Quantum error correction is an essential ingredient in the development of quan- tum technologies. Its core subject is to investigate ways to embed quantum Hilbert spaces into a physical system such that this subspace is robust against small imperfections in the physical systems. This task is exceedingly complex: for one, this is due to the vast diversity of possible physical systems with dif- ferent inherent structure to use. For another, every different physical setting also comes with different types of dominant imperfections that need to be protected against. Bred by the complexity of this technological ambition, research on quantum error correction has developed into a large field of research that ranges from questions about the engineering of small systems with a single photon to the creation of macroscopic topological phases of matter and models of complex emergent physics. A quintessential tool in quantum error correction is the stabilizer formalism, which tames complicated quantum systems by enforcing symmetries. A Gottesman-Kitaev-Preskill (GKP) code is a stabilizer code that creates a log- ical subspace within the infinite dimensional Hilbert space of a collection of quantum harmonic oscillators by endowing it with translational symmetries. While practical approaches to GKP codes consider the infinitude of the Hilbert space, as well as the infinitude of the translational symmetry group as obstacles for implementation, in theory these are precisely the features that make the theory of GKP codes particularly rich, well behaved and well-connected to fascinating topics in mathematics. The purpose of this thesis is to explore these connections: to understand the coding theoretic- and practical properties of GKP codes, utilizing its rich mathematical foundation, and to provide a foundation for future research. Along this journey we discover – through the looking glass of GKP codes – how quantum error correction in general fits into a fabulous mathematical world and formulate a series of dreams about possible directions of research.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that is characterized by autoimmune-driven inflammation, resulting in myelin destruction and damage to neuronal axons and cell bodies. These alterations manifest as CNS lesions in magnetic resonance imaging (MRI). In MS patients, MRI has shown the presence of cerebral gadolinium (Gd) retention following repeated injections of mainly linear gadolinium-based contrast agents (GBCAs). Using the experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we previously observed that EAE mice exhibited enhanced cerebellar short-term Gd retention compared to healthy controls (HC) following injections of gadopentetate dimeglumine. Since MS patients generally undergo multiple contrast-enhanced (CE) MRIs throughout their lives, the concern of augmented Gd retention and potential long-term consequences may be specifically relevant for them. This thesis aimed to investigate the long-term character of inflammation-promoted brain Gd retention and contributing factors after repeated application of linear gadopentetate or macrocyclic gadobutrol. By combining longitudinal T1 mapping of the brain and cross-sectional (laser ablation-) inductively coupled plasma mass spectrometry (LA-/ICP-MS) assessments of blood and cerebellum, we took an interdisciplinary approach to address Gd retention patterns and kinetics in EAE and HC mice. MRI calibration was performed to assess the impact of inflammation on Gd bonds and compare the binding behavior of the two tested GBCAs. In addition, this thesis presents the establishment of an ex vivo model of living brain tissue and its utilization to determine Gd-induced neurocytotoxicity under naïve and inflammatory conditions. Within this model, the retained Gd content was visualized by Imaging Mass Cytometry (IMC), and quantified by ICP-MS. Quantitative T1 relaxometry and LA-ICP-MS results confirmed that in EAE mice Gd retention was enhanced after injections of both GBCAs. While gadopentetate led to persistent retention, particularly inside the inflamed cerebellar nuclei (CN), gadobutrol caused weak and diffuse Gd content, which cleared over the observational period. MRI calibration showed that in vivo MRI underestimated the T1 effect of Gd after the administration of gadopentetate, suggesting that Gd may be partially bound in insoluble deposits. After incubation with gadopentetate ex vivo, retained Gd content at approximately 1.5 mM led to a reduction in neuronal viability, which further decreased under inflammatory conditions. Taken together, the results indicate that inflammation promotes the extent of Gd brain retention, particularly after linear GBCA administration, and significantly influences its retention pattern, binding to endogenous ligands, and cytotoxic potential. Thus, multiple administrations of mainly linear GBCAs may pose a long-term risk for patients suffering from chronic neuroinflammatory disorders like MS.

This thesis focuses on the development of FTJ devices using a Hf0.5Zr0.5O2 (HZO) ferroelectric layer, demonstrating their compatibility with CMOS integration and their applicability in neuromorphic hardware. A bilayer structure comprising metal- ferroelectric-dielectric-metal layers with a ∼ 10 nm HZO ferroelectric layer and a thin tunneling Al2O3 layer has been investigated.

We examine the impact of dielectric positioning, metal electrode placement (with W and TiN), and dielectric thickness on device performance. Additionally, we explore the role of charge traps in the dielectric or at the dielectric-ferroelectric interface, and the influence of the fabrication process on charge trap density and polarization switching behavior. W bottom electrode is found to give optimized device performance, and positioning Al2O3 next to the bottom electrode further enhances the device performance in terms of ON current and ON/OFF ratio. Furthermore, longer pulses are necessary to stabilize higher remnant polarization due to charge trap dynamics.

We also analyze various electrical parameters affecting FTJ device performance, demonstrating that the cycling waveform significantly influences the wake-up process and the resulting remnant polarization in TiN-Al2O3-HZO-W FTJ devices. Square waveforms outperform triangular waveforms, yielding higher remnant polarization (PR) post-wake-up. By employing an asymmetric waveform for field cycling and adjusting the pulse width, the PR and the ON/OFF ratio after wake-up are significantly improved.

Finally, we explore the integration of bilayer FTJ devices into CMOS back-end-of- line (BEOL) processes, demonstrating a 1T1C circuit by connecting an FTJ in the BEOL with an nMOS transistor in the front-end-of-line. Measurements on standalone FTJ devices in the BEOL reveal an ON/OFF ratio of 18 and an ON current density of 24.5 μA/cm2. Crucially, BEOL fabrication has negligible impact on transistor characteristics, and the 1T1C circuit exhibits a 2.6-fold amplification of the FTJ ON current. The FTJ devices integrated on the CMOS-BEOL demonstrate multiple resistance states with the application of partial switching Reset and Set pulses. These FTJ devices have the potential to be utilized in neuromorphic hardware systems.

The fascinating vision of molecular nanotechnology lies in the use of single molecules as machines or devices and the controlled assembly of molecular matter at the nanometer scale (nanomanufacturing). The possibility to manipulate and control things on a small scale was first introduced by Richard Feynman in his famous 1959 speech “There’s plenty of room at the bottom”. Resulting applications, like electronic circuits, sensors or nano-machines, would, due to their small dimensions, open the door to completely new technologies, with advantages in cost, operation speed (efficiency) and power dissipation. In contrast to top-down approaches (e.g. by improving lithographic techniques), the use of molecules reveals several important advantages: 1. Molecules have nano-scale dimensions by nature: Thus, the use of single molecules automatically leads to structural dimensions at the atomic scale. The top-down miniaturization of existing applications and devices requires fundamental improvements of conventional fabrication techniques, which are limited. 2. Molecular recognition: Intermolecular interactions can be used to grow molecular nanostructures. Molecules are known to self-organize according to their chemical properties and to self-assemble in topologies that reflect the interactions between them. By controlling the chemistry of the involved molecules, various structures of different size and shapes can be produced. 3. Capabilities of organic chemistry: By choosing the structure and composition of a molecule, chemical synthesis can be used to produce molecules of precisely defined properties. 4. Functions: Molecules can have specific functions, for instance switching between different states (of characteristic optical, magnetic and electronic properties). In fact, the latter is a fundamental concept in nature, where many molecules have multiple stable isomers.

