@phdthesis{Stauf2024, author = {Stauf, Alisa}, title = {Scherfestigkeit an indirekten Kompositmaterialien und (Hybrid-) Keramiken vor und nach k{\"u}nstlicher Probenalterung - Ein Modellversuch zur Pr{\"u}fung eines intraoralen Reparaturprotokolls f{\"u}r indirekte Restaurationen}, doi = {10.25972/OPUS-35121}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351212}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Gegenstand dieser Arbeit war die Ermittlung der Scherfestigkeit von Kompositreparaturen auf unterschiedlichen Materialien und der Einfluss k{\"u}nstlicher Probenalterung auf den Haftverbund. Ziel war es hier{\"u}ber ein m{\"o}glichst einfaches Reparaturprotokoll f{\"u}r die klinische Anwendung zu pr{\"u}fen. In der Versuchsreihe wurden neun verschiedene Materialien (SR Nexco®, Gradia® Plus, Estenia™ C\&B®, Grandio Blocs®, Tetric® CAD, Brilliant Crios®, VITA Enamic®, VITABLOCS® Mark II, IPS e.max® CAD) nach einem festgelegten Konditionierungsprotokoll (Sandstrahlen vs. Flusss{\"a}ure{\"a}tzung und Monobond® Plus-Applikation, anschließend 3M™ Scotchbond™ Universal Plus Adh{\"a}siv) mit Kompositzylindern (3M™ Filtek™ Supreme XTE Universal Komposit) verklebt. In einem Scherversuch wurden die Haftwerte des Klebeverbundes ermittelt sowie die vorkommenden Versagensmuster untersucht. Werden alle 216 untersuchten Pr{\"u}fk{\"o}rper betrachtet, so ist hervorzuheben, dass alle Pr{\"u}fzylinder Scherkr{\"a}ften von {\"u}ber 21 MPa standhielten. Dennoch zeigten sich Unterschiede unter den Materialgruppen. In den Kontrollgruppen zeigte Estenia™ C\&B® mit ±34,5 MPa die h{\"o}chste Scherfestigkeit. Die modellierbaren Verblend-komposite erreichten mit ±29,6 MPa h{\"o}here Haftwerte als die CAD/CAM Komposite (±24,1 MPa) und die keramischen Werkstoffe (±26,7 MPa). Eine k{\"u}nstliche Probenalterung wirkte sich signifikant auf die Verbundfestigkeit aus. Im gesamten Probenkorpus war zwischen den Kontrollgruppen und den Gruppen mit Temperaturwechselbehandlung vor und nach Verklebung eine Reduktion der Scherkraft um ±10,6 MPa zu beobachten. Insgesamt hatte eine Temperaturwechselbehandlung einzig vor Verklebung der Proben zumeist eine geringere Auswirkung auf den Haftverbund verglichen mit Alterung vor und nach Verklebung. Mit einer Inzidenz von 74,5 \% war ein koh{\"a}siver Bruch im Ausgangsmaterial das dominierende Versagensmuster. Daraus l{\"a}sst sich ableiten, dass ein ad{\"a}quates Konditionierungsprotokoll gew{\"a}hlt wurde. Auch auf das Versagensmuster hatte die Temperaturwechselbehandlung einen signifikanten Einfluss, wobei koh{\"a}sive Br{\"u}che zunahmen. Die vorliegende Arbeit konnte zeigen, dass Reparaturen in vitro auch zwischen unterschiedlichen Materialklassen suffiziente Haftverbunde erzielen k{\"o}nnen, obgleich der Verbund bei Kompositen verl{\"a}sslicher erscheint. Die ermittelten hohen Scherkr{\"a}fte verdeutlichen, dass die M{\"o}glichkeit einer Reparatur am Patienten in jedem Fall in Erw{\"a}gung gezogen werden sollte, bevor eine Restauration vollst{\"a}ndig ausgetauscht wird.}, subject = {Scherfestigkeit}, language = {de} } @phdthesis{Aulbach2024, author = {Aulbach, Felix}, title = {Sekund{\"a}rdatenanalyse der Versorgungsrealit{\"a}t von BARMER Patient*innen mit Schmerzen nach operativem inguinalen- oder femoralen Hernienverschluss als Hinweis auf CPIP}, doi = {10.25972/OPUS-35074}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350744}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die vorliegende Arbeit befasst sich mit der Beschreibung des Status quo der Versorgungsrealit{\"a}t von BARMER Patient*innen, welche nach operativem inguinalen- oder femoralen Hernienverschluss an Schmerzen litten und geht in weiterer Folge dessen Hinweisen auf CPIP nach. Es fand die Sekund{\"a}rdatenanlyse von Routinedaten der BARMER Krankenkasse Anwendung. Die Stichprobe umfasste 11221 Patient*innen, von denen 77.7\% unter keinen Leistenschmerzen im pr{\"a}- oder postoperativen Zusammenhang mit dem Eingriff litten, bezeichnet als Gruppe „Pain 0". 4.2\% litten sowohl innerhalb von 365 Tagen vor- als auch nach dem Krankenhausaufenthalt an Schmerzen, was als chronisch zu bezeichnen war und unter Gruppe „Pain 2" gef{\"u}hrt wurde. 8.5\% der Patient*innen litten nur innerhalb von 365 Tagen nach Entlassung an Schmerzen, was nur im erweiterten Sinne auf CPIP hinwies, da der Ausschluss der ersten 90 Tage postoperativ nicht in der Definition der Gruppe enthalten war. Diese Patient*innen geh{\"o}rten der Gruppe „Pain 1" an. Die Gruppe „Pain 3" umfasste diejenigen 9.6\% der Patient*innen, welche innerhalb von 365 Tagen pr{\"a}operativ an Schmerzen litten. Obwohl keine postoperativen Leistenschmerzen f{\"u}r diese Patient*innen codiert worden sind, stellte sich eine bessere Versorgung als die der Gruppe „Pain 0" dar. Patient*innen der Gruppe „Pain 2" mit der l{\"a}ngsten Schmerzerfahrung wurden signifikant besser versorgt. Diese Gruppe, welche an chronischen, postoperativen, inguinalen Schmerzen litt, zeichnete sich durch eine signifikant j{\"u}ngere Patient*innenklientel aus. Der Anteil an Frauen war signifikant h{\"o}her. Begleitende psychiatrische Komorbidit{\"a}ten traten signifikant h{\"a}ufiger auf. Die Versorgung dieser Patient*innengruppe war signifikant besser, allerdings vor allem hinsichtlich der psychologischen und psychiatrischen Betreuung nicht ausreichend gut. Die Mehrzahl der Analysen war hochsignifikant, deren Effektst{\"a}rke fiel klein aus.}, subject = {Hernie}, language = {de} } @phdthesis{MeyerHeintze2024, author = {Meyer-Heintze, Simon}, title = {Holocene pedosedimentary sequences as archives for paleoenvironmental reconstructions}, doi = {10.25972/OPUS-34909}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349098}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Human-environment interaction has significantly altered the pedosphere since the Neolithic, if not since the early Holocene. In the course of clearance, agriculture, and (wood) pasture soils have been deeply modified or eroded. These types of land use practices but above all forms of sedentariness spread alongside floodplains and trajectories were oriented towards loess covered areas where fertile soils could develop. Besides this, also peripheral / marginal regions were settled due to population pressure or other factors. Evidence for landscape history and development can be found within archeological sites but also overbank deposits and anthropogenic slope deposits document vast transformation processes. The presented investigations took place within the natural region of the Windsheimer Bucht which is locat-ed in the district of Middle Franconia in northern Bavaria, Germany. In this area, Holocene soils predomi-nantly developed within mudstones of the Middle to Upper Triassic. The soil texture is extremely clay-rich which renders the soils problematic with regard to cultivation management. As a peculiarity, the gypsum underlying the mudstones is prone to karstification processes and resulting proceeding geomorphological processes shape the surface of the landscape. In the course of gypsum mining the karst forms are being exposed and archeological findings are being documented. The latter mainly date back to a span from the Neolithic to the Iron Age, but partly are of Younger Paleolithic origin. Especially subsidence sinkholes are capable of storing pedosediments of several meters in thickness. Despite the high clay content and connect-ed pedoturbation processes, the excavated sequences are stratigraphically and pedologically well-differentiated. The archives occur in the context of settlement structures such as pits and postholes; there-fore, they developed at the interface of natural developments and human impact on their surroundings. The main original research questions that were formulated within the general frame of a project funded by the Deutsche Forschungsgemeinschaft (DFG-projects Te295/15-1 and -2 and Fa390/9-1 and -2) focused on the attractors of the peripheral region for early settlers, the pedological conditions before land use, but also the impact of humans on soils and karst dynamics through time. In the course of the in hand study, the pedosedimentary archives have been approached with a multimethodological toolset which consisted of field analyses, soil morphological analyses from micro- to macro-scale, spectrophotometric (color), (laser) granulometric, and (iron-) pedochemical analyses. The numerical chronological frame was spanned by radiocarbon dating of different organic remains and bulk material if soil organic carbon was supposed-ly high. The result is a multi-dimensional data set that consists of analyses on different spatial scales but also on different levels of measurement. Thus, qualitative, semi-quantitative, and quantitative data consti-tute the basis for discussion. While the grain-size analyses underline the general sedimentological differen-tiation of the records and further affirm the high clay content within the pedosedimentary layers, iron-pedochemical analyses indicate an interplay between oxidation of iron and its chemical reduction. This is also manifested within the spectrophotometric record. Especially the versatile pedogenic characteristics that have been identified by field analyses are confirmed within the thin sections and, by considering all different analyses, the polygenic character of the pedosediments is emphasized. After stressing the general pedological specificities among the different investigated sites within the re-search area, for the collected data, the research further branches into the subjects of general notions on pedogenesis in clayey material and the classification of the respective pedosediments according to paleo-pedological concepts but also recent schemes. Concerning the latter, it becomes evident that established principles cannot be applied to the studied pedosediments without major adaptions. This underlines the specific characteristics of the material. The basis for further interpretations is the evaluation of the multi-level data set for the single records with regard to profile development and pedogenic processes. Hereby, the main drivers of pedogenesis could be identified, which are karst dynamics, land use, and subtle changes in parent material due to the admixture of slope deposits that contain allochthonous eolian material. The latter underlines the importance of Pleis-tocene preconditioning for understanding Holocene landscape dynamics. At the same time, a differentia-tion between the mentioned factors and Holocene climate development is difficult. The following compila-tion of record and localities within the given time frame unveils synchronous as well as asynchronous de-velopments; however, a clear connection between phases of Holocene climate and pedogenesis within the pedosediments cannot be established. Instead, it becomes evident that site specific factors or those that act on the scale of the micro-catchment of the investigated records are decisive. The aforementioned main topics of the project are also considered in the in hand study from a soil-geographic perspective: it is possible that before land use, there was an insular or thin cover by loess sedi-ments or at least upper layers (according to the concept of periglacial cover beds) which constituted the parent material for Holocene soil formation. The according soils, which were superior for agricultural purposes compared to those developed on the autochthonous mudstones, were eroded which exposed the clayey Upper to Middle Triassic beds. Erosion was aggravated due to the impermeable mudstones which enhanced overland flow and interflow within the overlying silty (loessic) material. This is further support-ed by the notions on erodibility of the clayey material that are derived from the comparison of conven-tional and laser granulometric analyses: probably, the clayey pedosediments are capable of forming micro-aggregates that can easily be eroded during heavy rainfall events despite the general consent that material with heavy texture should be rather resistant. The study presents a comprehensive view on clay-rich pedosediments and the complex effects of human-environment interaction on pedogenic as well as sedimentary processes through time that have not been investigated in such detail before. In this context, the multi-level soil morphological analyses and their necessity for a genetic interpretation with regard to the influence of natural versus anthropogenic factors need to be emphasized. Based on quantitative laboratory analytical data only, a respective differentiation would not be possible. This underlines the importance of the chosen soil-geographic multi-methodological approach for answering questions with regard to human-environment interaction but also geoarcheology in general.}, subject = {Geoarch{\"a}ologie}, language = {en} } @article{WiesslerTalucciPiroetal.2024, author = {Wiessler, Anna-Lena and Talucci, Ivan and Piro, Inken and Seefried, Sabine and H{\"o}rlin, Verena and Baykan, Bet{\"u}l B. and T{\"u}z{\"u}n, Erdem and Schaefer, Natascha and Maric, Hans M. and Sommer, Claudia and Villmann, Carmen}, title = {Glycine receptor β-targeting autoantibodies contribute to the pathology of autoimmune diseases}, series = {Neurology: Neuroimmunology \& Neuroinflammation}, volume = {11}, journal = {Neurology: Neuroimmunology \& Neuroinflammation}, number = {2}, doi = {10.1212/NXI.0000000000200187}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349958}, year = {2024}, abstract = {Background and Objectives Stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyRα subunit-binding autoantibodies with subsequent changes in function and surface numbers were reported. GlyR autoantibodies have also been described in patients with focal epilepsy. Autoimmune reactivity against the GlyRβ subunits has not yet been shown. Autoantibodies against GlyRα1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyRβ making it not unlikely that GlyRβ-specific autoantibody (aAb) exist and contribute to the disease pathology. Methods In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRβ. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRβ binding and define aAb binding to distinct protein regions. Preadsorption approaches of aAbs using living cells and the purified extracellular receptor domain were further used. Finally, functional consequences for inhibitory neurotransmission upon GlyRβ aAb binding were resolved by whole-cell patch-clamp recordings. Results Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRβ aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRβ colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRβ aAb from both patients to its target impair glycine efficacy. Discussion Our study establishes GlyRβ as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRβ impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRβ aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.}, language = {en} } @article{BreyerGruenerKleinetal.2024, author = {Breyer, Maximilian and Gr{\"u}ner, Julia and Klein, Alexandra and Finke, Laura and Klug, Katharina and Sauer, Markus and {\"U}{\c{c}}eyler, Nurcan}, title = {\(In\) \(vitro\) characterization of cells derived from a patient with the GLA variant c.376A>G (p.S126G) highlights a non-pathogenic role in Fabry disease}, series = {Molecular Genetics and Metabolism Reports}, volume = {38}, journal = {Molecular Genetics and Metabolism Reports}, issn = {22144269}, doi = {10.1016/j.ymgmr.2023.101029}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350295}, year = {2024}, abstract = {Highlights • The GLA variant S126G is not associated with Fabry symptoms in the presented case • S126G has no effect on α-GAL A activity or Gb3 levels in this patient • S126G sensory neurons show no electrophysiological abnormalities Abstract Fabry disease (FD) is a life-limiting disorder characterized by intracellular globotriaosylceramide (Gb3) accumulations. The underlying α-galactosidase A (α-GAL A) deficiency is caused by variants in the gene GLA. Variants of unknown significance (VUS) are frequently found in GLA and challenge clinical management. Here, we investigated a 49-year old man with cryptogenic lacunar cerebral stroke and the chance finding of the VUS S126G, who was sent to our center for diagnosis and initiation of a costly and life-long FD-specific treatment. We combined clinical examination with in vitro investigations of dermal fibroblasts (HDF), induced pluripotent stem cells (iPSC), and iPSC-derived sensory neurons. We analyzed α-GAL A activity in iPSC, Gb3 accumulation in all three cell types, and action potential firing in sensory neurons. Neurological examination and small nerve fiber assessment was normal except for reduced distal skin innervation. S126G iPSC showed normal α-GAL A activity compared to controls and no Gb3 deposits were found in all three cell types. Baseline electrophysiological characteristics of S126G neurons showed no difference compared to healthy controls as investigated by patch-clamp recordings. We pioneer multi-level cellular characterization of the VUS S126G using three cell types derived from a patient and provide further evidence for the benign nature of S126G in GLA, which is of great importance in the management of such cases in clinical practice.}, language = {en} } @article{JaenschEvdokimovEgenolfetal.2024, author = {J{\"a}nsch, Sarah and Evdokimov, Dimitar and Egenolf, Nadine and Meyer zu Altenschildesche, Caren and Kreß, Luisa and {\"U}{\c{c}}eyler, Nurcan}, title = {Distinguishing fibromyalgia syndrome from small fiber neuropathy: a clinical guide}, series = {Pain Reports}, volume = {9}, journal = {Pain Reports}, number = {1}, doi = {10.1097/PR9.0000000000001136}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350306}, year = {2024}, abstract = {Introduction: Fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) are distinct pain conditions that share commonalities and may be challenging as for differential diagnosis. Objective: To comprehensively investigate clinical characteristics of women with FMS and SFN to determine clinically applicable parameters for differentiation. Methods: We retrospectively analyzed medical records of 158 women with FMS and 53 with SFN focusing on pain-specific medical and family history, accompanying symptoms, additional diseases, and treatment. We investigated data obtained using standardized pain, depression, and anxiety questionnaires. We further analyzed test results and findings obtained in standardized small fiber tests. Results: FMS patients were on average ten years younger at symptom onset, described higher pain intensities requiring frequent change of pharmaceutics, and reported generalized pain compared to SFN. Pain in FMS was accompanied by irritable bowel or sleep disturbances, and in SFN by paresthesias, numbness, and impaired glucose metabolism (P < 0.01 each). Family history was informative for chronic pain and affective disorders in FMS (P < 0.001) and for neurological disorders in SFN patients (P < 0.001). Small fiber pathology in terms of skin denervation and/or thermal sensory threshold elevation was present in 110/158 (69.7 \%) FMS patients and 39/53 (73.6 \%) SFN patients. FMS patients mainly showed proximally reduced skin innervation and higher corneal nerve branch densities (p<0.001) whereas SFN patients were characterized by reduced cold detection and prolonged electrical A-delta conduction latencies (P < 0.05). Conclusions: Our data show that FMS and SFN differ substantially. Detailed pain, drug and family history, investigating blood glucose metabolism, and applying differential small fiber tests may help to improve diagnostic differentiation and targeted therapy.}, language = {en} } @phdthesis{Pitsch2024, author = {Pitsch, Maximilian Jonathan}, title = {Zyklisches Adenosinmonophosphat (cAMP) als {\"A}quivalent akkumulierter neuronaler Evidenz}, doi = {10.25972/OPUS-35129}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351292}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die vier Crz-Neurone des ventralen Nervensystems von Drosophila melanogaster sammeln Evidenz, wann im Rahmen eines Paarungsakts zirka 6 Minuten vergangen sind. Diese Entscheidung ist f{\"u}r die m{\"a}nnliche Fliege von Bedeutung, da das M{\"a}nnchen vor Ablauf dieser ~6 Minuten, welche den Zeitpunkt der Ejakulation darstellen, eher das eigene Leben opfern w{\"u}rde, als dass es die Paarung beenden w{\"u}rde. Nach Ablauf der ~6 Minuten f{\"a}llt die Motivation des M{\"a}nnchens dagegen dramatisch ab. Im Rahmen der vorliegenden Arbeit wurde zun{\"a}chst mittels optogenetischer neuronaler Inhibitionsprotokolle sowie Verhaltensanalysen das Ph{\"a}nomen der Evidenz-akkumulation in den Crz-Neuronen genauer charakterisiert. Dabei zeigte sich, dass die akkumulierte Evidenz auch w{\"a}hrend einer elektrischen Inhibition der Crz-Neurone persistierte. Dieses Ergebnis warf die Hypothese auf, dass das {\"A}quivalent der akkumulierten Evidenz in den Crz-Neuronen biochemischer Natur sein k{\"o}nnte. Es wurde daraufhin ein Hochdurchsatzscreening-Verfahren entwickelt, mittels dessen 1388 genetische Manipulationen der Crz-Neurone durchgef{\"u}hrt und auf eine {\"A}nderung der Evidenzakkumulation getestet wurden. Nur ~30 genetische Manipulationen zeigten eine ver{\"a}nderte Evidenzakkumulation, wobei die meisten dieser Manipulationen den cAMP-Signalweg betrafen. Mittels der optogenetischen Photoadenylatzyklase bPAC, einer Reihe weiterer genetischer Manipulationen des cAMP-Signalwegs sowie der ex vivo Kalzium-Bildgebung und Fluoreszenzlebensdauer-Mikroskopie konnte best{\"a}tigt werden, dass cAMP das {\"A}quivalent der in den Crz-Neuronen spannungsabh{\"a}ngig akkumulierten Evidenz darstellt, wobei die Kombination dieser Methoden nahelegte, dass der Schwellenwert der Evidenzakkumulation durch die cAMP-Bindungsaffinit{\"a}t der regulatorischen PKA-Untereinheiten festgelegt sein k{\"o}nnte. Mittels genetischer Mosaikexperimente sowie bildgebenden Verfahren konnte dar{\"u}ber hinaus gezeigt werden, dass innerhalb des Crz-Netzwerks eine positive R{\"u}ckkopplungsschleife aus rekurrenter Aktivit{\"a}t sowie der cAMP-Akkumulation besteht, welche, sobald die cAMP-Spiegel den Schwellenwert erreichen, zu einem netzwerkweit synchronisierten massiven Kalziumeinstrom f{\"u}hrt, was die Abgabe des Crz-Signals an nachgeschaltete Netzwerke triggert. Dieses Ph{\"a}nomen k{\"o}nnte ein Analogon des Aktionspotenzials auf Netzwerkebene sowie auf Intervallzeitskalen darstellen und wurde als „Eruption" bezeichnet. Genetische, optogenetische sowie Bildgebungsexperimente konnten zeigen, dass die CaMKII derartige Eruptionen durch Niedrighalten der cAMP-Spiegel unterdr{\"u}ckt, was den Zeitmessmechanismus des ersten beschriebenen Intervallzeitmessers CaMKII offenlegt.}, subject = {Evidenz}, language = {de} } @phdthesis{Krumma2024, author = {Krumma, Judith Josefine Birgitta}, title = {Morphologie und bildgebende Ver{\"a}nderung in der Magnetresonanztomographie bei p{\"a}diatrischen Patienten/innen mit Rezidiven eines kranialen Ependymoms - Kohorte der Deutschen HIT- REZ Studie}, doi = {10.25972/OPUS-35149}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351498}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In dieser Arbeit wurde einerseits retrospektiv untersucht, wie sich supratentorielle und infratentorielle Ependymome bildmorphologisch unterscheiden, ob Lokalrezidive eines Ependymoms dessen Bildeigenschaften teilen und welche Art von Rezidiven im Verlauf auftreten k{\"o}nnen. Die von uns beschriebenen Bildcharakteristika der Ependymome decken sich zum gr{\"o}ßten Teil mit bereits ver{\"o}ffentlichten Studien. Supratentorielle Ependymome unterscheiden sich signifikant in ihrer Bildmorphologie im Vergleich zu Ependymome der hintern Sch{\"a}delgrube. Alle p{\"a}diatrischen Ependymompatienten/innen in unserem Kollektiv erkrankten an mindestens einem Rezidiv. Am h{\"a}ufigsten traten Lokalrezidive gefolgt von Meningeosen im ersten Rezidiv auf. Seltener fanden sich transiente postradiogene L{\"a}sionen, Diffuse intrinsische Ponsgliome und extraneurale Metastasen. Der bildmorphologische Vergleich, Primarius versus Lokalrezidiv ergab {\"u}berwiegend {\"a}hnliche bildgebende Eigenschaften vor allem im Signalverhalten, Tumorbegrenzung und KM-Aufnahme sowie KM anreichernder Tumoranteil. Die kranielle Meningeose pr{\"a}sentierte sich zum ersten Rezidivzeitpunkt different zum Prim{\"a}rtumor. Die extraneuralen Metastasen hatten bildcharakteristisch {\"A}hnlichkeiten zum Prim{\"a}rtumor. Bei der Bewertung neuer intraparenchymaler L{\"a}sionen sollte immer der zeitliche Zusammenhang zur letzten Therapie und damit m{\"o}gliche vor{\"u}bergehende postradiologischen Ver{\"a}nderungen ber{\"u}cksichtigt werden. Letztlich ist das p{\"a}diatrische Ependymom und Ependymomrezidiv ein komplexes und immer noch unvollst{\"a}ndiges erfasstes Krankheitsbild. Durch umfangreichere Studien und die Zusammenf{\"u}hrung dieser Ergebnisse k{\"o}nnte schlussendlich die Komplexit{\"a}t des Krankheitsbildes und somit die Therapieoptionen verbessert werden. Durch unsere Studie gelang einerseits die Beschreibung und der Vergleich des prim{\"a}ren Ependymoms bez{\"u}glich supra- und infratentorieller Lokalisation und andererseits gelang eine neuroradiologische Beschreibung von Ependymomrezidiven im Vergleich zum prim{\"a}ren Ependymom, wodurch in Zukunft die Nachsorge der Ependymomrezidive und die Therapieoptionen optimiert werden k{\"o}nnten.}, subject = {Ependymom}, language = {de} } @phdthesis{WidmaiergebWirth2024, author = {Widmaier [geb. Wirth], Lisa Marie}, title = {K{\"u}nstliche Intelligenz zur vollst{\"a}ndig automatisierten FRS-Auswertung: Bewertung der Auswertequalit{\"a}t verschiedener kommerzieller Anbieter im Vergleich zu einem menschlichen Goldstandard}, doi = {10.25972/OPUS-35180}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351803}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Ziel der vorliegenden Studie war es, verschiedene kommerzielle Anbieter f{\"u}r KI-gest{\"u}tzte FRS-Analysen hinsichtlich ihrer Genauigkeit mit einem menschlichen Goldstandard zu vergleichen. Auf 50 FRS wurden durch zw{\"o}lf erfahrene Untersucher 15 Landmarken identifiziert, auf deren Basis neun relevante Parameter vermessen wurden. Der Medianwert dieser zw{\"o}lf Auswertungen wurde f{\"u}r jeden Parameter auf jedem FRS als Goldstandard definiert und als Referenz f{\"u}r die Vergleiche mit vier verschiedenen kommerziellen KI-Anbietern (DentaliQ.ortho, WebCeph, AudaxCeph, CephX) festgelegt. Die statistische Auswertung erfolgte mittels ANOVA mit Messwiederholung, paarweiser Vergleiche mittels Post-hoc-Test und Bland-Altman-Plots. DentaliQ.ortho zeigte f{\"u}r alle neun untersuchten Parameter keinen statistisch signifikanten Unterschied zum menschlichen Goldstandard und es konnte insgesamt von einer hohen Genauigkeit der Auswertungen ausgegangen werden. Auch f{\"u}r WebCeph war kein statistisch signifikanter Unterschied zum menschlichen Goldstandard zu verzeichnen. Allerdings war die Pr{\"a}zision im Vergleich zu den anderen Anbietern f{\"u}r alle Parameter am geringsten und der proportionale Fehler bei nahezu allen Parametern am h{\"o}chsten. AudaxCeph wies f{\"u}r sieben Parameter statistisch signifikante Unterschiede zum menschlichen Goldstandard auf. F{\"u}r CephX wurden f{\"u}r f{\"u}nf Parameter statistisch signifikante Unterschiede zum menschlichen Goldstandard ermittelt. Insbesondere f{\"u}r die dentale Analyse war f{\"u}r alle untersuchten kommerziellen KI-Anbieter eine vergleichsweise niedrigere Genauigkeit zu verzeichnen. Die Ergebnisse zeigen, dass noch deutliche Qualit{\"a}tsunterschiede zwischen den kommerziellen KI-Anbietern f{\"u}r die vollst{\"a}ndig automatisierte FRS-Analyse bestehen. Vor dem Hintergrund der Zeitersparnis und Qualit{\"a}tssicherung sind KI zwar vielversprechend, sollten aber zum aktuellen Zeitpunkt nur unter Aufsicht durch menschliche Experten zum Einsatz kommen.}, subject = {Kieferorthop{\"a}die}, language = {de} } @phdthesis{Seitzer2024, author = {Seitzer, Moritz}, title = {Quality and composition of anthelmintic medicines available in Eastern and Western Africa: an \({in-vitro}\) analysis of Albendazole, Mebendazole and Praziquantel}, doi = {10.25972/OPUS-35094}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350947}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Even though the international combat against Neglected Tropical Diseases such as schistosomiasis or soil-transmitted helminthiases depends on reliable therapeutics, anthelminthic pharmacovigilance has been neglected on many national African drug markets. Therefore, quality and composition of 88 different batches of Albendazole, Mebendazole and Praziquantel locally collected from randomly selected facilities in Western Burkina Faso, Southeast C{\^o}te d'Ivoire, Southwest Ghana and Northwest Tanzania were analysed. Visual examination of both packaging and samples was performed according to the WHO 'Be Aware' tool. Products were then screened with the GPHF Minilab, consisting of tests of mass uniformity, disintegration times and thin-layer chromatography (TLC). Confirmatory tests were performed according to international pharmacopoeiae, applying assays for dissolution profiles and high-performance liquid chromatography (HPLC). Despite minor irregularities, appearance of the products did not hint at falsified medicines. However, 19.6 \% of the brands collected in Ghana and Tanzania were not officially licensed for sale. Mass uniformity was confirmed in 53 out of 58 brands of tablets. 41 out of 56 products passed disintegration times; 10 out of the 15 failing products did not disintegrate at all. TLC results did not reveal any falsifications or pronounced dosing errors. HPLC findings confirmed the TLC results despite shifted specification limits: ten of the 83 tested batches contained less than 90 \%, none more than 110 \% label claim. However, no more than 46.3 \% (31 / 67) of the tablet batches assayed passed the respective criteria for dissolution. In the four study countries, no falsified anthelminthic medicine was encountered. The active pharmaceutical ingredient was not found to either exceed or distinctively fall below specification limits. Galenic characteristics as most critical criteria however, especially dissolution profiles, revealed substantial deficits.}, subject = {Wurmmittel}, language = {en} } @phdthesis{Schindler2024, author = {Schindler, Paul}, title = {Stellenwert der Strahlentherapie beim fortgeschrittenen adrenokortikalen Karzinom}, doi = {10.25972/OPUS-34930}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349304}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das adrenokortikale Karzinom (ACC) ist eine seltene Tumorerkrankung der Nebennierenrinde. Die Prognose ist im Allgemeinen ung{\"u}nstig und vom Tumorstadium sowie von weiteren tumor- und patientenspezifischen Faktoren abh{\"a}ngig. Die chirurgische Komplettresektion stellt das bisher einzige kurative Behandlungsverfahren dar. Dabei gibt es bisher f{\"u}r sonstige Lokaltherapien beim fortgeschrittenen bzw. rezidivierten ACC kaum umfangreiche Daten, welche die entsprechende lokale Wirksamkeit belegen. Neben der Operation stellt die Strahlentherapie eine bisher effektive Therapieoption bei verschiedenen anderen Tumorerkrankungen hinsichtlich Tumorkontrolle, Vertr{\"a}glichkeit und Zug{\"a}nglichkeit dar. Allerdings ist diese Option in der Behandlung des fortgeschrittenen ACC als Lokaltherapie bislang nicht mit zufriedenstellenden Datens{\"a}tzen umf{\"a}nglich untersucht. Ziel dieser Studie war es, anhand einer retrospektiven Datenanalyse aus dem European Network for the Study of Adrenal Tumours (ENSAT) den Stellenwert der Strahlentherapie als Lokaltherapie beim fortgeschrittenen bzw. rezidivierten ACC zu untersuchen. Es wurden insgesamt 132 F{\"a}lle hinsichtlich strahlentherapeutischer Dosis, Lokalkontrolle, progressionsfreiem {\"U}berleben, Gesamt{\"u}berleben, objektivem Ansprechen, Vertr{\"a}glichkeit und Risikofaktoren untersucht. Hierbei konnte gezeigt werden, dass die Anwendung einer hohen biologischen Effektivdosis mit einer verbesserten lokalen Tumorkontrolle einhergeht. Insgesamt zeigte sich eine gute Vertr{\"a}glichkeit der strahlentherapeutischen Behandlung. Die Ergebnisse dieser Arbeit legen nahe, dass wahrscheinlich weitere Risikofaktoren mit Rezidiven dieser Tumorart einhergehen, allerdings weitere Untersuchungen (z.B. randomisierte prospektive Studien) erfordern. Letztendlich stellt diese Arbeit auch die angewandten Dosis- und Fraktionierungskonzepte der vergangenen Jahrzente bei der Behandlung des ACC dar.}, subject = {Nebennierenrindenkrebs}, language = {de} } @phdthesis{Bauer2024, author = {Bauer, Maria Franziska}, title = {Perioperative {\"A}nderung der Ventilationsverteilung und der Lungenfunktion bei Patienten nach intraabdominellen Operationen - Untersuchung mit Hilfe der Elektroimpedanztomographie}, doi = {10.25972/OPUS-34567}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-345676}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Postoperative pulmonale Komplikationen (PPC) stellen den Hauptgrund f{\"u}r erh{\"o}hte Morbidit{\"a}t und Mortalit{\"a}t sowie eine l{\"a}ngere station{\"a}re Liegedauer nach chirurgischen Eingriffen dar. Die Elektrische Impedanztomographie (EIT) erm{\"o}glicht als strahlungsfreie Methode die bettseitige Visualisierung der regionalen pulmonalen Ventilation in einem thorakalen Querschnittsbereich {\"u}ber den zeitlichen Verlauf. Die Hauptfragestellung dieser Studie war die perioperativen Ver{\"a}nderungen der regionalen pulmonalen Ventilation bei spontanatmenden Patienten nach abdominalchirurgischen Eingriffen in Allgemeinnarkose bis in die sp{\"a}te postoperative Phase zu untersuchen. Zus{\"a}tzlich untersuchten wir die Lungenfunktion mittels Spirometrie. Wir nahmen eine Verschiebung der pulmonalen Ventilation in dorso-ventraler Richtung an, sowie eine postoperativ reduzierte Vitalkapazit{\"a}t, z.B. durch Atelektasen oder Pleuraerg{\"u}sse. In die prospektive Observationsstudie wurden 36 erwachsene Patienten eingeschlossen, die sich einem elektiven abdominalchirurgischen Eingriff unter Allgemeinan{\"a}sthesie unterzogen und ein mittleres Risiko gem{\"a}ß ARISCAT Score f{\"u}r die Entwicklung von PPC aufwiesen. Pr{\"a}operativ, sowie am 1. und 3. postoperativen Tag erfolgte die Untersuchung der pulmonalen Ventilation mittels EIT in Spontanatmung, Errechnung des Center of Ventilation (COV), sowie eine Lungenfunktionspr{\"u}fung mittels Spirometrie. Nach abdominalchirurgischen Operationen kam es zu einer statistisch signifikanten und bis zum 3. postoperativen Tag anhaltenden Verschiebung der pulmonalen Ventilation nach ventral (COVy pr{\"a}op. 16,5; 1. Tag postop. 17,8; 3. Tag postop. 17,4). Zudem zeigte sich eine anhaltend reduzierte Forcierten Vitalkapazit{\"a}t in \% vom Sollwert (FVC\%Soll): pr{\"a}op. 93\%; 1. Tag postop. 58\%; 3. Tag postop. 64\%. Am 3. postoperativen Tag bestand unter forcierter Atmung eine negative Assoziation zwischen der {\"A}nderung des COVy und der {\"A}nderung der FVC\%Soll. PPC traten bei 10 Patienten in Form von respiratorischer Insuffizienz, Atelektase und Pleuraerguss auf. Bei diesen Patienten zeigte die EIT keine komplikationsspezifischen Bilder. Abdominalchirurgische Operationen hatten hat einen relevanten Einfluss auf die postoperative regionale Lungenventilation und somit auf die Entstehung von PPC. Die EIT hilft die Entstehung von PPC besser zu verstehen und Strategien zur Vermeidung solcher im klinischen Alltag zu implementieren.}, subject = {Ventilation}, language = {de} } @book{Braun2024, author = {Braun, Ludwig}, title = {Pedisequa Camenae minoris. Zur Begleitung durch weitere neulateinische Epen Italiens.}, edition = {2. Auflage, verbessert und erg{\"a}nzt}, doi = {10.25972/OPUS-35254}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352544}, publisher = {Universit{\"a}t W{\"u}rzburg}, pages = {605}, year = {2024}, abstract = {Ein Hilfsangebot f{\"u}r die, die immer schon alle die interessanten Werke der neulateinischen Epik aus Italien lesen wollten, die heute so bequem im Internet stehen, aber nie die Zeit daf{\"u}r fanden: Rund 50 wenig bekannte Epen aus f{\"u}nf Jahrhunderten werden in griffiger Zusammenfassung des Inhalts geboten, mit grundlegenden Verst{\"a}ndnishilfen und Hinweisen auf die besonders gelungenen wie auch auf weniger gegl{\"u}ckte Stellen. Die Darstellung wird hier in zweiter, korrigierter und erg{\"a}nzter Auflage vorgelegt. Die Sammlung erweitert und erg{\"a}nzt die bereits gedruckt erschienene Zusammenstellung „Ludwig Braun, Pedisequa Camenae. Zur Begleitung durch kaum bekannte Meisterwerke der neulateinischen Epik Italiens. Noctes Neolatinae 38, Hildesheim/Z{\"u}rich/New York 2020."}, subject = {Epik}, language = {de} } @phdthesis{Haefner2024, author = {H{\"a}fner, Alena}, title = {Reaktivit{\"a}t eines \(ortho\)-phenylenverbr{\"u}ckten Diborans und Darstellung von gespannten C\(_2\)B\(_2\)-Ringsystemen}, doi = {10.25972/OPUS-34802}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348020}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die Dissertation befasst sich mit der Reaktivit{\"a}t von 1,2-Bis(dichlorboryl)benzol. Im ersten Kapitel wird auf die Problematik bei dessen Synthese eingegangen. Der zweite Teil der Arbeit befasst sich mit der Bildung von entsprechenden Boran-Addukten mit verschiedenen Lewis-Basen. Das dritte Kapitel beschreibt die Synthese eines neuartigen, vollst{\"a}ndig unges{\"a}ttigten 1,2-Diboretdiradikals, welches durch die schrittweise Reduktion des 1,2-[(CAAC)BCl2]2-Benzols erhalten wurde. Dar{\"u}ber hinaus konnte bei dieser schrittweisen Reduktion ebenfalls das einfache Borylradikal, das nicht-cyclische Diradikal und das dianionische gespannte C2B2-Ringsystem erhalten werden. Anf{\"a}ngliche Reaktivit{\"a}tsstudien zum 1,2-Diboretdiradikal zeigen zudem, dass die B-B-Bindung durch Umsetzung mit Kohlenstoffmonoxid gespalten und so ein Bisborylen dargestellt werden kann. Im vierten Kapitel konnte das 1,2-Bis(dichlorboryl)benzol durch Transmetallierungsreaktionen zu verschiedenen, sich in ihren Eigenschaften stark unterscheidenden, Verbindungen umgesetzt werden. So konnte das fluoreszierende ortho-phenylenverbr{\"u}ckte Bis-9-Borafluoren erhalten werden, aus welchem durch W{\"a}rmezufuhr das ebenfalls fluoreszierendes diboraanthracenartige Umlagerungsprodukt gewonnen werden konnte. Beide Verbindungen wurden auf ihre photophysikalischen und elektrochemischen Eigenschaften untersucht. Weiterhin konnten polycyclische Boracyclen mit C10B2-Ger{\"u}st erhalten werden, bei welchen instantan die selektive Bildung von zwei chiralen Zentren {\"u}ber eine Vielzahl an B-C-Bindungsbr{\"u}chen und -kn{\"u}pfungen beobachtet wurde. Zuletzt konnte ein thermisch empfindliches, potentiell explosives Azid-verbr{\"u}cktes Azidoboran dargestellt werden, bei welchem eine Staudinger-artige Reaktivit{\"a}t beobachtet werden konnte.