@article{AbdaKrysciakKrohnMoltetal.2015, author = {Abda, Ebrahim M. and Krysciak, Dagmar and Krohn-Molt, Ines and Mamat, Uwe and Schmeisser, Christel and F{\"o}rstner, Konrad U. and Schaible, Ulrich E. and Kohi, Thomas A. and Nieman, Stefan and Streit, Wolfgang R.}, title = {Phenotypic Heterogeneity Affects Stenotrophomonas maltophilia K279a Colony Morphotypes and \(\beta\)-Lactamase Expression}, series = {Frontiers in Microbiology}, volume = {6}, journal = {Frontiers in Microbiology}, number = {1373}, doi = {10.3389/fmicb.2015.01373}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-136446}, year = {2015}, abstract = {Phenotypic heterogeneity at the cellular level in response to various stresses, e.g., antibiotic treatment has been reported for a number of bacteria. In a clonal population, cell-to-cell variation may result in phenotypic heterogeneity that is a mechanism to survive changing environments including antibiotic therapy. Stenotrophomonas rnaltophilia has been frequently isolated from cystic fibrosis patients, can cause numerous infections in other organs and tissues, and is difficult to treat due to antibiotic resistances. S. maltophilia K279a produces the Li and L2 beta-lactamases in response to beta-lactam treatment. Here we report that the patient isolate S. rnaltophilia K279a diverges into cellular subpopulations with distinct but reversible morphotypes of small and big colonies when challenged with ampicillin. This observation is consistent with the formation of elongated chains of bacteria during exponential growth phase and the occurrence of mainly rod-shaped cells in liquid media. RNA-seq analysis of small versus big colonies revealed differential regulation of at least seven genes among the colony morphotypes. Among those, bleu and bla(L2) were transcriptionally the most strongly upregulated genes. Promoter fusions of b/a(L1) and b/a(L2) genes indicated that expression of both genes is also subject to high levels of phenotypic heterogeneous expression on a single cell level. Additionally, the comE homolog was found to be differentially expressed in homogenously versus heterogeneously bla(L2) expressing cells as identified by RNA(seq) analysis. Overexpression of cornE in S. maltophilia K279a reduced the level of cells that were in a bla(L2)-ON mode to 1\% or lower. Taken together, our data provide strong evidence that S. maltophilia K279a populations develop phenotypic heterogeneity in an ampicillin challenged model. This cellular variability is triggered by regulation networks including b/a(L1), b/a(L2), and comE.}, language = {en} } @article{AdelfingerBesslerCeciletal.2015, author = {Adelfinger, Marion and Bessler, Simon and Cecil, Alexander and Langbein-Laugwitz, Johanna and Frentzen, Alexa and Gentschev, Ivaylo and Szalay, Aladar A.}, title = {Preclinical Testing Oncolytic Vaccinia Virus Strain GLV-5b451 Expressing an Anti-VEGF Single-Chain Antibody for Canine Cancer Therapy}, series = {Viruses}, volume = {7}, journal = {Viruses}, doi = {10.3390/v7072811}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125705}, pages = {4075-4092}, year = {2015}, abstract = {Virotherapy on the basis of oncolytic vaccinia virus (VACV) strains is a novel approach for canine cancer therapy. Here we describe, for the first time, the characterization and the use of VACV strain GLV-5b451 expressing the anti-vascular endothelial growth factor (VEGF) single-chain antibody (scAb) GLAF-2 as therapeutic agent against different canine cancers. Cell culture data demonstrated that GLV-5b451 efficiently infected and destroyed all four tested canine cancer cell lines including: mammary carcinoma (MTH52c), mammary adenoma (ZMTH3), prostate carcinoma (CT1258), and soft tissue sarcoma (STSA-1). The GLV-5b451 virus-mediated production of GLAF-2 antibody was observed in all four cancer cell lines. In addition, this antibody specifically recognized canine VEGF. Finally, in canine soft tissue sarcoma (CSTS) xenografted mice, a single systemic administration of GLV-5b451 was found to be safe and led to anti-tumor effects resulting in the significant reduction and substantial long-term inhibition of tumor growth. A CD31-based immuno-staining showed significantly decreased neo-angiogenesis in GLV-5b451-treated tumors compared to the controls. In summary, these findings indicate that GLV-5b451 has potential for use as a therapeutic agent in the treatment of CSTS.}, language = {en} } @article{AdolfiCarreiraJesusetal.2015, author = {Adolfi, Mateus C. and Carreira, Ana C. O. and Jesus, L{\´a}zaro W. O. and Bogerd, Jan and Funes, Rejane M. and Schartl, Manfred and Sogayar, Mari C. and Borella, Maria I.}, title = {Molecular cloning and expression analysis of dmrt1 and sox9 during gonad development and male reproductive cycle in the lambari fish, Astyanax altiparanae}, series = {Reproductive Biology and Endocrinology}, volume = {13}, journal = {Reproductive Biology and Endocrinology}, number = {2}, doi = {10.1186/1477-7827-13-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126486}, year = {2015}, abstract = {Background The dmrt1 and sox9 genes have a well conserved function related to testis formation in vertebrates, and the group of fish presents a great diversity of species and reproductive mechanisms. The lambari fish (Astyanax altiparanae) is an important Neotropical species, where studies on molecular level of sex determination and gonad maturation are scarce. Methods Here, we employed molecular cloning techniques to analyze the cDNA sequences of the dmrt1 and sox9 genes, and describe the expression pattern of those genes during development and the male reproductive cycle by qRT-PCR, and related to histology of the gonad. Results Phylogenetic analyses of predicted amino acid sequences of dmrt1 and sox9 clustered A. altiparanae in the Ostariophysi group, which is consistent with the morphological phylogeny of this species. Studies of the gonad development revealed that ovary formation occurred at 58 days after hatching (dah), 2 weeks earlier than testis formation. Expression studies of sox9 and dmrt1 in different tissues of adult males and females and during development revealed specific expression in the testis, indicating that both genes also have a male-specific role in the adult. During the period of gonad sex differentiation, dmrt1 seems to have a more significant role than sox9. During the male reproductive cycle dmrt1 and sox9 are down-regulated after spermiation, indicating a role of these genes in spermatogenesis. Conclusions For the first time the dmrt1 and sox9 were cloned in a Characiformes species. We show that both genes have a conserved structure and expression, evidencing their role in sex determination, sex differentiation and the male reproductive cycle in A. altiparanae. These findings contribute to a better understanding of the molecular mechanisms of sex determination and differentiation in fish.}, language = {en} } @article{AfonsoGrunzHoffmeierMuelleretal.2015, author = {Afonso-Grunz, Fabian and Hoffmeier, Klaus and M{\"u}ller, S{\"o}ren and Westermann, Alexander J. and Rotter, Bj{\"o}rn and Vogel, J{\"o}rg and Winter, Peter and Kahl, G{\"u}nter}, title = {Dual 3'Seq using deepSuperSAGE uncovers transcriptomes of interacting Salmonella enterica Typhimurium and human host cells}, series = {BMC Genomics}, volume = {16}, journal = {BMC Genomics}, number = {323}, doi = {10.1186/s12864-015-1489-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143230}, year = {2015}, abstract = {Background: The interaction of eukaryotic host and prokaryotic pathogen cells is linked to specific changes in the cellular proteome, and consequently to infection-related gene expression patterns of the involved cells. To simultaneously assess the transcriptomes of both organisms during their interaction we developed dual 3'Seq, a tag-based sequencing protocol that allows for exact quantification of differentially expressed transcripts in interacting pro-and eukaryotic cells without prior fixation or physical disruption of the interaction. Results: Human epithelial cells were infected with Salmonella enterica Typhimurium as a model system for invasion of the intestinal epithelium, and the transcriptional response of the infected host cells together with the differential expression of invading and intracellular pathogen cells was determined by dual 3'Seq coupled with the next-generation sequencing-based transcriptome profiling technique deepSuperSAGE (deep Serial Analysis of Gene Expression). Annotation to reference transcriptomes comprising the operon structure of the employed S. enterica Typhimurium strain allowed for in silico separation of the interacting cells including quantification of polycistronic RNAs. Eighty-nine percent of the known loci are found to be transcribed in prokaryotic cells prior or subsequent to infection of the host, while 75\% of all protein-coding loci are represented in the polyadenylated transcriptomes of human host cells. Conclusions: Dual 3'Seq was alternatively coupled to MACE (Massive Analysis of cDNA ends) to assess the advantages and drawbacks of a library preparation procedure that allows for sequencing of longer fragments. Additionally, the identified expression patterns of both organisms were validated by qRT-PCR using three independent biological replicates, which confirmed that RELB along with NFKB1 and NFKB2 are involved in the initial immune response of epithelial cells after infection with S. enterica Typhimurium.