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Amtliche Bekanntmachungen, 55. Jahrgang, Nr. 36
No full text9. Satzung zur Änderung der Satzung der Studierendenschaft der Rheinischen Friedrich-Wilhelms-Universität Bonn - SÄS 9 - vom 13. Juni 202
A Celestial Story of Supersymmetry: Inflation and Reheating in the Early Universe
Get PDFThe Standard Model of particle physics and Big Bang cosmology have been successfully used to describe the evolution and current state of the Universe. However, they are known to be incomplete as they leave several unanswered questions, including inflation, dark matter, dark energy, the baryon asymmetry of the universe, and neutrino masses. This thesis presents several models that aim to answer these questions within the framework of supersymmetry and supergravity. We begin by constructing scalar potentials that support slow roll inflation using a single chiral superfield and discuss how to satisfy cosmic microwave background constraints. We then consider how to incorporate supersymmetry breaking effects into account, which leads to a bound on the supersymmetry breaking scale and the inflation scale. After finishing this simple model, we turn to consider how to apply modular symmetry in inflation. Modular symmetry is a strong constraint as well as a useful handle in understanding the dynamics of inflation. In particular, we consider how to construct scalar potentials that resolve the flavor puzzles and simultaneously give rise to inflation. This combination naturally provides the necessary channels for reheating and predicts that the inflaton primarily decays to heavy right-handed neutrinos. By explicit calculation, we show that if the inflaton mass is high enough, this process can be used to produce the baryon asymmetry of the universe. In the end, we discuss a mechanism that produces dark matter at the end of inflation, known as gravitational particle production. We compare the relic abundance of dark matter in supergravity models and non-supersymmetric models, identifying the parameter space that generates sufficient dark matter
Problems and intuitions : Reflections on the question of how "intuitive reasoning" leads to avoidable problems
Get PDFThe goal of this thesis is to present good reasons for thinking that some problems central to philosophical discussions rest on a partly misguided methodological approach that can be safely discarded. More precisely, it is the contention of this work that a variety of philosophical difficulties and puzzles arise due to, among other things, an overly liberal usage of what is referred to as "intuitive reasoning" in this dissertation.
Among the problems that might turn out to be resolvable through a more critical attitude towards intuitive reasoning are classic, but also more recently described, philosophical paradoxes. The philosophical strategy for dealing with these problems, as defended in this work, is mainly illustrated through a discussion of an epistemological paradox called the "Cartesian paradox".
For a very rough characterization of intuitive reasoning, one can, at first, point out that appeals to the supposed "obviousness", "plausibility", or "undeniability" of certain propositions are essential to this kind of reasoning. These appeals are then used by the intuitive reasoner to justify philosophical claims. And among the claims justified by an appeal to their supposed "obviousness", "plausibility", or "undeniability" are claims central to the formulation of philosophical difficulties. If this intuitive reasoning is kept in check by suitably restrained skepticism, then certain philosophical difficulties become avoidable. For if a proposition central to a philosophical difficulty lacks the justification it usually gains from intuitive reasoning, then the difficulty itself loses its pressing nature.
After an introduction that presents the goals and main lines of reasoning of this thesis, the first part of the work begins with a look back into the philosophical past, where the views of thinkers who have shared a more critical attitude towards intuitive reasoning are briefly discussed. In the first part, the philosophical debate surrounding the so-called "Cartesian paradox" is introduced, and it is explained why trying to solve philosophical paradoxes is a worthwhile endeavor. Sections 1.6. and 1.7. are the core of this thesis, as they lay out the central ideas of the strategy for addressing philosophical difficulties. Section 1.8., in which a variety of possible problems for the proposed strategy are discussed, concludes the first part of the thesis.
