@phdthesis{HennyKrahmer2023, author = {Henny-Krahmer, Ulrike}, title = {Genre Analysis and Corpus Design: Nineteenth Century Spanish-American Novels (1830-1910)}, doi = {10.25972/OPUS-31999}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319992}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {This work in the field of digital literary stylistics and computational literary studies is concerned with theoretical concerns of literary genre, with the design of a corpus of nineteenth-century Spanish-American novels, and with its empirical analysis in terms of subgenres of the novel. The digital text corpus consists of 256 Argentine, Cuban, and Mexican novels from the period between 1830 and 1910. It has been created with the goal to analyze thematic subgenres and literary currents that were represented in numerous novels in the nineteenth century by means of computational text categorization methods. The texts have been gathered from different sources, encoded in the standard of the Text Encoding Initiative (TEI), and enriched with detailed bibliographic and subgenre-related metadata, as well as with structural information. To categorize the texts, statistical classification and a family resemblance analysis relying on network analysis are used with the aim to examine how the subgenres, which are understood as communicative, conventional phenomena, can be captured on the stylistic, textual level of the novels that participate in them. The result is that both thematic subgenres and literary currents are textually coherent to degrees of 70-90 \%, depending on the individual subgenre constellation, meaning that the communicatively established subgenre classifications can be accurately captured to this extent in terms of textually defined classes. Besides the empirical focus, the dissertation also aims to relate literary theoretical genre concepts to the ones used in digital genre stylistics and computational literary studies as subfields of digital humanities. It is argued that literary text types, conventional literary genres, and textual literary genres should be distinguished on a theoretical level to improve the conceptualization of genre for digital text analysis.}, subject = {Gattungstheorie}, language = {en} } @phdthesis{Reber2023, author = {Reber, Sibylle}, title = {Einfluss von Multimorbidit{\"a}t und Niereninsuffizienz auf die Serumkonzentration von Antidepressiva sowie Assoziation zum Therapieergebnis bei einem Patientenkollektiv der Neurogerontopsychiatrischen Tagesklinik W{\"u}rzburg}, doi = {10.25972/OPUS-32176}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321765}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Die vorliegende retrospektive Untersuchung arbeitete mit Daten von 153 Patienten der Neurogerontopsychiatrischen Tagesklinik W{\"u}rzburg. Dabei wurde zum einen gepr{\"u}ft, ob multimorbide Patienten und niereninsuffiziente Patienten h{\"o}here dosiskorrigierte Serumkonzentrationen der Antidepressiva Escitalopram, Sertralin, Venlafaxin und Mirtazapin aufwiesen. Zum anderen erfolgte die Untersuchung, ob hohe Serumkonzentrationen der vier genannten Antidepressiva zu einem besseren Therapieergebnis f{\"u}hrten. F{\"u}r die Berechnungen wurden die letzten vor Entlassung erhobenen Laborparameter verwendet. Es erfolgte die Berechnung der dosiskorrigierten Serumkonzentration. 76 Patienten (49,7 \%) wurden als multimorbide eingestuft. Es zeigten sich f{\"u}r die dosiskorrigierte Serumkonzentration des aktiven Metaboliten O-Desmethyl-Venlafaxin statistisch signifikant h{\"o}here Konzentrationen bei der multimorbiden Subgruppe. Ferner zeigte sich bei 140 Patienten eine Niereninsuffizienz (91,5 \%). F{\"u}r die dosiskorrigierte Konzentration von O-Desmethyl Venlafaxin, die dosiskorrigierte Summenserumkonzentration aus Venlafaxin und O-Desmethyl- Venlafaxin sowie die dosiskorrigierte Serumkonzentration von Sertralin ließen sich statistisch signifikant h{\"o}here Konzentrationen bei einer zunehmenden Einschr{\"a}nkung der Nierenfunktion nachweisen. Es zeigte sich kein Einfluss der H{\"o}he der dosiskorrigierten Serumkonzentration der Antidepressiva auf das Therapieergebnis in der vorliegenden Arbeit. Mit der vorliegenden Arbeit konnte gezeigt werden, dass sowohl Multimorbidit{\"a}t als auch Niereninsuffizienz einen Einfluss auf die Verstoffwechselung und auch die dosiskorrigierte Serumkonzentration der Antidepressiva Venlafaxin und Sertralin haben. Daher ergibt sich die Schlussfolgerung, dass bei {\"a}lteren Patienten, welche von Multimorbidit{\"a}t oder Niereninsuffizienz betroffen sind, eine Dosisanpassung und regelm{\"a}ßige Kontrollen der Serumkonzentration im Sinne eines Therapeutischen Drug Monitoring erfolgen sollten.}, subject = {Pharmakokinetik}, language = {de} } @phdthesis{Steingrueber2023, author = {Steingr{\"u}ber, Marcus}, title = {Die perkutane transluminale Zangenbiopsie bili{\"a}rer Strikturen: Eine neuartige Methode}, doi = {10.25972/OPUS-32172}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321721}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Das Ziel der Studie bestand darin, die Durchf{\"u}hrbarkeit, Effizienz und Sicherheit der perkutanen transluminalen Zangenbiopsie bei bili{\"a}ren Strikturen nach „Cross and push" Technik am Universit{\"a}tsklinikum W{\"u}rzburg zu evaluieren. Die Gewinnung der Zangenbiopsie bei den insgesamt 17 Patienten erfolgte an den baugleichen Angiographieeinheiten der interventionellen radiologischen Abteilung. Die Schaffung des bili{\"a}ren Zugangsweges wurde per Feinnadelpunktion oder {\"u}ber einen bereits einliegenden Drainagekatheter durchgef{\"u}hrt. Nach Vordirigieren einer armierten F{\"u}hrungsschleuse bis unmittelbar vor die Stenose wurden die Gewebeproben mittels Biopsiezange entnommen. Auf diese Weise sollte ein Abknicken des Instrumentariums durch die fibrotische Beschaffenheit der Striktur vermieden und so die Gewebegewinnung erleichtert werden. Im Anschluss folgten die PTCD-Neuanlage bzw. der Katheterwechsel sowie die histologische Auswertung der Zangenbiopsie. Die Dokumentation umfasste den technischen Erfolg, die Biopsieanzahl sowie -gr{\"o}ße, die Untersuchungs- und die Fluoroskopiezeit, das Dosisfl{\"a}chenprodukt, die Repr{\"a}sentativit{\"a}t der Biopsien und die Komplikationsrate. Die technische Erfolgsrate lag bei 100 \%. Bei zehn Patienten und Patientinnen (58,8 \%) wurde in der Zangenbiopsie ein Malignom best{\"a}tigt. Bei sieben Betroffenen (41,2 \%) ergab die Zangenbiopsie einen benignen Befund, wobei dieser in zwei F{\"a}llen (11,8 \%) falsch negativ war. Die Kriterien der Repr{\"a}sentativit{\"a}t wurden bei elf Patienten und Patientinnen (64,7 \%) erf{\"u}llt. Die mediane Biopsiezahl betrug 4 und die Biopsiegr{\"o}ße war 1 - 2 mm. Bei einer medianen Untersuchungszeit von 24 min bemaß sich die mediane Fluoroskopiezeit auf 7,6 min. Das mediane DAP f{\"u}r alle Interventionen betrug 2.593 μGym2. Zu einer Majorkomplikation kam es bei einer Patientin (5,9 \%). Bei der perkutanen transluminalen Zangenbiopsie nach „Cross and push" Technik handelt es sich um ein effektives und sicheres Verfahren zur histologischen Beurteilung bili{\"a}rer Strikturen mit einer moderaten Komplikationsrate. Die Anwendung sollte besonders bei proximalen Strikturen in Betracht gezogen werden, wenn die ERCP oder alternative Verfahren nicht erfolgreich waren und parallel eine Entlastung der Cholestase via PTCD intendiert oder bereits vorhanden ist. Zur weiteren Evaluation der Methode ist zuk{\"u}nftig die Betrachtung eines gr{\"o}ßeren Patientenkollektives n{\"o}tig. Um das Verfahren mit Alternativmethoden vergleichen zu k{\"o}nnen, bedarf es randomisierter kontrollierter Studien.}, language = {de} } @phdthesis{Wagner2023, author = {Wagner, Camilla Olga Luise}, title = {Prognostischer Wert eines Echokardiographie-basierten Risikoscores bei Patient*innen mit isch{\"a}mischer Herzinsuffizienz und reduzierter Ejektionsfraktion}, doi = {10.25972/OPUS-32178}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321786}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Zielsetzung Entwicklung einer umfassenden echokardiographiebasierten Score-Methode zur Risikobewertung von Patienten mit isch{\"a}mischer Herzinsuffizienz (IHF) und reduzierter linksventrikul{\"a}rer Ejektionsfraktion (<50\%). Methoden In diese Studie wurden 1355 IHF-Patienten mit einer Ejektionsfraktion <50\% aufgenommen, die mittlere klinische Nachbeobachtungszeit betrug 25 Monate. Mit Hilfe multivariabler Cox-Hazard-Modelle wurden die Zusammenh{\"a}nge zwischen echokardiographischen Variablen [einschließlich 13 Standardparameter und globaler longitudinaler Dehnung (GLS)] und den wichtigsten unerw{\"u}nschten Ergebnissen [einschließlich Gesamtmortalit{\"a}t, kardiovaskul{\"a}rem Tod und kardiovaskul{\"a}r bedingten Krankenhausaufenthalten] bewertet. Ergebnisse Die Gesamtmortalit{\"a}t, die kardiovaskul{\"a}re Mortalit{\"a}t und das kombinierte Risiko f{\"u}r kardiovaskul{\"a}re Ereignisse, einschließlich Tod und Krankenhausaufenthalt, betrugen 29,2 \%, 18,2 \% bzw. 41,1 \%. Rechtsventrikul{\"a}rer mittlerer Hohlraumdurchmesser (RVD) >38 mm, systolische Exkursion der mitralen Anularebene (MAPSE) <8 mm, systolische Exkursion der Trikuspidalebene (TAPSE) <12 mm, Verh{\"a}ltnis zwischen transmissaler Fr{\"u}hflussgeschwindigkeit und mitraler Anularebene (E/E') >14. 5, systolischer Pulmonalarteriendruck (sPAP) >38mmHg und absolute GLS<8\% wurden in den multivariablen Cox-Modellen als unabh{\"a}ngige echokardiographische Marker f{\"u}r ein schlechteres klinisches Ergebnis identifiziert.Auf der Grundlage dieser Marker wurde ein echokardiographischer Risikoscore (Echo Risk Score, von 0 bis 6 Punkten) erstellt, und die Patienten wurden in drei Risikogruppen eingeteilt: ein Score von 0 bis 1 als geringes Risiko, ein Score von 2 bis 3 als mittleres Risiko und ein Score von 4-6 als hohes Risiko. Nach Adjustierung f{\"u}r alle klinischen Kovariaten hatten Hochrisikopatienten im Vergleich zu Patienten mit niedrigem Risiko ein zwei- bis dreifach erh{\"o}htes Gesamtmortalit{\"a}tsrisiko (HR 2,42, 95\% CI 1,81-3,24), ein erh{\"o}htes Risiko f{\"u}r kardiovaskul{\"a}re Ereignisse (HR 2,75, 95\% CI 1,88-4,02) und ein erh{\"o}htes kombiniertes Risiko f{\"u}r kardiovaskul{\"a}re Ereignisse (HR 1,84, 95\% CI 1,43-2,36). Eine erh{\"o}hte Vorhersagekraft wurde nach Hinzuf{\"u}gung des Echo-Risiko-Scores entweder zu dem Modell mit klinischen Risikofaktoren oder zu dem Modell mit klinischen Risikofaktoren und N-terminalem Prohormon des natriuretischen Peptids des Gehirns festgestellt (alle P<0,001). Fazit Der neuartige echokardiografiebasierte Risikoscore ist signifikant und unabh{\"a}ngig mit der Gesamtmortalit{\"a}t und der kardiovaskul{\"a}ren Mortalit{\"a}t oder Hospitalisierung bei Patienten mit isch{\"a}mischer Herzinsuffizienz und reduzierter Ejektionsfraktion assoziiert. Weitere Studien sind erforderlich, um die Vorhersagekraft dieses echokardiographiebasierten Risikoscores bei Patienten mit isch{\"a}mischer Herzinsuffizienz und reduzierter Ejektionsfraktion zu validieren.}, subject = {Ultraschallkardiografie}, language = {de} } @phdthesis{Captan2023, author = {Captan, Nina}, title = {Beurteilbarkeit der ostialer Gef{\"a}ßabschnitte in der diagnostischen Koronarangiographie - Ein Vergleich der Angiographie mit Computertomographie}, doi = {10.25972/OPUS-32174}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321746}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Im Rahmen dieser Studie haben wir untersucht, ob die bei der diagnostischen Koronarangiographie gewählten Projektionen eine adäquate Darstellung der ostialen Gefäßabschnitte ermöglichen. Hierzu wurde im Rahmen einer retrospektiven Studie ein Patientenkollektiv von 54 Probanden eingeschlossen, bei denen sowohl ein Kardio-CT als auch eine diagnostische Herzkatheteruntersuchung durchgef{\"u}hrt worden war. Mithilfe des Kardio-CTs wurde die Line of Perpendicularity (LoP) der ostialen Koronargefäßabschnitte der LCA und der RCA ermittelt. Hieraus können die optimalen Angulationen f{\"u}r die angiographische Darstellung der ostialen Gefäßabschnitte abgeleitet werden. Im nächsten Schritt wurde {\"u}berpr{\"u}ft, ob die während der diagnostischen Koronarangiographie gewählten Projektionen auf dieser LoP (mit einer Divergenz von ± 10°) lagen. Zusätzlich haben wir untersucht, ob interventionell erfahrenen Kardiologen in der Lage sind, die Koronarangiographie im Hinblick auf die Qualit{\"a}t der Darstellung des Ostiums zu beurteilen. Ferner wurde verglichen, ob die in der Literatur empfohlenen Standardprojektionen eine optimale Darstellung der ostialen Segmente erlauben. Bei 81\% aller Patienten wurde der ostiumnahe Abschnitt der linken Koronararterie unverk{\"u}rzt dargestellt, wohingegen die Darstellung der rechten Koronararterie nur bei 44\% der Patienten ad{\"a}quat war. Der Vergleich der LoP zeigte, dass es große interindividuelle Unterschiede der Koronarostiumanatomie gibt. Daraus kann abgeleitet werden, dass mit sog. „Standardprojektionen" nur bei einem Teil der Patienten eine optimale und somit unverk{\"u}rzte Darstellung der ostialen Koronarsegmente m{\"o}glich wird. Bei einem beträchtlichen Anteil der Patienten muss man diese Projektionen variieren, um das Ostium bestmöglich darzustellen. Eine CT-basierte Bestimmung der Line of Perpendicularity kann dazu beitragen, die geeigneten Projektionen w{\"a}hrend einer Herzkatheteruntersuchung einzustellen und so die interindividuellen Verhältnisse der Koronaranatomie zu ber{\"u}cksichtigen.}, subject = {Koronarangiographie}, language = {de} } @phdthesis{RothgebFischer2023, author = {Roth [geb. Fischer], Jennifer}, title = {Verbesserung der Mitralklappeninsuffizienz bei Patienten mit Aortenklappenstenose nach kathetergest{\"u}tztem perkutanen Aortenklappenersatz}, doi = {10.25972/OPUS-32223}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322237}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {In dieser klinisch retrospektiven Studie wurden 95 Patienten mit schwerer Aortenstenose und gleichzeitiger zumindest leicht- bis mittelgradiger Mitralklappeninsuffizienz vor und nach kathetergest{\"u}tztem AKE untersucht. Ziel war es, eine Verbesserung der MI nach TAVI zu detektieren und Pr{\"a}diktoren f{\"u}r eine m{\"o}gliche Verbesserung zu identifizieren, um solchen Patienten die individuell optimale Versorgung zu gew{\"a}hrleisten. Methoden: Zu Beginn der Studie wurde bei jedem Patienten eine umfangreiche echokardiographische Untersuchung durchgef{\"u}hrt, welche im Nachhinein manuell ausgewertet werden konnte. Dar{\"u}ber hinaus wurden allgemeine klinische Daten, wie beispielsweise Blutdr{\"u}cke und Vorerkrankungen erfasst, sowie eine routinem{\"a}ßige Blutentnahme durchgef{\"u}hrt. Nach TAVI wurde erneut eine echokardiographische Untersuchung vorgenommen, die sp{\"a}ter wiederum ausgewertet werden konnte. Ergebnisse: Alle Patienten wurden anhand der Ver{\"a}nderung der Mitralinsuffizienz nach TAVI in die Gruppen „keine Verbesserung" und „Verbesserung" unterteilt. Bei 71,6\% der Patienten konnte eine Verbesserung der MI nach TAVI verzeichnet werden, 32,6\% der Patienten zeigten sogar eine signifikante Verbesserung von mindestens zwei Schweregraden im Vergleich zur Baseline-Echokardiografie. Bei der Auswertung der echokardiografischen Daten konnte ein niedriger mittlerer transaortaler Druck (AV Pmean) als unabh{\"a}ngiger multivariater Pr{\"a}diktor identifiziert werden. Dar{\"u}ber hinaus konnte eine signifikant h{\"o}here {\"U}berlebensrate in der Patientengruppe „Verbesserung" der MI im Vergleich zur Gruppe „keine Verbesserung" nachgewiesen werden. Im Hinblick auf die 30-Tages-Mortalit{\"a}t unterschieden sich die beiden Gruppen nicht. Zusammenfassung: Patienten mit schwerer Aortenstenose leiden h{\"a}ufig auch an einer Mitralinsuffizienz. In dieser Studie konnte eine signifikante Verbesserung der MI nach TAVI nachgewiesen werden. Aus den erhobenen Daten l{\"a}sst sich schließen, dass eine ausf{\"u}hrliche echokardiographische Voruntersuchung mit genauer Mitbeurteilung der Mitralklappe bei TAVI-Patienten unerl{\"a}sslich ist und dass diese wichtige Erkenntnisse {\"u}ber den weiteren Verlauf einer gleichzeitig bestehenden MI liefern kann. So k{\"o}nnte ein alleiniger kathetergest{\"u}tzter Aortenklappenersatz bei sorgf{\"a}ltig ausgew{\"a}hlten Patienten eine vern{\"u}nftige Therapieoption bei Patienten mit kombinierter Aorten- und Mitralklappenerkrankung sein.}, subject = {Mitralinsuffizienz}, language = {de} } @phdthesis{Messinger2023, author = {Messinger, Julia}, title = {Die Effekte von IVIG auf die Antik{\"o}rperbindung und Komplementablagerung bei Anti-Neurofascin-positiver Nodo-Paranodopathie}, doi = {10.25972/OPUS-32110}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321109}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Autoantik{\"o}rper gegen nodo-paranodale Proteine des Ranvier'schen Schn{\"u}rrings wie Neurofascin-155 (NF-155), Contactin-1 und Caspr wurden in der Literatur bei Patienten/Patientinnen mit Immunneuropathien beschrieben. Bei zwei bis zehn Prozent der Patienten/Patientinnen mit Immunneuropathien k{\"o}nnen Autoantik{\"o}rper gegen Isoformen des Neurofascin detektiert werden. Patienten/Patientinnen mit Autoantik{\"o}rpern gegen NF-155 weisen gemeinsame klinische Merkmale auf, unter anderem einen schweren Verlauf mit subakutem Beginn, vorwiegend motorischen Defiziten, Tremor und einem schlechten Ansprechen auf eine Therapie mit intraven{\"o}sen Immunglobulinen (IVIG). Ein Grund f{\"u}r Letzteres k{\"o}nnte sein, dass es sich {\"u}berwiegend um Autoantik{\"o}rper der Subklasse IgG4 handelt, die als anti-inflammatorisch gelten und kein Komplement aktivieren. Neben der IgG4-Subklasse k{\"o}nnen bei manchen Erkrankten auch die proinflammatorischen IgG-Subklassen 1 bis 3 nachgewiesen werden. Bei der Anti-Pan-Neurofascin (155/140/186) Polyneuropathie zeigt sich klinisch h{\"a}ufig ein fulminanter Ph{\"a}notyp mit IgG3 Pr{\"a}dominanz. Das Ziel dieser Studie war, die Autoantik{\"o}rper-induzierte Komplementablagerung zu detektieren, sowie die Rolle der IgG Subklasse und die Effekte von IVIG auf Antik{\"o}rperbindung, Komplementaktivierung und Effektorfunktionen zu untersuchen. Hierzu wurde das Serum von 212 Probanden/-innen mit der Verdachtsdiagnose einer entz{\"u}ndlichen Neuropathie auf Autoantik{\"o}rper gegen NF-155 mittels ELISA und Bindungsversuchen an M{\"a}usezupfnerven gescreent. Im Fall eines positiven Ergebnisses dienten zellbasierte Bindungsversuche mit NF-155-transfizierten HEK-293- Zellen als Best{\"a}tigungstest. Die Effekte unterschiedlicher IVIG Konzentrationen auf die Antik{\"o}rperbindung und Komplementablagerung wurden in ELISA, Komplementbindungsassays und zellbasierten Verfahren getestet. Außerdem wurde mithilfe von LDH-Zytotoxizit{\"a}tsmessungen die Komplement-induzierte Zelllyse sowie die Effekte von IVIG untersucht. Klinische Daten wurden retrospektiv ausgewertet. F{\"u}nf Patienten/Patientinnen mit hohen Autoantik{\"o}rpertitern gegen NF-155 und ein Patient mit Anti-Pan-Neurofascin Autoantik{\"o}rpern konnten in der Studie detektiert werden. Der Patient mit Autoantik{\"o}rpern gegen alle drei Isoformen des Neurofascins und IgG3-Pr{\"a}dominanz zeigte die deutlichste Komplementablagerung. Bei drei Patienten/Patientinnen, die IgG1, IgG2 und IgG4 aufwiesen, war eine Aktivierung des Komplementsystems zu beobachten, w{\"a}hrend bei zwei Patienten mit pr{\"a}dominanter IgG4-Antik{\"o}rpersubklasse keine Komplementablagerung nachweisbar war. Bei Letzteren war eine Therapie mit IVIG in der Vorgeschichte erfolglos, w{\"a}hrend es bei zwei der Patienten/Patientinnen mit anderen IgG-Subklassen und Komplementbindung unter IVIG Therapie zu einer m{\"a}ßigen bis deutlichen Symptombesserung in der Akutphase kam. Eine Koinkubation mit IVIG f{\"u}hrte in den ELISA basierten und zellbasierten Versuchen zu keinem Effekt auf die Autoantik{\"o}rperbindung an das Zielantigen, jedoch zu einer deutlichen Reduktion der Antik{\"o}rper-vermittelten Komplementbindung. Diese Reduktion war sowohl bei Koinkuabtion von IVIG mit dem Komplementfaktor C1q als auch bei Pr{\"a}inkubation von IVIG vor C1q Gabe zu sehen. Bei zwei der Patienten/Patientinnen mit hohen Komplementablagerungen konnte eine erh{\"o}hte Zytotoxizit{\"a}t nachgewiesen werden, welche bei Zugabe von IVIG verringert wurde. Schlussfolgernd ist die Autoantik{\"o}rper-induzierte Komplementablagerung abh{\"a}ngig von der pr{\"a}dominanten IgG Subklasse. IVIG f{\"u}hrt zu einer deutlichen, konzentrationsabh{\"a}ngigen Reduktion der Komplementablagerung, sowie m{\"o}glicher zytotoxischer Effektorfunktionen wie die Zytolyse myelinisierter Schwannzellen oder Nervenaxonen. Dar{\"u}ber hinaus k{\"o}nnte die Subklassenanalyse von Erkrankten das Therapieansprechen auf IVIG vorhersagen und sollte daher eine wichtige Rolle in der Diagnostik der Nodo-Paranodopathie spielen. IVIG sowie andere {\"u}ber das Komplementsystem wirkende Therapeutika k{\"o}nnen in der Behandlung der schwer betroffenen Patienten/Patientinnen, insbesondere bei Anti-Pan-Neurofascin positiver Neuropathie, in Betracht gezogen werden.}, subject = {Komplement }, language = {de} } @phdthesis{BenKraiem2023, author = {Ben-Kraiem, Adel}, title = {Temporal characterization of the blood nerve barrier and specialized pro resolving mediators as therapeutic targets in neuropathy}, doi = {10.25972/OPUS-32079}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320797}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Abstract Neuropathic pain affects 6.9 to 10\% of the general population, arises from lesion or disease of the somatosensory nervous system and is still challenging to treat. Indeed, current treatments efficacy are relatively low and present strong side effects. To that extent, identifying new targets and developing new treatment strategies constitute a priority. The blood nerve barrier consists of the endoneurial micro-blood vessels and the perineurium sealed by tight junctions constituted of tight junction proteins such claudin-5 and claudin-1. As the functional blood nerve barrier allows nerve tissue protection from external elements and maintains homeostasis, a destabilization or a disruption leads to infiltration of immunocytes promoting neuroinflammation and increased inflammatory mediators that can sensitize nociceptors and enhance pain. Thus resealing the blood nerve barrier in case of neuropathic pain could be a possible treatment strategy. Specialised proresolving mediators such lipoxin A4 and resolvin D1 are small lipids that bind to receptors such the formylpeptide recptor 2 (FPR2) and resolve inflammation. Specially resolvin D1 as anti-inflammatory and analgesic properties. Thus using resolvin D1 or eventually other specialized proresolving mediators in neuropathic pain could reseal the blood nerve barrier and resolve neuropathic pain. The present work aimed to characterize the blood nerve barrier in a preclinical model of diabetic polyneuropathy and nerve injury (chronic constriction injury) and to identify specialized proresolving mediators that seal the blood nerve barrier and thereby alleviate neuropathic pain. In diabetic polyneuropathy, the blood nerve barrier is permeable only to small molecules, which is due to the loss of claudin-1 in the perineurium and a reduced number of blood vessel- associated macrophages. Interestingly, blood nerve barrier permeability did not occur until four to eight weeks after diabetes induction, whereas mechanical hyperalgesia was measurable as early as two weeks. This suggests a pain-maintaining rather than a pain-triggering role of the blood nerve barrier. In case of chronic constriction injury, a resolution process of both mechanical and thermal hyperalgesia occurs between three to six weeks after injury. Here, the blood nerve barrier is permeable to both small and large molecules from the beginning. The pain recovery process occurs primarily in parallel with the sealing of the endoneurial barrier to large molecules such as fibrinogen from the plasma and its degradation. Perineurium is still permeable nine weeks after injury. Metabolomic analyses show that especially precursors of Resolvin D1 as well as its receptor FPR2, are upregulated at the beginning of pain resolution. Application of resolvin D1 loaded nanoparticles or agonists of FPR2 at the injury site before the onset of pain resolution accelerates the process and fibrinogen is no longer detectable in the endoneurium. Depending on the nerve damage, the blood nerve barrier is affected to varying degrees. Direct mechanical trauma and the accompanying inflammation lead to a more pronounced and long-lasting permeability - independent hyperalgesia. Possibly permeability, at least for small molecules, is important for prolonged reparative processes. In the nerve, permeability of capillaries in particular depends not only on tight junctions but also on other cells: in addition to macrophages, pericytes could also have a sealing effect. Endoneurial fibrinogen triggers pain; the exact mechanism remains to be investigated. Resolvin-containing nanoparticles were particularly effective and could be used locally as they contain endogenous substances in non- toxic particles.}, language = {en} } @phdthesis{Renner2023, author = {Renner, Tobias}, title = {Neue adh{\"a}sive mineral-organische Knochenzemente auf Basis von Phosphoserin und Magnesiumphosphaten bzw. -oxiden}, doi = {10.25972/OPUS-32321}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323210}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Heutige chirurgische Situationen k{\"o}nnen zeitweise den Einsatz eines Knochenkleber erfordern, welcher sich jedoch noch nicht in der klinischen Praxis etablieren konnte. In j{\"u}ngster Vergangenheit haben mit Phosphoserin modifizierte Zemente (PMC) auf der Grundlage von Verbindungen zwischen o-Phosphoserin (OPLS) und Calciumphosphaten wie Tetracalciumphosphat (TTCP) oder α-Tricalciumphosphat (α-TCP) an Popularit{\"a}t gewonnen. Ebenso bekommen chelatbildende Magnesiumphosphatzemente als mineralische Knochenadh{\"a}sive mehr Zuspruch. In dieser Arbeit wurden neue mineralorganische Knochenzemente auf der Basis von Phosphoserin und Magnesiumphosphaten oder -oxiden untersucht, die hervorragende Hafteigenschaften besitzen. Diese wurden mittels R{\"o}ntgenbeugung, Fourier-Infrarot-Spektroskopie und Elektronenmikroskopie analysiert und mechanischen Tests unterzogen, um die Haftfestigkeit am Knochen nach Alterung unter physiologischen Bedingungen zu bestimmen. Die neuartigen biomineralischen Klebstoffe zeigen eine ausgezeichnete Haftfestigkeit an Knochen mit etwa 6,6-7,3 MPa unter Scherbelastung. Die Adh{\"a}sive sind auch aufgrund ihres koh{\"a}siven Versagensmusters und ihres duktilen Charakters vielversprechend. In diesem Zusammenhang sind die neuen adh{\"a}siven Zemente den derzeit vorherrschenden Knochenadh{\"a}siven {\"u}berlegen. Erg{\"a}nzend wurde versucht, dieses neue System mit unterschiedlichen Additiven zu modifizieren. Dabei wurde Mannit erfolgreich als Porogen verwendet. Dreiarmiges sternf{\"o}rmiges NCO-sP(EO-stat-PO) sollte die adh{\"a}siven Eigenschaften und das Leistungspotenzial unter Wasser verbessern. Zuletzt wurden mit Glycerol pr{\"a}fabrizierte Pasten hergestellt, welche gelagert werden k{\"o}nnen und bei Kontakt mit Wasser aush{\"a}rten. Generell ist zu betonen, dass k{\"u}nftige Bem{\"u}hungen um Knochenklebstoffe aus Phosphoserin und Mg2+ sehr lohnenswert erscheinen.}, subject = {Phosphoserin}, language = {de} } @phdthesis{Jonas2023, author = {Jonas, Wenzel Till}, title = {Komparative Analyse des Einflusses zielgerichteter Therapeutika auf den immunologischen Ph{\"a}notyp im BRAF-V600-mutierten Melanom}, doi = {10.25972/OPUS-32323}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323239}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Die Einf{\"u}hrung von zielgerichteter Therapie und Immuntherapie hat die Behandlungsm{\"o}glichkeiten des Melanoms revolutioniert. Jedoch profitieren viele Patienten nicht langfristig von diesen Therapien. Derzeit werden klinische Studien durchgef{\"u}hrt, die zielgerichtete Therapie und Immuntherapie miteinander kombinieren. In dieser Arbeit wurden in vitro Untersuchungen an den drei BRAF-V600E-mutieren Melanomzelllinien UACC 257, Malme 3M und Sk-Mel 5 unter kombinierter MAPK-Inhibitortherapie durchgef{\"u}hrt. Es wurden die aus der klinischen Routine bekannten Kombinationen aus BRAF- und MEK-Inhibitor - Vemurafenib und Cobimetinib, Dabrafenib und Trametinib sowie Encorafenib und Binimetinib - verwendet. Es wurde untersucht, ob obige zielgerichtete Therapeutika einen Effekt auf immunologische Marker im Melanom haben und ob sich eine der Kombinationen in ihrer Wirkung signifikant von den {\"u}brigen unterscheidet. Mittels MTS-Assay und Zellzyklusanalysen konnte eine konzentrationsabh{\"a}ngige Wirkung der Inhibitoren gezeigt und in ihrer Wirkung vergleichbare Inhibitorkonzentrationen eingestellt werden. Unter kombinierter MAPK-Inhibitortherapie zeigte sich ein begrenzter Effekt auf die theoretische Immunogenit{\"a}t des Melanoms. So konnte eine erh{\"o}hte MHC-I-Expression (+14 \%) und eine verminderte PD-L1-Expression (-24 \%) gezeigt werden. Die gew{\"a}hlten Dosen an Inhibitoren induzierten keinen ER-Stress. Ebenso konnte keine Ekto-Calreticulin-Expression auf lebenden Zellen nachgewiesen werden. Zwischen den drei Inhibitorkombinationen zeigten sich keine signifikanten Unterschiede. Die in dieser Arbeit gezeigten begrenzten immunologischen Effekte unter kombinierter MAPK-Inhibitortherapie legen nahe, dass eine Kombination mit Immuntherapie in Teilen synergistisch wirken k{\"o}nnte. Hier sind die Ergebnisse weiterer Studien abzuwarten, die zielgerichtete und Immuntherapie miteinander kombinieren, um ein tiefgreifenderes Verst{\"a}ndnis bzgl. etwaiger Synergien zu generieren. Da zwischen den Inhibitorkombinationen keine signifikanten Unterschiede hinsichtlich ihrer Wirkung auf die Immunogenit{\"a}t des Melanoms gefunden wurden, ist anzunehmen, dass sie sich grunds{\"a}tzlich alle gleichermaßen f{\"u}r eine Kombination mit einer Immuntherapie eignen. Die gezeigte MHC-I-Erh{\"o}hung trat bereits bei geringen Inhibitorkonzentrationen auf. M{\"o}glicherweise gen{\"u}gt bei einer Kombination mit Immuntherapie bereits eine niedrige Dosis der zielgerichteten Therapie, um die Immuntherapie zu boostern. Um die Frage nach einer m{\"o}glichen Kombinationstherapie fortw{\"a}hrend zu analysieren, sollten zus{\"a}tzliche Aspekte der Immunogenit{\"a}t unter kombinierter MAPK-Inhibitortherapie untersucht und die Inhibitortitration zum Vergleich der zielgerichteten Therapeutika weiter pr{\"a}zisiert werden.}, subject = {Melanom}, language = {de} } @article{Haveman2023, author = {Haveman, Rense}, title = {Phytosociological notes on hedges in South Ayrshire, Scotland}, series = {Forum Geobotanicum}, volume = {11}, journal = {Forum Geobotanicum}, issn = {1867-9315}, doi = {10.3264/FG.2023.0420}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312634}, pages = {1-7}, year = {2023}, abstract = {On the basis of four relev{\´e}es of hedges around Straiton en Dailly in South Ayrshire, Scotland, some features of hedges are discussed. On the basis of the brambles, the vegetation of these hedges can be assigned to the Pruno-Rubion sprengelii, which comprises the bramble scrubs of circumneutral and nutrient rich soils in West Europe (Haveman et al. 2017, Haveman \& de Ronde 2019). Until now, this alliance was thought to be restricted to the northwestern edge of the European continent, but based on these relev{\´e}es and the known distribution area of Rubus nemoralis and Rubus polyanthemus, both characteristic for the Pruno-Rubion sprengelii, large parts of North England and Scotland have to be included in the distribution area of the alliance. The Pruno-Rubion sprengelii is optimally developed in rather narrow structures, like hedges, which are pruned every year. Here, brambles and herbs alike can grow with and under the shrubs, facilitated by the light that reaches large parts of the ground. Where the economic base of hedges perishes, they are not longer maintained, and the shrubs can grow out to their natural proportions. This changes the amount of light reaching the surface in the inner parts of the thicket, changing the competition between the species. The brambles as well as the herbs are displaced to the outer edges of the scrub, and the vegetation "dissociates" in a high-growing scrub, a fore-mantle ("cuff") with brambles, and a fringe with perennial herbs. These elements can hardly ever be assigned to the Pruno-Rubion anymore. The Pruno-Rubion sprengelii in optima forma is a scrub in which the three elements (shrubs, brambles, and herbs) grow closely intertwined. This is rarely found in natural landscapes, and thus the alliance is a typical element of the old farmer landscape. What is more: the typical species of the alliance, like Rubus nemoralis and R. polyanthemus, could only evolve after the landscape was opened by farmers in the last six millennia (Matzke-Hajek 1997), giving way to Rubus ulmifolius to expand its distribution area. This caused an explosion of hybrids which stabilised through apomixis into the wealth of Rubus species inhibiting the West European landscape nowadays (Sochor et al. 2015). Many of these species have their original home in a man-made landscape. Therefore, the Pruno-Rubion sprengelii can be characterised as a "farmers alliance" pur sang.