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Development of Reversed Chimeric Antigen Receptor Regulatory T cells for Type 1 Diabetes Therapy
No full textType 1 diabetes (T1D) is an irreversible autoimmune disease, where genetic and environmental risk factors contribute to the progressive beta cell disruption. Despite the advancement of research and therapies, T1D remains incurable, and patients require insulin replacement for their survival. Immunotherapies appear to be a promising alternative to restore imbalanced homeostasis and possibly stop the progression of T1D. However, most options available nowadays may either compromise the general immune system or be less effective due to lacking specificity. Regulatory T cells (Tregs) play a crucial role in maintaining immune balance. In this project, our objective is to establish an immunotherapy harnessing Tregs to potentially suppress the islet autoimmunity in a specific and controllable manner. We hypothesized that an established chimeric antigen receptor (CAR) strategy, specifically reversed CAR (RevCAR) platform, can effectively redirect and activate Tregs. Therefore, I aimed to develop a pancreatic islet-directed RevCAR Treg platform and explore its clinical potential.
The islet-directed RevCAR Treg platform comprises three main parts that need to be established. First, to imitate the environment in islets in vitro, cell lines stably expressing islet-specific target antigens (TA cells) were developed using lentiviral transduction. The expression was further confirmed by flow cytometry. Second, according to respective target antigens, individual target modules (RevTM) serving as the adaptor to crosslink TA cells and RevCAR Tregs were generated. Their production yields and binding capacities to TA cells were also characterized. Third, RevCAR Tregs were expanded and genetically modified from apheresis samples in a GMP-compliant large scale. Phenotypic analyses were done to assess the stability and Treg characteristics of the final product. The functionality of these islet-specific RevCAR Treg platform was further tested in activation and suppression assays.
In this study, GLP1R, IA2, DPP6, and GPR142 were identified as islet-enriched target antigens for the development of RevCAR Tregs with potential for T1D therapy. PC3 and Panc89 cell lines were genetically modified to stably express these antigens as target antigen cells and respective antigen-specific moieties were selected to produce 5B9- and 7B6- based RevTMs. Individual RevTM targeting GLP1R, IA2, or DPP6 were demonstrated to have specific binding capacities; furthermore, RevTMs facilitated specific lysis of target cells by RevCAR T cells, indicating cellular functions were inducible via the islet-specific RevCAR system. For GPR142, as no suitable antigen-specific moieties were found, I commenced a collaboration to generate antibodies for this purpose. As a result, 9 monoclonal antibodies targeting the extracellular domain of GPR142 (aa1-152) were generated. From these, two clones with high binding capacity were chosen to construct RevTMs specific for GPR142. RevCAR Tregs could be generated in a large GMP-compliant scale with a minor contamination of CD8+ T cells. However, the transduction rate of Tregs with Rev was relatively low (40%), which dropped further to 20% after freeze-thawing and dead-cell-removal process. For targets IA2 and DPP6, a specific activation of RevCAR Tregs, evident by elevated activation-marker profiles, was achieved upon co-culture with both target antigen cells and respective RevTMs. Neither TA cells nor RevTMs alone were able to activate RevCAR Tregs. However, the RevTMs did not lead to further Treg-mediated suppression of T cells as compared to RevCAR Tregs alone, possibly due to the background activation conferred during the expansion procedure.
To conclude, the functional components of the in-vitro RevCAR Treg platform targeting islet antigens were established and their functionality was verified. Though more in-depth functional studies are required, my project demonstrates that the strategy using RevCAR Tregs targeting selected islet antigens is feasible and lays a foundation for a potential therapeutic approach in T1D
Infodienst Landwirtschaft / Informations- und Servicestelle Löbau mit Fachschule für Landwirtschaft
No full text
Synthesis of high-performance supercapacitor electrode materials based on polyaniline and carbons
No full textThe development of today's electronic devices depends significantly on energy sources that are both highly efficient and incorporate a high energy density and power density. The use of supercapacitors has a great deal of potential in this regard. Polyaniline (PANI) has demonstrated significant promise in the development of supercapacitors due to its high specific capacitance, high flexibility, electrical conductivity, and affordable cost. Carbon components have been extensively studied as effective electrode materials in supercapacitors due to their distinctive hierarchical structure, exceptional electrical and mechanical properties, and large specific surface area.