}, subject = {Biradikal}, language = {de} } @phdthesis{Englert2024, author = {Englert, Nils}, title = {Die Rolle der NO-sensitiven Guanylyl-Cyclase in der Lungenfibrose der Maus}, doi = {10.25972/OPUS-34805}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348054}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die idiopathische Lungenfibrose (IPF) stellt eine chronische Krankheit mit einer schlechten Prognose dar. Die Erkrankung zeichnet sich durch ein dysfunktionales Alveolarepithel, die Formation von α-smooth muscle actin (α-SMA)-positiven Myofibroblasten, eine starke Kollagendeposition sowie eine fehlgeleitete Inflammation aus. In der Vermittlung dieser pro-fibrotischen Effekte spielt das Zytokin transforming growth factor β (TGF-β) eine Schl{\"u}sselrolle. Aufgrund des t{\"o}dlichen Verlaufs der IPF und der limitierten Therapieoptionen ist die Entdeckung neuer Behandlungsans{\"a}tze erforderlich. Der NO/cGMP-Signalweg ist in der Modulation grundlegender physiologischer Vorg{\"a}nge wie der Blutdruckregulation und der Peristaltik involviert. Hierbei spielt die NO-sensitive Guanylyl-Cyclase (NO-GC) als NO-Rezeptor eine fundamentale Rolle. In der Lunge wird die NO-GC in glatten Muskelzellen und Perizyten exprimiert. W{\"a}hrend das Enzym in glatten Muskelzellen die Relaxation der glatten Muskulatur vermittelt, reguliert die NO-GC in Perizyten die Angiogenese, die Kapillardurchl{\"a}ssigkeit und den Blutfluss. Neben den physiologischen Aufgaben wurden anti-fibrotische sowie anti-inflammatorische Effekte der NO-GC in Herz, Leber, Niere und Haut beschrieben. Daher wurde im Rahmen dieser Arbeit die NO-GC auf eine anti-fibrotische und anti-inflammatorische Bedeutung in der Lungenfibrose der Maus {\"u}berpr{\"u}ft. Hierzu wurden Wildtyp- (WT) und globale NO-GC-Knockout-M{\"a}use (GCKO) untersucht. Die Fibrose wurde durch einmalige, orotracheale Bleomycin-Gabe induziert und zu unterschiedlichen Zeitpunkten (Tag 7 und 21) untersucht. Unbehandelte (Tag 0) Tiere dienten als Kontrolle. Im ersten Teil dieser Arbeit wurde die NO-GC auf eine anti-fibrotische Wirkung untersucht. Mittels Immunfluoreszenz wurde das Verhalten der α-SMA-positiven Myofibroblasten in den platelet-derived growth factor receptor β (PDGFRβ)-positiven fibrotischen Regionen untersucht. Der Kollagengehalt wurde mithilfe eines Hydroxyprolin-Kollagenassays ermittelt. Die untersuchten Fibrose-Kriterien waren in beiden Genotypen an Tag 21 st{\"a}rker ausgepr{\"a}gt als an Tag 7. An Tag 21 konnten im GCKO mehr α-SMA-positive Myofibroblasten, ausgepr{\"a}gtere PDGFRβ-positive fibrotische Areale und ein h{\"o}herer Kollagengehalt als im WT festgestellt werden. Zudem zeigten die GCKO-Tiere ein schlechteres {\"U}berleben als WT-M{\"a}use. Diese Ergebnisse wiesen auf eine {\"u}berschießende fibrotische Antwort im GCKO und somit auf eine anti-fibrotische Wirkung der NO-GC in der Bleomycin-induzierten Lungenfibrose hin. Dass an Tag 21 die Fibrose im GCKO st{\"a}rker ausfiel als im WT, konnte mit dem signifikant h{\"o}heren TGF-β-Gehalt in der bronchoalveol{\"a}ren Lavagefl{\"u}ssigkeit (BALF) im GCKO erkl{\"a}rt werden. Das Fehlen der NO-GC im GCKO k{\"o}nnte zu einem Wegfall der Inhibierung der TGF-β-vermittelten, pro-fibrotischen Effekte durch die NO-GC f{\"u}hren. Weitere Studien sind erforderlich, um die Hypothese zu belegen und zugrundeliegende Mechanismen aufzukl{\"a}ren. Die de novo Entstehung von Myofibroblasten, die maßgeblich an der Kollagensynthese beteiligt sind, stellt ein entscheidendes Fibrose-Merkmal dar. Umso bedeutender ist die Identifikation zweier Myofibroblasten-Subtypen, die sich in Lokalisation, NO-GC-Expression und Herkunft unterscheiden: (1) interstitielle, NO-GC-positive Myofibroblasten, die von Perizyten abstammen und Kollagen Typ I produzieren, und (2) intra-alveol{\"a}re, NO-GC-negative Myofibroblasten, deren Ursprung noch nicht abschließend gekl{\"a}rt ist. Die Anwesenheit beider Myofibroblasten-Typen konnte zu beiden untersuchten Zeitpunkten nach Bleomycin-Gabe best{\"a}tigt werden. Die NO-GC-Expression der Alveolarwand-st{\"a}ndigen Myofibroblasten, deren Abstammung von NO-GC-positiven Perizyten sowie deren dauerhafte Pr{\"a}senz sprechen f{\"u}r eine relevante Rolle der NO-GC in der murinen Lungenfibrose. In weiteren Untersuchungen m{\"u}ssen die exakten Funktionen und spezifische Marker der Myofibroblasten-Subtypen identifiziert werden. Im zweiten Teil dieser Arbeit wurde die NO-GC auf anti-inflammatorische Effekte in der Bleomycin-induzierten Lungenfibrose untersucht. Mittels HE-F{\"a}rbung und Immunfluoreszenz wurden lymphozyt{\"a}re Infiltrate an Tag 21 im GCKO festgestellt, was auf einen modulatorischen Einfluss der NO-GC auf das Immunsystem hindeutete. An Tag 21 wurden in der BALF von GCKO-Tieren signifikant mehr Gesamtimmunzellen, Lymphozyten und neutrophile Granulozyten als im WT gez{\"a}hlt, was auf eine starke Einwanderung von Immunzellen und somit auf eine ausgepr{\"a}gte Entz{\"u}ndung in GCKO-Lungen hinwies. Folglich k{\"o}nnte die NO-GC eine anti-inflammatorische Rolle {\"u}ber die Regulation der Immigration von Immunzellen in der Bleomycin-induzierten Lungenfibrose spielen. In der Literatur werden pro- und anti-fibrotische Effekte der Immunzellen in der murinen Lungenfibrose diskutiert. Durch Korrelationsanalysen wurde ein positiver Zusammenhang zwischen der Gesamtimmunzellzahl und der TGF-β-Konzentration an Tag 21 festgestellt. In verschiedenen Studien wurde ein pro-fibrotischer Einfluss der Immunzellen {\"u}ber die Aktivierung/Sekretion von TGF-β beschrieben. Die Abwesenheit der NO-GC im GCKO k{\"o}nnte also {\"u}ber die verst{\"a}rkte Immigration von Immunzellen in einem erh{\"o}hten TGF-β-Gehalt resultieren und so zu einer {\"u}berschießenden fibrotischen Reaktion an Tag 21 f{\"u}hren. Auf welche Weise die NO-GC die Einwanderung der Immunzellen in der Bleomycin-induzierten Lungenfibrose beeinflusst, muss in weiteren Studien untersucht werden. Zusammenfassend deuten die Daten dieser Arbeit auf eine anti-inflammatorische und anti-fibrotische Rolle der NO-GC in der Lungenfibrose der Maus hin.}, subject = {Lunge}, language = {de} } @phdthesis{Andelovic2024, author = {Andelovic, Kristina}, title = {Characterization of arterial hemodynamics using mouse models of atherosclerosis and tissue-engineered artery models}, doi = {10.25972/OPUS-30360}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303601}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Within this thesis, three main approaches for the assessment and investigation of altered hemodynamics like wall shear stress, oscillatory shear index and the arterial pulse wave velocity in atherosclerosis development and progression were conducted: 1. The establishment of a fast method for the simultaneous assessment of 3D WSS and PWV in the complete murine aortic arch via high-resolution 4D-flow MRI 2. The utilization of serial in vivo measurements in atherosclerotic mouse models using high-resolution 4D-flow MRI, which were divided into studies describing altered hemodynamics in late and early atherosclerosis 3. The development of tissue-engineered artery models for the controllable application and variation of hemodynamic and biologic parameters, divided in native artery models and biofabricated artery models, aiming for the investigation of the relationship between atherogenesis and hemodynamics Chapter 2 describes the establishment of a method for the simultaneous measurement of 3D WSS and PWV in the murine aortic arch at, using ultra high-field MRI at 17.6T [16], based on the previously published method for fast, self-navigated wall shear stress measurements in the murine aortic arch using radial 4D-phase contrast MRI at 17.6 T [4]. This work is based on the collective work of Dr. Patrick Winter, who developed the method and the author of this thesis, Kristina Andelovic, who performed the experiments and statistical analyses. As the method described in this chapter is basis for the following in vivo studies and undividable into the sub-parts of the contributors without losing important information, this chapter was not split into the single parts to provide fundamental information about the measurement and analysis methods and therefore better understandability for the following studies. The main challenge in this chapter was to overcome the issue of the need for a high spatial resolution to determine the velocity gradients at the vascular wall for the WSS quantification and a high temporal resolution for the assessment of the PWV without prolonging the acquisition time due to the need for two separate measurements. Moreover, for a full coverage of the hemodynamics in the murine aortic arch, a 3D measurement is needed, which was achieved by utilization of retrospective navigation and radial trajectories, enabling a highly flexible reconstruction framework to either reconstruct images at lower spatial resolution and higher frame rates for the acquisition of the PWV or higher spatial resolution and lower frame rates for the acquisition of the 3D WSS in a reasonable measurement time of only 35 minutes. This enabled the in vivo assessment of all relevant hemodynamic parameters related to atherosclerosis development and progression in one experimental session. This method was validated in healthy wild type and atherosclerotic Apoe-/- mice, indicating no differences in robustness between pathological and healthy mice. The heterogeneous distribution of plaque development and arterial stiffening in atherosclerosis [10, 12], however, points out the importance of local PWV measurements. Therefore, future studies should focus on the 3D acquisition of the local PWV in the murine aortic arch based on the presented method, in order to enable spatially resolved correlations of local arterial stiffness with other hemodynamic parameters and plaque composition. In Chapter 3, the previously established methods were used for the investigation of changing aortic hemodynamics during ageing and atherosclerosis in healthy wild type and atherosclerotic Apoe-/- mice using the previously established methods [4, 16] based on high-resolution 4D-flow MRI. In this work, serial measurements of healthy and atherosclerotic mice were conducted to track all changes in hemodynamics in the complete aortic arch over time. Moreover, spatially resolved 2D projection maps of WSS and OSI of the complete aortic arch were generated. This important feature allowed for the pixel-wise statistical analysis of inter- and intragroup hemodynamic changes over time and most importantly - at a glance. The study revealed converse differences of local hemodynamic profiles in healthy WT and atherosclerotic Apoe-/- mice, with decreasing longWSS and increasing OSI, while showing constant PWV in healthy mice and increasing longWSS and decreasing OSI, while showing increased PWV in diseased mice. Moreover, spatially resolved correlations between WSS, PWV, plaque and vessel wall characteristics were enabled, giving detailed insights into coherences between hemodynamics and plaque composition. Here, the circWSS was identified as a potential marker of plaque size and composition in advanced atherosclerosis. Moreover, correlations with PWV values identified the maximum radStrain could serve as a potential marker for vascular elasticity. This study demonstrated the feasibility and utility of high-resolution 4D flow MRI to spatially resolve, visualize and analyze statistical differences in all relevant hemodynamic parameters over time and between healthy and diseased mice, which could significantly improve our understanding of plaque progression towards vulnerability. In future studies the relation of vascular elasticity and radial strain should be further investigated and validated with local PWV measurements and CFD. Moreover, the 2D histological datasets were not reflecting the 3D properties and regional characteristics of the atherosclerotic plaques. Therefore, future studies will include 3D plaque volume and composition analysis like morphological measurements with MRI or light-sheet microscopy to further improve the analysis of the relationship between hemodynamics and atherosclerosis. Chapter 4 aimed at the description and investigation of hemodynamics in early stages of atherosclerosis. Moreover, this study included measurements of hemodynamics at baseline levels in healthy WT and atherosclerotic mouse models. Due to the lack of hemodynamic-related studies in Ldlr-/- mice, which are the most used mouse models in atherosclerosis research together with the Apoe-/- mouse model, this model was included in this study to describe changing hemodynamics in the aortic arch at baseline levels and during early atherosclerosis development and progression for the first time. In this study, distinct differences in aortic geometries of these mouse models at baseline levels were described for the first time, which result in significantly different flow- and WSS profiles in the Ldlr-/- mouse model. Further basal characterization of different parameters revealed only characteristic differences in lipid profiles, proving that the geometry is highly influencing the local WSS in these models. Most interestingly, calculation of the atherogenic index of plasma revealed a significantly higher risk in Ldlr-/- mice with ongoing atherosclerosis development, but significantly greater plaque areas in the aortic arch of Apoe-/- mice. Due to the given basal WSS and OSI profile in these two mouse models - two parameters highly influencing plaque development and progression - there is evidence that the regional plaque development differs between these mouse models during very early atherogenesis. Therefore, future studies should focus on the spatiotemporal evaluation of plaque development and composition in the three defined aortic regions using morphological measurements with MRI or 3D histological analyses like LSFM. Moreover, this study offers an excellent basis for future studies incorporating CFD simulations, analyzing the different measured parameter combinations (e.g., aortic geometry of the Ldlr-/- mouse with the lipid profile of the Apoe-/- mouse), simulating the resulting plaque development and composition. This could help to understand the complex interplay between altered hemodynamics, serum lipids and atherosclerosis and significantly improve our basic understanding of key factors initiating atherosclerosis development. Chapter 5 describes the establishment of a tissue-engineered artery model, which is based on native, decellularized porcine carotid artery scaffolds, cultured in a MRI-suitable bioreactor-system [23] for the investigation of hemodynamic-related atherosclerosis development in a controllable manner, using the previously established methods for WSS and PWV assessment [4, 16]. This in vitro artery model aimed for the reduction of animal experiments, while simultaneously offering a simplified, but completely controllable physical and biological environment. For this, a very fast and gentle decellularization protocol was established in a first step, which resulted in porcine carotid artery scaffolds showing complete acellularity while maintaining the extracellular matrix composition, overall ultrastructure and mechanical strength of native arteries. Moreover, a good cellular adhesion and proliferation was achieved, which was evaluated with isolated human blood outgrowth endothelial cells. Most importantly, an MRI-suitable artery chamber was designed for the simultaneous cultivation and assessment of high-resolution 4D hemodynamics in the described artery models. Using high-resolution 4D-flow MRI, the bioreactor system was proven to be suitable to quantify the volume flow, the two components of the WSS and the radStrain as well as the PWV in artery models, with obtained values being comparable to values found in literature for in vivo measurements. Moreover, the identification of first atherosclerotic processes like intimal thickening is achievable by three-dimensional assessment of the vessel wall morphology in the in vitro models. However, one limitation is the lack of a medial smooth muscle cell layer due to the dense ECM. Here, the utilization of the laser-cutting technology for the generation of holes and / or pits on a microscale, eventually enabling seeding of the media with SMCs showed promising results in a first try and should be further investigated in future studies. Therefore, the proposed artery model possesses all relevant components for the extension to an atherosclerosis model which may pave the way towards a significant improvement of our understanding of the key mechanisms in atherogenesis. Chapter 6 describes the development of an easy-to-prepare, low cost and fully customizable artery model based on biomaterials. Here, thermoresponsive sacrificial scaffolds, processed with the technique of MEW were used for the creation of variable, biomimetic shapes to mimic the geometric properties of the aortic arch, consisting of both, bifurcations and curvatures. After embedding the sacrificial scaffold into a gelatin-hydrogel containing SMCs, it was crosslinked with bacterial transglutaminase before dissolution and flushing of the sacrificial scaffold. The hereby generated channel was subsequently seeded with ECs, resulting in an easy-to-prepare, fast and low-cost artery model. In contrast to the native artery model, this model is therefore more variable in size and shape and offers the possibility to include smooth muscle cells from the beginning. Moreover, a custom-built and highly adaptable perfusion chamber was designed specifically for the scaffold structure, which enabled a one-step creation and simultaneously offering the possibility for dynamic cultivation of the artery models, making it an excellent basis for the development of in vitro disease test systems for e.g., flow-related atherosclerosis research. Due to time constraints, the extension to an atherosclerosis model could not be achieved within the scope of this thesis. Therefore, future studies will focus on the development and validation of an in vitro atherosclerosis model based on the proposed bi- and three-layered artery models. In conclusion, this thesis paved the way for a fast acquisition and detailed analyses of changing hemodynamics during atherosclerosis development and progression, including spatially resolved analyses of all relevant hemodynamic parameters over time and in between different groups. Moreover, to reduce animal experiments, while gaining control over various parameters influencing atherosclerosis development, promising artery models were established, which have the potential to serve as a new platform for basic atherosclerosis research.}, subject = {H{\"a}modynamik}, language = {en} } @phdthesis{He2024, author = {He, Feng}, title = {Drug Discovery based on Oxidative Stress and HDAC6 for Treatment of Neurodegenerative Diseases}, doi = {10.25972/OPUS-25349}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-253497}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Most antioxidants reported so far only achieved limited success in AD clinical trials. Growing evidences suggest that merely targeting oxidative stress will not be sufficient to fight AD. While multi-target directed ligands could synergistically modulate different steps in the neurodegenerative process, offering a promising potential for treatment of this complex disease. Fifteen target compounds have been designed by merging melatonin and ferulic acid into the cap group of a tertiary amide HDAC6 inhibitor. Compound 10b was screened as the best hybrid molecule exhibit potent HDAC6 inhibition and potent antioxidant capacity. Compound 10b also alleviated LPS-induced microglia inflammation and led to a switch from neurotoxic M1 to the neuroprotective M2 microglial phenotype. Moreover, compound 10b show pronounced attenuation of spatial working memory and long-term memory damage in an in vivo AD mouse model. Compound 10b can be a potentially effective drug candidate for treatment of AD and its druggability worth to be further studied. We have designed ten novel neuroprotectants by hybridizing with several common antioxidants, including ferulic acid, melatonin, lipoic acid, and trolox. The trolox hybrid compound exhibited the most potent neuroprotective effects in multiple neuroprotection assays. Besides, we identified the synergistic effects between trolox and vitamin K derivative, and our trolox hybrid compound showed comparable neuroprotection with the mixture of trolox and vitamin K derivative. We have designed and synthesized 24 quinone derivatives based on five kinds of different quinones including ubiquinone, 2,3,5-trimethyl-1,4-benzoquinone, memoquin, thymoquinone, and anthraquinone. Trimethylbenzoquinone and thymoquinone derivatives showed more potent neuroprotection than other quinones in oxytosis assay. Therefore, trimethylbenzoquinone and thymoquinone derivatives can be used as lead compounds for further mechanism study and drug discovery for treatment of neurodegenerative disease. We designed a series of photoswitchable HDAC inhibitors, which could be effective molecular tools due to the high spatial and temporal resolution. In total 23 target compounds were synthesized and photophysicochemically characterized. Azoquinoline-based compounds possess more thermally stable cis-isomers in buffer solution, which were further tested in enzyme-based HDAC inhibition assay. However, none of those tested compounds show significant differences in activities between trans-isomers and corresponding cis-isomers.}, subject = {Alzheimerkrankheit}, language = {en} } @phdthesis{XavierdeSouza2024, author = {Xavier de Souza, Aline}, title = {Ecophysiological adaptations of the cuticular water permeability within the Solanaceae family}, doi = {10.25972/OPUS-22539}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225395}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The cuticle, a complex lipidic layer synthesized by epidermal cells, covers and protects primary organs of all land plants. Its main function is to avoid plant desiccation by limiting non-stomatal water loss. The cuticular properties vary widely among plant species. So far, most of the cuticle-related studies have focused on a limited number of species, and studies addressing phylogenetically related plant species are rare. Moreover, comparative studies among organs from the same plant species are still scarce. Thus, this study focus on organ-specificities of the cuticle within and between plant species of the Solanaceae family. Twenty-seven plant species of ten genera, including cultivated and non- cultivated species, were investigated to identify potential cuticular similarities. Structural, chemical and functional traits of fully expanded leaves, inflated fruiting calyces, and ripe fruits were analyzed. The surface morphology was investigated by scanning electron microscopy. Leaves were mainly amphistomatic and covered by an epicuticular wax film. The diversity and distribution of trichomes varied among species. Only the leaves of S. grandiflora were glabrous. Plant species of the Leptostemonum subgenus had numerous prickles and non-glandular stellate trichomes. Fruits were stomata-free, except for S. muricatum, and a wax film covered their surface. Last, lenticel- like structures and remaining scars of broken trichomes were found on the surface of some Solanum fruits. Cuticular water permeability was used as indicators of the cuticular transpiration barrier efficiency. The water permeability differed among plant species, organs and fruit types with values ranging up to one hundred-fold. The minimum leaf conductance ranged from 0.35 × 10-5 m s-1 in S. grandiflora to 31.54 × 10-5 m s-1 in S. muricatum. Cuticular permeability of fruits ranged from 0.64 × 10-5 m s-1 in S. dulcamara (fleshy berry) to 34.98 × 10-5 m s-1 in N. tabacum (capsule). Generally, the cuticular water loss of dry fruits was about to 5-fold higher than that of fleshy fruits. Interestingly, comparisons between cultivated and non-cultivated species showed that wild species have the most efficient cuticular transpiration barrier in leaves and fruits. The average permeability of leaves and fruits of wild plant species was up to three-fold lower in comparison to the cultivated ones. Moreover, ripe fruits of P. ixocarpa and P. peruviana showed two-times lower cuticular transpiration when enclosed by the inflated fruiting calyx. The cuticular chemical composition was examined using gas chromatography. Very-long-chain aliphatic compounds primarily composed the cuticular waxes, being mostly dominated by n- alkanes (up to 80\% of the total wax load). Primary alkanols, alkanoic acids, alkyl esters and branched iso- and anteiso-alkanes were also frequently found. Although in minor amounts, sterols, pentacyclic triterpenoids, phenylmethyl esters, coumaric acid esters, and tocopherols were identified in the cuticular waxes. Cuticular wax coverages highly varied in solanaceous (62- fold variation). The cuticular wax load of fruits ranged from 0.55 μg cm-2 (Nicandra physalodes) to 33.99 μg cm-2 (S. pennellii), whereas the wax amount of leaves varied from 0.90 μg cm-2 (N. physalodes) to 28.42 μg cm-2 (S. burchellii). Finally, the wax load of inflated fruiting calyces ranged from 0.56 μg cm-2 in P. peruviana to 2.00 μg cm-2 in N. physalodes. For the first time, a comparative study on the efficiency of the cuticular transpiration barrier in different plant organs of closely related plant species was conducted. Altogether, the cuticular chemical variability found in solanaceous species highlight species-, and organ-specific wax biosynthesis. These chemical variabilities might relate to the waterproofing properties of the plant cuticle, thereby influencing leaf and fruit performances. Additionally, the high cuticular water permeabilities of cultivated plant species suggest a potential existence of a trade-off between fruit organoleptic properties and the efficiency of the cuticular transpiration barrier. Last, the high cuticular water loss of the solanaceous dry fruits might be a physiological adaptation favouring seed dispersion.}, subject = {Kutikula}, language = {en} } @phdthesis{Neitz2024, author = {Neitz, Hermann}, title = {Hydrophobic recognition motifs in functionalized DNA}, doi = {10.25972/OPUS-34838}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348382}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In w{\"a}ssriger Umgebung spielen hydrophobe Wechselwirkungen eine wichtige Rolle f{\"u}r die DNA. Die Einf{\"u}hrung von Modifikationen, die auf hydrophoben aromatischen Einheiten basieren, kann die Erkennung und Reaktivit{\"a}t von funktionellen Gruppen in der DNA steuern. Modifikationen k{\"o}nnen durch ein k{\"u}nstliches R{\"u}ckgrat oder in Form einer Erweiterung der Nukleobasen eingebracht werden und so zu zus{\"a}tzlichen Eigenschaften der DNA f{\"u}hren. Diese Dissertation befasst sich mit der Verwendung von hydrophoben Einheiten zur Funktionalisierung von DNA. Im ersten Teil der Arbeit wurde das Tolanmotiv (Diphenylacetylen) in Kombination mit dem acyclischen R{\"u}ckgrat von GNA und BuNA verwendet, um Erkennungseinheiten im DNA-Kontext zu erzeugen. Die gezielte Fluorierung der aromatischen Ringe des Tolan-Bausteins bildete die Grundlage f{\"u}r eine supramolekulare Sprache, die auf Aren-Fluoroaren-Wechselwirkungen basiert. Die spezifische Erkennung wurde mittels thermodynamischer, kinetischer und NMR-spektroskopischer Methoden untersucht. Im zweiten Teil der Arbeit wurden Desoxyuridin-Derivate mit einer hydrophoben aromatischen Modifikation hergestellt und in die DNA-Doppelhelix eingebaut. Die Bestrahlung mit UV-Licht f{\"u}hrte zu einer [2+2]-Cycloaddition zwischen zwei modifizierten Nukleosiden in der DNA. Das Reaktionsprodukt wurde strukturell charakterisiert und die Reaktion in verschiedenen biochemischen und nanotechnologischen DNA-Anwendungen eingesetzt.}, subject = {Supramolekulare Chemie}, language = {en} } @techreport{OPUS4-35271, type = {Working Paper}, title = {Krisen, Potenziale und Perspektiven der EU - Die mainEUropa Blogs 2017 bis 2021}, editor = {M{\"u}ller-Brandeck-Bocquet, Gisela}, issn = {2625-6193}, doi = {10.25972/OPUS-35271}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352715}, pages = {146}, year = {2024}, abstract = {Dieses f{\"u}nfte Jean Monnet Paper f{\"u}gt alle 36 mainEUropa-Blogs, die zwischen 2017 und 2021 an der mit einem Jean Monnet Lehrstuhl ausgezeichneten Professur f{\"u}r Europaforschung und Internationale Beziehungen der Universit{\"a}t W{\"u}rzburg verfasst wurden, zu einer einheitlichen Publikation zusammen. Die mainEUropa-Blogs wollten {\"u}ber ausgew{\"a}hlte Aspekte der EU-Politik aktuell, knapp und leicht verst{\"a}ndlich informieren; damit haben sie dem EU-Geschehen der Jahre 2017 bis 2021 aus jeweils aktuellen Anl{\"a}ssen den Puls genommen und zu einem besseren Verst{\"a}ndnis der EU-Politik- und Entscheidungsprozesse beigetragen. Die Blog-Themen sind breit gef{\"a}chert und bilden somit ausgew{\"a}hlte Ereignisse und Weichenstellungen aus der j{\"u}ngeren Integrationsgeschichte ab. Die Themen reichen {\"u}ber klimapolitische Beschl{\"u}sse, das Ringen um den Erhalt bzw. die Wiederherstellung der Rechtstaatlichkeit in einigen EU-Mitgliedstaaten, das Endlos-Drama des Brexits, wichtige Wahlen in der EU und ausgew{\"a}hlten Mitgliedstaaten bis hin zu neuen Entwicklungen in der EU-Außen-, Sicherheits- und Verteidigungspolitik sowie zu den {\"u}berraschend zupackenden Antworten der EU auf die Covid-19-Pandemie. Ein Blick auf die europapolitische Agenda der im Dezember 2021 angetretenen rot-gr{\"u}n-gelben Ampel-Bundesregierung beschließt die Reihe. Denn 2021 endete auch das die mainEUropa-Blogs tragende Jean Monnet Projekt, so dass das vorliegende f{\"u}nfte Jean Monnet Paper auch das letzte sein wird.}, subject = {Europ{\"a}ische Union}, language = {de} } @phdthesis{Nadernezhad2024, author = {Nadernezhad, Ali}, title = {Engineering approaches in biofabrication of vascularized structures}, doi = {10.25972/OPUS-34589}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-345892}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Biofabrication technologies must address numerous parameters and conditions to reconstruct tissue complexity in vitro. A critical challenge is vascularization, especially for large constructs exceeding diffusion limits. This requires the creation of artificial vascular structures, a task demanding the convergence and integration of multiple engineering approaches. This doctoral dissertation aims to achieve two primary objectives: firstly, to implement and refine engineering methods for creating artificial microvascular structures using Melt Electrowriting (MEW)-assisted sacrificial templating, and secondly, to deepen the understanding of the critical factors influencing the printability of bioink formulations in 3D extrusion bioprinting. In the first part of this dissertation, two innovative sacrificial templating techniques using MEW are explored. Utilizing a carbohydrate glass as a fugitive material, a pioneering advancement in the processing of sugars with MEW with a resolution under 100 microns was made. Furthermore, by introducing the "print-and-fuse" strategy as a groundbreaking method, biomimetic branching microchannels embedded in hydrogel matrices were fabricated, which can then be endothelialized to mirror in vivo vascular conditions. The second part of the dissertation explores extrusion bioprinting. By introducing a simple binary bioink formulation, the correlation between physical properties and printability was showcased. In the next step, employing state-of-the-art machine-learning approaches revealed a deeper understanding of the correlations between bioink properties and printability in an extended library of hydrogel formulations. This dissertation offers in-depth insights into two key biofabrication technologies. Future work could merge these into hybrid methods for the fabrication of vascularized constructs, combining MEW's precision with fine-tuned bioink properties in automated extrusion bioprinting.}, subject = {3D-Druck}, language = {en} } @phdthesis{Weber2024, author = {Weber, Justus C.}, title = {Development and preclinical assessment of ROR2-specific CAR-T cells for the treatment of clear cell renal cell carcinoma and multiple myeloma}, doi = {10.25972/OPUS-31039}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-310399}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Adoptive immunotherapy using chimeric antigen receptor (CAR)-modified T cells is an effective treatment for hematological malignancies that are refractory to conventional chemotherapy. To address a wider variety of cancer entities, there is a need to identify and characterize additional target antigens for CAR-T cell therapy. The two members of the receptor tyrosine kinase-like orphan receptor family, ROR1 and ROR2, have been found to be overexpressed on cancer cells and to correlate with aggressive cancer phenotypes. Recently, ROR1-specific CAR-T cells have entered testing in phase I clinical trials, encouraging us to assess the suitability of ROR2 as a novel target for CAR-T cell therapy. To study the therapeutic potential of targeting ROR2 in solid and hematological malignancies, we selected two representative cancer entities with high unmet medical need: renal cell carcinoma and multiple myeloma. Our data show that ROR2 is commonly expressed on primary samples and cell lines of clear cell renal cell carcinoma and multiple myeloma. To study the efficacy of ROR2-specific CAR T cell therapy, we designed two CAR constructs with 10-fold binding affinity differences for the same epitope of ROR2. We found both cell products to exhibit antigen-specific anti-tumor reactivity in vitro, including tumor cell lysis, secretion of the effector cytokines interleukin-2 (IL-2) and interferon-gamma (IFNγ), and T cell proliferation. In vivo studies revealed ROR2 specific CAR-T cells to confer durable responses, significant survival benefits and long-term persistence of CAR-expressing T cells. Overall, there was a trend towards more potent anti-tumor efficacy upon treatment with T cells that expressed the CAR with higher affinity for ROR2, both in vitro and in vivo. We performed a preclinical safety and toxicology assessment comprising analyses of ROR2 expression in healthy human and murine tissues, cross-reactivity, and adoptive T cell transfer in immunodeficient mice. We found ROR2 expression to be conserved in mice, and low-level expression was detectable in the male and female reproductive system as well as parts of the gastrointestinal tract. CAR-T cells targeting human ROR2 were found to elicit similarly potent reactivity upon recognition of murine ROR2. In vivo analyses showed transient tissue-specific enrichment and activation of ROR2-specific CAR-T cells in organs with high blood circulation, such as lung, liver, or spleen, without evidence for clinical toxicity or tissue damage as determined by histological analyses. Furthermore, we humanized the CAR binding domain of ROR2-specific CAR-T cells to mitigate the risk of adverse immune reactions and concomitant CAR-T cell rejection. Functional analyses confirmed that humanized CARs retained their specificity and functionality against ROR2-positive tumor cells in vitro. In summary, we show that ROR2 is a prevalent target in RCC and MM, which can be addressed effectively with ROR2-specific CAR-T cells in preclinical models. Our preliminary toxicity studies suggest a favorable safety profile for ROR2-specific CAR-T cells. These findings support the potential to develop ROR2-specific CAR-T cells clinically to obtain cell products with broad utility.}, subject = {CAR-T-Zell-Therapie}, language = {en} } @phdthesis{Pres2024, author = {Pres, Sebastian}, title = {Detection of a plasmon-polariton quantum wave packet by coherent 2D nanoscopy}, doi = {10.25972/OPUS-34824}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348242}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Plasmonic nanostructures are considered promising candidates for essential components of integrated quantum technologies because of their ability to efficiently localize broad-band electromagnetic fields on the nanoscale. The resulting local near field can be understood as a spatial superposition of spectrally different plasmon-polariton modes due to the spectrally broad optical excitation, and thus can be described as a classical wave packet. Since plasmon polaritons, in turn, can transmit and receive non-classical light states, the exciting question arises to what extent they have to be described as quantum mechanical wave packets, i.e. as a superposition of different quantum states. But how to probe, characterize and eventually manipulate the quantum state of such plasmon polaritons? Up to now, probing at room temperatures relied completely on analyzing quantum optical properties of the corresponding in-going and out-going far-field photon modes. However, these methods so far only allow a rather indirect investigation of the plasmon-polariton quantum state by means of transfer into photons. Moreover, these indirect methods lack spatial resolution and therefore do not provide on-site access to the plasmon-polariton quantum state. However, since the spectroscopic method of coherent two-dimensional (2D) nanoscopy offers the capability to follow the plasmon- polariton quantum state both in Hilbert space and in space and time domain a complete characterization of the plasmon polariton is possible. In this thesis a versatile coherent 2D nanoscopy setup is presented combining spectral tunability and femtosecond time resolution with spatial resolution on the nanometer scale due to the detection of optically excited nonlinear emitted electrons via photoemission electron microscopy (PEEM). Optical excitation by amplitude- and phase-shaped, systematically-modified and interferometric-stable multipulse sequences is realized, and characterized via Fourier-transform spectral interferometry (FTSI). This linear technique enables efficient data acquisition in parallel to a simultaneously performed experiment. The full electric-field reconstruction of every generated multipulse sequence is used to analyze the effect of non-ideal pulse sequences on the two-dimensional spectral data of population-based multidimensional spectroscopy methods like, e.g., the coherent 2D nanoscopy applied in this thesis. Investigation of the spatially-resolved nonlinear electron emission yield from plasmonic gold nanoresonators by coherent 2D nanoscopy requires a quasi-particle treatment of the addressed plasmon-polariton mode and development of a quantum model to adequately describe the plasmon-assisted multi-quantum electron emission from nanostructures. Good agreement between simulated and experimental data enables to connect certain spectral features to superpositions of non-adjacent plasmon-polariton quantum states, i.e, non-adjacent occupation-number states of the underlying quantized, harmonic oscillator, thus direct probing of the plasmon-polariton quantum wave packet at the location of the nanostructure. This is a necessary step to locally control and manipulate the plasmon-polariton quantum state and thus of general interest for the realization of nanoscale quantum optical devices.