}, subject = {Brombeere}, language = {en} } @article{Gottschlich2023, author = {Gottschlich, G{\"u}nter}, title = {Hieracium rotundatum subsp. silvae-bavaricae, eine neue Hieracium-Sippe aus dem Bayerischen Wald (Deutschland)}, series = {Forum Geobotanicum}, volume = {11}, journal = {Forum Geobotanicum}, issn = {1867-9315}, doi = {10.3264/FG.2023.0912}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-327145}, pages = {8-14}, year = {2023}, abstract = {Hieracium rotundatum subsp. silvae-bavaricae is described as new for science and illustrated. The new subspecies belongs to a group of species (H. rotundatum, H. transylvanicum) whose main distribution is in the Balkans. The changeful nomenclatural history of the species name is described. Diagnostic features to distinguish the growth habit-similar species H. murorum, H. rotundatum and H. transylvanicum are discussed. Particular attention is drawn to the importance of the development of the basic leaf cycle. Contrary to previous knowledge, the northwestern distribution limit of H.rotundatum extends now to southeastern Bavaria. During the search for H. rotundatum a morphologically conspicuous subspecies of H. rotundatum could be detected, which is described here as new.}, subject = {Habichtskraut}, language = {de} } @phdthesis{Majewski2023, author = {Majewski, Lisa}, title = {Input-Output-Analyse zur Ermittlung der regional{\"o}konomischen Effekte des Tourismus in Schutzgebieten : Eine Adaption der Methodik an internationale Standards am Fallbeispiel Biosph{\"a}rengebiet Schwarzwald}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, isbn = {978-3-95826-216-4}, issn = {0510-9833}, doi = {10.25972/WUP-978-3-95826-217-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-316545}, school = {W{\"u}rzburg University Press}, pages = {XVI, 444}, year = {2023}, abstract = {Schutzgebiete gelten laut der Convention on Biological Diversity als Fl{\"a}cheninstrument zum Schutz der Biodiversit{\"a}t. Menschen profitieren davon unter anderem durch die Nutzung als touristische Attraktion. Sch{\"a}tzungen zufolge werden weltweit etwa acht Mrd. Besuche zur Wahrnehmung des Naturerlebnisangebots der Schutzgebiete erreicht, woraus direkte Besucherausgaben in H{\"o}he von 600 Mrd. US-\$ resultieren. Schutzgebiete sind damit auch bedeutende Wirtschaftsmotoren der regionalen {\"O}konomien. Deutschlands Nationalparks z{\"a}hlen j{\"a}hrlich etwa 53 Mio. Besuchstage, deren t{\"a}gliche Ausgaben vor Ort einen Bruttoumsatz in H{\"o}he von 2,78 Mrd. € generieren. Die touristische Wertsch{\"o}pfung betr{\"a}gt 1,45 Mrd. €. Die weiteren 65 Mio. Besuchstage in deutschen Biosph{\"a}renreservaten erwirtschaften einen Bruttoumsatz in H{\"o}he von 2,94 Mrd. €. Das Einkommen von 172.000 Personen ist vom Tourismus in deutschen Nationalparken und Biosph{\"a}renreservaten abh{\"a}ngig. Im Rahmen einer ersten Studie zu den regional{\"o}konomischen Effekten des Nationalparks Berchtesgaden im Jahr 2002 wurde die touristische Wertsch{\"o}pfungsanalyse als Standardmethode der deutschen Schutzgebietsforschung etabliert. Im Laufe der Jahre wurde sie dahingehend modifiziert, ein vergleichbares, weil standardisiertes Vorgehen anwenden zu k{\"o}nnen. Die internationale Forschung manifestiert mit der Herausgabe eines Leitfadens einen anderen Standard zur regional{\"o}konomischen Wirkungsanalyse des Tourismus in Schutzgebieten: die Input-Output-Analyse. Schutzgebietsverwaltungen in den USA, Kanada, Brasilien, Namibia, S{\"u}dafrika und Finnland f{\"u}hren f{\"u}r ihr Besuchermonitoring Input-Output-Analysen durch. Diese sind im Vergleich zur Wertsch{\"o}pfungsanalyse als der validiere Ansatz einzustufen, weil damit ein Rechenwerk gegeben ist, womit indirekte Vorleistungs- und induzierte Konsumwirkungen zuverl{\"a}ssig quantifiziert werden k{\"o}nnen. Die Wertsch{\"o}pfungsanalyse arbeitet hingegen mit pauschalen Wertsch{\"o}pfungsquoten f{\"u}r alle touristischen Wirtschaftszweige und auf jeder Maßstabsebene. Aufgrund der fehlenden Datenverf{\"u}gbarkeit konnte die Input-Output-Analyse in Deutschland bisher nicht angewandt werden. Eine potenzielle Datenquelle er{\"o}ffnete sich durch das US-amerikanische Modellierungsunternehmen IMPLAN, welches Input-Output-Tabellen f{\"u}r die regionale Ebene der EU anbot. IMPLAN-Daten werden auch vom US-amerikanischen National Park Service verwendet. Die vorliegende Arbeit versteht sich als methodische Weiterentwicklung regional{\"o}konomischer Wirkungsanalysen in Deutschlands Schutzgebieten zur Adaption an internationale Standards. Dazu erfolgt die Applikation der Input-Output-Analyse f{\"u}r das Fallbeispiel des Biosph{\"a}rengebiets Schwarzwald, dessen Regional{\"o}konomie einen {\"u}berschaubaren Analyserahmen bietet. Der Nationalpark Schwarzwald wurde als Vergleichsregion zur Validierung der Ergebnisse untersucht. F{\"u}r eine erweiterte Einordnung der touristischen Multiplikatorwirkung in der Schwarzwaldregion wurde eine multiregionale Input-Output-Analyse durchgef{\"u}hrt, die sich auf die Gebietsabgrenzung der beiden Naturparke Schwarzwald Mitte/Nord und S{\"u}dschwarzwald bezieht. Zur Quantifizierung der direkten Wirkungsebene wurden touristische Kenngr{\"o}ßen der amtlichen Statistik entnommen. Die Berechnung von direkten Wertsch{\"o}pfungsquoten erfolgte gem{\"a}ß ihrer Definition als die in der Region verbleibende Wertsch{\"o}pfung am touristischen Produktionswert. Mittels der Input-Output-Analyse wurden die indirekten und induzierten Effekte des Tourismus im Biosph{\"a}rengebiet Schwarzwald ermittelt. Aus den regionalen Input-Output-Tabellen wurden inverse Koeffizienten abgeleitet, welche die regional{\"o}konomischen Multiplikatoren anzeigen. Zwei Multiplikatortypen wurden f{\"u}r die touristischen Kenngr{\"o}ßen Output, Wertsch{\"o}pfung und Besch{\"a}ftigung berechnet: Typ I-Multiplikatoren bemessen die indirekten Vorleistungseffekte touristischer Ausgaben. Typ II-Multiplikatoren inkludieren auch die induzierten Konsumeffekte. In einem mehrstufigen Prozess der Analyse von weiteren Fallbeispielen k{\"o}nnen regional{\"o}konomische Multiplikatoren f{\"u}r verschiedene Gebietseinheiten validiert und so ganzheitlich abgestimmt f{\"u}r das deutsche Schutzgebietssystem adaptiert werden. Dadurch k{\"o}nnte die Input-Output-Analyse als neue Standardmethode f{\"u}r ein dauerhaftes regional{\"o}konomisches Monitoring in deutschen Schutzgebieten etabliert werden.}, language = {de} } @phdthesis{Elspass2023, author = {Elspaß, Susanne Irmgard}, title = {H{\"a}ufigkeit und Bedeutung f{\"u}r Mortalit{\"a}t, kardiopulmonale Funktion und Komorbidit{\"a}ten einer schlafbezogenen Atmungsst{\"o}rung mit einem Apnoe-Hypopnoe-Index gr{\"o}ßer-gleich f{\"u}nfzehn pro Stunde bei pulmonal-arterieller Hypertonie und chronisch thromboembolischer pulmonaler Hypertonie}, doi = {10.25972/OPUS-32286}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322869}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Mehrere vorangegangene kleinere Studien zeigen einen Zusammenhang zwischen pulmonaler Hypertonie (PH) und einer schlafbezogenen Atmungsst{\"o}rung (u.a. obstruktive und zentrale Schlafapnoe). Die beiden Erkrankungen scheinen sich gegenseitig zu beeinflussen, wobei oftmals nicht gekl{\"a}rt werden kann, ob die pulmonale Hypertonie urs{\"a}chlich f{\"u}r die Schlafapnoe ist oder umgekehrt. F{\"u}r die vorliegende Untersuchung wurden Daten monozentrisch retrospektiv {\"u}ber einen Zeitraum von 2,5 Jahren ausgewertet. Die Daten stammen von Patienten der Pulmonalen-Hypertonie-Ambulanz der Missioklinik in W{\"u}rzburg. Insgesamt werden 174 Patienten mit gesicherter PAH oder CTEPH untersucht und anhand einer durchgef{\"u}hrten Polygraphie in die beiden Gruppen AHI<15/h und AHI≥15/h eingeteilt. In der vorliegenden Arbeit wurde bei PAH- und CTEPH-Patienten untersucht, ob sie sich je nach der H{\"o}he des Apnoe-Hypopnoe-Index AHI < bzw. ≥ 15/h hinsichtlich der Mortalit{\"a}t, H{\"a}modynamik, ihrer Leistungsf{\"a}higkeit und der sonstigen kardiopulmonalen Funktion unterscheiden. Es werden zudem Unterschiede beim Auftreten diverser Komorbidit{\"a}ten betrachtet. Etwa ein F{\"u}nftel der untersuchten PAH-Patienten (20,5 \%) und ebenso der CTEPH-Patienten (21,4 \%) weist eine schlafbezogene Atmungsst{\"o}rung mit einem AHI≥15/h auf. Zur genaueren Analyse wird im Ergebnisteil die Studienpopulation in PAH und PAH+CTEPH getrennt. In beiden Erhebungen k{\"o}nnen keine signifikanten Differenzen bez{\"u}glich der Mortalit{\"a}t zwischen den Patienten mit AHI<15/h und AHI≥15/h festgestellt werden. Bei PAH-Patienten mit AHI≥15/h waren Arrhythmien h{\"a}ufiger zu finden und der pulmonalkapill{\"a}re Verschlussdruck (PCWP) war h{\"o}her, das Herzzeitvolumen war bei Patienten mit AHI ≥15/h signifikant niedriger. Weitere signifikante Unterschiede betreffen die alveolo-arterielle Sauerstoffdruckdifferenz, welche bei Patienten mit AHI <15/h h{\"o}her ist und die Gamma-GT-Serumkonzentration, welche bei Patienten mit AHI≥15/h signifikant h{\"o}her zu finden war. Insgesamt ist das Kollektiv mit AHI≥15/h signifikant {\"a}lter als die Patienten mit AHI<15/h. Bei der Auswertung des durch Pooling erstellten Kollektivs von PAH+CTEPH-Patienten haben die Patienten mit einem AHI≥15/h signifikant mehr Herzrhythmusst{\"o}rungen (p=0,004). Auch ist in diesem Kollektiv der PCWP bei Patienten mit AHI≥15/h signifikant h{\"o}her als bei Patienten mit AHI<15/h. Die Analyse des PAH+CTEPH-Kollektivs zeigt zudem Unterschiede im systolischen Blutdruck unter maximaler Belastung, der bei Patienten mit AHI<15/h h{\"o}her ist, und bei der alveolo-arteriellen Sauerstoffdruckdifferenz, die bei Patienten mit AHI<15/h h{\"o}her ausf{\"a}llt. Zudem ist der rechte Vorhof in der Echokardiographie im Kollektiv mit AHI≥15/h signifikant gr{\"o}ßer. Auch im Kollektiv mit PAH+CTEPH haben die Patienten mit AHI≥15/h eine signifikant h{\"o}here Gamma-GT-Serumkonzentration. Die Ergebnisse der Untersuchung zeigen, dass PAH- und CTEPH-Patienten mit einem AHI≥15/h vergleichbare funktionelle Werte aufweisen als Patienten mit einem AHI<15/h. Auffallend ist, dass Arrhythmien, die wiederum urs{\"a}chlich f{\"u}r Erkrankungen des Herz-Kreislauf-Systems sein k{\"o}nnen, in der Gruppe der PAH-/CTEPH-Patienten mit h{\"o}herem AHI geh{\"a}uft auftreten. Hier kann ein direkter Zusammenhang mit dem in diesem Kollektiv ebenfalls signifikant erh{\"o}hten pulmonalkapill{\"a}ren Verschlussdruck vermutet werden, da Vorhofflimmern {\"u}ber eine Erh{\"o}hung des linksatrialen Drucks beg{\"u}nstigt wird. In Relation zu einem Großteil der Vorg{\"a}ngerstudien, welche sich mit den Themen PAH/CTEPH und schlafbezogene Atmungsst{\"o}rungen auseinandersetzen, weist vorliegende Arbeit unter Ber{\"u}cksichtigung der Seltenheit der Erkrankungen PAH und CTEPH durch das Pooling eine nicht zu untersch{\"a}tzende Fallzahl auf. Eine m{\"o}gliche Schwachstelle der vorliegenden Untersuchung, n{\"a}mlich das unterschiedliche Verh{\"a}ltnis der beiden Untersuchungspopulationen AHI<15/h bzw. AHI≥15/h l{\"a}sst sich ebenfalls durch die niedrigen Pr{\"a}valenzen der Erkrankungen relativieren. Interessant w{\"a}re eine weitere Untersuchung mit der Differenzierung AHI<30/h und AHI≥30/h. Ergeben sich hier Auff{\"a}lligkeiten, k{\"o}nnte auch eine prospektive Studie mit Nachuntersuchung nach erfolgter Therapie erfolgen, um deren Auswirkungen auf die Schlafapnoe und pulmonale Hypertonie zu bewerten. Erg{\"a}nzend k{\"o}nnte auch noch die Tagesschl{\"a}frigkeit im Verlauf erfasst werden, z.B. anhand der Epworth sleepiness scale.}, subject = {Pulmonale Hypertonie}, language = {de} } @phdthesis{Heinz2023, author = {Heinz, Christine Silvia}, title = {Synthesis of Analogues and Hybrid Ligands of Pilocarpine for the Study of Muscarinic Receptor Dynamics}, doi = {10.25972/OPUS-28148}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281486}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Muscarinic acetylcholine receptors (mAChRs) are involved in signal transmission at the synapses of the parasympathetic nervous system. The five subtypes of mAChRs regulate various body functions such as heart function, gland secretion, memory, and learning. For the development of drugs with the least side-effects possible, the molecular causes of subtype selectivity and signalling bias are under investigation. In this context, the study of dualsteric ligands binding simultaneously to the orthosteric and the allosteric binding sites of the receptor is of high interest. To date, dualsteric ligands were synthesised as hybrids of full agonists or superagonists being the orthosteric element, linked to known subtype selective allosteric fragments. In this work, the existing library was expanded to hybrid ligands based on the partial agonist pilocarpine. A suitable linker attachment point to pilocarpine was investigated. For this aim, pilocarpine (2), isopilocarpine (15), pilosinine (16) and desmethyl pilosinine (35) were synthesised as orthosteric ligands and orthosteric fragments for the construction of the hybrid molecules (Figure 42). Pilocarpine was liberated from the commercial hydrochloride or nitrate salt and isopilocarpine was generated by epimerisation of pilocarpine. Pilosinine was synthesised in a Michael addition reaction of a dithiane carrying the imidazole moiety 82 onto the lactone precursor furan-2(5H)-one (83) followed by complete deprotection (Figure 43a).[133] The desmethyl pilosinine (35) was obtained in a newly developed synthetic route based on a Horner-Wadsworth-Emmons (HWE) reaction to build the methylene bridge between the imidazole aldehyde and the precursor of the lactone moiety 57 (Figure 43b). All four orthosters were converted to the respective dualsteric compounds with a naphmethonium fragment as allosteric moiety. The four orthosteric fragments and the four hybrid molecules with a linker length of six methylene units were tested for their dose dependent G protein recruitment at the receptor subtypes M1-5 using a mini-G nanoBRET assay. The study of the orthosteric ligands revealed that pilocarpine has the highest ability of all four orthosters to induce activity at all receptor subtypes. A change of the cis- to a trans-configuration of the lactone substituents or a complete removal of the ethyl substituent provoked a significant reduction of activity. Removal of the methyl substituent of the imidazole moiety led to improved receptor activation. The efficacies of the hybrid ligands show that the linker attachment at the imidazole moiety of pilocarpine and its analogues does not abolish activity and hybrid formation of isopilocarpine even improved receptor activation. Thus, the linker attachment point seems a valid choice, but linker length might not be optimum. In contrast to the orthosters, the trans-substitution of the lactone was advantageous for receptor activation of the hybrid ligands. The hybrid without a methyl substituent at the imidazole (69) had an increased efficacy. Additionally, the naphmethonium fragment lowered the maximum effect of pilocarpine, whereas the activity of isopilocarpine was increased. The intensity of both effects was influenced by the subtype selectivity produced by naphmethonium leading, in the case of the pilocarpine hybrid, to less decreased responses or, in the case of the isopilocarpine hybrid, to more increased responses at the M2 and M4 receptors. The results generally lead to the assumption that the allosteric moiety strongly influences the binding poses of the hybrid ligands so that the orthosteric fragments do not interact with the binding site in the same way as the orthosters alone. A second project was based on molecular dynamics simulations of the binding pose of pilocarpine,[73] leading to the hypothesis that the partial agonism of pilocarpine results from an equilibrium between an agonistic and an antagonistic binding pose at the orthosteric binding site of the receptor. The ratio of occupancy of both binding poses determines the observed efficacy of pilocarpine. The orthosteric binding site provides more space for the ethyl substituent in the supposed antagonistic pose than in the agonistic binding pose. This hypothesis was tested by the synthesis and pharmacological evaluation of pilocarpine analogues with alkyl substituents of different sizes at the lactone (16, 31a, c, d) (Figure 44). The analogues with larger alkyl residues are expected to shift the equilibrium towards the antagonistic binding pose, the analogues with smaller residues should have the inverse effect. The synthesis of the pilocarpine analogues was first attempted as a mixture of stereoisomers which were supposed to be separated at the end of the synthetic route. The racemic mixture of the thermodynamically more stable trans-isomers of the target compounds was prepared in a one-pot Michael-addition-alkylation reaction of a dithiane imidazole onto furan-2(5H)-one similarly to the synthesis of pilosinine (Figure 45). The resulting enolate was quenched by an iodoalkane to achieve alkylation of the lactone and subsequent complete deprotection yielded the racemic trans-analogues of pilocarpine.[133] After unsuccessful attempts of chiral resolution, the mixture of trans-isomers was converted to a mixture of all four possible diastereomers in a kinetic epimerisation reaction.[95] A separation of the stereoisomers was not possible in this project so only the racemic molecule 16 (pilosinine, R = H) was obtained from this synthetic route. For the selective synthesis of the cis-isomers following a patent from Reimann,[146] both stereocenters of the target molecules were produced in the last synthetic step by a syn-hydrogenation of the α,β-unsaturated precursor (Figure 46). The racemic pilocarpine analogues, except the butyl derivative (31d), were purified by crystallisation as their nitrate salts. This provided the racemic mixtures with less than 8\% of the trans-isomers as impurity. The racemic pilocarpine (2), itself, was obtained with 15\% trans-impurity and was used as reference compound. Additionally, the possibility of chiral resolution by chromatographic methods was demonstrated in the case of the methyl derivative (31a). The pharmacological testing of the desired enantiomer of 31a is in progress.}, subject = {Muskarinrezeptor}, language = {en} } @techreport{NordPetzke2023, author = {Nord, Ilona and Petzke, Judith}, title = {Religious Education in the digital change. Concepts and reflections from a German context}, doi = {10.25972/OPUS-32280}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322802}, pages = {30}, year = {2023}, abstract = {The article presents results from the project Religious Education Laboratory digital (RELab digital): At a time when exclusive access to religion in the classroom seems less and less plausible, the concept of digital religion education we propose leads back to the existential needs for religion. It can refer to the thematic fields of digital religions, which in turn are not new for religious education, but remix its traditions and themes in the mirror of transforming communication cultures: authority, community, truth, communication, autonomy, religion, identity, and ritual. Chapter 1 contains a description of the project structure. Chapter 2 is dedicated to the pedagogical challenge of teaching Religious Education (RE) in the digital change. Chapter 3 reflects from a pedagogical standpoint on empirical findings of the project, which were developed in the context of classroom observations and interviews. Chapter 4 focuses on topics related to the profession of teachers: What self-concepts are pursued by teachers of Religious Education and/or can be reconstructed through the way they act in the classroom? How can the often critical perceptions of teachers who use digital media in religious education be put to good use in the future? The conclusion bundles the most important insights and highlights examples of further research.}, subject = {Digitalisierung}, language = {en} } @phdthesis{GoebneeKlaus2023, author = {G{\"o}b [n{\´e}e Klaus], Vanessa Aline Domenica}, title = {Pathomechanisms underlying ischemic stroke}, doi = {10.25972/OPUS-28672}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286727}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Every year, stroke affects over 100 million people worldwide and the number of cases continues to grow. Ischemic stroke is the most prevalent form of stroke and rapid restoration of blood flow is the primary therapeutic aim. However, recanalization might fail or reperfusion itself induces detrimental processes leading to infarct progression. Previous studies identified platelets and immune cells as drivers of this so-called ischemia/reperfusion (I/R) injury, establishing the concept of ischemic stroke as thrombo-inflammatory disease. Reduced cerebral blood flow despite recanalization promoted the hypothesis that thrombus formation within the cerebral microcirculation induces further tissue damage. The results presented in this thesis refute this: using complementary methodologies, it was shown that infarct growth precedes the occurrence of thrombi excluding them as I/R injury-underlying cause. Blood brain barrier disruption is one of the hallmarks of ischemic stroke pathology and was confirmed as early event during reperfusion injury in the second part of this study. Abolished platelet α-granule release protects mice from vascular leakage in the early reperfusion phase resulting in smaller infarcts. Using in vitro assays, platelet α-granule-derived PDGF-AB was identified as one factor contributing to blood-brain barrier disruption. In vivo visualization of platelet activation would provide important insights in the spatio-temporal context of platelet activation in stroke pathology. As platelet signaling results in elevated intracellular Ca2+ levels, this is an ideal readout. To overcome the limitations of chemical calcium indicators, a mouse line expressing an endogenous calcium reporter specifically in platelets and megakaryocytes was generated. Presence of the reporter did not interfere with platelet function, consequently these mice were characterized in in vivo and ex vivo models. Upon ischemic stroke, neutrophils are among the first cells that are recruited to the brain. Since for neutrophils both, beneficial and detrimental effects are described, their role was investigated within this thesis. Neither neutrophil depletion nor absence of NADPH-dependent ROS production (Ncf-/- mice) affected stroke outcome. In contrast, abolished NET-formation in Pad4-/- mice resulted in reduced infarct sizes, revealing detrimental effects of NETosis in the context of ischemic stroke, which might become a potential therapeutic target. Cerebral venous (sinus) thrombosis, CV(S)T is a rare type of stroke with mainly idiopathic onset. Whereas for arterial thrombosis a critical contribution of platelets is known and widely accepted, for venous thrombosis this is less clear but considered more and more. In the last part of this thesis, it was shown that fab-fragments of the anti-CLEC-2 antibody INU1 trigger pathological platelet activation in vivo, resulting in foudroyant CVT accompanied by heavy neurological symptoms. Using this novel animal model for CVT, cooperative signaling of the two platelet receptors CLEC-2 and GPIIb/IIIa was revealed as major trigger of CVT and potential target for treatment.}, subject = {Schlaganfall}, language = {en} } @phdthesis{Scheuplein2023, author = {Scheuplein, Nicolas Julian}, title = {Synthesis and Characterization of Antimicrobial Inhibitors of the "Macrophage Infectivity Potentiator" Protein and Fluorescent Probes}, doi = {10.25972/OPUS-32189}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321892}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {This dissertation focuses on Mip (macrophage infectivity potentiator protein) inhibitors in response to increasing antibiotic resistance. The study follows an antivirulence approach, which aims to inhibit the non-essential Mip protein without exerting too much selective pressure. Three focus areas were (1) development and synthesis of a fluorescent probe for screening Mip inhibitors via fluorescence polarization; (2) design and synthesis of broad spectrum Mip inhibitors bearing a side chain; and (3) understanding the metabolism of Mip inhibitors and identification of active metabolites. A sub-study addressed the biotinylation of anti-leishmanial compounds from Valeriana wallichii rhizomes, with three tracer molecules synthesized for future pull-down experiments.}, subject = {Antibiotikum}, language = {en} } @phdthesis{Reinermann2023, author = {Reinermann, Sophie}, title = {Earth Observation Time Series for Grassland Management Analyses - Development and large-scale Application of a Framework to detect Grassland Mowing Events in Germany}, doi = {10.25972/OPUS-32273}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322737}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Grasslands shape many landscapes of the earth as they cover about one-third of its surface. They are home and provide livelihood for billions of people and are mainly used as source of forage for animals. However, grasslands fulfill many additional ecosystem functions next to fodder production, such as storage of carbon, water filtration, provision of habitats and cultural values. They play a role in climate change (mitigation) and in preserving biodiversity and ecosystem functions on a global scale. The degree to what these ecosystem functions are present within grassland ecosystems is largely determined by the management. Individual management practices and the use intensity influence the species composition as well as functions, like carbon storage, while higher use intensities (e.g. high mowing frequencies) usually show a negative impact. Especially in Central European countries, like in Germany, the determining influence of grassland management on its physiognomy and ecosystem functions leads to a large variability and small-scale alternations of grassland parcels. Large-scale information on the management and use intensity of grasslands is not available. Consequently, estimations of grassland ecosystem functions are challenging which, however, would be required for large-scale assessments of the status of grassland ecosystems and optimized management plans for the future. The topic of this thesis tackles this gap by investigating the major grassland management practice in Germany, which is mowing, for multiple years, in high spatial resolution and on a national scale. Earth Observation (EO) has the advantage of providing information of the earth's surface on multi-temporal time steps. An extensive literature review on the use of EO for grassland management and production analyses, which was part of this thesis, showed that in particular research on grasslands consisting of small parcels with a large variety of management and use intensity, like common in Central Europe, is underrepresented. Especially the launch of the Sentinel satellites in the recent past now enables the analyses of such grasslands due to their high spatial and temporal resolution. The literature review specifically on the investigation of grassland mowing events revealed that most previous studies focused on small study areas, were exploratory, only used one sensor type and/or lacked a reference data set with a complete range of management options. Within this thesis a novel framework to detect grassland mowing events over large areas is presented which was applied and validated for the entire area of Germany for multiple years (2018-2021). The potential of both sensor types, optical (Sentinel-2) and Synthetic Aperture Radar (SAR) (Sentinel-1) was investigated regarding grassland mowing event detection. Eight EO parameters were investigated, namely the Enhanced Vegetation Index (EVI), the backscatter intensity and the interferometric (InSAR) temporal coherence for both available polarization modes (VV and VH), and the polarimetric (PolSAR) decomposition parameters Entropy, K0 and K1. An extensive reference data set was generated based on daily images of webcams distributed in Germany which resulted in mowing information for grasslands with the entire possible range of mowing frequencies - from one to six in Germany - and in 1475 reference mowing events for the four years of interest. For the first time a observation-driven mowing detection approach including data from Sentinel-2 and Sentinel-1 and combining the two was developed, applied and validated on large scale. Based on a subset of the reference data (13 grassland parcels with 44 mowing events) from 2019 the EO parameters were investigated and the detection algorithm developed and parameterized. This analysis showed that a threshold-based change detection approach based on EVI captured grassland mowing events best, which only failed during periods of clouds. All SAR-based parameters showed a less consistent behavior to mowing events, with PolSAR Entropy and InSAR Coherence VH, however, revealing the highest potential among them. A second, combined approach based on EVI and a SARbased parameter was developed and tested for PolSAR Entropy and InSAR VH. To avoid additional false positive detections during periods in which mowing events are anyhow reliably detected using optical data, the SAR-based mowing detection was only initiated during long gaps within the optical time series (< 25 days). Application and validation of these approaches in a focus region revealed that only using EVI leads to the highest accuracies (F1-Score = 0.65) as combining this approach with SAR-based detection led to a strong increase in falsely detected mowing events resulting in a decrease of accuracies (EVI + PolSAR ENT F1-Score = 0.61; EVI + InSAR COH F1-Score = 0.61). The mowing detection algorithm based on EVI was applied for the entire area of Germany for the years 2018-2021. It was revealed that the largest share of grasslands with high mowing frequencies (at least four mowing events) can be found in southern/south-eastern Germany. Extensively used grassland (mown up to two times) is distributed within the entire country with larger shares in the center and north-eastern parts of Germany. These patterns stay constant in general, but small fluctuations between the years are visible. Early mown grasslands can be found in southern/south-eastern Germany - in line with high mowing frequency areas - but also in central-western parts. The years 2019 and 2020 revealed higher accuracies based on the 1475 mowing events of the multi-annual validation data set (F1-Scores of 0.64 and 0.63), 2018 and 2021 lower ones (F1-Score of 0.52 and 0.50). Based on this new, unprecedented data set, potential influencing factors on the mowing dynamics were investigated. Therefore, climate, topography, soil data and information on conservation schemes were related to mowing dynamics for the year 2020, which showed a high number of valid observations and detection accuracy. It was revealed that there are no strong linear relationships between the mowing frequency or the timing of the first mowing event and the investigated variables. However, it was found that for intensive grassland usage certain climatic and topographic conditions have to be fulfilled, while extensive grasslands appear on the entire spectrum of these variables. Further, higher mowing frequencies occur on soils with influence of ground water and lower mowing frequencies in protected areas. These results show the complex interplay between grassland mowing dynamics and external influences and highlight the challenges of policies aiming to protect grassland ecosystem functions and their need to be adapted to regional circumstances.}, subject = {Gr{\"u}nland}, language = {en} } @unpublished{WarmdtFrischRatzetal.2023, author = {Warmdt, Julia and Frisch, Henrik and Ratz, Christoph and Pohlmann-Rother, Sanna}, title = {Digital lesen und erz{\"a}hlen. Eine Projektwoche f{\"u}r den inklusiven Anfangsunterricht}, series = {F{\"o}rdermagazin Grundschule}, journal = {F{\"o}rdermagazin Grundschule}, edition = {accepted version}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-328443}, year = {2023}, abstract = {Das Digital Storytelling bietet Sch{\"u}ler:innen im inklusiven Anfangsunterricht vielf{\"a}ltige M{\"o}glichkeiten der Teilhabe am Unterricht. Lesen Sie in diesem Beitrag, wie die Kinder eine digitale Geschichte auf unterschiedliche Art rezipieren und weitererz{\"a}hlen k{\"o}nnen.}, subject = {Bilderbuch}, language = {de} } @article{MehmoodAlsalehWantetal.2023, author = {Mehmood, Rashid and Alsaleh, Alanoud and Want, Muzamil Y. and Ahmad, Ijaz and Siraj, Sami and Ishtiaq, Muhammad and Alshehri, Faizah A. and Naseem, Muhammad and Yasuhara, Noriko}, title = {Integrative molecular analysis of DNA methylation dynamics unveils molecules with prognostic potential in breast cancer}, series = {BioMedInformatics}, volume = {3}, journal = {BioMedInformatics}, number = {2}, issn = {2673-7426}, doi = {10.3390/biomedinformatics3020029}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321171}, pages = {434 -- 445}, year = {2023}, abstract = {DNA methylation acts as a major epigenetic modification in mammals, characterized by the transfer of a methyl group to a cytosine. DNA methylation plays a pivotal role in regulating normal development, and misregulation in cells leads to an abnormal phenotype as is seen in several cancers. Any mutations or expression anomalies of genes encoding regulators of DNA methylation may lead to abnormal expression of critical molecules. A comprehensive genomic study encompassing all the genes related to DNA methylation regulation in relation to breast cancer is lacking. We used genomic and transcriptomic datasets from the Cancer Genome Atlas (TGCA) Pan-Cancer Atlas, Genotype-Tissue Expression (GTEx) and microarray platforms and conducted in silico analysis of all the genes related to DNA methylation with respect to writing, reading and erasing this epigenetic mark. Analysis of mutations was conducted using cBioportal, while Xena and KMPlot were utilized for expression changes and patient survival, respectively. Our study identified multiple mutations in the genes encoding regulators of DNA methylation. The expression profiling of these showed significant differences between normal and disease tissues. Moreover, deregulated expression of some of the genes, namely DNMT3B, MBD1, MBD6, BAZ2B, ZBTB38, KLF4, TET2 and TDG, was correlated with patient prognosis. The current study, to our best knowledge, is the first to provide a comprehensive molecular and genetic profile of DNA methylation machinery genes in breast cancer and identifies DNA methylation machinery as an important determinant of the disease progression. The findings of this study will advance our understanding of the etiology of the disease and may serve to identify alternative targets for novel therapeutic strategies in cancer.