}, language = {en} } @article{AlavipanahWegmannQureshietal.2015, author = {Alavipanah, Sadroddin and Wegmann, Martin and Qureshi, Salman and Weng, Qihao and Koellner, Thomas}, title = {The role of vegetation in mitigating urban land surface temperatures: a case study of Munich, Germany during the warm season}, series = {Sustainability}, volume = {7}, journal = {Sustainability}, doi = {10.3390/su7044689}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143447}, pages = {4689-4706}, year = {2015}, abstract = {The Urban Heat Island (UHI) is the phenomenon of altered increased temperatures in urban areas compared to their rural surroundings. UHIs grow and intensify under extreme hot periods, such as during heat waves, which can affect human health and also increase the demand for energy for cooling. This study applies remote sensing and land use/land cover (LULC) data to assess the cooling effect of varying urban vegetation cover, especially during extreme warm periods, in the city of Munich, Germany. To compute the relationship between Land Surface Temperature (LST) and Land Use Land Cover (LULC), MODIS eight-day interval LST data for the months of June, July and August from 2002 to 2012 and the Corine Land Cover (CLC) database were used. Due to similarities in the behavior of surface temperature of different CLCs, some classes were reclassified and combined to form two major, rather simplified, homogenized classes: one of built-up area and one of urban vegetation. The homogenized map was merged with the MODIS eight-day interval LST data to compute the relationship between them. The results revealed that (i) the cooling effect accrued from urban vegetation tended to be non-linear; and (ii) a remarkable and stronger cooling effect in terms of LST was identified in regions where the proportion of vegetation cover was between seventy and almost eighty percent per square kilometer. The results also demonstrated that LST within urban vegetation was affected by the temperature of the surrounding built-up and that during the well-known European 2003 heat wave, suburb areas were cooler from the core of the urbanized region. This study concluded that the optimum green space for obtaining the lowest temperature is a non-linear trend. This could support urban planning strategies to facilitate appropriate applications to mitigate heat-stress in urban area.}, language = {en} } @inproceedings{AliMontenegro2015, author = {Ali, Qasim and Montenegro, Sergio}, title = {A Simple Approach to Quadrocopter Formation Flying Test Setup for Education and Development}, series = {INTED2015 Proceedings}, booktitle = {INTED2015 Proceedings}, publisher = {International Academy of Technology, Education and Development (IATED)}, isbn = {978-84-606-5763-7}, issn = {2340-1079}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114495}, pages = {2776 -- 2784}, year = {2015}, abstract = {A simple test setup has been developed at Institute of Aerospace Information Technology, University of W{\"u}rzburg, Germany to realize basic functionalities for formation flight of quadrocopters. The test environment is planned to be utilized for developing and validating the algorithms for formation flying capability in real environment as well as for education purpose. An already existing test bed for single quadrocopter was extended with necessary inter-communication and distributed control mechanism to test the algorithms for formation flights in 2 degrees of freedom (roll / pitch). This study encompasses the domain of communication, control engineering and embedded systems programming. Bluetooth protocol has been used for inter-communication between two quadrocopters. A simple approach of PID control in combination with Kalman filter has been exploited. MATLAB Instrument Control Toolbox has been used for data display, plotting and analysis. Plots can be drawn in real-time and received information can also be stored in the form of files for later use and analysis. The test setup has been developed indigenously and at considerably low cost. Emphasis has been placed on simplicity to facilitate students learning process. Several lessons have been learnt during the course of development of this setup. Proposed setup is quite flexible that can be modified as per changing requirements.}, subject = {Flugk{\"o}rper}, language = {en} } @article{AlizadehradKruegerEngstleretal.2015, author = {Alizadehrad, Davod and Kr{\"u}ger, Timothy and Engstler, Markus and Stark, Holger}, title = {Simulating the complex cell design of Trypanosoma brucei and its motility}, series = {PLOS Computational Biology}, volume = {11}, journal = {PLOS Computational Biology}, number = {1}, doi = {10.1371/journal.pcbi.1003967}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144610}, pages = {e1003967}, year = {2015}, abstract = {The flagellate Trypanosoma brucei, which causes the sleeping sickness when infecting a mammalian host, goes through an intricate life cycle. It has a rather complex propulsion mechanism and swims in diverse microenvironments. These continuously exert selective pressure, to which the trypanosome adjusts with its architecture and behavior. As a result, the trypanosome assumes a diversity of complex morphotypes during its life cycle. However, although cell biology has detailed form and function of most of them, experimental data on the dynamic behavior and development of most morphotypes is lacking. Here we show that simulation science can predict intermediate cell designs by conducting specific and controlled modifications of an accurate, nature-inspired cell model, which we developed using information from live cell analyses. The cell models account for several important characteristics of the real trypanosomal morphotypes, such as the geometry and elastic properties of the cell body, and their swimming mechanism using an eukaryotic flagellum. We introduce an elastic network model for the cell body, including bending rigidity and simulate swimming in a fluid environment, using the mesoscale simulation technique called multi-particle collision dynamics. The in silico trypanosome of the bloodstream form displays the characteristic in vivo rotational and translational motility pattern that is crucial for survival and virulence in the vertebrate host. Moreover, our model accurately simulates the trypanosome's tumbling and backward motion. We show that the distinctive course of the attached flagellum around the cell body is one important aspect to produce the observed swimming behavior in a viscous fluid, and also required to reach the maximal swimming velocity. Changing details of the flagellar attachment generates less efficient swimmers. We also simulate different morphotypes that occur during the parasite's development in the tsetse fly, and predict a flagellar course we have not been able to measure in experiments so far.}, language = {en} } @misc{Altenburger2015, author = {Altenburger, Roland}, title = {Cao, Juan: In der Sackgasse oder auf dem Weg zu einem neuen Paradigma? Die Erforschung des Romans Der Traum der roten Kammer (Rotologie) im 21. Jahrhundert (Lun Wen: Studien zur Geistesgeschichte und Literatur in China; 17). Wiesbaden: Harrassowitz Verlag, 2013. XII, 256 S. ISBN 978-3-447-06992-2}, series = {Asiatische Studien - {\´E}tudes Asiatiques}, volume = {69}, journal = {Asiatische Studien - {\´E}tudes Asiatiques}, number = {1}, issn = {0004-4717}, doi = {10.1515/asia-2015-0013}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193941}, pages = {255-261}, year = {2015}, abstract = {No abstract available.