}, subject = {Coherent Multidimensional Spectroscopy}, language = {en} } @phdthesis{Albrecht2024, author = {Albrecht, Christina}, title = {Kardiorestriktiver Knockout desmosomaler Proteine f{\"u}hrt zu einer Beeintr{\"a}chtigung der elektromechanischen Kopplung ohne mitochondriale Dysfunktion bei arrhythmogener Kardiomyopathie}, doi = {10.25972/OPUS-34847}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348472}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Arrhythmogene Kardiomyopathie (ACM) ist eine genetische Herzerkrankung, die durch Herzinsuffizienz, ventrikul{\"a}re Arrhythmien und pl{\"o}tzlichen Herztod gekennzeichnet ist. Mutationen in desmosomalen Proteinen der Zelladh{\"a}sion, wie Plakophilin 2 (PKP2) und Plakoglobin (PG), sind die h{\"a}ufigste Ursache der famili{\"a}ren ACM. Wie gest{\"o}rte Zelladh{\"a}sion zum ACM-Ph{\"a}notyp f{\"u}hrt, ist jedoch nur teilweise gekl{\"a}rt. Potentielle Mechanismen sind eine gest{\"o}rte Kalzium-(Ca2+)-Hom{\"o}ostase, mitochondrialer oxidativer Stress und metabolische St{\"o}rungen. Ziel dieser Studie ist es, die mitochondriale Energetik und die Ca2+ -Hom{\"o}ostase in kardio-restriktiven PKP2-Knockout-M{\"a}usen (KO) im Alter von 4, 8 und 12 Wochen sowie in PG-Knockout- M{\"a}usen im Alter von 6 Wochen zu untersuchen. Vier Wochen alte PKP2-KO-M{\"a}use zeigten fr{\"u}he Anzeichen von ACM, w{\"a}hrend alle anderen Altersgruppen typische Kennzeichen von ACM rekapitulierten. Kontraktilit{\"a}t, die damit verbundenen Ca2+ - Transienten, der Redoxstatus und das mitochondriale Membranpotenzial (ΔΨm) isolierter Kardiomyozyten wurden mit einem IonOptix-System bei elektrischer und β- adrenerger Stimulation untersucht. Alle desmosomalen KO-Kardiomyozyten zeigten eine verringerte diastolische Sarkomerl{\"a}nge, was auf eine diastolische Dysfunktion hinwies. In allen PKP2 KO Kardiomyozyten lag außerdem ein erh{\"o}hter intrazellul{\"a}rer Ca2+ -Spiegel vor, w{\"a}hrend in den PG KO-Kardiomyozyten das intrazellul{\"a}rer Ca2+ unver{\"a}ndert war. PKP2 KO- und PG KO-Kardiomyozyten wiesen keine Ca2+ - Sensibilisierung der Myofilamente auf. Zur weiteren Bewertung der mitochondrialen Funktion wurde eine hochaufl{\"o}sende Respirometrie in isolierten Herzmitochondrien bei gleichzeitiger {\"U}berwachung von ΔΨm in PKP2 KO und PG KO M{\"a}usen durchgef{\"u}hrt, welche in allen Versuchs- und Kontrollgruppen vergleichbar war. Im Verlauf der Versuche blieb der Redoxstatus stabil und es konnte kein Exzess reaktiver Sauerstoffspezies (ROS) festgestellt werden. Daraus konnte gefolgert werden, dass weder PKP2 KO noch PG KO-M{\"a}use eine beeintr{\"a}chtigte mitochondriale Atmung aufwiesen. Diese Studie zeigt, dass isolierte PKP2 KO- oder PG KO-Kardiomyozyten EC-Kopplungsdefekte ohne mitochondriale Dysfunktion aufwiesen. Eine mitochondriale Dysfunktion konnte als treibender Faktor f{\"u}r die Progression des ACM- Ph{\"a}notyps in den vorgestellten Mausmodellen ausgeschlossen werden. Weitere Studien sind erforderlich, um die mitochondriale Funktion im Zusammenhang mit ACM zu entschl{\"u}sseln.}, subject = {Herzmuskelkrankheit}, language = {de} } @phdthesis{Ibrahim2024, author = {Ibrahim, Eslam Samir Ragab}, title = {Unraveling the function of the old yellow enzyme OfrA in \(Staphylococcus\) \(aureus\) stress response}, doi = {10.25972/OPUS-28960}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-289600}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Biological systems are in dynamic interaction. Many responses reside in the core concepts of biological systems interplay (competition and cooperation). In infection situation, the competition between a bacterial system and a host is shaped by many stressors at spatial and temporal determinants. Reactive chemical species are universal stressors against all biological systems since they potentially damage the basic requirements of these systems (nucleic acids, proteins, carbohydrates, and lipids). Either produced endogenously or exogenously, reactive chemical species affect the survival of pathogens including the gram-positive Staphylococcus aureus (S. aureus). Therefore, bacteria developed strategies to overcome the toxicity of reactive species. S. aureus is a widely found opportunistic pathogen. In its niche, S. aureus is in permanent contact with surrounding microbes and host factors. Deciphering the deterministic factors in these interactions could facilitate pinpointing novel bacterial targets. Identifying the aforementioned targets is crucial to develop new strategies not only to kill the pathogenic organisms but also to enhance the normal flora to minimize the pathogenicity and virulence of potential pathogens. Moreover, targeting S. aureus stress response can be used to overcome bacterial resistance against host-derived factors. In this study, I identify a novel S. aureus stress response factor against reactive electrophilic, oxygen, and hypochlorite species to better understand its resilience as a pathogen. Although bacterial stress response is an active research field, gene function is a current bottleneck in characterizing the understudied bacterial strategies to mediate stress conditions. I aimed at understanding the function of a novel protein family integrated in many defense systems of several biological systems. In bacteria, fungi, and plants, old yellow enzymes (OYEs) are widely found. Since the first isolation of the yellow flavoprotein, OYEs are used as biocatalysts for decades to reduce activated C=C bonds in α,β-unsaturated carbonyl compounds. The promiscuity of the enzymatic catalysis is advantageous for industrial applications. However, the physiological function of OYEs, especially in bacteria, is still puzzling. Moreover, the relevance of the OYEs in infection conditions remained enigmatic.   Here, I show that there are two groups of OYEs (OYE flavin oxidoreductase, OfrA and OfrB) that are encoded in staphylococci and some firmicutes. OfrA (SAUSA300_0859) is more conserved than OfrB (SAUSA300_0322) in staphylococci and is a part of the staphylococcal core genome. A reporter system was established to report for ofrA in S. aureus background. The results showed that ofrA is induced under electrophilic, oxidative, and hypochlorite stress. OfrA protects S. aureus against quinone, methylglyoxal, hydrogen peroxide, and hypochlorite stress. Additionally, the results provide evidence that OfrA supports thiol-dependent redox homeostasis. At the host-pathogen interface, OfrA promotes S. aureus fitness in murine macrophage cell line. In whole human blood, OfrA is involved in S. aureus survival indicating a potential clinical relevance to bacteraemia. In addition, ofrA mutation affects the production of the virulence factor staphyloxanthin via the upper mevalonate pathway. In summary, decoding OfrA function and its proposed mechanism of action in S. aureus shed the light on a conserved stress response within multiple organisms.}, subject = {Staphylococcus aureus}, language = {en} } @phdthesis{Kopic2024, author = {Kopic, Eva}, title = {On the physiological role of post-translational regulation of the \(Arabidopsis\) guard cell outward rectifying potassium channel GORK}, doi = {10.25972/OPUS-34880}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348806}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das streng regulierte Gleichgewicht zwischen CO2-Aufnahme und Transpiration ist f{\"u}r Pflanzen essentiell und h{\"a}ngt von kontrollierten Turgor{\"a}nderungen ab, die durch die Aktivit{\"a}t verschiedener Anionen- und Kationenkan{\"a}le verursacht werden. Diese Kan{\"a}le sind Teil von Signalkaskaden, die z. B. durch Phytohormone wie ABA (Abscisins{\"a}ure) und JA (Jasmonat) ausgel{\"o}st werden, die beide bei Trockenstress in den Schließzellen wirken. Dar{\"u}ber hinaus ist bekannt, dass JA an der Reaktion der Pflanze auf Pathogenbefall oder Verwundung beteiligt ist. GORK (guard cell outward rectifying K+ channel) ist der einzige bekannte, ausw{\"a}rts gleichrichtende K+-Kanal in Schließzellen und somit f{\"u}r den K+-Efflux beim Schließen der Stomata verantwortlich. Im Rahmen dieser Arbeit konnte nachgewiesen werden, dass GORK ein wesentlicher Bestandteil des JA-induzierten Stomatschlusses ist. Dies gilt f{\"u}r beide Ausl{\"o}ser, sowohl die Blattverwundung als auch die direkte Anwendung von JA. Patch-Clamp-Experimente an Protoplasten von Schließzellen untermauerten dieses Ergebnis, indem sie GORK-K+-Ausw{\"a}rtsstr{\"o}me als direktes Ziel von JA-Signalen entlarvten. Da bekannt ist, dass zytosolische Ca2+-Signale sowohl bei ABA- als auch bei JA-Signalen eine Rolle spielen, wurde die Interaktion von GORK mit Ca2+-abh{\"a}ngigen Kinasen untersucht. Eine antagonistische Regulation von GORK durch CIPK5-CBL1/9-Komplexe und ABI2 konnte durch DEVC (double electrode voltage clamp) sowie Protein-Protein-Interaktions-Experimente identifiziert und durch in-vitro Kinase-Assays untermauert werden. Patch-Clamp-Aufzeichnungen an Protoplasten von Schließzellen der cipk5-2 Funktions-Verlust-Mutante zeigten die Bedeutung von CIPK5 f{\"u}r den JA-induzierten Stomaschluss via Aktivierung von GORK. Die Interaktion verschiedener CDPKs (Ca2+-abh{\"a}ngige Proteinkinasen) mit GORK wurde ebenfalls untersucht. Neben der Ca2+-Signal{\"u}bertragung ist auch die Produktion von ROS (reaktive Sauerstoffspezies) f{\"u}r die ABA- und MeJA-Signal{\"u}bertragung von Bedeutung. In DEVC-Experimenten konnte ein reversibler Effekt von ROS auf die GORK-Kanalaktivit{\"a}t nachgewiesen werden, was ein Teil der Erkl{\"a}rung f{\"u}r diese ROS-Effekte bei ABA- und MeJA-Signalen sein k{\"o}nnte.}, subject = {Spalt{\"o}ffnung}, language = {en} } @phdthesis{Triyasmono2024, author = {Triyasmono, Liling}, title = {Development and Application of Quantitative \(^1\)H NMR Spectroscopy and Chemometrics for Quality Determination of Red Fruit (\(Pandanus\) \(conoideus\), Lam.) Oil}, doi = {10.25972/OPUS-30272}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-302726}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this thesis, a new approach of a qNMR method has been investigated to demonstrate the reliability and importance of this method as an alternative solution for analyzing oil quality parameters, especially in RFO, which has particular characteristics (red color). This study also includes the chemometric evaluation of spectral data for authentication, visual grouping, and prediction of RFO quality based on the degree of unsaturation, FFA value, and unsaturated fatty acid content. The analytical measurement procedure of NMR spectroscopy begins with optimization of the analytical acquisition parameters, including effect of solvent, effect of sample concentration, selection of appropriate internal standards, determination of T1, and method validation. Furthermore, the results of the method development were interpreted to RFO samples evaluation, which began with determining the assignment of signal spectra for the determination of AV, SV, EV, and IV simultaneously with: the hydrolysis approach and standard addition of palmitic acid.}, subject = {NMR-Spektroskopie}, language = {en} } @article{HartmannsbergerScribaGuidolinetal.2024, author = {Hartmannsberger, Beate and Scriba, Sabrina and Guidolin, Carolina and Becker, Juliane and Mehling, Katharina and Doppler, Kathrin and Sommer, Claudia and Rittner, Heike L.}, title = {Transient immune activation without loss of intraepidermal innervation and associated Schwann cells in patients with complex regional pain syndrome}, series = {Journal of Neuroinflammation}, volume = {21}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-023-02969-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357164}, year = {2024}, abstract = {Background Complex regional pain syndrome (CRPS) develops after injury and is characterized by disproportionate pain, oedema, and functional loss. CRPS has clinical signs of neuropathy as well as neurogenic inflammation. Here, we asked whether skin biopsies could be used to differentiate the contribution of these two systems to ultimately guide therapy. To this end, the cutaneous sensory system including nerve fibres and the recently described nociceptive Schwann cells as well as the cutaneous immune system were analysed. Methods We systematically deep-phenotyped CRPS patients and immunolabelled glabrous skin biopsies from the affected ipsilateral and non-affected contralateral finger of 19 acute (< 12 months) and 6 chronic (> 12 months after trauma) CRPS patients as well as 25 sex- and age-matched healthy controls (HC). Murine foot pads harvested one week after sham or chronic constriction injury were immunolabelled to assess intraepidermal Schwann cells. Results Intraepidermal Schwann cells were detected in human skin of the finger—but their density was much lower compared to mice. Acute and chronic CRPS patients suffered from moderate to severe CRPS symptoms and corresponding pain. Most patients had CRPS type I in the warm category. Their cutaneous neuroglial complex was completely unaffected despite sensory plus signs, e.g. allodynia and hyperalgesia. Cutaneous innate sentinel immune cells, e.g. mast cells and Langerhans cells, infiltrated or proliferated ipsilaterally independently of each other—but only in acute CRPS. No additional adaptive immune cells, e.g. T cells and plasma cells, infiltrated the skin. Conclusions Diagnostic skin punch biopsies could be used to diagnose individual pathophysiology in a very heterogenous disease like acute CRPS to guide tailored treatment in the future. Since numbers of inflammatory cells and pain did not necessarily correlate, more in-depth analysis of individual patients is necessary.}, language = {en} } @article{MittermeierSeidelScheineretal.2024, author = {Mittermeier, Sabrina and Seidel, Alexandra and Scheiner, Christin and Kleindienst, Nikolaus and Romanos, Marcel and Buerger, Arne}, title = {Emotional dysregulation and its pathways to suicidality in a community-based sample of adolescents}, series = {Child and Adolescent Psychiatry and Mental Health}, volume = {18}, journal = {Child and Adolescent Psychiatry and Mental Health}, issn = {1753-2000}, doi = {10.1186/s13034-023-00699-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357501}, year = {2024}, abstract = {Objective Effective suicide prevention for adolescents is urgently needed but difficult, as suicide models lack a focus on age-specific influencing factors such as emotional dysregulation. Moreover, examined predictors often do not specifically consider the contribution to the severity of suicidality. To determine which adolescents are at high risk of more severe suicidality, we examined the association between emotional dysregulation and severity of suicidality directly as well as indirectly via depressiveness and nonsuicidal self-injury. Method Adolescents from 18 high schools in Bavaria were included in this cross-sectional and questionnaire-based study as part of a larger prevention study. Data were collected between November 2021 and March 2022 and were analyzed from January 2023 to April 2023. Students in the 6th or 7th grade of high school (11-14 years) were eligible to participate. A total of 2350 adolescents were surveyed and data from 2117 students were used for the analyses after excluding incomplete data sets. Our main outcome variable was severity of suicidality (Paykel Suicide Scale, PSS). Additionally, we assessed emotional dysregulation (Difficulties in Emotion Regulation Scale, DERS-SF), depressiveness (Patient Health Questionnaire, PHQ-9) and nonsuicidal self-injury (Deliberate Self-Harm Inventory, DSHI). Results In total, 2117 adolescents (51.6\% female; mean age, 12.31 years [standard deviation: 0.67]) were included in the structural equation model (SEM). Due to a clear gender-specific influence, the model was calculated separately for male and female adolescents. For male adolescents, there was a significant indirect association between emotional dysregulation and severity of suicidality, mediated by depressiveness (β = 0.15, SE = .03, p = .008). For female adolescents, there was a significant direct path from emotional dysregulation to severity of suicidality and also indirect paths via depressiveness (β = 0.12, SE = .05, p = 0.02) and NSSI (β = 0.18, SE = .04, p < .001). Conclusions Our results suggest that gender-related risk markers in 11-14-year-olds need to be included in future suicide models to increase their predictive power. According to our findings, early detection and prevention interventions based on emotion regulation skills might be enhanced by including gender-specific adjustments for the co-occurrence of emotional dysregulation, depressiveness, and nonsuicidal self-injury in girls and the co-occurrence of emotional dysregulation and depressiveness in boys.}, language = {en} } @phdthesis{Chen2024, author = {Chen, Xinyu}, title = {How natural walking changes occipital alpha oscillations and concurrently modulates cognitive processes}, doi = {10.25972/OPUS-35295}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352958}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Humans actively interact with the world through a wide range of body movements. To understand human cognition in its natural state, we need to incorporate ecologically relevant body movement into our account. One fundamental body movement during daily life is natural walking. Despite its ubiquity, the impact of natural walking on brain activity and cognition has remained a realm underexplored. In electrophysiology, previous studies have shown a robust reduction of ongoing alpha power in the parieto-occipital cortex during body movements. However, what causes the reduction of ongoing alpha, namely whether this is due to body movement or prevalent sensory input changes, was unknown. To clarify this, study 1 was performed to test if the alpha reduction is dependent on visual input. I compared the resting state alpha power during natural walking and standing, in both light and darkness. The results showed that natural walking led to decreased alpha activity over the occipital cortex compared to standing, regardless of the lighting condition. This suggests that the movement-induced modulation of occipital alpha activity is not driven by visual input changes during walking. I argue that the observed alpha power reduction reflects a change in the state of the subject based on disinhibition induced by walking. Accordingly, natural walking might enhance visual processing and other cognitive processes that involve occipital cortical activity. I first tested this hypothesis in vision. Study 2 was performed to examine the possible effects of natural walking across visual processing stages by assessing various neural markers during different movement states. The findings revealed an amplified early visual response, while a later visual response remain unaffected. A follow-up study 3 replicated the walking-induced enhancement of the early visual evoked potential and showed that the enhancement was dependent on specific stimulus-related parameters (eccentricity, laterality, distractor presence). Importantly, the results provided evidence that the enhanced early visual responses are indeed linked to the modulation of ongoing occipital alpha power. Walking also modulated the stimulus-induced alpha power. Specifically, it showed that when the target appeared in the fovea area without a distractor, walking exhibited a significantly reduced modulation of alpha power, and showed the largest difference to standing condition. This effect of eccentricity indicates that during later visual processing stages, the visual input in the fovea area is less processed than in peripheral areas while walking. The two visual studies showed that walking leads to an enhancement in temporally early visual processes which can be predicted by the walking-induced change in ongoing alpha oscillation likely marking disinhibition. However, while walking affects neural markers of early sensory processes, it does not necessarily lead to a change in the behavioural outcome of a sensory task. The two visual studies suggested that the behavioural outcome seems to be mainly based on later processing stages. To test the effects of walking outside the visual domain, I turned to audition in study 4. I investigated the influence of walking in a particular path vs. simply stepping on auditory processing. Specifically, the study tested whether enhanced processing due to natural walking can be found in primary auditory brain activity and whether the processing preferences are dependent on the walking path. In addition, I tested whether the changed spatial processing that was reported in previous visual studies can be seen in the auditory domain. The results showed enhanced sensory processing due to walking in the auditory domain, which was again linked to the modulation of occipital alpha oscillation. The auditory processing was further dependent on the walking path. Additionally, enhanced peripheral sensory processing, as found in vision, was also present in audition. The findings outside vision supported the idea of natural walking affecting cognition in a rather general way. Therefore in my study 5, I examined the effect of natural walking on higher cognitive processing, namely divergent thinking, and its correlation with the modulation of ongoing alpha oscillation. I analyzed alpha oscillations and behavioural performance during restricted and unrestricted movement conditions while subjects completed a Guilford's alternate uses test. The results showed that natural walking, as well as missing body restriction, reduces the occipital alpha ongoing power independent of the task phase which goes along with higher test scores. The occipital alpha power reduction can therefore be an indicator of a changed state that allows improved higher cognitive processes. In summary, the research presented in this thesis highlights that natural walking can change different processes in the visual and auditory domain as well as higher cognitive processes. The effect can be attributed to the movement of natural walking itself rather than to changes in sensory input during walking. The results further indicate that the walking-induced modulation of ongoing occipital alpha oscillations drives the cognitive effects. We therefore suggest that walking changes the inhibitory state which can influence awareness and attention. Such a mechanism could facilitate an adaptive enhancement in cognitive processes and thereby optimize movement-related behaviour such as navigation.}, subject = {Walking}, language = {en} } @misc{Schnermann2024, type = {Master Thesis}, author = {Schnermann, Sophia Victoria}, title = {The impact of China's e-mobility development on German motor vehicle manufacturers}, doi = {10.25972/OPUS-35327}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-353276}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Compared to other countries, China was particularly early in developing a comprehensive set of policies to promote electric mobility (e-mobility). The aim of this study is to examine how China's e-mobility development - through changes in formal institutions as well as market forces - has affected German passenger car manufacturers and their competitive environment and positions. The study is guided by two strands of research: new institutional economics and strategic management literature. A holistic multiple-case design is used to analyze five German case study firms. Qualitative interview data are collected through interviews and analyzed using a thematic analysis. The results show that the electric transformation in China has been shaped by changes in formal institutions at the macro, meso, and micro levels. Interestingly, the case study firms were affected not only by changes in China's formal institutions but also by disparities between institutions in China and Europe. Furthermore, the data suggest that German car manufacturers are facing an increasingly competitive environment in China: at least four forces in Porter's five-forces model seem to have intensified in recent years. The extent to which the case study firms have been affected by these developments may depend on the industry segments in which they are positioned. However, it can be argued that the electric transition has blurred the lines between traditional segments of the car industry to some extent. The interview data do not provide evidence that any of the German car brands have substantially changed their positioning, but they do suggest that some of the case study companies did not have an adequate offering for the Chinese market at the time of the interviews. In addition, the study finds that China's transition to e-mobility has led to changes in various parts of the German automakers' value chains, including production, sales, marketing, services, research and development, and procurement. Whether these changes will ultimately result in competitive advantage, parity, or disadvantage remains to be seen.}, subject = {Institutionen{\"o}konomie}, language = {en} } @misc{OPUS4-36110, title = {BLICK 2023 - Jahrbuch der Julius-Maximilians-Universit{\"a}t W{\"u}rzburg}, volume = {2023}, organization = {Julius-Maximilians-Universit{\"a}t W{\"u}rzburg}, issn = {2192-1431}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361103}, year = {2024}, abstract = {Die Entwicklung der Universit{\"a}t W{\"u}rzburg im Jahr 2023.}, subject = {Bericht}, language = {de} } @phdthesis{Allgaier2024, author = {Allgaier, Johannes}, title = {Machine Learning Explainability on Multi-Modal Data using Ecological Momentary Assessments in the Medical Domain}, doi = {10.25972/OPUS-35118}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351189}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Introduction. Mobile health (mHealth) integrates mobile devices into healthcare, enabling remote monitoring, data collection, and personalized interventions. Machine Learning (ML), a subfield of Artificial Intelligence (AI), can use mHealth data to confirm or extend domain knowledge by finding associations within the data, i.e., with the goal of improving healthcare decisions. In this work, two data collection techniques were used for mHealth data fed into ML systems: Mobile Crowdsensing (MCS), which is a collaborative data gathering approach, and Ecological Momentary Assessments (EMA), which capture real-time individual experiences within the individual's common environments using questionnaires and sensors. We collected EMA and MCS data on tinnitus and COVID-19. About 15 \% of the world's population suffers from tinnitus. Materials \& Methods. This thesis investigates the challenges of ML systems when using MCS and EMA data. It asks: How can ML confirm or broad domain knowledge? Domain knowledge refers to expertise and understanding in a specific field, gained through experience and education. Are ML systems always superior to simple heuristics and if yes, how can one reach explainable AI (XAI) in the presence of mHealth data? An XAI method enables a human to understand why a model makes certain predictions. Finally, which guidelines can be beneficial for the use of ML within the mHealth domain? In tinnitus research, ML discerns gender, temperature, and season-related variations among patients. In the realm of COVID-19, we collaboratively designed a COVID-19 check app for public education, incorporating EMA data to offer informative feedback on COVID-19-related matters. This thesis uses seven EMA datasets with more than 250,000 assessments. Our analyses revealed a set of challenges: App user over-representation, time gaps, identity ambiguity, and operating system specific rounding errors, among others. Our systematic review of 450 medical studies assessed prior utilization of XAI methods. Results. ML models predict gender and tinnitus perception, validating gender-linked tinnitus disparities. Using season and temperature to predict tinnitus shows the association of these variables with tinnitus. Multiple assessments of one app user can constitute a group. Neglecting these groups in data sets leads to model overfitting. In select instances, heuristics outperform ML models, highlighting the need for domain expert consultation to unveil hidden groups or find simple heuristics. Conclusion. This thesis suggests guidelines for mHealth related data analyses and improves estimates for ML performance. Close communication with medical domain experts to identify latent user subsets and incremental benefits of ML is essential.}, subject = {Maschinelles Lernen}, language = {en} } @article{StanglPoppReisetal.2024, author = {Stangl, Stephanie and Popp, Maria and Reis, Stefanie and Sitter, Magdalena and Saal-Bauernschubert, Lena and Schießer, Selina and Kranke, Peter and Choorapoikayil, Suma and Weibel, Stephanie and Meybohm, Patrick}, title = {Reported outcomes in patients with iron deficiency or iron deficiency anemia undergoing major surgery: a systematic review of outcomes}, series = {Systematic Reviews}, volume = {13}, journal = {Systematic Reviews}, doi = {10.1186/s13643-023-02431-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357213}, year = {2024}, abstract = {Background Iron deficiency (ID) is the leading cause of anemia worldwide. The prevalence of preoperative ID ranges from 23 to 33\%. Preoperative anemia is associated with worse outcomes, making it important to diagnose and treat ID before elective surgery. Several studies indicated the effectiveness of intravenous iron supplementation in iron deficiency with or without anemia (ID(A)). However, it remains challenging to establish reliable evidence due to heterogeneity in utilized study outcomes. The development of a core outcome set (COS) can help to reduce this heterogeneity by proposing a minimal set of meaningful and standardized outcomes. The aim of our systematic review was to identify and assess outcomes reported in randomized controlled trials (RCTs) and observational studies investigating iron supplementation in iron-deficient patients with or without anemia. Methods We searched MEDLINE, CENTRAL, and ClinicalTrials.gov systematically from 2000 to April 1, 2022. RCTs and observational studies investigating iron supplementation in patients with a preoperative diagnosis of ID(A), were included. Study characteristics and reported outcomes were extracted. Outcomes were categorized according to an established outcome taxonomy. Quality of outcome reporting was assessed with a pre-specified tool. Reported clinically relevant differences for sample size calculation were extracted. Results Out of 2898 records, 346 underwent full-text screening and 13 studies (five RCTs, eight observational studies) with sufficient diagnostic inclusion criteria for iron deficiency with or without anemia (ID(A)) were eligible. It is noteworthy to mention that 49 studies were excluded due to no confirmed diagnosis of ID(A). Overall, 111 outcomes were structured into five core areas including nine domains. Most studies (92\%) reported outcomes within the 'blood and lymphatic system' domain, followed by "adverse event" (77\%) and "need for further resources" (77\%). All of the latter reported on the need for blood transfusion. Reported outcomes were heterogeneous in measures and timing. Merely, two (33\%) of six prospective studies were registered prospectively of which one (17\%) showed no signs of selective outcome reporting. Conclusion This systematic review comprehensively depicts the heterogeneity of reported outcomes in studies investigating iron supplementation in ID(A) patients regarding exact definitions and timing. Our analysis provides a systematic base for consenting to a minimal COS. Systematic review registration PROSPERO CRD42020214247}, language = {en} } @phdthesis{SeyferthZapf2024, author = {Seyferth-Zapf, Maria}, title = {F{\"o}rderung interkultureller Kompetenz unter Verwendung digitaler Medienangebote und Gestaltung medialer Beitr{\"a}ge. Praxis- und theorieorientierte Entwicklung und Evaluation eines Unterrichtskonzepts f{\"u}r die Sekundarstufe I.}, doi = {10.25972/OPUS-34932}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349328}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Angesichts aktueller und zur{\"u}ckliegender Migrations- und Fluchtprozesse in Deutschland kommen Jugendliche der Residenzgesellschaft in verschiedenen Bereichen ihres Lebens mit Menschen mit Flucht- oder Migrationserfahrung in Kontakt, woraus sich Chancen und Entwicklungspotenziale, aber auch Herausforderungen ergeben. Beispielsweise kann vermehrter interkultureller Kontakt auf individueller Ebene zur Weiterentwicklung von Toleranz und Empathie f{\"u}hren. Jedoch k{\"o}nnen Jugendliche der Residenzgesellschaft auf vermehrte Zuwanderung auch mit einem Gef{\"u}hl der Unsicherheit und einer ablehnenden Haltung gegen{\"u}ber Menschen mit Flucht- oder Migrationserfahrung reagieren. Diese Reaktionen k{\"o}nnen durch einseitige oder negative Medienberichte zum Themenkomplex Flucht und Migration verst{\"a}rkt werden. Um Chancen und Entwicklungspotenziale aussch{\"o}pfen sowie Herausforderungen im Kontext von Flucht und Migration bew{\"a}ltigen zu k{\"o}nnen, m{\"u}ssen Jugendliche in der Entwicklung interkultureller Kompetenz gef{\"o}rdert werden. Interkulturelle Kompetenz ist eine wesentliche Voraussetzung f{\"u}r das Zusammenleben in einer pluralistischen Gesellschaft und daher ein bedeutsames Bildungs- und Erziehungsziel f{\"u}r Schule und Unterricht. Die Zielstellung der vorliegenden Forschungsarbeit ist demnach die praxis- und theorieorientierte Entwicklung und Evaluation eines Unterrichtskonzepts zur F{\"o}rderung interkultureller Kompetenz unter Verwendung digitaler Medienangebote und Gestaltung medialer Beitr{\"a}ge. Hinsichtlich theoretischer Grundlagen zu interkultureller Kompetenz wird vor dem Hintergrund eines an Offenheit, Prozesshaftigkeit und Heterogenit{\"a}t orientierten Kulturbegriffs Interkulturalit{\"a}t als sozialer Prozess verstanden, in dem sich Personen unterschiedlicher kultureller bzw. kollektiver Zugeh{\"o}rigkeiten begegnen, miteinander interagieren und kommunizieren. Interkulturelle Kompetenz setzt sich aus Wissen (kognitive Dimension), Einstellungen (affektive Dimension) sowie Verhaltensweisen (behaviorale Dimension) zusammen und es wird angenommen, dass diese erlernt und gef{\"o}rdert werden kann. Vorgehensweisen zur Entwicklung interkultureller Kompetenz sollten die kognitive, affektive und behaviorale Dimension interkultureller Kompetenz adressieren, die Reflexion authentischer, kritischer {\"U}berschneidungssituationen einbeziehen sowie realweltliche, interkulturelle Begegnungen als Lerngelegenheiten aufgreifen. Bez{\"u}glich theoretischer Grundlagen zum Lehren und Lernen mit Medien stellt vor dem Hintergrund verschiedener Ans{\"a}tze zum Lehren und Lernen mit Medien die handlungs- und entwicklungsorientierte Didaktik eine bedeutsame Grundlage f{\"u}r die vorliegende Forschungsarbeit dar. Sie wird bez{\"u}glich der Prinzipien der Situations-, Bed{\"u}rfnis-, Erfahrungs- und Entwicklungsorientierung, der Bedeutsamkeit komplexer, lernprozessanregender Aufgabenstellungen und einer idealtypischen Strukturierung von Unterricht mit theoretischen Grundlagen interkultureller Kompetenz und Vorgehensweisen zu ihrer F{\"o}rderung in Beziehung gesetzt. Hinsichtlich des forschungsmethodischen Vorgehens wird auf Basis einer Gegen{\"u}berstellung verschiedener Ans{\"a}tze der gestaltungsorientierten Bildungsforschung der Ansatz einer praxis- und theorieorientierten Entwicklung und Evaluation von Konzepten unterrichtlichen Handelns f{\"u}r die vorliegende Forschungsarbeit begr{\"u}ndet ausgew{\"a}hlt und seine Umsetzung erl{\"a}utert. Im Rahmen der ersten Studie wird auf der Basis theoretischer und empirischer Grundlagen interkultureller Kompetenz und didaktischer Zug{\"a}nge ein p{\"a}dagogisches Konzept zur F{\"o}rderung interkultureller Kompetenz von Sch{\"u}lerinnen und Sch{\"u}lern der Sekundarstufe I unter Verwendung digitaler Medien entwickelt und f{\"u}r eine achte Klasse am Gymnasium konkretisiert. Das Konzept wird hinsichtlich seiner Zielerreichung sowie auftretender Nebenwirkungen unter Einsatz von Mixed Methods evaluiert. Die Ergebnisse weisen unter anderem darauf hin, dass das entwickelte Unterrichtskonzept zur F{\"o}rderung interkultureller Kompetenz der Sch{\"u}lerinnen und Sch{\"u}ler beigetragen hat. Die zweite Studie stellt eine erg{\"a}nzende qualitative Studie dar, mit dem Ziel, die gemeinsame Mediengestaltung in Zusammenarbeit von Lernenden mit und ohne Flucht- bzw. Migrationserfahrung als bedeutsame Lernaktivit{\"a}t des Unterrichtskonzepts vertiefend zu untersuchen und Vorgehensweisen des kollaborativen Gestaltungsprozesses, die aus der Perspektive der Sch{\"u}lerinnen und Sch{\"u}ler wichtig sind, zu identifizieren. Hierzu werden die subjektiven Sichtweisen der Gymnasiastinnen und Gymnasiasten auf die Gestaltung medialer Beitr{\"a}ge in interkultureller Begegnung unter Bezugnahme auf interkulturelle Sensibilit{\"a}t in Fokusgruppen erhoben und qualitativ-inhaltsanalytisch ausgewertet. Die Ergebnisse der qualitativen Inhaltsanalyse zeigen, dass im Rahmen der Mediengestaltung verschiedene Komponenten interkultureller Sensibilit{\"a}t angesprochen wurden. Beispielsweise geben einige Gymnasiastinnen und Gymnasiasten an, dass ihnen sowohl die Zusammenarbeit mit den Mittelsch{\"u}lerinnen und -sch{\"u}lern als auch die gemeinsame Mediengestaltung Freude bereitete. In der dritten Studie werden die von den Sch{\"u}lerinnen und Sch{\"u}lern gestalteten Medienbeitr{\"a}ge aus interkulturell-kommunikativer und medienbezogener Perspektive vertiefend analysiert. Die Auswertung erfolgt durch qualitative Inhaltsanalysen hinsichtlich wesentlicher Aspekte der Kommunikationssituation, der Medienmerkmale sowie Bezugspunkten zur behavioralen Dimension interkultureller Kompetenz. Aus den Ergebnissen der Videoanalysen geht unter anderem hervor, dass die interkulturellen Begegnungssituationen, die im Rahmen der Beitr{\"a}ge dargestellt werden, aus kommunikationstheoretischer Perspektive komplex und vielschichtig sind. Nach einer abschließenden kritischen Methodenreflexion werden Ergebnisse der Studien zusammengef{\"u}hrt und interpretiert. Beispielsweise geht aus der Zusammenf{\"u}hrung der Ergebnisse aus der ersten und der zweiten Studie hervor, dass sich zwischen Pre- und Post-Test eine statistisch signifikante Steigerung des Mittelwertes der Komponente Aufmerksamkeit w{\"a}hrend der interkulturellen Interaktion ergibt, was unter Ber{\"u}cksichtigung der Resultate aus den Fokusgruppen als gesteigertes Interesse der Probandinnen und Probanden an den Sch{\"u}lerinnen und Sch{\"u}lern der Mittelschulklasse im Laufe der gemeinsamen Videogestaltung gedeutet werden kann. Die vergleichende Betrachtung von Ergebnissen aus der ersten und der dritten Studie zeigt, dass mit einer Steigerung des Summenscores der behavioralen Dimension interkultureller Kompetenz Bez{\"u}ge zu verschiedenen Komponenten der behavioralen Dimension im Rahmen der gestalteten Videos in Verbindung stehen. Hinsichtlich der Konsequenzen f{\"u}r zuk{\"u}nftige Forschung wird abschließend auf die Notwendigkeit der Entwicklung von Verfahren zur Erfassung interkultureller Kompetenz von Jugendlichen mit unzureichenden Deutschkenntnissen verwiesen. Bez{\"u}glich der Praxis in Schule und Unterricht ist die F{\"o}rderung interkultureller Kompetenz unter Verwendung und Gestaltung digitaler Medienangebote bzw. -beitr{\"a}ge als schulische Querschnittsaufgabe aller Jahrgangsstufen, F{\"a}cher und Schulformen wahrzunehmen. Insgesamt leistet die vorliegende Forschungsarbeit damit einen Beitrag zur Verkn{\"u}pfung der F{\"o}rderung interkultureller Kompetenz mit der interkulturell-kooperativen Gestaltung medialer Beitr{\"a}ge.