PSA (tapes) are permanently sticky adhesives that can be applied by slight pres-sure to a large variety of surfaces. This easy application has led to the wide-spread use of PSA not only in the DIY sector but also in the construction, rail-way vehicle, and automotive industries, where the fire behavior of the materials is of crucial importance. The fire behavior of PSA-bonded materials is therefore a research topic of high interest to industry and academia. Due to the viscoelas-tic state of PSA, it is a challenge to develop well compatible flame retardants that do not bloom out or migrate to the adhesive surface and degrade the adhe-sion between the substrate and the adhesive. To overcome this problem, phos-phorus flame retardants, as a very versatile class of flame retardants that can be modified to meet the specific demands of the polymer matrix, are a good choice for a PSA matrix. A further advantage of phosphorus-based flame retardants is that they are effective at low concentrations, allowing the PSA tapes to keep their mechanical properties. They act in several modes of protection, depending on the chemical environment of phosphorus within the flame retardant and the polymer matrix in which they are used. The state of art is to develop phosphorus-based flame retardant PSA tapes that perform well in flammability tests and expect them to have beneficial influence in the bonded product, without this relationship being proven. The questions of how different flame retardants work in PSA and PSA tapes and how these flame retardant adhesives influence the burning behavior of bonded materials is elab-orated on in this doctoral dissertation. In the first step of this dissertation, the fire behavior and pyrolysis of commer-cially available phosphorus-based flame retardant adhesives (tapes) were ana-lyzed and compared to adhesive tapes without flame retardant to gain a basic understanding of how adhesive tapes behave in fire and how flame retardants affect this behavior. Fire behavior analysis was performed in different fire sce-narios and bond designs established in a multi-methodical approach. The reac-tion of the adhesive tape to a small flame was investigated as a free standing object, bonded one-sided onto different substrates, and as sandwich like bonds (substrate/tape/substrate). The interaction between flame retardant, adhesive matrix, carrier, and substrate was explained by systematically examining the pyrolysis of the adhesive, the flammability of the tapes, and the fire behavior of bonded materials in an ignition and a developing fire scenario. Py-GC/MS, TGA FTIR, PCFC and hot-stage FTIR measurements were used to identify the mode of action of the flame retardant and its interaction with the PSA matrix. The flammability tests, UL 94, OI, and the single-flame source test identified the effect of the flame retardant on the flammability of the tape and the effect on the flammability of bonded materials. Measuring and comparing the fire be-havior of the bonded and monolithic materials in the cone calorimeter led to an understanding of how PSA tapes influence the fire behavior of bonded sub-strates. The fire behavior of different monolithic and bonded substrates with a wide spectrum of burning characteristics was investigated to gain information on the substrate specificity of the tape influence. The second step of the dissertation consisted in preparing differently phospho-rus-based flame retardant PSA and PSA tapes. One predominantly gas phase ac-tive, one condensed phase active and one covalently bonded phosphorus flame retardant were used in a PSA matrix which mainly consisted of poly(n-butyl acrylate). Determining the adhesion and cohesion properties of the PSA tapes guaranteed the possible application as PSA tape. Their flame retardant mecha-nism and decomposition and combustion behavior were analyzed thoroughly in Py-GC/MS, TGA FTIR, hot-stage FTIR and PCFC to gain precise insights into the chemical and physical mechanisms that govern the pyrolysis process. The dif-ferent modes of actions and mechanisms were subsequently connected to the flammability of adhesive tapes which were prepared from the synthesized flame retardant PSA and assessed in UL 94 and OI. In the last step of this systematic doctoral dissertation, the self-prepared adhe-sive tapes were used to bond different substrates whose fire behaviors were then investigated in different fire scenarios simulating ignition, developing and fully developed fire. This made it possible to connect the pyrolysis mechanism, mode of action, and fire behavior of the free standing adhesive tapes with the fire behavior of bonded materials. Different carriers (AL and PET) were used in different substrates (wood, bisphenol-A polycarbonate, polymethyl methacry-late) to yield in an understanding of the influence of the adhesive tape carrier on the burning behavior of the individual substrates. The first step shows that phosphorus flame retardants significantly improve the flammability of the commercially available adhesive tapes. The gas phase active flame retardant resulted in a UL 94 V-2 rating and a large increase (5.3 vol.-%) in OI, and significantly changed the burning behavior in the single-flame source test. Tape-bonded materials behaved substantially different from their mono-lithic counterparts in cone calorimeter measurements, where the adhesive tape mostly acted as an insulating barrier separating the bonded substrate layers. This separation led to new fire risks in PC and increased the FIGRA up to 20% and the PHRR up to 26%. Cone calorimeter measurements also showed that phosphorus flame retardants and carriers must be tailored to each other because they can react and degrade the protective properties of the carrier, as it was the case for the AL carrier in combination with a commercial phosphorus flame re-tardant. The strong enhancing effect of the flame retardant on the flammability of the non-bonded adhesive tapes was not present in adhesive tape-bonded ma-terials where the fire behavior was determined by the substrates. During the second step of this dissertation, the individual decomposition of the PSA matrix and the flame retardants were analyzed in Py-GC/MS, TGA FTIR and PCFC and detailed decomposition and flame retardant mechanisms were postu-lated. The gas phase active DOB 11 released PO and PO2 radicals at low temper-atures resulting in a V-2 UL 94 rating at small concentrations. The condensed phase active flame retardant, RDP, improved the charring of the PSA tape sur-face, as it is suspected to be a precursor of phosphoric/ polyphosphoric acid. These acids lead to elimination reactions which result in unsaturated structures and finally enhanced char formation. The small amount of RDP had, normalized on the p-concentration and compared to the other flame retardants, the biggest positive effect on the OI of the adhesive tape. DOPO-pentyl-methacrylate alone has a low decomposition temperature (starting at 300 °C) but was covalently bonded to the polymer backbone and therefore decomposed together with the polymer (starting at 350° C). It released PO and PO2 radicals that improved the flammability in all fire tests. In addition to its beneficial influence on the fire behavior, the covalently bonded flame retardant also increased the mechanical properties at elevated temperatures, which is an important parameter for PSA tapes. The pyrolysis and flammability of these different flame retardant types for PSA show that the phosphorus flame retardants have individual advantages and need to be tailored to the matrix and the application. The third and final step of this doctoral dissertation focusses on the fire behav-ior of self-prepared adhesive tapes with different flame retardant PSA and dif-ferent carriers used to bond substrates representative of automative, railway vehicle, and construction applications. Cone calorimeter measurements showed that it is not the adhesives and the flame retardants in the PSA matrix that result in changes in the fire behavior, but rather the choice of carrier. In the case of PMMA, for example, an AL carrier can improve the fire behavior by acting as a barrier to protect the underlying material, leading to a 25% reduction in MARHE and a 30% reduction in PHRR compared to a PET carrier. The same AL carrier used in PC substrates resulted in a 30% increase of MARHE and FIGRA, indi-cating higher fire hazards and poorer performance in the cone calorimeter test. To determine the transferability of the results obtained for adhesive tapes to other adhesives, the fire behavior of adhesive tape-bonded materials was com-pared to materials bonded by liquid thin-layer adhesives. Similar effects of the liquid adhesives were obtained in the cone calorimeter, suggesting that the find-ings for the burning behavior of adhesive tape bonds are likely to be general-izable to materials that are bonded by other adhesives. Overall, a fundamental understanding of the fire behavior of adhesive tapes and bonded materials was generated and the individual effect of different flame re-tardants for PSA tapes was investigated thoroughly. Based on the new findings, the state of the art PSA development is questioned and new, more end applica-tion focused research is suggested. The strong impact of adhesive gaps in several tape-bonded materials provides a promising outlook for future research in-to the fire behavior of materials bonded by other adhesives and using different substrates and applications.

