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Institute
- Graduate School of Life Sciences (130)
- Theodor-Boveri-Institut für Biowissenschaften (26)
- Medizinische Klinik und Poliklinik I (22)
- Institut für Anorganische Chemie (17)
- Lehrstuhl für Orthopädie (17)
- Institut für Pharmazie und Lebensmittelchemie (16)
- Physikalisches Institut (16)
- Institut für Organische Chemie (15)
- Medizinische Klinik und Poliklinik II (15)
- Institut für Psychologie (13)
Sonstige beteiligte Institutionen
- Helmholtz Institute for RNA-based Infection Research (HIRI) (2)
- Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg (2)
- Anthropology Department University of Tennessee, Knoxville (1)
- Bungando Medical Centre, Mwanza, Tanzania (1)
- CHC Würzburg (Comprehensive Hearing Center) (1)
- CUHAS Catholic university of health and allied science, Mwanza, Tanzania (1)
- Caritas-Krankenhaus Bad Mergentheim (1)
- Carl-Ludwig-Institut für Physiologie, Universität Leipzig (1)
- Center for Computational and Theoretical Biology (CCTB), Universität Würzburg (1)
- Chair of Experimental Biomedicine I (1)
This thesis aimed at searching for new effective agents against Multidrug-Resistant Enterobacteriaceae. This is necessitated by the urgent need for new and innovative antibacterial agents addressing the critical priority pathogens prescribed by the World Health Organization (WHO). Among the available means for antibiotics discovery and development, nature has long remained a proven, innovative, and highly reliable gateway to successful antibacterial agents. Nevertheless, numerous challenges surrounding this valuable source of antibiotics among other drugs are limiting the complete realization of its potential. These include the availability of good quality data on the highly potential natural sources, limitations in methods to prepare and screen crude extracts, bottlenecks in reproducing biological potentials observed in natural sources, as well as hurdles in isolation, purification, and characterization of natural compounds with diverse structural complexities.
Through an extensive review of the literature, it was possible to prepare libraries of plant species and phytochemicals with reported high potentials against Escherichia coli and Klebsiella pneumnoniae. The libraries were profiled to highlight the existing patterns and relationships between the reported antibacterial activities and studied plants’ families and parts, the type of the extracting solvent, as well as phytochemicals’ classes, drug-likeness and selected parameters for enhanced accumulation within the Gram-negative bacteria. In addition, motivations, objectives, the role of traditional practices and other crucial experimental aspects in the screening of plant extracts for antibacterial activities were identified and discussed.
Based on the implemented strict inclusion criteria, the created libraries grant speedy access to well-evaluated plant species and phytochemicals with potential antibacterial activities. This way, further studies in yet unexplored directions can be pursued from the indicated or related species and compounds. Moreover, the availability of compound libraries focusing on related bacterial species serves a great role in the ongoing efforts to develop the rules of antibiotics penetrability and accumulation, particularly among Gram-negative bacteria. Here, in addition to hunting for potential scaffolds from such libraries, detailed evaluations of large pool compounds with related antibacterial potential can grant a better understanding of structural features crucial for their penetration and accumulation. Based on the scarcity of compounds with broad structural diversity and activity against Gram-negative bacteria, the creation and updating of such libraries remain a laborious but important undertaking.
A Pressurized Microwave Assisted Extraction (PMAE) method over a short duration and low-temperature conditions was developed and compared to the conventional cold maceration over a prolonged duration. This method aimed at addressing the key challenges associated with conventional extraction methods which require long extraction durations, and use more energy and solvents, in addition to larger quantities of plant materials. Furthermore, the method was intended to replace the common use of high temperatures in most of the current MAE applications. Interestingly, the yields of 16 of 18 plant samples under PMAE over 30 minutes were found to be within 91–139% of those obtained from the 24h extraction by maceration. Additionally, different levels of selectivity were observed upon an analytical comparison of the extracts obtained from the two methods. Although each method indicated selective extraction of higher quantities or additional types of certain phytochemicals, a slightly larger number of additional compounds were observed under maceration. The use of this method allows efficient extraction of a large number of samples while sparing heat-sensitive compounds and minimizing chances for cross-reactions between phytochemicals.
Moreover, findings from another investigation highlighted the low likelihood of reproducing antibacterial activities previously reported among various plant species, identified the key drivers of poor reproducibility, and proposed possible measures to mitigate the challenge. The majority of extracts showed no activities up to the highest tested concentration of 1024 µg/mL. In the case of identical plant species, some activities were observed only in 15% of the extracts, in which the Minimum Inhibitory Concentrations (MICs) were 4 – 16-fold higher than those in previous reports. Evaluation of related plant species indicated better outcomes, whereby about 18% of the extracts showed activities in a range of 128–512 μg/mL, some of the activities being superior to those previously reported in related species.
Furthermore, solubilizing plant crude extracts during the preparation of test solutions for Antibacterial Susceptibility Testing (AST) assays was outlined as a key challenge. In trying to address this challenge, some studies have used bacteria-toxic solvents or generally unacceptable concentrations of common solubilizing agents. Both approaches are liable to give false positive results. In line with this challenge, this study has underscored the suitability of acetone in the solubilization of crude plant extracts. Using acetone, better solubility profiles of crude plant extracts were observed compared to dimethyl sulfoxide (DMSO) at up to 10 %v/v. Based on lacking toxicity against many bacteria species at up to 25 %v/v, its use in the solubilization of poorly water-soluble extracts, particularly those from less polar solvents is advocated.
In a subsequent study, four galloylglucoses were isolated from the leaves of Paeonia officinalis L., whereby the isolation of three of them from this source was reported for the first time. The isolation and characterization of these compounds were driven by the crucial need to continually fill the pre-clinical antibiotics pipeline using all available means. Application of the bioautography-guided isolation and a matrix of extractive, chromatographic, spectroscopic, and spectrometric techniques enabled the isolation of the compounds at high purity levels and the ascertainment of their chemical structures.
Further, the compounds exhibited the Minimum Inhibitory Concentrations (MIC) in a range of 2–256 µg/mL against Multidrug-Resistant (MDR) strains of E. coli and K. pneumonia exhibiting diverse MDR phenotypes. In that, the antibacterial activities of three of the isolated compounds were reported for the first time. The observed in vitro activities of the compounds resonated with their in vivo potentials as determined using the Galleria mellonella larvae model. Additionally, the susceptibility of the MDR bacteria to the galloylglucoses was noted to vary depending on the nature of the resistance enzymes expressed by the MDR bacteria. In that, the bacteria expressing enzymes with higher content of aromatic amino acids and zero or positive net charges were generally more susceptible. Following these findings, a plausible hypothesis for the observed patterns was put forward.
The generally challenging pharmacokinetic properties of galloylglucoses limit their further development into therapeutic agents. However, the compounds can replace or reduce the use of antibiotics in livestock keeping as well as in the treatment of septic wounds and topical or oral cavity infections, among other potential uses.
Using nature-inspired approaches, a series of glucovanillin derivatives were prepared following feasible synthetic pathways which in most cases ensured good yields and high purity levels. Some of the prepared compounds showed MIC values in a range of 128 – 512 μg/mL against susceptible and MDR strains of Klebsiella pneumoniae, Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Enterococcus faecium (VRE). These findings emphasize the previously reported essence of small molecular size, the presence of protonatable amino groups and halogen atoms, as well as an amphiphilic character, as crucial features for potential antibacterial agents.
Due to the experienced limited success in the search for new antibacterial agents using purely synthetic means, pursuing semi-synthetic approaches as employed in this study are highly encouraged. This way, it is possible to explore broader chemical spaces around natural scaffolds while addressing their inherent limitations such as solubility, toxicity, and poor pharmacokinetic profiles.
Aufgrund der immer älterwerdenden Bevölkerung kommt der Prävention von altersbedingten muskuloskelettalen Erkrankungen wie der Osteoporose und der Sarkopenie eine herausragende Bedeutung zu. Insbesondere für die Sarkopenie gibt es heute und auf absehbare Zeit keine kausale medikamentöse Therapie. Somit stellt der Erhalt einer intakten Muskulatur durch körperliche Aktivität die zentrale Säule für eine langfristig muskuloskelettale Gesundheit dar. Die aktuelle, wissenschaftliche Datenlage zeigt hierbei für progressives Krafttraining im Alter valide Ergebnisse. Durch die gezielte Beanspruchung der Muskulatur kann bis ins hohe Alter dem natürlichen Verlust der Muskelmasse und -qualität entgegengewirkt werden. Ein gezieltes Training der Wirbelsäule-umgebenden Muskulatur ist vor allem bei Menschen mit Osteoporose sinnvoll. Durch starke Rückenmuskeln werden wichtige Alltagsbewegungen unterstützt und das Sturzrisiko kann reduziert werden. Ein klassisches progressives Krafttraining ist jedoch bei älteren Menschen nicht immer durchführbar, da diese oft an zusätzlichen Erkrankungen leiden, welche ein intensives Krafttraining verbieten, oder allgemein zu schwach für eine solche Trainingsmodalität sind. Ziel dieser Studie war zusätzlich zum Krafttraining alternative Trainingsmethoden zu testen, welche einfach und sicher im Alter integrierbar sind und keine sportlichen Vorkenntnisse der Teilnehmer erfordern. Im Fokus stand dabei die Kräftigung der Rumpfmuskulatur. Alternativ zum klassischen, progressivem Krafttraining (KT) wurden daher sogenannte Low-Impact-Methoden getestet, konkret handelte es sich dabei um Ganzkörpervibrationstraining (WBV), das tägliche Tragen einer federnden Rückenorthese (OT) und Qi Gong (QG) als atmungs- und bewegungsorientiertes Konzept.
Das Krafttraining zeigte dabei die größten Verbesserungen in der Rumpfkraft, dem primären Endpunkt der Studie. Bei der Extensionskraft zeigte sich eine Zunahme von 28,0%. (p=0,008) und bei der Flexionskraft von 17,2% (p=0,008). Doch auch das WBV-Training und das Tragen der Rückenorthese zeigten Verbesserungen der Rumpfkraft. Das QG-Training zeigte kaum Veränderungen der Rumpfkraft. Im Gruppenvergleich war die KT-Gruppe der QG-Gruppe in der Entwicklung der Extensionskraft signifikant überlegen. Auch wenn die alternativen Trainingsmethoden keine signifikanten Ergebnisse im primären Endpunkt dieser Studie zeigten, kam es zu signifikanten Verbesserungen in den sekundären Endpunkten. In der WBV-Gruppe kam es zu einem signifikanten Anstieg der Handkraft (p=0,023) und im CRT (p=0,007). In der OT-Gruppe war der CRT signifikant besser geworden (p=0,003). In der QG-Gruppe kam es zu tendenziellen Verbesserungen einiger Leistungsparameter, jedoch waren diese statistisch überwiegend nicht signifikant. Ein wesentlicher Aspekt dieser Arbeit war jedoch, dass unabhängig von der jeweiligen Trainingsmodalität, vor allem die Teilnehmer, die ein erhöhtes Risiko für muskuläre Defizite hatten, also Probanden ≥80 Jahre, Menschen mit präsarkopenem Muskelstatus, oder multimorbide Teilnehmer, am meisten von den Trainingsinterventionen profitierten. Hier fiel vor allem die signifikante Zunahme der Rumpfflexion in allen drei Subgruppen auf. Bei den Probanden ≥80 Jahren kam es in der Rumpfflexion zu einer Zunahme von 10,3% (p=0,017), bei den präsarkopenen Probanden von 2,9% (p=0,035) und bei den Multimorbiden von 16,3% (p=0,001). Eine starke Rumpfvorderseite führt zu einer aufrechten Haltung, ermöglicht Alltagsaktivitäten wie Treppensteigen oder das Aufstehen von einem Stuhl und kann durch eine verbesserte Balance das Sturzrisiko vermindern. Bedeutsam ist auch, dass die Muskelmasse bei den präsarkopenen Probanden, unabhängig vom Training, signifikant gestiegen war und somit Sport auch bei einer reduzierten Muskelmasse sehr effektiv sein kann. Zudem verbesserte sich der CRT bei den präsarkopenen und multimorbiden Probanden signifikant, was umso erfreulicher ist, bedenkt man die Assoziation mit einer reduzierten Fähigkeit von einem Stuhl aufzustehen und einer erhöhten Mortalität. Schlussendlich zeigen die Ergebnisse dieser Studie, dass Trainingsmodalitäten, die gezielt die Rumpfmuskulatur adressieren, wie z.B. ein speziell zusammengestelltes Krafttraining, auch in höherem Alter und bei Vorliegen eines erhöhten Frakturrisikos positive Effekte erzielen und zu signifikanten Verbesserungen der Rumpfkraft führen können. Allerdings zeigen auch weniger spezifische low-impact Trainingskonzepte durchaus positive Entwicklungen und stellen vor allem eine sichere Alternative mit nur geringem Anforderungsprofil dar. Besonders erfreulich scheint vor allem die Verbesserung der Parameter der Probanden mit einem erhöhten Risiko für muskuläre Defizite unabhängig von der zugelosten Trainingsintervention. Diese Ergebnisse stellen eine wertvolle Grundlage für zukünftige Forschungsvorhaben dar, welchen unter Berücksichtigung der globalen demographischen Entwicklungen sicherlich erhebliche Bedeutung zukommen wird.
The recent pandemic has reminded the public that basic research in virology is pivotal for human health. Understanding the mechanisms of successful viral replication and the role of host factors can help to combat viral infections and prevent future pandemics.
Our lab has published the first SARS-CoV-2 RNA-protein interaction atlas, laying the foundation to investigate the interplay between viral RNA and host RNA binding proteins (RBP). Based on this, my project created the largest collection of binding profiles of host and viral RBPs on SARS-CoV-2 RNA to date. This revealed the host protein SND1 as the first human RBP that specifically binds negative sense viral RNA at the 5´ end, a region associated with viral transcription initiation. The binding profile shares similarities with the viral RBP nsp9, which binds the 5´ ends of positive and negative sense SARS-CoV-2 RNA. Depletion of SND1 shows reduced levels of viral RNA revealing it as a proviral host factor. To decode the underlying molecular mechanism, I characterized the protein-protein interactions of SND1 in SARS-CoV-2 infected and uninfected cells. Infection remodels the protein interactors of SND1 from general RNA biology to membrane association and viral RNA synthesis. Upon infection, SND1 specifically interacts with nsp9, the RBP that shares the same binding region on the negative strand of SARS-CoV-2 RNA. Recent work demonstrates that nsp9 is NMPylated in vitro suggesting a functional role of nsp9 in priming of viral RNA synthesis. I was able to show that nsp9 is covalently linked to the 5´ ends of SARS-CoV-2 RNA during infection of human cells. Analysing the covalent bond of nsp9 with the viral RNA on nucleotide level shows close proximity to the initiation sites of viral RNA synthesis, suggesting that nsp9 acts as a protein-primer of SARS-CoV-2 RNA synthesis. SND1 modulates the distribution of nsp9 on the viral RNA, since depletion of SND1 results in imbalanced occupancy of nsp9 at the 5´ends of viral RNA.
This study is the first to provide evidence for the priming mechanism of SARS-CoV-2 in authentic viral replication and further reveals how this mechanism is modulated by the host RBP SND1. Detailed knowledge about priming of viral RNA synthesis can help to find targeted antivirals that could be used to fight coronaviral infections.
In this thesis, the usage of onion-like carbon (OLC) for energy storage applications was researched regarding sustainability, performance and processability. This work targets to increase the scientific understanding regarding the role of OLC in electrodes and to facilitate a large-scale production, which is the foundation for commercial application. Research was devoted to increase the knowledge in the particular field, to yield synergistic approaches and a shared value regarding sustainability and performance.
Effect of Tjap1 knock-down on blood-brain barrier properties under normal and hypoxic conditions
(2023)
Stroke is one of the leading causes of mortality and disability worldwide. The blood-brain barrier (BBB) plays an important role in maintaining brain homeostasis by tightly regulating the exchange of substances between circulating blood and brain parenchyma. BBB disruption is a common pathologic feature of stroke and traumatic brain injury. Understanding the cellular and molecular events that affect the BBB after ischaemic brain injury is important to improve patient prognosis.