}, subject = {Interkulturelle Kompetenz}, language = {de} } @phdthesis{Bayer2024, author = {Bayer, Florian}, title = {Investigating electromagnetic properties of topological surface states in mercury telluride}, doi = {10.25972/OPUS-35212}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352127}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {This doctoral thesis investigates magneto-optical properties of mercury telluride layers grown tensile strained on cadmium telluride substrates. Here, layer thicknesses start above the usual quantum well thickness of about 20 nm and have a upper boundary around 100 nm due to lattice relaxation effects. This kind of layer system has been attributed to the material class of three-dimensional topological insulators in numerous publications. This class stands out due to intrinsic boundary states which cross the energetic band gap of the layer's bulk. In order to investigate the band structure properties in a narrow region around the Fermi edge, including possible boundary states, the method of highly precise time-domain Terahertz polarimetry is used. In the beginning, the state of the art of Teraherz technology at the start of this project is discussed, moving on to a detailed description and characterization of the self-built measurement setup. Typical standard deviation of a polarization rotation or ellipticity measurement are on the order of 10 to 100 millidegrees, according to the transmission strength through investigated samples. A range of polarization spectra, depending on external magnetic fields up to 10 Tesla, can be extracted from the time-domain signal via Fourier transformation. The identification of the actual band structure is done by modeling possible band structures by means of the envelope function approximation within the framework of the k·p method. First the bands are calculated based on well-established model parameters and from them the possible optical transitions and expected ellipticity spectra, all depending on external magnetic fields and the layer's charge carrier concentration. By comparing expected with measured spectra, the validity of k·p models with varying depths of detail is analyzed throughout this thesis. The rich information encoded in the ellipitcity spectra delivers key information for the attribution of single optical transitions, which are not part of pure absorption spectroscopy. For example, the sign of the ellipticity signals is linked to the mix of Landau levels which contribute to an optical transition, which shows direct evidence for bulk inversion asymmetry effects in the measured spectra. Throughout the thesis, the results are compared repeatedly with existing publications on the topic. It is shown that the models used there are often insufficient or, in worst case, plainly incorrect. Wherever meaningful and possible without greater detours, the differences to the conclusions that can be drawn from the k·p model are discussed. The analysis ends with a detailed look on remaining differences between model and measurement. It contains the quality of model parameters as well as different approaches to integrate electrostatic potentials that exist in the structures into the model. An outlook on possible future developments of the mercury cadmium telluride layer systems, as well as the application of the methods shown here onto further research questions concludes the thesis.}, subject = {Quecksilbertellurid}, language = {en} } @phdthesis{Endres2024, author = {Endres, Leo Maximilian}, title = {Development of multicellular \(in\) \(vitro\) models of the meningeal blood-CSF barrier to study \(Neisseria\) \(meningitidis\) infection}, doi = {10.25972/OPUS-34621}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-346216}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Neisseria meningitidis (the meningococcus) is one of the major causes of bacterial meningitis, a life-threatening inflammation of the meninges. Traversal of the meningeal blood-cerebrospinal fluid barrier (mBCSFB), which is composed of highly specialized brain endothelial cells (BECs), and subsequent interaction with leptomeningeal cells (LMCs) are critical for disease progression. Due to the human-exclusive tropism of N. meningitidis, research on this complex host-pathogen interaction is mostly limited to in vitro studies. Previous studies have primarily used peripheral or immortalized BECs alone, which do not retain relevant barrier phenotypes in culture. To study meningococcal interaction with the mBCSFB in a physiologically more accurate context, BEC-LMC co-culture models were developed in this project using BEC-like cells derived from induced pluripotent stem cells (iBECs) or hCMEC/D3 cells in combination with LMCs derived from tumor biopsies. Distinct BEC and LMC layers as well as characteristic expression of cellular markers were observed using transmission electron microscopy (TEM) and immunofluorescence staining. Clear junctional expression of brain endothelial tight and adherens junction proteins was detected in the iBEC layer. LMC co-culture increased iBEC barrier tightness and stability over a period of seven days, as determined by sodium fluorescein (NaF) permeability and transendothelial electrical resistance (TEER). Infection experiments demonstrated comparable meningococcal adhesion and invasion of the BEC layer in all models tested, consistent with previously published data. While only few bacteria crossed the iBEC-LMC barrier initially, transmigration rates increased substantially over 24 hours, despite constant high TEER. After 24 hours of infection, deterioration of the barrier properties was observed including loss of TEER and altered expression of tight and adherens junction components. Reduced mRNA levels of ZO-1, claudin-5, and VE-cadherin were detected in BECs from all models. qPCR and siRNA knockdown data suggested that transcriptional downregulation of these genes was potentially but not solely mediated by Snail1. Immunofluorescence staining showed reduced junctional coverage of occludin, indicating N. meningitidis-induced post-transcriptional modulation of this protein, as previous studies have suggested. Together, these results suggest a potential combination of transcellular and paracellular meningococcal traversal of the mBCSFB, with the more accessible paracellular route becoming available upon barrier disruption after prolonged N. meningitidis infection. Finally, N. meningitidis induced cellular expression of pro-inflammatory cytokines and chemokines such as IL-8 in all mBCSFB models. Overall, the work described in this thesis highlights the usefulness of advanced in vitro models of the mBCSFB that mimic native physiology and exhibit relevant barrier properties to study infection with meningeal pathogens such as N. meningitidis.}, subject = {Bakterielle Hirnhautentz{\"u}ndung}, language = {en} } @phdthesis{Schmid2024, author = {Schmid, Kerstin}, title = {Integrative, three-dimensional \(in\) \(silico\) modeling of gas exchange in the human alveolus}, doi = {10.25972/OPUS-35182}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351823}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die Lunge erf{\"u}llt durch den Austausch von Atemgasen eine {\"u}berlebenswichtige Aufgabe. Der Gasaustausch erfolgt durch einen einfachen, aber entscheidenden passiven Diffusionsprozess. Dieser findet in den Alveolen statt, ballonartigen Strukturen, die an die peripheren Atemwege grenzen. Alveolen sind von einem dichten Netz aus kleinen Kapillaren umgeben. Hier kommt die eingeatmete Luft in unmittelbare N{\"a}he zu dem vom Herzen kommenden sauerstoffarmen Blut und erm{\"o}glicht den Austausch von Sauerstoff und Kohlenstoffdioxid {\"u}ber deren Konzentrationsgradienten. Die Effizienz des Gasaustauschs kann anhand von Indikatoren wie der Sauerstoffdiffusionskapazit{\"a}t der Lunge und der Reaktionshalbzeit gemessen werden. Beim Menschen besteht eine betr{\"a}chtliche Diskrepanz zwischen physiologischen Sch{\"a}tzungen der Diffusionskapazit{\"a}t und der theoretischen Maximalkapazit{\"a}t unter optimalen strukturellen Bedingungen (der morphologischen Sch{\"a}tzung). Diese Diskrepanz wird durch eine Reihe ineinandergreifender Faktoren beeinflusst, darunter strukturelle Elemente wie die Oberfl{\"a}che und die Dicke der Diffusionsbarriere sowie physiologische Faktoren wie die Blutflussdynamik. Um die verschiedenen Rollen dieser Faktoren zu entschl{\"u}sseln, untersuchten wir, wie die morphologischen und physiologischen Eigenschaften der menschlichen alveol{\"a}ren Mikroumgebung kollektiv und individuell den Prozess des Gasaustauschs beeinflussen. Zu diesem Zweck entwickelten wir einen integrativen in silico Ansatz, der 3D morphologische Modellierung und Simulation von Blutfluss und Sauerstofftransport kombiniert. Im Mittelpunkt unseres Ansatzes steht die Simulationssoftware Alvin, die als interaktive Plattform f{\"u}r das zugrundeliegende mathematische Modell des Sauerstofftransports in der Alveole dient. Unser r{\"a}umlich-zeitliches Modell wurde durch die Integration und Erweiterung bestehender mathematischer Modelle entwickelt und liefert Ergebnisse, die mit experimentellen Daten im Einklang stehen. Alvin erm{\"o}glicht eine immersive Auseinandersetzung mit dem simulierten Gasaustausch, indem sie Parameter{\"a}nderungen in Echtzeit und die Ausf{\"u}hrung mehrerer Simulationsinstanzen gleichzeitig erm{\"o}glicht w{\"a}hrend sie ein detailliertes quantitatives Feedback liefert. Die beteiligten morphologischen und physiologischen Parameter wurden mit einem Fokus auf der Mikrovaskulatur weiter untersucht. Durch die Zusammenstellung stereologischer Daten aus der Literatur und geometrischer 3D-Modellierung erstellten wir ein "sheet-flow" Modell als realistische Darstellung des menschlichen alveol{\"a}ren Kapillarnetzwerks. Blutfluss wurde mit Hilfe numerischer Str{\"o}mungsdynamik simuliert. Unsere Ergebnisse stimmen mit fr{\"u}heren Sch{\"a}tzungen {\"u}berein und unterstreichen die entscheidende Rolle von Viskosit{\"a}tsmodellen bei der Vorhersage des Druckabfalls in der Mikrovaskulatur. Dar{\"u}ber hinaus zeigten wir, wie unser Ansatz genutzt werden kann, um strukturelle Details wie die Konnektivit{\"a}t des alveol{\"a}ren Kapillarnetzes mit dem Gef{\"a}ßbaum anhand von Blutflussindizes zu untersuchen. Es ist wichtig zu betonen, dass wir uns bislang auf verschiedene Datenquellen st{\"u}tzten und dass f{\"u}r weitere Fortschritte eine experimentelle Vailidierung erforderlich ist. Die Integration unserer Ergebnisse in Alvin erm{\"o}glichte die Quantifizierung des simulierten Gasaustauschprozesses {\"u}ber die Sauerstoffdiffusionskapazit{\"a}t und die Reaktionshalbzeit. Neben der Bewertung der kollektiven Einfl{\"u}sse der morphologischen und physiologischen Eigenschaften erleichterte unsere interaktive Software auch die Bewertung einzelner Parameter{\"a}nderungen. Die Betrachtung des Blutvolumens und der f{\"u}r den Gasaustausch zur Verf{\"u}gung stehenden Oberfl{\"a}che ergab lineare Korrelationen mit der Diffusionskapazit{\"a}t. Die Blutflussgeschwindigkeit hatte einen positiven, nichtlinearen Effekt auf die Diffusionskapazit{\"a}t. Die Reaktionshalbzeit best{\"a}tigte, dass der Gasaustauschprozess in der Regel nicht diffusionslimitiert ist. Insgesamt lieferte unser Alveolenmodell einen Wert f{\"u}r die Diffusionskapazit{\"a}t, der in der Mitte der fr{\"u}heren physiologischen und morphologischen Sch{\"a}tzung lag. Daraus l{\"a}sst sich schließen, dass Ph{\"a}nomene auf Alveolarebene zu 50\% der Limitierung der Diffusionskapazit{\"a}t beitragen, die in vivo eintreten. Zusammenfassend l{\"a}sst sich sagen, dass unser integrativer in silico Ansatz verschiedene strukturelle und funktionelle Einfl{\"u}sse auf den alveol{\"a}ren Gasaustausch aufschl{\"u}sselt und damit die traditionelle Forschung in der Atemwegsforschung erg{\"a}nzt. Zus{\"a}tzlich zeigen wir seinen Nutzen in der Lehre oder bei der Interpretation ver{\"o}ffentlichter Daten auf. Um unser Verst{\"a}ndnis zu verbessern, sollten k{\"u}nftige Arbeiten vorrangig darauf ausgerichtet sein, einen zusammenh{\"a}ngenden experimentellen Datensatz zu erhalten und ein geeignetes Viskosit{\"a}tsmodell f{\"u}r Blutflusssimulationen zu finden.}, subject = {Gasaustausch}, language = {en} } @unpublished{OdenwaldGabiattiBrauneetal.2024, author = {Odenwald, Johanna and Gabiatti, Bernardo and Braune, Silke and Shen, Siqi and Zoltner, Martin and Kramer, Susanne}, title = {Beyond BioID: Streptavidin outcompetes antibody fluorescence signals in protein localization and readily visualises targets evading immunofluorescence detection}, series = {eLife}, journal = {eLife}, doi = {10.7554/eLife.95028.1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360704}, year = {2024}, abstract = {Immunofluorescence is a common method to localise proteins within their cellular context via fluorophore labelled antibodies and for some applications without alternative. However, some protein targets evade detection due to low protein abundance or accessibility issues. In addition, some imaging methods require a massive reduction in antigen density thus impeding detection of even medium-abundant proteins.Here, we show that the fusion of the target protein to TurboID, a biotin ligase labelling lysine residues in close proximity, and subsequent detection of biotinylation by fluorescent streptavidin offers an "all in one" solution to the above-mentioned restrictions. For a wide range of target proteins tested, the streptavidin signal was significantly stronger than an antibody signal, markedly improving the imaging sensitivity in expansion microscopy and correlative light and electron microscopy, with no loss in resolution. Importantly, proteins within phase-separated regions, such as the central channel of the nuclear pores, the nucleolus or RNA granules, were readily detected with streptavidin, while most antibodies fail to label proteins in these environments. When TurboID is used in tandem with an HA epitope tag, co-probing with streptavidin and anti-HA can be used to map antibody-accessibility to certain cellular regions. As a proof of principle, we mapped antibody access to all trypanosome nuclear pore proteins (NUPs) and found restricted antibody labelling of all FG NUPs of the central channel that are known to be phase-separated, while most non-FG Nups could be labelled. Lastly, we show that streptavidin imaging can resolve dynamic, temporally and spatially distinct sub-complexes and, in specific cases, reveal a history of dynamic protein interaction.In conclusion, streptavidin imaging has major advantages for the detection of lowly abundant or inaccessible proteins and in addition, can provide information on protein interactions and biophysical environment.}, language = {en} } @phdthesis{Schneider2024, author = {Schneider, Kira}, title = {Die Panoramafreiheit - Eine internationale Untersuchung}, doi = {10.25972/OPUS-35128}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351285}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Gegenstand der Arbeit ist eine internationale Untersuchung der urheberrechtlichen Schranke der sogenannten Panoramafreiheit oder Freiheit des Straßenbildes. Durch diese Schranke wird das Urheberrecht an Werken im {\"o}ffentlichen Raum eingeschr{\"a}nkt. Auf unionsrechtlicher Ebene sieht die Richtlinie 2001/29/EG in Art. 5 Abs. 3 lit. h eine fakultative Schranke zugunsten der Freiheit des Straßenbildes vor. Diese fakultative Schranke wurde von den Mitgliedstaaten der Europ{\"a}ischen Union sehr unterschiedlich in nationales Recht umgesetzt. Nach \S 59 des deutschen Urheberrechtsgesetzes ist es zul{\"a}ssig, Werke, die sich bleibend an {\"o}ffentlichen Wegen, Straßen oder Pl{\"a}tzen befinden, mit Mitteln der Malerei oder Graphik, durch Lichtbild oder durch Film zu vervielf{\"a}ltigen, zu verbreiten und {\"o}ffentlich wiederzugeben. Daneben gibt es auch Mitgliedstaaten, die die Schranke nicht oder nur eingeschr{\"a}nkt in nationales Recht umgesetzt haben. Auch L{\"a}nder außerhalb der Europ{\"a}ischen Union sehen in nationalen Urheberrechtsgesetzen Regelungen zugunsten der Freiheit des Straßenbildes vor. Daher wurden im Rahmen der Arbeit verschiedene nationale Regelungen zur Panoramafreiheit gegen{\"u}bergestellt, um die wesentlichen Unterschiede zwischen den Vorschriften zu untersuchen und herauszuarbeiten.}, subject = {Panoramafreiheit}, language = {de} } @phdthesis{Wild2024, author = {Wild, Emanuel}, title = {Ist bei Kraftfahrzeugen eine Ankn{\"u}pfung an den Registrierungsort der Lex rei sitae vorzuziehen?}, doi = {10.25972/OPUS-35156}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351561}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {„Die Doktorarbeit befasst sich mit der Frage, ob bei Kraftfahrzeugen eine Ankn{\"u}pfung an den Registrierungsort der Lex rei sitae vorzuziehen sein k{\"o}nnte. Im Rahmen der Arbeit wird zu Beginn ermittelt, nach welchem Recht die {\"u}berpr{\"u}ften L{\"a}nder das anwendbare Recht bei Kraftfahrzeugen bestimmen. Sodann wird er{\"o}rtert, ob der Registrierungsort in den {\"u}berpr{\"u}ften L{\"a}ndern {\"u}berhaupt rechtssicher und stabil bestimmt werden kann. Dabei wird insbesondere auf die nationalen Vorschriften zur Registrierung von Kraftfahrzeugen und den weiteren Ankn{\"u}pfungsm{\"o}glichkeiten, wie Fahrzeugzulassungsbescheinigung und KFZ-Kennzeichen, eingegangen. Anhand von Beispielsf{\"a}llen werden abschließend die m{\"o}glichen Ver{\"a}nderungen, durch eine Ankn{\"u}pfung an den Registrierungsort im Gegen-satz zur lex rei sitae, gegen{\"u}bergestellt. Ebenso wird die Frage der res in transitu, als auch die Frage, wie mit gestohlenen Fahrzeugen umgegangen werden kann, behandelt. Im Ergebnis kann eine rechtssichere Bestimmung des anwendbaren Rechts best{\"a}tigt wer-den."}, subject = {Lex rei sitae}, language = {de} } @phdthesis{Schuerger2024, author = {Sch{\"u}rger, Peter}, title = {Information-Theoretical Studies on Time-Dependent Quantum Systems}, doi = {10.25972/OPUS-35221}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352215}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this thesis, we apply the information-theoretic approach in the context of quantum dynamics and wave packet motion: Information-theoretic measures are calculated from position and momentum densities, which are obtained from time-dependent quantum wave functions. The aim of this thesis is to benchmark, analyze and interpret these quantities and relate their features to the wave packet dynamics. Firstly, this is done for the harmonic oscillator (HO) with and without static disorder. In the unperturbed HO, the analytical study of coherent and squeezed states reveals time-dependent entropy expressions related to the localization of the wave function. In the disordered HO, entropies from classical and quantum dynamics are compared for short and long times. In the quantum case, imprints of wave packet revivals are found in the entropy. Then, the energy dependence of the entropy for very long times is discussed. Secondly, this is donefor correlated electron-nuclear motion. Here, entropies derived from the total, electronic and nuclear density, respectively, are calculated in position and momentum space for weak and strong adiabatic electronic coupling. The correlation between electron and nucleus is investigated using different correlation measures, where some of these functions are sensitive to the nodal structure of the wave function. An analytic ansatz to interpret the information-theoretical quantities is applied as well.}, subject = {St{\"o}rungstheorie}, language = {en} } @phdthesis{Trinks2024, author = {Trinks, Nora Isabel}, title = {Super-resolution fluorescence microscopic visualization and analysis of interactions between human immune cells and \(Aspergillus\) \(fumigatus\)}, doi = {10.25972/OPUS-26640}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266407}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The mold Aspergillus fumigatus (A. fumigatus) is known as human pathogen and can cause life-threatening infections in humans with a weakened immune system. This is a known complication in patients receiving glucocorticoids, e.g. after hematopoietic stem cell transplantation or solid organ transplantation. Although research in the field of immune cell/fungus interaction has discovered key strategies how immune cells fight against infectious fungi, our knowledge is still incomplete. In order to develop effective treatment options against fungal infections, a detailed understanding of their interactions is crucial. Thus, visualization of immune cell and fungus is an excellent approach to gain further knowledge. For a detailed view of such interaction processes, a high optical resolution on nanometer scale is required. There is a variety of super resolution microscopy techniques, enabling fluorescence imaging beyond the diffraction limit. This work combines the use of three complementary super resolution microscopy techniques, in order to study immune cell/fungus interaction from different points of view. Aim of this work is the introduction of the recently invented imaging technique named expansion microscopy (ExM) for the study of immune cell/fungus interactions. The core aspect of this method is the physical magnification of the specimen, which increases the distance between protein structures that are close to each other and which can therefore be imaged separately. The simultaneous magnification of primary human natural killer (NK) cells and A. fumigatus hyphae was established in this work using ExM. Reorganization of cytoskeletal components of interacting NK cells was demonstrated here, by expansion of the immunological synapse (IS), formed between NK cells and A. fumigatus. In addition, reorganization of the microtubule-organizing center (MTOC) towards fungal hyphae and an accumulation of actin at the IS has been observed. Furthermore, ExM has been used to visualize lytic granules of NK cells after degranulation. After magnification of the specimen, lysosome associated protein 1 (LAMP1) was shown to surround perforin. In absence of the plasma membrane-exposed degranulation marker LAMP1, a "ring-shaped" structure was often observed for fluorescently labeled perforin. Volume calculation of lytic granules demonstrated the benefit of ExM. Compared to pre-expansion images, analyses of post-expansion images showed two volume distributions for degranulated and non-degranulated NK cells. In addition, this work emphasizes the importance of determining the expansion factor for a structure in each species, as variations of expansion factors have been observed. This factor, as well as possible sample distortions should be considered, when ExM is used in order to analyze the interaction between two species. A second focus of this work is the visualization of a chimeric antigen receptor (CAR), targeting an epitope on the cell wall of A. fumigatus. Structured illumination microscopy (SIM) revealed that the CAR is part of the immunological synapse of primary human CAR T cells and CAR-NK-92 cells. At the interaction site, an accumulation of the CAR was observed, as well as the presence of perforin. CAR accumulation at fungal hyphae was further demonstrated by automated live cell imaging of interacting CAR-NK-92 cells, expressing a fluorescent fusion protein. Additionally, the use of direct stochastic optical reconstruction microscopy (dSTORM) gave first insights in CAR expression levels on the basal membrane of CAR-NK-92 cells, with single molecule sensitivity. CAR cluster analyses displayed a heterogeneous CAR density on the basal membrane of transfected NK 92 cells. In summary, this work provides insights into the application of ExM for studying the interaction of primary human NK cells and A. fumigatus for the first time. Furthermore, this thesis presents first insights regarding the characterization of an A. fumigatus-targeting CAR, by applying super-resolution fluorescence microscopy, like SIM and dSTORM.}, subject = {Mikroskopie}, language = {en} } @article{MeinertJessenHufnageletal.2024, author = {Meinert, Madlen and Jessen, Christina and Hufnagel, Anita and Kreß, Julia Katharina Charlotte and Burnworth, Mychal and D{\"a}ubler, Theo and Gallasch, Till and Da Xavier Silva, Thamara Nishida and Dos Santos, Anc{\´e}ly Ferreira and Ade, Carsten Patrick and Schmitz, Werner and Kneitz, Susanne and Friedmann Angeli, Jos{\´e} Pedro and Meierjohann, Svenja}, title = {Thiol starvation triggers melanoma state switching in an ATF4 and NRF2-dependent manner}, series = {Redox Biology}, volume = {70}, journal = {Redox Biology}, doi = {10.1016/j.redox.2023.103011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350328}, year = {2024}, abstract = {The cystine/glutamate antiporter xCT is an important source of cysteine for cancer cells. Once taken up, cystine is reduced to cysteine and serves as a building block for the synthesis of glutathione, which efficiently protects cells from oxidative damage and prevents ferroptosis. As melanomas are particularly exposed to several sources of oxidative stress, we investigated the biological role of cysteine and glutathione supply by xCT in melanoma. xCT activity was abolished by genetic depletion in the Tyr::CreER; Braf\(^{CA}\); Pten\(^{lox/+}\) melanoma model and by acute cystine withdrawal in melanoma cell lines. Both interventions profoundly impacted melanoma glutathione levels, but they were surprisingly well tolerated by murine melanomas in vivo and by most human melanoma cell lines in vitro. RNA sequencing of human melanoma cells revealed a strong adaptive upregulation of NRF2 and ATF4 pathways, which orchestrated the compensatory upregulation of genes involved in antioxidant defence and de novo cysteine biosynthesis. In addition, the joint activation of ATF4 and NRF2 triggered a phenotypic switch characterized by a reduction of differentiation genes and induction of pro-invasive features, which was also observed after erastin treatment or the inhibition of glutathione synthesis. NRF2 alone was capable of inducing the phenotypic switch in a transient manner. Together, our data show that cystine or glutathione levels regulate the phenotypic plasticity of melanoma cells by elevating ATF4 and NRF2.}, language = {en} } @article{NollWuerthner2024, author = {Noll, Niklas and W{\"u}rthner, Frank}, title = {Bioinspired water preorganization in confined space for efficient water oxidation catalysis in metallosupramolecular ruthenium architectures}, series = {Accounts of Chemical Research}, volume = {57}, journal = {Accounts of Chemical Research}, number = {10}, issn = {0001-4842}, doi = {10.1021/acs.accounts.4c00148}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361232}, pages = {1538-1549}, year = {2024}, abstract = {Conspectus Nature has established a sustainable way to maintain aerobic life on earth by inventing one of the most sophisticated biological processes, namely, natural photosynthesis, which delivers us with organic matter and molecular oxygen derived from the two abundant resources sunlight and water. The thermodynamically demanding photosynthetic water splitting is catalyzed by the oxygen-evolving complex in photosystem II (OEC-PSII), which comprises a distorted tetramanganese-calcium cluster (CaMn\(_4\)O\(_5\)) as catalytic core. As an ubiquitous concept for fine-tuning and regulating the reactivity of the active site of metalloenzymes, the surrounding protein domain creates a sophisticated environment that promotes substrate preorganization through secondary, noncovalent interactions such as hydrogen bonding or electrostatic interactions. Based on the high-resolution X-ray structure of PSII, several water channels were identified near the active site, which are filled with extensive hydrogen-bonding networks of preorganized water molecules, connecting the OEC with the protein surface. As an integral part of the outer coordination sphere of natural metalloenzymes, these channels control the substrate and product delivery, carefully regulate the proton flow by promoting pivotal proton-coupled electron transfer processes, and simultaneously stabilize short-lived oxidized intermediates, thus highlighting the importance of an ordered water network for the remarkable efficiency of the natural OEC. Transferring this concept from nature to the engineering of artificial metal catalysts for fuel production has fostered the fascinating field of metallosupramolecular chemistry by generating defined cavities that conceptually mimic enzymatic pockets. However, the application of supramolecular approaches to generate artificial water oxidation catalysts remained scarce prior to our initial reports, since such molecular design strategies for efficient activation of substrate water molecules in confined nanoenvironments were lacking. In this Account, we describe our research efforts on combining the state-of-the art Ru(bda) catalytic framework with structurally programmed ditopic ligands to guide the water oxidation process in defined metallosupramolecular assemblies in spatial proximity. We will elucidate the governing factors that control the quality of hydrogen-bonding water networks in multinuclear cavities of varying sizes and geometries to obtain high-performance, state-of-the-art water oxidation catalysts. Pushing the boundaries of artificial catalyst design, embedding a single catalytic Ru center into a well-defined molecular pocket enabled sophisticated water preorganization in front of the active site through an encoded basic recognition site, resulting in high catalytic rates comparable to those of the natural counterpart OEC-PSII. To fully explore their potential for solar fuel devices, the suitability of our metallosupramolecular assemblies was demonstrated under (electro)chemical and photocatalytic water oxidation conditions. In addition, testing the limits of structural diversity allowed the fabrication of self-assembled linear coordination oligomers as novel photocatalytic materials and long-range ordered covalent organic framework (COF) materials as recyclable and long-term stable solid-state materials for future applications.}, language = {en} } @article{KirchnerSchrammIvanovaetal.2024, author = {Kirchner, Philipp H. and Schramm, Louis and Ivanova, Svetlana and Shoyama, Kazutaka and W{\"u}rthner, Frank and Beuerle, Florian}, title = {A water-stable boronate ester cage}, series = {Journal of the American Chemical Society}, volume = {146}, journal = {Journal of the American Chemical Society}, number = {8}, issn = {0002-7863}, doi = {10.1021/jacs.3c12002}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361245}, pages = {5305-5315}, year = {2024}, abstract = {The reversible condensation of catechols and boronic acids to boronate esters is a paradigm reaction in dynamic covalent chemistry. However, facile backward hydrolysis is detrimental for stability and has so far prevented applications for boronate-based materials. Here, we introduce cubic boronate ester cages 6 derived from hexahydroxy tribenzotriquinacenes and phenylene diboronic acids with ortho-t-butyl substituents. Due to steric shielding, dynamic exchange at the Lewis acidic boron sites is feasible only under acid or base catalysis but fully prevented at neutral conditions. For the first time, boronate ester cages 6 tolerate substantial amounts of water or alcohols both in solution and solid state. The unprecedented applicability of these materials under ambient and aqueous conditions is showcased by efficient encapsulation and on-demand release of β-carotene dyes and heterogeneous water oxidation catalysis after the encapsulation of ruthenium catalysts.}, language = {en} } @phdthesis{Dehmer2024, author = {Dehmer, Markus}, title = {A novel USP11-TCEAL1-mediated mechanism protects transcriptional elongation by RNA Polymerase II}, doi = {10.25972/OPUS-36054}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360544}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Deregulated expression of MYC oncoproteins is a driving event in many human cancers. Therefore, understanding and targeting MYC protein-driven mechanisms in tumor biology remain a major challenge. Oncogenic transcription in MYCN-amplified neuroblastoma leads to the formation of the MYCN-BRCA1-USP11 complex that terminates transcription by evicting stalling RNAPII from chromatin. This reduces cellular stress and allows reinitiation of new rounds of transcription. Basically, tumors with amplified MYC genes have a high demand on well orchestration of transcriptional processes-dependent and independent from MYC proteins functions in gene regulation. To date, the cooperation between promoter-proximal termination and transcriptional elongation in cancer cells remains still incomplete in its understanding. In this study the putative role of the dubiquitinase Ubiquitin Specific Protease 11 (USP11) in transcription regulation was further investigated. First, several USP11 interaction partners involved in transcriptional regulation in neuroblastoma cancer cells were identified. In particular, the transcription elongation factor A like 1 (TCEAL1) protein, which assists USP11 to engage protein-protein interactions in a MYCN-dependent manner, was characterized. The data clearly show that TCEAL1 acts as a pro-transcriptional factor for RNA polymerase II (RNAPII)-medi- ated transcription. In detail, TCEAL1 controls the transcription factor S-II (TFIIS), a factor that assists RNAPII to escape from paused sites. The findings claim that TCEAL1 outcompetes the transcription elongation factor TFIIS in a non-catalytic manner on chromatin of highly expressed genes. This is reasoned by the need regulating TFIIS function in transcription. TCEAL1 equili- brates excessive backtracking and premature termination of transcription caused by TFIIS. Collectively, the work shed light on the stoichiometric control of TFIIS demand in transcriptional regulation via the USP11-TCEAL1-USP7 complex. This complex protects RNAPII from TFIIS-mediated termination helping to regulate productive transcription of highly active genes in neuroblastoma.}, subject = {Transkription}, language = {en} } @misc{Werner2024, type = {Master Thesis}, author = {Werner, Lennart}, title = {Terrain Mapping for Autonomous Navigation of Lunar Rovers}, doi = {10.25972/OPUS-35826}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-358268}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Autonomous mobile robots operating in unknown terrain have to guide their drive decisions through local perception. Local mapping and traversability analysis is essential for safe rover operation and low level locomotion. This thesis deals with the challenge of building a local, robot centric map from ultra short baseline stereo imagery for height and traversability estimation. Several grid-based, incremental mapping algorithms are compared and evaluated in a multi size, multi resolution framework. A new, covariance based mapping update is introduced, which is capable of detecting sub- cellsize obstacles and abstracts the terrain of one cell as a first order surface. The presented mapping setup is capable of producing reliable ter- rain and traversability estimates under the conditions expected for the Cooperative Autonomous Distributed Robotic Exploreration (CADRE) mission. Algorithmic- and software architecture design targets high reliability and efficiency for meeting the tight constraints implied by CADRE's small on-board embedded CPU. Extensive evaluations are conducted to find possible edge-case scenar- ios in the operating envelope of the map and to confirm performance parameters. The research in this thesis targets the CADRE mission, but is applicable to any form of mobile robotics which require height- and traversability mapping.