@article{HedrichMuellerBeckeretal.2018, author = {Hedrich, Rainer and Mueller, Thomas D. and Becker, Dirk and Marten, Irene}, title = {Structure and Function of TPC1 Vacuole SV Channel Gains Shape}, series = {Molecular Plant}, volume = {11}, journal = {Molecular Plant}, doi = {10.1016/j.molp.2018.03.017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228046}, pages = {764-775}, year = {2018}, abstract = {Plants and animals in endosomes operate TPC1/SV-type cation channels. All plants harbor at least one TPC1 gene. Although the encoded SV channel was firstly discovered in the plant vacuole membrane two decades ago, its biological function has remained enigmatic. Recently, the structure of a plant TPC1/SV channel protein was determined. Insights into the 3D topology has now guided site-directed mutation approaches, enabling structure-function analyses of TPC1/SV channels to shed new light on earlier findings. Fou2 plants carrying a hyperactive mutant form of TPC1 develop wounding stress phenotypes. Recent studies with fou2 and mutants that lack functional TPC1 have revealed atypical features in local and long-distance stress signaling, providing new access to the previously mysterious biology of this vacuolar cation channel type in planta.}, language = {en} } @article{VerheijenStevensGentieretal.2018, author = {Verheijen, Bert M. and Stevens, Jo A. A. and Gentier, Romina J. G. and van't Hekke, Christian D. and van den Hove, Daniel L. A. and Hermes, Denise J. H. P. and Steinbusch, Harry W. M. and Ruijter, Jan M. and Grimm, Marcus O. W. and Haupenthal, Viola J. and Annaert, Wim and Hartmann, Tobias and van Leeuwen, Fred W.}, title = {Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model}, series = {Neurobiology of Aging}, volume = {72}, journal = {Neurobiology of Aging}, doi = {10.1016/j.neurobiolaging.2018.08.011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233185}, pages = {62-71}, year = {2018}, abstract = {Amyloid-β (Aβ) plaques are a prominent pathological hallmark of Alzheimer's disease (AD). They consist of aggregated Aβ peptides, which are generated through sequential proteolytic processing of the transmembrane protein amyloid precursor protein (APP) and several Aβ-associated factors. Efficient clearance of Aβ from the brain is thought to be important to prevent the development and progression of AD. The ubiquitin-proteasome system (UPS) is one of the major pathways for protein breakdown in cells and it has been suggested that impaired UPS-mediated removal of protein aggregates could play an important role in the pathogenesis of AD. To study the effects of an impaired UPS on Aβ pathology in vivo, transgenic APPSwe/PS1ΔE9 mice (APPPS1) were crossed with transgenic mice expressing mutant ubiquitin (UBB+1), a protein-based inhibitor of the UPS. Surprisingly, the APPPS1/UBB+1 crossbreed showed a remarkable decrease in Aβ plaque load during aging. Further analysis showed that UBB+1 expression transiently restored PS1-NTF expression and γ-secretase activity in APPPS1 mice. Concurrently, UBB+1 decreased levels of β-APP-CTF, which is a γ-secretase substrate. Although UBB+1 reduced Aβ pathology in APPPS1 mice, it did not improve the behavioral deficits in these animals.}, language = {en} } @phdthesis{Liu2024, author = {Liu, Yang}, title = {Predictions for Composite Higgs Models Using Gauge/Gravity Duality}, doi = {10.25972/OPUS-37083}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370833}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {This thesis is dedicated to construct a non-abelian holographic dynamical minimal composite Higgs model. We first build a non-abelian bottom-up AdS/YM model that can explain the QCD meson spectrum well. The model is made non-abelian by considering non-abelian DBI action in the top-down model. We then change the dual theory from the QCD to the minimal composite Higgs model U (4)/Sp(4). By adding a second explicit U (4) → Sp(4) breaking through the NJL interaction at the boundary, we managed to construct a composite Higgs phase and a technicolor phase in this model. The transition between the two phases is also realized, which is controlled by the NJL coupling. This thesis is based on the works [1, 2].}, subject = {Higgs-Modell}, language = {en} } @phdthesis{Fuhl2024, author = {Fuhl, Lucas}, title = {Photolumineszenzmikroskopie und -spektroskopie endohedraler Farbstoffe in Bornitridnanor{\"o}hren}, doi = {10.25972/OPUS-37115}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371150}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Im Rahmen der vorliegenden Dissertation wurde untersucht, wie die Einkapselung organischer Farbstoffmolek{\"u}le in Bornitridnanor{\"o}hren (BNNTs) die photophysikalischen Eigenschaften der Fluorophore beeinflusst. Als Farbstoffe wurden hierbei alpha-Quaterthiophen (4T), alpha-Sexithiophen (6T), alpha-Octithiophen (8T) sowie Nilrot (NR) ausgew{\"a}hlt. Die eingesetzten BNNTs besitzen einen nominellen Durchmesser von \(5 \pm 2\)nm. F{\"u}r die Charakterisierung der reinen Farbstoffe und der hybriden Systeme aus Farbstoff und Nanor{\"o}hre kam ein Laboraufbau zum Einsatz, der neben Absorptions- und Photolumineszenz (PL)-Spektroskopie auch PL-Mikroskopie erm{\"o}glicht. Zus{\"a}tzlich l{\"a}sst sich damit auch eine zeitaufgel{\"o}ste Untersuchung der PL (engl. time correlated single photon counting, TCSPC) im Ensemble und an einzelnen, separierten Nano-Objekten (mit Farbstoff gef{\"u}llte BNNTs) umsetzen. In Kapitel 5 wurden zun{\"a}chst die freien Farbstoffe in L{\"o}sung charakterisiert. Es hat sich gezeigt, dass sowohl 4T als auch NR im verwendeten L{\"o}semittel Dimethylformamid (DMF) l{\"o}slich sind, wohingegen 6T und 8T hier eine geringere L{\"o}slichkeit zeigen. Die unterschiedlichen Verl{\"a}ufe der konzentrationsabh{\"a}ngigen PL-Spektren f{\"u}r 4T und 6T in DMF lassen sich vermutlich auf diesen L{\"o}slichkeitsunterschied zur{\"u}ckf{\"u}hren. Zudem wurden Extinktionskoeffizienten f{\"u}r 4T und NR mittels konzentrationsabh{\"a}ngiger Absorptionsspektren bestimmt und es zeigte sich eine gute {\"U}bereinstimmung mit der Literatur. F{\"u}r 6T und 8T war eine Bestimmung aufgrund der geringen L{\"o}slichkeit nicht m{\"o}glich, weshalb auf Literaturwerte zur{\"u}ckgegriffen wurde oder diese extrapoliert wurden (8T). In Kapitel 6 erfolgte die detaillierte Charakterisierung der mit Oligothiophenen gef{\"u}llten BNNTs. Die Bef{\"u}llung wurde dabei im Wesentlichen nach einem von C. Allard publizierten Verfahren durchgef{\"u}hrt und auf die zus{\"a}tzlichen Fluorophore 4T, 8T und NR {\"u}bertragen. F{\"u}r Messungen mittels UV-Vis-Spektroskopie in L{\"o}sung bzw. Dispersion hat sich beim Farbstoff 6T gezeigt, dass sich das Absorptionsmaximum von 407nm (freies 6T) hin zu 506nm (6T@BNNT) verschiebt. Ursache hierf{\"u}r ist vermutlich die Bildung von J-Aggregaten im Inneren der R{\"o}hren. Die entsprechenden PL-Spektren von freiem 6T und dem Hybridsystem zeigen dabei keine signifikanten Unterschiede. F{\"u}r konzentrationsabh{\"a}ngige PL-Spektren von 6T@BNNT ergibt sich (anders als bei freiem 6T in DMF) keine {\"A}nderung des Verlaufs der Kurven, was als ein Indiz f{\"u}r eine erfolgreiche Einkapselung gedeutet werden kann. Durch Kombination von Rasterkraft- und PL-Mikroskopie konnten die Außendurchmesser von einzelnen 6T@BNNT Objekten ermittelt und in direkten Zusammenhang mit deren photophysikalischen Eigenschaften gebracht werden. Bei einer Analyse der Polarisation des Emissionslichtes von 6T@BNNT in Abh{\"a}ngigkeit des Außendurchmessers ließ sich jedoch keine klare Korrelation zwischen Struktur und Emissionscharakteristiken erkennen. Diese Beobachtung l{\"a}sst sich vermutlich dadurch erkl{\"a}ren, dass mit Hilfe der Rasterkraftmikroskopie lediglich der Außendurchmesser der (teils mehrwandigen) BNNTs bestimmt werden kann. Die entscheidende Gr{\"o}ße an dieser Stelle ist allerdings der innere Durchmesser der BNNTs, welcher die Ausrichtung und damit auch die Polarisation der Farbstoffmolek{\"u}le beeinflusst. Ein Vergleich des mittleren maximalen Polarisationsgrades der jeweiligen Hybridsysteme hat gezeigt, dass 4T@BNNT den geringsten und 6T@BNNT mit den h{\"o}chsten Wert aufweist. Dies best{\"a}tigt die Annahme, dass mit zunehmender Molek{\"u}ll{\"a}nge die Polarisation, aufgrund des h{\"o}heren Templat-Effektes der R{\"o}hre, zunimmt. 8T@BNNT liegt zwischen den beiden anderen Werten, was dieser Annahme widerspricht. Der mittlere Verkippungswinkel der eingekapselten Farbstoffmolek{\"u}le gegen{\"u}ber der R{\"o}hrenachse liegt f{\"u}r 4T@BNNT bei etwa 16° und ist damit etwas gr{\"o}ßer als derjenige von 6T@BNNT. Somit zeigt sich auch hier, dass k{\"u}rzere Molek{\"u}le mehr sterische Freiheitsgerade im Innern der R{\"o}hren besitzen. F{\"u}r 8T@BNNT liegt der Winkel bei ca. 28° und widerspricht abermals der Annahme. TCSPC-Messungen an freien Oligothiophen-Farbstoffen sowie an den hybriden Systemen zeigten, dass die Fluoreszenzlebensdauer \(\tau\) f{\"u}r 4T und 6T (jeweils in DMF) infolge der Einkapselung deutlich zunimmt wenn die Hybridsysteme ebenfalls in DMF dispergiert sind. Die ermittelten Werte f{\"u}r \(\tau\) der separierten Nanoobjekte lagen f{\"u}r 4T@BNNT und 6T@BNNT unterhalb der entsprechenden in DMF. F{\"u}r 8T bzw. 8T@BNNT ergab sich eine deutlich k{\"u}rzerer Lebensdauer der separierten Nanoobjekte im Vergleich zum freien Farbstoff in kolloidaler Suspension. Ein erster Ansatz, um den zugrundeliegende Mechanismus aufzukl{\"a}ren, bestand darin, die TCSPC-Spektren (f{\"u}r 6T in DMF und 6T@BNNT in DMF) hinsichtlich der einzelnen Zerfallskan{\"a}le zu analysieren. Die erhaltenen Ergebnisse deuteten darauf hin, dass bei freiem 6T in DMF andere Zerfallskan{\"a}le dominieren als beim Hybridsystem 6T@BNNT (in DMF). Eine Korrelation der Fluorezenslebensdauer von 6T@BNNT vom {\"a}ußeren Durchmesser der Nanor{\"o}hren zeigte keinen eindeutigen Zusammenhang. Die Charakterisierung von Nilrot bzw. NR@BNNT (analog zu den Oligothiophenen) erfolgte in Kapitel 4. Auch hier zeigte sich eine Verschiebung des PL-Spektrums des Fluorophores durch die Einkapselung in die BNNTs. Allerdings ist das PL-Spektrum des Hybridsystems (NR@BNNT) um etwa 20nm hypsochrom verschoben. Nilrot ist in der Literatur zudem als Nanosonde zur Ermittlung der Permittivit{\"a}t des L{\"o}semittels bzw. der Umgebung bekannt. Dies erlaubte eine Absch{\"a}tzung der relativen Permittiv{\"a}t im Inneren der BNNTs. Der ermittelte Wert von ca. 4 f{\"u}r ein isoliertes NR@BNNT Objekt deutet auf eine relativ unpolare Umgebung im R{\"o}hreninneren hin. Zum Vergleich dazu, liegt der Wert von freiem NR in DMF bei 47, was die relativ hohe Polarit{\"a}t von DMF best{\"a}tigt. Der ermittelte Wert f{\"u}r die mittlere maximale Polarisation lag leicht {\"u}ber dem der hybriden Systeme aus Oligothiophenen und Nanor{\"o}hren. F{\"u}r die Auslenkung der NR-Molek{\"u}le gegen{\"u}ber der R{\"o}hrenachse ergab sich ein Winkel von etwa 16°, was im Bereich der Werte von 4T@BNNT und 6T@BNNT liegt. Die Messung der zeitaufgel{\"o}sten Fluoreszenz von freiem und eingekapseltem Nilrot hat ergeben, dass auch in diesem Fall eine Verk{\"u}rzung der Lebensdauer (von 4091 ps auf 812 ps) erfolgte. Eine solche Verk{\"u}rzung der Lebensdauer von Chromophoren wird in der Literatur unter anderem mit der Bildung von J-Aggregaten in Zusammenhang gebracht.}, subject = {Fluoreszenzmikroskopie}, language = {de} } @phdthesis{Schuhmair2024, author = {Schuhmair, Leah Sophia}, title = {Etablierung eines in-situ-Immunfluoreszenzf{\"a}rbeverfahrens zur dreidimensionalen Darstellung und Quantifizierung der Immunzellinfiltration in experimentellen Tumoren}, doi = {10.25972/OPUS-37094}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370945}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Brustkrebs ist die h{\"a}ufigste diagnostizierte Krebserkrankung weltweit. Trotz der vielf{\"a}ltigen Behandlungsm{\"o}glichkeiten endet die Diagnose Brustkrebs in vielen F{\"a}llen noch immer t{\"o}dlich. Aus diesem Grund ist die Entwicklung neuer Therapieans{\"a}tze wichtig. Ein Therapieansatz, der in den letzten zehn Jahren immer mehr an Bedeutung gewonnen hat, ist die Immuntherapie. Allerdings konnte sie bei Brustkrebs noch keine großen Erfolge erzielen. Ursache hierf{\"u}r ist die geringe Immunzellinfiltration in Brusttumoren. Um Brustkrebs f{\"u}r Immuntherapie empf{\"a}nglicher zu machen, m{\"u}ssten Immuntherapeutika in Kombination mit Medikamenten angewendet werden, die die Immunzellinfiltration steigern. Um die Wirksamkeit solcher Medikamente in pr{\"a}klinischen Studien zu testen, braucht es eine Methode, mit der man die T-Zellverteilung innerhalb des Tumors darstellen kann. F{\"u}r umfassendes Verst{\"a}ndnis ist dreidimensionale Darstellung der Zellen im Tumor notwendig, da es einen großen Unterschied macht, ob sich die T-Zellen im Tumorstroma oder in unmittelbarer N{\"a}he zu den Tumorzellen befinden. Die starke Fibrotisierung der Extrazellul{\"a}ren Matrix, die typisch f{\"u}r Brusttumoren ist, erschwert nicht nur die Immunzellinfiltration, sondern auch die Diffusion der fluoreszierenden Antik{\"o}rper ins Gewebe. Im Zuge dieser Arbeit wurde eine Methode entwickelt, um im dreidimensionalen CD4 und CD8-positive T-Zellen in Brusttumoren darzustellen. Dies gelang mittels Immunfluoreszenzf{\"a}rbung und anschließender dreidimensionaler Aufnahme mithilfe optischer Sektionierung am Lichtblattmikroskop. Erreicht wurde dies durch deutliche Erh{\"o}hung der Inkubationszeiten, aggressive Permeabilisierung des Gewebes, Testen unterschiedlicher Antik{\"o}rper bzw. Antik{\"o}rperkombinationen und Entf{\"a}rbung sowie Kl{\"a}rung des Tumorgewebes. Dar{\"u}ber hinaus konnten erste Schritte in der nachtr{\"a}glichen Bearbeitung der Aufnahmen inklusive Rekonstruktion der Zellen gemacht werden. F{\"u}r die Anwendung des Verfahrens in Studien zur Medikamentenwirksamkeit ist noch weitere Optimierung notwendig.}, subject = {Immunfluoreszenz}, language = {de} } @phdthesis{Adolf2024, author = {Adolf, Jonas Michael}, title = {Die Zusammenarbeit zwischen der station{\"a}ren beziehungsweise teilstation{\"a}ren psychotherapeutischen Behandlung und niedergelassenen Psychotherapeut:innen}, doi = {10.25972/OPUS-37109}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371098}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das Ziel der vorliegenden Arbeit war es die aktuelle Versorgungskontinuit{\"a}t in der psychotherapeutischen Versorgung hinsichtlich der Zusammenarbeit des (teil-)station{\"a}ren und des ambulanten Sektors aus Sicht der niedergelassenen Psychotherapeut:innen zu untersuchen, diese in den wissenschaftlichen Kontext einzuordnen und - falls m{\"o}glich - erste M{\"o}glichkeiten zur Verbesserung der derzeitigen Versorgungskontinuit{\"a}t aufzuzeigen. In Zusammenarbeit mit dem Arbeitsbereich f{\"u}r Medizinische Psychologie und Psychotherapie im Zentrum f{\"u}r psychische Gesundheit des Universit{\"a}tsklinikums W{\"u}rzburg wurde hierzu ein Fragebogen entwickelt und acht ausgew{\"a}hlten psychotherapeutischen Fachgesellschaften beziehungsweise Psychotherapeutenkammern mit der Bitte um Weiterleitung an deren Mitglieder zugesandt. In der vorliegenden Studie wurden - neben einer Globalbeurteilung - im Speziellen die Teil-aspekte des Austauschs, der entsprechenden Rahmenbedingungen und die Bereitstellung des poststation{\"a}ren ambulanten Psychotherapieplatzes betrachtet. Die Studienergebnisse bilden den derzeitigen Status Quo der psychotherapeutischen Versorgungslage aus Sicht der niedergelassenen Psychotherapeut:innen ab und weisen im Zuge dessen auf einige Defizite in den untersuchten Teilaspekten hin. Die aufgestellten Nebenfragestellungen zeigen gleichsam aber auch Ansatzunkte f{\"u}r L{\"o}sungen auf. Aufgrund der besonderen Relevanz der aufgezeigten Ergebnisse, gilt es - zur Erm{\"o}glichung einer ad{\"a}quaten kontinuierlichen psychotherapeutischen Versorgung - eine weitergehende Betrach-tung der aufgezeigten Defizite vorzunehmen. F{\"u}r ein umfassendes Bild sind zudem kongruente Folgearbeiten mit dem Augenmerk auf der Sichtweise der (teil-)station{\"a}ren Behandlungseinrichtungen und der Patient:innen notwendig. Insbesondere vor dem Hintergrund der limitierten M{\"o}glichkeiten der vorliegenden Arbeit gilt es große repr{\"a}sentative und nationale Studien anzustreben. Hierzu w{\"a}re die Etablierung zentral verwalteter Register zur B{\"u}ndelung der bisherigen und zuk{\"u}nftigen Forschungsarbeiten im Bereich der Psychotherapie w{\"u}nschenswert. Vor allem vor dem Hintergrund zahlreicher Modellprojekte erscheint dies sinnvoll und k{\"o}nnte einen wichtigen Beitrag zur Optimierung der derzeitigen psychotherapeutischen Forschungs- und Versorgungslage beitragen.}, subject = {Psychotherapie}, language = {de} } @phdthesis{Weiss2024, author = {Weiß, Eva Maria}, title = {Einfluss von Makrophagen auf autophagische Vorg{\"a}nge in Schwann´schen Zellen unter den Bedingungen von Nervenl{\"a}sion und genetisch bedingter Neuropathie}, doi = {10.25972/OPUS-36967}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369674}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Charcot-Marie-Tooth (CMT) Neuropathien stellen als h{\"a}ufigste erblich bedingte neurologische Erkrankungen eine Gruppe genetisch heterogener, chronisch progredienter peripherer Polyneuropathien dar. Die Lebensqualit{\"a}t der Patienten ist bei fehlender kurativer Therapieoption vor allem durch motorische und sensorische Defizite deutlich eingeschr{\"a}nkt. In verschiedenen Studien konnte die pathophysiologische Relevanz einer sekund{\"a}ren Entz{\"u}ndungsreaktion, insbesondere durch Makrophagen und Lymphozyten vermittelt, in Mausmodellen dreier CMT1 Subtypen (CMT1A, CMT1B, CMT1X) aufgezeigt werden. Auch in Folge einer L{\"a}sion peripherer Nerven ist eine akute Entz{\"u}ndungsreaktion von entscheidender Bedeutung, wobei sich bereits Gemeinsamkeiten zwischen der postl{\"a}sionalen Waller´schen Degeneration (WD) und CMT1 Neuropathien identifizieren ließen. W{\"a}hrend die aktive Beteiligung der Autophagie Schwann´scher Zellen (hier kurz SZ Autophagie genannt) an der Myelindegradation im Falle einer WD jedoch vielfach beschrieben wurde, ist {\"A}hnliches in CMT1 Neuropathien bisher nur unzureichend untersucht. Da in einer Studie in Cx32def Mausmodellen der CMT1X Erkrankung auch nach Reduktion endoneuraler Makrophagen anhaltende Demyelinisierung beobachtet werden konnte, sollte das Vorkommen von SZ Autophagie sowie deren m{\"o}gliche Beeinflussung durch Makrophagen in diesen Myelinmutanten untersucht werden. In der vorliegenden Arbeit wurden sowohl Wildtyp (Wt) M{\"a}use in ex vivo und in vivo Modellen einer WD als auch Cx32def Myelinmutanten zweier Altersstufen (4 und 12 Monate) mit einem niedermolekularen CSF1-Rezeptor-Inhibitor (CSF1RI) zur Reduktion endoneuraler Makrophagen behandelt, wobei sich vergleichende histochemische bzw. immunhistochemische Analysen peripherer Nerven behandelter und unbehandelter Tiere anschlossen. Im Rahmen der Etablierung immunhistochemischer Methodik zeigte sich hierbei unter den kontrollierten Bedingungen einer ex vivo Ischiasnervenkultur eine vermehrte Aktivierung der SZ Autophagie in behandelten Wt M{\"a}usen. Auch 4 Monate alte behandelte Cx32def Tiere wiesen, verglichen mit unbehandelten Myelinmutanten bzw. Wt M{\"a}usen derselben Altersstufe, eine vermehrte autophagische Aktivit{\"a}t in SZ auf. Diese scheint sich jedoch im weiteren Verlauf der Erkrankung zu reduzieren, da im Falle der 12 Monate alten Cx32def Modelltiere weniger autophagisch aktive SZ Profile bzw. kaum Unterschiede zwischen behandelten und unbehandelten Tieren beobachtet werden konnten. Die Ergebnisse lassen somit eine m{\"o}gliche aktive Beteiligung von SZ Autophagie insbesondere in der Pathophysiologie der fr{\"u}hen Phase einer CMT1X Erkrankung sowie deren Beeinflussung durch endoneurale Makrophagen vermuten. Dies sollte vornehmlich in der Entwicklung von Therapiestrategien der CMT1X bedacht werden, da sich eine fr{\"u}he Reduktion pathophysiologisch relevanter endoneuraler Makrophagen somit auch nachteilig auf die Myelinintegrit{\"a}t auswirken k{\"o}nnte.}, subject = {Schwann-Zelle}, language = {de} } @phdthesis{RuppertgebRapp2024, author = {Ruppert [geb. Rapp], Elisabeth Marlene}, title = {Einfluss von sozialem Stress und 5-Htt-Genotyp: Quantitative Untersuchung der Morphologie von Neuronen der lateralen Amygdala und der CA3-Region des Hippocampus von M{\"a}usen der Serotonintransporter-Knockout-Linie}, doi = {10.25972/OPUS-36948}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369488}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In dieser Arbeit wurde der Einfluss sozialer Stresserfahrung sowie des 5-Htt-Genotyps auf die neuronale Morphologie bestimmter Hirnregionen anhand eines Mausmodells untersucht. Es wurde in mit Golgi-Cox gef{\"a}rbten Gehirnen der 5-HTT-KO-Linie in der lateralen Amygdala (LA) die Apikal- und Basaldendriten pyramidenzell{\"a}hnlicher Neurone und die Apikaldendriten der Pyramidenzellen der Cornu ammonis (CA)3-Region des Hippocampus mithilfe des Neurolucidasystems rekonstruiert und die so gewonnenen Daten anschließend statistisch ausgewertet. Die erzielten Ergebnisse belegen, dass vor allem die Erfahrung von sozialem Verteidigungsstress aber auch der 5-Htt-Genotyp (WT, HET, KO) im Mausmodell signifikanten Einfluss auf die Morphologie der Neurone der LA und der CA3-Region besitzen. Um die in dieser Arbeit mit allen drei 5-Htt-Genotypen erzielten Ergebnisse der LA-Neurone besser mit den Ergebnissen von Nietzer und Bonn (nur WT, KO) vergleichen zu k{\"o}nnen (Nietzer et al., 2011), wurden die von mir erhobenen Daten nicht nur in einem 3er-Vergleich, sondern auch einem 2er-Vergleich (WT vs. KO) statistisch analysiert. Untersuchungen der LA-Neurone aller drei 5-Htt-Genotypen zeigen, dass sozialer Stress zu einer Zunahme der Komplexit{\"a}t der Dendritenb{\"a}ume durch l{\"a}ngere und auch st{\"a}rker verzweigte Dendriten vor allem in der Gruppe der WT-M{\"a}use f{\"u}hrt. HET- und KO-M{\"a}use zeigten keinen entsprechenden Stress-Effekt. Dar{\"u}ber hinaus zeigten sich deutliche Genotypeffekte. Unabh{\"a}ngig vom Stresserleben besitzen HET-M{\"a}use l{\"a}ngere Dendriten als WT-M{\"a}use sowie eine h{\"o}here Spinedichte als WT- und KO-M{\"a}use. Die Hypothese, die in der Arbeit von Nietzer et al. aufgestellt wurde, dass eine vollst{\"a}ndige 5-HTT-Defizienz zu mehr Spines f{\"u}hrt, ließ sich hier weder durch den 3er- noch durch den 2er-Vergleich replizieren. Die Pyramidenzellen der CA3-Region, die in dieser Studie zum ersten Mal analysiert wurden, zeigen in Bezug auf die durch den Stress ausgel{\"o}sten Ver{\"a}nderungen ein im Vergleich zu den LA-Neuronen entgegengesetzten Effekt. Der soziale Stress f{\"u}hrt hier zu einer Dendritenatrophie in der WT-Gruppe mit k{\"u}rzeren und weniger komplexen Dendriten. Außerdem f{\"u}hrte er zu einer geringeren Spinedichte bei den HET-M{\"a}usen. Es zeigten sich klare Genotypeffekte, unabh{\"a}ngig von der Stresserfahrung, mit einer reduzierten Spinedichte der KO-M{\"a}use gegen{\"u}ber den WT-M{\"a}usen und einer nur in den Kontrollen detektierten, reduzierten Spinedichte der KO-M{\"a}use im Vergleich zu den WT- und HET-M{\"a}usen. Sowohl in der LA als auch in der CA3-Region lassen sich Kompensationsmechanismen des 5-HTT-Defizits der HET-Tiere vermuten, {\"u}ber die die KO-Tiere nicht verf{\"u}gen. Die in LA und CA3 gezeigten gegens{\"a}tzlichen Auswirkungen des sozialen Stresses weisen auf die unterschiedlichen Funktionen dieser beiden Regionen im Furchtkreislauf und/oder bei der Verarbeitung von Stress hin. Dar{\"u}ber hinaus deutet diese Arbeit darauf hin, dass Arbeiten mit {\"a}hnlichen Untersuchungsmethoden und sogar gleichem Untersuchungsmaterial unterschiedliche Ergebnisse liefern k{\"o}nnen.