK-1 epitope pentasaccharide in strictly linear approach. From this investigation it was concluded that identification of approved building blocks was key to accomplish the assembly of synthetically challenging oligosaccharides by using AGA. Chapter 4 of this dissertation presents the automated synthesis of oligosaccharides containing challenging 1,2-cis glycosidic linkages, one of the most challenging carbohydrates to date. In contrast to previous result, leaving groups affected the automated installation of α- galactosidic or β-mannosidic linkages. Remote participation effects by acetyl group(s) at C3 and C4/C6 was in depth studied to identify a set of building blocks introducing 1,2-cis glycosidic linkages with good to excellent stereoselectivity. Taking advantage of “approved” building blocks enabled the synthesis of Globo-H and α-glucans containing multiple 1,2-cis glycosidic linkages. As a result of researches performed in previous Chapters 2 to 4, Chapter 5 describes the reliable and rapid assembly of oligosaccharides using the commercially available automated glycan synthesizer, Glyconeer 2.1, monosaccharide building blocks, and a linker- functionalized polystyrene solid support. Protocols for purification using HPLC and quality- control using IM-MS for the oligosaccharide products have been standardized. Synthetic glycans prepared in this way are useful reagents as the basis for glycan arrays, diagnostics, and carbohydrate based vaccines.View less
Pluripotent stem cells (PSCs) have the ability to undergo indefinite self-renewal while giving rise to the three germ layers. This remarkable capacity has turned PSCs to be a fundamental cell source for regenerative medicine research and applications. The derivation of induced pluripotent stem cells (iPSCs) over a decade ago has sparked a widespread enthusiasm and opportunity for personalized autologous cell-based therapies in a wide array of diseases. However, the development of optimized disease models and iPSC-derived products heavily relies on the generation of homogenous culture systems for the cell type of interest, which currently presents one of the major hindrances towards the use of PSC derivatives in therapeutic applications. The cerebral cortex is an excellent example of a tissue with enormous heterogeneity that introduces immense challenges for in vitro disease models and therapeutic applications. Our lab mainly focuses on studying the development of the cerebral cortex, particularly investigating the development of cortical neural stem cells (NSCs). Our goal is to devise approaches for the differentiation of PSCs into founder NSC building blocks. We put particular emphasis on achieving high purity that will enable studying authentic cell fate decisions that are associated with regional patterning, self-renewal and differentiation processes that shape the cortex. A homogeneous early cortical population will also enable extracting a more reliable molecular identity of those cells, which can then be used for meaningful disease modeling and for devising sophisticated approaches to induce or maintain self-renewal of such populations in vitro. However, recent research from our lab has shown that current methods to derive early cortical progenitors from PSCs are highly diverse and yield heterogeneous populations containing both cortical and non-cortical cell types. This results in heterogeneous founder NSC populations, limiting their use as a universal pure NSC source. To overcome this hurdle, our lab established a streamlined method known as Triple-i paradigm to derive homogenous starting cortical progenitors both in neural rosettes (2D) and in organoids (3D) platforms. The main objectives of this thesis are to identify early signals that modulate temporal and regional fates within developing founder cortical NSC populations, focusing on small non-coding RNA (miRNAs), which are known to be key regulators of many developmental processes including stem cell proliferation and lineage specifications. These miRNAs guide the early development in a spatiotemporal manner by regulating the expression of multiple gene networks at the post-transcriptional level. They are abundantly expressed in the developing neural tube that eventually gives rise to different regions of central nervous system, including the cerebral cortex. However, it is unknown whether they have the capacity to specify a particular brain region in the cortex such as archicortex that consists of cortical hem, hippocampus and choroid plexus. In this study, we have identified a miRNA important for the specification of archicortex and interrogated its role in cell fate specification using a battery of molecular and cellular studies. First, we employed in vitro human embryonic stem cell-based models (2D monolayer and 3D cerebral organoid) for the derivation of founder neural stem cell and their progression. We then identified a list of miRNAs that are specifically expressed in this early neural stem cell stage, among which we found hsa-miR-20b-5p to be one of the highly expressed microRNAs in early NSCs derived under both monolayer culture and cerebral organoids. Second, by overexpressing hsa-miR-20b-5p in cerebral organoids, we provided evidence that this miRNA is involved in the stepwise specification of choroid plexus of archicortex, by caudalizing the early cortical NSC, due to modulation of WNT and BMP signalling components. In addition, cellular immunostainings displayed a characteristic presence of giant but thin single- layer vesicles positive for choroid plexus markers in miR-20b overexpressing organoids, as opposed to pseudostratified cortical neural rosettes in wildtype organoids. Furthermore, we showed that co-overexpression of miR-20b with of its main target CCND1, lead to the generation of cortical hem/hippocampus organoids. Altogether, through an extensive miRNA-sequencing, single cell RNA-sequencing and cellular immunofluorescence studies, we revealed the expression of hsa-miR-20b-5p in early neural stem cells, its role in the specification of the archicortex lineages and its part as a cell fate modulator for converting cortical organoids towards choroid plexus structures.View less
Different physical cues are known to affect mesenchymal stem cell (MSC) behavior, indicating a complex relationship between the cell and its microenvironment. Mechanical strain and temperature changes are examples of cues that are relevant in vitro and in vivo. However, the combined effects of multiple physical cues on MSCs remained unclear. Traditional mechanical devices used in cell research have limitations on the integration of various factors and high-throughput applications. The requirement of new biomaterials to integrate the multiple external stimuli was arising to figure out the complex cellular mechanisms. The thermoresponsive mechanical strain was investigated to achieve the aim of using active biomaterials to study the combined effects on human MSCs. Poly (ℇ-caprolactone)-butyl acrylate (PCL-BA) copolymer sheet actuators were programmed so that the reversible shape change could be controlled by temperature changes between 37 °C and 10 °C. A thermochamber was used to culture the human adipose-derived stem cells (ADSCs) on the shape-memory polymer sheet actuators. 