}, subject = {Mondfahrzeug}, language = {en} } @phdthesis{Zhang2024, author = {Zhang, Tengyu}, title = {Development of Modified polylysine based antibody conjugated nanoparticles with tumor-restricted, FcγR-independent stimulatory activity by targeting Fn14}, doi = {10.25972/OPUS-35865}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-358650}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this study, we developed an innovative nanoparticle formulation to facilitate the delivery of antitumor antibodies to tumor sites. The study commenced with the utilization of 13 bispecific antibody fusion proteins, which targeted the Fn14 receptor, thereby validating the pivotal role of crosslinking in Fn14 receptor activation. Subsequently, gold nanoparticles were activated using COOH-PEG-SH in combination with EDC/NHS, and subsequently conjugated with two Fn14-targeting antibodies, PDL192 and 5B6. Following this, a pH-sensitive shell was generated on the outer layer of the antibody-coupled gold nanoparticles through the application of chemically modified polylysine. The resultant complexes, termed MPL-antibody-AuNP, demonstrated a release profile reminiscent of the tumor microenvironment (TME). Notably, these complexes released antibody-AuNPs only in slightly acidic conditions while remaining intact in neutral or basic environments. Functionality analysis further affirmed the pH-sensitive property of MPL-antibody-AuNPs, demonstrating that the antibodies only initiated potent Fn14 activation in slightly acidic environments. This formulation holds potential for applicability to antibodies or ligands targeting the 80 TNFRSF family, given that gold nanoparticles successfully served as platforms for antibody crosslinking, thereby transforming these antibodies into potent agonists. Moreover, the TME disintegration profile of MPL mitigates the potential cytotoxic effects of antibodies, thereby circumventing associated adverse side effects. This study not only showcases the potential of nanoparticle formulations in targeted therapy, but also provides a solid foundation for further investigations on their clinical application in the context of targeting category II TNFRSF receptors with antibodies or ligands.}, subject = {Immuntherapie}, language = {en} } @phdthesis{Schwebs2024, author = {Schwebs, Marie}, title = {Structure and dynamics of the plasma membrane: a single-molecule study in \(Trypanosoma\) \(brucei\)}, doi = {10.25972/OPUS-27569}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275699}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The unicellular, flagellated parasite Trypanosoma brucei is the causative agent of human African sleeping sickness and nagana in livestock. In the last decades, it has become an established eukaryotic model organism in the field of biology, as well as in the interdisciplinary field of biophysics. For instance, the dense variant surface glycoprotein (VSG) coat offers the possibility to study the dynamics of GPI-anchored proteins in the plasma membrane of living cells. The fluidity of the VSG coat is not only an interesting object of study for its own sake, but is critically important for the survival of the parasite in the mammalian host. In order to maintain the integrity of the coat, the entire VSG coat is recycled within a few minutes. This is surprisingly fast for a purely diffusive process with the flagellar pocket (FP) as the sole site for endo- and exocytosis. Previous studies characterising VSG dynamics using FRAP reported diffusion coefficients that were not sufficient to to enable fast turnover based on passive VSG randomisation on the trypanosome surface. In this thesis, live-cell single-molecule fluorescence microscopy (SMFM) was employed to elucidate whether VSG diffusion coefficients were priorly underestimated or whether directed forces could be involved to bias VSGs towards the entrance of the FP. Embedding the highly motile trypanosomes in thermo-stable hydrogels facilitated the investigation of VSG dynamics on living trypanosomes at the mammalian host's temperature of 37°C. To allow for a spatial correlation of the VSG dynamics to the FP entrance, a cell line was employed harbouring a fluorescently labelled structure as a reference. Sequential two-colour SMFM was then established to allow for recording and registration of the dynamic and static single-molecule information. In order to characterise VSG dynamics, an algorithm to obtain reliable information from short trajectories was adapted (shortTrAn). It allowed for the quantification of the local dynamics in two distinct scenarios: diffusion and directed motion. The adaptation of the algorithm to the VSG data sets required the introduction of an additional projection filter. The algorithm was further extended to take into account the localisation errors inherent to single-particle tracking. The results of the quantification of diffusion and directed motion were presented in maps of the trypanosome surface, including an outline generated from a super-resolved static structure as a reference. Information on diffusion was displayed in one map, an ellipse plot. The colour code represented the local diffusion coefficient, while the shape of the ellipses provided an indication of the diffusion behaviour (aniso- or isotropic diffusion). The eccentricity of the ellipses was used to quantify deviations from isotropic diffusion. Information on directed motion was shown in three maps: A velocity map, representing the amplitude of the local velocities in a colour code. A quiver plot, illustrating the orientation of directed motion, and a third map which indicated the relative standard error of the local velocities colour-coded. Finally, a guideline based on random walk simulations was used to identify which of the two motion scenarios dominated locally. Application of the guideline to the VSG dynamics analysed by shortTrAn yielded supermaps that showed the locally dominant motion mode colour-coded. I found that VSG dynamics are dominated by diffusion, but several times faster than previously determined. The diffusion behaviour was additionally characterised by spatial heterogeneity. Moreover, isolated regions exhibiting the characteristics of round and elongated traps were observed on the cell surface. Additionally, VSG dynamics were studied with respect to the entrance of the FP. VSG dynamics in this region displayed similar characteristics compared to the remainder of the cell surface and forces biasing VSGs into the FP were not found. Furthermore, I investigated a potential interference of the attachment of the cytoskeleton to the plasma membrane with the dynamics of VSGs which are anchored to the outer leaflet of the membrane. Preliminary experiments were conducted on osmotically swollen trypanosomes and trypanosomes depleted for a microtubule-associated protein anchoring the subpellicular microtubule cytoskeleton to the plasma membrane. The measurements revealed a trend that detachment of the cytoskeleton could be associated with a reduction in the VSG diffusion coefficient and a loss of elongated traps. The latter could be an indication that these isolated regions were caused by underlying structures associated with the cytoskeleton. The measurements on cells with an intact cytoskeleton were complemented by random walk simulations of VSG dynamics with the newly determined diffusion coefficient on long time scales not accessible in experiments. Simulations showed that passive VSG randomisation is fast enough to allow for a turnover of the full VSG coat within a few minutes. According to an estimate based on the known rate of endocytosis and the newly determined VSG diffusion coefficient, the majority of exocytosed VSGs could escape from the FP to the cell surface without being immediately re-endocytosed.}, subject = {Trypanosoma brucei}, language = {en} } @phdthesis{Schlesinger2024, author = {Schlesinger, Tobias}, title = {Autolog zellbesiedelte Matrix zum Verschluss gastraler Inzisionen: Eine Machbarkeitsstudie im Schweinemodell}, doi = {10.25972/OPUS-30583}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305832}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Einleitung: Strukturelle Defekte der gastrointestinalen Hohlorgane stellen ein allgegen-w{\"a}rtiges Problem im klinischen Alltag dar. Sie entstehen meist auf dem Boden einer ent-z{\"u}ndlichen oder tumor{\"o}sen Grunderkrankung und k{\"o}nnen außerdem traumatisch sowie durch medizinische Eingriffe hervorgerufen werden. In der Folge kommt es zur Kontami-nation des umliegenden Gewebes mit Magen- bzw. Darminhalt, wodurch delet{\"a}re Folgen wie eine systemische Infektion, also eine Sepsis mit Multiorganversagen drohen k{\"o}nnen. Vor diesem Hintergrund sind gastrointestinale Defekte immer als potenziell lebensbedroh-lich f{\"u}r den Patienten zu betrachten. Die ad{\"a}quate und kausale Behandlung erfolgt je nach {\"A}tiologie und Zustand des Patienten durch eine Operation oder eine endoskopische Inter-vention. Hierzu stehen zahlreiche etablierte, operative und interventionelle Therapieme-thoden zur Verf{\"u}gung. In manchen F{\"a}llen stoßen die etablierten Techniken jedoch an ihre Grenzen. Bei Patienten mit schwerwiegenden Komorbidit{\"a}ten oder im Rahmen neuer me-dizinischer Verfahren sind Innovationen gefragt. Die Grundidee der vorliegenden Arbeit ist die Entwicklung einer biotechnologischen Therapieoption zur Versorgung gastrointesti-naler Hohlorganperforationen. Methoden: Zur Durchf{\"u}hrung einer Machbarkeitsstudie wurden zehn G{\"o}ttinger Mi-nischweine in zwei Gruppen mit jeweils 5 Tieren aufgeteilt. Den Tieren der Experimental-gruppe wurden Hautbiopsien entnommen und daraus Fibroblasten isoliert, welche vo-r{\"u}bergehend konserviert wurden. Unter Verwendung von azellularisiertem Schweinedarm erfolgte die Herstellung von Implantaten nach den Prinzipien des Tissue Engineerings. Die Tiere beider Gruppen wurden einer Minilaparotomie und einer ca. 3cm-Inzision der Ma-genvorderwand unterzogen. Die anschließende Versorgung wurde in der Experimental-gruppe durch Implantation der neuartigen Konstrukte erzielt. In der Kontrollgruppe wur-de im Sinne des Goldstandards eine konventionelle Naht durchgef{\"u}hrt. Anschließend wurden die Tiere f{\"u}r vier Wochen beobachtet. Eine bzw. zwei Wochen nach dem pri-m{\"a}ren Eingriff wurde bei allen Tieren beider Gruppen eine Laparoskopie bzw. Gastrosko-pie durchgef{\"u}hrt. Am Ende der klinischen Observationsphase wurden die Versuchstiere get{\"o}tet und die entsprechenden Magenareale zur histologischen Untersuchung explantiert. Ergebnisse: Die Herstellung der Implantate konnte auf der Basis standardisierter zellbio-logischer Methoden problemlos etabliert werden. Alle Tiere beider Gruppen {\"u}berlebten den Prim{\"a}reingriff sowie das vierw{\"o}chige Nachbeobachtungsintervall und zeigten dabei keine klinischen Zeichen m{\"o}glicher Komplikationen. Die durchgef{\"u}hrten Laparoskopien und Gastroskopien ergaben bei keinem der Tiere Hinweise auf Leckagen oder lokale Infek-tionsprozesse. Die histologische Aufarbeitung zeigte im Bereich des urspr{\"u}nglichen De-fekts eine bindegewebige {\"U}berbr{\"u}ckung sowie ein beginnendes Remodeling der Magen-schleimhaut in beiden Gruppen. Schlussfolgerungen: Durch die Verkn{\"u}pfung von Einzelprozessen der Zellkultur und dem Großtier-OP konnte ein neues Verfahren zum Verschluss gastrointestinaler Defekt erfolgreich demonstriert und etabliert werden. Das Projekt konnte reibungslos durchge-f{\"u}hrt werden und lieferte Ergebnisse, die dem Goldstandard nicht unterlegen waren. Auf-grund der kleinen Fallzahl und weiterer methodischer Limitationen sind jedoch nur einge-schr{\"a}nkt Schlussfolgerungen m{\"o}glich, weshalb die Durchf{\"u}hrung gr{\"o}ßerer und gut geplan-ter Studien notwendig ist. Die Erkenntnisse dieser Pilotstudie liefern eine solide Basis f{\"u}r die Planung weiterf{\"u}hrender Untersuchungen.}, subject = {Magenkrankheit}, language = {de} } @phdthesis{Bieniussa2024, author = {Bieniussa, Linda Ilse}, title = {Different effects of conditional Knock-Out of Stat3 on the sensory epithelium of the Organ of Corti}, doi = {10.25972/OPUS-35143}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351434}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die Cochlea von S{\"a}ugetieren nimmt Schall als Reaktion auf Vibrationen an frequenzabh{\"a}ngigen Positionen entlang des Cochlea-Kanals wahr. Die sensorischen {\"a}ußeren Haarzellen, die von St{\"u}tzzellen umgeben sind, wirken als Signalverst{\"a}rker, indem sie ihre Zelll{\"a}nge ver{\"a}ndern k{\"o}nnen. Dies wird als Elektromotilit{\"a}t bezeichnet. Um eine korrekte elektrische {\"U}bertragung bei mechanischen Kr{\"a}ften zu gew{\"a}hrleisten, ist ein gewisser Widerstand des sensorischen Epithels eine Voraussetzung f{\"u}r die fehlerfreie Weiterleitung von H{\"o}rinformationen. Dieser Widerstand wird durch Mikrotubuli und deren posttranslationalen Modifikationen in den St{\"u}tzzellen des sensorischen Epithels der Cochlea gew{\"a}hrleistet. Stat3 ist ein Transkriptionsfaktor, der an verschiedenen Phosphorylierungsstellen, sowie je nach Zelltyp und aktiviertem Signalweg an vielen zellul{\"a}ren Prozessen wie Differenzierung, Entz{\"u}ndung, Zell{\"u}berleben und Mikrotubuli-Dynamik beteiligt ist. W{\"a}hrend Stat3 ein breites Spektrum an intrazellul{\"a}ren Funktionen hat, stellte sich die Frage, wie und ob Stat3 in den Zellen des Cortischen Organ einen Einfluss auf den H{\"o}rprozess hat. Um dies zu testen, wurde das Cre/loxp-System verwendet, um Stat3 in den {\"a}ußeren Haarzellen oder den St{\"u}tzzellen entweder vor oder nach H{\"o}rbeginn von M{\"a}usen konditional auszuschalten. Um das H{\"o}rverm{\"o}gen zu erfassen, wurden DPOAE- und ABR-Messungen durchgef{\"u}hrt, w{\"a}hrend molekulare und morphologische Untersuchungen mittels Sequenzierung und Immunhistochemie durchgef{\"u}hrt wurden. Eine konditioneller Knock-Out von Stat3 vor und nach dem Beginn des H{\"o}rens in {\"a}ußeren Haarzellen f{\"u}hrt zu leichten H{\"o}rsch{\"a}den, w{\"a}hrend Synapsen, Nervenfasern und Mitochondrien nicht betroffen waren. Die Analyse der Sequenzierung von {\"a}ußeren Haarzellen aus M{\"a}usen mit konditionellem Knock-Out vor dem Beginn des H{\"o}rens ergab eine St{\"o}rung der zellul{\"a}ren Hom{\"o}ostase und der extrazellul{\"a}ren Signale. Ein konditioneller Knock-Out von Stat3 in den {\"a}ußeren Haarzellen nach Beginn des H{\"o}rens f{\"u}hrte zu einem fr{\"u}h-entz{\"u}ndlichen Signalweg mit erh{\"o}hter Zytokinproduktion und der Hochregulierung des NF-κB-Wegs. In den St{\"u}tzzellen f{\"u}hrte ein kondioneller Knock-Out von Stat3 nur nach dem Beginn des H{\"o}rens zu einer H{\"o}rbeeintr{\"a}chtigung. Synapsen, Nervensoma und -fasern waren jedoch von einem konditionellen Knock-Out von Stat3 in St{\"u}tzzellen nicht betroffen. Dennoch war die detyronisierte Modifikation der Mikrotubuli ver{\"a}ndert, was zu einer Instabilit{\"a}t der St{\"u}tzzellen, insbesondere der Phalangealforts{\"a}tze, f{\"u}hrte, was wiederum zu einer Instabilit{\"a}t des Epithels w{\"a}hrend des H{\"o}rvorgangs f{\"u}hrte. Zusammenfassend l{\"a}sst sich sagen, dass ein konditioneller Knock-Out von Stat3 in Zellen des Cortischen Organs zu einer H{\"o}rst{\"o}rung f{\"u}hrte. W{\"a}hrend ein konditioneller Knock-Out in {\"a}ußeren Haarzellen eine erh{\"o}hte Zytokinproduktion zur Folge hatte, verloren die St{\"u}tzzellen ihre Zellstabilit{\"a}t aufgrund einer verminderten detyronisierten Modifikation der Mikrotubuli. Insgesamt deuten die Ergebnisse darauf hin, dass Stat3 ein wichtiges Protein f{\"u}r die H{\"o}rleistung ist. Es sind jedoch weitere Untersuchungen des molekularen Mechanismus erforderlich, um die Rolle von Stat3 in den Zellen des Corti-Organs zu verstehen.}, subject = {Audiologie}, language = {en} } @phdthesis{WagenhaeusergebVonhausen2024, author = {Wagenh{\"a}user [geb. Vonhausen], Yvonne}, title = {Thermodynamic Investigations on the Dimerization and Anti-Cooperative Self-Assembly of Dipolar Merocyanines}, doi = {10.25972/OPUS-35211}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352111}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Dipolar merocyanines are very attractive supramolecular building blocks, as they combine interesting functional properties with strong, directional intermolecular interactions. The pyridine dioxocyano-pyridine (PYOP) chromophore (Chapter 2.2), used in this thesis, stands out because of its exceptionally high ground state dipole moment (g ~ 17 D), in combination with the option to retain good solubility also in unpolar solvents, by decoration with solubilizing groups. The reliable binding motif of anti-parallel -stacking due to dipole-dipole interactions has allowed the design of molecular building blocks that form assemblies of predictable geometry. The intense unstructured charge transfer UV/Vis absorption band (eg ~ 10.7 D) is a result of the dominant contribution of the zwitterionic resonance structure which brings the PYOP chromophore just beyond the cyanine limit in solvents of low polarity (c2 = 0.60, 1,4 dioxane). The high sensitivity of the S0 - S1 UV/Vis absorption band to the environment manifests itself in a pronounced negative solvatochromism and strong H-type exciton coupling within -stacked PYOP assemblies. In accordance with the classical molecular exciton theory, an increasing hypsochromic shift of the dominant absorption band of these H aggregates can be observed as the stack size increases up to about six chromophores, where it levels out at about max ~ 440 nm (CHCl3). This allows a uniquely simple estimation of the number of interacting chromophores within the self-assembled structure from a single UV/Vis absorption spectrum of an aggregate. The defined and well investigated PYOP dimer formation was employed in this thesis to probe the applicability and limitations of concentration-, temperature-, and solvent-dependent self-assembly studies (Chapter 3). Straightforward theoretical models to evaluate datasets of concentration-, temperature-, and solvent-dependent UV/Vis absorption by nonlinear regression analysis were derived for the case of dimer formation (Chapter 2.1). Although the dimer model is well known and widely applied in literature, this detailed derivation is helpful to understand assumptions and potential problems of the different approaches for the determination of thermodynamic parameters. This helps to decide on the most appropriate method to analyse a system of interest. In this regard it should be noted that covering a large portion of the self-assembly process with the experimental data is a prerequisite for the accuracy of the analysis. Additionally, many of the insights can also be transferred to other self-assembly systems like supramolecular polymerization or host-guest interactions. The concentration-dependent analysis is the most straightforward method to investigate self-assembly equilibria. No additional assumptions, besides mass balance and mass action law, are required. Since it includes the least number of parameters (only K, if M/D are known), it is the most, or even only, reliable method, to elucidate the self-assembly mechanism of an unknown system by model comparison. To cover a large concentration range, however, the compound must be soluble enough and generally sample amounts at least in the low mg scale must be available. The temperature-dependent analysis has the advantage that all thermodynamic parameters G0, H0 and S0 can be obtained from a single sample in one automated measurement. However, the accessible temperature-range is experimentally often quite limited and dependent on the solvent. For systems which do not show the transition from monomer to aggregate in a narrow temperature range, as given for, e.g., cooperative aggregation or processes with a high entropy contribution, often not the entire self-assembly process can be monitored. Furthermore, the assumptions of temperature-independent extinction coefficients of the individual species as well as temperature-independent H0 and S0 must be met. Monte Carlo simulations of data sets demonstrated that even minor changes in experimental data can significantly impact the optimized values for H0 and S0. This is due to the redundancy of these two parameters within the model framework and even small thermochromic effects can significantly influence the results. The G0 value, calculated from H0 and S0, is, however, still rather reliable. Solvent-dependent studies can often cover the entire self-assembly process from monomeric (agg = 0) to the fully aggregated state (agg = 1). However, for dyes with strong solvatochromic effects, such as the dipolar merocyanines investigated in this thesis, the results are affected. Also, the assumption of a linear relation of the binding energy G0 and the fraction of denaturating solvent f, which is based on linear free energy relationships between G0 and the solvent polarity, can lead to errors. Especially when specific solvent effects are involved. For the evaluation of experimental data by nonlinear regression, general data analysis software can be used, where user-defined fit models and known parameters can be implemented as desired. Alternatively, multiple specialized programs for analysing self-assembly data are available online. While the latter programs are usually more user-friendly, they have the disadvantage of being a "black box" where only pre-implemented models can be used without the option for the user to adapt models or parameters for a specific system. In Chapter 3 comprehensive UV/Vis absorption datasets are presented for the dimerization of merocyanine derivative 1 in 1,4-dioxane, which allowed for the first time a direct comparison of the results derived from concentration-, temperature-, and solvent-dependent self-assembly studies. The results for the binding constant K and corresponding G0 from the concentration- and temperature-dependent analysis were in very good agreement, also in comparison to the results from ITC. For the temperature-dependent analysis, though, multiple datasets of samples with different concentration had to be evaluated simultaneously to cover a meaningful part of the self-assembly process. Furthermore, a significant dependence of the optimized parameters H0 and S0 on the wavelength chosen for the analysis was observed. This can be rationalized by the small thermochromic shifts of both the monomer and the dimer UV/Vis absorption band. The results from the solvent-dependent evaluation showed the largest deviation, as expected for the highly solvatochromic merocyanine dye. However, even here by evaluation at 491 and 549 nm the deviation for G0 was only 2.5 kJ mol1 (9\%) with respect to the results from the concentration-dependent analysis (G0 = 29.1 kJ mol1). Thus, despite the strong solvatochromism of the dipolar chromophore, it can still be considered a reliable method for estimating the binding strength. Furthermore, multiple repetitions of the concentration-, temperature-, and solvent-dependent studies provided insight into the reproducibility of the results and possible sources of experimental errors. In all cases, the deviations of the results were small (G0 < 0.4 kJ mol1) and within the same range as the fit error from the nonlinear regression analysis. The insights from these studies were an important basis for the in-depth investigation of a more complex supramolecular system in Chapter 4, as a single method is often not enough to capture the full picture of a more complicated self-assembly process. To elucidate the anti-cooperative self-assembly of the chiral merocyanine 2, a combination of multiple techniques had to be applied. Solvent-dependent UV/Vis absorption studies in CH2Cl2/MCH mixtures showed the step-wise assembly of the merocyanine monomer (max(M) = 549 nm, CH2Cl2) to first a dimer (max(D) = 498 nm, CH2Cl2/MCH 15:85) by dipole-dipole interactions, and then a -stacked higher aggregate (max(H) = 477 nm, MCH), with pronounced H-type coupling. The thermodynamic evaluation of this data, however, suffered from the severe solvatochromism, especially of the monomeric species (max(M, CH2Cl2) = 549 nm, max(M, MCH) = 596 nm). Therefore, concentration-dependent studies were performed at three different temperatures (298, 323, 353 K) to elucidate the self-assembly mechanism and determine reliable thermodynamic parameters. The studies at elevated temperatures were hereby necessary, to obtain experimental data over a larger agg--range. Due to the pronounced difference in the thermodynamic driving force for dimerization and higher aggregate formation (KD/K5 = 6500) a concentration range exists in MCH where almost exclusively the dimer species of 2 is present, before further self-assembly by dispersion interactions occurs. Therefore, the data could be evaluated independently for the two self-assembly steps. The self-assembly of dimers into the higher aggregate could not be described by the isodesmic model but was fitted satisfactorily to a pentamer model. This rather small size of about ten -stacked PYOP chromophores was, furthermore, consistently indicated by AFM, VPO and DOSY NMR measurements. Based on 1D and 2D NMR data as well as the strong bisignate CD signal of the higher aggregate in combination with TD-DFT calculations, a P-helical stack is proposed as its structure. The small size can be rationalized by the anti-cooperative self-assembly mechanism and the sterical demand of the solubilizing trialkoxyphenyl and the chiral tetralin substituents. Additionally, the aliphatic shell formed by the solubilizing chains around the polar chromophore stack, can account for the exceptionally high solubility of 2 in MCH (> 15 mg mL1). These combined studies of the self-assembly process enabled the identification of suitable conditions for the investigation of fluorescence properties of the individual aggregate species. Aggregation-induced emission enhancement was observed for the almost non-emissive monomer (Fl(M) = 0.23\%), which can be rationalized by the increasing rigidification within the dimer (Fl(D) = 2.3\%) and the higher aggregate (Fl(H) = 4.5\%). The helical chirality of the PYOP decamer stack, furthermore, gave rise to a strong CPL signal with a large glum value of 0.011. The important conclusion of this thesis is that the temperature- and solvent-dependent analyses are valid alternatives to the classical concentration-dependent analysis to determine thermodynamic parameters of self-assembly equilibria. Although, for a specific supramolecular system, one approach might be favourable over the others for a variety of reasons. The experimental limitations often demand a combination of techniques to fully elucidate a self-assembly process and to gain insights in the aggregate structure. The anti-cooperative merocyanine self-assembly, which was described here for the first time for the PYOP merocyanine 2, is no exception. Besides the interest in the merocyanine assemblies from a structural and functional point of view, the insights gained from the presented studies can also be transferred to other self-assembly systems and be a guide to find the most appropriate analysis technique.}, subject = {Merocyanine}, language = {en} } @phdthesis{Herok2024, author = {Herok, Christoph}, title = {Quantum Chemical Exploration of Potential Energy Surfaces: Reaction Cycles and Luminescence Phenomena}, doi = {10.25972/OPUS-35218}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352185}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {This work aims at elucidating chemical processes involving homogeneous catalysis and photo-physical relaxation of excited molecules in the solid state. Furthermore, compounds with supposedly small singlet-triplet gaps and therefore biradicaloid character are investigated with respect to their electro-chemical behavior. The work on hydroboration catalysis via a reduced 9,10-diboraanthracene (DBA) was preformed in collaboration with the Wagner group in Frankfurt, more specifically Dr. Sven Prey, who performed all laboratory experiments. The investigation of delayed luminescence properties in arylboronic esters in their solid state was conducted in collaboration with the Marder group in W{\"u}rzburg. The author of this work took part in the synthesis of the investigated compounds while being supervised by Dr. Zhu Wu. The final project was a collaboration with the group of Anukul Jana from Hyderabad, India who provided the experimental data.}, subject = {Simulation}, language = {en} } @unpublished{BrennerZinkWitzingeretal.2024, author = {Brenner, Marian and Zink, Christoph and Witzinger, Linda and Keller, Angelika and Hadamek, Kerstin and Bothe, Sebastian and Neuenschwander, Martin and Villmann, Carmen and von Kries, Jens Peter and Schindelin, Hermann and Jeanclos, Elisabeth and Gohla, Antje}, title = {7,8-Dihydroxyflavone is a direct inhibitor of pyridoxal phosphatase}, series = {eLife}, journal = {eLife}, doi = {10.7554/eLife.93094.2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350446}, year = {2024}, abstract = {Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades. Still, the molecular mechanisms linking vitamin B6 to these pathologies remain poorly understood, and whether vitamin B6 supplementation improves cognition is unclear as well. Pyridoxal phosphatase (PDXP), an enzyme that controls levels of pyridoxal 5'-phosphate (PLP), the co-enzymatically active form of vitamin B6, may represent an alternative therapeutic entry point into vitamin B6-associated pathologies. However, pharmacological PDXP inhibitors to test this concept are lacking. We now identify a PDXP and age-dependent decline of PLP levels in the murine hippocampus that provides a rationale for the development of PDXP inhibitors. Using a combination of small molecule screening, protein crystallography and biolayer interferometry, we discover and analyze 7,8-dihydroxyflavone (7,8-DHF) as a direct and potent PDXP inhibitor. 7,8-DHF binds and reversibly inhibits PDXP with low micromolar affinity and sub-micromolar potency. In mouse hippocampal neurons, 7,8-DHF increases PLP in a PDXP-dependent manner. These findings validate PDXP as a druggable target. Of note, 7,8-DHF is a well-studied molecule in brain disorder models, although its mechanism of action is actively debated. Our discovery of 7,8-DHF as a PDXP inhibitor offers novel mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain.}, language = {en} } @inproceedings{OPUS4-35480, title = {Deutsch-franz{\"o}sischer Kunst- und Kulturtransfer der fr{\"u}hen Neuzeit im europ{\"a}ischen Kontext}, series = {Young Research on the Renaissance (YOURRS)}, volume = {1}, booktitle = {Young Research on the Renaissance (YOURRS)}, editor = {Leuschner, Eckhard and Frommel, Sabine}, doi = {10.25972/OPUS-35480}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-354804}, pages = {125}, year = {2024}, abstract = {Die vorliegenden Texte sind die verschriftlichten und redigierten Beitr{\"a}ge eines internationalen Kolloquiums, das - organisiert von der {\´E}cole Pratique des Hautes {\´E}tudes, PSL, Paris, vom Institut f{\"u}r Kunstgeschichte der Universit{\"a}t W{\"u}rzburg und der Universit{\"a}t Ja{\´e}n - vom 1. bis 4. Juni 2022 in Paris stattfand und finanziell von der Deutsch-Franz{\"o}sischen Hochschule unterst{\"u}tzt wurde.}, subject = {Renaissance}, language = {mul} } @phdthesis{Krampert2024, author = {Krampert, Laura}, title = {Dynamics of cardiac neutrophil diversity in murine myocardial infarction}, doi = {10.25972/OPUS-34957}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349576}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {After myocardial infarction, an inflammatory response is induced characterized by a sterile inflammation, followed by a reparative phase in order to induce cardiac healing. Neutrophils are the first immune cells that enter the ischemic tissue. Neutrophils have various functions in the ischemic heart, such as phagocytosis, production of reactive oxygen species or release of granule components. These functions can not only directly damage cardiac tissue, but are also necessary for initiating reparative effects in post-ischemic healing, indicating a dual role of neutrophils in cardiac healing after infarction. In recent years, evidence has been growing that neutrophils show phenotypic and functional differences in distinct homeostatic and pathogenic settings. Preliminary data of my working group using single-cell RNA-sequencing revealed the time- dependent heterogeneity of neutrophils, with different populations showing distinct gene expression profiles in ischemic hearts of mice, including the time-dependent appearance of a SiglecFhigh neutrophil population. To better understand the dynamics of neutrophil heterogeneity in the ischemic heart, my work aimed to validate previous findings at the protein level, as well as to investigate whether the distinct neutrophil populations show functional differences. Furthermore, in vivo depletion experiments were performed in order to modulate circulating neutrophil levels. Hearts, blood, bone marrow and spleens were processed and analyzed from mice after 1 day and 3 days after the onset of cardiac ischemia and analyzed using flow cytometry. Results showed that the majority of cardiac neutrophils isolated at day 3 after myocardial infarction were SiglecFhigh, whereas nearly no SiglecFhigh neutrophils could be isolated from ischemic hearts at day 1 after myocardial infarction. No SiglecFhigh neutrophils could be found in the blood, spleen and bone marrow either after 1 day or 3 days after myocardial infarction, indicating that the SiglecFhigh state of neutrophils is unique to the ischemic cardiac tissue. When I compared SiglecFhigh and SiglecFlow neutrophils regarding their phagocytosis activity and ROS production, SiglecFhigh neutrophils showed a higher phagocytosis ability than their SiglecFlow counterparts, as well as higher ROS production capacity. In vivo depletion experiments could not achieve successful and efficient depletion of cardiac neutrophils either 1 day or 3 days after myocardial infarction, but led to a shift of a higher percentage of SiglecFhigh expressing neutrophils in the depletion group. Bone marrow neutrophil levels only showed partial depletion at day 3 after MI. Regarding blood neutrophils, depletion efficiently reduced circulating neutrophils at both time points, 1 and 3 days after MI. To summarize, this work showed the time-dependent presence of different neutrophil states in the ischemic heart. The main population of neutrophils isolated 3 days after MI showed a high expression of SiglecF, a unique state that could not be detected at different time points or other organs. These SiglecFhigh neutrophils showed functional differences regarding their phagocytosis ability and ROS production. Further investigation is needed to reveal what role these SiglecFhigh neutrophils could play within the ischemic heart. To better target neutrophil depletion in vivo, more efficient or different anti-neutrophil strategies are needed.}, subject = {Neutrophiler Granulozyt}, language = {en} } @phdthesis{Aido2024, author = {Aido, Ahmed}, title = {Development of anti-TNF antibody-gold nanoparticles (anti-TNF-AuNPs)}, doi = {10.25972/OPUS-34921}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349212}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Gold nanoparticles of diameter ca. 60 nm have been synthesized based on Turkevich and Frens protocols. We have demonstrated that the carboxyl-modified gold nanoparticles can be coupled covalently with antibodies (Ab) of interest using the EDC/NHS coupling procedure. Binding studies with Ab-grafted AuNPs and GpL fusion proteins proved that conjugation of AuNPs with antibodies enables immobilization of antibodies with preservation of a significant antigen binding capacity. More importantly, our findings showed that the conjugation of types of anti-TNF receptors antibodies such as anti-Fn14 antibodies (PDL192 and 5B6) (Aido et al., 2021), anti-CD40, anti-4-1BB and anti-TNFR2 with gold nanoparticles confers them with potent agonism. Thus, our results suggest that AuNPs can be utilized as a platform to immobilize anti-TNFR antibodies which, on the one hand, helps to enhance their agonistic activity in comparison to "free" inactive antibodies by mimicking the effect of cell-anchored antibodies or membrane-bound TNF ligands and, on the other hand, allows to develop new generations of drug delivery systems. These constructs are characterized with their biocompatibility and their tunable synthesis process. In a further work part, we combined the benefits of the established system of Ab-AuNPs with materials used widely in the modern biofabrication approaches such as the photo-crosslinked hydrogels, methacrylate-modified gelatin (GelMA), combined with embedded variants of human cell lines. The acquired results demonstrated clearly that the attaching of proteins like antibodies to gold nanoparticles might reduce their release rate from the crosslinked hydrogels upon the very low diffusion of gold nanoparticles from the solid constructs to the surrounding medium yielding long-term local functioning proteins-attached particles. Moreover, our finding suggests that hydrogel-embedded AuNP-immobilized antibodies, e.g. anti-TNFα-AuNPs or anti-IL1-AuNPs enable local inhibitory functions, To sum up, our results demonstrate that AuNPs can act as a platform to attach anti-TNFR antibodies to enhance their agonistic activity by resembling the output of cell-anchoring or membrane bounding. Gold nanoparticles are considered, thus, as promising tool to develop the next generation of drug delivery systems, which may contribute to cancer therapy. On top of that, the embedding of anti-inflammatory-AuNPs in the biofabricated hydrogel presents new innovative strategy of the treatment of autoinflammatory diseases.}, subject = {Nanopartikel}, language = {en} } @phdthesis{Kobs2024, author = {Kobs, Konstantin}, title = {Think outside the Black Box: Model-Agnostic Deep Learning with Domain Knowledge}, doi = {10.25972/OPUS-34968}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349689}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Deep Learning (DL) models are trained on a downstream task by feeding (potentially preprocessed) input data through a trainable Neural Network (NN) and updating its parameters to minimize the loss function between the predicted and the desired output. While this general framework has mainly remained unchanged over the years, the architectures of the trainable models have greatly evolved. Even though it is undoubtedly important to choose the right architecture, we argue that it is also beneficial to develop methods that address other components of the training process. We hypothesize that utilizing domain knowledge can be helpful to improve DL models in terms of performance and/or efficiency. Such model-agnostic methods can be applied to any existing or future architecture. Furthermore, the black box nature of DL models motivates the development of techniques to understand their inner workings. Considering the rapid advancement of DL architectures, it is again crucial to develop model-agnostic methods. In this thesis, we explore six principles that incorporate domain knowledge to understand or improve models. They are applied either on the input or output side of the trainable model. Each principle is applied to at least two DL tasks, leading to task-specific implementations. To understand DL models, we propose to use Generated Input Data coming from a controllable generation process requiring knowledge about the data properties. This way, we can understand the model's behavior by analyzing how it changes when one specific high-level input feature changes in the generated data. On the output side, Gradient-Based Attribution methods create a gradient at the end of the NN and then propagate it back to the input, indicating which low-level input features have a large influence on the model's prediction. The resulting input features can be interpreted by humans using domain knowledge. To improve the trainable model in terms of downstream performance, data and compute efficiency, or robustness to unwanted features, we explore principles that each address one of the training components besides the trainable model. Input Masking and Augmentation directly modifies the training input data, integrating knowledge about the data and its impact on the model's output. We also explore the use of Feature Extraction using Pretrained Multimodal Models which can be seen as a beneficial preprocessing step to extract useful features. When no training data is available for the downstream task, using such features and domain knowledge expressed in other modalities can result in a Zero-Shot Learning (ZSL) setting, completely eliminating the trainable model. The Weak Label Generation principle produces new desired outputs using knowledge about the labels, giving either a good pretraining or even exclusive training dataset to solve the downstream task. Finally, improving and choosing the right Loss Function is another principle we explore in this thesis. Here, we enrich existing loss functions with knowledge about label interactions or utilize and combine multiple task-specific loss functions in a multitask setting. We apply the principles to classification, regression, and representation tasks as well as to image and text modalities. We propose, apply, and evaluate existing and novel methods to understand and improve the model. Overall, this thesis introduces and evaluates methods that complement the development and choice of DL model architectures.}, subject = {Deep learning}, language = {en} } @phdthesis{Werthmueller2024, author = {Werthm{\"u}ller, Dominic Pascal}, title = {Relevance of bioaccessibility for the oral bioavailability of poorly water-soluble drugs}, doi = {10.25972/OPUS-29920}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299200}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Poor or variable oral bioavailability is of major concern regarding safety and efficacy for the treatment of patients with poorly water-soluble drugs (PWSDs). The problem statement of this work involves a pharmaceutical development perspective, the physicochemical basis of the absorption process and physiological / biopharmaceutical aspects. A methodology was developed aiming at closing the gap between drug liberation and dissolution on the one hand and the appearance of drug in the blood on the other. Considering what is out of control from a formulation development perspective, a clear differentiation between bioavailability and bioaccessibility was necessary. Focusing on the absorption process, bioaccessibility of a model compound, a poorly soluble but well permeable weak base, was characterized by means of flux across artificial biomimetic membranes. Such setups can be considered to reasonably mimic relevant oral absorption resistances in vitro in terms of diffusion through an unstirred water layer (UWL) and a lipidic barrier. Mechanistic understanding of the driving force for permeation was gained by differentiating drug species and subsequently linking them to the observed transfer rates using a bioaccessibility concept. The three key species that need to be differentiated are molecularly dissolved drug, drug associated in solution with other components (liquid reservoir) and undissolved drug (solid reservoir). An innovative approach to differentiate molecularly dissolved drug from the liquid reservoir using ultracentrifugation in combination with dynamic light scattering as control is presented. A guidance for rational formulation development of PWSDs is elaborated based on the employed model compound. It is structured into five guiding questions to help drug formulation scientists in selecting drug form, excipients and eventually the formulation principle. Overall, the relevance but also limitations of characterizing bioaccessibility were outlined with respect to practical application e.g. in early drug formulation development.}, subject = {Bioverf{\"u}gbarkeit}, language = {en} } @phdthesis{Hoerner2024, author = {H{\"o}rner, Michaela}, title = {The role of inflammation in hereditary spastic paraplegia type 11}, doi = {10.25972/OPUS-30336}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303368}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Hereditary spastic paraplegias (HSPs) are genetically-determined, neurodegenerative disorders characterized by progressive weakness and spasticity of the lower limbs. Spastic paraplegia type 11 (SPG11) is a complicated form of HSP, which is caused by mutations in the SPG11 gene encoding spatacsin, a protein possibly involved in lysosomal reformation. Based on our previous studies demonstrating that secondary neuroinflammation can be a robust amplifier of various genetically-mediated diseases of both the central and peripheral nervous system, we here test the possibility that neuroinflammation may modify the disease outcome also in a mouse model for SPG11. Spg11-knockout (Spg11-/-) mice develop early walking pattern and behavioral abnormalities, at least partially reflecting motor, and behavioral changes typical for patients. Furthermore, we detected a progressive increase in axonal damage and axonal spheroid formation in the white and grey matter compartments of the central nervous system of Spg11-/- mice. This was accompanied by a concomitant substantial increase of secondary inflammation by cytotoxic CD8+ and CD4+ T-lymphocytes. We here provide evidence that disease-related changes can be ameliorated/delayed by the genetic deletion of the adaptive immune system. Accordingly, we provide evidence that repurposing clinically approved immunomodulators (fingolimod/FTY720 or teriflunomide), that are in use for treatment of multiple sclerosis (MS), also improve disease symptoms in mice, when administered in an early (before neural damage) or late (after/during neural damage) treatment regime. This work provides strong evidence that immunomodulation can be a therapeutic option for the still untreatable SPG11, including its typical neuropsychological features. This poses the question if inflammation is not only a disease amplifier in SPG11 but can act as a unifying factor also for other genetically mediated disorders of the CNS. If true, this may pave the way to therapeutic options in a wide range of still untreatable, primarily genetic, neurological disorders by repurposing approved immunomodulators.}, subject = {Entz{\"u}ndung}, language = {en} } @article{GutzeitWellerMuthetal.2024, author = {Gutzeit, Julian and Weller, Lisa and Muth, Felicitas and K{\"u}rten, Jens and Huestegge, Lynn}, title = {Eye did this! Sense of agency in eye movements}, series = {Acta Psychologica}, volume = {243}, journal = {Acta Psychologica}, doi = {10.1016/j.actpsy.2023.104121}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349819}, year = {2024}, abstract = {This study investigates the sense of agency (SoA) for saccades with implicit and explicit agency measures. In two eye tracking experiments, participants moved their eyes towards on-screen stimuli that subsequently changed color. Participants then either reproduced the temporal interval between saccade and color-change (Experiment 1) or reported the time points of these events with an auditory Libet clock (Experiment 2) to measure temporal binding effects as implicit indices of SoA. Participants were either made to believe to exert control over the color change or not (agency manipulation). Explicit ratings indicated that the manipulation of causal beliefs and hence agency was successful. However, temporal binding was only evident for caused effects, and only when a sufficiently sensitive procedure was used (auditory Libet clock). This suggests a feebler connection between temporal binding and SoA than previously proposed. The results also provide evidence for a relatively fast acquisition of sense of agency for previously never experienced types of action-effect associations. This indicates that the underlying processes of action control may be rooted in more intricate and adaptable cognitive models than previously thought. Oculomotor SoA as addressed in the present study presumably represents an important cognitive foundation of gaze-based social interaction (social sense of agency) or gaze-based human-machine interaction scenarios. Public significance statement: In this study, sense of agency for eye movements in the non-social domain is investigated in detail, using both explicit and implicit measures. Therefore, it offers novel and specific insights into comprehending sense of agency concerning effects induced by eye movements, as well as broader insights into agency pertaining to entirely newly acquired types of action-effect associations. Oculomotor sense of agency presumably represents an important cognitive foundation of gaze-based social interaction (social agency) or gaze-based human-machine interaction scenarios. Due to peculiarities of the oculomotor domain such as the varying degree of volitional control, eye movements could provide new information regarding more general theories of sense of agency in future research.}, language = {en} } @techreport{BolzNaumannRichter2024, type = {Working Paper}, author = {Bolz, Simon J. and Naumann, Fabrice and Richter, Philipp M.}, title = {Unilateral Environmental Policy and Offshoring}, doi = {10.25972/OPUS-35903}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359033}, pages = {66}, year = {2024}, abstract = {Expanding on a general equilibrium model of offshoring, we analyze the effects of a unilateral emissions tax increase on the environment, income, and inequality. Heterogeneous firms allocate labor across production tasks and emissions abatement, while only the most productive can benefit from lower labor and/or emissions costs abroad and offshore. We find a non-monotonic effect on global emissions, which decline if the initial difference in emissions taxes is small. For a sufficiently large difference, global emissions rise, implying emissions leakage of more than 100\%. The underlying driver is a global technique effect: While the emissions intensity of incumbent non-offshoring firms declines, the cleanest firms start offshoring. Moreover, offshoring firms become dirtier, induced by a reduction in the foreign effective emissions tax in general equilibrium. Implementing a BCA prevents emissions leakage, reduces income inequality in the reforming country, but raises inequality across countries.}, subject = {Umweltpolitik}, language = {en} } @techreport{OPUS4-35963, title = {Platelets - Molecular, cellular and systemic functions in health and disease}, editor = {Nieswandt, Bernhard}, organization = {Collaborative Research Centre/Transregio 240}, doi = {10.25972/OPUS-35963}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-359636}, pages = {25}, year = {2024}, abstract = {Besides their central role in haemostasis and thrombosis, platelets are increasingly recognised as versatile effector cells in inflammation, the innate and adaptive immune response, extracellular matrix reorganisation and fibrosis, maintenance of barrier and organ integrity, and host response to pathogens. These platelet functions, referred to as thrombo-inflammation and immunothrombosis, have gained major attention in the COVID-19 pandemic, where patients develop an inflammatory disease state with severe and life-threatening thromboembolic complications. In the CRC/TR 240, a highly interdisciplinary team of basic, translational and clinical scientists explored these emerging roles of platelets with the aim to develop novel treatment concepts for cardiovascular disorders and beyond. We have i) unravelled mechanisms leading to life-threatening thromboembolic complica-tions following vaccination against SARS-CoV-2 with adenoviral vector-based vaccines, ii) identified unrecognised functions of platelet receptors and their regulation, offering new potential targets for pharmacological intervention and iii) developed new methodology to study the biology of megakar-yocytes (MKs), the precursor cells of platelets in the bone marrow, which lay the foundation for the modulation of platelet biogenesis and function. The projects of the CRC/TR 240 built on the unique expertise of our research network and focussed on the following complementary fields: (A) Cell bi-ology of megakaryocytes and platelets and (B) Platelets as regulators and effectors in disease. To achieve this aim, we followed a comprehensive approach starting out from in vitro systems and animal models to clinical research with large prospective patient cohorts and data-/biobanking. Despite the comparably short funding period the CRC/TR 240 discovered basic new mechanisms of platelet biogenesis, signal transduction and effector function and identified potential MK/platelet-specific molecular targets for diagnosis and therapy of thrombotic, haemorrhagic and thrombo-inflammatory disease states.}, subject = {Thrombozyt}, language = {en} } @phdthesis{SpaethgebLutz2024, author = {Sp{\"a}th [geb. Lutz], Johanna}, title = {Oberfl{\"a}chenfunktionalisierte Gold- und Silbernanopartikel auf Basis von Thioether-Poly(glycidol) f{\"u}r potenzielle biomedizinische Anwendungen - Auswirkungen auf Stabilit{\"a}t, Proteinkoronabildung und Biodistribution}, doi = {10.25972/OPUS-35066}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350662}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Based on previous results showing that thioether modification of gold nanoparticles (AuNPs), especially coating with a multivalent system, yielded in excellent colloidal stability, the first aim of this thesis was to prove whether functionalization of silver nanoparticles (AgNPs) with thioether also has a comparable or even enhanced stabilization efficacy compared with the gold standard of coating with thiols and, particularly, whether the multivalency of polymers leads to stable AgNPs conjugates. Herein, AgNPs coated with mono- and multivalent thiol- and thioether polymers were prepared to systematically investigate the adsorption kinetics onto the silver surface as well as the colloidal stability after exposure to different conditions relevant for biomedical application. Although the thioether-polymers showed a slower immobilization onto AgNPs, same or mostly even better stabilization was exhibited than for the thiol analogs. As multivalent thioether-poly(glycidol) (PG) is already proven as a promising candidate for AuNP modification and stabilization, the second aim of this thesis was to examine the stealth behavior of thioether-PG, side-chain functionalized with various hydrophobic (alkyl and cholesteryl) units, to gain a deeper understanding of AuNP surface functionalization in terms of protein adsorption and their subsequent cellular uptake by human monocyte-derived macrophages. For this purpose, citrate-stabilized AuNPs were modified with the amphiphilic polymers by ligand exchange reaction, followed by incubation in human serum. The various surface amphiphilicities affected protein adsorption to a certain extent, with less hydrophobic particle layers leading to a more inhibited protein binding. Especially AuNPs functionalized with PG carrying the longest alkyl chain showed differences in the protein corona composition compared to the other polymer-coated NPs. In addition, PGylation, and especially prior serum incubation, of the NPs exhibited reduced macrophage internalization. As the use of mammals for in vivo experiments faces various challenges including increasing regulatory hurdles and costs, the third aim of this thesis was to validate larvae of the domestic silkworm Bombyx mori as an alternative invertebrate model for preliminary in vivo research, using AuNPs with various surface chemistry (one PEG-based modification and three PG-coatings with slightly hydrophobic functionalization, as well as positively and negatively charges) for studying their biodistribution and elimination. 6 h and 24 h after intra-hemolymph injection the Au content in different organ compartments was measured with ICP-MS, showing that positively charged particles appeared to be eliminated most rapidly through the midgut, while AuNPs modified with PEG, alkyl-functionalized PG and negatively charged PG exhibited long-term bioavailability in the silkworm body.}, subject = {Nanopartikel}, language = {en} } @phdthesis{Leonhardt2024, author = {Leonhardt, Jonas S.}, title = {Entwicklung von Gesundheitskompetenz zur Unterst{\"u}tzung der Lebensqualit{\"a}t - Eine Fragebogen basierte Analyse zur Erfassung des subjektiven Beratungsbedarfs sowie der Motivationslage krebskranker Patienten im Hinblick auf die Etablierung eines tagesklinischen Therapie- und Schulungsangebotes (KOI Tagesklinik) an der Universit{\"a}tsklinik W{\"u}rzburg}, doi = {10.25972/OPUS-35713}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357139}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Komplement{\"a}rmedizinische Angebote in der Onkologie erleben eine hohe Nachfrage. Diese Studie sollte kl{\"a}ren, ob bei Patienten ein Mehrbedarf an ganzheitlichen, tagesklinischen Angeboten besteht. Im Rahmen dieser Fragebogen-basierten Analyse sollten Zielgruppen identifiziert werden, die besonders hiervon profitieren k{\"o}nnten. Mithilfe eines Fragebogens wurden zwischen 08/2019 und 10/2020 294 ambulant behandelte onkologische Patienten des Comprehensive Cancer Centers Mainfranken an der Universit{\"a}tsklinik W{\"u}rzburg befragt. Der Fragebogen ist angelehnt an das etablierte Curriculum Mind-Body-Medizin der Kliniken Essen-Mitte und umfasst zehn Untergruppen. Statistisch signifikante Zusammenh{\"a}nge wurden durch Anwendung des Chi-Quadrat Tests ermittelt. In allen untersuchten Lebensbereichen fanden sich Hinweise auf einen Mehrbedarf an komplement{\"a}rmedizinischen Angeboten. Ein Drittel der Patienten gab an, aus eigener Kraft keine {\"u}berdauernden Lebensstil{\"a}nderungen herbeif{\"u}hren zu k{\"o}nnen. Das h{\"o}chste Gesundheitsbewusstsein zeigte sich in den Bereichen Ern{\"a}hrung, Bewegung und Entspannung. Trotzdem f{\"u}hrte ein Großteil der Befragten empfohlene Maßnahmen nicht durch. Insbesondere die Bereiche Schlaf, Energielevel und psychische Belastung wiesen das gr{\"o}ßte Verbesserungspotential auf. Defizite in diesen Bereichen beeinflussten sich gegenseitig und konnten mit Unzufriedenheit und negativen Gedanken sowie geringer Ver{\"a}nderungsmotivation in Verbindung gebracht werden. Besonders betroffen waren erwerbst{\"a}tige Patienten im Alter zwischen 40-65 Jahren. Frauen zeigten sich deutlich motivierter als M{\"a}nner komplement{\"a}rmedizinische Angebote zu nutzen. Gem{\"a}ß unseren Ergebnissen und evidenzbasierten Empfehlungen der S3-Leitlinie Komplement{\"a}rmedizin ergibt sich ein Mehrbedarf nach folgenden Angeboten: Supervidierte Sportprogramme, MBSR, Tai Chi/ Qigong, individuelle Ern{\"a}hrungsberatung und Selbsthilfegruppen f{\"u}r Angeh{\"o}rige. Durch Vermittlung von Gesundheitsbewusstsein sollten insbesondere Patientengruppen motiviert werden, die aus eigener Kraft ihre Situation nicht verbessern k{\"o}nnen. Um den Erfolg von gesundheitsf{\"o}rdernden Lebensstil{\"a}nderungen {\"u}berdauernd zu sichern, ist weitere Unterst{\"u}tzung n{\"o}tig.}, subject = {Onkologie}, language = {de} } @phdthesis{Ulrich2024, author = {Ulrich, Johannes}, title = {Molekulare Charaktierisierung einer DyP-Typ Peroxidase des Humanparasiten \(Echinococcus\) \(multilocularis\)}, doi = {10.25972/OPUS-35714}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357143}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die Alveol{\"a}re Echinokokkose (AE) ist eine t{\"o}dliche Infektionserkrankung, die durch den parasit{\"a}ren Plattwurm Echinococcus multilocularis verursacht wird. Genomanalysen von E. multilocularis ergaben ein Gen, das laut Vorhersage f{\"u}r eine DyP-Typ Peroxidase codiere. Ziel dieser Arbeit ist die biologische Funktion des codierten Enzyms besser zu verstehen und Hinweise auf eine m{\"o}gliche Rolle in der Abwehr von Reaktiven Sauerstoffspezies (ROS) zu erlangen. Das Gen wurde heterolog in E. Coli exprimiert und molekulare Charakteristika des Gens mit bioinformatischen und molekularbiologischen Methoden untersucht. Quantitative RT-PCR Untersuchungen gaben Aufschluss {\"u}ber das Transkriptprofil von emipox in unterschiedlichen Entwicklungsstadien von E. mulitlocularis. Mittels Whole-Mount In Situ-Hybridisierung (WMISH) wurden die Transkripte zudem lokalisiert und ihre Beziehung zum Stammzellsystem von E. multilocularis n{\"a}her untersucht. Die Zugeh{\"o}rigkeit von EmIPOX zur Gruppe der DyP-Typ Peroxidasen wurde best{\"a}tigt. Homologe beim Menschen kommen nicht vor. Es konnte nachgewiesen werden, dass Transkripte von emipox auch, aber keinesfalls ausschließlich, in Stammzellen vorliegen. {\"U}berdurchschnittlich viele Transkripte liegen im aktivierten Protoscolex und im Metacestoden ex vivo aus einer infizierten Wirtsleber vor. Untersuchungen zur Enzymaktivit{\"a}t von EmIPOX zeigten neben einer Peroxidase- auch eine Katalaseaktivit{\"a}t. Die vorliegende Arbeit ist die erste Charakterisierung einer DyP-Typ Peroxidase bei Tieren. Sie legt nahe, dass EmIPOX eine Rolle in der Entgiftung von ROS in E. multilocularis spielt und stellt den Charakter von EmIPOX als potenzieller pharmakologischer Zielstruktur heraus.}, subject = {Fuchsbandwurm}, language = {de} } @unpublished{Dandekar2024, author = {Dandekar, Thomas}, title = {How do qubits interact? Implications for fundamental physics}, doi = {10.25972/OPUS-35743}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357435}, pages = {42}, year = {2024}, abstract = {Proteins fold in water and achieve a clear structure despite a huge parameter space. Inside a (protein) crystal you have everywhere the same symmetries as there is everywhere the same unit cell. We apply this to qubit interactions to do fundamental physics: We modify cosmological inflation: we replace the big bang by a condensation event in an eternal all-encompassing ocean of free qubits. Rare interactions of qubits in the ocean provide a nucleus or seed for a new universe (domain), as the qubits become decoherent and freeze-out into defined bit ensembles. Next, we replace inflation by a crystallization event triggered by the nucleus of interacting qubits to which rapidly more and more qubits attach (like in everyday crystal growth). The crystal unit cell guarantees same symmetries (and laws of nature) everywhere inside the crystal, no inflation scenario is needed. Interacting qubits solidify, quantum entropy decreases in the crystal, but increases outside in the ocean. The interacting qubits form a rapidly growing domain where the n**m states become separated ensemble states, rising long-range forces stop ultimately further growth. After this very early modified steps, standard cosmology with the hot fireball model takes over. Our theory agrees well with lack of inflation traces in cosmic background measurements. Applying the Hurwitz theorem to qubits we prove that initiation of qubit interactions can only be 1,2,4 or 8-dimensional (agrees with E8 symmetry of our universe). Repulsive forces at ultrashort distances result from quantization, long-range forces limit crystal growth. The phase space of the crystal agrees with the standard model of the basic four forces for n quanta. It includes all possible ensemble combinations of their quantum states m, a total of n**m states. We describe a six-bit-ensemble toy model of qubit interaction and the repulsive forces of qubits for ultra-short distances. Neighbor states reach according to transition possibilities (S-matrix) with emergent time from entropic ensemble gradients. However, in our four dimensions there is only one bit overlap to neighbor states left (almost solid, only below Planck´s quantum is liquidity left). The E8 symmetry of heterotic string theory has six curled-up, small dimensions. These keep the qubit crystal together and never expand. We give energy estimates for free qubits vs bound qubits, misplacements in the qubit crystal and entropy increase during qubit crystal formation. Implications are fundamental answers, e.g. why there is fine-tuning for life-friendliness, why there is string theory with rolled-up dimension and so many free parameters. We explain by cosmological crystallization instead of inflation the early creation of large-scale structure of voids and filaments, supercluster formation, galaxy formation, and the dominance of matter: the unit cell of our crystal universe has a matter handedness avoiding anti-matter. Importantly, crystals come and go in the qubit ocean. This selects for the ability to lay seeds for new crystals, for self-organization and life-friendliness. Vacuum energy gets appropriate low inside the crystal by its qubit binding energy, outside it is 10**20 higher. Scalar fields for color interaction/confinement and gravity could be derived from the qubit-interaction field.}, language = {en} } @techreport{KindermannFrommTheureretal.2024, type = {Working Paper}, author = {Kindermann, Katharina and Fromm, Julia and Theurer, Caroline and Kr{\"u}ger, Nadine}, title = {It's storytime: Ein digitales M{\"a}rchenprojekt f{\"u}r den Englischunterricht in der Grundschule}, doi = {10.25972/OPUS-35304}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-353045}, pages = {12}, year = {2024}, abstract = {In diesem Beitrag wird zun{\"a}chst das Konzept des digital storytelling mit dem Tablet im fr{\"u}hen Fremdsprachenunterricht methodisch-didaktisch gerahmt (Kapitel 1). Daran anschließend wird die Bedeutung lernunterst{\"u}tzender Maßnahmen in einem solchen digital gest{\"u}tzten und potenziell kreativit{\"a}tsf{\"o}rdernden Unterrichtssetting erl{\"a}utert (Kapitel 2). In Kapitel 3 folgt die Vorstellung der Unterrichtsreihe „It's storytime - Let's create our own digital fairy tale". Im Verlauf dieser Unterrichtsreihe, die auch als Projektwoche angelegt werden kann, rezipieren die Sch{\"u}ler:innen zun{\"a}chst eigenst{\"a}ndig M{\"a}rchen in englischer Sprache, die aus dem deutschen und angloamerikanischen Sprachraum bekannt sind. Die M{\"a}rchen liegen f{\"u}r das Tablet multimedial aufbereitet vor. Anschließend entwickeln die Lernenden auf Grundlage des erarbeiteten gattungsspezifischen Wortschatzes ein eigenes multimediales M{\"a}rchen. Alle f{\"u}r die Unterrichtsreihe ben{\"o}tigten digitalen und analogen Materialien stehen als Download zur Verf{\"u}gung und k{\"o}nnen f{\"u}r den eigenen Unterricht genutzt und adaptiert werden.}, subject = {Medienkompetenz}, language = {de} } @phdthesis{Dekant2024, author = {Dekant, Raphael H.}, title = {Species-differences in the \(in\) \(vitro\) biotransformation of trifluoroethene (HFO-1123)}, doi = {10.25972/OPUS-31403}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-314035}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {1,1,2-trifluoroethene (HFO-1123) is intended for use as a refrigerant. Inhalation studies on HFO-1123 in rats suggested a low potential for toxicity, with no-observed-adverse-effect levels greater then 20,000 ppm. However, single inhalation exposure of Goettingen Minipigs and New Zealand White Rabbits resulted in mortality. It was assumed that conjugation of HFO-1123 with glutathione, via glutathione S-transferase, gives rise to S-(1,1,2-trifluoroethyl)-L-glutathione (1123-GSH), which is then transformed to the corresponding cysteine S-conjugate (S-(1,1,2-trifluoroethyl)-L-cysteine, 1123-CYS). Subsequent beta-lyase mediated cleavage of 1123-CYS may result in monofluoroacetic acid, a potent inhibitor of aconitase. Species-differences in 1123-GSH formation and 1123-CYS cleavage to MFA may explain species-differences in HFO-1123 toxicity. This study was designed to test the hypothesis, that GSH-dependent biotransformation and subsequent beta-lyase mediated formation of monofluoroacetic acid, a potent inhibitor of aconitase in the citric acid cycle, may play a key role in HFO-1123 toxicity and to evaluate if species-differences in the extent of MFA formation may account for the species-differences in HFO-1123 toxicity. The overall objective was to determine species-differences in HFO-1123 biotransformation in susceptible vs. less susceptible species and humans as a basis for human risk assessment. To this end, in vitro biotransformation of HFO-1123 and 1123-CYS was investigated in renal and hepatic subcellular fractions of mice, rats, humans, Goettingen Minipigs and NZW Rabbits. Furthermore, cytotoxicity and metabolism of 1123-CYS was assessed in cultured renal epithelial cells. Enzyme kinetic parameters for beta-lyase mediated cleavage of 1123-CYS in renal and hepatic cytosolic fractions were determined, and 19F-NMR was used to identify fluorine containing metabolites arising from 1123-CYS cleavage. Quantification of 1123-GSH formation in hepatic S9 fractions after incubation with HFO-1123 was performed by LC-MS/MS and hepatic metabolism of HFO-1123 was monitored by 19F-NMR. Rates of 1123-GSH formation were increased in rat, mouse and NZW Rabbit compared to human and Goettingen hepatic S9, indicating increased GSH dependent biotransformation in rats, mouse and NZW Rabbits. NZW Rabbit hepatic S9 exhibited increased 1123-GSH formation in the presence compared to the absence of acivicin, a specific gamma-GT inhibitor. This indicates increased gamma-GT mediated cleavage of 1123-GSH in NZW Rabbit hepatic S9 compared to the other species. 19F-NMR confirmed formation of 1123-GSH as the main metabolite of GSH mediated biotransformation of HFO-1123 in hepatic S9 fractions next to F-. Increased F- formation was detected in NZW Rabbit and Goettingen Minipig hepatic S9 in the presence of an NADPH regenerating system, indicating a higher rate of CYP-450 mediated metabolism in these species. Based on these findings, it is possible that CYP-450 mediated metabolism may contribute to HFO-1123 toxicity. In contrast to the increased formation of 1123-GSH in rat, mouse and NZW Rabbit hepatic S9 (compared to human and Goettingen Minipig), enzyme kinetic studies revealed a significantly higher beta-lyase activity towards 1123-CYS in renal cytosol of Goettingen Minipigs compared to cytosol from rats, mice, humans and NZW Rabbits. However, beta-lyase cleavage in renal NZW Rabbit cytosol was slightly increased compared to rat, mouse and human renal cytosols. 19F-NMR analysis confirmed increased time-dependent formation of MFA in renal Goettingen Minipig cytosol and NZW Rabbit (compared to human and rat cytosolic fractions). Three structurally not defined MFA-derivatives were detected exclusively in NZW Rabbit and Goettingen Minipig cytosols. Also, porcine kidney cells were more sensitive to cytotoxicity of 1123-CYS compared to rat and human kidney cells. Overall, increased beta-lyase mediate cleavage of 1123-CYS to MFA in Goettingen Minipig and NZW Rabbit kidney (compared to human and rat) may support the hypothesis that enzymatic cleavage by beta-lyases may account for the species-differences in HFO-1123 toxicity. However, the extent of GST mediated biotransformation in the liver as the initial step in HFO-1123 metabolism does not fully agree with this hypothesis, since 1123-GSH formation occurs at higher rates in rat, mouse and NZW Rabbit S9 as compared to the Goettingen Minipig. Based on the inconsistencies between the extent of GST and beta-lyase mediated biotransformation of HFO-1123 obtained by this study, a decisive statement about an increased biotransformation of HFO-1123 in susceptible species with a direct linkage to the species-specific toxicity cannot be drawn. Resulting from this, a clear and reliable conclusion regarding the risk for human health originating from HFO-1123 cannot be made. However, considering the death of Goettingen Minipigs and NZW Rabbits after inhalation exposure of HFO-1123 at concentrations great than 500 ppm and greater than 1250 ppm, respectively, this indicates a health concern for humans under peak exposure conditions. For a successful registration of HFO-1123 and its use as a refrigerant, further in vitro and in vivo investigations addressing uncertainties in the species-specific toxicity of HFO-1123 are urgently needed.}, subject = {Biotransformation}, language = {en} } @article{SteinhardtCejkaChenetal.2024, author = {Steinhardt, Maximilian J. and Cejka, Vladimir and Chen, Mengmeng and B{\"a}uerlein, Sabrina and Sch{\"a}fer, Julia and Adrah, Ali and Ihne-Schubert, Sandra M. and Papagianni, Aikaterini and Kort{\"u}m, K. Martin and Morbach, Caroline and St{\"o}rk, Stefan}, title = {Safety and tolerability of SGLT2 inhibitors in cardiac amyloidosis — a clinical feasibility study}, series = {Journal of Clinical Medicine}, volume = {13}, journal = {Journal of Clinical Medicine}, number = {1}, issn = {2077-0383}, doi = {10.3390/jcm13010283}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-356024}, year = {2024}, abstract = {Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1\% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5\% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients.}, language = {en} } @phdthesis{Scherz2024, author = {Scherz, Jan}, title = {Weak Solutions to Mathematical Models of the Interaction between Fluids, Solids and Electromagnetic Fields}, doi = {10.25972/OPUS-34920}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349205}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {We analyze the mathematical models of two classes of physical phenomena. The first class of phenomena we consider is the interaction between one or more insulating rigid bodies and an electrically conducting fluid, inside of which the bodies are contained, as well as the electromagnetic fields trespassing both of the materials. We take into account both the cases of incompressible and compressible fluids. In both cases our main result yields the existence of weak solutions to the associated system of partial differential equations, respectively. The proofs of these results are built upon hybrid discrete-continuous approximation schemes: Parts of the systems are discretized with respect to time in order to deal with the solution-dependent test functions in the induction equation. The remaining parts are treated as continuous equations on the small intervals between consecutive discrete time points, allowing us to employ techniques which do not transfer to the discretized setting. Moreover, the solution-dependent test functions in the momentum equation are handled via the use of classical penalization methods. The second class of phenomena we consider is the evolution of a magnetoelastic material. Here too, our main result proves the existence of weak solutions to the corresponding system of partial differential equations. Its proof is based on De Giorgi's minimizing movements method, in which the system is discretized in time and, at each discrete time point, a minimization problem is solved, the associated Euler-Lagrange equations of which constitute a suitable approximation of the original equation of motion and magnetic force balance. The construction of such a minimization problem is made possible by the realization that, already on the continuous level, both of these equations can be written in terms of the same energy and dissipation potentials. The functional for the discrete minimization problem can then be constructed on the basis of these potentials.}, subject = {Fluid-Struktur-Wechselwirkung}, language = {en} } @phdthesis{Blahetek2024, author = {Blahetek, Gina}, title = {The role of alternative intronic polyadenylation on microRNA biogenesis in melanoma}, doi = {10.25972/OPUS-25474}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254743}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {mRNA is co- or post-transcriptionally processed from a precursor mRNA to a mature mRNA. In addition to 5'capping and splicing, these modifications also include polyadenylation, the addition of a polyA tail to the 3'end of the mRNA. In recent years, alternative polyadenylation in particular has increasingly been taken into account as a mechanism for regulating gene expression. It is assumed that approximately 70-75 \% of human protein coding genes contain alternative polyadenylation signals, which are often located within intronic sequences of protein-coding genes. The use of such polyadenylation signals leads to shortened mRNA transcripts and thus to the generation of C-terminal shortened protein isoforms. Interestingly, the majority of microRNAs, small non-coding RNAs that play an essential role in post-transcriptional gene regulation, are also encoded in intronic sequences of protein-coding genes and are co-transcriptionally expressed with their host genes. The biogenesis of microRNA has been well studied and is well known, but mechanisms that may influence the expression regulation of mature microRNAs are just poorly understood. In the presented work, I aimed to investigate the influence of alternative intronic polyadenylation on the biogenesis of microRNAs. The human ion channel TRPM1 could already be associated with melanoma pathogenesis and truncated isoforms of this protein have already been described in literature. In addition, TRPM1 harbors a microRNA, miR211, in its sixth intron, which is assumed to act as a tumor suppressor. Since both, TRPM1 and miR211 have already been associated with melanoma pathogenesis, the shift towards truncated transcripts during the development of various cancers is already known and it has been shown that certain microRNAs play a crucial role in the development and progression of melanoma, melanoma cell lines were used as an in vitro model for these investigations.