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Gallbladder cancer (GBC) is a lethal cancer with poor prognosis associated with high invasiveness and poor response to chemotherapy and radiotherapy. New therapeutic approaches are urgently needed in order to improve survival and response rates of GBC patients. We screened 130 small molecule inhibitors on a panel of seven GBC cell lines and identified the HSP90 inhibitor 17-AAG as one of the most potent inhibitory drugs across the different lines. We tested the antitumor efficacy of 17-AAG and geldanamycin (GA) in vitro and in a subcutaneous preclinical tumor model NOD-SCID mice. We also evaluated the expression of HSP90 by immunohistochemistry in human GBC tumors.
In vitro assays showed that 17-AAG and GA significantly reduced the expression of HSP90 target proteins, including EGFR, AKT, phospho-AKT, Cyclin B1, phospho-ERK and Cyclin D1. These molecular changes were consistent with reduced cell viability and cell migration and promotion of G2/M cell cycle arrest and apoptosis observed in our in vitro studies.
In vivo, 17-AAG showed efficacy in reducing subcutaneous tumors size, exhibiting a 69.6% reduction in tumor size in the treatment group compared to control mice (p < 0.05).
The HSP90 immunohistochemical staining was seen in 182/209 cases of GBC (87%) and it was strongly expressed in 70 cases (33%), moderately in 58 cases (28%), and weakly in 54 cases (26%).
Our pre-clinical observations strongly suggest that the inhibition of HSP90 function by HSP90 inhibitors is a promising therapeutic strategy for gallbladder cancer that may benefit from new HSP90 inhibitors currently in development.
The detailed biophysical mechanisms through which transcranial magnetic stimulation (TMS) activates cortical circuits are still not fully understood. Here we present a multi-scale computational model to describe and explain the activation of different pyramidal cell types in motor cortex due to TMS. Our model determines precise electric fields based on an individual head model derived from magnetic resonance imaging and calculates how these electric fields activate morphologically detailed models of different neuron types. We predict neural activation patterns for different coil orientations consistent with experimental findings. Beyond this, our model allows us to calculate activation thresholds for individual neurons and precise initiation sites of individual action potentials on the neurons’ complex morphologies. Specifically, our model predicts that cortical layer 3 pyramidal neurons are generally easier to stimulate than layer 5 pyramidal neurons, thereby explaining the lower stimulation thresholds observed for I-waves compared to D-waves. It also shows differences in the regions of activated cortical layer 5 and layer 3 pyramidal cells depending on coil orientation. Finally, it predicts that under standard stimulation conditions, action potentials are mostly generated at the axon initial segment of cortical pyramidal cells, with a much less important activation site being the part of a layer 5 pyramidal cell axon where it crosses the boundary between grey matter and white matter. In conclusion, our computational model offers a detailed account of the mechanisms through which TMS activates different cortical pyramidal cell types, paving the way for more targeted application of TMS based on individual brain morphology in clinical and basic research settings.
R-flurbiprofen is the non-COX-inhibiting enantiomer of flurbiprofen and is not converted to S-flurbiprofen in human cells. Nevertheless, it reduces extracellular prostaglandin E2 (PGE2) in cancer or immune cell cultures and human extracellular fluid. Here, we show that R-flurbiprofen acts through a dual mechanism: (i) it inhibits the translocation of cPLA2α to the plasma membrane and thereby curtails the availability of arachidonic acid and (ii) R-flurbiprofen traps PGE2 inside of the cells by inhibiting multidrug resistance–associated protein 4 (MRP4, ABCC4), which acts as an outward transporter for prostaglandins. Consequently, the effects of R-flurbiprofen were mimicked by RNAi-mediated knockdown of MRP4. Our data show a novel mechanism by which R-flurbiprofen reduces extracellular PGs at physiological concentrations, particularly in cancers with high levels of MRP4, but the mechanism may also contribute to its anti-inflammatory and immune-modulating properties and suggests that it reduces PGs in a site- and context-dependent manner.
Purpose: Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC).
Methods: A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing.
Results: Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited.
Conclusions: Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI–TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.
In this thesis we study strongly correlated electron systems within the Density Functional Theory (DFT) in combination with the Dynamical Mean-Field Theory (DMFT).
First, we give an introduction into the theoretical methods and then apply them to study realistic materials. We present results on the hole-doped 122-family of the iron-based superconductors and the transition-metal oxide SrVO3. Our investigations show that a proper treatment of strong electronic correlations is necessary to describe the experimental observations.