}, language = {de} } @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} } @article{AmmarThahoulyHanaueretal.2015, author = {Ammar, Mohamed Raafet and Thahouly, Tamou and Hanauer, Andr{\´e} and Stegner, David and Nieswandt, Bernhard and Vitale, Nicolas}, title = {PLD1 participates in BDNF-induced signalling in cortical neurons}, series = {Scientific Reports}, volume = {5}, journal = {Scientific Reports}, number = {14778}, doi = {10.1038/srep14778}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-139962}, year = {2015}, abstract = {The brain-derived neurotrophic factor BDNF plays a critical role in neuronal development and the induction of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms underlying these BDNF effects have not been firmly established. Using in vitro cultures of cortical neurons from knockout mice for Pld1 and Rsk2, BDNF was observed to induce a rapid RSK2-dependent activation of PLD and to stimulate BDNF ERK1/2-CREB and mTor-S6K signalling pathways, but these effects were greatly reduced in Pld1\(^{-/-}\) neurons. Furthermore, phospho-CREB did not accumulate in the nucleus, whereas overexpression of PLD1 amplified the BDNF-dependent nuclear recruitment of phospho-ERK1/2 and phospho-CREB. This BDNF retrograde signalling was prevented in cells silenced for the scaffolding protein PEA15, a protein which complexes with PLD1, ERK1/2, and RSK2 after BDNF treatment. Finally PLD1, ERK1/2, and RSK2 partially colocalized on endosomal structures, suggesting that these proteins are part of the molecular module responsible for BDNF signalling in cortical neurons.}, language = {en} } @article{AndersenBogstedDybkaretal.2015, author = {Andersen, Jens Peter and B{\o}gsted, Martin and Dybk{\ae}r, Karen and Mellqvist, Ulf-Henrik and Morgan, Gareth J. and Goldschmidt, Hartmut and Dimopoulos, Meletios A. and Einsele, Hermann and San Miguel, Jes{\´u}s and Palumbo, Antonio and Sonneveld, Pieter and Johnsen, Hans Erik}, title = {Global myeloma research clusters, output, and citations: a bibliometric mapping and clustering analysis}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0116966}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144214}, pages = {e0116966}, year = {2015}, abstract = {Background International collaborative research is a mechanism for improving the development of disease-specific therapies and for improving health at the population level. However, limited data are available to assess the trends in research output related to orphan diseases. Methods and Findings We used bibliometric mapping and clustering methods to illustrate the level of fragmentation in myeloma research and the development of collaborative efforts. Publication data from Thomson Reuters Web of Science were retrieved for 2005-2009 and followed until 2013. We created a database of multiple myeloma publications, and we analysed impact and co-authorship density to identify scientific collaborations, developments, and international key players over time. The global annual publication volume for studies on multiple myeloma increased from 1,144 in 2005 to 1,628 in 2009, which represents a 43\% increase. This increase is high compared to the 24\% and 14\% increases observed for lymphoma and leukaemia. The major proportion (> 90\% of publications) was from the US and EU over the study period. The output and impact in terms of citations, identified several successful groups with a large number of intra-cluster collaborations in the US and EU. The US-based myeloma clusters clearly stand out as the most productive and highly cited, and the European Myeloma Network members exhibited a doubling of collaborative publications from 2005 to 2009, still increasing up to 2013. Conclusion and Perspective Multiple myeloma research output has increased substantially in the past decade. The fragmented European myeloma research activities based on national or regional groups are progressing, but they require a broad range of targeted research investments to improve multiple myeloma health care.}, language = {en} } @article{AndreattaPauli2015, author = {Andreatta, Marta and Pauli, Paul}, title = {Appetitive vs. aversive conditioning in humans}, series = {Frontiers in Behavioral Neuroscience}, volume = {9}, journal = {Frontiers in Behavioral Neuroscience}, number = {128}, doi = {10.3389/fnbeh.2015.00128}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148614}, year = {2015}, abstract = {In classical conditioning, an initially neutral stimulus (conditioned stimulus, CS) becomes associated with a biologically salient event (unconditioned stimulus, US), which might be pain (aversive conditioning) or food (appetitive conditioning). After a few associations, the CS is able to initiate either defensive or consummatory responses, respectively. Contrary to aversive conditioning, appetitive conditioning is rarely investigated in humans, although its importance for normal and pathological behaviors (e.g., obesity, addiction) is undeniable. The present study intents to translate animal findings on appetitive conditioning to humans using food as an US. Thirty-three participants were investigated between 8 and 10 am without breakfast in order to assure that they felt hungry. During two acquisition phases, one geometrical shape (avCS+) predicted an aversive US (painful electric shock), another shape (appCS+) predicted an appetitive US (chocolate or salty pretzel according to the participants' preference), and a third shape (CS) predicted neither US. In a extinction phase, these three shapes plus a novel shape (NEW) were presented again without US delivery. Valence and arousal ratings as well as startle and skin conductance (SCR) responses were collected as learning indices. We found successful aversive and appetitive conditioning. On the one hand, the avCS+ was rated as more negative and more arousing than the CS and induced startle potentiation and enhanced SCR. On the other hand, the appCS+ was rated more positive than the CS and induced startle attenuation and larger SCR. In summary, we successfully confirmed animal findings in (hungry) humans by demonstrating appetitive learning and normal aversive learning.}, language = {en} } @article{AndronicShirakashiPickeletal.2015, author = {Andronic, Joseph and Shirakashi, Ryo and Pickel, Simone U. and Westerling, Katherine M. and Klein, Teresa and Holm, Thorge and Sauer, Markus and Sukhorukov, Vladimir L.}, title = {Hypotonic Activation of the Myo-Inositol Transporter SLC5A3 in HEK293 Cells Probed by Cell Volumetry, Confocal and Super-Resolution Microscopy}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {3}, doi = {10.1371/journal.pone.0119990}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126408}, year = {2015}, abstract = {Swelling-activated pathways for myo-inositol, one of the most abundant organic osmolytes in mammalian cells, have not yet been identified. The present study explores the SLC5A3 protein as a possible transporter of myo-inositol in hyponically swollen HEK293 cells. To address this issue, we examined the relationship between the hypotonicity-induced changes in plasma membrane permeability to myo-inositol Pino [m/s] and expression/localization of SLC5A3. Pino values were determined by cell volumetry over a wide tonicity range (100-275 mOsm) in myo-inositol-substituted solutions. While being negligible under mild hypotonicity (200-275 mOsm), Pino grew rapidly at osmolalities below 200 mOsm to reach a maximum of ∼3 nm/s at 100-125 mOsm, as indicated by fast cell swelling due to myo-inositol influx. The increase in Pino resulted most likely from the hypotonicity-mediated incorporation of cytosolic SLC5A3 into the plasma membrane, as revealed by confocal fluorescence microscopy of cells expressing EGFP-tagged SLC5A3 and super-resolution imaging of immunostained SLC5A3 by direct stochastic optical reconstruction microscopy (dSTORM). dSTORM in hypotonic cells revealed a surface density of membrane-associated SLC5A3 proteins of 200-2000 localizations/μm2. Assuming SLC5A3 to be the major path for myo-inositol, a turnover rate of 80-800 myo-inositol molecules per second for a single transporter protein was estimated from combined volumetric and dSTORM data. Hypotonic stress also caused a significant upregulation of SLC5A3 gene expression as detected by semiquantitative RT-PCR and Western blot analysis. In summary, our data provide first evidence for swelling-mediated activation of SLC5A3 thus suggesting a functional role of this transporter in hypotonic volume regulation of mammalian cells.