We have previously shown that microRNA-212/132 is elevated in hypoxic brain microvascular endothelial cells and acts through suppressing the expression of direct microRNA-212/132 target genes with function at the BBB: claudin-1, junctional adhesion molecule 3 (Jam3) and tight-junction associated protein 1 (Tjap1). While the role of claudin-1 and Jam3 at the BBB is well known, the role of Tjap1 is still unclear. The aim of this work was therefore to characterize the role of Tjap1 in brain endothelial cells using a knock-down (KD) approach in established murine in vitro BBB models cEND and cerebEND. Tjap1 KD was established by stable transfection of a plasmid expressing shRNA against Tjap1. The successful downregulation of Tjap1 mRNA and protein was demonstrated by qPCR and Western blot. Tjap1 KD resulted in impaired barrier properties of endothelial cells as shown by lower TEER values and higher paracellular permeability. Interestingly, the Tjap1 KD cells showed lower cell viability and proliferation but migrated faster in a wound healing assay. In the tube formation assay, Tjap1 KD cell lines showed a lower angiogenic potential due to a significantly lower tube length and number as well as a lower amount of branching points in formed capillaries. Tjap1 KD cells showed changes in gene and protein expression. The TJ proteins claudin-5, Jam3 and ZO-1 were significantly increased in Tjap1 KD cell lines, while occludin was strongly decreased. In addition, efflux pump P-glycoprotein was downregulated in Tjap1 KD cells. Oxygen-glucose deprivation (OGD) is a method to mimic stroke in vitro. Brain endothelial cell lines treated with OGD showed lower barrier properties compared to cells cultured under normal condition. These effects were more severe in Tjap1 KD cells, indicating active Tjap1 involvement in the OGD response in brain microvascular endothelial cells.
We thus have shown that Tjap1 contributes to a tight barrier of the BBB, regulates cell viability and proliferation of endothelial cells, suppresses their migration and promotes new vessel formation. This means that Tjap1 function is important for mature BBB structure in health and disease.
This thesis consists of three studies investigating the influence media literacy has on political variables, cognitive variables, and learning. Adolescents from 13 years of age and young adults are included in the studies. This thesis is divided into three chapters. Study I and II are one comprehensive study, but will be presented separately for better readability. Chapter I provides the reader with background knowledge for the original studies presented in chapter II includes information about media use, different conceptualizations of media literacy and its development over the lifetime, as well as media literacy’s impact on cognitive and political variables. Additionally, current literature on the comparison of the learning outcomes of different kinds of texts (written, auditory, and audiovisual) is presented, with a differentiation between text-based information and inferences. In chapter II, the original studies are placed in the current state of research and presented in detail. In chapter III, a critical discussion of the studies is conducted, and a general model of the influence media literacy has on the investigated cognitive and political factors is presented, followed by a conclusion of the research.
The theoretical foundation of this thesis is three models of media literacy proposed by Groeben (2002, 2004), Hobbs (1997), and Potter (1998, 2016). These three models are similar in that they define media literacy as a multifactorial construct with skills that develop further in the course of life. Their ideas are integrated and developed further, leading to our own model of media literacy. It encompasses five scales: media sign literacy, distinction between reality and fiction, knowledge of media law, knowledge of media effects, and production skills. Thereupon, the assessment tool Würzburg Media Literacy Test (WMK; Würzburger Medienkompetenztest) is designed.
There is evidence that media use and media literacy influence socio-political factors. Young adults name the internet as the main source of information on political topics (see Pasek et al., 2006), and knowledge demonstrably fosters political participation (Delli Carpini & Keeter, 1996). However, the kind of participation activity regarded is important (Quintelier & Vissers, 2008), as sometimes real-life participation is supplemented by online activities (Quan-Haase & Wellman, 2002). Media literacy is the key to evaluating the quality of information from media. Whether or not a direct link between media literacy and political interest exists has, as far as I know, not yet been investigated. Several studies have shown that precursors and subcomponents of media literacy have the capacity to influence cognitive variables. For instance, children with higher media sign literacy possess better reading proficiency (Nieding et al., 2017) and are better at collecting information and drawing inferences from hypermedia and films (Diergarten et al., 2017) as compared to children with low literacy. These precursors and subcomponents are more efficient in processing medial sign systems, reducing cognitive load, and consequently, liberating cognitive capacity for other mental tasks (Sweller, 1988). Paino and Renzulli (2012) showed that highly computer-proficient adolescents exhibit better mathematics and reading abilities. Different types of media influence the learning process differently, and the learning process can be enhanced by combining these different types of media, if the material is prepared according to the research findings and Mayer’s (2002) cognitive theory of multimedia learning. Similarly, a reduction in cognitive load takes place and more resources can be invested in the learning process itself (Mayer & Moreno, 2003; Sweller, 1988). It is not easy to answer the question of whether one medium is superior for learning to another. Generally, adults learn best from written texts (e.g., Byrne & Curtis, 2000), and audiovisual and auditory texts are comparable (e.g., Hayes et al., 1986); however, there is little research regarding the comparison of the latter two.
Study I examined whether media literacy has a positive impact on interest in politics and the political self-concept. A sample of 101 13-to 20-year-olds was drawn. The control variables were intelligence, socio-economic status (SES), openness to experiences, perspective-taking, age, and sex. Additionally, an evaluation of the WMK was conducted, which indicated good construct validity and excellent overall reliability. Media literacy was positively associated with interest in politics, political self-concept, and perspective-taking but not with openness. In hierarchical regressions and path analysis, a direct influence of media literacy and openness on interest in politics could be found. Political self-concept was solely influenced by interest in politics. Although media literacy had no direct influence on political self-concept, it influenced its precursor interest in politics and was thus expected to have distal influence. The results of the first study confirm previous findings (e.g., Vecchione & Caprara, 2009), where political self-concept is regarded as a precursor of political participation. In conclusion, the findings of study I suggested that by stimulating political interest, media literacy could, mediated through political self-concept, foster political participation.
Study II (which was conducted on the same sample as study I) was concerned with the question of whether highly media-literate adolescent and young adult participants exhibit better academic skills (mathematics; reading) and academic achievement (grades) compared to less media-literate participants. Additionally, to obtain information about potential development during adolescence, a group of 50 13-year-olds was compared with a group of 51 19-year-olds in terms of their media literacy. The control variables were intelligence, SES, sex, and age. The results showed that a significant development of media literacy took place during adolescence (∆M = .17), agreeing with Potter’s (1998, 2013) development theory of media literacy. Media literacy was significantly correlated with reading skills and school grades. Regarding adults, media literacy was also significantly correlated with mathematical skills; the association was greater than that with reading skills. However, no connection with mathematical skills was found for adolescents. To control for the influence of age and intelligence, which were both associated with media literacy, hierarchical regressions and path analyses were conducted. The results revealed that media literacy had a greater impact on grades and academic abilities than intelligence. These results are in line with those obtained by Paino and Renzulli (2012).
Study III investigated whether media literacy helps young adults to better learn from three kinds of media, a written, an auditory, and an audio-visual text, and which medium achieves the best learning results. Three groups of 91 young adults were compared (written, auditory, and audio-visual text) in terms of their learning outcomes. These outcomes were conceptualized as directly stated information in the text (assessed by text-based questions) and inferential learning (inference questions). A computer-based short version of the WMK was applied to assess media literacy, which should be optimized in the future. The control variables were intelligence, verbal ability, media usage, prior knowledge, and SES. In hierarchical regression, media literacy turned out to be a significant predictor of text inferences, even when other relevant variables, such as intelligence, were controlled for. Inferences foster the building of the situation model, which is believed by many authors to be true comprehension of a text (Zwaan & Radvansky, 1998). The outcomes of study III support Ohler’s (1994) assumption that media literacy fosters the creation of a more elaborated situational model. Text-based questions were only influenced by prior knowledge. As assumed by Potter (1998, 2016), the media literacy of young adults in the Western world suffices to extract relevant facts from educational learning material. Both subjects were best in the written text condition for text-based and inference question results. Audiovisual and auditory texts showed no significant differences. The written text condition did not excel in the auditory text condition for inferences. The results accord with those obtained by, for instance, Byrne and Curtis (2000).
Taken together, these studies show that media literacy can influence several cognitive and political variables. It stimulates political interest, reading comprehension, school grades, and mathematical abilities in young adults, as well as drawing inferences from different kinds of texts. Additionally, media literacy develops further during adolescence.
Permafrost degradation is observed all over the world as a consequence of climate change and the associated Arctic amplification, which has severe implications for the environment. Landslides, increased rates of surface deformation, rising likelihood of infrastructure damage, amplified coastal erosion rates, and the potential turnover of permafrost from a carbon sink to a carbon source are thereby exemplary implications linked to the thawing of frozen ground material. In this context, satellite earth observation is a potent tool for the identification and continuous monitoring of relevant processes and features on a cheap, long-term, spatially explicit, and operational basis as well as up to a circumpolar scale.
A total of 325 articles published in 30 different international journals during the past two decades were investigated on the basis of studied environmental foci, remote sensing platforms, sensor combinations, applied spatio-temporal resolutions, and study locations in an extensive review on past achievements, current trends, as well as future potentials and challenges of satellite earth observation for permafrost related analyses. The development of analysed environmental subjects, utilized sensors and platforms, and the number of annually published articles over time are addressed in detail. Studies linked to atmospheric features and processes, such as the release of greenhouse gas emissions, appear to be strongly under-represented. Investigations on the spatial distribution of study locations revealed distinct study clusters across the Arctic. At the same time, large sections of the continuous permafrost domain are only poorly covered and remain to be investigated in detail. A general trend towards increasing attention in satellite earth observation of permafrost and related processes and features was observed. The overall amount of published articles hereby more than doubled since the year 2015. New sources of satellite data, such as the Sentinel satellites and the Methane Remote Sensing LiDAR Mission (Merlin), as well as novel methodological approaches, such as data fusion and deep learning, will thereby likely improve our understanding of the thermal state and distribution of permafrost, and the effects of its degradation. Furthermore, cloud-based big data processing platforms (e.g. Google Earth Engine (GEE)) will further enable sophisticated and long-term analyses on increasingly larger scales and at high spatial resolutions.
In this thesis, a specific focus was put on Arctic permafrost coasts, which feature increasing vulnerability to environmental parameters, such as the thawing of frozen ground, and are therefore associated with amplified erosion rates. In particular, a novel monitoring framework for quantifying Arctic coastal erosion rates within the permafrost domain at high spatial resolution and on a circum-Arctic scale is presented within this thesis. Challenging illumination conditions and frequent cloud cover restrict the applicability of optical satellite imagery in Arctic regions. In order to overcome these limitations, Synthetic Aperture RADAR (SAR) data derived from Sentinel-1 (S1), which is largely independent from sun illumination and weather conditions, was utilized. Annual SAR composites covering the months June–September were combined with a Deep Learning (DL) framework and a Change Vector Analysis (CVA) approach to generate both a high-quality and circum-Arctic coastline product as well as a coastal change product that highlights areas of erosion and build-up. Annual composites in the form of standard deviation (sd) and median backscatter were computed and used as inputs for both the DL framework and the CVA coastal change quantification. The final DL-based coastline product covered a total of 161,600 km of Arctic coastline and featured a median accuracy of ±6.3 m to the manually digitized reference data. Annual coastal change quantification between 2017–2021 indicated erosion rates of up to 67 m per year for some areas based on 400 m coastal segments. In total, 12.24% of the investigated coastline featured an average erosion rate of 3.8 m per year, which corresponds to 17.83 km2 of annually eroded land area. Multiple quality layers associated to both products, the generated DL-coastline and the coastal change rates, are provided on a pixel basis to further assess the accuracy and applicability of the proposed data, methods, and products.
Lastly, the extracted circum-Arctic erosion rates were utilized as a basis in an experimental framework for estimating the amount of permafrost and carbon loss as a result of eroding permafrost coastlines. Information on permafrost fraction, Active Layer Thickness (ALT), soil carbon content, and surface elevation were thereby combined with the aforementioned erosion rates. While the proposed experimental framework provides a valuable outline for quantifying the volume loss of frozen ground and carbon release, extensive validation of the utilized environmental products and resulting volume loss numbers based on 200 m segments are necessary. Furthermore, data of higher spatial resolution and information of carbon content for deeper soil depths are required for more accurate estimates.
In der vorliegenden Arbeit wurde das Vorkommen neu erworbener N-Glykosylierungsmotive in t(14;18)-positiven und -negativen FL der lokalisierten (FL I/II) und fortgeschrittenen Stadien (FL III/IV), sowie zum Zeitpunkt der Primärdiagnose und des Rezidivs untersucht. Dabei wurde der jeweilige Haupttumorklon mit Hilfe von „Next Generation Sequencing“ und unter Verwendung des „LymphoTrack® Assays“ in einer Serie von 68 kryoasservierten FL identifiziert 36 t(14;18)-negative und 32 t(14;18)-positive FL. Die Frequenz neu erworbener N-Glykosylierungsmotive unterschied sich signifikant zwischen t(14;18)-positiven und -negativen PD/R-FL III/IV, während man zwischen t(14;18)-positiven und -negativen PD/R-FL I/II keinen Unterschied beobachten konnte. Des Weiteren zeigten t(14;18)-negative PD/R-FL I-IV im Vergleich zu t(14;18)-positiven PD/R-FL I-IV signifikant häufiger einen Zugewinn neuer N-Glykosylierungsmotive in der FR3 Region des BCL2 Gens, sowie eine vermehrte Nutzung des IGHV4-34 Keimbahngens. Interessanterweise beschränkte sich die Nutzung des IGHV4-34 Gens auf PD-FL und konnte in R-FL nicht nachgewiesen werden. Da sowohl das Vorkommen neu erworbener N-Glykosylierungsmotive in FR3 als auch die Nutzung von IGHV4-34 im Zusammenhang mit Autoimmunerkrankungen beschrieben wurden, deuten unsere Ergebnisse darauf hin, dass die Subgruppe der t(14;18)-negativen FL im pathologischen Prozess der Onkogenese mehr auf die Stimulation durch (Auto)-Antigene als durch die Stimulation des B-Zell Rezeptors mit Lektinen (DC-SIGN) angewiesen sein könnte.
From simply ringing a bell to preparing a five-course menu, human behavior commonly causes changes in the environment. Such episodes where an agent acts, thereby causing changes in their environment constitute the sense of agency. In this thesis four series of experi-ments elucidate how the sense of agency is represented in complex action-event sequences, thereby bridging a gap between basic cognitive research and real-life practice. It builds upon extensive research on the sense of agency in unequivocal sequences consisting of single ac-tions and distinct, predominantly auditory, outcomes. Employing implicit as well as explicit measures, the scope is opened up to multi-step sequences.
The experiments show that it is worthwhile devoting more research to complex action-event sequences. With a newly introduced auditory measure (Chapter II), common phenomena such as temporal binding and a decrease in agency ratings following distorted feedback were replicated in multi-step sequences. However, diverging results between traditional implicit and explicit measures call for further inspection. Multisensory integration appears to gain more weight when multiple actions have to be performed to attain a goal leading to more accurate representations of the own actions (Chapter III). Additionally, freedom of choice (Chapter III) as well as early spatial ambiguity altered the perceived timing of outcomes, while late spatial ambi-guity (Chapter IV) and the outcome’s self-relevance did not (Chapter V). The data suggests that the cognitive system is capable of representing multi-step action-event sequences implicitly and explicitly. Actions and sensory events show a temporal attraction stemming from a bias in the perception of outcomes. Explicit knowledge about causing an event-sequence facilitates neither feelings of control nor taking authorship. The results corroborate current theorizing on the un-derpinnings of temporal binding and the divergence between traditional implicit and explicit measures of the sense of agency. Promising avenues for further research include structured analyses of how much inferred causality contributes to implicit and explicit measures of agency as well as finding alternative measures to capture conceptual as well as non-conceptual facets of the agency experience with one method.
Das Ziel der experimentellen Studie war die Erprobung der (bereits in vitro erfolgreich getesteten) Ca(OH)2-Beschichtung In vivo unter dem Aspekt, ob und inwieweit die antibakteriellen und somit auch antiinflammatorischen bzw. entzündungsmoderierenden Eigenschaften der Ca(OH)2-Beschichtung eine sinnvolle und effektive Ergänzung zu den bisher erfolgreich eingesetzten Calciumphosphat(CaP)-Beschichtungen mit bewiesenen, guten proosseointegrativen Eigenschaften bei lasttragenden Implantaten sein können.
Zusammenfassend kann festgestellt werden, dass die Ergebnisse der In vitro Untersuchung durch die In vivo Versuche in den Bereichen 0-100 KBE grundsätzlich als gestützt gelten können. Die Zuverlässigkeit der Wirkung durch Ca(OH)2 nimmt jedoch mit steigender KBE-Zahl ab, sodass weitere Testreihen sinnvoll sind.
In der vorliegenden Dissertation wurde das Zusammenspiel von enterischen Gliazellen (EGC) und Darmepithelzellen (Caco-2) thematisiert, wobei der Fokus auf der Bedeu-tung des neurotrophen Faktors GDNF für die Interaktion zwischen den beiden genann-ten Zelltypen lag. Weiterhin wurde evaluiert, ob die Tyrosinkinase RET auch in Darme-pithelzellen für die GDNF-Signaltransduktion unter Ruhebedingungen und bei Entzün-dungen verantwortlich ist.