The second part of the work explores how restrained skepticism towards intuitive reasoning can not only be used to dissolve paradoxes but can also be applied to fruitfully address conceptual philosophical questions. Finally, the third part examines some of the philosophical heritage of the Vienna Circle and how it could be combined with the outlook defended in this thesis. This attempt at a "combination" serves the goal of formulating a philosophical stance that is better equipped than others to free itself from various puzzles, difficulties, and queries by which philosophers are often plagued
Inhibition of gap junctions as a novel treatment strategy for medulloblastoma
Get PDFThe discovery of communicative cellular networks has reshaped our understanding of brain tumor biology. Despite the growing knowledge of Cx43-based GJ as key drivers of malignant intercellular connectivity in several malignant brain tumors, the significance of GJ in MB remains largely unknown. This thesis investigates whether MB harbors tumor networks mediated by Cx43-based GJs and explores their functional role.
Using IF and WB, Cx43-based GJ expression was confirmed in non-WNT/non-SHH MB cell lines (Med8A and D283). MFA and TO were used as clinically-feasible pharmacological GJ-blockers. MFA and TO demonstrated reduced intercellular connectivity pharmacologically thus enhanced sensitivity to CCNU-mediated cytotoxicity, as shown through real-time imaging and flow cytometry. RNA sequencing revealed that the combination of MFA and CCNU disrupted cellular homeostasis by activating wound-healing mechanisms in Med8A cells.
A Cx43 KO model, generated using CRISPR/Cas9, confirmed the pivotal role of Cx43 in maintaining intercellular connectivity and the pharmacological inhibition from MFA and TO. The absence of Cx43 resulted in fewer neighboring connections in Med8A cells, making them more vulnerable to CCNU treatment.
These findings suggest that Cx43-based GJs contribute to MB tumor networks and may play a key role in mediating resistance to chemotherapy. Targeting these networks pharmacologically offers a potential strategy to enhance the efficacy of chemotherapeutic agents like CCNU in MBs
Functional characterization of inositol pyrophosphate pyrophosphatases in plants
Get PDFThe consequences of the climate and biodiversity crisis present an increasingly challenge for the agricultural sector to ensure food security for a growing world population. The optimal nutrient supply of plants is a critical factor in maintaining or increasing yields, especially of essential macronutrients such as phosphorus (P). It is therefore important to gain a deeper understanding of the processes involved in P uptake, in form of inorganic phosphate (Pi), and the mechanisms regulating Pi homeostasis in plants. Recent research has identified the involvement of the signaling molecules inositol pyrophosphates (PP-InsPs) in the process of Pi signaling and homeostasis in plants. The biosynthesis of PP-InsPs relies on balanced phosphorylation and dephosphorylation of inositol phosphates (InsPs) and PP-InsPs. However, the current state of knowledge regarding PP-InsP dephosphorylation is notably limited in comparison to InsP/PP-InsP phosphorylation. Therefore, the objective of this thesis was to identify and characterize putative PP-InsP pyrophosphatases in plants. We found that recombinant proteins of all five Arabidopsis Plant and Fungi Atypical Dual Specificity Phosphatases (PFA-DSP1-5) display pyrophosphatase activity with a high specificity for the 5 β-phosphate of PP-InsPs. Heterologous expression in Nicotiana benthamiana leaves provided evidence that Arabidopsis PFA-DSP1 also displays a 5-β-phosphate-specific PP-InsP pyrophosphatase activity in planta. Moreover, we identified a family of Arabidopsis NUDIX hydrolases (NUDTs) that group into two closely related subclades. Through in vitro assays, heterologous expression systems, and higher-order gene-edited mutants, we found that subclade I NUDTs preferentially hydrolyze 4-InsP7, while subclade II NUDTs target 3-InsP7. In higher-order mutants of subclade II NUDTs, we observed defects in both Pi and iron homeostasis, accompanied by increased levels of 1/3-InsP7 and 5-InsP7. Ectopic expression of NUDTs from both subclades induced local Pi starvation responses (PSRs), while RNA-seq analyses comparing WT and nudt12/13/16 loss-of-function plants indicate additional PSR-independent roles and a potential involvement of 1/3-InsP7 in the regulation of plant defense.