}, language = {en} } @phdthesis{AnjanaVaman2015, author = {Anjana Vaman, Vamadevan Sujatha}, title = {LASP1, a newly identified melanocytic protein with a possible role in melanin release, but not in melanoma progression}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116316}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {LIM and SH3 protein 1 (LASP1) is a nucleocytoplasmic scaffolding protein. LASP1 interacts with various cytoskeletal proteins via its domain structure and is known to participate in physiological processes of cells. In the present study, a detailed investigation of the expression pattern of LASP1 protein in normal skin, melanocytic nevi and melanoma was carried out and the melanocyte-specific function of LASP1 was analyzed. LASP1 protein was identified in stratum basale of skin epidermis and a very high level was detected in nevi, the benign tumor of melanocyte. In the highly proliferative basal cells, an additional distinct nuclear localization of the protein was noted. In different tumor entities, an elevated LASP1 expression and nuclear localization, correlated positively with malignancy and tumor grade. However, LASP1 level was determined to be very low in melanoma and even reduced in metastases. Melanoma is distinguished as the first tumor tested to date - that displayed an absence of elevated LASP1 expression. In addition no significant relation was observed between LASP1 protein expression and clinicopathological parameters in melanoma. The epidermal melanin unit of skin comprises of melanocytes and keratinocytes. Melanocytes are specialized cells that synthesize the photo protective coloring pigment, melanin inside unique organelles called melanosomes. The presence of LASP1 in melanocytes is reported for the first time through this study and the existence was confirmed by immunoblotting analysis in cultured normal human epidermal melanocyte (NHEM) and in melanoma cell lines, along with the immunohistostaining imaging in normal skin and in melanocytic nevi. LASP1 depletion in MaMel2 cells revealed a moderate increase in the intracellular melanin level independently of de novo melanogenesis, pointing to a partial hindrance in melanin release. Immunofluorescence images of NHEM and MaMel2 cells visualized co-localization of LASP1 with dynamin and tyrosinase concomitant with melanosomes at the dendrite tips of the cells. Melanosome isolation experiments by sucrose density gradient centrifugation clearly demonstrated the presence of LASP1 and the melanosome specific markers tyrosinase and TRP1 in late stage melanosomes. The study identified LASP1 and dynamin as novel binding partners in melanocytes and provides first evidence for the existence of LASP1 and dynamin (a protein well-known for its involvement in vesicle formation and budding) in melanosomes. Co-localization of LASP1 and dynamin along the dendrites and at the tips of the melanocytes indicates a potential participation of the two proteins in the membrane vesicle fission at the plasma membrane. In summary, a possible involvement of LASP1 in the actin-dynamin mediated membrane fission and exocytosis of melanin laden melanosome vesicles into the extracellular matrix is suggested.}, subject = {Melanom}, language = {en} } @phdthesis{Ansorg2015, author = {Ansorg, Kay}, title = {Development of Accurate Physically Grounded Force Fields for Intermolecular Cation-\$\pi\$ Interactions based on SAPT Energy Decomposition Analysis and Computational Investigation of Covalent Irreversible Vinyl Sulfone-based Protease Inhibitors}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131084}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Part 1 of this work describes the development of accurate physically grounded force fields for intermolecular Cation-π interactions based on SAPT energy decomposition analysis. The presented results demonstrate the benefits of the used DFT-SAPT method to describe non-bonding interactions. First of all, this method is able to reproduce the high level CCSD(T) energy values but using much less computational time. Second it provides the possibility to separate the total intermolecular interaction energy into several physically meaningful contributions. The relative contributions of the dimers investigated can be seen in Fig. 6.16. In Tab. 6.3 the percentage contribution of the attractive energy parts to the stabilization energy is shown. The polarization energy is important for the NH+...C6H6 interaction, whereas it becomes less crucial considering other dimers. The dispersion energy contribution is large in the case of the C6H6...H2O dimers, whereas it is relatively less important for the NH+...C6H6 interaction. The electrostatic energy contributes a large amount of stabilizing energy in all considered dimer interactions. ...}, subject = {Kraftfeld}, language = {en} } @article{AppelScholzMuelleretal.2015, author = {Appel, Mirjam and Scholz, Claus-J{\"u}rgen and M{\"u}ller, Tobias and Dittrich, Marcus and K{\"o}nig, Christian and Bockstaller, Marie and Oguz, Tuba and Khalili, Afshin and Antwi-Adjei, Emmanuel and Schauer, Tamas and Margulies, Carla and Tanimoto, Hiromu and Yarali, Ayse}, title = {Genome-Wide Association Analyses Point to Candidate Genes for Electric Shock Avoidance in Drosophila melanogaster}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0126986}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-152006}, pages = {e0126986}, year = {2015}, abstract = {Electric shock is a common stimulus for nociception-research and the most widely used reinforcement in aversive associative learning experiments. Yet, nothing is known about the mechanisms it recruits at the periphery. To help fill this gap, we undertook a genome-wide association analysis using 38 inbred Drosophila melanogaster strains, which avoided shock to varying extents. We identified 514 genes whose expression levels and/or sequences covaried with shock avoidance scores. We independently scrutinized 14 of these genes using mutants, validating the effect of 7 of them on shock avoidance. This emphasizes the value of our candidate gene list as a guide for follow-up research. In addition, by integrating our association results with external protein-protein interaction data we obtained a shock avoidance- associated network of 38 genes. Both this network and the original candidate list contained a substantial number of genes that affect mechanosensory bristles, which are hairlike organs distributed across the fly's body. These results may point to a potential role for mechanosensory bristles in shock sensation. Thus, we not only provide a first list of candidate genes for shock avoidance, but also point to an interesting new hypothesis on nociceptive mechanisms.