Photon upconversion is a non-linear process where multiple photons are absorbed, and a single photon with higher energy than the incident ones is emitted. This process is often achieved by lanthanide ions, such as Erbium ions which are generally embedded in optical inert crystals like Sodium-Yttrium-(tetra) Fluoride. The ability of the Erbium ions to covert the near-infrared photons into shorter infrared, visible and ultraviolet wavelengths opens up many applications such as life sciences and photovoltaics. The efficiency of the photon upconversion through Erbium ions strongly depends on Erbium ion’s ability to absorb near-infrared photons. Unfortunately, Erbium, like any other lanthanide group element, is not an efficient near-infrared absorber. Their small absorption cross-section requires intense laser excitation power densities to obtain considerable upconversion luminescence. This requirement limits its applicability for practical applications. In this thesis, an approach to enhance photon upconversion of the Erbium-doped and Erbium - Ytterbium co-doped Sodium-Yttrium-(tetra)Fluoride upconversion nanoparticles is studied by harvesting strongly enhanced near-fields on silicon metasurfaces. The aim is to reduce the required external excitation power densites for efficient photon upconversion luminescence and to gain a better understanding of resonant phenomena on silicon metasurfaces. To fulfil this aim, the resonant phonemonon on Silicon metasurface resulting strong near fields and photo-physical dynamics of the upconversion nanoparticles are meticulously investigated by experimental and theoretical methods. As an upconversion enhancing platform, large area (25 cm2) silicon mono- and double-layer metasurfaces with hexagonal lattice are produced by a nanoimprinting lithography based method. The resonant phenomena on silicon metasurfaces, such as leaky modes and bound states in continuum on silicon metasurfaces are probed by optical spectroscopy and aided with finite difference element simulations. In the light of the numerical calculations, the spectral position of the leaky modes of silicon metasurface is engineered by a single and simple production parameter;silicon metasurface thickness. The excitation power density-dependent upconversion dynamics of the upconversion nanoparticles in solution are examined. The results on excitation power density dependent measurements shed on light electonic transition dynamics and luminescence quenching processes. By placing the upconversion nanoparticles on the silicon metasurface and variation of the incident angle, the effect of the 1550 nm light coupling with leaky metasurface modes on upconversion luminescence is in- vestigated. The efficient coupling results in more than 2000-fold enhanced photon upconversion emission on silicon metasurfaces when it is compared with the emission of upconversion nanoparticles on a planar silicon surface. Moreover, upconversion of Erbium-Ytterbium co-doped upconversion nanoparticles in polymer matrix is studied. The upconversion of the polymer-upconversion nanoparticle layer are investigated with 980 nm laser excitation. The enhanced photon upcoversion on metasurface more than 1000-fold is observed under 980 nm excitation. These results pave the way to achieve efficient upconversion luminescence even at low excitation power densities inspiring applications in the fields of biophotonics and photovoltaics.

Cells as the fundamental units of life, exhibit significant complexity, hosting intricate networks of biochemical processes and structural components which enable them to perform a vast array of functions necessary for the survival and adaptation of living organisms. The dynamic and diverse nature of cells causes them to constantly interact and adapt to environmental cues. Cell types and morphologies vary widely among organisms and tissues, reflecting the discrete functions and specialized roles in maintaining the viability of the biosystems involved. Abnormalities in cell size and shape can be associated with pathological conditions, which can be monitored via imaging techniques and used for diagnostic purposes. During the processes of endocytosis and exocytosis, the plasma membrane can form invaginations and exhibit shape remodeling events. The ability of the plasma membrane to undergo dynamic morphological alterations allows cells to control cellular communication, recognition processes, adhesion and immune responses as well as the transport of substances between the cell interior and exterior environment. The plasma membrane composed of a diverse arrangement of lipids, proteins and carbohydrates, plays an important role in maintaining the structural integrity and metabolic activities of cells thus taking part in the regulation of the cellular homeostasis. However, the diverse components of the plasma membrane and their various roles in the extracellular and intracellular activities make them very challenging and complex to characterize.

The structural and functional complexity of the plasma membrane has required the construction of simpler membrane models for the investigation of membrane dynamics. These models can also characterize the individual effects and properties of membrane components during cellular interactions and transport processes. Model membranes can be manipulated with external stimuli. Among them, light irradiation offers several advantages as a non-invasive, reversible, biocompatible and facile tool to provide high spatiotemporal control in biomimicry of cellular events. One of the efficient approaches to utilize light for the manipulation of membrane models is to prepare biomimetic platforms with photoswitchable lipids which can reversibly change their molecular conformation upon light irradiation. In this doctoral thesis, we have developed a light-triggered, multifunctional, and smart biomimetic platform by using phosphatidylcholine (referred as POPC here and in the main text), one of the most abundant phospholipids in animal cells, combined with a photoswitchable azobenzene lipid analog (referred as azo-PC). This platform was designed to provide an optical control of the membrane properties, shape, and molecular transport in the biomimetic system through the photoisomerization of azo-PC under UV and blue light.

First, we comprehensively investigated the reversibility, kinetics and effects of photoswitching on the material properties of varying compositions of azo-PC containing minimalistic membrane models including giant unilamellar vesicles (GUVs) as minimal cell-size models, Langmuir monolayers, large unilamellar vesicles and supported lipid bilayers, and combined the results from a variety of experimental approaches to those obtained from molecular dynamics simulations. These investigations showed that azo-PC photoisomerization induces dynamic alterations in membrane properties, affecting bilayer packing, elasticity, and interleaflet interactions. Using a method based on vesicle electrodeformation and optical microscopy, we revealed how the photolipid, introduced at various fractions, alters the membrane area upon isomerization and found excellent agreement with simulations. UV illumination of azo-PC GUVs triggered trans-to-cis photoisomerization, resulting in a significant increase in membrane area and a ten-fold decrease in bending rigidity. Trans azo-PC bilayers were found to be thicker than POPC bilayers but exhibited higher specific membrane capacitance and dielectric constant. This suggests an enhanced ability to store electrical charges across the membrane. Furthermore, incubation of preformed POPC GUVs with azo-PC rendered them photoresponsive, suggesting therapeutic potential for optical control of cellular activities. By using a wide range of experimental and computational approaches, we collected accurate results about the characterization of the light-induced modifications in azo-PC containing membranes, which also allowed us to discuss the discrepancies in the previously reported values in the literature and explain the origins of these discrepancies.

