The aim of this work was the identification and the subsequent fine tuning of a convenient synthetic route from commercially available phenylalanine to pentafluorophosphates, as well as the incorporation of these fluorine-rich, amphiphilic phosphotyrosine mimetics in peptides. Although acid sensibility of pentafluorophosphates hampered the identification of a protocol compatible with solid phase peptide synthesis (SPPS), this was ultimately achieved using an excess of fluorides that allowed the synthesis of mono and bivalent model peptides. After the synthesis on solid support, the determination of the inhibitory potential against protein tyrosine phosphatase 1B (PTP1B) was determined in a photometric assay. Furthermore, in a joint research work it was possible to further investigate properties and potential of this moiety, including the crystal structure and the lipophilicity of the first pentafluorinated amino acid.Weniger anzeigen
Complex carbohydrates, also referred to as glycans, are ubiquitous in nature and represent one of the major classes of biopolymers. In contrast to peptides and oligonucleotides whose structure is directly related to specific genes, glycans are not directly encoded in the DNA. Instead, their structure is the result of a dynamic biosynthetic pathway that is heavily affected by environmental factors. Consequently, glycans are extremely diverse and exhibit branched sites, as well as a complex regio- and stereochemistry. A common way to address this complexity is liquid chromatography (LC) in combination with spectroscopic and mass spectrometric (MS) detection. It allows for high throughput measurements and can identify the general building block composition of a glycan, but it often fails to unambiguously assign the linkage between building blocks. The type of linkage, however, is a key factor for the three-dimensional structure of the glycan and therefore its biological functions. A promising alternative, which is sensitive to the globular structure of a glycan, is ion mobility-mass spectrometry (IM-MS). In addition to the separation based on the mass-to-charge (m/z) ratio, IM-MS allows to distinguish ions based on their size, shape, and charge. LC-MS and IM-MS both showed enormous potential for the analysis of glycans as standalone techniques, each providing a different level of information. However, there are very few examples of combining both approaches into a consistent LC-IM-MS workflow. In this thesis, it was investigated if IM-MS can be hyphenated to classical LC-MS workflows to enable a comprehensive structural elucidation of complex N-glycans. As sample preparation for LC-MS usually includes the modification of the reducing end of the glycan, the first step was to study the effect of these derivatizations on the quality of IMS separation. The problem was addressed by the systematic study of a set of six isomeric fucose-containing blood group antigens that are derivatized with the most common fluorescent tags using IMS. The quality of the separation was evaluated by comparing the CCS values of all species in positive and negative ion mode as well as with adduct ions. Afterwards, the application of LC-IMS-MS for the investigation of complex N-glycans was demonstrated. For this purpose, the glycans from human alpha-1-acid glycoprotein (hAGP) were investigated to identify the sialylation (α2,3- vs α2,6-linked residues) and fucosylation (core vs terminal) patterns. It was shown that IMS enables the structural elucidation of even highly sialylated glycans up to tetraantennary species without changing the sample preparation and within a single LC run. The main parameters that are obtained from LC-IMS-MS measurements are retention times, mass-to-charge-ratios, and drift times, which represent a powerful dataset to identify glycan isomers. However, retention times in LC and drift times in IMS depend significantly on instrumental parameters and are difficult to compare between experiments. We therefore introduced an internal calibration method for the conversion of retention times into universal glucose units (GU) and drift times into collisional cross-sections (CCS). It was shown that the internal calibration approach enabled a faster, more accurate analysis for both LC and IMS without loss in calibration accuracy or informational content. Overall, the addition of IMS into classical LC-MS workflows is straightforward and only requires minor adaptions in sample preparation and data treatment. It enables a fast and accurate identification of structural motifs and complements the informational content of LC-MS experiments. LC-IM-MS therefore represents a powerful combinational approach for the comprehensive analysis of complex N-glycans.Weniger anzeigen
Nature is based on self-assembling systems that generate functional structures. Inspired by nature, programmable artificial architectures have been developed, often making use of synthetic peptides and nucleic acids. In contrast, only limited examples of programmable carbohydrate assemblies have been reported. This can be partially ascribed to the limited knowledge of carbohydrates’ structure. Structural complexity, heterogeneity of natural carbohydrate samples, and the lack of suitable analytic techniques have prevented the molecular level description of carbohydrate materials. The introduction of synthetic model systems, able to generate chemically defined assemblies, could help the understanding of carbohydrate materials. Here, simple and well-defined oligosaccharides were employed to create model systems to study supramolecular carbohydrate-based assemblies and produce useful data for the formation of tailor-made materials. This approach also shined light on the interactions involved in the formation of natural systems, such as bacterial biofilms, where carbohydrate and peptides interact to form valuable nanocomposites. In chapter 2, I investigated the supramolecular structure formation of synthetic oligosaccharides. Systematic variation in their chain length, substitution pattern, and glycosidic linkages, generated distinctive morphologies, including spherical particles or fiber-like structures. The compounds showed unique intrinsic optical properties (e.g. red edge excitation shift), highly dependent on their aggregation status. Potential applications of glycomaterials in bioimaging and optical devices are envisioned. Among these six compounds, disaccharide 13 (13-D in chapter 3), growing into needle-like structures, offered the perfect model system to explore details of oligosaccharide assemblies and optimize analytical techniques to study carbohydrate materials. The stability of the assembly enabled the implementation of microcrystal electron diffraction (MicroED) for oligosaccharide samples. This technique allowed for the reconstruction of the crystal unit cell and permitted correlating the local molecular organization with the supramolecular assembly. Synthetic analogous of compound 13 with specific single-site modifications were designed to identify key stabilizing interactions. The combination of organic chemistry and electron diffractions methods will be implemented to reveal molecular details of natural polysaccharide assemblies. In chapter 4, a new model system was introduced to study bacterial biofilms, nanocomposites of cellulose and proteins (e.g. curli fibers). Specific E. Coli strains produce phosphoethanolamine (pEtN) cellulose as part of their protective biofilms, providing increased adhesion. I employed synthetic peptides and oligosaccharides to generate artificial biofilm and study the role of pEtN cellulose in biofilm formation. Different amounts and patterns of pEtN substitution in the oligosaccharide modulated the length and aggregation tendency of the peptide fibers. The mechanical properties of the protein-carbohydrate network were affected by the chemical nature of the carbohydrate component, with high adhesion measured for highly substituted pEtN cellulose analogues. Synthetic oligosaccharides able to interrupt fibrillary assembly were identified and could serve as promising drug candidates for the treatment of neurological diseases or as antibacterial agents. Overall, the synthetic oligosaccharide models presented in this thesis will establish the foundation of our understanding of carbohydrate interactions in nature and will promote several applications of carbohydrate materials in nanobiotechnology.Weniger anzeigen