Als Grundlage diente ein Ko-Kultur-Modell mit Caco-2 und EGC. Durch Permeabili-täts- und Widerstandsmessungen wurden die Auswirkungen von GDNF auf Zell-Monolayer ermittelt. Effekte auf die Barrieredifferenzierung wurden anhand subkon-fluenter Zell-Monolayer charakterisiert, wohingegen die Auswirkungen auf Entzün-dungsstimuli an konfluenten Zellen untersucht wurden. Veränderungen von Junktions-proteinen wurden mit Immunfluoreszenzfärbungen und Western-Blot-Analysen aufge-zeigt. Abschließend erfolgte eine Analyse humaner Gewebeproben von Patienten mit und ohne chronisch-entzündlichen Darmerkrankungen (CED) in Bezug auf deren GDNF-Expression.
Die verwendeten intestinalen Epithelzellen exprimieren die GDNF-Rezeptoren GFRα1, GFRα2, GFRα3 und RET. Nach Etablierung des Kultursystems zeigten Permeabilitäts-messungen, Messungen des Epithelwiderstandes sowie Immunfluoreszenz-Färbungen, dass die Differenzierung der Darmepithelzellen in der Ko-Kultur mit EGC durch GDNF vermittelt wird. Zudem war eine GDNF-abhängige, barrierestabilisierende Wirkung in einem Inflammationsmodell zu beobachten. Weiterhin wurde nachgewiesen, dass GDNF-Effekte auf Enterozyten auch im Darmepithel über die RET-Tyrosinkinase mit nachfolgender Hemmung des p38-MAPK-Signalwegs bedingt werden. Eine Stimulation der EGC mit Zytokinen bestätigte eine Hochregulation der GDNF-Expression und Sek-retion. In humanen Proben war intestinales GDNF bei schwerer Entzündung reduziert.
Zusammenfassend wurde erstmalig der Nachweis erbracht, dass von EGC sezerniertes GDNF die Differenzierung der Barriere in Darmepithelzellen induziert und diese gegen einen Zytokin-vermittelten Zusammenbruch schützt. Dies wird über eine RET-abhängige Regulation der p38-MAPK vermittelt. Die Reduktion der GDNF-Konzentration in transmuralen Gewebeproben von Patienten mit CED trägt möglicher-weise zur Pathogenese der CED bei.
2009 ratifizierte Deutschland die UN-Behindertenrechtskonvention (UN-BRK) und verpflichtete sich damit gesetzlich zur Umsetzung von Inklusion in allen Lebensbereichen. In der aktuellen gesellschaftspolitischen Debatte liegt ein besonderer Fokus auf dem Bereich der Bildung, wobei die Maßnahme Schulbegleitung maßgeblich zur Teilhabe von Kindern und Jugendlichen mit sogenanntem sonderpädagogischem Förderbedarf an Bildung beiträgt. Ziel der vorliegen-den Arbeit ist es, die aktuelle Umsetzung schulischer Inklusion in Deutschland kritisch einzuordnen, die Maßnahme Schulbegleitung differenziert darzustellen sowie Strukturen und Dynamiken der professionalisierungsbedürftigen Praxis von Schulbegleitung sowohl theoretisch als auch empirisch zu untersuchen. Ausgehend von einer rekonstruktiven Sozialforschung (Videographische Aufzeichnung | Sequenzanalytische Auswertung) sollen die vorliegenden Forschungsergebnisse den aktuellen wissenschaftlichen sowie bildungspolitischen Diskurs hinsichtlich schulischer Inklusion im Allgemeinen und der Maßnahme Schulbegleitung im Besonderen erweitern.
Seit jeher üben Roboter eine Faszination auf den Menschen aus. Es ist die Ähnlichkeit zum Menschen, die technische Systeme, die mit einer höheren Intelligenz ausgestattet sind, gleichermaßen faszinierend wie erschreckend erscheinen lässt. Der Gedanke daran, technische Kreaturen zu erschaffen, die uns erhabenen menschlichen Wesen „das Wasser reichen“ oder uns gar übertreffen können, lässt uns nicht mehr los. Die Erkenntnis von dem Nutzen, den uns derartige Wesen in allen denkbaren Bereichen bringen könnten, mündet jedoch sehr schnell in eine Skepsis im Hinblick auf eine Entmündigung und Entwertung des Menschen. Denn schon heute, obgleich die Forschung in vielen Bereichen noch in den Kinderschuhen steckt, geraten wir in zahlreichen Lebensbereichen in Kontakt mit technischen Systemen, die eine starke Wirkung auf uns ausüben und viele grundlegende Fragen aufwerfen.
Die Arbeit widmet sich der ethischen Dimension autonomer (Pflege-)Systeme und thematisiert zu diesem Zweck konkrete Anwendungsszenarien. Dabei geht es nicht um allgemeine ethische Fragen, sondern konkret um den Aspekt der Vereinbarkeit autonomer technischer Systeme mit der Menschenwürde ihrer Nutzer. Auch der Gesichtspunkt des Einflusses von autonomen technischen Innovationen auf das Selbstverständnis des Menschen (Menschenbild) ist Teil der Arbeit.
Als Maßstab für moderne technische Entwicklungen dient der Würdegrundsatz aufgrund seiner enormen Bedeutung für das Recht sowie für das zugrundeliegende und allgemeine Menschenbild. Im Rahmen einer an einem humanistischen Weltbild orientierten Gesellschaft steht die Menschenwürde als oberster Wert, dem moralische und rechtliche Entwicklungen gerecht werden müssen, über allem. Daher gilt es, moderne Entwicklungen immer auch im Hinblick auf ihre Vereinbarkeit mit der Menschenwürde zu überprüfen. So lässt sich feststellen, ob ein Regulierungsbedarf besteht und wie Regulierungen im Einzelnen auszugestalten sind.
Gleichzeitig muss aber auch die Menschenwürde gesellschaftlichen Entwicklungen gerecht werden. Demgemäß wird sie vom Bundesverfassungsgericht als Grundsatz, der sich aktuellen Herausforderungen stellt und zur Erzwingung eines gesellschaftlichen Diskurses führt, angesehen.
Die hiesige Arbeit soll einen Beitrag zu der bereits angestoßenen gesellschaftlichen Debatte rund um den technischen Fortschritt und konkret um die Probleme, die mit der zunehmenden Autonomie technischer Systeme einhergehen, leisten.
Untersucht wurde der Einfluss mehrerer Chemotherapeutika auf den Chemokinrezeptor CXCR4 in
Myelomzelllinien auf Ebene des Promotors, der mRNA und der Rezeptorverteilung, wobei drei
Substanzen (Etoposid, Bortezomib und Dexamethason) als potenzielle Suppressoren des Promotors ausgemacht werden konnten. Abhängig vom Myelom-Zelltyp und der Dosierung können so evtl.
Rückschlüsse auf die beobachtete Suppression von CXCR4 bei erkrankten Patienten mit hoher CXCR4-Aktivität (hier: Malignes Myelom) durch die begleitende Chemotherapie gezogen werden, welche eine Diagnostik und Therapie bei diesen Patienten erschwert.
Hintergrund: Hintergrund für diese Arbeit waren Beobachtungen in klinischen Fallstudien von Lapa et al. am Universitätsklinikum Würzburg, die sich auf CXCR4 bezogen, welches u.a. bei Patienten mit
Multiplem Myelom überexprimiert wird und dadurch bereits als Target für Diagnostik und Therapie in der Klinik Anwendung findet. Dabei konnte bei PET-CT Untersuchungen in der Nuklearmedizin beobachtet werden, dass es durch die begleitende Chemotherapie der Patienten zu einer Suppression des markierten CXCR4-Signals kam, so dass es nicht mehr zur Verlaufsbeobachtung und
vor allem nicht mehr zur Radiotherapie und Therapiekontrolle verwendet werden konnte.
Um den Einfluss und mögliche Interaktionen der Chemotherapeutika auf CXCR4 zu untersuchen, war es Ziel dieser Arbeit, ein vergleichbares Szenario in-vitro nachzustellen und Einflüsse messbar zu
machen, um so mögliche Ansätze und Verbesserungsvorschläge für die klinische Anwendung zu
liefern.
Methoden/Ergebnisse: Hierfür wurden im ersten Teil INA-6 (Myelomzellen) und Mesenchymale
Stammzellen (MSC) kultiviert, in Ko-Kultur gebracht und nach einer bestimmten Zeit wieder getrennt, um anschließend den gegenseitigen Einfluss in Bezug auf CXCR4 zu messen. Zudem wurde der Einfluss von Dexamethason untersucht. Es zeigte sich eine enge Bindung zwischen INA-6 und MSC
sowie eine hohe CXCR4-Aktivität bei INA-6, jedoch konnte keine Induktion der CXCR4-Aktivität in MSC durch INA-6-Kontakt oder Dexamethason quantifiziert werden. Die Immunzytologie erwies sich aufgrund einer schweren Anfärbbarkeit von CXCR4 – auch mit verschiedensten Antikörpern und sogar Liganden-gekoppeltem Farbstoff– als kaum auswertbar, wobei eine Darstellung von CXCR4
generell aber gelang.
Der CXCR4-Promotor wurde mittels Software genauer analysiert, wobei einige relevante Bindestellen, u.a. für Glukokortikoide und NFkB gefunden wurden. Die Herstellung eines CXCR4-
pGl4.14-Promotor-Konstrukts war erfolgreich, ebenso dessen Einschleusung in Myelomzellen. Auch gelang die Herstellung stabiler transfizierter INA-6, sodass mit diesen anschließend konstantere Ergebnisse erzielt werden konnten.
Im größten Teil der Arbeit wurden geeignete Chemotherapeutika-Konzentrationen ermittelt und in Viabilitäts- und Apoptose-Versuchen überprüft. Die Stimulationsversuche mit diesen zeigten variable
Effekte abhängig vom Zelltyp (INA-6, MM1S), jedoch konnten Bortezomib, Etoposid und
Dexamethason konzentrationsabhängig als starke Suppressoren der CXCR4-Aktivität ausgemacht
werden, was sich v.a. auf Ebene der Promotoraktivität – gemessen mittels Luciferase - zeigte. Interpretation: In-vitro konnten somit drei potenzielle Suppressoren der CXCR4-Aktivität ausgemacht
werden: Etoposid, Bortezomib und Dexamethason. Zumindest beim INA-6-Zelltyp fiel dieser Effekt deutlich aus, wobei in der Klinik der entsprechende Zelltyp sowie die Dosierung der Medikamente berücksichtigt werden müssen. Hinzu kommen weitere Einflussfaktoren des menschlichen Körpers,
die nicht berücksichtig werden konnten. Die genauen Mechanismen der Suppression könnten sich aus den Bindestellen des Promotors erklären, die von uns analysiert wurden, aber auf die in weiteren Arbeiten noch näher eingegangen werden muss.
Single-molecule dynamics at a bottleneck: a systematic study of the narrow escape problem in a disc
(2023)
Diffusion facilitates numerous reactions within the biological context of a cell. It is remarkable how the cost-efficient random process of Brownian motion promotes fast reactions. From the narrow escape theory, it is possible to determine the mean first passage time of such processes based on their reaction space and diffusion coefficient. The narrow escape theory of Brownian particles is characterized by a confining domain with reflective boundaries and a small reaction site. In this thesis, the mean first passage time was systematically tested in a disc as a function of the escape opening size in vitro and in silico. For the in vitro experiments, a model system of patterned supported-lipid bilayers (SLB) was established. Such a model is prepared by a combined colloid metalization approach, where a gold scaffold on glass facilitates assembly of SLB patches of distinct sizes through vesicle fusion. The model setup was evaluated and found to match all necessary requirements to test the nar- row escape problem in vitro. In particular, the reflectivity of the boundaries, the unhindered, free diffusion of the tracer lipids, and the distinct area were assessed. Observed results of the mean first passage time agreed with the theory of the narrow escape problem. There was excellent agreement in both absolute values and across a range of small escape opening sizes. Additionally, I developed a straightforward method, a correction factor, to calculate the mean first passage time from incomplete experimental traces. By re-scaling the mean first passage time to the fraction of particles that escaped, I was able to overcome the lifetime limitations of fluorescent probes. Previously inaccessible measurements of the mean first passage time relying on fluorescent probes will be made possible through this approach. The in vitro experiments were complemented with various in silico experiments. The latter were based on random walk simulations in discs, mimicking the in vitro situation with its uncertainties. The lifetime of single particles was either set sufficiently long to allow all particles to escape, or was adjusted to meet the lifetime limitations observed in the in vitro experiments. A comparison of the mean first passage time from lifetime-unlimited particles to the corrected, lifetime-limited particles did support the use of the correction factor. In agreement with the narrow escape theory, it was experimentally found that the mean first passage time is independent of the start point of the particle within the domain. This is when the particle adheres to a minimum distance to the escape site. In general, the presented random walk simulations do accurately represent the in vitro experiments in this study. The required hardware for the establishment of an astigmatism-based 3D system was installed in the existing microscope. The first attempts to analyze the obtained 3D imaging data gave insight into the potential of the method to investigate molecule dynamics in living trypanosome cells. The full functionality will be realized with the ongoing improvement of image analysis outside of this thesis.
SPRED 2 wirkt inhibitorisch auf den Ras/ERK-MAPK-Signalweg. Im Knockout Mausmodell
zeigen sich einige schwerwiegende phänotypische Eigenschaften, unter anderem zeigen sich
ein genereller Minderwuchs, veränderte hormonelle Regelkreise, neurologische Auffälligkeiten,
eine deutlich verringerte Lebenserwartung, sowie kardiale Veränderungen. Besonders
schwerwiegende SPRED 2 KO typische Ausprägungen im Herzen sind hierbei eine myokardiale
Fibrosierung, eine myokardiale Hypertrophie und Herzrhythmusstörungen.
In dieser Arbeit wurden insbesondere kardiale Veränderungen auf Zell- und Proteinebene
untersucht. Zur Proteinanalyse der Kardiomyozyten wurden Western Blots und eine Schnittbildgebung
angefertigt. Für eine funktionelle Untersuchung wurden isolierte vitale Kardiomyozyten
mittels Fluoreszenzfarbstoffen untersucht und unter elektrischer Stimulation beobachtet.
Desweiteren wurden isolierte Mitochondrien auf ihren Stoffwechsel und eventuelle
Defekte hin analysiert. Hierbei konnte gezeigt werden, dass junge SPRED2 KO Mäuse keine
wesentlichen hämodynamischen Einschränkungen aufweisen und eine gute Kompensationsfähigkeit
gegenüber einer Nachlaststeigerung aufweisen. Auch gezeigt werden konnte, dass
Veränderungen im Rahmen der Zellkontraktion beim Kalziumhaushalt und Membranpotential
existieren und im Zusammenhang mit einer verminderten Expression von SERCA und CaV1.2
stehen. Bei der Untersuchung von Mitochondrien konnten keine wesentlichen Defizite der
mitochondrialen Funktion der SPRED 2 KO Mäuse gefunden werden. In diesem Zusammenhang
ist die bekannte Störung der Autophagie am ehesten Ursache für eine gesteigerte Fibrosierung,
sowie der gesteigerten Apoptose der Kardiomyozyten. In Folge dessen könnten die
oben beschriebenen Veränderungen des Kalziumhaushaltes der Kardiomyozyten stehen und
letztendlich über maligne Herzrhythmusstörungen zum vorzeitigen Versterben führen.
Allogenic hematopoietic stem cell transplantation (allo-HCT) is a curative therapy for the treatment of malignant and non-malignant bone marrow diseases. The major complication of this treatment is a highly inflammatory reaction known as Graft-versus-Host Disease (GvHD). Cyclosporin A (CsA) and tacrolimus are used to treat GvHD which limits inflammation but also interferes with the anticipated Graft-versus-Leukemia (GvL) effect. These drugs repress conventional T cells (Tcon) along with regulatory T cells (Treg), which are important for both limiting GvHD and supporting GvL. Both of these drugs inhibit calcineurin (CN), which dephosphorylates and activates the nuclear factor of activated T-cells (NFAT) family of transcription factors. Here, we make use of our Cd4cre.Cas9+ mice and developed a highly efficient non-viral CRISPR/Cas9 gene editing method by gRNA-only nucleofection. Utilizing this technique, we demonstrated that unstimulated mouse T cells upon NFATc1 or NFATc2 ablation ameliorated GvHD in a major mismatch mouse model. However, in vitro pre-stimulated mouse T cells could not achieve long-term protection from GvHD upon NFAT single-deficiency. This highlights the necessity of gene editing and transferring unstimulated human T cells during allo-HCT. Indeed, we established a highly efficient ribonucleoprotein (RNP)-mediated CRISPR/Cas9 gene editing for NFATC1 and/or NFATC2 in pre-stimulated as well as unstimulated primary human T cells. In contrast to mouse T cells, not NFATC1 but NFATC2 deficiency in human T cells predominantly affected proinflammatory cytokine production. However, either NFAT single-knockout kept cytotoxicity of human CD3+ T cells untouched against tumor cells in vitro. Furthermore, mouse and human Treg were unaffected upon the loss of a single NFAT member. Lastly, NFATC1 or NFATC2-deficient anti-CD19 CAR T cells, generated with our non-viral ‘one-step nucleofection’ method validated our observations in mouse and human T cells. Proinflammatory cytokine production was majorly dependent on NFATC2 expression, whereas, in vitro cytotoxicity against CD19+ tumor cells was undisturbed in the absence of either of the NFAT members. Our findings emphasize that NFAT single-deficiency in donor T cells is superior to CN-inhibitors as therapy during allo-HCT to prevent GvHD while preserving GvL in patients.
