@phdthesis{Janzen2022,
  author    = {Janzen, Dieter},
  title     = {Functional analysis of ion channels and neuronal networks in 2D and 3D \(in\) \(vitro\) cell culture models},
  doi       = {10.25972/OPUS-25170},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-251700},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {In the central nervous system, excitatory and inhibitory signal transduction processes are mediated by presynaptic release of neurotransmitters, which bind to postsynaptic receptors. Glycine receptors (GlyRs) and GABAA receptors (GABAARs) are ligand-gated ion channels that enable synaptic inhibition. One part of the present thesis elucidated the role of the GlyRα1 β8 β9 loop in receptor expression, localization, and function by means of amino acid substitutions at residue Q177. This residue is underlying a startle disease phenotype in the spontaneous mouse model shaky and affected homozygous animals are dying 4-6 weeks after birth. The residue is located in the β8 β9 loop and thus part of the signal transduction unit essential for proper ion channel function. Moreover, residue Q177 is involved in a hydrogen network important for ligand binding. We observed no difference in ion channel trafficking to the cellular membrane for GlyRα1Q177 variants. However, electrophysiological measurements demonstrated reduced glycine, taurine, and β alanine potency in comparison to the wildtype protein. Modeling revealed that some GlyRα1Q177 variants disrupt the hydrogen network around residue Q177. The largest alterations were observed for the Q177R variant, which displayed similar effects as the Q177K mutation present in shaky mice. Exchange with structurally related amino acids to the original glutamine preserved the hydrogen bond network. Our results underlined the importance of the GlyR β8 β9 loop for proper ion channel gating. GlyRs as well as GABAARs can be modulated by numerous allosteric substances. Recently, we focused on monoterpenes from plant extracts and showed positive allosteric modulation of GABAARs. Here, we focused on the effect of 11 sesquiterpenes and sesquiterpenoids (SQTs) on GABAARs. SQTs are compounds naturally occurring in plants. We tested SQTs of the volatile fractions of hop and chamomile, including their secondary metabolites generated during digestion. Using the patch-clamp technique on transfected cells and neurons, we were able to observe significant GABAAR modulation by some of the compounds analyzed. Furthermore, a possible binding mechanism of SQTs to the neurosteroid binding site of the GABAAR was revealed by modeling and docking studies. We successfully demonstrated GABAAR modulation by SQTs and their secondary metabolites. The second part of the thesis investigated three-dimensional (3D) in vitro cell culture models which are becoming more and more important in different part of natural sciences. The third dimension allows developing of complex models closer to the natural environment of cells, but also requires materials with mechanical and biological properties comparable to the native tissue of the encapsulated cells. This is especially challenging for 3D in vitro cultures of primary neurons and astrocytes as the brain is one of the softest tissues found in the body. Ultra-soft matrices that mimic the neuronal in vivo environment are difficult to handle. We have overcome these challenges using fiber scaffolds created by melt electrowriting to reinforce ultra-soft matrigel. Hence, the scaffolds enabled proper handling of the whole composites and thus structural and functional characterizations requiring movement of the composites to different experimental setups. Using these scaffold-matrigel composites, we successfully established methods necessary for the characterization of neuronal network formation. Before starting with neurons, a mouse fibroblast cell line was seeded in scaffold-matrigel composites and transfected with the GlyR. 3D cultured cells displayed high viability, could be immunocytochemically stained, and electrophysiologically analyzed. In a follow-up study, primary mouse cortical neurons in fiber-reinforced matrigel were grown for up to 21 days in vitro. Neurons displayed high viability, and quantification of neurite lengths and synapse density revealed a fully formed neuronal network already after 7 days in 3D culture. Calcium imaging and patch clamp experiments demonstrated spontaneous network activity, functional voltage-gated sodium channels as well as action potential firing. By combining ultra-soft hydrogels with fiber scaffolds, we successfully created a cell culture model suitable for future work in the context of cell-cell interactions between primary cells of the brain and tumor cells, which will help to elucidate the molecular pathology of aggressive brain tumors and possibly other disease mechanisms.},