50 × 50 µm grids were created on the underside of the actuator sheets to observe the shape change of polymer and cells. Cell morphology, orientation, and migration were observed and recorded using time-lapse microscopy. The dual stimuli of temperature change and mechanical strain were translated into intracellular signals, such as calcium oscillation and nuclei translocation of the mechanical sensors, which were characterized using chemical reagents and immunostaining. Further, epigenetic histone modification of hADSCs was analyzed using chromatin immunoprecipitation quantitative real-time PCR (ChIP-qPCR). Finally, adipogenesis and osteogenesis of the hADSCs were studied to evaluate MSC differentiation capacity with the combined physical cues. The effect of temperature changes on adipocyte dedifferentiation was demonstrated by quantifying lipid accumulation in mature adipocytes. The expression of lipid accumulation-related genes and cell proliferation capacity were analyzed to investigate the dedifferentiation properties. In this work, the PCL-BA shape-memory polymer actuator elongated more than 10% at 10 °C, and contracted when returned to 37 °C. The mechanical strain was generated with the polymer actuator's elongation, which modified the cell morphology and increased cell migration. The periodic temperature change and mechanical strain induced calcium influx into cells; meanwhile, the mechanical strain promoted nuclei translocation of the YAP and RUNX2. The dual stimuli further increased the epigenetic acetylation of histone H3 lysine 9 (H3K9ac) and enhanced the expression level of osteogenesis-related genes and proteins. In addition, the dual stimuli of temperature change and mechanical strain induced the focal adhesion activation by regulation of integrin and myosin light chain (MLC) phosphorylation. As a result, cytoskeleton organization and focal adhesion activation were reduced by pretreatment of the MSCs with temperature changes but enhanced with mechanical strain changes. Temperature change alone decreased the cell migration velocity on SMPA substrate, while temperature change and mechanical strain combined increased cell migration velocity. Further, the cyclic temperature change (10 - 37 °C) decreased intracellular lipid of mature adipocytes and increased free fatty acids (FFA) outside. Simultaneously, mature adipocyte marker FABP4 was significantly down-regulated, while the brown adipocyte-related genes UCP1, PGC-1α, and PRDM16 were up-regulated. Ki67 represents the proliferation marker that was increased after the treatment of temperature change. The transformation of mature adipocytes and increasing proliferation capacity indicates the promotion of adipocyte dedifferentiation. The shape-memory polymer actuator sheet is an active biomaterial that can generate mechanical strain with simple temperature control. This artificial muscle allows the combined influence of multiple physical cues on stem cells to be studied. We found the combinative effects of the interplay of mechanical and temperature stimuli on MSC behavior and lineage commitment change, instead of the typical single effect on MSCs. We also established the adipocyte dedifferentiation with periodic temperature changes, which might be used to generate alternative stem cell sources and improve the MSC-based cell therapy in regenerative medicine.View less
Over the last few years, data has often been described as the oil of the 21st century, e.g., by Bhageshpur (2019). Just as access to oil dominated power and development in the last century, this claim implies that personal data is not only assumed to be similarly valuable, but also equally as influential in politics and society as oil once was. However, oil sources mainly diverge in their accessibility, quality, quantity, and cost of exploitation but, once extracted and refined theses sources may lead to roughly similar products. Data also differs in these four categories but, additionally, data sources typically lead to very specific insights. One single data source is often neither sufficient to answer important and complex scientific (or economic) questions nor to make any predictions with fine granularity and high precision. In such cases, combining data from different sources that provide additional aspects to the problem at hand is one promising approach to achieve these aims.
In this dissertation, combining data sources is conducted for two purposes. Part I of this work focuses on combining data to achieve additional understanding. In the paper presented in Part I, the authors analyze reasons why students drop out of undergraduate courses in economics and business administration. From a university perspective, administrative data is readily available, e.g., which modules are completed in which semester, how many educational credit points are achieved by each student in each semester. Socioeconomic data at individual level, however, is usually unavailable to university administrations. In order to overcome this hurdle, the authors proposed and executed a novel prospective study design. A survey was conducted on students starting the second semester and the data was combined with administrative longitudinal data. Hence, the authors were able to analyze individual studying behavior conditioned on a large pool of socio-demographic variables. Among other results, the authors were able to show that college admission grades have a negligibly small impact on the achievements made on Bachelor degree courses. This finding stands in strong contrast to college admission policies in Germany that strongly focus on high-school grades for college admission.
The second purpose of data-combination, as discussed in this work, is the combination of data-sources to improve the precision of predictions. Part II consists of three papers from the field of small area estimation (SAE). In SAE problems, there is some survey data typically available that contains the (VOI). However, an indicator of interest needs to be estimated on some subgroup level by a function of the VOI. Such levels usually consist of a geographic region but are not limited to this. In the context of SAE, these subgroups are called areas. With an increasing number of areas, the quantity of observations available per area decreases, often leading to areas with very few or even without any observations (out-of-sample areas). In such situations, a prediction with reasonable reliability becomes impossible when only relying on the available survey data. One possibility to overcome this burden is to couple the survey data with additional data, such as administrative or census data. Frequently, these data sources do not contain the VOI, thus rendering a direct estimation of the indicator impossible. However, if similar covariates are available in the survey and census, a feasible approach is to assume a model for the VOI that holds, both in the survey and census, to estimate the model on the survey data and then to combine the model estimates with the more numerous census data that enables prediction. This general method is often referred to as “borrowing strength.” Such model-based approaches are roughly divided into two classes, depending on the data availability and resulting requirements on the models. First, if the data is available for each individual of interest, e.g., a citizen or household, unit-levels are used. For area-level models, on the other hand, data is only available in aggregated form at area level.