The main objective of this study was to test whether subjects with different degrees of bruxism differ regarding EMG parameters and whether CES intervention affects those parameters. The hypothesis was that CES influences EMG parameters and after its’ cessation, all EMG parameters return to baseline (exposure–response relationship).
For this purpose, forty subjects were examined, 16 men and 24 women, matched for age and gender and assigned randomly in the intervention (N=20) and control group (N=20). The procedure was as follows: 1-week inactive GC (N=40), 2 weeks inactive/active GC (N=20/N=20), 2 weeks inactive GC (N=40). Each interval was followed by a surface EMG recording from eight muscle parts (right and left anterior -, medial -, and posterior masseter and right and left anterior temporalis) under force-controlled feedback (BiteFork®) with three submaximal bite forces. The resulting EMG activity is expressed as RMS % MVC and RMS at MVC. The statistics is performed with t-test, one-way rmANOVA, and Friedman rmANOVA on ranks, according to the distribution of the data. The significance level was set at p≤0.05.
The results generated from the within-groups and between-groups comparison were mostly not statistically significant and could therefore not offer clinically relevant conclu-sions.
However, it cannot be excluded that a higher submaximal bite force and an extended intervention interval would have rendered different outcomes. The insufficient study sample resulted in a low observed power which makes the findings prone to Type II er-ror. It can be concluded that this study did not find any substantiating differences be-tween the EMG values of participants with various bruxism activity and that CES could not influence the studied EMG parameters in the two weeks intervention time.
Our hypothesis which supposes that subjects with high and low bruxism activity differ in RMS % MVC could not be verified. However, with the gained knowledge, it is recom-mended to further elaborate a definite bruxism diagnosis by using portable EMG devices.
Serum half-life elongation as well as the immobilization of small proteins like cytokines is still one of the key challenges for biologics. This accounts also for cytokines, which often have a molecular weight between 5 and 40 kDa and are therefore prone to elimination by renal filtration and sinusoidal lining cells. To solve this problem biologics are often conjugated to poly(ethylene glycol) (PEG), which is the gold standard for the so called PEGylation. PEG is a synthetic, non-biodegradable polymer for increasing the hydrodynamic radius of the conjugated protein to modulate their pharmacokinetic performance and prolong their therapeutic outcome. Though the benefits of PEGylation are significant, they also come with a prize, which is a loss in bioactivity due to steric hindrance and most often the usage of heterogeneous bioconjugation chemistries. While PEG is a safe excipient in most cases, an increasing number of PEG related side-effects, such as immunological responses like hypersensitivity and accelerated blood clearance upon repetitive exposure occur, which highlights the need for PEG alternative polymers, that can replace PEG in such cases.
Another promising method to significantly prolong the residence time of biologics is to immobilize them at a desired location. To achieve this, the transglutaminase (TG) Factor XIIIa (FXIIIa), which is an important human enzyme during blood coagulation can be used. FXIIIa can recognize specific peptide sequences that contain a lysine as substrates and link them covalently to another peptide sequence, that contains a glutamine, forming an isopeptide bond. This mechanism can be used to link modified proteins, which have a N- or C-terminal incorporated signal peptide by mutation, to the extracellular matrix (ECM) of tissues.
Additionally, both above-described methods can be combined. By artificially introducing a TG recognition sequence, it is possible to attach an azide group containing peptide site-specifically to the TG, recognition sequence. This allows the creation of a site-selective reactive site at the proteins N- or C-terminus, which can then be targeted by cyclooctyne functionalized polymers, just like amber codon functionalized proteins.
This thesis has focused on the two cytokines human Interferon-α2a (IFN-α2a) and human, as well as murine Interleukin-4 (IL-4) as model proteins to investigate the above-described challenges. IFN-α2a has been chosen as a model protein because it is an approved drug since 1986 in systemic applications against some viral infections, as well as several types of cancer. Furthermore, IFN-α2 is also approved in three PEGylated forms, which have different molecular weights and use different conjugation techniques for polymer attachment. This turns it into an ideal candidate to compare new polymers against the gold standard PEG. Interleukin-4 (IL-4) has been chosen as the second model protein due to its similar size and biopotency. This allows to compare found trends from IFN-α2a with another bioconjugate platform and distinguish between IFN-α2a specific, or general trends. Furthermore, IL-4 is a promising candidate for clinical applications as it is a potent anti-inflammatory protein, which polarizes macrophages from the pro-inflammatory M1 state into the anti-inflammatory M2 state.
The chirality of the interlocked bay-arylated perylene motif is investigated upon its material prospect and the enhancement of its chiroptical response to the NIR spectral region. A considerable molecular library of inherently chiral perylene bisimides (PBIs) was utilized as acceptors in organic solar cells to provide decent device performances and insights into the structure-property relationship of PBI materials within a polymer blend. For the first time in the family of core-twisted PBIs, the effects of enantiopurity on the device performance was thoroughly investigated. The extraordinary structural sensitivity of CD spectroscopy served as crucial analytical tool to bridge the highly challenging gap between molecular properties and device analytics by proving the excitonic chirality of a helical PBI dimer. The chirality of this perylene motif could be further enhanced on a molecular level by both the expansion and the enhanced twisting of the π-scaffold to achieve a desirable strong chiroptical NIR response introducing a new family of twisted QBI-based nanoribbons. These achievements could be substantially further developed by expanding this molecular concept to a supramolecular level. The geometrically demanding supramolecular arrangement necessary for the efficient excitonic coupling was carefully encoded into the molecular design. Accordingly, the QBIs could form the first J-type aggregate constituting a fourfold-stranded superhelix of a rylene bisimide with strong excitonic chirality. Therefore, this thesis has highlighted the mutual corroboration of experimental and theoretical data from the molecular to the supramolecular level. It has demonstrated that for rylene bisimide dyes, the excitonic contribution to the overall chiroptical response can be designed and rationalized. This can help to pave the way for new organic functional materials to be used for
chiral sensing or chiral organic light-emitting devices.
In this work, dRNA-seq (differential RNA sequencing) and RNAtag-seq were applied to first define the global transcriptome architecture of C. difficile, followed by Hfq RIP-seq (RNA immunoprecipitation followed by RNA-seq) and RIL-seq (RNA interaction by ligation and sequencing) to characterize the Hfq-mediated sRNA interactome on a transcriptome-wide scale. These approaches resulted in the annotation of > 60 novel sRNAs. Notably, it not only revealed 50 Hfq-bound sRNAs, but also > 1000 mRNA-sRNA interactions, confirming Hfq as a global RNA matchmaker in C. difficile. Similar to its function in Gram-negative species, deletion of Hfq resulted in decreased sRNA half-lives, providing evidence that Hfq affects sRNA stability in C. difficile. Finally, several sRNAs and their function in various infection relevant conditions were characterized. The sRNA nc085 directly interacts with the two-component response regulator eutV, resulting in regulation of ethanolamine utilization, an abundant intestinal carbon and nitrogen source known to impact C. difficile pathogenicity. Meanwhile, SpoY and SpoX regulate translation of the master regulator of sporulation spo0A in vivo, thereby affecting sporulation initiation. Furthermore, SpoY and SpoX deletion significantly impacts C. difficile gut colonization and spore burden in a mouse model of C. difficile infection.
Forkhead box O transcription factors are a family of proteins involved in cellular processes downstream of the Insulin-PI3K-PKB pathway. In response to extra- or intracellular stresses, for example starvation or oxidative stress, FoxOs are required to direct cell cycle progression and apoptosis. In endothelial cells, they induce apoptosis, and their deregulation is linked to diseases involving the insulin pathway, such as diabetes. FoxOs also exhibit a complex role in tumour transformation: here their main function is to suppress tumorigenesis. In both physiological and cancer contexts, FoxO activation leads to the transcription of some general targets, such as p27kip1 or IGFBP1. The FoxOs can also induce tissue-specific genes, as ANGPT2 and BIM in the endothelium.
In endothelial cells, another pathway with a pivotal function is the MEK5/ERK5 MAPK signalling way. Its activation promotes cell survival and proliferation in stressful conditions, e.g., when blood vessels are exposed to the shear forces exerted by the blood stream. Furthermore, recent data described ERK5 as a kinase directing tumour resistance upon therapy-induced stress.
Comparing their reported roles in various tumours and in the endothelium, FoxO proteins and the MEK5/ERK5 MAPK cascade appear to exert opposite functions. First non-published data confirmed the hypothesis that FoxO factors are subject to a negative modulation by the MEK5/ERK5 pathway. Hence, one goal of this PhD project was to further characterise this crosstalk at molecular level. The major mechanism of FoxO regulation is the balance among several post translational modifications, such as phosphorylation, acetylation, and ubiquitination. Most importantly, the PKB dependent phosphorylation of FoxOs negatively controls their activity, and it is critical for their subcellular localization. Therefore, the regulation of FoxO localization as mechanism of ERK5 dependent suppression was studied, but the results presented in this thesis argue against this hypothesis. However, additional experiments are required to explore the impact of ERK5 activity on FoxO post-translational modifications.
FoxO activity can also be modulated by the interaction with other proteins, which in turn could explain general- and tissue-specific gene expression. Thus, another objective of this work was to investigate FoxO3-interactome in endothelial cells and the impact of MEK5/ERK5 activation on it. As published in (Fusi et al. 2022) and presented here, this analysis unveiled TRRAP as new FoxO bound protein in several cell types. Moreover, the interaction did not rely on the capacity of the FoxOs to bind their consensus DNA sequences at the promoter of target genes. Functional data demonstrated that TRRAP is required for FoxO-dependent gene transcription in endothelial and osteosarcoma cells. In addition, TRRAP expression in the endothelium is important for FoxO induced apoptosis. In summary, the interaction between FoxO factors and TRRAP revealed a new regulatory mechanism of FoxO-dependent gene transcription. It remains to be analysed whether the MEK5/ERK5 cascade may exert its suppressive effect on FoxO activity by interfering with their binding to TRRAP and whether such a mechanism may be relevant for tumorigenesis.
Regulatory T cells (Tregs) are the masters of immune regulation controlling inflammation and tolerance, tissue repair and homeostasis. Multiple immunological diseases result from altered Treg frequencies and Treg dysfunction. We hypothesized that augmenting Treg function and numbers would prevent inflammatory disease whereas inhibiting or depleting Tregs would improve cancer immunotherapy.
In the first part of this thesis, we explored whether in vivo activation and expansion of Tregs would impair acute graft-versus-host disease (aGvHD). In this inflammatory disease, Tregs are highly pathophysiological relevant and their adoptive transfer proved beneficial on disease outcome in preclinical models and clinical studies. IL-2 has been recognized as a key cytokine for Treg function. Yet, attempts in translating Treg expansion via IL-2 have remained challenging, due to IL-2s extremely broad action on other cell types including effector T cells, NK cells, eosinophils and vascular leakage syndrome, and importantly, due to poor pharmacokinetics in vivo. We addressed the latter issue using an IL-2-IgG-fusion protein (irrIgG-IL-2) with improved serum retention and demonstrated profound Treg expansion in vivo in FoxP3-luciferase reporter mice. Further, we augmented Treg numbers and function via the selective-TNF based agonists of TNFR2 (STAR2). Subsequently, we tested a next-generation TNFR2 agonist, termed NewSTAR, which proved even more effective. TNFR2 stimulation augmented Treg numbers and function and was as good as or even superior to the IL-2 strategy. Finally, in a mouse model of aGvHD we proved the clinical relevance of Treg expansion and activation with irrIgG-IL-2, STAR2 and NewSTAR. Notably, the TNFR2 stimulating constructs were outstanding as we observed not the IL-2 prototypic effects on other cell populations and no severe side effects.
In the second part of this thesis, we explored Tregs in pancreatic ductal adenocarcinoma (PDAC) and developed targeting strategies. Among several tumor entities in which Tregs impact survival, preclinical and clinical data demonstrated their negative role on PDAC. In our studies we employed the orthotopic syngeneic Panc02 model in immunocompetent mice. Based on flow cytometric analysis of the tumor microenvironment we propose TIGIT and TNFRSF members as novel therapeutic targets. Surprisingly, we found that blocking TNFR2 did not interfere with intratumoral Treg accumulation. However, we decreased the highly abundant intratumoral Tregs when we disrupted the tumor extracellular matrix. In PDAC, Treg manipulation alone did not lead to tumor regression and we propose that an additional immune boost may be necessary for efficient tumor immune surveillance and cancer clearance. This contrasts with aGvHD, in which Treg manipulation alone was sufficient to improve disease outcome.
Conclusively, we demonstrated the enormous medical benefit of Treg manipulation. Our promising data obtained with our newly developed powerful tools highlight the potential to translate our findings into clinical practice to therapeutically target human Tregs in patients. With novel TNFR2 agonists (STAR2, NewSTAR) we augmented Treg numbers and function as (or even more) effectively than with IL-2, without causing adverse side effects. Importantly, exogenous in vivo Treg expansion protected mice from aGvHD. For the therapy of PDAC, we identified novel targets on Tregs, notably TIGIT and members of the TNFRSF. We demonstrated that altering the extracellular tumor matrix can efficiently disrupt the Treg abundance in tumors. These novel targeting strategies appear as attractive new treatment options and they may benefit patients suffering from inflammatory disease and cancer in the future.
Many arthropods such as mosquitoes, ticks, bugs, and flies are vectors for the transmission of pathogenic parasites, bacteria, and viruses. Among these, the unicellular parasite Trypanosoma brucei (T. brucei) causes human and animal African trypanosomiases and is transmitted to the vertebrate host by the tsetse fly. In the fly, the parasite goes through a complex developmental cycle in the alimentary tract and salivary glands ending with the cellular differentiation into the metacyclic life cycle stage. An infection in the mammalian host begins when the fly takes a bloodmeal, thereby depositing the metacyclic form into the dermal skin layer. Within the dermis, the cell cycle-arrested metacyclic forms are activated, re-enter the cell cycle, and differentiate into proliferative trypanosomes, prior to dissemination throughout the host.
Although T. brucei has been studied for decades, very little is known about the early events in the skin prior to systemic dissemination. The precise timing and the mechanisms controlling differentiation of the parasite in the skin continue to be elusive, as does the characterization of the proliferative skin-residing trypanosomes. Understanding the first steps of an infection is crucial for developing novel strategies to prevent disease establishment and its progression.
A major shortcoming in the study of human African trypanosomiasis is the lack of suitable infection models that authentically mimic disease progression. In addition, the production of infectious metacyclic parasites requires tsetse flies, which are challenging to keep. Thus, although animal models - typically murine - have produced many insights into the pathogenicity of trypanosomes in the mammalian host, they were usually infected by needle injection into the peritoneal cavity or tail vein, bypassing the skin as the first entry point. Furthermore, animal models are not always predictive for the infection outcome in human patients. In addition, the relatively small number of metacyclic parasites deposited by the tsetse flies makes them difficult to trace, isolate, and study in animal hosts.
The focus of this thesis was to develop and validate a reconstructed human skin equivalent as an infection model to study the development of naturally-transmitted metacyclic parasites of T. brucei in mammalian skin. The first part of this work describes the development and characterization of a primary human skin equivalent with improved mechanical properties. To achieve this, a computer-assisted compression system was designed and established. This system allowed the improvement of the mechanical stability of twelve collagen-based dermal equivalents in parallel through plastic compression, as evaluated by rheology. The improved dermal equivalents provided the basis for the generation of the skin equivalents and reduced their contraction and weight loss during tissue formation, achieving a high degree of standardization and reproducibility. The skin equivalents were characterized using immunohistochemical and histological techniques and recapitulated key anatomical, cellular, and functional aspects of native human skin. Furthermore, their cellular heterogeneity was examined using single-cell RNA sequencing - an approach which led to the identification of a remarkable repertoire of extracellular matrix-associated genes expressed by different cell subpopulations in the artificial skin. In addition, experimental conditions were established to allow tsetse flies to naturally infect the skin equivalents with trypanosomes.