  subject      = {Zellkultur},
  language  = {en}
}
@phdthesis{Dombrovski2022,
  author    = {Dombrovski, Veaceslav},
  title     = {Software Framework to Support Operations of Nanosatellite Formations},
  isbn      = {978-3-945459-38-6},
  doi       = {10.25972/OPUS-24931},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-249314},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {Since the first CubeSat launch in 2003, the hardware and software complexity of the nanosatellites was continuosly increasing. To keep up with the continuously increasing mission complexity and to retain the primary advantages of a CubeSat mission, a new approach for the overall space and ground software architecture and protocol configuration is elaborated in this work. The aim of this thesis is to propose a uniform software and protocol architecture as a basis for software development, test, simulation and operation of multiple pico-/nanosatellites based on ultra-low power components. In contrast to single-CubeSat missions, current and upcoming nanosatellite formation missions require faster and more straightforward development, pre-flight testing and calibration procedures as well as simultaneous operation of multiple satellites. A dynamic and decentral Compass mission network was established in multiple active CubeSat missions, consisting of uniformly accessible nodes. Compass middleware was elaborated to unify the communication and functional interfaces between all involved mission-related software and hardware components. All systems can access each other via dynamic routes to perform service-based M2M communication. With the proposed model-based communication approach, all states, abilities and functionalities of a system are accessed in a uniform way. The Tiny scripting language was designed to allow dynamic code execution on ultra-low power components as a basis for constraint-based in-orbit scheduler and experiment execution. The implemented Compass Operations front-end enables far-reaching monitoring and control capabilities of all ground and space systems. Its integrated constraint-based operations task scheduler allows the recording of complex satellite operations, which are conducted automatically during the overpasses. The outcome of this thesis became an enabling technology for UWE-3, UWE-4 and NetSat CubeSat missions.},
  subject      = {Kleinsatellit},
  language  = {en}
}
@phdthesis{Kreiser2022,
  author    = {Kreiser, Laura},
  title     = {Hartgewebe-chirurgische Therapie der obstruktiven Schlafapnoe des Erwachsenen - eine Literaturanalyse mit Evidenztabellen},
  doi       = {10.25972/OPUS-25208},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252084},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {Ein nicht erholsamer Schlaf kann vielf{\"a}ltige Konsequenzen sowohl gesundheitlicher als auch {\"o}konomischer Art aufweisen. Das durch den demografischen Wandel in seiner Bedeutung zunehmende obstruktive Schlafapnoesyndrom kann mit seinen gesundheitlichen Risiken weitreichende Auswir- kungen auf das Individuum besitzen sowie signifikante gesellschaftliche Risiken und Kosten bergen. Wichtig erscheint demnach, sich der Bedeutung dieser Erkrankung bewusst zu werden und die Notwendigkeit der Therapie zu erkennen. Ziel dieser Arbeit bestand darin, die knochenchirurgischen Therapiemethoden als kausalen Therapieansatz der OSA aus der Prim{\"a}rliteratur darzustellen, deren Wirksamkeit insbesondere im Vergleich zur CPAP-Therapie zu eruieren und darauf aufbauend gegebenenfalls notwendige Diagnostik und pr{\"a}disponierende Faktoren f{\"u}r einen chirurgischen Erfolg herauszuarbeiten. Dies geschah im Rahmen der Leitlinienerstellung der aktuellen S3-Leitlinie Nicht erholsamer Schlaf/Schlafst{\"o}rungen, Kapitel „Schlafbezogene Atmungsst{\"o}rungen bei Erwachsenen". Hierbei konnten nach definierten Ein- und Ausschlusskriterien in der Datenbank PubMed und den Literaturverzeichnissen relevanter