Universität Stuttgart
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Item Open Access Proton-conducting membranes for the artificial leaf(2023) Bosson, Karell; Tovar, Günter E. M. (Prof.)With the aim of producing proton conducting membranes with improved proton conductivity and mechanical properties, the poly(pentafluorostyrene)-b-(butyl acrylate) (PPFS-b-PBuA) system was investigated. The study mainly focuses on the influence of the forming polymer nanostructures on the conductivity properties of the membranes. A series of well-defined PPFS-b-PBuA block copolymers (BCPs) were synthesized via nitroxide-mediated controlled radical polymerization (NMP). Spontaneous self-assembly of the BCP element was induced via a targeted change in polymer composition. Moreover, by adjusting the molar composition via enrichment of one of the blocks after synthesis, controlled self-assembly of the BCPs was realized. This was done by combining the corresponding homopolymer with the block copolymer to form a polymer blend - one of the blocks mixed to the BCP. Forming such polymer blends expanded the range of available techniques for tailoring the morphology for desired applications. Sulfonation of BCPs for the preparation of proton-conducting membranes was carried out by a para-fluoro thiol "click" reaction using sodium 3-mercapto-1-propanesulfonate (SMPS). The accessibility of fluorine in the para position of the phenylene group of PPFS provides countless opportunities for polymer functionalization by nucleophilic substitution. After modification of BCP, the self-assembly ability was retained, and higher conductivities were obtained compared to random copolymers. In addition, complementary studies were conducted on the use of printing techniques for membrane upscaling and evaluation of their life cycle.Item Open Access Operational scenarios optimization for resupply of crew and cargo of an International gateway Station located near the Earth-Moon-Lagrangian point-2(2016) Lizy-Destrez, Stéphanie; Messerschmid, Ernst (Prof. Dr.)In the context of future human space exploration missions in the solar system (with an horizon of 2025) and according to the roadmap proposed by ISECG (International Space Exploration Coordination Group) [1], a new step could be to maintain as an outpost, at one of the libration points of the Earth-Moon system, a space station. This would ease access to far destinations as Moon, Mars and asteroids and would allow testing some innovative technologies, before employing them for far distant human missions. One of the main challenges will be to maintain permanently, and ensure on board crew health thanks to an autonomous space medical center docked to the proposed space station, as a Space haven. Then the main problem to solve is to manage the station servitude, during deployment (modules integration) and operational phase. Challenges lie, on a global point of view, in the design of the operational scenarios and, on a local point of view, in trajectories selection, so as to minimize velocity increments (energy consumption) and transportation duration (crew safety). Which recommendations could be found out as far as trajectories optimization is concerned, that would fulfill energy consumption, transportation duration and safety criterion? What would technological hurdles be to rise for the building of such Space haven? What would be performances to aim at for critical sub-systems? Expected results of this study could point out research and development perspectives for human spaceflight missions and above all, in transportation field for long lasting missions. Thus, the thesis project, presented here, aims starting from global system life-cycle decomposition, to identify by phase operational scenario and optimize resupply vehicle mission.Item Open Access Optimizing aerosol-based sample delivery for single particle imaging at X-ray Free-Electron Lasers : pushing the limits: boosting data collection, minimizing background noise, and expanding sample compatibility(2024) Rafie-Zinedine, Safi; Heymann, Michael (Jun.Prof. Dr.)One of the most promising applications of X-ray Free Electron Lasers (XFELs) is the imaging of isolated particles, such as proteins, using single-particle X-ray diffractive imaging (SPI). This technique can provide high-resolution structural information on individual particles and facilitate the study of dynamic processes at the nanoscale. SPI, employing gas phase injection through an aerodynamic