The humanized non-depleting anti-CD4 monoclonal antibody Tregalizumab (BT-061) is able to selectively activate the suppressive function of regulatory T cells and has been investigated up to phase 2b in clinical trials in patients suffering from rheumatoid arthritis (RA).
A pharmacokinetic-pharmacodynamic model, which is based on clinical data from RA and healthy subjects, used the cell surface CD4-down-modulation as marker of the antibodies' activity. This model surprisingly revealed a stronger effect of Tregalizumab in healthy subjects compared to RA patients. This thesis presents a series of experiments performed to understand this phenomenon.
To counteract oxidative stress, which is strongly associated with RA pathophysiology, the organism employs the small oxidoreductase thioredoxin-1 (Trx1). Therefore, augmented expression and secretion of Trx1 was seen in many studies the synovial fluid and plasma of RA patients. Moreover, the binding site of Tregalizumab is in close proximity to a disulfide bond in domain 2 (D2) of CD4, which is a known target for a reduction by Trx1. So, this thesis also evaluated the influence of Trx1 on binding of Tregalizumab to its target CD4.
With the experiments reported herein, it was possible to demonstrate that specific reduction of the D2 disulfide bond of CD4 by Trx1 led to diminished binding of Tregalizumab to recombinant human soluble CD4 (rh sCD4) and membrane-bound CD4 on T cells from a human leukemia cell line and peripheral blood mononuclear cells (PBMC). Moreover, the experiments revealed that this caused changes in the Tregalizumab-induced CD4 signalling pathway via the lymphocyte-specific protein tyrosine kinase p56Lck.
In summary, this thesis provides evidence that high Trx1 levels in RA patients compared to healthy subjects are a potential valid reason for diminished binding of Tregalizumab to CD4-positive T cells and offers an explanation for the observed decreased CD4 down-modulation in RA patients in comparison with healthy subjects. It emphasizes that binding of Tregalizumab is impaired in a particular way in RA patients.
We designed and fielded an experimental module in the 2014 HRS which seeks to measure older persons’ willingness to voluntarily defer claiming of Social Security benefits. In addition we evaluate the stated willingness of older individuals to work longer, depending on the Social Security incentives offered to delay claiming their benefits. Our project extends previous work by analyzing the results from our HRS module and comparing findings from other data sources, which included very much smaller samples of older persons. We show that half of the respondents would delay claiming if no work requirement were in place under the status quo, and only slightly fewer, 46 percent, with a work requirement. We also asked respondents how large a lump sum they would need with or without a work requirement. In the former case, the average amount needed to induce delayed claiming was about $60,400, while when part-time work was required, the average was $66,700. This implies a low utility value of leisure foregone of only $6,300, or about 10 percent of older households’ income.
On average young people \undersave" whereas old people \oversave" with respect to the rational expectations model of life-cycle consumption and savings. According to numerous studies on subjective survival beliefs, young people also \underestimate" whereas old people \overestimate" their objective survival chances on average. We take a structural behavioral economics approach to jointly address both empirical phenomena by embedding subjective survival beliefs that are consistent with these biases into a rank-dependent utility (RDU) model over life-cycle consumption. The resulting consumption behavior is dynamically inconsistent. Considering both naive and sophisticated RDU agents we show that within this framework underestimation of young age and overestimation of old age survival probabilities may (but need not) give rise to the joint occurrence of undersaving and oversaving. In contrast to this RDU model, the familiar quasi-hyperbolic discounting (QHD), which is nested as a special case, cannot generate oversaving.
We test two hypotheses, based on sexual selection theory, about gender differences in costly social interactions. Differential selectivity states that women invest less than men in interactions with new individuals. Differential opportunism states that women’s investment in social interactions is less responsive to information about the interaction’s payoffs. The hypotheses imply that women’s social networks are more stable and path dependent and composed of a greater proportion of strong relative to weak links. During their introductory week, we let new university students play an experimental trust game, first with one anonymous partner, then with the same and a new partner. Consistent with our hypotheses, we find that women invest less than men in new partners and that their investments are only half as responsive to information about the likely returns to the investment. Moreover, subsequent formation of students’ real social networks is consistent with the experimental results: being randomly assigned to the same introductory group has a much larger positive effect on women’s likelihood of reporting a subsequent friendship.