}, language = {en} } @article{StratosRinasSchroepferetal.2023, author = {Stratos, Ioannis and Rinas, Ingmar and Schr{\"o}pfer, Konrad and Hink, Katharina and Herlyn, Philipp and B{\"a}umler, Mario and Histing, Tina and Bruhn, Sven and M{\"u}ller-Hilke, Brigitte and Menger, Michael D. and Vollmar, Brigitte and Mittlmeier, Thomas}, title = {Effects on bone and muscle upon treadmill interval training in hypogonadal male rats}, series = {Biomedicines}, volume = {11}, journal = {Biomedicines}, number = {5}, issn = {2227-9059}, doi = {10.3390/biomedicines11051370}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319266}, year = {2023}, abstract = {Testosterone deficiency in males is linked to various pathological conditions, including muscle and bone loss. This study evaluated the potential of different training modalities to counteract these losses in hypogonadal male rats. A total of 54 male Wistar rats underwent either castration (ORX, n = 18) or sham castration (n = 18), with 18 castrated rats engaging in uphill, level, or downhill interval treadmill training. Analyses were conducted at 4, 8, and 12 weeks postsurgery. Muscle force of the soleus muscle, muscle tissue samples, and bone characteristics were analyzed. No significant differences were observed in cortical bone characteristics. Castrated rats experienced decreased trabecular bone mineral density compared to sham-operated rats. However, 12 weeks of training increased trabecular bone mineral density, with no significant differences among groups. Muscle force measurements revealed decreased tetanic force in castrated rats at week 12, while uphill and downhill interval training restored force to sham group levels and led to muscle hypertrophy compared to ORX animals. Linear regression analyses showed a positive correlation between bone biomechanical characteristics and muscle force. The findings suggest that running exercise can prevent bone loss in osteoporosis, with similar bone restoration effects observed across different training modalities.}, language = {en} } @article{SchmitzStormsKochetal.2023, author = {Schmitz, Sophia M. and Storms, Sebastian and Koch, Alexander and Stier, Christine and Kroh, Andreas and Rheinwalt, Karl P. and Schipper, Sandra and Hamesch, Karim and Ulmer, Tom F. and Neumann, Ulf P. and Alizai, Patrick H.}, title = {Insulin resistance is the main characteristic of metabolically unhealthy obesity (MUO) associated with NASH in patients undergoing bariatric surgery}, series = {Biomedicines}, volume = {11}, journal = {Biomedicines}, number = {6}, issn = {2227-9059}, doi = {10.3390/biomedicines11061595}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319213}, year = {2023}, abstract = {(1) Background: Metabolically healthy obesity (MHO) is a concept that applies to obese patients without any elements of metabolic syndrome (metS). In turn, metabolically unhealthy obesity (MUO) defines the presence of elements of metS in obese patients. The components of MUO can be divided into subgroups regarding the elements of inflammation, lipid and glucose metabolism and cardiovascular disease. MUO patients appear to be at greater risk of developing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) compared to MHO patients. The aim of this study was to evaluate the influence of different MUO components on NAFLD and NASH in patients with morbid obesity undergoing bariatric surgery. (2) Methods: 141 patients undergoing bariatric surgery from September 2015 and October 2021 at RWTH Aachen university hospital (Germany) were included. Patients were evaluated pre-operatively for characteristics of metS and MUO (HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension). Intraoperatively, a liver biopsy was taken from the left liver lobe and evaluated for the presence of NAFLD or NASH. In ordinal regression analyses, different factors were evaluated for their influence on NAFLD and NASH. (3) Results: Mean BMI of the patients was 52.3 kg/m\(^2\) (36-74.8, SD 8.4). Together, the parameters HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension accounted for a significant amount of variance in the outcome, with a likelihood ratio of χ\(^2\) (9) = 41.547, p < 0.001, for predicting the presence of NASH. Only HOMA was an independent predictor of NASH (B = 0.102, SE = 0.0373, p = 0.007). Evaluation of steatosis showed a similar trend (likelihood ratio χ\(^2\) (9) = 40.272, p < 0.001). Independent predictors of steatosis were HbA1c (B = 0.833, SE = 0.343, p = 0.015) and HOMA (B = 0.136, SE = 0.039, p < 0.001). (4) Conclusions: The above-mentioned model, including components of MUO, was significant for diagnosing NASH in patients with morbid obesity undergoing bariatric surgery. Out of the different subitems, HOMA independently predicted the presence of NASH and steatosis, while HbA1c independently predicted steatosis and fibrosis. Taken together, the parameter of glucose metabolism appears to be more accurate for the prediction of NASH than the parameters of lipid metabolism, inflammation or the presence of cardiovascular disease.}, language = {en} } @article{EilsbergerKreisslReinersetal.2023, author = {Eilsberger, Friederike and Kreissl, Michael C. and Reiners, Christoph and Holzgreve, Adrien and Luster, Markus and Pfestroff, Andreas}, title = {Application of the American Thyroid Association risk assessment in patients with differentiated thyroid carcinoma in a German population}, series = {Biomedicines}, volume = {11}, journal = {Biomedicines}, number = {3}, issn = {2227-9059}, doi = {10.3390/biomedicines11030911}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311226}, year = {2023}, abstract = {Background: The American Thyroid Association (ATA) uses criteria to assess the risk for persistent disease in differentiated thyroid carcinoma (DTC) after radioiodine therapy (RAI). There are no data available showing that this classification can be adopted unadjusted by Germany. Aim: The aim of our study is to investigate whether the ATA classification can be applied to a German population for short-term prognosis. Furthermore, we investigated the influence of an age cutoff value. Methods: We retrospectively analyzed 121 patients who were referred to our tertiary referral center. Patients were classified into risk categories, and the therapy response was determined according to ATA. Results: A total of 73/83 (88\%) ATA low-risk patients and 12/19 (63\%) intermediate-risk patients showed an excellent response; 2/19 (11\%) high-risk patients had a biochemical, and 6 (31\%) had a structural incomplete response. Of all 39 patients ≥55 years, 84\% had an excellent response. Using a cut off of 50 years, 50/62 (81\%) of the older patients showed an excellent response. Conclusion: The ATA risk classification is able to estimate the response to RAI therapy in a German population. A shift from 55 to 50 years as an age cutoff value does not result in any relevant change in the treatment response.}, language = {en} } @phdthesis{Seiler2023, author = {Seiler, Jonas}, title = {Die Expression des Vitamin-D-Rezeptors und der 24-Hydroxylase in Knochenmetastasen unterschiedlicher Entit{\"a}t}, doi = {10.25972/OPUS-32182}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321827}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Knochenmetastasen sind unter den drei h{\"a}ufigsten Manifestationsorten metastatischer Absiedelungen von fortgeschrittenen Tumorerkrankungen. Dabei sind insbesondere Patientinnen und Patienten mit Prostata- und Mammakarzinom von Knochenmetastasen betroffen. Diese Knochenmetastasen f{\"u}hren h{\"a}ufig zu einer deutlichen Verschlechterung der Lebensqualit{\"a}t und zu einer Begrenzung der Therapieoptionen auf lediglich palliative Ans{\"a}tze. Die biologisch aktive Form von Vitamin D3, 1,25(OH)2-Vitamin D3, zeigt in pr{\"a}klinischen Studien antiproliferative und differenzierende Effekte auf Tumorzellen (101, 102, 104), die haups{\"a}chlich durch die Bindung an den Vitamin D-Rezeptor (VDR) vermittelt werden. Dar{\"u}berhinaus konnte pr{\"a}klinisch gezeigt werden, dass eine niedrige Expression des VDRs, ligandenunabh{\"a}ngig, die Knochenmetastasierung und das Tumorwachstum beg{\"u}nstigt (118). Eine niedrige VDR-Expression ist in Prim{\"a}rtumoren in klinischen Studien mit aggressiven Tumoreigenschaften assoziiert (111, 113, 115) und kann zudem mit einer erh{\"o}hten/fr{\"u}heren oss{\"a}ren Metastasierung einhergehen (167). Zudem gibt es Hinweise auf einen dysregulierten 1,25(OH)2-Vitamin D3-Katabolismus durch eine erh{\"o}hte Expression des 1,25(OH)2-Vitamin D3 katabolisierenden Enzyms CYP24A1/24-Hydroxylase in prim{\"a}rem Tumorzellen (70, 121, 122). Durch die Untersuchungen der Prim{\"a}rtumoren ist damit zu hypothetisieren, dass die Expression des VDRs und von CYP24A1 bei der Tumorprogression und Knochenmetastasierung von Bedeutung sein k{\"o}nnte. Entsprechende Untersuchungen des VDRs und der 24-Hydroxylase in Knochenmetastasen fehlen allerdings. Deshalb wurde in dieser Arbeit die Expression des VDRs und von CYP24A1 in Knochenmetastasen unterschiedlicher Prim{\"a}rtumoren von 66 Patientinnen und Patienten untersucht und m{\"o}gliche Assoziationen mit aggressiven Tumoreigenschaften analysiert. Der VDR konnte sowohl im Zytoplasma als auch im Nukleus nachgewiesen werden, w{\"a}hrend CYP24A1 nur im Zytoplasma lokalisiert war. Dabei wiesen insgesamt 71 \% der Knochenmetastasen eine hohe VDR-Expression im Nukleus und 56 \% im Zytoplasma auf. 59 \% der Knochenmetastasen wiesen eine hohe Expression des VDRs insgesamt auf. CYP24A1 war ebenso in 59 \% der Knochenmetastasen hoch exprimiert. Bei der Auswertung des Zusammenhangs zwischen den TNM-Stadien und des Gradings zeigte sich ein nicht signifikanter Trend von schlecht differenzierten Tumoren hin zu einer niedrigeren nukle{\"a}ren VDR-Expression (p=0.07, siehe Abbildung 33). Bez{\"u}glich der T-Stadien zeigten sich keine Unterschiede der Expression des VDRs und von CYP24A1 in den Knochenmetastasen zwischen lokal fortgeschrittenen und kleinen Prim{\"a}rtumoren. Weiterhin hatten Patientinnen und Patienten mit Lymphknotenmetastasen tendenziell eine verminderte VDR- und auch CYP24A1-Expression in den Knochenmetastasen im Vergleich zu Patienten und Patientinnen ohne Lymphknotenmetastasen (pVDR=0.15, pCYP24A1=0.06, siehe Abbildung 35). Außerdem hatten Patientinnen und Patienten mit multiple metastasierten Tumoren eine signifikant niedrigere nukle{\"a}re VDR- und auch CYP24A1-Expression im Vergleich zu Patientinnen und Patienten mit ausschließlich oss{\"a}rer Metastasierung (pVDR=0.03, pCYP24A1=0.01, Abbildung 36). Die Proteinexpression des VDRs- und von CYP24A1 korrelierten signifikant (p=0.001). Somit konnte mit dieser Arbeit die Proteinexpression des VDRs und von CYP24A1 in Knochenmetastasen durch Immunhistologie nachgewiesen werden. Insgesamt wurde der VDR und CYP24A1 von Knochenmetastasen diverser Entit{\"a}t unterschiedlich stark exprimiert. Jedoch k{\"o}nnten insbesondere Patienten mit VDR-exprimierenden Knochenmetastasen von einer Vitamin D3-Supplementierung profitieren, die h{\"a}ufig einen 25-OH-Vitamin D3 Mangel zeigen (165, 166). Ebenso k{\"o}nnte eine Untersuchung auf einen niedrigen VDR-Status in Prim{\"a}rtumoren dabei helfen, Krebspatienten mit einem hohen Metastasierungsrisiko zu identifizieren. Allerdings sind weitere und gr{\"o}ßere Studien inbesondere mit Evaluation des gesamten Vitamin D-Metabolismus und -Signalwegs notwendig, um diesen Zusammenhang weiter zu untersuchen.}, subject = {Vitamin D3}, language = {de} } @phdthesis{Lauruschkat2023, author = {Lauruschkat, Chris David}, title = {Entwicklung funktioneller Immunassays zur Detektion der humanen Immunantwort auf das opportunistische Pathogen \(Aspergillus\) \(fumigatus\)}, doi = {10.25972/OPUS-31983}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319835}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Aspergillus fumigatus ist ein opportunistisches fungales Humanpathogen, das ein breites Erkrankungsspektrum von der invasiven Aspergillose (IA) in immunkompromittierten Patienten bis zu einer Reihe von Hypersensitivit{\"a}tserkrankungen in immunkompetenten Individuen hervorrufen kann. Die Diagnostik f{\"u}r A. fumigatus assoziierte Krankheitsbilder beruht auf mehreren diagnostischen Tests, die auch in ihrer Kombination oft zu sp{\"a}ten und unzuverl{\"a}ssigen Diagnosen f{\"u}hren, was wiederum zu einer suboptimalen Patientenversorgung, erh{\"o}hter Mortalit{\"a}t und gesteigerten Kosten f{\"u}r das Gesundheitssystem f{\"u}hrt. Es besteht daher die unbedingte Notwendigkeit, neue und bessere diagnostische Tests zur Detektion von A. fumigatus zu entwickeln. T Zell Assays sind vielversprechende, innovative diagnostische Tests, die bereits f{\"u}r andere Infektionskrankheiten in der Routinediagnostik eingesetzt werden. Erste Versuche wurden bereits unternommen, diese Assays auch f{\"u}r A. fumigatus assoziierte Erkrankungen einzusetzen. Die g{\"a}ngigsten, auf mononukle{\"a}ren Zellen des peripheren Blutes (PBMC)-basierten T Zell Assays sind der Enzyme-linked Immunosorbent Assay (ELISA), Enzyme-linked Immuno Spot Assay (ELISPOT) und die Durchflusszytometrie. Das Ziel dieser Dissertation war die Entwicklung eines klinisch einsetzbaren T-Zell-Assays f{\"u}r A. fumigatus assoziierte Erkrankungen. Die in der Literatur beschriebenen Assays zeigten in unseren Experimenten bei der Anwendung f{\"u}r mykologische Fragestellungen eine hohe Suszeptibilit{\"a}t gegen{\"u}ber bereits kurzen pr{\"a}analytischen Lagerzeiten und Krykonservierung, was einen klinischen Einsatz erschwerte. Wir entwickelten deshalb einen Vollblut basierten ELISA (VB-ELISA) mit dualer Kostimulation (α-CD28 und α-CD49d), hoher Reproduzierbarkeit und verbesserter Robustheit gegen{\"u}ber pr{\"a}analytischen Einflussfaktoren. Der VB ELISA konnte hohe Differenzen zwischen Typ 1 T Helferzellen (Th1) , Th2 und Th17 Zytokinkonzentrationen bei Patienten mit Aspergillus assoziierten Hypersensitivit{\"a}tskrankheitsbildern und Kontrollpatienten feststellen. Um zu testen, ob dieser Anstieg auf die Erkrankung zur{\"u}ckzuf{\"u}hren ist oder auch bei hoher Aspergillus-Umweltexposition vorzufinden ist, wurde der Assay in Aspergillus exponierten gesunden {\"o}kologischen Landwirten getestet. In dieser Gruppe fanden wir ebenfalls eine erh{\"o}hte Th1 und Th2 Expansion und Zytokinsekretion gegen{\"u}ber gesunden Kontrollspendern, jedoch wurde nur ein geringer Anstieg des Th17 Signalzytokines IL-17 detektiert. Die Detektion von IL-17 im VB-ELISA in Kombination mit anderen Zytokinmarkern ist daher ein vielversprechender Biomarker f{\"u}r die Diagnose von A. fumigatus assoziierten Hypersensitivit{\"a}tserkrankungen. Neben diesen Hypersensitivit{\"a}tserkrankungen haben wir den VB-ELISA auch in immunkompromittierten Patienten nach allogener Stammzelltransplantation (alloSZT), einer Hochrisikogruppe f{\"u}r die IA und die durch das humane Cytomegalovirus (HCMV) ausgel{\"o}ste Zytomegalie, evaluiert. W{\"a}hrend in unserer monozentrischen Pilotstudie aufgrund der geringen Inzidenz keine Evaluation an IA-Patienten erfolgen konnte, wurde mittels VB-ELISA eine hohe Konkordanz der HCMV-spezifischen T Zell Antwort mit der HCMV Serologie sowie eine vergleichbare Leistung zum ELISPOT, dem am h{\"a}ufigsten eingestetzen Assay f{\"u}r diese Fragestellung, festgestellt. Zusammenfassend haben wir mit dem VB ELISA einen vielversprechenden und breitfl{\"a}chig im Spektrum A. fumigatus assoziierter Erkrankungen einsetzbaren T Zell Assay entwickelt, der in der Zukunft in großen Studien mit klar definierten Patientenkohorten getestet werden sollte. Auf Grund von Daten aus Folgestudien, die auf dieser Arbeit basieren, ist des Weiteren davon auszugehen, dass der VB-ELISA auf Grund seiner St{\"a}rken potenziell in einer Vielzahl von Anwendungsgebieten und Pathogenen (eine Folgestudie mit SARS-CoV-2 wurde vor kurzem ver{\"o}ffentlicht) universell eingesetzt werden kann. Neben der Immundiagnostik f{\"u}r diverse Infektionserkrankungen k{\"o}nnte der Assay außerdem f{\"u}r T Zell Antworten auf Vakzinierungen und Immuntherapien, in vivo Experimente und in vitro Toxizit{\"a}tstests verwendet werden.}, subject = {Immunologie}, language = {de} } @phdthesis{Scheffler2023, author = {Scheffler, Lukas}, title = {Molecular beam epitaxy of the half-Heusler antiferromagnet CuMnSb}, doi = {10.25972/OPUS-32283}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322839}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {This work presents a newly developed method for the epitaxial growth of the half-Heusler antiferromagnet CuMnSb. All necessary process steps, from buffer growth to the deposition of a protective layer, are presented in detail. Using structural, electrical, and magnetic characterization, the material parameters of the epitaxial CuMnSb layers are investigated. The successful growth of CuMnSb by molecular beam epitaxy is demonstrated on InAs (001), GaSb (001), and InP (001) substrates. While CuMnSb can be grown pseudomorphically on InAs and GaSb, the significant lattice mismatch for growth on InP leads to relaxation already at low film thicknesses. Due to the lower conductivity of GaSb compared to InAs, GaSb substrates are particularly suitable for the fabrication of CuMnSb layers for lateral electrical transport experiments. However, by growing a high-resistive ZnTe interlayer below the CuMnSb layer, lateral transport experiments on CuMnSb layers grown on InAs can also be realized. Protective layers of Ru and Al2O3 have proven to be suitable for protecting the CuMnSb layers from the environment. Structural characterization by high resolution X-ray diffraction (full width at half maximum of 7.7 ′′ of the rocking curve) and atomic force microscopy (root mean square surface roughness of 0.14 nm) reveals an outstanding crystal quality of the epitaxial CuMnSb layers. The half-Heusler crystal structure is confirmed by scanning transmission electron microscopy and the stoichiometric material composition by Rutherford backscattering spectrometry. In line with the high crystal quality, a new minimum value of the residual resistance of CuMnSb (𝜌0 = 35 μΩ ⋅ cm) could be measured utilizing basic electrical transport experiments. An elaborate study of epitaxial CuMnSb grown on GaSb reveals a dependence of the vertical lattice parameter on the Mn/Sb flux ratio. This characteristic enables the growth of tensile, unstrained, and compressive strained CuMnSb layers on a single substrate material. Additionally, it is shown that the N{\´e}el temperature has a maximum of 62 K at stoichiometric material composition and thus can be utilized as a selection tool for stoichiometric CuMnSb samples. Mn-related defects are believed to be the driving force for these observations. The magnetic characterization of the epitaxial CuMnSb films is performed by superconducting quantum interference device magnetometry. Magnetic behavior comparable to the bulk material is found, however, an additional complex magnetic phase appears in thin CuMnSb films and/or at low magnetic fields, which has not been previously reported for CuMnSb. This magnetic phase is believed to be localized at the CuMnSb surface and exhibits both superparamagnetic and spin-glass-like behavior. The exchange bias effect of CuMnSb is investigated in combination with different in- and out-of-plane ferromagnets. It is shown that the exchange bias effect can only be observed in combination with in-plane ferromagnets. Finally, the first attempts at the growth of fully epitaxial CuMnSb/NiMnSb heterostructures are presented. Both magnetic and structural studies by secondary-ion mass spectrometry indicate the interdiffusion of Cu and Ni atoms between the two half-Heusler layers, however, an exchange bias effect can be observed for the CuMnSb/NiMnSb heterostructures. Whether this exchange bias effect originates from exchange interaction between the CuMnSb and NiMnSb layers, or from ferromagnetic inclusions in the antiferromagnetic layer can not be conclusively identified.}, subject = {Molekularstrahlepitaxie}, language = {en} } @techreport{NordPetzkeAdametal.2023, author = {Nord, Ilona and Petzke, Judith and Adam, Oliver and Luthe, Simon}, title = {Lehrkr{\"a}fte und digitaler Wandel. Religionsdidaktische sowie professionsbezogene Reflexionen aus dem Projekt Religious Education Laboratory digital (RELab digital)}, doi = {10.25972/OPUS-31978}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319789}, pages = {24}, year = {2023}, abstract = {Der Beitrag pr{\"a}sentiert didaktische Ertr{\"a}ge aus dem Projekt Religious Education Laboratory digital (RELab digital). Unter Kapitel 1 findet sich eine Beschreibung des Projektaufbaus. Kapitel 2 ist der religionsp{\"a}dagogischen Herausforderung eines Digital Religions-Unterrichts gewidmet. Kapitel 3 reflektiert den Einsatz digitaler Medien in religionsp{\"a}dagogischer Praxis im Spannungsfeld von Erwartungen und Unterrichtsrealit{\"a}ten. Kapitel 4 fokussiert professionsbezogene Themen: Welchen Selbstkonzepten folgen Religionslehrkr{\"a}fte bzw. welche sind durch ihr Handeln im Unterricht rekonstruierbar? Wie k{\"o}nnen die Spannungen, die im Unterricht zwischen der Nutzung von digitalen Medien und ihrer Deutung durch die Lehrkr{\"a}fte aufkommen, produktiv f{\"u}r einen zukunftsf{\"a}higen Religionsunterricht aufgenommen werden? In einer Zeit, in der der exklusive Zugriff auf Religion im Unterricht immer weniger plausibel erscheint, f{\"u}hrt das von uns vorgeschlagene Konzept eines Digital Religions -Unterricht zur{\"u}ck zu den existentiellen Bed{\"u}rfnissen nach Religion. Es kann auf die Themenfelder der Digital Religions Bezug nehmen, die ihrerseits keineswegs neu f{\"u}r den Religionsunterricht sind, sondern seine Traditionen und Themen im Spiegel sich transformierender Kommunikationskulturen remixen: Autorit{\"a}t, Gemeinschaft, Wahrheit, Kommunikation, Autonomie, Religion, Identit{\"a}t und Ritual.}, subject = {Digitalisierung}, language = {de} } @phdthesis{Forster2023, author = {Forster, Andr{\´e}}, title = {Targeting Temporally Stable Vulnerability Factors in the Prediction of Long-Term Courses of Depression: Diagnostic Considerations and Therapeutic Protocols Based on Transcranial Ultrasonic Neuromodulation of Endophenotypes}, doi = {10.25972/OPUS-27906}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-279065}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Depressive disorders represent one of the main sources for the loss of healthy years of life. One of the reasons for this circumstance is the recurrent course of these disorders, which can be interrupted by current therapeutic approaches, especially in the shortterm, but seem to be maintained at least in part in the long-term. Subsequently, on one hand, this thesis deals with methodological measurement issues in the longitudinal prediction of depressive courses. On the other hand, it addresses two currently discussed neuroscience-based treatment approaches, which are investigated experimentally in a basic-psychological manner and reviewed in the light of their potential to translate results to the application in patient care. These two approaches each address potential mechanisms that may negatively impact long-term disease trajectories: First, stable endophenotypes for vulnerability factors that could regain control over the organism and reactivate maladaptive experiences, or behaviors with increasing temporal distance from therapeutic methods are focused on. In the studies presented, these were influenced by a recently rediscovered method of neuromodulation (transcranial low-intensity focused ultrasound) which is discussed in light of its unique capability to address even deepest, subcortical regions at a high spatial resolution. Lastly, as a second approach, an experimental design for the use of reconsolidation interference is presented, which could provide a first insight into the applicability of corresponding protocols in the field of depressive disorders and thus contribute to the modification, instead of inhibition, of already mentioned endophenotypes. In sum, methodological considerations for monitoring and predicting long-term courses of depression are deducted before two approaches are discussed that could potentially exert positive influences on the recurrent nature of depressive symptoms on their own, in combination with each other, or as augmentation for existing therapeutic procedures.}, subject = {Depression}, language = {en} } @phdthesis{Breil2023, author = {Breil, Christina}, title = {Look at me and I will feel you: eye contact and social understandig}, doi = {10.25972/OPUS-27802}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-278021}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {One of the features that defines humans as extraordinarily social beings is their striking susceptibility to the gaze of others. The research reported in this dissertation was undertaken to advance our understanding of the role of gaze cues in low-level attentional and higher-order cognitive processes. In particular, effects of gaze were examined with regard to three aspects of human cognition: (1) social attention, (2) social interaction and (3) social understanding. Chapter 1 consists of three manuscripts that investigate the boundary conditions of attention capture by direct gaze and how gaze direction is integrated with facial context information. Manuscript 1 and 2 suggest two necessary requirements for attention capture by direct gaze: a meaningful holistic facial context and sharp foveal vision, respectively. Manuscript 3 shows approach/avoidance-congruency effects between gaze direction and emotion expression on attention. Chapter 2 of this dissertation explores the role of gaze in more naturalistic social scenarios. Manuscript 4 demonstrates that gaze behavior during a conversation shapes our perception of another person. Manuscript 5 builds on these findings by showing that these perceptions define our willingness to act in a prosocial way towards our interaction partner. Finally, chapter 3 adopts a broader perspective on social cognition research with a special focus on methodological aspects. Manuscript 6 is a review highlighting the significance of methodological aspects in social cognition research and stressing the importance of sophisticated decisions on task and stimulus materials. Manuscript 7 introduces a new instrument for the assessment of social understanding in adolescents. Initial application in a young sample group indicates that an understanding of another person's mental states is a capacity that is still developing throughout adolescence. Both manuscripts of this final chapter include eye tracking data that suggest a relationship between gaze behavior and social understanding, a finding that further emphasizes the complex and multifaceted nature of social cognition. I conclude from the findings of this dissertation that research can benefit from adopting a broad view in terms of methodological as well as temporal aspects in order to capture human social cognition in its entirety.}, subject = {Blick}, language = {en} } @incollection{Kreutzer2023, author = {Kreutzer, Ansgar}, title = {„Die im Dunkeln sieht man doch." Christliche Offenbarung als Wahrnehmungsschulung f{\"u}r sozialen Ausschluss}, series = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, booktitle = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, editor = {Keul, Hildegund}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, doi = {10.25972/WUP-978-3-95826-203-4-257}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325377}, publisher = {W{\"u}rzburg University Press}, pages = {257-275}, year = {2023}, abstract = {No abstract available.}, language = {de} } @incollection{Czapski2023, author = {Czapski, Jutta}, title = {Verwundbares Antlitz. Die Menschenrechte im Denken von Emmanuel Levinas}, series = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, booktitle = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, editor = {Keul, Hildegund}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, doi = {10.25972/WUP-978-3-95826-203-4-237}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325365}, publisher = {W{\"u}rzburg University Press}, pages = {237-255}, year = {2023}, abstract = {No abstract available.}, language = {de} } @incollection{Keul2023, author = {Keul, Hildegund}, title = {Zwischenruf: Toxische Theologien - toxische Therapien. Der uns{\"a}gliche Fall des Tony Anatrella}, series = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, booktitle = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, editor = {Keul, Hildegund}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, doi = {10.25972/WUP-978-3-95826-203-4-197}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325345}, publisher = {W{\"u}rzburg University Press}, pages = {197-204}, year = {2023}, abstract = {No abstract available.}, language = {de} } @incollection{Keul2023, author = {Keul, Hildegund}, title = {Sexuelle Gewalt und Machtmissbrauch in „Neuen Geistlichen Gemeinschaften" - {\"u}ber die gef{\"a}hrlichen Seiten dessen, was Menschen heilig ist}, series = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, booktitle = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, editor = {Keul, Hildegund}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, doi = {10.25972/WUP-978-3-95826-203-4-131}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325320}, publisher = {W{\"u}rzburg University Press}, pages = {131-168}, year = {2023}, abstract = {No abstract available.}, language = {de} } @incollection{BauerAmin2023, author = {Bauer-Amin, Sabine}, title = {Emergente Vulnerabilit{\"a}t von Gefl{\"u}chteten im Aufnahmeland: Homo Saber}, series = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, booktitle = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, editor = {Keul, Hildegund}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, doi = {10.25972/WUP-978-3-95826-203-4-23}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325280}, publisher = {Universit{\"a}t W{\"u}rzburg}, pages = {23-55}, year = {2023}, abstract = {No abstract available.}, language = {de} } @incollection{Leimgruber2023, author = {Leimgruber, Ute}, title = {Welche Erinnerung z{\"a}hlt? Die UnSichtbarkeit geschlechtsspezifischer Gewalt im Raum der Kirche}, series = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, booktitle = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, editor = {Keul, Hildegund}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, doi = {10.25972/WUP-978-3-95826-203-4-103}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325311}, publisher = {W{\"u}rzburg University Press}, pages = {103-130}, year = {2023}, abstract = {No abstract available.}, language = {de} } @incollection{Heek2023, author = {Heek, Andreas}, title = {„M{\"a}nnlich und weiblich schuf Gott sie" (Gen 1,27)? Trans- und Intergeschlechtlichkeit als Herausforderung f{\"u}r Theologie und kirchliche Lehre}, series = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, booktitle = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, editor = {Keul, Hildegund}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, doi = {10.25972/WUP-978-3-95826-203-4-169}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325335}, publisher = {W{\"u}rzburg University Press}, pages = {169-196}, year = {2023}, abstract = {No abstract available.}, language = {de} } @incollection{Lessenich2023, author = {Lessenich, Stephan}, title = {Leben machen und sterben lassen: Die Politik mit der Vulnerabilit{\"a}t}, series = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, booktitle = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, editor = {Keul, Hildegund}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, doi = {10.25972/WUP-978-3-95826-203-4-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325271}, publisher = {Universit{\"a}t W{\"u}rzburg}, pages = {1-21}, year = {2023}, abstract = {No abstract available.}, language = {de} } @incollection{Hoefner2023, author = {H{\"o}fner, Steven}, title = {Das Westjordanland - Wo Vulnerabilit{\"a}ten ein politisches Vakuum erzeugen und damit gef{\"a}hrlich werden}, series = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, booktitle = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, editor = {Keul, Hildegund}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, doi = {10.25972/WUP-978-3-95826-203-4-79}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325303}, publisher = {W{\"u}rzburg University Press}, pages = {79-99}, year = {2023}, abstract = {No abstract available.}, language = {de} } @incollection{Kirchschlaeger2023, author = {Kirchschl{\"a}ger, Peter G.}, title = {Verletzbarkeit und Menschenrechte}, series = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, booktitle = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, editor = {Keul, Hildegund}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, doi = {10.25972/WUP-978-3-95826-203-4-209}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325359}, publisher = {W{\"u}rzburg University Press}, pages = {209-236}, year = {2023}, abstract = {No abstract available.