Collectively, the results presented in thesis show not only new insights into the roles of PFA DSPs and NUDTs in regulating PP-InsP signaling pathways in plants, but also provide the genetic tools to uncover more general roles of PP-InsPs in plant physiology and plant development.Die Ernährungssicherung einer wachsenden Weltbevölkerung wird durch die Folgen der Klima- und Biodiversitätskrise zu einer zunehmenden Herausforderung für den Agrarsektor. Eine optimale Nährstoffversorgung der Pflanzen, vor allem mit essenziellen Makronährstoffen wie Phosphor (P), ist entscheidend für die Aufrechterhaltung oder Steigerung der Erträge. Um die Aufnahmeeffizienz von P, in Form von anorganischem Phosphat (Pi), zu erhöhen, ist es wichtig die Mechanismen zu verstehen, welche die Pi-Homöostase in Pflanzen regulieren. Aktuelle Forschungsarbeiten haben gezeigt, dass die Signalmoleküle Inositolpyrophosphate (PP-InsPs) an den Prozessen der Pi-Homöostase in Pflanzen beteiligt sind. Obwohl die Biosynthese von PP-InsPs auf einer ausgewogenen Phosphorylierung und Dephosphorylierung von Inositolphosphaten (InsPs) und PP-InsPs basiert, ist der Kenntnisstand über die Dephosphorylierung von PP-InsPs limitiert. Das Ziel dieser Arbeit war es, PP-InsP Pyrophosphatasen in Pflanzen zu identifizieren und zu charakterisieren. Mit in vitro Analysen und der heterologen Expression von Arabidopsis Plant and Fungi Atypical Dual Specificity Phosphatases (PFA-DSPs) in Hefen und Tabak haben wir gezeigt, dass diese Enzyme eine PP InsP Pyrophosphatase Aktivität mit einer hohen Spezifität für das 5-β-Phosphat aufweisen. Darüber hinaus haben wir sieben Arabidopsis NUDIX-type (NUDT) Hydrolasen identifiziert, die eine PP-InsP Pyrophosphatase Aktivität aufweisen und sich im phylogenetischen Baum in zwei Untergruppen einteilen lassen. Mit Hilfe von in vitro Analysen, heterologen Expressionssystemen und Gen-Knockout-Mutanten fanden wir heraus, dass die Gruppe I NUDT Hydrolasen bevorzugt 4-InsP7 hydrolysieren, während Gruppe II NUDT Hydrolasen eine Spezifität für 3-InsP7 aufweisen. In der Arabidopsis dreifach Knockout-Mutante nudt12/13/16 haben wir Defekte in der Pi- und Eisen-Homöostase beobachtet, zusammen mit erhöhten 1/3-InsP7 und 5-InsP7 Konzentrationen. Darüber hinaus zeigte die heterologe Expression von Arabidopsis NUDT Hydrolasen aus beiden Gruppen eine lokale Pi-Defizit Reaktion (PSR) in Tabakblättern. Die Transkriptomanalyse der Mutante nudt12/13/16 lieferte zudem Hinweise darauf, dass PP-InsPs auch an PSR-unabhängigen Prozessen beteiligt sein könnten, wie beispielsweise 1/3-InsP7 an der Regulierung der Pflanzenabwehr.