lens stack (ALS), has attracted significant attention due to its low background scattering and suitability for high-rate data collection. Despite these advantages, these SPI experiments encounter several challenges, especially with smaller and lighter biomolecule particles. These include low signal strength, limited collected datasets, high background scattering, and issues with sample compatibility in delivery system. In this doctoral thesis, I address the latter three challenges by developing and optimizing traditional electrospray-based gas phase sample delivery systems for SPI at XFELs. My research aims to enhance particle transmission efficiency, reduce background scattering, and expand the conductivity range of these systems to enable high-resolution imaging of smaller biological particles. I have developed three modified electrospray systems based on the traditional system to improve SPI at XFELs: enhanced electrospray, helium electrospray (He-ES), and coaxial helium electrospray (CHeES). The enhanced electrospray, upgraded from the traditional system by exploring different neutralizers and geometries, achieves an eightfold increase in particle transmission efficiency by employing a VUV neutralizer and optimizing the counter electrode's orifice size. This enhanced system achieves over 40% particle transmission from solution to the X-ray interaction region. The He-ES system uses a 3D-printed nozzle to reduce N2 and CO2 usage compared to traditional electrospray while ensuring stable sample delivery. It enhances particle delivery efficiency tenfold for 26 nm-sized biological particles and decreases gas load in the interaction chamber by 80%. Lastly, the CHeES system uses a coaxial 3D-printed nozzle to accommodate a broader conductivity range up to 40 000 µS/cm-eight times higher than traditional systems, and to lower background noise using He-ES technique. In tests at the European XFEL, the CHeES system notably lowered background noise by more than threefold in helium mode. My findings indicate improvements in transmission efficiency, background noise reduction, and sample versatility in SPI experiments, potentially enhancing both data quality and quantity. These advancements could yield higher-resolution structures and expand the scope for studying diverse biological and material science samples. My research has broader implications for structural biology, as obtaining higher-resolution structures is crucial for understanding the atomic structure of proteins and other biomolecules.Item Open Access Characterization of persister-cell derived ovarian cancer cells and methods for advanced 3D cell and tissue culture(2021) Böpple, Kathrin; Kontermann, Roland (Prof. Dr.)Item Open Access Collective modes of the superconducting condensate(2023) Haenel, Rafael; Daghofer, Maria (Prof. Dr.)When a continuous symmetry is spontaneously broken, collective modes emerge. Usually, their spectrum is dominated by the low-energy physics of massless Goldstone modes. Superconductors, that break U(1) symmetry, are different. Here, the Goldstone boson is gapped out due to the Anderson-Higgs mechanism. The superconducting condensate can therefore host a zoo of massive collective excitations that are stable for lack of a gapless decay channel. The most prominent of them is the Higgs mode. Spectroscopy of collective modes can serve as a probe to reveal the nature of the superconducting state. In this thesis, we study the signatures of collective modes in nonlinear optical experiments. We explore the theoretical description of a new spectroscopic excitation scheme. We show how impurity scattering significantly enhances the optical Higgs mode response. We apply group theoretical methods to multi-order-parameter theories and investigate microscopic signatures of coupled modes in third harmonic generation experiments. We study the phenomenology and collective mode spectrum of an exotic system of twisted cuprate bilayers that supports topological superconductivity. Finally, we propose a novel device implementation of the superconducting diode effect. These results contribute to the emerging field of collective mode spectroscopy.Item Open Access Novel functions of aberrant cyclin D1/CDK4 activity in mantle cell lymphoma and consequences for proteasome inhibitor treatment(2022) Heine, Simon; Olayioye, Monilola (Prof. Dr.)Mantle cell lymphoma (MCL) is an aggressive B cell-non-Hodgkin lymphoma with generally poor outcome and only transient