}, language = {en} } @phdthesis{Appold2015, author = {Appold, Christian}, title = {Symbolische BDD-basierte Modellpr{\"u}fung asynchroner nebenl{\"a}ufiger Systeme}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137029}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Today, information and communication systems are ubiquitous and consist very often of several interacting and communicating components. One reason is the widespread use of multi-core processors and the increasing amount of concurrent software for the efficient usage of multi-core processors. Also, the dissemination of distributed emergent technologies like sensor networks or the internet of things is growing. Additionally, a lot of internet protocols are client-server architectures with clients which execute computations in parallel and servers that can handle requests of several clients in parallel. Systems which consist of several interacting and communicating components are often very complex and due to their complexity also prone to errors. Errors in systems can have dramatic consequenses, especially in safety-critical areas where human life can be endangered by incorrect system behavior. Hence, it is inevitable to have methods that ensure the proper functioning of such systems. This thesis aims on improving the verifiability of asynchronous concurrent systems using symbolic model checking based on Binary Decision Diagrams (BDDs). An asynchronous concurrent system is a system that consists of several components, from which only one component can execute a transition at a time. Model checking is a formal verification technique. For a given system description and a set of desired properties, the validity of the properties for the system is decided in model checking automatically by software tools called model checkers. The main problem of model checking is the state-space explosion problem. One approach to reduce this problem is the use of symbolic model checking. There, system states and transitions are not stored explicitely as in explicit model checking. Instead, in symbolic model checking sets of states and sets of transitions are stored and also manipulated together. The data structure which is used in this thesis to store those sets are BDDs. BDD-based symbolic model checking has already been used successful in industry for several times. Nevertheless, BDD-based symbolic model checking still suffers from the state-space explosion problem and further improvements are necessary to improve its applicability. Central operations in BDD-based symbolic model checking are the computation of successor and predecessor states of a given set of states. Those computations are called image computations. They are applied repeatedly in BDD-based symbolic model checking to decide the validity of properties for a given system description. Hence, their efficient execution is crucial for the memory and runtime requirements of a model checker. In an image computation a BDD for a set of transitions and a BDD for a set of states are combined to compute a set of successor or predecessor states. Often, also the size of the BDDs to represent the transition relation is critical for the successful use of model checking. To further improve the applicability of symbolic model checking, we present in this thesis new data structures to store the transition relation of asynchronous concurrent systems. Additionally, we present new image computation algorithms. Both can lead to large runtime and memory reductions for BDD-based symbolic model checking. Asynchronous concurrent systems often contain symmetries. A technique to exploit those symmetries to diminish the state-space explosion problem is symmetry reduction. In this thesis we also present a new efficient algorithm for symmetry reduction in BDD-based symbolic model checking.}, subject = {Programmverifikation}, language = {de} } @article{ArdeltEbbingAdamsetal.2015, author = {Ardelt, Peter U. and Ebbing, Jan and Adams, Fabian and Reiss, Cora and Arap, Wadih and Pasqualini, Renata and Bachmann, Alexander and Wetterauer, Ulrich and Riedmiller, Hubertus and Kneitz, Burkard}, title = {An anti-ubiquitin antibody response in transitional cell carcinoma of the urinary bladder}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0118646}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143711}, pages = {e0118646}, year = {2015}, abstract = {Background To use combinatorial epitope mapping ("fingerprinting") of the antibody response to identify targets of the humoral immune response in patients with transitional cell carcinoma (TCC) of the bladder. Methods A combinatorial random peptide library was screened on the circulating pool of immunoglobulins purified from an index patient with a high risk TCC (pTa high grade plus carcinoma in situ) to identify corresponding target antigens. A patient cohort was investigated for antibody titers against ubiquitin. Results We selected, isolated, and validated an immunogenic peptide motif from ubiquitin as a dominant epitope of the humoral response. Patients with TCC had significantly higher antibody titers against ubiquitin than healthy donors (p<0.007), prostate cancer patients (p<0.0007), and all patients without TCC taken together (p<0.0001). Titers from superficial tumors were not significantly different from muscle invasive tumors (p = 0.0929). For antibody response against ubiquitin, sensitivity for detection of TCC was 0.44, specificity 0.96, positive predictive value 0.96 and negative predictive value 0.41. No significant titer changes were observed during the standard BCG induction immunotherapy. Conclusions This is the first report to demonstrate an anti-ubiquitin antibody response in patients with TCC. Although sensitivity of antibody production was low, a high specificity and positive predictive value make ubiquitin an interesting candidate for further diagnostic and possibly immune modulating studies.}, language = {en} } @phdthesis{ArjonaEsteban2015, author = {Arjona Esteban, Alhama}, title = {Merocyanine Dyes as Organic Semiconductors for Vacuum-processed Solar Cell and Transistor Devices}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129096}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {The present thesis comprises the synthesis of new functional merocyanine dyes, the study of their electro-optical properties as well as solid state packing and their application as p-type semiconductor materials in transistor and solar cell devices. The absorption properties of the obtained compounds could be modified by variation of the donor unit, the introduction of electron-withdrawing substituents in the acceptor unit or elongation of the polymethine chain. For a particular dye, the absorption band could be shifted by more than 160 nm by increasing the solvent polarity due to a conformational switch between a merocyanine-like and a cyanine-like structure. Single crystal analyses revealed that the studied dyes tend to pack either in an antiparallel fashion forming dimers with no overall dipole moment or in a staircase-like pattern where the dipole moments point to the same direction and are only balanced by another staircase oriented in the opposite direction (stair dimer). With respect to application as semiconductor materials, the latter packing arrangement resulted most favorable for charge carrier mobility. We concluded that this packing motif is preserved in the solar cell devices, where the selenium-containing dye afforded the highest performance of this series for an optimized planar-mixed heterojunction solar cell (6.2 \%).}, subject = {Merocyanine}, language = {en} } @phdthesis{Arnold2015, author = {Arnold, Nicole}, title = {Reaktivit{\"a}t von Boranen gegen{\"u}ber {\"U}bergangsmetall-Lewis-Basen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125447}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Im Rahmen der vorliegenden Arbeit wurden Dihydroborane (H2BR) sowie Dihalogenborane (X2BR) mit {\"U}bergangsmetall-Lewis-Basen umgesetzt und die Reaktivit{\"a}t der auf diese Weise erhaltenen {\"U}bergangsmetall-Bor-Komplexe eingehend untersucht. So wurde eine Serie neuer Borylkomplexe des Typs trans-[Pt{B(Br)R'}Br(PR3)2] dargestellt und mit Salzen schwach-koordinierender Anionen umgesetzt. Diese Studien sollten die Triebkraft f{\"u}r die Bildung kationischer Borylenkomplexe n{\"a}her beleuchten. Die experimentellen Ergebnisse zeigen, dass eine Substitution in ortho-Position des borgebundenen Arylliganden f{\"u}r den notwendigen [1,2]-Halogenshift vom Bor- zum Platinzentrum und somit zur Realisierung einer Pt=B-Mehrfachbindung unabdingbar ist. Demnach reagieren Komplexe mit para-substituierten Arylliganden bei Halogenidabstraktion aus Borylkomplexen zu T-f{\"o}rmigen, kationischen Borylplatinkomplexen, w{\"a}hrend die Duryl-substituierten Analoga unter [1,2]-Halogenwanderung in kationische Borylenplatinkomplexe {\"u}berf{\"u}hrt werden. Neben dem Substitutionsmuster des borgebundenen Arylliganden wurde auch der Einfluss des Phosphanliganden untersucht. Die Molek{\"u}lstrukturen der Borylkomplexe 2 und 4 im Festk{\"o}rper zeigen grundlegende Unterschiede im strukturellen Aufbau. Der Durylsubstituent ist in 2 im Vergleich zur (Ph-4-tBu)-Einheit in 4 deutlich aus der {Br2-Pt-B-Br1}-Ebene herausgedreht (2: Pt-B-C1-C2: 31.4(1); 4: 4.3(7)°), was vermutlich einen [1,2]-Halogenshift in 2 beg{\"u}nstigt. Die Pt-B-Bindungen der kationischen Borylenkomplexe 6 (1.861(5) {\AA}) und 7 (1.863(5) {\AA}) sind deutlich