Next, we demonstrated the application of photoswitching of azo-PC doped GUVs for the transport of protein-rich droplets by performing light-triggered endocytosis of biomolecular condensates. Protein-rich condensates are phase separated membraneless organelles acting as vessels for biochemical reactions in cells during important cellular processes including signal transduction and gene expression. In our studies, condensates were prepared from the plant protein glycinin, which is a prominent storage protein in soybeans. UV-light-induced trans-to-cis photoisomerization of azo-PC results in an instantaneous increase in vesicle area, which promotes the wetting of GUVs by condensates and their rapid endocytosis for an appropriate condensate-vesicle size ratio. The process is fully reversible by exposure to blue light, allowing precise spatiotemporal control of the condensate-membrane interaction. The affinity of the protein condensates to the membrane, and the kinetics, reversibility and degree (whether partial or complete) of the engulfment processes were quantified from confocal microscopy images. Theoretical estimations confirmed that the adhesion of protein condensates to azo-PC vesicles in cis conformation under UV irradiation is energetically favorable. Experimental results, in good agreement with theoretical estimations, demonstrated that light and azo-PC photoisomerization can be employed as a versatile system to modify membrane-condensate interactions in a fast and reversible manner. To the best of our knowledge, this is the first study in the literature to utilize photoisomerization to control the delivery process of a biomacromolecule across a minimalistic artificial cell, providing a promising approach for further exploration in the control of cellular transport of biomacromolecules.

Lastly, employing azo-PC photoisomerization we established optical control of the activity of mechanosensitive ion channels reconstituted in GUV membrane, which enabled the transport of small molecules across the membrane. These pore-forming transmembrane proteins can open and close in response to changes in membrane properties and tension. As a model protein, we used the bacterial mechanosensitive ion channel of large conductance (MscL) and reconstituted it into azo-PC containing GUVs. Labeling MscL with a dye allowed us to monitor the reconstitution process through confocal microscopy, determine critical parameters of the reconstitution process and develop a protocol for the reconstitution of MscL into azo-PC containing GUVs. In order to understand the initial conformation of the incorporated MscL in the GUV membrane, the vesicles were subjected to a permeability test by adding a water-soluble, membrane-impermeable sulforhodamine dye to the external medium of the GUVs. Most of the GUVs remained impermeable, indicating that the majority pf MscL in the membrane stayed in the closed state after reconstitution. This trend changed when UV/blue illumination was applied to the MscL-reconstituted azo-PC vesicles. UV/blue illumination altered the membrane properties of azo-PC doped GUVs and triggered the opening of the MscL channel, as monitored by the permeation of the sulforhodamine molecules across the GUV membrane. Our preliminary results showed that light can be used as an efficient tool to catalytically activate the MscL channel. Further studies should focus extensively on the optimization and characterization of MscL reconstitution and gating processes.

Overall, our findings in this doctoral thesis provide an essential background for understanding and optimizing light-triggered drug delivery platforms and photoregulation of shape-dependent cellular processes such as endocytosis, exocytosis and intercellular trafficking through azo-PC photoisomerization. Considering our results on the control of membrane shape, mechanics and trafficking by light irradiation, photoisomerization may be used as a promising biomedical alternative for cell repair processes. Photoswitchable biomimetic platforms can be further developed as light-triggered smart activators for high-precision regulation of cellular mechanisms.

Mosquito-borne alphaviruses like Chikungunya virus (CHIKV) and Mayaro virus (MAYV), which caused endemic outbreaks involving millions of patients over the past decades, pose an emerging threat due to climate-driven expansion of the virus vectors. Recently, the first vaccine against CHIKV was approved by the FDA, however, the lack of antiviral treatments underscores the need for a deeper understanding of virus-host interactions, potentially leading to the development of novel antiviral strategies. In this thesis, we investigate the role of ubiquitin-specific protease 10 (USP10) in the context of CHIKV and MAYV. Our findings demonstrate that USP10 overexpression significantly reduces infection rates for both alphaviruses. This antiviral effect is independent of USP10's deubiquitinase activity and instead relies on its interaction with the stress granule protein G3BP, mediated by a specific motif (FGDF) within USP10. Notably, USP10 overexpression disrupts the formation of stress granules during CHIKV infection, likely by sequestering G3BP and preventing its aggregation. Exploring the impact of USP10 on different stages of the viral replication cycle, our findings suggest that USP10 primarily targets the later stages, inhibiting the formation and release of new virus particles. In contrast, CHIKV glycoprotein-mediated entry and viral RNA replication are not significantly affected by USP10. Analogously to USP10, CHIKV nonstructural protein 3 (nsP3) binds G3BP via two FGDF motifs. Cells infected with G3BP binding-deficient mutants displayed no reduction in viral infection upon USP10 overexpression, underlining a critical role of the G3BP-nsP3 interaction in the antiviral effect of USP10. Finally, we explored the emergence of potential escape variants after serial passaging of CHIKV under selection pressure by USP10 overexpression. Notably, mutations were observed in the nsP2 and E2 proteins, suggesting potential rescue mutations in these proteins counteracting the antiviral activity of USP10. This highlights the selective pressure exerted by USP10, highlighting its importance as an antiviral factor. In conclusion, this thesis establishes USP10 as a potent cellular inhibitor of alphavirus infection. By targeting the G3BP-nsP3 interaction, USP10 offers a promising path for the development of novel antiviral strategies.

Spermatozoa are considered phenotypically equivalent because, during spermatogenesis, their precursor cells are organized in a syncytium where they share mRNA through intercellular bridges. This assumed phenotypic equivalence is challenged by a selfish genetic element encoded by the t-haplotype. The mouse t-haplotype is a naturally occurring variant of mouse chromosome 17 that shows high transmission from heterozygous (t/+) males due to a poison/antidote mechanism. t-Distorter genes exert detrimental effects on all sperm of these males. The t-responder, which can counterbalance these effects, remains restricted to the t-sperm, leading to their selective rescue and transmission ratio distortion (TRD) in favor of the t-chromosome. I first investigated whether energy metabolism contributes to the altered flagellar function, causative for t-haplotype TRD via the glycolysis enzyme phosphoglycerate kinase 2 (Pgk2). Pgk2 is overexpressed in mice with t-chromosomes. I generated male mutants carrying a t-specific Pgk2 knockout allele (tw5Pgk2∆/+) and showed that sperm of mutant tw5Pgk2∆/+ mice have increased progressivity, which suggests an improvement of wild-type sperm performance (which in t/+ are compromised by t-distorters). An important goal of this work was to evaluate whether TRD is a more widespread phenomenon and whether other genes, independent of the t-haplotype, can also cause TRD. Four candidate genes, Spata45, Tex29, Tex46, and Txndc2, were selected based on two criteria: late expression during spermatogenesis and minimal sharing among haploid spermatids. I generated reporter mouse lines of each gene and analyzed the distribution of their transcripts in the seminiferous tubules. Tex29 was shown to be restricted to the haploid spermatid encoding it. I then generated a Tex29 heterozygous loss-of-function mutant and showed that the transmission of the mutant allele was not affected. In addition, to study the function of Spata45, Tex29 and Tex46. I generated homozygous knockout mutants of these genes and examined whether they exhibit sterility or subfertility phenotypes. Spata45-/- and Tex29-/- males showed no fertility defects. However, Tex46-/- males are sterile demonstrating that Tex46 is essential for male fertility. Tex46-/- mice have normal testes, typical seminiferous tubule structures and can produce spermatozoa. However, the morphology of the sperm head reveals malformations affecting the arrangement of the plasma membrane, the internal and external acrosomal membranes, and the apical hook. Although Tex46-/- sperm cannot fertilize oocytes with zona pellucida, they successfully fertilize zona pellucida-free oocytes. It is proposed here that Tex46-/- sperm have an impaired acrosome reaction and are therefore unable to cross the zona pellucida. In this work a novel gene has been identified, that is critical for male fertility in mice, and may also play an important role in human male fertility.

In this work, a general and direct method for the synthesis of silver(I) perfluoroalcoholates has been investigated, including an examination of their structural properties in both solid state and solution, as well as an evaluation of their effectiveness as transfer reagents. The synthesis was performed by reaction of AgF with corresponding perfluorinated carbonyl compounds in acetonitrile (MeCN). The obtained silver(I) perfluoroalcoholates in MeCN were found to be stable at –18 °C over months. X-ray crystallographic analysis of the perfluoroalcoholate single crystals revealed a structure characterized by silver centers bridged by alcoholate ligands, while two alcohol ligands coordinate to one silver center. In acetonitrile solutions, Ag[OCF3] adopts a variety of structural forms as shown by IR spectroscopy. Furthermore, these silver(I) perfluoroalcoholates were found to be valuable as user-friendly transfer reagents, facilitating the synthesis of Cu[OCF3], Cu[OC2F5], [PPh4][Au(CF3)3(OCF3)], and various fluorinated alkyl ethers. Trifluoromethyl fluorosulfonate (CF3OSO2F) and trifluoromethoxysulfur pentafluoride (CF3OSF5), both bearing the ‒OCF3 moiety, were investigated regarding their dielectric behav-ior. Both compounds exhibit higher breakdown voltages compared to sulfur hexafluoride (SF6), with averaged relative breakdown voltages of 1.3 ± 0.2 for CF3OSO2F and 1.4 ± 0.2 for CF3OSF5, compared to 1.0 for SF6. This makes them promising candidates for dielectric appli-cations where higher voltage tolerance is necessary. During an electrical breakdown, both compounds, CF3OSO2F and CF3OSF5, decompose in a rate similar to that of the dielectric (CF3)2CFCN. The decomposition behavior was analyzed using IR spectroscopy and GC-IR techniques to identify the decomposition products. Moreover, the molecular structures of these compounds were successfully obtained using in situ crystallization methods. In addition, eval-uations of their physical properties, including vapor pressure, critical parameters, and melting points, were performed. These assessments further demonstrated the viability and perfor-mance of these materials as dielectric materials.

This work includes new methods for the introduction of fluorinated groups into organic molecules as well as investigations into photoredox catalysed C-F activation. The evaluation of benzothiazolium (BT) salts as deoxygenative trifluoromethylthiolation and fluorination reagents provided new insights into the Lewis acidity and mechanistic properties of BT-reagents. Both the polymerisation of tetrahydrofuran (THF) to trifluoromethylthioethers and the α-deprotonation of THF could be observed and investigated. BT-SCF3 could also be used for the synthesis of amides via acyl fluoride intermediates, which offers new application possibilities of the BT-reagents for fluorination reactions. The investigation of sulphur hexafluoride and bis(trifluoromethyl)peroxide (BTMP) as radical sources for pentafluorosulphanylation and trifluoromethoxylation reactions is also presented. BTMP can be used for the synthesis of α-OCF3 ketones and silyl enol ethers, as well as for the synthesis of allyl-OCF3 products starting from silylated compounds without any activators. In addition, studies on the Wagenknecht reaction with new reaction partners for the direct synthesis of SF5 compounds were presented and mechanistic properties of the reaction were identified based on the results. The thesis also discusses the photoredox catalysed reaction of α-fluoroacetophenones with silylated coupling partners, with the presented method showing new routes to polyfunctionalised synthetic building blocks.

The growing global demand for metals needed for the green energy transition has led to renewed exploration efforts. Ancient sedimentary basins contain a number of important resources such as zinc (Zn) and lead (Pb), and sometimes germanium (Ge), gallium (Ga), and indium (In). Some of the largest Zn deposits are called clastic-dominant (CD-type) deposits because they are hosted in clastic rocks like mudstones and siltstones. These deposits are thought to have formed when metal-rich fluids from deep in the Earth’s crust were expelled towards the surface along faults. However, many aspects of this overall model are not well understood. For example, the composition of the ancient metal-rich fluids is largely unknown, along with the mechanisms by which metals are deposited to form economic enrichments in certain locations.

The Selwyn Basin (Canada) contains a number of important CD-type deposits that formed hundreds of millions of years ago. The rocks hosting these deposits are now incorporated into the Canadian Cordillera, meaning they have been uplifted and deformed. This can make it challenging to interpret the rocks and understand how the deposit formation (mineralization) occurred. As a result, it is crucial to carefully examine samples that preserve some of the key primary features of the host rocks and the deposits.

This project evaluates aspects of the CD-type deposit model using various approaches that utilize two sample sets. 1) Barite- and pyrite-rich samples from the Late Devonian Canol Formation in Canada, which contain no Zn, Pb sulfides and formed at the same time as those rocks containing the deposits at other locations, were used to determine how the ancient environment was before the deposits formed. 2) Mineralized rock samples from a newly discovered CD-type deposit (Boundary Zone, Canada) were utilized to evaluate i) how these deposits formed, ii) the physicochemical properties of the metal-rich fluids, and iii) what essential metals are present. To answer some of the abovementioned questions, these two sample groups were used to make petrographic, mineralogical, and geochemical observations across various scales, from hand specimen to microscopic levels.

Data obtained through detailed petrographic and isotopic analyses indicate that the barite and pyrite in the Canol Formation formed during early diagenesis and that biological activity was critical for converting sulfate to sulfide. Similar mineral phases are observed in the samples from the Boundary Zone, where sulfide formed during early diagenesis likely reacted with metal-bearing hydrothermal fluids during an initial stage of ore formation. The first stage is dominated by fine-grained sphalerite formed as layers due to the replacement of quartz (and barite) components of the rocks. A second ore stage consists of several sphalerite types forming in cracks within the same rocks after fracturing. Critical metals, including Ge and deleterious components like Hg, occur in high amounts in the sphalerite from both the mineralized stages. Furthermore, experiments conducted on tiny droplets of fluids trapped within sphalerite and quartz indicate that the mineralizing fluids consist of variable salinity and homogenization temperature ranging from low (around 120 °C) during the early ore-forming stages to high (around 260 °C) at a later period. This suggests that the Boundary Zone deposit formed due to mixing of these fluids at some point.

Altogether, this thesis provides significant insights into components of the CD-type deposit model. It shows how vital microbial activities were during the formation of rocks that later host these deposits and also highlights prolonged hydrothermal fluid flow that could form multiple mineralization types. These findings are valuable for exploration strategies in the Macmillan Pass district and similar geological settings.

Lymphocytes require a certain time frame (24-48 hours) after their activation to fully develop effector functions. Hence, most studies have focused on characterizing splicing switches after this period. However, shortly after lymphocyte activation (0h to 4 hours), rapid gene expression changes occur, resulting in cytokines production and their secretion, as well as the initiation of cell proliferation, and differentiation. The expression of immediate early genes (IEG) is transiently induced upon T cell activation, with regulation being independent of de novo protein synthesis. This process relies on phosphorylation cascades that target the transcription machinery. In this project, we hypothesized that similar signaling cascades might also target the splicing machinery to induce immediate early splicing (IES). We aimed to delineate this concept and characterize its function in T cell and B cell activation. Furthermore, we investigated whether IES switches influence the translational machinery or whether they operate independently of this process. Through in silico bioinformatic analysis and biochemical wet lab experiments, we identified the rapid and transient retention of short introns among several genes within the first 1.5 hours of lymphocyte activation. This concerted splicing switch is independent of de novo protein synthesis. Further analysis showed its specific regulation by RAF/MEK/ERK1/2-mediated phosphorylation of the splicing factor - hnRNPC2. This hnRNPC isoform originates from an alternative 5’ splice site (A5SS) usage and contains 13 additional amino acids compared to hnRNPC1. Moreover, the T cell specificity of IES is preserved by the involvement of the kinase PKCθ, which is highly expressed in T cells. This is not the case in B cells, suggesting the involvement of another kinase in the hnRNPC2-controlled IES switch. IES affects many components of the translation apparatus, including transcripts encoding ribosomal proteins and translation factors, such as eukaryotic initiation factor eIF5A. Furthermore, we observed an hnRNPC2-dependent reduction in de novo translation during the hours immediately following T cell activation. We suggested that this reduction is mediated by the IES switch, as inducing the IES protein variant in eIF5A alone is sufficient to reduce translation globally. Altogether, we present a new paradigm for fast and transient alternative splicing regulation and suggest a fundamental role of IES in coordinating different layers of gene expression upon T cell activation.

Bone marrow plasma cells (BMPC) are terminally differentiated, non-dividing effector cells of the B cell lineage, dedicated to secrete specific antibodies essential for an effective immune response. Survival of plasma cells depends on various factors, including soluble mediators, intrinsic and extrinsic signals, and adhesion to surrounding cells enabling their maintenance within the bone marrow microenvironment. In prior studies, we and others have described a population of BMPC lacking CD19 that express a pro-survival and distinctly mature phenotype. In order to further address the heterogeneity of human BMPC subsets, we analyzed the interrelation of CD19 and CD56 expression using both flow cytometry and single-cell RNA sequencing (scRNA-seq) in human BMPC and included SARS-CoV-2 (receptor binding domain/RBD) and tetanus toxoid (TT) specific BMPC for comparison. In this thesis, we show for the first time that basic mRNA vaccination against SARS-CoV 2 elicits a phenotypically diverse population of RBD-specific BMPC. Our findings indicate that the frequency of RBD- and TT-specific BMPC is comparable. Specifically, both RBD- and TT-specific BMPC predominantly expressed IgG, while RBD-specific BMPC showed elevated levels of IgA in comparison to TT-specific BMPC. RBD-specific BMPC comprise 34.0% of PCs lacking CD19, compared to 59.0% in TT-specific BMPC among individuals who received SARS-CoV-2 vaccination 6 months prior to the analysis. Moreover, we found that CD56+ BMPC were characteristically enriched within TT-specific BMPC and almost absent among RBD-specific BMPC. IgA was more frequent in the CD56- compartment compared to CD56+ BMPC. Furthermore, we evaluated for the first time the co-expression of CD56 together with CD19 by antigen-specific and total BMPC. This phenotypic analysis by both multiparametric flow cytometry and scRNA-seq demonstrated a unique expression of CD19 and CD56 on these antigen-specific BMPC. The scRNA-seq studies provided evidence that NCAM1+ is predominantly expressed by CD19low BMPC. Particularly, the NCAM1+ BMPC subset lacking CD19 expression exhibits phenotypes that may be associated with PC population stability, increased survival potential and longevity. The study provides evidence for distinct phenotypic characteristics (in particular CD56/NCAM1 expression and CD19 co-expression), molecular mRNA expression (including cell-cell adhesion, endopeptidase activity etc.), and functional attributes (IgG, IgA, IgG-IgA-) by RBD-specific versus TT-specific BMPC. Thus, these BMPC subsets manifest significant differences across these domains but clearly indicate that BMPC heterogeneity likely is a signature of the initiating antigen together with characteristics of the prior immune response, both defining particular lifestyles of BMPC specificities.

Objectives: Accurate segmentation of intracerebral hemorrhage (ICH) and intra-ventricular hemorrhage (IVH) is essential for initial ICH volume estimation, which is a pivotal predictor for 30-day mortality rate. This study aimed to validate and enhance the performance of the DeepBleed, the first publicly available neural network model that allows for 3D segmentation of ICH and IVH. Methods: We conducted a retrospective analysis using a multicenter dataset with pa-tients of ICH and IVH from three European stroke centers. The dataset was divided into a training, validation, and test cohort. Model performance was assessed using dice score (DSC), sensitivity, and positive predictive values (PPV) metrics, both in the origi-nal (OM) and retrained model (RM) for each ICH location. T-test and multivariate linear regression were used to compare the DSC between the models and identify variables associated with DSC. Pearson correlation coefficients were calculated to evaluate vol-umetric agreement with the ground truth (GT), and intraclass correlation coefficient (ICC) to evaluate segmentation agreement with expert raters. Results: A total of 1040 patients were included in the study. Median DSC, sensitivity, and PPV for the OM and RM were comparable. Furthermore, for infratentorial hemor-rhage, the RM showed improvement in median DSC for brainstem and cerebellum compared to the OM. Hemorrhage volume and location were found to be significant factors influencing the DSC (p < 0.05). Additionally, automated segmentations demon-strated strong agreement with the ground truth in terms of volumetric measurements (r > 0.90), and they also exhibited excellent interrater reliability with the expert raters (ICC ≥ 0.9, p <0.001). Conclusions: Our study provided the first external validation of the publicly available DeepBleed network for spontaneous ICH in which the model showed an overall good generalization. After retraining the networks, accuracy improved significantly in seg-menting infratentorial hemorrhages, which are associated with poor prognosis. The automatic segmentations were strongly correlated with the GT in terms of volumetric measurements and ICC, making DeepBleed suitable for further automatic quantifica-tion of initial ICH volume.

Hintergrund: Notaufnahmen verzeichnen seit Jahren steigende Zahlen von Patient*innen mit weniger dringlichem Behandlungsbedarf. Diese Notaufnahmepatient*innen könnten oft adäquater in der Primärversorgung behandelt werden. In der EMAPREPARE-Studie wurde in einer Pilotintervention die potenzielle Umsteuerung von nicht hausärztlich angebundenen Patient*innen in die Primärversorgung erforscht. Es wurde Informationsmaterial zu Versorgungsalternativen zur Verfügung gestellt und eine optionale hausärztliche Terminvermittlung angeboten. Das qualitative Studienmodul, welches dieser Dissertation zugrunde liegt, untersucht die Sicht von Teilnehmer*innen der Pilotstudie auf diese Intervention. Zudem sollten Motive dieser Patient*innen sowie ihre Erfahrungen mit der hausärztlichen Versorgung aufgezeigt werden, die zum Inanspruchnahmeverhalten beitragen könnten. Methodik: Für den qualitativen Studienteil der Mixed-Methods-Pilotstudie EMAPREPARE wurden Telefoninterviews mit 32 weniger dringlichen Notaufnahmepatient*innen ohne bestehende hausärztliche Anbindung mittels eines semi-strukturierten Leitfadens geführt. Die Daten wurden auf Grundlage der qualitativen Inhaltsanalyse ausgewertet. Ergebnisse: Die Interviews zeigen, dass sowohl die Informationsbroschüre zu Behandlungsalternativen als auch die Vermittlung eines Termins bei einer hausärztlichen Praxis von den Befragten gut angenommen und weitgehend positiv bewertet wurden. Das Informationsmaterial sollte aus Sicht der Patient*innen online und auch an anderen Orten als der Notaufnahme verfügbar gemacht werden. Die Terminvermittlung wurde als hilfreich eingeschätzt, um künftig eine langfristige Bindung an die hausärztliche Versorgung herzustellen. Die interviewten Patient*innen berichteten zudem heterogene Faktoren, die potenziell beeinflussend für ihr bisheriges gesundheitliches Nutzungsverhalten gewesen sein könnten. In diesem Kontext wurden unter anderem ein seltener Bedarf nach gesundheitlicher Versorgung, ein ausgeprägtes Mobilitätsverhalten sowie mangelndes Wissen über die Rolle der/des Hausärzt*in und bestehende Versorgungsoptionen thematisiert. Allerdings scheinen auch geringes Vertrauen und negative Erfahrungen mit hausärztlicher Versorgung zur fehlenden Inanspruchnahme von Primärversorgung beizutragen. Schlussfolgerungen: In der interviewten Gruppe von weniger dringlichen Notaufnahmepatient*innen besteht eine prinzipielle Offenheit gegenüber einer Umsteuerung in die Primärversorgung. Dies deutet darauf hin, dass sowohl edukative als auch organisatorische Bemühungen vielversprechende Ansätze für die Zukunft darstellen können. Eine vermehrte Inanspruchnahme hausärztlicher Versorgung, verbunden mit einer Stärkung der Versorgungskontinuität und gegebenenfalls der Gesundheitskompetenz, kann sich potenziell positiv auf die künftige Entscheidungsfindung von Patient*innen mit akuten Gesundheitsproblemen auswirken.

Hintergrund Das Ziel dieser Arbeit war es anhand existierender Literatur eine Abschätzung des Risikos allergischer Wirkungen von Dental-Werkstoffen bezüglich Häufigkeit und Bedeutung abzugeben. Dazu wurden verschiedene Möglichkeiten der Allergietestung diskutiert. Aufgrund der umfassenden Studienlage wurde sich für den Epikutantest zur Beantwortung der Fragestellung entschieden. Methodik Es wurde eine Literaturrecherche in der Medline Datenbank über die Pubmed Suchmaske zu Epikutanteststudien durchgeführt. Hierzu wurden 33 internationale Patchtest-Studien für eine allgemeine Auswertung herangezogen. Die studienübergreifende Summe der Patienten betrug 72000 von denen 52000 mindestens eine positive Reaktion auf ein Kontaktallergen aufzeigten. Zusätzlich wurde auch die Häufigkeit allergischer Kontaktreaktionen für Metalle und Kunststoffe ausgewertet und miteinander verglichen. Resultate Top 10 Rangliste der Häufigkeit der Allergene: 1. Ni 19 %, 2. Duftstoffmix I 8 %, 3. Kobalt 7 %, 4. Perubalsam 6 %, 5 Chrom 4 %, 6. Kolophonium 3 %, 7. Paraphenylendiamin 2%, 8. Formaldehyd 2%, 9. Neomycinsulfat 2%, 10. Thiomersal 2%. Die Metallauswertung ergab: 1. Ni 19 %, 2. Au 9%, 3. Co 8 %, 4. Hg 7 %, 5. Pd 7 %, 6. Amalgam 6 %, 7. Cr 5 %, 8. Cu 4 %, 9. V 3 %, 10. Sn 1%. Die Recherche zu Allergien gegenüber Keramikbestandteilen ergab keine Treffer. 9 Die Kunststoffauswertung ergab folgende Häufigkeiten: 1. Hydroxypropylacrylat 5 %, 2. 2-Hydroxypropylmethacrylat 4 %, 3. 2-hydroxyethylmethacrylat 3 %, 4. Ethylacrylat 3 %, 5. Ethylmethacrylat 2 %, 6. Ethylenglycoldimethacrylat 2 %, 7. 2-Hydroxyethylacrylat 2 %, 8. Triethyleneglycoldiacrylat 2 %, 9. Methylmethacrylat 2 %, 10. Diethylenglycoldiacrylat 2 %, 11. Tetrahydrofurfurylmethacrylat 1 %, 12. Epoxidharz 1% Rangliste Dentalmaterialien: 1. Ni 20 %, 2. Ethylmethacrylat 20 %, 3. Hydroxypropylactylat 19 %, 4. Methylmethacrylat 17 %, 5. Ethylenglycoldimethacrylat 16 %, 6. 1.4-Butandioldimethacrylat 16 %, 7. 2-hydroxyethylmethacrylat 16 %, 8. Triethylengylcoldimethacrylat 15%, 9. Benzoylperoxid 13 %, 10. 2- Hydroxypropylmethacrylat 13 %, 11. Au 10 %, 12. Co 10 %, 13. Ethylacrylat 8 %, 14. Duftstoffmix 1 8 %, 15. Pd 8 % Fazit Metalle stellen in groß angelegten Studien, die bedeutendste Gruppe von Kontaktallergenen dar. Nickel ist das häufigste metallische Allergen. Gold ist überraschenderweise ein stärkeres Allergen als Kobalt und Chrom. Dies spricht aus allergieprophylaktischer Sicht für die Verwendung von Nichtedellegierungen aus den zuletzt genannten Metallen. Kunststoffe spielen als Allergene in der breiten Bevölkerung eine deutlich geringere Rolle. Bei beruflich exponierten Personen wie Zahntechnikern sind diese dagegen ein sehr starkes Kontaktallergen. Da keine Hinweise auf Keramikallergien gefunden wurden, sind Vollkeramiken aus allergologischer Sicht die günstigsten zahntechnischen Materialien für festsitzenden Zahnersatz.

Ischemic stroke is a major challenge to the healthcare system and one of the leading causes for long-term disability. Many promising drugs tested in preclinical stroke studies have failed to translate into the clinical routine, raising the question of how good com-monly used preclinical stroke models are and how to address apparent deficits of translational stroke research. Assessing functional outcome after stroke in mice is challenging and well established protocols for side specific behavioral tests are lacking. The most common model for induction of experimental stroke produces variable lesion volumes, contributing to the complexity of stroke research. Finally, while predictors of functional outcome after stroke are well described in humans, no systematic study in mice has been performed. To fully comprehend the mouse as a model animal, it would be useful to identify factors that determine functional outcome and to assess how similar those factors are to predictors described in humans. In a first step, a skilled reaching task was established in mice. Next, behavioral and imaging data from fifteen studies using the newly established protocol were pooled, resulting in a dataset that included 215 mice. Variance of lesion volumes resulting from different arterial occlusion times were compared. Furthermore, the dataset was used to develop machine learning based prediction models for the functional outcome after stroke. Tested predictors were the degree of initial deficit, lesion volume and stroke localization. With the help of the staircase test, a side-specific motor functional deficit over the period of three weeks after stroke was observable, as were different recovery trajectories similar to those described in stroke patients. Longer arterial occlusion times resulted in a lower variance of lesion volumes. The lesion volume could be used to predict the degree of the early deficit after stroke, especially in mice with small cortical lesions. The best predictor of long-term outcome was the degree of the early deficit, but incorporating the localization of the stroke increased the accuracy of imaging-based predictors. The described results deepen the understanding of the mouse as a model animal in stroke research and display reassuring parallels to stroke patients. In the future, the design of preclinical studies could be refined using the developed prediction models to guide treatment decisions.

Multiple sclerosis (MS) is the most prevalent neurological disease of chronic inflammation within the central nervous system (CNS). The disease course of MS is highly variable, where some patients show complete remission of symptoms, while others present a pro- gressive deterioration. In this work, induced pluripotent stem cells (iPSCs) were gener- ated from three MS patients with a mild disease course (benign MS, BMS) and three patients with a progressive disease course (progressive MS, PMS). The main goal was identifying mechanistic insights into the mild disease progression of benign MS through patient-specific iPSC-derived neurons and astrocytes. A combinatory treatment of inflammatory cytokines (TNFα/IL-17A) in patient specific neu- rons led to neuronal damage in both clinical phenotypes. In co-cultures of patient-specific astrocytes with a neuronal control line, it could be shown that TNFα/IL-17A treatment in BMS co-cultures resulted in less neuronal damage than in PMS co-cultures. A single-cell transcriptome analysis of neurons descended from BMS co-cultures demonstrated acti- vation of neuronal-resilience pathways. Whereas, neurons from PMS co-cultures featured expression patterns of neurodegenerative diseases. Furthermore, TNFα/IL-17A treated BMS astrocytes resulted in a differential gene expression of growth factors LIF, TGF-β1 and BDNF. A supernatant analysis confirmed the secretion of these factors within BMS co-cultures and a treatment of TNFα/IL-17A exposed neurons with these supernatants led to a neuroprotective outcome. The regulation of the JAK-STAT pathway was identified as a possible mechanism of the TNFα/IL-17A treatment. In conclusion, these results demonstrate the potential outcome of targeted modulation of astrocytes into a neuroprotective phenotype. This could contribute to therapies to pre- vent permanent neuronal damage and subsequently, dampening the disease course of progressive MS.

Einleitung: Die körperliche Leistungsfähigkeit unterliegt verschiedenen Abhängigkeiten, insbesondere der muskulären Sauerstoffverfügbarkeit. Die möglichst akkurate und dabei leicht anzuwendende Bestimmung der Leistungsfähigkeit ist eine wichtige Voraussetzung für die Einschätzung von Trainingseffekten. Unter Berücksichtigung der mechanischen Leistungsabgabe (MPO), des maximalen Sauerstoffverbrauchs (VO2max), der Sauerstoffgewebeverfügbarkeit und der Effizienz von Bewegungsmustern, sollte in dieser Arbeit der Zusammenhang von Trainingsstatus und Geschlecht mit der subjektiv wahrgenommenen Anstrengung (RPE), als leicht bestimmbarer Parameter, verglichen werden. Methoden: 63 Probanden_innen im Alter von 18 – 40 mit einem BMI zwischen 18,5 – 25, wurden in Gruppen von trainierten bzw. untrainierten Frauen und Männern unterteilt. In einem Bruce-Leistungstest wurde die VO2max bestimmt, sowie Bewegungsmuster kontinuierlich mit einem Akzelerometer aufgezeichnet und die RPE-Werte in jeder Stufe mittels Borg-Scala bestimmt. Vor und nach dem Bruce-Test erfolgten Bioimpedanzanalysen. Blutgasanalysen (BGA) und tonometrisch bestimmte Sauerstoff- Hämoglobin-Bindungskurven dienten zur Einschätzung der Sauerstoffabgabefähigkeit an das Gewebe. Ergebnisse: Unter Berücksichtigung von VO2max, MPO und Körperzusammensetzung zeigte sich eine größere Belastung für weibliche und untrainierte Personen im Vergleich zu männlichen und trainierten Teilnehmern. Die individuellen RPE-Werte korrelierten am besten mit der mechanischen Leistung pro Skelettmuskelmasse (MPOSMM). Die Hämoglobin-Sauerstoff-Affinität zeigte keine trainingsbezogenen Unterschiede, jedoch eine Geschlechtsabhängigkeit. Männer wiesen in Ruhe eine höhere Affinität von Sauerstoff zum Hämoglobin auf, die mit niedrigeren 2,3-Bisphosphoglycerat-Werten und höheren Hämoglobinkonzentrationen korrelierte. Unter Belastung erreichten Männer im Vergleich zu Frauen niedrigere pH Werte, so dass bei maximaler Leistung die Sauerstoffabgabefähigkeit von Männern und Frauen vergleichbar war. Zusammenfassung 2 Das Regularitätsprofil der Bewegungsmuster zeigte keine Geschlechterunterschiede, sondern deutliche Trainingsabhängigkeiten. Trainierte Proband_innen erreichten bspw. eine 19 % längere Testdauer und 32 %längere Ermüdungsphase bei höherem Regelmäßigkeitsindex. Diskussion: Nicht die Sauerstoffabgabefähigkeit, sondern die Körperzusammensetzung stellte sich als entscheidender Faktor einer besseren Testleistung der Männer heraus. Die Ergebnisse zeigen, dass Frauen bezogen auf ihre SMM höhere VO2SMM und MPOSMM Werte, einhergehend mit vergleichsweise höheren RPE-Werten, aufweisen, als bisher angenommen. Es konnte gezeigt werden, dass die subjektiv wahrgenommene Anstrengung unter Berücksichtigung von Geschlecht und Körperzusammensetzung eine gute Einschätzung der Leistungsfähigkeit ermöglicht.