Das zwischenstaatliche Gewaltverbot steht im Zentrum der völkerrechtlichen Aufmerksamkeit. Auf bewaffnete Konflikte auf dem afrikanischen Kontinent trifft dies nur begrenzt zu. An dieses Defizit knüpft die Autorin ab der Zeitwende 1989/90 an. Dabei überschreitet sie die traditionellen Grenzen des Gewaltverbots und analysiert, inwieweit dies, v. a. durch die Fortentwicklung der Menschenrechtslehre, eine inhaltliche Änderungen erfahren hat, die auch die militärische Anwendung von Gewalt im Innern eines Staates ächtet (ius contra bellum internum). Ein weiterer Schwerpunkt sind Interventionen durch Regionalorganisation. Hierbei wird untersucht, ob multilaterale Interventionen schon dann gewohnheitsrechtliche Akzeptanz erfahren, wenn sie entweder formell oder materiell rechtmäßig sind. Zumindest solche, die durch den UN-Sicherheitsrat autorisiert sind, können diese sog. Baugenehmigungsthese für sich in Anspruch nehmen. Doch auch ohne UN-Mandat vermögen humanitäre Interventionen regionaler Organisationen in engen Grenzen völkerrechtmäßig sein.
Samples of freshly fallen snow were collected at the high alpine research station Jungfraujoch (Switzerland) in February and March 2006 and 2007, during the Cloud and Aerosol Characterization Experiments (CLACE) 5 and 6. In this study a new technique has been developed and demonstrated for the measurement of organic acids in fresh snow. The melted snow samples were subjected to solid phase extraction and resulting solution analysed for organic acids by HPLC-MS-TOF using negative electrospray ionization. A series of linear dicarboxylic acids from C5 to C13 and phthalic acid, were identified and quantified. In several samples the biogenic acid pinonic acid was also observed. In fresh snow the median concentration of the most abundant acid, adipic acid, was 0.69 µg L−1 in 2006 and 0.70 µg L−1 in 2007. Glutaric acid was the second most abundant dicarboxylic acid found with median values of 0.46 µg L−1 in 2006 and 0.61 µg L−1 in 2007, while the aromatic acid phthalic acid showed a median concentration of 0.34 µg L−1 in 2006 and 0.45 µg L−1 in 2007. The concentrations in the samples from various snowfall events varied significantly, and were found to be dependent on the back trajectory of the air mass arriving at Jungfraujoch. Air masses of marine origin showed the lowest concentrations of acids whereas the highest concentrations were measured when the air mass was strongly influenced by boundary layer air.
Der bisher in Deutschland sehr selten gemeldete Neophyt Phedimus stolonifer wurde im Jahr 2015 in Frankfurt am Main anscheinend erstmals für Hessen nachgewiesen. Das individuenreiche Vorkommen längs eines Bachlaufes wird beschrieben. Eine Einbürgerung kann aufgrund der kurzen Beobachtungsdauer bislang nicht konstatiert werden.
Massive global spread of multidrug-resistant (MDR) Salmonella spp. expressing extended-spectrum beta-lactamase (ESBL) and additional resistance to fluoroquinolones has often been attributed to high international mobility as well as excessive use of oral antibiotics in livestock farming. However, MDR Salmonella spp. have not been mentioned as a widespread pathogen in clinical settings so far. We demonstrate the case of a 25-year-old male with primary sclerosing cholangitis who tested positive for MDR Salmonella enterica serotype Choleraesuis expressing ESBL and fluoroquinolone resistance. The pathogen was supposedly acquired during a trip to Thailand, causing severe fever, cholangitis and pancreatitis. To our knowledge, this is the first report of Salmonella enterica serotype Choleraesuis in Europe expressing such a multidrug resistance pattern. ESBL resistance of Salmonella enterica spp. should be considered in patients with obstructive biliary tract pathology and travel history in endemic countries.
