@article{DuskeClausKroneetal.2024, author = {Duske, Helene and Claus, Heike and Krone, Manuel and L{\^a}m, Thi{\^e}n-Tr{\´i}}, title = {Prevalence of piperacillin/tazobactam resistance in invasive \(Haemophilus\) \(influenzae\) in Germany}, series = {JAC-Antimicrobial Resistance}, volume = {6}, journal = {JAC-Antimicrobial Resistance}, number = {1}, issn = {2632-1823}, doi = {10.1093/jacamr/dlad148}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350424}, year = {2024}, abstract = {Background Haemophilus influenzae (Hi) is a Gram-negative bacterium that may cause sepsis or meningitis, treatment of which mainly includes β-lactam antibiotics. Since 2019 EUCAST breakpoints for piperacillin/tazobactam have been available. Little is known about the prevalence and mechanisms of piperacillin/tazobactam resistance in Hi. Objectives To provide reliable prevalence data for piperacillin/tazobactam resistance in Hi in Germany, to evaluate different antibiotic susceptibility testing methods and to examine possible resistance mechanisms. Methods According to EUCAST breakpoints, the MIC for piperacillin/tazobactam resistance is >0.25 mg/L. All invasive Hi in Germany from 2019 were examined by gradient agar diffusion (GAD) for piperacillin/tazobactam susceptibility. Piperacillin/tazobactam broth microdilution (BMD), piperacillin GAD on tazobactam-containing agar [piperacillin GAD on Mueller-Hinton agar with horse blood (MH-F)/tazobactam) and piperacillin/tazobactam agar dilution (AD) were used for confirmation. Phenotypic testing was complemented by ftsI sequencing. Results Piperacillin/tazobactam GAD resulted in 2.9\% (21/726) resistant Hi. BMD did not confirm piperacillin/tazobactam resistance. Two strains were found resistant by AD, of which one was also resistant using piperacillin GAD on MH-F/tazobactam. Overall, we found two strains with a piperacillin/tazobactam MIC >0.25 mg/L in at least two different tests (0.3\%). Both were β-lactamase-producing amoxicillin/clavulanate-resistant with PBP3 mutations characterized as group III-like+. Relevant PBP3 mutations occurred in six strains without phenotypic piperacillin/tazobactam resistance. These mutations suggest a reduced efficacy of β-lactam antibiotics in these isolates. Conclusions Piperacillin/tazobactam resistance prevalence in invasive Hi is low in Germany. Reduced susceptibility was correlated with PBP3 mutations, in particular with group III mutations.}, language = {en} } @phdthesis{MaierverhHartmann2024, author = {Maier [verh. Hartmann], Carina Ramona}, title = {Regulation of the Mevalonate Pathway by the Deubiquitinase USP28 in Squamous Cancer}, doi = {10.25972/OPUS-34874}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-348740}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The reprogramming of metabolic pathways is a hallmark of cancer: Tumour cells are dependent on the supply with metabolites and building blocks to fulfil their increased need as highly proliferating cells. Especially de novo synthesis pathways are upregulated when the cells of the growing tumours are not able to satisfy the required metabolic levels by uptake from the environment. De novo synthesis pathways are often under the control of master transcription factors which regulate the gene expression of enzymes involved in the synthesis process. The master regulators for de novo fatty acid synthesis and cholesterogenesis are sterol regulatory element-binding proteins (SREBPs). While SREBP1 preferably controls the expression of enzymes involved in fatty acid synthesis, SREBP2 regulates the transcription of the enzymes of the mevalonate pathway and downstream processes namely cholesterol, isoprenoids and building blocks for ubiquinone synthesis. SREBP activity is tightly regulated at different levels: The post-translational modification by ubiquitination decreases the stability of active SREBPs. The attachment of K48-linked ubiquitin chains marks the transcription factors for the proteasomal degradation. In tumour cells, high levels of active SREBPs are essential for the upregulation of the respective metabolic pathways. The increased stability and activity of SREBPs were investigated in this thesis. SREBPs are ubiquitinated by the E3 ligase Fbw7 which leads to the subsequential proteolysis of the transcription factors. The work conducted in this thesis identified the counteracting deubiquitination enzyme USP28 which removes the ubiquitin chains from SREBPs and prevents their proteasomal degradation. It further revealed that the stabilization of SREBP2 by USP28 plays an important role in the context of squamous cancers. Increased USP28 levels are associated with a poor survival in patients with squamous tumour subtypes. It was shown that reduced USP28 levels in cell lines and in vivo result in a decrease of SREBP2 activity and downregulation of the mevalonate pathway. This manipulation led to reduced proliferation and tumour growth. A direct comparison of adenocarcinomas and squamous cell carcinomas in lung cancer patients revealed an upregulation of USP28 as well as SREBP2 and its target genes. Targeting the USP28-SREBP2 regulatory axis in squamous cell lines by inhibitors also reduced cell viability and proliferation. In conclusion, this study reports evidence for the importance of the mevalonate pathway regulated by the USP28-SREBP2 axis in tumour initiation and progression of squamous cancer. The combinatorial inhibitor treatment of USP28 and HMGCR, the rate limiting enzyme of the mevalonate pathway, by statins opens the possibility for a targeted therapeutic treatment of squamous cancer patients.}, subject = {Ubiquitin}, language = {en} } @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} } @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} } @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{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} }