Die in dieser Arbeit vorgestellten Ergebnisse liefern nicht nur neue Erkenntnisse über die Rolle von PFA-DSPs und NUDTs bei der Regulierung von PP-InsP-Signalwegen in Pflanzen, sondern auch das genetische Werkzeug, um allgemeinere Rollen von PP-InsPs in der Pflanzenphysiologie und Pflanzenentwicklung zu erforschen
Establishment and specification analysis of iPS cell derived liver sinusoidal endothelial-like cells from Hemophilia A patients for the detection of endogenous FVIII
No full textThe current state of the art in this field of Hemophilia A basic research comprises cellular models that either overexpress FVIII levels (Fantacini, 2016; Liu et al., 2014) or are incubated with FVIII products (Kannicht, 2020; Peyron, 2018; Peyvandi et al., 2018) which is unable to confirm or correlate to the endogenous FVIII expression. To study the mechanism and progression of Hemophilia A in its most native form, Liver sinusoidal endothelial cells (LSEC) make a good model since they are known to be non-hematopoietic antigen presenting cells (nhAPC) which could express MHC I and II (Carman et al., 2015) i.e. presentation of both endogenous and exogenous antigens. Understanding the endogenous FVIII expression is of utmost interest in disease modelling for Hemophilia A since the mutation specific variation in patients could provide an insight into the intracellular fate of the molecule. LSEC-like cells were differentiated from pluripotent stem cells in vitro of healthy donor and hemophila A patients, including those with nonsense mutations, R1960X and R2228X and an intron 22 inversion mutation. We confirmed the differentiation to a mesoderm and angioblasts; and the presence of LSEC-specific markers such as F8, Lyve1 and STAB2. Detection of endogenous factor VIII protein in its natural state is crucial to differentiate between the healthy and mutated version as well as understand its effect in hemophilia A disease progression. This study for the first time identifies distinct endogenous peptides, adding complexity to the molecular landscape in patients. Proteomic analysis revealed an upregulation in the EIF2 signalling pathway in patients that led to the identification of 43 significant proteins associated with ER functions suggesting an accumulated protein response in patient with nonsense mutation in the C2 domain. 4 fold higher RNSP1 levels in R2228X was associated EJC-mediated mRNA decay related absence in detection of FVIII peptides. This study further explored potential modulators associated with F8 gene and protein expression in hemophilia A patients. Inhibition of NMD may have an impact on the levels of its substrates and is expected to result in an accumulation of the PTC-carrying transcripts in the cell thereby enabling a better read-through responsiveness. Hence, we hypothesized that inhibiting NMD and allowing for a subsequent read-through could augment F8 expression in patients. We identified NMD inhibitor 14 (NMDI-14) as a small molecule inhibitor of the NMD pathway (Martin et al., 2014) in combination with Geneticin and PTC-124 to synergistically enhance the expression of F8 in LSEC-LCs from two HA patients with nonsense mutation R1960X, R2228X and a patient with intron 22 inversion mutation. We employed readthrough agents and/or nonsense mediated mRNA inhibitors to analyse the influence of downstream targets of the unfolded protein response and its impact on the F8 expression levels. We confirmed that the modulation of UPR-NMD feedback loop via synergistic effects of read through agents and nonsense mediated mRNA decay inhibitors can increase F8 transcript levels with an albeit variable response
Slavery and strong asymmetrical dependencies : escalating social controls and the dynamics of exclusion and inclusion
Get PDFThe paper looks for a general analytical perspective that allows to understand and compare slavery and its related institutions (serfdom, debt slavery, forced labour) in premodern and modern societies. The paper starts with a theory of asymmetrical control that identifies six cumulative dimensions of social control and thereby allows to understand the totalizing character of social relations based on a multiplicity of unilateral controls. In opposition to control arise balancing operations. Any specific institution of asymmetrical dependency can then be described by an equilibrium of control and balancing operations.
In the next step, the paper explores the historical space that creates social role categories such as stranger, guest, slave, member, kin – and looks at all of them as special cases and combinations of inclusion and exclusion. This points to the relevance of the theory of inclusion and exclusion, which makes visible that all strong asymmetrical dependencies are based on combinations of constitutive exclusions (from fundamental societal forms of belongingness) with imposed inclusions that are characterized by their control intensity and totality. These are paradoxical structures and they mirror the other paradox that the ultradependents of premodern societies are as much dishonoured as they are valued because of their extensive contributions to societal functioning. Their totalizing inclusion takes place in households and organizational contexts and therefore they do not build a stratum of their own in society.
