@phdthesis{Abbas2024,
  author    = {Abbas, Eid Nagy Eid},
  title     = {Demotic Texts from Medinet Habu (Philological, Paleographical, and Cultural Study)},
  doi       = {10.25972/OPUS-35265},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352653},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {The current study presents a new a group of Demotic ostraca in the belongings of the Cairo Museum. A large part of this group stem from Medinet Habu in the western bank of modern Luxor in Upper Egypt and was discovered in the beginning of the thirties of the last century by the Chicago Oriental Institute (recently renamed as Institute for the Study of Ancient Cultures 'ISAC'). A small portion of the collection under consideration come from other Upper Egyptian provenances including Gebelein, Edfu, Kom Ombo, and possibly elsewhere in Thebes. The main goal of the present dissertation is to decipher, translate, and provide a philological, paleographical, and cultural analysis of the group of texts in question. The results of this study are spread over two main parts, the first of which is dedicated to the main and largest part of the collection, i.e. ostraca from Medinet Habu, while the second is concerned with ostraca from other places. The first part comprises of five sections beginning with receipts of money and in-kind payments including some receipts for the payments of the different capitation charges in the Ptolemaic and Roman Periods, a few for land-related payments, as well as others related to different Ptolemaic monopolies or trades such as a receipt for the price of oil, one for the linen tax, in addition to a unique receipt for the rarely attested fish tax. The second section includes accounts and lists of different kinds be it monetary, in-kind, agriculture, or any other type of lists or accounts that record different everyday transactions. The following section presents a relatively different type of lists, namely lists of personal names. The fourth section incorporates a variety of texts of different concerns, e.g. texts of religious nature, letters, temples oaths, or other private documents. Unidentified texts occupy the fifth and final section of the first part. The second part of the study, which comprises texts that originate from different Upper Egyptian localities, includes three sections, i.e. receipts, accounts, and lists of names.},
  language  = {en}
}
@phdthesis{AbdelRahman2003,
  author    = {Abdel Rahman, Faisal Mirghani},
  title     = {Systematic analysis of genes expressed in the retinal pigment epithelium (RPE) and identification of candidates for genetic susceptibility to age-related macular degeneration (AMD)},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-7053},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2003},
  abstract  = {Age related macular degeneration (AMD) is the leading cause of visual impairment in the elderly and the major cause of blindness in the developed world. To date, the molecular mechanisms underlying the disease are not well understood although in recent years a primary involvement of the retinal pigment epithelium (RPE) has become evident. The aim of the present study is to systematically analyse genes which are differentially expressed in the RPE, and to assess their possible association with mechanisms and pathways likely to be related to retinal disease, in particular AMD. Towards this goal, 2379 expressed sequence tags (ESTs) were established from an inhouse generated RPE cDNA library. This library was constructed by using the suppression subtraction hybridization (SSH) technique which normalises redundant sequences and ensures enrichment of rare transcripts. In a first phase, 1002 ESTs were sequenced and subjected to comprehensive alignment with public nucleotide and protein databases. A search of the 1002 ESTs against the human genome draft sequence yielded 168 known genes, 51 predicted genes, 15 unknown transcripts and 41 clones with no significant similarity. Reverse Northern blot hybridization was performed for 318 EST clusters to identify abundantly expressed genes in the RPE and to prioritize subsequent analyses. Representative clones were spotted onto a nylon membrane and hybridized with cDNA probes of driver (heart and liver) and tester (RPE) used in the cDNA library construction. Subsequently, 107 EST clusters were subjected to Northern blot hybridizations. These analyses identified 7 RPE-specific, 3 retina-specific, 7 RPE/retina-specific, and 7 tissue restricted transcripts, while 29 EST clusters were ubiquitously expressed, and evaluation was not possible for another 54 EST clusters. Of the 24 transcripts with specific or restricted expression, 16 clones were selected for further characterization. The predicted gene MGC2477 and 2 novel isoforms of the human transient receptor potential cation channel, subfamily M, member 3 (TRPM3) were cloned and further described in detail. In addition, polymorphic variations for these 2 genes as well as for the human MT-Protocadherin gene were determined. For MGC2477, 15 single nucleotide polymorphisms (SNPs) were identified, with 13 having a frequency of the minor allele greater than 20\%. 10 of the 15 SNPs have not been reported in so far in public SNP repertoires. Partial assessment of the TRPM3 gene yielded 35 SNPs. Of these, 30 (85.7\%) were highly frequent (0.17-0.5\%), and 14 (40\%) were novel. The MT-Protocadherin gene revealed 35 SNPs, including 28 (80\%) with high frequency of the minor allele. 23 (65.7\%) were novel SNPs. These SNPs will be used to construct the most common haplotypes. These will be used in case/control association studies in 400 AMD patients and 200 ethnically and aged matched controls to assess a possible contribution of these genes in the etiology of AMD.},
  subject      = {Senile Makuladegeneration / Pigmentepithel / Genexpression},
  language  = {en}
}
@phdthesis{Abdelmohsen2010,
  author    = {Abdelmohsen, Usama Ramadan},
  title     = {Antimicrobial Activities from Plant Cell Cultures and Marine Sponge-Associated Actinomycetes},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-51483},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {This thesis is divided into three parts with the main goal allocating novel antimicrobial compounds that could be used as future antibiotics. The first part aimed to evaluate the potential of plant suspension cultures for the production of antimicrobial proteins. The extracellular, intracellular and cell wall bound fractions of seven heterotrophic and photomixotrophic plant cell suspension cultures treated with nine different elicitors were tested for the elicitor dependent production of antimicrobial proteins. Bioactivities were tested against a selected panel of human isolates including Gram-positive and Gram-negative bacteria as well as fungi using the disc diffusion assay. The intracellular fractions of elicited cell cultures were more active than extracellular fractions while the cell wall bound fractions showed lowest activities. Among the 21 fractions tested, the intracellular fraction of Lavendula angustifolia elicited with DC3000 was most active against Candida maltosa. The second most active fraction was the intracellular fraction of Arabidopsis thaliana elicited with salicylic acid which was moreover active against all test strains. The antimicrobial activity of elicited Arabidopsis thaliana cell cultures was tested by bioautography to locate the antimicrobial proteins in the crude extract. The intracellular fraction of photomixotrophic Arabidopsis thaliana cells elicited with salicylic acid was selected for further gel filtration chromatography on S-200 column leading to the purification of one 19 kDa antimicrobially active protein, designated, AtAMP. Our findings suggest that elicited plant cell cultures may present a new promising alternative source of antimicrobial proteins. The second part comprises the isolation of actinomycetes associated with marine sponges and testing the bioactivities of new species for further investigations. Actinobacterial communities of eleven taxonomically different sponges that had been collected from offshore Ras Mohamed (Egypt) and from Rovinj (Croatia) were investigated by a culture-based approach using different standard media for isolation of actinomycetes and media enriched with aqueous sponge extract to target rare and new actinomycete species. Phylogenetic characterization of 52 representative isolates out of 90 based on almost complete sequences of genes encoding 16S rRNA supported their assignment to 18 different actinomycete genera. Altogether 14 putatively new species were identified based on sequence similarity values below 98.2\% to other strains in the NCBI database. The use of M1 agar amended with aqueous sponge extract yielded a putative new genus related to Rubrobacter which highlighting the need for innovative cultivation protocols. Biological activity testing showed that five isolates were active against Gram-positives only, one isolate was active against Candida albicans only and one isolate showed activity against both groups of pathogens. Moreover, the antiparasistic activity was documented for four isolates. These results showed a high diversity of actinomycetes associated with marine sponges as well as highlighted their potential to produce anti-infective agents. The third part of the thesis focused on the isolation and structure elucidation of new bioactive compounds. Streptomyces strain RV15 recovered from sponge Dysidea tupha, was selected for further chemical analysis by virtue of the fact that it exhibited the greatest antimicrobial potential against Staphylococcus aureus as well as Candida albicans among the all tested strains. Moreover, members of the genus Streptomyces are well known as prolific producers of interesting pharmacologically active metabolites. Chemical analysis of the methanolic crude extract using different chromatographic tools yielded four new compounds. The structures of the new compounds were spectroscopically elucidated to be four new cyclic peptides, namely, cyclodysidins A-D. Their bioactivity was tested against different proteases, bacteria and Candida as well as tumor cell lines. The compounds did not show any significant activities at this point.},
  subject      = {Antimikrobieller Wirkstoff},
  language  = {en}
}
@phdthesis{Aboagye2019,
  author    = {Aboagye, Benjamin},
  title     = {Behavioral and physiologic consequences of inducible inactivation of the \(Tryptophan\) \(hydroxylase\) 2 gene in interaction with early-life adversity},
  doi       = {10.25972/OPUS-17358},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173581},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Disruptions in brain serotonin (5-hydroxytryptamine, 5-HT) signaling pathways have been associated with etiology and pathogenesis of various neuropsychiatric disorders, but specific neural mechanisms of 5-HT function are yet to be fully elucidated. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme for brain 5-HT synthesis. Therefore, in this study a tamoxifen (Tam)-inducible cre-mediated conditional gene (Tph2) knockout in adult mouse brain (Tph2icKO) has been established to decipher the specific role of brain 5-HT in the regulation of behavior in adulthood. Immunohistochemistry and high-performance liquid chromatography (HPLC) were used first to test the efficacy of Tam-inducible inactivation of Tph2 and consequential reduction of 5-HT in adult mouse brain. Tam treatment resulted in ≥90\% reduction in the number of 5-HT immuno-reactive cells in the anterior raphe nuclei. HPLC revealed a significant reduction in concentration of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) in selected brain regions of Tph2icKO, indicating the effectiveness of the protocol used. Second, standard behavioral tests were used to assess whether reduced brain 5-HT concentrations could alter anxiety-, fear- and depressive-like behavior in mice. No altered anxiety- and depressive-like behaviors were observed in Tph2icKO compared to control mice (Tph2CON) in all indices measured, but Tph2icKO mice exhibited intense and sustained freezing during context-dependent fear memory retrieval. Tph2icKO mice also exhibited locomotor hyperactivity in the aversive environments, such as the open field, and consumed more food and fluid than Tph2CON mice. Lastly, the combined effect of maternal separation (MS) stress and adult brain 5-HT depletion on behavior was assessed in male and female mice. Here, MS stress, 5-HT depletion and their interaction elicited anxiety-like behavior in a sex-dependent manner. MS reduced exploratory behavior in both male and female mice. Reduced 5-HT enhanced anxiety in female, but not in male mice. Furthermore, expression of genes related to the 5-HT system and emotionality (Tph2, Htr1a, Htr2a, Maoa and Avpr1a) was assessed by performing a quantitative real-time PCR. In Tph2icKO mice there was a reduction in expression of Tph2 in the raphe nuclei of both male and female mice. Interaction between MS stress and 5-HT deficiency was detected showing increased Htr2a and Maoa expression in raphe and hippocampus respectively of female mice. In male mice, MS stress and 5-HT depletion interaction effects reduced Avpr1a expression in raphe, while the expression of Htr1a, Htr2a and Maoa was differentially altered by 5-HT depletion and MS in various brain regions.},
  subject      = {Anxiety},
  language  = {en}
}
@phdthesis{Abt2019,
  author    = {Abt, Raimond},
  title     = {Implementing Aspects of Quantum Information into the AdS/CFT Correspondence},
  doi       = {10.25972/OPUS-18801},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188012},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {In recent years many discoveries have been made that reveal a close relation between quantum information and geometry in the context of the AdS/CFT correspondence. In this duality between a conformal quantum field theory (CFT) and a theory of gravity on Anti-de Sitter spaces (AdS) quantum information quantities in CFT are associated with geometric objects in AdS. Subject of this thesis is the examination of this intriguing property of AdS/CFT. We study two central elements of quantum information: subregion complexity -- which is a measure for the effort required to construct a given reduced state -- and the modular Hamiltonian -- which is given by the logarithm of a considered reduced state. While a clear definition for subregion complexity in terms of unitary gates exists for discrete systems, a rigorous formulation for quantum field theories is not known. In AdS/CFT, subregion complexity is proposed to be related to certain codimension one regions on the AdS side. The main focus of this thesis lies on the examination of such candidates for gravitational duals of subregion complexity. We introduce the concept of \textit{topological complexity}, which considers subregion complexity to be given by the integral over the Ricci scalar of codimension one regions in AdS. The Gauss-Bonnet theorem provides very general expressions for the topological complexity of CFT\(_2\) states dual to global AdS\(_3\), BTZ black holes and conical defects. In particular, our calculations show that the topology of the considered codimension one bulk region plays an essential role for topological complexity. Moreover, we study holographic subregion complexity (HSRC), which associates the volume of a particular codimension one bulk region with subregion complexity. We derive an explicit field theory expression for the HSRC of vacuum states. The formulation of HSRC in terms of field theory quantities may allow to investigate whether this bulk object indeed provides a concept of subregion complexity on the CFT side. In particular, if this turns out to be the case, our expression for HSRC may be seen as a field theory definition of subregion complexity. We extend our expression to states dual to BTZ black holes and conical defects. A further focus of this thesis is the modular Hamiltonian of a family of states \(\rho_\lambda\) depending on a continuous parameter \(\lambda\). Here \(\lambda\) may be associated with the energy density or the temperature, for instance. The importance of the modular Hamiltonian for quantum information is due to its contribution to relative entropy -- one of the very few objects in quantum information with a rigorous definition for quantum field theories. The first order contribution in \(\tilde{\lambda}=\lambda-\lambda_0\) of the modular Hamiltonian to the relative entropy between \(\rho_\lambda\) and a reference state \(\rho_{\lambda_0}\) is provided by the first law of entanglement. We study under which circumstances higher order contributions in \(\tilde{\lambda}\) are to be expected. We show that for states reduced to two entangling regions \(A\), \(B\) the modular Hamiltonian of at least one of these regions is expected to provide higher order contributions in \(\tilde{\lambda}\) to the relative entropy if \(A\) and \(B\) saturate the Araki-Lieb inequality. The statement of the Araki-Lieb inequality is that the difference between the entanglement entropies of \(A\) and \(B\) is always smaller or equal to the entanglement entropy of the union of \(A\) and \(B\). Regions for which this inequality is saturated are referred to as entanglement plateaux. In AdS/CFT the relation between geometry and quantum information provides many examples for entanglement plateaux. We apply our result to several of them, including large intervals for states dual to BTZ black holes and annuli for states dual to black brane geometries.},
  subject      = {AdS-CFT-Korrespondenz},
  language  = {en}
}
@phdthesis{Adamek2011,
  author    = {Adamek, Julian},
  title     = {Classical and Quantum Aspects of Anisotropic Cosmology},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-65908},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {The idea that our observable Universe may have originated from a quantum tunneling event out of an eternally inflating false vacuum state is a cornerstone of the multiverse paradigm. Modern theories that are considered as an approach towards the ultraviolet-complete fundamental theory of particles and gravity, such as the various types of string theory, even suggest that a vast landscape of different vacuum configurations exists, and that gravitational tunneling is an important mechanism with which the Universe can explore this landscape. The tunneling scenario also presents a unique framework to address the initial conditions of our observable Universe. In particular, it allows to introduce deviations from the cosmological concordance model in a controlled and well-motivated way. These deviations are a central topic of this work. An important feature in most of the theories mentioned above is the presumed existence of additional space dimensions in excess of the three which we observe in our every-day experience. It was realized that these extra dimensions could avoid our detection if they are compactified to microscopic length scales far beyond the reach of current experiments. There also seem to be natural mechanisms available for dynamical compactification in those theories. These typically lead to a vast landscape of different vacuum configurations which also may differ in the number of macroscopic dimensions, only the total number of dimensions being determined by the theory. Transitions between these vacuum configurations may hence open up new directions which were previously compact, spontaneously compactify some previously macroscopic directions, or otherwise re-arrange the configuration of compact and macroscopic dimensions in a more general way. From within the bubble Universe, such a process may be perceived as an anisotropic background spacetime - intuitively, the dimensions which open up may give rise to preferred directions. If our 3+1 dimensional observable Universe was born in a process as described above, one may expect to find traces of a preferred direction in cosmological observations. For instance, two directions could be curved like on a sphere, while the third space direction is flat. Using a scenario of gravitational tunneling to fix the initial conditions, I show how the primordial signatures in such an anisotropic Universe can be obtained in principle and work out a particular example in more detail. A small deviation from isotropy also has phenomenological consequences for the later evolution of the Universe. I discuss the most important effects and show that backreaction can be dynamically important. In particular, under certain conditions, a buildup of anisotropic stress in different components of the cosmic fluid can lead to a dynamical isotropization of the total stress-energy tensor. The mechanism is again demonstrated with the help of a physical example.},
  subject      = {Kosmologie},
  language  = {en}
}
@phdthesis{AdelAbdelrehimMohamedSoliman2019,
  author    = {Adel Abdelrehim Mohamed Soliman, Hadya},
  title     = {Structural Equation Modeling of Factors Influencing EFL Reading comprehension: Comparative study between Egypt and Germany},
  doi       = {10.25972/OPUS-18695},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186957},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {In most foreign language learning contexts, there are only rare chance for contact with native speakers of the target language. In such a situation, reading plays an important role in language acquisition as well as in gaining cultural information about the target language and its speakers. Previous research indicated that reading in foreign language is a complex process, which is influenced by various linguistic, cognitive and affective factors. The aim of the present study was to test two structural models of the relationship between reading comprehension in native language (L1), English language (L2) reading motivation, metacognitive awareness of L2 reading strategies, and reading comprehension of English as a foreign language among the two samples. Furthermore, the current study aimed to examine the differences between Egyptian and German students in their perceived usage of reading strategies during reading English texts, as well as to explore the pattern of their motivation toward reading English texts. For this purpose, 401 students were recruited from Germany (n=200) and Egypt (n=201) to participate in the current study. In order to have information about metacognitive awareness of reading strategies, a self-report questionnaire (SORS) developed by Moktari and Sheory (2002) was used. While the L2 reading motivation variable, was measured by a reading motivation survey (L2RMQ) which was based on reviewed reading motivation research. In addition, two reading tests were administrated one to measure reading comprehension for native language (German/Arabic) and the other to measure English reading comprehension. To analyze the collected data, descriptive statistics and independent t-tests were performed. In addition, further analysis using structural equation modeling was applied to test the strength of relationships between the variables under study. The results from the current research revealed that L1 reading comprehension, whether in a German or Arabic language, had the strongest relationship with L2 reading comprehension. However, the relationship between L2 intrinsic reading motivation was not proven to be significant in either the German or Egyptian models. On the other hand, the relationship between L2 extrinsic reading motivation, metacognitive awareness of reading strategies, and L2 reading comprehension was only proven significant in the German sample. The discussion of these results along with their pedagogical implications for education and practice will be illustrated in the following study.},
  subject      = {Leseverstehen},
  language  = {en}
}
@phdthesis{Adenugba2021,
  author    = {Adenugba, Akinbami Raphael},
  title     = {Functional analysis of the gene organization of the pneumoviral attachment protein G},