Studien 50 Studien mit insgesamt 1461 Patienten und zumeist niedrigem Evidenzgrad identifiziert werden, die eine Behandlung der OSA mittels Maxillomandibul{\"a}rem Advancement MMA, Genioglossus Advancement GA oder der Distraktionsosteogenese DO analysierten. Nach neustem Kenntnisstand erscheinen der Apopnoe-Hypopnoe-Index AHI sowie Respiratory-Disturbance-Index RDI als alleiniges Erfolgskriterium obsolet, eine ganzheitliche Betrachtung des Patienten ist unabdingbar. Notwendig ist eine umfassende Diagnostik, welche {\"u}ber eine Polysomnografie hinausgeht. Das MMA zeigt sich im Rahmen dieser Literaturanalyse als erfolgreichste knochenchirurgische Therapiemethode. Auch wenn ein niedriger BMI sowie AHI und eine gering ausgepr{\"a}gte Tagessymptomatik positive pr{\"a}diktive Faktoren f{\"u}r einen Therapieerfolg darstellen, erscheint die MMA auch bei sorgf{\"a}ltig ausgew{\"a}hlten Patienten mit hohem BMI und schwerwiegender OSA erfolgsversprechend, deren Wirksamkeit mit der den Goldstandard setzenden CPAP Therapie in vielf{\"a}ltigen Aspekten ohne signifikanten Unterschied verglichen werden kann. Hierzu z{\"a}hlen unter anderem polysomnografische Werte sowie die Schlafarchitektur und subjektive Ver{\"a}nderungen wie beispielsweise die Tagesm{\"u}digkeit, quantifiziert anhand der Epworth Sleepiness Scale und die subjektive Zufriedenheit. Daneben erfolgte eine detaillierte Auswertung kephalometrischer Daten, der postoperativen Zufriedenheit, des Schnarchens sowie Komplikationen der Behandlungen. Schwierig erscheint allerdings auf der Basis des heutigen Wissenstandes pr{\"a}zise Grenzwerte festzulegen, anhand derer der Einsatz einer chirurgischen Therapie empfohlen werden kann. Die Tatsache der fehlenden Notwendigkeit einer kontinuierlichen Therapie ist ein wichtiger Vorteil dieser kausalen Therapiemethoden. Dennoch ben{\"o}tigt die Schlafmedizin als Querschnittsfach eine Bewertung der therapeutischen Methoden aus unterschiedlichen Sichtweisen. Die knochenchirurgischen Verfahren jedoch lediglich als Zweitlinientherapie anzusehen erscheint nach aktuellem Kenntnisstand obsolet. Die geringe Anzahl an qualitativ hochwertigen Studien erschweren eine differenzierte Aussage. Weitere Studien hoher Evidenz werden zuk{\"u}nftig notwendig sein, um die knochenchirurgischen Therapiemethoden als festen Bestandteil einer f{\"a}cher{\"u}bergreifenden Therapie der OSA zu etablieren.},
  subject      = {Schlafapnoe},
  language  = {de}
}
@phdthesis{Moeller2022,
  author    = {M{\"o}ller, Jan},
  title     = {Mechanisms and consequences of µ-opioid receptor dimerization},
  doi       = {10.25972/OPUS-21986},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219862},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {One third of all market approved drugs target G protein coupled receptors (GPCRs), covering a highly diverse spectrum of indications reaching from acute anti-allergic treatment over bloodpressure regulation, Parkinson's disease, schizophrenia up to the treatment of severe pain. GPCRs are key signaling proteins that mostly function as monomers, but for several receptors constitutive dimer formation has been described and in some cases is essential for function. I have investigated this problem using the μ-opioid receptor (µOR) as a model system - based both on its pharmacological importance and on specific biochemical data suggesting that it may present a particularly intriguing case of mono- vs- dimerization. The µOR is the prime target for the treatment of severe pain. In its inactive conformation it crystallizes as homodimer when bound to the antagonist β- funaltrexamine (β-FNA), whereas the active, agonist-bound receptor crystallizes as a monomer. Using single-molecule microscopy combined with superresolution techniques on intact cells, I describe here a dynamic monomer-dimer equilibrium of µORs where dimer formation is driven by specific agonists. The agonist DAMGO, but not morphine, induces dimer formation in a process that correlates temporally and, in its agonist, and phosphorylation dependence with β-arrestin2 binding to the receptors. This dimerization is independent from but may precede µOR internalization. Furthermore, the results show that the μOR tends to stay, on the cell surface, within compartments defined by actin fibers and its mobility is modulated by receptor activation. These data suggest a new level of GPCR regulation that links receptor compartmentalization and dimer formation to specific agonists and their downstream signals.},