Finally, the paper looks at global modernity and its non-hierarchical character. It tries to find out why strong asymmetrical dependencies persist in an egalitarian society. The reason seems to be that asymmetrical dependencies change from being normal institutions in hierarchical societies to being oppositional and deviant institutions in horizontal societies that because of their looseness and complexity are not able to suppress the multiple possibilities of opposition, deviance and alienation
Effects of mucilage and extracellular polymeric substances on soil gas diffusion
Get PDFGas exchange in the soil is determined by the size and connectivity of air-filled pores. Thereby, water saturation, soil compaction, and organic matter fraction are the main barriers for gas movement in soil. For optimal growth, life in soil requires a balance between water and oxygen content. However, fluctuations in moisture conditions challenge this balance. By exuding mucilage and extracellular polymeric substances (EPS), plants and bacteria can alter the physical properties of the soil in their vicinity. It is considered that by releasing these hydrogel-like substances, plants and bacteria increase their resilience against drought stress. However, we still lack knowledge on how these substances affect the soil gas diffusion. An improved understanding of the complex interactions between plants, bacteria, and soil, which have great implications for root water and nutrient uptake, and biogeochemical turnover and respiration processes in the soil, could provide valuable insights for optimizing crop performance and improving water and nutrient use efficiency.
The focus of this thesis was to investigate the effect of mucilage and EPS on soil gas diffusion, aiming to improve understanding of gas diffusion processes in soil by explaining the geometric alterations of the pore space induced by mucilage and EPS. Laboratory measurements were conducted to determine soil gas diffusion coefficient (Dp) supported by advanced imaging techniques such as X-ray Computed Tomography (X-ray CT) and Environmental Scanning Electron Microscopy (ESEM) to quantify and visualize mucilage-induced alterations of the pore space and simulations to characterize the geometric distribution of mucilage within soil during the drying process.
Initially, a conceptual model was developed to describe alterations in the pore space geometry induced by mucilage under dry soil conditions. Laboratory measurements indicated that mucilage decreases the gas diffusion coefficient under dry conditions without affecting bulk density or porosity. Depending on its content in the soil, mucilage forms various structures within the pore space. The evolution of these structures was explained via pore scale modeling based on identifying the elastic strength of rhizodeposition during soil drying. Next, the influence of mucilage on soil gas diffusion at different water contents during a drying-rewetting cycle was investigated. In soils without mucilage, a hysteresis in the gas diffusion coefficient was observed. The extent of the hysteresis depended on particle size. Furthermore, X-ray CT imaging indicated a hysteresis in gas-phase connectivity for samples without mucilage. The effect diminished with increasing mucilage content. In addition, ESEM imaging of sandy soil samples mixed with mucilage confirmed the formation of liquid structures in the pore space. However, these structures showed slightly different shapes in comparison to those in glass bead samples, likely due to the higher surface roughness of soil particles. Finally, diffusion measurements conducted on soil samples containing EPS demonstrated a similar effect of EPS and mucilage on gas diffusivity.
In conclusion, the findings of this thesis suggest that plants and bacteria balance oxygen availability and water content by releasing polymeric substances, even under fluctuating moisture conditions. Through these exudates, they employ similar strategies to engineer their surroundings, modifying the physical properties of their local environment in ways that enhance their survival and resilience
Analyse von Sialinsäuren in der humanen Retina : Ein Pilotversuch mit Etablierung eines Verfahrens zur Detektion von Polysialinsäuren
Get PDFPolysialinsäuren sind polymere Kohlenhydratverbindungen, die im zentralen Nervensystem nicht nur an Entwicklungs- und Regenerationsprozessen beteiligt sind, sondern auch eine Rolle in der Regulation zellulärer und humoraler Immunreaktionen spielen. Entzündungsprozesse haben das Potential Gewebe zu schädigen, und ihre Beteiligung konnte bei einer Vielzahl von neurodegenerativen Erkrankungen gezeigt werden. Ziel dieser Arbeit war deshalb, im Rahmen eines Pilotversuchs mittels zum Teil neuer Verfahren Erkenntnisse zum Vorkommen von Sialinsäuren in der Retina humaner Gewebespender (n = 5, 3m/2w) zu gewinnen und mögliche assoziierte Faktoren zu beschreiben.