The CDK inhibitor SNS-032 had previously exerted promising anti-neuroblastoma activity via CDK7 and 9 inhibition. ABCB1 expression was identified as major determinant of SNS-032 resistance. Here, we investigated the role of ABCB1 in acquired SNS-032 resistance. In contrast to ABCB1-expressing UKF-NB-3 sub-lines resistant to other ABCB1 substrates, SNS-032-adapted UKF-NB-3 (UKF-NB-3rSNS- 032300nM) cells remained sensitive to the non-ABCB1 substrate cisplatin and were completely re-sensitized to cytotoxic ABCB1 substrates by ABCB1 inhibition. Moreover, UKF-NB-3rSNS-032300nM cells remained similarly sensitive to CDK7 and 9 inhibition as UKF-NB-3 cells. In contrast, SHEPrSNS-0322000nM, the SNS-032-resistant sub-line of the neuroblastoma cell line SHEP, displayed low level SNS-032 resistance also when ABCB1 was inhibited. This discrepancy may be explained by the higher SNS-032 concentrations that were used to establish SHEPrSNS-0322000nM cells, since SHEP cells intrinsically express ABCB1 and are less sensitive to SNS-032 (IC50 912 nM) than UKF-NB-3 cells (IC50 153 nM). In conclusion, we show that ABCB1 expression represents the primary (sometimes exclusive) resistance mechanism in neuroblastoma cells with acquired resistance to SNS-032. Thus, ABCB1 inhibitors may increase the SNS-032 efficacy in ABCB1-expressing cells and prolong or avoid resistance formation.
The Hepatitis C virus (HCV) infects more than 170 million individuals worldwide and causes challenging HCV-related diseases. Unfortunately, there is no vaccine available. Therefore, a better understanding of the HCV life cycle is urgently needed to develop more effective and better tolerated therapies.
It has been reported that the secretory pathway plays an essential role for the release of HCV, and the SNARE complexes are a central factor controlling intracellular vesicular trafficking. Recently, our group observed that α-taxilin that binds to free syntaxin 4 prevents the SNARE complex formation and exerts an inhibitory effect on the release of HCV particles. Therefore, it was analyzed whether the t-SNARE protein syntaxin 4 is involved in the HCV life cycle.
An increased intracellular amount of syntaxin 4 was found in HCV-positive cells, while the level of syntaxin 4-specific transcripts was decreased as observed in HCV-positive Huh7.5 cells and in HCV-infected primary human hepatocytes (PHH). Since in HCV-positive cells a significant longer half-life of syntaxin 4 was found, the decreased expression is overcompensated, leading to the elevated amount of syntaxin 4. Overexpression of syntaxin 4 increases the amount of secreted infectious viral particles, while silencing of syntaxin 4 expression decreases the number of released viral particles, which indicates that HCV could use the SNARE-dependent secretory pathway for viral release. Confocal immunofluorescence microscopy and co-immunoprecipitation experiments revealed that syntaxin 4 interacts with HCV core and NS5A. To identify the binding domain, various mutants of syntaxin 4 were generated. Based on these mutants, it was found that the H3 domain of syntaxin 4 interacts with core. These data show that the t-SNARE protein syntaxin 4 is an essential cellular factor for HCV morphogenesis and secretion.
HCV induces autophagy, and in HCV-infected cells a major fraction of the de novo synthesized viral particles is not released but intracellularly degraded. Syntaxin 17 is an autophagosomal SNARE required for the fusion of autophagosomes with lysosomes to form autolysosomes and thereby to deliver the enclosed contents for degradation. Therefore, we aim to investigate whether syntaxin 17 is a relevant factor for the HCV life cycle by regulating the fusion between autophagosomes and lysosomes. It was found that HCV-positive cells possess a decreased amount of syntaxin 17, and HCV reduces the intracellular level of syntaxin 17 by NS5A-mediated interruption of c-Raf signaling, which triggers the syntaxin 17 transcription, and by HCV-dependently induced autophagy. Overexpression of syntaxin 17 decreases the intracellular amount of viral particles and reduces the number of released infectious viral particles by favoring the formation of autolysosomes, in which HCV particles can be degraded. Vice versa, inhibition of syntaxin 17 expression by specific siRNAs results in an elevated amount of intracellular viral particles and increases the number of released viral particles by impaired autophagosome-lysosome fusion. Confocal immunofluorescence microscopy analyses show a fraction of core protein in autophagosomes as stained by lysotracker and the autophagy maker p62. These data identify syntaxin 17 as a novel factor controlling the release of HCV and reveal the autophagosome-autolysosome fusion as an essential step affecting the equilibrium between the release of infectious viral particles and lysosomal degradation of intracellular viral particles.
Taken together, these data identify the t-SNARE proteins syntaxin 4 and syntaxin 17 as essential cellular factors for HCV morphogenesis and secretion.