}, language = {de} } @incollection{Pistrol2023, author = {Pistrol, Florian}, title = {Der K{\"o}rper zwischen Abh{\"a}ngigkeit und Widerstand. Mit Judith Butler unterwegs zu einer Politik der Vulnerabilit{\"a}t}, series = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, booktitle = {UnSichtbar. Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, editor = {Keul, Hildegund}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, doi = {10.25972/WUP-978-3-95826-203-4-57}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325292}, publisher = {W{\"u}rzburg University Press}, pages = {57-78}, year = {2023}, abstract = {No abstract available.}, language = {de} } @phdthesis{Kraff2023, author = {Kraff, Nicolas Johannes}, title = {Analyse raumzeitlicher Ver{\"a}nderungen und ontologische Kategorisierung morphologischer Armutserscheinungen - Eine globale Betrachtung mithilfe von Satellitenbildern und manueller Bildinterpretation}, doi = {10.25972/OPUS-32026}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320264}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Die st{\"a}dtische Umwelt ist in steter Ver{\"a}nderung, vor allem durch den Bau, aber auch durch die Zerst{\"o}rung von st{\"a}dtischen Elementen. Die formelle Entwicklung ist ein Prozess mit langen Planungszeitr{\"a}umen und die bebaute Landschaft wirkt daher statisch. Dagegen unterliegen informelle oder spontane Siedlungen aufgrund ihrer stets unvollendeten st{\"a}dtischen Form einer hohen Dynamik - so wird in der Literatur berichtet. Allerdings sind Dynamik und die morphologischen Merkmale der physischen Transformation in solchen Siedlungen, die st{\"a}dtische Armut morphologisch repr{\"a}sentieren, auf globaler Ebene bisher kaum mit einer konsistenten Datengrundlage empirisch untersucht worden. Hier setzt die vorliegende Arbeit an. Unter der Annahme, dass die erforschte zeitliche Dynamik in Europa geringer ausf{\"a}llt, stellt sich die generelle Frage nach einer katalogisierten Erfassung physischer Wohnformen von Armut speziell in Europa. Denn Wohnformen der Armut werden oft ausschließlich mit dem ‚Globalen S{\"u}den' assoziiert, insbesondere durch die Darstellung von Slums. Tats{\"a}chlich ist Europa sogar die Wiege der Begriffe ‚Slum' und ‚Ghetto', die vor Jahrhunderten zur Beschreibung von Missst{\"a}nden und Unterdr{\"u}ckung auftauchten. Bis heute weist dieser facettenreiche Kontinent eine enorme Vielfalt an physischen Wohnformen der Armut auf, die ihre Wurzeln in unterschiedlichen Politiken, Kulturen, Geschichten und Lebensstilen haben. Um {\"u}ber diese genannten Aspekte Aufschluss zu erlangen, bedarf es u.a. der Bildanalyse durch Satellitenbilder. Diese Arbeit wird daher mittels Fernerkundung bzw. Erdbeobachtung (EO) sowie zus{\"a}tzlicher Literaturrecherchen und einer empirischen Erhebung erstellt. Um Unsicherheiten konzeptionell und in der Erfassung offenzulegen, ist die Methode der manuellen Bildinterpretation von Armutsgebieten kritisch zu hinterfragen. Das {\"u}bergeordnete Ziel dieser Arbeit ist eine bessere Wissensbasis {\"u}ber Armut zu schaffen, um Maßnahmen zur Reduzierung von Armut entwickeln zu k{\"o}nnen. Die Arbeit dient dabei als eine Antwort auf die Nachhaltigkeitsziele der Vereinten Nationen. Es wird Grundlagenforschung betrieben, indem Wissensl{\"u}cken in der Erdbeobachtung zu physisch-baulichen bzw. morphologischen Erscheinungen von Armut auf Geb{\"a}ude-Ebene explorativ analysiert werden. Die Arbeit wird in drei Forschungsthemen bzw. Studienteile untergliedert: Ziel des ersten Studienteils ist die globale raumzeitliche Erfassung von Dynamiken durch Ankn{\"u}pfung an bisherige Kategorisierungen von Armutsgebieten. Die bisherige Wissensl{\"u}cke soll gef{\"u}llt werden, indem {\"u}ber einen Zeitraum von etwa sieben Jahren in 16 dokumentierten Manifestationen st{\"a}dtischer Armut anhand von Erdbeobachtungsdaten eine zeitliche Analyse der bebauten Umwelt durchgef{\"u}hrt wird. Neben einer global verteilten Gebietsauswahl wird die visuelle Bildinterpretation (MVII) unter Verwendung von hochaufl{\"o}senden optischen Satellitendaten genutzt. Dies geschieht in Kombination mit in-situ- und Google Street View-Bildern zur Ableitung von 3D-Stadtmodellen. Es werden physische Raumstrukturen anhand von sechs r{\"a}umlichen morphologischen Variablen gemessen: Anzahl, Gr{\"o}ße, H{\"o}he, Ausrichtung und Dichte der Geb{\"a}ude sowie Heterogenit{\"a}t der Bebauung. Diese ‚temporale Analyse' zeigt zun{\"a}chst sowohl inter- als auch intra-urbane Unterschiede. Es lassen sich unterschiedliche, aber generell hohe morphologische Dynamiken zwischen den Untersuchungsgebieten finden. Dies dr{\"u}ckt sich in vielf{\"a}ltiger Weise aus: von abgerissenen und rekonstruierten Gebieten bis hin zu solchen, wo Ver{\"a}nderungen innerhalb der gegebenen Strukturen auftreten. Geographisch gesehen resultiert in der Stichprobe eine fortgeschrittene Dynamik, insbesondere in Gebieten des Globalen S{\"u}dens. Gleichzeitig l{\"a}sst sich eine hohe r{\"a}umliche Variabilit{\"a}t der morphologischen Transformationen innerhalb der untersuchten Gebiete beobachten. Trotz dieser teilweise hohen morphologischen Dynamik sind die r{\"a}umlichen Muster von Geb{\"a}udefluchten, Straßen und Freifl{\"a}chen {\"u}berwiegend konstant. Diese ersten Ergebnisse deuten auf einen geringen Wandel in Europa hin, weshalb diese europ{\"a}ischen Armutsgebiete im folgenden Studienteil von Grund auf erhoben und kategorisiert werden. Ziel des zweiten Studienteils ist die Erschaffung einer neuen Kategorisierung, speziell f{\"u}r das in der Wissenschaft unterrepr{\"a}sentierte Europa. Die verschiedenen Formen nicht indizierter Wohnungsmorphologien werden erforscht und kategorisiert, um das bisherige globale wissenschaftliche ontologische Portfolio f{\"u}r Europa zu erweitern. Hinsichtlich dieses zweiten Studienteils bietet eine Literaturrecherche mit mehr als 1.000 gesichteten Artikeln die weitere Grundlage f{\"u}r den folgenden Fokus auf Europa. Auf der Recherche basierend werden mittels der manuellen visuellen Bildinterpretation (engl.: MVII) erneut Satellitendaten zur Erfassung der physischen Morphologien von Wohnformen genutzt. Weiterhin kommen selbst definierte geographische Indikatoren zu Lage, Struktur und formellem Status zum Einsatz. Dar{\"u}ber hinaus werden gesellschaftliche Hintergr{\"u}nde, die durch Begriffe wie ‚Ghetto', ‚Wohnwagenpark', ‚ethnische Enklave' oder ‚Fl{\"u}chtlingslager' beschrieben werden, recherchiert und implementiert. Sie sollen als Erkl{\"a}rungsansatz f{\"u}r Armutsviertel in Europa dienen. Die Stichprobe der europ{\"a}ischen, insgesamt aber unbekannten Grundgesamtheit verdeutlicht eine große Vielfalt an physischen Formen: Es wird f{\"u}r Europa eine neue Kategorisierung von sechs Hauptklassen entwickelt, die von ‚einfachsten Wohnst{\"a}tten' (z. B. Zelten) {\"u}ber ‚behelfsm{\"a}ßige Unterk{\"u}nfte ' (z. B. Baracken, Container) bis hin zu ‚mehrst{\"o}ckigen Bauten' - als allgemeine Taxonomie der Wohnungsnot in Europa - reicht. Die Untersuchung zeigt verschiedene Wohnformen wie z. B. unterirdische oder mobile Typen, verfallene Wohnungen oder große Wohnsiedlungen, die die Armut im Europa des 21. Jahrhunderts widerspiegeln. {\"U}ber die Wohnungsmorphologie hinaus werden diese Klassen durch die Struktur und ihren rechtlichen Status beschrieben - entweder als geplante oder als organisch-gewachsene bzw. weiterhin als formelle, informelle oder hybride (halblegale) Formen. Geographisch lassen sich diese {\"a}rmlichen Wohnformen sowohl in st{\"a}dtischen als auch in l{\"a}ndlichen Gebieten finden, mit einer Konzentration in S{\"u}deuropa. Der Hintergrund bei der Mehrheit der Morphologien betrifft Fl{\"u}chtlinge, ethnische Minderheiten und sozio{\"o}konomisch benachteiligte Menschen - die ‚Unterprivilegierten'. Ziel des dritten Studienteils ist eine kritische Analyse der Methode. Zur Erfassung all dieser Siedlungen werden heutzutage Satellitenbilder aufgrund der Fortschritte bei den Bildklassifizierungsmethoden meist automatisch ausgewertet. Dennoch spielt die MVII noch immer eine wichtige Rolle, z.B. um Trainingsdaten f{\"u}r Machine-Learning-Algorithmen zu generieren oder f{\"u}r Validierungszwecke. In bestimmten st{\"a}dtischen Umgebungen jedoch, z.B. solchen mit h{\"o}chster Dichte und struktureller Komplexit{\"a}t, fordern spektrale und textur-basierte Verflechtungen von {\"u}berlappenden Dachstrukturen den menschlichen Interpreten immer noch heraus, wenn es darum geht einzelne Geb{\"a}udestrukturen zu erfassen. Die kognitive Wahrnehmung und die Erfahrung aus der realen Welt sind nach wie vor unumg{\"a}nglich. Vor diesem Hintergrund zielt die Arbeit methodisch darauf ab, Unsicherheiten speziell bei der Kartierung zu quantifizieren und zu interpretieren. Kartiert werden Dachfl{\"a}chen als ‚Fußabdr{\"u}cke' solcher Gebiete. Der Fokus liegt dabei auf der {\"U}bereinstimmung zwischen mehreren Bildinterpreten und welche Aspekte der Wahrnehmung und Elemente der Bildinterpretation die Kartierung beeinflussen. Um letztlich die Methode der MVII als drittes Ziel selbstkritisch zu reflektieren, werden Experimente als sogenannte ‚Unsicherheitsanalyse' geschaffen. Dabei digitalisieren zehn Testpersonen bzw. Probanden/Interpreten sechs komplexe Gebiete. Hierdurch werden quantitative Informationen {\"u}ber r{\"a}umliche Variablen von Geb{\"a}uden erzielt, um systematisch die Konsistenz und Kongruenz der Ergebnisse zu {\"u}berpr{\"u}fen. Ein zus{\"a}tzlicher Fragebogen liefert subjektive qualitative Informationen {\"u}ber weitere Schwierigkeiten. Da die Grundlage der hierf{\"u}r bisher genutzten Kategorisierungen auf der subjektiven Bildinterpretation durch den Menschen beruht, m{\"u}ssen etwaige Unsicherheiten und damit Fehleranf{\"a}lligkeiten offengelegt werden. Die Experimente zu dieser Unsicherheitsanalyse erfolgen quantifiziert und qualifiziert. Es lassen sich generell große Unterschiede zwischen den Kartierungsergebnissen der Probanden, aber eine hohe Konsistenz der Ergebnisse bei ein und demselben Probanden feststellen. Steigende Abweichungen korrelieren mit einer steigenden baustrukturellen (morphologischen) Komplexit{\"a}t. Ein hoher Grad an Individualit{\"a}t bei den Probanden {\"a}ußert sich in Aspekten wie z.B. Zeitaufwand beim Kartieren, in-situ Vorkenntnissen oder Vorkenntnissen beim Umgang mit Geographischen Informationssystemen (GIS). Nennenswert ist hierbei, dass die jeweilige Datenquelle das Kartierungsverfahren meist beeinflusst. Mit dieser Studie soll also auch an der Stelle der angewandten Methodik eine weitere Wissensl{\"u}cke gef{\"u}llt werden. Die bisherige Forschung komplexer urbaner Areale unter Nutzung der manuellen Bildinterpretation implementiert oftmals keine Unsicherheitsanalyse oder Quantifizierung von Kartierungsfehlern. Fernerkundungsstudien sollten k{\"u}nftig zur Validierung nicht nur zweifelsfrei auf MVII zur{\"u}ckgreifen k{\"o}nnen, sondern vielmehr sind Daten und Methoden notwendig, um Unsicherheiten auszuschließen. Zusammenfassend tr{\"a}gt diese Arbeit zur bisher wenig erforschten morphologischen Dynamik von Armutsgebieten bei. Es werden inter- wie auch intra-urbane Unterschiede auf globaler Ebene pr{\"a}sentiert. Dabei sind allgemein hohe morphologische Transformationen zwischen den selektierten Gebieten festzustellen. Die Ergebnisse deuten auf einen grundlegenden Kenntnismangel in Europa hin, weshalb an dieser Stelle angekn{\"u}pft wird. Eine {\"u}ber Europa verteilte Stichprobe erlaubt eine neue morphologische Kategorisierung der großen Vielfalt an gefundenen physischen Formen. Die Menge an Gebieten erschließt sich in einer unbekannten Grundgesamtheit. Zur Datenaufbereitung bisheriger Analysen m{\"u}ssen Satellitenbilder manuell interpretiert werden. Das Verfahren birgt Unsicherheiten. Als kritische Selbstreflexion zeigt eine Reihe von Experimenten signifikante Unterschiede zwischen den Ergebnissen der Probanden auf, verdeutlicht jedoch bei ein und derselben Person Best{\"a}ndigkeit.}, subject = {Slum}, language = {de} } @book{OPUS4-32281, title = {UnSichtbar : Interdisziplin{\"a}re Stimmen zu Vulnerabilit{\"a}t, Vulneranz und Menschenrechten}, editor = {Keul, Hildegund}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, isbn = {978-3-95826-202-7}, doi = {10.25972/WUP-978-3-95826-203-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322810}, publisher = {W{\"u}rzburg University Press}, pages = {II, 278}, year = {2023}, abstract = {Wo etwas Verborgenes, das vom {\"o}ffentlichen Diskurs ausgeschlossen wurde, pl{\"o}tzlich sichtbar wird, ereignen sich Offenbarungen. Wenn es dabei um Menschenrechte geht, so entsteht ein prek{\"a}rer Augenblick, der große Chancen und zugleich un{\"u}bersehbare Risiken birgt. Verworfenes Leben kann sich Bahn brechen; oder es wird durch schmerzliche Vulneranz erneut verfemt und zerst{\"o}rt. In Verwundungen, die an der Schwelle des UnSichtbaren geschehen, tritt die Vulnerabilit{\"a}t der Menschenrechte hervor. Das vorliegende Buch erscheint 2023 und damit 75 Jahre nach der "Allgemeinen Erkl{\"a}rung der Menschenrechte" der Vereinten Nationen. Menschenrechte sind eine gegen viele Widerst{\"a}nde und mit großen Opfern durchgesetzte Errungenschaft der Menschheit. Heute werden sie erneut zu einem verletzten und verletzbaren Gut. Daher analysiert das Buch die ambivalente Macht der Vulnerabilit{\"a}t an signifi kanten Diskursorten der Gegenwart; es legt die Vulneranz der katholischen Kirche bez{\"u}glich Missbrauch, Vertuschung und Gendertrouble frei; und es fragt nach der offenbarenden Kraft an jener Schwelle, wo die Menschenrechte in Gefahr sind. Mit Beitr{\"a}gen von Prof. Dr. Stephan Lessenich, Dr. Sabine Bauer-Amin, Florian Pistrol, Steven H{\"o}fner, Prof. Dr. Ute Leimgruber, Prof. Dr. Hildegund Keul, Dr. Andreas Heek, Prof. Dr. Peter G. Kirchschl{\"a}ger, Dr. Jutta Czapski, Prof. Dr. Ansgar Kreutzer.}, language = {de} } @phdthesis{Preitschopf2023, author = {Preitschopf, Tobias}, title = {Disentangling the Formation of PAHs in Extreme Environments by IR/UV Double Resonance Spectroscopy}, doi = {10.25972/OPUS-32279}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322791}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Polycyclic Aromatic Hydrocarbons (PAHs) are considered as key building blocks in the formation of carbonaceous particles such as soot. In our immediate surroundings, they are mainly generated in incomplete combustion processes and are further considered as carriers of the Unidentified Infrared Bands which are detected in a wide variety of astrophysical envelopes in the interstellar medium. Currently, astrochemical as well as combustion related models favour small resonance stabilized radicals (RSR) as major contributors to PAHs in sequential reactions. Therefore, we generated two RSR under well-defined conditions to investigate their contribution to PAH formation in a pyrolysis microreactor. The various reaction products were identified by IR/UV ion dip spectroscopy which combines the mass-selectivity of UV light with the structural sensitivity of IR radiation. Finally, we investigated the intermolecular interactions in azaphenanthrene dimers in combination with high-level theoretical calculations and found a preferential formation of pi-stacked van der Waals cluster in a molecular jet expansion.}, subject = {Infrarotspektroskopie}, language = {en} } @phdthesis{Nemec2023, author = {Nemec, Katarina}, title = {Modulation of parathyroid hormone 1 receptor (PTH1R) signaling by receptor activity-modifying proteins (RAMPs)}, doi = {10.25972/OPUS-28858}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288588}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {The receptor activity-modifying proteins (RAMPs) are ubiquitously expressed membrane proteins that interact with several G protein-coupled receptors (GPCRs), the largest and pharmacologically most important family of cell surface receptors. RAMPs can regulate GPCR function in terms of ligand-binding, G-protein coupling, downstream signaling, trafficking, and recycling. The integrity of their interactions translates to many physiological functions or pathological conditions. Regardless of numerous reports on its essential importance for cell biology and pivotal role in (patho-)physiology, the molecular mechanism of how RAMPs modulate GPCR activation remained largely elusive. This work presents new insights that add to the common understanding of the allosteric regulation of receptor activation and will help interpret how accessory proteins - RAMPs - modulate activation dynamics and how this affects the fundamental aspects of cellular signaling. Using a prototypical class B GPCR, the parathyroid hormone 1 receptor (PTH1R) in the form of advanced genetically encoded optical biosensors, I examined RAMP's impact on the PTH1R activation and signaling in intact cells. A panel of single-cell FRET and confocal microscopy experiments as well canonical and non-canonical functional assays were performed to get a holistic picture of the signaling initiation and transduction of that clinically and therapeutically relevant GPCR. Finally, structural modeling was performed to add molecular mechanistic details to that novel art of modulation. I describe here that RAMP2 acts as a specific allosteric modulator of PTH1R, shifting PTH1R to a unique pre-activated state that permits faster activation in a ligand-specific manner. Moreover, RAMP2 modulates PTH1R downstream signaling in an agonist-dependent manner, most notably increasing the PTH-mediated Gi3 signaling sensitivity and kinetics of cAMP accumulation. Additionally, RAMP2 increases PTH- and PTHrP-triggered β-arrestin2 recruitment to PTH1R and modulates cytosolic ERK1/2 phosphorylation. Structural homology modeling shows that structural motifs governing GPCR-RAMP interaction originate in allosteric hotspots and rationalize functional modulation. Moreover, to interpret the broader role of RAMP's modulation in GPCRs pharmacology, different fluorescent tools to investigate RAMP's spatial organization were developed, and novel conformational biosensors for class B GPCRs were engineered. Lastly, a high throughput assay is proposed and prototyped to expand the repertoire of RAMPs or other membrane protein interactors. These data uncover the critical role of RAMPs in GPCR activation and signaling and set up a novel platform for studying GPCR modulation. Furthermore, these insights may provide a new venue for precise modulation of GPCR function and advanced drug design.}, subject = {G-Protein gekoppelter Rezeptor}, language = {en} } @phdthesis{Sivarajan2023, author = {Sivarajan, Rinu}, title = {Engineered Human Airway Mucosa for Modelling Respiratory Infections: Characterisation and Applications}, doi = {10.25972/OPUS-32241}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322414}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Respiratory infections are a significant health concern worldwide, and the airway epithelium plays a crucial role in regulating airway function and modulating inflammatory processes. However, most studies on respiratory infections have used cell lines or animal models, which may not accurately reflect native physiological conditions, especially regarding human pathogens. We generated human nasal mucosa (hNM) and tracheobronchial mucosa (hTM) models to address this issue using primary human airway epithelial cells and fibroblasts. We characterised these human airway tissue models (hAM) using high speed video microscopy, single cell RNA sequencing, immunofluorescence staining, and ultrastructural analyses that revealed their complexity and cellular heterogeneity. We demonstrated that Bordetella pertussis virulence factor adenylate cyclase toxin (CyaA) elevated the intracellular production of cyclic adenosine monophosphate (cAMP) and secretion of interleukin (IL) 6, IL 8, and human beta defensin 2 (HBD2). In addition, we compared the responses of the tissue models from two different anatomical sites (the upper and lower respiratory mucosa) and are the first to report such differential susceptibility towards CyaA using 3D primary airway cell derivedmodels. The effect of toxin treatment on the epithelial barrier integrity of the tissue models was assessed by measuring the flux of fluorescein isothiocyanate (FITC)-conjugated dextran across the models. Though we observed a cell type specific response with respect to intracellular cAMP production and IL 6, IL 8, and HBD2 secretion in the models treated with CyaA on the apical side, the epithelial membrane barrier integrity was not compromised. In addition to toxin studies, using these characterised models, we established viral infection studies for Influenza A (IAV), Respiratory Syncytial Virus subtype B (RSV), and severe acute respiratory syndrome coronavirus 2. We visualised the morphological consequences of the viral infection using ultrastructural analysis and immunofluorescence. We verified the effective infection in hAM by measuring the viral RNA using RTqPCR and detected elevated cytokine levels in response to infection using biochemical assays. In contrast to cell lines, studies on viral infection using hAM demonstrated that infected areas were localized to specific regions. This led to the formation of infection hotspots, which were more likely to occur when models derived from different donors were infected separately with all three viruses. IAV infected tissue models replicate the clinical findings of H1N1 infection, such as mucus hypersecretion, cytokine release, and infection-associated epithelial cell damage.Finally, we paved the steps towards understanding the impact of IAV infection on disease models. We generated hTM from biopsies obtained from chronic obstructive pulmonary disease (COPD) patients. As a model to study the impact of COPD on respiratory infections, considering the increase in COPD cases in the past decade and the continued predicted increase in the future. We established the IAV infection protocol to capture the early infection signatures in non-COPD and COPD conditions using scRNA-seq. We investigated the infection kinetics of IAV (H1N1-clinical isolate) in hTM and found that viruses were actively released approximately 24 hours post infection. The scRNA-seq data from the hTM derived from non-COPD and COPD patients, revealed lower levels of SCGB1A1 (club cell marker) gene expression in the COPD-control group compared to the non-COPD control group, consistent with previous clinical studies. Furthermore, we observed that IAV infection elevated SCGB1A1 gene expression especially in secretory cells of both the COPD and non COPD groups. This may imply the role of club cells as early responders during IAV infection providing epithelial repair, regeneration, and resistance to spread of infection. This is the first study to address the molecular diversity in COPD and non-COPD disease models infected with IAV investigating the early response (6 h) of specific cell types in the human lower airways towards infection using scRNA-seq. These findings highlight the potential interplay between COPD, IAV infection, and altered vulnerability to other viral infections and respiratory illnesses making the hAM applicable for addressing more specific research questions and validating potential targets, such as SCGB1A1 targeted therapy for chronic lung diseases. Our findings demonstrate the potential of the hNM and hTM for investigating respiratory infections, innate immune responses, and trained immunity in non-immune cells. Our experiments show that hAM may represent a more accurate representation of the native physiological condition and improve our understanding of the disease mechanisms. Furthermore, these models promote non-animal research as they replicate clinical findings. We can further increase their complexity by incorporating dynamic flow systems and immune cells catered to the research question.}, subject = {Atemwege}, language = {en} } @article{OkudaLenzSeitzetal.2023, author = {Okuda, Takumi and Lenz, Ann-Kathrin and Seitz, Florian and Vogel, J{\"o}rg and H{\"o}bartner, Claudia}, title = {A SAM analogue-utilizing ribozyme for site-specific RNA alkylation in living cells}, series = {Nature Chemistry}, journal = {Nature Chemistry}, doi = {10.1038/s41557-023-01320-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-328762}, year = {2023}, abstract = {Post-transcriptional RNA modification methods are in high demand for site-specific RNA labelling and analysis of RNA functions. In vitro-selected ribozymes are attractive tools for RNA research and have the potential to overcome some of the limitations of chemoenzymatic approaches with repurposed methyltransferases. Here we report an alkyltransferase ribozyme that uses a synthetic, stabilized S-adenosylmethionine (SAM) analogue and catalyses the transfer of a propargyl group to a specific adenosine in the target RNA. Almost quantitative conversion was achieved within 1 h under a wide range of reaction conditions in vitro, including physiological magnesium ion concentrations. A genetically encoded version of the SAM analogue-utilizing ribozyme (SAMURI) was expressed in HEK293T cells, and intracellular propargylation of the target adenosine was confirmed by specific fluorescent labelling. SAMURI is a general tool for the site-specific installation of the smallest tag for azide-alkyne click chemistry, which can be further functionalized with fluorophores, affinity tags or other functional probes.}, language = {en} } @phdthesis{Jia2023, author = {Jia, Xiaoxi}, title = {Augmented Lagrangian Methods invoking (Proximal) Gradient-type Methods for (Composite) Structured Optimization Problems}, doi = {10.25972/OPUS-32374}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323745}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {This thesis, first, is devoted to the theoretical and numerical investigation of an augmented Lagrangian method for the solution of optimization problems with geometric constraints, subsequently, as well as constrained structured optimization problems featuring a composite objective function and set-membership constraints. It is then concerned to convergence and rate-of-convergence analysis of proximal gradient methods for the composite optimization problems in the presence of the Kurdyka--{\L}ojasiewicz property without global Lipschitz assumption.}, subject = {Optimierung}, language = {en} } @phdthesis{Krenzer2023, author = {Krenzer, Adrian}, title = {Machine learning to support physicians in endoscopic examinations with a focus on automatic polyp detection in images and videos}, doi = {10.25972/OPUS-31911}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319119}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Deep learning enables enormous progress in many computer vision-related tasks. Artificial Intel- ligence (AI) steadily yields new state-of-the-art results in the field of detection and classification. Thereby AI performance equals or exceeds human performance. Those achievements impacted many domains, including medical applications. One particular field of medical applications is gastroenterology. In gastroenterology, machine learning algorithms are used to assist examiners during interventions. One of the most critical concerns for gastroenterologists is the development of Colorectal Cancer (CRC), which is one of the leading causes of cancer-related deaths worldwide. Detecting polyps in screening colonoscopies is the essential procedure to prevent CRC. Thereby, the gastroenterologist uses an endoscope to screen the whole colon to find polyps during a colonoscopy. Polyps are mucosal growths that can vary in severity. This thesis supports gastroenterologists in their examinations with automated detection and clas- sification systems for polyps. The main contribution is a real-time polyp detection system. This system is ready to be installed in any gastroenterology practice worldwide using open-source soft- ware. The system achieves state-of-the-art detection results and is currently evaluated in a clinical trial in four different centers in Germany. The thesis presents two additional key contributions: One is a polyp detection system with ex- tended vision tested in an animal trial. Polyps often hide behind folds or in uninvestigated areas. Therefore, the polyp detection system with extended vision uses an endoscope assisted by two additional cameras to see behind those folds. If a polyp is detected, the endoscopist receives a vi- sual signal. While the detection system handles the additional two camera inputs, the endoscopist focuses on the main camera as usual. The second one are two polyp classification models, one for the classification based on shape (Paris) and the other on surface and texture (NBI International Colorectal Endoscopic (NICE) classification). Both classifications help the endoscopist with the treatment of and the decisions about the detected polyp. The key algorithms of the thesis achieve state-of-the-art performance. Outstandingly, the polyp detection system tested on a highly demanding video data set shows an F1 score of 90.25 \% while working in real-time. The results exceed all real-time systems in the literature. Furthermore, the first preliminary results of the clinical trial of the polyp detection system suggest a high Adenoma Detection Rate (ADR). In the preliminary study, all polyps were detected by the polyp detection system, and the system achieved a high usability score of 96.3 (max 100). The Paris classification model achieved an F1 score of 89.35 \% which is state-of-the-art. The NICE classification model achieved an F1 score of 81.13 \%. Furthermore, a large data set for polyp detection and classification was created during this thesis. Therefore a fast and robust annotation system called Fast Colonoscopy Annotation Tool (FastCAT) was developed. The system simplifies the annotation process for gastroenterologists. Thereby the i gastroenterologists only annotate key parts of the endoscopic video. Afterward, those video parts are pre-labeled by a polyp detection AI to speed up the process. After the AI has pre-labeled the frames, non-experts correct and finish the annotation. This annotation process is fast and ensures high quality. FastCAT reduces the overall workload of the gastroenterologist on average by a factor of 20 compared to an open-source state-of-art annotation tool.}, subject = {Deep Learning}, language = {en} } @article{BruennertSeupelGoyaletal.2023, author = {Br{\"u}nnert, Daniela and Seupel, Raina and Goyal, Pankaj and Bach, Matthias and Schraud, Heike and Kirner, Stefanie and K{\"o}ster, Eva and Feineis, Doris and Bargou, Ralf C. and Schlosser, Andreas and Bringmann, Gerhard and Chatterjee, Manik}, title = {Ancistrocladinium A induces apoptosis in proteasome inhibitor-resistant multiple myeloma cells: a promising therapeutic agent candidate}, series = {Pharmaceuticals}, volume = {16}, journal = {Pharmaceuticals}, number = {8}, issn = {1424-8247}, doi = {10.3390/ph16081181}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362887}, year = {2023}, abstract = {The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI) resistance, and in primary MM cells, but not in non-malignant blood cells. Concomitant treatment with the PI carfilzomib or the histone deacetylase inhibitor panobinostat strongly enhanced the ancistrocladinium A-induced apoptosis. Mass spectrometry with biotinylated ancistrocladinium A revealed significant enrichment of RNA-splicing-associated proteins. Affected RNA-splicing-associated pathways included genes involved in proteotoxic stress response, such as PSMB5-associated genes and the heat shock proteins HSP90 and HSP70. Furthermore, we found strong induction of ATF4 and the ATM/H2AX pathway, both of which are critically involved in the integrated cellular response following proteotoxic and oxidative stress. Taken together, our data indicate that ancistrocladinium A targets cellular stress regulation in MM and improves the therapeutic response to PIs or overcomes PI resistance, and thus may represent a promising potential therapeutic agent.}, language = {en} } @article{BucheltBloetheKuenzeretal.2023, author = {Buchelt, Sebastian and Bl{\"o}the, Jan Henrik and Kuenzer, Claudia and Schmitt, Andreas and Ullmann, Tobias and Philipp, Marius and Kneisel, Christof}, title = {Deciphering small-scale seasonal surface dynamics of rock glaciers in the Central European Alps using DInSAR time series}, series = {Remote Sensing}, volume = {15}, journal = {Remote Sensing}, number = {12}, issn = {2072-4292}, doi = {10.3390/rs15122982}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362939}, year = {2023}, abstract = {The Essential Climate Variable (ECV) Permafrost is currently undergoing strong changes due to rising ground and air temperatures. Surface movement, forming characteristic landforms such as rock glaciers, is one key indicator for mountain permafrost. Monitoring this movement can indicate ongoing changes in permafrost; therefore, rock glacier velocity (RGV) has recently been added as an ECV product. Despite the increased understanding of rock glacier dynamics in recent years, most observations are either limited in terms of the spatial coverage or temporal resolution. According to recent studies, Sentinel-1 (C-band) Differential SAR Interferometry (DInSAR) has potential for monitoring RGVs at high spatial and temporal resolutions. However, the suitability of DInSAR for the detection of heterogeneous small-scale spatial patterns of rock glacier velocities was never at the center of these studies. We address this shortcoming by generating and analyzing Sentinel-1 DInSAR time series over five years to detect small-scale displacement patterns of five high alpine permafrost environments located in the Central European Alps on a weekly basis at a range of a few millimeters. Our approach is based on a semi-automated procedure using open-source programs (SNAP, pyrate) and provides East-West displacement and elevation change with a ground sampling distance of 5 m. Comparison with annual movement derived from orthophotos and unpiloted aerial vehicle (UAV) data shows that DInSAR covers about one third of the total movement, which represents the proportion of the year suited for DInSAR, and shows good spatial agreement (Pearson R: 0.42-0.74, RMSE: 4.7-11.6 cm/a) except for areas with phase unwrapping errors. Moreover, the DInSAR time series unveils spatio-temporal variations and distinct seasonal movement dynamics related to different drivers and processes as well as internal structures. Combining our approach with in situ observations could help to achieve a more holistic understanding of rock glacier dynamics and to assess the future evolution of permafrost under changing climatic conditions.}, language = {en} } @article{WinterSchulzSchmitteretal.2023, author = {Winter, Anna and Schulz, Stefan M. and Schmitter, Marc and M{\"u}ller-Richter, Urs and K{\"u}bler, Alexander and Kasper, Sylvia and Hartmann, Stefan}, title = {Comprehensive geriatric assessment and quality of life aspects in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)}, series = {Journal of Clinical Medicine}, volume = {12}, journal = {Journal of Clinical Medicine}, number = {17}, issn = {2077-0383}, doi = {10.3390/jcm12175738}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363096}, year = {2023}, abstract = {To define frailty in older cancer patients, the aim of this study was to assess the geriatric status and quality of life (QoL) aspects in patients suffering from recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC) under palliative treatment. A comprehensive geriatric assessment (CGA) was performed on 21 r/m HNSCC patients at two defined assessments, and the QoL aspects and the impact of descriptive data were evaluated. The Kolmogorov-Smirnov test, Spearman's rho correlation, and two-way mixed ANOVA were used for statistical analysis. All patients were found to be "frail". Pain, fatigue, and the burden of illness were the highest-rated symptoms. Oral function and orofacial appearance were highly impaired. A significant impact of descriptive data on the CGA and QoL results was found (all p ≤ 0.05). Thus, the CGA results revealed high frailty, severe comorbidities, and high impairments in QoL aspects. The CGA and QoL results were negatively affected by the primary HNSCC treatment approach, the need for prosthetic treatment, and worse oral functional capacity. Therefore, frailty in r/m HNSCC patients seems to be multidimensional. The evaluation of the CGA and QoL aspects in r/m HNSCC patients can be recommended to detect special needs, organize aftercare, and improve the support for frail and vulnerable cancer patients to create a multidisciplinary treatment approach.}, language = {en} } @article{HellerReiterLeichtetal.2023, author = {Heller, Bianca and Reiter, Florian P. and Leicht, Hans Benno and Fiessler, Cornelia and Bergheim, Ina and Heuschmann, Peter U. and Geier, Andreas and Rau, Monika}, title = {Salt-intake-related behavior varies between sexes and is strongly associated with daily salt consumption in obese patients at high risk for MASLD}, series = {Nutrients}, volume = {15}, journal = {Nutrients}, number = {18}, issn = {2072-6643}, doi = {10.3390/nu15183942}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363107}, year = {2023}, abstract = {Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) imposes a significant burden on Westernized regions. The Western diet, high in salt intake, significantly contributes to disease development. However, there are a lack of data on salt literacy and salt intake among MASLD patients in Germany. Our study aims to analyze daily salt intake and salt-intake-related behavior in MASLD patients. Methods: 234 MASLD patients were prospectively included. Daily salt intake and salt-intake-related behavior were assessed via a food frequency questionnaire (FFQ—DEGS) and a salt questionnaire (SINU). Statistical analyses were performed using SPSS. Results: Mean daily salt intake was higher in men than in women (7.3 ± 5 g/d vs. 5.3 ± 4 g/d; p \< 0.001). There was significant agreement between increased daily salt intake (6 g/d) and the behavioral salt index (SI) (p \< 0.001). Men exhibited higher SI scores compared to women, indicating lower awareness of salt in everyday life. Multivariate analysis identified specific salt-intake-related behaviors impacting daily salt consumption. Conclusions: Our study reveals a strong link between daily salt intake and salt-intake-related behavior, highlighting sex-specific differences in an MASLD cohort. To enhance patient care in high-cardiovascular-risk populations, specific behavioral approaches may be considered, including salt awareness, to improve adherence to lifestyle changes, particularly in male patients.}, language = {en} } @article{HartmannKnierimMaureretal.2023, author = {Hartmann, Nico and Knierim, Maria and Maurer, Wiebke and Dybkova, Nataliya and Hasenfuß, Gerd and Sossalla, Samuel and Streckfuss-B{\"o}meke, Katrin}, title = {Molecular and functional relevance of Na\(_V\)1.8-induced atrial arrhythmogenic triggers in a human SCN10A knock-out stem cell model}, series = {International Journal of Molecular Sciences}, volume = {24}, journal = {International Journal of Molecular Sciences}, number = {12}, issn = {1422-0067}, doi = {10.3390/ijms241210189}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362708}, year = {2023}, abstract = {In heart failure and atrial fibrillation, a persistent Na\(^+\) current (I\(_{NaL}\)) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that Na\(_V\)1.8 contributes to arrhythmogenesis by inducing a I\(_{NaL}\). Genome-wide association studies indicate that mutations in the SCN10A gene (Na\(_V\)1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these Na\(_V\)1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial SCN10A-KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the I\(_{NaL}\) and action potential duration. Ca\(^{2+}\) measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca\(^{2+}\) leak. The I\(_{NaL}\) was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of Na\(_V\)1.8. No effects on atrial APD\(_{90}\) were detected in any groups. Both SCN10A KO and specific blockers of Na\(_V\)1.8 led to decreased Ca\(^{2+}\) spark frequency and a significant reduction of arrhythmogenic Ca\(^{2+}\) waves. Our experiments demonstrate that Na\(_V\)1.8 contributes to I\(_{NaL}\) formation in human atrial CMs and that Na\(_V\)1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore Na\(_V\)1.8 could be a new target for antiarrhythmic strategies.}, language = {en} } @article{EwaldFuchsBoegeleinetal.2023, author = {Ewald, Andrea and Fuchs, Andreas and Boegelein, Lasse and Grunz, Jan-Peter and Kneist, Karl and Gbureck, Uwe and Hoelscher-Doht, Stefanie}, title = {Degradation and bone-contact biocompatibility of two drillable magnesium phosphate bone cements in an in vivo rabbit bone defect model}, series = {Materials}, volume = {16}, journal = {Materials}, number = {13}, issn = {1996-1944}, doi = {10.3390/ma16134650}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362824}, year = {2023}, abstract = {The use of bone-cement-enforced osteosynthesis is a growing topic in trauma surgery. In this context, drillability is a desirable feature for cements that can improve fracture stability, which most of the available cement systems lack. Therefore, in this study, we evaluated a resorbable and drillable magnesium-phosphate (MgP)-based cement paste considering degradation behavior and biocompatibility in vivo. Two different magnesium-phosphate-based cement (MPC) pastes with different amounts of phytic acid (IP 6) as setting retarder (MPC 22.5 and MPC 25) were implanted in an orthotopic defect model of the lateral femoral condyle of New Zealand white rabbits for 6 weeks. After explantation, their resorption behavior and material characteristics were evaluated by means of X-ray diffraction (XRD), porosimetry measurement, histological staining, peripheral quantitative computed tomography (pQCT), cone-beam computed tomography (CBCT) and biomechanical load-to-failure tests. Both cement pastes displayed comparable results in mechanical strength and resorption kinetics. Bone-contact biocompatibility was excellent without any signs of inflammation. Initial resorption and bone remodeling could be observed. MPC pastes with IP 6 as setting retardant have the potential to be a valuable alternative in distinct fracture patterns. Drillability, promising resorption potential and high mechanical strength confirm their suitability for use in clinical routine.}, language = {en} } @article{HeinzWildEidmannetal.2023, author = {Heinz, Tizian and Wild, Moritz and Eidmann, Annette and Weißenberger, Manuel and Rak, Dominik and Nedopil, Alexander Johannes and Rudert, Maximilian and Stratos, Ioannis}, title = {Impact of COVID-19 on fracture incidence in germany: a comparative age and gender analysis of pre- and post-outbreak periods}, series = {Healthcare}, volume = {11}, journal = {Healthcare}, number = {15}, issn = {2227-9032}, doi = {10.3390/healthcare11152139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362686}, year = {2023}, abstract = {In March 2020, Germany imposed a nationwide lockdown to curb the spread of COVID-19, prompting questions about the impact on the incidence of common fractures. This study examined 15 fracture types in pre-outbreak (2010-2019) and post-outbreak (2020-2021) periods, using data categorized by age (18-64 years, 65 years) and sex (male, female). Linear regression assessed annual growth rates, and mean fracture numbers were compared across periods for significant differences. Results indicated a positive correlation between fracture incidence rates and time for various types, such as cervical, thoracic, lumbar, and pelvic spine fractures, rib fractures, femoral neck, pertrochanteric femur, femoral shaft, and ankle fractures. Frequencies of proximal humerus, distal radius, femoral neck, pertrochanteric femur, femoral shaft, and ankle fractures in 2020 and 2021 were within predicted ranges from previous years. However, rib fractures and spinal fractures (cervical, thoracic, lumbar, and pelvic spine) occurred less frequently during this time. Notably, this study found a consistent decline in most fracture types for individuals aged 18-64 after the pandemic's onset, while the fracture incidence of hip fractures, often referred to as fragility fractures, for those over 65 remained unchanged. Fibula fractures showed the most considerable decrease in both age groups. In conclusion, the COVID-19 pandemic substantially impacted fracture incidence, with lower rates among individuals under 65 and unchanged fragility fractures in the elderly population.}, language = {en} } @article{EidmannHeinzOberfeldetal.2023, author = {Eidmann, Annette and Heinz, Tizian and Oberfeld, Jan and Weißenberger, Manuel and Rudert, Maximilian and Stratos, Ioannis}, title = {Epidemiology and trends in cartilage surgery of the foot and ankle in Germany: an analysis of national healthcare billing and reporting data from 2006 to 2020}, series = {Medicina}, volume = {59}, journal = {Medicina}, number = {7}, issn = {1648-9144}, doi = {10.3390/medicina59071256}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362835}, year = {2023}, abstract = {Background and objectives: Cartilage surgery constitutes a standard intervention in foot and ankle procedures. Currently, there is a lack of epidemiological data on its frequency, age distribution, and surgical options for cartilage surgery. This study aimed to investigate the current landscape of cartilage surgery in Germany and identify the most common procedures from an epidemiological standpoint. Materials and methods: Medical billing and reporting data from the Federal Statistical Office of Germany, encompassing the period 2006-2020, was examined, including all foot and ankle cartilage surgical procedures (summarized under OPS codes 5-812 and 5-801). The dataset incorporated information on the affected joint, patient age and sex, and surgery type. Each surgical procedure was categorized as "debridement", "regeneration" or "refixation". Linear and nonlinear regression analyses were employed, with a statistical significance threshold of 0.05. Results: From the total of 136,501 procedures conducted during the study period, the most frequently performed interventions were microfracture (58,252) and chondroplasty (56,135), and thus, debridement procedures were in the leading position. The use of acellular membranes was the most used regenerative technique (n = 11,414). At the ankle joint, interventions were mostly arthroscopic and in men, while foot cartilage surgeries were preferably performed via open surgery and mostly in women. Age distribution analysis revealed two primary peaks: the first in the 20-25-year-old group (ankle and foot) and the second in the 45-50-year-old group (ankle) and 55-60-year-old group (foot). Refixation and regenerative procedures were more frequent among younger individuals, while debriding procedures were more frequent among older individuals. Regenerative procedures, particularly in the ankle, significantly increased over time. Conclusions: Cartilage surgery of the foot and ankle was common, with two primary age groups predominantly affected. Notably, recent years have witnessed a considerable rise in cartilage regenerative procedures.}, language = {en} } @article{BuchmannBaumannMengetal.2023, author = {Buchmann, J. and Baumann, N. and Meng, K. and Semrau, J. and Kuhl, J. and Pfeifer, K. and Vogel, H. and Faller, H.}, title = {Volitional Action Control and Depression in Chronic Pain: Does Action versus State Orientation Moderate the Relations of Pain-Related Cognitions to Depression?}, series = {Current Psychology}, volume = {42}, journal = {Current Psychology}, issn = {1046-1310}, doi = {10.1007/s12144-021-01914-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308508}, pages = {7591-7608}, year = {2023}, abstract = {In this study, we examined the conditional indirect and direct relations of pain-related cognitions to depression. Subjective helplessness was included as presumably mediating the relations of catastrophizing and thought suppression to depression due to motivational deficits. In addition, moderating effects of dispositional action versus state orientation were analyzed, whereby state orientation indicates volitional deficits in coping with distress. The study was based on self-report data from 536 patients with chronic non-specific low back pain at the beginning of inpatient rehabilitation. Moderated mediation analyses were performed. The indirect catastrophizing- and thought suppression-depression relations were (partially) mediated by subjective helplessness; and moderated by failure-related action versus state orientation. Moreover, action versus state orientation moderated the direct relation of thought suppression to depression. Results suggest that catastrophizing, thought suppression, and subjective helplessness do not lead to depression unless associated with self-regulatory inability (i.e., state orientation). In contrast, action-oriented patients more effectively self-regulate pain-related emotions, disengage from rumination, and distract from pain and thus better avoid the debilitating effects of negative pain-related cognitions on depression. Future research and treatment may more strongly focus on the role of motivational and volitional deficits underlying learned helplessness and depression in chronic pain.}, language = {en} } @article{StichtWeinreich2023, author = {Sticht, Oliver and Weinreich, Melina}, title = {Obdach, Speisung und Heilung. Zur Geschichte des Seelhauses an der Juliuspromenade in W{\"u}rzburg}, series = {W{\"u}rzburger Di{\"o}zesangeschichtsbl{\"a}tter}, volume = {86}, journal = {W{\"u}rzburger Di{\"o}zesangeschichtsbl{\"a}tter}, issn = {0342-3093}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-361319}, pages = {359-375}, year = {2023}, abstract = {Das 1379 gestiftete Seelhaus befindet sich seit 1587 an der heutigen Juliuspromenade in W{\"u}rzburg. Urspr{\"u}nglich zur Beherbergung bed{\"u}rftiger Reisender eingerichtet, entwickelte es sich seit dem 17. Jahrhundert zum Alterssitz f{\"u}r M{\"a}gde und Hausangestellte, bevor es im 19. Jahrhundert ganz aufgel{\"o}st wurde. Durch den Kauf der Hausnummern 9-11 durch die Oberzeller Schwestern 1927 erlebte sein karitativer Auftrag bis zur Zerst{\"o}rung am 16. M{\"a}rz 1945 eine Wiederbelebung.}, subject = {Seelhaus W{\"u}rzburg}, language = {de} } @phdthesis{Engelmann2023, author = {Engelmann, Daria Marie}, title = {Regulation of Mammalian Phosphoglycolate Phosphatase}, doi = {10.25972/OPUS-19957}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199577}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Mammalian phoshoglycolate phosphatase (PGP, also known as AUM) belongs to the ubiquitous HAD superfamily of phosphatases. As several other members of HAD phosphatases, the Mg2+-dependent dephosphorylation is conducted via a nucleophilic attack from a conserved aspartate residue in the catalytic cleft. The protein structure of PGP could not yet be solved entirely. Only a hybrid consisting of the PGP cap and the PDXP core (pyridoxal phosphatase, closest enzyme paralog) was crystallizable so far. PGP is able to efficiently dephosphorylate 2-phosphoglycolate, 2-phospho-L-lactate, 4-phospho-D-erythronate, and glycerol-3-phosphate in vitro which makes them likely physiological substrates. The first three substrates can be derived from metabolic side reactions (during glycolysis) and inhibit key enzymes in glycolysis and pentose phosphate pathway, the latter is situated at the intersection between glycolysis and lipogenesis. 2-phosphoglycolate can also be released in the context of repair of oxidative DNA damage. The activity of purified PGP can be reversibly inhibited by oxidation - physiologically likely in association with epidermal growth factor (EGF) signal transduction. In fact, an association between persistently lacking PGP activity (via downregulation) and the presence of hyperphosphorylated proteins after EGF stimulation has been identified. Reversible oxidation and transient inactivation of PGP may be particularly important for short-term and feedback regulatory mechanisms (as part of the EGF signaling). Furthermore, cellular proliferation in PGP downregulated cells is constantly reduced. Whole-body PGP inactivation in mice is embryonically lethal. Despite the many well-known features and functions, the knowledge about PGP is still incomplete. In the present work the influence of reactive oxygen species (ROS) on PGP activity in cells und a possible connection between oxidative stress and the proliferation deficit of PGP downregulated cells was investigated. For the experiments, a spermatogonial cell line was used (due to the high PGP expression in testis). PGP activity can be reversibly inhibited in cellular lysates by H2O2 (as a ROS representative). Reversible oxidation could thus indeed be physiologically important. More oxidative DNA damage (by bleomycin) showed no PGP-dependent effects here. EGF stimulation (as an inducer of transient and well-controlled ROS production), low concentrations of menadione (as an oxidant) and N-acetylcysteine (as an antioxidant) were able to approximate the proliferation rate in PGP downregulated cells to that of control cells. The redox regulation of PGP could thus have an influence on cellular proliferation as a feedback mechanism - a mechanism that could not take place in PGP downregulated cells. However, the connections are probably even more complex and cannot be elucidated by a sole examination of the proliferation rate. The present results can thus only be regarded as preliminary experiments. For a better understanding of the features and functions of PGP, this work then focused on specific regulation of enzyme activity by pharmacologically applicable small molecules. Four potent inhibitors had previously been identified in a screening campaign. In this work, three of these four inhibiting compounds could be further characterized in experiments with highly purified, recombinant murine and human PGP. Compounds \#2 and \#9 showed competitive inhibition properties with a markedly rising KM value with little or no change in vmax. The results were consistent for all tested protein variants: the murine and the human PGP as well as a PGP/PDXP hybrid protein. Compound \#1 was the most potent and interesting PGP-inhibitory molecule: less change in KM and a constant decrease in vmax as well as a lower impact on the PGP/PDXP hybrid hint at a mixed mode of inhibition as a combination of competitive and non-competitive inhibition. The characterization of the potential inhibitors can serve as a basis for further structural analysis and studies on the complex physiological role of PGP.}, subject = {Phosphoglykolatphosphatase}, language = {en} } @phdthesis{Behnke2023, author = {Behnke, Jennifer Kim}, title = {Charakterisierung der Krankheitsprogression im genetischen hm\(^2\)α-SYN-39 Mausmodell des Morbus Parkinson}, doi = {10.25972/OPUS-30204}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-302040}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {In dieser Arbeit wurde die Krankheitsprogression im Parkinson-Mausmodell hm2α-SYN-39 mit zunehmendem Alter charakterisiert. Die M{\"a}use wurden in 4 Altersgruppen (2-3, 7-8, 11-12, 16-17 Monate) mit motorischen Verhaltenstests auf einen Parkinson-Ph{\"a}notyp untersucht. Zudem erfolgten Untersuchungen des dopaminergen Systems zur Detektion von neurochemischen Ver{\"a}nderungen und einer Neurodegeneration im nigrostriatalen Trakt. Weiterhin wurden neuroinflammatorische Prozesse des adaptiven und angeborenen IS in der SN und im Striatum mittels immunhistochemischer F{\"a}rbungen beurteilt. Ein Parkinson-Ph{\"a}notyp in diesem Mausmodell zeigte sich nur leicht ausgepr{\"a}gt, sodass der Rotarod- und Zylinder-Test lediglich den Hinweis auf eine nicht-signifikante Einschr{\"a}nkung der Motorik erbrachte. Dennoch ergab die stereologische Quantifizierung TH- und Nissl-positiver Zellen in der SNpc der hm2α-SYN-39 M{\"a}use eine altersabh{\"a}ngige, signifikant-progrediente Reduktion der dopaminergen Neurone mit zunehmendem Alter. Eine signifikant niedrigere TH-positive Zellzahl dieser tg M{\"a}use zeigte sich ab einem Alter von 16-17 Monaten verglichen zu gleichaltrigen wt Tieren. Dagegen war die Neurodegeneration im Striatum etwas weniger ausgepr{\"a}gt. Die tg M{\"a}use pr{\"a}sentierten im Alter von 16-17 Monaten eine nicht-signifikante Erniedrigung der dopaminergen Terminalen verglichen zu gleichaltrigen wt Tieren. Ein DA-Mangel im Striatum der tg M{\"a}use konnte mittels HPLC best{\"a}tigt werden. Bis zum Alter von 16-17 Monaten wurde eine signifikante Reduktion der DA-Level von 23,2 \% verglichen zu gleichaltrigen wt M{\"a}usen gezeigt. Außerdem erniedrigt waren die striatalen Level von NA und 5-HAT bei tg M{\"a}usen, passend zu den bisherigen Ergebnissen bei Parkinson-Patienten. Immunhistochemische Untersuchungen einer Neuroinflammation im nigrostriatalen Trakt ergaben eine tendenziell erh{\"o}hte Infiltration von CD4- und CD8-positiven T-Zellen bei hm2α-SYN-39 M{\"a}usen mit zunehmendem Alter, wobei die Infiltration CD8-positiver Zellen ausgepr{\"a}gter war als bei CD4-positiven Zellen. Eine noch deutlichere neuroinflammatorische Reaktion zeigte das angeborene IS. Hierbei ergab die immunhistologische Quantifizierung CD11b-positiver mikroglialer Zellen einen hochsignifikanten Anstieg im nigrostriatalen Trakt bei hm2α-SYN-39 M{\"a}usen schon im jungen Alter. Zusammenfassend pr{\"a}sentierte dieses Parkinson-Mausmodell eine langsam-progrediente Parkinson-Pathologie mit begleitender Neuroinflammation im nigrostriatalen Trakt w{\"a}hrend des Alterns, wobei die Immunantwort der mikroglialen Zellen zu einem fr{\"u}heren Zeitpunkt einsetzte als die T-Zellinfiltration und Neurodegeneration. Dieses Mausmodell bietet zahlreiche M{\"o}glichkeiten zur zuk{\"u}nftigen Erforschung der Pathophysiologie beim MP. Generell weist diese Arbeit auf eine bedeutende Rolle neuroinflammatorischer Prozesse in der Krankheitsprogression der Parkinsonerkrankung hin und soll dazu ermutigen Neuroinflammation durchaus intensiver in tg Tiermodellen zu untersuchen.}, subject = {Parkinson-Krankheit}, language = {de} } @phdthesis{Jovic2023, author = {Jovic, Sebastian}, title = {Die Healing Response Technik - langfristige Ergebnisse nach Anmeißelung des vorderen Kreuzbandes bei Partialrupturen}, doi = {10.25972/OPUS-29904}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299040}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Minimalinvasive Behandlungsmethoden von Partialrupturen des VKBs wurden seit den 1990 er Jahren diskutiert. Erstmalige Ergebnisse ver{\"o}ffentlichte Richard Steadman 2006 und stellte diese Methode als Alternative zur Kreuzbandersatzplastik vor (Steadman, 2006). Ziel dieser Arbeit war es zu untersuchen, ob die Healing Response Technik eine suffiziente, langfristige Therapieoption bei Partialrupturen des VKBs ist. Bei der Healing Response Technik wird arthroskopisch das verletzte VKB auf seine Stabilit{\"a}t untersucht und die Ruptur anschließend klassifiziert. Bei einer Partialruptur wird der proximale Ansatz des VKBs angemeißelt. Dadurch kommt es zu reaktiven Einblutungen, Einsprossen von mesenchymalen Stammzellen und Wachstumsfaktoren. Erfolgt eine suffiziente Vernarbung kann eine Stabilisierung des VKBs erzielt werden. Das Patientenkollektiv wurde in einem Zeitraum von 2005-2010 im Sporthopaedicum in Straubing mittels Healing Response Technik operativ versorgt. Einschlusskriterien waren ein stattgehabtes Trauma, eine kernspintomografisch beschriebene Ruptur oder Partialruptur des VKB, ein positiver Lachman-Test mit unsicherem oder vorhandenem Anschlag, ein maximal einfach positiver Pivot Shift Test, sowie eine subjektive Instabilit{\"a}t. Es wurden 163 Patienten eingeschlossen. Das initiale Nachuntersuchungsintervall betrug 4,5 Jahre. Die Langzeitergebnisse wurden mittels Mixed-Mode-Befragung mit einem Follow up von 11,4 Jahren erfasst. Insgesamt konnten so 138 Patienten nachuntersucht werden. Die Differenz der Roliometer Messung konnte von pr{\"a}operativ 10 ± 2 mm auf postoperativ 7 ± 2 mm signifikant verbessert werden. Der postoperative Lyshom Score betrug 90 ±12 Punkte. Der Tegner Activity Score lag bei 5 ± 2. Im Langzeitfollow-up betrug die Revisionsrate 13\% mit einem Revisionszeitpunkt von 51 ± 30 Monaten. 8\% der befragten Patienten erlitten eine Reruptur. 93\% der Patienten beurteilten ihr Kniegelenk subjektiv als stabil. Somit stellt die Healing Response Technik unter Ber{\"u}cksichtigung der Einschlusskriterien und der intraoperativen Befunderhebung eine suffiziente Therapieoption f{\"u}r Partialrupturen des VKBs dar.}, subject = {Kreuzband}, language = {de} } @phdthesis{Steininger2023, author = {Steininger, Michael}, title = {Deep Learning for Geospatial Environmental Regression}, doi = {10.25972/OPUS-31312}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313121}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Environmental issues have emerged especially since humans burned fossil fuels, which led to air pollution and climate change that harm the environment. These issues' substantial consequences evoked strong efforts towards assessing the state of our environment. Various environmental machine learning (ML) tasks aid these efforts. These tasks concern environmental data but are common ML tasks otherwise, i.e., datasets are split (training, validatition, test), hyperparameters are optimized on validation data, and test set metrics measure a model's generalizability. This work focuses on the following environmental ML tasks: Regarding air pollution, land use regression (LUR) estimates air pollutant concentrations at locations where no measurements are available based on measured locations and each location's land use (e.g., industry, streets). For LUR, this work uses data from London (modeled) and Zurich (measured). Concerning climate change, a common ML task is model output statistics (MOS), where a climate model's output for a study area is altered to better fit Earth observations and provide more accurate climate data. This work uses the regional climate model (RCM) REMO and Earth observations from the E-OBS dataset for MOS. Another task regarding climate is grain size distribution interpolation where soil properties at locations without measurements are estimated based on the few measured locations. This can provide climate models with soil information, that is important for hydrology. For this task, data from Lower Franconia is used. Such environmental ML tasks commonly have a number of properties: (i) geospatiality, i.e., their data refers to locations relative to the Earth's surface. (ii) The environmental variables to estimate or predict are usually continuous. (iii) Data can be imbalanced due to relatively rare extreme events (e.g., extreme precipitation). (iv) Multiple related potential target variables can be available per location, since measurement devices often contain different sensors. (v) Labels are spatially often only sparsely available since conducting measurements at all locations of interest is usually infeasible. These properties present challenges but also opportunities when designing ML methods for such tasks. In the past, environmental ML tasks have been tackled with conventional ML methods, such as linear regression or random forests (RFs). However, the field of ML has made tremendous leaps beyond these classic models through deep learning (DL). In DL, models use multiple layers of neurons, producing increasingly higher-level feature representations with growing layer depth. DL has made previously infeasible ML tasks feasible, improved the performance for many tasks in comparison to existing ML models significantly, and eliminated the need for manual feature engineering in some domains due to its ability to learn features from raw data. To harness these advantages for environmental domains it is promising to develop novel DL methods for environmental ML tasks. This thesis presents methods for dealing with special challenges and exploiting opportunities inherent to environmental ML tasks in conjunction with DL. To this end, the proposed methods explore the following techniques: (i) Convolutions as in convolutional neural networks (CNNs) to exploit reoccurring spatial patterns in geospatial data. (ii) Posing the problems as regression tasks to estimate the continuous variables. (iii) Density-based weighting to improve estimation performance for rare and extreme events. (iv) Multi-task learning to make use of multiple related target variables. (v) Semi-supervised learning to cope with label sparsity. Using these techniques, this thesis considers four research questions: (i) Can air pollution be estimated without manual feature engineering? This is answered positively by the introduction of the CNN-based LUR model MapLUR as well as the off-the-shelf LUR solution OpenLUR. (ii) Can colocated pollution data improve spatial air pollution models? Multi-task learning for LUR is developed for this, showing potential for improvements with colocated data. (iii) Can DL models improve the quality of climate model outputs? The proposed DL climate MOS architecture ConvMOS demonstrates this. Additionally, semi-supervised training of multilayer perceptrons (MLPs) for grain size distribution interpolation is presented, which can provide improved input data. (iv) Can DL models be taught to better estimate climate extremes? To this end, density-based weighting for imbalanced regression (DenseLoss) is proposed and applied to the DL architecture ConvMOS, improving climate extremes estimation. These methods show how especially DL techniques can be developed for environmental ML tasks with their special characteristics in mind. This allows for better models than previously possible with conventional ML, leading to more accurate assessment and better understanding of the state of our environment.}, subject = {Deep learning}, language = {en} } @phdthesis{Eismann2023, author = {Eismann, Simon}, title = {Performance Engineering of Serverless Applications and Platforms}, doi = {10.25972/OPUS-30313}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303134}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Serverless computing is an emerging cloud computing paradigm that offers a highlevel application programming model with utilization-based billing. It enables the deployment of cloud applications without managing the underlying resources or worrying about other operational aspects. Function-as-a-Service (FaaS) platforms implement serverless computing by allowing developers to execute code on-demand in response to events with continuous scaling while having to pay only for the time used with sub-second metering. Cloud providers have further introduced many fully managed services for databases, messaging buses, and storage that also implement a serverless computing model. Applications composed of these fully managed services and FaaS functions are quickly gaining popularity in both industry and in academia. However, due to this rapid adoption, much information surrounding serverless computing is inconsistent and often outdated as the serverless paradigm evolves. This makes the performance engineering of serverless applications and platforms challenging, as there are many open questions, such as: What types of applications is serverless computing well suited for, and what are its limitations? How should serverless applications be designed, configured, and implemented? Which design decisions impact the performance properties of serverless platforms and how can they be optimized? These and many other open questions can be traced back to an inconsistent understanding of serverless applications and platforms, which could present a major roadblock in the adoption of serverless computing. In this thesis, we address the lack of performance knowledge surrounding serverless applications and platforms from multiple angles: we conduct empirical studies to further the understanding of serverless applications and platforms, we introduce automated optimization methods that simplify the operation of serverless applications, and we enable the analysis of design tradeoffs of serverless platforms by extending white-box performance modeling.}, subject = {Leistungsbewertung}, language = {en} } @phdthesis{Wagner2023, author = {Wagner, Jan Cetric}, title = {Maximalnetzplan zur reaktiven Steuerung von Produktionsabl{\"a}ufen}, isbn = {978-3-945459-43-0}, doi = {10.25972/OPUS-30545}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305452}, school = {Universit{\"a}t W{\"u}rzburg}, pages = {182}, year = {2023}, abstract = {In produzierenden Unternehmen werden verschiedene Vorgehensweisen zur Planung, {\"U}berwachung und Steuerung von Produktionsabl{\"a}ufen eingesetzt. Einer dieser Methoden wird als Vorgangsknotennetzplantechnik bezeichnet. Die einzelnen Produktionsschritte werden als Knoten definiert und durch Pfeile miteinander verbunden. Die Pfeile stellen die Beziehungen der jeweiligen Vorg{\"a}nge zueinander und damit den Produktionsablauf dar. Diese Technik erlaubt den Anwendern einen umfassenden {\"U}berblick {\"u}ber die einzelnen Prozessrelationen. Zus{\"a}tzlich k{\"o}nnen mit ihr Vorgangszeiten und Produktfertigstellungszeiten ermittelt werden, wodurch eine ausf{\"u}hrliche Planung der Produktion erm{\"o}glicht wird. Ein Nachteil dieser Technik begr{\"u}ndet sich in der alleinigen Darstellung einer ausf{\"u}hrbaren Prozessabfolge. Im Falle eines St{\"o}rungseintritts mit der Folge eines nicht durchf{\"u}hrbaren Vorgangs muss von dem origin{\"a}ren Prozess abgewichen werden. Aufgrund dessen wird eine Neuplanung erforderlich. Es werden Alternativen f{\"u}r den gest{\"o}rten Vorgang ben{\"o}tigt, um eine Fortf{\"u}hrung des Prozesses ungeachtet der St{\"o}rung zu erreichen. Innerhalb dieser Arbeit wird daher eine Erweiterung der Vorgangsknotennetzplantechnik beschrieben, die es erlaubt, erg{\"a}nzend zu dem geplanten Soll-Prozess Alternativvorg{\"a}nge f{\"u}r einzelne Vorg{\"a}nge darzulegen. Diese Methode wird als Maximalnetzplan bezeichnet. Die Alternativen werden im Falle eines St{\"o}rungseintritts automatisch evaluiert und dem Anwender in priorisierter Reihenfolge pr{\"a}sentiert. Durch die Verwendung des Maximalnetzplans kann eine aufwendige Neuplanung vermieden werden. Als Anwendungsbeispiel dient ein Montageprozess, mithilfe dessen die Verwendbarkeit der Methode dargelegt wird. Weiterf{\"u}hrend zeigt eine zeitliche Analyse zufallsbedingter Maximalnetzpl{\"a}ne eine Begr{\"u}ndung zur Durchf{\"u}hrung von Alternativen und damit den Nutzen des Maximalnetzplans auf. Zus{\"a}tzlich sei angemerkt, dass innerhalb dieser Arbeit verwendete Begrifflichkeiten wie Anwender, Werker oder Mitarbeiter in maskuliner Schreibweise niedergeschrieben werden. Dieses ist ausschließlich der Einfachheit geschuldet und nicht dem Zweck der Diskriminierung anderer Geschlechter dienlich. Die verwendete Schreibweise soll alle Geschlechter ansprechen, ob m{\"a}nnlich, weiblich oder divers.}, subject = {Produktionsplanung}, language = {de} } @phdthesis{Tcakaev2023, author = {Tcakaev, Abdul-Vakhab}, title = {Soft X-ray Spectroscopic Study of Electronic and Magnetic Properties of Magnetic Topological Insulators}, doi = {10.25972/OPUS-30378}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303786}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {After the discovery of three-dimensional topological insulators (TIs), such as tetradymite chalcogenides Bi\$_2\$Se\$_3\$, Bi\$_2\$Te\$_3\$ and Sb\$_2\$Te\$_3\$ - a new class of quantum materials characterized by their unique surface electronic properties - the solid state community got focused on topological states that are driven by strong electronic correlations and magnetism. An important material class is the magnetic TI (MTI) exhibiting the quantum anomalous Hall (QAH) effect, i.e. a dissipationless quantized edge-state transport in the absence of external magnetic field, originating from the interplay between ferromagnetism and a topologically non-trivial band structure. The unprecedented opportunities offered by these new exotic materials open a new avenue for the development of low-dissipation electronics, spintronics, and quantum computation. However, the major concern with QAH effect is its extremely low onset temperature, limiting its practical application. To resolve this problem, a comprehensive understanding of the microscopic origin of the underlying ferromagnetism is necessary. V- and Cr-doped (Bi,Sb)\$_2\$Te\$_3\$ are the two prototypical systems that have been widely studied as realizations of the QAH state. Finding microscopic differences between the strongly correlated V and Cr impurities would help finding a relevant model of ferromagnetic coupling and eventually provide better control of the QAH effect in these systems. Therefore, this thesis first focuses on the V- and Cr-doped (Bi,Sb)\$_2\$Te\$_3\$ systems, to better understand these differences. Exploiting the unique capabilities of x-ray absorption spectroscopy and magnetic circular dichroism (XAS/XMCD), combined with advanced modeling based on multiplet ligand-field theory (MLFT), we provide a detailed microscopic insight into the local electronic and magnetic properties of these systems and determine microscopic parameters crucial for the comparison with theoretical models, which include the \$d\$-shell filling, spin and orbital magnetic moments. We find a strongly covalent ground state, dominated by the superposition of one and two Te-ligand-hole configurations, with a negligible contribution from a purely ionic 3+ configuration. Our findings indicate the importance of the Te \$5p\$ states for the ferromagnetism in (Bi, Sb)\$_2\$Te\$_3\$ and favor magnetic coupling mechanisms involving \$pd\$-exchange. Using state-of-the-art density functional theory (DFT) calculations in combination with XMCD and resonant photoelectron spectroscopy (resPES), we reveal the important role of the \$3d\$ impurity states in mediating magnetic exchange coupling. Our calculations illustrate that the kind and strength of the exchange coupling varies with the impurity \$3d\$-shell occupation. We find a weakening of ferromagnetic properties upon the increase of doping concentration, as well as with the substitution of Bi at the Sb site. Finally, we qualitatively describe the origin of the induced magnetic moments at the Te and Sb sites in the host lattice and discuss their role in mediating a robust ferromagnetism based on a \$pd\$-exchange interaction scenario. Our findings reveal important clues to designing higher \$T_{\text{C}}\$ MTIs. Rare-earth ions typically exhibit larger magnetic moments than transition-metal ions and thus promise the opening of a wider exchange gap in the Dirac surface states of TIs, which is favorable for the realization of the high-temperature QAH effect. Therefore, we have further focused on Eu-doped Bi\$_2\$Te\$_3\$ and scrutinized whether the conditions for formation of a substantial gap in this system are present by combining spectroscopic and bulk characterization methods with theoretical calculations. For all studied Eu doping concentrations, our atomic multiplet analysis of the \$M_{4,5}\$ x-ray absorption and magnetic circular dichroism spectra reveals a Eu\$^{2+}\$ valence, unlike most other rare earth elements, and confirms a large magnetic moment. At temperatures below 10 K, bulk magnetometry indicates the onset of antiferromagnetic ordering. This is in good agreement with DFT results, which predict AFM interactions between the Eu impurities due to the direct overlap of the impurity wave functions. Our results support the notion of antiferromagnetism coexisting with topological surface states in rare-earth doped Bi\$_2\$Te\$_3\$ and corroborate the potential of such doping to result in an antiferromagnetic TI with exotic quantum properties. The doping with impurities introduces disorder detrimental for the QAH effect, which may be avoided in stoichiometric, well-ordered magnetic compounds. In the last part of the thesis we have investigated the recently discovered intrinsic magnetic TI (IMTI) MnBi\$_6\$Te\$_{10}\$, where we have uncovered robust ferromagnetism with \$T_{\text{C}} \approx 12\$ K and connected its origin to the Mn/Bi intermixing. Our measurements reveal a magnetically intact surface with a large moment, and with FM properties similar to the bulk, which makes MnBi\$_6\$Te\$_{10}\$ a promising candidate for the QAH effect at elevated temperatures. Moreover, using an advanced ab initio MLFT approach we have determined the ground-state properties of Mn and revealed a predominant contribution of the \$d^5\$ configuration to the ground state, resulting in a \$d\$-shell electron occupation \$n_d = 5.31\$ and a large magnetic moment, in excellent agreement with our DFT calculations and the bulk magnetometry data. Our results together with first principle calculations based on the DFT-GGA\$+U\$, performed by our collaborators, suggest that carefully engineered intermixing plays a crucial role in achieving a robust long-range FM order and therefore could be the key for achieving enhanced QAH effect properties. We expect our findings to aid better understanding of MTIs, which is essential to help increasing the temperature of the QAH effect, thus facilitating the realization of low-power electronics in the future.}, subject = {Topologischer Isolator}, language = {en} } @phdthesis{Huber2023, author = {Huber, Stephan}, title = {Proxemo: Documenting Observed Emotions in HCI}, doi = {10.25972/OPUS-30573}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305730}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {For formative evaluations of user experience (UX) a variety of methods have been developed over the years. However, most techniques require the users to interact with the study as a secondary task. This active involvement in the evaluation is not inclusive of all users and potentially biases the experience currently being studied. Yet there is a lack of methods for situations in which the user has no spare cognitive resources. This condition occurs when 1) users' cognitive abilities are impaired (e.g., people with dementia) or 2) users are confronted with very demanding tasks (e.g., air traffic controllers). In this work we focus on emotions as a key component of UX and propose the new structured observation method Proxemo for formative UX evaluations. Proxemo allows qualified observers to document users' emotions by proxy in real time and then directly link them to triggers. Technically this is achieved by synchronising the timestamps of emotions documented by observers with a video recording of the interaction. In order to facilitate the documentation of observed emotions in highly diverse contexts we conceptualise and implement two separate versions of a documentation aid named Proxemo App. For formative UX evaluations of technology-supported reminiscence sessions with people with dementia, we create a smartwatch app to discreetly document emotions from the categories anger, general alertness, pleasure, wistfulness and pride. For formative UX evaluations of prototypical user interfaces with air traffic controllers we create a smartphone app to efficiently document emotions from the categories anger, boredom, surprise, stress and pride. Descriptive case studies in both application domains indicate the feasibility and utility of the method Proxemo and the appropriateness of the respectively adapted design of the Proxemo App. The third part of this work is a series of meta-evaluation studies to determine quality criteria of Proxemo. We evaluate Proxemo regarding its reliability, validity, thoroughness and effectiveness, and compare Proxemo's efficiency and the observers' experience to documentation with pen and paper. Proxemo is reliable, as well as more efficient, thorough and effective than handwritten notes and provides a better UX to observers. Proxemo compares well with existing methods where benchmarks are available. With Proxemo we contribute a validated structured observation method that has shown to meet requirements formative UX evaluations in the extreme contexts of users with cognitive impairments or high task demands. Proxemo is agnostic regarding researchers' theoretical approaches and unites reductionist and holistic perspectives within one method. Future work should explore the applicability of Proxemo for further domains and extend the list of audited quality criteria to include, for instance, downstream utility. With respect to basic research we strive to better understand the sources leading observers to empathic judgments and propose reminisce and older adults as model environment for investigating mixed emotions.}, subject = {Gef{\"u}hl}, language = {en} } @article{ThieleRichterHilger2023, author = {Thiele, Jonas A. and Richter, Aylin and Hilger, Kirsten}, title = {Multimodal brain signal complexity predicts human intelligence}, series = {eNeuro}, volume = {10}, journal = {eNeuro}, number = {2}, doi = {10.1523/ENEURO.0345-22.2022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312949}, year = {2023}, abstract = {Spontaneous brain activity builds the foundation for human cognitive processing during external demands. Neuroimaging studies based on functional magnetic resonance imaging (fMRI) identified specific characteristics of spontaneous (intrinsic) brain dynamics to be associated with individual differences in general cognitive ability, i.e., intelligence. However, fMRI research is inherently limited by low temporal resolution, thus, preventing conclusions about neural fluctuations within the range of milliseconds. Here, we used resting-state electroencephalographical (EEG) recordings from 144 healthy adults to test whether individual differences in intelligence (Raven's Advanced Progressive Matrices scores) can be predicted from the complexity of temporally highly resolved intrinsic brain signals. We compared different operationalizations of brain signal complexity (multiscale entropy, Shannon entropy, Fuzzy entropy, and specific characteristics of microstates) regarding their relation to intelligence. The results indicate that associations between brain signal complexity measures and intelligence are of small effect sizes (r ∼ 0.20) and vary across different spatial and temporal scales. Specifically, higher intelligence scores were associated with lower complexity in local aspects of neural processing, and less activity in task-negative brain regions belonging to the default-mode network. Finally, we combined multiple measures of brain signal complexity to show that individual intelligence scores can be significantly predicted with a multimodal model within the sample (10-fold cross-validation) as well as in an independent sample (external replication, N = 57). In sum, our results highlight the temporal and spatial dependency of associations between intelligence and intrinsic brain dynamics, proposing multimodal approaches as promising means for future neuroscientific research on complex human traits.}, language = {en} } @phdthesis{Mitschke2023, author = {Mitschke, Vanessa}, title = {Facing Enemies. Modulation of Revenge Interactions based on Opponent State Indicators of Suffering}, doi = {10.25972/OPUS-29938}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299389}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Research on revenge often treats vengeful acts as singular one-way experiences, an approach which fails to account for the social nature and functions of revenge. This dissertation aims to integrate emotional punishment reactions into dynamic revenge sequences to investigate the affective and cognitive consequences of revenge within a social interaction. Exacting revenge can evoke intense affective consequences, from feelings of guilt to the genuine enjoyment of the suffering of others. In Chapter 2, affective responses towards suffering opponents and the regulation of aggression based on the appraisal of distinct suffering indicators were investigated. Results indicate that the observation of opponent pain evokes positive affect (measured via facial muscle contractions during the observation), which is followed by a downregulation of subsequent punishment. Both, positive affective reactions and the downregulation of punishment, were only observed following pain and not sadness expressions. Empathic distress, indexed by negative affective reactions, was only present following the observation of pain in non-provoking opponents. Showcasing the modulation of empathy related processes due to provocation and competition. In Chapter 3, a significant escalation of punishment, when being confronted with Schadenfreude, was observed. Results are interpreted as supporting the assumption that opponent monitoring processes inform subsequent action selection. The observation of opponent smiles led to imitation behavior (facial mimicry), which was partially attenuated due to previous provocation. The different functions of smile mimicry in the context of the aggressive competitive setting are discussed as containing simulation aspects (to aid in opponent understanding) and as a potential mirroring of dominance gestures, to avoid submission. In an additional series of studies, which are presented in Chapter 4, changes in memory of opponent faces following vengeful encounters were measured. Based on provocation, and punishment outcomes (pain \& anger), face memory was distorted, resulting in more positive representations of opponents that expressed pain. These results are discussed as evidence of the impact of outcome appraisals in the formation of opponent representations and are theorized to aid empathy avoidance in future interactions. The comparison of desired and observed opponent states, is theorized to result in appraisals of the punishment outcomes, which evoke affective states, inform the action selection of subsequent punishments, and are integrated into the representation of the opponent in memory. Overall, the results indicate that suffering cues that are congruent with the chosen punishment action are appraised as positive, evoking an increase in positive affect. The emergence of positive affect during the observation of successful aggressive actions supports recent theories about the chronification of aggressive behavior based on reinforcement learning. To allow positive affect to emerge, affective empathic responses, such as distress, are theorized to be suppressed to facilitate the goal attainment process. The suffering of the opponent constitutes the proximate goal during revenge taking, which highlights the importance of a theoretical differentiation of proximate and ultimate goals in revenge to allow for a deeper understanding of the underlying motives of complex revenge behavior.}, subject = {Aggression}, language = {en} } @article{NollGrossShoyamaetal.2023, author = {Noll, Niklas and Groß, Tobias and Shoyama, Kazutaka and Beuerle, Florian and W{\"u}rthner, Frank}, title = {Folding-Induced Promotion of Proton-Coupled Electron Transfers via Proximal Base for Light-Driven Water Oxidation}, series = {Angewandte Chemie International Edition}, volume = {62}, journal = {Angewandte Chemie International Edition}, number = {7}, doi = {10.1002/anie.202217745}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312020}, year = {2023}, abstract = {Proton-coupled electron-transfer (PCET) processes play a key role in biocatalytic energy conversion and storage, for example, photosynthesis or nitrogen fixation. Here, we report a series of bipyridine-containing di- to tetranuclear Ru(bda) macrocycles 2 C-4 C (bda: 2,2′-bipyridine-6,6′-dicarboxylate) to promote O-O bond formation. In photocatalytic water oxidation under neutral conditions, all complexes 2 C-4 C prevail in a folded conformation that support the water nucleophilic attack (WNA) pathway with remarkable turnover frequencies of up to 15.5 s\(^{-1}\) per Ru unit respectively. Single-crystal X-ray analysis revealed an increased tendency for intramolecular π-π stacking and preorganization of the proximal bases close to the active centers for the larger macrocycles. H/D kinetic isotope effect studies and electrochemical data demonstrate the key role of the proximal bipyridines as proton acceptors in lowering the activation barrier for the crucial nucleophilic attack of H\(_{2}\)O in the WNA mechanism.}, language = {en} } @article{PreitschopfSturmStroganovaetal.2023, author = {Preitschopf, Tobias and Sturm, Floriane and Stroganova, Iuliia and Lemmens, Alexander K. and Rijs, Anouk M. and Fischer, Ingo}, title = {IR/UV Double Resonance Study of the 2-Phenylallyl Radical and its Pyrolysis Products}, series = {Chemistry - A European Journal}, volume = {29}, journal = {Chemistry - A European Journal}, number = {13}, doi = {10.1002/chem.202202943}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312338}, year = {2023}, abstract = {Isolated 2-phenylallyl radicals (2-PA), generated by pyrolysis from a nitrite precursor, have been investigated by IR/UV ion dip spectroscopy using free electron laser radiation. 2-PA is a resonance-stabilized radical that is considered to be involved in the formation of polycyclic aromatic hydrocarbons (PAH) in combustion, but also in interstellar space. The radical is identified based on its gas-phase IR spectrum. Furthermore, a number of bimolecular reaction products are identified, showing that the self-reaction as well as reactions with unimolecular decomposition products of 2-PA form several PAH efficiently. Possible mechanisms are discussed and the chemistry of 2-PA is compared with the one of the related 2-methylallyl and phenylpropargyl radicals.}, language = {en} } @phdthesis{Diebold2023, author = {Diebold, Mathias}, title = {Virtuelles Screening und Entwicklung selektiver Liganden des Aurora-A - MYCN Komplexes und computergest{\"u}tzte Methoden zur Analyse und Design von PROTACs}, doi = {10.25972/OPUS-31759}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-317594}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Die Interaktion des onkogenen Transkriptionsfaktors MYCN mit der Ser/Thr Kinase Aurora-A verhindert dessen Abbau {\"u}ber das Ubiquitin Proteasomsystem indem die Rekrutierung des SCF FbxW7 Komplexes verhindert wird. Die Kinase nimmt mit der Bindung an MYCN eine aktive Konformation ein und erh{\"a}lt somit die F{\"a}higkeit zur Kinaseaktivit{\"a}t ohne die sonst notwendige Phosphorylierung von Thr288 oder die Anwesenheit eines Aktivators wie TPX2. Da hohe MYCN Konzentrationen Tumore wie Neuroblastome antreiben, ist die St{\"o}rung der Komplexbildung mit Aurora-A eine valide Strategie zur Entwicklung von Chemotherapeutika. Einige Inhibitoren von Aurora-A wie Alisertib (MLN8237) sind in der Lage, eine Konformations{\"a}nderung in der Kinase zu verursachen, die mit der Bindung von MYCN inkompatibel ist und auf diese Weise den Abbau des Transkriptionsfaktors induziert. Da Aurora-A wichtige Funktionen in der Mitose {\"u}bernimmt, k{\"o}nnte eine direkte Adressierung des Komplexes anstelle einer systemischen Inhibition der Kinase vielversprechender sein. Ziel des Projektes war die Identifizierung von Molek{\"u}len, die selektiv an das Interface des Aurora-A - MYCN Komplexes binden und weiter optimiert werden k{\"o}nnen, um einen gezielten Abbau des Transkriptionsfaktors {\"u}ber einen PROTAC Ansatz zu erm{\"o}glichen. Virtuelle Screenings und molekulardynamische Simulationen wurden durchgef{\"u}hrt, um kommerziell erh{\"a}ltliche Verbindungen zu identifizieren, welche mit einer Bindetasche des Komplexes interagieren, die nur zustande kommt, wenn beide Proteine miteinander interagieren. Aus einem ersten Set von zehn potentiellen Liganden wurde f{\"u}r vier eine selektive Interaktion mit dem Protein - Protein Komplex gegen{\"u}ber Aurora-A oder MYCN alleine in STD-NMR Experimenten best{\"a}tigt. Zwei der Hits besaßen ein identisches Grundger{\"u}st und wurden als Ausganspunkt f{\"u}r die Optimierung zu potenteren Liganden genutzt. Das Ger{\"u}st wurde fragmentweise vergr{\"o}ßert und in Richtung besserer in-silico Ergebnisse und Funktionalisierung zur Anbringung von E3-Ligase-Liganden optimiert. Neun dieser Liganden der zweiten Generation wurden synthetisiert. Um quantitative Bindungsdaten zu erhalten, wurde ein kovalent verkn{\"u}pftes Aurora-A - MYCN Konstrukt entworfen. Die strukturelle und funktionale Integrit{\"a}t wurde in STD-NMR und BLI Experimenten mit bekannten Aurora-A Inhibitoren best{\"a}tigt, sowie in NMR-basierten ATPase Assays. Zus{\"a}tzlich konnte die Kristallstruktur des Konstrukts gel{\"o}st und damit die Validit{\"a}t des Designs best{\"a}tigt werden. Quantitative Messungen der synthetisierten Molek{\"u}le identifizierten HD19S als Hit mit einer zehnfach h{\"o}heren Affinit{\"a}t f{\"u}r das Aurora-A - MYCN Konstrukt im Vergleich zu der Kinase allein. Zus{\"a}tzlich wurden in-silico Untersuchungen zu PROTACs der Aurora-A Kinase durchgef{\"u}hrt. Interaktionen zwischen Aurora-A, der E3-Ligase Cereblon und den Liganden wurden modelliert und f{\"u}r die Erkl{\"a}rung unterschiedlicher Aktivit{\"a}ten der eingesetzten PROTACs verwendet. Zudem zeigte das aktivste PROTAC eine hohe Selektivit{\"a}t f{\"u}r Aurora-A gegen{\"u}ber Aurora-B, obwohl die verwendete Erkennungseinheit (Alisertib) an beide Aurora-Proteine bindet. Dieser Umstand konnte durch energetische Analysen von molekulardynamischen Simulationen der tern{\"a}ren Komplexe erkl{\"a}rt werden. Optimierungsm{\"o}glichkeiten f{\"u}r eine effizientere Degradation von Aurora-A durch die PROTACs wurden basierend auf modifizierten Erkennungseinheiten und verbesserten Linkern untersucht.}, subject = {Arzneimitteldesign}, language = {de} } @misc{LangePohlmannRother2023, author = {Lange, Sarah D{\´e}sir{\´e}e and Pohlmann-Rother, Sanna}, title = {Skalenhandbuch zur BLUME I-FB Fragebogenstudie zu den {\"U}berzeugungen von Grundschullehrkr{\"a}ften zum Umgang mit Mehrsprachigkeit}, doi = {10.25972/OPUS-30611}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-306110}, year = {2023}, abstract = {Ziel der Studie ist es, berufsbezogene {\"U}berzeugungen von Grundschullehrkr{\"a}ften zum Umgang mit Mehrsprachigkeit im unterrichtlichen Kontext anhand einer online-Fragebogenstudie zu erfassen. Das Thema Mehrsprachigkeit ist von hoher und wachsender p{\"a}dagogischer und gesellschaftlicher Relevanz, da Lehrkr{\"a}fte t{\"a}glich sprachlicher Heterogenit{\"a}t begegnen. Im Unterricht stehen sie vor der Aufgabe, innerhalb eines einsprachig gepr{\"a}gten institutionellen Rahmens eine Sprachbildung f{\"u}r alle Kinder zu erm{\"o}glichen und dabei dem grundschulp{\"a}dagogischen Anspruch nachzukommen, die sprachlichen Ausgangslagen der Sch{\"u}lerinnen und Sch{\"u}ler wertsch{\"a}tzend und reflexiv einzubeziehen. Angesichts dieser Herausforderungen wird mit dem Vorhaben auf die folgenden Forschungsdesiderata reagiert: Der Umgang mit Mehrsprachigkeit - insbesondere in Bezug auf berufst{\"a}tige Grundschullehrkr{\"a}fte und deren {\"U}berzeugungen - wurde bisher nicht umfassend untersucht. Methodisch leistet die Studie einen Beitrag zu einer differenzierten und umf{\"a}nglicheren quantitativen Operationalisierung berufsbezogener {\"U}berzeugungen von Lehrkr{\"a}ften.}, subject = {Mehrsprachigkeit}, language = {de} } @phdthesis{Dippell2023, author = {Dippell, Marvin}, title = {Constraint Reduction in Algebra, Geometry and Deformation Theory}, doi = {10.25972/OPUS-30167}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301670}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {To study coisotropic reduction in the context of deformation quantization we introduce constraint manifolds and constraint algebras as the basic objects encoding the additional information needed to define a reduction. General properties of various categories of constraint objects and their compatiblity with reduction are examined. A constraint Serre-Swan theorem, identifying constraint vector bundles with certain finitely generated projective constraint modules, as well as a constraint symbol calculus are proved. After developing the general deformation theory of constraint algebras, including constraint Hochschild cohomology and constraint differential graded Lie algebras, the second constraint Hochschild cohomology for the constraint algebra of functions on a constraint flat space is computed.}, subject = {Differentialgeometrie}, language = {en} } @phdthesis{Wendlinger2023, author = {Wendlinger, Simone Alice}, title = {Function of Peripheral Blood Eosinophils in Melanoma}, publisher = {Cancers (Basel)}, doi = {10.25972/OPUS-30119}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301194}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Despite accounting for only a small proportion of all skin cancers, malignant melanoma displays a serious health risk with increasing incidence and high mortality rate. Fortunately, advances in the treatment of malignant melanoma now prolong survival and enhance response and treatment efficacy. Established biomarkers help evaluate disease progression and facilitate choosing appropriate and individual treatment options. However, the need for easily accessible and reliable biomarkers is rising to predict patient-specific clinical outcome. Eosinophil infiltration into the tumor and high peripheral eosinophil counts prior and during treatment have been associated with better response in patients for various cancer entities, including melanoma. An analysis of a heterogeneous study cohort reported high serum ECP levels in non-responders. Hence, eosinophil frequency and serum ECP as a soluble eosinophil-secreted mediator were suggested as prognostic biomarkers in melanoma. We examined whether melanoma patients treated with first-line targeted therapy could also benefit from the effects of eosinophils. In total, 243 blood and serum samples from patients with advanced melanoma were prospectively and retrospectively collected before and after drug initiation. To link eosinophil function to improved clinical outcome, soluble serum markers and peripheral blood counts were used for correlative studies using a homogeneous study cohort. In addition, functional and phenotypical characterizations provided insights into the expression profile and activity of freshly isolated eosinophils, including comparisons between patients and healthy donors. Our data showed a significant correlation between high pre-treatment blood eosinophil counts and improved response to targeted therapy and by trend to combinatorial immunotherapy in patients with metastatic melanoma. In accordance with previous studies our results links eosinophil blood counts to better response in melanoma patients. High pre-treatment ECP serum concentration correlated with response to immunotherapy but not to targeted therapy. Eosinophils from healthy donors and patients showed functional and phenotypical similarities. Functional assays revealed a strong cytotoxic potential of blood eosinophils towards melanoma cells in vitro, inducing apoptosis and necrosis. In addition, in vitro cytotoxicity was an active process of peripheral eosinophils and melanoma cells with bidirectional features and required close cell-cell interaction. The extent of cytotoxicity was dose-dependent and showed susceptibility to changes in physical factors like adherence. Importantly, we provide evidence of an additive tumoricidal function of eosinophils and combinatorial targeted therapy in vitro. In summary, we give valuable insights into the complex and treatment-dependent role of eosinophils in melanoma. As a result, our data support the suggestion of eosinophils and their secreted mediators as potential prognostic biomarkers. It will take additional studies to examine the molecular mechanisms that underlie our findings.}, subject = {Melanom}, language = {en} } @phdthesis{Ramge2023, author = {Ramge, Vanessa Magali}, title = {Untersuchung der Genotoxizit{\"a}t von Pyrrolizidinalkaloiden \(in\) \(vitro\) am Beispiel von Riddelliin und Lasiocarpin}, doi = {10.25972/OPUS-31979}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319793}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {PA sind nat{\"u}rliche Pflanzeninhaltsstoffe, die wegen ihres genotoxischen Potentials bekannt sind. Nach Applikation mikromolarer Konzentrationen k{\"o}nnen bei in vitro Untersuchungen von Leberzellen chromosomale Sch{\"a}den detektiert werden. PA stehen im Verdacht nach Aufnahme bei Menschen hepatotoxische und kanzerogene Wirkungen nach sich zu ziehen. In dieser Studie wurden Lasiocarpin und Riddelliin an der humanen Leberkarzinomzelllinie Huh6 auf Genotoxizit{\"a}t getestet. Die ausgew{\"a}hlten Methoden waren der MK-Test, der alkalische und der FPG Comet Assay und die γ-H2AX-F{\"a}rbung. In den Vorversuchen mit BaP und CPA wurde gezeigt, dass die Zellen durch Prodrugs genotoxisch gesch{\"a}digt werden. Zusammenfassend kann gesagt werden, dass Riddelliin und Lasiocarpin im MK-Test eine dosisabh{\"a}ngige, genotoxische Wirkung auf die Huh6 Zellen haben. Der Einfluss von Lasiocarpin war im MK-Test im Vergleich zum Einfluss von Riddelliin bei geringerer Konzentration detektierbar. Nach einer simultanen Behandlung der Huh6 Zellen mit verschiedenen PA kann konkludiert werden, dass keine signifikante Erh{\"o}hung an DNA-Sch{\"a}den im Vergleich zu Behandlungen mit den Einzelsubstanzen festgestellt werden konnte, was m{\"o}glicherweise auf eine Ersch{\"o}pfung der metabolischen Kapazit{\"a}t der Zellen zur{\"u}ckzuf{\"u}hren ist. Insgesamt ist es den Ergebnissen zufolge wahrscheinlich, dass die Entstehung von Crosslinks durch Lasiocarpin und Riddelliin eher eine Rolle in der Genotoxizit{\"a}tsinduktion auf Huh6 Zellen spielen als oxidativer Stress. Doppelstrangbr{\"u}che konnten nicht als sicherer Induktor von Genotoxizit{\"a}t identifiziert werden. Die Besonderheiten der Stoffwechselwege einzelner PA und die Spezifizierung einzelner, f{\"u}r die Metabolisierung relevanter Enzyme sollte in Zukunft Gegenstand der Forschung sein, um die kumulativen Wirkungen von PA besser nachzuvollziehen und die f{\"u}r den Menschen entstehenden Risiken durch die Aufnahme von PA konkretisieren zu k{\"o}nnen.}, subject = {Pyrrolizidinalkaloide}, language = {de} } @article{GrueneLondiGillettetal.2023, author = {Gr{\"u}ne, Jeannine and Londi, Giacomo and Gillett, Alexander J. and St{\"a}hly, Basil and Lulei, Sebastian and Kotova, Maria and Olivier, Yoann and Dyakonov, Vladimir and Sperlich, Andreas}, title = {Triplet Excitons and Associated Efficiency-Limiting Pathways in Organic Solar Cell Blends Based on (Non-) Halogenated PBDB-T and Y-Series}, series = {Advanced Functional Materials}, volume = {33}, journal = {Advanced Functional Materials}, number = {12}, doi = {10.1002/adfm.202212640}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312164}, year = {2023}, abstract = {The great progress in organic photovoltaics (OPV) over the past few years has been largely achieved by the development of non-fullerene acceptors (NFAs), with power conversion efficiencies now approaching 20\%. To further improve device performance, loss mechanisms must be identified and minimized. Triplet states are known to adversely affect device performance, since they can form energetically trapped excitons on low-lying states that are responsible for non-radiative losses or even device degradation. Halogenation of OPV materials has long been employed to tailor energy levels and to enhance open circuit voltage. Yet, the influence on recombination to triplet excitons has been largely unexplored. Using the complementary spin-sensitive methods of photoluminescence detected magnetic resonance and transient electron paramagnetic resonance corroborated by transient absorption and quantum-chemical calculations, exciton pathways in OPV blends are unravelled employing the polymer donors PBDB-T, PM6, and PM7 together with NFAs Y6 and Y7. All blends reveal triplet excitons on the NFA populated via non-geminate hole back transfer and, in blends with halogenated donors, also by spin-orbit coupling driven intersystem crossing. Identifying these triplet formation pathways in all tested solar cell absorber films highlights the untapped potential for improved charge generation to further increase plateauing OPV efficiencies.}, language = {en} } @techreport{Stanka2023, type = {Working Paper}, author = {Stanka, Hans}, title = {Autonomy Reconsidered: Conceptualising a Phenomenon on the Verges of Self-Government and Self-Governance}, issn = {2698-2684}, doi = {10.25972/OPUS-32077}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320771}, pages = {28}, year = {2023}, abstract = {For decades autonomy has been utilised as a concept in various social sciences, like sociology, political science, law and philosophy. Certain concepts of autonomy have always reflected the needs of the respective disciplines that made use of the term, but also ever infringed on the interpretation of autonomy in other disciplines. Most notably, conceptualisations of international and constitutional law have found their way into bordering sciences, like political science. The result: a legal positivist view prevailing in the conceptualisations of autonomy within political and administrative sciences. As this working paper points out, this perspective does not do justice to the complex phenomenon autonomy is or may be in social and political reality. Hence, the paper argues for a differentiated concept of autonomy, splitting it into autonomy claims, actors, process, rights and powers, regimes, and their institutions. The empirical world suggests a salience of formally and informally lived types of autonomy, especially in Latin America, due to the region's indigenous population often living outside of, or within the limited reach of the state. Therefore, the paper aims to incorporate the dimension of informality - lacking in previous legal positivist approaches. Autonomy regimes could be entrenched in international, constitutional, or secondary law, or they could be tolerated by the state or seized by autonomy claimants by force. From a theoretical or conceptual perspective, the dimension of (in)formality facilitates the incorporation of autonomy into the discussion on governance and government, mostly on the local or regional level. Thus, the paper establishes autonomy regimes as a concept located at the verges of (self-)government and (self-)governance.}, subject = {Staat}, language = {en} } @article{Kestler2023, author = {Kestler, Thomas}, title = {Exploring the Relationship Between Social Movement Organizations and the State in Latin America}, series = {Politics and Governance}, volume = {11}, journal = {Politics and Governance}, number = {2}, issn = {2183-2463}, doi = {10.17645/pag.v11i2.6383}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321152}, pages = {346-356}, year = {2023}, abstract = {Under conditions of weak statehood, societal actors are supposed to assume functions usually attributed to the state. Social self-organization is expected to emerge when the state leaves important social problems unattended. Should social self-organization, therefore, be regarded as a reaction to state weakness and as compensation for state failure in the provision of basic services? Does society organize itself on its own in areas where the state is absent or ineffective? By the example of two Latin American social movements, this article aims to show that social self-organization—at least on a larger scale—is not independent of the state, but rather a result of a dynamic interaction with the state. The two examples this article explores are the middle-class Venezuelan neighborhood movement and the Argentine piquetero movement of unemployed workers. Both movements emerged as reactions to the state's failure and retreat from essential social functions and both developed into extensive and influential social actors. For that reason, they can be regarded as crucial cases for observing the patterns and conditions of social self-organization and autonomous collective action within the specific Latin American context. Despite their different backgrounds and social bases, the two cases reveal remarkable similarities. They show that the emergence and development of self-organized social groups cannot be conceived simply as a reaction to state weakness, but rather should be viewed as a dynamic interaction with the state.}, language = {en} } @misc{Schilling2023, type = {Master Thesis}, author = {Schilling, Sheila Elisabeth}, title = {Schaf-Woll-Geschichten. Multispezies-Perspektiven auf die Beziehung von Schafen und Menschen}, doi = {10.25972/OPUS-31959}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319595}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Schafe leben seit einigen Jahrtausenden mit Menschen zusammen und mit ihnen durchwandert ihre Wolle unsere Kulturen und Gesellschaften. Ausgangspunkt der vorliegenden Arbeit ist der gegenw{\"a}rtig geringe monet{\"a}re Wert von Schafwolle, der in den letzten dreißig Jahren in Deutschland stark gesunken ist. Basierend auf ethnografischen Methoden der Feldforschung, teilnehmende Beobachtung und Interviews, verfolgt die vorliegende Arbeit Spuren von Schafwolle und fragt dabei nach den Ber{\"u}hrungs- und Kontaktpunkten, die im Alltag zwischen Schafen, Menschen und Wolle entstehen. Menschen, die mit Schafen leben, werfen verschiedene Perspektiven auf die sogenannte Nutztierhaltung sowie auf l{\"a}ndliches Wirtschaften und Leben. Schafe und Schafwolle werden hier als Miterz{\"a}hlende und Mitgestaltende im Prozess der Entstehung von Schaf-Woll-Geschichten betrachtet. Besonders die Perspektiven auf Schafwolle regen an, tierliche Materialit{\"a}ten im Allgemeinen neu zu denken und zu reflektieren. So l{\"a}dt die vorliegende Arbeit dazu ein, Menschen, Tiere und Materialit{\"a}ten st{\"a}rker in den Wissensgenerierungsprozess zu integrieren sowie nach dem besonderen Wissen zu suchen, das eben jene mehr-als-menschliche Akteur*innen mit uns teilen.}, subject = {Europ{\"a}ische Ethnologie}, language = {de} } @phdthesis{Abel2023, author = {Abel, Daniel Karl-Joseph}, title = {Weiterentwicklung der Bodenhydrologie des regionalen Klimamodells REMO}, doi = {10.25972/OPUS-31146}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311468}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Die Bodenfeuchte stellt eine essenzielle Variable f{\"u}r den Energie-, Feuchte- und Stoffaustausch zwischen Landoberfl{\"a}che und Atmosph{\"a}re dar. Ihre Auswirkungen auf Temperatur und Niederschlag sind vielf{\"a}ltig und komplex. Die in Klimamodellen verwendeten Schemata zur Simulation der Bodenfeuchte, auch bodenhydrologische Schemata genannt, sind aufgrund des Ursprungs der Klimamodelle aus Wettermodellen jedoch h{\"a}ufig sehr stark vereinfacht dargestellt. Bei Klimamodellen, die Simulationen mit einer groben Aufl{\"o}sung von mehreren Zehner- oder Hunderterkilometern rechnen, k{\"o}nnen viele Prozesse vernachl{\"a}ssigt werden. Da die Aufl{\"o}sung der Klimamodelle jedoch stetig steigt und mittlerweile beim koordinierten Projekt regionaler Klimamodelle CORDEX-CORE standardm{\"a}ßig bei 0.22° Kantenl{\"a}nge liegt, m{\"u}ssen auch h{\"o}her aufgel{\"o}ste Daten und mehr Prozesse simuliert werden. Dies gilt erst recht mit Blick auf konvektionsaufl{\"o}sende Simulationen mit wenigen Kilometern Kantenl{\"a}nge. Mit steigenden Modellaufl{\"o}sungen steigt zugleich die Komplexit{\"a}t und Differenziertheit der Fragestellungen, die mit Hilfe von Klimamodellen beantwortet werden sollen. An diesem Punkt setzt auch das Projekt BigData@Geo an, in dessen Rahmen die vorliegende Arbeit entstand. Ziel dieses Projektes ist es, hochaufgel{\"o}ste Klimainformationen f{\"u}r den bayerischen Regierungsbezirk Unterfranken f{\"u}r Akteure aus der Land- und Forstwirtschaft sowie dem Weinbau zur Verf{\"u}gung zu stellen. Auf diesen angewandten und grundlegenden Anforderungen und Zielsetzungen basierend, bedarf auch das in dieser Arbeit verwendete regionale Klimamodell REMO (Version 2015) der weiteren Entwicklung. So ist das Hauptziel der Arbeit das bestehende einschichtige bodenhydrologische Schema durch ein mehrschichtiges zu ersetzen. Der Vorteil mehrerer simulierter Bodenschichten besteht darin, dass nun die vertikale Bewegung des Wassers in Form von Versickerung und kapillarem Aufstieg simuliert werden kann. Dies geschieht auf der Basis bodenhydrologischer Parameter, deren Wert in Abh{\"a}ngigkeit vom Boden und der Bodenfeuchte {\"u}ber die Wasserr{\"u}ckhaltekurve bestimmt wird. F{\"u}r diese Kurve existieren verschiedene Parametrisierungen, von denen die Ans{\"a}tze von Clapp-Hornberger und van Genuchten verwendet wurden. Außerdem kann die Bodenfeuchte nun bis zu einer Tiefe von circa 10 m beziehungsweise der Tiefe des anstehenden Gesteins simuliert werden. Damit besteht im Gegensatz zum vorherigen Schema, dessen Tiefe auf die Wurzeltiefe beschr{\"a}nkt ist, die M{\"o}glichkeit, dass Wasser auch unterhalb der Wurzeln zur Verf{\"u}gung stehen kann und somit die absolute im Boden verf{\"u}gbare Wassermenge zunimmt. Die Schichtung erlaubt dar{\"u}ber hinaus die Verdunstung aus unbewachsenem Boden lediglich auf Basis des in der obersten Schicht verf{\"u}gbaren Wassers. Ein weiterer Prozess, der dank der Schichtung und der weiter unten erl{\"a}uterten Datens{\"a}tze neu parametrisiert werden kann, ist die Infiltration. F{\"u}r die Verwendung des Schemas sind Informationen {\"u}ber bodenhydrologische Parameter, die Wurzeltiefe und die Tiefe bis zum anstehenden Gestein erforderlich. Entsprechende Datens{\"a}tze m{\"u}ssen hierf{\"u}r aufbereitet und in das Modell eingebaut werden. Bez{\"u}glich der Wurzeltiefe wurden drei sich bez{\"u}glich der Tiefe, der Definition und der verf{\"u}gbaren Aufl{\"o}sung stark voneinander unterscheidende Datens{\"a}tze verglichen. Letztendlich wird die Wurzeltiefe aus dem mit einer anderen REMO-Version gekoppelten Vegetationsmodul iMOVE verwendet, da zuk{\"u}nftig eine Kopplung dieses Moduls mit dem mehrschichtigen Boden geplant ist und die Wurzeltiefen damit konsistent sind. Zudem ist die zugrundeliegende Aufl{\"o}sung der Daten hoch und es werden maximale Wurzeltiefen ber{\"u}cksichtigt, die besonders wichtig f{\"u}r die Simulation von Landoberfl{\"a}che-Atmosph{\"a}re-Interaktionen sind. Diese Vorteile brachten die anderen Datens{\"a}tze nicht mit. In der finalen Modellversion werden f{\"u}r die Tiefe bis zum anstehenden Gestein und die Korngr{\"o}ßenverteilungen die Daten von SoilGrids verwendet. Ein Vergleich mit anderen Bodendatens{\"a}tzen fand in einer parallel laufenden Dissertation statt (Ziegler 2022). Bei SoilGrids ist hervorzuheben, dass die Korngr{\"o}ßenverteilungen in einer hohen r{\"a}umlichen Aufl{\"o}sung (1 km^2 oder h{\"o}her) und mit mehreren vertikalen Schichten vorliegen. Gegen{\"u}ber dem urspr{\"u}nglich in REMO verwendeten Datensatz mit einer Kantenl{\"a}nge von 0.5° und ohne vertikale Differenzierung ist dies eine starke Verbesserung der Eingangsdaten. Dazu kommt, dass die Korngr{\"o}ßenverteilungen die Verwendung kontinuierlicher Pedotransferfunktionen statt f{\"u}nf diskreter Texturklassen, denen f{\"u}r die bodenhydrologischen Parameter fixe Tabellenwerte zugewiesen werden, erm{\"o}glichen. Dies f{\"u}hrt zu einer deutlich besseren Differenzierung des heterogenen Bodens. Im Rahmen der Arbeit wurden insgesamt 19 Simulationen f{\"u}r Europa und ein erweitertes Deutschlandgebiet mit Aufl{\"o}sungen von 0.44° beziehungsweise 0.11° f{\"u}r den Zeitraum 2000 bis 2018 gerechnet. Dabei zeigte sich, dass die Einf{\"u}hrung des mehrschichtigen Bodenschemas gegen{\"u}ber dem einschichtigen Schema zu einer Verringerung der Bodenfeuchte in der Wurzeltiefe f{\"u}hrt. Nichtsdestotrotz nimmt die absolute Wassermenge des Bodens durch die Ber{\"u}cksichtigung des Bodens unterhalb der Wurzelzone zu. Bezogen auf die einzelnen Schichten wird die Bodenfeuchte damit zwar untersch{\"a}tzt, im Laufe der Modellentwicklung kann jedoch eine Verbesserung im Vergleich zu ERA5 erzielt werden. Das neue Schema f{\"u}hrt zu einer Verringerung der Evapotranspiration, die {\"u}ber alle Schritte der Modellentwicklung und besonders w{\"a}hrend der Sommermonate auftritt. Im Vergleich zu Validationsdaten von ERA5 und GLEAM zeigt sich, dass dies eine Verbesserung dieser Gr{\"o}ße bedeutet, die sowohl in der Fl{\"a}che als auch beim Fehler und in der Verteilung auftritt. Gleiches l{\"a}sst sich f{\"u}r den Oberfl{\"a}chenabfluss sagen. Hierf{\"u}r implementierte Schemata (Philip, Green-Ampt), die anders als das standardm{\"a}ßig verwendete Improved-Arno-Schema bodenhydrologische Parameter ber{\"u}cksichtigen, konnten eine weitere Verbesserung im Flachland zeigen. In Gebirgsregionen nahm der Fehler durch die nicht enthaltene Ber{\"u}cksichtigung der Hangneigung jedoch zu, sodass in der finalen Modellversion auf das Improved-Arno-Schema zur{\"u}ckgegriffen wurde. Die Temperatur steigt durch die urspr{\"u}ngliche Version des mehrschichtigen Schemas zun{\"a}chst an, was zu einer {\"U}ber- statt der vorherigen Untersch{\"a}tzung gegen{\"u}ber E-OBS f{\"u}hrt. Die Modellentwicklung resultiert zwar in einer Reduzierung der Temperatur, jedoch f{\"a}llt diese zu stark aus, sodass der Temperaturfehler letztendlich gr{\"o}ßer als in der einschichtigen Modellversion ist. Da die Evapotranspiration jedoch maßgeblich verbessert wurde, kann dieser Fehler eventuell auf ein {\"u}berm{\"a}ßiges Tuning der Temperatur zur{\"u}ckgef{\"u}hrt werden. Die Betrachtung von Hitzeereignissen am Beispiel der Sommer 2003 und 2018 hat gezeigt, dass die Modellentwicklung dazu beitr{\"a}gt, diese Ereignisse besser als das einschichtige Schema zu simulieren. Zwar trifft dies nicht auf das r{\"a}umliche Verhalten der mittleren Temperatur zu, jedoch auf deren zeitlichen Verlauf. Hinzu kommt die bessere Simulation der t{\"a}glichen Extrem- und besonders der Minimaltemperatur, was zu einer Erh{\"o}hung der t{\"a}glichen Temperaturspanne f{\"u}hrt. Diese wird von Klimamodellen in der Regel zu stark untersch{\"a}tzt. Durch die Ber{\"u}cksichtigung der vertikalen Wasserfl{\"u}sse hat sich jedoch auch gezeigt, dass noch enormes Entwicklungspotenzial mit Blick auf (boden)hydrologische Prozesse besteht. Dies gilt in besonderem Maße f{\"u}r zuk{\"u}nftige Simulationen mit konvektionserlaubender Aufl{\"o}sung. So sollten subskalige Informationen des Bodens und der Orographie ber{\"u}cksichtigt werden. Dies dient einerseits der Repr{\"a}sentation vorliegender Heterogenit{\"a}ten und kann andererseits, wie am Beispiel der Infiltrationsschemata dargelegt, zur Verbesserung bestehender Prozesse beitragen. Da die simulierte Drainage durch das mehrschichtige Bodenschema im gleichen Maße zu- wie der Oberfl{\"a}chenabfluss abnimmt und das Wasser dem Modell in der Folge nicht weiter zur Verf{\"u}gung steht, sollte zuk{\"u}nftig auch Grundwasser im Modell ber{\"u}cksichtigt werden. Eine Vielzahl von Studien konnte einen Mehrwert durch die Implementierung dieser Variable und damit verbundener Prozesse feststellen. Mittelfristig ist jedoch insgesamt die Kopplung an ein hydrologisches Modell zu empfehlen, um die bei hochaufl{\"o}senden Simulationen relevanten Prozesse angemessen repr{\"a}sentieren zu k{\"o}nnen. Hierf{\"u}r bieten sich beispielsweise ParFlow oder mHM an. Insgesamt ist festzuhalten, dass das mehrschichtige Bodenschema einen Mehrwert liefert, da schwer zu simulierende und in der Postprozessierung zu korrigierende Variablen wie die Evapotranspiration und der Oberfl{\"a}chenabfluss deutlich besser modelliert werden k{\"o}nnen als mit dem einschichtigen Schema. Dies gilt auch f{\"u}r die Extremtemperaturen. Beides ist klar auf die Schichtung des Bodens und damit einhergehender Prozesse zur{\"u}ckzuf{\"u}hren. Bez{\"u}glich der Daten zeigt sich, dass die Wurzeltiefe, die Ber{\"u}cksichtigung von SoilGrids und die vertikale Bodeninformation f{\"u}r die weitere Optimierung verantwortlich sind. Dar{\"u}ber hinaus ist der h{\"o}here Informationsgehalt, der anhand der geschichteten Bodenfeuchte zur Verf{\"u}gung steht, ebenfalls als Mehrwert einzustufen.}, subject = {Klima}, language = {de} } @phdthesis{Imam2023, author = {Imam, Nasir}, title = {Molecular basis of collybistin conformational activation}, doi = {10.25972/OPUS-31145}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311458}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {The nervous system relies on an orchestrated assembly of complex cellular entities called neurons, which are specifically committed to information management and transmission. Inter-neuronal communication takes place via synapses, membrane-membrane junctions which ensure efficient signal transfer. Synaptic neurotransmission involves release of presynaptic neurotransmitters and their reception by cognate receptors at postsynaptic terminals. Inhibitory neurotransmission is primarily mediated by the release of neurotransmitters GABA (γ-Aminobutyric acid) and glycine, which are precisely sensed by GABA type-A receptors (GABAARs) and glycine receptors (GlyRs), respectively. GABAAR assembly and maintenance is coordinated by various postsynaptic neuronal factors including the scaffolding protein gephyrin, the neuronal adaptor collybistin (CB) and cell adhesion proteins of the neuroligin (NL) family, specifically NL2 and NL4. At inhibitory postsynaptic specializations, gephyrin has been hypothesized to form extended structures underneath the plasma membrane, where its interaction with the receptors leads to their stabilization and impedes their lateral movement. Gephyrin mutations have been associated with various brain disorders, including autism, schizophrenia, Alzheimer's disease, and epilepsy. Furthermore, gephyrin loss is lethal and causes mice to die within the first post-natal day. Gephyrin recruitment from intracellular deposits to postsynaptic membranes primarily relies on the adaptor protein CB. As a moonlighting protein, CB, a guanine nucleotide exchange factor (GEF), also catalyzes a nucleotide exchange reaction, thereby regenerating the GTP-bound state of the small GTPase Cdc42 from its GDP-bound form. The CB gene undergoes alternative splicing with the majority of CB splice variants featuring an N-terminal SH3 domain followed by tandem Dbl-homology (DH) and pleckstrin-homology (PH) domains. Previous studies demonstrated that the most widely expressed, SH3-domain containing splice variant (CB2SH3+) preferentially adopts a closed conformation, in which the N-terminally located SH3 domain forms intra-molecular interaction with the DH-PH domain tandem. Previous cell-based studies indicated that SH3 domain-encoding CB variants remain untargeted and colocalize with intracellular gephyrin deposits and hence require additional factors which interact with the SH3 domain, thus inducing an open or active conformation. The SH3 domain-deficient CB isoform (CB2SH3-), on the contrary, adopts an open conformation, which possess enhanced postsynaptic gephyrin-clustering and also effectively replenishes the GTP-bound small GTPase-Cdc42 from its GDP-bound state. Despite the fundamental role of CB as a neuronal adaptor protein maintaining the proper function of inhibitory GABAergic synapses, its interactions with the neuronal scaffolding protein gephyrin and other post synaptic neuronal factors remain poorly understood. Moreover, CB interaction studies with the small GTPase Cdc42 and TC10, a closely related member of Cdc42 subfamily, remains poorly characterized. Most importantly, the roles of the neuronal factors and small GTPases in CB conformational activation have not been elucidated. This PhD dissertation primarily focuses on delineating the molecular basis of the interactions between CB and postsynaptic neuronal factors. During the course of my PhD dissertation, I engineered a series of CB FRET (F{\"o}rster Resonance Energy Transfer) sensors to characterize the CB interaction with its binding partners along with outlining their role in CB conformational activation. Through the aid of these CB FRET sensors, I analyzed the gephyrin-CB interaction, which, due to technical limitations remained unaddressed for more than two decades (refer Chapter 2 for more details). Subsequently, I also unraveled the molecular basis of the interactions between CB and the neuronal cell adhesion factor neuroligin 2 (refer chapter 2) and the small GTPases Cdc42 and TC10 (refer chapter 3) and describe how these binding partners induce a conformational activation of CB. In summary, this PhD dissertation provides strong evidence of a closely knit CB communication network with gephyrin, neuroligin and the small GTPase TC10, wherein CB activation from closed/inactive to open/active states is effectively triggered by these ligands.}, language = {en} } @misc{Zhang2023, type = {Master Thesis}, author = {Zhang, Shenxishuai}, title = {Conflicts and Anxieties over Money in Late Ming Vernacular Stories}, doi = {10.25972/OPUS-31673}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-316733}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {The present study discusses money and conflicts and anxiety over money in late Ming vernacular stories and contextualizes these stories in the contemporary society of economic prosperity and rapid changes. The high monetization and extensive use of silver and copper cash as currency brought both wealth and conflicts in various aspects of society. Eleven vernacular stories from several collections are adopted as source materials for the close examination, including Jingshi tongyan (Stories to Caution the World, 1624) and Xingshi hengyan (Stories to Awaken the World, 1627) by Feng Menglong (1574-1646) and the two Pai'an jingqi (Slapping the Table in Amazement, 1628 and 1632) collections by Ling Mengchu (1580-1644), etc. The analysis then focuses on the relationship between money and four topics, the late Ming context, social relations, gender ideals, and religion. Multiple voices and various viewpoints in these narratives show human beings' struggles in taming and dominating money, the increasingly familiar and essential object in everyday life. Generally, when people cannot control money properly, there is a fear of its detrimental power to humans and social relations within and beyond families. On the contrary, characters, who are able to control money, are praised.}, subject = {Geld}, language = {en} } @incollection{Schoenfeld2023, author = {Sch{\"o}nfeld, Sophie}, title = {Western Constructions of Disability and Local Systems of Knowledge: A Look at the Problematic Aspects of Intercultural Work}, series = {Global Cultural Studies? Engaged Scholarship between National and Transnational Frames}, booktitle = {Global Cultural Studies? Engaged Scholarship between National and Transnational Frames}, editor = {Jetter, Tobias}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, doi = {10.25972/WUP-978-3-95826-207-2-113}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305910}, publisher = {W{\"u}rzburg University Press}, pages = {113-128}, year = {2023}, abstract = {No abstract available.}, subject = {Behinderung}, language = {en} } @masterthesis{Schiffmann2023, type = {Bachelor Thesis}, author = {Schiffmann, Luisa}, title = {Medialer Konflikt um ein kulinarisches Kulturgut: Analyse des Diskurses zur Kimchi-/Paocai-Kontroverse in ausgew{\"a}hlten chinesischen und s{\"u}dkoreanischen Onlinezeitungen}, doi = {10.25972/OPUS-31191}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311919}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Die vorliegende Arbeit analysiert die chinesisch-s{\"u}dkoreanische Kontroverse um die Herkunft von Kimchi (kimch'i 김치) beispielhaft f{\"u}r Dispute um kulturelle Eigenheiten anhand von Material aus Online-Medien. Mittels prim{\"a}r qualitativer und sekund{\"a}r auch quantitativer Methoden und einer wissenssoziologischen Diskursanalyse, die sich auf theoretische und methodische Konzepte von Agenda-Setting, Framing und Nationenbilder st{\"u}tzt, untersucht die Arbeit, welche Selbstbilder und Bilder des „Anderen" in englischsprachigen Berichten koreanischer und chinesischer Onlinezeitungen produziert werden. Besonders im Vordergrund stehen dabei die sprachlichen Mittel, argumentativen Strategien und diskursiven Praktiken, die bei der Darstellung der Ereignisse eingesetzt werden. Dabei erg{\"a}nzt die vorliegende Arbeit bisherige Forschung, die sich entweder auf die Metaebene bezieht oder aber ein nationales Publikum betrachtet, um die Perspektive des internationalen Publikums von Online-Medien. Die Untersuchung kommt zu dem Ergebnis, dass ein deutlicher Unterschied in der Agenda chinesischer und koreanischer Medien besteht, und zwar sowohl hinsichtlich der Inhalte, der Argumentationsstruktur, als auch des anvisierten Publikums.}, subject = {Diskursanalyse}, language = {de} } @book{AgbokhanSandigHaasetal.2023, author = {Agbokhan, Serena and Sandig, Anna and Haas, Thea and Valentin, Francesca and Gasteiger, Annika and von Keller, Anna and Friedmann, Fiona and Wicht, Rebecca and Wintermeyer, Nina and Hofmann, Anna-Lena and Liebich, Alexander and B{\"o}rdlein, Sophie and L{\"u}deritz, Cathrin and Philipp, Sonja and Watermann, Anne and Hercher, Anna}, title = {Insights;}, editor = {Nelson-Teutsch, Hannah}, isbn = {978-3-945459-44-7}, doi = {10.25972/OPUS-31700}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-317007}, publisher = {Universit{\"a}t W{\"u}rzburg}, pages = {99}, year = {2023}, abstract = {The cluster of texts assembled here were imagined, crafted, and brought together as a collaborative writing project that emerged from the seminar titled "Words Matter Worlds: Activist Scholarship and Literary Praxis," which convened over the course of the 2021/22 winter semester as an offering of the American Studies department of the Julius-Maximilians-Universit{\"a}t W{\"u}rzburg. Like the seminar that nurtured the considerations that evolve here, these contributions engage with how scholarly writing practices in general, and literary and cultural studies in particular, can remake the world.}, subject = {Aktivist}, language = {en} } @phdthesis{Rudingsdorfer2023, author = {Rudingsdorfer, Jonathan}, title = {Zur Leistungsrelevanz des situativen Flow-Erlebens bei Nachwuchsfußballerinnen}, doi = {10.25972/OPUS-30275}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-302752}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Die Arbeit untersucht die Leistungsrelevanz allgemeiner psychischer Leistungsfaktoren im Kontext der Talentf{\"o}rderung im weiblichen Nachwuchsfußball. Hierbei werden die Zusam- menh{\"a}nge zwischen drei psychischen Dispositionen sowie einem psychischen Zustand und der aktuellen Spielkompetenz untersucht, wobei folgende Leistungsfaktoren fokussiert werden: die dispositionelle Handlungsorientierung, die dispositionelle Lageorientierung, die grunds{\"a}tzliche Entscheidungskompetenz sowie das situative Flow-Erleben. Auf Grundlage der Flow-Theorie und der Theorie der Handlungskontrolle sowie dem aktu- ellen Forschungsstand wird angenommen, dass mit steigendem Flow-Erleben eine Zunahme der aktuellen Spielkompetenz einhergeht und dieser psychische Zustand zudem den Zusam- menhang zwischen den ausgew{\"a}hlten Dispositionen und der aktuellen Spielkompetenz voll- st{\"a}ndig vermittelt. Die beiden Theorien und der aktuelle Forschungsstand lassen f{\"u}r eine aus- gepr{\"a}gte dispositionelle Handlungsorientierung sowie eine hohe Entscheidungskompetenz eine Zunahme und f{\"u}r eine ausgepr{\"a}gte dispositionelle Lageorientierung eine Abnahme des Flow- Erlebens vermuten. Die Zusammenh{\"a}nge werden mit und ohne vorheriger Stressinduktion und unter Ber{\"u}cksichtigung theoretisch abgeleiteter Kontrollvariablen untersucht. Der Arbeit liegt eine quantitative Querschnittsstudie zugrunde, die bei 139 Nachwuchsspie- lerinnen aus acht verschiedenen Vereinen in Deutschland durchgef{\"u}hrt wurde. Die Datenaus- wertung erfolgt mittels multipler linearer Regressionsanalysen und linearer Strukturgleichungs- modelle. Das Flow-Erleben erweist sich als leistungsf{\"o}rderlicher Zustand und verl{\"a}sslicher Mediator des Zusammenhangs zwischen beiden dispositionellen Arten der Handlungskontrolle und der Spielkompetenz. Die dispositionelle Handlungsorientierung stellt einen positiven und die dis- positionelle Lageorientierung einen negativen Pr{\"a}diktor f{\"u}r das Flow-Erleben dar. In Bezug auf die Entscheidungskompetenz k{\"o}nnen die theoretischen Annahmen nicht best{\"a}tigt werden. Auf dieser Grundlage erfolgen Implikationen f{\"u}r die sportp{\"a}dagogische Praxis und die zuk{\"u}nftige Forschungsarbeit zum Flow-Erleben im weiblichen Nachwuchsfußball.}, subject = {Talentf{\"o}rderung}, language = {de} } @phdthesis{Schardt2023, author = {Schardt, Simon}, title = {Agent-based modeling of cell differentiation in mouse ICM organoids}, doi = {10.25972/OPUS-30194}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301940}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Mammalian embryonic development is subject to complex biological relationships that need to be understood. However, before the whole structure of development can be put together, the individual building blocks must first be understood in more detail. One of these building blocks is the second cell fate decision and describes the differentiation of cells of the inner cell mass of the embryo into epiblast and primitive endoderm cells. These cells then spatially segregate and form the subsequent bases for the embryo and yolk sac, respectively. In organoids of the inner cell mass, these two types of progenitor cells are also observed to form, and to some extent to spatially separate. This work has been devoted to these phenomena over the past three years. Plenty of studies already provide some insights into the basic mechanics of this cell differentiation, such that the first signs of epiblast and primitive endoderm differentiation, are the expression levels of transcription factors NANOG and GATA6. Here, cells with low expression of GATA6 and high expression of NANOG adopt the epiblast fate. If the expressions are reversed, a primitive endoderm cell is formed. Regarding the spatial segregation of the two cell types, it is not yet clear what mechanism leads to this. A common hypothesis suggests the differential adhesion of cell as the cause for the spatial rearrangement of cells. In this thesis however, the possibility of a global cell-cell communication is investigated. The approach chosen to study these phenomena follows the motto "mathematics is biology's next microscope". Mathematical modeling is used to transform the central gene regulatory network at the heart of this work into a system of equations that allows us to describe the temporal evolution of NANOG and GATA6 under the influence of an external signal. Special attention is paid to the derivation of new models using methods of statistical mechanics, as well as the comparison with existing models. After a detailed stability analysis the advantages of the derived model become clear by the fact that an exact relationship of the model parameters and the formation of heterogeneous mixtures of two cell types was found. Thus, the model can be easily controlled and the proportions of the resulting cell types can be estimated in advance. This mathematical model is also combined with a mechanism for global cell-cell communication, as well as a model for the growth of an organoid. It is shown that the global cell-cell communication is able to unify the formation of checkerboard patterns as well as engulfing patterns based on differently propagating signals. In addition, the influence of cell division and thus organoid growth on pattern formation is studied in detail. It is shown that this is able to contribute to the formation of clusters and, as a consequence, to breathe some randomness into otherwise perfectly sorted patterns.}, subject = {Mathematische Modellierung}, language = {en} } @phdthesis{Stahlhut2023, author = {Stahlhut, Philipp}, title = {Konzeption und Aufbau einer Nanofokus Labor CT Anlage in Reflexionsgeometrie auf Basis eines Rasterelektronenmikroskops}, doi = {10.25972/OPUS-30264}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-302648}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {In der vorliegenden Arbeit werden die Konzeption und Realisierung eines Computertomographen zur Materialanalyse auf Basis eines Rasterelektronenmikroskops mit einem r{\"a}umlichen Aufl{\"o}sungsverm{\"o}gen im Nanometerbereich diskutiert. Durch einen fokussierten Elektronenstrahl, der mit einer Beschleunigungsspannung von 30 kV auf eine mikrostrukturierte Wolframnadel mit einem Spitzenradius von bis zu 50 nm gezielt wird, entsteht ein kleiner R{\"o}ntgenbrennfleck {\"u}ber den mit geometrischer Vergr{\"o}ßerung hochaufl{\"o}sende Projektionen eines zu untersuchenden Objekts erzeugt werden. Durch Rotation des Testobjekts werden Projektionen aus verschiedenen Blickwinkeln aufgenommen und {\"u}ber einen speziellen Rekonstruktionsalgorithmus zu einem 3-dimensionalen Bild zusammengef{\"u}gt. Bei der Beurteilung der Einzelkomponenten des Ger{\"a}ts wird insbesondere auf Struktur, Form und den elektrochemischen Herstellungsprozess der R{\"o}ntgenquelle eingegangen. Eine ausreichend genaue Positionierung von Messobjekt und R{\"o}ntgenbrennfleck wird {\"u}ber Piezoachsen realisiert, w{\"a}hrend die Stabilit{\"a}t des R{\"o}ntgenbrennflecks {\"u}ber die Elektronenoptik des Rasterelektronenmikroskops und die Form der Quellnadel optimiert wird. Das r{\"a}umliche Aufl{\"o}sungsverm{\"o}gen wird {\"u}ber die Linienspreizfunktion an Materialkanten abgesch{\"a}tzt. F{\"u}r eine Wolfram-Block-Quelle ergibt sich dabei ein Aufl{\"o}sungsverm{\"o}gen von 325 nm - 400 nm in 3D, w{\"a}hrend der Quellfleck einer Wolframnadel das Aufl{\"o}sungsverm{\"o}gen der Anlage auf 65 nm - 90 nm in 2D und 170 nm - 300 nm in 3D bei Messungen an einem AlCu29-Testobjekt anhebt. Außerdem werden die Auswirkungen der Phasenkontrastcharakteristik der R{\"o}ntgenquelle auf die rekonstruierten Bilder nach Anwendung eines Paganin-Filters diskutiert. Dabei zeigt sich, dass durch Anwendung des Filters ein verbessertes Signal-zu-Rausch-Verh{\"a}ltnis auf Kosten der r{\"a}umlichen Bildaufl{\"o}sung erzielt werden kann. Eine Vergleichsmessung mit einem kommerziell verf{\"u}gbaren R{\"o}ntgenmikroskop zeigt die St{\"a}rken des vorgestellten Systems bei Untersuchung von stark absorbierenden Messobjekten. Das kompakte Design erlaubt eine Weiterentwicklung in Richtung eines nanoCT-Moduls als Upgrade Option f{\"u}r Rasterelektronenmikroskope im Gegensatz zu den weitaus teureren bisher verbreiteten nanoCT-Ger{\"a}ten.}, subject = {Computertomographie}, language = {de} } @phdthesis{Schulte2023, author = {Schulte, Annemarie}, title = {\(In\) \(vitro\) reprogramming of glial cells from adult dorsal root ganglia into nociceptor-like neurons}, doi = {10.25972/OPUS-30311}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303110}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Plexus injury often occurs after motor vehicle accidents and results in lifelong disability with severe neuropathic pain. Surgical treatment can partially restore motor functions, but sensory loss and neuropathic pain persist. Regenerative medicine concepts, such as cell replacement therapies for restoring dorsal root ganglia (DRG) function, set high expectations. However, up to now, it is unclear which DRG cell types are affected by nerve injury and can be targeted in regenerative medicine approaches. This study followed the hypothesis that satellite glial cells (SGCs) might be a suitable endogenous cell source for regenerative medicine concepts in the DRG. SGCs originate from the same neural crest-derived cell lineage as sensory neurons, making them attractive for neural repair strategies in the peripheral nervous system. Our hypothesis was investigated on three levels of experimentation. First, we asked whether adult SGCs have the potential of sensory neuron precursors and can be reprogrammed into sensory neurons in vitro. We found that adult mouse DRG harbor SGC-like cells that can still dedifferentiate into progenitor-like cells. Surprisingly, expression of the early developmental transcription factors Neurog1 and Neurog2 was sufficient to induce neuronal and glial cell phenotypes. In the presence of nerve growth factor, induced neurons developed a nociceptor-like phenotype expressing functional nociceptor markers, such as the ion channels TrpA1, TrpV1 and NaV1.9. In a second set of experiments, we used a rat model for peripheral nerve injury to look for changes in the DRG cell composition. Using an unbiased deep learning-based approach for cell analysis, we found that cellular plasticity responses after nerve injury activate SGCs in the whole DRG. However, neither injury-induced neuronal death nor gliosis was observed. Finally, we asked whether a severe nerve injury changed the cell composition in the human DRG. For this, a cohort of 13 patients with brachial plexus injury was investigated. Surprisingly, in about half of all patients, the injury-affected DRG showed no characteristic DRG tissue. The complete entity of neurons, satellite cells, and axons was lost and fully replaced by mesodermal/connective tissue. In the other half of the patients, the basic cellular entity of the DRG was well preserved. Objective deep learning-based analysis of large-scale bioimages of the "intact" DRG showed no loss of neurons and no signs of gliosis. This study suggests that concepts for regenerative medicine for restoring DRG function need at least two translational research directions: reafferentation of existing DRG units or full replacement of the entire multicellular DRG structure. For DRG replacement, SGCs of the adult DRG are an attractive endogenous cell source, as the multicellular DRG units could possibly be rebuilt by transdifferentiating neural crest-derived sensory progenitor cells into peripheral sensory neurons and glial cells using Neurog1 and Neurog2.}, subject = {Spinalganglion}, language = {en} } @phdthesis{WeidergebOswald2023, author = {Weider [geb. Oswald], Margareta}, title = {Mundgesundheit von Hypophosphatasie-Patienten und Gendefekttr{\"a}gern - eine patientenorientierte Querschnittsstudie}, doi = {10.25972/OPUS-30278}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-302781}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Diese Studie evaluiert die Mundgesundheit von Hypophosphatasie (HPP)-Patienten und beinhaltet die Untersuchungen folgender Kenngr{\"o}ßen: erster Milchzahnverlust, Anzahl fehlender Z{\"a}hne, DMF/T-Index (Kari{\"o}s/Fehlend/Gef{\"u}llt), Blutung auf Sondierung (BOP), Sondierungstiefen (PPD), klinisches Attachmentniveau (CAL), Zahnlockerungen und kombinierter CDC/AAP Parodontal-Index. Die Daten wurden zwischen HHP-Patienten mit einer und zwei Mutationen auf dem f{\"u}r die alkalische Phosphatase kodierenden Genabschnitt (ALPL-Gen), sowie mit den Ergebnissen der DMS V verglichen, welche die Mundgesundheit der deutschen Allgemeinbev{\"o}lkerung repr{\"a}sentiert. 80 Patienten wurden untersucht; 64 von ihnen waren weiblich, 18 m{\"a}nnlich. Das Mittlere Alter lag bei 46,4 Jahren. 55 Studienteilnehmer wiesen eine Mutation und 18 zwei Mutationen des ALPL-Gens auf (n=7 keine Testung). Patienten, die von zwei Mutationen des f{\"u}r die alkalische Phosphatase kodierenden Genabschnitts betroffen waren, zeigten ein h{\"o}heres Risiko f{\"u}r Parodontitis und Zahnverlust als HPP-Patienten mit nur einer Mutation, sowie im Vergleich mit der deutschen Allgemeinbev{\"o}lkerung. Allerdings stiegen auch bei Patienten mit nur einer Mutation mit zunehmendem Lebensalter die Auspr{\"a}gungen parodontaler Erkrankungen, sowie die Zahnverlustrate im Vergleich zur Durchschnittsbev{\"o}lkerung in Deutschland.}, subject = {Hypophosphatasie}, language = {de} } @phdthesis{Hartmann2023, author = {Hartmann, Sebastian Erich}, title = {Mobbing und Straining im {\"o}ffentlichen Dienst : Eine rechtliche W{\"u}rdigung juristisch vernachl{\"a}ssigter, aber real existenter Ph{\"a}nomene}, doi = {10.25972/OPUS-31672}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-316724}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Mobbing und Straining sind Ph{\"a}nomene, die in Deutschland bislang kaum rechtliche Beachtung erfahren haben, obgleich sie real existieren, eine Vielzahl von Personen betreffen und immense wirtschaftliche Sch{\"a}den verursachen. So begegnet man diesen Ph{\"a}nomenen zuweilen mit allgemeinen Rechtsinstrumenten, was eine Herausforderung darstellt und mitunter an Grenzen st{\"o}ßt. Im ersten Teil der Arbeit wird ein umfassender {\"U}berblick dar{\"u}ber gegeben, welche Anspr{\"u}che in Betracht kommen und welche rechtlichen M{\"o}glichkeiten f{\"u}r betroffene Personen bestehen. In einer systematischen Darstellung wird aufgezeigt, wie reale Lebensvorg{\"a}nge im Kontext von Mobbing und Straining unter bestehende Rechtsvorschriften subsumiert werden k{\"o}nnen. Im Fokus steht insbesondere der Bereich des {\"o}ffentlichen Dienstes, der aufgrund seiner speziellen Rahmenbedingungen vielfach rechtliche und tats{\"a}chliche Besonderheiten aufweist, die es zu ber{\"u}cksichtigen gilt, wie etwa die Amtshaftung. Neben der rechtlichen Aufarbeitung h{\"a}lt der zweite Teil der Arbeit eine deutschlandweite Studie mit rund 2.300 Teilnehmenden zum Thema Straining und Mobbing im {\"o}ffentlichen Dienst bereit, deren Ergebnisse erstmalig Aussagen und R{\"u}ckschl{\"u}sse zum Strainingaufkommen in Deutschland zulassen. Ferner liefert die umfassende empirische Untersuchung vertiefte Erkenntnisse zur Existenz und Bedeutung der Ph{\"a}nomene Straining und Mobbing im Kontext des {\"o}ffentlichen Dienstes.}, subject = {Mobbing}, language = {de} } @article{WeibelPoppReisetal.2023, author = {Weibel, Stephanie and Popp, Maria and Reis, Stefanie and Skoetz, Nicole and Garner, Paul and Sydenham, Emma}, title = {Identifying and managing problematic trials: A research integrity assessment tool for randomized controlled trials in evidence synthesis}, series = {Research Synthesis Methods}, volume = {14}, journal = {Research Synthesis Methods}, number = {3}, doi = {10.1002/jrsm.1599}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318236}, pages = {357 -- 369}, year = {2023}, abstract = {Evidence synthesis findings depend on the assumption that the included studies follow good clinical practice and results are not fabricated or false. Studies which are problematic due to scientific misconduct, poor research practice, or honest error may distort evidence synthesis findings. Authors of evidence synthesis need transparent mechanisms to identify and manage problematic studies to avoid misleading findings. As evidence synthesis authors of the Cochrane COVID-19 review on ivermectin, we identified many problematic studies in terms of research integrity and regulatory compliance. Through iterative discussion, we developed a research integrity assessment (RIA) tool for randomized controlled trials for the update of this Cochrane review. In this paper, we explain the rationale and application of the RIA tool in this case study. RIA assesses six study criteria: study retraction, prospective trial registration, adequate ethics approval, author group, plausibility of methods (e.g., randomization), and plausibility of study results. RIA was used in the Cochrane review as part of the eligibility check during screening of potentially eligible studies. Problematic studies were excluded and studies with open questions were held in awaiting classification until clarified. RIA decisions were made independently by two authors and reported transparently. Using the RIA tool resulted in the exclusion of >40\% of studies in the first update of the review. RIA is a complementary tool prior to assessing "Risk of Bias" aiming to establish the integrity and authenticity of studies. RIA provides a platform for urgent development of a standard approach to identifying and managing problematic studies.}, language = {en} } @article{BellutBieberKraftetal.2023, author = {Bellut, Maximilian and Bieber, Michael and Kraft, Peter and Weber, Alexander N. R. and Stoll, Guido and Schuhmann, Michael K.}, title = {Delayed NLRP3 inflammasome inhibition ameliorates subacute stroke progression in mice}, series = {Journal of Neuroinflammation}, volume = {20}, journal = {Journal of Neuroinflammation}, number = {1}, doi = {10.1186/s12974-022-02674-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300599}, year = {2023}, abstract = {Background Ischemic stroke immediately evokes a strong neuro-inflammatory response within the vascular compartment, which contributes to primary infarct development under vessel occlusion as well as further infarct growth despite recanalization, referred to as ischemia/reperfusion injury. Later, in the subacute phase of stroke (beyond day 1 after recanalization), further inflammatory processes within the brain parenchyma follow. Whether this second wave of parenchymal inflammation contributes to an additional/secondary increase in infarct volumes and bears the potential to be pharmacologically targeted remains elusive. We addressed the role of the NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome in the subacute phase of ischemic stroke. Methods Focal cerebral ischemia was induced in C57Bl/6 mice by a 30-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with the NLRP3 inhibitor MCC950 therapeutically 24 h after or prophylactically before tMCAO. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 7 after tMCAO. Results Infarct sizes on day 7 after tMCAO decreased about 35\% after delayed and about 60\% after prophylactic NLRP3 inhibition compared to vehicle. Functionally, pharmacological inhibition of NLRP3 mitigated the local inflammatory response in the ischemic brain as indicated by reduction of infiltrating immune cells and reactive astrogliosis. Conclusions Our results demonstrate that the NLRP3 inflammasome continues to drive neuroinflammation within the subacute stroke phase. NLRP3 inflammasome inhibition leads to a better long-term outcome—even when administered with a delay of 1 day after stroke induction, indicating ongoing inflammation-driven infarct progression. These findings may pave the way for eagerly awaited delayed treatment options in ischemic stroke.}, language = {en} } @phdthesis{Saulin2023, author = {Saulin, Anne Christin}, title = {Sustainability of empathy as driver for prosocial behavior and social closeness: insights from computational modelling and functional magnetic resonance imaging}, doi = {10.25972/OPUS-30555}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305550}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Empathy, the act of sharing another person's affective state, is a ubiquitous driver for helping others and feeling close to them. These experiences are integral parts of human behavior and society. The studies presented in this dissertation aimed to investigate the sustainability and stability of social closeness and prosocial decision-making driven by empathy and other social motives. In this vein, four studies were conducted in which behavioral and neural indicators of empathy sustainability were identified using model-based functional magnetic resonance imaging (fMRI). Applying reinforcement learning, drift-diffusion modelling (DDM), and fMRI, the first two studies were designed to investigate the formation and sustainability of empathy-related social closeness (study 1) and examined how sustainably empathy led to prosocial behavior (study 2). Using DDM and fMRI, the last two studies investigated how empathy combined with reciprocity, the social norm to return a favor, on the one hand and empathy combined with the motive of outcome maximization on the other hand altered the behavioral and neural social decision process. The results showed that empathy-related social closeness and prosocial decision tendencies persisted even if empathy was rarely reinforced. The sustainability of these empathy effects was related to recalibration of the empathy-related social closeness learning signal (study 1) and the maintenance of a prosocial decision bias (study 2). The findings of study 3 showed that empathy boosted the processing of reciprocity-based social decisions, but not vice versa. Study 4 revealed that empathy-related decisions were modulated by the motive of outcome maximization, depending on individual differences in state empathy. Together, the studies strongly support the concept of empathy as a sustainable driver of social closeness and prosocial behavior.}, subject = {Einf{\"u}hlung }, language = {en} } @phdthesis{Grimm2023, author = {Grimm, Philipp Martin}, title = {Locally driven complex plasmonic nanoantenna systems}, doi = {10.25972/OPUS-30315}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303152}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Metallic nanostructures possess the ability to support resonances in the visible wavelength regime which are related to localized surface plasmons. These create highly enhanced electric fields in the immediate vicinity of metal surfaces. Nanoparticles with dipolar resonance also radiate efficiently into the far-field and hence serve as antennas for light. Such optical antennas have been explored during the last two decades, however, mainly as standalone units illuminated by external laser beams and more recently as electrically driven point sources, yet merely with basic antenna properties. This work advances the state of the art of locally driven optical antenna systems. As a first instance, the electric driving scheme including inelastic electron tunneling over a nanometer gap is merged with Yagi-Uda theory. The resulting antenna system consists of a suitably wired feed antenna, incorporating a tunnel junction, as well as several nearby parasitic elements whose geometry is optimized using analytical and numerical methods. Experimental evidence of unprecedented directionality of light emission from a nanoantenna is provided. Parallels in the performance between radiofrequency and optical Yagi-Uda arrays are drawn. Secondly, a pair of electrically connected antennas with dissimilar resonances is harnessed as electrodes in an organic light emitting nanodiode prototype. The organic material zinc phthalocyanine, exhibiting asymmetric injection barriers for electrons and holes, in conjunction with the electrode resonances, allows switching and controlling the emitted peak wavelength and directionality as the polarity of the applied voltage is inverted. In a final study, the near-field based transmission-line driving of rod antenna systems is thoroughly explored. Perfect impedance matching, corresponding to zero back-reflection, is achieved when the antenna acts as a generalized coherent perfect absorber at a specific frequency. It thus collects all guided, surface-plasmon mediated input power and transduces it to other nonradiative and radiative dissipation channels. The coherent interplay of losses and interference effects turns out to be of paramount importance for this delicate scenario, which is systematically obtained for various antenna resonances. By means of the here developed semi-analytical toolbox, even more complex nanorod chains, supporting topologically nontrivial localized edge states, are studied. The results presented in this work facilitate the design of complex locally driven antenna systems for optical wireless on-chip communication, subwavelength pixels, and loss-compensated integrated plasmonic nanocircuitry which extends to the realm of topological plasmonics.}, subject = {Plasmonik}, language = {en} } @phdthesis{Lichter2023, author = {Lichter, Katharina}, title = {Die Ultrastruktur von Aktiven Zonen in hippocampalen Moosfaserboutons}, doi = {10.25972/OPUS-30312}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303126}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {In nervous systems, synapses precisely orchestrate information transfer and memory formation. Active zones (AZ) are specialized subcellular compartments at the presynaptic mesoscale which process synaptic transmission on an ultrastructural level. The AZ cytomatrix including the essential scaffold protein Rab3 interacting molecule (RIM) enables exocytosis of synaptic vesicles. A deficiency of the locally most abundant protein isoform RIM1α diminishes long-term potentiation in a complex central mammalian synapse - the connection of hippocampal mossy fiber boutons (MFB) to cornu ammonis (CA)3 pyramidal neurons. Behaviourally, these mice present with learning impairment. The present MD thesis addresses the so far unknown three-dimensional (3D) AZ ultrastructure of MFBs in acute hippocampal slices of wild-type and RIM1α-/- mice. In a first set of experiments, a standardized protocol for near-to-native synaptic tissue preparation at MFBs using high-pressure freezing and freeze substitution and 3D modelling using electron tomography was developed and established. Based on the excellent preservation of synaptic tissue using this protocol, the AZ ultrastructure in both genotypes was quantified in detail up to an individual docked synaptic vesicle using custom-written programming scripts. The experiments demonstrate that deficiency of RIM1α leads to multidimensional alter-ation of AZ 3D ultrastructure and synaptic vesicle pools in MFBs. (Tightly) docked synaptic vesicles - ultrastructural correlates of the readily releasable pool - are reduced, decentralized, and structurally modified, whereas the more distant vesicle pool clusters more densely above larger and more heterogenous AZ surfaces with higher synaptic clefts. The present thesis contributes to a more comprehensive understanding regarding the role of RIM1α for (tight) vesicle docking and organization at MFBs. Furthermore, the precise 3D ultrastructural analysis of MFB AZs in this thesis provides the necessary mor-phological basis for further studies to correlate synaptic ultrastructure with presynaptic plasticity and memory dysfunction in RIM1α-/- mice using advanced electrophysiological and behavioral techniques.}, subject = {Hippocampus}, language = {de} } @phdthesis{FetivaMora2023, author = {Fetiva Mora, Maria Camila}, title = {Changes in chromatin accessibility by oncogenic YAP and its relevance for regulation of cell cycle gene expression and cell migration}, doi = {10.25972/OPUS-30291}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-302910}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Various types of cancer involve aberrant cell cycle regulation. Among the pathways responsible for tumor growth, the YAP oncogene, a key downstream effector of the Hippo pathway, is responsible for oncogenic processes including cell proliferation, and metastasis by controlling the expression of cell cycle genes. In turn, the MMB multiprotein complex (which is formed when B-MYB binds to the MuvB core) is a master regulator of mitotic gene expression, which has also been associated with cancer. Previously, our laboratory identified a novel crosstalk between the MMB-complex and YAP. By binding to enhancers of MMB target genes and promoting B-MYB binding to promoters, YAP and MMB co-regulate a set of mitotic and cytokinetic target genes which promote cell proliferation. This doctoral thesis addresses the mechanisms of YAP and MMB mediated transcription, and it characterizes the role of YAP regulated enhancers in transcription of cell cycle genes. The results reported in this thesis indicate that expression of constitutively active, oncogenic YAP5SA leads to widespread changes in chromatin accessibility in untransformed human MCF10A cells. ATAC-seq identified that newly accessible and active regions include YAP-bound enhancers, while the MMB-bound promoters were found to be already accessible and remain open during YAP induction. By means of CRISPR-interference (CRISPRi) and chromatin immuniprecipitation (ChIP), we identified a role of YAP-bound enhancers in recruitment of CDK7 to MMB-regulated promoters and in RNA Pol II driven transcriptional initiation and elongation of G2/M genes. Moreover, by interfering with the YAP-B-MYB protein interaction, we can show that binding of YAP to B-MYB is also critical for the initiation of transcription at MMB-regulated genes. Unexpectedly, overexpression of YAP5SA also leads to less accessible chromatin regions or chromatin closing. Motif analysis revealed that the newly closed regions contain binding motifs for the p53 family of transcription factors. Interestingly, chromatin closing by YAP is linked to the reduced expression and loss of chromatin-binding of the p53 family member Np63. Furthermore, I demonstrate that downregulation of Np63 following expression of YAP is a key step in driving cellular migration. Together, the findings of this thesis provide insights into the role of YAP in the chromatin changes that contribute to the oncogenic activities of YAP. The overexpression of YAP5SA not only leads to the opening of chromatin at YAP-bound enhancers which together with the MMB complex stimulate the expression of G2/M genes, but also promotes the closing of chromatin at ∆Np63 -bound regions in order to lead to cell migration.}, subject = {Chromatin}, language = {en} } @phdthesis{Sauer2023, author = {Sauer, Christian}, title = {Development, Simulation and Evaluation of Mobile Wireless Networks in Industrial Applications}, doi = {10.25972/OPUS-29923}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299238}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Manyindustrialautomationsolutionsusewirelesscommunicationandrelyontheavail- ability and quality of the wireless channel. At the same time the wireless medium is highly congested and guaranteeing the availability of wireless channels is becoming increasingly difficult. In this work we show, that ad-hoc networking solutions can be used to provide new communication channels and improve the performance of mobile automation systems. These ad-hoc networking solutions describe different communi- cation strategies, but avoid relying on network infrastructure by utilizing the Peer-to- Peer (P2P) channel between communicating entities. This work is a step towards the effective implementation of low-range communication technologies(e.g. VisibleLightCommunication(VLC), radarcommunication, mmWave communication) to the industrial application. Implementing infrastructure networks with these technologies is unrealistic, since the low communication range would neces- sitate a high number of Access Points (APs) to yield full coverage. However, ad-hoc networks do not require any network infrastructure. In this work different ad-hoc net- working solutions for the industrial use case are presented and tools and models for their examination are proposed. The main use case investigated in this work are Automated Guided Vehicles (AGVs) for industrial applications. These mobile devices drive throughout the factory trans- porting crates, goods or tools or assisting workers. In most implementations they must exchange data with a Central Control Unit (CCU) and between one another. Predicting if a certain communication technology is suitable for an application is very challenging since the applications and the resulting requirements are very heterogeneous. The proposed models and simulation tools enable the simulation of the complex inter- action of mobile robotic clients and a wireless communication network. The goal is to predict the characteristics of a networked AGV fleet. Theproposedtoolswereusedtoimplement, testandexaminedifferentad-hocnetwork- ing solutions for industrial applications using AGVs. These communication solutions handle time-critical and delay-tolerant communication. Additionally a control method for the AGVs is proposed, which optimizes the communication and in turn increases the transport performance of the AGV fleet. Therefore, this work provides not only tools for the further research of industrial ad-hoc system, but also first implementations of ad-hoc systems which address many of the most pressing issues in industrial applica- tions.}, subject = {Industrie}, language = {en} } @phdthesis{Hamann2023, author = {Hamann, Catharina Sophia}, title = {Fear and anxiety disorders - interaction of AVP and OXT brain systems with the serotonergic system}, doi = {10.25972/OPUS-30333}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303338}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Anxiety disorders pose a great burden onto society and economy and can have devastating consequences for affected individuals. Treatment options are still limited to psychopharmacotherapy originally developed for the treatment of depression and behavioral therapy. A combination of genetic traits together with aversive events is most likely the cause of these diseases. Gene x environment studies are trying to find a link between genetic traits and specific negative circumstances. In a first study, we focused on social anxiety disorder (SAD), which is the second most-common anxiety disorder after specific phobias. We used a social fear conditioning (SFC) paradigm, which is able to mimic the disease in a mouse model. We wanted to investigate protein levels, as well as mRNA expression of immediate early genes (IEGs), to determine brain areas affected by the paradigm. We also included genes of the vasopressin (AVP)-, oxytocin (OXT)-, neuropeptide Y (NPY)-, and the serotonin system, to investigate the effects of SFC on neurotransmitter gene expression levels in brain regions related to social as well as fear-related behavior. AVP and OXT regulate a lot of different social and anxiety-related behaviors, both positive and negative. Finding a link between different neurotransmitter systems in the development of anxiety disorders could help to identify potential targets for new treatment approaches, which are desperately needed, because the rate of patients not responding to available treatment is very high. We were able to show altered gene expression of the IEGs cFos and Fosl2, as well as a change in number and density of cFOS-positive cells in the dorsal hippocampus, indicating an influence of SFC on neuronal activity. Our results reveal a possible involvement of anterior dentate gyrus (DG), as well as cornu ammonis area 1 (CA1) and CA3 in the dorsal hippocampus during the expression of social fear. Contrary to our hypothesis, we were not able to see changes in neuronal activity through expression changes of IEGs in the amygdala. Significant higher IEG immunoreactivity and gene expression in the dorsal hippocampus of animals without fear conditioning (SFC-), compared to animals with fear conditioning (SFC+), indicate an involvement of different hippocampal regions in two possible scenarios. Either as elevated gene expression in SFC- animals compared to SFC+ animals or as reduction in SFC+ animals compared to SFC- animals. However, this question cannot be answered without an additional control of basal IEG-activity without social interaction. The NPY system in general and the neuropeptide y receptor type 2 in particular seem to be involved in regulating the response to social fear, mostly through the septum region. In addition to that, a possible role for the induction of social fear response could be identified in the serotonergic system and especially the serotonin receptor 2a of the PVN. In a second study we focused on changes in the serotonergic system. A polymorphism in the human serotonin transporter (5-HTT) gene is associated with higher risks for the development of anxiety disorders. This makes the 5-HTT a widely used target to study possible causes and the development of anxiety disorders. In mice, a genetically induced knockout of the 5-Htt gene is associated with increased anxiety-like behavior. High amounts of stress during pregnancy, also known as prenatal stress, significantly increase the risk to develop psychiatric disorders for the unborn child. We utilized a prenatal stress paradigm in mice heterozygous for the 5-Htt gene. Some of the animals which had been subjected to prenatal stress showed noticeably "unsocial" interaction behavior towards conspecifics. Again, we were searching for links between the serotonergic system and AVP- and OXT systems. Through quantitative gene expression analysis, we were able to show that both AVP and OXT neuromodulator systems are affected through prenatal stress in female mice, but not in male mice. The 5-Htt genotype seems to be only slightly influential to AVP, OXT or any other neurotransmitter system investigated. Gene expression of AVP and OXT brain systems is highly influenced through the estrous cycle stages of female mice. Additionally, we analyzed the AVP and OXT neuropeptide levels of mice with different 5-Htt genotypes and in both sexes, in order to see whether the production of AVP and OXT is influenced by 5-Htt genotype. On neuropeptide level, we were able to identify a sex difference for vasopressin-immunoreactive (ir) cells in the PVN, with male mice harboring significantly more positive cells than female mice.}, subject = {Serotonin}, language = {en} }