Many common methods in SAE assume normally distributed residuals, not only for the model estimation, but more crucially when using the census data for prediction and the estimation of precision. Therefore, deviations from normality have severe consequences and lead to less precise point estimates and misleading shrunk error estimates. The paper presented in Chapter 2 proposes the use of data-driven transformations, resulting in smaller deviations from normality and thus improved point and precision estimates. Chapter 3 presents the R-package emdi that implements not only the latter methodology, but also allows for the usage of various area-level Fay-Herriot models. emdi focuses on user-friendliness and provides many useful functionalities to support the user through every step, from model estimation through the analysis of model assumptions to visualize the results end enable their exportation. However, when deviations from normality are too severe, different model types are more suitable. Chapter 4 presents the R-package ammlogit, which allows the user to work with a multinomial VOI. The corresponding paper introduces a new methodology for prediction and a revised bootstrap mean squared error estimation. Like emdi, ammlogit is designed to be user-friendly and narrow the gap between research and practitioners. Still, the method used in ammlogit also uses distributional assumptions, as the counts are assumed to be conditionally multinomially distributed and the area-level error terms are assumed to be identically normally distributed.
A model class without distributional assumptions are quantile-type regression models. M-Quantile models have been used in SAE since Chambers and Tzavidis (2006). However, the related mixed quantile regression models have not yet been consequently applied to small area problems, even though they are a naturally robust alternative to the widely used linear mixed regression models that dominate research and application. In parts, this may be due to remaining uncertainties about their symptotic properties. Therefore, in the paper presented in Part III, the asymptotic normality of the corresponding maximum likelihood estimates is proven and a plugin-variance estimator is derived.View less
Die stets ansteigende Zahl an Krebserkrankungen mit einhergehendem tödlichem Verlauf erfordert die stetige Weiter- und Neuentwicklung von entsprechenden Therapien, welche Tumorspezifisch agieren müssen. Vor allem schwerwiegende Nebeneffekte, die häufig bei den gängigen Radio- und Chemotherapien auftreten, gilt es zu minimieren. Der Aufbau von Antikörper-Wirkstoff-Konjugaten (ADC) vereint hier das zielgerichtete Wirken durch den Antikörper mit der Toxizität der Wirkstoffkomponente und so sind bereits acht dieser ADCs durch die Food and Drug Administration zugelassen worden. In dieser Arbeit wurde deswegen ein ADC aus Panitumumab, einem vollständig humanen IgG2-Antikörper mit geringem immunogenem Potential, und Dianthin, einem hoch toxischen pflanzlichen und enzymatisch wirkenden Protein, reproduzierbar mit einem Wirkstoff-zu-Antikörper-Verhältnis (DAR) von ~1 und einer molekularen Masse von ~180 kDa erzeugt. Dabei wurde die Bindungsaffinität von Dianthin-Panitumumab (DPan) zum Zielrezeptor EGFR, welcher vorwiegend von Krebszellen in einem Übermaß exprimiert wird, unvermindert gegenüber Panitumumab mit einem KD-Wert von 1.5 × 10^-10 M bestimmt. Die enzymatische Aktivität von DPan im Vergleich zu Dianthin war aufgrund der Kopplung um ~50 % von 312.2 auf 153.3 pmol(Adenin)/pmol(Protein)/h vermindert, jedoch bewies das ADC DPan in vitro ein enormes selektives und zielzellspezifisch zytotoxisches Potential, wobei in Kombination mit dem glykosylierten Triterpenoid SO1861 als Endosomal Escape Enhancer eine bemerkenswerte mittlere Effektivität von 0.00022 / 0.00006 nM (IncuCyte-Echtzeitmessung / MTT-Assay) erreicht wurde. Das zytotoxische Potential der Kombinationsbehandlung konnte weiterführend in einem 3D-Sphäroid-Versuch unter realitätsnahen Tumorbedingungen nachgewiesen werden. Ebenso konnte in dieser Arbeit erstmals gezeigt werden, dass DPan weiterhin und vergleichbar zu Panitumumab in der Lage ist, die Antikörperabhängige zellvermittelte Zytotoxizität (ADCC) über PBMCs und Monozyten auszulösen, um somit einen additiven antitumoralen Effekt zu erzeugen. Das in vitro hervorragend zytotoxisch wirkende ADC DPan zeigte dagegen in vivo an tumortragenden Mäusen eine im Vergleich zu Panitumumab leicht verminderte antitumorale Wirkung, wobei in Kombination mit SO1861 die Wirkung signifikant gesteigert wurde. Die eingesetzte Dosis mit 3.3 µg lag dabei weit unter der höchst verträglichen Dosis ohne schwerwiegende Nebeneffekte mit 126 µg. Untersuchungen der Biodistribution von Radionuklid (99mTc) markierten DPan und Panitumumab zeigten indes eine unterschiedliche Kinetik. Beide Proteine zeigten bezüglich der Konzentration im Tumor erst am Ende des untersuchten Zeitraums von 18 h die höchste Konzentration , wobei Panitumumab dominierend im Tumor akkumulierte. Die allgemeine Biodistribution im Körper betrachtend zeigte Panitumumab eine vermehrte Plasmapräsenz im Blut-Pool, wohingegen DPan stark in der Leber und Milz akkumulierte. Ferner konnte gezeigt werden, dass Dianthin bereits im Blutplasma geringfügig aus dem ADC abgespalten wird, vermutlich weil hier ein spaltbarer SPDP-Linker verwendet wurde. Da DPan in Kombination mit SO1861 aber in vitro ein hervorragendes antitumorales Potential zeigte, welches in vivo nicht gänzlich zum Tragen kam, sollte trotzdem in zukünftigen Arbeiten an der Optimierung der In-vivo-Effizienz von DPan gearbeitet werden.View less
“Compliance and Non-Compliance with the FATF Recommendations: Policy Transfer in Areas of Limited Statehood” explains how national anti-money laundering (AML) policies develop in relation to the international policy standard of the Financial Action Task Force (FATF). The literature holds that both money laundering and AML policies are highly relevant for public security, integrity of the international financial system as well as for anyone interested in effective international regulatory regimes. Money laundering is mostly linked to profit oriented transnational organised crime. Estimates of its total annual volume stand at around 3.6% of global gross domestic product (UNODC, 2011, p. 9). Many observers therefore see preventing and controlling money laundering as a worthwhile investment in combatting organised crime. The FATF’s approach of AML policy as financial market regulation makes it a relevant factor in international financial market governance. The interest of scholars of international regimes stems mainly from the FATF’s alleged high capacity to create rule compliance, despite the voluntary nature of its 40 Recommendations.