  subject      = {Opiatrezeptor},
  language  = {en}
}
@phdthesis{Sauter2022,
  author    = {Sauter, Amelie Judith},
  title     = {Herzratenvariabilit{\"a}t assoziiert mit der Zunahme von Suizidgedanken w{\"a}hrend der antidepressiven Therapie in Zusammenhang mit Traumatisierungen in der Kindheit},
  doi       = {10.25972/OPUS-25177},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-251779},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {Die Depression ist eine Erkrankung mit einer hohen Pr{\"a}valenz, die mit einem hohen Risiko f{\"u}r Suizidalit{\"a}t assoziiert ist. Traumata w{\"a}hrend der Kindheit gelten als einer der Hauptrisikofaktoren f{\"u}r Depressionen und Suizide. Die Assoziation einer Hyperaktivit{\"a}t des adrenergen Nervensystems und sowohl Depressionen als auch Suizidalit{\"a}t ist gut belegt. Mit einer antidepressiven Behandlung k{\"o}nnen suizidale Handlungen verhindert werden, jedoch gibt es eine Subgruppe, in der Suizidgedanken w{\"a}hrend der Therapie neu auftreten oder sich intensivieren (TWOSI). W{\"a}hrend bereits mehrere genetische Polymorphismen mit dem Auftreten von Suizidgedanken w{\"a}hrend der Therapie assoziiert werden konnten, gibt es noch keine geeignete Methode, diese Patienten vor Therapiebeginn zu identifizieren, um deren Krankheitsverlauf genauer zu {\"u}berwachen. Im Rahmen unserer Studie untersuchten wir station{\"a}re Patienten mit einer depressiven Episode mittels eines Langzeit-EKGs zur Messung der Herzfrequenz und verschiedener Herzratenvariabilit{\"a}tsparameter. Außerdem wurde bei Studieneinschluss durch einen Selbstbeurteilungsfragebogen verschiedene Formen einer Traumatisierung in der Kindheit erhoben und sowohl bei Aufnahme als auch in den darauffolgenden Wochen eine Fremdbeurteilungsskala zur Erfassung der Suizidgedanken durchgef{\"u}hrt. Dabei zeigte sich, dass elf der insgesamt 89 Patienten ein Neuauftreten oder eine Verschlechterung von Suizidgedanken zeigten. Hierbei stellte sich heraus, dass TWOSI� Patienten schwerwiegendere emotionale Missbrauchserfahrungen in ihrer Kindheit erlebt hatten. Zudem zeigten diese Patienten eine h{\"o}here adrenerge Aktivit{\"a}t, widergespiegelt durch eine erh{\"o}hte Herzfrequenz und eine niedrigere Herzratenvariabilit{\"a}t. Somit k{\"o}nnte sich mit zunehmender Schwere der Kindheitstraumatisierung ein {\"U}berwiegen der sympathischen Aktivit{\"a}t ergeben, und daraus wiederum ein h{\"o}heres Risiko f{\"u}r die Intensivierung der Suizidgedanken w{\"a}hrend der Behandlung. Messungen des autonomen Nervensystems k{\"o}nnten in Zukunft als Werkzeug dienen, Patienten mit einem erh{\"o}hten Risiko f{\"u}r TWOSI zu identifizieren.},
  subject      = {Herzfrequenzvariabilit{\"a}t},
  language  = {de}
}
@misc{Neitzke2022,
  type      = {Master Thesis},
  author    = {Neitzke, Hannes},
  title     = {"Maskulin und Feminin schuf er sie" - Die Personennamen in der Hebr{\"a}ischen Bibel im Lichte der Geschlechterdifferenz unter besonderer Ber{\"u}cksichtigung der Frauennamen},
  doi       = {10.25972/OPUS-25197},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-251972},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {Diese Magisterarbeit untersucht die althebr{\"a}ischen biblischen und epigraphischen Personennamen unter dem Gesichtspunkt des Geschlechts. Nach einem Durchgang durch die Forschungsgeschichte zu Frauennamen werden verschiedene Definitionsm{\"o}glichkeiten f{\"u}r den Begriff „Frauenname" diskutiert. Die Spezifika von Frauennamen werden mithilfe der Datenbank ,Althebr{\"a}ische Personennamen' (DAHPN) ermittelt und gedeutet, abschließend wird auf die Geburt und Namengebung von T{\"o}chtern in der Hebr{\"a}ischen Bibel eingegangen.},
  subject      = {Bibel. Altes Testament},
  language  = {de}
}
@book{Wagner2022,
  author    = {Wagner, Horst-G{\"u}nter},
  title     = {Golf von Neapel : Landschaftswandel durch Verst{\"a}dterung},
  publisher = {wbg Academic},
  address   = {Darmstadt},
  isbn      = {978-3-534-40635-7},
  doi       = {10.25972/OPUS-25052},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250525},
  publisher      = {Universit{\"a}t W{\"u}rzburg},
  pages     = {172},
  year      = {2022},