In the second part of the project, the development of the trypanosomes in the artificial skin was investigated in detail. This included the establishment of methods to successfully isolate skin-dwelling trypanosomes to determine their protein synthesis rate, cell cycle and metabolic status, morphology, and transcriptome. Microscopy techniques to study trypanosome motility and migration in the skin were also optimized. Upon deposition in the artificial skin by feeding tsetse, the metacyclic parasites were rapidly activated and established a proliferative population within one day. This process was accompanied by: (I) reactivation of protein synthesis; (II) re-entry into the cell cycle; (III) change in morphology; (IV) increased motility. Furthermore, these observations were linked to potentially underlying developmental mechanisms by applying single-cell parasite RNA sequencing at five different timepoints post-infection.
After the initial proliferative phase, the tsetse-transmitted trypanosomes appeared to enter a reversible quiescence program in the skin. These quiescent skin-residing trypanosomes were characterized by very slow replication, a strongly reduced metabolism, and a transcriptome markedly different from that of the deposited metacyclic forms and the early proliferative trypanosomes. By mimicking the migration from the skin to the bloodstream, the quiescent phenotype could be reversed and the parasites returned to an active proliferating state. Given that previous work has identified the skin as an anatomical reservoir for T. brucei during disease, it is reasonable to assume that the quiescence program is an authentic facet of the parasite's behavior in an infected host.
In summary, this work demonstrates that primary human skin equivalents offer a new and promising way to study vector-borne parasites under close-to-natural conditions as an alternative to animal experimentation. By choosing the natural transmission route - the bite of an infected tsetse fly - the early events of trypanosome infection have been detailed with unprecedented resolution. In addition, the evidence here for a quiescent, skin-residing trypanosome population may explain the persistence of T. brucei in the skin of aparasitemic and asymptomatic individuals. This could play an important role in maintaining an infection over long time periods.
The cancer stem cell hypothesis is a cancer development model which elicited great interest in the last decades stating that cancer heterogeneity arises from a stem cell through asymmetrical division. The Cancer Stem Cell subset is described as the only population to be tumorigenic and having the potential to renew. Conventional therapy often fails to eradicate CSC resulting in tumor relapse. Consequently, it is of great inter-est to eliminate this subset of cells to provide the best patient outcome. In the last years several approaches to target CSC were developed, one of them being immunotherapeu-tic targeting with antibodies. Since markers associated with CSC are also expressed on normal stem cells or healthy adjacent tissue in colorectal cancer, dual targeting strate-gies are preferred over targeting only a single antigen. Subsequently, the idea of dual targeting two CSC markers in parallel by a newly developed split T cell-engaging anti-body format termed as Hemibodies emerged. In a preliminary single cell RNA sequenc-ing analysis of colorectal cancer cells CD133, CD24, CD166 and CEA were identified as suitable targets for the combinatorial targeting strategy. Therefore, this study focused on trispecific and trivalent Hemibodies comprising a split binding moiety against CD3 and a binding moiety against either CD133, CD24, CD166 or CEA to overcome the occurrence of resistance and to efficiently eradicate all tumor cells including the CSC compartment. The study showed that the Hemibody combinations CD133xCD24, CD133xCD166 and CD133xCEA are able to eliminate double positive CHO cells with high efficacy while having a high specificity indicated by no killing of single antigen positive cells. A thera-peutic window ranging between one to two log levels could be achieved for all combina-tions mentioned above. The combinations CD133xCD24 and CD133xCD166 further-more proved its efficacy and specificity on established colorectal cancer cell lines. Be-sides the evaluation of specificity and efficacy the already introduced 1st generation of Hemibodies could be improved into a 2nd generation Hemibody format with increased half-life, stability and production yield. In future experiments the applicability of above-mentioned Hemibodies will be proven on patient-derived micro tumors to also include variables like tumor microenvironment and infiltration.
The bile system in vertebrates is an evolutionary conserved endogenous solubilization system for hydrophobic fats and poorly water-soluble vitamins. Bile pours out from the gallbladder through the common bile duct into the duodenum triggered by cholecystokinin. Cholecystokinin is released from enteroendocrine cells after food intake. The small intestine is also the absorption site of many orally administered drugs. Most emerging drug candidates belong to the class of poorly water-soluble drugs (PWSDs). Like hydrophobic vitamins, these PWSDs might as well be solubilized by bile. Therefore, this natural system is of high interest for drug formulation strategies. Simulated intestinal fluids containing bile salts (e.g., taurocholate TC) and phospholipids (e.g., lecithin L) have been widely applied over the last decade to approximate the behavior of PWSDs in the intestine. Solubilization by bile can enhance the oral absorption of PWSDs being at least in part responsible for the positive “food effect”. The dissolution rate of PWSDs can be also enhanced by the presence of bile. Furthermore, some PWSDs profit from supersaturation stabilization by bile salts. Some excipients solubilizing PWSDs seemed to be promising candidates for drug formulation when investigated in vitro without bile. When tested in vivo, these excipients reduced the bioavailability of drugs. However, these observations have been hardly examined on a molecular level and general links between bile interaction in vitro and bioavailability are still missing.
This thesis investigated the interplay of bile, PWSDs, and excipients on a molecular level, providing formulation scientists a blueprint for rational formulation design taking bile/PWSD/excipient/ interaction into account. The first chapter focus on an in silico 1H nuclear magnetic resonance (NMR) spectroscopy-based algorithm for bile/drug interaction prediction. Chapter II to IV report the impact of excipients on bioavailability of PWSDs interacting with bile. At last, we summarized helpful in vitro methods for drug formulation excipient choice harnessing biopharmaceutic solubilization in chapter V.
Chapter I applies 1H NMR studies with bile and drugs on a large scale for quantitative structure-property relationship analysis. 141 drugs were tested in simulated intestinal media by 1H NMR. Drug aryl-proton signal shifts were correlated to in silico calculated molecular 2D descriptors. The probability of a drug interacting with bile was dependent on its polarizability and lipophilicity, whereas interaction with lipids in simulated intestinal media components was dependent on molecular symmetry, lipophilicity, hydrogen bond acceptor capability, and aromaticity. The probability of a drug to interact with bile was predictive for a positive food effect. This algorithm might help in the future to identify a bile and lipid interacting drug a priori.
Chapter II investigates the impact of excipients on bile and free drug fraction. Three different interaction patterns for excipients were observed. The first pattern defined excipients that interacted with bile and irreversibly bound bile. Therefore, the free drug fraction of bile interacting drugs increased. The second pattern categorized excipients that formed new colloidal entities with bile which had a high affinity to bile interacting drugs. These colloids trapped the drug and decreased the free drug fraction. The last excipient pattern described excipients that formed supramolecular structures in coexistence with bile and had no impact on the free drug fraction. These effects were only observed for drugs interacting with bile (Perphenazine and Imatinib). Metoprolol’s free drug fraction, a compound not interacting with bile, was unaffected by bile or bile/excipient interaction. We hypothesized that bile/excipient interactions may reduce the bioavailability of bile interacting drugs.
Chapter III addresses the hypothesis from chapter II. A pharmacokinetic study in rats revealed that the absorption of Perphenazine was reduced by bile interacting excipients due to bile/excipient interaction. The simultaneous administration of excipient patterns I and II did not further reduce or enhance Perphenazine absorption. Conversely, the absorption of Metoprolol was not impacted by excipients. This reinforced the hypothesis, that drugs interacting with bile should not be formulated with excipients also interacting with bile.
Chapter IV further elaborates which in vitro methods using simulated intestinal fluids are predictive for a drug’s pharmacokinetic profile. The PWSD Naporafenib was analyzed in vitro with simulated intestinal fluids and in presence of excipients regarding solubility, supersaturation, and free drug fraction. Naporafenib showed a strong interaction with TC/L from simulated bile. Assays with TC/L, but not without identified one excipient as possibly bioavailability reducing, one as supersaturation destabilizing, and the last as bile not interacting and supersaturation stabilizing excipient. A pharmacokinetic study in beagle dogs outlined and confirmed the in vitro predictions.
The Appendix summarizes in vivo predictive methods as presented in chapter I to IV and rationalizes experimental design paving the way towards a biopharmaceutic excipient screening. The first presented preliminary decision tree is transformed into a step-by-step instruction. The presented decision matrix might serve as a blueprint for processes in early phase drug formulation development.
In summary, this thesis describes how a drug can be defined as bile interacting or non-interacting and gives a guide as well how to rate the impact of excipients on bile. We showed in two in vivo studies that bile/excipient interaction reduced the bioavailability of bile interacting drugs, while bile non-interacting drugs were not affected. We pointed out that the bile solubilization system must be incorporated during drug formulation design. Simulated gastrointestinal fluids offer a well-established platform studying the fate of drugs and excipients in vivo. Therefore, rational implementation of biopharmaceutic drug and excipient screening steers towards efficacy of oral PWSD formulation design.
In der vorliegenden Arbeit wurden spontane Lautäußerungen (Komfortlaute) von normalhörenden Säuglingen und Säuglinge mit einer hochgradig sensorineuralen Hörstörung untersucht. Dabei handelte es sich um Teilnehmer und Teilnehmerinnen einer Kohortenstudie, die gemeinsam vom Comprehensive Hearing Center (CHC) und dem Zentrum für vorsprachliche Entwicklung und Entwicklungsstörung (ZVES) durchgeführt wurde. Ziel der Arbeit war es die einfachsten Vokalisationstypen aus dem Komfortlautrepertoire zu analysieren, um der Frage nachzugehen, ob es bereits bei rein phonatorisch erzeugten Vokalisationen Unterschiede zwischen den Säuglingen beider Gruppen geben könnte.
In der Stichprobe von 8 sensorineural hörgestörten und 18 normalhörenden Säuglingen und insgesamt 1236 Vokanten fanden sich statistisch signifikante Unterschiede in der Melodiekontur. Die normalhörenden Säuglinge wiesen einen signifikant höheren Anteil an komplexen Melodiestrukturen im Vergleich zu den hochgradig hörgeschädigten Säuglingen auf. Keine inhaltlich bedeutsamen Unterschiede fanden sich in der Vokalisationslänge der Vokanten. Allerdings zeigte eine einfache rhythmische Analyse doppelbögiger Vokanten in beiden Gruppen, dass die fehlende auditorische Erfahrung in der hörgestörten Gruppe zu einer von dem Rhythmus der normalhörenden Säuglinge geäußerten Vokanten abwich. Insgesamt hat die vorliegende Untersuchung gezeigt, dass es bereits in einem sehr frühen Alter und bei sehr einfachen Lautäußerungen zu Unterschieden in Vokalisationseigenschaften kommt.
Adrenocortical carcinoma (ACC) is a rare, but highly aggressive endocrine malignancy. Tumor-related hypercortisolism is present in 60 % of patients and associated with worse outcome. While cancer immunotherapies have revolutionized the treatment of many cancer entities, the results of initial studies of different immune checkpoint inhibitors in ACC were heterogeneous. Up to now, five small clinical trials with a total of 121 patients have been published and demonstrated an objective response in only 17 patients. However, one of the studies, by Raj et al., reported a clinically meaningful disease control rate of 52 % and a median overall survival of almost 25 months suggesting that a subgroup of ACC patients may benefit from immunotherapeutic approaches. Following the hypothesis that some ACCs are characterized by a glucocorticoid-induced T lymphocytes depletion, several studies were performed as part of the presented thesis. First, the immune cell infiltration in a large cohort of 146 ACC specimens was investigated. It was demonstrated for the first time, and against the common assumption, that ACCs were infiltrated not only by FoxP3+ regulatory T cells (49.3 %), but also that a vast majority of tumor samples was infiltrated by CD4+ TH cells (74 %) and CD8+ cytotoxic T cells (84.3 %), albeit the immune cell number varied heterogeneously and was rather low (median: 7.7 CD3+ T cells / high power field, range: 0.1-376). Moreover, the presence of CD3+-, CD4+- and CD8+ ACC-infiltrating lymphocytes was associated with an improved recurrence-free (HR: 0.31 95 % CI 0.11-0.82) and overall survival (HR: 0.47 96 % CI 0.25-0.87). Particularly, patients with tumor-infiltrating CD4+ TH cells without glucocorticoid excess had a significantly longer overall survival compared to patients with T cell-depleted ACC and hypercortisolism (121 vs. 27 months, p = 0.004). Hence, the impact of glucocorticoids might to some extent be responsible for the modest immunogenicity in ACC as hypercortisolism was reversely correlated with the number of CD4+ TH cells. Accordingly, CD3+ T cells co-cultured with steroidogenic NCI-H295R ACC cells demonstrated in vitro an enhanced anti-tumoral cytotoxicity by secreting 747.96 ±225.53 pg/ml IFN-γ in a therapeutically hormone-depleted microenvironment (by incubation with metyrapone), versus only 276.02 ±117.46 pg/ml IFN-γ in a standard environment with glucocorticoid excess.
Other potential biomarkers to predict response to immunotherapies are the immunomodulatory checkpoint molecules, programmed cell death 1 (PD-1) and its ligand PD-L1, since both are targets of antibodies used therapeutically in different cancer entities. In a subcohort of 129 ACCs, expressions of both molecules were heterogeneous (PD-1 17.4 %, range 1-15; PD-L1 24.4 %, range 1 - 90) and rather low. Interestingly, PD-1 expression significantly influenced ACC patients´ overall (HR: 0.21 95 % CI 0.53-0.84) and progression- free survival (HR: 0.30 95 % CI 0.13-0.72) independently of established factors, like ENSAT tumor stage, resection status, Ki67 proliferation index and glucocorticoid excess, while PD-L1 had no impact.
In conclusion, this study provides several potential explanations for the heterogeneous results of the immune checkpoint therapy in advanced ACC. In addition, the establishment of PD-1 as prognostic marker can be easily applied in routine clinical care, because it is nowadays anyway part of a detailed histo-pathological work-up. Furthermore, these results provide the rationale and will pave the way towards a combination therapy using immune checkpoint inhibitors as well as glucocorticoid blockers. This will increase the likelihood of re-activating the immunological anti-tumor potential in ACC. However, this will have to be demonstrated by additional preclinical in vivo experiments and finally in clinical trials with patients.
The human African trypanosomiasis is a neglected tropical disease, which is caused by the protozoan Trypanosoma brucei and transmitted by the bite of the tsetse fly. An untreated infection leads to death. However, only a few drugs with significant drawbacks are currently available for treatment. In this thesis, quinolone amides with an antitrypanosomal activity were synthesized and their biological and physicochemical properties were measured. New structure-activity relationships and a promising lead structure were discovered.
Bone morphogenetic proteins (BMPs) are involved in various aspects of cell-cell communication in complex life forms. They act as morphogens, help differentiate different cell types from different progenitor cells in development, and are involved in many instances of intercellular communication, from forming a body axis to healing bone fractures, from sugar metabolism to angiogenesis. If the same protein or protein family carries out many functions, there is a demand to regulate and fine-tune their biological activities, and BMPs are highly regulated to generate cell- and context-dependent outcomes.
Not all such instances can be explained yet. Growth/differentiation factor (GDF)5 (or BMP14) synergizes with BMP2 on chondrogenic ATDC5 cells, but antagonizes BMP2 on myoblastic C2C12 cells. Known regulators of BMP2/GDF5 signal transduction failed to explain this context-dependent difference, so a microarray was performed to identify new, cell-specific regulatory components. One identified candidate, the fibroblast growth factor receptor (FGFR)2, was analyzed as a potential new co-receptor to BMP ligands such as GDF5: It was shown that FGFR2 directly binds BMP2, GDF5, and other BMP ligands in vitro, and FGFR2 was able to positively influence BMP2/GDF5-mediated signaling outcome in cell-based assays. This effect was independent of FGFR2s kinase activity, and independent of the downstream mediators SMAD1/5/8, p42/p44, Akt, and p38. The elevated colocalization of BMP receptor type IA and FGFR2 in the presence of BMP2 or GDF5 suggests a signaling complex containing both receptors, akin to other known co-receptors of BMP ligands such as repulsive guidance molecules.
This unexpected direct interaction between FGF receptor and BMP ligands potentially opens a new category of BMP signal transduction regulation, as FGFR2 is the second receptor tyrosine kinase to be identified as BMP co-receptor, and more may follow. The integration of cell surface interactions between members of the FGF and BMP family especially may widen the knowledge of such cellular communication mechanisms which involve both growth factor families, including morphogen gradients and osteogenesis, and may in consequence help to improve treatment options in osteochodnral diseases.