Yet the available quantitative data on compliance with the FATF Recommendations at country level shows a picture that does not support the narrative of an overall highly effective compliance regime. There is plenty of empirical variance between countries that has yet to be explained. Measures for levels of statehood, understood as “the ability of the state to enforce collectively binding decisions” (Börzel & Risse, 2010, p. 118), reveal a wide scattering of FATF compliance, particularly in the middle-ground between countries with highly consolidated statehood and those with particularly low levels in closely related policy fields like public security and bureaucratic capacity.
This work engages with this observation by developing a bespoke analytical toolkit of AML governance configurations that takes account of actors and institutions as well as governance as a process shaped by power differentials. In this approach, the state is only one of many potential actors that influence policy transfer from the international to the national level. These actors can either apply hierarchical or non-hierarchical governance modes. These are expected to be more or less effective in fostering compliance, depending on their institutional embeddedness and resource endowments of governance actors. In addition to the state, in particularly financial and non-financial market actors appear as additional key AML governance providers that are at the same time recipients of governance services.
The resulting picture is a strongly intertwined mesh of external and domestic actors, institutions and power sources. To adequately reflect this in a generalizable model of a governance configuration explaining AML policy transfer that is specific for areas of limited statehood, the existing typology is expanded to include: Transnational Delegation. This model acknowledges the empirical result that AML governance is transnational in nature by involving public and private actors, both external and domestic. They are woven together at the same time by organised crime using transnational financial markets to launder their money as well as the attempts of different actors to provide AML governance services for this market. AML might thus be understood by definition as an area of limited statehood as long as no transnational state exists that has “the ability to enforce collectively binding decisions” (Börzel & Risse, 2010, p. 118) on transnational financial markets. While the FATF delegates AML governance to state and non-state actors, it lacks hierarchical enforcement power for this task. It depends on governance provision by third parties in order create a credible shadow of hierarchy. What emerges instead as a function equivalent to statehood is a distinctive mix of hierarchical and non-hierarchical governance modes that can lead to a more complete policy transfer. This seems most promising by connecting transnational financial market regulation with domestic organised crime centred enforcement policies.View less
In recent years, Mindfulness-Based Interventions (MBI) have gained popularity as a modern psychotherapeutic approach, primarily in English-speaking countries. A growing body of evidence demonstrates the clinical benefits of MBI for a wide range of symptoms experienced in Schizophrenia Spectrum Disorders (SSD). However, research in German- speaking countries remains scarce. Against this background, the present dissertation aims to contribute to the available body of literature by developing and validating a Mindfulness-Based Group Therapy (MBGT) for the treatment of inpatients with schizophrenia spectrum disorders. This comprehensive research study will include both qualitative and quantitative data analysis concerning the three subprojects revealed below. A qualitative research design based on inductive thematic analysis in the form of a semi- structured interview guide was developed and 27 interviews were conducted with inpatients having SSD after attending a mindfulness-based intervention in study one. Analyses revealed two domains (content and function) of MBI. The domain content had further subcategories, including core elements, as well as effects on emotions, cognition, and symptoms changes. The second domain was related to the relevance of perception of context and transfer to everyday life. Overall, individuals reported improvements on several clinical parameters and gave an in- depth understanding of underlying processes and mechanisms at action. Based on these outcomes, a novel Mindfulness-Based Group Therapy (MBGT) was developed for the first time in the German language through a fundamental participatory and iterative research process and finally published in a manual's printed book form. Moreover, historical concerns regarding the therapeutic utility of mindfulness for SSD are discussed, while recommendations and careful adaptations are given to implement MBI in inpatient and outpatient settings as a part of an editorial article. In study two, the newly translated German version of the Southampton Mindfulness Questionnaire (SMQ) was validated regarding convergent and divergent validity, reliability, factor structure, and treatment sensitivity while providing evidence for clinical practice and research for healthy individuals, mediators, and clinical groups. In the third study, a rater-blinded randomized controlled trial was conducted to assess the feasibility, acceptability, and preliminary outcomes of MBGT with inpatients having SSD. Results showed high protocol adherence and retention rates indicating feasibility and acceptability. Furthermore, various improvements were revealed on clinical- and process dimensions compared with treatment-as-usual. Overall, the present dissertation gives compelling evidence regarding the effects of mindfulness for SSD and adds a modern psychological treatment option for this marginalized patient group.View less
The present dissertation is concerned with the study of problems from toric and numerical algebraic geometry, as well as mathematical population genetics from the perspective of discrete geometry. The introductory Chapter 1 contains a short summary of the results. Furthermore, we introduce the objects stemming from discrete geometry which play a central role in the following, and fix the corresponding notation.
Chapter 2 is devoted to the examination of Newton-Okounkov bodies and Newton-Okounkov functions. We consider the case of toric varieties. First, we give a combinatorial proof for the existence and uniqueness of Zariski decomposition on toric surfaces. Based on this, we construct an isomorphism between the polytope associated to a torus-invariant divisor and the Newton-Okounkov body of a non-toric flag. Subsequently, we give an explicit description of Newton-Okounkov functions in the completely toric case and an approach to determining functions coming from valuations in a general point. We formulate combinatorial criteria on the polytopes involved and prove that in these cases the function can be fully described using our approach. The developed techniques can be applied to prove the rationality of certain Seshadri constants. We explain the connection and show rationality as a dependency of a combinatorial condition. Furthermore, we construct a class of examples to which existing criteria do not apply, and show rationality in these cases.
In Chapter 3, we deal with models from mathematical population genetics and their description in polyhedral language. First, we define different spaces of phylogenetic trees and then define the Kingman n-coalescent process in terms of a suitable density. Based on this, we define a forgetful map for varying sample sizes and show how the corresponding density can be derived from it. Finally, we consider the multispecies coalescent process and describe it in polyhedral language. In particular, we show how the conditional probability of the occurrence of a certain gene tree, given a species tree, can be described in terms of a density on our space of phylogenetic trees.
The focus of Chapter 4 is the investigation of the tropical version of Smale's famous 17th problem. The original question, whether it is possible to find a common solution of n given polynomials in n unknowns in expected polynomial time, translates into a problem from discrete geometry: finding a fully mixed cell in a triangulation of a Cayley polytope induced by the randomized input data. We explain this version of the problem and, based on it, analyze an approach to solving it by means of a homotopy continuation. In particular, we give an example that could lead to a lower bound in the input data that is exponential.View less
The daunting complexity of the brain emerges from the large number of neurons it contains and their compartmentalized synaptic interactions at axon terminals and dendrites. Generation of functional neuronal networks requires robust, unambiguous developmental processes to ensure synapse-specific neuronal partner choice and subsequent maintenance mechanisms to keep neurons and particularly synapses healthy and functional over a long time. Defects in wiring and maintenance mechanisms are associated with neuropsychiatric and neurodegenerative disorders. Having regard to the importance of protein quality control mechanism both during development and function of the nervous system, in this doctoral work, I investigated possible local roles of lysosomal degradation pathways including ubiquitous and neuron-specific endolysosomal degradation and autophagy at axon terminals. Using live imaging in intact Drosophila brains and novel acidification-sensing degradation probes, first, we reported a direct live observation of local protein degradation at axon terminals in large, acidified compartments. These acidic, degradative endocytic compartments undergo continuous flux of fusion and fission of smaller compartments that is reflected by their molecular composition at a given time. Therefore, we named these compartments ‘local hubs’ as they behave as sort-and-degrade stations for local protein turnover at axon terminals. Secondly, we reported differential, cargo-specific sorting of plasma and synaptic vesicle membrane proteins into distinct hubs via two molecularly distinct pathways. Although plasma membrane protein sorting and degradation depends on ubiquitous Rab GTPase, Rab7, synaptic vesicle membrane protein sorting and degradation is Rab7-independent and operated by previously characterized synaptic vesicle proteins V100 and n-Syb. V100, as a subunit of a proton pump, particularly affects acidification of synaptic vesicles hubs, whereas n-Syb is required for the delivery of golgi-derived microvesicles containing acidic hydrolases into synaptic vesicle hubs. Interestingly, autophagy does not overlap with any of these local degradation pathways. Following their formation at axon terminals, they enter in axons without engaging in any fusion/fission events, hence morphologically and dynamically distinct from local hub compartments. Despite several reports on formation of autophagosomes at axon terminals, potential physiological roles it may exert still remain largely unknown, especially during neural circuit assembly. Live imaging of developing Drosophila photoreceptor axon terminals with autophagosome markers revealed their formation at the tip of synaptogenic filopodia followed by destabilization of these structures. Consistent with this observation, loss of function analyses of autophagy in developing Drosophila photoreceptors revealed increased stability of synaptogenic filopodia and subsequent increase in synapse numbers. More importantly, autophagy-deficient neurons connect to several aberrant synaptic partners causing neuronal miswiring. Finally, adult flies with miswired brains due to loss of autophagy show distinct and predictable behavioral phenotypes such as prolonged, repetitive visual attention to objects. Interestingly, development at colder temperatures exerts similar effect on filopodial stability as in loss of autophagy where axonal filopodia slow down and stabilize more synaptogenic filopodia. This effect on filopodia stability further leads to increased synapse formation and recruitment of aberrant synaptic partners changing brain wiring pattern. Collectively, these results demonstrate that filopodia kinetics play an important role to restrict or facilitate synaptic partnerships between neurons in close proximity during brain wiring. In conclusion, my doctoral work contributed to better understanding of local functions of protein degradation machineries and developmental temperature during brain wiring and maintenance. Unexpected roles of such cellular mechanisms and external factors in establishing proper neuronal circuits point to the fact that combinatorial action of several factors in time and space during brain development contribute to the final outcome, a functional brain.View less
Bei Hamstern treten Tumore regelmäßig auf, jedoch gibt es nur wenige wissenschaftliche Studien zu diesem Thema, insbesondere über das Vorkommen von Tumoren bei Heimtierhamstern. Eine retrospektive Studie (Publikation 1) über das Auftreten spontaner Tumore bei 177 Heimtierhamstern erfasste Daten aus verschiedenen pathologischen Instituten in ganz Deutschland. Davon waren 78 Tiere männlich und 75 weiblich. Das mediane Alter der Hamster lag bei zwölf Monaten. Hauttumore konnten am häufigsten nachgewiesen werden (71%, 126/177), wobei der Hauptteil epithelialen Ursprungs war (66%; 91/126). Soweit die genaue Hamsterart bekannt war, zeigte sich, dass Syrische Hamster (52%, 30/58) seltener betroffen waren als Zwerghamsterarten (85%, 47/55). Tumore des hämatopoetischen Systems kamen am zweithäufigsten vor (17%, 30/177). Tumore anderer Organsysteme, wie der endokrinen Organe und des Verdauungsapparates (1.7%, 3/177) sowie andere Tumore (jeweils 4%, 7/177), kamen selten vor. Die Überlebenszeit war in 31 von 177 Fällen bekannt und lag zwischen 0 und mehr als 672 Tagen. Sowohl Syrische Hamster als auch Zwerghamsterarten können verschiedenste Arten von Tumoren aufweisen. Während bei Zwerghamsterarten häufiger Tumore der Haut festgestellt wurden, waren Syrische Hamster häufiger von Tumoren des hämatopoetischen Systems betroffen. Es gab keinen nennenswerten Unterschied zwischen Syrischen Hamstern und Zwerghamsterarten bezüglich einer Alters- oder Geschlechtsprädisposition für bestimmte Tumore. Um eine größere Datenmenge zu erhalten, sind weitere Studien nötig. Publikation 2 beschreibt das Auftreten eines Granulosazelltumors bei einer Mongolischen Rennmaus (Meriones unguiculatus). Die zwei Jahre alte Mongolische Rennmaus wurde aufgrund eines auffallend prallen Abdomens vorgestellt. Röntgenologisch zeigte sich ein Detailverlust im Abdomen. Sonographisch wurde eine gut abgegrenzte, kavernöse Umfangsvermehrung unklaren Ursprung nachgewiesen. Bei der Laparotomie konnte diese Umfangsvermehrung chirurgisch entfernt werden. Es handelte sich um einen zystischen, hormonell aktiven Granulosazelltumor des Ovars. Das Tier überlebte postoperativ 18 Monate. Es kam zu keiner weiteren Pathologie des Geschlechtsapparates. Operation, Anästhesie und Nachversorgung wurden beschrieben. Publikation 3 beschreibt das Auftreten beidseitiger Granulosazelltumore und hyperplastischer Uterusveränderungen bei einem Afrikanischen Weißbauchigel (Atelerix albiventris). Ein fünfjähriger, weiblicher Afrikanischer Weißbauchigel wurde aufgrund von Anorexie und blutigem Scheidenausfluss vorgestellt. Röntgenologisch wurde eine weichteildichte Verschattung im kaudalen Abdomen nachgewiesen. Sonographisch konnte eine vermehrte Flüssigkeitsfüllung und Verbreiterung beider Uterushörner nachgewiesen werden. Es wurde eine Ovariohysterektomie durchgeführt und die pathohistologische Untersuchung ergab Granulosazelltumoren beider Ovarien vom Sertolizelltyp sowie einzelne Zysten. Zusätzlich wurde eine glandulär-zystische Hyperplasie des Endometriums mit Ausbildung von Polypen und Dilatation der Uteruswand festgestellt. Das Tier überlebte postoperativ 365 Tage. Der Ablauf des chirurgischen Eingriffs mit Anästhesie und Analgeise Analgesie wird beschrieben. Jede der Kleinsäugerarten kann spezifische Neoplasien aufweisen, weshalb Angaben zu diesen Tumoren folglich nicht zwischen den Spezies übertragbar sind und individuell bewertet werden müssen. Aufgrund der Tumorvielfalt bei Kleinsäugern können auch eventuelle Therapieansätze nicht vollständig aus der Kleintiermedizin übernommen werden.View less
In meiner Arbeit mache ich mir das Streben nach Anerkennung als Leitmotiv für eine systematische Rekonstruktion der Philosophie von John Locke zunutze. Es stellt nicht nur ein zentrales Element von Lockes psychologischer Theorie dar, sondern kann darüber hinaus als Schlüssel zur Deutung der historischen und kulturpessimistischen Partien der Zwei Abhandlungen herangezogen werden. Denn es ist das Verlangen nach Anerkennung, nicht das nach Selbsterhaltung, das in Gestalt von Gier und Herrschsucht zur Ursache sozialer Konflikte avanciert, sobald ihm mit Geld und politischen Institutionen dauerhafte Möglichkeiten zur pathologischen Entfaltung (als Wunsch nach Überlegenheit) zur Verfügung stehen. Das Streben nach Anerkennung ermöglicht zudem ein tieferes Verständnis dafür, wieso Lockes Bemühungen um eine Besserung der sittlichen Verhältnisse nicht nur moralischer, sondern ebenso politischer Natur sind. Denn die konventionalistische Tendenz dieses Verlangens hat zur Folge, dass sowohl das Gesetz der Meinung als auch das bürgerliche Gesetz (zwei für Locke zentrale moralische Regelsets) ihre Kraft zum Besseren einbüßen: Sie richten das Handeln der Menschen – zumal das der Herrschenden – an den korrumpierten Wertmaßstäben des Status Quo aus. Hierdurch wird das Gedankenexperiment des Naturzustands erforderlich, das sich als Lockes Versuch lesen lässt, die pazifizierenden Potenziale des göttlichen Gesetzes in Form einer philosophischen Demonstration auszuloten. Letztere mündet in der Forderung nach einer Schaffung von politischen Institutionen, die eine effektive Befriedung der zuvor erörterten sozialen Konflikte garantieren sollen. Auch dabei spielt das Streben nach Anerkennung eine Rolle. So lässt es sich nicht nur verwenden, um die ideologiekritische Stoßrichtung der Ersten Abhandlung zu erklären; es kann auch zur Interpretation des in der Zweiten Abhandlung erdachten Gemeinwesens fruchtbar gemacht werden: Dieses stellt Lockes Versuch dar, politisch ergiebige, weil gemeinwohlförderliche Institutionen der Anerkennung zu ersinnen. Insbesondere das Konzept des Vertrauens (»trust«) vermag so einer innovativen Neudeutung zugeführt zu werden. Aber auch die anderen sozialen Sphären individueller Autonomie, die im Rahmen der Zweiten Abhandlung vorgesehen sind, lassen eine anerkennungstheoretische Lesart zu. Lockes »Liberalismus« hat mithin eine expressive Dimension, weil Freiheit und Rationalität für ihn anerkennungsfunktionale Güter darstellen.View less
This study proposes that – rather than trying to discern the normative value of Afropolitanism as an identificatory concept, politics, ethics or aesthetics – Afropolitanism may be best approached as a distinct historical and cultural moment, that is, a certain historical constellation that allows us to glimpse the shifting and multiple silhouettes which Africa, as signifier, as real and imagined locus, embodies in the globalized, yet predominantly Western, cultural landscape of the 21st century. As such, Making Black History looks at contemporary fictions of the African or Black Diaspora that have been written and received in the moment of Afropolitanism. Discursively, this moment is very much part of a diasporic conversation that takes place in the US and is thus informed by various negotiations of Blackness, race, class, and cultural identity. Yet rather than interpreting Afropolitan literatures (merely) as a rejection of racial solidarity, as some commentators have, they should be read as ambivalent responses to post-racial discourses dominating the first decade of the 21st century, particularly in the US, which oscillate between moments of intense hope and acute disappointment.View less
Cancer is thought to arise from the accumulation of genetic changes in the DNA of the patient. Mutations can occur during replication of cells or from external factors. Given the current knowledge of gene regulation it is not yet possible to link cancer phenotypes directly to the genetic alterations. Despite the vast increase of available high-throughput molecular data, the in silico identification of disease genes for multi-factorial diseases such as cancer is still a challenging task. Perturbation of entire modules in cellular networks, and genetic, as well as non-genetic gene alternations, contribute to tumorigenesis. This necessitates the development of predictive models able to effectively integrate and process different data modalities. Most approaches cannot combine multi-dimensional molecular data with gene-gene interactions and the few methods that achieve that are hard to interpret. In this thesis, I introduce EMOGI, an explainable machine learning method based on Graph Convolutional Networks (GCNs) to predict cancer genes by combining multi-omics data, such as mutations, copy number changes, DNA methylation and gene expression profiles across different cancers, together with Protein-Protein Interaction (PPI) networks. By profiting from different data representations, EMOGI was more accurate than previous methods in predicting known cancer genes, with an average increase in area under the precision-recall curve of 3% – 37% across different PPI networks and data sets. We applied the Layer-Wise Relevance Propagation (LRP) technique to learn the molecular features that contributed to the classification of each individual cancer gene. We also identified relevant cancer modules in the PPI network, and stratified genes according to whether their classification was mainly driven by the interactome, mutation rate or alterations in either DNA methylation or gene expression. We propose a new high-confidence list of 165 putative novel cancer genes which do not harbour recurrent alterations, but rather participate in PPIs with well-known cancer drivers. We functionally validated those novel predictions with publicly available loss-of-function screens. We believe that our results might open new diagnostic and therapeutic avenues in precision oncology, and that our method can applied to predict biomarkers for other complex diseases.View less
This work is about the formation of identities, especially of women identities, built at the turn from the nienteenth century to the twentieth century on the boundaries and inside the countries of the comarca pampeana, subscribed in the works of Eduarda Mansilla, José Hernández, Eduardo Acevedo, Javier de Viana, Alcides Maya and Simoes Lopes using theoretical approaches of Angel Rama, Ligia Chiappini Moraes Leite, Judith Butler and Michel Foucault.View less
The glucocorticoid receptor (GR) is a transcription factor which becomes activated upon binding to glucocorticoids, a class of steroid hormones. Upon activation, GR binds to various genomic locations and induces large-scale changes in transcription and chromatin structure. Clinically, GR is an important therapeutic target, since glucocorticoids are widely applied to treat autoimmune and inflammatory conditions. However, long-term treatment with glucocorticoids is associated with glucocorticoid-resistance and severe side-effects. At the molecular level, the effects of prolonged GR activation on a cell’s transcriptional responses are not fully understood. Here, I investigated if exposure to glucocorticoids results in long-term changes in chromatin and transcription. In addition, I studied GR’s genomic binding preferences by investigating mechanisms that shape DNA binding specificities between GR and its paralog, the androgen receptor (AR). In the first part of the thesis, I investigated the immediate and the long-term effects of GR activation on chromatin and transcription. By examining GR binding as well as glucocorticoid-induced changes in chromatin accessibility and transcription, I found that genomic regions that lose chromatin accessibility were enriched near downregulated genes. Interestingly, these ‘closing’ regions were largely not bound by GR, indicating that repression, in part, does not depend on nearby GR binding and might occur through indirect effects of GR activation. To study the long-term effects of GR activation, I investigated changes in chromatin accessibility and transcription after washout of glucocorticoids. GR-induced changes in chromatin accessibility were found to be reversible following a 24-hour washout period. Similarly, transcriptional activity reverted to basal levels after washout. Moreover, I tested if a prior exposure to hormone changes the response to a subsequent treatment. Most genes showed similar transcriptional responses upon hormone-re-stimulation compared to the first stimulation. However, the GR-target gene ZBTB16 showed enhanced upregulation upon reinduction, suggesting that prior glucocorticoid exposure results in priming of this gene. Single-cell analysis showed that enhanced expression of ZBTB16 upon reinduction was a consequence of an increased probability of cells transcribing the gene as well as individual cells showing increased ZBTB16 transcription. In the second part of the thesis, I assayed the role of chromatin and DNA sequence in generating divergent genomic binding patterns of transcription factors with nearly identical DNA-binding preferences, specifically, GR and its paralog AR. Investigating binding of GR and AR in the same cell type revealed that both transcription factors occupy overlapping as well as unique sites. Examining the chromatin landscape at receptor binding regions showed that many GR-specific sites were situated within relatively inaccessible chromatin, suggesting that binding specificity is, in part, achieved through GR’s ability to bind to inaccessible chromatin. Furthermore, motif enrichment analysis at GR- and AR-specific regions provided further evidence that the receptors exhibit subtle differences in the recognition sequences they preferentially bind to. Lastly, analysis of GC-content revealed that receptor-specific binding is also driven by GC-content at the binding sites and the larger surrounding area, as mean GC-content was found to to be higher at GR- compared to AR-specific sites. In summary, these results provide evidence that GR is capable of inducing gene-specific transcriptional memory, even though GR-induced chromatin structural and transcriptional changes are largely reversible. Given GR’s biological role as an effector to fluctuating levels of glucocorticoids, the reversibility of GR-induced chromatin and transcriptional changes is to be expected. However, future experiments involving longer, or more frequently repeated, hormone exposures might yield insights into the underlying mechanisms of glucocorticoid resistance and side-effects associated with long-term glucocorticoid treatment. Furthermore, the chromatin landscape as well as DNA sequence composition contribute to driving receptor-specific genomic occupancy of GR and AR. These findings might represent a general mechanism that shapes differential binding among paralogous transcription factors and could contribute to our understanding of how genomic binding specificities are established for other related transcription factors.View less
Salt-rich icy particles within Saturn’s E-ring are thought to originate from frozen aerosolized droplets of the salty seawater of Enceladus’ subsurface ocean. They are ejected into space, through fractures in the moon’s south polar region, within a plume of gas and ice particles. Some of these icy particles can escape the gravity of Enceladus thanks to their high velocities, and become E-ring particles, which typically have relatively young (no more than 200 years) ages. Therefore, it is believed that the salt-rich grains reflect the composition of the subsurface ocean water.
The in situ mass spectra of E-ring and plume icy particles, produced by the Cosmic Dust Analyzer (CDA) impact ionization mass spectrometer onboard the Cassini spacecraft, reveal significant compositional diversity within the salt-rich population. Understanding the compositions of dissolved substance, including salt, silica, and organics, within the grains, and thus in the ocean, can provide crucial constraints for geochemical models of Enceladus’ subsurface ocean environment.
The research presented in this thesis investigates the compositional diversity of the in situ mass spectra and hence the salt-rich icy particles and attempts to quantify the variations in grain composition with the aid of analogue mass spectra generated in the laboratory.
In this work, the in situ mass spectra and thus the salt-rich icy particles are classified into various compositional groups and subtypes. The major subtype distributions of E-ring spectra/particles with respect to distance to Saturn, impact speed and size have been studied and the contrast between the E-ring population and plume population examined. The major findings are: The `sodium-rich and potassium-poor' spectra (and hence icy particles) are the majority among both E-ring and plume salt-rich populations, while `potassium-rich and sodium-poor' spectra and `both sodium and potassium-rich' spectra are rare. Carbonate and chloride-containing spectra are mutually exclusive in most cases. The `sodium-rich and potassium-poor' spectra (and hence icy particles) are further classified into Subtypes A, B, H, C, D, E and L according to the presence and relative amplitudes of carbonate and chloride related peaks. Among them Subtypes A, B, C, D and L are the majorities in E-ring spectra. A part of ice particles producing Subtype A and Subtype L spectra at lower impact speed could produce Subtype B spectra at higher impact speed. While abundances of the major sodium subtypes are comparable in the E-ring salt-rich populations, the ultra carbonate-rich subtype, which is named as Subtype A, spectra are much more frequent than the spectra of other subtypes in the plume salt-rich population, which implies that the majority of the ultra carbonate rich (Subtype A) ice particles do not have enough energy to escape from the gravity of Enceladus and reach the E-ring or that the E-ring grains are older and rapidly lose their carbonate signature. The spatial distribution of the subtypes and relative peak amplitudes implies the carbonate and chloride compounds in the ice particles are lost slowly with time. The impact speed distributions of the subtypes and relative peak amplitudes for the spectra of E-ring salt-rich ice particles imply higher impact speeds tend to break up carbonate molecules and thus lower the amplitudes of carbonate related peaks.
To quantify the grains' compositions, a Laser Induced Liquid Beam Ion Desorption (LILBID) technique was used to desorb and ionize a wide range of Enceladean ocean-like solutions containing dissolved salts. The resulting ions were then measured by a reflectron-type time of flight mass spectrometer. Since the laser desorption mechanism simulates the ice grain impact process occurring on the CDA target, spectra produced in the laboratory from a large range of well-characterized salt solutions can be used to determine the CDA-applicable spectral appearances of substances within the ice grains emitted from Enceladus’ ocean.
Firstly, the composition parameter space, with NaOH, NaCl, and Na2CO3 as endmembers, for the four major subtypes of salt-rich ice particle were explored via spectra mimicking. After this, I reconstructed the mass spectra from chloride-rich and carbonate-rich Enceladus ocean analogues, into which trace concentrations of a wide range of geochemically-relevant salts, silica and organics were been dissolved, to evaluate their detection limits for CDA impact ionization mass spectra of the frozen ocean droplets. ocean droplets.View less