}, subject = {Polyadenylierung}, language = {en} } @unpublished{SeitzJungnickelKleiberetal.2024, author = {Seitz, Florian and Jungnickel, Tina and Kleiber, Nicole and Kretschmer, Jens and Dietzsch, Julia and Adelmann, Juliane and Bohnsack, Katherine E. and Bohnsack, Markus T. and H{\"o}bartner, Claudia}, title = {Atomic mutagenesis of N\(^6\)-methyladenosine reveals distinct recognition modes by human m\(^6\)A reader and eraser proteins}, series = {Journal of the American Chemical Society}, journal = {Journal of the American Chemical Society}, doi = {10.1021/jacs.4c00626}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352376}, year = {2024}, abstract = {N\(^6\)-methyladenosine (m\(^6\)A) is an important modified nucleoside in cellular RNA associated with multiple cellular processes and is implicated in diseases. The enzymes associated with the dynamic installation and removal of m\(^6\)A are heavily investigated targets for drug research, which requires detailed knowledge of the recognition modes of m\(^6\)A by proteins. Here, we use atomic mutagenesis of m\(^6\)A to systematically investigate the mechanisms of the two human m\(^6\)A demethylase enzymes FTO and ALKBH5 and the binding modes of YTH reader proteins YTHDF2/DC1/DC2. Atomic mutagenesis refers to atom-specific changes that are introduced by chemical synthesis, such as the replacement of nitrogen by carbon atoms. Synthetic RNA oligonucleotides containing site-specifically incorporated 1-deaza-, 3-deaza-, and 7-deaza-m\(^6\)A nucleosides were prepared by solid-phase synthesis and their RNA binding and demethylation by recombinant proteins were evaluated. We found distinct differences in substrate recognition and transformation and revealed structural preferences for the enzymatic activity. The deaza m\(^6\)A analogues introduced in this work will be useful probes for other proteins in m\(^6\)A research.}, language = {en} } @phdthesis{Held2024, author = {Held, Helena}, title = {The effectiveness of non-occlusal therapies in relation to the chronicity of temporomandibular disorders: a systematic review with meta-analysis}, doi = {10.25972/OPUS-34799}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-347990}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Background: That a differentiated treatment of subjects with low and high levels of disabling pain might be necessarily has only been suspected but not sufficiently confirmed so far. Furthermore, the effectiveness of extraoral therapy methods for TMD is still controversial in the literature. The present work could make an important contribution to this. Objectives: Five systematic reviews with meta-analysis were conducted to investigate the efficacy of extraoral therapies (acupuncture, laser, medication, psychosocial interventions, and physiotherapy) in the treatment of TMD in relation to the degree of chronicity of pain. Literature sources: With this objective, the databases Pubmed/MEDLINE, EMBASE, Cochrane Library, Livivo, OpenGrey, drks.de, Clinicaltrials.gov. were searched. Criteria for the selection of suitable studies: Adults suffering from painful TMD and treated with either acupuncture, laser, medication, psychosocial interventions, or physiotherapy. The studies were then examined for evidence in the subjects' characteristics suggesting that they were suffering from chronic TMD in terms of pain dysfunction. These included a high score on the GCPS, resistance to undergone treatments, multilocular pain, depression, and regular use of pain medication. The effectiveness of the five interventions was then differentiated according to the suspected degree of chronicity. Effectiveness was assessed by the following outcomes: patient- related current pain intensity, MMO, pain on palpation, temporomandibular joint sounds, depression, and somatization. Study evaluation: After the assessment of the studies, the quality assessment (Risk of Bias Tool of the Cochrane Institute) and the extraction of the data were conducted. After that five meta-analyses were carried out for each of the five interventions using the Review Manager of the Cochrane Institute (RevMan 5.3) Results: Acupuncture and dry needling were statistically significantly more effective in providing short-term pain relief compared to the control group in patients with low disability pain (p=0.04) and (p=0.02), respectively. Acupuncture or dry needling did not show a significant result in the improvement of MMO in the short-term period. Laser therapy is more effective in relieving pain (p<0.0001) and functional outcomes (p=0.03) in the short term compared to placebo for low disability pain. Botulinum toxin (p=0.003) and NSAIDs (p=0.03) showed significantly better short-term improvement in pain intensity for high disability pain. Low disability pain is significantly better treated by psychosocial interventions than by other treatments in terms of long-term pain relief (more than 12 months) (p=0.02). Patients with high disability pain had significantly lower depression scores after psychosocial interventions than after other treatments (p=0.008). Physiotherapy showed a statistically significant short-term analgesic effect in patients with high disability pain compared to placebo (p=0.04). Manual Therapy (MT) showed a statistically significant short-term analgesic effect in high disability pain compared to the control group (p=0.01). Patients with low disability pain showed a statistically significant short-term pain-relieving effect with the single intervention of MT in combination with exercise compared to the control groups (p=0.003). A statistically significant result in the improvement of MMO was found in the short-term period in low disability pain for the single interventions of physiotherapy (p=0.008) and physiotherapy in combination with another treatment compared to other treatments (p=0.03), MT compared to the control group (p=0.03) and physiotherapy compared to splint therapy (p=0.03). Clinical conclusion: Individual interventions of the five extraoral therapies confirm the hypothesis that painful TMDs respond differently to established therapies depending on the degree of chronic pain-related disability and that the prognosis of therapy is significantly influenced by the degree of chronic pain- related disability of the condition, according to the GCPS. Registration number of the review at PROSPERO: CRD42020202558 Keywords: meta-analysis, systematic review, temporomandibular disorders, extra oral therapy, acupuncture, laser, medication, psychosocial interventions, physiotherapy, low disability, high disability, pain, chronification}, subject = {Metaanalyse}, language = {en} } @phdthesis{Horn2024, author = {Horn, Daniela}, title = {Kardiotoxizit{\"a}t von CTRPs und das Vorkommen der CTRP-Rezeptoren in Kardiomyozyten}, doi = {10.25972/OPUS-34902}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349029}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die C1q/tumor necrosis factor-related proteins (CTRPs) sind eine Ligandenfamilie aus sezernierten Plasmaproteinen, welche sich in ihrem Grundbauplan {\"a}hneln. Daten aus der Literatur deuten darauf hin, dass sie zum Teil positive Effekte auf den Stoffwechsel und das Herz-Kreislaufsystem besitzen und somit eine m{\"o}gliche therapeutische Zielstruktur darstellen. W{\"a}hrend f{\"u}r manche CTRPs bereits Rezeptoren identifiziert werden konnten, ist f{\"u}r andere immer noch nicht gekl{\"a}rt, an welche Rezeptoren sie binden oder {\"u}ber welche sie diese Wirkungen erzielen. Um die CTRPs zuk{\"u}nftig therapeutisch nutzen zu k{\"o}nnen, muss die Wirkung der CTRPs auf verschiedene Zellen weiter analysiert werden. Daf{\"u}r wurden in dieser Arbeit Zellen, auf die Expression bereits bekannter CTRP-Rezeptoren hin, untersucht. Des Weiteren wurden die durch CTRP2, CTRP3, CTRP4, CTRP9A, CTRP10, CTRP11, CTRP13 und CTRP14 induzierten {\"A}nderungen in der ATP- und Laktatproduktion als Surrogatparameter f{\"u}r Kardiotoxizit{\"a}t in den Kardiomyozytenzelllinien H9c2 und AC16 getestet, um potenziell kardiotoxische Wirkungen fr{\"u}hzeitig erkennen zu k{\"o}nnen. Es konnte gezeigt werden, dass die CTRPs sicher f{\"u}r Kardiomyozyten zu sein scheinen, was eine wichtige Grundlage f{\"u}r die therapeutische Nutzbarkeit darstellt.}, subject = {Herzmuskelzelle}, language = {de} } @phdthesis{Witteler2024, author = {Witteler, Charlotte Marie}, title = {Untersuchung des zellbiologischen Verhaltens von Fibroblasten in modifizierten Gelatine-Methacrylat basierten Harzen f{\"u}r den volumetrischen Biodruck}, doi = {10.25972/OPUS-34946}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349460}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Was vor einigen Jahren undenkbar erschien, k{\"o}nnte zuk{\"u}nftig m{\"o}glich sein: Krankes Gewebe mit Gesundem ersetzen, das in vitro mit modernsten Biofabrikationstechniken hergestellt wird. Dabei werden bisherige Grenzen {\"u}berschritten: W{\"a}hrend lichtbasierte Biodruckverfahren wie die Zwei-Photonen-Polymerisation Aufl{\"o}sungen bis in den Nanometerbereich erzielen, erm{\"o}glicht der Volumetrische Biodruck (VB) den Druck zentimetergroßer Konstrukte in wenigen Sekunden. Diese Geschwindigkeiten erweisen sich unter Biodruckverfahren als konkurrenzlos und werden erreicht, da das Bioharz nicht konsekutiv, sondern zugleich vernetzt wird. Einschr{\"a}nkend gilt bislang nur der Mangel an geeigneten Bioharzen f{\"u}r den VB. Daher besch{\"a}ftigt sich vorliegende Arbeit mit der Charakterisierung und Modifikation eines daf{\"u}r geeigneten Bioharzes: Gelatine-Methacrylat (GelMA). Dank seiner Zusammensetzung {\"a}hnelt das etablierte Hydrogelsystem der Extratrazellularmatrix: Der Gelatine-Anteil erm{\"o}glicht Biokompatibilit{\"a}t und Bioaktivit{\"a}t durch zelladh{\"a}sive sowie degradierbare Aminos{\"a}ure-Sequenzen. Zugleich k{\"o}nnen durch photovernetzbare Methacryloyl-Substituenten Konstrukte mit einer Formstabilit{\"a}t bei 37 °C erzeugt werden. Zun{\"a}chst wurde das Bioharz zellbiologisch charakterisiert, indem mit der embryonalen Mausfibroblasten-Zelllinie NIH-3T3 beladene GelMA-Zylinder gegossen, photopolymerisiert und kultiviert wurden. Im Verlauf einer Woche wurde die Zytokompatibilit{\"a}t der Gele anhand der Proliferationsf{\"a}higkeit (PicoGreen-Assay), des Metabolismus (CCK-8-Assay) und der Vitalit{\"a}t (Live/Dead-Assay) der Zellen beurteilt. Dabei wurden Polymerkonzentrationen von 6 - 8 \% sowie GelMA-Harze zweier verschiedener Molekulargewichte verglichen. Alle hergestellten Gele erwiesen sich als zytokompatibel, 6 \% ige Gele ließen im Inneren jedoch zus{\"a}tzlich eine beginnende Zellspreizung zu und ein niedriges GelMA-Molekulargewicht verst{\"a}rkte die gemessene Proliferation. Die sich anschließende mechanische und physikalische Charakterisierung belegte, dass h{\"o}her konzentrierte Gele einen gr{\"o}ßeren E-Modul aufwiesen und damit steifer waren. Eine Modifikation der Gele mit Fibronektin beeinflusste die Zellvertr{\"a}glichkeit weder positiv noch negativ und die Zugabe von Kollagen war wegen Entmischungseffekten nicht bewertbar. Es liegt die Vermutung nah, dass eine weitere Reduktion der Polymerkonzentration und damit Verringerung der Gelsteifigkeit der Schl{\"u}ssel f{\"u}r mehr Zellspreizung und -wachstum ist. Da jedoch die Druckbarkeit des Bioharzes die weitere Senkung des GelMA-Gehalts limitiert, sollten zun{\"a}chst Methoden entwickelt werden, welche die Netzwerkdichte des GelMAs anderweitig herabsetzen.}, subject = {3D Bioprinting}, language = {de} } @phdthesis{Caspari2024, author = {Caspari, Almut}, title = {Effektivit{\"a}t von APD421 (Amisulprid zur i.v.-Injektion) zur PONV-Therapie nach fehlgeschlagener PONV-Prophylaxe. Eine prospektive, randomisierte, Placebo-kontrollierte Doppelblindstudie.}, doi = {10.25972/OPUS-34733}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-347331}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Postoperative {\"U}belkeit und postoperatives Erbrechen (PONV) sind eine der h{\"a}ufigsten und f{\"u}r Patient*innen unangenehmsten Nebenwirkungen einer Allgemeinan{\"a}sthesie. Trotz jahrzehntelanger Forschung und der Vielfalt an mittlerweile bekannten Maßnahmen und Substanzen zur PONV-Prophylaxe und -Therapie gibt es noch keine Strategie, die eine sichere Vermeidung oder stets wirksame Therapie von PONV garantieren kann. In vorangegangenen Studien zeigte Amisulprid als Dopaminantagonist an den Rezeptortypen D2 und D3 vielversprechende Ergebnisse zur PONV-Prophylaxe und -Therapie. Die dieser Arbeit zugrunde liegende prospektive, randomisierte, Placebo-kontrollierte Doppelblindstudie untersuchte die Wirksamkeit einer Einzeldosis APD421 5 mg bzw. 10 mg zur Therapie von manifestem PONV nach fehlgeschlagener PONV-Prophylaxe. „Complete Response" (CR) wurde definiert als das Ausbleiben jeglicher weiterer emetischer Episoden im Zeitraum von 30 Minuten bis 24 Stunden nach Applikation des Studienmedikaments sowie keine Gabe von antiemetischer Rescue-Medikation im gesamten Zeitraum bis 24 Stunden nach Applikation des Studienmedikaments. Die CR-Raten lagen bei 41,7\% f{\"u}r APD421 10 mg, 33,8\% f{\"u}r APD421 5 mg und 28,5\% f{\"u}r Placebo, wobei die Studienarme jeweils 230, 237 bzw. 235 Patient*innen umfassten. Eine Dosis APD421 10 mg zeigte somit statistisch signifikante {\"U}berlegenheit in der PONV-Therapie gegen{\"u}ber Placebo. Auch hinsichtlich sekund{\"a}rer Studienendpunkte wie Auftreten bzw. St{\"a}rke von {\"U}belkeit, W{\"u}rgen oder Erbrechen und Bedarf an Rescue-Medikation war APD421 10 mg gegen{\"u}ber Placebo {\"u}berlegen. Eine Dosis von 5 mg APD421 zeigte f{\"u}r die meisten Endpunkte hingegen keine statistisch signifikante {\"U}berlegenheit gegen{\"u}ber Placebo. Limitationen der Studie liegen im Ausschluss von Patientengruppen wie beispielsweise Kindern oder bestimmten Vorerkrankungen und dem mit {\"u}ber 90\% sehr hohen Anteil weiblicher Patient*innen. Es bleiben weitere Studien abzuwarten, die APD421 einem direkten Vergleich mit bislang etablierten Substanzen zur PONV-Therapie unterziehen, um den k{\"u}nftigen Stellenwert der Substanz im klinischen Alltag einsch{\"a}tzen zu k{\"o}nnen.}, subject = {Amisulprid}, language = {de} } @phdthesis{Radun2024, author = {Radun, Victoria}, title = {Quantitative Fundusautofluoreszenz bei systemischer (Hydroxy-)Chloroquin Therapie: ein Jahr follow-up.}, doi = {10.25972/OPUS-34868}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348688}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {CQ und HCQ werden h{\"a}ufig zur Behandlung von Erkrankungen aus dem rheumatischen Formenkreis wie z.B. SLE oder RA eingesetzt. Die lange Anwendung birgt das Risiko der Entwicklung einer CQ/HCQ-assoziierten Makulopathie. Diese ist charakterisiert durch den irreversiblen Verlust von Photorezeptoren und RPE und im Verlauf progredienten Visusverlust. Die QAF-Bildgebung ist eine nicht-invasive, innovative Methode zur Diagnostik krankhafter Netzhautver{\"a}nderungen. Durch entsprechende technische Modifikationen eines cSLO sind inzwischen quantitative Aussagen bei Verlaufskontrollen der FAF derselben Patienten und Patientinnen sowie interpersonelle Vergleiche m{\"o}glich. In der vorliegenden Studie wurden 32 CQ/HCQ Patienten und Patientinnen {\"u}ber den Zeitraum von einem Jahr mittels multimodaler Bildgebung (IR-, FAF bei 488 nm und 787 nm, QAF bei 488 nm, rotfreie Aufnahmen sowie SD-OCT Bilder) auf BEM-typische Ver{\"a}nderungen am Augenhintergrund gescreent bzw. Verlaufskontrollen bei bekannter BEM durchgef{\"u}hrt. Die QAF Entwicklung innerhalb eines Jahres wurde quantitativ und r{\"a}umlich analysiert. Hierbei zeigte sich eine den erwarteten Alterseffekt {\"u}bersteigende Erh{\"o}hung der QAF. Dies k{\"o}nnte durch eine erh{\"o}hte Lipofuzingenese oder metabolische Aktivit{\"a}t der Netzhaut erkl{\"a}rt werden. Die vorgestellten Methoden k{\"o}nnten zuk{\"u}nftig eine n{\"u}tzliche Erweiterung zu den bereits bestehenden Diagnostik-Tools f{\"u}r Screening auf BEM sein. Bei CQ/HCQ Patienten und Patientinnen zeigt sich eine grunds{\"a}tzlich erh{\"o}hte QAF gegen{\"u}ber der Kontrollgruppe ohne das Medikament. Im Ein-Jahres-Verlauf gab es einige Patienten und Patientinnen, die einen {\"u}berdurchschnittlich starken Anstieg der QAF zeigen. Es bleibt zu kl{\"a}ren, ob diese Ausreißer Hinweise auf die sp{\"a}tere Entwicklung einer BEM liefern. So k{\"o}nnte die QAF im klinischen Alltag Anwendung finden und vor allem bei Verlaufskontrollen zus{\"a}tzliche Informationen bieten.}, subject = {Chloroquin}, language = {de} } @phdthesis{Peter2024, author = {Peter, Lisa Susanne}, title = {Chronische Graft-versus-Host-Erkrankung im p{\"a}diatrischen Setting - Identifikation von Charakteristika mit Fokus auf die Immunrekonstitution dendritischer Zellen}, doi = {10.25972/OPUS-34954}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349546}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die cGvHD ist eine relevante Komplikation der aHSCT. Sie hat Einfluss auf die Morbidit{\"a}t und Mortalit{\"a}t nach der aHSCT. Die genaue Pathogenese ist unbekannt. Ein Einfluss dendritscher Zellen als Schl{\"u}sselzellen immunologischer Prozesse auf die Entstehung einer cGvHD ist wahrscheinlich. In dieser Studie erfassten wir patient:innen und aHSCT-bezogene Daten 61 stammzelltransplantierter Kinder und Jugendlicher sowie deren m{\"o}glichen Einfluss auf das Auftreten einer cGvHD. Zudem wurde die Rekonstitution der Immunzellen, insbesondere der DCs, nach der aHSCT evaluiert. Die Rekonstitution der Lymphozyten sowie die Zytokinexpression der T-Zellen w{\"a}hrend der Rekonstitution verhielt sich {\"a}hnlich zu vorherigen Studien. Signifikante Unterschiede zwischen Patient:innen mit oder ohne cGvHD zeigten sich nicht konsistent. Die Rekonstitution der DCs erfolgte innerhalb von 60-100 Tagen. Stabile Werte zeigten sich jedoch fr{\"u}hestens ein Jahr nach der aHSCT. W{\"a}hrend des Engraftments war der Anteil CCR7+ DCs bei Patient:innen erh{\"o}ht, die eine TBI erhalten hatten. Ein hoher Anteil CCR7+ DCs wirkte sich zu jedem Zeitpunkt positiv auf das Gesamt{\"u}berleben aus. Trat eine h{\"o}hergradige aGvHD auf, konnte eine verminderte absolute und relative Zellzahl 60-365 Tage nach der aHSCT f{\"u}r DCs insgesamt und mDCs erfasst werden, f{\"u}r pDCs 60-100 Tage nach aHCST. Zwischen der Rekonstitution der DCs und dem Auftreten einer cGvHD konnten wir vier Korrelationen beobachten. Der absolute und relative Zahlenwert an mDCs war w{\"a}hrend des Engraftments bis Tag 60-100 vermindert. Der absolute und relative Zahlenwert an DCs insgesamt war ab Tag 101-365 vermindert. Ein erh{\"o}hter Anteil an pDCs konnte ab Tag 101-365 sowie zu Beginn einer cGvHD bestimmt werden. Der Anteil monozyt{\"a}rer DCs war ab Tag 60-100 erh{\"o}ht. Die Pathogenese der cGvHD bleibt weiter teilweise unklar. Unsere Daten suggerieren einen Einfluss der DCs auf die Entstehung einer cGvHD.}, subject = {Dendritische Zelle}, language = {de} } @misc{Fulst2024, type = {Master Thesis}, author = {Fulst, Fabienne}, title = {Sprachideologien in den Sozialen Medien - Laienlinguistische Verbreitung und Verhandlung von sprachlichem Wissen auf Instagram}, isbn = {978-3-945459-48-5}, issn = {1864-9238}, doi = {10.25972/OPUS-35147}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351476}, school = {Universit{\"a}t W{\"u}rzburg}, pages = {68}, year = {2024}, abstract = {Sprachideologien als zugrundeliegende Annahmen {\"u}ber Sprachstrukturen und Sprachgebrauch schlagen sich h{\"a}ufig in metasprachlichen Diskursen und vor allem im laienlinguistischen Austausch {\"u}ber Sprache nieder. Die einschl{\"a}gige Forschung zu derartigen Metasprachdiskursen hat sich bislang nur vereinzelt dem laienlinguistischen Austausch in den Sozialen Medien gewidmet. Um Einblicke in laienlinguistische Metasprachdiskurse j{\"u}ngerer Generationen zu geben, untersucht die vorliegende Studie die Beitr{\"a}ge sowie die dazugeh{\"o}rigen Kommentare zweier Instagram-Profile, die regelm{\"a}ßig sprachliches Wissen vermitteln, hinsichtlich ihrer sprachideologischen Standpunkte. Hierzu wurde das stancetaking der Nutzenden untersucht, d.h. es wurde nachvollzogen, wie sich Sprachteilnehmende lexikalisch, grammatisch, aber auch im Rahmen multimodaler M{\"o}glichkeiten der Plattform (z.B. Farben, Emojis, Likes) zu Sprache und zu anderen Sprachteilnehmenden positionieren. Es zeigt sich, dass vor allem sprachrichtigkeitsideologische Einstellungen in den untersuchten Beitr{\"a}gen vorzufinden sind. Varianten werden hier explizit sprachlich als richtig oder falsch oder auch implizit mittels farblicher Markierungen gekennzeichnet. Standardideologische Annahmen kommen in den Beitr{\"a}gen h{\"a}ufig in der Orientierung an kodifizierenden Institutionen und in der Abgrenzung zu einer Umgangssprache zum Tragen, wobei die Beitr{\"a}ge von einer Thematisierung des Standardbegriffs absehen. Vereinzelt werden die Sprachrichtigkeits- und die Standardideologie in den Kommentaren durch Nutzende in Frage gestellt; insbesondere, wenn diese sich als linguistisch Sachkundige positionieren.}, subject = {Linguistik}, language = {de} } @phdthesis{Fischer2024, author = {Fischer, Dominik}, title = {Die Handlungsmechanismen der Europ{\"a}ischen Union zur Sicherung ihrer Werte}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, isbn = {978-3-95826-224-9}, doi = {10.25972/WUP-978-3-95826-225-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325586}, school = {W{\"u}rzburg University Press}, pages = {IX, 219}, year = {2024}, abstract = {Die vorliegende Arbeit widmet sich den Reaktionsm{\"o}glichkeiten, welche die Rechtsordnung der Europ{\"a}ischen Union ihren Organen zur Sicherung der in Artikel 2 EUV kodifizierten Werte zur Verf{\"u}gung stellt. Die Europ{\"a}ische Union wird hierbei in ihrer Eigenschaft als Wertegemeinschaft, die sich insbesondere auf demokratischen, rechtsstaatlichen und menschenrechtlichen Zielen und Vorstellungen gr{\"u}ndet, beleuchtet. Neben der Analyse der Werteklausel nach Artikel 2 EUV setzt sich die Dissertation im Kern sowohl mit den pr{\"a}ventiven als auch repressiven Instrumenten des unionalen Prim{\"a}r- und Sekund{\"a}rrechts zur Sicherung des Wertekanons auseinander. Im Wege eines systematischen Vergleichs erfolgt abschließend eine Bewertung der verschiedenen Handlungsmechanismen.}, subject = {Beitritt}, language = {de} } @phdthesis{Wilhelms2024, author = {Wilhelms, Benedikt Paul Maria}, title = {Chemische, biologische und physikalische Eigenschaften von Propofol/Hydroxypropyl-β-Cyclodextrin (Propofol/HPβCD) und Na-Propofolat/Hydroxypropyl-β-Cyclodextrin (Na-Propofolat/HPβCD)}, doi = {10.25972/OPUS-34887}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348876}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Trotz des breiten, klinischen Einsatzes des Propofols haben sich aufgrund bestehender Nebenwirkungen zunehmend Bestrebung entwickelt, alternative Formulierungen zur Lipidemulsion zu finden. In dieser Arbeit wurden die Substanzen Propofol/HPβCD und Na-Propofolat/HPβCD als alternative Formulierungen des Propofols mittels 1H-NMR-Spektroskopie, molekularer Modellierungen, DSC-Messungen, Zytotoxizit{\"a}tstests (MTT-Test, LDH-Assay, EZ4U-Test) und dem Comet-Assay als Genotoxizit{\"a}tstest auf biologische, chemische und physikalische Eigenschaften untersucht. Die Frage nach der Komplexbildung zwischen Propofol und HPβCD l{\"a}sst sich nicht allein auf Basis des 1D-1H-NMR-Spektrums beantworten. Allerdings l{\"a}sst sich mit Hilfe der 1H-NMR-Spektroskopie f{\"u}r Na-Propofolat/HPβCD das Vorliegen als deprotonierte Form nachweisen. Anderseits legen aber die DSC-Messungen eine Komplexbildung zwischen Propofol und HPβCD nahe. Zum einen ergibt sich das aus den unterschiedlichen Glas{\"u}bergangstemperaturen der Substanzen. Zum anderen zeigt der Kurvenverlauf f{\"u}r HPβCD als auch f{\"u}r Na-Propofolat/HPβCD und Propofol/HPβCD keinen Verdampfungspeak bis zu der untersuchten maximalen Temperatur von 280 °C trotz des Propofol-Siedepunktes von 256 °C. Die molekularen Modellierungen legen nahe, dass die Bindung zwischen Propofol und Cyclodextrin {\"u}ber die Isopropylgruppen des Propofols erfolgt, wobei der aromatische Ring nicht in die Cavit{\"a}t des Cyclodextrinringes eindringt. Aus den molekularen Modellierungen ergeben sich Enthalpiewerte, die in ihrer Gr{\"o}ßenordnung schwachen Wasserstoffbr{\"u}ckenbindungen entsprechen. F{\"u}r das Na-Propofolat/HPβCD l{\"a}sst sich eine leichtere Abspaltung des Propofols aus dem Komplex voraussagen, wohingegen f{\"u}r Propofol/HPβCD die Abspaltung langsamer, aber {\"u}ber einen l{\"a}ngeren Zeitraum erfolgen d{\"u}rfte. Im Vergleich zu der hohen Zytotoxizit{\"a}t des Propofols als Lipidemulsion ergibt sich aus den an der CerebEND-Zelllinie durchgef{\"u}hrten Zyotoxizit{\"a}tstests f{\"u}r HPβCD, Propofol/HPβCD und Na-Propofolat/HPβCD kein Nachweis einer Zytotoxizit{\"a}t nach 24-st{\"u}ndiger Exposition. Die Resultate zeigen f{\"u}r die drei Testverfahren die jeweils gleiche Reihenfolge mit der h{\"o}chsten Zellvitalit{\"a}t f{\"u}r die mit Na-Propofolat/HPβCD behandelten Zellen und der niedrigsten Zellvitalit{\"a}t f{\"u}r HPβCD. In dem Comet-Assay zeigt sich nach 24-st{\"u}ndiger Exposition bei 37 °C f{\"u}r HPβCD, Propofol/HPβCD und Na-Propofolat/HPβCD keine genotoxische Wirkung an der HL-60-Zelllinie. Die Ergebnisse dieser Arbeit sprechen f{\"u}r die Fortsetzung der Untersuchungen von Propofol/HPβCD und Na-Propofolat/HPβCD als aussichtsreiche Option der Propofol-Formulierungen.}, subject = {Propofol}, language = {de} } @phdthesis{Helmel2024, author = {Helmel, Jacqueline Larissa}, title = {Untersuchung der Expressionslevel des Gens NR3C1 bei {\"a}ngstlich-depressiven Personen in Zusammenhang mit der Funktion der Hypothalamus-Hypophysen-Nebennierenrinden-Achse und Ber{\"u}cksichtigung von Kindheitstraumatisierungen}, doi = {10.25972/OPUS-34865}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348652}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die {\"a}ngstliche Depression stellt einen Subtypus der Depression dar, der noch nicht ausreichend erforscht ist und somit eine Herausforderung im klinischen Alltag darstellt. Laut der bisherigen Literatur sind genetische Unterschiede sowie Kindheitstraumatisierungen an der Pathophysiologie von Depressionen beteiligt und mitverantwortlich f{\"u}r die Auspr{\"a}gung des Subtypus {\"a}ngstliche Depression. In dieser Untersuchung wurde erforscht, ob es unterschiedliche Genexpressionslevel des Gens NR3C1 zwischen {\"a}ngstlich-depressiven und nicht-{\"a}ngstlich-depressiven Personen gibt. Zus{\"a}tzlich wurde gepr{\"u}ft, ob Kindheitstraumatisierungen einen weiteren Einfluss auf die Genexpression der beiden Subtypen der Depression haben. Es zeigte sich, dass {\"a}ngstlich-depressive Personen in Woche 1 bis 4 h{\"o}here HAM-D-Summenwerte erzielten, mit zus{\"a}tzlichen Kindheitstraumatisierungen wurden die h{\"o}chsten HAM-D-Werte festgestellt. Diese Gruppe hatte geh{\"a}uft Kindheitstraumata im Fragebogen angegeben, die Traumata Emotionale Misshandlung und K{\"o}rperliche Vernachl{\"a}ssigung kamen signifikant h{\"a}ufiger vor. Anhand dieser durchgef{\"u}hrten Studie konnten zusammengefasst werden, dass sich die Genexpressionslevel von NR3C1 zwischen den beiden Subtypen als unterschiedlich erwies. Zus{\"a}tzlich scheinen die beiden Kindheitstraumata Emotionale Misshandlung und K{\"o}rperliche Vernachl{\"a}ssigung einen weiteren Einfluss auf die Genexpression von NR3C1 zu haben. Die unterschiedliche Genexpression von NR3C1 deutet auf verschiedene Funktionsweisen des GR zwischen den Subtypen hin. Dies k{\"o}nnte f{\"u}r die Verlaufsbeurteilung und Therapieans{\"a}tze der Erkrankung von Bedeutung sein. Die h{\"a}ufiger vorkommenden Kindheitstraumatisierungen bei {\"a}ngstlich-depressiven Personen k{\"o}nnen als ein pathophysiologischer Baustein f{\"u}r die Entstehung der {\"a}ngstlichen Depression gesehen werden. Daher ist es umso wichtiger, das {\"U}berpr{\"u}fen von erlebten Kindheitstraumata bei initialer Befragung in den klinischen Alltag mitaufzunehmen. Da auch der Depressionsschweregrad durch Kindheitstraumatisierungen in dieser Studie zunahm, ergeben sich daraus m{\"o}gliche Konsequenzen f{\"u}r die therapeutische Planung.}, subject = {{\"A}ngstliche Depression}, language = {de} } @phdthesis{Fischer2024, author = {Fischer, Julian}, title = {Charakterisierung von Zone 1-Sternzellen in der murinen Leber}, doi = {10.25972/OPUS-34810}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348100}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die im Rahmen der Arbeit erzielten Ergebnisse liefern neue Erkenntnisse {\"u}ber einen neuen Sternzellsubtyp der murinen Leber. Bei Gewebeverletzung differenzieren Sternzellen im Allgemeinen zu Myofibroblasten, welche Extrazellul{\"a}rmatrix produzieren. Des Weiteren sind Sternzellen die Perizyten der Leber und spielen eine Rolle in der Angiogenese und Gef{\"a}ßremodellierung. Der in pr{\"a}limin{\"a}ren Untersuchungen identifizierte Sternzellsubtyp zeichnet sich durch die Expression von tdTomato in Abh{\"a}ngigkeit des SMMHC-Promotors aus (SMMHC/tdTomato\(^+\) Sternzellen). In dieser Arbeit wurden SMMHC/tdTomato\(^+\) Sternzellen immunhistochemisch unter physiologischen und fibrotischen Bedingungen untersucht. Mit Hilfe von Lineage Tracing konnte zun{\"a}chst die Zellmauserung der SMMHC/tdTomato\(^+\) Sternzellen gezeigt werden. Durch Leberzonen-spezifische Marker wurde daraufhin nachgewiesen, dass SMMHC/tdTomato\(^+\) Sternzellen in Zone 1 des Leberazinus lokalisiert sind, weswegen diese Zellen im Weiteren „Zone 1-HSC" genannt wurden. Als potenzielle Progenitorzellnische der Zone 1-HSC wurde das Portalfeld eingegrenzt. Außerdem wurde die Funktion der Zone 1-HSC in der CCl\(_4\)-induzierten Leberfibrose untersucht. Es stellte sich heraus, dass Zone 1-HSC bereits fr{\"u}h in der Fibrose die Zonierung verlieren und diese auch nach Regenerationszeit nicht wiederhergestellt wird. Es wurde nachgewiesen, dass Zone 1-HSC nicht zu Myofibroblasten differenzieren. Stattdessen spielen Zone 1-HSC m{\"o}glicherweise eine Rolle in der sinusoidalen Kapillarisierung in Folge einer CCl\(_4\)-induzierten Fibrose.}, subject = {Fibrose}, language = {de} } @phdthesis{Gastberger2024, author = {Gastberger, Katharina}, title = {Einfluss der perizellul{\"a}ren Matrix auf die Produktion extrazellul{\"a}rer Matrix von nativen porcinen Chondrozyten im 3D-Bioprinting in Agarose-Hydrogelen \(in\) \(vitro\)}, doi = {10.25972/OPUS-34716}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-347168}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Chondrozyten stellen die zellul{\"a}re Komponente von hyalinem Knorpel dar, der die Gelenkfl{\"a}chen diarthrotischer Gelenke bedeckt. {\"U}ber die perizellul{\"a}re Matrix (PZM) sind sie mit der extrazellul{\"a}ren Matrix des Knorpelgewebes, die im Wesentlichen aus Wasser, Kollagen-Typ-II (Koll-II) und Glykosaminoglykan (GAG) gebildet wird, verbunden. Die PZM gilt als wichtiges modulatorisches und protektives Element in der Signal- und Mechanotransduktion sowie f{\"u}r die Hom{\"o}ostase innerhalb des Knorpelgewebes. Degenerative und inflammatorische Prozesse f{\"u}hren zu irreparablen Sch{\"a}den der Gewebearchitektur und -funktionalit{\"a}t. Die Regenerative Medizin strebt den Ersatz destruierter Gelenkfl{\"a}chen durch mittels Tissue Engineering hergestellten Neoknorpel an. 3D-Bioprinting gilt hier als attraktive Methode, nimmt jedoch {\"u}ber Scherkr{\"a}fte w{\"a}hrend des Druckvorgangs auch sch{\"a}digenden Einfluss auf das {\"U}berleben oder die Funktionalit{\"a}t der Zellen. Zielsetzung dieser Arbeit war es, den m{\"o}glichen protektiven Einfluss der PZM w{\"a}hrend des Druckvorgangs zu untersuchen. Aus porcinem Frischknorpel isolierte Chondrozyten wurden nach cast bzw. 3D-Bioprinting in Agarose-Biotinte hinsichtlich ihres {\"U}berlebens und ihrer Syntheseleistung von knorpelspezifischem Koll-II und GAG untersucht. Chondrozyten ohne PZM wurden mit Chondrozyten verglichen, die nach enzymatischer Isolation noch perizellul{\"a}r Kollagen-Typ-VI als Marker der PZM aufwiesen. Chondrozyten mit PZM zeigten allgemein eine st{\"a}rkere Produktion von Koll-II als Chondrozyten ohne PZM. Nach 3D-Bioprinting konnte f{\"u}r Chondrozyten ohne PZM eine signifikant geringere Produktion von GAG nachgewiesen werden als in der cast-Vergleichsgruppe, w{\"a}hrend dies f{\"u}r Chondrozyten mit PZM nicht gezeigt werden konnte. Der gezeigte protektive Einfluss der PZM gegen{\"u}ber Scherkr{\"a}ften w{\"a}hrend des Druckvorgangs er{\"o}ffnet neue Methoden f{\"u}r das Cartilage Tissue Engineering. Weitere Untersuchungen sind notwendig, um dies zu best{\"a}tigen und die Translation in die klinische Forschung erm{\"o}glichen.}, subject = {Hyaliner Knorpel}, language = {de} } @phdthesis{Etter2024, author = {Etter, Sonja}, title = {Einfluss von beruflicher \(Aspergillus\) \(fumigatus\)-Exposition auf die adaptive Immunantwort via ELISpot und Western Blot}, doi = {10.25972/OPUS-34858}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348582}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Bereits in Vorstudien konnte dargelegt werden, dass eine signifikante Korrelation zwischen der T-Zell-Zytokin-Antwort und der berufs- bzw. umweltbedingten Schimmelpilzbelastung besteht. Ziel der vorliegenden Studie war, eine m{\"o}gliche Kombination von Biomarkern ausfindig zu machen, die ver{\"a}nderte T-Zell-Antworten auf A. fumigatus- Antigene bei beruflich Exponierten im Vergleich zu Kontrollprobanden/-innen vorhersagen kann. Um geeignete Marker f{\"u}r das Bio-Monitoring zu finden, wurden zur T-Zell-Aktivierung ein myzeliales A. fumigatus - Lysat und 12 proteinogene Antigene in ELISpot-Versuchen f{\"u}r die Signaturzytokine IFN-γ (TH1), IL-5 (TH2) und IL-17A (TH17) der Haupt-TH-Subpopulationen getestet. Es zeigten sich bei den Biolandwirten/-innen erwartungsgem{\"a}ß erh{\"o}hte TH1- und TH2-Antworten auf die Mehrzahl der verwendeten spezifischen A. fumigatus-Antigene, die m{\"o}glicherweise eine Schimmelpilzbelastung serologisch nachweisbar machen. Insbesondere die spezifischen A. fumigatus-Antigene Aspf22, CatB und CipC konnten eine Trennsch{\"a}rfe zwischen den beiden Kohorten hinsichtlich ihrer IFN-γ- und IL-5-Zytokinantwort erzielen. Unterschiede in der TH17-Antwort aufgrund chronischer beruflicher Sporenbelastung ohne Krankheitskorrelat konnten nicht explizit festgestellt werden. Weiterhin ergab sich, dass erh{\"o}hte TH2-Immunreaktionen, sofern sie mit einer ad{\"a}quaten TH1-gerichteten Immunantwort einhergehen und damit eine ausgeglichene TH2/TH1-Balance besteht, nicht zwangsl{\"a}ufig zu Hypersensitivit{\"a}tserkrankungen f{\"u}hren. Im Vergleich zu Langzeitexponierten wurden teilweise {\"u}berlappende TH-Zellfrequenzen bei beruflich exponierten Biolandwirten/-innen ermittelt. Welche entscheidende Rolle Treg-Zellen bei der Eind{\"a}mmung {\"u}berschießender Immunantworten einnehmen, kann hieraus erahnt werden.}, subject = {Schimmelpilzallergie}, language = {de} } @phdthesis{Schiffmaier2024, author = {Schiffmaier, Jana}, title = {Parathormon als potentielle Therapiestrategie der Odonto-Hypophosphatasie - Untersuchungen in einem dentogenen \(in-vitro\)-Modell}, doi = {10.25972/OPUS-34915}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349152}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Hypophosphatasie (HPP) beschreibt eine seltene Erbkrankheit, die haupts{\"a}chlich durch heterozygote Mutationen im ALPL-Gen verursacht wird. Diese f{\"u}hren zu einer verminderten Aktivit{\"a}t der gewebeunspezifischen alkalischen Phosphatase (TNAP). Neben skelettalen Symptomen sind Zahnanomalien wie der vorzeitige Verlust von Milchz{\"a}hnen ohne resorbierte Wurzel sowie eine gest{\"o}rte Mineralisierung der Zahnhart-substanzen ein typisches Merkmal der HPP. Die zugrunde liegenden molekularen Mechanismen sind bisher noch nicht vollst{\"a}ndig verstanden. In der vorliegenden Arbeit wurden Zelllinien des parodontalen Ligaments mit Mutationen im ALPL-Gen charakterisiert, um anschließend m{\"o}gliche Therapiestrategien f{\"u}r die HPP auf molekularer Ebene zu untersuchen. Im Rahmen der basalen Charakterisierung wurden die Zelllinien hinsichtlich der TNAP-Expression (Immunhistochemie, Western Blot), des Stoffwechselprofils (ATP-Assay) und des osteogenen Differenzierungspotenzials (Alizarin-F{\"a}rbung) analysiert. Von Interesse war auch, ob durch CRISPR/Cas9-basiertes Genediting Off-Target Mutationen entstanden sind. Zur Untersuchung der molekularen Auswirkungen von PTH, welches die ALPL-Expression steigern kann, wurden zwei Protokolle etabliert, die eine kontinuier-liche, kurzzeitige bzw. intermittierende Pr{\"a}senz von PTH in-vitro imitieren. Anschließend wurde die ALPL-Expression (qPCR) sowie TNAP-Aktivit{\"a}t (CSPD-Assay) ermittelt. Die basale TNAP-Expression war variabel und reichte vom v{\"o}lligen Fehlen in den Zell-linien mit Deletionen bis hin zu einer starken TNAP-Expression in der Zelllinie mit einer heterogenen Punktmutation. Eine niedrige Expression ging mit einer verringerten Zell-proliferation sowie extrazellul{\"a}ren ATP einher. Es zeigte sich ein unterschiedliches Mineralisierungspotenzial, das haupts{\"a}chlich das TNAP-Expressionsniveau in den verschiedenen Zelllinien widerspiegelt, w{\"a}hrend die PTH-Stimulation keine Wirkung auf die Differenzierung hatte. Im Gegensatz zu klinischen Beobachtungen deuten die Ergebnisse auf eine hohe Korrelation zwischen Genotyp und Ph{\"a}notyp in-vitro hin, die in-vivo noch best{\"a}tigt werden m{\"u}ssen. Die Sequenzierung best{\"a}tigte, dass durch die Geneditierung keine Off-Target Mutationen aufgetreten sind, welche somit keinen limitierenden Faktor hinsichtlich der Differenzierungskapazit{\"a}t darstellen k{\"o}nnen. Die Stimulation mit PTH f{\"u}hrte zwar nicht zu einer gesteigerten ALPL-Expression, doch konnte die TNAP-Aktivit{\"a}t in den ALPL-defizienten Zelllinien punktuell gesteigert werden und bildet somit eine solide Basis f{\"u}r weitere Experimente, die zur Therapieentwicklung f{\"u}r die Odonto-HPP beitragen k{\"o}nnen.