Bei der Gesamtsialinsäurekonzentration ergaben sich signifikante Unterschiede zwischen den Retinaproben verschiedener Spender. Die Polysialinsäurekonzentration zeigte keinen signifikanten Unterschied zwischen den Proben verschiedener Spender. Immunhistochemisch waren Polysialinsäuren vor allem im Bereich der inneren Retinaschichten nachweisbar, während sich für Trisialinsäuren eine homogenere Färbung in der gesamten Retina zeigte. Bezüglich des Einflusses von Alter und Geschlecht zeigte sich in den immunhistochemischen Experimenten eine signifikant höhere Anfärbbarkeit von Oligo- und Polysialinsäuren in höherem Alter und bei weiblichen Spendern.
Es konnte eine altersabhängige Zunahme der Anzahl und CD68-Färbungsintensität von Mikroglia, sowie der Gentranskription des inflamatorischen Zytokins IL1β in der humanen Retina nachgewiesen werden. Beim Vergleich der Geschlechter zeigte sich bei weiblichen Spendern eine höhere Anzahl von Iba1-positiven Mikrogliazellen, jedoch wurde nur der mikrogliale Homöostase-assoziierte Marker TMEM119 auch höher transkribiert. Zwischen Anzahl und Aktivität von Mikroglia, sowie der Gentranskription inflammatorischer Zytokine und den untersuchten Sialinsäuren ließ sich eine positive Korrelation der Transkription von TMEM119 mit der Gesamtsialinsäuremenge nachweisen. Darüber hinaus ergaben die Sialinsäurefärbungen lediglich Hinweise auf schichtspezifische Veränderungen, ohne dass ein konklusives Gesamtbild ableitbar war.
Die Gentranskription der untersuchten Sialyltransferasen zeigte klare Hinweise auf eine Abhängigkeit vom Alter oder der Transkription von Mikroglia- und Entzündungsmarkern. Das Geschlecht, die Gesamtsialinsäurekonzentration und die Polysialinsäurekonzentration hatten hier keinen signifikanten Einfluss.
Perspektivisch sollten weitere neue zum Beispiel auf Massenspektrometrie basierende Verfahren zur genaueren Analyse der Komplexität unterschiedlicher Mono-, Oligo und Polysialinsäuren etabliert und an einer größeren Stichprobe untersucht werden.
Durch genauere Kenntnisse von Eigenschaften und Vorkommen von Sialinsäuren in humanen Retinae eröffnen sich Perspektiven für die klinische Anwendung als Therapie entzündlicher und degenerativer Erkrankungen der Netzhaut
Validierung prädiktiver Scores für schwere Verläufe von COVID-19 : eine retrospektive Single-Center-Studie in der Augusta-Klinik Bochum 2020-2023
Get PDFEinführung
Im Rahmen der COVID-19-Pandemie sind verschiedene Scores zur Prognoseabschätzung verwendet worden. Diese Arbeit validiert die Vorhersagekraft von CRB-65, CURB-65, PSI, qSOFA und 4CMS bei COVID-19-Patienten, vergleicht diese untereinander und im Verlauf der Pandemie.
Methoden
Es handelt sich um eine retrospektive Studie an der Augusta-Kranken-Anstalt in Bochum. Eingeschlossen wurden sämtliche Patienten, die aufgrund von COVID-19 hospitalisiert worden sind. Insbesondere wurde eine Phase vor Omikron (03/2020-12/2021) und mit Omikron (01/2022-03/2023).
Ergebnisse
Bei insgesamt n=622 Patienten lag bei n=348 (56,2%) eine Pneumonie vor mit einer Gesamtmortalität von 16,2% (n=101 Patienten) mit signifikantem Unterschied zwischen den Phasen (71 (23,1%) in der ersten vs 30 (9,2%) in der zweiten Phase, p
Schlussfolgerung
Alle Scores konnten sicher ein Patientenklientel mit niedrigem Mortalitätsrisiko bei hospitalisierten Patienten mit COVID-19 identifizieren, wobei der 4CMS der beste Prädiktor war, der PSI bei Patienten mit Pneumonie war nicht unterlegen. Die unterschiedlichen Phasen der Pandemie hatten keinen Einfluss auf die Vorhersagekraft der untersuchten Scores