}, subject = {Serotoninstoffwechsel}, language = {de} } @phdthesis{Kluepfel2024, author = {Kl{\"u}pfel, Marina Anna}, title = {Lagedarstellung und -Bewertung durch den Einsatz des Windm{\"u}hlenmodells - Einf{\"u}hrung und Nutzung im Rahmen der SARS-CoV-2 Pandemie}, doi = {10.25972/OPUS-36959}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369595}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Bei Großschadensereignissen oder Katastrophen arbeiten die Einsatzkr{\"a}fte verschiedener Organisationen und Krankenh{\"a}user zusammen, um die Schadenslage zu bew{\"a}ltigen. F{\"u}r die Koordinierung dieser Eins{\"a}tze ben{\"o}tigen die F{\"u}hrungskr{\"a}fte ein m{\"o}glichst genaues Bild der aktuellen Lage. Auch im Rahmen der SARS-CoV-2- Pandemie war eine {\"U}bersicht {\"u}ber die Versorgungslage der Krankenh{\"a}user erforderlich, um m{\"o}gliche lokale Ressourcenengp{\"a}sse fr{\"u}hzeitig zu erkennen und durch geeignete Maßnahmen zu beheben. Zu diesem Zweck wurde in Bayern im November 2021 das Windm{\"u}hlen-Modell eingef{\"u}hrt. Basierend auf einer Online-Plattform meldeten die zust{\"a}ndigen Bezirkskoordinierenden der bayerischen Regierungsbezirke t{\"a}glich die Versorgungslage ihrer Kliniken anhand der Komponenten Personal, Material und Raum. Außerdem gab es die M{\"o}glichkeit zur Dokumentation von Patientenverlegungen. Die {\"u}ber die Windm{\"u}hlen-Onlineplattform gesammelten Lagemeldungen und dokumentierten Verlegungen des Zeitraums von 21. November 2021 bis 20. Februar 2022 wurden in der vorliegenden Arbeit detailliert aufbereitet. Zus{\"a}tzlich wurden die erfassten Daten statistisch ausgewertet und mit den {\"o}rtlichen 7-Tage-Inzidenzwerten des SARS-CoV-2-Virus verglichen. Durch das Windm{\"u}hlen-Modell konnten Unterschiede in der Versorgungslage zwischen den Regierungsbezirken sehr effektiv sichtbar gemacht werden. Insgesamt waren Intensivstationen deutlich st{\"a}rker belastet als Normalstationen. Die Versorgungsqualit{\"a}t war in Covid-Bereichen st{\"a}rker beeintr{\"a}chtigt als auf Stationen ohne Covid-Patienten. Es konnte nachgewiesen werden, dass die Windm{\"u}hlen-Lagemeldungen nicht allein die regionalen Inzidenzwerte, sondern die tats{\"a}chliche Versorgungssituation vor Ort abbilden. Die dokumentierten Interhospitaltransfers erfolgten von Regionen mit hohen Inzidenzwerten und schlechter Ressourcenverf{\"u}gbarkeit in Bezirke mit weniger kritischer Versorgungslage. Damit konnten aus den Windm{\"u}hlen-Lagemeldungen auch konkrete Handlungskonsequenzen, wie strategische Patientenverlegungen, abgeleitet werden. Lagemeldungen sind wichtig f{\"u}r die abgestimmte Zusammenarbeit verschiedener Stellen bei der Bew{\"a}ltigung einer Krise. Die etablierten Systeme zur Lageerfassung sind meist quantitativ ausgelegt und nur wenig skalierbar. Die Anwendung in einem neuen Kontext erfordert oft zeitaufw{\"a}ndige Anpassungen. Im Gegensatz dazu bietet das Windm{\"u}hlen-Modell eine skalierbare, eher qualitativ ausgerichtete Lagedarstellung und ist aufgrund seines unkomplizierten Aufbaus innerhalb k{\"u}rzester Zeit f{\"u}r eine Nutzung in verschiedensten Schadenslagen adaptierbar.}, subject = {Katastrophenmedizin}, language = {de} } @phdthesis{Nair2024, author = {Nair, Radhika Karal}, title = {Structural and biochemical characterization of USP28 inhibition by small molecule inhibitors}, doi = {10.25972/OPUS-28174}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281742}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Ubiquitination is an important post-translational modification that maintains cellular homeostasis by regulating various biological processes. Deubiquitinases (DUBs) are enzymes that reverse the ubiquitination process by catalyzing the removal of ubiquitin from a substrate. Abnormal expression or function of DUBs is often associated with the onset and progression of various diseases, including cancer. Ubiquitin specific proteases (USPs), which constitute the largest family of DUBs in humans, have become the center of interest as potential targets in cancer therapy as many of them display increased activity or are overexpressed in a range of malignant tumors or the tumor microenvironment. Two related members of the USP family, USP28 and USP25, share high sequence identities but play diverse biological roles. USP28 regulates cell proliferation, oncogenesis, DNA damage repair and apoptosis, whereas USP25 is involved in the anti-viral response, innate immunity and ER-associated degradation in addition to carcinogenesis. USP28 and USP25 also exhibit different oligomeric states - while USP28 is a constitutively active dimer, USP25 assumes an auto-inhibited tetrameric structure. The catalytic domains of both USP28 and USP25 comprise the canonical, globular USP-domain but contain an additional, extended insertion site called USP25/28 catalytic domain inserted domain (UCID) that mediates oligomerization of the proteins. Disruption of the USP25 tetramer leads to the formation of an activated dimeric protein. However, it is still not clear what triggers its activation. Due to their role in maintaining and stabilizing numerous oncoproteins, USP28 and USP25 have emerged as interesting candidates for anti-cancer therapy. Recent advances in small-molecular inhibitor development have led to the discovery of relatively potent inhibitors of USP28 and USP25. This thesis focuses on the structural elucidation of USP28 and the biochemical characterization of USP28/USP25, both in complex with representatives of three out of the eight compound classes reported as USP28/USP25-specific inhibitors. The crystal structures of USP28 in complex with the AZ compounds, Vismodegib and FT206 reveal that all three inhibitor classes bind into the same allosteric pocket distant from the catalytic center, located between the palm and the thumb subdomains (the S1-site). Intriguingly, this binding pocket is identical to the UCID-tip binding interface in the USP25 tetramer, rendering the protein in a locked, inactive conformation. Formation of the binding pocket in USP28 requires a shift in the helix α5, which induces conformational changes and local distortion of the binding channel that typically accommodates the C-terminal tail of Ubiquitin, thus preventing catalysis and abrogating USP28 activity. The key residues of the USP28-inhibitor binding pocket are highly conserved in USP25. Mutagenesis studies of these residues accompanied by biochemical and biophysical assays confirm the proposed mechanism of inhibition and similar binding to USP25. This work provides valuable insights into the inhibition mechanism of the small molecule compounds specifically for the DUBs USP28 and USP25. The USP28-inhibitor complex structures offer a framework to develop more specific and potent inhibitors.}, subject = {Unique Selling Proposition}, language = {en} } @article{KampfBauerReiter2018, author = {Kampf, Thomas and Bauer, Wolfgang Rudolf and Reiter, Theresa}, title = {Improved post-processing strategy for MOLLI based tissue characterization allows application in patients with dyspnoe and impaired left ventricular function}, series = {Zeitschrift f{\"u}r Medizinische Physik}, volume = {28}, journal = {Zeitschrift f{\"u}r Medizinische Physik}, doi = {10.1016/j.zemedi.2017.07.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325481}, pages = {25-35}, year = {2018}, abstract = {Contrast and non-contrast MRI based characterization of myocardium by T1-mapping will be of paramount importance to obtain biomarkers, e.g. fibrosis, which determines the risk of heart failure patients. T1-mapping by the standard post-processing of the modified look-locker inversion recovery (MOLLI) lacks of accuracy when trying to reduce its duration, which on the other hand, is highly desirable in patients with heart failure. The recently suggested inversion group fitting (IGF) technique, which considers more parameters for fitting, has a superior accuracy for long T1 times despite a shorter duration. However, for short T1 values, the standard method has a superior precision. A conditional fitting routine is proposed which ideally takes advantage of both algorithms. Materials and methods All measurements were performed on a 1.5 T clinical scanner (ACHIEVA, Philips Healthcare, The Netherlands) using a MOLLI 5(n)3(n)3 prototype with n(heart beats) being a variable waiting time between inversion experiments. Phantom experiments covered a broad range of T1 times, waiting times and heart rates. A saturation recovery experiment served as a gold standard for T1 measurement. All data were analyzed with the standard MOLLI, the IGF fit and the conditional fitting routine and the obtained T1 values were compared with the gold standard. In vivo measurements were performed in a healthy volunteer and a total of 34 patients with normal findings, dilative cardiomyopathy and amyloidosis. Results Theoretical analysis and phantom experiments provided a threshold value for an apparent IGF determining processing with IGF post processing for values above, or switching to the standard technique for values below. This was validated in phantoms and patients measurements. A reduction of the waiting time to 1 instead of 3 heart beats between the inversion experiments showed reliable results. The acquisition time was reduced from 17 to 13 heart beats. The in vivo measurements showed ECV values between 25\% (18-33\%; SD 0.03) in the healthy, 30\% (22-40\%; SD 0.04) in patients with DCM and 45\% (30-60\%; SD 0.9) in patients with amyloidosis. Conclusion The adopted post-processing algorithm determines long T1 values with high accuracy and short T1 values while maintaining a high precision. Based on reduction of waiting time, and independence of heart rate, it shortens breath hold duration and allows fast T1-mapping, which is frequently a prerequisite in patients with cardiac diseases.}, language = {en} } @article{NanadikarVergelLeonBorowiketal.2019, author = {Nanadikar, Maithily S. and Vergel Leon, Ana M. and Borowik, Sergej and Hillemann, Annette and Zieseniss, Anke and Belousov, Vsevolod V. and Bogeski, Ivan and Rehling, Peter and Dudek, Jan and Katschinski, D{\"o}rthe M.}, title = {O2 affects mitochondrial functionality ex vivo}, series = {Redox Biology}, volume = {22}, journal = {Redox Biology}, doi = {10.1016/j.redox.2019.101152}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232217}, year = {2019}, abstract = {Mitochondria have originated in eukaryotic cells by endosymbiosis of a specialized prokaryote approximately 2 billion years ago. They are essential for normal cell function by providing energy through their role in oxidizing carbon substrates. Glutathione (GSH) is a major thiol-disulfide redox buffer of the cell including the mitochondrial matrix and intermembrane space. We have generated cardiomyocyte-specific Grx1-roGFP2 GSH redox potential (EGSH) biosensor mice in the past, in which the sensor is targeted to the mitochondrial matrix. Using this mouse model a distinct EGSH of the mitochondrial matrix (-278.9 ± 0.4 mV) in isolated cardiomyocytes is observed. When analyzing the EGSH in isolated mitochondria from the transgenic hearts, however, the EGSH in the mitochondrial matrix is significantly oxidized (-247.7 ± 8.7 mV). This is prevented by adding N-Ethylmaleimide during the mitochondria isolation procedure, which precludes disulfide bond formation. A similar reducing effect is observed by isolating mitochondria in hypoxic (0.1-3\% O2) conditions that mimics mitochondrial pO2 levels in cellulo. The reduced EGSH is accompanied by lower ROS production, reduced complex III activity but increased ATP levels produced at baseline and after stimulation with succinate/ADP. Altogether, we demonstrate that oxygenation is an essential factor that needs to be considered when analyzing mitochondrial function ex vivo.}, language = {en} } @article{UeceylerUrlaubMayeretal.2019, author = {{\"U}{\c{c}}eyler, Nurcan and Urlaub, Daniela and Mayer, Christine and Uehlein, Sabrina and Held, Melissa and Sommer, Claudia}, title = {Tumor necrosis factor-α links heat and inflammation with Fabry pain}, series = {Molecular Genetics and Metabolism}, volume = {127}, journal = {Molecular Genetics and Metabolism}, doi = {https://doi.org/10.1016/j.ymgme.2019.05.009}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229190}, pages = {200-206}, year = {2019}, abstract = {Fabry disease (FD) is an X-linked lysosomal storage disorder associated with pain triggered by heat or febrile infections. We modelled this condition by measuring the cytokine expression of peripheral blood mononuclear cells (PBMC) from FD patients in vitro upon stimulation with heat and lipopolysaccharide (LPS). We enrolled 67 FD patients and 37 healthy controls. We isolated PBMC, assessed their gene expression of selected pro- and anti-inflammatory cytokines, incubated them with heat, LPS, globotriaosylceramide (Gb3), and tumor necrosis factor-α (TNF), and measured TNF secretion in the supernatant and intracellular Gb3 accumulation, respectively. We found increased TNF, interleukin (IL-)1β, and toll-like receptor 4 (TLR4) gene expression in FD men (p < .05 to p < .01). TNF and IL-10 were higher, and IL-4 was lower in the subgroup of FD men with pain compared to controls (p < .05 to p < .01). Hereby, TNF was only increased in FD men with pain and classical mutations (p < .05) compared to those without pain. PBMC from FD patients secreted more TNF upon stimulation with LPS (p < .01) than control PBMC. Incubation with Gb3 and an additional α-galactosidase A inhibitor did not further increase TNF secretion, but incubation with TNF greatly increased the Gb3 load in FD PBMC compared to controls (p < .01). Also, LPS incubation and heat challenge (40 °C) increased Gb3 accumulation in PBMC of patients compared to baseline (p < .05 each), while no alterations were observed in control PBMC. Our data show that TNF holds a crucial role in the pathophysiology of FD associated pain, which may open a novel perspective for analgesic treatment in FD pain.}, language = {en} } @article{KampfReiterBauer2018, author = {Kampf, Thomas and Reiter, Theresa and Bauer, Wolfgang Rudolf}, title = {An analytical model which determines the apparent T1 for Modified Look-Locker Inversion Recovery - Analysis of the longitudinal relaxation under the influence of discontinuous balanced (classical MOLLI) and spoiled gradient echo readouts}, series = {Zeitschrift f{\"u}r Medizinische Physik}, volume = {28}, journal = {Zeitschrift f{\"u}r Medizinische Physik}, doi = {10.1016/j.zemedi.2017.07.004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325498}, pages = {150-157}, year = {2018}, abstract = {Quantitative nuclear magnetic resonance imaging (MRI) shifts more and more into the focus of clinical research. Especially determination of relaxation times without/and with contrast agents becomes the foundation of tissue characterization, e.g. in cardiac MRI for myocardial fibrosis. Techniques which assess longitudinal relaxation times rely on repetitive application of readout modules, which are interrupted by free relaxation periods, e.g. the Modified Look-Locker Inversion Recovery = MOLLI sequence. These discontinuous sequences reveal an apparent relaxation time, and, by techniques extrapolated from continuous readout sequences, a putative real T1 is determined. What is missing is a rigorous analysis of the dependence of the apparent relaxation time on its real partner, readout sequence parameters and biological parameters as heart rate. This is provided in this paper for the discontinuous balanced steady state free precession (bSSFP) and spoiled gradient echo readouts. It turns out that the apparent longitudinal relaxation rate is the time average of the relaxation rates during the readout module, and free relaxation period. Knowing the heart rate our results vice versa allow to determine the real T1 from its measured apparent partner.}, language = {en} } @article{MindenSchnetgerPufaletal.2018, author = {Minden, Vanessa and Schnetger, Bernhard and Pufal, Gesine and Leonhardt, Sara D.}, title = {Antibiotic-induced effects on scaling relationships and on plant element contents in herbs and grasses}, series = {Ecology and Evolution}, volume = {8}, journal = {Ecology and Evolution}, doi = {10.1002/ece3.4168}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224094}, pages = {6699-6713}, year = {2018}, abstract = {Plant performance is correlated with element concentrations in plant tissue, which may be impacted by adverse chemical soil conditions. Antibiotics of veterinary origin can adversely affect plant performance. They are released to agricultural fields via grazing animals or manure, taken up by plants and may be stored, transformed or sequestered by plant metabolic processes. We studied the potential effects of three antibiotics (penicillin, sulfadiazine, and tetracycline) on plant element contents (macro- and microelements). Plant species included two herb species (Brassica napus and Capsella bursa-pastoris) and two grass species (Triticum aestivum and Apera spica-venti), representing two crop species and two noncrop species commonly found in field margins, respectively. Antibiotic concentrations were chosen as to reflect in vivo situations, that is, relatively low concentrations similar to those detected in soils. In a greenhouse experiment, plants were raised in soil spiked with antibiotics. After harvest, macro- and microelements in plant leaves, stems, and roots were determined (mg/g). Results indicate that antibiotics can affect element contents in plants. Penicillin exerted the greatest effect both on element contents and on scaling relationships of elements between plant organs. Roots responded strongest to antibiotics compared to stems and leaves. We conclude that antibiotics in the soil, even in low concentrations, lead to low-element homeostasis, altering the scaling relationships between roots and other plant organs, which may affect metabolic processes and ultimately the performance of a plant.}, language = {en} } @article{DuellLammersDjureticetal.2019, author = {Duell, Johannes and Lammers, Philip E. and Djuretic, Ivana and Chunyk, Allison G. and Alekar, Shilpa and Jacobs, Ira and Gill, Saar}, title = {Bispecific Antibodies in the Treatment of Hematologic Malignancies}, series = {Clinical Pharmacology \& Therapeutics}, volume = {106}, journal = {Clinical Pharmacology \& Therapeutics}, doi = {10.1002/cpt.1396}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226392}, pages = {781-791}, year = {2019}, abstract = {Monoclonal antibody therapies are an important approach for the treatment of hematologic malignancies, but typically show low single-agent activity. Bispecific antibodies, however, redirect immune cells to the tumor for subsequent lysis, and preclinical and accruing clinical data support single-agent efficacy of these agents in hematologic malignancies, presaging an exciting era in the development of novel bispecific formats. This review discusses recent developments in this area, highlighting the challenges in delivering effective immunotherapies for patients.}, language = {en} } @article{SteinStenchlyCoulibalyetal.2018, author = {Stein, Katharina and Stenchly, Kathrin and Coulibaly, Drissa and Pauly, Alain and Dimobe, Kangbeni and Steffan-Dewenter, Ingolf and Konat{\´e}, Souleymane and Goetze, Dethardt and Porembski, Stefan and Linsenmair, K. Eduard}, title = {Impact of human disturbance on bee pollinator communities in savanna and agricultural sites in Burkina Faso, West Africa}, series = {Ecology and Evolution}, volume = {8}, journal = {Ecology and Evolution}, doi = {10.1002/ece3.4197}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239999}, pages = {6827-6838}, year = {2018}, abstract = {All over the world, pollinators are threatened by land-use change involving degradation of seminatural habitats or conversion into agricultural land. Such disturbance often leads to lowered pollinator abundance and/or diversity, which might reduce crop yield in adjacent agricultural areas. For West Africa, changes in bee communities across disturbance gradients from savanna to agricultural land are mainly unknown. In this study, we monitored for the impact of human disturbance on bee communities in savanna and crop fields. We chose three savanna areas of varying disturbance intensity (low, medium, and high) in the South Sudanian zone of Burkina Faso, based on land-use/land cover data via Landsat images, and selected nearby cotton and sesame fields. During 21 months covering two rainy and two dry seasons in 2014 and 2015, we captured bees using pan traps. Spatial and temporal patterns of bee species abundance, richness, evenness and community structure were assessed. In total, 35,469 bee specimens were caught on 12 savanna sites and 22 fields, comprising 97 species of 32 genera. Bee abundance was highest at intermediate disturbance in the rainy season. Species richness and evenness did not differ significantly. Bee communities at medium and highly disturbed savanna sites comprised only subsets of those at low disturbed sites. An across-habitat spillover of bees (mostly abundant social bee species) from savanna into crop fields was observed during the rainy season when crops are mass-flowering, whereas most savanna plants are not in bloom. Despite disturbance intensification, our findings suggest that wild bee communities can persist in anthropogenic landscapes and that some species even benefitted disproportionally. West African areas of crop production such as for cotton and sesame may serve as important food resources for bee species in times when resources in the savanna are scarce and receive at the same time considerable pollination service.}, language = {en} } @article{LiHanTessaroloetal.2019, author = {Li, Ru-Jin and Han, Muxin and Tessarolo, Jacopo and Holstein, Julian J. and L{\"u}bben, Jens and Dittrich, Birger and Volkmann, Christian and Finze, Maik and Jenne, Carsten and Clever, Guido H.}, title = {Successive Photoswitching and Derivatization Effects in Photochromic Dithienylethene-Based Coordination Cages}, series = {ChemPhotoChem}, volume = {3}, journal = {ChemPhotoChem}, doi = {10.1002/cptc.201900038}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236815}, pages = {378-383}, year = {2019}, abstract = {A new series of [Pd2(L)4] cages based on photochromic dithienylethene (DTE) ligands allowed us to gain insight into the successive photoswitching of multiple DTE moieties in a confined metallo-supramolecular assembly. Three new X-ray structures of [Pd2(o-L4)4], [Pd2(o-L1)2(c-L1)2] and [Pd2(c-L1)4] (o-L and c-L = open and closed forms of DTE ligands, respectively) were obtained. The structures deliver snapshots of three different combinations of DTE photoisomeric states within the cage, facilitating a comparison of the all-open with the all-closed, and most notably, an intermediate form where open and closed switches co-exist in the same cage. Moreover, a series of spherical anionic borate clusters was introduced in order to study their roles in the light-controllable host-guest chemistry. The binding guests show higher affinities with the flexible open cage [Pd2(o-L1)4] than with the rigid closed cage [Pd2(c-L1)4]. For the [B12F12]2- guest, thermodynamic data obtained from NMR experiments was compared to results from isothermal titration calorimetry (ITC).