}, subject = {Hypophosphatasie}, language = {de} } @phdthesis{Cejka2024, author = {Cejka, Vladimir}, title = {Prognostische Relevanz von Fettgewebesurrogaten bei Patienten mit chronischer Niereninsuffizienz - Auswertungen der prospektiven German Chronic Kidney Disease Studie}, doi = {10.25972/OPUS-34926}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349266}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Einleitung: In dieser Arbeit wurde die Auswirkung der Fettgewebesurrogate Halsumfang (HU), Taillenumfang (TU) und Body Mass Index (BMI) auf die Prognose bei Patienten mit chronischer Niereninsuffizienz untersucht. Methoden: Datengrundlage dieser Arbeit war die German Chronic Kidney Disease (GCKD) Beobachtungsstudie. Eingeschlossen wurden Erwachsene mit GFR 30-60 ml/min/1,73m² oder GFR > 60 ml/min/1,73m² mit offensichtlicher Proteinurie. Ausschlusskriterien waren: nicht-kaukasische Ethnie, Organtransplantation, Malignome und Herzinsuffizienz NYHA IV. Untersuchte kombinierte Endpunkte (EP) waren: 1) 4P-MACE (Herzinfarkt, Schlaganfall, kardiovaskul{\"a}rer Tod, pAVK-Ereignis) 2) Tod jeglicher Ursache 3) Nierenversagen (Dialyse, Transplantation). Es wurden Cox-Regressionen mit HU, TU, und BMI f{\"u}r jeden EP, adjustiert f{\"u}r Alter, Geschlecht, Nikotinkonsum, Diabetes mellitus, arterielle Hypertonie, LDL-Cholesterin, GFR, Urin-Albumin/Kreatinin Ratio (UACR) und CRP berechnet. Interaktionsterme des jeweiligen Surrogats mit dem Geschlecht wurden eingeschlossen. Ergebnisse: Von den 4537 analysierten Studienteilnehmern, waren 59\% M{\"a}nner mit einem Durchschnittsalter von 60 (±12) Jahren, einer mittleren GFR von 50 (±18) ml/min/1,73m² und einem UACR-Median von 49 (10-374) mg/g. Der mittlere HU war 42,7 (±3,6) cm bei M{\"a}nnern und 37,2 (±3,7) cm bei Frauen, der mittlere TU 107,6 (±13,6) cm bei M{\"a}nnern und 97,0 (±16,3) cm bei Frauen und der mittlere BMI 29,7 (±5,9) kg/m². Die mittlere Beobachtungszeit betrug 6,5 Jahre. Der TU war signifikant mit Tod assoziiert, mit einer HR von 1,014 pro cm (95\% KI 1,005-1,024). HU war signifikant mit Tod bei Frauen assoziiert, Interaktionsterm HR 1,080 pro cm (95\% KI 1,009-1,155). Der BMI hatte keinen signifikanten Einfluss auf untersuchte EP. Schlussfolgerung: Bei Patienten mit mittel- bis schwergradig eingeschr{\"a}nkter Nierenfunktion steigern ein erh{\"o}hter TU (bei beiden Geschlechtern), sowie bei Frauen ein erh{\"o}hter HU das Risiko f{\"u}r Tod jeglicher Ursache.}, subject = {Fettsucht}, language = {de} } @phdthesis{Fuhl2024, author = {Fuhl, Isabell}, title = {Untersuchung der synaptischen Lokalisation des heteromeren Glycin-Rezeptors in einem neuen Mausmodell der \(Startle\) Erkrankung - mit Fokus auf die GlyR-β-Untereinheit -}, doi = {10.25972/OPUS-34832}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348328}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Der Glycin-Rezeptor ist Teil der inhibitorischen liganden-gesteuerten Ionenkan{\"a}le im ZNS und wird am st{\"a}rksten im adulten R{\"u}ckenmark sowie im Hirnstamm exprimiert. In der Nerv-Muskel-Synapse sind GlyR f{\"u}r die rekurrente Hemmung der Motoneuronen wichtig und steuern das Gleichgewicht zwischen Erregung und Hemmung der Muskelzellen. F{\"u}r die glycinerge Neurotransmission sind neben den pr{\"a}synaptischen GlyR 𝛼1 insbesondere postsynaptische GlyR 𝛼1/𝛽 verantwortlich. Durch Mutationen des GlyR entsteht das Erkrankungsbild der Hyperekplexie mit {\"u}bersteigerter Schreckhaftigkeit, Muskelsteifheit und Apnoe. Haupturs{\"a}chlich daf{\"u}r sind Mutationen im GLRA1-Gen. Die shaky Maus stellt ein gutes Modell zur Erforschung dieser seltenen Erkrankung dar. Die shaky Missense-Mutation Q177K in der extrazellul{\"a}ren 𝛽8-𝛽9 Schleife der Glycin- Rezeptor-𝛼1-Untereinheit zeigte strukturell ein gest{\"o}rtes Wasserstoffbr{\"u}ckennetzwerk. Funktionell konnten eingeschr{\"a}nkt leitf{\"a}hige Ionenkan{\"a}le identifiziert werden. Der letale Ph{\"a}notyp {\"a}ußert sich beim homozygoten shaky Tier durch Schrecksymptome mit einem einhergehenden zunehmenden Gewichtsverlust. Die Quantifizierung der Oberfl{\"a}chenexpression deutete auf einen Verlust synaptischer GlyR 𝛼1/𝛽 hin. Aussagen bez{\"u}glich der GlyR-𝛽-Untereinheit, die Teil des synaptischen GlyR Komplexes ist, waren aufgrund fehlender stabiler Antik{\"o}rper bisher nicht m{\"o}glich. Das neuartige KI- Mausmodell Glrb eos exprimiert endogen fluoreszierende 𝛽 -Untereinheiten und erm{\"o}glicht damit erstmalig eine Betrachtung der GlyR- 𝛽-Expression in Tiermodellen der Startle Erkrankung. Ziel dieser Arbeit war es, die Auswirkungen der shaky Mutation auf die Interaktion mit der 𝛽 -Untereinheit und Gephyrin zu erforschen. Daf{\"u}r wurden Markerproteine der glycinergen Synapse in R{\"u}ckenmarksneuronen der Kreuzung Glrb eos x Glra1 sh gef{\"a}rbt und quantifiziert. Die durchgef{\"u}hrte Gewichtsbestimmung der Nachkommen im zeitlichen Verlauf zeigte keinen Einfluss der eingef{\"u}gten mEos4b-Sequenz auf das K{\"o}rpergewicht der Tiere und schließt damit funktionelle Einschr{\"a}nkungen bedingt durch die mEos4b-Sequenz aus. Zur Verst{\"a}rkung des 𝛽 eos-Signals wurde ein Antik{\"o}rper verwendet. Die Quantifizierung der GlyR- 𝛽- Untereinheit an R{\"u}ckenmarksneuronen zeigte f{\"u}r homozygote shaky Tiere im Vergleich zum Wildtyp signifikant reduzierte 𝛽eos Oberfl{\"a}chenexpressionen in Gephyrin Clustern sowie signifikant erniedrigte Kolokalisationen von Gephyrin/𝛼1, 𝛽eos/𝛼1 und 𝛽eos/Gephyrin. Die mutierte GlyR-𝛼1- Untereinheit wurde hingegen vermehrt an der Oberfl{\"a}che in shaky Tieren exprimiert. Die Ergebnisse der R{\"u}ckenmarksschnitte unterst{\"u}tzen diese Befunde aus den Prim{\"a}rneuronen. Die Untersuchung der Pr{\"a}synapse erbrachte f{\"u}r Glrb eos/eos x Glra1 sh/sh eine signifikant verminderte Synapsin und Synapsin/𝛼1 Expression. Die Ergebnisse dieser Arbeit erweitern die Daten fr{\"u}herer Arbeiten zur shaky Maus und zeigen einen starken Verlust synaptischer GlyR 𝛼 1/ 𝛽 an der Oberfl{\"a}che von Motoneuronen. Ein m{\"o}glicher kompensatorischer Versuch durch erh{\"o}hte 𝛼1 Expression bleibt infolge der Funktionsbeeintr{\"a}chtigung dieser mutierten GlyR- 𝛼 1 Rezeptoren erfolglos mit letalem Ausgang. In vorherigen Arbeiten wurde vermutet, dass die Mutation in der extrazellul{\"a}ren Bindungsstelle in der Lage ist, Konformations{\"a}nderungen in die TM3-TM4-Schleifenstruktur zu {\"u}bertragen und dadurch die Gephyrin Bindung und synaptische Verankerung zu st{\"o}ren. Die Daten dieser Arbeit st{\"u}tzen diese Annahme und weisen dar{\"u}ber hinaus auf eine gest{\"o}rte Rezeptorkomplexbindung hin. Die vorliegende Arbeit tr{\"a}gt somit zum besseren Verst{\"a}ndnis der Startle Erkrankung auf synaptischer Ebene bei.}, subject = {Glycinrezeptor}, language = {de} } @phdthesis{vanBraam2024, author = {van Braam, Lara}, title = {Psychopharmakotherapie in Schwangerschaft und Stillzeit: Dynamik der Wirkstoffspiegel in Schwangerschaft und Stillzeit und Auswirkungen auf das Neugeborene}, doi = {10.25972/OPUS-33066}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-330668}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Schwangerschaft und Stillzeit gehen mit erheblichen metabolischen Ver{\"a}nderungen des m{\"u}tterlichen Organismus einher. Bis dato ist {\"u}ber die Pharmakokinetik von Psychopharmaka in dieser Zeit wenig bekannt. In unserer naturalistischen Beobachtungsstudie untersuchten wir 61 Frauen hinsichtlich der Dynamik psychotroper Medikamente innerhalb der Schwangerschaft und Stillzeit im Serum und teils in der Muttermilch. Zudem erhoben wir Eckdaten der Entwicklung der exponierten Kinder innerhalb des ersten Lebensjahres. Bis auf Citalopram stellten wir bei allen analysierten Medikamenten Spiegelabf{\"a}lle in der Schwangerschaft fest: vom ersten zum zweiten Trimenon fielen die Spiegel bei Escitalopram, Sertralin, Duloxetin, Amitriptylin, Clomipramin und Quetiapin. W{\"a}hrend wir in der Sp{\"a}tschwangerschaft bei Escitalopram, Venlafaxin, Clomipramin, Mirtazapin, Aripiprazol und Quetiapin eine weitere Reduktion der Serumkonzentrationen protokollierten, blieben die Spiegel von Amitriptylin stabil, die Sertralin-Spiegel erholten sich sogar partiell. Citalopram zeigte keine {\"A}nderung der Serumspiegel. Direkt postpartal kam es bei allen Medikamenten zu einem Spiegelanstieg. Im postpartalen Verlauf zeigten die einzelnen Medikamente widerspr{\"u}chliche Dynamiken. Hohe Penetrationsraten in die Muttermilch wiesen Escitalopram und Venlafaxin auf; Duloxetin, Clomipramin und Quetiapin gingen kaum bzw. nicht in die Muttermilch {\"u}ber. Wir fanden keine signifikanten Unterschiede zwischen in utero nicht exponierten zu exponierten Kindern bez{\"u}glich Geburtsparametern wie Schwangerschaftswoche, K{\"o}rpermaße oder APGAR-Wert. W{\"a}hrend die nicht exponierten Kinder vermehrt unter leichten Auff{\"a}lligkeiten direkt postpartal litten, wiesen die exponierten Neugeborenen mehr mittelschwere Auff{\"a}lligkeiten auf. Hinsichtlich der Entwicklung innerhalb des ersten Lebensjahres (gemessen an groben Entwicklungsmeilensteinen) ergaben sich keine signifikanten Unterschiede. Im klinischen Alltag tr{\"a}gt das Therapeutische Drug Monitoring als indirekte Methode zur Kontrolle aller an der Metabolisierung beteiligten Faktoren enorm zur Steigerung der Sicherheit und Effektivit{\"a}t der individuellen Pharmakotherapie bei. Die pharmakokinetische Dynamik f{\"a}llt bei manchen Medikamenten jedoch interindividuell sehr unterschiedlich aus (insbesondere bei Sertralin); hier stellt eine initiale Genotypisierung der Cytochrom-P450-Enzyme ein großes Potential dar, um bereits zu Beginn einer Schwangerschaft {\"u}ber die voraussichtliche pharmakokinetische Dynamik im Bilde zu sein und m{\"o}glicher Unter- bzw. {\"U}berdosierung mit potentiell fruchtsch{\"a}digender Wirkung vorbeugen zu k{\"o}nnen.}, subject = {Pharmakokinetik}, language = {de} } @phdthesis{Skornicka2024, author = {Skornicka, Johannes}, title = {Analyse des modulierenden Effekts von pegyliertem IGF-1 (pegIGF-1) auf die H{\"o}rfunktion von pmn-M{\"a}usen}, doi = {10.25972/OPUS-34912}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349125}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die Maus mit progressiver motorischer Neuropathie (PMN) ist ein Modell f{\"u}r eine vererbte motorische Neuropathie mit progressiver Neurodegeneration. Die Degeneration der Axone geht mit homozygoten Mutationen des TBCE- Gens einher, das f{\"u}r das Tubulin-Chaperon-E- Protein kodiert. TBCE ist f{\"u}r die korrekte Dimerisierung von Alpha- und Beta-Tubulin verantwortlich. Auffallend ist, dass die PMN-Maus nach dem normalen Beginn des H{\"o}rens auch einen progressiven H{\"o}rverlust entwickelt, der durch die Degeneration des H{\"o}rnervs und den Verlust der {\"a}ußeren Haarzellen (OHC) gekennzeichnet ist. Die Entwicklung dieser neuronalen und cochle{\"a}ren Pathologie ist Wirkung von peg-IGF-1 auf das auditorische System durch Behandlung ab dem 15. postnatalen Tag (p15). Die histologische Analyse ergab positive Auswirkungen auf die OHC-Synapsen der medialen olivocochle{\"a}ren (MOC) neuronalen Fasern und eine kurzfristige Abschw{\"a}chung des OHC-Verlustes. Peg-IGF-1 war in der Lage, die Desorganisation der OHC-Synapsen bedingt wiederherzustellen und die Bereitstellung von cholinerger Acetyltransferase in den Pr{\"a}synapsen aufrechtzuerhalten. Zur Beurteilung der auditorischen Funktion wurden frequenzspezifische Hirnstammreaktionen und otoakustische Emissionen mit Verzerrungsprodukten bei Tieren mit p21 und p28 aufgezeichnet. Trotz der positiven Auswirkungen auf die MOC-Fasern und die OHC konnte jedoch keine Wiederherstellung des H{\"o}rverm{\"o}gens erreicht werden. Die vorliegende Arbeit zeigt, dass die synaptische Pathologie der efferenten MOC-Fasern in PMN-M{\"a}usen eine besondere Form der "efferenten auditorischen Neuropathie" darstellt. Peg-IGF-1 zeigte eine otoprotektive Wirkung, indem es die Degeneration von OHCs und efferenten Synapsen verhinderte. Es sind jedoch verst{\"a}rkte Anstrengungen zur Optimierung der Behandlung erforderlich, um nachweisbare Verbesserungen der H{\"o}rleistung zu erzielen.}, subject = {Cochlea}, language = {de} } @phdthesis{Liebner2024, author = {Liebner, Felix}, title = {Linksschenkelblock als Prognosemarker f{\"u}r das Mortalit{\"a}tsrisiko bei Herzinsuffizienz-PatientInnen mit mittelgradiger oder reduzierter Ejektionsfraktion und normaler Nierenfunktion}, doi = {10.25972/OPUS-34848}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348487}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Wie diese und auch weitere Studien gezeigt haben, ist die Pr{\"a}valenz der PatientInnen mit einer LVEF zwischen 36-49\% und einem begleitenden LSB nicht zu untersch{\"a}tzen. Ziel der vorliegenden Arbeit war es zum einen, zu untersuchen, ob ein LSB einen signifikanten Einfluss auf die Mortalit{\"a}t und kardiovaskul{\"a}re Sterblichkeit bei sowohl HFmrEF- als auch HFrEF-PatientInnen hat und zum anderen, ob es einen Zusammenhang zwischen einem LSB und der Nierenfunktion gibt. Methoden: Unsere retrospektive Studie untersuchte 2152 PatientInnen mit echokardiographisch best{\"a}tigter HI, die sich zwischen 2009 und 2017 in der Universit{\"a}tsklinik W{\"u}rzburg vorstellten. Das mittleres Alter betrug 69 Jahre (±13 Jahre) und 72,5\% der HFmrEF-Gruppe und 75,7\% der HFrEF-Gruppe waren m{\"a}nnlich. Jeder Patient erhielt ein durchschnittliches Follow-Up-von 25 Monaten (13-39 Monate). Zun{\"a}chst wurden beide Gruppen direkt bez{\"u}glich des Vorhandenseins eines LSB miteinander verglichen. Die mit in die Studie aufgenommenen PatientInnen wurden anschließend in zwei gr{\"o}ßere Gruppen eingeteilt. Dabei konnten 1011 PatientInnen der HFmrEF-Gruppe zugeteilt werden, 125 PatientInnen mit und 886 ohne LSB. In der HFrEF-Gruppe befanden sich 1141 PatientInnen, 281 mit und 860 ohne LSB. Die HFrEF-Gruppe wurde zudem erneut hinsichtlich der Nierenfunktion aufgeteilt. Von den 1141 HFrEF-PatientInnen wurden 648 in die Gruppe mit erhaltener Nierenfunktion aufgeteilt und 493 HFrEF-PatientInnen in die Gruppe mit eingeschr{\"a}nkter Nierenfunktion. Ergebnisse: In der HFmrEF-Subgruppe zeigten sich keine relevanten Auswirkungen durch das Vorhandensein oder Fehlen eines LSB auf die Gesamtmortalit{\"a}t und die kardiovaskul{\"a}re Mortalit{\"a}t. Auch in der HFrEF-Gruppe hatte das Vorhandensein eines LSB keine signifikante Relevanz f{\"u}r die Gesamtmortalit{\"a}t (34,5\% vs. 31,6\%, p=0,165). Das Risiko an einem kardiovaskul{\"a}ren Ereignis zu versterben war allerdings f{\"u}r HFrEF-PatientInnen mit LSB deutlich h{\"o}her als f{\"u}r PatientInnen ohne LSB (86,3\% vs. 82,2\%, p=0,041). Nach Adjustierung von Alter, Geschlecht, BMI, KHK sowie Schlaganfall war der Einfluss eines LSB nicht mehr signifikant. Es zeigte sich jedoch, dass HFrEF-PatientInnen mit LSB und normaler Nierenfunktion eine mehr als zweifach erh{\"o}hte kardiovaskul{\"a}re Sterblichkeit haben (8,2\% vs. 16,2\%, p=0,002). Nach dieser Feststellung wurde gesondert auf weitere Komorbidit{\"a}ten als m{\"o}gliche Einflussfaktoren eingegangen. Unabh{\"a}ngig von dem Vorhandensein eines LSB hatten PatientInnen mit eingeschr{\"a}nkter Nierenfunktion eine deutlich erh{\"o}hte Mortalit{\"a}t verglichen mit PatientInnen ohne Nierendysfunktion. Hingegen beeinflusste ein LSB bei HFrEF-PatientInnen mit erhaltener Nierenfunktion das {\"U}berleben deutlich. LSB-PatientInnen mit erhaltener Nierenfunktion verstarben h{\"a}ufiger an einem kardiovaskul{\"a}ren Ereignis als HFrEF-PatientInnen mit normaler Nierenfunktion ohne LSB (86,3\% vs. 82,2\%, p=0,041). Um diese Untersuchung weiter zu vertiefen, wurde die HFrEF-Gruppe anhand der EF erneut in drei Subgruppen eingeteilt. Hierbei konnte eindeutig festgestellt werden, dass PatientInnen mit LSB, erhaltener Nierenfunktion und einer BLEF ≤ 30\% vor Adjustierung von Alter, Geschlecht, BMI, Schlaganfall und KHK signifikant h{\"a}ufiger kardiovaskul{\"a}r verstarben als PatientInnen ohne LSB. Des Weiteren fiel besonders die Subgruppe mit einer BLEF zwischen 36 und 39\% auf. Denn vor Adjustierung der kardiovaskul{\"a}ren Mortalit{\"a}t zeigte sich ein signifikant erh{\"o}hte Mortalit{\"a}tsrate f{\"u}r PatientInnen mit LSB. Nach Adjustierung der Einflussfaktoren war der prozentuale Anteil immer noch erh{\"o}ht, lediglich nicht mehr signifikant. Somit gibt diese Studie den Anreiz, weitere prospektive Studien mit einem gr{\"o}ßeren Stichprobenumfang durchzuf{\"u}hren, um diese Annahme zu best{\"a}tigen. Zudem sollte in weiteren Studien untersucht werden, ob speziell f{\"u}r HFrEF-PatientInnen mit LSB und einer EF zwischen 36 und 39\% eine CRT einen positiven therapeutischen Effekt bringen k{\"o}nnte.}, subject = {Herzinsuffizienz}, language = {de} } @phdthesis{Eckert2024, author = {Eckert, Lisa Doreen}, title = {Multimodale Verfahren zum Eisenstoffwechsel bei ADHS - Vergleichende Bildgebung}, doi = {10.25972/OPUS-34829}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348295}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die Aufmerksamkeitsdefizit-/Hyperaktivit{\"a}tsst{\"o}rung (ADHS) geh{\"o}rt weltweit zu den bedeutendsten psychiatrischen Erkrankungen des Kinder- und Jugendalters. Die Pathomechanismen sind aktuell noch nicht vollst{\"a}ndig gekl{\"a}rt, wobei es deutliche Hinweise auf hirnorganische Ver{\"a}nderungen gibt. Die transkranielle Sonographie stellt eine nicht-invasive Methode dar, strukturelle Unterschiede tiefer Hirnstrukturen zu untersuchen. Bereits in vorangegangenen Studien konnte mit der Methode eine Ver{\"a}nderung der Echogenit{\"a}t der Substantia nigra (SN) bei Kindern mit ADHS im Vergleich zu gesunden Kontrollprobanden nachgewiesen werden. In dieser Studie sollen nun die m{\"o}glichen physiologischen Hintergr{\"u}nde der erh{\"o}hten Echogenit{\"a}t der Substantia Nigra in Zusammenschau mit bildgebenden Verfahren betrachtet werden. Hierzu wurde in der vorliegenden multimodalen Studie bei 20 m{\"a}nnlichen Kindern mit ADHS im Alter zwischen 8 und 12 Jahren eine transkranielle Ultraschalluntersuchung (TCS) zur Bestimmung der echogenen Fl{\"a}che der Substantia Nigra sowie ein neuromelaninsensitives cMRT zur Bestimmung des neuromelaninassoziierten Volumens der SN, sowie des neuromelaninassoziierten Kontrastes SN/Cb durchgef{\"u}hrt. Als Kennwerte des peripheren Eisenhaushalts wurden die Konzentrationen von Eisen, Ferritin und Transferrin im Blut bestimmt. In die Auswertung gingen außerdem die St{\"a}rke der ADHS-Symptomatik (Strength and Difficulties Questionaire, SDQ; Fremdbeurteilungsbogen bei ADHS, FBB-ADHS), die kognitive Begabung ({\"u}ber CFT-20-R) und das Alter der Probanden ein. Psychiatrische Komorbidit{\"a}t wurde mit Hilfe der Child Behaviour Checklist (CBCL) erhoben.}, subject = {Aufmerksamkeitsdefizit-Syndrom}, language = {de} } @phdthesis{Pekarek2024, author = {Pek{\´a}rek, Luk{\´a}š}, title = {Single-Molecule Approaches To Study Frameshifting Mechanisms}, doi = {10.25972/OPUS-34611}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-346112}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The RNAs of many viruses contain a frameshift stimulatory element (FSE) that grants access to an alternate reading frame via -1 programmed ribosomal frameshifting (PRF). This -1PRF is essential for effective viral replication. The -1PRF efficiency relies on the presence of conserved RNA elements within the FSE, such as a slippery sequence, spacer, and a downstream secondary structure - often a hairpin or a pseudoknot. The PRF efficiency is also affected by trans-acting factors such as proteins, miRNAs and metabolites. The interactions of these factors with the RNA and the translation machinery have not yet been completely understood. Traditional ensemble methods used previously to study these events focus on the whole population of molecular species. This results in innate averaging of the molecular behavior and a loss of heterogeneity information. Here, we first established the experimental workflow to study the RNA structures and the effect of potential trans-acting factors using single-molecule force spectroscopy technique, optical tweezers. Additionally, to streamline the data analysis, we developed an algorithm for automatized data processing. Next, we harnessed this knowledge to study viral RNA elements responsible for stimulation of PRF and how the presence of trans-acting factors affects the RNA behavior. We further complemented these single-molecule structural data with ensemble functional assays to gain a complex view on the dynamics behind the programmed ribosomal frameshifting. Specifically, two different viral RNA elements have been studied in the presented work. First, the dynamics of SARS-CoV-2 FSE and the role of extended sequences have been explored. Then, the mode of action of the host-encoded trans-acting factor ZAP-S inhibition of SARS-CoV-2 PRF has been examined. Finally, the mechanism of the trans-acting viral factor induced PRF in Encephalomyocarditis virus (EMCV) has been uncovered.}, language = {en} } @phdthesis{Cronje2024, author = {Cronj{\´e}, Johrine}, title = {Trust towards Virtual Humans in Immersive Virtual Reality and Influencing Factors}, doi = {10.25972/OPUS-34814}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348143}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Virtual humans (VHs) hold immense potential for collaboration in social virtual reality (VR). As VR technology advances, it's vital to assess the psychological effects on VH trust and user privacy to build meaningful social interactions in VR. In social VR, users must be able to trust the VHs they interact with as they navigate through socio-cultural activities. The evaluation of trustworthiness in VHs profoundly impacts interaction quality and user willingness to engage. Conversely, untrustworthy VHs can harm user experiences, privacy, and VR engagement. To address this, we conducted immersive VR studies, exploring how psychological factors influence user's VH trust evaluation under various psychological conditions. This research is pivotal for developing strategies to enhance user privacy, establish secure VR environments, and create a foundation of trust that supports immersive socio-cultural experiences in VR. To date, there are no established interpersonal trust measurement tools specifically for VHs in VR. In study 1 (the familiarity study) of the current thesis the VR-adjusted version of the social conditioned place preference paradigm (SCPP) by Kiser et al., (2022) was identified as a potential trust measurement tool. We tested whether the familiarity of a VH influenced trust as measured with the SCPP paradigm and other self-defined outcome measures, in a Computer Augmented Virtual Environment (CAVE). The CAVE is a VR system that combines immersive VR with real-world elements. It consists of a room-sized space where the walls are used as projection screens to display virtual scenes and objects. In this within - subject design (n = 20), half of the participants were familiarized with one VH and tasked to explore and interact in a realistic looking virtual art museum environment. The participant's evaluation of the VH's trustworthiness was measured as well as their subsequent trust behaviours. Results revealed no significant differences in the evaluation of the VH's trustworthiness nor any behavioural differences between conditions. The findings of the impact of a VH's familiarity on trust is inconclusive due to the major limitations of the paradigm. We concluded that the SCPP paradigm needs further validation and the proposed proxies of trust need to be re-evaluated. The findings were considered in the following study. The virtual maze paradigm design of Hale, (2018) was identified as a potential trust measurement tool, however several limitations are associated with its use to measure trust in VR. In study 2 (a validation study), improvements were made to the virtual maze paradigm of Hale, (2018) and a variant of this paradigm was implemented. We conducted a validation study with 70 participants in a between-subject design with VH trustworthiness as the between-subject factor. Participants wore a head-mounted display (HMD), to deliver an immersive VR experience. In our version of the virtual maze, it was the task of the users (the trustors) to navigate through a maze in VR, where they could interact with a VH (the trustee). They could choose to ask for advice and follow the advice from the VH if they wanted to. The number of times participants asked and followed advice and the time it took to respond to the given advice served as behavioural proxies/measures of trust. The two conditions (trustworthy vs. untrustworthy) did not differ in the content of the advice but in the appearance, tone of voice and engagement of the trustees (allegedly an avatar controlled by other participants). Results indicated that the experimental manipulation was successful, as participants rated the VH as more trustworthy in the trustworthy condition compared with the VH in the untrustworthy condition. Importantly, this manipulation affected the trust behaviour of participants, who, in the trustworthy condition, asked for advice and followed advice more often, indicating that the paradigm is sensitive to differences in VH's trustworthiness. Thus, our paradigm can be used to measure differences in interpersonal trust towards VHs and may serve as a valuable research tool for researchers who study trust in VR. Therefore, study 2 fills the gap in the literature, for an interpersonal trust measurement tool specifically for VHs in VR. Two experimental studies, with a sample size of 50 participants each, utilized the virtual maze paradigm where participants entered 12 rooms under different conditions. We examined the influence of cognitive load (CL) on trust towards VH in VR in study 3 (Cognitive load study), and the influence of emotional affect (Emotional affect study) on trust towards VH in VR in study 4 (EA study). In both studies, we assessed participant's evaluation of a VH's trustworthiness, along with three behavioural indicators of trust in the maze task: 1) frequency of advice asked, 2) frequency of advice followed, and 3) the time taken by participants to execute the received advice. In study 3, the CL was manipulated with the auditory 1-back task in the high cognitive load condition (HCL). In study 4, the Autobiographical Emotional Memory Task (AEMT) was used to manipulate the EA of participants in the negative emotional affect (NEA) condition. As an additional manipulation, while participants were immersed in VR, they were exposed to 12 negative pictures and sounds that was presented simultaneously to strengthen the initial manipulation. The manipulation of the within-subject factors (CL and EA) was successful in both studies, as significant differences between conditions were observed in both studies (higher CL in the HCL condition and a more negative EA in the NEA condition). However, only CL influenced participant's evaluation of the VH's trustworthiness. The VH were evaluated as significantly more trustworthy after the HCL condition. Despite the difference in trust evaluation, there was no difference in advice asking or following. Participants in study 4 asked and followed advice due to their trust in the VH and asked and followed advice equally often in both conditions. Importantly, significant differences were observed in the participants response times in both studies. In study 3 during the HCL condition participants followed advice quicker. The order in which the conditions were presented influenced the experience of CL. Participants experienced higher levels of CL and responded to advice significantly faster when low cognitive load (LCL) was presented as the first condition compared with LCL as the second condition. In study 4 participants in the NEA condition followed advice slower similar to the findings of study 3. The order in which the conditions were presented had a significant effect on the EA. Participants asked and followed advice less when the NEA condition was presented first compared with when it is presented second. Possible explanations for the findings are discussed in the thesis. Overall, this thesis offers a novel tool for trust measurement (the virtual maze paradigm) and contributes to understanding the role of psychological factors in trust towards virtual humans in virtual reality.}, subject = {Virtuelle Realit{\"a}t}, language = {en} } @phdthesis{Lu2024, author = {Lu, Jinping}, title = {The vacuolar TPC1 channel and its luminal calcium sensing site in the luminal pore entrance}, doi = {10.25972/OPUS-25135}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-251353}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The slowly activating vacuolar SV/TPC1 channel is ubiquitously expressed in plants and provides a large cation conductance in the vacuolar membrane. Thereby, monovalent (K+, Na+) and in principle also divalent cations, such as Ca2+, can pass through the channel. The SV/TPC1 channel is activated upon membrane depolarization and cytosolic Ca2+ but inhibited by luminal calcium. With respect to the latter, two luminal Ca2+ binding sites (site 1 Asp240/Asp454/Glu528, site 2 Glu239/Asp240/Glu457) were identified to coordinate luminal Ca2+. In this work, the characteristics of the SV/TPC1 channels in terms of regulation and function were further elucidated, focusing on the TPC1s of Arabidopsis thaliana and Vicia faba. For electrophysiological analysis of the role of distinct pore residues for channel gating and luminal Ca2+ sensing, TPC1 channel variants were generated by site-directed mutagenesis and transiently expressed as eGFP/eYFP-fusion constructs in Arabidopsis thaliana mesophyll protoplasts of the TPC1 loss-of-function mutant attpc1-2. 1. As visualized by confocal fluorescence laser-scanning microscopy, all AtTPC1 (WT, E605A/Q, D606N, D607N, E605A/D606N, E605Q/D606N/D607N, E457N/E605A/D606N) and VfTPC1 channel variants (WT, N458E/A607E/ N608D) were correctly targeted to the vacuole membrane. 2. Patch-clamp studies revealed that removal of one of the negative charges at position Glu605 or Asp606 was already sufficient to promote voltage-dependent channel activation with higher voltage sensitivity. The combined neutralization of these residues (E605A/D606N), however, was required to additionally reduce the luminal Ca2+ sensitivity of the AtTPC1 channel, leading to hyperactive AtTPC1 channels. Thus, the residues Glu605/Asp606 are functionally coupled with the voltage sensor of AtTPC1 channel, thereby modulating channel gating, and form a novel luminal Ca2+ sensing site 3 in AtTPC1 at the luminal entrance of the ion transport pathway. 3. Interestingly, this novel luminal Ca2+ sensing site 3 (Glu605/Asp606) and Glu457 from the luminal Ca2+ sensing site 2 of the luminal Ca2+-sensitive AtTPC1 channel were neutralized by either asparagine or alanine in the TPC1 channel from Vicia faba and many other Fabaceae. Moreover, the VfTPC1 was validated to be a hyperactive TPC1 channel with higher tolerance to luminal Ca2+ loads which was in contrast to the AtTPC1 channel features. As a result, VfTPC1 but not AtTPC1 conferred the hyperexcitability of vacuoles. When AtTPC1 was mutated for the three VfTPC1-homologous polymorphic site residues, the AtTPC1 triple mutant (E457N/E605A/D606N) gained VfTPC1-like characteristics. However, when VfTPC1 was mutated for the three AtTPC1-homologous polymorphic site residues, the VfTPC1 triple mutant (N458E/A607E/N608D) still sustained VfTPC1-WT-like features. These findings indicate that the hyperactivity of VfTPC1 is achieved in part by the loss of negatively charged amino acids at positions that - as part of the luminal Ca2+ sensing sites 2 and 3 - are homologous to AtTPC1-Glu457/Glu605/Asp606 and are likely stabilized by other unknown residues or domains. 4.The luminal polymorphic pore residues (Glu605/Asp606 in AtTPC1) apparently do not contribute to the unitary conductance of TPC1. Under symmetrical K+ conditions, a single channel conductance of about 80 pS was determined for AtTPC1 wild type and the AtTPC1 double mutant E605A/D606A. This is in line with the three-fold higher unitary conductance of VfTPC1 (232 pS), which harbors neutral luminal pore residues at the homologous sites to AtTPC1. In conclusion, by studying TPC1 channel from Arabidopsis thaliana and Vicia faba, the present thesis provides evidence that the natural TPC1 channel variants exhibit differences in voltage gating, luminal Ca2+ sensitivity and luminal Ca2+ binding sites.}, language = {en} } @phdthesis{ZimmermannneePapp2024, author = {Zimmermann [n{\´e}e Papp], Lena}, title = {Platelets as modulators of blood-brain barrier disruption and inflammation in the pathophysiology of ischemic stroke}, doi = {10.25972/OPUS-30285}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-302850}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Ischemia-reperfusion injury (I/R injury) is a common complication in ischemic stroke (IS) treatment, which is characterized by a paradoxical perpetuation of tissue damage despite the successful re-establishment of vascular perfusion. This phenomenon is known to be facilitated by the detrimental interplay of platelets and inflammatory cells at the vascular interface. However, the spatio-temporal and molecular mechanisms underlying these cellular interactions and their contribution to infarct progression are still incompletely understood. Therefore, this study intended to clarify the temporal mechanisms of infarct growth after cerebral vessel recanalization. The data presented here could show that infarct progression is driven by early blood-brain-barrier perturbation and is independent of secondary thrombus formation. Since previous studies unravelled the secretion of platelet granules as a molecular mechanism of how platelets contribute to I/R injury, special emphasis was placed on the role of platelet granule secretion in the process of barrier dysfunction. By combining an in vitro approach with a murine IS model, it could be shown that platelet α-granules exerted endothelial-damaging properties, whereas their absence (NBEAL2-deficiency) translated into improved microvascular integrity. Hence, targeting platelet α-granules might serve as a novel treatment option to reduce vascular integrity loss and diminish infarct growth despite recanalization. Recent evidence revealed that pathomechanisms underlying I/R injury are already instrumental during large vessel occlusion. This indicates that penumbral tissue loss under occlusion and I/R injury during reperfusion share an intertwined relationship. In accordance with this notion, human observational data disclosed the presence of a neutrophil dominated immune response and local platelet activation and secretion, by the detection of the main components of platelet α-granules, within the secluded vasculature of IS patients. These initial observations of immune cells and platelets could be further expanded within this thesis by flow cytometric analysis of local ischemic blood samples. Phenotyping of immune cells disclosed a yet unknown shift in the lymphocyte population towards CD4+ T cells and additionally corroborated the concept of an immediate intravascular immune response that is dominated by granulocytes. Furthermore, this thesis provides first-time evidence for the increased appearance of platelet-leukocyte-aggregates within the secluded human vasculature. Thus, interfering with immune cells and/or platelets already under occlusion might serve as a potential strategy to diminish infarct expansion and ameliorate clinical outcome after IS.}, subject = {Schlaganfall}, language = {en} } @phdthesis{Okorn2024, author = {Okorn, Alexander}, title = {Synthese und Reaktivit{\"a}t von PAH-substituierten Diborenen und Dihydroanthracendiyl-verbr{\"u}ckten Diborverbindungen}, doi = {10.25972/OPUS-34836}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348368}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die vorliegende Arbeit besch{\"a}ftig sich mit der Synthese und Reaktivit{\"a}t von Phosphan-stabilisierten Diborenen, die auf Grund ihres Substitutionsmusters {\"u}ber ein erh{\"o}htes Reaktivit{\"a}tsverm{\"o}gen verf{\"u}gen. Der erste Teil dieser Arbeit beschreibt die Synthese von polycyclischen aromatischen Kohlenwasserstoff (PAH)-substituierten, Trimethylphosphan-stabilisierten Diborenen. Im zweiten Abschnitt dieser Arbeit wird die Synthese von Diborenen beschrieben, welche in einer Dihydroanthracendiyl-verbr{\"u}ckten Ringstruktur eingebunden sind.}, language = {de} } @book{SmithPasqualiniMachtEllgring2024, author = {Smith Pasqualini, Marcia and Macht, Michael and Ellgring, Heiner}, title = {Cognitive Behavioral Therapy for People with Parkinson's Disease and Caregivers : A Guide for Mental Health Professionals}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, isbn = {978-3-95826-226-3}, doi = {10.25972/WUP-978-3-95826-227-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-345196}, publisher = {W{\"u}rzburg University Press}, pages = {xii, 344}, year = {2024}, abstract = {The need for mental health support within the Parkinson's disease (PD) community has never been greater, yet many practitioners lack the knowledge or experience to address the unique challenges associated with PD. This book serves as a practical guide for mental health professionals to assist individuals with PD and caregivers through the use of cognitive-behavioral therapy techniques, with the goal of enhancing their well-being and quality of life. The book includes a review of information about PD and mental health, and four structured group programs designed to address issues that are common in people with PD and caregivers: • Coping with stress and illness • Communicating about PD • Emotional expression in PD • Interventions for caregivers The programs presented in this book can be utilized as they are, personalized for individual use, or adapted for research protocols. Additionally, the information can serve as a valuable resource for people with PD and their family members, who can learn about PD and be introduced to evidence-based strategies that can be used conjointly with professionals to improve their experience of living with PD.}, subject = {Parkinson-Krankheit}, language = {en} }