  doi       = {10.25972/OPUS-12814},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128146},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {The putative attachment protein G of pneumonia virus of mice (PVM), a member of the Pneumoviruses, is an important virulence factor with so far ambiguous function in a virus-cell as well as in virus-host context. The sequence of the corresponding G gene is characterized by significant heterogeneity between and even within strains, affecting the gene and possibly the protein structure. This accounts in particular for the PVM strain J3666 for which two differing G gene organizations have been described: a polymorphism in nucleotide 65 of the G gene results in the presence of an upstream open reading frame (uORF) that precedes the main ORF in frame (GJ366665A) or extension of the major G ORF for 18 codons (GJ366665U). Therefore, this study was designed to analyse the impact of the sequence variations in the respective G genes of PVM strains J3666 and the reference strain 15 on protein expression, replication and virulence. First, the controversy regarding the consensus sequence of PVM J3666 was resolved. The analysis of 45 distinct cloned fragments showed that the strain separated into two distinct virus populations defined by the sequence and structure of the G gene. This division was further supported by nucleotide polymorphisms in the neighbouring M and SH genes. Sequential passage of this mixed strain in the cell line standardly used for propagation of virus stocks resulted in selection for the GJ366665A-containing population in one of two experiments pointing towards a moderate replicative advantage. The replacement of the G gene of the recombinant PVM 15 with GJ366665A or GJ366665U, respectively, using a reverse genetic approach indicated that the presence of uORF within the GJ366665A significantly reduced the expression of the main G ORF on translational level while the potential extension of the ORF in GJ366665U increased G protein expression. In comparison, the effect of the G gene-structure on virus replication was inconsistent and dependent on cell line and type. While the presence of uORF correlated with a replication advantage in the standardly used BHK-21 cells and primary murine embryonic fibroblasts, replication in the murine macrophage cell line RAW 264.7 did not. In comparison, the GJ366665U variant was not associated with any effect on replication in cultured cells at all. Nonetheless, in-vivo analysis of the recombinant viruses associated the GJ366665U gene variant, and hence an increased G expression, with higher virulence whereas the GJ366665A gene, and therefore an impaired G expression, conferred an attenuated phenotype to the virus. To extend the study to other G gene organizations, a recombinant PVM expressing a G protein without the cytoplasmic domain and for comparison a G-deletion mutant, both known to be attenuated in vivo, were studied. Not noticed before, this structure of the G gene was associated with a 75\% reduction in G protein expression and a significant attenuation of replication in macrophage-like cells. This attenuation was even more prominent for the virus lacking G. Taking into consideration the higher reduction in G protein levels compared to the GJ366665A variant indicates that a threshold amount of G is required for efficient replication in these cells. In conclusion, the results gathered indicated that the expression levels of the G protein were modulated by the sequence of the 5' untranslated region of the gene. At the same time the G protein levels modulated the virulence of PVM.},
  subject      = {G glycoprotein},
  language  = {en}
}
@phdthesis{Adhikari2024,
  author    = {Adhikari, Bikash},
  title     = {Targeted degradation of Myc-interacting oncoproteins},
  doi       = {10.25972/OPUS-31732},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-317326},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {The hallmark oncoprotein Myc is a major driver of tumorigenesis in various human cancer entities. However, Myc's structural features make it challenging to develop small molecules against it. A promising strategy to indirectly inhibit the function of Myc is by targeting its interactors. Many Myc-interacting proteins have reported scaffolding functions which are difficult to target using conventional occupancy- driven inhibitors. Thus, in this thesis, the proteolysis targeting chimera (PROTAC) approach was used to target two oncoproteins interacting with Myc which promote the oncogenicity of Myc, Aurora-A and WDR5. PROTACs are bifunctional small molecules that bind to the target protein with one ligand and recruit a cellular E3- ligase with the other ligand to induce target degradation via the ubiquitin- proteasome system. So far, the most widely used E3-ligases for PROTAC development are Cereblon (CRBN) and von Hippel-Lindau tumor suppressor (VHL). Furthermore, there are cases of incompatibility between some E3-ligases and proteins to bring about degradation. Hence there is a need to explore new E3- ligases and a demand for a tool to predict degradative E3-ligases for the target protein in the PROTAC field. In the first part, a highly specific mitotic kinase Aurora-A degrader, JB170, was developed. This compound utilized Aurora-A inhibitor alisertib as the target ligand and thalidomide as the E3-ligase CRBN harness. The specificity of JB170 and the ternary complex formation was supported by the interactions between Aurora-A and CRBN. The PROTAC-mediated degradation of Aurora-A induced a distinct S- phase defect rather than mitotic arrest, shown by its catalytic inhibition. The finding demonstrates that Aurora-A has a non-catalytic role in the S-phase. Furthermore, the degradation of Aurora-A led to apoptosis in various cancer cell lines. In the second part, two different series of WDR5 PROTACs based on two protein- protein inhibitors of WDR5 were evaluated. The most efficient degraders from both series recruited VHL as a E3-ligase and showed partial degradation of WDR5. In addition, the degradation efficiency of the PROTACs was significantly affected by the linker nature and length, highlighting the importance of linker length and composition in PROTAC design. The degraders showed modest proliferation defects at best in cancer cell lines. However, overexpression of VHL increased the degradation efficiency and the antiproliferative effect of the PROTACs. In the last part, a rapamycin-based assay was developed to predict the degradative E3-ligase for a target. The assay was validated using the WDR5/VHL and Aurora- A/CRBN pairs. The result that WDR5 is degraded by VHL but not CRBN and Aurora-A is degraded by CRBN, matches observations made with PROTACs. This technique will be used in the future to find effective tissue-specific and essential E3-ligases for targeted degradation of oncoproteins using PROTACs. Collectively, the work presented here provides a strategy to improve PROTAC development and a starting point for developing Aurora-A and WDR5 PROTACs for cancer therapy.},
  subject      = {Degradation},
  language  = {en}
}
@phdthesis{Adler2021,
  author    = {Adler, Florian Rudolf},
  title     = {Electronic Correlations in Two-dimensional Triangular Adatom Lattices},
  doi       = {10.25972/OPUS-24175},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241758},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {Two-dimensional triangular lattices of group IV adatoms on semiconductor substrates provide a rich playground for the investigation of Mott-Hubbard physics. The possibility to combine various types of adatoms and substrates makes members of this material class versatile model systems to study the influence of correlation strength, band filling and spin-orbit coupling on the electronic structure - both experimentally and with dedicated many-body calculation techniques. The latter predict exotic ground states such as chiral superconductivity or spin liquid behavior for these frustrated lattices, however, experimental confirmation is still lacking. In this work, three different systems, namely the \(\alpha\)-phases of Sn/SiC(0001), Pb/Si(111), and potassium-doped Sn/Si(111) are investigated with scanning tunneling microscopy and photoemission spectroscopy in this regard. The results are potentially relevant for spintronic applications or quantum computing. For the novel group IV triangular lattice Sn/SiC(0001), a combined experimental and theoretical study reveals that the system features surprisingly strong electronic correlations because they are boosted by the substrate through its partly ionic character and weak screening capabilities. Interestingly, the spectral function, measured for the first time via angle-resolved photoemission, does not show any additional superstructure beyond the intrinsic \(\sqrt{3} \times \sqrt{3} R30^{\circ}\) reconstruction, thereby raising curiosity regarding the ground-state spin pattern. For Pb/Si(111), preceding studies have noted a phase transition of the surface reconstruction from \(\sqrt{3} \times \sqrt{3} R30^{\circ}\) to \(3 \times 3\) at 86 K. In this thesis, investigations of the low-temperature phase with high-resolution scanning tunneling microscopy and spectroscopy unveil the formation of a charge-ordered ground state. It is disentangled from a concomitant structural rearrangement which is found to be 2-up/1-down, in contrast to previous predictions. Applying an extended variational cluster approach, a phase diagram of local and nonlocal Coulomb interactions is mapped out. Based on a comparison of theoretical spectral functions with scattering vectors found via quasiparticle interference, Pb/Si(111) is placed in said phase diagram and electronic correlations are found to be the driving force of the charge-ordered state. In order to realize a doped Mott insulator in a frustrated geometry, potassium was evaporated onto the well-known correlated Sn/Si(111) system. Instead of the expected insulator-to-metal transition, scanning tunneling spectroscopy data indicates that the electronic structure of Sn/Si(111) is only affected locally around potassium atoms while a metallization is suppressed. The potassium atoms were found to be adsorbed on empty \(T_4\) sites of the substrate which eventually leads to the formation of two types of K-Sn alloys with a relative potassium content of 1/3 and 1/2, respectively. Complementary measurements of the spectral function via angle-resolved photoemission reveal that the lower Hubbard band of Sn/Si(111) gradually changes its shape upon potassium deposition. Once the tin and potassium portion on the surface are equal, this evolution is complete and the system can be described as a band insulator without the need to include Coulomb interactions.},
  subject      = {Rastertunnelmikroskopie},
  language  = {en}
}
@phdthesis{Adler2012,
  author    = {Adler, Melanie},
  title     = {New approaches to improve prediction of drug-induced liver injury},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69512},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2012},
  abstract  = {Das h{\"a}ufige Scheitern neuer Arzneistoffkandidaten aufgrund von Lebertoxizit{\"a}t in pr{\"a}klinischen und klinischen Studien stellt ein erhebliches Problem in der Entwicklung von neuen Arzneimitteln dar. Deshalb ist es wichtig, neue Ans{\"a}tze zu entwickeln, mit deren Hilfe unerw{\"u}nschte Wirkungen von Arzneimitteln fr{\"u}her und zuverl{\"a}ssiger erkannt werden k{\"o}nnen. Um die Vorhersage von Lebertoxizit{\"a}t in pr{\"a}klinischen Studien zu verbessern, wurden im Rahmen dieser Arbeit zwei wesentliche Ans{\"a}tze gew{\"a}hlt: 1) die Evaluierung neuer Biomarker, durch die Lebertoxizit{\"a}t zuverl{\"a}ssiger und empfindlicher detektiert werden k{\"o}nnte und 2.) wirkmechanistische Untersuchungen mittels Toxcicogenomics f{\"u}r ein besseres Verst{\"a}ndnis der zugrunde liegenden Mechanismen der Arzneimittel-induzierten Toxizit{\"a}t. Ein Ziel dieser Arbeit war, die F{\"a}higkeit einiger neuer potenzieller Biomarker (NGAL, Thiostatin, Clusterin und PON1) zu bewerten, Arzmeimittel-induzierte Lebertoxizit{\"a}t in Ratten fr{\"u}hzeitig zu erkennen. Die Ergebnisse zeigen, dass PON1 und Clusterin infolge eines durch die verabreichten Arzneistoffkandidaten verursachten Leberschadens nicht konsistent ver{\"a}ndert waren. Diese beiden Marker sind daher, verglichen mit bestehenden klinisch-chemischen Markern, nicht f{\"u}r eine sichere Vorhersage von Arzneistoff-induzierten Lebersch{\"a}den geeignet. Bei Thiostatin und NGAL zeigte sich hingegen ein zeit- und dosisabh{\"a}ngiger Anstieg im Serum und Urin behandelter Tiere. Diese Ver{\"a}nderungen, die gut mit der mRNA Expression im Zielorgan {\"u}bereinstimmten, korrelierten mit dem Schweregrad der Arzneistoff-induzierten Lebersch{\"a}den. Die Analyse mittels ROC zeigte, Thiostatin im Serum, nicht aber NGAL, ein besserer Indikator f{\"u}r Arzneimittel-induzierte hepatobili{\"a}re Sch{\"a}den ist als die routinem{\"a}ßig verwendeten klinische-chemischen Marker, wie z.B. die Leberenzyme ALP, ALT und AST. Thiostatin wird jedoch als Akute-Phase-Protein in einer Vielzahl von Geweben exprimiert und kann somit nicht spezifisch als Lebermarker betrachtet werden. Dennoch zeigen unsere Ergebnisse, dass Thiostatin als sensitiver, minimal-invasiver diagnostischer Marker f{\"u}r Entz{\"u}ndungsprozesse und Gewebesch{\"a}den eine sinnvolle Erg{\"a}nzung in der pr{\"a}klinischen Testung auf Lebertoxizit{\"a}t darstellt. Im zweiten Teil dieser Arbeit wurde mittels RNA-Interferenz das pharmakologische Target des Arzneistoffkandidaten BAY16, der Glukagonrezeptor, auf mRNA-Ebene gehemmt und anhand von Genexpressionsanalysen untersucht, ob die pharmakologisch-bedingte Modulation des Glukagonrezeptors eine Rolle in der Toxizit{\"a}t von BAY16 spielt. Desweiteren sollten diese Arbeiten Aufschluss geben, welche molekularen Ver{\"a}nderungen auf die pharmakologische Wirkung des Arzneistoffs zur{\"u}ckzuf{\"u}hren sind, und daher f{\"u}r den Mechanismus der Toxizit{\"a}t m{\"o}glicherweise wenig relevant sind. W{\"a}hrend BAY16 in Konzentrationen von 75 µM starke zytotoxische Wirkungen aufwies, hatte die siRNA vermittelte Depletion des Glukagonrezeptors keinen Einfluss auf die Vitalit{\"a}t prim{\"a}rer Rattenhepatozyten. Daraus l{\"a}sst sich ableiten, dass die Hepatotoxizi{\"a}t von BAY16 in vitro und in vivo nicht mit der pharmakologischen Modulation des Glukagonrezeptors assoziiert ist. Diese Ergebnisse wurden durch die Tatsache gest{\"u}tzt, dass die meisten der durch BAY16 induzierten Genexpressionsver{\"a}nderungen unabh{\"a}ngig von der pharmakologischen Modulation des Glucagonrezeptors auftraten. Diese beobachteten off-target-Effekte beinhalteten Ver{\"a}nderungen im Fremdstoffmetabolismus, oxidativer Stress, erh{\"o}hte Fetts{\"a}uresynthese und Ver{\"a}nderungen im Cholesterol- und Gallens{\"a}uremetabolismus. Obwohl Ver{\"a}nderungen in diesen molekularen Mechanismen zum Fortschreiten eines Leberschadens beitragen k{\"o}nnen, ist es anhand dieser Daten nicht m{\"o}glich einen eindeutigen Mechanismus f{\"u}r die Toxizit{\"a}t von BAY16 abzuleiten. In dieser Arbeit konnte jedoch gezeigt werden, dass die Anwendung der siRNA-Technologie einen neuen methodischen Ansatz darstellt, um Mechanismen arzneimittelbedingter Toxizit{\"a}t besser verstehen zu k{\"o}nnen.},
  subject      = {Biomarker},
  language  = {en}
}
@phdthesis{Afify2007,
  author    = {Afify, Samar},
  title     = {Drug targeting delivery systems for treatment of Raf-1 induced lung tumors in mice},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-22249},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {The aim of the present study was to design different dosage forms as carrier systems to deliver sorafenib to the lung of BXB-23 transgenic mice using different routes of administration. Three dosage forms were used one of them was an oil-in-water emulsion and the oral route was chosen for this experiment. The other delivery system was a liposome preparation for intratracheal instillation. In this case the oral route was considered as a control experiment. The last dosage form was PLGA microspheres. Before sorafenib administration it was important to develop a HPLC method to assess sorafenib absorption after its administration and to determine its concentrations in mouse serum. The HPLC method allowed sorafenib quantification in small volumes (30 µl) of mouse serum and tissues. The developed HPLC method was validated resulting in satisfactory selectivity, good linearity, good accuracy and precision over the concentration range examined. Sorafenib was successfully incorporated in a fat emulsion (o/w) using a traditional method resulting in a white homogenous emulsion and no particle aggregation was observed. Sorafenib exhibited antitumor activity on the lung adenoma in BXB-23 transgenic mice when administered orally (2 mg sorafenib per mouse) in the emulsion preparation. The determined effect was an approximately 29 \% reduction in the tumor area of the adenoma foci and a proliferation reduction. In order to improve the pharmacological effects of sorafenib on the lung adenoma in BXB-23 mice, the targeting of sorafenib directly to the site of action (the lung) was an attractive concept. For this purpose the intratracheal route was used. Since sorafenib administration by instillation required incorporation of sorafenib in a dosage form suitable for its lipophilic nature, a liposome suspension was the second dosage form used. A lyophilization method was employed for sorafenib liposome preparation utilizing dilauroylphosphatidylcholine (DLPC) which is safe and tolerable for the lung. Incorporation of sorafenib in the liposomes did not influence the particle size and its distribution. The sorafenib liposomes showed high encapsulation efficiency, good stability at 4 °C for one month and satisfactory in vitro release properties and inhibited Raf-1 mediated activation of ERK in cell culture assay. In a pharmacokinetic experiment sorafenib loaded liposomes were instilled directly into the lung. The results revealed that a significant level of sorafenib was achieved in the lung tissues after 2 hours and then reduced after 48 h and remained nearly constant for one week. On the other hand, only traces of sorafenib were found in the mice serum up to 48 h. Subsequently, the pharmacological activity of sorafenib (1 mg per mouse) was studied when delivered in a liposomal suspension intratracheally to treat the lung adenoma of BXB-23 mice. The data of this experiment demonstrated that sorafenib intratracheal instillation resulted in a reduction of tumor area of adenoma foci (67 \%) and an elevation of the percent of apoptotic cells. In contrast, prolongation of the treatment period did not further enhance sorafenib activity on the lung adenoma. This previous finding suggested a development of multidrug resistance (MDR) by the adenoma foci cells against sorafenib instillation, which was examined by immunohistochemistry staining. The percent of MDR positive cells was higher after two and three weeks sorafenib liposome instillation treatment than that after one week treatment. The last dosage form used for sorafenib was microspheres, which were prepared by emulsion-diffusion-evaporation method using biodegradable PLGA 50:50 resulting in a white lyophilized powder. The system was characterized physicochemically and revealed a good microspheres yield, high encapsulation efficiency, a homogenous particle size distribution and slow in vitro release of sorafenib. The other strategy studied in the present research project was gene delivery to target the lung bearing tumor of BXB-23 mice using a non-viral vector (polyethylenimine). Polyethylenimine (PEI) was used to investigate its efficiency in transfecting lung bearing tumor of BXB-23 mice model and its ability to transfect the adenoma foci cells. LacZ, which encodes Beta-galactosidase was used in the present study as a reporter gene and was complexed with PEI before delivered intravenously. A high LacZ expression in the alveolar region with some expression in the adenoma foci was observed. On contrary, a low LacZ expression in the alveoli and in the adenoma foci was achieved after instillation of the same polyplex intratracheally.},
  subject      = {Maus},
  language  = {en}
}
@phdthesis{Agarwal2010,
  author    = {Agarwal, Shruti},
  title     = {Functional characterization of four CDK-like kinases and one Calmodulin-dependent kinase of the human malaria parasite, Plasmodium falciparum},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-48522},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {Malaria still persists as one of the deadliest infectious disease in addition to AIDS and tuberculosis. lt is a leading cause of high mortality and morbidity rates in the developing world despite of groundbreaking research on global eradication of the disease initiated by WHO, about half a century ago. Lack of a commercially available vaccine and rapid spread of drug resistance have hampered the attempts of extinguishing malaria, which still leads to an annual death toll of about one million people. Resistance to anti-malarial compounds thus renders search for new target proteins imperative. The kinome of the human malaria parasite Plasmodium falciparum comprises representatives of most eukaryotic protein kinase groups, including kinases which regulate proliferation and differentiation processes. Several reports till date have suggested involvement of parasite kinases in the human host and as well as in the mosquito vector. Kinases essential for life cycle stages of the parasite represent promising targets for anti-malarial compounds thus, provoking characterization of additional malarial kinases. Despite extensive research on most plasmodial enzymes, very little information is available regarding the four identified members of the cyclin dependent kinase like kinase (CLK) family. Thus, the present thesis dealt with the functional characterization of four members of the PfCLK kinase family of the parasite denoted as PfCLK-1/Lammer, PfCLK-2, PfCLK-3 and PfCLK-4 with a special focus on the first two kinases. Additionally, one Ca2+/Calmodulin dependent putative kinase-related protein, PfPKRP, presumed to be involved in sexual stage development of the parasite, was investigated for its expression in the life cycle of the parasite. In other eukaryotes, CLK kinases regulate mRNA splicing through phosphorylation of Serine/Arginine-rich proteins. Transcription analysis revealed abundance of PfCLK kinase genes throughout the asexual blood stages and in gametocytes. By reverse genetics approach it was demonstrated that all four kinases are essential for completion of the asexual replication cycle of P. falciparum. PfCLK 1/Lammer possesses two nuclear localization signals and PfCLK-2 possesses one of these signals upstream of the C-terminal catalytic domains. Protein level expression and sub-cellular localization of the two kinases was determined by generation of antiserum directed against the kinase domains of the respective kinase. Indirect immunofluorescence, Western blot and electron microscopy data confirm that the kinases are primarily localized in the parasite nucleus, and in vitro assays show that both enzymes are associated with phosphorylation activity. Finally, mass spectrometric analysis of co immunoprecipitated proteins shows interactions of the two PfCLK kinases with proteins, which have putative nuclease, phosphatase or helicase functions. PfPKRP on the other hand is predominantly expressed during gametocyte differentiation as identified from transcriptional analysis. Antiserum directed against the catalytic domain of PfPKRP detected the protein expression profile in both asexual and gametocyte parasite lysates. Via immunofluorescence assay, the kinase was localized in the parasite cytoplasm in a punctuated manner, mostly in the gametocyte stages. Reverse genetics resulted in the generation of PfPKRP gene-disruptant parasites, thus demonstrating that unlike CLK kinases, PfPKRP is dispensable for asexual parasite survival and hence might have crucial role in sexual development of the parasite. On one hand, characterization of PfCLK kinases exemplified the kinases involved in parasite replication cycle. Successful gene-disruption and protein expression of PfPKRP kinase on the other hand, demonstrated a role of the kinase in sexual stage development of the parasite. Both kinase families therefore, represent potential candidates for anti-plasmodial compounds.},
  subject      = {Plasmodium falciparum},
  language  = {en}
}
@phdthesis{Agarwal2008,
  author    = {Agarwal, Vaibhav},