The first part of this thesis focused on the development of PANI/carbon composites through the utilization of in-situ chemical oxidative polymerization. Carbon materials, specifically carbide-derived carbons (CDCs) and multi-walled carbon nanotubes (MWCNTs), as well as a combination of them, were used as a carbon component. The main goal was to create electrode materials that exhibited both a high specific capacitance and a high energy density by implementing the combined benefits of electric double-layer capacitors (EDLCs) and pseudocapacitance.
The second part of this thesis focused on the manufacturing of electrodes and supercapacitors utilizing the composites produced. Initially, various electrode inks consisting of PANI/carbon composites were produced using an eco-friendly chitosan binder. Following that, PANI/carbon electrodes and supercapacitors were fabricated using the doctor blade method. Sodium sulfate (Na2SO4) was utilized as the neutral electrolyte in each electrochemical test. A detailed investigation was carried out to evaluate the specific capacitance, power density, and energy density values of the manufactured supercapacitors with the aim of achieving superior performance for energy storage purposes
Field Studies on the Effect of Bioaugmentation with Bacillus amyloliquefaciens FZB42 on Plant Accumulation of Rare Earth Elements and Selected Trace Elements
No full textThis study is an investigation of the effect of soil bioaugmentation (inoculation) on a field scale with the commercially available product RhizoVital®42, containing Bacillus amyloliquefaciens FZB4, on element bioavailability, plant biomass production, as well as accumulation of rare earth elements (REEs), germanium, and selected trace elements. Zea mays and Helianthus annuus were selected as test plants. Post-harvest, results showed inoculation increased biomass production of Z. mays and H. annuus by 24% and 26%, albeit insignificant at p ≤ 0.05. Bioaugmentation enhanced Z. mays shoot content of P, Cd, and Ge by percentages between 73% and 80% (significant only for Ge) and decreased shoot content of REET, Pb, and Cu by 28%, 35%, and 59%, respectively. For H. annuus grown on bioaugmented soil, shoot content of Ca, Cu, Ge, REET, and Pb increased by over 40%, with a negligible decrease observed for Cd. Summarily, results suggest that bioaugmentation with Bacillus amyloliquefaciens FZB42 could enhance biomass production, increase soil element bioavailability enhance, and increase or reduce plant accumulation of target elements. Additionally, differences in P use efficiency could influence bioaugmentation effects on P accumulation
Tracking the impact of memory suppression on individual memory representations
No full textWe all experience moments in our life, that we would rather forget. Some people are even haunted by unpleasant memories, that involuntarily intrude into their awareness and harm their well-being. Intrusions - unwanted, unintended, recurrent memories - are a hallmark symptom in psychological disorders, like post-traumatic stress disorder, depression, or anxiety disorder. Fortunately, we are not fully at the mercy of involuntary retrieval processes. Research over the last two decades has shown that active suppression of memory retrieval can eventually lead to forgetting. Memories that have repeatedly been suppressed, are more often forgotten later on than control memories. This phenomenon is called suppression-induced forgetting. Neuroimaging studies have revealed that during suppression the dorsolateral prefrontal cortex shuts down retrieval processes in the hippocampus and other memory-related regions. However, the sustained effects of suppression on the memory remain unknown. The current thesis aims to close this gap and characterize the behavioral, neural, and emotional aftereffects of memory suppression. (i) A large meta-analysis confirms that suppression-induced forgetting is a robust phenomenon in healthy participants. Moreover, it indicates that this mechanism is deficient in participants with (sub)clinical manifestations of depression and anxiety. This suggests that memory suppression is an adaptive mechanism, that helps maintain our well- being. (ii) A replication and mini-meta-analysis corroborate that suppression can even weaken complex aversive scene memories. The employed methodological procedure allows us to study the effects of suppression in a fine-grained and naturalistic way. (iii) We thus adapted the procedure in an fMRI study and investigated for the first time the neural aftereffects of