The microbiome plays a key role in the maintenance of health, as well as in the pathogenesis of various diseases including hypertension and cardiovascular disease. The global aim of my thesis was to understand the role of bacteria in hypertensive organ damage, and to develop a new method for the precise phenotyping of proteins and microbiota-derived metabolites within the GI tract. To address the former, I used germ-free mice (GF), which are devoid of bacteria, to investigate if bacterial colonization modulates the response to a hypertensive stimulus. Compared with fully colonized (COL) mice, hypertensive GF mice showed significantly more severe renal damage, which was associated with increased systemic and local inflammatory responses. The hypertension-induced differences in the heart were less pronounced than in the kidney. Furthermore, metabolites within the serum from these mice showed broadscale differences elicited by hypertension in GF and COL mice. These results highlight that the presence of intestinal bacteria and bacterially produced metabolites, in particular short-chain fatty acids, inhibits inflammatory responses and hypertension-induced organ damage. These findings emphasize the importance of the homeostasis between the host and its colonizing microbes in hypertensive disease. Next-generation sequencing (NGS) and metabolomics analyses from fecal samples are typically used to characterize the dysbiotic state, providing an inventory of the microbes or microbial products. Both serum and fecal measurements present challenges because they are indirect measurements of the compartment of interest, the microenvironment of the gastrointestinal (GI) tract in the host. The prevailing hypothesis within the field is that metabolites and small molecules in the GI tract, which can be either host- or microbially-derived, impact the polarization and function of immune cells, thereby impacting inflammation in the gut and in distal organ systems (e.g., the heart and the kidney). Currently, no direct methods are available to evaluate the microenvironmental signature which is presumed to exist within the interstitial fluid (IF) of the GI tract. I applied two known methods to isolate the IF from the GI tract, to directly assess the local microenvironment at the site-of-action. Here I have shown that the isolation of GI IF reflects a unique compartment which had previously been largely uncharacterized. The IF from both rats and mice was found to contain elevated levels of SCFA within the lower intestinal segments, whereas the levels in the upper GI tract were not different from serum. I was also able to identify proteins which were specific to a given GI region (e.g., REG3G, LGALS1) within the IF using two independent methods. In conclusion, with these newly established methods for obtaining IF from different segments in the intestine, it is now possible to characterize the intestinal micromilieu in detail. In the future, IF isolation may facilitate a better understanding of the host’s interactions with the microbiome in health and disease.Weniger anzeigen
Rye and rapeseed meal (RSM) are interesting alternatives to wheat and soybean meal (SBM) for the nutrition of weaner piglets, especially regarding current challenges of pig production with respect to climate change and globalized trading of feed components. Rye tolerates more extreme temperatures and lower soil quality than wheat, rapeseed is adapted better to local climate conditions than soybean. The level of inclusion of rye and RSM into piglets’ diets was limited in the past due to the practical evidence of a lower palatability and anti-nutritional factors. Nonetheless, the content of dietary fibre increases with the inclusion of rye and RSM instead of wheat and SBM which might have beneficial effects on digestive physiology and resident microbiota. Moreover, recent studies showed that the feeding of high levels of rye and RSM did not reduce growth performance and feed intake of young pigs. However, research on the combined feeding of rye and RSM in piglets is scarce. Therefore, the aim of this study was to investigate the effects of rye and RSM included at a high dietary inclusion level in comparison to wheat and SBM on growth performance, protein, amino acid, and non-starch-polysaccharide (NSP) digestibility, physical characteristics of the digesta, intestinal morphology, and the composition and metabolic activity of intestinal microbiota in weaner pigs. A feeding trial was conducted with 88 piglets. At weaning at the age of 28 days, the piglets were randomly allocated to four groups and housed two piglets per pen. They were fed one of four isonitrogenous, pelleted diets ad libitum (n = 11): wheat/SBM, wheat/RSM, rye/SBM, and rye/RSM. Dietary inclusion level was 48 % for the cereals, 25 % for SBM, and 30 % for RSM. The diets were analysed for nutrient composition including total dietary fibre and NSP. Body weight gain and feed intake were recorded weekly and faecal consistency was scored daily. After 33 days, one piglet per pen was euthanized for the assessment and collection of digesta and the measurement of intestinal morphology. Digesta samples were analysed for pH value, viscosity, dry matter and nutrient digestibility, bacterial metabolites, and relative abundance of microbiota. The rye-based diets contained more soluble NSP than wheat-based diets. The RSM-based diets were higher in insoluble NSP compared to SBM. Growth performance was not affected by rye, but RSM reduced weight gain (p = 0.024) and feed intake (p = 0.037) compared to SBM. Rye and RSM decreased apparent ileal digestibility of crude protein and amino acids (p < 0.05). Colonic and faecal digestibility of NSP was higher in rye-fed piglets (p < 0.001, p = 0.001, respectively), lower in RSM-fed piglets (p < 0.001). Rye-fed pigs showed a more acidic and viscous small intestinal digesta (p = 0.045, p = 0.013, respectively), and a higher relative weight of the colon tissue (p < 0.001). Concentration of short-chain fatty acids was higher in rye-fed piglets in jejunum and colon (p < 0.001, p = 0.016, respectively). RSM lowered jejunal concentration of short-chain fatty acids (p = 0.001). Rye increased the relative abundance of Firmicutes and decreased Proteobacteria in the jejunum (p = 0.039, p = 0.002, respectively). Firmicutes were decreased and Actinobacteria (jejunum, colon, faeces: p < 0.050), jejunal Proteobacteria (p = 0.019) and colonic Bacteroidetes (p = 0.014) were increased in RSM-fed pigs compared to SBM. In conclusion, this study showed that rye and RSM can be used as alternatives to wheat and SBM in compound feed for weaner piglets without or with only a minor reduction of growth performance and protein digestibility and without any negative effect on animal health. In fact, the inclusion level of rye and RSM may be higher than previously recommended. Effects on digestive physiology and intestinal microbiota were mainly associated with the different composition of dietary fibre of the investigated feed components. The high content of soluble dietary fibre in rye was more degradable than wheat fibre, caused an increased microbial fermentative activity but did not induce a shift of the colonic microbiota. RSM was most likely too high in insoluble dietary fibre which led to the reduction of protein digestibility and bacterial metabolic activity as well an increased relative abundance of Actinobacteria and Bacteroidetes which are known to degrade insoluble fibre. Future research is warranted to elucidate further possible beneficial features of rye and RSM, to evaluate the optimum dietary inclusion level of these feed components, and to improve the understanding of the mechanisms, including host-microbiota interaction, that facilitate targeted practical use of rye and RSM instead of wheat and SBM in pig nutrition.Weniger anzeigen