  title     = {Role of PspC interaction with human polymeric immunoglobulin receptor and Factor H in Streptococcus pneumoniae infections and host cell induced signalling},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-36526},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2008},
  abstract  = {Streptococcus pneumoniae ist ein Gram-positives Bakterium und ein Kommensale des humanen Nasenrachenraums. Pneumokokken sind andererseits auch die Verursacher schwerer lokaler Infektionen wie der Otitis media, Sinusitis und von lebensbedrohenden invasiven Erkrankungen. So sind Pneumokokken die wichtigsten Erreger einer ambulant erworbenen Pneumonie und sie sind h{\"a}ufige Verursacher von Septik{\"a}mien und bakteriellen Meningitiden. Die initiale Phase der Pathogenese ist verbunden mit der Besiedelung der mukosalen Epithelzellen des Rachenraumes. Diese Kolonisierung erleichtert die Aufnahme der Bakterien in die Zelle bzw. deren Dissemination in submukosale Bereiche und den Blutstrom. Die Konversion des Kommensalen zu einem invasiven Mikroorganismus ist assoziiert mit der Anpassung des Krankheitserregers an die verschiedenen Wirtsnischen und wird auf der Wirtsseite durch die Zerst{\"o}rung der transepithelialen Barriere begleitet. Die Anpassung des Erregers ist vermutlich ein in hohem Grade regulierter Prozess. Die Oberfl{\"a}che von Streptococcus pneumoniae ist mit Proteinen bedeckt, die kovalent oder nicht kovalent mit der Zellwand verkn{\"u}pft sind. Eine einzigartige Gruppe von Oberfl{\"a}chenproteinen in der Zellwand der Pneumokokken sind die cholinbindenden Proteine (CBPs). F{\"u}r einige der CBPs konnte bereits die Bedeutung f{\"u}r die Virulenz gezeigt werden. PspC, auch als SpsA oder CbpA bezeichnet, ist ein multifunktionales Oberfl{\"a}chenprotein, das als Adhesin und Faktor H-Bindungsprotein eine wichtige Rolle in der Pathogenese der Pneumokokken hat. PspC vermittelt als Adhesin die Anheftung der Bakterien an die mukosalen Epithelzellen, indem es human-spezifisch an die sekretorische Komponente (SC) des polymeren Immunoglobulinrezeptors (pIgR) bindet. SC ist die Ektodom{\"a}ne des pIgR und PspC kann ebenso die freie SC binden oder an die SC des sekretorischen IgA Molek{\"u}ls binden. PspC interagiert auch mit dem l{\"o}slichen Komplement Faktor H. Die SC und der Faktor erkennen zwei verschiedene Epitope im bakteriellen PspC Protein. Der genaue Mechanismus der jeweiligen Interaktionen unter physiologischen- bzw. wirtspezifischen Bedingungen ist noch nicht vollst{\"a}ndig verstanden. In dieser Arbeit wurde die Auswirkung der PspC Interaktion mit dem humanen pIgR (hpIgR) bzw. dem Faktor H auf die Virulenz der Pneumokokken und die Wirtszellantwort, d.h. die induzierten Signalkaskaden in den eukaryotischen Zellen untersucht. Die molekulare Analyse und die Verwendung von spezifischen pharmakologischen Inhibitoren der Signalmolek{\"u}le zeigten, dass verschiedene Signalmolek{\"u}le an der PspC-pIgR vermittelten Internalisierung beteiligt sind. Die Aktivierung, d.h. die Phosphorylierung der Signalmolek{\"u}le wurde in Immunblots demonstriert. Die Studien zeigten, dass das Aktinzytoskelett und die Mikrotubuli f{\"u}r die bakterielle Aufnahme essentiell sind. Es konnte auch zum ersten Mal nachgewiesen werden, dass Cdc42 die entscheidende GTPase f{\"u}r die Invasion der Pneumokokken in die Wirtsepithelzellen, vermittelt {\"u}ber den PspC-hpIgR Mechanismus, ist. Der Einsatz von PI3-kinase und Akt Kinase Inhibitoren reduzierte signifikant die hpIgR-vermittelte Aufnahme der Pneumokokken in die Wirtszelle. Zus{\"a}tzlich durchgef{\"u}hrte Infektionen von hpIgR exprimierenden Zellen zeigten eine zeitabh{\"a}ngige Phosphorylierung von Akt und der p85\&\#945; Untereinheit der PI3-Kinase. Damit ist neben der GTPase Cdc42 der PI3K und Akt Signalweg entscheidend f{\"u}r die PspC-pIgR vermittelte Invasion der Pneumokokken. Des Weiteren sind an der Infektion mit Pneumokokken auch die Protein Tyrosin Kinasen Src, ERK1/2 und JNK beteiligt. Dabei wird die Src Kinase unabh{\"a}ngig von der PI3K in hpIgR exprimierenden Zellen aktiviert. Inhibitionsexperimente und genetische Knockdown Versuche mit siRNA bewiesen, dass die Endozytose der Pneumokokken {\"u}ber PspC-pIgR ein Clathrin und Dynamin abh{\"a}ngiger Mechanismus ist. Im weiterenn Teil der Arbeit wurde der Einfluss des PspC gebundenen Faktor H auf die Anheftung an und Invasion in die Epithelzellen analysiert. Die Bindung von Faktor H erfolgte unabh{\"a}ngig vom PspC-Subtyp. Die Bindungsversuche bewiesen, dass die Kapselmenge negativ korreliert mit der Bindung des Faktor H. Der Einsatz von Faktor H aus Maus oder Ratte zeigte keine typische Bindung. Daraus kann abgeleitet werden, dass diese Interaktion humanspezifisch ist. Die Infektionsexperimente demonstrierten, dass Faktor H die Adh{\"a}renz und die Invasion der Bakterien in die Nasenrachenraumzellen (Detroit562), alveol{\"a}ren Lungenepithelzellen (A549) und humanen Hirnendothelzellen (HBMEC) steigert. Der Faktor H hat Heparin Bindestellen. Diese Bindestellen vermitteln die Adh{\"a}renz der Faktor H gebundenen Pneumokokken mit Epithelzellen. Inhibitionsstudien mit spezifischen monoklonalen Antik{\"o}rpern, die gegen die short consensus repeats (SCRs) von Faktor H gerichtet waren, konnten die essentielle Bedeutung der SCR19-20 f{\"u}r die Anheftung der Pneumokokken {\"u}ber Faktor H an die Wirtszellen nachweisen. Die Faktor H vermittelte Assoziation der Pneumokokken an polymorphonukle{\"a}re Leukozyten (PMNs) erfolgt {\"u}ber das Integrin CD11b/CD18. Die weiteren Inhibitionsstudien zeigten dann auch zum ersten Mal den Einfluss des Aktinzytoskeletts der Wirtszelle auf die Faktor H-vermittelten bakterieller Internalisierung und den dabei bedeutsamen Signaltransduktionswegen in der eukaryotischen Zelle. Dabei wurden insbesondere die Proteintyrosinkinasen und die PI3K als wichtige Signalmolek{\"u}le f{\"u}r die Faktor H vermittelte Invasion der Pneumokokken identifiziert. Die in dieser Arbeit erhaltenen Resultate belegen, dass die Faktor H vermittelte Infektion der Zellen mit S. pneumoniae ein konzertierter Mechanismus ist, bei dem Oberfl{\"a}chen-Glycosaminoglycane, Integrine und Signaltransduktionswege der Wirtsepithelzellen involviert sind. Des Weiteren wurde aufgezeigt, dass die PspC-pIgR-vermittelte Invasion in mukosale Epithelzellen unterschiedliche Signalwege wie z.B. den PI3K und Akt Weg induziert und abh{\"a}ngig von Cdc42 und einer Clathrin vermittelten Endozytosemechanismus ist.},
  subject      = {Streptococcus pneumoniae},
  language  = {en}
}
@phdthesis{Agnetta2019,
  author    = {Agnetta, Luca},
  title     = {Novel Photoswitchable and Dualsteric Ligands Acting on Muscarinic Acetylcholine Receptors for Receptor Function Investigation},
  doi       = {10.25972/OPUS-18717},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187170},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {G protein-coupled receptor research looks out for new technologies to elucidate the complex processes of receptor activation, function and downstream signaling with spatiotemporal resolution, preferably in living cells and organisms. A thriving approach consists in making use of the unsurpassed properties of light, including its high precision in space and time, noninvasiveness and high degree of orthogonality regarding biological processes. This is realized by the incorporation of molecular photoswitches, which are able to effectively respond to light, such as azobenzene, into the structure of a ligand of a given receptor. The muscarinic acetylcholine receptors belong to class A GPCRs and have received special attention in this regard due to their role as a prototypic pharmacological system and their therapeutic potential. They mediate the excitatory and inhibitory effects of the neurotransmitter acetylcholine and thus regulate diverse important biological processes, especially many neurological functions in our brain. In this work, the application of photopharmacological tool compounds to muscarinic receptors is presented, consisting of pharmacophores extended with azobenzene as light-responsive motif. Making use of the dualsteric concept, such photochromic ligands can be designed to bind concomitantly to the orthosteric and allosteric binding site of the receptor, which is demonstrated for BQCAAI (M1) and PAI (M2) and may lead to subtype- and functionalselective photoswitchable ligands, suitable for further ex vivo and in vivo studies. Moreover, photoswitchable ligands based on the synthetic agonist iperoxo were investigated extensively with regard to their photochemical behavior and pharmacological profile, outlining the advantages and challenges of using red-shifted molecular photoswitches, such as tetraortho- fluoro azobenzene. For the first time on a GPCR it was examined, which impact the different substitution pattern has on both the binding and the activity on the M1 receptor. Results show that substituted azobenzenes in photopharmacological compounds (F4-photoiperoxo and F4-iper-azo-iper) not just represent analogs with other photophysical properties but can exhibit a considerably different biological profile that has to be investigated carefully. The achievements gained in this study can give important new insights into the binding mode and time course of activation processes, enabling precise spatial and temporal resolution of the complex signaling pathway of muscarinic receptors. Due to their role as exemplary model system, these findings may be useful for the investigation into other therapeutically relevant GPCRs.},
  subject      = {Muscarinrezeptor},
  language  = {en}
}
@phdthesis{Ahmad2012,
  author    = {Ahmad, Ruhel},
  title     = {Neurogenesis from parthenogenetic human embryonic stem cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75935},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2012},
  abstract  = {Imprinted genes play important roles in brain development. As the neural developmental capabilities of human parthenogenetic embryonic stem cells (hpESCs) with only a maternal genome were not assessed in great detail, hence here the potential of hpESCs to differentiate into various neural subtypes was determined. In addition DNA methylation and expression of imprinted genes upon neural differentiation was also investigated. The results demonstrated that hpESC-derived neural stem cells (hpNSCs) showed expression of NSC markers Sox1, Nestin, Pax6, and Musashi1 (MS1), the silencing of pluripotency genes (Oct4, Nanog) and the absence of activation of neural crest (Snai2, FoxD3) and mesodermal (Acta1) markers. Moreover, confocal images of hpNSC cultures exhibited ubiquitous expression of NSC markers Nestin, Sox1, Sox2 and Vimentin. Differentiating hpNSCs for 28 days generated neural subtypes with neural cell type-specific morphology and expression of neuronal and glial markers, including Tuj1, NeuN, Map2, GFAP, O4, Tau, Synapsin1 and GABA. hpNSCs also responded to region-specific differentiation signals and differentiated into regional phenotypes such as midbrain dopaminergic- and motoneuron-type cells. hpESC-derived neurons showed typical neuronal Na+/K+ currents in voltage clamp mode, elicited multiple action potentials with a maximum frequency of 30 Hz. Cell depicted a typical neuron-like current pattern that responded to selective pharmacological blockers of sodium (tetrodotoxin) and potassium (tetraethylammonium) channels. Furthermore, in hpESCs and hpNSCs the majority of CpGs of the differentially methylated regions (DMRs) KvDMR1 were methylated whereas DMR1 (H19/Igf2 locus) showed partial or complete absence of CpG methylation, which is consistent with a parthenogenetic (PG) origin. Upon differentiation parent-of-origin-specific gene expression was maintained in hpESCs and hpNSCs as demonstrated by imprinted gene expression analyses. Together this shows that despite the lack of a paternal genome, hpNSCs are proficient in differentiating into glial- and neuron-type cells, which exhibit electrical activity similar to newly formed neurons. Moreover, maternal-specific gene expression and imprinting-specific DNA-methylation are largely maintained upon neural differentiation. hpESCs are a means to generate histocompatible and disease allele-free ESCs. Additionally, hpESCs are a unique model to study the influence of imprinting on neurogenesis.},
  subject      = {Embryonale Stammzelle},
  language  = {en}
}
@phdthesis{Ahmed2014,
  author    = {Ahmed, Arabe},
  title     = {Assessing particle deposition in a representative in vitro model of the rat respiratory tract},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-104912},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {The aim of this thesis was to develop an in vitro model (IVR) of the rat lung for the purpose of investigating the deposition of drug particles in the rat airways. The model attempted to account for the affect of drug product characteristics and physiological parameters on deposition in the lungs. In addition, the model outputs were compared with in vivo lung deposition results from live rats and in silico predictions using published computer model of lung deposition in pre-clinical species. Initial work focussed on developing an aerosol exposure system capable of dosing small rodent to a range of airborne test materials. The system consists of two main parts; a fluidised bed aerosol generator and connection of the generator output to a nose only exposure chamber capable of accommodating 12 small animals in a single layer. In addition, an aerodynamic particle spectrometer (APS) was installed for continuously measuring the size distribution and airborne concentration of aerosol particles generated in the exposure chamber. System validation showed acceptable degree of variation of the test material tested, Fluorescent Microspheres (FMS) throughout the exposure chamber (CV < 15.0\%). Particle size (MMAD ± GSD) using the APS was shown to be stable throughout the exposure periods. The IVR model developed in this project was based on a number of euthanased (n=7), female Sprague-Dawley rats (weight: 372 ± 56 g), which underwent high-resolution micro-CT scans. The physical model consisted of five sub sections; Extra-Thoracic region containing the snout and nasophyarynx, trachea-bronchial region containing the trachea, bronchi, and bronchioles. All sections of the model were attached to one another in numerical order and housed within a containment unit. At the rear end of the cast, a flexible diaphragm was attached in order to collect the fraction of inhaled particles exiting the TB section and possibly reaching the lung, referred to as the Post-TB section. A study was conducted to assess the influence of inhalation parameters such as the breathing frequency and tidal volume on total and regional dose distribution using FMS as test material. The major finding of this study was the demonstration of the model sensitivity to changes in breathing parameters especially respiratory frequency, where the data showed increased deposition in the peripheral regions of the model with decreased respiratory frequency. Other studies assessed the effect of particle characteristics on deposition on the IVR model, such as particle size, dose increase and formulation changes. The results assessing particle size effect showed a slightly higher deposition levels for the 4µm sized particles versus 2µm sized particles in the head region; 90.8 ± 3.6\% and 88.2 ± 6.6\%. However, this difference did not reach statistical significance (P> 0.05) probably due to the polydispersity of aerosolised FMS particles. In addition, the regional deposition analysis showed an increased lung peripheral deposition with the smaller particles. In addition, the model was shown to be sensitive to changes in formulation composition mediated by inclusion of MgSt. The next stage of work was to validate the model in terms of comparison with lung deposition for in vivo rats. For lung deposition comparison, the absolute amount deposited in the IVR lung model (expressed as µg/kg) was shown to have a reasonably strong correlation with in vivo lung concentration measures (µg/kg); R2= 0.66, P < 0.05. Compounds were predicted well and within 2-folds of the measured lung deposition values. However, knowing the variability in biological systems and the multiple components required to estimate lung doses, predictions within 2-fold of the measured values would seem reasonable In terms of comparison with in silico model predictions using MPPD, similar deposition levels were noted between the two models, particularly when the data was expressed as percentage of total particles inhaled. The data showed the highest deposition levels were noted in the head region (> 80\%) and less than 5.0\% deposition for the peripheral lung fractions. With regards to using the IVR model to assess the relationship between dose, particle size and efficacy, an in vivo study using FP with different particle sizes (2.0 and 4.0 µm) but same doses ( 100 and 1000 µg/kg). This study demonstrated that exposure of rat to FP powder resulted in a dose-dependent inhibition of neutrophils in BAL fluids. However, a clear difference in neutrophils suppression was demonstrated for equivalent doses but different particle sizes of FP, where the smaller FP particles (2.0 µm) induced a greater level of neutrophils suppression in comparison with larger FP particles (4.0 µm). In addition, a reasonably good correlation for the relationship between lung deposition in the IVR model and a neutrophils suppression level was demonstrated. Furthermore this data support the hypothesis that regional deposition is an important determinant in efficacy. Therefore, this suggests that the IVR model may be a useful as a tool to describe in vivo efficacy with in vitro data. However, further studies should be conducted to evaluate the validity of this model and relationship. The IVR model has a number of important limitations. First, the model is based on scans up to generation four of the rat respiratory tract as this represented the limits of the micro-CT scanning technology at the time of this study. Therefore deposition in the deeper region of the lung may not be reflected precisely in the IVR model. Second, the regional deposition data generated using the model tended to show an overestimation of deposition in head region and an underestimation of deposition in the peripheral regions of the lung, in comparison with in vivo lung deposition data. Third, the current model does not take into account lung clearance. However, the amount of the drug present in the in vivo lungs is dependent on numerous physiological processes such as dissolution, passive or active absorption into the systemic circulation, binding to lung tissue and mucociliary clearance. Consequently, the results generated using this IVR model for drug molecules with high lung clearance rate should be treated with some caution. Future work extending this research could go in a number of directions. In this research, a representative model of the rat respiratory tract was constructed from analysis of imaging data from a number of euthanised Sprague-Dawley rats. This model represented the "average respiratory tract" in terms of dimensions of Sprague-Dawley rats. However, there is considerable variability in the airway dimensions between rats. This variability encompasses a number of factors such as the strains of rats, sex and age, and disease state. Thus, it may be possible to produce a small number of airway models to represent small and large rats and scaled to represent the extrathoracic and peripheral regions based on literature reports of their dimensions in different rat populations. This approach will then enable the effect of intersubject airway dimensions for different rat populations on aerosol deposition to be thoroughly examined. In addition, due to the limitation of the micro-CT technology used to construct the physical IVR model, detailed morphology only up to generation 4 were captured. However, recent advances in MRI technology, such as the use of in situ-MRI based scanning technology have enabled rat airway morphometry to be extended to 16 airway generation. This coupled with improvements in the resolutions of rapid-prototyping process means it may be possible to construct a rat model that reflects the in vivo lung morphology more accurately, and thus enable greater understanding of the link between aerosol deposition and airway geometry. In conclusion, a model cast of the rat lung was developed and validated to allow the deposition of inhaled particles in the rat lung to be investigated. The model may be used to estimate the lung concentration in vivo rats in preference to exposure concentration measurements based on filter samples which have been shown to be a poor indicator of the lung concentration immediately after exposure. In addition, the model has the potential to be used along with live rats in an inhalation rig in pulmonary pharmaceutics research and may facilitate in development of inhaled formulations to target specific regions within the lung as well as screening of inhaled drugs in preclinical setting.},
  subject      = {Ratte},
  language  = {en}
}
@phdthesis{Ahrens2020,
  author    = {Ahrens, Lea Marlen},
  title     = {The Role of Attentional Control and Fear Acquisition and Generalization in Social Anxiety Disorder},