Infectious diseases caused by pathogenic microorganisms are one of the largest socioeconomic burdens today. Although infectious diseases have been studied for decades, in numerous cases, the precise mechanisms involved in the multifaceted interaction between pathogen and host continue to be elusive. Thus, it still remains a challenge for researchers worldwide to develop novel strategies to investigate the molecular context of infectious diseases in order to devise preventive or at least anti-infective measures. One of the major drawbacks in trying to obtain in-depth knowledge of how bacterial pathogens elicit disease is the lack of suitable infection models to authentically mimic the disease progression in humans. Numerous studies rely on animal models to emulate the complex temporal interactions between host and pathogen occurring in humans. While they have greatly contributed to shed light on these interactions, they require high maintenance costs, are afflicted with ethical drawbacks, and are not always predictive for the infection outcome in human patients. Alternatively, in-vitro two-dimensional (2D) cell culture systems have served for decades as representatives of human host environments to study infectious diseases. These cell line-based models have been essential in uncovering virulence-determining factors of diverse pathogens as well as host defense mechanisms upon infection. However, they lack the morphological and cellular complexity of intact human tissues, limiting the insights than can be gained from studying host-pathogen interactions in these systems.
The focus of this thesis was to establish and innovate intestinal human cell culture models to obtain in-vitro reconstructed three-dimensional (3D) tissue that can faithfully mimic pathogenesis-determining processes of the zoonotic bacterium Campylobacter jejuni (C. jejuni). Generally employed for reconstructive medicine, the field of tissue engineering provides excellent tools to generate organ-specific cell culture models in vitro, realistically recapitulating the distinctive architecture of human tissues. The models employed in this thesis are based on decellularized extracellular matrix (ECM) scaffolds of porcine intestinal origin. Reseeded with intestinal human cells, application of dynamic culture conditions promoted the formation of a highly polarized mucosal epithelium maintained by functional tight and adherens junctions. While most other in-vitro infection systems are limited to a flat monolayer, the tissue models developed in this thesis can display the characteristic 3D villi and crypt structure of human small intestine.
First, experimental conditions were established for infection of a previously developed, statically cultivated intestinal tissue model with C. jejuni. This included successful isolation of bacterial colony forming units (CFUs), measurement of epithelial barrier function, as well as immunohistochemical and histological staining techniques. In this way, it became possible to follow the number of viable bacteria during the infection process as well as their translocation over the polarized epithelium of the tissue model. Upon infection with C. jejuni, disruption of tight and adherens junctions could be observed via confocal microscopy and permeability measurements of the epithelial barrier. Moreover, C. jejuni wildtype-specific colonization and barrier disruption became apparent in addition to niche-dependent bacterial localization within the 3D microarchitecture of the tissue model. Pathogenesis-related phenotypes of C. jejuni mutant strains in the 3D host environment deviated from those obtained with conventional in-vitro 2D monolayers but mimicked observations made in vivo. Furthermore, a genome-wide screen of a C. jejuni mutant library revealed significant differences for bacterial factors required or dispensable for interactions with unpolarized host cells or the highly prismatic epithelium provided by the intestinal tissue model. Elucidating the role of several previously uncharacterized factors specifically important for efficient colonization of a 3D human environment, promises to be an intriguing task for future research.
At the frontline of the defense against invading pathogens is the protective, viscoelastic mucus layer overlying mucosal surfaces along the human gastrointestinal tract (GIT). The development of a mucus-producing 3D tissue model in this thesis was a vital step towards gaining a deeper understanding of the interdependency between bacterial pathogens and host-site specific mucins. The presence of a mucus layer conferred C. jejuni wildtype-specific protection against epithelial barrier disruption by the pathogen and prevented a high bacterial burden during the course of infection. Moreover, results obtained in this thesis provide evidence in vitro that the characteristic corkscrew morphology of C. jejuni indeed grants a distinct advantage in colonizing mucous surfaces.
Overall, the results obtained within this thesis highlight the strength of the tissue models to combine crucial features of native human intestine into accessible in-vitro infection models. Translation of these systems into infection research demonstrated their ability to expose in-vivo like infection outcomes. While displaying complex organotypic architecture and highly prismatic cellular morphology, these tissue models still represent an imperfect reflection of human tissue. Future advancements towards inclusion of human primary and immune cells will strive for even more comprehensive model systems exhibiting intricate multicellular networks of in-vivo tissue. Nevertheless, the work presented in this thesis emphasizes the necessity to investigate host-pathogen interactions in infection models authentically mimicking the natural host environment, as they remain among the most vital parts in understanding and counteracting infectious diseases.
A closer look at long-established drugs: enantioselective protein binding and stability studies
(2023)
The aim of this work was to investigate older, established drugs. The extent of the protein binding of chiral ephedra alkaloids to AGP and of ketamine to albumin was determined. Since enantiomers of these drugs are individual available, the focus was on possible enantioselective binding and structural moieties involved in the binding.
Previously published work suggested that ephedrine and pseudoephedrine can bind stereoselectively to proteins other than albumin in serum. For the determination of the extent of protein binding, the established ultrafiltration with subsequent chiral CE analysis was used. To determine the influence of basicity on binding, the drugs methylephedrine and norephedrine were also analyzed. Drug binding to AGP increased with increasing basicity as follows: norephedrine < methylephedrine < ephedrine < pseudoephedrine. pKaff was determined both graphically using the Klotz plot and mathematical indicating a low affinity of the ephedra alkaloids to AGP. Using STD-NMR spectroscopy experiments the aromatic protons and the C-CH3 side chain were shown to be most strongly involved in binding, which could be confirmed by molecular docking experiments in more detail. For all drugs, van der Waals-, π π , cationic interactions, hydrogen bonds, and a formation of a salt bridge were observed. The individual enantiomers showed no significant differences and thus the binding of ephedra alkaloids to AGP is not significant.
In contrast to the ephedra alkaloids, the possible enantioselective binding to albumin was investigated for R and S ketamine. Again, ultrafiltration followed by CE analysis was performed. The binding of ketamine to one main binding site could be identified. A non-linear fit was used for the determination of pKaff. Using the NMR methods STD-NMR, waterLOGSY-NMR, and CPMG-NMRspectroscopy: the aromatic protons as well as the protons of the NCH3 methyl group showed the largest signal intensity changes, while the cyclohexanone protons showed the smallest changes. pKaff was also determined by the change in the chemical shift at different drug-protein ratios. These obtained values confirm the values obtained from ultrafiltration. Based on this, ketamine is classified as a low-affinity ligand to albumin. There were no significant differences between the individual enantiomers and thus the binding of ketamine to albumin is not a stereoselective process.
Using statistical design of experiments an efficient chiral CE method for determining the extent of protein binding of R and S ketamine to albumin was developed and validated according to ICH Q2 (R1) guideline.
The stability of ketamine was also investigated because a yellowish discoloration of an aqueous solution of ketamine developed under heat. XRPD investigations showed the same crystal structure for all batches examined. An untargeted screening using LC HRMS as well as LC UV measurements showed no degradation of ketamine or the presence of impurities in stress and non-stressed ketamine solutions, confirming the stability of ketamine under the stress conditions investigated. The lower the quality of the water used in the stress tests, the more intense the yellow discoloration occurred. The impurity or the mechanism that causes the yellow discoloration could not be identified.
Fabry disease (FD), an X-linked lysosomal storage disorder, is caused by variants in the gene α-galactosidase A (GLA). As a consequence, the encoded homonymous enzyme GLA is not produced in sufficient amount or does not function properly. Subsequently, globotriaosylceradmide (Gb3), the target substrate of GLA, starts accumulating in several cell types, especially neurons and endothelial cells. FD patients suffer from multiorgan symptoms including cardiomyopathy, nephropathy, stroke, and acral burning pain. It is suggested that the impact of pathological Gb3 accumulation, inflammatory and hypoxic processes, and vasculopathy are contributing to the specific FD pain phenotype. Thus, we investigated the role of inflammation, hypoxia, and vasculopathy on molecular level in dorsal root ganglia (DRG) of the GLA knockout (KO) mouse model. Further, we investigated pain-like characteristics of GLA KO mice at baseline (BS), after capsaicin administration, and after repeated enzyme replacement therapy (ERT) administration for a period of 1.5 years. Acquired data showed disturbances in immune response markers represented by downregulated inflammation-associated genes and lower numbers of CD206+ macrophages in DRG of GLA KO mice. Hypoxic mechanisms were active in DRG of GLA KO mice reflected by increased gene expression of hypoxia- and DNA damage-associated targets, higher numbers of hypoxia-inducible factor 1α-positive (HIF1α+) and carbonic anhydrase 9-positive (CA9+) neurons in DRG of GLA KO mice, and DRG neuronal HIF1α cytosolic-nuclear translocation in GLA KO mice. Vascularization in DRG of GLA KO mice was reduced including lower numbers of blood vessel branches and reduced total blood vessel length. Pain-like behavior of the GLA KO mouse model revealed no mechanical hypersensitivity at BS but age-dependent heat hyposensitivity, which developed also age-matched wild type (WT) mice. Capsaicin administration under isoflurane anesthesia did not elicit the development of nocifensive behavior in GLA KO mice after mechanical or heat stimulation. Repeated ERT administration did not show a clear effect in GLA KO mice in terms of restored heat hyposensitivity to BS paw withdrawal latencies. In summary, we demonstrated the impact of disturbed immune response markers, active hypoxic mechanisms, and reduced vascularization on molecular FD pathophysiology.
Die dem Formenkreis der Dystonien zugrundeliegenden, pathophysiologischen Grundlagen sind bislang nicht abschließend geklärt. Für die DYT-TOR1A Dystonie ist bekannt, dass eine 3-bp Deletion eines GAG-Codons im TOR1A-Gen auf Chromosom 9 einen Funktionsverlust des Proteins TorsinA bewirkt. Dieser Funktionsverlust wird als auslösender Faktor für die Entstehung der DYT-TOR1A Dystonie angenommen. Nichtsdestotrotz entwickeln lediglich circa 30% der Mutationsträger eine dystone Bewegungsstörung. Als Grund dafür wird eine Two-hit Hypothese diskutiert, die zusätzlich zur genetischen Prädisposition einen Umweltfaktor wie ein peripheres Trauma für die Entstehung von Symptomen postuliert. Durch eine standardisierte Quetschläsion des N. ischiadicus konnte mit dieser Arbeit bei DYT1KI Mäusen, die die ∆GAG-Mutation im endogenen Genom tragen, ein dystoner Phänotyp hervorgerufen werden. Mit den Aufzeichnungen der Mäuse im TST wurde ein neuronales Netzwerk mittels der Software „DeepLabCut“ trainiert, sodass die Dystonie-ähnlichen Bewegungen automatisiert erfasst und ausgewertet werden konnten. Das Netzwerk trägt dazu bei, dem vorwiegend klinischen Syndrom der Dystonie eine objektive kinematische Charakterisierung zu bieten und kann auf andere TSTs anderer Nagermodelle übertragen werden. Ferner wurde überprüft, ob die beobachteten Bewegungen durch Unterschiede in der Regeneration nach der Nervenquetschung zustande kamen. Elektroneurographien zeigten jedoch diesbezüglich keine Unterschiede zwischen wt und DYT1KI Tieren. Darüber hinaus sind mikromorphologische Prozesse im zentralen und peripheren Nervensystem Gegenstand dieser Studie. Einerseits konnten wir mittels Immunzellfärbungen von T-, B-Zellen, Makrophagen und Mikroglia feststellen, dass sowohl zentral als auch peripher kein Anhalt darauf besteht, dass die beim DYT1KI Mausmodell entstandenen Dystonie-ähnlichen Bewegungen auf einer Dysfunktion oder Aktivierung des Immunsystems, wie es bei anderen neurologischen Erkrankungen bereits nachgewiesen wurde, eine Rolle spielt. Andererseits konnte anhand stereologischer Messungen gezeigt werden, dass bei den naiven DYT1KI Tieren im Vergleich zu wt Tieren dopaminerge Neurone der SN in der Anzahl verringert und im Volumen vergrößert sind, was auf einen Endophänotypen hinweist. Bei den symptomatischen, nervengequetschten DYT1KI Mäusen zeigte sich wiederum eine weitere, signifikante Zunahme der Hypertrophie der dopaminergen Neurone als Hinweis auf eine unmittelbar mit dem dystonen Phänotypen in Zusammenhang stehende Veränderung. Zusammenfassend konnte ein symptomatisches Mausmodell von hoher translationaler Bedeutung etabliert werden, in dem sich Hinweise für eine dopaminerge Dysregulation ergaben und welches für weitere Studien, insbesondere therapeutischer Art, eingesetzt werden könnte.
Die dieser Arbeit zugrundliegenden Untersuchungen am postmortalen Hirngewebe und an den korrespondierenden Proben postmortalen Liquor cerebrospinalis (CSF) konnten einen Zusammenhang der Dichte der parenchymalen TMEM119-positiven Mikroglia und der der CSF belegen. Innerhalb der analysierten Kompartimente bestehend aus Kortex, Marklager und CSF ergaben sich weit gefächerte Messwerte zur jeweiligen Dichte der immuno-positiven Mikroglia. Die Ergebnisse implizierten eine schnelle Reaktion der Mikroglia im Hirngewebe und einen zeitverzögerten Nachweis von immuno-positiven Mikroglia in der CSF. Signifikante Effekte von Alter, Geschlecht, Hirngewicht und insbesondere einem steigenden Postmortalintervall konnten als potenzielle Einflussfaktoren hinsichtlich der CSF-Intensität ausgeschlossen werden. Eine positive Korrelation ergab sich hingegen zwischen der Mikroglia-Dichte der CSF und den Angaben bezüglich erfolgter Reanimationsmaßnahmen der eingeschlossenen Sterbefälle als Hinweis auf einen relevanten Zusammenhang mit dem zerebralen Blutfluss.
Neben dem ursprünglich angestrebten isolierten Vergleich zwischen der TMEM119-positiven Mikroglia-Profildichte der CSF, des Kortex und der des Markraums ergaben sich nach Analyse weiterhin morphologische Auffälligkeiten der identifizierten Mikroglia und teils spezifische Verteilungsmuster. Die abschnittsweise laminäre Anordnung der Zellen in den kortikalen Gewebeanteilen wies insbesondere in den supragranulären Schichten nahe der Hirnoberfläche strukturell auffällige Mikroglia-Profile mit annähernd rundem Zellkörper und wenigen bis keinen Zellfortsätzen auf. Ein annähernd identisches Bild konnte im perivaskulären Marklager festgestellt werden und wies auf einen Zusammenhang zum Übertritt der Mikroglia in die CSF sowie eine Assoziation zu den medullären Gefäßen hin. Der erstmalige Nachweis des aktiven Übertritts der TMEM119-positiven Mikroglia durch die weiche Hirnhaut implizierte einen aktiven Zugangsweg der Zellen in die CSF unter Ausbildung eines amöboid erscheinenden Phänotyps neben einem lediglich diffusen und passiven Übertritt der Zellen unter pathologischen Bedingungen.
Die durchgeführten Untersuchungen belegen das enorme Potenzial der postmortalen CSF als Untersuchungsmedium insbesondere im Hinblick auf die Erhebung der Mikroglia-Dichte und die Analyse der Mikroglia-Morphologie in Bezug auf neuropathologische Beteiligung im ZNS und damit verbundenen Fragestellungen.
Für die Verwendung von zellbasierten Therapeutika ist vor allem die korrekt Identifikation
sowohl vom Ausgangsmaterial wie auch dem produziertem Material von
zentraler Wichtigkeit. In dieser Arbeit wurde eine Methodik entwickelt, welche eine
nicht-invasive Klassifizierung von Zellen und zellulärer Entwicklung aufgrund ihrer
zweidimensionalen Magnetresonanz-Korrelationsspektren ermöglichte.
Hierzu wurde ein mobiler MR-Scanner mit einer Feldstärke von 0.5T und einem Isozentrum
von 1 cm3 verwendet. Aufgrund der kompakten und leichten Bauweise war
es möglich, das System in normalen Zellkulturlaboren zu verwenden. Von den Proben
wurde ein zweidimensionales T1/T2 -Korrelationsspektrum aufgenommen, anhand
dessen die Zellen klassifiziert werden sollten. Mithilfe von Agarose-Dotagraf® -Zell-
Phantomen konnte die Stabilität und Reproduzierbarkeit des Messsystems und der
verwendeten Sequenz validiert werden.
Aufgrund der unter Umständen recht langen Messzeiten der MR-Technologie war
auch die Handhabung und Kultur der Zellproben während des Messprozesses von
großer Bedeutung. Um hierfür den Durchsatz an Proben zu erhöhen, wurde eine kostengünstige
und ebenfalls mobile Robotikanlage entwickelt. Diese basierte auf dem
kommerziell erhältlichen Roboterarm Braccio, welcher durch einen Arduino Mega
Mikrocontroller gesteuert wurde. Mit bis zu 24 Proben pro Tag konnte durch die
Automatisierung der Durchsatz an Proben um den Faktor 3 – 4 gesteigert werden.
Durch den entwickelten Prozess war es möglich, eine umfangreiche Datenbank –
bestehend aus 362 unabhängigen Messungen (biologische Replikate) – aufzubauen.
Die Datenbank enthielt Messungen von zehn unterschiedlichen Zelllinien. Zusätzlich
wurden T1/T2 -Korrelationsspektren von mesenchymalen Stromazellen (MSCs)
vor und nach deren Differenzierung zu Adipocyten aufgenommen, um ihre zelluläre
Entwicklung nicht-invasiv charakterisieren zu können.
Die aufgenommenen Daten wurden mithilfe einer geeigneten Support Vector Machine
wie auch angepassten künstlichen neuronalen Netzwerken klassifiziert. Mithilfe
dieser Methoden konnten die Zelllinien und MSCs anhand ihrer aufgenommenen
Korrelationsspektren mit einer Genauigkeit von bis zu 98% klassifiziert werden.
Diese hohe Treffsicherheit legte den Schluss nahe, dass die Kombination aus nichtinvasiver,
zweidimensionaler T1/T2 -MR-Relaxometrie und der Verwendung von geeigneten
Methoden des machine learning und der künstlichen Intelligenz eine effiziente
Methodik für die nicht-invasive Klassifizierung von Zellen sowie zellulärer
Entwicklung darstellt.
Im Rahmen dieser Arbeit wurde die Reaktivität des Phosphorans (C2F5)3PF2 gegenüber Lewis-Basen (N-heterozyklische Carbene und Phosphane) und gegenüber verschiedenen Übergangsmetall-Fluoridokomplexen untersucht. Im ersten Teil werden die Lewis-Säure/Base-Addukte zwischen (C2F5)3PF2 und verschiedenen
N-heterozyklischen Carbenen (NHCs) beschrieben. Der Fokus des zweiten Teils der Arbeit liegt auf der Darstellung kationischer Komplexe ausgehend von neutralen d-Block-Metallfluoriden, welche durch Fluorid-Transfer auf das Lewis-acide (C2F5)3PF2 erfolgt. Hierbei wurden Komplexe verschiedener Übergangsmetalle (Ti, Ni, Cu) verwendet, wodurch der Fluorid-Transfer auf das Phosphoran quer über die 3d-Reihe untersucht wurde. Im letzten Kapitel dieser Arbeit wurden die Synthese und die Anwendung von Kationen des Typs [(NHC)Cu]+ eingehender untersucht. Dazu wurde zunächst die Synthese der Ausgangsverbindungen [(NHC)Cu(F)] modifiziert. Anschließend wurden diese Fluorido-Komplexe auf deren Reaktivität gegenüber (C2F5)3PF2 untersucht. Nachfolgend wurden die Reaktivität von [(Dipp2Im)Cu(C6Me6)]FAP in Ligandenaustauschreaktionen bzw. die Synthese von Komplexen [(Dipp2Im)Cu(LB)]FAP (LB = Lewis-Base) eingehender untersucht.
Die Pyridoxal-5‘-Phosphat Phosphatase (PDXP), auch bekannt als Chronophin (CIN), ist eine HAD-Phosphatase, die beim Menschen ubiquitär exprimiert wird und eine entscheidende Rolle im zellulären Vitamin-B6-Metabolismus einnimmt. PDXP ist in der Lage Pyridoxal-5‘-Phosphat (PLP), die co-enzymatisch aktive Form von Vitamin B6, zu dephosphorylieren. In-vivo Studien mit Mäusen zeigten, dass die Abwesenheit von PDXP mit verbesserten kognitiven Leistungen und einem verringerten Wachstum von Hirntumoren assoziiert ist. Dies begründet die gezielte Suche nach einem pharmakologischen Inhibitor für PDXP. Ein Hochdurchsatz-Screen legte nahe, dass 7,8-Dihydroxyflavon (7,8-DHF) hierfür ein potenzieller Kandidat ist. Zahlreiche Studien beschreiben bereits vielfältige positive neurologische Effekte nach in-vivo Administration von 7,8-DHF, allerdings bleibt der genaue Wirkmechanismus umstritten und wird bis dato nicht mit PDXP in Zusammenhang gebracht. Ziel dieser Arbeit ist es, die Inhibition von PDXP durch 7,8-DHF näher zu charakterisieren und damit einen Beitrag zur Beantwortung der Frage zu leisten, ob PDXP an den 7,8-DHF-induzierten Effekten beteiligt ist.
Hierzu wurde der Effekt von 7,8-DHF auf die enzymatische Aktivität von rekombinant hergestelltem, gereinigtem PDXP in in-vitro Phosphatase-Assays charakterisiert. Um die Selektivität von 7,8-DHF gegenüber PDXP zu untersuchen, wurden fünf weitere HAD-Phosphatasen getestet. Unter den analysierten Phosphatasen zeigte einzig die dem PDXP nah verwandte Phosphoglykolat Phosphatase (PGP) eine geringer ausgeprägte Sensitivität gegen 7,8-DHF. Ein Vergleich von 7,8-DHF mit sechs strukturell verwandten, hydroxylierten Flavonen zeigte, dass 7,8-DHF unter den getesteten Substanzen die höchste Potenz und Effektivität aufwies. Außerdem wurde eine Co-Kristallisation von PDXP mit 7,8-DHF durchgeführt, deren Struktur bis zu einer Auflösung von 2,0 Å verfeinert werden konnte. Die in der Kristallstruktur identifizierte Bindungsstelle von 7,8-DHF an PDXP wurde mittels verschiedener, neu generierter PDXP-Mutanten enzymkinetisch bestätigt. Zusammenfassend zeigen die hier beschriebenen Ergebnisse, dass 7,8-DHF ein direkter, selektiver und vorwiegend kompetitiver Inhibitor der PDXP-Aktivität ist, mit einer IC50 im submikromolaren Bereich.
Die Ergebnisse dieser in-vitro Untersuchungen motivieren zu weiterer Forschung bezüglich der 7,8-DHF-vermittelten Inhibition der PDXP-Aktivität in Zellen, um die Frage beantworten zu können, ob PDXP auch in-vivo ein relevantes Target für 7,8-DHF darstellt.
Regulatory T cells (Treg) are critical immune cells to ensure immune homeostasis. Treg do so by establishing tolerance to self-antigens as well as food-derived antigens. Additionally, they fine-tune immune responses to limit the damage caused by inevitable inflammation during the resolution of an ongoing infection or anti-tumor response. Despite countless efforts to gain a detailed understanding of the mechanisms Treg utilize to regulate adaptive immune responses, in vivo evidence is rather limited. We were interested in the cell-cell interactions of Treg and their spatio-temporal dynamics during a viral infection. We sought to address Interleukin-2 (IL-2) competition as a viable mechanism to control anti-viral CD8 T cell responses. We used intra-vital 2-photon imaging to analyze the interactions between Treg and activated T cells during viral infection. Additionally, we performed multiple loss- and gain-of-function experiments, addressing the IL-2 active signaling of CD8, CD4, and regulatory T cells to understand the competitive sensing of IL-2. Finally, we performed single-cell RNA sequencing to understand the cell-intrinsic differences in Treg caused by infection. We found that IL-2 competition by Treg limits the CD8 T cell response and can alter the differentiation of CD8 T cells. Furthermore, we show that Treg do not arrest in proximity to CD8 T cells for prolonged periods and therefore are unlikely to regulate CD8 T cells via contact-dependent mechanisms previously proposed. Our data support an area control model in which Treg scavenge IL-2 while actively migrating through the LN, constantly limiting access to IL-2. Establishing CD4 T cells as the major source of IL-2 during the later phases of infection, we provide direct evidence that Treg compete with CD8 T cells for CD4-derived IL-2. Finally, we show that IL-2 limitation is in correlation with CD25 expression levels and has an impact on the differentiation of CD8 T cells. Altering the differentiation of CD8 T cells to increase effector or memory functions has huge implications in clinical treatments, e.g ’checkpoint immunotherapy’. Especially in scenarios like checkpoint immunotherapy, where an efficient expansion of CD8 T cells is vital to the success of the treatment, it is invaluable to understand the spatio-temporal dynamics of Treg. Not only can the expansion phase be optimized, but also side effects can be better controlled by ensuring the adequate timing of treatments and boosting the anti-inflammatory response after the initial establishment of CD8 T cells. On top of this, the gained understanding of the regulatory mechanism of Treg can help to enhance the efficacy of autoimmune disorder treatments. Overall, this study addressed highly relevant questions in the Treg field and answered aspects of Treg regulation, refining their mode of action and the spatio-temporal dynamics during viral infection, providing evidence for IL-2 competition as a major regulatory mechanism controlling antiviral CD8 T cell responses.
Strong correlations caused by interaction in systems of electrons can bring about unusual physical phenomena due to many-body quantum effects that cannot properly be captured by standard electronic structure methods like density functional theory. In this thesis, we apply the state-of-the-art continuous-time quantum Monte Carlo algorithm in hybridization expansion (CT-HYB) for the strongly correlated multi-orbital Anderson impurity model (AIM) to the solution of models of magnetic impurities on metallic surfaces and, via dynamical mean-field theory (DMFT), to the solution of a lattice model, the multi-orbital Hubbard model with Hund's coupling.
A concise introduction to the theoretical background focuses on information directly relevant to the understanding of applied models, methods, and the interpretation of results. It starts with a discussion of the AIM with its parameters and its solution in the path integral formalism, the basis of the CT-HYB algorithm. We consider its derivation and implementation in some detail before reviewing the DMFT approach to correlated lattice models and the interpretation of the single-particle Green's function.
We review two algorithmic developments for the CT-HYB algorithm that help to increase the performance of calculations especially in case of a complex structure of the interaction matrix and allow the precise calculation of self-energies and vertex functions also at intermediate and higher frequencies.
Our comparative analysis of Kondo screening in the cobalt on copper impurity system points out the importance of an accurate interaction matrix for qualitatively correct Kondo temperatures and the relevance of all d-orbitals in that case. Theoretical modeling of cobalt impurities in copper "atomic wires" fails to reproduce variations and partial absence of Kondo resonances depending on the wire size. We analyze the dependence of results on parameters and consider possible reasons for the discrepancy. Different Kondo temperatures of iron adatoms adsorbed on clean or oxygen-reconstructed niobium in the normal state are qualitatively reproduced, with the adsorption distance identified as major factor and implications for the superconducting state pointed out.
Moving on to lattice problems, we demonstrate the connection between Hund's coupling, shown to cause first-order character of the interaction-driven Mott transition at half-filling in the two-orbital Hubbard model, and a phase separation zone ending in a quantum critical point at finite doping. We touch on similarities in realistic models of iron-pnictide superconductors. We analyze the manifestation of the compressibility divergence at the finite-temperature critical points away from half-filling in the eigenbasis of the two-particle generalized susceptibility. A threshold for impurity susceptibility eigenvalues that indicates divergence of the DMFT lattice compressibility and distinguishes thermodynamic stability and instability of DMFT solutions is determined.
Das Ziel der Arbeit ist die Erfassung und Analyse sakraler sowie profaner Gebäudetüren des griechischen Mutterlandes von der archaischen bis in die hellenistische Zeit. Im Vordergrund stehen hierbei vor allem Bau- und Gestaltungsfragen der zwar nicht mehr erhaltenen Türflügel, hinsichtlich derer sich jedoch anhand in situ befindlicher Schwellen sowie gefundener Beschläge Rückschlüsse ziehen lassen. Können somit unter anderem Aussagen bezüglich Ausmaß, Flügelanzahl sowie Befestigungstechnik der Türverschlüsse getroffen werden, sind Material- und Gestaltungsfragen oftmals nur mit Hilfe der erhaltenen Darstellungen auf Bildträgern sowie Schriftquellen zu beantworten. Da das Gros der auf Bildträgern in Erscheinung tretenden Türen des untersuchten zeitlichen Rahmens hauptsächlich auf der bemalten Keramik zu finden ist, wird unter dem Aspekt der Darstellungsweisen und bildlichen Semantik auf diese Abbildungen ein weiteres Hauptaugenmerk gelegt.
Platelets have a key physiological role in haemostasis however, inappropriate thrombus formation can lead to cardiovascular diseases such as myocardial infarction or stroke. Although, such diseases are common worldwide there are comparatively few anti-platelet drugs, and these are associated with an increased risk of bleeding. Platelets also have roles in thrombo-inflammation, immuno-thrombosis and cancer, in part via C-type lectin-like receptor 2 (CLEC-2) and its ligand podoplanin. Although CLEC-2 contributes to these diseases in mice, as well as to thrombus stability, it is unclear whether CLEC-2 has similar roles in humans, particularly as human CLEC-2 (hCLEC-2) cannot be investigated experimentally in vivo.
To investigate hCLEC-2 in vivo, we generated a humanised CLEC-2 mouse (hCLEC-2KI) model, as well as a novel monoclonal antibody, HEL1, that binds to a different site than an existing antibody, AYP1. Using these antibodies, we have provided proof of principle for the use of hCLEC-2KI mice to test potential therapeutics targeting hCLEC-2, and shown for the first time that hCLEC-2 can be immunodepleted, with little effect on haemostasis. However, our results have also suggested that there are species differences in the role of CLEC-2 in arterial thrombosis. We further confirmed this using human blood where blocking CLEC-2 ligand binding had no effect on thrombosis, whereas we confirmed a minor role for mouse CLEC-2 in thrombus stability. We also investigated the effect of blocking CLEC-2 signalling using the Bruton’s tyrosine kinase inhibitor PRN473 on CLEC-2 mediated immuno-thrombosis in a Salmonella typhimurium infection model. However, no effect on thrombosis was observed suggesting that CLEC-2 signalling is not involved.
Overall, our results suggest that there may be differences in the role of human and mouse CLEC-2, at least in arterial thrombosis, which could limit the potential of CLEC-2 as an anti-thrombotic target. However, it appears that the interaction between CLEC-2 and podoplanin is conserved and therefore CLEC-2 could still be a therapeutic target in immuno-thrombosis, thrombo-inflammation and cancer. Furthermore, any potential human specific therapeutics could be investigated in vivo using hCLEC-2KI mice.
In Vitro Toxizität der Nanopartikel Graphen und Siliciumdioxid für die Medikamentenapplikation
(2023)
Graphen und Siliciumdioxid Nanopartikel sind als Trägersubstanz für Medikamente beim Drug Targeting von Interesse. Diese Arbeit ist eine toxikologische Untersuchung der Nanopartikel Graphen und Siliciumdioxid im Zellmodell. Dabei wurden Graphen Nanopartikel mit einer Dicke von 6 bis 8 nm und einer Breite von 15 µm verwendet. Die verwendeten Siliciumdioxid Nanopartikel waren kugelförmig und porös mit einer Partikel-Größe von 5 bis 20 nm. Die dosisabhängige Toxizität (Konzentrationen 0,01 mg/ml, 0,1 mg/ml und 1 mg/ml, Inkubation über 24 Stunden) gegenüber 5 verschiedenen Zelllinien (cerebEND, Caco-2, Hep G2, HEK-293, H441) wurde geprüft. Dabei kamen Zellviabilitätstests (CellTiter-Glo Assay, EZ4U-Test) zum Einsatz. Zudem wurde mit den Apoptose-Markern Bax und Caspase-3 auf Gen- und Proteinebene (Polymerasekettenreaktion und Western Blot) überprüft, ob eine Apoptose eingeleitet wurde.
Zur Untersuchung der Zellviabilität wurde der CellTiter-Glo Assay verwendet. Für Graphen Nanopartikel zeigte sich ab einer Konzentration von 1 mg/ml bei den Zelllinien HEK-293 und H441 ein statistisch signifikanter Abfall der Zellviabilität. CerebEND und Hep G2 Zellen reagierten auf Graphen Nanopartikel ab einer Konzentration von 1 mg/ml ebenfalls mit einem deutlichen Abfall der Zellviabilität, diese Ergebnisse waren jedoch nicht statistisch signifikant. Die Zelllinie Caco-2 zeigte sich von den Graphen Nanopartikeln unbeeindruckt, es kam zu keiner statistisch signifikanten Veränderung der Zellviabilität. Siliciumdioxid Nanopartikel bewirkten ab einer Konzentration von 1 mg/ml einen statistisch signifikanten Abfall der Zellviabilität bei den Zelllinien cerebEND, HEK-293 und H441. HepG2 Zellen zeigten bei 1 mg/ml Siliciumdioxid einen deutlichen aber statistisch nicht signifikanten Abfall der Zellviabilität. Die Zelllinie Caco-2 erwies sich auch bei Siliciumdioxid Nanopartikel als äußerst robust und zeigte keine statistisch signifikanten Veränderungen der Zellviabilität.
Messungen der Zellviabilität auf Grundlage von Adsorptionsmessung, wie beim EZ4U-Test, hatten sich als ungeeignet erwiesen, da die Eigenfarbe der Nanopartikel Graphen und Siliciumdioxid mit dieser Messung interferierte.
Zudem wurde geprüft, ob die bei einem Teil der Zelllinien eingetretene toxische Wirkung der Nanopartikel ab einer Konzentration von 1 mg/ml durch Nekrose oder durch Apoptose zustande kam. Die Polymerasekettenreaktion zeigte mit einer einzigen Ausnahme keine statistisch signifikante Erhöhung der Genexpression für Bax und Caspase-3 und gab somit auch keine Hinweise auf die Einleitung einer Apoptose. Im Western Blot zeigte sich keine statistisch signifikante Erhöhung der Proteinexpression von Bax und Caspase-3. Zudem konnte im Western Blot auch keine aktivierte Caspase-3 nachgewiesen werden. Somit lagen auf Grundlage von Polymerasekettenreaktion und Western Blot keine Hinweise auf das Eintreten einer Apoptose vor. Die toxische Wirkung der Nanopartikel Graphen und Siliciumdioxid, die bei einem Teil der Zelllinien ab einer Konzentration von 1 mg/ml nachgewiesen werden konnte, beruhte demnach auf Nekrose.
Ziel dieser Arbeit war es, den Einfluss psychosozialer Belastungsfaktoren auf den Verlauf einer Stammzelltransplantation zu untersuchen. Die primäre Fragestellung war, ob sich das Vorliegen einer posttraumatischen Belastungsstörung (PTSD) auf die Dauer der Immunrekonstitution, gemessen an der Aplasiezeit, auswirkt. Der Untersuchung liegen Daten aus der Medizinischen Klinik und Poliklinik II des Universitätsklinikums Würzburg zugrunde, die im Rahmen einer monozentrischen Querschnittsstudie erhoben wurden. An der Studie nahmen 50 Patienten mit der Diagnose eines Multiplen Myeloms teil, die am Tag ihrer ersten autologen Stammzelltransplantation befragt wurden. Anhand von Fragebögen konnten die Patienten Angaben zu ihrer individuellen psychischen Belastung machen. Für die statistische Auswertung wurden die Angaben aus dem NCCN-Distress-Thermometer und dem PCL-C ausgewertet.
In der vorliegenden Arbeit wurden retrospektiv Daten von 321 Fällen eines fortgeschrit-
tenen Mammakarzinoms ausgewertet. Beobachtungsdaten lagen bis einschließlich Juli
1998 vor. Ein Fokus dieser Arbeit lag auf der Trichotomie der HER2-Ausprägung und
deren prognostischen Wert im Verlauf einer metastasierten Brustkrebserkrankung. In
einer neueren Entwicklung wurde HER2-low als Nomenklatur einer Subgruppe etabliert
für jene Mammakarzinome, die als IHC 1+ oder IHC 2+ gelten und ein negatives ISH-
Ergebnis aufweisen. Neue Studien-Ergebnisse zeigten einen signifikanten klinischen
Vorteil der Therapie mit HER2-basierten Antikörper-Wirkstoff-Konjugaten für HER2-low
Patientinnen (91).
Der Anteil der HER2-low Mammakarzinome nahm im Laufe einer fortgeschrittenen
Brustkrebserkrankung kontinuierlich zu und lag bei 39,3 % im Primärtumor, bei 47,7 %
im ersten Rezidiv und bei 47,8 % in einer zweiten Fernmetastase. Parallel vergrößerte
sich die HER2-positive Subgruppe, wobei sich die HER2-negative Kohorte folglich ver-
kleinerte. Es konnte entsprechend der aktuellen Literatur (117,156) eine Assoziation (p
< 0.001) des HER2-low Subtypen und HR-positiven Mammakarzinomen gezeigt werden.
HER2-low nahm in HR-positiven/Her2-negativen Mammakarzinomen im Laufe der Me-
tastasierung zu (56,7 % - 64,1 % - 75,6 %). Der Anteil der HER2-low-Expression im
Triple-negativen Subtypen initial bei 14,6 % und vergrößerte sich konstant (48,2 % - 50
%). Ein Verlust der HER2-Ausprägung im Krankheitsverlauf korrelierte statistisch signi-
fikant mit einem besseren OS (Hazards Ratio 0,533, 95%-KI[0,316, 0,898], p = .018).
Die Gruppe mit einer HER2-Konversion zu einer schwächeren Ausprägung wies im di-
rekten Vergleich zur Gruppe mit einer Her2-Konversion zu einer stärkeren Ausprägung
ein 21,0 Monate längeres Überleben auf (p = 0.177). Die Entwicklung eines HER2-posi-
tiven Primärtumor zu einer HER2-low Metastase (Hazards Ratio 0,385, 95%-KI[0,17,
0.874], p = .023), eine Veränderung von einem HER2-0 Primärtumor zu einer HER2-low
Metastase (Hazards Ratio 0,124, 95%-KI[0,023, 0,655], p = .014) sowie die ausblei-
bende Veränderung eines HER2-low Primärtumor zu einer Fernmetastase (Hazards Ra-
tio 0,169, 95%-KI[0,035, 0,813], p = .027) wurden in dieser Analyse als weitere protektive
Faktoren nachgewiesen. Kein klinisch-pathologischer oder therapeutischer Faktor
konnte als signifikanter Einflussfaktor auf eine Konversion im HER2-Rezeptor identifi-
ziert werden. Die Ergebnisse dieser Arbeit lassen keine klare Aussage darüber treffen,
ob die Anpassung der tumorspezifischen Therapie nach einer Rezeptorkonversion das
OS verbessert.
Conspiracy theories and fake news are receiving wide media coverage and their proliferation has motivated academic research on the driving factors irrational cognition and behavior. This dissertation focuses on individuals' beliefs about knowledge and knowing, which are commonly referred to as epistemic beliefs. The term post-truth epistemic beliefs is proposed and defined as a strong trust in one’s intuition, a low need to align opinions with evidence, and the strong conviction that truth is a matter of power. Across six online studies, a mediation model is proposed and tested. It includes the core of all dark traits, the Dark Factor of Personality (D), as an antecedent of post-truth epistemic beliefs, and irrational cognition and behavior as consequences. Manuscript #1 comprises four studies showing that post-truth epistemic beliefs are rooted in D and predict increased endorsement of COVID-19 conspiracy theories as well as less engagement in health-protective behavior against COVID-19. Manuscript #2 includes a US nationally representative study suggesting that post-truth epistemic beliefs and D predict a lower probability of having been vaccinated against COVID-19. Manuscript #3 presents a repeated measures experiment indicating that the nexus of D and post-truth epistemic beliefs also predicts less discernment between fake and accurate news. These findings highlight a major insight and a serious challenge for rational communication: Some individuals deliberately disregard (scientific) evidence and rational decision-making. Against this background, the need to foster the epistemological development of students and educators is emphasized.
Im Rahmen dieser Dissertation wurde geprüft, welchen Verlauf die kognitiven Leistungen von Patienten nach der operativen Resektion eines intrakraniellen Meningeoms nahmen und ob hierbei Unterschiede zwischen den Personen bestanden, die eine anschließende Rehabilitation absolvierten, sowie jenen, die keine weiteren Maßnahmen erhielten.
Mit der ersten Hypothese wurde angenommen, dass Patienten ohne Rehabilitation drei Monate nach der Operation ihre kognitiven Fähigkeiten im Vergleich zu einer Woche nach dem Eingriff verbessern. Dies konnte nicht eindeutig bestätigt werden, da eine Steigerung der Leistungen in dieser Patientengruppe nur in fünf der sechzehn Teilgebiete erreicht wurde. Die zweite Hypothese basierte auf der Annahme, dass Patienten mit einer Rehabilitationsmaßnahme Leistungssteigerungen in den getesteten Gebieten zeigten. Der Vergleich fand eine Woche nach dem operativen Eingriff und drei Monate nach der Operation statt. Diese Hypothese kann durch die vorliegenden Ergebnisse im Rahmen der Konzentrationsleistung zumindest eingeschränkt bejaht werden. Es ließen sich zwei signifikante Unterschiede der Ergebnisse der Patienten mit anschließender Rehabilitation beobachten. Hier konnte im ergänzend zur ANOVA berechneten t-Test ein signifikanter Unterschied bei der Leistungssteigerung der Patienten mit anschließender Rehabilitation nachgewiesen werden. Des Weiteren kam es in dieser Patientengruppe zu gesteigerten Leistungen in vierzehn von sechzehn Teilgebieten. Im Falle der dritten Hypothese sollte exploriert werden, ob die Patientengruppe mit anschließender Rehabilitationsmaßnahme im Vergleich zur Patientengruppe ohne weitere Maßnahmen eine größere Leistungssteigerung erfuhr. Dabei konnte eine leichte Tendenz beobachtet werden. Es wurden Verbesserungen der Patientengruppe mit Rehabilitation gegenüber den Patienten ohne weitere Maßnahmen in neun von sechzehn Kategorien beobachtet. Somit lässt sich die Annahme stützen, dass eine postoperative Rehabilitationsmaßnahme sich positiv auf die kognitiven Leistungen bei Meningeom-Patienten auswirkt.
PONV ist eine häufige und für Patient*innen belastende Nebenwirkung nach einer Allgemeinanästhesie. Trotz der Vielzahl an Studien zu den zahlreichen antiemetischen Medikamenten gibt es bisher keinen Überblick über die Effizienz und Sicherheit all dieser Medikamente. Im Rahmen des Cochrane-Reviews „Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: a network meta-analysis“ wurden RCTs zur Prävention von PONV nach Allgemeinanästhesie bei Erwachsenen gesucht. Zu den primären Endpunkten gehörten Erbrechen 0-24 Stunden, schwere unerwünschte Ereignisse und unerwünschte Ereignisse, zu den sekundären Endpunkten Substanz-spezifische Nebenwirkungen, frühes und spätes postoperatives Erbrechen, Übelkeit und vollständiger Behandlungserfolg. In dieser Dissertation wurden die Vergleiche mit mindestens zehn Studien auf das Vorliegen eines Publikationsbias überprüft. Die Beurteilung des Publikationsbias erfolgte unter Anwendung verschiedener Tests (Funnel Plots, contour-enhanced Funnel Plot, Arcsine Test, Trim-and-Fill-Methode). Bei sieben von den 64 analysierten Vergleichen wurde der Verdacht auf einen Publikationsbias gestellt. Für den primären Endpunkt Erbrechen 0-24 Stunden wurde bei zwei Vergleichen (Droperidol vs. Placebo und Metoclopramid vs. Ondansetron) ein Publikationsbias vermutet, für die sekundären Endpunkte Übelkeit bei drei Vergleichen (Tropisetron vs. Placebo, Dexamethason-Ondansetron vs. Dexamethason, Dexamethason-Ondansetron vs. Ondansetron) und für den vollständigen Behandlungserfolg bei zwei Vergleichen (Droperidol vs. Placebo, Ondansetron vs. Placebo). Die Effektschätzer der restlichen 54 Vergleiche sind hinsichtlich der klinischen Relevanz robust und eine Verzerrung durch einen Publikationsbias wurde nicht vermutet.
Der Weg von der Entwicklung bis zur Zulassung neuer Virostatika ist bis heute mit hohen Kosten und einem großen Zeitaufwand verbunden. Sollten jedoch bereits zugelassene antivirale Medikamente eine Wirkung auf andere virale Infektionen zeigen, könnte dieser Prozess stark verkürzt werden. Daher war es Ziel dieser Arbeit, den Effekt von zugelassenen Medikamenten, gegen HSV-1, mCMV, hCMV, RSV, Parainfluenzavirus-3, DENV-2, CHIKV, Poliovirus, Masernvirus und HIV-1 zu evaluieren. Getestet wurden die Polymeraseinhibitoren ACV, GCV, CDV, sowie das neuere Medikament T-705 und die reversen Transkriptase-Inhibitoren TDF, 3TC, AZT und ABC. Außerdem die Proteaseinhibitoren SMV, GRV, DCV, LDV, ELB, VEL, SOF und DSV.
TDF senkte in einer Konzentration von 10 µM die Infektiosität von HSV-1 und mCMV bis zu 1 Größenordnung. Auch ABC senkte die Infektiosität von HSV-1 und mCMV in einer Konzentration von 30 µM um 0,4 bzw. 0,6 Größenordnungen. AZT und ELB senkten die Infektiosität bei Infektionen mit HSV-1 in einer Konzentration von 30 µM um 0,4 Größenordnungen. VEL senkte die Infektiosität von mCMV bis zu einer Konzentration von 2 µM um 0,7 Größenordnungen. Durch die Substanzen ELB und LDV konnte die Replikation von DENV-2 bei einer Konzentration von 10 µM um 0,6 bzw. 0,8 Größenordnungen gesenkt werden. Die Substanzen zeigten jedoch keinen Effekt auf Infektionen mit CHIKV und Poliovirus, sodass für beide Substanzen ein virusspezifischer Effekt anzunehmen ist. Es wurde keine Wirkung der Substanzen gegen Infektionen mit Masernvirus, RSV oder Parainfluenzavirus-3 in den Versuchen beobachtet. Es wurde gezeigt, dass die verwendeten Methoden eine schnelle und effektive Möglichkeit darstellen, neue direkt-antivirale Medikamente zu etablieren. Zudem stellen die gefundenen Wirkstoffe eine gute Grundlage als Leitsubstanzen zur Entwicklung neuer Wirkstoffe dar. Weitere Versuche mit Kombinationen der wirksamen Substanzen sollten zur weiteren Therapiefindung durchgeführt werden. Damit hat die vorgelegte Arbeit eine hohe Relevanz für die weitere Forschung.
Hintergrund
Die Versorgung Schwerverletzter setzt das zügige Erkennen
lebensbedrohlicher Verletzungen und deren Priorisierung voraus. Hierzu verfügt
das Universitätsklinikum Würzburg seit 2018 über ein Doppelschockraumkonzept mit
Ganzkörper-CT, fahrbarer CT-Gantry und einer mobilen Schutzwand, wodurch zwei
Personen nahezu simultan behandelt werden können. Das Ziel der vorliegenden Arbeit
war zum Einen mögliche Spezifika von simultan versorgten Patienten und Patientinnen
zu identifizieren und zum Anderen die Evaluation möglicher Unterschiede in der Qualität
der Versorgung in einem Doppel- und einem Einzelschockraum, insbesondere der Zeit
bis zur CT-Bildgebung und bis zum Beginn operativer Maßnahmen.
Methodik Im Rahmen einer retrospektiven Untersuchung wurden die Patientendaten
aller Schockraumaufnahmen des Universitätsklinikums Würzburg vom 1. Mai 2019 bis
zum 29. April 2020 analysiert. Die Datensätze wurden bei einer simultanen Versorgung
im Schockraum der Doppelschockraumgruppe (Gruppe 1) und bei einer alleinigen
Versorgung der Einzelschockraumgruppe (Gruppe 2) zugeordnet.
Ergebnisse 10,9 % aller Schockraumaufnahmen wurden simultan im Schockraum
versorgt (46 von 423). Personen aus Gruppe 1 verunglückten häufiger bei PKW-Unfällen
(47,8 % vs. 19,6 %; p < 0,05). Keine Unterschiede fanden sich bezüglich Alter,
Geschlecht, ASA, ISS und präklinischer Versorgung. Die Klinik bei der Aufnahme
unterschied sich nicht bezüglich A-, B-, C- und D-Problemen, allerdings litten Personen
aus Gruppe 1 häufiger unter Schmerzen (hier als E-Problem nach ATLS klassifiziert)
(45,7 % vs. 29,2 %; p < 0,05). Die Versorgung im Schockraum (Instrumentierung,
Medikamentenapplikation, Transfusion) ergab keine relevanten Unterschiede.
Insbesondere zeigte sich keine klinisch relevante Verzögerung bei simultan versorgten
Patienten und Patientinnen bis zur CT-Bildgebung oder dem Beginn operativer
Maßnahmen (tCT: 8 vs. 6 min (Gruppe 1 vs. Gruppe 2), p < 0,05; tOP: 99 vs. 90 min
(Gruppe 1 vs. Gruppe 2), p < 0,05). Auch das Outcome in beiden Gruppen war
vergleichbar.
Diskussion Die simultane Versorgung zweier Schwerverletzter stellt hohe
Anforderungen an Personal, Ausstattung und Organisation. Das in dieser Arbeit
untersuchte Doppelschockraumkonzept kann auch bei simultan versorgten Patienten
und Patientinnen eine bestmögliche Versorgung auf individualmedizinischem Niveau
gewährleistet werden.