responses to conventional chemotherapy. Cells of MCL patients are characterized by an aberrant high cyclin D1-driven cyclin-dependent kinase 4 (CDK4) activity. Recently, the ubiquitin proteasome system (UPS) inhibitor bortezomib has been approved for the treatment of relapsed/refractory MCL and has shown promising results in first-line treatment of MCL patients. However, little is known about how the aberrant cyclin D1-driven CDK4 activity does affect the treatment efficacy of UPS inhibitors in MCL. The present work aimed to identify novel functions for cyclin D1/CDK4 activity in MCL that regulate the efficacy of proteasome inhibitor treatment. In this study, the efficacy of proteasome inhibitor treatment was found to depend on the aberrant cyclin D1/CDK4 activity in MCL. Inhibition of cyclin D1/CDK4 activity with the CDK4 inhibitor palbociclib antagonized bortezomib induced cell death in MCL cells. Moreover, the antioxidant defense protein sestrin 3 was identified to be strongly regulated by cyclin D1-driven CDK4 activity. Although, bortezomib efficacy was demonstrated to be regulated by reactive oxygen species (ROS) or antioxidants, changes in sestrin 3 expression levels are not responsible for cell death regulation after UPS blockage in MCL. Furthermore, even though targeting cyclin D1/CDK4 activity with palbociclib induces cell cycle arrest, changes in cell cycle distribution after cyclin D1/CDK4 inhibition also do not mediate the antagonizing effect on bortezomib induced cell death. Astonishingly, it could be demonstrated that cyclin D1/CDK4 inhibition antagonizes the bortezomib induced cell death through a reduction of NOXA protein accumulation. It could also be shown that this mechanism is not exclusive for the proteasome inhibitor bortezomib but also applies to other agents that depend on NOXA protein accumulation for efficient cell death induction in MCL cells. Importantly, results of the present study revealed that this regulation of NOXA protein levels by cyclin D1/CDK4 activity is not associated with a reduction of NOXA transcript levels but is mediated by the regulation of NOXA protein stability. This identified novel function of cyclin D1/CDK4 to regulate NOXA protein half-life in the presence of UPS blockage is mediated by the autophagic degradation machinery. This study identified, the regulation of autophagic activity as a novel cell cycle independent function of cyclin D1/CDK4 activity in MCL. In this context, it was demonstrated that inhibition of cyclin D1/CDK4 activity by palbociclib treatment induces autophagic activity in MCL. Cyclin D1/CDK4 and autophagic activity, however, are not linked by the common autophagy regulating pathways, AMP-activated protein kinase (AMPK) or ROS. In addition, genetic or pharmacological inhibition of autophagic activity reverses the palbociclib mediated antagonism on bortezomib induced cell death and NOXA protein accumulation. Remarkably, this study demonstrates that the NOXA protein can be targeted for proteasomal as well as autophagosomal degradation. Targeting NOXA protein for degradation through selective autophagy might be mediated through a LC3-interacting region (LIR) motif that was identified in the amino acid sequence of the NOXA protein. Interestingly, combination of bortezomib with known autophagy inhibitors potentiates cell death induction as well as NOXA protein accumulation compared to bortezomib treatment alone. Furthermore, screening for a highly efficient combinatorial blockade of the UPS and the ALP revealed that the fatty acid synthase (FASN) inhibitor orlistat can be repositioned for autophagy inhibition. Consequently, the combinatorial treatment with bortezomib and orlistat leads to a very efficient NOXA protein induction and caspase dependent cell death in MCL cells. This cell death is again dependent on the aberrant high cyclin D1/CDK4 activity. The expression levels of certain other apoptotic proteins, however, are not affected by the combinatorial treatment. In conclusion, the present study revealed the regulation of autophagic activity as a novel function of cyclin D1/CDK4 activity in MCL. These findings are of utmost importance for the treatment of MCL patients, as combination of proteasome inhibitors with autophagy inhibitors could greatly improve therapy outcomes or overcome bortezomib resistances. In addition to known autophagy inhibitors, treatment options could include conventional drugs that are repurposed for targeting the autophagic