k{\"u}rzer als im neutralen Borylkomplex 2 (2.004(4) {\AA}), was ein eindeutiger Beleg f{\"u}r den Mehrfachbindungscharakter der Pt-B-Bindungen in 6 und 7 ist. Demzufolge scheint der sterische Anspruch des borgebundene Arylsubstituenten entscheidend f{\"u}r den Reaktionspfad bei Halogenidabstraktionen und somit f{\"u}r die Bildung kationischer Borylenplatinkomplexe zu sein, w{\"a}hrend diesen Studien zu Folge der Einfluss der Ligandensph{\"a}re am Platinzentrum eher eine untergeordnete Rolle spielt. Des Weiteren gelang die Synthese der neuartigen heteroleptischen Platinkomplexe [Pt(cAACMe)(PiPr3)] (13) und [Pt(cAACMe)(PCy3)] (14) durch Umsetzung von [Pt(PCy3)2] und [Pt(PiPr3)2] mit dem cyclischen (Alkyl)(Amino)Carben cAACMe (Schema 34, A), bzw. durch Umsetzung von [Pt(nbe)2(PCy3)] (Schema 34, B) mit cAACMe. Die Darstellung des literaturbekannten homoleptischen Komplexes [Pt(cAACMe)2] (11) konnte durch Reaktion von [Pt(nbe)3] mit cAACMe deutlich vereinfacht werden bei gleichzeitiger Steigerung der Ausbeute (96\%, Literatur: 79\%). Die ungew{\"o}hnlich intensiv orangene Farbe dieser Verbindungsklasse geht laut DFT-Rechnungen auf die elektronische Anregung aus dem HOMO in das LUMO zur{\"u}ck, wobei haupts{\"a}chlich die π-Wechselwirkungen zwischen den Platin- und Carbenkohlenstoffatomen des cAACMe-Liganden beteiligt sind (DFT-Rechnungen von Dr. Mehmet Ali Celik). Auch in ihren strukturellen Eigenschaften sind sich 11 - 14 sehr {\"a}hnlich, wohingegen deutliche Unterschiede in deren Elektrochemie und Reaktivit{\"a}t beobachtet wurden. So konnte f{\"u}r 11 eine quasi-reversible Oxidationswelle (E1/2 = -0.30 V gegen [Cp2Fe]/[Cp2Fe]+ in THF) bestimmt werden, w{\"a}hrend die heteroleptischen Komplexe 13 und 14 (Epa = -0.09 V; -0.11 V) sowie deren Vorl{\"a}ufer [Pt(PCy3)2] und [Pt(PiPr3)2] (Epa = 0.00 V; +0.12 V) irreversible Oxidationswellen zeigen. Demnach kann 13 und 14 im Vergleich zu [Pt(PCy3)2] und [Pt(PiPr3)2] ein gr{\"o}ßeres Reduktionsverm{\"o}gen zugeordnet werden. Reaktivit{\"a}tsstudien zeigen, dass der homoleptische Komplex 11 inert gegen{\"u}ber vielen Substraten wie z.B. Boranen, Diboranen(4) und Lewis-S{\"a}uren ist. Im Gegensatz dazu haben sich die heteroleptischen Komplexe 13 und 14 als deutlich reaktiver erwiesen, womit diese eine Mittelstellung zwischen 11 und der Spezies [Pt(PR3)2] einnimmt. Die Umsetzung von [Pt(cAACMe)(PiPr3)] (13) mit BBr3 und Br2BPh lieferte die Borylkomplexe 18 und 19, welche vollst{\"a}ndig charakterisiert wurden. Die Reaktivit{\"a}t von 13 und 14 gegen{\"u}ber den Lewis-S{\"a}uren GaCl3 und HgCl2 zeigt ebenfalls Analogien zu der von Bis(phosphan)platinkomplexen. Reaktion mit GaCl3 f{\"u}hrte hierbei zur Bildung der MOLP-Komplexe [(cAACMe)(PiPr3)Pt→GaCl3] (21) und [(cAACMe)(PCy3)Pt→GaCl3] (22), w{\"a}hrend die oxidative Addition der Hg-Cl-Bindung an das Platinzentrum von 14 im Komplex [PtCl(HgCl)(cAACMe)(PiPr3)] (23) resultierte. Die Synthese von 23 gelang auch durch Umsetzung mit Kalomel unter Abscheidung eines {\"A}quivalentes elementaren Quecksilbers. Ein weiterer Schwerpunkt dieser Arbeit lag auf der {\"U}bergangsmetall-vermittelten Dehydrokupplung von Dihydroboranen. Die Umsetzung von [Pt(cAACMe)(PiPr3)] (13) mit BBr3 und Br2BPh lieferte die Borylkomplexe 18 und 19, welche vollst{\"a}ndig charakterisiert wurden. Die Reaktivit{\"a}t von 13 und 14 gegen{\"u}ber den Lewis-S{\"a}uren GaCl3 und HgCl2 zeigt ebenfalls Analogien zu der von Bis(phosphan)platinkomplexen. Reaktion mit GaCl3 f{\"u}hrte hierbei zur Bildung der MOLP-Komplexe [(cAACMe)(PiPr3)Pt→GaCl3] (21) und [(cAACMe)(PCy3)Pt→GaCl3] (22), w{\"a}hrend die oxidative Addition der Hg-Cl-Bindung an das Platinzentrum von 14 im Komplex [PtCl(HgCl)(cAACMe)(PiPr3)] (23) resultierte. Die Synthese von 23 gelang auch durch Umsetzung mit Kalomel unter Abscheidung eines {\"A}quivalentes elementaren Quecksilbers. Ein weiterer Schwerpunkt dieser Arbeit lag auf der {\"U}bergangsmetall-vermittelten Dehydrokupplung von Dihydroboranen. Vor Beginn dieser Reaktivit{\"a}tsstudien wurde zun{\"a}chst eine vereinfachte Syntheseroute f{\"u}r Dihydroborane entwickelt. Durch Umsetzung von Cl2BDur mit HSiEt3 konnte auf diese Weise der Syntheseaufwand deutlich verringert und die Ausbeute an H2BDur von 74\% auf 98\% deutlich gesteigert werden. Zur Dehydrokupplung wurden neben Gold-, Rhodium- und Iridiumkomplexen auch Platinkomplexe mit H2BDur umgesetzt. Die Untersuchungen mit Gold- und Rhodiumverbindungen erwiesen sich hierbei als erfolglos und die Umsetzung der Iridiumpincerkomplexe [(PCP)IrH2] 26 und 27 (tBuPCP, AdPCP) mit H2BDur lieferte die Boratkomplexe 28 und 29 mit κ2-koordinierten {H2BHDur}-Liganden. Analog konnte bei Umsetzung von 26 mit H2BThx der Boratkomplex 30 spektroskopisch beobachtet, jedoch nicht isoliert werden. Bei den Komplexen 28 - 30 handelt es sich um die ersten κ2-σ:σ-Dihydroboratkomplexe mit sterisch anspruchsvollen Arylsubstituenten. Neben den Iridiumpincerkomplexen wurde auch der Komplex [Cp*IrCl2]2 mit H2BDur umgesetzt. Die Bildung des Boratkomplexes 34 ist mit einem [1,2]-Shift eines Chloratoms von Iridium auf das Borzentrum verbunden. Die Reaktivit{\"a}t von H2BDur gegen{\"u}ber [Pt(PCy3)2] zeigte eine starke Abh{\"a}ngigkeit h{\"a}ngt von der St{\"o}chiometrie. Bei der 1:1-Umsetzung konnten sowohl die farblosen Verbindungen trans-[(PCy3)2PtH2] und Cy3P→BH2Dur (48) isoliert werden, als auch die beiden dunkelroten Verbindungen [(Cy3P)3Pt3(2-B2Dur2)] (36) und [{(PCy3)Pt}4(2-BDur)2(4-BDur)] (37), kristallographisch untersucht werden. Der B-B-Abstand im π-Diborenkomplex 36 (1.614(6) {\AA}) deutet eindeutig auf die Gegenwart einer B=B-Doppelbindung hin, wobei das Diboren side-on gebunden an zwei der drei Platinatome des Pt3-Ger{\"u}sts koordiniert ist. Die Zusammensetzung von 36 und 37 konnte auch durch Elementaranalysen best{\"a}tigt werden. Die Bildung von 36 und 37 deuten auch darauf hin, dass bei dieser Art der Dehydrokupplung multimetallische Wechselwirkungen eine wichtige Rolle f{\"u}r die Stabilisierung der borzentrierten Liganden spielen. So konnten bei der Reaktion von [Pt(PCy3)2] mit zwei {\"A}quivalenten H2BDur neben Cy3P→BH2Dur (48) auch zwei weitere zweikernige Platinverbindungen isoliert und vollst{\"a}ndig charakterisiert werden. Erhitzen der Reaktionsl{\"o}sung auf 68°C f{\"u}r 170 Minuten f{\"u}hrte hierbei zur Bildung von [{(Cy3P)Pt}2(μ-BDur)(ƞ2:(μ-B)-HB(H)Dur)] (38) mit zwei verbr{\"u}ckenden borzentrierten Liganden, einem Borylen- (BDur) und einem Boranliganden (BH2Dur), welche im 11B{1H}-NMR Spektrum bei δ = 101.3 und δ = 32.8 ppm detektiert wurden. Die R{\"o}ntgenstrukturanalyse von 38 l{\"a}sst einen signifikanten σ-BH-Hinbindungsanteil des Boranliganden zu einem der Platinzentren vermuten, was einen anteiligen Pt2→B-Bindungscharakter andeutet. Dieser Befund konnte auch durch DFT-Rechnungen von Dr. William Ewing best{\"a}tigt werden. Die Studien haben auch gezeigt, dass die Bildung von 38 {\"u}ber eine Zwischenstufe verl{\"a}uft, den hypercloso-Cluster [{(Cy3P)HPt}2(μ-H){μ:ƞ2-B2Dur2(μ-H)}] (39) mit einer tetraedrischen {Pt2B2}-Einheit, zwei terminalen Pt-H-Bindungen sowie je einen die Pt-Pt- bzw. B-B-Bindung verbr{\"u}ckenden Hydridliganden. 39 erwies sich als anf{\"a}llig gegen{\"u}ber H2-Eliminierung und lagert bei Raumtemperatur innerhalb von Tagen, bzw. bei 68°C innerhalb einer Stunde unter B-B-Bindungsbruch quantitativ in 38 um, welche selbst keinen direkten Bor-Bor-Kontakt mehr aufweist. Auf Grundlage der beschriebenen Resultate wurde zudem ein einfacher Zugang zu zweikernigen Platinkomplexen entwickelt. Demnach gelang es, den literaturbekannten zweikernigen Komplex [Pt2(μ:ƞ2-dppm)3] (50) (dppm = Ph2PCH2PPh2) durch Umsetzung von [Pt(nbe)3] mit dppm in guten Ausbeuten zu synthetisieren. Des Weiteren wurde die Reaktivit{\"a}t von 50 gegen{\"u}ber verschiedenen Lewis-S{\"a}uren untersucht. Ein Großteil dieser Umsetzungen war mit der Bildung von schwer l{\"o}slichen Feststoffen verbunden, weshalb lediglich bei der Reaktion mit Br2BPh und Br2BMes geringe Mengen an definiertem Produkt isoliert und durch R{\"o}ntgenstrukturanalyse charakterisiert werden konnten. Demnach f{\"u}hrte die Umsetzung von 50 mit Br2BPh oder Br2BMes zur oxidativen Addition beider B-Br-Bindungen an je eines der Platinzentren und der Bildung der verbr{\"u}ckenden Borylenplatinkomplexe 51 und 52. NMR-spektroskopische Studien deuteten eine analoge Reaktivit{\"a}t von Br2BDur und Br2BFc an, wobei die Komplexe 53 und 54 noch nicht vollst{\"a}ndig charakterisiert werden konnten.