}, language = {en} } @article{AngayFriedrichPinneckeretal.2018, author = {Angay, Oguzhan and Friedrich, Mike and Pinnecker, J{\"u}rgen and Hintzsche, Henning and Stopper, Helga and Hempel, Klaus and Heinze, Katrin G.}, title = {Image-based modeling and scoring of Howell-Jolly Bodies in human erythrocytes}, series = {Cytometry Part A}, volume = {93}, journal = {Cytometry Part A}, doi = {10.1002/cyto.a.23123}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221140}, pages = {305-313}, year = {2018}, abstract = {The spleen selectively removes cells with intracellular inclusions, for example, detached nuclear fragments in circulating erythrocytes, called Howell-Jolly Bodies (HJBs). With absent or deficient splenic function HJBs appear in the peripheral blood and can be used as a simple and non-invasive risk-indicator for fulminant potentially life-threatening infection after spleenectomy. However, it is still under debate whether counting of the rare HJBs is a reliable measure of splenic function. Investigating HJBs in premature erythrocytes from patients during radioiodine therapy gives about 10 thousand times higher HJB counts than in blood smears. However, we show that there is still the risk of false-positive results by unspecific nuclear remnants in the prepared samples that do not originate from HJBs, but from cell debris residing above or below the cell. Therefore, we present a method to improve accuracy of image-based tests that can be performed even in non-specialized medical institutions. We show how to selectively label HJB-like clusters in human blood samples and how to only count those that are undoubtedly inside the cell. We found a "critical distance" dcrit referring to a relative HJB-Cell distance that true HJBs do not exceed. To rule out false-positive counts we present a simple inside-outside-rule based on dcrit—a robust threshold that can be easily assessed by combining conventional 2D imaging and straight-forward image analysis. Besides data based on fluorescence imaging, simulations of randomly distributed HJB-like objects on realistically modelled cell objects demonstrate the risk and impact of biased counting in conventional analysis. © 2017 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC.}, language = {en} } @article{MuentzeNordbeck2019, author = {M{\"u}ntze, Jonas and Nordbeck, Peter}, title = {Response to "Oral Chaperone Therapy Migalastat for the Treatment of Fabry Disease: Potentials and Pitfalls of Real-World Data"}, series = {Clinical Pharmacology \& Therapeutics}, volume = {106}, journal = {Clinical Pharmacology \& Therapeutics}, doi = {10.1002/cpt.1533}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231600}, pages = {927-928}, year = {2019}, abstract = {No abstract available}, language = {en} } @article{OPUS4-31409, title = {Electron and photon energy calibration with the ATLAS detector using 2015-2016 LHC proton-proton collision data}, series = {Journal of Instrumentation}, volume = {14}, journal = {Journal of Instrumentation}, organization = {The ATLAS Collaboration}, doi = {10.1088/1748-0221/14/03/P03017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-314093}, pages = {1-58}, year = {2019}, abstract = {This paper presents the electron and photon energy calibration obtained with the ATLAS detector using about 36 fb(-1) of LHC proton-proton collision data recorded at root s = 13 TeV in 2015 and 2016. The different calibration steps applied to the data and the optimization of the reconstruction of electron and photon energies are discussed. The absolute energy scale is set using a large sample of Z boson decays into electron-positron pairs. The systematic uncertainty in the energy scale calibration varies between 0.03\% to 0.2\% in most of the detector acceptance for electrons with transverse momentum close to 45 GeV. For electrons with transverse momentum of 10 GeV the typical uncertainty is 0.3\% to 0.8\% and it varies between 0.25\% and 1\% for photons with transverse momentum around 60 GeV. Validations of the energy calibration with J/psi -> e(+)e(-) decays and radiative Z boson decays are also presented.}, language = {en} } @article{HartkeSprengerSahmetal.2019, author = {Hartke, Juliane and Sprenger, Philipp P. and Sahm, Jacqueline and Winterberg, Helena and Orivel, J{\´e}r{\^o}me and Baur, Hannes and Beuerle, Till and Schmitt, Thomas and Feldmeyer, Barbara and Menzel, Florian}, title = {Cuticular hydrocarbons as potential mediators of cryptic species divergence in a mutualistic ant association}, series = {Ecology and Evolution}, volume = {9}, journal = {Ecology and Evolution}, doi = {10.1002/ece3.5464}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227857}, pages = {9160-9176}, year = {2019}, abstract = {Upon advances in sequencing techniques, more and more morphologically identical organisms are identified as cryptic species. Often, mutualistic interactions are proposed as drivers of diversification. Species of the neotropical parabiotic ant association between Crematogaster levior and Camponotus femoratus are known for highly diverse cuticular hydrocarbon (CHC) profiles, which in insects serve as desiccation barrier but also as communication cues. In the present study, we investigated the association of the ants' CHC profiles with genotypes and morphological traits, and discovered cryptic species pairs in both genera. To assess putative niche differentiation between the cryptic species, we conducted an environmental association study that included various climate variables, canopy cover, and mutualistic plant species. Although mostly sympatric, the two Camponotus species seem to prefer different climate niches. However in the two Crematogaster species, we could not detect any differences in niche preference. The strong differentiation in the CHC profiles may thus suggest a possible role during speciation itself either by inducing assortative mating or by reinforcing sexual selection after the speciation event. We did not detect any further niche differences in the environmental parameters tested. Thus, it remains open how the cryptic species avoid competitive exclusion, with scope for further investigations.}, language = {en} } @article{FrantzFalcaoPiresBalligandetal.2018, author = {Frantz, Stefan and Falcao-Pires, Ines and Balligand, Jean-Luc and Bauersachs, Johann and Brutsaert, Dirk and Ciccarelli, Michele and Dawson, Dana and de Windt, Leon J. and Giacca, Mauro and Hamdani, Nazha and Hilfiker-Kleiner, Denise and Hirsch, Emilio and Leite-Moreira, Adelino and Mayr, Manuel and Thum, Thomas and Tocchetti, Carlo G. and van der Velden, Jolanda and Varricchi, Gilda and Heymans, Stephane}, title = {The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC}, series = {European Journal of Heart Failure}, volume = {20}, journal = {European Journal of Heart Failure}, doi = {10.1002/ejhf.1138}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229091}, pages = {445-459}, year = {2018}, abstract = {Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies.}, language = {en} } @article{deBoerDeKeulenaerBauersachsetal.2019, author = {de Boer, Rudolf A. and De Keulenaer, Gilles and Bauersachs, Johann and Brutsaert, Dirk and Cleland, John G. and Diez, Javier and Du, Xiao-Jun and Ford, Paul and Heinzel, Frank R. and Lipson, Kenneth E. and McDonagh, Theresa and Lopez-Andres, Natalia and Lunde, Ida G. and Lyon, Alexander R. and Pollesello, Piero and Prasad, Sanjay K. and Tocchetti, Carlo G. and Mayr, Manuel and Sluijter, Joost P. G. and Thum, Thomas and Tsch{\"o}pe, Carsten and Zannad, Faiez and Zimmermann, Wolfram-Hubertus and Ruschitzka, Frank and Filippatos, Gerasimos and Lindsey, Merry L. and Maack, Christoph and Heymans, Stephane}, title = {Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology}, series = {European Journal of Heart Failure}, volume = {21}, journal = {European Journal of Heart Failure}, doi = {10.1002/ejhf.1406}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223613}, pages = {272-285}, year = {2019}, abstract = {Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins — resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research.}, language = {en} } @article{KoenigZundelKrimmeretal.2019, author = {K{\"o}nig, Kerstin and Zundel, Petra and Krimmer, Elena and K{\"o}nig, Christian and Pollmann, Marie and Gottlieb, Yuval and Steidle, Johannes L. M.}, title = {Reproductive isolation due to prezygotic isolation and postzygotic cytoplasmic incompatibility in parasitoid wasps}, series = {Ecology and Evolution}, volume = {9}, journal = {Ecology and Evolution}, doi = {10.1002/ece3.5588}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222796}, pages = {10694-10706}, year = {2019}, abstract = {The reproductive barriers that prevent gene flow between closely related species are a major topic in evolutionary research. Insect clades with parasitoid lifestyle are among the most species-rich insects and new species are constantly described, indicating that speciation occurs frequently in this group. However, there are only very few studies on speciation in parasitoids. We studied reproductive barriers in two lineages of Lariophagus distinguendus (Chalcidoidea: Hymenoptera), a parasitoid wasp of pest beetle larvae that occur in human environments. One of the two lineages occurs in households preferably attacking larvae of the drugstore beetle Stegobium paniceum ("DB-lineage"), the other in grain stores with larvae of the granary weevil Sitophilus granarius as main host ("GW-lineage"). Between two populations of the DB-lineage, we identified slight sexual isolation as intraspecific barrier. Between populations from both lineages, we found almost complete sexual isolation caused by female mate choice, and postzygotic isolation, which is partially caused by cytoplasmic incompatibility induced by so far undescribed endosymbionts which are not Wolbachia or Cardinium. Because separation between the two lineages is almost complete, they should be considered as separate species according to the biological species concept. This demonstrates that cryptic species within parasitoid Hymenoptera also occur in Central Europe in close contact to humans.}, language = {en} } @article{KendallRaderGagicetal.2019, author = {Kendall, Liam K. and Rader, Romina and Gagic, Vesna and Cariveau, Daniel P. and Albrecht, Matthias and Baldock, Katherine C. R. and Freitas, Breno M. and Hall, Mark and Holzschuh, Andrea and Molina, Francisco P. and Morten, Joanne M. and Pereira, Janaely S. and Portman, Zachary M. and Roberts, Stuart P. M. and Rodriguez, Juanita and Russo, Laura and Sutter, Louis and Vereecken, Nicolas J. and Bartomeus, Ignasi}, title = {Pollinator size and its consequences: Robust estimates of body size in pollinating insects}, series = {Ecology and Evolution}, volume = {9}, journal = {Ecology and Evolution}, doi = {10.1002/ece3.4835}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325705}, pages = {1702-1714}, year = {2019}, abstract = {Body size is an integral functional trait that underlies pollination-related ecological processes, yet it is often impractical to measure directly. Allometric scaling laws have been used to overcome this problem. However, most existing models rely upon small sample sizes, geographically restricted sampling and have limited applicability for non-bee taxa. Allometric models that consider biogeography, phylogenetic relatedness, and intraspecific variation are urgently required to ensure greater accuracy. We measured body size as dry weight and intertegular distance (ITD) of 391 bee species (4,035 specimens) and 103 hoverfly species (399 specimens) across four biogeographic regions: Australia, Europe, North America, and South America. We updated existing models within a Bayesian mixed-model framework to test the power of ITD to predict interspecific variation in pollinator dry weight in interaction with different co-variates: phylogeny or taxonomy, sexual dimorphism, and biogeographic region. In addition, we used ordinary least squares regression to assess intraspecific dry weight ~ ITD relationships for ten bees and five hoverfly species. Including co-variates led to more robust interspecific body size predictions for both bees and hoverflies relative to models with the ITD alone. In contrast, at the intraspecific level, our results demonstrate that the ITD is an inconsistent predictor of body size for bees and hoverflies. The use of allometric scaling laws to estimate body size is more suitable for interspecific comparative analyses than assessing intraspecific variation. Collectively, these models form the basis of the dynamic R package, "pollimetry," which provides a comprehensive resource for allometric pollination research worldwide.}, language = {en} } @article{HillaertHovestadtVandegehuchteetal.2018, author = {Hillaert, Jasmijn and Hovestadt, Thomas and Vandegehuchte, Martijn L. and Bonte, Dries}, title = {Size-dependent movement explains why bigger is better in fragmented landscapes}, series = {Ecology and Evolution}, volume = {8}, journal = {Ecology and Evolution}, doi = {10.1002/ece3.4524}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320322}, pages = {10754-10767}, year = {2018}, abstract = {Body size is a fundamental trait known to allometrically scale with metabolic rate and therefore a key determinant of individual development, life history, and consequently fitness. In spatially structured environments, movement is an equally important driver of fitness. Because movement is tightly coupled with body size, we expect habitat fragmentation to induce a strong selection pressure on size variation across and within species. Changes in body size distributions are then, in turn, expected to alter food web dynamics. However, no consensus has been reached on how spatial isolation and resource growth affect consumer body size distributions. Our aim was to investigate how these two factors shape the body size distribution of consumers under scenarios of size-dependent and size-independent consumer movement by applying a mechanistic, individual-based resource-consumer model. We also assessed the consequences of altered body size distributions for important ecosystem traits such as resource abundance and consumer stability. Finally, we determined those factors that explain most variation in size distributions. We demonstrate that decreasing connectivity and resource growth select for communities (or populations) consisting of larger species (or individuals) due to strong selection for the ability to move over longer distances if the movement is size-dependent. When including size-dependent movement, intermediate levels of connectivity result in increases in local size diversity. Due to this elevated functional diversity, resource uptake is maximized at the metapopulation or metacommunity level. At these intermediate levels of connectivity, size-dependent movement explains most of the observed variation in size distributions. Interestingly, local and spatial stability of consumer biomass is lowest when isolation and resource growth are high. Finally, we highlight that size-dependent movement is of vital importance for the survival of populations or communities within highly fragmented landscapes. Our results demonstrate that considering size-dependent movement is essential to understand how habitat fragmentation and resource growth shape body size distributions—and the resulting metapopulation or metacommunity dynamics—of consumers.}, language = {en} } @article{NolteHermannLingenPlatscheketal.2019, author = {Nolte, Kathleen and Hermann-Lingen, Christoph and Platschek, Lars and Holzendorf, Volker and Pilz, Stefan and Tomaschitz, Andreas and D{\"u}ngen, Hans-Dirk and Angermann, Christiane E. and Hasenfuß, Gerd and Pieske, Burkert and Wachter, Rolf and Edelmann, Frank}, title = {Vitamin D deficiency in patients with diastolic dysfunction or heart failure with preserved ejection fraction}, series = {ESC Heart Failure}, volume = {6}, journal = {ESC Heart Failure}, doi = {10.1002/ehf2.12413}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232303}, pages = {262-270}, year = {2019}, abstract = {Aims Vitamin D deficiency is prevalent in heart failure (HF), but its relevance in early stages of heart failure with preserved ejection fraction (HFpEF) is unknown. We tested the association of 25-hydroxyvitamin D [25(OH)D] serum levels with mortality, hospitalizations, cardiovascular risk factors, and echocardiographic parameters in patients with asymptomatic diastolic dysfunction (DD) or newly diagnosed HFpEF. Methods and results We measured 25(OH)D serum levels in outpatients with risk factors for DD or history of HF derived from the DIAST-CHF study. Participants were comprehensively phenotyped including physical examination, echocardiography, and 6 min walk test and were followed up to 5 years. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire. We included 787 patients with available 25(OH)D levels. Median 25(OH)D levels were 13.1 ng/mL, mean E/e′ medial was 13.2, and mean left ventricular ejection fraction was 59.1\%. Only 9\% (n = 73) showed a left ventricular ejection fraction <50\%. Fifteen per cent (n = 119) of the recruited participants had symptomatic HFpEF. At baseline, participants with 25(OH)D levels in the lowest tertile (≤10.9 ng/L; n = 263) were older, more often symptomatic (oedema and fatigue, all P ≤ 0.002) and had worse cardiac [higher N-terminal pro-brain natriuretic peptide (NT-proBNP) and left atrial volume index, both P ≤ 0.023], renal (lower glomerular filtration rate, P = 0.012), metabolic (higher uric acid levels, P < 0.001), and functional (reduced exercise capacity, 6 min walk distance, and SF-36 physical functioning score, all P < 0.001) parameters. Increased NT-proBNP, uric acid, and left atrial volume index and decreased SF-36 physical functioning scores were independently associated with lower 25(OH)D levels. There was a higher risk for lower 25(OH)D levels in association with HF, DD, and atrial fibrillation (all P ≤ 0.004), which remained significant after adjusting for age. Lower 25(OH)D levels (per 10 ng/mL decrease) tended to be associated with higher 5 year mortality, P = 0.05, hazard ratio (HR) 1.55 [1.00; 2.42]. Furthermore, lower 25(OH)D levels (per 10 ng/mL decrease) were related to an increased rate of cardiovascular hospitalizations, P = 0.023, HR = 1.74 [1.08; 2.80], and remained significant after adjusting for age, P = 0.046, HR = 1.63 [1.01; 2.64], baseline NT-proBNP, P = 0.048, HR = 1.62 [1.01; 2.61], and other selected baseline characteristics and co-morbidities, P = 0.043, HR = 3.60 [1.04; 12.43]. Conclusions Lower 25(OH)D levels were associated with reduced functional capacity in patients with DD or HFpEF and were significantly predictive for an increased rate of cardiovascular hospitalizations, also after adjusting for age, NT-proBNP, and selected baseline characteristics and co-morbidities.}, language = {en} } @article{BavendiekBerlinerAguirreDavilaetal.2019, author = {Bavendiek, Udo and Berliner, Dominik and Aguirre D{\´a}vila, Lukas and Schwab, Johannes and Maier, Lars and Philipp, Sebastian A. and Rieth, Andreas and Westenfeld, Ralf and Piorkowski, Christopher and Weber, Kristina and H{\"a}nselmann, Anja and Oldhafer, Maximiliane and Schallhorn, Sven and von der Leyen, Heiko and Schr{\"o}der, Christoph and Veltmann, Christian and St{\"o}rk, Stefan and B{\"o}hm, Michael and Koch, Armin and Bauersachs, Johann}, title = {Rationale and design of the DIGIT-HF trial (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure): a randomized, double-blind, placebo-controlled study}, series = {European Journal of Heart Failure}, volume = {21}, journal = {European Journal of Heart Failure}, organization = {DIGIT-HF Investigators and Committees}, doi = {10.1002/ejhf.1452}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221548}, pages = {676-684}, year = {2019}, abstract = {Aims Despite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides - although regularly used for HF treatment - remains unclear. DIGIT-HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF). Methods Patients with chronic HF, New York Heart Association (NYHA) functional class III-IV and left ventricular ejection fraction (LVEF) ≤ 40\%, or patients in NYHA functional class II and LVEF ≤ 30\% are randomized 1:1 in a double-blind fashion to treatment with digitoxin (target serum concentration 8-18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all-cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all-cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF. Conclusion The DIGIT-HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all-cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment.}, language = {en} } @phdthesis{Hinsch2024, author = {Hinsch, Jan Per}, title = {Die Geschichte der Metalllegierungen in der zahn{\"a}rztlichen Prothetik und Technologie}, doi = {10.25972/OPUS-37128}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371285}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die vorliegende Promotionsstudie leistet durch Gewinnung neuer Erkenntnisse zur zahnmedizinisch (technik-)historischen Forschung mittels der Erarbeitung und Darstellung einer chronologisch geordneten Entwicklungsgeschichte der zahn{\"a}rztlich-prothetisch verwendeten Metalllegierungen sowie ihrer dentalen Technologie einen eigenst{\"a}ndigen Forschungsbeitrag und tr{\"a}gt damit zu neuen Erkenntnissen in der zahnmedizinisch-historischen Forschung bei. Als problematisch stellte sich zu Beginn des 19. Jahrhunderts die Kunst des Legierens selbst heraus. So legierten und fertigten die Zahn{\"a}rzte ihre Metalllegierungen bis zum Ende des 19. Jahrhunderts meistens noch selbst, bedienten sich an vorlegierten Dukatengoldlegierungen oder beauftragten Goldschmiede. Diverse n{\"u}tzliche Legierungskompositionen wurden schriftlich von Pionieren der Zahnheilkunde und den ersten, erfahrensten Prothetikern dieser Zeit in deren fr{\"u}hen Lehrb{\"u}chern und Ver{\"o}ffentlichungen festgehalten und damit der breiten Zahn{\"a}rzteschaft zug{\"a}nglich gemacht. Mit ihrem Engagement wurde der Weg von der Empirie nicht nur bis zur Verwissenschaftlichung der Zahnmedizin geebnet, sondern zugleich der Fortschritt der dentalen Materialwissenschaft und besonders der Verarbeitungstechnologie dentaler Metalllegierungen eingel{\"a}utet. Erst zu Beginn des 20. Jahrhunderts etablierte sich durch Forschung und Vernetzung von Chemie, Metallurgie, Industrie und Zahnmedizin eine sach- und fachkundige zahn{\"a}rztliche Werkstoffkunde mit speziellen prothetisch geeigneten Metalllegierungen. Die verschiedenen Typenbezeichnungen Goldersatzlegierungen, Austauschlegierungen, Alternativlegierungen oder Aufbrennlegierungen waren in jeder Epoche einem tiefgreifenden Wandel unterworfen und charakteristisch f{\"u}r die jeweilige Zeit. Eine wichtige Erkenntnis aus dieser Studie ist, dass politisch-{\"o}konomische Ver{\"a}nderungen, insbesondere schwankende Edelmetallpreise, Inflation, politische Beschr{\"a}nkungen aufgrund von (vor-)kriegswirtschaftlichen Sparmaßnahmen sowie Gesundheitsreformen und Kostend{\"a}mpfungsgesetze einen erheblichen Einfluss auf die Zahn{\"a}rzte und die zahnmedizinisch-prothetische Rehabilitation ihrer Patienten hatte. Die indikationsgerechte Metalllegierungsauswahl und die damit verbundenen optimalen Materialeigenschaften f{\"u}r Zahnersatz und Patienten stellten Zahn{\"a}rzte damals wie heute vor eine Herausforderung.