  doi       = {10.25972/OPUS-17162},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171622},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Although Social Anxiety Disorder (SAD) is one of the most prevalent mental disorders, still little is known about its development and maintenance. Cognitive models assume that deviations in attentional as well as associative learning processes play a role in the etiology of SAD. Amongst others, deficits in inhibitory attentional control as well as aberrations during fear generalization, which have already been observed in other anxiety disorders, are two candidate mechanisms that might contribute to the onset and retention of SAD. However, a review of the literature shows that there is a lack of research relating to these topics. Thus, the aim of the present thesis was to examine in which way individuals with SAD differ from healthy controls regarding attentional control and generalization of acquired fear during the processing of social stimuli. Study 1 tested whether impairment in the inhibitory control of attention is a feature of SAD, and how it might be influenced by emotional expression and gaze direction of an interactional partner. For this purpose, individuals with SAD and healthy controls (HC) participated in an antisaccade task with faces displaying different emotional expressions (angry, neutral and happy) and gaze directions (direct and averted) serving as target stimuli. While the participants performed either pro- or antisaccades in response to the peripherally presented faces, their gaze behavior was recorded via eye-tracking, and ratings of valence and arousal were obtained. Results revealed that both groups showed prolonged latencies and increased error rates in trials with correct anti- compared to prosaccades. However, there were no differences between groups with regard to response latency or error rates, indicating that SAD patients did not exhibit impairment on inhibitory attentional control in comparison to HC during eye-tracking. Possible explanations for this finding could be that reduced inhibitory attentional control in SAD only occurs under certain circumstances, for example, when these individuals currently run the risk of being negatively evaluated by others and not in the mere presence of phobic stimuli, or when the cognitive load of a task is so high that it cannot be unwound by compensatory strategies, such as putting more effort into a task. As not only deviations in attentional, but also associative learning processes might be pathogenic markers of SAD, these mechanisms were further addressed in the following experiments. Study 2 is the first that attempted to investigate the generalization of conditioned fear in patients with SAD. To this end, patients with SAD and HC were conditioned to two neutral female faces serving as conditioned stimuli (CS+: reinforced; CS-: non-reinforced) and a fearful face paired with a loud scream serving as unconditioned stimulus (US). Fear generalization was tested by presenting morphs of the two faces (GS: generalization stimuli), which varied in their similarity to the original faces. During the whole experiment, self-report ratings, heart rate (HR) and skin conductance responses (SCR) were recorded. Results demonstrated that SAD patients rated all stimuli as less pleasant and more arousing, and overestimated the occurrence of the US compared to HC, indicating a general hyperarousal in individuals with SAD. In addition, ratings and SCR indicated that both groups generalized their acquired fear from the CS+ to intermediate GSs as a function of their similarity to the CS+. However, except for the HR data, which indicated that only SAD patients but not HC displayed a generalization response in this measure, most of the results did not support the hypothesis that SAD is characterized by overgeneralization. A plausible reason for this finding could be that overgeneralization is just a key characteristic of some anxiety disorders and SAD is not one of them. Still, other factors, such as comorbidities in the individuals with SAD, could also have had an influence on the results, which is why overgeneralization was further examined in study 3. The aim of study 3 was to investigate fear generalization on a neuronal level. Hence, high (HSA) and low socially anxious participants (LSA) underwent a conditioning paradigm, which was an adaption of the experimental design used study 2 for EEG. During the experiment, steady-state visually evoked potentials (ssVEPs) and ratings of valence and arousal were recorded. Analyses revealed significant generalization gradients in all ratings with highest fear responses to the CS+ and a progressive decline of these reactions with increasing similarity to the CS-. In contrast, the generalization gradient on a neuronal level showed highest amplitudes for the CS+ and a reduction in amplitude to the most proximal, but not distal GSs in the ssVEP signal, which might be interpreted as lateral inhibition in the visual cortex. The observed dissociation among explicit and implicit measures points to different functions of behavioral and sensory cortical processes during fear generalization: While the ratings might reflect an individual's consciously increased readiness to react to threat, the lateral inhibition pattern in the occipital cortex might serve to maximize the contrast among stimuli with and without affective value and thereby improve adaptive behavior. As no group differences could be observed, the finding of study 2 that overgeneralization does not seem to be a marker of SAD is further consolidated. In sum, the conducted experiments suggest that individuals with SAD are characterized by a general hyperarousal during the exposition to disorder-relevant stimuli as indicated by enhanced arousal and reduced valence ratings of the stimuli compared to HC. However, the hypotheses that reduced inhibitory attentional control and overgeneralization of conditioned fear are markers of SAD were mostly not confirmed. Further research is required to elucidate whether they only occur under certain circumstances, such as high cognitive load (e.g. handling two tasks simultaneously) or social stress (e.g. before giving a speech), or whether they are not characteristics of SAD at all. With the help of these findings, new interventions for the treatment of SAD can be developed, such as attentional bias modification or discrimination learning.},
  subject      = {Sozialangst},
  language  = {en}
}
@phdthesis{Aido2024,
  author    = {Aido, Ahmed},
  title     = {Development of anti-TNF antibody-gold nanoparticles (anti-TNF-AuNPs)},
  doi       = {10.25972/OPUS-34921},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349212},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {Gold nanoparticles of diameter ca. 60 nm have been synthesized based on Turkevich and Frens protocols. We have demonstrated that the carboxyl-modified gold nanoparticles can be coupled covalently with antibodies (Ab) of interest using the EDC/NHS coupling procedure. Binding studies with Ab-grafted AuNPs and GpL fusion proteins proved that conjugation of AuNPs with antibodies enables immobilization of antibodies with preservation of a significant antigen binding capacity. More importantly, our findings showed that the conjugation of types of anti-TNF receptors antibodies such as anti-Fn14 antibodies (PDL192 and 5B6) (Aido et al., 2021), anti-CD40, anti-4-1BB and anti-TNFR2 with gold nanoparticles confers them with potent agonism. Thus, our results suggest that AuNPs can be utilized as a platform to immobilize anti-TNFR antibodies which, on the one hand, helps to enhance their agonistic activity in comparison to "free" inactive antibodies by mimicking the effect of cell-anchored antibodies or membrane-bound TNF ligands and, on the other hand, allows to develop new generations of drug delivery systems. These constructs are characterized with their biocompatibility and their tunable synthesis process. In a further work part, we combined the benefits of the established system of Ab-AuNPs with materials used widely in the modern biofabrication approaches such as the photo-crosslinked hydrogels, methacrylate-modified gelatin (GelMA), combined with embedded variants of human cell lines. The acquired results demonstrated clearly that the attaching of proteins like antibodies to gold nanoparticles might reduce their release rate from the crosslinked hydrogels upon the very low diffusion of gold nanoparticles from the solid constructs to the surrounding medium yielding long-term local functioning proteins-attached particles. Moreover, our finding suggests that hydrogel-embedded AuNP-immobilized antibodies, e.g. anti-TNFα-AuNPs or anti-IL1-AuNPs enable local inhibitory functions, To sum up, our results demonstrate that AuNPs can act as a platform to attach anti-TNFR antibodies to enhance their agonistic activity by resembling the output of cell-anchoring or membrane bounding. Gold nanoparticles are considered, thus, as promising tool to develop the next generation of drug delivery systems, which may contribute to cancer therapy. On top of that, the embedding of anti-inflammatory-AuNPs in the biofabricated hydrogel presents new innovative strategy of the treatment of autoinflammatory diseases.},
  subject      = {Nanopartikel},
  language  = {en}
}
@phdthesis{Aigner2023,
  author    = {Aigner, Max},
  title     = {Establishing successful protocols and imaging pipelines for Expansion Microscopy in murine blood platelets},
  doi       = {10.25972/OPUS-30900},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-309003},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Platelets play an important role in the body, since they are part of the hemostasis system, preventing and stopping blood loss. Nevertheless, when platelet or coagulation system function are impaired, uncontrolled bleedings but also irreversible vessel occlusion followed by ischemic tissue damage can occur. Therefore, understanding platelet function and activation, mechanisms which are controlled by a variety of platelet membrane receptors and other factors is important to advance out knowledge of hemostasis and platelet malfunction. For a complete picture of platelet function and their modulating behavior it is desired to be able to quantify receptor distributions and interactions of these densely packed molecular ensembles in the membrane. This challenges scientists for several reasons. Most importantly, platelets are microscopically small objects, challenging the spatial resolution of conventional light microscopy. Moreover, platelet receptors are highly abundant on the membrane so even super-resolution microscopy struggles with quantitative receptor imaging on platelets. With Expansion microscopy (ExM), a new super-resolution technique was introduced, allowing resolutions to achieve super-resolution without using a super-resolution microscope, but by combining a conventional confocal microscopy with a highly processed sample that has been expanded physically. In this doctoral thesis, I evaluated the potential of this technique for super-resolution platelet imaging by optimizing the sample preparation process and establishing an imaging and image processing pipeline for dual-color 3D images of different membrane receptors. The analysis of receptor colocalization using ExM demonstrated a clear superiority compared to conventional microscopy. Furthermore, I identified a library of fluorescently labeled antibodies against different platelet receptors compatible with ExM and showed the possibility of staining membrane receptors and parts of the cytoskeleton at the same time.},
  subject      = {Mikroskopie},
  language  = {en}
}
@phdthesis{Akakpo2019,
  author    = {Akakpo, Martin Gameli},
  title     = {The influence of learner characteristics on interactions to seek and share information in e-learning: A media psychology perspective},
  doi       = {10.25972/OPUS-18593},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-185934},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Research on the deployment and use of technology to assist learning has seen a significant rise over the last decades (Aparicio et al., 2017). The focus on course quality, technology, learning outcome and learner satisfaction in e-learning has led to insufficient attention by researchers to individual characteristics of learners (Cidral et al., 2017 ; Hsu et al., 2013). The current work aims to bridge this gap by investigating characteristics identified by previous works and backed by theory as influential individual differences in e-learning. These learner characteristics have been suggested as motivational factors (Edmunds et al., 2012) in decisions by learners to interact and exchange information (Luo et al., 2017). In this work e-learning is defined as interaction dependent information seeking and sharing enabled by technology. This is primarily approached from a media psychology perspective. The role of learner characteristics namely, beliefs about the source of knowledge (Schommer, 1990), learning styles (Felder \& Silverman, 1988), need for affect (Maio \& Esses, 2001), need for cognition (Cacioppo \& Petty, 1982) and power distance (Hofstede, 1980) on interactions to seek and share information in e-learning are investigated. These investigations were shaped by theory and empirical lessons as briefly mentioned in the next paragraphs. Theoretical support for investigations is derived from the technology acceptance model(TAM) by psychologist Davis (1989) and the hyper-personal model by communication scientist Walther (1996). The TAM was used to describe the influence of learner characteristics on decisions to use e-learning systems (Stantchev et al., 2014). The hyper-personal model described why computer-mediated communication thrives in e-learning (Kaye et al., 2016) and how learners interpret messages exchanged online (Hansen et al., 2015). This theoretical framework was followed by empirical reviews which justified the use of interaction and information seeking-sharing as key components of e-learning as well as the selection of learner characteristics. The reviews provided suggestions for the measurement of variables (K{\"u}hl et al., 2014) and the investigation design (Dascalau et al., 2015). Investigations were designed and implemented through surveys and quasi experiments which were used for three preliminary studies and two main studies. Samples were selected from Germany and Ghana with same variables tested in both countries. Hypotheses were tested with interaction and information seeking-sharing as dependent variables while beliefs about the source of knowledge, learning styles, need for affect, need for cognition and power distance were independent variables. Firstly, using analyses of variance, the influence of beliefs about the source of knowledge on interaction choices of learners was supported. Secondly, the role of need for cognition on interaction choices of learners was supported by results from a logistic regression. Thirdly, results from multiple linear regressions backed the influence of need for cognition and power distance on information seeking-sharing behaviour of learners. Fourthly, the relationship between need for affect and need for cognition was supported. The findings may have implications for media psychology research, theories used in this work, research on e-learning, measurement of learner characteristics and the design of e-learning platforms. The findings suggest that, the beliefs learners have about the source of knowledge, their need for cognition and their power distance can influence decisions to interact and seek or share information. The outlook from reviews and findings in this work predicts more research on learner characteristics and a corresponding intensity in the use of e-learning by individuals. It is suggested that future studies investigate the relationship between learner autonomy and power distance. Studies on inter-cultural similarities amongst e-learners in different populations are also suggested.},
  subject      = {e-learning},
  language  = {en}
}
@phdthesis{Akhrif2020,
  author    = {Akhrif, Atae},
  title     = {The BOLD Signal is more than a Brain Activation Index},
  doi       = {10.25972/OPUS-20729},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207299},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {In the recent years, translational studies comparing imaging data of animals and humans have gained increasing scientific interests with crucial findings stemming from both, human and animal work. In order to harmonize statistical analyses of data from different species and to optimize the transfer of knowledge between them, shared data acquisition protocols and combined statistical approaches have to be identified. Following this idea, methods of data analysis, which have until now mainly been used to model neural responses of electrophysiological recordings from rodent data, were applied on human hemodynamic responses (i.e. Blood-Oxygen-Level-Dependent BOLD signal) as measured via functional magnetic resonance imaging (fMRI). At the example of two attention and impulsivity networks, timing dynamics and amplitude of the fMRI signal were determined (study 1). Study 2 described the same parameters frequency-specifically, and in study 3, the complexity of neural processing was quantified in terms of fractality. Determined parameters were compared with regard to the subjects' task performance / impulsivity to validate findings with regard to reports of the current scientific debate. In a general discussion, overlapping as well as additional information of methodological approaches were discussed with regard to its potential for biomarkers in the context of neuropsychiatric disorders.},
  subject      = {funktionelle Kernspintomographie},
  language  = {en}
}
@phdthesis{Akhrif2023,
  author    = {Akhrif, Atae},
  title     = {The BOLD Signal is more than a Brain Activation Index},
  doi       = {10.25972/OPUS-32287},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322879},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {In the recent years, translational studies comparing imaging data of animals and humans have gained increasing scientific interests with crucial findings stemming from both, human and animal work. In order to harmonize statistical analyses of data from different species and to optimize the transfer of knowledge between them, shared data acquisition protocols and combined statistical approaches have to be identified. Following this idea, methods of data analysis, which have until now mainly been used to model neural responses of electrophysiological recordings from rodent data, were applied on human hemodynamic responses (i.e. Blood-Oxygen-Level- Dependent BOLD signal) as measured via functional magnetic resonance imaging (fMRI). At the example of two attention and impulsivity networks, timing dynamics and amplitude of the fMRI signal were determined (study 1). Study 2 described the same parameters frequency-specifically, and in study 3, the complexity of neural processing was quantified in terms of fractality. Determined parameters were compared with regard to the subjects' task performance / impulsivity to validate findings with regard to reports of the current scientific debate. In a general discussion, overlapping as well as additional information of methodological approaches were discussed with regard to its potential for biomarkers in the context of neuropsychiatric disorders.},
  subject      = {funktionelle Kernspintomographie},
  language  = {en}
}
@phdthesis{Akimzhanov2005,
  author    = {Akimzhanov, Askar M.},
  title     = {Epigenetic repression of the NFATc1 transcription factor in human lymphomas},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-12921},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2005},
  abstract  = {We examined the regulation of NFATc1 in different lymphomas and observed an inversed correlation between the methylation status and expression of NFATc1. Our data demonstrate that aberrant DNA methylation associated with chromatin remodeling within nfatc1 locus is a major mechanism for the repression of NFATc1 expression, suggesting that the DNA methylation-mediated transcriptional silencing of NFATc1 may be a critical event in the tumorogenesis of ALCLs and cHLs. Furthermore, the DNA methylation of human nfatc1 promoter region could be used as a novel biomarker of tumor progression. Our results indicate a close link between the loss of immunoreceptor signaling and NFATc1 expression in human lymphomas. For both ALCLs and cHLs, defects in immunoreceptor signaling have been described which result in a loss of receptor-mediated gene expression programs (Schwering et al., 2003; Bonzheim et al., 2004; Marafioti et al., 2004). In T cells, one indicator gene of these programs appears to be the nfatc1 gene whose expression is controlled by TCR signals (Chuvpilo et al., 2002a). In contrast, in T cells NFATc1 expression is unaffected by TCR signals, and NFATc2 was found to be expressed at normal levels in ALCLs and cHLs (L.K., unpubl. data). Moreover, the activity of NF-kappaB factors which can bind to certain NFAT binding sites and share a distantly-related DNA binding domain with NFATs is strongly elevated in cHL cells (Bargou et al., 1997; Hinz et al., 2001; Hinz et al., 2002) suggesting that NFATs and NF-kappaBs exert very different effects on generation and maintenance of Hodgkin's lymhomas. However, it should be mentioned that in Burkitt's and further B cell lymphomas in which NFATc1 proteins are strongly expressed and controlled by receptor signals (Kondo et al., 2003), they could exert a promoting function in tumor development. The genes of p53 family members p63 and p73 are prominent examples for mammalian genes whose products can act both as oncoproteins and tumor suppressor genes (Hibi et al., 2000; Stiewe and Putzer, 2002), and it is likely that more genes exist which encode both tumor suppressors and oncoproteins. It remains to be shown whether the nfatc1 gene is one of them.},
  subject      = {Lymphom},
  language  = {en}
}
@phdthesis{Akindeinde2012,
  author    = {Akindeinde, Saheed Ojo},
  title     = {Numerical Verification of Optimality Conditions in Optimal Control Problems},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76065},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2012},
  abstract  = {This thesis is devoted to numerical verification of optimality conditions for non-convex optimal control problems. In the first part, we are concerned with a-posteriori verification of sufficient optimality conditions. It is a common knowledge that verification of such conditions for general non-convex PDE-constrained optimization problems is very challenging. We propose a method to verify second-order sufficient conditions for a general class of optimal control problem. If the proposed verification method confirms the fulfillment of the sufficient condition then a-posteriori error estimates can be computed. A special ingredient of our method is an error analysis for the Hessian of the underlying optimization problem. We derive conditions under which positive definiteness of the Hessian of the discrete problem implies positive definiteness of the Hessian of the continuous problem. The results are complemented with numerical experiments. In the second part, we investigate adaptive methods for optimal control problems with finitely many control parameters. We analyze a-posteriori error estimates based on verification of second-order sufficient optimality conditions using the method developed in the first part. Reliability and efficiency of the error estimator are shown. We illustrate through numerical experiments, the use of the estimator in guiding adaptive mesh refinement.},
  subject      = {Optimale Kontrolle},
  language  = {en}
}
@phdthesis{AlBaidhani2018,
  author    = {Al-Baidhani, Mohammed},
  title     = {Spectroscopy as a tool to investigate the high energy optical properties of nanostructured magnetically doped topological insulator},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157221},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2018},
  abstract  = {In this dissertation the electronic and high-energy optical properties of thin nanoscale films of the magnetic topological insulator (MTI) (V,Cr)y(BixSb1-x)2-yTe3 are studied by means of X-ray photoelectron spectroscopy (XPS) and electron energy-loss spectroscopy (EELS). Magnetic topological insulators are presently of broad interest as the combination of ferromagnetism and spin-orbit coupling in these materials leads to a new topological phase, the quantum anomalous Hall state (QAHS), with dissipation less conduction channels. Determining and controlling the physical properties of these complex materials is therefore desirable for a fundamental understanding of the QAHS and for their possible application in spintronics. EELS can directly probe the electron energy-loss function of a material from which one can obtain the complex dynamic dielectric function by means of the Kramers-Kronig transformation and the Drude-Lindhard model of plasmon oscillations. The XPS core-level spectra in (V,Cr)y(BixSb1-x)2-yTe3 are analyzed in detail with regards to inelastic background contributions. It is shown that the spectra can be accurately described based on the electron energy-loss function obtained from an independent EELS measurement. This allows for a comprehensive and quantitative analysis of the XPS data, which will facilitate future core-level spectroscopy studies in this class of topological materials. From the EELS data, furthermore, the bulk and surface optical properties were estimated, and compared to ab initio calculations based on density functional theory (DFT) performed in the GW approximation for Sb2Te3. The experimental results show a good agreement with the calculated complex dielectric function and the calculated energy-loss function. The positions of the main plasmon modes reported here are expected to be generally similar in other materials in this class of nanoscale TI films. Hence, the present work introduces EELS as a powerful method to access the high-energy optical properties of TI thin films. Based on the presented results it will be interesting to explore more systematically the effects of stoichiometry, magnetic doping, film thickness and surface morphology on the electron-loss function, potentially leading to a better understanding of the complex interplay of structural, electronic, magnetic and optical properties in MTI nanostructures.},
  subject      = {Topologischer Isolator},
  language  = {en}
}
@phdthesis{AlFarajat2001,
  author    = {Al-Farajat, Mohammad},
  title     = {Hydrogeo-Eco-Systems in Aquaba/Jordan - Coasts and Region},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-1182066},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2001},