}, subject = {Metallorganische Verbindungen}, language = {de} } @phdthesis{Arva2015, author = {Arva, Ana-Lioara}, title = {Aktuelle Aspekte der pharmako-mechanischen Rekanalisation von Gef{\"a}ßverschl{\"u}ssen bei akutem Hirninfarkt}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118417}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Fragestellung Die Prognose eines akuten Hirninfarktes bei Verschluss einer proximalen Hirnarterie ist trotz der intraven{\"o}sen Thrombolyse mit rtPA ung{\"u}nstig. Kann die kombinierte pharmaco-mechanische Rekanalisation von proximalen Gef{\"a}ßverschl{\"u}ssen bei akutem Hirninfarkt zu einer Verbesserung des klinischen Ergebnisses f{\"u}hren? Methoden Wir analysierten retrospektiv 66 konsekutiv aufgenommene Patienten (36m, 30w; mittleres Alter 61 Jahre (23-86 Jahre), die von 2010 bis 2012 kombiniert pharmako-mechanisch intra-arteriell behandelt wurden. 32 Patienten wiesen einen kombinierten ACI-/M1-Verschluss, 23 einen M1-Verschluss und 11 eine Basilaristhrombose auf. Mittlerer NIHSS lag bei 23. 57 Patienten erhielten eine kombinierte pharmaco-mechanische Therapie, 3 Patienten wurden lediglich pharmakologisch und 6 Patienten rein mechanisch rekanalisiert. Rekanalisierung bei 35 Patienten mit einem Stent-Retriever (32 Patienten mit pREset, 3 Patienten mit SOLITAIRE) erfolgt. Bei 46 Patienten wurde rtPA und bei 32 Patienten Tirofiban als Bridging Verfahren eingesetzt. Eine Stentanlage erfolgte in 28,78\% der F{\"a}lle. Ergebnisse Die erzielten Rekanalisationsraten lagen bei 89,4\% bei einer mittleren Dauer der Intervention von 96 Minuten (53,03\% unter 90 Min.). Ein g{\"u}nstiges klinisches Ergebnis nach mRS (mRS 0-2) wurde bei 48\% der Patienten erreicht. Die Rate an symptomatischen intrazerebralen Blutungen lag bei 4,55\%. Die Mortalit{\"a}t war 19,7\%. Die multivariate Regressionsanalyse ergab als modifizierbare Prediktoren f{\"u}r ein g{\"u}nstiges Outcome die Dauer bis zur Rekanalisation und die Gabe von rtPA. Schlussfolgerungen Die kombinierte endovaskul{\"a}re pharmako-mechanische Therapie kann die Mortalit{\"a}t und Morbidit{\"a}t von Schlaganfallpatienten mit Verschl{\"u}ssen einer proximalen Hirnarterie reduzieren.}, subject = {Hirninfarkt}, language = {de} } @article{AsareKyeiForkuorVenus2015, author = {Asare-Kyei, Daniel and Forkuor, Gerald and Venus, Valentijn}, title = {Modeling Flood Hazard Zones at the Sub-District Level with the Rational Model Integrated with GIS and Remote Sensing Approaches}, series = {Water}, volume = {7}, journal = {Water}, doi = {10.3390/w7073531}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151581}, pages = {3531 -- 3564}, year = {2015}, abstract = {Robust risk assessment requires accurate flood intensity area mapping to allow for the identification of populations and elements at risk. However, available flood maps in West Africa lack spatial variability while global datasets have resolutions too coarse to be relevant for local scale risk assessment. Consequently, local disaster managers are forced to use traditional methods such as watermarks on buildings and media reports to identify flood hazard areas. In this study, remote sensing and Geographic Information System (GIS) techniques were combined with hydrological and statistical models to delineate the spatial limits of flood hazard zones in selected communities in Ghana, Burkina Faso and Benin. The approach involves estimating peak runoff concentrations at different elevations and then applying statistical methods to develop a Flood Hazard Index (FHI). Results show that about half of the study areas fall into high intensity flood zones. Empirical validation using statistical confusion matrix and the principles of Participatory GIS show that flood hazard areas could be mapped at an accuracy ranging from 77\% to 81\%. This was supported with local expert knowledge which accurately classified 79\% of communities deemed to be highly susceptible to flood hazard. The results will assist disaster managers to reduce the risk to flood disasters at the community level where risk outcomes are first materialized.}, language = {en} } @article{AtakLanglhoferSchaeferetal.2015, author = {Atak, Sinem and Langlhofer, Georg and Schaefer, Natascha and Kessler, Denise and Meiselbach, Heike and Delto, Carolyn and Schindelin, Hermann and Villmann, Carmen}, title = {Disturbances of ligand potency and enhanced degradation of the human glycine receptor at affected positions G160 and T162 originally identified in patients suffering from hyperekplexia}, series = {Frontiers in Molecular Neuroscience}, volume = {8}, journal = {Frontiers in Molecular Neuroscience}, number = {79}, doi = {10.3389/fnmol.2015.00079}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144818}, year = {2015}, abstract = {Ligand-binding of Cys-loop receptors is determined by N-terminal extracellular loop structures from the plus as well as from the minus side of two adjacent subunits in the pentameric receptor complex. An aromatic residue in loop B of the glycine receptor (GIyR) undergoes direct interaction with the incoming ligand via a cation-π interaction. Recently, we showed that mutated residues in loop B identified from human patients suffering from hyperekplexia disturb ligand-binding. Here, we exchanged the affected human residues by amino acids found in related members of the Cys-loop receptor family to determine the effects of side chain volume for ion channel properties. GIyR variants were characterized in vitro following transfection into cell lines in order to analyze protein expression, trafficking, degradation and ion channel function. GIyR α1 G160 mutations significantly decrease glycine potency arguing for a positional effect on neighboring aromatic residues and consequently glycine-binding within the ligand-binding pocket. Disturbed glycinergic inhibition due to T162 α1 mutations is an additive effect of affected biogenesis and structural changes within the ligand-binding site. Protein trafficking from the ER toward the ER-Golgi intermediate compartment, the secretory Golgi pathways and finally the cell surface is largely diminished, but still sufficient to deliver ion channels that are functional at least at high glycine concentrations. The majority of T162 mutant protein accumulates in the ER and is delivered to ER-associated proteasomal degradation. Hence, G160 is an important determinant during glycine binding. In contrast, 1162 affects primarily receptor biogenesis whereas exchanges in functionality are secondary effects thereof.}, language = {en} } @phdthesis{Ataya2015, author = {Ataya, Mahmoud}, title = {Evaluation des Einsatzes von Active controlled motion (ACM) nach operativ versorgten Sprunggelenksbr{\"u}chen des Types Danis-Weber-B und C mit Notwendigkeit einer Teilbelastung f{\"u}r 6 Wochen postoperativ}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114593}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Bei den sehr h{\"a}ufigen Sprunggelenksfrakturen von Typ Weber-B und -C ist oftmals nur eine limitierte Belastung f{\"u}r die ersten 6 postoperativen Wochen m{\"o}glich, was die funktionelle Nachbehandlung erschwert. Dies f{\"u}hrt wahrscheinlich zu einer Steigerung der arbeitsunf{\"a}higkeitsdauer. Die aktivkontrollierte Nachbehandlung bietet unserer Meinung nach ein standarisiertes Verfahren, das eine selbstst{\"a}ndige, regelm{\"a}ßige und sichere Handhabung erlaubt, welche man in der Rehabilitation von operativ versorgten Sprunggelenksfrakturen nutzen k{\"o}nnte. Das Ziel der Studie war herauszufinden, ob der Einsatz einer Aktiv-kontrollierten Bewegungsschiene (ACM) nach operativ versorgten Sprunggelenksbr{\"u}chen des TypesDanis- Weber-B und -C mit der Notwendigkeit einer Teilbelastung von 6 Wochen postoperativ einen Einfluss auf die Ergebnisse nach 6 und 12 Wochen hat. In der Literatur wurde keine Studie {\"u}ber den Einfluss einer solchen Bewegungsschiene im Vergleich zu einer alleinigen Physiotherapie auf den Ergebnissen nach operativ versorgten Sprunggelenksbr{\"u}chen gefunden. Als einzige Studie dieser Art haben wir herausgefunden, dass dies zu einer besseren Funktion des verletzten Sprunggelenkes und zu einer k{\"u}rzeren Arbeitsunf{\"a}higkeitsdauer f{\"u}hrt. Dadurch kann ein sozio{\"o}konomischer Vorteil erzielt werden.