}, subject = {Prothetik}, language = {de} } @phdthesis{Franken2024, author = {Franken, Robert}, title = {Precision Predictions for \(\mathrm W^+ \mathrm W^-\) Scattering at the LHC}, doi = {10.25972/OPUS-36944}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369445}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this thesis we examine the vector boson scattering (VBS) process \(\mathrm p \mathrm p \to \mathrm e^+ \nu_\mathrm e\mu^-\bar\nu_\mu\mathrm j\mathrm j +X\) (short: \(\mathrm W^+\mathrm W^-\) scattering) at NLO accuracy in two experimental setups by performing a Monte Carlo analysis of a \(13\,\mathrm{TeV}\) LHC run. \(\mathrm W^+\mathrm W^-\) scattering shows similarities and differences compared to the scattering of other vector bosons. We present a detailed description of the types of appearing subprocesses and background processes. We give insight into our code which solves the problems we are faced within \(\mathrm W^+\mathrm W^-\) scattering. This is especially the presence of the Higgs-boson resonance in the fiducial phase-space region. Particular attention is dedicated to the permutation of resonances. The integrated signal cross section at LO \(\mathcal O(\alpha^6)\) amounts to \(2.6988(3)\,\mathrm{fb}\) and \(1.5322(2)\,\mathrm{fb}\), respectively, in the two experimental setups. The LO QCD-induced background of \(\mathcal O(\alpha_\mathrm s^2\alpha^4)\) amounts to \(6.9115(9)\,\mathrm{fb}\) and \(1.6923(3)\,\mathrm{fb}\). The EW corrections to the signal are \(-11.4\\%\) and \(-6.7\\%\), the QCD corrections amount to \(-5.2\\%\) and \(-23.0\\%\). The EW corrections to the background are \(-8.3\\%\) and \(-5.3\\%\), the QCD corrections amount to \(-30.3\\%\) and \(-77.6\\%\). Our results for the QCD corrections and the QCD-induced background include a large uncertainty from varying the renormalisation and factorisation scale, and we discuss improvements for future calculations. We show the differential cross sections with unique features of \(\mathrm W^+\mathrm W^-\) scattering compared to other VBS processes and investigate in particular the subprocess of Higgs-boson production by using a modified version of our setups.}, subject = {W-Boson}, language = {en} } @phdthesis{Diehl2024, author = {Diehl, Janina Marie Christin}, title = {Ecology and evolution of symbiont management in ambrosia beetles}, doi = {10.25972/OPUS-32121}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321213}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The relationship between a farmer and their cultivated crops in agriculture is multifaceted, with pathogens affecting both the farmer and crop, and weeds that take advantage of resources provided by farmers. For my doctoral thesis, I aimed to gain a comprehensive understanding of the ecology and symbiosis of fungus farming ambrosia beetles. Through my research, I discovered that the microbial composition of fungus gardens, particularly the mutualists, is significantly influenced by the presence of both adults and larvae. The recognition of both beneficial and harmful symbionts is crucial for the success of ambrosia beetles, who respond differently depending on their life stage and the microbial species they encounter, which can contribute to the division of labour among family groups. The presence of antagonists and pathogens in the fungus garden depends on habitat and substrate quality, and beetle response to their introduction results in behavioural and developmental changes. Individual and social immunity measures, as well as changes in bacterial and fungal communities, were detected as a result of pathogen introduction. Additionally, the ability of ambrosia beetles to establish two nutritional fungal species depends on several factors. These insects must strike a balance between their essential functions and adapt to the constantly changing ecological and social conditions, which demonstrates their adaptive flexibility. However, interpreting data from laboratory studies should be approached with caution, as the natural environment allows for more flexibility and the potential for other beneficial symbionts to become more prominent if required. To aid in my research, I designed primers that use the 'fungal large subunit' (LSU) as genetic marker to identify and differentiate mutualistic and antagonistic fungi in X. saxesenii. The primers were able to distinguish closely related species of the Ophiostomataceae and other fungal symbionts. This allowed me to associate the abundance of key fungal taxa with factors such as the presence of beetles, the nest's age and condition, and the various developmental stages present. My primers are a valuable tool for understanding fungal communities, including their composition and the identification of previously unknown functional symbionts. However, some aspects should be approached with caution due to the exclusion of non-amplified taxa in the relative fungal community compositions.}, subject = {{\"O}kologie}, language = {en} } @phdthesis{Baumann2024, author = {Baumann, Johannes}, title = {Induced Superconductivity in HgTe Quantum Point Contacts}, doi = {10.25972/OPUS-36940}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369405}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this thesis, the Josephson effect in mercury telluride based superconducting quantum point contacts (SQPCs) is studied. Implementing such confined structures into topological superconductors has been proposed as a means to detect and braid Majorana fermions. For the successful realization of such experiments though, coherent transport across the constriction is essential. By demonstrating the Josephson effect in a confined topological system, the presented experiments lay the foundation for future quantum devices that can be used for quantum computation. In addition, the experiments also provide valuable insights into the behavior of the Josephson effect in the low-channel limit (N<20). Due to the confinement of the weak link, we can also study the Josephson effect in a topological insulator, where the edge modes interact. In conclusion, this thesis discusses the fabrication of, and low-temperature measurements on mercury telluride quantum point contacts embedded within Josephson junctions. We find that the merging of the currently used fabrication methods for mercury telluride quantum point contacts and Josephson junctions does not yield a good enough device quality to resolve subbands of the quantum point contact as quantization effects in the transport properties. As we attribute this to the long dry etching time that is necessary for a top-contact, the fabrication process was adapted to reduce the defect density at the superconductor-semiconductor interface. Employing a technique that involves side contacting the mercury telluride quantum well and reducing the size of the mercury telluride mesa to sub-micrometer dimensions yields a quantized supercurrent across the junction. The observed supercurrent per mode is in good agreement with theoretical predictions for ballistic, one-dimensional modes that are longer than the Josephson penetration depth. Moreover, we find that oscillatory features superimpose the plateaus of the supercurrent and the conductance. The strength of these oscillatory features are sample-dependent and complicate the identification of plateaus. We suggest that the oscillatory features originate mainly from local defects and the short gate electrode. Additionally, resonances are promoted within the weak link if the transparency of the superconductor-HgTe interface differs from one. Furthermore, the research explores the regimes of the quantum spin Hall effect and the 0.5 anomaly. Notably, a small yet finite supercurrent is detected in the QSH regime. In samples fabricated from thick mercury telluride quantum wells, the supercurrent appears to vanish when the quantum point contact is tuned into the regime of the 0.5 anomaly. For samples fabricated from thin mercury telluride quantum wells, the conductance as well as the supercurrent vanish for strong depopulation. In these samples though, the supercurrent remains detectable even for conductance values significantly below 2 e²/h. Numerical calculation reproduce the transport behavior of the superconducting quantum point contacts. Additionally, the topological nature of the weak link is thoroughly investigated using the supercurrent diffraction pattern and the absorption of radio frequency photons. The diffraction pattern reveals a gate independent, monotonous decay of \$I_\text{sw}(B)\$, which is associated with the quantum interference of Andreev bound states funneled through the quantum point contact. Interestingly, the current distribution in the weak link appears unaffected as the quantum point contact is depleted. In the RF measurements, indications of a 4π periodic supercurrent are observed as a suppression of odd Shapiro steps. The ratio of the 4π periodic current to the 2π periodic current appears to decrease for smaller supercurrents, as odd Shapiro steps are exclusively suppressed for large supercurrents. Additionally, considering the observation that the supercurrent is small when the bulk modes in the quantum point contact are fully depleted, we suggest that the re-emerging of odd Shapiro steps is a consequence of the group velocity of the edge modes being significantly suppressed when the bulk modes are absent. Consequently, the topological nature of the superconducting quantum point contact is only noticeable in the transport properties when bulk modes are transmitted through the superconducting quantum point contact. The shown experiments are the first demonstration of mercury telluride superconducting quantum point contacts that exhibit signatures of quantization effects in the conductance as well as the supercurrent. Moreover, the experiments suggest that the regime of interacting topological edge channels is also accessible in mercury telluride superconducting quantum point contacts. This is potentially relevant for the realization of Majorana fermions and their application in the field of quantum computation.}, subject = {Topologischer Isolator}, language = {en} } @phdthesis{Kappenberger2024, author = {Kappenberger, Jeannette Sarah}, title = {Biochemical characterization of the TFIIH translocase XPB from \(Chaetomium\) \(thermophilum\)}, doi = {10.25972/OPUS-24409}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244096}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {DNA repair and gene expression are two major cellular processes that are fundamental for the maintenance of biological life. Both processes require the enzymatic activity of the super family 2 helicase XBP, which is an integral subunit of the general transcription factor TFIIH. During transcription initiation, XPB catalyzes the initial melting of promoter DNA enabling RNA polymerase II to engage with the coding DNA strand and start gene transcription. In nucleotide excision repair, XPB acts in concert with the other TFIIH helicase XPD causing strand separation around a lesion site. Mutations within the genes encoding XPB or other TFIIH subunits are associated with different cancer types as well as with the autosomal recessive disorders Xeroderma Pigmentosum and trichothiodystrophy and rarely combined features of Xeroderma Pigmentosum and Cockayne syndrome. In the last few years, great progress has been made towards unraveling the structure of TFIIH and its individual subunits including XPB. These structural insights tremendously improved our understandings with respect to the molecular interactions within this intriguing protein complex. However, the underlying regulation mechanisms that functionally control XPB during transcription and repair remained largely elusive. We thus executed the biochemical characterization of this protein to investigate the functional network that regulates XPB within the scaffold of TFIIH. Due to their enhanced stability compared to the human proteins, we utilized the proteins that originate from the thermophilic fungus Chaetomium thermophilum for this purpose as a model organism for eukaryotic TFIIH. The present work provides novel insights into the enzymatic function and regulation of XPB. We could show that both, DNA and the TFIIH subunit p52 stimulate XPB's ATPase activity and that the p52-mediated activity is further boosted by p8, another subunit within TFIIH. Surprisingly, DNA can activate XPB's ATPase activity to a greater extent than its TFIIH interaction partners p52/p8, but when both, i.e. p52/p8 and DNA are present at the same time, p52 dominates the activation and the enzymatic speed is maintained at the level observed through the sole activation of p52/p8. We thus defined p52 as the master regulator of XPB that simultaneously activates and represses XPB's enzymatic activity. Based on a correlative mutagenesis study of the main interface between p52 and XPB that was set into context with recent structural data, a model for the p52-mediated activation and speed limitation of XPB's ATPase was proposed. The research on XPB's ATPase was expanded with the investigation of the inhibition mechanism of XPB's ATPase via the natural compound Triptolide. Furthermore, we investigated XPB's DNA translocase function and could observe that XPB can only perform its translocase movement when it is fully incorporated into core TFIIH and this translocase movement is further enhanced by the nucleotide excision repair factor XPA. Fluorescence polarization measurements with nucleotide analogues revealed that XPB displays the highest affinity towards DNA in the ADP + Pi bound state and its binding is weakened when ADP is bound or the nucleotide is dissociated from the enzyme, suggesting a movement on the DNA during the distinct states of the ATPase cycle. Finally, the well-known and highly conserved RED motif was found to be the crucial element in XPB to enable this translocase movement. Combined, the data presented in this work provide novel insights into the intricate regulation network that controls XPB's enzymatic activity within TFIIH and furthermore show that XPB's enzymatic activity is tightly controlled by various factors.}, subject = {DNS-Reparatur}, language = {en} } @phdthesis{Boenninger2024, author = {B{\"o}nninger, Solveig Eva}, title = {F{\"o}rderliche und hinderliche Faktoren im Trauerprozess von Nahestehenden eines*r Verstorbenen}, doi = {10.25972/OPUS-36431}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-364319}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Laut Statistischem Bundesamt (Destatis) starben allein im Jahr 2020 zirka 985.500 Menschen. Die h{\"a}ufigsten Todesursachen waren Herz-Kreislauf- und Krebs-Erkrankungen (vgl. Destatis 2020). Die meisten Menschen haben den Wunsch zuhause zu sterben, doch die Mehrheit stirbt in Krankenh{\"a}usern, Alten- und Pflegeheimen (vgl. DHPV 2017; Dasch et al. 2015). Der Tod eines nahestehenden Menschen kann bei Hinterbliebenen zu großen Belastungen, gesundheitlichen Problemen sowie einer gesteigerten Mortalit{\"a}t f{\"u}hren (vgl. Stroebe et al. 2007). Ziel dieser Arbeit war es, mit Hilfe von halbstandardisierten Interviews mit 30 Trauernden Faktoren herauszuarbeiten, die sich f{\"o}rderlich oder hinderlich auf den Trauerprozess auswirken k{\"o}nnen. Die Interviews wurden mit der Transkriptionssoftware f4transkript verschriftlicht und mittels qualitativer Inhaltsanalyse nach Mayring ausgewertet. Es entstand ein Kategoriensystem mit je vier Oberkategorien innerhalb der zwei Hauptkategorien, F{\"o}rderliche und Hinderliche Faktoren. Folgende Faktoren konnten identifiziert werden: F{\"o}rderliche Faktoren in der Oberkategorie Betreuung der erkrankten und trauernden Person sind eine gute Symptomkontrolle sowie der verst{\"a}ndnisvolle Umgang mit den Nahestehenden, w{\"a}hrend mangelhafte Kommunikation wiederum hinderlich f{\"u}r eine positive Trauerbew{\"a}ltigung ist. In der Oberkategorie Intrapersonale Faktoren sind die Antizipation des Todes sowie die Auseinandersetzung mit der Trauer f{\"o}rderlich, w{\"a}hrend negative Gef{\"u}hle (z.B. Schuldgef{\"u}hle, Hilfslosigkeit) sich in besagter Hinsicht hinderlich auswirken. In der Oberkategorie Beziehung zur verstorbenen Person k{\"o}nnen die optimale Nutzung der verbliebenen Zeit sowie der offene Umgang mit der Erkrankung f{\"o}rderliche Faktoren darstellen, w{\"a}hrend ein "schwieriger" Abschied sowie ungekl{\"a}rte Konflikte oder offene Fragen Hindernisse f{\"u}r den Trauerprozess sein k{\"o}nnen. In der Oberkategorie Soziales Umfeld sind die unaufgeforderte Unterst{\"u}tzung, die emotionale Begleitung sowie ein flexibler Arbeitgeber f{\"o}rderlich. Streitigkeiten innerhalb der Familie und Unverst{\"a}ndnis der Mitmenschen dagegen sind hinderlich. Eine gute und w{\"u}rdevolle Sterbebegleitung, wie sie in der Palliativmedizin in der Regel gew{\"a}hrleistet ist, ist von großer Bedeutung f{\"u}r einen gelingenden Trauerprozess. Daher sollte eine palliative Haltung disziplin{\"u}bergreifend vorangebracht und ausgebaut werden. In der Gesellschaft sollte Trauernden mehr Toleranz und Verst{\"a}ndnis entgegengebracht und offen mit dem Thema Tod und Sterben umgegangen werden.}, subject = {Trauer}, language = {de} } @phdthesis{Funke2024, author = {Funke, Caroline}, title = {Untersuchung des Tumorgef{\"a}ßbildes an murinen Tumormodellen unter antiangiogener Therapie mit Axitinib und mG6-31}, doi = {10.25972/OPUS-36982}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369820}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die Tumorangiogenese ist ein Prozess, der zur Ausbildung eines tumoreigenen Gef{\"a}ßnetzwerks f{\"u}hrt und kritisch ist f{\"u}r die Progression des Tumorwachstums, sowie f{\"u}r dessen Malignisierung und Metastasierung. Zytokine wie VEGF und PDGF steuern angiogene Prozesse. Die resultierende Tumorvaskulatur ist jedoch dysfunktional und unterscheidet sich in Struktur und Funktion stark von normalen Gef{\"a}ßen. Die antiangiogene Therapie richtet sich gegen die Tumorvaskulatur indem Angiogenese-induzierende Signalwege inhibiert werden. Es existieren zahlreiche therapeutische Ans{\"a}tze, zu denen u.a. Anti-VEGF- Antik{\"o}rper und Rezeptortyrosinkinaseinhibitoren z{\"a}hlen. Ziel der antiangiogenen Therapie ist es, die Ausbildung neuer Blutgef{\"a}ße im Tumor zu stoppen sowie existierende unreife Blutgef{\"a}ße zu zerst{\"o}ren. Das Konzept der Gef{\"a}ßnormalisierung beschreibt im Rahmen der antiangiogenen Therapie Prozesse, die zu einer transienten Verbesserung dieser defekten Tumorvaskulatur und zu ihrer tendenziellen Angleichung an Struktur und Funktion von normalen Gef{\"a}ßen f{\"u}hren sollen. In dieser Studie wurden Ver{\"a}nderungen von Gef{\"a}ßparametern in murinen AT3- Mammakarzinomen und murinen Lewis-lung-Karzinomen miteinander verglichen, die entweder (a) mit mG6-31, einem monoklonalen Anti-VEGF- Antik{\"o}rper, (b) mit Axitinib, einem niedermolekularen VEGF-R-/PDGF-R- Tyrosinkinaseinhibitor antiangiogen behandelt oder (c) nicht behandelt wurden. Ziel war es dabei, Aussagen {\"u}ber die antiangiogene Wirksamkeit sowie die Gef{\"a}ß- normalisierende Effektivit{\"a}t der o.g. Antiangiogenetika zu treffen. In einer bereits abgeschlossenen Forschungsarbeit von Ascheid (vgl. Absatz 7.2) wurden mit dem gleichen Experimentalaufbau wie zuvor beschrieben ebenfalls murine Tumoren hinsichtlich makroskopischer Gef{\"a}ßstruktur und -organisation untersucht. Dabei wurde aufgezeigt, dass Gef{\"a}ß-normalisierende Prozesse durch o.g. Angiogenetika in geringem Umfang stattfanden. Die durchgef{\"u}hrte Studie zielte darauf ab, die bereits erfassten Resultate zu komplettieren und somit eine abschließende Aussage {\"u}ber das Auftreten von Gef{\"a}ßnormalisierung zu erm{\"o}glichen. 88 In den mG6-31-/Axitinib-/unbehandelten AT3-/LLC-Tumorschnitten wurden die Parameter Gef{\"a}ßdichte, Apoptoserate, Proliferationsrate, Perizytenbesatz, Intaktheit der vaskul{\"a}ren Basalmembran und endotheliale Expression von TRPC6-Kan{\"a}len immunhistochemisch bzw. mittels Immunfluoreszenz detektiert, mikroskopisch aufgenommen und quantifiziert. Diese Arbeit zeigt, dass Axitinib deutliche antiangiogene Effekte in der Tumorvaskulatur hervorruft, mG6-31 hingegen wirkt schw{\"a}cher antiangiogen. Im Unterschied zu den Ergebnissen aus Ascheids Arbeit (Ascheid, 2018) konnten- Effekte auf der Ebene der individuellen Blutgef{\"a}ße nachgewiesen werden, die in der Literatur als Anzeichen f{\"u}r eine Gef{\"a}ßnormalisierung beschrieben werden. Wiederum waren diese Effekte unter Axitinib st{\"a}rker ausgepr{\"a}gt als unter mG6- 31-Behandlung. Die Resultate beider Forschungsarbeiten zusammengefasst betrachtet, kann man feststellen, dass die Zusammenfassung der gef{\"a}ßver{\"a}ndernden Effekte, die antiangiogene Wirkstoffe hervorrufen, unter dem Begriff „Normalisierung" in Frage gestellt werden sollte.}, subject = {Antiangiogenese}, language = {de} } @phdthesis{Yabe2024, author = {Yabe, Marie}, title = {Untersuchung des Mental Rotation-Paradigmas bei Patienten mit fokaler Dystonie}, doi = {10.25972/OPUS-36392}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363927}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das mR-Paradigma beschreibt die F{\"a}higkeit Objekte gedanklich zu drehen und erfordert dabei komplexe neuronale Prozesse. Bisherige Studien konnten nicht kl{\"a}ren, ob es ein spezifisches Muster der Beeintr{\"a}chtigung im mR-Test bei fokalen Dystonien gibt. Die {\"u}bergeordnete Fragestellung der vorliegenden Arbeit war, ob eine verlangsamte Reaktion bei der mR von k{\"o}rperlichen Abbildungen einen stabilen Endoph{\"a}notyp fokaler Dystonien darstellt. Die Zielsetzung war die {\"U}berpr{\"u}fung der Hypothesen, 1) dass bisherige Ergebnisse, die eine verl{\"a}ngerte Reaktionszeit von CD-Patienten bei der mR von k{\"o}rperlichen Abbildungen aufzeigten, reproduzierbar sind und 2) dass eine erh{\"o}hte Reaktionszeit bei der mR von k{\"o}rperlichen Abbildungen auch bei Patienten mit BSP vorliegt. Um dabei die mR m{\"o}glichst spezifisch zu untersuchen, wurden folgende sekund{\"a}re Hypothesen formuliert: a) die kognitive Leistungsf{\"a}higkeit und b) das allgemeine Reaktionsverm{\"o}gen der Teilnehmer stellen potenzielle St{\"o}rfaktoren f{\"u}r die Reaktionszeit bei der mR-Aufgabe dar. Diese wurden neben der H{\"a}ndigkeit und der allgemeinen Geschicklichkeit systematisch erhoben. 