Der Sufi-Meister und Dichter Ken’ân Rifâî gilt als eine der bedeutendsten und einflussreichsten Persönlichkeiten der osmanisch-türkischen Sufi-Tradition im 20. Jahrhundert. Sein Leben zwischen den Jahren 1867-1950, welches die vier Phasen, die Monarchie, die erste und zweite Verfassungsperiode (1876 und 1908), die Republik (1923) und auch die Anfangsphase der Demokratie (1950) umfasst, und seine Lehre reflektieren die Entwicklung, die Umwälzung und den letzten Zustand, die das sufische Leben im letzten Zeitabschnitt des Osmanischen Reiches und nach der Ṭarīqa-Phase in der Periode der Republik erlebt und erreicht hat. Ken’ân Rifâî fungierte zwischen den Jahren 1908-1925 als Tekke-Scheich, und zwar bis 1925, wo alle vorhandenen Tekkes in der Türkei gesetzlich verboten und dementsprechend geschlossen wurden...
Bartonella Adhäsin A (BadA), das zur Gruppe der TAAs gehört, ist ein essentieller Pathogenitätsfaktor von B. henselae und übernimmt während des Infektionsverlaufs wichtige Funktion wie Autoagglutination, Adhärenz an ECM-Proteine und Endothelzellen. BadA weist die für die für die Proteinklasse der TAAs charakteristische modulare Architektur bestehend aus N-terminaler Kopf-Domäne, Stiel-Domäne, Hals-Domäne und C-terminaler Membrananker-Domäne auf. Der modulare Aufbau des Proteins deutet daraufhin, dass bestimmte Domänen mit bestimmten biologischen Funktionen des Proteins verknüpft sind. Zur Untersuchung dieser Hypothese wurden Deletionsmutanten des BadA generiert.
Die Generierung weiterer BadA-Deletionsmutanten wird durch das langsame Wachstum des Erregers und die geringe Auswahl an molekularbiologischen Werkzeugen zur genetischen Manipulation von B. henselae erschwert. Daher sollte in ersten Teil dieser Arbeit ein Expressionsmodell für Deletionsmutanten des BadA etabliert und charakterisiert werden. Dies sollte am Beispiel des trunkierten BadA, BadA HN23, durchgeführt werden. Hierzu sollten drei Hybrid-Varianten des BadA HN23 erstellt werden: (i) Austausch der BadA-Signalsequenz gegen die E. coli OmpA-Signalsequenz, (ii) Austausch der BadA-Membrananker-Domäne gegen die YadA-Membrananker-Domäne sowie (iii) Austausch von sowohl der BadA-Signalsequenz als auch der BadA-Membrananker-Domäne gegen die bereits genannten Elemente. Danach sollten die konstruierten BadA HN23 Hybride und das BadA HN23 in induzierbare Expressionsvektoren kloniert und spezielle E. coli-Expressionsstämme mit diesen Plasmiden transformiert werden. Bei erfolgreicher Expression sollten die optimalen Bedingungen für die Expression (Temperatur, Induktorkonzentration) ermittelt werden und an-schließend die biologische Funktion der heterolog exprimierten BadA HN23 Hybride überprüft werden.
Der erste Abschnitt der hier vorliegenden Arbeit zeigte folgende Ergebnisse:
1) Die beschrieben BadA HN23 Hybrid Konstrukte wurden durch Austausch von: (i) BadA-Signalsequenz gegen E. coli OmpA-Signalsequenz im BadA HN23,
(ii) BadA-Membrananker-Domäne gegen YadA-Membrananker-Domäne im BadA HN23 und
(iii) Austausch von BadA-Signalsequenz und BadA-Membrananker-Domäne gegen E. coli OmpA-Signalsequenz und YadA-Membrananker-Domäne im BadA HN23 generiert.
Die BadA HN23 Hybride und BadA HN23 wurden in Expressionsvektoren kloniert und E. coli Omp2, E. coli Omp8 und E. coli Omp8ΔdegP transformiert.
2) Alle BadA HN23 Hybrid-Konstrukte und BadA HN23 lagen in einer monomeren und trimeren Form vor.
3) Durch IFT und - Durchflusszytometrie-Untersuchungen wurde die Oberflächenexpression der einzelnen Konstrukte quantifiziert. Es zeigte sich, dass es deutliche Unterschiede in der Menge des auf der Zelloberfläche befindlichen jeweiligen BadA HN23 Proteins gab. Dabei wiesen die Konstrukte, die die YadA-Membrananker-Domäne besaßen (BadA HN23 Hybrid 2 und 3), die stärkste Oberflächenexpression auf.