  abstract  = {In vielen mediterranen K{\"u}stenniederungen entstand seit 1950 infolge von Gebirgsentv{\"o}lkerung, Infrastrukturausbau, neuer Gewerbe sowie illegaler Baut{\"a}tigkeit ein fast l{\"u}ckenloses Verst{\"a}dterungsband. Am Golf von Neapel konnte dieser Landschaftswandel {\"u}ber eine lange Zeit beobachtet und durch zahlreiche Vergleichsfotos, Kartierungen, Luft- und Satellitenbilder und Interviews dokumentiert werden. Horst-G{\"u}nter Wagner zeigt in diesem Band die Ver{\"a}nderungen der K{\"u}stenebene und erl{\"a}utert ihre Ursachen.},
  subject      = {Golf von Neapel},
  language  = {de}
}
@phdthesis{Kasaragod2022,
  author    = {Kasaragod, Vikram Babu},
  title     = {Biochemical and Structural Basis for the Moonlighting Function of Gephyrin},
  doi       = {10.25972/OPUS-14307},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143077},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {Neurons are specialized cells dedicated to transmit the nerve impulses throughout the human body across specialized structures called synapses. At the synaptic terminals, a crosstalk between multiple macromolecules regulates the structure and function of the presynaptic nerve endings and the postsynaptic recipient sites. Gephyrin is the central organizer at inhibitory postsynaptic specializations and plays a crucial role in the organization of these structures by anchoring GABAA receptors (GABAAR) and glycine receptors (GlyR) to the postsynaptic membrane. This 93 kDa protein features an N-terminal G domain and a C-terminal E domain and the latter interacts directly with the intracellular loop between transmembrane helices 3 and 4 of certain subunits of the GlyRs and GABAARs. Biochemical and structural analyses have already provided valuable insights into the gephyrin-GlyR interaction. Interestingly, biochemical studies on the gephyrin-GABAAR interaction demonstrated that the GABAARs also depend on the same binding site as the GlyRs for the interaction with the gephyrin, but the molecular basis for this receptor specific interaction of gephyrin was still unknown. Co-crystal structures of GephE-GABAAR α3- derived peptides with supporting biochemical data presented in this study deciphered the receptor-specific interactions of gephyrin in atomic detail. In its moonlighting function, gephyrin also catalyzes the terminal step of the evolutionarily conserved molybdenum cofactor biosynthesis. Molybdenum, an essential transition element has to be complexed with a pterin-based cofactor resulting in the formation of the molybdenum cofactor (Moco). Moco is an essential component at the active site of all molybdenum-containing enzymes with the exception of nitrogenase. Mutations in enzymes involved in this pathway lead to a rare yet severe disease called Moco deficiency, which manifest itself in severe neurodevelopmental abnormalities and early childhood death. Moco biosynthesis follows a complex multistep pathway, where in the penultimate step, the N-terminal G domain of gephyrin activates the molybdopterin to form an adenylated molybdopterin intermediate. In the terminal step, this intermediate is then transferred to the C-terminal E domain of gephyrin, which catalyzes the metal insertion and deadenylation reaction to form active Moco. Previous biochemical and structural studies provided valuable insights into the penultimate step of the Moco biosynthesis but the terminal step remained elusive. Through the course of my dissertation, I crystallized the C-terminal E domain in the apo-form as well as in complex with ADP and AMP. These structures shed lightonto the deadenylation reaction and the formation of a ternary E-domain-ADP-Mo/W complex and thus provide structural insight into the metal insertion mechanism. Moreover, the structures also provided molecular insights into a mutation leading to Moco deficiency. Finally, ternary complexes of GephE, ADP and receptor-derived peptides provided first clues regarding the integration of gephyrin's dual functionality. In summary, during the course of the dissertation I was able to derive high resolution structural insights into the interactions between gephyrin and GABAARs, which explain the receptor-specific interaction of gephyrin and, furthermore, these studies can be extended in the future to understand GABAAR subunit-specific interactions of gephyrin. Finally, the understanding of Moco biosynthesis shed light on the molecular basis of the fatal Moco deficiency.},
  subject      = {Gephyrin},
  language  = {en}
}