23 CD-Patienten und 23 gesunde Kontrollpersonen sowie 21 BSP- und 19 HFS-Patienten wurden hinsichtlich Geschlechterverteilung, Alter und Bildungsstand verglichen. Zudem wurden H{\"a}ndigkeit, Fingergeschicklichkeit, allgemeine Reaktionszeit und kognitiver Status jedes Teilnehmers erhoben. Im mR-Test wurden Fotos von K{\"o}rperteilen (Hand, Fuß oder Kopf) und einem nicht-k{\"o}rperlichen Objekt (Auto) gezeigt, die in sechs verschiedene Winkelgrade um die eigene Achse in der Bildebene rotiert waren. Die Teilnehmer wurden gebeten, die Lateralit{\"a}t des dargestellten Bildes per Tastendruck anzugeben. Bewertet wurden sowohl Geschwindigkeit als auch Richtigkeit der Antworten. Im Vergleich zu gesunden Kontrollpersonen schnitten CD- und HFS-Patienten bei der mR der H{\"a}nde schlechter ab, w{\"a}hrend die BSP-Patienten vergleichbare Leistungen zeigten. Es bestand ein signifikanter Zusammenhang zwischen einer verl{\"a}ngerten mR-Reaktionszeit und reduzierten MoCA-Scores sowie einer erh{\"o}hten mR-Reaktionszeit und verl{\"a}ngerter allgemeiner Reaktionszeit. Nach Ausschluss der Patienten mit MCI zeigten CD-Patienten, nicht jedoch HFS-Patienten, im Vergleich zur gesunden Kontrollgruppe weiterhin verlangsamte Reaktionszeiten der H{\"a}nde. Die vorliegende Studie konnte die Frage, ob eine verlangsamte Reaktion bei der mR von k{\"o}rperlichen Abbildungen einen stabilen Endoph{\"a}notyp fokaler Dystonien darstellt, nicht sicher beantworten. Es stellte sich jedoch heraus, dass Kognition und allgemeine Reaktionszeit starke Einflussfaktoren bei der mR-Aufgabe sind. Dies wurde in den fr{\"u}heren Arbeiten nicht ber{\"u}cksichtigt und stellt daher ein neues und wichtiges Ergebnis dar. Die verlangsamte Reaktion bei der mR der H{\"a}nde bei CD-Patienten auch nach Ausschluss von Patienten mit MCI l{\"a}sst ein spezifisches Defizit der F{\"a}higkeit der mR vermuten. Das Vorliegen einer tiefergreifenden zugrundeliegenden Netzwerkst{\"o}rung, die sich auf die Leistung im mR-Test auswirkt, w{\"a}re dabei denkbar.}, language = {de} } @phdthesis{Grimm2024, author = {Grimm, Anne Rosemarie}, title = {Prognostische Determinanten im kardiogenen und septischen Schock}, doi = {10.25972/OPUS-36995}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369953}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In diese monozentrische retrospektive Studie eingeschlossen wurden insgesamt 132 Patienten mit Schock, darunter 75 Patienten mit kardiogenem- und 57 Patienten mit septischem Schock. Um potentielle Pr{\"a}diktoren f{\"u}r die Krankenhaussterblichkeit zu finden, wurden folgende Paramater untersucht: Alter, Geschlecht, BMI, kardiovaskul{\"a}re Risikofaktoren und Vorerkrankungen, Vitalparameter bei Aufnahme inkl. Schockindex, laborchemische Parameter inkl. BGA, maximaler Laktatanstieg im Verlauf, Interventionen inklusive Reanimation, Beatmung, Akutrevaskularisation und Anlage von mechanischen Kreislaufunterst{\"u}tzungssystemen, Katecholamintherapie und h{\"a}modynamisches Monitoring mit dem PiCCO-Verfahren. Hauptergebnis unserer Studie ist eine erhebliche Krankenhaussterblichkeit von 50\% bei einem mittleren Aufenthalt von 14 Tagen ohne signifikanten Unterschied zwischen kardiogenem- (45\%) und septischem Schock (55\%), obgleich Patienten mit kardiogenem Schock signifikant {\"a}lter und h{\"a}ufiger kardiovaskul{\"a}r vorerkrankt waren. Pr{\"a}diktoren f{\"u}r die Krankenhaussterblichkeit waren bei Patienten mit kardiogenem Schock die H{\"o}he des maximalen Laktatanstiegs, das Auftreten eines akuten Nierenversagens, die H{\"o}he der Transaminasen als Marker einer Schockleber, die fehlende M{\"o}glichkeit einer Akutrevaskularisation und die H{\"o}he des Troponins als Marker f{\"u}r das Ausmaß des Myokardschadens. Pr{\"a}diktoren f{\"u}r die Krankenhaussterblichkeit im septischen Schock waren ebenfalls die H{\"o}he des maximalen Laktatanstiegs, die Notwendigkeit einer Reanimation, sowie H{\"o}he des ELWI. Die {\"u}brigen klinischen, laborchemischen und h{\"a}modynamischen Parameter waren weder beim kardiogenen- noch beim septischen Schock pr{\"a}diktiv f{\"u}r die Mortalit{\"a}t. Die beste Strategie zur Senkung der hohen Mortalit{\"a}t beider Schockformen besteht in der Prophylaxe des jeweiligen Schockgeschehens. Bei bereits in Gang gesetzten Circulus vitiosus, m{\"u}ssen zuk{\"u}nftige Studien kl{\"a}ren, welches h{\"a}modynamische Monitoring zusammen mit klinischen Befunden und ggf. Bildgebung ein optimiertes Volumen- und Katecholamin-Management erlaubt. Bei Patienten mit kardiogenem Schock bleibt zu kl{\"a}ren, ob die in unserer Studie gefundene erhebliche Krankenhaussterblichkeit von 45\% durch den gezielten Einsatz moderner, perkutan implantierbarer Kreislaufunterst{\"u}tzungssysteme gebessert werden kann. Bei Patienten mit septischem Schock ist insbesondere bei pneumogener Sepsis das rechtzeitige Erkennen und die Therapie eines ARDS eine bleibende Herausforderung. Zuk{\"u}nftige Studien an gr{\"o}ßeren Patientenkollektiven m{\"u}ssen kl{\"a}ren, ob die Bestimmung des ELWI mit dem PiCCO-Verfahren hilfreich ist, die Entstehung eines ARDS fr{\"u}hzeitig erkennen und behandeln zu k{\"o}nnen.}, subject = {Schock}, language = {de} } @phdthesis{Pickert2024, author = {Pickert, Julia Felicia}, title = {Untersuchungen zum Einfluss des Insulin-like growth factor Rezeptors auf Signalnetzwerke im Multiplen Myelom}, doi = {10.25972/OPUS-36981}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369815}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das MM ist eine maligne Erkrankung, die von biologischer und klinischer Heterogenit{\"a}t gepr{\"a}gt ist. Sie ist durch die monoklonale Vermehrung von Plasmazellen charakterisiert. In vorangegangenen Studien wurde eine H{\"a}ufung von Mutationen in RTK nachgewiesen. Diese gingen mit einem negativen Einfluss auf das {\"U}berleben von MM Patientinnen und Patienten einher. Im Rahmen dieser Arbeit wurde der Einfluss des IGF1R an HMZL mittels siRNA-vermitteltem IGF1R-Knockdown untersucht und dessen Effekt auf das Signalnetzwerk mittels Western Blot Analysen ermittelt. Um die Heterogenit{\"a}t des MM besser abzubilden, wurden sechs verschiedenen HMZL ausgew{\"a}hlt. Der IGF1R-Knockdown war in allen HMZL sowohl anhand der Reduktion der IGF1R-Expression als auch der IGF1R-Aktivierung deutlich nachweisbar. Stellvertretend f{\"u}r den PI3K/AKT Signalweg wurde die AKT-Aktivierung untersucht, welche nach IGF1R-Knockdown in allen Linien abnahm. Im Ras/Raf/MEK/ERK Signalweg fiel eine deutliche Reduktion der ERK1/2- und MEK-Aktivierung in den von PCL stammenden HMZL L-363 und MM.1S, sowie in JJN-3 mit der Hochrisikotranslokation t(14;16) auf. Entsprechend der Beobachtungen f{\"u}r die AKT-Aktivierung, nahm die PYK2-Aktivierung in allen HMZL nach IGF1R-Knockdown ab, was auf ein Zusammenspiel von IGF1R, PYK2 und AKT in allen HMZL hindeutet. Zuk{\"u}nftige Untersuchungen werden zeigen, ob IGF1R Inhibitoren alleine oder in Kombination mit z.B. AKT, PYK2 oder Proteasomen-Inhibitoren in bestimmten molekularen MM Subgruppen ein effektives therapeutisches Ziel sind.}, subject = {Plasmozytom}, language = {de} } @phdthesis{Dorband2024, author = {Dorband, Moritz}, title = {Geometric Phases and Factorisation in Quantum Physics and Gravity}, doi = {10.25972/OPUS-37093}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370937}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this thesis I explore the interplay of geometry and quantum information theory via the holographic principle, with a specific focus on geometric phases in quantum systems like two interacting qubits, and how they relate to entanglement measures and Hilbert space factorisation. I establish geometric phases as an indicator for Hilbert space factorsiation, both in an abstract sense using von Neumann operator algebras as well as applied to the eternal black hole within the AdS/CFT correspondence. For the latter case I show that geometric phases allow to diagnose non-factorisation from a boundary point of view. I also introduce geometric quantum discord as a second geometric measure for non-factorisation and reveals its potential implications for the study of black hole microstates.}, subject = {AdS-CFT-Korrespondenz}, language = {en} } @phdthesis{Dietz2024, author = {Dietz, Maximilian}, title = {Synthese und Reaktivit{\"a}t neutraler Diboraarene}, doi = {10.25972/OPUS-32109}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321098}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die vorliegende Arbeit befasst sich mit der Darstellung und Reaktivit{\"a}t neutraler Diboraarene, wobei im ersten Teil die Synthese neuer Metallkomplexe eines cAAC-stabilisierten (cAAC = cyclisches Alkyl(amino)carben) 1,4-Diborabenzols sowie deren Folgereaktivit{\"a}t im Fokus steht. Im zweiten Abschnitt wird die Reaktivit{\"a}t des Diborabenzols und eines cAAC-stabilisierten 9,10-Diboraanthracens gegen{\"u}ber Hauptgruppenelementverbindungen untersucht und vergleichend gegen{\"u}bergestellt. Darauffolgend werden neben der Synthese neuer Metallkomplexe des Diboraanthracens auch weitere Reaktivit{\"a}tsuntersuchungen der Verbindung behandelt. Der letzte Teil der Arbeit befasst sich mit der Darstellung neuartiger neutraler und cAAC-stabilisierter Diboraacene {\"u}ber eine Modulation des π-Systems. Dabei wird der synthetische Zugang zu einem 1,4-Diboranaphthalin und einem 6,13-Diborapentacen erm{\"o}glicht und ausgew{\"a}hlte Reaktivit{\"a}ten beider Verbindungen demonstriert.}, subject = {Bor}, language = {de} } @phdthesis{Beudert2024, author = {Beudert, Matthias}, title = {Bioinspired Modification and Functionalization of Hydrogels for Applications in Biomedicine}, doi = {10.25972/OPUS-32288}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322887}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Over the years, hydrogels have been developed and used for a huge variety of different applications ranging from drug delivery devices to medical products. In this thesis, a poly(2-methyl-2-oxazoline) (POx) / poly(2-n-propyl-2-oxazine) (POzi) bioink was modified and analyzed for the use in biofabrication and targeted drug delivery. In addition, the protein fibrinogen (Fbg) was genetically modified for an increased stability towards plasmin degradation for its use as wound sealant. In Chapter 1, a thermogelling, printable POx/POzi-based hydrogel was modified with furan and maleimide moieties in the hydrophilic polymer backbone facilitating post-printing maturation of the constructs via Diels-Alder chemistry. The modification enabled long-term stability of the hydrogel scaffolds in aqueous solutions which is necessary for applications in biofabrication or tissue engineering. Furthermore, we incorporated RGD-peptides into the hydrogel which led to cell adhesion and elongated morphology of fibroblast cells seeded on top of the scaffolds. Additional printing experiments demonstrate that the presented POx/POzi system is a promising platform for the use as a bioink in biofabrication. Chapter 2 highlights the versatility of the POx/POzi hydrogels by adapting the system to a use in targeted drug delivery. We used a bioinspired approach for a bioorthogonal conjugation of insulin-like growth factor I (IGF-I) to the polymer using an omega-chain-end dibenzocyclooctyne (DBCO) modification and a matrix metalloprotease-sensitive peptide linker. This approach enabled a bioresponsive release of IGF-I from hydrogels as well as spatial control over the protein distribution in 3D printed constructs which makes the system a candidate for the use in personalized medicine. Chapter 3 gives a general overview over the necessity of wound sealants and the current generations of fibrin sealants on the market including advantages and challenges. Furthermore, it highlights trends and potential new strategies to tackle current problems and broadens the toolbox for future generations of fibrin sealants. Chapter 4 applies the concepts of recombinant protein expression and molecular engineering to a novel generation of fibrin sealants. In a proof-of-concept study, we developed a new recombinant fibrinogen (rFbg) expression protocol and a Fbg mutant that is less susceptible to plasmin degradation. Targeted lysine of plasmin cleavage sites in Fbg were exchanged with alanine or histidine in different parts of the molecule. The protein was recombinantly produced and restricted plasmin digest was analyzed using high resolution mass spectrometry. In addition to that, we developed a novel time resolved screening protocol for the detection of new potential plasmin cleavage sites for further amino acid exchanges in the fibrin sealant.}, subject = {Hydrogel}, language = {en} } @phdthesis{Elsner2024, author = {Elsner, Vianne}, title = {Vergleich von Selbst- und Fremdeinsch{\"a}tzung hinsichtlich der kommunikativen Kompetenz von Medizinstudenten in einem Anamnesegespr{\"a}ch mit Schauspielpatienten}, doi = {10.25972/OPUS-34973}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349737}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das Verst{\"a}ndnis der Beziehung zwischen Arzt und Patient befindet sich im Wandel. Die Patientenorientiertheit gewinnt an Relevanz, wobei insbesondere die Arzt-Patienten-Kommunikation in den Fokus r{\"u}ckt. Es ist belegt, dass eine effektive Kommunikation einen positiven Einfluss auf den emotionalen und den physiologischen Zustand des Patienten hat. Folglich wurde in den letzten Jahren auch hierzulande der Bereich Kommunikation in der universit{\"a}ren Ausbildung von {\"A}rzten zunehmend thematisiert - seit der {\"A}nderung der Approbationsordnung 2012 ist die Gespr{\"a}chsf{\"u}hrung offiziell Gegenstand der {\"a}rztlichen Ausbildung. Das Studium ist jedoch nach wie vor stark vom technisch-naturwissenschaftlichen Paradigma der Medizin gepr{\"a}gt. Die F{\"a}higkeit, sich selbst hinsichtlich seiner kommunikativen F{\"a}higkeiten einzusch{\"a}tzen, stellt ein wichtiges Merkmal angehender {\"A}rzte dar. Bestehende Studien zeigen auf, dass bei Medizinstudenten Diskrepanzen zwischen der Selbst- und der Fremdeinsch{\"a}tzung in unterschiedlichen Kompetenzfeldern bestehen. Um aus Fehlern lernen zu k{\"o}nnen, ben{\"o}tigt es zum einen die F{\"a}higkeit zur Eigenreflexion. Erg{\"a}nzend wird ein regelm{\"a}ßiger Abgleich der Selbsteinsch{\"a}tzung mit einer Fremdeinsch{\"a}tzung im Sinne einer „Realit{\"a}tskonfrontation" ben{\"o}tigt. Durch das Feedback k{\"o}nnen individuelle Differenzen hinsichtlich der kommunikativen F{\"a}higkeiten aufgezeigt, um dadurch dem Studenten den Anreiz zu geben, eine fortw{\"a}hrende Weiterbildung der eigenen kommunikativen F{\"a}higkeiten bereits im Studium zu etablieren. In der vorliegenden Studie wurde daher untersucht, inwieweit die Selbsteinsch{\"a}tzung von einem Studenten nach einem Anamnesegespr{\"a}ch mit der Fremdeinsch{\"a}tzung {\"u}bereinstimmt. Hierf{\"u}r wurde ein Anamnesegespr{\"a}ch mit einem Schauspielpatienten durch den Studenten, einen Experten sowie den betroffenen Schauspielpatienten bewertet. Mittels Cohens Kappa wurde die {\"U}bereinstimmung zwischen den Raterpaaren Student und Experte, Student und Schauspielpatient sowie der Fremdeinsch{\"a}tzung zwischen Schauspielpatient und Experte berechnet. Erg{\"a}nzend wurde der Einfluss der Variablen Selbstwirksamkeit (allgemein und spezifisch hinsichtlich der Anamneseerhebung), Empathie, Geschlecht, Alter und berufliche Vorerfahrung auf die {\"U}bereinstimmung von Selbst- und Fremdeinsch{\"a}tzung untersucht. Es konnte eine geringe {\"U}bereinstimmung zwischen allen drei Raterpaaren (Student \& Experte, Student \& Schauspielpatient sowie Schauspielpatient \& Experte) nachgewiesen werden. Die geringste {\"U}bereinstimmung zeigte sich zwischen der Selbst- und Fremdeinsch{\"a}tzung von Student und Experte, die gr{\"o}ßte {\"U}bereinstimmung in der Fremdeinsch{\"a}tzung zwischen Schauspielpatient und Experte. Die Hypothese bez{\"u}glich der {\"U}bersch{\"a}tzung der Studenten im Vergleich zur Fremdeinsch{\"a}tzung wurde nicht best{\"a}tigt. Weiter konnte eine h{\"o}here {\"U}bereinstimmung zwischen Selbst- und Fremdeinsch{\"a}tzung des Schauspielpatienten bei Studenten mit einem h{\"o}heren Maß an Empathie gezeigt werden. Bez{\"u}glich des Geschlechterunterschiedes konnte nachgewiesen werden, dass weibliche Studenten eine h{\"o}here {\"U}bereinstimmung zwischen Selbst- und Fremdeinsch{\"a}tzung mit Schauspielpatienten aufweisen. Auch in der Fremdeinsch{\"a}tzung durch Schauspielpatienten und Experten ist bei weiblichen Studenten eine h{\"o}here {\"U}bereinstimmung zu finden. Die Variablen Selbstwirksamkeit, Alter, berufliche Vorerfahrung sowie Selbstwirksamkeit hinsichtlich der Anamneseerhebung zeigen keine statistisch signifikanten Zusammenh{\"a}nge mit der {\"U}bereinstimmung zwischen Selbst- und Fremdeinsch{\"a}tzung. Der Vergleich zwischen der Gruppe, die ein Anamnesegespr{\"a}ch f{\"u}hrte, und derjenigen, die kein Anamnesegespr{\"a}ch f{\"u}hrte, zeigte, dass Studenten mit einer h{\"o}heren Selbstwirksamkeit eher ein Gespr{\"a}ch f{\"u}hrten. Die Ergebnisse dieser Arbeit verdeutlichen, dass angehende {\"A}rzte R{\"u}ckmeldung bez{\"u}glich ihrer kommunikativen Kompetenz ben{\"o}tigen, um durch die Fremdeinsch{\"a}tzung das Selbstbild ihrer Kompetenz erweitern zu k{\"o}nnen. {\"U}ber etwaige Diskrepanzen zwischen Fremdeinsch{\"a}tzung und Selbsteinsch{\"a}tzung erhalten sie konkretes Feedback, so dass das Kommunikationstraining an ihre individuellen Lernbedarfe angepasst werden kann. Hierf{\"u}r ist der Vergleich der Selbsteinsch{\"a}tzung eines Schauspielpatientengespr{\"a}ches mit der Fremdeinsch{\"a}tzung eine gut in der Ausbildungspraxis einzusetzende Methode.}, subject = {Arzt-Patient-Beziehung}, language = {de} } @phdthesis{KanmegneTamga2024, author = {Kanmegne Tamga, Dan Emmanuel}, title = {Modelling Carbon Sequestration of Agroforestry Systems in West Africa using Remote Sensing}, doi = {10.25972/OPUS-36926}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369269}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The production of commodities such as cocoa, rubber, oil palm and cashew, is the main driver of deforestation in West Africa (WA). The practiced production systems correspond to a land managment approach referred to as agroforestry systems (AFS), which consist of managing trees and crops on the same unit of land.Because of the ubiquity of trees, AFS reported as viable solution for climate mitigation; the carbon sequestrated by the trees could be estimated with remote sensing (RS) data and methods and reported as emission reduction efforts. However, the diversity in AFS in relation to their composition, structure and spatial distribution makes it challenging for an accurate monitoring of carbon stocks using RS. Therefore, the aim of this research is to propose a RS-based approach for the estimation of carbon sequestration in AFS across the climatic regions of WA. The main objectives were to (i) provide an accurate classification map of AFS by modelling the spatial distribution of the classification error; (ii) estimate the carbon stock of AFS in the main climatic regions of WA using RS data; (iii) evaluate the dynamic of carbon stocks within AFS across WA. Three regions of interest (ROI) were defined in Cote d'Ivoire and Burkina Faso, one in each climatic region of WA namely the Guineo-Congolian, Guinean and Sudanian, and three field campaigns were carried out for data collection. The collected data consisted of reference points for image classification, biometric tree measurements (diameter, height, species) for biomass estimation. A total of 261 samples were collected in 12 AFS across WA. For the RS data, yearly composite images from Sentinel-1 and -2 (S1 and S2), ALOS-PALSAR and GEDI data were used. A supervised classification using random forest (RF) was implemented and the classification error was assessed using the Shannon entropy generated from the class probabilities. For carbon estimation, different RS data, machine learning algorithms and carbon reference sources were compared for the prediction of the aboveground biomass in AFS. The assessment of the carbon dynamic was carried between 2017 and 2021. An average carbon map was genrated and use as reference for the comparison of annual carbon estimations, using the standard deviation as threshold. As far as the results are concerned, the classification accuracy was higher than 0.9 in all the ROIs, and AFS were mainly represented by rubber (38.9\%), cocoa (36.4\%), palm (10.8\%) in the ROI-1, mango (15.2\%) and cashew (13.4\%) in ROI-2, shea tree (55.7\%) and African locust bean (28.1\%) in ROI-3. However, evidence of misclassification was found in cocoa, mango, and shea butter. The assessment of the classification error suggested that the error level was higher in the ROI-3 and ROI-1. The error generated from the entropy was able to reduced the level of misclassification by 63\% with 11\% of loss of information. Moreover, the approach was able to accuretely detect encroachement in protected areas. On carbon estimation, the highest prediction accuracy (R²>0.8) was obtained for a RF model using the combination of S1 and S2 and AGB derived from field measurements. Predictions from GEDI could only be used as reference in the ROI-1 but resulted in a prediction error was higher in cashew, mango, rubber and cocoa plantations, and the carbon stock level was higher in African locust bean (43.9 t/ha), shea butter (15 t/ha), cashew (13.8 t/ha), mango (12.8 t/ha), cocoa (7.51 t/ha) and rubber (7.33 t/ha). The analysis showed that carbon stock is determined mainly by the diameter (R²=0.45) and height (R²=0.13) of trees. It was found that crop plantations had the lowest biodiversity level, and no significant relationship was found between the considered biodiversity indices and carbon stock levels. The assessment of the spatial distribution of carbon sources and sinks showed that cashew plantations are carbon emitters due to firewood collection, while cocoa plantations showed the highest potential for carbon sequestration. The study revealed that Sentinel data could be used to support a RS-based approach for modelling carbon sequestration in AFS. Entropy could be used to map crop plantations and to monitor encroachment in protected areas. Moreover, field measurements with appropriate allometric models could ensure an accurate estimation of carbon stocks in AFS. Even though AFS in the Sudanian region had the highest carbon stocks level, there is a high potential to increase the carbon level in cocoa plantations by integrating and/or maintaining forest trees.}, subject = {Sequestrierung}, language = {en} } @phdthesis{Makowski2024, author = {Makowski, Lisa Maria}, title = {Erfahrungen von Haus{\"a}rztInnen mit der COVID-19-Pandemie und deren Folgen auf die PatientInnenversorgung - eine qualitative Studie}, doi = {10.25972/OPUS-37123}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371233}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Haus{\"a}rztInnen sind f{\"u}r die Prim{\"a}rversorgung von PatientInnen mit COVID-19 zust{\"a}ndig. Zum Zeitpunkt der Planung und Durchf{\"u}hrung dieser Studie ließen sie kaum Untersuchungen zu den Erfahrungen von Haus{\"a}rztInnen w{\"a}hrend der ersten Pandemiewelle finden. Das Ziel der Arbeit war, durch eine qualitative Datenerhebung Einblicke zu gewinnen, wie Haus{\"a}rztInnen die ersten Monate der COVID-19-Pandemie erlebt haben. Die Untersuchung war Teil einer {\"u}bergeordneten Querschnittsstudie, in der Erhebungen mit strukturierten Frageb{\"o}gen und qualitativen Befragungen stattfanden. F{\"u}r den qualitativen Abschnitt wurden semistrukturierte Interviews mit 22 Haus{\"a}rztInnen aus vier Bundesl{\"a}ndern durchgef{\"u}hrt. Die Einladung zur Teilnahme erfolgte mit der Aussendung von Frageb{\"o}gen im Rahmen der quantitativen Datenerhebung. Die Daten wurden anhand der inhaltlich strukturierenden qualitativen Inhaltsanalyse nach Kuckartz ausgewertet. In der Studie zeigte sich, dass Haus{\"a}rztInnen ihr Praxismanagement und ihre PatientInnenversorgung in der Pandemie rasch umstrukturieren mussten. Mangel an Schutzmaterialien, die Trennung infekti{\"o}ser PatientInnen und schnell wechselnde Vorgaben wurden als große Herausforderungen identifiziert. In den Interviews wurden außerdem Bedenken {\"u}ber die Folgen der sozialen Distanzierung auf die therapeutische Beziehung ge{\"a}ußert. Teamarbeit in der Praxis und kollegialer Austausch in Gemeinschaftspraxen stellten besonders wichtige Faktoren dar, um die zahlreichen Herausforderungen zu {\"u}berwinden. Die Teilnehmenden nahmen sich selbst als Vorbilder mit einer hohen Verantwortung f{\"u}r die Gesundheit ihrer PatientInnen wahr.. Sie betonten die Relevanz von klaren und konsistenten Regelungen durch den {\"o}ffentlichen Gesundheitsdienst sowie von zuverl{\"a}ssigen Informationen. Um die haus{\"a}rztliche Versorgung in zuk{\"u}nftigen Pandemien zu unterst{\"u}tzen, sollten b{\"u}rokratische H{\"u}rden so weit wie m{\"o}glich reduziert und verst{\"a}ndliche Informationen bereitgestellt werden. Da Haus{\"a}rztInnen eine zentrale Rolle in der Beratung und Therapie von PatientInnen mit COVID-19 spielten, erscheint deren konsistente Einbeziehung in Entscheidungsprozesse durch Institutionen des {\"o}ffentlichen Gesundheitsdienstes von besonderer Wichtigkeit.}, subject = {Hausarzt}, language = {de} } @phdthesis{Weis2024, author = {Weis, Philipp}, title = {Translationale Untersuchung zur Anwendung der durchflusszytometrischen Bestimmung \(Aspergillus\) \(fumigatus\) spezifischer T-Zellen in der Diagnostik von Aspergillosen}, doi = {10.25972/OPUS-37114}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371145}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Bei Patienten mit invasiver Aspergillose fanden sich gegen{\"u}ber gesunden Probanden deutlich erh{\"o}hte Werte A. fumigatus spezifischer CD154+/CD4+ Zellen. Die Anwendbarkeit dieses Assays im klinischen Routinebetrieb und bei gegen{\"u}ber A. fumigatus epxonierten Probanden und Patienten sollte in dieser translationalen Arbeit untersucht werden. F{\"u}r den vorbeschriebenen Assay zur Bestimmung CD154+/CD4+ Zellen aus aufgereinigten PBMCs zeigt diese Arbeit eine signifikant reduzierte Detektionsrate nach Blutprobenlagerung von {\"u}ber 2 Stunden. In der Literatur beschriebene Verfahren zur verl{\"a}ngerten Lagerungszeit von heparinisierten Blutproben mittels vorhergehender Dilution und Agitation erm{\"o}glichen keine Verl{\"a}ngerung pr{\"a}analytischer Lagerungszeiten {\"u}ber 6 Stunden. Die Kryokonservierung frisch aufbereiteter PBMCs bei -20 C vor Bestimmung A. fumigatus spezifischer T-Zellen wird als Versandm{\"o}glichkeit in einem multizentrischen Setting gezeigt. Um die klinische Anwendbarkeit zu verbessern, wird ein Vollblutprotokoll zur Detektion A. fumigatus spezifischer CD154+/CD4+ Zellen demonstriert, das die Verwendung von bettseitig mit Vollblut beimpften Blutmonovetten mit vorgelegtem A. fumigatus-Lysat erm{\"o}glicht. Die Anwendung des Assays zur Bestimmung A. fumigatus spezifischer T-Zellen wurde bei h{\"a}matoonkologischen Patienten vor und drei Monate nach Stammzelltransplantation untersucht. Insbesondere eine reduzierte Zellzahl der gemessenen Lymphozyten ist hier ein limitierender Faktor der erfolgreichen Messung. Aufgrund der generell nied- rigen Erfolgsrate von 20 \% bzw. 54 \% vor bzw. nach HSCT ist die Anwendbarkeit des Assays in diesem Kollektiv fraglich. Die Erhebung von Expositionsfaktoren gesunder Probanden gegen{\"u}ber A. fumigatus erm{\"o}glicht die Einteilung in eine schwach und stark gegen{\"u}ber A. fumigatus exponierte Gruppe mit signifikant erh{\"o}htem Anteil A. fumigatus spezifischer CD154+/CD4+ Zellen. Hierzu tr{\"a}gt insbesondere das Vorliegen antigenspezifischer T-Ged{\"a}chtniszellen als Korrelat einer langfristigen Exposition bei. Retrospektiv fand sich auch nach kurzfris- tiger beruflicher Exposition ein Anstieg CD154+/CD4+ spezifischer T-Zellen. Dies legt eine Verwendung CD154+/CD4+ spezifischer T-Zellen als Biomarker in Bereichen der umweltmedizinischen Abkl{\"a}rung von Schimmelpilzexposition oder der Diagnostik allergischer Erkrankungen nahe.}, subject = {Aspergillus fumigatus}, language = {de} } @phdthesis{Kussberger2024, author = {Kußberger, Julia Bettina}, title = {Protein - Biomarker zur Unterscheidung zwischen unipolarer und bipolarer Depression}, doi = {10.25972/OPUS-37110}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371109}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die Diagnosestellung von unipolarer und bipolarer Depression basiert bis heute ausschließlich auf der Bewertung klinischer Symptome. Objektive biochemische Marker, wie sie bei zahlreichen somatischen Krankheiten zur Diagnosestellung angewendet werden, sind bisher nicht verf{\"u}gbar. Da sich die beide Krankheitsbilder vor allem in der depressiven Episode stark {\"a}hneln, ist eine Unterscheidung in diesem Krankheitsstadium h{\"a}ufig nicht eindeutig m{\"o}glich. Dies kann zu Fehldiagnosen, einer Verschlechterung des Krankheitsverlaufs, einer erh{\"o}hten Krankheitslast und h{\"o}heren Gesundheitskosten f{\"u}hren. Periphere Biomarker w{\"a}ren daher wertvoll, um die klinische Diagnosestellung zu unterst{\"u}tzen und eine ad{\"a}quate Behandlung fr{\"u}hzeitige zu erm{\"o}glichen. In einer vorherigen Studie der Arbeitsgruppe haben Proteom-Analysen bestimmte Proteine wie den Wachstumsfaktor PDGF-BB und das Thrombospondin TSP-1 identifiziert, die potenziell als Biomarker fungieren k{\"o}nnten. In der vorliegenden Studie wurde untersucht, ob sich die Konzentration von PDGF-BB und TSP-1 im Blut zwischen Patient*innen mit unipolarer bzw. bipolarer Depression signifikant unterscheidet. Es konnte gezeigt werden, dass PDGF-BB bei unipolaren Patientinnen signifikant niedriger ist als bei bipolaren Patientinnen und gesunden Kontrollpersonen. Zudem sank die PDGF-BB-Konzentration bei bipolaren Patientinnen w{\"a}hrend einer remittierten Episode im Vergleich zu einer depressiven Episode signifikant ab. Im Gegensatz dazu zeigte TSP-1 keine signifikanten Unterschiede zwischen den Patient*innengruppen und Kontrollpersonen. Die Arbeit konnte zeigen, dass PDGF-BB das Potenzial hat, als diagnostischer Biomarker f{\"u}r die Unterscheidung zwischen unipolarer und bipolarer Depression zu dienen, w{\"a}hrend TSP-1 in dieser Hinsicht nicht geeignet erscheint. Weitere Forschung ist jedoch notwendig, um die Rolle von PDGF-BB in der Pathogenese affektiver Erkrankungen besser zu verstehen und seinen Einsatz als Biomarker im klinischen Alltag zu validieren.  }, subject = {Differentialdiagnose}, language = {de} } @phdthesis{BeckgebLiebetanz2024, author = {Beck [geb. Liebetanz], Lina}, title = {Die Rolle CD8\(^+\) T-Zellen in der Atherosklerose}, doi = {10.25972/OPUS-37134}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371344}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Atherosklerose ist eine chronisch inflammatorische Erkrankung der Gef{\"a}ßw{\"a}nde, bei der sowohl die angeborene als auch die erworbene Immunantwort beteiligt ist. Von Monozyten abstammende Makrophagen spielen eine Schl{\"u}sselrolle bei der Entstehung atherosklerotischer L{\"a}sionen. Durch die Aufnahme modifizierte Lipide (z.B. oxLDL) werden sie zu Schaumzellen, sezernieren inflammatorische Zytokine und befeuern somit die vaskul{\"a}re Entz{\"u}ndungsreaktion. Makrophagen k{\"o}nnen jedoch auch sch{\"u}tzende Funktionen wahrnehmen, bspw. durch die antiinflammatorische Aufnahme apoptotischer Zellen, die Efferozytose. Um den Einfluss CD8+ T-Zellen auf Makrophagen zu bestimmen, wurde ein in vitro Model gew{\"a}hlt, in dem aktivierte CD8+ T-Zellen mit aus Knochenmark isolierten Makrophagen kokultiviert wurden. Zun{\"a}chst konnte gezeigt werden, dass CD8+ T-Zellen die oxLDL Aufnahme und Schaumzellbildung der Makrophagen f{\"o}rdern, assoziiert mit der gesteigerten Expression des oxLDL Rezeptors CD36 und verminderten Expression des reversen Cholesterintransporters ABCA1. Zus{\"a}tzlich reduzierten CD8+ T-Zellen die Phagozytose apoptotischer Zellen und die Sekretion des antiinflammatorischen Zytokins IL-10 als Antwort auf die Aufnahme apoptotischer Zellen, was auf eine verminderte Efferozytose hindeutet. Zudem f{\"o}rderten CD8+ T-Zellen die Expression des proinflammatorischen M1-Polarisationsmarker iNOS in Makrophagen und die Sekretion des proatherogenen Chemokins CCL2. Durch die Zugabe neutralisierender Antik{\"o}rper in die in vitro Kultur konnte gezeigt werden, dass die aufgef{\"u}hrten Prozesse teilweise von den klassischen Effektorzytokinen der CD8+ T-Zellen, INFγ und TNFα, abh{\"a}ngen. Zusammenfassend zeigen unsere Daten, dass CD8+ T-Zellen die Ausbildung eines proatherogenen Ph{\"a}notyps der Makrophagen, durch die Steigerung der Schaumzellbildung und F{\"o}rderung der proinflammatorischen Makrophagenpolarisation, sowie die Inhibierung der antiinflammatorischen Efferozytosefunktion, bewirken.}, subject = {Immunit{\"a}t }, language = {de} } @phdthesis{vanDorp2024, author = {van Dorp, Joel}, title = {Site-specific biomolecule modification for directed surface attachment}, doi = {10.25972/OPUS-36953}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369536}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Site-directed bioorthogonal conjugation techniques have substantially advanced research in numerous areas. Their exceptional value reflects in the extent of applications, that have been realized with spacial-controlled bioorthogonal reactions. Specific labeling of surfaces, proteins, and other biomolecule allows for new generations of drug delivery, tracking, and analyzing systems. With the continuous advance and refinement of available methods, this field of research will become even more relevant in the time to come. Yet, as individual as the desired purpose is, as different can be the most suitable modification strategy. In this thesis, two different bioconjugation approaches, namely CuAAC and factor XIIIa mediated ligation, are used in distinct application fields, featuring eGFP as a model protein showcasing the advantages as well as the challenges of each technique. The introduction of a unique accessible functionality is the most critical feature of a site-specific reaction, and the first considerable hurdle to clear. While most surfaces, peptides, or small molecules might require less expenditure to modulate, equipping large biomolecules like proteins with additional traits requires careful consideration to preserve the molecule's stability and function. Therefore, the first section of this project comprises the engineering of eGFP via rational design. Initially, wild-type eGFP was subcloned, expressed, and characterized to serve as a reference value for the designed variants. Subsequently, eGFP was mutated and expressed to display a recognition site for factor XIIIa. Additionally, a second mutant harbored a TAG-codon to enable amber codon suppression and consequently the incorporation of the alkyne bearing unnatural amino acid Plk to support a CuAAC reaction. Fluorescence spectroscopy was used to confirm that the fluorescent properties of all expressed muteins were identically equal to wild-type eGFP, which is a reliable marker for the intact barrel structure of the protein. Trypsin digestion and HPLC were deployed to confirm each protein variant's correct sequence and mass. The second part of this work focuses on the conjugation of cargo molecules deploying the chosen approaches. Solid-phase peptide synthesis was used to create a peptide that served as a lysine donor substrate in the crosslinking mechanism of FXIIIa. Additionally, the peptide was provided with a cysteine moiety to allow for highly flexible and simple loading of desired cargo molecules via conventional thiol-Michael addition, thus establishing an adaptive labeling platform. The effective ligation was critically reviewed and confirmed by monitoring the exact mass changes by HPLC. Protocols for attaching payloads such as biotin and PEG to the linker peptide were elaborated. While the biotin construct was successfully conjugated to the model protein, the eGFP-PEG linkage was not achieved judging by SDS-PAGE analysis. Furthermore, featuring isolated peptide sequences, the properties of the FXIIIa-mediated reaction were characterized in detail. Relative substrate turnover, saturation concentrations, by-product formation, and incubation time were comprehensively analyzed through HPLC to identify optimal reaction conditions. CuAAC was successfully used to label the Plk-eGFP mutein with Azide-biotin, demonstrated by western blot imaging. Within the last part of this study, the application of the conjugation systems was extended to different surfaces. As regular surfaces do not allow for immediate decoration, supplementary functionalization techniques like gold-thiol interaction and silanization on metal oxides were deployed. That way gold-segmented nanowires and Janus particles were loaded with enoxaparin and DNA, respectively. Nickel and cobalt nanowires were modified with silanes that served as linker molecules for subsequent small molecule attachment or PEGylation. Finally, the eGFP muteins were bound to a particle surface in a site-specific manner. Beads displaying amino groups were utilized to demonstrate the effective use of FXIIIa in surface modification. Moreover, the bead's functional moieties were converted to azides to enable CuAAC "Click Chemistry" and direct comparison. Each modification was analyzed and confirmed through fluorescence microscopy.}, subject = {Proteinglutamin-Glutamyltransferase }, language = {en} } @phdthesis{Fohmann2024, author = {Fohmann, Ingo}, title = {The Role of Sphingosine 1-phosphate and S1PR1-3 in the Pathophysiology of Meningococcal Meningitis}, doi = {10.25972/OPUS-36976}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369764}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Neisseria meningitidis (N. meningitidis) is an obligate human pathogen which causes live-threatening sepsis and meningitis. The fatality rate after meningococcal infection is high and surviving patients often suffer from severe sequelae. To cause meningitis, N. meningitidis must overcome the endothelium of the blood-brain barrier. The bacterium achieves this through the interaction with endothelial surface receptors leading to alternations of the cellular metabolism and signaling, which lastly results in cellular uptake and barrier traversal of N. meningitidis. Sphingosine 1-phosphate (S1P) is a lipid mediator that belongs to the class of sphingolipids and regulates the integrity of the blood-brain barrier through the interaction with its cognate receptors S1P receptors 1-3 (S1PR1-3). In this study, high performance liquid chromatography coupled with mass spectrometry (LC-MS/MS) was used to generate a time-resolved picture of the sphingolipid metabolism in a brain endothelial cell line (hCMEC/D3) upon meningococcal infection. Among various changes, S1P was elevated in the cellular compartment as well as in the supernatant of infected hCMEC/D3s. Analysis of mRNA expression in infected hCMEC/D3s with quantitative real-time polymerase chain reaction (RT-qPCR) revealed that the increase in S1P could be attributed to the enhanced expression of the S1P-generating enzyme sphingosine kinase 1 (SphK1). Antibody-based detection of SphK1 protein or phosphorylation at SphK1 residue Serine 225 in hCMEC/D3 plasma membrane fractions via Western Blot revealed that N. meningitidis also induced SphK1 phospho-activation and recruitment to the plasma membrane. Importantly, recruitment of SphK1 to the plasma membrane increases the probability of substrate encounter, thus elevating SphK activity. Enhanced SphK activity was also reflected on a functional level, as detected by a commercially available ATP depletion assay used for measuring the enzymatic activity of SphK. Infection of hCMEC/D3 cells with pilus-deficient mutants resulted in a lower SphK activation compared to the N. meningitidis wild type strain. hCMEC/D3 treatment with pilus-enriched protein fractions showed SphK activation similar to the infection with living bacteria and could be ascribed to pilus interaction with the membrane-proximal domain of cellular surface receptor CD147. Inhibition of SphK1 or SphK2 through pre-treatment with specific inhibitors or RNA interference reduced uptake of N. meningitidis into hCMEC/D3 cells, as measured with Gentamicin protection assays. Released S1P induced the phospho-activation of epidermal growth factor receptor (EGFR) via S1PR2 activation, whose expression was also increasing during infection. Furthermore, S1PR2 blockage had a preventive effect on bacterial invasion into hCMEC/D3 cells. On the contrary, activation of S1PR1+3 also reduced bacterial uptake, indicating an opposing regulatory role of S1PR1+3 and S1PR2 during N. meningitidis uptake. Moreover, SphK2 inhibition prevented inflammatory cytokine expression as well as release of interleukin-8 after N. meningitidis infection. Taken together, this study demonstrates the central role of S1P and its cognate receptors S1PR1-3 in the pathophysiology of meningococcal meningitis.}, subject = {Blut-Hirn-Schranke}, language = {en} } @phdthesis{MathewSchmitt2024, author = {Mathew-Schmitt, Sanjana}, title = {Development of blood-brain barrier spheroid models based on human induced pluripotent stem cells (hiPSCs) and investigation of shear stress on hiPSC-derived brain capillary endothelial-like cells}, doi = {10.25972/OPUS-32247}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322475}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {A highly regulated microenvironment is essential in maintaining normal functioning of the central nervous system (CNS). The existence of a biological barrier, termed as the blood-brain barrier (BBB), at the blood to brain interface effectively allows for selective passage of substances and pathogens into the brain (Kadry, Noorani et al. 2020). The BBB chiefly serves in protecting the brain from extrinsic toxin entry and pathogen invasions. The BBB is formed mainly by brain capillary endothelial cells (BCECs) which are responsible for excluding ∼ 100\% of large-molecule neurotherapeutics and more than 98\% of all small-molecule drugs from entry into the brain. Minimal BBB transport of major potential CNS drugs allows for attenuated effective treatments for majority of CNS disorders (Appelt-Menzel, Oerter et al. 2020). Animals are generally used as model systems to study neurotherapeutic delivery into the brain, however due to species based disparity, experimental animal models lead to several false positive or false negative drug efficacy predictions thereby being unable to fully predict effects in humans (Ruck, Bittner et al. 2015). An example being that over the last two decades, much of the studies involving animals lead to high failure rates in drug development with ~ 97\% failure in cancers and ~ 99\% failure for Alzheimer´s disease (Pound 2020). Widespead failures in clinical trials associated with neurological disorders have resulted in questions on whether existing preclinical animal models are genuinely reflective of the human condition (Bhalerao, Sivandzade et al. 2020). Apart from high failure rates in humans, the costs for animal testings is extremely high. According to the Organisation for Economic Co-operation and Development (OECD), responsible for determining animal testing guidelines and methodology for government, industry, and independent laboratories the average cost of a single two-generation reproductive animal toxicity study worldwide is 318,295 € and for Europe alone is ~ 285,842 € (Van Norman 2019). Due to these reasons two separate movements exist within the scientific world, one being to improve animal research and the other to promote new approach methodologies with the European government setting 2025 - 2035 as a deadline for gradually disposing the use of animals in pharmaceutical testing (Pound 2020). The discovery of human induced pluripotent stem cell (hiPSC) technology in 2006 (Takahashi and Yamanaka 2006, Takahashi, Tanabe et al. 2007) revolutionized the field of drug discovery in-vitro. HiPSCs can be differentiated into various tissue types that mimic disease phenotypes, thereby offering the possibility to deliver humanized in-vitro test systems. With respect to the BBB, several strategies to differentiate hiPSCs to BCECs (iBCECs) are reported over the years (Appelt-Menzel, Oerter et al. 2020). However, iBCECs are said to possess an epithelial or undifferentiated phenotype causing incongruity in BBB lineage specifications (Lippmann, 7 Azarin et al. 2020). Therefore, in order to identify a reliable differentiation strategy in deriving iBCECs possessing hallmark BBB characteristics, which can be used for downstream applications, the work in this thesis compared two methods, namely the co-differentiation (CD) and the directed differentiation (DD). Briefly, CD mimics a brain like niche environment for iBCEC specification (Lippmann, Al-Ahmad et al. 2014), while DD focuses on induction of the mesoderm followed by iBCEC specification (Qian, Maguire et al. 2017). The results obtained verified that while iBCECs derived via CD, in comparison to human BCEC cell line hCMEC/D3 showed the presence of epithelial transcripts such as E-Cadherin (CDH1), and gene level downregulation of endothelial specific platelet endothelial cell adhesion molecule-1 (PECAM-1) and VE-cadherin (CDH5) but demonstrated higher barrier integrity. The CD strategy essentially presented iBCECs with a mean trans-endothelial electrical resistance (TEER) of ~ 2000 - 2500 Ω*cm2 and low permeability coefficients (PC) of < 0.50 μm/min for small molecule transport of sodium fluorescein (NaF) and characteristic BCEC tight junction (TJ) protein expression of claudin-5 and occludin. Additionally, iBCECs derived via CD did not form tubes in response to angiogenic stimuli. DD on the other hand resulted in iBCECs with similar down regulations in PECAM-1 and CDH5 gene expression. They were additionally characterized by lower barrier integrity, measured by mean TEER of only ~ 250 - 450 Ω*cm2 and high PC of > 5 μm/min in small molecule transport of NaF. Although iBCECs derived via DD formed tubes in response to angiogenic stimuli, they did not show positive protein expression of characteristic BCEC TJs such as claudin-5 and occludin. These results led to the hypothesis that maturity and lineage specification of iBCECs could be improved by incorporating in-vivo like characteristics in-vitro, such as direct co-culture with neurovascular unit (NVU) cell types via spheroid formation and by induction of shear stress and fluid flow. In comparison to standard iBCEC transwell mono-cultures, BBB spheroids showed enhanced transcript expression of PECAM-1 and reduced expression of epithelial markers such as CDH1 and claudin-6 (CLDN6). BBB spheroids showed classical BCEC-like ultrastructure that was identified by TJ particles on the protoplasmic face (P-face) and exoplasmic face (E-face) of the plasma membrane. TJ strands were organized as particles and particle-free grooves on the E-face, while on the P-face, partly beaded particles and partly continuous strands were identified. BBB spheroids also showed positive protein expression of claudin-5, VE-cadherin, PECAM-1, glucose transporter-1 (GLUT-1), P-glycoprotein (P-gp) and transferrin receptor-1 (Tfr-1). BBB spheroids demonstrated higher relative impedance percentages in comparison to spheroids without an iBCEC barrier. Barrier integrity assessments additionally corresponded with lower permeability to small molecule tracer NaF, with spheroids containing iBCECs showing higher relative fluorescence unit percentages (RFU\%) of ~ 90\% in apical compartments, compared to ~ 80\% in spheroids without iBCECs. In summary, direct cellular contacts in the complex spheroid model resulted in enhanced maturation of iBCECs. 8 A bioreactor system was used to further assess the effect of shear stress. This system enabled inclusion of fluidic flow and shear stress conditions in addition to non-invasive barrier integrity measurements (Choi, Mathew et al. 2022). iBCECs were cultured for a total of seven days post differentiation (d17) within the bioreactor and barrier integrity was non-invasively monitored. Until d17 of long-term culture, TEER values of iBCECs steadily dropped from ~ 1800 Ω*cm2 ~ 400 Ω*cm2 under static conditions and from ~ 2500 Ω*cm2 to ~ 250 Ω*cm2 under dynamic conditions. Transcriptomic analyses, morphometric analyses and protein marker expression showed enhanced maturation of iBECs under long-term culture and dynamic flow. Importantly, on d10 claudin-5 was expressed mostly in the cytoplasm with only ~ 5\% iBCECs showing continuous staining at the cell borders. With increase in culture duration, iBCECs at d17 of static culture showed ~ 18\% of cells having continuous cell border expression, while dynamic conditions showed upto ~ 30\% of cells with continuous cell-cell border expression patterns. Similarly, ~ 33\% of cells showed cell-cell border expression of occludin on d10 with increases to ~ 55\% under d17 static and up to ~ 65\% under d17 dynamic conditions, thereby indicating iBCEC maturation. In conclusion, the data presented within this thesis demonstrates the maturation of iBCECs in BBB spheroids, obtained via direct cellular contacts and by the application of flow and shear stress. Both established novel models need to be further validated for pharmaceutical drug applications together with in-vitro-in-vivo correlations in order to exploit their full potential.}, subject = {Blut-Hirn-Schranke}, language = {en} } @phdthesis{GamboaVargas2024, author = {Gamboa Vargas, Juan Fernando}, title = {Receptors of the TNFSF in the biology and regulation of Tregs}, doi = {10.25972/OPUS-36980}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369801}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this work we expanded upon a study from our group where a ligand-based TNF-α mutein was developed to engage specifically TNFR2 and not TNFR1 activating Tregs and expanding them, which in an allo-HCT context conferred protection from GvHD. Fusing TNF trimers to the heavy chain of an Fc-dead and mouse irrelevant antibody, a new generation of this agonist was developed called NewSTAR2. It is believed that other members of the TNFSF can also target Tregs, therefore additional agonists against DR3 and GITR were developed under the same principles as for NewSTAR2. Phenotyping analysis of the expression of these three receptors were done to confirm their specificity for Tregs before in vitro and in vivo testings with mice or murine splenic cells. A potent expansion of Tregs was seen with NewSTAR2 and the other agonists as well as upregulation of activation markers on Tregs. Thorough analyses with NewSTAR2-treated mice showed how Tregs in several immune and non-immune organs were expanded and upregulated immunomodulatory receptors. A miniature suppressive assay and other cocultures with responder cells confirmed their enhanced suppression over unstimulated Tregs through contact dependent and independent mechanisms. Despite other myeloid cells also being increased after treatment, no undesired effects were observed under steady-state and prophylactic administration of a single dose of NewSTAR2 improved survival frequencies and lessened development of clinical symptoms. Prophylactic treatment with the other TNFRSF agonists showed similar protection yet Fc(DANA)-muTL1A was superior in in terms of less death events and lower clinical score. It was found that not all the three TNFSF members have redundant functions as development of skin lesions was observed with GITRL-based agonist Fc(DANA)-muGITRL, although its expansion of Tregs in steady-state was remarkable with no apparent adverse effects. Neither agonist had an impact on donor cell engraftment or allorective T cell response, however NewSTAR2-treatmend proved to reduce inflammation in small intestine and liver. This work is proof of concept of the effectivity of selectively engaging TNFSF to activate Tregs and expand them systemically allowing them to control strong and complex immune interactions like those governing GvHD.}, subject = {Regulatorischer T-Lymphozyt}, language = {en} } @article{CalderonPenaSuarezetal.2019, author = {Calderon, Dayana and Pe{\~n}a, Luis and Suarez, Ang{\´e}lica and Villamil, Carolina and Ramirez-Rojas, Adan and Anzola, Juan M. and Garc{\´i}a-Betancur, Juan C. and Cepeda, Martha L. and Uribe, Daniel and Del Portillo, Patricia and Mongui, Alvaro}, title = {Recovery and functional validation of hidden soil enzymes in metagenomic libraries}, series = {MicrobiologyOpen}, volume = {8}, journal = {MicrobiologyOpen}, doi = {10.1002/mbo3.572}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222016}, year = {2019}, abstract = {The vast microbial diversity on the planet represents an invaluable source for identifying novel activities with potential industrial and therapeutic application. In this regard, metagenomics has emerged as a group of strategies that have significantly facilitated the analysis of DNA from multiple environments and has expanded the limits of known microbial diversity. However, the functional characterization of enzymes, metabolites, and products encoded by diverse microbial genomes is limited by the inefficient heterologous expression of foreign genes. We have implemented a pipeline that combines NGS and Sanger sequencing as a way to identify fosmids within metagenomic libraries. This strategy facilitated the identification of putative proteins, subcloning of targeted genes and preliminary characterization of selected proteins. Overall, the in silico approach followed by the experimental validation allowed us to efficiently recover the activity of previously hidden enzymes derived from agricultural soil samples. Therefore, the methodology workflow described herein can be applied to recover activities encoded by environmental DNA from multiple sources.}, language = {en} } @article{GermainBrandBurlinaetal.2018, author = {Germain, Dominique P. and Brand, Eva and Burlina, Alessandro and Cecchi, Franco and Garman, Scott C. and Kempf, Judy and Laney, Dawn A. and Linhart, Aleš and Mar{\´o}di, L{\´a}szl{\´o} and Nicholls, Kathy and Ortiz, Alberto and Pieruzzi, Federico and Shankar, Suma P. and Waldek, Stephen and Wanner, Christoph and Jovanovic, Ana}, title = {Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study}, series = {Molecular Genetics \& Genomic Medicine}, volume = {6}, journal = {Molecular Genetics \& Genomic Medicine}, doi = {10.1002/mgg3.389}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232976}, pages = {492-503}, year = {2018}, abstract = {Background The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. Methods To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. Results In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31\%, females 8\%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17\% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3\%). Conclusion p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.}, language = {en} } @article{KasparOttHertigKasparetal.2019, author = {Kaspar-Ott, Irena and Hertig, Elke and Kaspar, Severin and Pollinger, Felix and Ring, Christoph and Paeth, Heiko and Jacobeit, Jucundus}, title = {Weights for general circulation models from CMIP3/CMIP5 in a statistical downscaling framework and the impact on future Mediterranean precipitation}, series = {The International Journal of Climatology}, volume = {39}, journal = {The International Journal of Climatology}, doi = {10.1002/joc.6045}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325628}, pages = {3639-3654}, year = {2019}, abstract = {This study investigates the projected precipitation changes of the 21st century in the Mediterranean area with a model ensemble of all available CMIP3 and CMIP5 data based on four different scenarios. The large spread of simulated precipitation change signals underlines the need of an evaluation of the individual general circulation models in order to give higher weights to better and lower weights to worse performing models. The models' spread comprises part of the internal climate variability, but is also due to the differing skills of the circulation models. The uncertainty resulting from the latter is the aim of our weighting approach. Each weight is based on the skill to simulate key predictor variables in context of large and medium scale atmospheric circulation patterns within a statistical downscaling framework for the Mediterranean precipitation. Therefore, geopotential heights, sea level pressure, atmospheric layer thickness, horizontal wind components and humidity data at several atmospheric levels are considered. The novelty of this metric consists in avoiding the use of the precipitation data by itself for the weighting process, as state-of-the-art models still have major deficits in simulating precipitation. The application of the weights on the downscaled precipitation changes leads to more reliable and precise change signals in some Mediterranean sub-regions and seasons. The model weights differ between sub-regions and seasons, however, a clear sequence from better to worse models for the representation of precipitation in the Mediterranean area becomes apparent.}, language = {en} } @article{MirzaVainshteinDiRonzaetal.2019, author = {Mirza, Myriam and Vainshtein, Anna and DiRonza, Alberto and Chandrachud, Uma and Haslett, Luke J. and Palmieri, Michela and Storch, Stephan and Groh, Janos and Dobzinski, Niv and Napolitano, Gennaro and Schmidtke, Carolin and Kerkovich, Danielle M.}, title = {The CLN3 gene and protein: What we know}, series = {Molecular Genetics \& Genomic Medicine}, volume = {7}, journal = {Molecular Genetics \& Genomic Medicine}, doi = {10.1002/mgg3.859}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224138}, year = {2019}, abstract = {Background One of the most important steps taken by Beyond Batten Disease Foundation in our quest to cure juvenile Batten (CLN3) disease is to understand the State of the Science. We believe that a strong understanding of where we are in our experimental understanding of the CLN3 gene, its regulation, gene product, protein structure, tissue distribution, biomarker use, and pathological responses to its deficiency, lays the groundwork for determining therapeutic action plans. Objectives To present an unbiased comprehensive reference tool of the experimental understanding of the CLN3 gene and gene product of the same name. Methods BBDF compiled all of the available CLN3 gene and protein data from biological databases, repositories of federally and privately funded projects, patent and trademark offices, science and technology journals, industrial drug and pipeline reports as well as clinical trial reports and with painstaking precision, validated the information together with experts in Batten disease, lysosomal storage disease, lysosome/endosome biology. Results The finished product is an indexed review of the CLN3 gene and protein which is not limited in page size or number of references, references all available primary experiments, and does not draw conclusions for the reader. Conclusions Revisiting the experimental history of a target gene and its product ensures that inaccuracies and contradictions come to light, long-held beliefs and assumptions continue to be challenged, and information that was previously deemed inconsequential gets a second look. Compiling the information into one manuscript with all appropriate primary references provides quick clues to which studies have been completed under which conditions and what information has been reported. This compendium does not seek to replace original articles or subtopic reviews but provides an historical roadmap to completed works.}, language = {en} } @article{JandkeGarzSchwankeetal.2018, author = {Jandke, Solveig and Garz, Cornelia and Schwanke, Daniel and Sendtner, Michael and Heinze, Hans-Jochen and Carare, Roxana O. and Schreiber, Stefanie}, title = {The association between hypertensive arteriopathy and cerebral amyloid angiopathy in spontaneously hypertensive stroke-prone rats}, series = {Brain Pathology}, volume = {28}, journal = {Brain Pathology}, doi = {10.1111/bpa.12629}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323279}, pages = {844-859}, year = {2018}, abstract = {We aimed to test the hypothesis that in spontaneously hypertensive stroke-prone rats (SHRSP), non-amyloid cerebral small vessel disease/hypertensive arteriopathy (HA) results in vessel wall injury that may promote cerebral amyloid angiopathy (CAA). Our study comprised 21 male SHRSP (age 17-44 weeks) and 10 age- and sex-matched Wistar control rats, that underwent two-photon (2PM) imaging of the arterioles in the parietal cortex using Methoxy-X04, Dextran and cerebral blood flow (CBF) measurements. Our data suggest that HA in SHRSP progresses in a temporal and age-dependent manner, starting from small vessel wall damage (stage 1A), proceeding to CBF reduction (stage 1B), non-occlusive (stage 2), and finally, occlusive thrombi (stage 3). Wistar animals also demonstrated small vessel wall damage, but were free of any of the later HA stages. Nearly half of all SHRSP additionally displayed vascular Methoxy-X04 positivity indicative of cortical CAA. Vascular β-amyloid deposits were found in small vessels characterized by thrombotic occlusions (stage 2 or 3). Post-mortem analysis of the rat brains confirmed the findings derived from intravital 2PM microscopy. Our data thus overall suggest that advanced HA may play a role in CAA development with the two small vessel disease entities might be related to the same pathological spectrum of the aging brain.}, language = {en} } @article{MollKellnerLeonhardtetal.2018, author = {Moll, Julia and Kellner, Harald and Leonhardt, Sabrina and Stengel, Elisa and Dahl, Andreas and B{\"a}ssler, Claus and Buscot, Fran{\c{c}}ois and Hofrichter, Martin and Hoppe, Bj{\"o}rn}, title = {Bacteria inhabiting deadwood of 13 tree species are heterogeneously distributed between sapwood and heartwood}, series = {Environmental Microbiology}, volume = {20}, journal = {Environmental Microbiology}, doi = {10.1111/1462-2920.14376}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224168}, pages = {3744-3756}, year = {2018}, abstract = {Deadwood represents an important structural component of forest ecosystems, where it provides diverse niches for saproxylic biota. Although wood-inhabiting prokaryotes are involved in its degradation, knowledge about their diversity and the drivers of community structure is scarce. To explore the effect of deadwood substrate on microbial distribution, the present study focuses on the microbial communities of deadwood logs from 13 different tree species investigated using an amplicon based deep-sequencing analysis. Sapwood and heartwood communities were analysed separately and linked to various relevant wood physico-chemical parameters. Overall, Proteobacteria, Acidobacteria and Actinobacteria represented the most dominant phyla. Microbial OTU richness and community structure differed significantly between tree species and between sapwood and heartwood. These differences were more pronounced for heartwood than for sapwood. The pH value and water content were the most important drivers in both wood compartments. Overall, investigating numerous tree species and two compartments provided a remarkably comprehensive view of microbial diversity in deadwood.}, language = {en} } @article{HilmersFriessBaessleretal.2018, author = {Hilmers, Torben and Friess, Nicolas and B{\"a}ssler, Claus and Heurich, Marco and Brandl, Roland and Pretzsch, Hans and Seidl, Rupert and M{\"u}ller, J{\"o}rg}, title = {Biodiversity along temperate forest succession}, series = {Journal of Applied Ecology}, volume = {55}, journal = {Journal of Applied Ecology}, doi = {10.1111/1365-2664.13238}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320632}, pages = {2756-2766}, year = {2018}, abstract = {1. The successional dynamics of forests—from canopy openings to regeneration, maturation, and decay—influence the amount and heterogeneity of resources available for forest-dwelling organisms. Conservation has largely focused only on selected stages of forest succession (e.g., late-seral stages). However, to develop comprehensive conservation strategies and to understand the impact of forest management on biodiversity, a quantitative understanding of how different trophic groups vary over the course of succession is needed. 2. We classified mixed mountain forests in Central Europe into nine successional stages using airborne LiDAR. We analysed α- and β-diversity of six trophic groups encompassing approximately 3,000 species from three kingdoms. We quantified the effect of successional stage on the number of species with and without controlling for species abundances and tested whether the data fit the more-individuals hypothesis or the habitat heterogeneity hypothesis. Furthermore, we analysed the similarity of assemblages along successional development. 3. The abundance of producers, first-order consumers, and saprotrophic species showed a U-shaped response to forest succession. The number of species of producer and consumer groups generally followed this U-shaped pattern. In contrast to our expectation, the number of saprotrophic species did not change along succession. When we controlled for the effect of abundance, the number of producer and saproxylic beetle species increased linearly with forest succession, whereas the U-shaped response of the number of consumer species persisted. The analysis of assemblages indicated a large contribution of succession-mediated β-diversity to regional γ-diversity. 4. Synthesis and applications. Depending on the species group, our data supported both the more-individuals hypothesis and the habitat heterogeneity hypothesis. Our results highlight the strong influence of forest succession on biodiversity and underline the importance of controlling for successional dynamics when assessing biodiversity change in response to external drivers such as climate change. The successional stages with highest diversity (early and late successional stages) are currently strongly underrepresented in the forests of Central Europe. We thus recommend that conservation strategies aim at a more balanced representation of all successional stages.}, language = {en} } @article{KwokUedaKadarietal.2018, author = {Kwok, Chee Keong and Ueda, Yuichiro and Kadari, Asifiqbal and G{\"u}nther, Katharina and Erg{\"u}n, S{\"u}leyman and Heron, Antoine and Schnitzler, Aletta C. and Rook, Martha and Edenhofer, Frank}, title = {Scalable stirred suspension culture for the generation of billions of human induced pluripotent stem cells using single-use bioreactors}, series = {Journal of Tissue Engineering and Regenerative Medicine}, volume = {12}, journal = {Journal of Tissue Engineering and Regenerative Medicine}, doi = {10.1002/term.2435}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234545}, pages = {e1076-e1087}, year = {2018}, abstract = {The production of human induced pluripotent stem cells (hiPSCs) in quantities that are relevant for cell-based therapies and cell-loaded implants through standard adherent culture is hardly achievable and lacks process scalability. A promising approach to overcoming these hurdles is the culture of hiPSCs in suspension. In this study, stirred suspension culture vessels were investigated for their suitability in the expansion of two hiPSC lines inoculated as a single cell suspension, with a free scalability between volumes of 50 and 2400 ml. The simple and robust two-step process reported here first generates hiPSC aggregates of 324 ± 71 μm diameter in 7 days in 125 ml spinner flasks (100 ml volume). These are subsequently dissociated into a single cell suspension for inoculation in 3000 ml bioreactors (1000 ml volume), finally yielding hiPSC aggregates of 198 ± 58 μm after 7 additional days. In both spinner flasks and bioreactors, hiPSCs can be cultured as aggregates for more than 40 days in suspension, maintain an undifferentiated state as confirmed by the expression of pluripotency markers TRA-1-60, TRA-1-81, SSEA-4, OCT4, and SOX2, can differentiate into cells of all three germ layers, and can be directed to differentiate into specific lineages such as cardiomyocytes. Up to a 16-fold increase in hiPSC quantity at the 100 ml volume was achieved, corresponding to a fold increase per day of 2.28; at the 1000 ml scale, an additional 10-fold increase was achieved. Taken together, 16 × 106 hiPSCs were expanded into 2 × 109 hiPSCs in 14 days for a fold increase per day of 8.93. This quantity of hiPSCs readily meets the requirements of cell-based therapies and brings their clinical potential closer to fruition.}, language = {en} } @article{BahramAnslanHildebrandetal.2019, author = {Bahram, Mohammad and Anslan, Sten and Hildebrand, Falk and Bork, Peer and Tedersoo, Leho}, title = {Newly designed 16S rRNA metabarcoding primers amplify diverse and novel archaeal taxa from the environment}, series = {Environmental Microbiology Reports}, volume = {11}, journal = {Environmental Microbiology Reports}, doi = {10.1111/1758-2229.12684}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221380}, pages = {487-494}, year = {2019}, abstract = {High-throughput studies of microbial communities suggest that Archaea are a widespread component of microbial diversity in various ecosystems. However, proper quantification of archaeal diversity and community ecology remains limited, as sequence coverage of Archaea is usually low owing to the inability of available prokaryotic primers to efficiently amplify archaeal compared to bacterial rRNA genes. To improve identification and quantification of Archaea, we designed and validated the utility of several primer pairs to efficiently amplify archaeal 16S rRNA genes based on up-to-date reference genes. We demonstrate that several of these primer pairs amplify phylogenetically diverse Archaea with high sequencing coverage, outperforming commonly used primers. Based on comparing the resulting long 16S rRNA gene fragments with public databases from all habitats, we found several novel family- to phylum-level archaeal taxa from topsoil and surface water. Our results suggest that archaeal diversity has been largely overlooked due to the limitations of available primers, and that improved primer pairs enable to estimate archaeal diversity more accurately.}, language = {en} } @article{HettichSchierjottRammetal.2019, author = {Hettich, Georg and Schierjott, Ronja A. and Ramm, Heiko and Graichen, Heiko and Jansson, Volkmar and Rudert, Maximilian and Traina, Francesco and Grupp, Thomas M.}, title = {Method for quantitative assessment of acetabular bone defects}, series = {Journal of Orthopaedic Research}, volume = {37}, journal = {Journal of Orthopaedic Research}, doi = {10.1002/jor.24165}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320226}, pages = {181-189}, year = {2019}, abstract = {The objective of the study was to suggest a novel quantitative assessment of acetabular bone defects based on a statistical shape model, validate the method, and present preliminary results. Two exemplary CT-data sets with acetabular bone defects were segmented to obtain a solid model of each defect pelvis. The pathological areas around the acetabulum were excluded and a statistical shape model was fitted to the remaining healthy bone structures. The excluded areas were extrapolated such that a solid model of the native pelvis per specimen resulted (i.e., each pelvis without defect). The validity of the reconstruction was tested by a leave-one-out study. Validation results showed median reconstruction errors of 3.0 mm for center of rotation, 1.7 mm for acetabulum diameter, 2.1° for inclination, 2.5° for anteversion, and 3.3 mm3 for bone volume around the acetabulum. By applying Boolean operations on the solid models of defect and native pelvis, bone loss and bone formation in four different sectors were assessed. For both analyzed specimens, bone loss and bone formation per sector were calculated and were consistent with the visual impression. In specimen_1 bone loss was predominant in the medial wall (10.8 ml; 79\%), in specimen_2 in the posterior column (15.6 ml; 46\%). This study showed the feasibility of a quantitative assessment of acetabular bone defects using a statistical shape model-based reconstruction method. Validation results showed acceptable reconstruction accuracy, also when less healthy bone remains. The method could potentially be used for implant development, pre-clinical testing, pre-operative planning, and intra-operative navigation. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 9999:1-9, 2018.}, language = {en} } @article{GreberPolatFlentjeetal.2019, author = {Greber, Johannes and Polat, B{\"u}lent and Flentje, Michael and Bratengeier, Klaus}, title = {Properties of the anisotropy of dose contributions: A planning study on prostate cases}, series = {Medical Physics}, volume = {46}, journal = {Medical Physics}, doi = {10.1002/mp.13308}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228237}, pages = {419-425}, year = {2019}, abstract = {Purpose To characterize the static properties of the anisotropy of dose contributions for different treatment techniques on real patient data (prostate cases). From this, we aim to define a class of treatment techniques with invariant anisotropy distribution carrying information of target coverage and organ-at-risk (OAR) sparing. The anisotropy presumably is a helpful quantity for plan adaptation problems. Methods The anisotropy field is analyzed for different intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) techniques for a total of ten planning CTs of prostate cases. Primary irradiation directions ranged from 5 to 15. The uniqueness of anisotropy was explored: In particular, the anisotropy distribution inside the planning treatment volume (PTV) and in its vicinity was investigated. Furthermore, deviations of the anisotropy under beam rotations were explored by direct plan comparison as an indicating the susceptibility of each planned technique to changes in the geometric plan configuration. In addition, plan comparisons enabled the categorization of treatment techniques in terms of their anisotropy distribution. Results The anisotropy profile inside the PTV and in the transition between OAR and PTV is independent of the treatment technique as long as a sufficient number of beams contribute to the dose distribution. Techniques with multiple beams constitute a class of almost identical and technique-independent anisotropy distribution. For this class of techniques, substructures of the anisotropy are particularly pronounced in the PTV, thus offering good options for applying adaptation rules. Additionally, the techniques forming the mentioned class fortunately allow a better OAR sparing at constant PTV coverage. Besides the characterization of the distribution, a pairwise plan comparison reveals each technique's susceptibility to deviations which decreases for an increasing number of primary irradiation directions. Conclusions Techniques using many irradiation directions form a class of almost identical anisotropy distributions which are assumed to provide a basis for improved adaptation procedures. Encouragingly, these techniques deliver quite invariant anisotropy distributions with respect to rotations correlated with good plan qualities than techniques using few gantry angles. The following will be the next steps toward anisotropy-based adaptation: first, the quantification of anisotropy regarding organ deformations; and second, establishing the interrelation between the anisotropy and beam shaping.}, language = {en} } @article{deRuijterHrynevichHaighetal.2018, author = {de Ruijter, Myl{\`e}ne and Hrynevich, Andrei and Haigh, Jodie N. and Hochleitner, Gernot and Castilho, Miguel and Groll, J{\"u}rgen and Malda, Jos and Dalton, Paul D.}, title = {Out-of-Plane 3D-Printed Microfibers Improve the Shear Properties of Hydrogel Composites}, series = {Small}, volume = {14}, journal = {Small}, doi = {10.1002/smll.201702773}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223666}, year = {2018}, abstract = {One challenge in biofabrication is to fabricate a matrix that is soft enough to elicit optimal cell behavior while possessing the strength required to withstand the mechanical load that the matrix is subjected to once implanted in the body. Here, melt electrowriting (MEW) is used to direct-write poly(ε-caprolactone) fibers "out-of-plane" by design. These out-of-plane fibers are specifically intended to stabilize an existing structure and subsequently improve the shear modulus of hydrogel-fiber composites. The stabilizing fibers (diameter = 13.3 ± 0.3 µm) are sinusoidally direct-written over an existing MEW wall-like structure (330 µm height). The printed constructs are embedded in different hydrogels (5, 10, and 15 wt\% polyacrylamide; 65\% poly(2-hydroxyethyl methacrylate) (pHEMA)) and a frequency sweep test (0.05-500 rad s-1, 0.01\% strain, n = 5) is performed to measure the complex shear modulus. For the rheological measurements, stabilizing fibers are deposited with a radial-architecture prior to embedding to correspond to the direction of the stabilizing fibers with the loading of the rheometer. Stabilizing fibers increase the complex shear modulus irrespective of the percentage of gel or crosslinking density. The capacity of MEW to produce well-defined out-of-plane fibers and the ability to increase the shear properties of fiber-reinforced hydrogel composites are highlighted.}, language = {en} } @article{HrynevichElciHaighetal.2018, author = {Hrynevich, Andrei and El{\c{c}}i, Bilge Ş. and Haigh, Jodie N. and McMaster, Rebecca and Youssef, Almoatazbellah and Blum, Carina and Blunk, Torsten and Hochleitner, Gernot and Groll, J{\"u}rgen and Dalton, Paul D.}, title = {Dimension-Based Design of Melt Electrowritten Scaffolds}, series = {Small}, volume = {14}, journal = {Small}, doi = {10.1002/smll.201800232}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322677}, year = {2018}, abstract = {The electrohydrodynamic stabilization of direct-written fluid jets is explored to design and manufacture tissue engineering scaffolds based on their desired fiber dimensions. It is demonstrated that melt electrowriting can fabricate a full spectrum of various fibers with discrete diameters (2-50 µm) using a single nozzle. This change in fiber diameter is digitally controlled by combining the mass flow rate to the nozzle with collector speed variations without changing the applied voltage. The greatest spectrum of fiber diameters was achieved by the simultaneous alteration of those parameters during printing. The highest placement accuracy could be achieved when maintaining the collector speed slightly above the critical translation speed. This permits the fabrication of medical-grade poly(ε-caprolactone) into complex multimodal and multiphasic scaffolds, using a single nozzle in a single print. This ability to control fiber diameter during printing opens new design opportunities for accurate scaffold fabrication for biomedical applications.}, language = {en} } @article{MuellerNossThornetal.2019, author = {M{\"u}ller, J{\"o}rg and Noss, Reed F. and Thorn, Simon and B{\"a}ssler, Claus and Leverkus, Alexandro B. and Lindenmayer, David}, title = {Increasing disturbance demands new policies to conserve intact forest}, series = {Conservation Letters}, volume = {12}, journal = {Conservation Letters}, doi = {10.1111/conl.12449}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224256}, year = {2019}, abstract = {Ongoing controversy over logging the ancient Białowieża Forest in Poland symbolizes a global problem for policies and management of the increasing proportion of the earth's intact forest that is subject to postdisturbance logging. We review the extent of, and motivations for, postdisturbance logging in protected and unprotected forests globally. An unprecedented level of logging in protected areas and other places where green-tree harvest would not normally occur is driven by economic interests and a desire for pest control. To avoid failure of global initiatives dedicated to reducing the loss of species, five key policy reforms are necessary: (1) salvage logging must be banned from protected areas; (2) forest planning should address altered disturbance regimes for all intact forests to ensure that significant areas remain undisturbed by logging; (3) new kinds of integrated analyses are needed to assess the potential economic benefits of salvage logging against its ecological, economic, and social costs; (4) global and regional maps of natural disturbance regimes should be created to guide better spatiotemporal planning of protected areas and undisturbed forests outside reserves; and (5) improved education and communication programs are needed to correct widely held misconceptions about natural disturbances.}, language = {en} } @article{SteigerwaldTimmermannKuehnetal.2018, author = {Steigerwald, Frank and Timmermann, Lars and K{\"u}hn, Andrea and Schnitzler, Alfons and Reich, Martin M. and Kirsch, Anna Dalal and Barbe, Michael Thomas and Visser-Vandewalle, Veerle and H{\"u}bl, Julius and van Riesen, Christoph and Groiss, Stefan Jun and Moldovan, Alexia-Sabine and Lin, Sherry and Carcieri, Stephen and Manola, Ljubomir and Volkmann, Jens}, title = {Pulse duration settings in subthalamic stimulation for Parkinson's disease}, series = {Movement Disorders}, volume = {33}, journal = {Movement Disorders}, doi = {10.1002/mds.27238}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239402}, pages = {165-169}, year = {2018}, abstract = {Background Stimulation parameters in deep brain stimulation (DBS) of the subthalamic nucleus for Parkinson's disease (PD) are rarely tested in double-blind conditions. Evidence-based recommendations on optimal stimulator settings are needed. Results from the CUSTOM-DBS study are reported, comparing 2 pulse durations. Methods A total of 15 patients were programmed using a pulse width of 30 µs (test) or 60 µs (control). Efficacy and side-effect thresholds and unified PD rating scale (UPDRS) III were measured in meds-off (primary outcome). The therapeutic window was the difference between patients' efficacy and side effect thresholds. Results The therapeutic window was significantly larger at 30 µs than 60 µs (P = ·0009) and the efficacy (UPDRS III score) was noninferior (P = .00008). Interpretation Subthalamic neurostimulation at 30 µs versus 60 µs pulse width is equally effective on PD motor signs, is more energy efficient, and has less likelihood of stimulation-related side effects. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.}, language = {en} } @article{ArlottiPalmisanoMinafraetal.2019, author = {Arlotti, Mattia and Palmisano, Chiara and Minafra, Brigida and Todisco, Massimiliano and Pacchetti, Claudio and Canessa, Andrea and Pozzi, Nicol{\´o} G. and Cilia, Roberto and Prenassi, Marco and Marceglia, Sara and Priori, Alberto and Rampini, Paolo and Barbieri, Sergio and Servello, Domenico and Volkmann, Jens and Pezzoli, Gianni and Isaias, Ioannis U.}, title = {Monitoring subthalamic oscillations for 24 hours in a freely moving Parkinson's disease patient}, series = {Movement Disorders}, volume = {34}, journal = {Movement Disorders}, doi = {10.1002/mds.27657}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221249}, pages = {757-759}, year = {2019}, abstract = {No abstract available}, language = {en} } @article{ZeinerPreusseGolebiewskaetal.2019, author = {Zeiner, Pia S. and Preusse, Corinna and Golebiewska, Anna and Zinke, Jenny and Iriondo, Ane and Muller, Arnaud and Kaoma, Tony and Filipski, Katharina and M{\"u}ller-Eschner, Monika and Bernatz, Simon and Blank, Anna-Eva and Baumgarten, Peter and Ilina, Elena and Grote, Anne and Hansmann, Martin L. and Verhoff, Marcel A. and Franz, Kea and Feuerhake, Friedrich and Steinbach, Joachim P. and Wischhusen, J{\"o}rg and Stenzel, Werner and Niclou, Simone P. and Harter, Patrick N. and Mittelbronn, Michel}, title = {Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas}, series = {Brain Pathology}, volume = {29}, journal = {Brain Pathology}, doi = {10.1111/bpa.12690}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233897}, pages = {513-529}, year = {2019}, abstract = {While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma-associated microglia/macrophages (GAMs), on patients' clinical course is still unclear. Thus, we aimed at assessing the immunohistochemical expression of selected microglia and macrophage markers in 344 gliomas (including gliomas from WHO grade I-IV). Furthermore, we analyzed a cohort of 241 IDH1R132H-non-mutant GBM patients for association of GAM subtypes and patient overall survival. Phenotypical properties of GAMs, isolated from high-grade astrocytomas by CD11b-based magnetic cell sorting, were analyzed by immunocytochemistry, mRNA microarray, qRT-PCR and bioinformatic analyses. A higher amount of CD68-, CD163- and CD206-positive GAMs in the vital tumor core was associated with beneficial patient survival. The mRNA expression profile of GAMs displayed an upregulation of factors that are considered as pro-inflammatory M1 (eg, CCL2, CCL3L3, CCL4, PTGS2) and anti-inflammatory M2 polarization markers (eg, MRC1, LGMN, CD163, IL10, MSR1), the latter rather being associated with phagocytic functions in the GBM microenvironment. In summary, we present evidence that human GBMs contain mixed M1/M2-like polarized GAMs and that the levels of different GAM subpopulations in the tumor core are positively associated with overall survival of patients with IDH1R132H-non-mutant GBMs.}, language = {en} } @article{IngendohTsakmakidisMikolaiWinkeletal.2019, author = {Ingendoh-Tsakmakidis, Alexandra and Mikolai, Carina and Winkel, Andreas and Szafrański, Szymon P. and Flak, Christine S. and Rossi, Angela and Walles, Heike and Stiesch, Meike}, title = {Commensal and pathogenic biofilms differently modulate peri-implant oral mucosa in an organotypic model}, series = {Cellular Microbiology}, volume = {21}, journal = {Cellular Microbiology}, doi = {10.1111/cmi.13078}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323077}, year = {2019}, abstract = {The impact of oral commensal and pathogenic bacteria on peri-implant mucosa is not well understood, despite the high prevalence of peri-implant infections. Hence, we investigated responses of the peri-implant mucosa to Streptococcus oralis or Aggregatibacter actinomycetemcomitans biofilms using a novel in vitro peri-implant mucosa-biofilm model. Our 3D model combined three components, organotypic oral mucosa, implant material, and oral biofilm, with structural assembly close to native situation. S. oralis induced a protective stress response in the peri-implant mucosa through upregulation of heat shock protein (HSP70) genes. Attenuated inflammatory response was indicated by reduced cytokine levels of interleukin-6 (IL-6), interleukin-8 (CXCL8), and monocyte chemoattractant protein-1 (CCL2). The inflammatory balance was preserved through increased levels of tumor necrosis factor-alpha (TNF-α). A. actinomycetemcomitans induced downregulation of genes important for cell survival and host inflammatory response. The reduced cytokine levels of chemokine ligand 1 (CXCL1), CXCL8, and CCL2 also indicated a diminished inflammatory response. The induced immune balance by S. oralis may support oral health, whereas the reduced inflammatory response to A. actinomycetemcomitans may provide colonisation advantage and facilitate later tissue invasion. The comprehensive characterisation of peri-implant mucosa-biofilm interactions using our 3D model can provide new knowledge to improve strategies for prevention and therapy of peri-implant disease.}, language = {en} } @article{MazonLaroucheStLouisetal.2018, author = {Mazon, Melody and Larouche, Val{\´e}rie and St-Louis, Maryse and Schindler, Detlev and Carreau, Madeleine}, title = {Elevated blood levels of Dickkopf-1 are associated with acute infections}, series = {Immunity, Inflammation and Disease}, volume = {6}, journal = {Immunity, Inflammation and Disease}, doi = {10.1002/iid3.232}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222171}, pages = {428-434}, year = {2018}, abstract = {Introduction Dickkopf-1 (DKK1) is a soluble protein and antagonist of the Wnt/β-catenin signaling pathway. DKK1 is found elevated in serum from patients affected with various types of cancers and in some instances, it is considered a diagnostic and prognostic biomarker. Elevated serum levels of DKK1 have also been detected in animal models of chronic inflammatory diseases. Previous work from our laboratory has demonstrated upregulation of DKK1 in cells and mouse models of the bone marrow failure (BMF) and cancer-prone disease Fanconi anemia (FA). The present study aimed to investigate whether DKK1 blood levels in patients are associated with FA or inflammatory responses to acute infections. Methods Plasma samples were collected from 58 children admitted to the Centre M{\`e}re-Enfant Soleil du Centre Hospitalier de Qu{\´e}bec-Universit{\´e} Laval with signs of acute infections. Blood plasma specimens were also collected from healthy blood donors at the H{\´e}ma-Qu{\´e}bec blood donor clinic. Plasmas from patients diagnosed with FA were also included in the study. DKK1 levels in blood plasmas were assessed by standard ELISA. Results Patients with acute infections showed dramatically high levels of DKK1 (6072 ± 518 pg/ml) in their blood compared to healthy blood donors (1726 ± 95 pg/ml). No correlations were found between DKK1 levels and C reactive protein (CRP) concentration, platelet numbers, or white blood cell counts. Patients with FA showed higher DKK1 plasma levels (3419 ± 147.5 pg/ml) than healthy blood donors (1726 ± 95 pg/ml) but significantly lower than patients with acute infections. Conclusion These findings suggest that blood DKK1 is elevated in response to infections and perhaps to inflammatory responses.}, language = {en} } @article{VanAsscheFicklFranciscoetal.2018, author = {Van Assche, Nele and Fickl, Stefan and Francisco, Helena and Gurzawska, Katarzyna and Milinkovic, Iva and Navarro, Jose M. and Torsello, Ferruccio and Thoma, Daniel S.}, title = {Guidelines for development of Implant Dentistry in the next 10 years regarding innovation, education, certification, and associations}, series = {Clinical Oral Implants Research}, volume = {29}, journal = {Clinical Oral Implants Research}, doi = {10.1111/clr.13154}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232150}, pages = {568-575}, year = {2018}, abstract = {Background During the third Summer Camp of European Association of Osseointegration (EAO), 40 junior representatives from various European societies and associations were brought together to discuss and explore the following topics in Implant Dentistry in the next 10 years: (I) certification, (II) societies and associations, (III) continuing education, and (IV) innovations. Aims The aims of all working groups were to identify and outline the present situation in the area of the selected topic and to propose improvements and innovations to be implemented in the following 10 years. Materials and methods Four different groups were assigned randomly to one of the four working units. The method to discuss the selected topics was World Caf{\`e}. The summaries of four topics were then given to all participants for peer review. Results and conclusions All four groups presented the conclusions and guidelines accordingly: (I) The recognition for Implant Dentistry and accreditation of training programs would lead to an improvement of the quality of care to the benefit of the patients; (II) Dental associations and societies have to continuously improve communication to meet needs of dental students, professionals, and patients (III) European Dental Board should be installed and become responsible for continue dental education; (IV) dental engineering, peri-implant diseases, and digital workflow in dentistry currently have limited tools that do not guarantee predictable results.}, language = {en} } @article{OPUS4-31382, title = {Dijet azimuthal correlations and conditional yields in \({pp}\) and \(p\) + Pb collisions at √S-NN=5.02 TeV with the ATLAS detector}, series = {Physical Review C}, volume = {100}, journal = {Physical Review C}, number = {3}, organization = {The ATLAS Collaboration}, doi = {10.1103/PhysRevC.100.034903}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313823}, pages = {1-24}, year = {2019}, abstract = {This paper presents a measurement of forward-forward and forward-central dijet azimuthal angular correlations and conditional yields in proton-proton (pp) and proton-lead (p + Pb) collisions as a probe of the nuclear gluon density in regions where the fraction of the average momentum per nucleon carried by the parton entering the hard scattering is low. In these regions, gluon saturation can modify the rapidly increasing parton distribution function of the gluon. The analysis utilizes 25 pb(-1) of pp data and 360 mu b(-1) of p + Pb data, both at root S-NN = 5.02 TeV, collected in 2015 and 2016, respectively, with the ATLAS detector at the Large Hadron Collider. The measurement is performed in the center-of-mass frame of the nucleon-nucleon system in the rapidity range between -4.0 and 4.0 using the two highest transverse-momentum jets in each event, with the highest transverse-momentum jet restricted to the forward rapidity range. No significant broadening of azimuthal angular correlations is observed for forward-forward or forward-central dijets in p + Pb compared to pp collisions. For forward-forward jet pairs in the proton-going direction, the ratio of conditional yields in p + Pb collisions to those in pp collisions is suppressed by approximately 20\%, with no significant dependence on the transverse momentum of the dijet system. No modification of conditional yields is observed for forward-central dijets.}, language = {en} }