}, subject = {Aktiv-kontrollierten Bewegungsschiene}, language = {de} } @article{Augustin2015, author = {Augustin, Jenny}, title = {?'Diversa, democr{\´a}tica y moderna? La imagen transmitida de la Real Academia Espa{\~n}ola en el discurso actual. Una mirada panor{\´a}mica}, series = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, volume = {1}, journal = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-139449}, pages = {29-57}, year = {2015}, abstract = {In 2013, three hundred years had passed since the foundation of the Real Academia Espa{\~n}ola (RAE). The celebrations accompanying this anniversary were extended across the year and came to a closure with the publication of the 23rd edition of the Diccionario de la lengua espa{\~n}ola in 2014. Spanish media followed the above-mentioned festivities with a detailed coverage. The purpose of this article is to study the image of the RAE conveyed through the media and the Internet, which can be subsumed under the three terms 'diverse, democratic and modern'. This form of representation is put into a broader context by considering the linguistic politics pursued by the RAE and the Asociaci{\´o}n de Academias de la Lengua Espa{\~n}ola (ASALE) under the keyword of panhispanism. Finally, a closer look is taken at El buen uso del espa{\~n}ol, a student manual published by the RAE and the ASALE in 2013, in relation to panhispanism and prescriptivism.}, subject = {Real Academia Espa{\~n}ola}, language = {es} } @phdthesis{Aulbach2015, author = {Aulbach, Stefan}, title = {Contributions to Extreme Value Theory in Finite and Infinite Dimensions: With a Focus on Testing for Generalized Pareto Models}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127162}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Extreme value theory aims at modeling extreme but rare events from a probabilistic point of view. It is well-known that so-called generalized Pareto distributions, which are briefly reviewed in Chapter 1, are the only reasonable probability distributions suited for modeling observations above a high threshold, such as waves exceeding the height of a certain dike, earthquakes having at least a certain intensity, and, after applying a simple transformation, share prices falling below some low threshold. However, there are cases for which a generalized Pareto model might fail. Therefore, Chapter 2 derives certain neighborhoods of a generalized Pareto distribution and provides several statistical tests for these neighborhoods, where the cases of observing finite dimensional data and of observing continuous functions on [0,1] are considered. By using a notation based on so-called D-norms it is shown that these tests consistently link both frameworks, the finite dimensional and the functional one. Since the derivation of the asymptotic distributions of the test statistics requires certain technical restrictions, Chapter 3 analyzes these assumptions in more detail. It provides in particular some examples of distributions that satisfy the null hypothesis and of those that do not. Since continuous copula processes are crucial tools for the functional versions of the proposed tests, it is also discussed whether those copula processes actually exist for a given set of data. Moreover, some practical advice is given how to choose the free parameters incorporated in the test statistics. Finally, a simulation study in Chapter 4 compares the in total three different test statistics with another test found in the literature that has a similar null hypothesis. This thesis ends with a short summary of the results and an outlook to further open questions.}, subject = {Extremwertstatistik}, language = {en} } @phdthesis{Awoye2015, author = {Awoye, Oy{\´e}monbad{\´e} Herv{\´e} Rodrigue}, title = {Implications of future climate change on agricultural production in tropical West Africa: evidence from the Republic of Benin}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122887}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Environmental interlinked problems such as human-induced land cover change, water scarcity, loss in soil fertility, and anthropogenic climate change are expected to affect the viability of agriculture and increase food insecurity in many developing countries. Climate change is certainly the most serious of these challenges for the twenty-first century. The poorest regions of the world - tropical West Africa included - are the most vulnerable due to their high dependence on climate and weather sensitive activities such as agriculture, and the widespread poverty that limits the institutional and economic capacities to adapt to the new stresses brought about by climate change. Climate change is already acting negatively on the poor smallholders of tropical West Africa whose livelihoods dependent mainly on rain-fed agriculture that remains the cornerstone of the economy in the region. Adaptation of the agricultural systems to climate change effects is, therefore, crucial to secure the livelihoods of these rural communities. Since information is a key for decision-making, it is important to provide well-founded information on the magnitude of the impacts in order to design appropriate and sustainable adaptation strategies. Considering the case of agricultural production in the Republic of Benin, this study aims at using large-scale climatic predictors to assess the potential impacts of past and future climate change on agricultural productivity at a country scale in West Africa. Climate signals from large-scale circulation were used because state-of-the art regional climate models (RCM) still do not perfectly resolve synoptic and mesoscale convective processes. It was hypothesised that in rain-fed systems with low investments in agricultural inputs, yield variations are widely governed by climatic factors. Starting with pineapple, a perennial fruit crops, the study further considered some annual crops such as cotton in the group of fibre crops, maize, sorghum and rice in the group of cereals, cowpeas and groundnuts belonging to the legume crops, and cassava and yams which are root and tuber crops. Thus the selected crops represented the three known groups of photosynthetic pathways (i.e. CAM, C3, and C4 plants). In the study, use was made of the historical agricultural yield statistics for the Republic of Benin, observed precipitation and mean near-surface air temperature data from the Climatic Research Unit (CRU TS 3.1) and the corresponding variables simulated by the regional climate model (RCM) REMO. REMO RCM was driven at its boundaries by the global climate model ECHAM 5. Simulations with different greenhouse gas concentrations (SRES-A1B and B1 emission scenarios) and transient land cover change scenarios for present-day and future conditions were considered. The CRU data were submitted to empirical orthogonal functions analysis over the north hemispheric part of Africa to obtain large-scale observed climate predictors and associated consistent variability modes. REMO RCM data for the same region were projected on the derived climate patterns to get simulated climate predictors. By means of cross-validated Model Output Statistics (MOS) approach combined with Bayesian model averaging (BMA) techniques, the observed climate predictors and the crop predictand were further on used to derive robust statistical relationships. The robust statistical crop models perform well with high goodness-of-fit coefficients (e.g. for all combined crop models: 0.49 ≤ R2 ≤ 0.99; 0.28 ≤ Brier-Skill-Score ≤ 0.90). Provided that REMO RCM captures the main features of the real African climate system and thus is able to reproduce its inter-annual variability, the time-independent statistical transfer functions were then used to translate future climate change signal from the simulated climate predictors into attainable crop yields/crop yield changes. The results confirm that precipitation and air temperature governed agricultural production in Benin in general, and particularly, pineapple yield variations are mainly influenced by temperature. Furthermore, the projected yield changes under future anthropogenic climate change during the first-half of the 21st century amount up to -12.5\% for both maize and groundnuts, and -11\%, -29\%, -33\% for pineapple, cassava, and cowpeas respectively. