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    D-2-hydroxyglutarate supports a tolerogenic phenotype with lowered major histocompatibility class II expression in non-malignant dendritic cells and acute myeloid leukemia cells

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    D-2-hydroxyglutarate (D-2-HG) accumulates in primary acute myeloid leukemia (AML) patients with mutated isocitrate dehydrogenase (IDH) and other malignancies. D-2-HG suppresses antitumor T cell immunity but little is known about potential effects on non-malignant myeloid cells. Here we show that D-2-HG impairs human but not murine dendritic cell (DC) differentiation, resulting in a tolerogenic phenotype with low major histocompatibility (MHC) class II expression. In line, IDH-mutated AML blasts exhibited lower expression of HLA-DP and were less susceptible to lysis by HLA-DP-specific T cells. Interestingly, D-2-HG reprogrammed metabolism towards increased lactate production in DCs and AML besides its expected impact on DNA demethylation. Vitamin C accelerated DNA demethylation, but only the combination of vitamin C and glycolytic inhibition lowered lactate levels and supported MHC class II expression. Our results indicate an unexpected link between the immunosuppressive metabolites 2-HG and lactic acid and suggest a potentially novel therapeutic strategy with combinations of anti-glycolytic drugs and epigenetic modulators (hypomethylating agents) or other therapeutics for the treatment of AML

    Asymmetric Hydrofunctionalisation Reactions Catalysed by 3d Transition Metal Complexes or Main Group Element Compounds

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    This thesis primarily reports on the synthesis and catalytic activity of main group and 3d transition metal-based complexes in hydrofunctionalisation reactions. Chapter 1 gives an overview of enantioselective (transfer) hydrogenation, hydroboration and hydrosilylation reactions. In Chapter 2 the catalytic activity of phosphacyclohexadienyl anions is compared with organolithium reagents and alkoxides in hydroboration reactions. Chapter 3 reports the synthesis of magnesium complexes bearing chiral β ketiminate ligands and their activity and selectivity in enantioselective hydrofunctionalisation reactions. Chapter 4 describes the use of chiral bis(aryl)acenaphthenequinonediimines (BIANs) as ligands in the 3d transition metal catalysed enantioselective transfer hydrogenation of olefins. Chapter 5 covers the synthesis of cobaltate phosphinine complexes featuring rare or novel coordination modes of the phosphinine. Finally, Chapter 6 gives a summary of the results described in this thesis and provides a short outlook on asymmetric hydrofunctionalisation reactions

    Verkürzte Mikroemboliedetektion bei Verdacht auf Endokarditis - eine Pilotstudie

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    Eine gefürchtete Komplikation der Erkrankung Endokarditis, insbesondere der infektiösen Endokarditis, stellt die Emboliegenität dar. Daraus resultiert ein hohes Risiko, im Verlauf dieser Krankheit, einen Schlaganfall zu erleiden, weshalb die Diagnose zeitnah gestellt werden sollte, um möglichst schnell und gezielt eine geeignete Therapie zu gewährleisten. Beim Verdacht auf eine Endokarditis stehen zur frühzeitigen Diagnostik verschiedene Techniken zur Verfügung, die jedoch zum Teil Nachteile, zeitliche Verzögerungen für den Patienten mit sich bringen oder eine zu geringe Sensitivität bzw. Spezifität besitzen. In der vorliegenden Dissertation wurde daher untersucht, ob der Einsatz der Mikroemboliedetektion mittels einer mobilen transkraniellen Duplexsonographie (TCCS/ TCD) über einen Zeitraum von nur zehn Minuten als ein schnelles und sicheres Verfahren die Verdachtsdiagnose einer Endokarditis stützen kann. Die dazu an insgesamt 33 Patienten durchgeführte verkürzte Mikroemboliedetektion mittels TCD ergab jedoch keinen eindeutig signifikanten Zusammenhang zwischen der Messung von Mikroembolien und dem Vorliegen einer Endokarditis. Bezieht man allerdings das zusätzlich retrospektiv aufgenommene Patientengut mit ein, lässt sich eine eindeutige Tendenz zu einem häufigeren Auftreten von detektierbaren MES im Rahmen einer Endokarditis erkennen. Zusammenfassend lässt sich sagen, dass diese Mikroembolidetektion mithilfe der TCD durchaus Vorteile mit sich bringen und gerade bei Hochrisikopatienten angewendet werden könnte, um schneller den Verdacht auf eine Endokarditis erhärten zu können - weitere Studien mit einer größeren Stoffmenge vorausgesetzt

    Reconstructing Disease Histories in Huge Discrete State Spaces

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    Many progressive diseases develop unnoticed and insidiously at the beginning. This leads to an observational gap, since the first data on the disease can only be obtained after diagnosis. Mutual Hazard Networks address this gap by reconstructing latent disease dynamics. They model the disease as a Markov chain on the space of all possible combinations of progression events. This space can be huge: Given a set of events, its size exceeds the number of atoms in the universe. Mutual Hazard Networks combine time-to-event modeling with generalized probabilistic graphical models, regularization, and modern numerical tensor formats to enable efficient calculations in large state spaces using compressed data formats. Here we review Mutual Hazard Networks and put them in the context of machine learning theory. We describe how the Mutual Hazard assumption leads to a compact parameterization of the models and show how modern tensor formats allow for efficient computations in large state spaces. Finally, we show how Mutual Hazard Networks reconstruct the most likely history of glioblastomas

    Comprehensive Functional Investigation of the Human Translocator Protein 18 kDa (TSPO) in a Novel Cellular Knockout Model - On the Trail of the Enigma

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    The translocator protein 18 kDa (TSPO), initially characterised in 1977 as a peripheral binding receptor for benzodiazepines, is an evolutionarily conserved outer mitochondrial protein ubiquitously expressed in almost all cell types, albeit in a tissue- and cell-specific manner. Physiological expression within the brain is relatively weak. However, pathological conditions, such as Alzheimer’s disease, multiple sclerosis, and cancer, can lead to upregulated TSPO expression, implying a role for TSPO in the pathophysiology of neurodegenerative, neuroinflammatory, and neoplastic diseases (Ammer et al., 2020; Rupprecht et al., 2010). Although TSPO is considered a multifunctional protein associated with various aspects of mitochondrial physiology, its precise role in mitochondrial homeostasis and its mechanisms of action remain elusive. This study aimed to analyse the effect of TSPO on the regulation of mitochondrial metabolism in a human cellular model. Therefore, using the CRISPR/Cas9 technology, TSPO knockout (KO) and control (CTRL) variants of human induced pluripotent stem cells (hiPSCs), reprogrammed from primary adult skin fibroblasts, were generated. In a multimodal phenotyping approach, parameters of cellular and mitochondrial functions were investigated and compared in neural progenitor cells, astrocytes, and neurons differentiated from hiPSC CTRL and KO cell lines. In those different cell types, the bioenergetic profile, as well as the mitochondrial membrane potential (MMP) and the Ca2+ homeostasis was assessed. Furthermore, oxidative stress, mitochondrial content, and cell size were evaluated. Functional characterisation of TSPO KO cells, as compared to CTRL cells, revealed altered Ca2+ levels in the cytosol and mitochondria, a depolarised MMP, and increased levels of reactive oxygen species (ROS), indicating an unbalanced redox state and oxidative stress. While the mitochondrial content seemed to be unchanged, the mitochondrial DNA copy number was significantly decreased in mitochondria devoid of TSPO. Notably, TSPO deficiency was accompanied by reduced expression of the voltage-dependent anion channel (VDAC). Respirometry experiments favoured the possible role of TSPO in regulating the bioenergetic status of the cell, as mitochondrial respiration and glycolysis were significantly reduced along with the deletion of TSPO protein expression. Interestingly, across all cell types, TSPO-KO cells were significantly smaller in size. Moreover, a significant decrease in the protein expression of TSPO and the TSPO-associated protein VDAC1 in a human cellular model of depression was observed, suggesting a potential link between TSPO and the pathomechanism of mitochondrial dysfunction in depression. Taken together, these findings point consistently towards the impairment of mitochondrial function in TSPO KO cells, contributing to the understanding of the multifaceted role of TSPO and setting the stage for further investigations to unravel the underlying mechanisms and its involvement in various physiological and pathological processes

    The renin angiotensin aldosterone system

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    In this review, we will cover (i) the proteolytic cascade of the RAAS, (ii) its regulation by multiple feedback-controlled parameters, and (iii) the major effects of the RAAS. For the effects of the RAAS, we focus on the role of the RAAS in the regulation of volume homeostasis and vascular tone, as major determinants of arterial blood pressure

    Aromas: Lovely to Smell and Nice Solvents for Polyphenols? Curcumin Solubilisation Power of Fragrances and Flavours

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    Natural aromas like cinnamaldehyde are suitable solvents to extract curcuminoids, the active ingredients found in the rhizomes of Curcuma longa L. In a pursuit to find other nature-based solvents, capable of solving curcumin, forty fragrances and flavours were investigated in terms of their solubilisation power. Aroma compounds were selected according to their molecular structure and functional groups. Their capabilities of solving curcumin were examined by UV–Vis spectroscopy and COSMO-RS calculations. The trends of these calculations were in accordance with the experimental solubilisation trend of the solubility screening and a list with the respective curcumin concentrations is given; σ-profiles and Gibbs free energy were considered to further investigate the solubilisation process of curcumin, which was found to be based on hydrogen bonding. High curcumin solubility was achieved in the presence of solvent (mixtures) with high hydrogen-bond-acceptor and low hydrogen-bond-donor abilities, like γ- and δ-lactones. The special case of DMSO was also examined, as the highest curcumin solubility was observed with it. Possible specific interactions of selected aroma compounds (citral and δ-hexalactone) with curcumin were investigated via 1H NMR and NOESY experiments. The tested flavours and fragrances were evaluated regarding their potential as green alternative solvents

    No role of working memory in the relation between mental rotation and postural stability

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    This study investigated the relationship between mental rotation ability and postural stability, with a focus on the role of the visuospatial sketchpad of working memory, as it has been found to be correlated with both concepts. A total of 87 healthy young adults completed a postural stability task on a force plate, a mental rotation task, and both spatial and object working memory tasks in a counterbalanced order. Bayesian correlations revealed weak positive correlations between mental rotation and postural stability, as well as a correlation between mental rotation and spatial working memory. A weak association was also observed between mental rotation and object working memory. No correlation was found between the working memory components and postural stability. Furthermore, the results showed that spatial working memory did not play a crucial role in predicting postural stability. We conclude that the visuospatial sketchpad, particularly the spatial working memory component, cannot explain the relationship between mental rotation and postural stability

    Iatrogene Netzhautdefekte nach intravitrealer operativer Medikamenteneingabe

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    Hintergrund Intravitreale operative Medikamenteneingaben (IVOM) stellen einen der häufigsten Eingriffe in der Medizin dar. Das Risikoprofil ist gering. Neben intraokularen Drucksteigerungen zählen insbesondere erregerbedingte Endophthalmitiden, Glaskörperblutungen und rhegmatogene Netzhautablösungen zu den gängigen Komplikationen. Darüber hinaus wurden auch einzelne Fälle von Linsenverletzungen sowie peripheren Netzhautdefekten und Makulaforamina in Assoziation mit vitreoretinalen Traktionen beschrieben. In der hier vorliegenden Fallserie berichten wir über scharfe iatrogene Netzhaut- bzw. Makulaverletzungen. Methoden Multizentrische Fallsammlung von IVOM-Patienten mit iatrogenen Netzhautdefekten, retrospektiv über den Zeitraum 2016 bis 2023. Ergebnisse Es konnten 9 Fälle (72 Jahre ± 8,1, 3 Augen pseudophak) mit einem iatrogenen retinalen Trauma nach IVOM zur Therapie einer neovaskulären altersbedingten Makuladegeneration (nAMD) dokumentiert werden. Während in 6 Fällen scharfe Verletzungen innerhalb der Makula vorlagen, waren die Läsionen in den anderen Fällen extramakulär lokalisiert. Schlussfolgerungen Iatrogene Netzhaut- und Makulaverletzungen sind seltene Komplikationen im Rahmen der IVOM und bei sachgemäßer Durchführung insbesondere mit Blick auf die Kanülenverwendung und die Wahl des Limbusabstands vermeidbar

    A dilute nematic gel produced by intramicellar segregation of two polyoxyethylene alkyl ether carboxylic acids

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    Motivation Surfactants like C8E8CH2COOH have such bulky headgroups that they cannot show the common sphere-to-cylinder transition, while surfactants like C18:1E2CH2COOH are mimicking lipids and form only bilayers. Mixing these two types of surfactants allows one to investigate the competition between intramicellar segregation leading to disc-like bicelles and the temperature dependent curvature constraints imposed by the mismatch between heads and tails. Experiments We establish phase diagrams as a function of temperature, surfactant mole ratio, and active matter content. We locate the isotropic liquid-isotropic liquid phase separation common to all nonionic surfactant systems, as well as nematic and lamellar phases. The stability and rheology of the nematic phase is investigated. Texture determination by polarizing microscopy allows us to distinguish between the different phases. Finally, SANS and SAXS give intermicellar distances as well as micellar sizes and shapes present for different compositions in the phase diagrams. Findings In a defined mole ratio between the two components, intramicellar segregation wins and a viscoelastic discotic nematic phase is present at low temperature. Partial intramicellar mixing upon heating leads to disc growth and eventually to a pseudo-lamellar phase. Further heating leads to complete random mixing and an isotropic phase, showing the common liquid–liquid miscibility gap. This uncommon phase sequence, bicelles, lamellar phase, micelles, and water-poor packed micelles, is due to temperature induced mixing combined with dehydration of the headgroups. This general molecular mechanism explains also why a metastable water-poor lamellar phase quenched by cooling can be easily and reproducibly transformed into a nematic phase by gentle hand shaking at room temperature, as well as the entrapment of air bubbles of any size without encapsulation by bilayers or polymers

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