  abstract  = {The coast of Aqaba and the Aqaba region (Jordan) were investigated on their hydrogeo-ecosystem. The results of the research were translated into digits to build a geo-spatial data base. The fillings of the graben aquifer receive indirect type of recharge through the side wadis which drain the highlands. Surface water balance was modeled for a period of 20 years of daily climate records using MODBIL program which attributes direct recharge to wet years only. The hydrodynamic fresh water/seawater interface in the coastal zones was investigated by applying vertical geoelectric surveys and models of several methods to confirm its coincidence with the aquifer's flow amounts, where human impacts in terms of over-pumping allowed more encroachment of seawater into land, and unintended recharge which led to seaward interface migration. A groundwater balance and solute transport were approached by developing a flow model from the hydrogeological and hydrochemical data. The nature of soil cover and aquifer whose physical properties enhance human impacts indicated the vulnerability of groundwater to pollution. This certainly threatens the marine ecology which forms the sink where the in-excess flow ends. The constructed digital background was exported into GIS to sub-zone the study area in terms of the aquifer's vulnerability to pollution risks using DRASTIC index. However, it was unable to meet all geo-spatial factors that proved to have significant impacts on the vulnerability. Consequently, a comprehensive index -SALUFT- was developed. This suggests the suitable land use units for each zone in the light of vulnerability grades aiming at protecting the available groundwater resources.},
  subject      = {Golf von Akaba},
  language  = {en}
}
@phdthesis{ALHijailan2019,
  author    = {AL-Hijailan, Reem Saud},
  title     = {Establishment of endothelialized cardiac tissue using human induced pluripotent stem cells generated cardiomyocytes},
  doi       = {10.25972/OPUS-17397},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173979},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Cardiovascular diseases are considered the leading cause of death worldwide according to the World Health Organization. Heart failure is the last stage of most of these diseases, where loss of myocardium leads to architectural and functional decline. The definitive treatment option for patients with CVDs is organ or tissue transplantation, which relies on donor availability. Therefore, generating an autologous bioengineered myocardium or heart could overcome this limitation. In addition, generating cardiac patches will provide ventricular wall support and enable reparative stem cells delivery to damaged areas. Although many hurdles still exist, a good number of researches have attempted to create an engineered cardiac tissue which can induce endogenous cardiac repair by replacing damaged myocardium. The present study provided cardiac patches in two models, one by a detergent coronary perfusion decellularization protocol that was optimized, and the other that resulted in a 3D cell-free extracellular matrix with intact architecture and preserved s-glycosaminoglycan and vasculature conduits. Perfusion with 1\% Sodium dodecyle sulfate (SDS) under constant pressure resulted in cell-free porcine scaffold within two and cell-free rat scaffold in 7 days, whereas scaffold perfused with 4\% sodium deoxycholate (SDO) was not able to remove cells completely. Re-reendothelialization of tissue vasculature was obtained by injecting human microvascular endothelial cell and human fibroblast in 2:1 ratio in a dynamic culture. One-week later, CD31 positive cells and endothelium markers were observed, indicating new blood lining. Moreover, functionality test of re-endothelialized tissue revealed improvement in clotting seen in decellularized tissues. When the tissue was ready to be repopulated, porcine induced pluripotent stem cells (PiPSc) were generated by transfected reprogramming of porcine skin fibroblast and then differentiated to cardiac cells following a robust protocol, for an autologous cardiac tissue model. However, due to the limitation in the PiPSc cell number, alternatively, human induced pluripotent stem cells generated cardiac cells were used. For reseeding a coculture of human iPSc generated cardiac cells, human mesenchymal stem cells and human fibroblast in 2:1:1 ratio respectively were used in a dynamic culture for 6-8 weeks. Contractions at different areas of the tissue were recorded at an average beating rate of 67 beats/min. In addition, positive cardiac markers (Troponin T), Fibroblast (vemintin), and mesenchymal stem cells (CD90) were detected. Not only that, but by week 3, MSC started differentiating to cardiac cells progressively until few CD90 positive cells were very few by week 6 with increasing troponin t positive cells in parallel. Electrophysiological and drug studies were difficult to obtain due to tissue thickness and limited assessment sources. However, the same construct was established using small intestine submucosa (SISer) scaffold, which recorded a spontaneous beating rate between 0.88 and 1.2 Hz, a conduction velocity of 23.9 ± 0.74 cm s-1, and a maximal contraction force of 0.453 ± 0.015 mN. Moreover, electrophysiological studies demonstrated a drug-dependent response on beating rate; a higher adrenalin frequency was revealed in comparison to the untreated tissue and isoproterenol administration, whereas a decrease in beating rate was observed with propranolol and untreated tissue. The present study demonstrated the establishment of vascularized cardiac tissue, which can be used for human clinical application.},
  language  = {en}
}
@phdthesis{AlOuran2005,
  author    = {Al-Ouran, Nedal},
  title     = {Environmental assessment, documentation and spatial modeling of heavy metal pollution along the Jordan Gulf of Aqaba using coral reefs as environmental indicator},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-14090},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2005},
  abstract  = {Two phases of reef sampling were carried out. The first included regular samples taken along the coastline of Aqaba (27km long) at depths of 4-15m, and used to determine spatial distribution of pollution. The second phase included three 20cm-deep cores obtained from within the industrial zone. These cores were drilled from pre-dated communities, where the growth rate was determined earlier to be 10mm y-1, therefore the core obtained represented a period of 20 years (i.e. 1980-2000). The cores were used to reconstruct the metal pollution history at the most heavily used site along the coast (industrial zone).All samples were examined with respect to their metal content of Cd, Pb, Cu, Zn, Ni, and Cr. Almost all of them have shown records above the calculated background values. Mean values of Cd, Pb, Cu, Zn, Ni and Cr recorded along the coast were 1,25; 4,26; 9,76; 11,40; 2,29 and 10,522, µg g-1 respectively, and for core samples 1.4; 4.2; 5.7; 6.4; 2.3 and 8.21 µg g-1 respectively. Spatial distribution of metal enrichment in reef samples have shown a general and clear increasing trend towards the south. Same increasing trend was also in core samples where the six metals have shown a prominent increasing trend towards the core surface indicating an increase of coastal activities during the last twenty years. High and relatively high values were recorded at the oil port, the industrial area and main port, and thus categorized as highly impacted areas. Intermediate metal content were recorded in samples of the north beach, and thus classified as being relatively impacted, where the lowest metal concentrations were observed at the marine reserve, the least impacted site along the coast. The high enrichment of metal is attributed mainly to anthropogenic impacts. The natural inputs of the six metals studied in the Gulf of Aqaba are generally very low, due to the geographic positions and the absence of wadi discharge and as a result of low rainfall. Several potential sources of heavy metals were investigated. The industrial-related activities, port operations and phosphate dust were among the main sources currently threatening the marine ecosystem in Aqaba. Applying the Principle Components Analysis method (PCA) to all samples taken along the coastline has resulted in categorizing three different groups according to their metal enrichment, the first is composed of samples taken from the north beach and the main port with intermediate to high enrichment, the second joined the samples of the marine park and the marine reserve with low and relatively low enrichment, and the last group joined samples of the industrial zone and the oil port with high enrichment. The Principle Component Scores were also utilized to confirm the spatial distribution and relationships of the examined heavy metals along the coast. Two models (interpolated by SURFER \&\#61666; 7.0 and ArcView\&\#61666; 3.2a) were developed, the first was based on the PC scores of the first component, and shows clearly the positive anomalies in metal concentrations along the coast. The second model was developed by plotting the second factor scores on a landuse map of Aqaba. According to these models, it has shown that the positive anomalies are associated with three different zones; industrial area, the main port and the oil port. The results have shown that coral reefs can be used as good environmental indicator for assessments and monitoring processes, and they can provide data and information on both the spatial distribution of pollution and their history. The present work is the first to document the environmental status along the whole coast of Aqaba and the first to use coral reef as a tool/ indicator.},
  subject      = {Golf von Akaba},
  language  = {en}
}
@phdthesis{Albert2018,
  author    = {Albert, Julian},
  title     = {Quantum Studies on Low-Dimensional Coupled Electron-Nuclear Dynamics},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161512},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2018},
  abstract  = {In the context of quantum mechanical calculations, the properties of non-adiabatic coupling in a small system, the Shin-Metiu model, is investigated. The transition from adiabatic to non-adiabatic dynamics is elucidated in modifying the electron-nuclear interaction. This allows the comparison of weakly correlated electron-nuclear motion with the case where the strong correlations determine the dynamics. The studies of the model are extended to include spectroscopical transitions being present in two-dimensional and degenerate four-wave mixing spectroscopy. Furthermore, the quantum and classical time-evolution of the coupled motion in the complete electron-nuclear phase space is compared for the two coupling cases. Additionally, the numerically exact electron flux within the weak coupling case is compared to the Born-Oppenheimer treatment. In the last part of the thesis, the model is extended to two dimensions. The system then possesses potential energy surfaces which exhibit a typical 'Mexican hat'-like structure and a conical intersection in the adiabatic representation. Thus, it is possible to map properties of the system onto a vibronic coupling (Jahn-Teller) hamiltonian. Exact wave-packet propagations as well as nuclear wave-packet dynamics in the adiabatic and diabatic representation are performed.},
  subject      = {Theoretische Chemie},
  language  = {en}
}
@phdthesis{Albert2019,
  author    = {Albert, Michael},
  title     = {Intelligent analysis of medical data in a generic telemedicine infrastructure},
  isbn      = {978-3-945459-26-3 (Online)},
  doi       = {10.25972/OPUS-17421},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-174213},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Telemedicine uses telecommunication and information technology to provide health care services over spatial distances. In the upcoming demographic changes towards an older average population age, especially rural areas suffer from a decreasing doctor to patient ratio as well as a limited amount of available medical specialists in acceptable distance. These areas could benefit the most from telemedicine applications as they are known to improve access to medical services, medical expertise and can also help to mitigate critical or emergency situations. Although the possibilities of telemedicine applications exist in the entire range of healthcare, current systems focus on one specific disease while using dedicated hardware to connect the patient with the supervising telemedicine center. This thesis describes the development of a telemedical system which follows a new generic design approach. This bridges the gap of existing approaches that only tackle one specific application. The proposed system on the contrary aims at supporting as many diseases and use cases as possible by taking all the stakeholders into account at the same time. To address the usability and acceptance of the system it is designed to use standardized hardware like commercial medical sensors and smartphones for collecting medical data of the patients and transmitting them to the telemedical center. The smartphone can also act as interface to the patient for health questionnaires or feedback. The system can handle the collection and transport of medical data, analysis and visualization of the data as well as providing a real time communication with video and audio between the users. On top of the generic telemedical framework the issue of scalability is addressed by integrating a rule-based analysis tool for the medical data. Rules can be easily created by medical personnel via a visual editor and can be personalized for each patient. The rule-based analysis tool is extended by multiple options for visualization of the data, mechanisms to handle complex rules and options for performing actions like raising alarms or sending automated messages. It is sometimes hard for the medical experts to formulate their knowledge into rules and there may be information in the medical data that is not yet known. This is why a machine learning module was integrated into the system. It uses the incoming medical data of the patients to learn new rules that are then presented to the medical personnel for inspection. This is in line with European legislation where the human still needs to be in charge of such decisions. Overall, we were able to show the benefit of the generic approach by evaluating it in three completely different medical use cases derived from specific application needs: monitoring of COPD (chronic obstructive pulmonary disease) patients, support of patients performing dialysis at home and councils of intensive-care experts. In addition the system was used for a non-medical use case: monitoring and optimization of industrial machines and robots. In all of the mentioned cases, we were able to prove the robustness of the generic approach with real users of the corresponding domain. This is why we can propose this approach for future development of telemedical systems.},
  subject      = {Telemedizin},
  language  = {en}
}
@phdthesis{AlbertWeissenberger2009,
  author    = {Albert-Weißenberger, Christiane},
  title     = {Regulation of the Flagellar Biogenesis in Legionella pneumophila},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-34335},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2009},
  abstract  = {The bacterial pathogen Legionella pneumophila replicates intracellularly in protozoa, but can also cause severe pneumonia, called Legionnaires' disease. The bacteria invade and proliferate in the alveolar macrophages of the human lung. L. pneumophila bacteria exhibit a biphasic life cycle: replicative bacteria are avirulent; in contrast, transmissive bacteria express virulence traits and flagella. Primarily aim of this thesis was to evaluate the impact of the regulatory proteins FleQ, FleR, and RpoN in flagellar gene regulation. Phenotypic analysis, Western blot and electron microscopy of regulatory mutants in the genes coding for FleQ, RpoN and FleR demonstrated that flagellin expression is strongly repressed and that these mutants are non-flagellated in transmissive phase. Transcriptomic studies of these putative flagellar gene expression regulators demonstrated that fleQ controls the expression of numerous flagellar biosynthetic genes. Together with RpoN, FleQ controls transcription of 14 out of 31 flagellar class II genes, coding for the basal body, hook, and regulatory proteins. Unexpectedly, 7 out of 15 late flagellar genes class III and IV) are expressed dependent on FleQ but independent of RpoN. Thus, in contrast to the commonly accepted view that enhancer binding proteins as FleQ always interact with RpoN to initiate transcription, our results strongly indicate that FleQ of L. pneumophila regulates gene expression RpoN-dependent as well as RpoN-independent. Moreover, transcriptome analysis of a fleR mutant strain elucidated that FleR does not regulate the flagellar class III genes as previously suggested. Instead FleR regulates together with RpoN numerous protein biosynthesis and metabolic genes. Based on these experimental results our modified model for the transcriptional regulation of flagellar genes in L. pneumophila is that flagellar class II genes are controlled by FleQ and RpoN, while flagellar class III and IV genes are controlled in a fleQ-dependent but rpoN-independent manner. Although all L. pneumophila strains share the same complex life style, various pathotypes have evolved. This is reflected by the genomes, which contain e.g. genomic islands. The genomic island Trb-1 of L. pneumophila Corby, carries all genes necessary for a type-IV conjugation system, an integrase gene and a putative oriT site. The second aim of this thesis was to investigate the implication of this genomic island in conjugative DNA transfer. Using conjugation assays we showed that the oriT site located on Trb-1 is functional and contributes to conjugation between different L. pneumophila strains. As this is the first oriT site of L. pneumophila known to be functional our results provide evidence that conjugation is a major mechanism for the evolution of new pathotypes in L. pneumophila.},
  subject      = {Legionella pneumophila},
  language  = {en}
}
@phdthesis{Alboteanu2007,
  author    = {Alboteanu, Ana Maria},
  title     = {The Noncommutative Standard Model : Construction Beyond Leading Order in Theta and Collider Phenomenology},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-24334},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {Trotz seiner pr{\"a}zisen {\"U}bereinstimmung mit dem Experiment ist die G{\"u}ltigkeit des Standardmodells (SM) der Elementarteilchenphysik bislang nur bis zu einer Energieskala von einigen hundert GeV gesichert. Abgesehen davon erweist sich schon das Einbinden der Gravitation in einer einheitlichen Beschreibung aller fundamentalen Wechselwirkungen als ein durch gew{\"o}hnliche Quantenfeldtheorie nicht zu l{\"o}sendes Problem. Das Interesse an Quantenfeldtheorien auf einer nichtkommutativen Raumzeit wurde durch deren Vorhersage als niederenergetischer Limes von Stringtheorien erweckt. Unabh{\"a}ngig davon, kann die Nichtlokalit{\"a}t einer solchen Theorie den Rahmen zur Einbeziehung der Gravitation in eine vereinheitlichende Theorie liefern. Die Hoffnung besteht, dass die Energieskala Lambda_NC, ab der solche Effekte sichtbar werden k{\"o}nnen und f{\"u}r die es einerlei theoretischen Vorhersagen gibt, schon bei der n{\"a}chsten Generation von Beschleunigern erreicht wird. Auf dieser Annahme beruht auch die vorliegende Arbeit, im Rahmen deren eine m{\"o}gliche Realisierung von Quantenfeldtheorien auf nichtkommutativer Raumzeit auf ihre ph{\"a}nomenologischen Konsequenzen hin untersucht wurde. Diese Arbeit ist durch fehlende LHC (Large Hadron Collider) Studien f{\"u}r nichkommutative Quantenfeldtheorien motiviert. Im ersten Teil des Vorhabens wurde der hadronische Prozess pp-> Z gamma -> l+l- gamma am LHC sowie die Elektron-Positron Paarvernichtung in ein Z-Boson und ein Photon am ILC (International Linear Collider) auf nichtkommutative Signale hin untersucht. Die ph{\"a}nomenlogischen Untersuchungen wurden im Rahmen dieses Modells in erster Ordnung des nichtkommutativen Parameters Theta durchgef{\"u}hrt. Eine nichtkommutative Raumzeit f{\"u}hrt zur Brechung der Rotationsinvarianz bez{\"u}glich der Strahlrichtung der einlaufenden Teilchen. Im differentiellen Wirkungsquerschnitt f{\"u}r Streuprozesse {\"a}ussert sich dieses als eine azimuthale Abh{\"a}ngigkeit, die weder im SM noch in anderen Modellen jenseits des SM auftritt. Diese klare, f\"ur nichtkommutative Theorien typische Signatur kann benutzt werden, um nichtkommutative Modelle von anderen Modellen, die neue Physik beschreiben, zu unterscheiden. Auch hat es sich erwiesen, dass die azimuthale Abh{\"a}ngigkeit des Wirkungsquerschnittes am besten daf\"ur geeignet ist, um die Sensitivit{\"a}t des LHC und des ILC auf der nichtkommutativen Skala \$\Lnc\$ zu bestimmen. Im ph{\"a}nomenologischen Teil der Arbeit wurde herausgefunden, dass Messungen am LHC f{\"u}r den Prozess pp-> Z gamma-> l+l- gamma nur in bestimmten F{\"a}llen auf nichtkommutative Effekte sensitiv sind. F{\"u}r diese F{\"a}lle wurde f{\"u}r die nichtkommutative Energieskala Lambda_NC eine Grenze von Lambda_NC > 1.2 TeV bestimmt. Diese ist um eine Gr{\"o}ßenordnung h{\"o}her als die Grenzen, die von bisherigen Beschleunigerexperimenten hergeleitet wurden. Bei einem zuk{\"u}nftigen Linearbeschleuniger, dem ILC, wird die Grenze auf Lambda_NC im Prozess e^+e^- -> Z gamma -> l^+ l^- gamma wesentlich erh{\"o}ht (bis zu 6 TeV). Abgesehen davon ist dem ILC gerade der f{\"u}r den LHC kaum zug{\"a}ngliche Parameterbereich der nichtkommutativen Theorie erschlossen, was die Komplementarit{\"a}t der beiden Beschleunigerexperimente hinsichtlich der nichtkommutativen Parameter zeigt. Der zweite Teil der Arbeit entwickelte sich aus der Notwendigkeit heraus, den G{\"u}ltigkeitsbereich der Theorie zu h{\"o}heren Energien hin zu erweitern. Daf{\"u}r haben wir den neutralen Sektor des nichtkommutativen SM um die n{\"a}chste Ordnung in Theta erg{\"a}nzt. Es stellte sich wider Erwarten heraus, dass die Theorie dabei um einige freie Parameter erweitert werden muss. Die zus{\"a}tzlichen Parameter sind durch die homogenen L{\"o}sungen der Eich{\"a}quivalenzbedingungen gegeben, welche Ambiguit\"aten der Seiberg-Witten Abbildungen darstellen. Die allgemeine Erwartung war, dass die Ambiguit{\"a}ten Feldredefinitionen entsprechen und daher in den Streumatrixelementen verschwinden m\"ussen. In dieser Arbeit wurde jedoch gezeigt, dass dies ab der zweiten Ordnung in Theta nicht der Fall ist und dass die Nichteindeutigkeit der Seiberg-Witten Abbildungen sich durchaus in Observablen niederschl{\"a}gt. Die Vermutung besteht, dass jede neue Ordnung in Theta neue Parameter in die Theorie einf{\"u}hrt. Wie weit und in welche Richtung die Theorie auf nichtkommutativer Raumzeit entwickelt werden muss, kann jedoch nur das Experiment entscheiden.},
  subject      = {Feldtheorie},
  language  = {en}
}
@phdthesis{AlcantarinoMenescal2012,
  author    = {Alcantarino Menescal, Luciana},
  title     = {In vivo characterization of genetic factors involved in Xmrk driven melanoma formation in Medaka (Oryzias latipes): a closer look at braf, Stat5 and c-myc},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-70762},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2012},
  abstract  = {Melanoma arises from the malignant transformation of melanocytes and is one of the most aggressive forms of human cancer. In fish of the genus Xiphophorus, melanoma development, although very rarely, happens spontaneously in nature and can be induced by interspecific crossing. The oncogenic receptor tyrosine kinase, Xmrk, is responsible for melanoma formation in these fishes. Since Xiphophorus are live-bearing fishes and therefore not compatible with embryonic manipulation and transgenesis, the Xmrk melanoma model was brought to the medaka (Oryzias latipes) system. Xmrk expression under the control of the pigment cell specific mitf promoter leads to melanoma formation with 100\% penetrance in medaka. Xmrk is an orthologue of the human epidermal growth factor receptor (EGFR) and activates several downstream signaling pathways. Examples of these pathways are the direct phosphorylation of BRAF and Stat5, as well as the enhanced transcription of C-myc. BRAF is a serine-threonine kinase which is found mutated at high frequencies in malignant melanomas. Stat5 is a transcription factor known to be constitutively activated in fish melanoma. C-myc is a transcription factor that is thought to regulate the expression of approximately 15\% of all human genes and is involved in cancer progression of a large number of different tumors. To gain new in vivo information on candidate factors known to be involved in melanoma progression, I identified and analysed BRAF, Stat5 and C-myc in the laboratory fish model system medaka. BRAF protein motifs are highly conserved among vertebrates and the results of this work indicate that its function in the MAPK signaling is maintained in medaka. Transgenic medaka lines carrying a constitutive active version of BRAF (V614E) showed more pigmented skin when compared to wild type. Also, some transiently expressing BRAF V614E fishes showed a disrupted eye phenotype. In addition, I was able to identify two Stat5 copies in medaka, named Stat5ab/a and Stat5ab/b. Sequence analysis revealed a higher similarity between both Stat5 sequences when compared to either human Stat5a or Stat5b. This suggests that the two Stat5 copies in medaka arose by an independent duplication processes. I cloned these two Stat5 present in medaka, produced constitutive active and dominant negative gene versions and successfully established transgenic lines carrying each version under the control of the MITF promoter. These lines will help to elucidate questions that are still remaining in Stat5 biology and its function in melanoma progression, like the role of Stat5 phosphorylation on tumor invasiveness. In a third project during my PhD work, I analysed medaka C-myc function and indentified two copies of this gene in medaka, named c-myc17 and c-myc20, according to the chromosome where they are located. I produced conditional transgenic medaka lines carrying the c-myc17 gene coupled to the hormone binding domain of the estrogen receptor to enable specific transgene activation at a given time point. Comparable to human C-myc, medaka C-myc17 is able to induce proliferation and apoptosis in vivo after induction. Besides that, C-myc17 long-term activation led to liver hyperplasia. In summary, the medaka models generated in this work will be important to bring new in vivo information on genes involved in cancer development. Also, the generated transgenic lines can be easily crossed to the melanoma developing Xmrk medaka lines, thereby opening up the possibility to investigate their function in melanoma progression. Besides that, the generated medaka fishes make it possible to follow the whole development of melanocytes, since the embryos are transparent and can be used for high throughput chemical screens.},
  subject      = {Japank{\"a}rpfling},
  language  = {en}
}
@phdthesis{Alexander2019,
  author    = {Alexander, Stephanie},
  title     = {Collective cancer cell invasion \(in\) \(vivo\): function of β1 and β3 integrins in perivascular invasion and resistance to therapy},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85435},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Pro-migratory signals mediated by the tumor microenvironment contribute to the cancer progression cascade, including invasion, metastasis and resistance to therapy. Derived from in vitro studies, isolated molecular steps of cancer invasion programs have been identified but their integration into the tumor microenvironment and suitability as molecular targets remain elusive. The purpose of the study was to visualize central aspects of tumor progression, including proliferation, survival and invasion by real-time intravital microscopy. The specific aims were to monitor the kinetics, mode, adhesion and chemoattraction mechanisms of tumor cell invasion, the involved guidance structures, and the response of invasion zones to anti-cancer therapy. To reach deeper tumor regions by optical imaging with subcellular resolution, near-infrared and infrared excited multiphoton microscopy was combined with a modified dorsal skinfold chamber model. Implanted HT-1080 fibrosarcoma and B16/F10 and MV3 melanoma tumors developed zones of invasive growth consisting of collective invasion strands that retained cell-cell contacts and high mitotic activity while invading at velocities of up to 200 μm per day. Collective invasion occurred predominantly along preexisting tissue structures, including blood and lymph vessels, collagen fibers and muscle strands of the deep dermis, and was thereby insensitive to RNAi based knockdown and/or antibody-based treatment against β1 and β3 integrins, chemokine (SDF-1/CXCL12) and growth factor (EGF) signaling. Therapeutic hypofractionated irradiation induced partial to complete regression of the tumor main mass, yet failed to eradicate the collective invasion strands, suggesting a microenvironmentally privileged niche. Whereas no radiosensitization was achieved by interference with EGFR or doxorubicin, the simultaneous inhibition of β1 and β3 integrins impaired cell proliferation and survival in spontaneously growing tumors and strongly enhanced the radiation response up to complete eradication of both main tumor and invasion strands. In conclusion, collective invasion in vivo is a robust process which follows preexisting tissue structures and is mainly independent of established adhesion and chemoattractant signaling. Due to its altered biological response to irradiation, collective invasion strands represent a microenvironmentally controlled and clinically relevant resistance niche to therapy. Therefore supportive regimens, such as anoikisinduction by anti-integrin therapy, may serve to enhance radio- and chemoefficacy and complement classical treatment regimens.},
  subject      = {Tumorzelle},
  language  = {en}
}
@phdthesis{Ali2017,
  author    = {Ali, Qasim},
  title     = {Distributed Control of Cooperating Mini UAVs},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140686},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2017},
  abstract  = {Mini Unmanned Aerial Vehicles (MUAVs) werden immer beliebtere Forschungsplattformen. Vor allem in den letzten Jahren ziehen sie aufgrund ihrer Erschwinglichkeit und ihrer Flexibilit{\"a}t, die es erlaubt sie in fast allen Lebensbereichen einzusetzen, betr{\"a}chtliche Aufmerksamkeit auf sich. MUAVs haben offensichtliche Vorteile gegen{\"u}ber bemannten Plattformen einschließlich ihrer viel geringeren Herstellungs- und Betriebskosten, Risikovermeidung f{\"u}r den menschlichen Piloten, der M{\"o}glichkeit sicher niedrig und langsam fliegen zu k{\"o}nnen, und Realisierung von Operationen, die {\"u}ber die inh{\"a}renten Grenzen des menschlichen K{\"o}rpers hinausgehen. Der Fortschritt in der Micro Electro-Mechanical System (MEMS) Technologie, Avionik und Miniaturisierung von Sensoren spielte auch eine bedeutende Rolle bei der Entwicklung der MUAVs. Diese Flugger{\"a}te reichen von einfachem Spielzeug aus dem Elektrofachhandel bis zu hoch entwickelten, kommerziellen Plattformen, die die Durchf{\"u}hrung neuer Aufgaben wie Offshore-Windkraftwerk Inspektionen, 3D-Modellierung von Geb{\"a}uden usw. erlauben. MUAVs sind auch umweltfreundlich, da sie weniger Luftverschmutzung und L{\"a}rm verursachen. Unbemannt ist daher un{\"u}bertroffen. Aktuelle Forschung konzentriert sich auf die M{\"o}glichkeit mehrere kosteng{\"u}nstige Flugger{\"a}te zusammen fliegen zu lassen, w{\"a}hrend die erforderliche relative r{\"a}umliche Trennungen beibehalten wird. Dies erm{\"o}glicht es effizient Aufgaben zu erf{\"u}llen im Vergleich zu einem einzigen sehr teuren Flugger{\"a}t. Durch die Redundanz entf{\"a}llt auch das Risiko des Scheiterns der Mission durch den Verlust eines einzigen Flugger{\"a}ts. Wertvolle Aufgaben, die kooperative Flugger{\"a}te ausf{\"u}hren k{\"o}nnen, sind beispielsweise gemeinsame Lasttransporte, Such- und Rettungsmissionen, mobile Kommunikationsrelais, Spr{\"u}hen von Pestiziden und Wetterbeobachtung. Obwohl die Realisierung von Fl{\"u}gen mit mehreren, gekoppelten UAVs komplex ist, rechtfertigen dennoch offensichtliche Vorteile diese m{\"u}hsame und aufw{\"a}ndige Entwicklungsarbeit. Verteilte Steuerung von kooperierenden Einheiten ist ein multidisziplin{\"a}res Thema, das es erfordert in diversifizierten Bereichen zu arbeiten. Dazu geh{\"o}ren MUAV Hardware und Software, Kommunikationstechniken f{\"u}r den notwendigen Informationsaustausch, Flugdynamik, Regelungstechnik, insbesondere f{\"u}r verteilte / kooperative Steuerungstechniken, Graphentheorie f{\"u}r Kommunikationstopologie Modellierung und Sensoren-Technologie wie Differential GPS (DGPS). F{\"u}r eine Flotte von Agenten, die in unmittelbarer N{\"a}he fliegen, ist eine genaue Positionsbestimmung zwingend n{\"o}tig um Kollisionen zu vermeiden und die Anforderungen f{\"u}r die meisten Missionen wie Georeferenzierung zu erf{\"u}llen. F{\"u}r solche Szenarien ist DGPS ein potenzieller Kandidat. Ein Teil der Forschung konzentriert sich daher auf die Entwicklung von DGPS Code. Eines der Module dieser Forschung war Hardware-Implementierung. Ein einfacher Test-Aufbau zur Realisierung von Basisfunktionalit{\"a}ten f{\"u}r Formationsflug von Quadrocoptern wurde am Lehrstuhl f{\"u}r Informationstechnik in der Luft- und Raumfahrt der Universit{\"a}t W{\"u}rzburg entwickelt. Diese Testumgebung kann nicht nur zur Pr{\"u}fung und Validierung von Algorithmen f{\"u}r Formationsflug in realer Umgebung genutzt werden, sondern dient auch zur Ausbildung von Studenten. Ein bereits vorhandener Pr{\"u}fstand f{\"u}r einzelne Quadrocopter wurde mit den notwendigen Kommunikation und verteilten Steuerung erweitert, um Algorithmen f{\"u}r Formationsfl{\"u}ge in drei Freiheitsgraden (Roll / Nick / Gier) zu testen. Diese Studie umfasst die Bereiche der Kommunikation, Steuerungstechnik und Embedded-System-Programmierung. Das Bluetooth-Protokoll wurde f{\"u}r die gegenseitige Kommunikation zwischen zwei Quadrocoptern verwendet. Eine einfache Technik der Proportional-Integral-Differential (PID) Steuerung in Kombination mit Kalman-Filter wurde genutzt. Die MATLAB Instrument Control Toolbox wurde f{\"u}r die Datenanzeige, die Analyse und das Plotten verwendet. Plots k{\"o}nnen in Echtzeit gezeichnet werden und empfangene Daten k{\"o}nnen auch in Form von Dateien zur sp{\"a}teren Verwendung und Analyse gespeichert werden. Das System wurde preisg{\"u}nstig, unter Ber{\"u}cksichtigung eines einfachen Aufbaus, entwickelt. Der vorgeschlagene Aufbau ist sehr flexibel und kann einfach an ver{\"a}nderte Anforderungen angepasst werden. Als verteiltes Steuerungsschema wurde ein zentralisierter, heterogener Formationsflug Positionsregler formuliert, der einen „explicit model following Linear Quadratic Regulator Proportional Integral (LQR PI)" Regler verwendet. Der Anf{\"u}hrer Quadrocopter ist ein stabiles Referenzmodell mit der gew{\"u}nschten Dynamik, deren Ausgang vollkommen von den beiden Wingmen Quadrocopter verfolgt wird. Der Anf{\"u}hrer selbst wird durch Pole Placement Steuerverfahren mit den gew{\"u}nschten Stabilit{\"a}tseigenschaften gesteuert, w{\"a}hrend die beiden Anh{\"a}nger durch robuste und adaptive LQR PI Steuerverfahren geregelt werden. F{\"u}r diese Studie wird ein Vollzustandsvektor der Quadrocopter betrachtet w{\"a}hrend nur die resultierende Leistung verfolgt wird. Die ausgew{\"a}hlte 3D Formationsgeometrie und die statische Stabilit{\"a}t bleibt unter einer Vielzahl von m{\"o}glichen St{\"o}rungen erhalten. Bei Kommunikationsverlust zwischen Anf{\"u}hrer und einem der Anh{\"a}nger, leitet der andere Anh{\"a}nger die Daten, die er vom Anf{\"u}hrer erhalten hat, an den betroffenen Anh{\"a}nger weiter. Die Stabilit{\"a}t des Regelsystems wurde unter Verwendung von Singul{\"a}rwerten analysiert. Der vorgeschlagene Ansatz f{\"u}r eng gekoppelten Formationsflug von MUAVs wurde mit Hilfe von umfangreichen Simulationen unter MATLAB® / Simulink® validiert und ergab viel versprechende Ergebnisse. Auch die Tracking-Leistung wurde f{\"u}r zeitlich ver{\"a}nderliche Befehle gezeigt. Die vorgeschlagene Architektur ist skalierbar und kann problemlos erweitert werden. Dieser Ansatz ist f{\"u}r die Szenarien geeignet, die eng gekoppelte Formationsflug ben{\"o}tigen, wie kooperatives Greifen oder gemeinsame Lasttransporte. Ein innovatives Framework f{\"u}r die Teamarbeit von zwei Quadrocopter Flotten wurde entwickelt. Als Beispielmission wurde ein Szenario gew{\"a}hlt, bei dem ein Feuer auf einer gr{\"o}ßeren Fl{\"a}che gel{\"o}scht werden muss. Jede Formation hat ihre angegebene Formationsgeometrie und eine zugewiesene Aufgabe. Die Lageregelung f{\"u}r die Quadrocopter in einer der Formationen wurde durch ein LQR PI-Regelschema, das auf „explicit model following" basiert, umgesetzt. Die Quadrocopter in anderen Formation werden durch ein LQR PI Servomechanismus Regelsystem gesteuert. Die beiden Steuersysteme werden in Bezug auf ihre Leistung und ihren Steuerungsaufwand verglichen. Beide Formationen werden durch entsprechende Bodenstationen durch virtuelle Anf{\"u}hrer kommandiert. Die Bodenstationen tauschen die befohlene H{\"o}heninformation aus, um gegenseitig eine sichere Trennung zwischen den Formationen zu gew{\"a}hrleisten. Die Quadrocopter k{\"o}nnen kommandierte Solltrajektorien folgen und {\"u}ber erw{\"u}nschten Punkten f{\"u}r eine vorgegebene Zeit schweben. Bei Kommunikationsverlust zwischen Bodenstation und einem der Quadcopter leitet der benachbarte Quadrocopter die Befehlsdaten, die er von der Bodenstation erhalten hat, an die betroffene Einheit weiter. Das vorgeschlagene Framework wurde durch umfangreiche Simulationen mit Hilfe von MATLAB® / Simulink® validiert und liefert sehr brauchbare Ergebnisse. Cluster-Rekonfiguration von Agenten wird in unserer Arbeit ebenfalls gezeigt. Dies erlaubt es die Formationsgeometrie w{\"a}hrend des Fluges auf eine beliebige neue Form umzuschalten. F{\"u}r die genannten Anwendungen sind Konsens Algorithmen nicht erw{\"u}nscht, da wir von den Quadrocopter Flotten fordern, dass sie dem von uns gew{\"a}hlten Weg folgen, und nicht ihren Weg selbst w{\"a}hlen. Eine Reihe der praktischen Probleme von Kommunikationsnetzen kann in geeigneter Weise durch Graphen dargestellt werden. Dies erleichtert die Problemformulierung und den Analyseprozess. Kommunikationstopologien f{\"u}r Netzwerke mit einer großen Anzahl von Einheiten, wie zum Beispiel Schw{\"a}rme von Luftfahrzeugen, k{\"o}nnen durch einen graphentheoretischen Ansatz untersucht werden. Um die Bildung solcher Probleme zu erleichtern, wird der Graph mit Hilfe der Laplace-Matrix dargestellt. Eigenwerte der Laplace-Matrix wurden in unserer Studie angemessene Ber{\"u}cksichtigung gegeben einen Einblick in die Graphen / Subgraphen Eigenschaften zu verleihen. Der gleiche wurden genutzt um die bekannte Euler Formel zu verallgemeinern und somit auf Graphen und Subgraphen anwendbar zu machen. Eine modifizierte Euler-Formel wird ebenfalls vorgestellt. Die Verwendung der Graphentheorie in verteilten / kooperativen Regelsystemen wird auch durch Simulationen gezeigt. Kooperative Kontrolschemas, die auf auf Konsens-Algorithmen beruhenden, wurden f{\"u}r die Lageregelung von Quadrocopter-Flotten, in denen kein expliziter Anf{\"u}hrer existiert, verwendet. Konsens-Algorithmen wurden in Kombination mit verschiedenen Steuersystemen verwendet, was zur Autonomie von Quadrocoptern beitr{\"a}gt. Die Steuersysteme, die f{\"u}r diesen Zweck verwendet werden, umfassen LQR PI-Regelung basierend auf „model following" und LQR PI Servo-Mechanismus. Die Regelungen wurden unter verschiedenen Kommunikationstopologien untersucht, darunter voll verbundene ungerichtete Graphen, gerichteten Graphen und Zyklus-Topologie. Der Informationsfluss unter den Agenten in einem Cluster wurde durch Laplace-Matrix modelliert. Die Auswirkungen von Eingangs Verzerrungen auf Konsens Werte wurden ebenfalls untersucht. Quadrocopter k{\"o}nnen durch gegenseitigen Konsens Flugbahnen verfolgen und die Zielpunkte erreichen. Die vorgeschlagenen Regelungssysteme wurden unter verschiedenen Kommunikationstopologien in Matlab / Simulink-Umgebung durch umfangreiche Simulationen validiert. Die Ergebnisse bescheinigen die Wirksamkeit der pr{\"a}sentierten Schemata mit dem zus{\"a}tzlichen Vorteil der Einfachheit der Umsetzung. Das vorgeschlagene Regelungssystem ist skalierbar f{\"u}r große Gruppen von MUAVs. F{\"u}r Formationsflug sind die Anforderungen an die Positionsgenauigkeit sehr hoch. GPS-Signale allein bieten keine ausreichend hohe Positionsgenauigkeit um die Anforderung zu erf{\"u}llen; eine Technik f{\"u}r die genauere Positionsbestimmung ist daher erforderlich, beispielsweise DGPS. Es existiert eine Anzahl von {\"o}ffentlichen Codes f{\"u}r die GPS-Positionsbestimmung und Baseline-Bestimmung im Offline-Modus. Es existiert jedoch keine Software f{\"u}r DGPS, die Korrekturfaktoren der Basisstationen nutzt, ohne auf Doppel Differenz Informationen zu vertrauen. Um dies zu erreichen, wurde eine Methodik in MATLAB-Umgebung f{\"u}r DGPS mit C/A Pseudoranges nur auf einzelne Frequenz L1 eingef{\"u}hrt es machbar f{\"u}r Empf{\"a}nger kosteng{\"u}nstig GPS zu nutzen. Unsere Basisstation wird an einem genau vermessen Referenzpunkt aufgestellt. Pseudoranges und geometrische Abst{\"a}nde werden an der Basisstation verglichen, um die Korrekturfaktoren zu berechnen. Diese Korrekturfaktoren, f{\"u}r aller g{\"u}ltigen Satelliten w{\"a}hrend einer Epoche, werden dann an einen Rover {\"u}bergeben. Das Rover ber{\"u}cksichtigt innerhalb der entsprechenden Epoche diese f{\"u}r seine eigene wahre Positionsbestimmung. Zur Validierung der vorgeschlagenen Algorithmen wird unsere Rover ebenfalls an einer vorbestimmten Stelle platziert. Der vorgeschlagene Code ist ein geeignetes und einfaches Werkzeug f{\"u}r die Nachbearbeitung von GPS-Rohdaten f{\"u}r eine genaue Positionsbestimmung eines Rover, z.B. eines UAV w{\"a}hrend der Post-Missionsanalyse.},
  subject      = {Micro Air Vehicle},
  language  = {en}
}
@phdthesis{Ali2007,
  author    = {Ali, Walid Wahid},
  title     = {Screening of plant suspension cultures for antimicrobial activities and characterization of antimicrobial proteins from Arabidopsis thaliana},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-24358},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {Die zunehmende Resistenz humanpathogener Mikroorganismen gegen bekannte Antibiotika bedingt die Notwendigkeit, nach neuen Quellen f{\"u}r die Produktion antimikrobieller Stoffe zu suchen. Als eine solche Quelle gelten besonders Pflanzen, da viele antimikrobielle Stoffe bei der Abwehr gegen invasierende Mikroorganismen bilden. Das Ziel der vorliegenden Arbeit besteht in der Charakterisierung von pflanzlichen Zellkulturen im Hinblick auf ihre F{\"a}higkeit, anitimkrobielle Aktivit{\"a}t gegen humanpathogene Mikroorganismen zu entwickeln. Dabei sollen aktive Proteine aufgereinigt und die kodierenden Gene isoliert werden. Dazu wurden zehn verschiede pflanzliche Suspensionskulturen in Anwesenheit von neun Elicitoren auf ihre antimikrobielle Aktivit{\"a}t gegen f{\"u}nf humanpathogene Mikroorganismen getestet. Dabei erwiesen sich die heterotrophen Kulturen im Vergleich zu den autotrophen als aktiver. Die h{\"o}chste antimikrobielle Aktivit{\"a}t wurde bei der intrazellul{\"a}ren Fraktion der mixotrophen Kultur von Arabidopsis thaliana nach Elicitierung mit Salicyls{\"a}ure nachgewiesen. Da in einem Pr{\"a}zipitat mit Ammoniumsulfat Aktivit{\"a}t gegen Candida maltosa nachgewiesen wurde, konnte angenommen werden, dass es sich bei der aktiven Komponente um ein Protein handelt. Durch Hochgeschwindigkeitszentrifugation wurde eine partielle Aufreinigung dieser aktiven Komponente erreicht. Die proteinoide Natur wurde durch Bioautographie best{\"a}tigt und das Molekulargewicht auf ca. 26kDa gesch{\"a}tzt. Mittels Gelfiltration und Massenspektrometrie wurde das Protein aufgereinigt. Die Mikrosequenzierung ergab ein Protein mit bisher unbekannter Funktion, das eine pflanzliche Stressdom{\"a}ne (PLAT) enth{\"a}lt. Das Protein wurde daraufhin als AtPDP1 (Arabidopsis thaliana Plat-Domain Protein 1) bezeichnet. Das Gen und ein zweites mit hochgradiger Homologie (AtPDP2) wurden in E. coli kloniert. Der Digital Northern zeigt an, das beide Gene durch verschiedene Pathogene induziert werden, sowie von Chemikalien, die pflanzliche Abwehr hervorrufen und weiterhin von Phytohormonen. Der Versuch, AtPDP1 unter die Kontrolle eines Promors einer Proteinase zu stellen, der Induzierbarkeit durch Elicitoren vermittelt, blieb erfolglos. Weiterhin wurden 13 Thaumatingene aus Arabidopsis thaliana in E. coli kloniert, da ihre antimikrobielle Aktivit{\"a}t bekannt ist, und ihre Expression durch verschiedene Stimuli induziert wird. Von diesen Genen zeigt der Digital Northern bei allen Stimuli eine maximale Expression f{\"u}r At1g75800, w{\"a}hrend At1g75050 minimal induziert ist. Diese Gene stehen f{\"u}r zuk{\"u}nftige Studien zur Verf{\"u}gung.},
  subject      = {-},
  language  = {en}
}
@phdthesis{Alkonyi2014,
  author    = {Alkonyi, Balint},
  title     = {Differential imaging characteristics and dissemination potential of pilomyxoid astrocytomas versus pilocytic astrocytomas},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116062},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Background and Aims: PMA is a recently described rare tumor entity occuring most often in young children. Due the worse outcome of PMA-patients as compared to children with pilocytic astrocytoma (PA), it has received a grade II assignment in the latest WHO classification. Nevertheless, increasing evidence suggests that the two tumor types are indeed pathologically and genetically related. The radiological differentiation of PMAs from PAs is challenging and the limited available data could not yet provide unequivocal distinguishing imaging features. Furthermore, it is not completely clarified whether PMA cases are associated with a higher rate of CSF dissemination compared to similarly young patients with PA. The aim of our study was firstly to compare MR/CT imaging features of these tumors, and secondly, to evaluate the occurrence of CSF dissemination. Material and Methods: The study population included 15 children with PMA and 32 children with PA. A third group consisted of eight children with PAs with focal pilomyxoid features. All cases had been registered in the German multicenter SIOP/HIT-LGG trials. The initial MRIs (and CT scans, if available) at establishing the diagnosis were retrospectively analyzed according to standardized criteria and the findings compared between PMAs and PAs. Furthermore, we compared the occurrence of imaging evidences of CSF tumor dissemination between children with PMA and PA, respectively. Results: The imaging appearance of PMAs and PAs was very similar. However, PAs tended to show more frequently cystic components (p=0.03). As opposed to PAs, PMAs did not have large tumor cysts. We did not find differences with respect to tumor size and tumor margin. Gadolinium enhancement of PMAs was significantly more frequently homogeneous (p=0.006). PMAs appeared to show more often intratumoral hemorrhages (p=0.047). Furthermore, suprasellar PMAs tended to have a more homogeneus texture on T2-weighted MR images (p=0.026). Within the subgroup < 6 years of age the PMA histology tended to have a larger effect on the occurrence of CSF dissemination than the age (p=0.05 vs.0.12). Conclusions: Although the radiological appearance of PMAs and PAs is similar, some imaging features, like enhancement pattern or presence of cysts or hemorrhage may help differentiating these low-grade gliomas. Our results corroborate previous scarce data suggesting higher rate of CSF dissemination in PMAs, even in the youngest patient population. Thus, in young children with a chiasmatic-hypothalamic tumor suggestive of a PMA, an intensive search for CSF dissemination along the entire neuraxis should be performed.},
  subject      = {Astrozytom},
  language  = {en}
}
@phdthesis{Allgaier2004,
  author    = {Allgaier, Axel},
  title     = {Aeolian sand movement in an arid linear dune ecosystem, Nizzana, Western Negev, Israel},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-14727},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2004},
  abstract  = {In a three-year study the current aeolian transportation processes were examined in a linear dune area previously used for grazing near Nizzana at the Israeli-Egyptian border. The research area was subject to heavy grazing across the border, which led to the total destruction of the natural vegetation in the period of 1967 to 1982. As a consequence, intensified aeolian activity and significant changes of the morphology of the dunes were observed. After the end of the grazingg on the Israeli side, a rapid return of the vegetation in the interdune corridors and on the footslopes of the dunes took place. In addition also a reduction of obviously active areas on the dune crests was observed. The situation on Egyptian territory west the border remained unchanged until today. This study is aimed at understanding the changed aeolian morphodynamics east the border. The emphasis was placed on the investigation of the spatial and temporal distribution of aeolian sand transport as well as on the influencing factors morphology, surface condition and vegetation.},
  subject      = {Negev},
  language  = {en}
}
@phdthesis{Allgaier2024,
  author    = {Allgaier, Johannes},
  title     = {Machine Learning Explainability on Multi-Modal Data using Ecological Momentary Assessments in the Medical Domain},
  doi       = {10.25972/OPUS-35118},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351189},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {Introduction. Mobile health (mHealth) integrates mobile devices into healthcare, enabling remote monitoring, data collection, and personalized interventions. Machine Learning (ML), a subfield of Artificial Intelligence (AI), can use mHealth data to confirm or extend domain knowledge by finding associations within the data, i.e., with the goal of improving healthcare decisions. In this work, two data collection techniques were used for mHealth data fed into ML systems: Mobile Crowdsensing (MCS), which is a collaborative data gathering approach, and Ecological Momentary Assessments (EMA), which capture real-time individual experiences within the individual's common environments using questionnaires and sensors. We collected EMA and MCS data on tinnitus and COVID-19. About 15 \% of the world's population suffers from tinnitus. Materials \& Methods. This thesis investigates the challenges of ML systems when using MCS and EMA data. It asks: How can ML confirm or broad domain knowledge? Domain knowledge refers to expertise and understanding in a specific field, gained through experience and education. Are ML systems always superior to simple heuristics and if yes, how can one reach explainable AI (XAI) in the presence of mHealth data? An XAI method enables a human to understand why a model makes certain predictions. Finally, which guidelines can be beneficial for the use of ML within the mHealth domain? In tinnitus research, ML discerns gender, temperature, and season-related variations among patients. In the realm of COVID-19, we collaboratively designed a COVID-19 check app for public education, incorporating EMA data to offer informative feedback on COVID-19-related matters. This thesis uses seven EMA datasets with more than 250,000 assessments. Our analyses revealed a set of challenges: App user over-representation, time gaps, identity ambiguity, and operating system specific rounding errors, among others. Our systematic review of 450 medical studies assessed prior utilization of XAI methods. Results. ML models predict gender and tinnitus perception, validating gender-linked tinnitus disparities. Using season and temperature to predict tinnitus shows the association of these variables with tinnitus. Multiple assessments of one app user can constitute a group. Neglecting these groups in data sets leads to model overfitting. In select instances, heuristics outperform ML models, highlighting the need for domain expert consultation to unveil hidden groups or find simple heuristics. Conclusion. This thesis suggests guidelines for mHealth related data analyses and improves estimates for ML performance. Close communication with medical domain experts to identify latent user subsets and incremental benefits of ML is essential.},
  subject      = {Maschinelles Lernen},
  language  = {en}
}
@phdthesis{Almeling2011,
  author    = {Almeling, Stefan},
  title     = {The use of aerosol-based detection systems in the quality control of drug substances},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64722},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {The work presented in this thesis was mainly targeted at exploring the capabilities of evaporation based LC detectors as well as further alternatives for the control of impurities in substances not exhibiting a suitable chromophore for UV-detection. In the course of the work carried out, several new methods for the identification, impurities control and composition testing of APIs were elaborated. An evaporation based detector that entered into the field of pharmaceutical analysis in the recent years was the Evaporative Light Scattering Detector (ELSD). However, non-reproducible spikes were reported when injecting concentrated test solutions as they are usually required for the control of impurities. The reasons, for the appearance of these spikes as well as possibilities for their avoidance were explored in a systematic study. Moreover, the dependence of the detector sensitivity on different eluent composition, eluent flow-rate and ELSD settings was investigated. In the course of the revision of the Ph.Eur. monographs for aspartic acid and alanine, a C18 reversed phase ion-pair LC method using 1 mmol/L of perfluoroheptanoic acid as an ion-pair reagent and a charged aerosol detector (CAD) was developed and fully validated for the purity control of Asp. The method was capable of separating the organic acids and major amino acids known to occur as process related impurities. With a slight modification, the method was also applicable for the purity control of Ala. Based on the developed LC-CAD method for the impurity control of alanine, a comparative study of the performance characteristics of different evaporation based LC detectors, i.e. ELSD, CAD and the recently developed Nano Quantity Analyte Detector (NQAD) was carried out. Additionally, an MS detector and qNMR were included in this study. It was found that the control of impurities in Alanine at an ICH conform level could be ensured using LC coupled to CAD, MSD and NQAD detection as well as by the use of qNMR. In terms of performance, prize and ease of use CAD and NQAD were found to be the most suitable alternatives. In terms of repeatability and sensitivity, the CAD appeared slightly superior to the NQAD. The quality of streptomycin sulfate is not sufficiently controlled by the current Ph.Eur. monograph in that an appropriate test for the control of the related substances is missing. A study was carried out to develop a C18 reversed phase ion-pair LC method using pentafluoropropionic acid as an ion-pair reagent and a CAD for the identification and control of the related substances. The developed method allowed the separation of 21 impurities from streptomycin. Moreover, coupling of the method to MS allowed the identification of the separated impurities. The method was shown to be sufficiently sensitive to control the related substances with a disregard limit of 0.1\% as it is normally applied in the Ph.Eur. for products derived from fermentation. Currently, the aescin content of horse-chestnut standardized dry extract is determined using a complex and laborious photometric determination. A more selective LC-UV assay determination for beta-aescin has been proposed for the Ph.Eur. draft monograph of horse-chestnut standardized dry extract. Possibilities were explored to further improve the LC-method using detection by CAD. It was demonstrated that by the use of a modified LC-CAD method several problems related to the differences in the UV-response of the various components contained in the active aescin fraction could be eliminated. Moreover the proposed reference standard strategy was reviewed. Eventually, it was demonstrated on the example of two different clusters of pharmacologically active peptides how low energy collision induced dissociation mass spectrometry (low energy CID-MS) can successfully be used for identification testing in pharmacopoeial monographs. In this respect, the combination of a direct confirmation of the molecular mass via the m/z-ratio of the molecule ions with structural sequence information obtained by low energy CID-MS experiments was found to deliver a higher degree of certainty of the identity of a given substance than the set of tests currently described in the monographs. A significant gain in efficiency and throughput and important reduction of the amount of sample consumed during testing were identified as being additional advantages of this approach. Taken together, it could be demonstrated on various examples how recent technological advancements in the field of analytical chemistry can contribute to improve the quality control of APIs.},
  subject      = {Elektronensprayionisations-Massenspektrometrie},
  language  = {en}
}
@phdthesis{AlonsoCanizal2020,
  author    = {Alonso Ca{\~n}izal, Maria Consuelo},
  title     = {Detection of ligand dependent Frizzled conformational changes},
  doi       = {10.25972/OPUS-17833},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178335},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Frizzled (FZD) are highly conserved receptors that belong to class F of the G protein-coupled receptor (GPCR) superfamily. They are involved in a great variety of processes during embryonic development, organogenesis, and adult tissue homeostasis. In particular, FZD5 is an important therapeutic target due to its involvement in several pathologies, such as tumorigenesis. Nevertheless, little is known regarding the activation of FZD receptors and the signal initiation, and their GPCR nature has been debated. In order to investigate the activation mechanism of these receptors, FRET (F{\"o}rster Resonance Energy Transfer)-based biosensors for FZD5 have been developed and characterized. A cyan fluorescent protein (CFP) was fused to the C-terminus of the receptor and the specific FlAsH-binding sequence (CCPGCC) was inserted within the 2nd or the 3rd intracellular loop. Single-cell FRET experiments performed using one of these sensors, V5-mFZD5-FlAsH436-CFP, reported structural rearrangements in FZD5 upon stimulation with the endogenous ligand WNT-5A. These movements are similar to those observed in other GPCRs using the same technique, which suggests an activation mechanism for FZD reminiscent of GPCRs. Furthermore, stimulation of the FZD5 FRET-based sensor with various recombinant WNT proteins in a microplate FRET reader allowed to obtain concentration-response curves for several ligands, being possible to distinguish between full and partial agonists. This technology allowed to address the selectivity between WNTs and FZD5 using a full-length receptor in living cells. In addition, G protein FRET-based sensors revealed that WNT-5A specifically induced Gαq activation mediated by FZD5, but not Gαi activation. Other WNT proteins were also able to induce Gαq activation, but with lower efficacy than WNT-5A. In addition, a dual DAG/calcium sensor further showed that WNT-5A stimulation led to the activation of the Gαq-dependent signaling pathway mediated by FZD5, which outcome was the activation of Protein Kinase C (PKC) and the release of intracellular calcium. Altogether, these data provide evidence that the activation process of FZD5 resembles the general characteristics of class A and B GPCR activation, and this receptor also mediates the activation of the heterotrimeric Gαq protein and its downstream signaling pathway. In addition, the FZD5 receptor FRET-based sensor provides a valuable tool to characterize the pharmacological properties of WNTs and other potential ligands for this receptor.},
  subject      = {Fluoreszenz-Resonanz-Energie-Transfer},
  language  = {en}
}
@phdthesis{Alrefai2014,
  author    = {Alrefai, Hani Gouda Alsaid},
  title     = {Molecular Characterization of NFAT Transcription Factors in Experimental Mouse Models},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97905},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {In this work we wanted to investigate the role of NFATc1 in lymphocyte physiology and in pathological conditions (eg. psoriasis). NFATc1 is part of the signal transduction pathways that regulates B cells activation and function. NFATc1 has different isoforms that are due to different promoters (P1 and P2), polyadenylation and alternative splicing. Moreover, we tried to elucidate the points of interactions between the NFAT and the NF-κB pathways in activated B-cell fate. NFAT and NF-κB factors share several properties, such as a similar mode of induction and architecture in their DNA binding domain. We used mice which over-express a constitutive active version of NFATc1/α in their B cells with -or without- an ablated IRF4. IRF4 inhibits cell cycle progression of germinal center B cell-derived Burkitt's lymphoma cells and induces terminal differentiation toward plasma cells. Our experiments showed that a 'double hit' in factors affecting B cell activation (NFATc1 in this case) and late B cell Differentiation (IRF4 in this case) alter the development of the B cells, lead to increase in their numbers and increase in stimulation induced proliferation. Therefore, the overall picture indicates a link between these 2 genes and probable carcinogenic alterations that may occur in B cells. We also show that in splenic B cells, c-Rel (of the NF-κB canonical pathway) Support the induction of NFATc1/αA through BCR signals. We also found evidence that the lack of NFATc1 affects the expression of Rel-B (of the NF-κB non-canonical pathway). These data suggest a tight interplay between NFATc1 and NF-κB in B cells, influencing the competence of B cells and their functions in peripheral tissues. We also used IMQ-induced psoriasis-like inflammation on mice which either lack NFATc1 from B cell. Psoriasis is a systemic chronic immunological disease characterized primarily by abnormal accelerated proliferation of the skin keratinocytes. In psoriasis, the precipitating event leads to immune cell activation. Our experiments showed that NFATc1 is needed for the development of psoriasis. It also showed that IL-10 is the link that enables NFAT from altering the B cell compartment (eg Bregs) in order to affect inflammation. The important role of B cell in psoriasis is supported by the flared up psoriasis-like inflammation in mice that lack B cells. Bregs is a special type of B cells that regulate other B cells and T cells; tuning the immunological response through immunomodulatory cytokines.},
  subject      = {Schuppenflechte},
  language  = {en}
}
@phdthesis{Altmann2014,
  author    = {Altmann, Michael},
  title     = {Environmentally conscious supply chain design},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-107760},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Sustainability has become a critical topic in all areas of supply chain management. As discussed earlier, drivers for this development can be identified as both internal and external phenomena. Since customers are one of the key stakeholders in supply chain management, special attention is paid to the impact of costumers´ behavior on sustainable supply chain design decisions. In this context, two main research questions were analyzed: 1.What is the appropriate way to design a supply chain according to environmentally-oriented requirements of customers? 2.What is the impact of customer´s behavior regarding both usage and return of products on supply chain design decisions in an environmentally conscious closed-loop supply chain environment? Therefore, three different optimization models with various main aspects are developed. To illustrate how the presented models can be applied in practical problem cases, guidelines for implementing an environmentally supply chain design project are presented.},
  subject      = {Supply Chain Management},
  language  = {en}
}
@phdthesis{Altmann2023,
  author    = {Altmann, Stephan},
  title     = {Characterization of Metabolic Glycoengineering in Mesenchymal Stromal Cells for its Application in thermoresponsive Bioinks},
  doi       = {10.25972/OPUS-29100},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-291003},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {This work developed during the first funding period of the subproject B05 in the framework of the interdisciplinary research consortium TRR 225 'From the Fundamentals of Biofabrication toward functional Tissue Models' and was part of a cooperation between the Orthopedic Department represented by Prof. Dr. Regina Ebert and the Institute of Organic Chemistry represented by Prof. Dr. J{\"u}rgen Seibel. This project dealed with cellular behavior during the bioprinting process and how to influence it by modifying the cell glycocalyx with functional target molecules. The focus was on the impact of potential shear stress, that cells experience when they get processed in thermoresponsive bioinks, and a way to increase the cell stiffness via metabolic glycoengineering to attenuate shear forces. For the characterization of the metabolic glycoengineering, four different peracetylated and four non-acetylated modified monosaccharides (two mannose and two sialic acid sugars) were tested in primary human mesenchymal stromal cells (hMSC) and telomerase-immortalized hMSC (hMSC-TERT). Viability results demonstrated a dose-dependent correlation for all sugars, at which hMSC-TERT seemed to be more susceptible leading to lower viability rates. The assessment of the incorporation efficiencies was performed by click chemistry using fluorescent dyes and revealed also a dose-dependent correlation for all mannose and sialic acid sugars, while glucose and galactose variants were not detected in the glycocalyx. However, incorporation efficiencies were highest when using mannose sugars in the primary hMSC. A subsequent analysis of the temporal retention of the incorporated monosaccharides showed a constant declining fluorescence signal up to 6 d for azido mannose in hMSC-TERT, whereas no signal could be detected for alkyne mannose after 2 d. Investigation of the differentiation potential and expression of different target genes revealed no impairment after incubation with mannose sugars, indicating a normal phenotype for hMSC-TERT. Following the successful establishment of the method, either a coumarin derivative or an artificial galectin 1 ligand were incorporated into the cell glycocalyx of hMSC-TERT as functional target molecule. The biophysical analysis via shear flow deformation cytometry revealed a slightly increased cell stiffness and lowered fluidity for both molecules. A further part of this project aimed to control lectin-mediated cell adhesion by artificial galectin 1 ligands. As that hypothesis was settled in the work group of Prof. Dr. J{\"u}rgen Seibel, this work supported with an initial characterization of galectin 1 as part of the hMSC biology. A stable galectin 1 expression at gene and protein level in both hMSC and hMSC-TERT could be confirmed, at which immunocytochemical stainings could detect the protein only in the glycocalyx. The treatment of hMSC-TERT with a galectin 1 ligand in different concentrations did not show an altered gene expression of galectin 1. However, these first data in addition to the investigation of stiffness confirmed the applicability of specific and artificial IV galectin 1 ligands in biofabrication approaches to alter cell properties of hMSC. To conclude, metabolic glycoengineering has been successfully implemented in hMSC and hMSC-TERT to introduce glycocalyx modifications which reside there for several days. A proof of concept was carried out by the increase of cell stiffness and fluidity by the incorporation of a coumarin derivative or an artificial galectin 1 ligand. For the characterization of shear stress impact on cells after printing in thermoresponsive bioinks, the processing of hMSC-TERT (mixing or additionally printing) with Pluronic F127 or Polyoxazoline-Polyoxazine (POx-POzi) polymer solution was investigated. While there were no changes in viability when using POx-POzi bioink, processing with Pluronic F127 indicated slightly lower viability and increased apoptosis activity. Assessment of cellular responses to potential shear stress showed no reorganization of the cytoskeleton independent of the bioink, but highly increased expression of the mechanoresponsive proto-oncogene c Fos which was more pronounced when using Pluronic F127 and just mixed with the bioinks. Interestingly, processing of the mechanoresponsive reporter cell line hMSC-TERT-AP1 revealed slightly elevated mechanotransduction activity when using POx-POzi polymer and just mixed with the bioinks as well. In conclusion, hMSC-TERT embedded in thermoresponsive bioinks might shortly experience shear stress during the printing process, but that did not lead to remarkable cell damage likely due to the rheological properties of the bioinks. Furthermore, the printing experiments also suggested that cells do not sense more shear stress when additionally printed.},
  subject      = {Glykobiologie},
  language  = {en}
}
@phdthesis{Altrichter2021,
  author    = {Altrichter, Steffen},
  title     = {Labeling approaches for functional analyses of adhesion G protein-coupled receptors},
  doi       = {10.25972/OPUS-20706},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207068},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {The superfamily of G protein-coupled receptors (GPCRs) comprises more than 800 members, which are divided into five families based on phylogenetic analyses (GRAFS classification): Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2 and Secretin. The adhesion G protein-coupled receptor (aGPCR) family forms with 33 homologs in Mammalia the second largest and least investigated family of GPCRs. The general architecture of an aGPCR comprises the GPCR characteristics of an extracellular region (ECR), a seven transmembrane (7TM) domain and an intracellular region (ICR). A special feature of aGPCRs is the extraordinary size of the ECR through which they interact with cellular and matricellular ligands via adhesion motif folds. In addition, the ECR contains a so-called GPCR autoproteolysis-inducing (GAIN) domain, which catalyzes autoproteolytic cleavage of the protein during maturation. This cleavage leads to the formation of an N-terminal (NTF) and a C-terminal fragment (CTF), which build a unit by means of hydrophobic interactions and therefore appear as a heterodimeric receptor at the cell surface. In the past, it has been shown that the first few amino acids of the CTF act as a tethered agonist (TA) that mediates the activation of the receptor through the interaction with the 7TM domain. However, the molecular mechanism promoting the TA-7TM domain interaction remains elusive. This work reveals a novel molecular mechanism that does not require the dissociation of the NTF-CTF complex to promote release of the TA and thus activation of the aGPCR. The introduction of bioorthogonal labels into receptorsignaling- relevant regions of the TA of various aGPCRs demonstrated that the TA is freely accessible within the intact GAIN domain. This suggests a structural flexibility of the GAIN domain, which allows a receptor activation independent of the NTF-CTF dissociation, as found in cleavage-deficient aGPCR variants. Furthermore, the present study shows that the cellular localization and the conformation of the 7TM domain depends on the activity state of the aGPCR, which in turn indicates that the TA mediates conformational changes through the interaction with the 7TM domain, which ultimately regulates the receptor activity. In addition, biochemical analyses showed that the GAIN domain-mediated autoproteolysis of the human aGPCR CD97 (ADGRE5/E5) promotes further cleavage events within the receptor. This suggests that aGPCRs undergo cleavage cascades, which are initialized by the autoproteolytic reaction of the GAIN domain. Thus, it can be assumed that aGPCRs are subject to additional proteolytic events. Finally, the constitutive internalization of the NTF and the CTF of E5 was demonstrated by various labeling methods. It was possible to label both fragments independently and to follow their subcellular location in vitro. In summary, these obtained results contribute to a better understanding about the molecular mechanisms of activity and signaling of aGPCRs.},
  subject      = {G-Protein gekoppelter Rezeptor},
  language  = {en}
}
@phdthesis{AlvarezLoeblich2018,
  author    = {Alvarez Loeblich, Paul Sebastian},
  title     = {Not Here, Not Now!
 - Situational Appropriateness, Negative Affect and the Experience of (Remote) Embarrassment. A Process Model.},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161354},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2018},
  abstract  = {Fremdsch{\"a}men or Fremdscham, a negative emotion which arises while observing someone behave inappropriately, comes to fame after the turn of the millennium in german speaking countries. There, they name it literally „other's shame" and it becomes obvious that this emotion happens most commonly while watching TV: reality shows, talent shows and bad comedies. The word even makes it to the dictionaries starting 2009, as its use increases unstoppably in everyday language, starting to get used in more and more situations, seemingly as a synonym of embarrassing or shameful. Still, a look in the emotional research on the subject returns exactly zero results as of 2011, leaving open the question as of what this emotion might be, and what it is not. The present wort aims at explaining not only the phenomenon of Fremdsch{\"a}men, but also the Emotion behind it - Embarrassment -, at a process level.},
  subject      = {Sozialpsychologie},
  language  = {en}
}
@phdthesis{Alzheimer2023,
  author    = {Alzheimer, Mona},
  title     = {Development of tissue-engineered three-dimensional infection models to study pathogenesis of \(Campylobacter\) \(jejuni\)},
  doi       = {10.25972/OPUS-19344},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193440},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Infectious diseases caused by pathogenic microorganisms are one of the largest socioeconomic burdens today. Although infectious diseases have been studied for decades, in numerous cases, the precise mechanisms involved in the multifaceted interaction between pathogen and host continue to be elusive. Thus, it still remains a challenge for researchers worldwide to develop novel strategies to investigate the molecular context of infectious diseases in order to devise preventive or at least anti-infective measures. One of the major drawbacks in trying to obtain in-depth knowledge of how bacterial pathogens elicit disease is the lack of suitable infection models to authentically mimic the disease progression in humans. Numerous studies rely on animal models to emulate the complex temporal interactions between host and pathogen occurring in humans. While they have greatly contributed to shed light on these interactions, they require high maintenance costs, are afflicted with ethical drawbacks, and are not always predictive for the infection outcome in human patients. Alternatively, in-vitro two-dimensional (2D) cell culture systems have served for decades as representatives of human host environments to study infectious diseases. These cell line-based models have been essential in uncovering virulence-determining factors of diverse pathogens as well as host defense mechanisms upon infection. However, they lack the morphological and cellular complexity of intact human tissues, limiting the insights than can be gained from studying host-pathogen interactions in these systems. The focus of this thesis was to establish and innovate intestinal human cell culture models to obtain in-vitro reconstructed three-dimensional (3D) tissue that can faithfully mimic pathogenesis-determining processes of the zoonotic bacterium Campylobacter jejuni (C. jejuni). Generally employed for reconstructive medicine, the field of tissue engineering provides excellent tools to generate organ-specific cell culture models in vitro, realistically recapitulating the distinctive architecture of human tissues. The models employed in this thesis are based on decellularized extracellular matrix (ECM) scaffolds of porcine intestinal origin. Reseeded with intestinal human cells, application of dynamic culture conditions promoted the formation of a highly polarized mucosal epithelium maintained by functional tight and adherens junctions. While most other in-vitro infection systems are limited to a flat monolayer, the tissue models developed in this thesis can display the characteristic 3D villi and crypt structure of human small intestine. First, experimental conditions were established for infection of a previously developed, statically cultivated intestinal tissue model with C. jejuni. This included successful isolation of bacterial colony forming units (CFUs), measurement of epithelial barrier function, as well as immunohistochemical and histological staining techniques. In this way, it became possible to follow the number of viable bacteria during the infection process as well as their translocation over the polarized epithelium of the tissue model. Upon infection with C. jejuni, disruption of tight and adherens junctions could be observed via confocal microscopy and permeability measurements of the epithelial barrier. Moreover, C. jejuni wildtype-specific colonization and barrier disruption became apparent in addition to niche-dependent bacterial localization within the 3D microarchitecture of the tissue model. Pathogenesis-related phenotypes of C. jejuni mutant strains in the 3D host environment deviated from those obtained with conventional in-vitro 2D monolayers but mimicked observations made in vivo. Furthermore, a genome-wide screen of a C. jejuni mutant library revealed significant differences for bacterial factors required or dispensable for interactions with unpolarized host cells or the highly prismatic epithelium provided by the intestinal tissue model. Elucidating the role of several previously uncharacterized factors specifically important for efficient colonization of a 3D human environment, promises to be an intriguing task for future research. At the frontline of the defense against invading pathogens is the protective, viscoelastic mucus layer overlying mucosal surfaces along the human gastrointestinal tract (GIT). The development of a mucus-producing 3D tissue model in this thesis was a vital step towards gaining a deeper understanding of the interdependency between bacterial pathogens and host-site specific mucins. The presence of a mucus layer conferred C. jejuni wildtype-specific protection against epithelial barrier disruption by the pathogen and prevented a high bacterial burden during the course of infection. Moreover, results obtained in this thesis provide evidence in vitro that the characteristic corkscrew morphology of C. jejuni indeed grants a distinct advantage in colonizing mucous surfaces. Overall, the results obtained within this thesis highlight the strength of the tissue models to combine crucial features of native human intestine into accessible in-vitro infection models. Translation of these systems into infection research demonstrated their ability to expose in-vivo like infection outcomes. While displaying complex organotypic architecture and highly prismatic cellular morphology, these tissue models still represent an imperfect reflection of human tissue. Future advancements towards inclusion of human primary and immune cells will strive for even more comprehensive model systems exhibiting intricate multicellular networks of in-vivo tissue. Nevertheless, the work presented in this thesis emphasizes the necessity to investigate host-pathogen interactions in infection models authentically mimicking the natural host environment, as they remain among the most vital parts in understanding and counteracting infectious diseases.},
  subject      = {Campylobacter jejuni},
  language  = {en}
}
@phdthesis{Amatobi2022,
  author    = {Amatobi, Kelechi Michael},
  title     = {Circadian clocks determine transport and membrane lipid oscillation in \(Drosophila\) hemolymph in complex interactions between nutrient-type, photic conditions and feeding behaviour},
  doi       = {10.25972/OPUS-24446},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244462},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {The interaction between circadian clocks and metabolism is of increasing interest, since clock dysfunction often correlates with metabolic pathologies. Many research articles have been published analysing the impact of factors such as circadian clock, light, feeding time and diet-type on energy homeostasis in various tissues/organs of organisms with most of the findings done in mammals. Little is known about the impact of circadian clock and the above-mentioned factors on circulating lipids, especially the transport form of lipids - diacylglycerol (DG) and membrane lipids such as phosphatidylethanolamine (PE) and phosphatidylcholine (PC) in the Drosophila hemolymph. The fruit fly Drosophila is a prime model organism in circadian, behaviour and metabolism research. To study the role of circadian clock and behaviour in metabolism, we performed an extensive comparative hemolymph lipid (diacylglycerol: DG, phosphatidylethanolamine: PE, phosphatidylcholine: PC) analysis using ultra performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-MS) between wild-type flies (WTCS) and clock disrupted mutants (per01). In addition, clock controlled food intake- feeding behaviour was investigated. Time-dependent variation of transport (DG) and membrane lipids (PE and PC) were not rhythmic in WTCS under constant darkness and in per01 under LD, suggesting an impact of light and clock genes on daily lipid oscillations. Day-time and night-time restriction of food led to comparable lipid profiles, suggesting that lipid oscillations are not exclusively entrained by feeding but rather are endogenously regulated. Ultradian oscillations in lipid levels in WTCS under LD were masked by digested fatty acids since lipid levels peaked more robustly at the beginning and end of light phase when flies were fed a lipid- and protein-free diet. These results suggest that metabolite (DG, PE and PC) oscillation is influenced by complex interactions between nutrient-type, photic conditions, circadian clock and feeding time. In conclusion, the results of this thesis suggest that circadian clocks determine transport and membrane lipid oscillation in Drosophila hemolymph in complex interactions between nutrient-type, photic conditions and feeding behaviour.},
  subject      = {Pharmaceutische Biologie},
  language  = {en}
}
@phdthesis{Ames2015,
  author    = {Ames, Christopher},
  title     = {Molecular Beam Epitaxy of 2D and 3D HgTe, a Topological Insulator},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151136},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2015},
  abstract  = {In the present thesis the MBE growth and sample characterization of HgTe structures is investigated and discussed. Due to the first experimental discovery of the quantum Spin Hall effect (QSHE) in HgTe quantum wells, this material system attains a huge interest in the spintronics society. Because of the long history of growing Hg-based heterostructures here at the Experimentelle Physik III in W{\"u}rzburg, there are very good requirements to analyze this material system more precisely and in new directions. Since in former days only doped HgTe quantum wells were grown, this thesis deals with the MBE growth in the (001) direction of undoped HgTe quantum wells, surface located quantum wells and three dimensional bulk layers. All Hg-based layers were grown on CdTe substrates which generate strain in the layer stack and provide therefore new physical effects. In the same time, the (001) CdTe growth was investigated on n-doped (001) GaAs:Si because the Japanese supplier of CdTe substrates had a supply bottleneck due to the Tohoku earthquake and its aftermath in 2011. After a short introduction of the material system, the experimental techniques were demonstrated and explained explicitly. After that, the experimental part of this thesis is displayed. So, the investigation of the (001) CdTe growth on (001) GaAs:Si is discussed in chapter 4. Firstly, the surface preparation of GaAs:Si by oxide desorption is explored and analyzed. Here, rapid thermal desorption of the GaAs oxide with following cool down in Zn atmosphere provides the best results for the CdTe due to small holes at the surface, while e.g. an atomic flat GaAs buffer deteriorates the CdTe growth quality. The following ZnTe layer supplies the (001) growth direction of the CdTe and exhibits best end results of the CdTe for 30 seconds growth time at a flux ratio of Zn/Te ~ 1/1.2. Without this ZnTe layer, CdTe will grow in the (111) direction. However, the main investigation is here the optimization of the MBE growth of CdTe. The substrate temperature, Cd/Te flux ratio and the growth time has to be adjusted systematically. Therefore, a complex growth process is developed and established. This optimized CdTe growth process results in a RMS roughness of around 2.5 nm and a FWHM value of the HRXRD w-scan of 150 arcsec. Compared to the literature, there is no lower FWHM value traceable for this growth direction. Furthermore, etch pit density measurements show that the surface crystallinity is matchable with the commercial CdTe substrates (around 1x10^4 cm^(-2)). However, this whole process is not completely perfect and offers still room for improvements. The growth of undoped HgTe quantum wells was also a new direction in research in contrast to the previous n-doped grown HgTe quantum wells. Here in chapter 5, the goal of very low carrier densities was achieved and therefore it is now possible to do transport experiments in the n - and p - region by tuning the gate voltage. To achieve this high sample quality, very precise growth of symmetric HgTe QWs and their HRXRD characterization is examined. Here, the quantum well thickness can now determined accurate to under 0.3 nm. Furthermore, the transport analysis of different quantum well thicknesses shows that the carrier density and mobility increase with rising HgTe layer thickness. However, it is found out that the band gap of the HgTe QW closes indirectly at a thickness of 11.6 nm. This is caused by the tensile strained growth on CdTe substrates. Moreover, surface quantum wells are studied. These quantum wells exhibit no or a very thin HgCdTe cap. Though, oxidization and contamination of the surface reduces here the carrier mobility immensely and a HgCdTe layer of around 5 nm provides the pleasing results for transport experiments with superconductors connected to the topological insulator [119]. A completely new achievement is the realization of MBE growth of HgTe quantum wells on CdTe/GaAs:Si substrates. This is attended by the optimization of the CdTe growth on GaAs:Si. It exposes that HgTe quantum wells grown in-situ on optimized CdTe/GaAs:Si show very nice transport data with clear Hall plateaus, SdH oscillations, low carrier densities and carrier mobilities up to 500 000 cm^2/Vs. Furthermore, a new oxide etching process is developed and analyzed which should serve as an alternative to the standard HCl process which generates volcano defects at some time. However, during the testing time the result does not differ in Nomarski, HRXRD, AFM and transport measurements. Here, long-time tests or etching and mounting in nitrogen atmosphere may provide new elaborate results. The main focus of this thesis is on the MBE growth and standard characterization of HgTe bulk layers and is discussed in chapter 6. Due to the tensile strained growth on lattice mismatched CdTe, HgTe bulk opens up a band gap of around 22 meV at the G-point and exhibits therefore its topological surface states. The analysis of surface condition, roughness, crystalline quality, carrier density and mobility via Nomarski, AFM, XPS, HRXRD and transport measurements is therefore included in this work. Layer thickness dependence of carrier density and mobility is identified for bulk layer grown directly on CdTe substrates. So, there is no clear correlation visible between HgTe layer thickness and carrier density or mobility. So, the carrier density is almost constant around 1x10^11 cm^(-2) at 0 V gate voltage. The carrier mobility of these bulk samples however scatters between 5 000 and 60 000 cm^2/Vs almost randomly. Further experiments should be made for a clearer understanding and therefore the avoidance of unusable bad samples.But, other topological insulator materials show much higher carrier densities and lower mobility values. For example, Bi2Se3 exhibits just density values around 1019 cm^(-2) and mobility values clearly below 5000 cm2/Vs. The carrier density however depends much on lithography and surface treatment after growth. Furthermore, the relaxation behavior and critical thickness of HgTe grown on CdTe is determined and is in very good agreement with theoretical prediction (d_c = 155 nm). The embedding of the HgTe bulk layer between HgCdTe layers created a further huge improvement. Similar to the quantum well structures the carrier mobility increases immensely while the carrier density levels at around 1x10^11 cm^(-2) at 0 V gate voltage as well. Additionally, the relaxation behavior and critical thickness of these barrier layers has to be determined. HgCdTe grown on commercial CdTe shows a behavior as predicted except the critical thickness which is slightly higher than expected (d_c = 850 nm). Otherwise, the relaxation of HgCdTe grown on CdTe/GaAs:Si occurs in two parts. The layer is fully strained up to 250 nm. Between 250 nm and 725 nm the HgCdTe film starts to relax randomly up to 10 \%. The relaxation behavior for thicknesses larger than 725 nm occurs than linearly to the inverse layer thickness. A explanation is given due to rough interface conditions and crystalline defects of the CdTe/GaAs:Si compared to the commercial CdTe substrate. HRXRD and AFM data support this statement. Another point is that the HgCdTe barriers protect the active HgTe layer and because of the high carrier mobilities the Hall measurements provide new transport data which have to be interpreted more in detail in the future. In addition, HgTe bulk samples show very interesting transport data by gating the sample from the top and the back. It is now possible to manipulate the carrier densities of the top and bottom surface states almost separately. The back gate consisting of the n-doped GaAs substrate and the thick insulating CdTe buffer can tune the carrier density for Delta(n) ~ 3x10^11 cm^(-2). This is sufficient to tune the Fermi energy from the p-type into the n-type region [138]. In this thesis it is shown that strained HgTe bulk layers exhibit superior transport data by embedding between HgCdTe barrier layers. The n-doped GaAs can here serve as a back gate. Furthermore, MBE growth of high crystalline, undoped HgTe quantum wells shows also new and extended transport output. Finally, it is notable that due to the investigated CdTe growth on GaAs the Hg-based heterostructure MBE growth is partially independent from commercial suppliers.},
  subject      = {Quecksilbertellurid},
  language  = {en}
}