4) Die biologische Funktion des BadA HN23 wurde mittels des E. coli Omp2 BadA HN23 Hybrid 3 charakterisiert. Heterolog exprimiertes BadA HN23 vermittelt Autoagglutination, die Adhärenz des Expressionsstammes an Kollagen G und Endothelzellen.
5) Die Expression des BadA HN23 führt zur signifikant verstärkten in-vivo-Pathogenität im Galleria mellonella-Infektionsmodell.
6) Das E. coli-Expressionsmodell lieferte keine Aussage über eventuelle immunodominate Funktionen des heterolog exprimierten BadA HN23, da auch mit im IFT als anti- B. henselae negativ eingestuften Patientenseren im WB ein BadA HN23 spezifisches Bandensignal detektiert wurde. Dot Blot-Experimente ermöglichten ebenfalls keine Aussage über eventuelle immunodominate Funktion des nativen BadA HN23, da das verwendete anti-B. henselae-positive Patientenserum unspezifische Reaktion gegenüber dem Kontrollstamm zeigte.
Für verschiedene TAAs ist beschrieben worden, dass sie die Serumresistenz der exprimierenden Spezies vermitteln. Daher sollte im zweiten Teil dieser Arbeit der Einfluss von BadA auf eventuelle Serumresistenz zweier B. henselae-Isolate untersucht werden. Dieser Teil lieferte folgende Ergebnisse:
1) B. henselae zeigte Sensitivität gegenüber normalem humanem Serum.
2) Sowohl BadA-positive als auch BadA-negative B. henselae-Isolate können Komplementinhibitoren wie Faktor H binden. Die dabei gebundene Menge ist relativ klein.
Die Expression von Deletionsmutanten des BadA in E. coli ist ein vielversprechendes Modell zur Analyse der Domänen-Funktionsbeziehung des BadA, da die meisten biologischen Funktionen einer homolog exprimierten BadA-Deletionsmutante reproduziert werden konnten und es sich bei E. coli um ein schnell wachsendes Bakterium, das sich leicht genetisch manipulieren lässt, handelt. Allerdings stellt das zytotoxische LPS des E. coli sowie das schnelle Wachstums der Bakterien eine Limitation des Expressionssystems dar, indem es Untersuchungen zum Einfluss der jeweiligen BadA-Deletionsmutante auf die Induktion der proangiogenetischen Wirtszellantwort verhindert oder Untersuchungen zum Einfluss der jeweiligen BadA-Deletionsmutante auf die Adhärenz an Endothelzellen deutlich erschwert. Außerdem kann eine mögliche Interaktion zwischen BadA bzw. BadA-Deletionsmutanten und dem TIVSS und zwischen BadA bzw. BadA-Deletionsmutanten und weiteren Adhäsinen (wie z.B. dem FHA) mit Hilfe dieses Expressionssystems nicht untersucht werden. Dies wäre nur im B. henselae Wildtyp-Stamm möglich.
Weltweit sind ca. 130–180 Millionen Menschen mit HCV infiziert und jährlich sterben etwa 500.000 Menschen an dessen Folgen. Die neuartigen Therapien versprechen zwar eine sehr hohe Heilungsrate, sind aber aufgrund ihrer enorm hohen Kosten nur in Industrieländern verfügbar. Noch immer gibt es keine prophylaktische Vakzinierung gegen HCV. Deshalb ist es wichtig, den HCV-Lebenszyklus und die Interaktion zwischen Wirtszelle und Virus detailliert zu verstehen, um die Entwicklung von Therapien und Impfungen zu ermöglichen. Außerdem kann ein fundiertes Wissen von HCV translatiert werden und auf neuartige Erreger der Familie der Flaviviridae, wie Denguevirus und Zikavirus, angewendet werden. Während der Zelleintritt und die Replikation von HCV relativ gut charakterisiert sind, bleiben die Assemblierung und Freisetzung der viralen Partikel schlecht verstandene Schritte des HCV-Lebenszyklus. In dieser Arbeit sollte die Rolle des zellulären Proteins α-Taxilin im Lebenszyklus von HCV untersucht werden. In einer späteren Phase der Arbeit wurde der endosomale Freisetzungsweg von HCV untersucht. Dazu wurden HCV Varianten generiert und charakterisiert, die Fluoreszenz-Proteine im NS5A- und E1-Protein enthalten, durch die es möglich ist, den Replikationskomplex und die Viruspartikel zu visualisieren und zu quantifizieren und den viralen Lebenszyklus dadurch besser untersuchen zu können...