suppression. We show that suppression renders memories less vivid and that this reduction in vividness is associated with reduced reinstatement of the individual neural memory trace in the parahippocampal cortex. After suppression, we find overall less evidence for the processing of complex aversive scenes across the brain. These findings indicate that suppression has a sustained effect on neural memory traces and subsequently leads to impoverished reinstatement of the neural memory trace. (iv) Finally, we investigated whether suppression can weaken emotional responses that are associated with unwanted memories. In a preregistered psychophysiological study, we simultaneously tested the effect of suppression on episodic fear memories, as well as associated conditioned fear responses. We show that fear memories become less accessible after suppression, but did not find the predicted weakening of the emotional response. Future studies will have to follow up on this question. The present thesis demonstrates that memory suppression has a sustained weakening effect on the behavioral and neural levels. Our findings also indicate that suppression is a powerful and adaptive mechanism that supports our well-being. The results are of particular relevance as deficient suppression may play a critical role in both the development and maintenance of psychological disorders
On-Surface Synthesis and Single Molecules Studied Using LT-SPM
No full textDas Verhalten von Molekülen auf Oberflächen ist der Schlüssel zum Verständnis nicht nur ihrer grundlegenden Eigenschaften, sondern kann auch Einblicke in die Reaktionsmechanik und rationale Designprinzipien liefern. Die Nutzung der Oberfläche als Plattform für neuartige Reaktionen, die über den Rahmen der Lösungssynthese hinausgehen, oder zur Auslösung von Konformationsänderungen wird durch den atomaren 'Reinraum' ermöglicht, den ein 5-K-Rastertunnelmikroskop (STM) bietet, das im Ultrahochvakuum (UHV) arbeitet. Mit der Spitze eines STM lassen sich molekulare Strukturen reproduzierbar und mit hoher räumlicher Auflösung verändern und untersuchen.
Im ersten Teil dieser Arbeit wurde die Selbstorganisation von zwei verschiedenen Molekülen auf Au(111) untersucht. Das erste Molekül, obwohl symmetrisch, adsorbiert in großen Inseln mit zwei unterschiedlichen Domänenstrukturen. Die Rolle der Substrattemperatur und ihre Auswirkungen auf die molekulare Dynamik wurden untersucht. Diese Bewertung wurde sowohl durch Heißabscheidung als auch durch Nachglühen des Substrats vorgenommen. Das zweite vorgestellte Molekül ist chiral und adsorbiert nachweislich in homo-chiralen Assemblies. Durch submolekulare Auflösung mit einer funktionalisierten STM-Spitze wurden die Struktur bestimmt und die elektronischen Eigenschaften untersucht. Für beide Moleküle wurde die Realisierbarkeit weiterer kovalenter Strukturen diskutiert.
Im zweiten Teil der Arbeit liegt der Schwerpunkt nicht nur auf Selbstanordnungen, sondern auf der Manipulation einzelner Moleküle. Im ersten Fall, einem Donor-Akzeptor-Molekül auf Thiophenbasis, wird festgestellt, dass es in zwei verschiedenen Konformationen in großen Inseln adsorbiert. Dieses Molekül kann von den Inseln weg manipuliert werden und mit Hilfe von inelastischen Tunnelelektronen reversibel zwischen den beiden Konformeren wechseln. Das zweite Molekül, ebenfalls vom Donor-Akzeptor-Typ, adsorbiert sowohl in einer planaren als auch in einer nicht-planaren Geometrie. Die Planarität kann durch Modifizierung der Selbstanordnung mit der STM-Spitze eingestellt werden.
Im dritten Teil der Arbeit wird die On-Surface-Synthese von zwei verschiedenen langen Acenen vorgestellt. Das erste, ein Isomer von Undecacene, wird mit Hilfe der Spitze synthetisiert, um eine Dehydrierungsreaktion auszulösen. Durch den Einsatz einer funktionalisierten Spitze und eines qPlus-Sensors für die berührungslose Rasterkraftmikroskopie (nc-AFM) konnte die chemische Struktur sowohl für das Zwischen- als auch für das Endprodukt der Reaktion eindeutig bestimmt werden. Die Entwicklung von Molekülorbitalen oder Resonanzen wurde im Detail untersucht, wobei sich eine hervorragende Übereinstimmung zwischen experimentellen Ergebnissen und theoretischen Berechnungen ergab. Das zweite gezeigte Molekül ist der Tetradecacene-Vorläufer, mit dem vierzehn kondensierte Benzolringe erzeugt werden sollen. Das Molekül weist eine gebrochene elektronische Konjugation auf. Nc-AFM und Scanning-Tunneling-Spektroskopie (STS) wurden eingesetzt, um diese elektronischen Hybridisierungsdefekte mit Defekten in der Acenestruktur zu korrelieren