Avian coronavirus, also known as infectious bronchitis virus (IBV), belongs to the genus Gammacoronavirus and is the causative agent of infectious bronchitis, a highly contagious respiratory disease in the poultry industry. In virology studies, reverse genetics systems based on BACs are extremely valuable because they allow us to manipulate viral genes. In our study, we assembled the complete genome of the IBV strain Beaudette-FUB into an artificial bacterial chromosome (BAC), producing an infectious BAC clone. From this constructed IBV BAC clone, we successfully rescued infectious viruses with identical growth characteristics to the parental viruses. To establish genetically stable EGFP viruses, we then inserted the EGFP ORF into 11 putative cleavage sites of 3CLpro. Of these, we identified three insertion sites located at the outermost 3’ end of the replicase gene– between the coding sequences of Nsp13 (helicase), Nsp14 (RNA exonuclease), Nsp15 (RNA endonuclease), and Nsp16 (RNA methyltransferase) could tolerate heterologous genes in the IBV genome. Additionally, we found that fluorescent proteins expressed by the replicase gene can be efficiently cleaved by the 3CLpro and released from the replicase polyprotein. Furthermore, we also determined the genetic stability of these three EGFP-replicase viruses. Among them, the engineered Nsp13-EGFP-Nsp14 virus still exhibited high stability in DF-1 cells after 20 serial passages. The colocalization results showed that EGFP, together with dsRNA or RdRp, accumulated in the well-defined foci at the early stage of infection. When the infection progressed, EGFP proteins were produced and distributed throughout the cytoplasm. Our studies have shown that the replicase-EGFP viruses could be used to study viral replication and transcription, to screen antiviral drugs on a large scale, to develop multivalent vaccines, and even that the potential positions could be applied to other coronaviruses.Weniger anzeigen
This thesis summarizes experimental work performed on thin-film metallic and magnetic systems by time-resolved soft X-ray reflectivity and magneto-optical Kerr effect measurements. The delay-time-dependent magnetization dynamics in Co, Mn, and Ni after laser excitation are investigated in layered systems. The work aims to study the effects of antiferromagnetic coupling on de- and remagnetization dynamics in an adjacent ferromagnetic film on the ultrafast timescale. The presented work bridges the timescale from the first femtoseconds to macroscopic dynamics after several microseconds. The thesis is divided into a literature review covering the treatment and scientific context of the investigated phenomena and experimental reports where the findings of this work are presented and discussed. The presentation of the experiments is divided into four chapters. First, differences between the ultrafast demagnetization in a Cu/Co/NiMn/Cu(001) system recorded at high and low sample base temperatures are investigated. The report shows that the antiferromagnetic alignment in the NiMn system, present at low temperature, facilitates a faster demagnetization of the adjacent Co layer compared to a magnetically disordered NiMn layer at high temperatures. The second investigation covers the timescale of laser excitation and presents experimental evidence of the optically induced intersite spin transfer in a (Co/Mn)x6/Cu(001) multilayer system. An increase in the magnetic contrast in the antiferromagnetically ordered Mn layer is observed. The magnetic contrast lives for the time of excitation and indicates a realignment of the magnetic moments of the interface layers of Mn in the direction of Co. The third chapter treats simulations of the X-ray reflectivity after laser excitation. The multilayer system investigated in the aforementioned experiment is analyzed with respect to its magneto-optical properties, and the observations recorded with the X-rays are directly correlated with the transient optical response function of the elements. Furthermore, we compare the results of the simulations of the X-ray reflectivity considering structural, electronic, and magnetic effects. The last presented study is concerned with time-dependent magnetization dynamics recorded in Pt/Co multilayers. We investigate the delay-time-dependent Kerr effect and present experimental evidence for different dynamics in a Pt/Co bilayer system compared to a Pt/MnPt/Pt/Co system. Lastly, we investigate the effects of the spatial pump-probe overlap on the magnetization dynamics and link the observation to thermal and lateral transport phenomena.Weniger anzeigen
In this thesis, a system for the application of flow-induced, physiologically relevant shear stress on mammalian cells was established. The circulation of cell culture medium in culture circuits was generated by peristaltic pumps, which can be operated with a self-built control unit. Culture chambers for different applications were computer-assisted designed, characterized by computational fluid dynamics and subsequently manufactured either by CNC milling or 3D printing. Using this system, shear-induced changes on the cellular functionality of in vitro barrier models were investigated. The application of low, physiologically relevant shear forces to an established intestinal epithelial cell line, HT29-MTX, resulted in increased mucus production, as well as structural reorganization of the confluent cell layer towards 3-dimensional villi-like structures. The results could be transferred from solid cell culture substrates to commercially available cell culture inserts bearing membranes, allowing us to develop an improved in vitro model of the intestinal barrier with a physiologically relevant mucus layer. We then proceeded with the endothelial barrier. Here, we investigated the effects of flow-induced stress comparatively for HUVECs and iPSC-ECs. Both cell types showed the characteristic alignment upon application of flow, as well as increased layer thicknesses and improved functionality of the endothelial glycocalyx. In addition, for the first time, we were able to detach isotropic (HUVECs) and anisotropic (iPSC-ECs) cell monolayers from thermoresponsive surfaces and wrapped them around a 3D-printed scaffold while maintaining alignment, which represents an important step toward the development of blood vessels in vitro. Finally, we implemented a similar tubular construct into dynamic culture. The indirect coculture of HUVECs with fibroblasts allowed intercellular communication and resulted in the formation of stable vascular networks, while a second independent circuit allowed perfusion of the tubular blood vessel mimick. In summary, we established a versatile and reliable platform for the application of physiological shear forces to flat and lumenized tissues, enabling the development of improved in vitro barrier models.Weniger anzeigen
Thionitrosylkomplexe sind im Vergleich mit den Nitrosylkomplexen deutlich weniger untersucht. In der Literatur wird dies oft mit dem Fehlen einer stabilen Thionitrosyl-Vorläuferverbindung, aus der die Komplexe leicht erhalten werden können, begründet. Nichtsdestotrotz wurden verschiedene Verfahren zur Synthese von Thionitrosylkomplexen entwickelt. Insbesondere die Reaktion von Nitridokomplexen mit Dischwefeldichlorid konnte in dieser Arbeit als effektive Syntheseroute für Thionitrosylkomplexe bestätigt werden. Zusätzlich konnten die so erhaltenen Phosphankomplexe [Re(NS)Cl3(PPh3)2] und [Tc(NS)Cl3(PPh3)2] als potentielle Startverbindungen für die Synthese weiterer Thionitrosylkomplexe getestet werden. Das Ziel der vorliegenden Arbeit, ist ist die Synthese neuer Thionitrosylkomplexe und die damit verbundene Erweiterung des Wissens um diese Ligandenklasse.Weniger anzeigen
Ist Zusammengehörigkeit auf Worte angewiesen? Bedeutet ein ‚Mehr‘ an Sprachigkeit zugleich ein ‚Mehr‘ an Zugehörigkeit? Diese Studie fragt nach der Bedeutung des Sprechens und Schreibens für die Mitteilung und den Vollzug von Gefühlen der Zugehörigkeit. In Auseinandersetzung mit dem Werk zweier literarischer Gegenwartsautorinnen, Herta Müller und Ilma Rakusa, entwickelt sie das affektpoetologische Programm eines Schreibens im Wi(e)derspruch, das literaturwissenschaftliche Verfahren erstmalig mit Ansätzen der sozialwissenschaftlich grundierten Zugehörigkeitsforschung verbindet und sich an ein interdisziplinär aufgeschlossenes Lesepublikum richtet. Anhand von Romanen, Erzählprosa, Reden, Essays, Poetik‑Vorlesungen, Gesprächen und Interviews der beiden Autorinnen arbeitet sie die je spezifischen Ausprägungen des komplexen Zusammenhangs zwischen Zugehörigkeit und Nicht‑Zugehörigkeit heraus, die sich in geteilten Gefühlen artikulieren und ein Bündel von Thesen belegen: Die Analyse des Schreibens im Widerspruch zeigt erstens auf, dass Zugehörigkeit keineswegs immer mit Wohlgefühlen wie Geborgenheit, Sicherheit, Wärme und Vertrauen assoziiert sein muss und wirkt somit den normativen Tendenzen entgegen, wie sie sowohl in Teilen der interdisziplinären belonging‑Forschung als auch in Teilen der alltäglichen und öffentlichen Rede über Zugehörigkeit vorherrschen. Zweitens macht die Untersuchung deutlich, dass Zugehörigkeit nicht erst durch Migration problematisch wird, sondern ihre dynamische Prozessualität auch und gerade in Kontexten zum Vorschein tritt, die als starr und unbeweglich dargestellt sind. Dieser dynamischen Prozessualität korrespondiert drittens die Bewegung des Schreibens durch verschiedene – schriftliche oder mündliche – Gattungen des Sprechens, die als Orte der Reflexion und Artikulation multipler, prekärer oder ambivalenter Erfahrungen der Zugehörigkeit fungieren und somit Antworten auf die bisher wenig erforschte Frage nach dem Zusammenhang von Zugehörigkeit und Sprache bieten. Die Poetiken der Nicht‑/Zugehörigkeit konstituieren sich als vielstimmige Sprechpoetiken, die immer auch das (Zu‑)Hören involvieren und daher, viertens, dialogische Konzepte von ‚Autorschaft‘ hervorbringen, welche die Unzertrennlichkeit von Leben und Literatur wiederholt und affektiv zur Geltung bringen. Die Untersuchung der Brüche und Widersprüche von Nicht‑/Zugehörigkeit in den Texten Müllers und Rakusas lädt dazu ein, zentrale literaturwissenschaftliche Grundbegriffe wie ‚Autorschaft‘, ‚Gattung‘ und ‚Werk‘ neu zu durchdenken. Sie eröffnet elementare Einsichten in ein vermeintlich selbstverständliches Gefühlsphänomen, das in den mobilen, globalisierten und durch Migration pluralisierten Gesellschaften der Gegenwart vielfältig herausgefordert wird und für das einzelne Individuum von existenzieller Tragweite ist. Die Arbeit zeigt auf, dass gerade die Auseinandersetzung mit literarischen Texten imstande ist, zu einem differenzierten Verständnis von Prozessen affektiver sozialer Verortung beizutragen und gibt damit Impulse für weitere Forschungen im Feld der transkulturellen Zugehörigkeits‑ und Gegenwartsliteraturforschung.Weniger anzeigen
To ensure that knowledge is not exclusive to a few, but available for the many, public agencies publish statistics as a public good - also called official statistics. Facing increasing competition about the prerogative of ’facts’, statistical agencies are expected to provide more disaggregated, frequent, granular and reliable statistics in a timely manner. Already today, enormous amounts of data are generated around us frequently as more and more parts of our lives move into the digital realm. Much of this information on human action is linked to place and time. Exploiting those spatio-temporal patterns may help to better understand underlying dependencies and trends in the socio-economic fabric of our society. Consequently, can official statistics leverage this new ”data deluge” and live up to the promises of better, more relevant statistics? In attempts to do so, the use of satellite imagery, mobile phone data, social network data and other new data sources for demographic or socio-economic mapping has drawn much attention in recent years. The thesis contributes to this field of research on applied statistics in two ways: Part I showcases how new data sources can be utilized to improve traditional statistical data collection techniques, notably censuses and surveys, especially in settings with weak national statistical systems. In contrast to the application-driven first part of the thesis, Part II focuses on overcoming methodological challenges in augmenting official statistics with new data sources, especially when combining these disparate data sources in the first place. The presented use cases and methodological contributions are just a few among many steps necessary to pave the way for alternative data sources to be utilized in the business processes of official statistics. But as enterprise data became an important pillar for measuring modern-day economic activity a century ago, as administrative data overhauled long-time census practices only recently, eventually (privately-held) non-statistical data from mobile and social networks, from satellite imagery or other sensors may find their way into mainstream official statistics one day to produce statistics in a more disaggregated, frequent, granular, reliable and timely manner after all.Weniger anzeigen
G-protein coupled receptors (GPCRs) represent the biggest family of membrane receptors. The physiological accessibility of drugs, their regulatory roles in a vast amount of physiological and pathophysiological processes, and their prevalence in many tissues are reasons why they are highly targeted in a therapeutic context. To exploit the modulatory capabilities of GPCRs prior knowledge of their mechanism of action on a molecular level is required. This is especially important for the successful application of rational structure-based drug design campaigns. Sphingosine-1-phosphate receptors (S1PR) has shown to be effective drug targets against multiple sclerosis (MS), but non-selective drugs suffer from serious adverse effects. Furthermore, targeting a single S1PR holds a lot of potentials to modulate different inflammatory and autoimmune diseases. In this thesis, we present in silico mechanistic models for the identification of crucial structural determinants to illuminate the molecular basis for Sphingosine-1-phosphate receptor selectivity and the general class A GPCR activation process. We employed extensive molecular dynamic (MD) simulation models of S1PR1-5 and performed a holistic comparative orthosteric protein-ligand interaction analysis of identified different binding modes of a pan-agonist to overcome the challenge of highly similar binding pockets between each subtype and rationally explained the selective behavior of marketed drugs Ozanimod and Siponimod used in multiple sclerosis therapy. Furthermore, we provide insights into the mechanism of class A GPCR activation and how dihedral angles of the protein backbone are involved in this process. By developing a data extraction and machine learning workflow we created predictive models for active and inactive state GPCR conformations and showed possible applications for GPCR homology models and MD simulation predictions in a fast and efficient way. The methods and workflow to apply the prediction models are provided as a python package on GitHub (github.com/TrungNgocNguyen/GPCRml). The unique and rational combination of state-of-the-art molecular modeling, data extraction and analysis, and machine learning methods demonstrate how explanatory in silico models can be developed to elevate the understanding of challenging problems in the field of GPCRs.Weniger anzeigen
Die Arbeit untersucht die Darstellung eurozentrischer Denkweisen in den Bildmedien der Archäologie Westasiens und ihren Einfluss auf die Darstellung der Vergangenheit sowie des Berufs der Archäologie in modernen Medien am Beispiel der Videospiele.
Im ersten Teil der Arbeit werden im Speziellen Rekonstruktionszeichnungen früher Archäologie untersucht und mit ihren Entstehungsgeschichten, den Biografien der Autor*innen und ihrer Rezeption detailliert analytisch untersucht. Dabei reichen die behandelten Zeichnungen von der ersten innerhalb westasiatischer Archäologie erstellten perspektivischen Rekonstruktion durch den britischen Archäologen Henry Layard bis zu den einflussreichen Zeichnungen des deutschen Architekten und Archäologen Walter Andrae. Die Untersuchungen arbeiten drei gemeinsame Indikatoren als Ausdruck eurozentrischer Denkweisen heraus: 1. Romantisierung/Idealisierung antiker Kulturen Westasiens 2. Ideelle Aneignung antiker Kulturen Westasiens durch Europa 3. Kulturelle Abgrenzung antiker Kulturen Westasiens
Im zweiten Teil der Arbeit wird ein Blick auf die Entwicklung der archäologischen Wissenschaft bis heute geworfen und insbesondere, wie sich moderne Rekonstruktionsvisualisierungen darstellen. Anhand von drei Fallbeispielen kann gezeigt werden, dass die im vorherigen Teil herausgearbeiteten Indikatoren in abgeschwächter Form immer noch Teil wissenschaftlich produzierter Rekonstruktionen sind.
Ein detaillierterer Blick wird aber auf die Entwicklung des Bilds der Vergangenheit und Archäologie in modernen Medien geworfen und dazu das Medium der Videospiele näher betrachtet. Die Untersuchung kultur- und subjektfokussierter Videospiele ergibt, dass stereotype Erwartungshaltungen das Bild von Vergangenheit und Archäologie in diesen Spielen prägen. Diese Erwartungshaltungen lassen sich in drei Gruppen (Imperialismus, Sozialdarwinismus und Orientalismus) aufteilen und finden ihren Ursprung in diversen Filmen und Figuren, die sich wiederum auf die in der frühen Archäologie etablierten Stereotype stützen.
Das letzte Kapitel schließlich bringt die Ergebnisse des ersten Teils mit denen des zweiten Teils zusammen und argumentiert, dass sich die Leitmotive der Videospiele in den Indikatoren früher archäologischer Rekonstruktionszeichnungen wiederfinden. Somit findet eine Tradierung eurozentrischer Denkweisen in modernen Videospielen statt. Den Abschluss bildet die Problematisierung dieser Ergebnisse und ein Ausblick wie damit umzugehen ist.Weniger anzeigen
The aim of this study was to biomechanically test ligaments in different preparations from dead horses and dogs with respect to their suitability as a substitute for the cranial cruciate ligament.
Native CrCL breakage tests: The biomechanical properties of the bilateral native cranial cruciate ligament (CrCL) from 28 dog were tested in different 5 geometrical stifle joint angles. The resulting biomechanical findings were related to the respective weights of the examined dogs, and were compared to the biomechanical properties of the CrCL.
Tendon breakage tests: The native suitability of canine common calcaneal tendons (CCCT) and canine radial carpal extensor tendons (CRCET) from 30 euthanised dogs, and native equine deep digital flexor tendons (EDDFT) were obtained from two horses (euthanised or recently deceased). These were treated with a variety of decellulariation, and subsequently recellularisation methods and the biomechanical changes were evaluated. By comparing the effects of various methods on the collagen structure and biomechanics, the aim of the study was to identify the most effective decellularisation method and to determine which decellularisation method has more impact biomechanically on recellularised ligaments. Moreover, a variety of combinations were investigated, including t-octylphenoxypolyethoxyethanol (Triton-X 100) and tri-n-butyl phosphate (TnBP), in order to determine which combination exhibited the greatest biomechanical decellularisation effect in dogs’ and horses’ tendons. The biomechanical properties of all CrCL and canine and equine tendons were investigated in breaking-strength and elongation tests. The breaking strength of the specimens was elongated at a loading rate of 0.1 kN/s, force interspace: 3000 – 4000 N, test velocity: 10 mm/min. By way of a general overview for native CrCL and tendon breakage tests, the average breaking strength was found for canine CrCL samples (M = 1187.4 N; SD = 425.3), Fmax 2454 and Fmin 441N. For decellularised canine and equine tendons (M = 401.3 N; SD = 121.6), Fmax 656.2 N and Fmin 160 N; as well as recellularised canine and equine tendons (M = 499.8 N; SD = 139.6), Fmax 797.1 N and Fmin 174 N were measured. The breaking strength of canine CrCL samples was significantly higher than the breaking strength of decellularised canine and equine tendons, as well as recellularised canine and equine tendons. The test showed a significant effect of native CrCL and implant materials on the breaking strength. Additionally, the results for the elongation of native CrCL samples (M = 15.7 mm; SD = 8.3) was higher than in decellularised canine and equine tendons (M = 13.6 mm; SD = 5.7) as well as recellularised canine and equine tendons (M = 14.0 mm; SD = 4.4). Information obtained during this study could be applied to prostheses used in dogs with CrCL rupture, and it was suggested that a constant factor related to body-weight could be used to evaluate the approximate strength and elasticity of the CrCL.Weniger anzeigen
Schwere bakterielle Pneumonien führen häufig zu einer Schädigung der Lunge. Ein bedeutender Erreger einer schweren Pneumonie ist das grampositive Bakterium Streptococcus pneumoniae. Im Verlauf einer Pneumokokkenpneumonie kann es durch direkten Einfluss von Pathogenitätsfaktoren sowie der körpereigenen Abwehrreaktion zu einer erhöhten endothelialen Permeabilität und einem pulmonalen Barriereversagen kommen, welches in schweren Fällen in ein akutes Lungenversagen münden kann. Angiopoietin-2 ist ein körpereigener Ligand des endothelial vorkommenden Tyrosinkinase-Rezeptors Tie-2. Das Protein hat einen bekannten proinflammatorischen und destabilisierenden Einfluss auf das Gefäßsystem und wird nach einer Stimulation mit Pneumolysin, einem Virulenzfaktor von Streptococcus pneumoniae, vermehrt vom pulmonalen Endothel ausgeschüttet. Die Bedeutung von Angiopoietin-2 in der schweren Pneumokokkenpneumonie ist noch unbekannt. Ziel der vorliegenden Doktorarbeit war es, den Einfluss von Angiopoietin-2 auf das inflammatorische Geschehen und die pulmonale Barrierestabilität in der schweren Pneumokokkenpneumonie mit einhergehendem akuten Lungenversagen näher zu untersuchen. Hierzu wurde ein konditionelles Angiopoietin-2-Knockout-Mausmodell verwendet. Der Knockout der gezüchteten Angiopoietin-2-loxP/loxP-Cre-ERT2 Mauslinie wurde in vivo mit Tamoxifen und in vitro mit 4 -Hydroxytamoxifen induziert. In anschließenden Versuchen wurde die Effizienz des induzierten Angiopoietin-2-Knockout untersucht. Hierbei zeigten die Angiopoietin-2-Knockout-Mäuse eine lückenhafte Gendeletion. Die induzierten Mäuse wiesen im Vergleich zu ihren nicht induzierbaren Geschwistertieren, welche als Kontrolle dienten, zwar eine deutlich verringerte Expression von Angiopoietin-2 auf, eine vollständige Deletion des Proteins konnte jedoch nicht erzielt werden. In vitro bestätigten die erhobenen Daten die bereits bekannte destabilisierende Wirkung von Angiopoietin-2 auf das pulmonale Endothel. Primäre murine pulmonale Endothelzellen von Angiopoietin-2-Knockout-Mäusen wiesen nach einer Stimulation mit Pneumolysin im Vergleich zu pulmonalen Endothelzellen von Kontrollmäusen einen geringeren Integritätsverlust des Zellmonolayers auf. In ergänzenden in vivo Studien zeigten die mit Streptococcus pneumoniae infizierten Angiopoietin-2-Knockout-Mäuse einen verringerten Angiopoietin-2-Plasmaspiegel als die Kontrollmäuse. Ein Unterschied im inflammatorischen Geschehen sowie der alveolokapillären Barierrefunktion war zwischen den Gruppen jedoch nicht ersichtlich, so dass die protektive Wirkung eines Angiopoietin-2-Knockout in der Pneumokokkenpneumonie in diesem Versuchssetting nicht bestätigt werden konnte. Gründe für die abweichenden Ergebnisse der in vitro und in vivo Studie könnten in der verwendeten Mauslinie, deren unvollständigen Induzierbarkeit, sowie im Versuchsdesign liegen. Die Untersuchung des Proteins auch im Hinblick auf die Notwendigkeit neuer innovativer Therapiestrategien bei einem Pneumonie-induzierten akuten Lungenversagen bleibt eine bedeutende Fragestellung. Neben der Erprobung weiterer Tamoxifen-Induktionsprotokolle zum Erreichen einer effektiveren Ang-2 Deletion, oder der Verwendung eines anderen in vivo Versuchdesigns (früherer Analysezeitpunkt oder Einsatz einer Antibiotikabehandlung), sollte die Verwendung einer anderen Mauslinie zur Erforschung des Einflusses von Angiopoietin-2 im Verlauf einer Pneumokokkenpneumonie in Betracht gezogen werden.Weniger anzeigen
Der erste Beitrag zu dieser Arbeit befasst sich mit den grundlegenden Aspekten der Komorbiditäten des Lymphödems (Manuskript 1). Manuskript 2 untersucht einen Aspekt grundlegender Wirkeffekte der manuellen Lymphdrainage auf das Gewebe. Die Komplexe Physikalische Entstauungstherapie (KPE), bestehend aus Kompressionstherapie, manueller Lymphdrainage, Bewegung und Hautpflege, ist weiterhin unbestrittener Standard in der Behandlung von Lymphödemen. Die zunehmend stärker werdende Evidenz zur Therapie von Lymphödemen hat in den letzten Jahren eine Betonung der Bedeutung der Kompressionstherapie mit sich gebracht. Nichtsdestotrotz werden immer wieder adjuvante, teils auch alternative Therapieverfahren vorgeschlagen, deren Wertigkeit aber immer wissenschaftlichen Kriterien standhalten und deshalb klinisch geprüft werden muss. In diesem Kontext wurden die Tiefenoszillation, die Anwendung sogenannter Lymphtapes, sowie neue Klettverschluss-basierte Kompressionsbandagen (medizinische adaptive Kompressionssysteme) jeweils in randomisierten, kontrollierten klinischen Studien bzw. experimentell untersucht (Manuskripte 3-6). Die explorative Prävalenzstudie deckte hohe Prävalenzen von Adipositas bei sekundären Lymphödemen sowie eine überraschend hohe Hypothyreoseprävalenz bei sekundären Lymphödempatienten auf. Dahingegen scheint die Genese des Lymphödems nicht entscheiden für die Erysipelprävalenz zu sein. Der transkutan gemessene Sauerstoffpartialdruck ist an lymphödematös veränderten Extremitäten reduziert. Manuelle Lymphdrainage verbessert den Sauerstoffpartialdruck, eine Behandlungsserie als Teil einer KPE kann ihn normalisieren. Elastische Tapes können für die Therapie von Lymphödemen nicht empfohlen werden, da sie, unter der Kompression angelegt, keine signifikante Wirkung auf Volumen oder subjektive Beschwerden zeigen. Als alleinige Therapie ohne Kompression kann gar es zu gefährlichen Volumenexazerbationen kommen. Tiefenoszillation (Lymphdrainage mit niedrigfrequent wechselnden elektromagnetischen Feldern) ist, als additive Anwendung gegenüber MLD allein, vorteilhaft bei der Therapie des sekundären Brustlymphödems. Medizinische adaptive Kompressionssysteme sind maßgefertigten Flachstrick-Kompressionsstrümpfen in der Erhaltungsphase der KPE nicht unterlegen. In-vivo-Druckmessungen untermauern deren therapeutische Effektivität.
Komorbiditäten des Lymphödems sollten bei diagnostischen und therapeutischen Strategien stärker berücksichtigt werden. Hierfür ist es auch notwendig, die vorhandenen Diagnostik- und Assessmentverfahren zu verbessern und zielgerichtet einzusetzen. Die Erforschung und Weiterentwicklung bestehender und etablierter Therapieverfahren muss weitergeführt, neue Therapieverfahren müssen kritisch hinterfragt werden und wissenschaftlichen Standards standhalten.Weniger anzeigen
This study aims to understand why established salespeople lack success in selling digital innovations and to identify whether uncovered phenomena are expandable beyond the digital innovation context and if distinct measures can be developed in that regard. Finally, this research intends to offer managerial levers and insights to academia on how to alleviate potential issues in terms of selling digital innovations.
To this end, the study begins with a literature review on the research fields of digital innovation and innovation selling. Examining key results of extant research in these fields reveals the foundational research void of a large disconnect between these two streams. In addition, the second part of the literature review explains this study’s key construct and its origin from a general conceptual standpoint. Three empirical studies are subsequently conducted.
First, Zeithaml et al.’s (2020) theory developing theories-in-use (TIU) approach is employed for an initial exploratory study. Drawing on 59 interviews with experts from two international manufacturers, this study identifies a mechanism that extant literature has not explored. That is, established industrial salespeople often refrain from digital innovation selling because they are afraid to lose their face when interacting with customers.
Second, drawing on 10 in-depth interviews with salespeople and managers from another global manufacturer, the subsequent empirical study provides an in-depth understanding of salespeople’s fear of losing face and its development process. The study indicates that the mechanism of fear of losing face is not only limited to the context of digital innovations but also appears in the broader context of innovation selling.
Third, an additional study examines whether salespeople’s fear of losing face can be distinctly measured and if the conceptual propositions are confirmable on quantitative bases. Based on exploratory and confirmatory factor analyses with data from 204 participants, the findings indicate that fear of losing face can be measured with strong construct validity by a scale of 10 items. In addition, the results of a structural equation modeling analysis offer nomological validity conveying that the conceptual propositions regarding the emergence of salespeople’s fear of losing face are mainly confirmed.
Based on these empirical studies, this study offers several contributions to academia. Additionally, the study provides concrete guidance for manufacturers that are troubled by digital innovation selling and innovation selling in general. Finally, the present study offers several impulses for further research and possesses certain limitations.Weniger anzeigen
Posttraumatic stress disorder (PTSD) is a prevalent and highly disturbing mental health condition that occurs in response to extremely distressing events during the lifetime. First, military personnel represent a high-risk population for the development of posttraumatic stress symptoms (PTSS) or the full-diagnostic spectrum of the disorder due to deployment- and combat-related stressors during their military career. Despite the existence of well established and efficacious psychotherapy treatments for PTSD, access to trauma-focused psychotherapy is limited and veterans in particular experience high barriers to accessing help from the mental health care system. A substantial proportion of affected veterans receive no or inadequate treatment, increasing the risk of secondary adverse mental and somatic health outcomes, reduced social and occupational functioning, and of the condition becoming chronic. Second, internet-based interventions (IBI), particularly internet-based cognitive behavioral therapies (iCBT), have been shown to be efficacious and widely accepted for the treatment of a range of psychiatric disorders, including PTSD. IBI can already be seen as playing a potentially important role in supplementing the landscape and provision of psychotherapeutic interventions, and this is set to grow further in the future. Indeed, IBI should be particularly beneficial for patients in rural areas with a restricted psychotherapy infrastructure, for patients with restricted mobility, and for patients who desire greater anonymity and more independence regarding the time and location of psychotherapy access. Third, the systematic and reliable assessment of objective indicators of symptom expression and symptom change is of increasing interest and relevance for psychotherapy research. This dissertation thesis aims at incorporating these three pillars in four studies: First, a diagnostic identification of PTSD in veterans of the German Armed Forces (GAF) according to the main diagnostic manuals the International Classification of Diseases and Related Health Problems (ICD) and the Diagnostic and Statistical Manual of Mental Disorders (DSM); second, a meta-analytical evaluation of the efficacy of IBI in PTSD; third, an assessment of patterns of visual attentional bias in (traumatized) veterans (with PTSS); and fourth, an exploration of the modifiability of attentional bias in veterans after receiving iCBT. STUDY 1 investigated the concordance of PTSD prevalence rates when transiting between the diagnostic criteria of the DSM-IV, DSM-5, ICD-10, and proposed ICD-11 in a sample of service members of the GAF. High levels of agreement emerged between the DSM-IV and the DSM-5, and between the DSM-5 and the proposed ICD-11. Prevalence rates were significantly higher according to the proposed ICD-11 compared to the ICD-10, mainly due to the deletion of the time criterion. STUDY 1 provides support for the identification of six ‘core’ PTSD symptoms according to the proposed ICD-11, presenting a high agreement rate with the set of twenty qualifiers according to the DSM-5. STUDY 2 provided meta-analytical evidence for the efficacy of IBI for the treatment of PTSD. Twenty randomized controlled trials (RCT) encompassing 21 comparisons were included, evaluating either iCBT or internet-based expressive writing (iEW) with passive or active control conditions. The results revealed that iCBT was more efficacious than passive control conditions at post-treatment assessment (0.66 ≤ g ≤ 0.83). No superiority of either iCBT or iEW was found in contrast to active control conditions. Subgroup analyses revealed no significant moderators of iCBT efficacy. More research is needed to prove the efficacy of IBI in contrast to active control treatments and further explore the impact of moderators on treatment efficacy. STUDY 3 measured patterns of attentional bias in GAF veterans with PTSS, traumatized veterans without PTSS, and unexposed healthy veterans. In a free-viewing task, participants were presented with pairs of combat-related and neutral pictures, of more general threat-related and neutral pictures, and of emotional and neutral faces, while their eye gazes were tracked. Further, the internal consistency of attentional bias indicators was calculated. The findings provide support for the maintenance hypothesis in PTSS. There was no robust evidence to support the hypothesis of hypervigilant behavior in PTSS. Findings on attentional bias variability remain unclear. Internal consistency varied across attentional bias indicators, highlighting the need for future research in this regard. STUDY 4 investigated the modifiability of attentional bias in veterans with PTSS through the provision of iCBT. In a free-viewing task, participants were presented with combat-related, general threat-related, and neutral pictures, and with faces with negative emotional valence and neutral facial expressions while their eye gazes were tracked. Attentional bias was examined pre- and post-intervention and at a three-month follow-up. No modifications in attentional bias were observable over time. Future investigations are warranted to systematically investigate objective measures of symptom expression and symptom change together with subjective symptom reporting and symptom change in response to psychotherapeutic treatment options. In summary, this dissertation thesis provides a threefold contribution to the current landscape of psychotherapy research: First, it supports the concordance between the DSM-5 and the ICD-11 diagnostic criteria for PTSD. Second, it proves the efficacy of IBI for PTSD. In view of the growing relevance of IBI as a supplement to psychotherapeutic care, future research needs to examine its long-term efficacy, whether it shows equal or superior efficacy compared to other active (control) treatments, potential side effects, and whether it may lead to a deterioration of symptoms. Moreover, studies should focus on tailoring IBI to the specific needs of different patient populations to ensure patients’ safety and satisfaction with IBI. Third, the present thesis underlines the need for systematic and reliable assessments of objective indicators of symptom presentation and of symptom change, in addition to subjective reports. Moreover, methodological approaches need to be extended to measure diverse dimensions of symptom presentation and symptom change and gain a better understanding of their interplay. A multidimensional diagnostic approach and treatment evaluation will be of key relevance for future intervention research and evidence-based practice.Weniger anzeigen
Official statistics are intended to support decision makers by providing reliable information on different population groups, identifying what their needs are and where they are located. This allows, for example, to better guide public policies and focus resources on the population most in need. Statistical information must have some characteristics to be useful for this purpose. This data must be reliable, up-to-date and also disaggregated at different domain levels, e.g., geographically or by sociodemographic groups (Eurostat, 2017). Statistical data producers (e.g., national statistical offices) face great challenges in delivering statistics with these three characteristics, mainly due to lack of resources. Population censuses collect data on demographic, economic and social aspects of all persons in a country which makes information at all domains of interest available. They quickly become outdated since they are carried out only every 10 years, especially in developing countries. Furthermore, administrative data sources in many countries have not enough quality to produce statistics that are reliable and comparable with other relevant sources. On the contrary, national surveys are conducted more frequently than censuses and offer the possibility of studying more complex topics. Due to their sample sizes, direct estimates are only published based on domains where the estimates reach a specific level of precision. These domains are called planned domains or large areas in this thesis, and the domains in which direct estimates cannot be produced due to lack of sample size or low precision will be called small areas or domains. Small area estimation (SAE) methods have been proposed as a solution to produce reliable estimates in small domains. These methods allow improving the precision of direct estimates, as well as providing reliable information in domains where the sample size is zero or where direct estimates cannot be obtained by combining data from censuses and surveys (Rao and Molina, 2015). Thereby, the variables obtained from both data sources are assumed to be highly correlated but the census actually may be outdated. In these cases, structure preservation estimation (SPREE) methods offer a solution when the target indicator is a categorical variable, with at least two categories (for example, the labor market status of an individual can be categorised as: ‘employed’, ‘unemployed’, and ‘out of labor force’). The population counts are arranged in contingency tables: by rows (domains of interest) and columns (the categories of the variable of interest) (Purcell and Kish, 1980). These types of estimators are studied in Part I of this work. In Chapter 1, SPREE methods are applied to produce postcensal population counts for the indicators that make up the ‘health’ dimension of the multidimensional poverty index (MPI) defined by Costa Rica. This case study is also used to illustrate the functionalities of the R spree package. It is a user-friendly tool designed to produce updated point and uncertainty estimates based on three different approaches: SPREE (Purcell and Kish, 1980), generalised SPREE (GSPREE) (Zhang and Chambers, 2004), and multivariate SPREE (MSPREE) (Luna-Hernández, 2016). SPREE-type estimators help to update population counts by preserving the census structure and relying on new and updated totals that are usually provided by recent survey data. However, two scenarios can jeopardise the use of standard SPREE methods: a) the indicator of interest is not available in the census data e.g., income or expenditure information to estimate monetary based poverty indicators, and b) the total margins are not reliable, for instance, when changes in the population distribution between areas are not captured correctly by the surveys or when some domains are not selected in the sample. Chapters 2 and 3 offer a solution for these cases, respectively. Chapter 2 presents a two-step procedure that allows obtaining reliable and updated estimates for small areas when the variable of interest is not available in the census. The first step is to obtain the population counts for the census year using a well-known small-area estimation approach: the empirical best prediction (EBP) (Molina and Rao, 2010) method. Then, the result of this procedure is used as input to proceed with the update for postcensal years by implementing the MSPREE (Luna-Hernández, 2016) method. This methodology is applied to the case of local areas in Costa Rica, where incidence of poverty (based on income) is estimated and updated for postcensal years (2012-2017). Chapter 3 deals with the second scenario where the population totals in local areas provided by the survey data are strengthened by including satellite imagery as an auxiliary source. These new margins are used as input in the SPREE procedure. In the case study in this paper, annual updates of the MPI for female-headed households in Senegal are produced. While the use of satellite imagery and other big data sources can improve the reliability of small-area estimates, access to survey data that can be matched with these novel sources is restricted for confidentiality reasons. Therefore, a data dissemination strategy for micro-level survey data is proposed in the paper presented in Part II. This strategy aims to help statistical data producers to improve the trade-off between privacy risk and utility of the data that they release for research purposes.Weniger anzeigen
In this work, we address the challenge of developing statistical shape models that account for the non-Euclidean nature inherent to (anatomical) shape variation and at the same time offer fast, numerically robust processing and as much invariance as possible regarding translation and rotation, i.e. Euclidean motion. With the aim of doing that we formulate a continuous and physically motivated notion of shape space based on deformation gradients. We follow two different tracks endowing this differential representation with a Riemannian structure to establish a statistical shape model. (1) We derive a model based on differential coordinates as elements in GL(3)+. To this end, we adapt the notion of bi-invariant means employing an affine connection structure on GL(3)+. Furthermore, we perform second-order statistics based on a family of Riemannian metrics providing the most possible invariance, viz. GL(3)+-left-invariance and O(3)-right-invariance. (2) We endow the differential coordinates with a non-Euclidean structure, that stems from a product Lie group of stretches and rotations. This structure admits a bi-invariant metric and thus allows for a consistent analysis via manifold-valued Riemannian statistics. This work further presents a novel shape representation based on discrete fundamental forms that is naturally invariant under Euclidean motion, namely the fundamental coordinates. We endow this representation with a Lie group structure that admits bi-invariant metrics and therefore allows for consistent analysis using manifold-valued statistics based on the Riemannian framework. Furthermore, we derive a simple, efficient, robust, yet accurate (i.e. without resorting to model approximations) solver for the inverse problem that allows for interactive applications. Beyond statistical shape modeling the proposed framework is amenable for surface processing such as quasi-isometric flattening. Additionally, the last part of the thesis aims on shape-based, continuous disease stratification to provide means that objectify disease assessment over the current clinical practice of ordinal grading systems. Therefore, we derive the geodesic B-score, a generalization of the of the Euclidean B-score, in order to assess knee osteoarthritis. In this context we present a Newton-type fixed point iteration for projection onto geodesics in shape space. On the application side, we show that the derived geodesic B-score features, in comparison to its Euclidean counterpart, an improved predictive performance on assessing the risk of total knee replacement surgery.Weniger anzeigen