degradation machinery. On the other hand, care must be taken when combining proteasome inhibitors with other chemotherapeutics that might impair cyclin D1/CDK4 activity or induce autophagy.Item Open Access Brought to light: the Bcl-2 transmembrane domain interactome elucidated by a bimolecular split luciferase assay and its impact on apoptosis signalling(2024) Beigl, Tobias B.; Morrison, Markus (Prof. Dr.)Apoptose ist eine Form des programmierten Zelltods, die häufig bei verschiedenen Krankheiten wie Krebs gestört ist. Ein Schlüsselereignis der Apoptose ist die Permeabilisierung der äußeren Mitochondrienmembran (MOMP), die von der B-Zell-Lymphom 2 (Bcl-2) Proteinfamilie gesteuert wird. Bcl-2-Proteine bilden ein komplexes Interaktionsnetzwerk, in dem sich pro- und anti-apoptotische Mitglieder gegenseitig zugunsten von Zelltod oder -Überleben hemmen. Das Netzwerk wird durch die Interaktion zwischen dem Bcl-2 Homologie 3 Motiv (BH3) und der hydrophoben Furche definiert. Eine neue Art von niedermolekularen Wirkstoffen, sogenannte BH3-Mimeticka, welche die hydrophobe Furche anti-apoptotischer Bcl-2 Proteine besetzen, ist wirksam in der Krebstherapie. Es verdichten sich jedoch Hinweise darauf, dass die weit weniger untersuchte C-terminale Transmembrandomäne (TMD) von Bcl-2 Proteinen, die traditionell als Membrananker fungiert, ebenfalls als Interaktionsfläche dienen kann. Zur weiteren Aufklärung der Interaktionen in der Bcl-2-Proteinfamilie über die TMD wurde ein zellbasierter Assay entwickelt und validiert, bei dem das mit TMDSequenzen fusionierte bimolekulare Luziferase-System NanoBiT mit gleichzeitiger Expression von Fluorophoren zur Signalnormalisierung kombiniert wird. Eine systematische Analyse der TMD-Interaktionen zwischen pro-apoptotischen Effektor-Bcl-2-Proteinen (BAX, BAK und BOK) und anti-apoptotischen Bcl-2-ähnlichen Proteinen (BCL-2, BCL-XL, BCL-W, MCL-1 und A1) offenbarte homotypische Interaktionen zwischen Effektor-TMDs und Interaktionen von Effektor-TMDs mit BCL-XL-TMD und BCL-W-TMD. Interessanterweise wurde eine bisher unbekannte Interaktion von BOK-TMD und BCL-2-TMD identifiziert. Die subzelluläre Lokalisierung Fluorophor-konjugierter TMD-Peptide verdeutlichte, dass einige TMDs präferentiell in Mitochondrien (BAX, BAK, BCL-XL, BCL-W) lokalisiert sind, während andere (BOK, BCL-2, MCL-1) vorwiegend mit dem endoplasmatischen Retikulum (ER) kolokalisiert sind. TMD-Austausch und Mutation in BAX bestätigten eine wichtige Rolle der BAX-TMD bei der BAX-Inhibition, während der TMD-Austausch in BAK einen vernachlässigbaren Einfluss auf die BAK-Regulierung durch BCL-2 hatte. Darüber hinaus hingen sowohl die Kolokalisierung von BOK und BCL-2 als auch die Hemmung des durch BOK-Überexpression induzierten Zelltods durch BCL-2 von den TMD Sequenzen ab. Dementsprechend modulierte TMD-Mutation von BCL-2 die Interaktion mit BOK-TMD, die subzelluläre Lokalisierung und die anti-apoptotische Kapazität von BCL-2. Letztlich steigerte die Abwesenheit von BCL-2 den BOK-abhängigen ER-Stress-induzierten Zelltod, was auf einen physiologischen Kontext für die funktionelle Bedeutung ihrer TMD-Interaktion hinweist. Somit hebt diese Arbeit hervor, dass die Aufklärung des Bcl-2-TMD-Interaktoms für unser Verständnis der Apoptose-Regulation wichtig ist und ebnet den Weg für zukünftige Untersuchungen der TMD als Ziel für klinische Interventionen.Item Open Access Proton-conducting (blend) membranes based on sulfonated/phosphonated and basic polymers(2024) De Azpiazu Nadal, Ignasi; Tovar, Günter (Prof.)Aiming at new proton-conducting membranes, this thesis deals with the syntheses and characterizations of highly sulfonated poly(arylene sulfides) and other polysulfides for application as polymer electrolytes. The study focuses mainly on the analysis of the polymer structures that would improve the conductivity of current proton conducting membranes while maintaining their mechanical stability. In a first step, several polymers are obtained from which poly(arylene sulfide)s polymers look more promising for further functionalization. They are obtained by using mild reaction conditions of a polycondensation reaction between 4,4 ́-thiobisbenzenethiol (TBBT) and decafluorobiphenyl. Optimization of this reaction allows for the obtainment of higher molecular weights than the ones reported in the literature. In a second step, poly(arylene sulfides) were phosphonated and sulfonated by a nucleophilic aromatic substitution (SNAr) displacement reaction of the fluorine atoms of the fluorinated polymer sub-units using different agents. Highly sulfonated polymers were obtained when using sodium 3-mercapto-1-propanesulfonate and resulted in water soluble ionomers. Kinetic studies of this reaction were performed and several new sulfonated poly(arylene sulfides) were obtained. Finally, stable polymer electrolyte membrane (PEM) with enhanced mechanical and chemical stability were obtained by blending these obtained ionomers with polybenzimidazole (PBIOO). These membranes were further characterized and in the best case a PEM with new sulfonated ionomer showed a conductivity 40 % higher than Nafion 212, used as a golden reference material. The best performing PEM’s obtained were further used in an electrolytic cell being part of eSCALED, a H2020 (MSC-ITN-2017. GA# 765376) European project which aim is to obtain a device that does the artificial photosynthesis in a more efficient way than the current devices.Item Open Access Investigation of tungsten exposed to fusion relevant intense H/He particle fluxes and thermal loads(2016) Lemahieu, Nathan; Tovar, Günter (Prof. Dr.)Item Open Access Strömungsdynamik und Stofftransport in einem Strahl-Kolonnenflotationsapparat zur Abtrennung oberflächenaktiver Substanzen aus wässrigen Stoffströmen(2020) Ziegler, Eike Eric; Hirth, Thomas (Prof. Dr. rer. nat.)Die Arbeit befasst sich mit der Untersuchung eines Strahl-Kolonnenflotationsapparates, der zur Reinigung und Konditionierung von Prozesswasser eingesetzt wird. Um den Einfluss der Strömungsdynamik auf den Stofftransport von oberflächenaktiven Substanzen (OAS) an die Phasengrenzfläche besser zu verstehen, wurden einzelne Bereiche des Apparates bezüglich der funktionalen Zusammenhänge zwischen den einzelnen Betriebsparametern näher untersucht. In einem ersten Schritt wurde die Strömungsdynamik in einem exemplarischen FSA mit Finite-Pointset-Method (FPM), einem punktbasierten Strömungssimulations-CFD-Programm, simuliert, um die Ausbreitung des Treibstrahles in der Mischkammer und dort auftretende lokale Strömungszonen zu visualisieren. Basierend auf den Simulationsergebnisse wurden fünf Treibdüsengeometrien gefertigt und für die Untersuchung der Blasenströmung im Flotationsbehälter hinzugezogen. Diese Treibdüsen wurden in ein handelsübliches Strahlapparatgehäuse eingesetzt, um zusätzlich zur Treibdüsengeometrie den Einfluss des Treibdruckes und von koaleszenzverändernden Substanzen auf die erzeugte Blasenströmung zu untersuchen. Durch Variation der Konzentration von sieben unterschiedlichen Salzen mit charakteristischen Ionenkombinationen und Fokus auf Natriumchlorid, wurde das Koaleszenzverhalten der Blasenströmung in einem Konzentrationsbereich zwischen 0 und 30 g/l unter Messung von Blasengröße und Gasanteil erfasst. Durch Definition einer Blasenaufstiegsfunktion, die den funktionalen Zusammenhang zwischen mittlerer Blasenaufstiegsgeschwindigkeit und Sauterdurchmesser in der Blasenströmung beschreibt, kann für die einzelnen Betriebszustände die Flussdichte der Phasengrenzfläche Sb approximiert werden, die als Schlüsselparameter zur Bestimmung der Flotationsrate gilt.Aufgrund der Inhibierung von Koaleszenz in der Blasenströmung fällt für kosmotrophe Salze die Blasengröße mit steigender Salzkonzentration entlang einer Exponential-Funktion. Hierdurch steigt der Gasanteil in dem Flotationsbehälter entlang einer Sigmoid-Funktion an und die Flussdichte der Phasengrenzfläche nimmt zu. Mit Sodium-Dodecyl-Sulfat (SDS) als oberflächenaktiver Modellsubstanz wurde dessen Abreicherung anhand von Batch-Versuchen unter Variation der Gasleerrohrgeschwindigkeit, der SDS-Konzentration und der NaCl-Konzentration mit einem hierfür entwickelten Gasanteilsensor messtechnisch erfasst. Aus den Messdaten wurde die Konzentrationsabnahme in Abhängigkeit der Flotationszeit berechnet und in Bezug zur Flussdichte der Phasengrenzfläche gesetzt. Die Ergebnisse wurden zur Erstellung eines Berechnungsprogramms genutzt, welches den Stofftransport an die Phasengrenzfläche durch eine flächenbezogene Anlagerungsfunktion berechnet. Diese ist entweder in ein Differentialgleichungssystem eingebettet oder wird in einer Berechnungsschleife mit thermodynamisch begründeter Adsorptionsisotherme genutzt. Damit kann der Einfluss von Gasleerrohrgeschwindigkeit und Flussdichte der Phasengrenzfläche auf die Flotation gezeigt und der Bezug zu der Abreicherung von OAS und den hierbei auftretenden Stofftransport hergestellt werden.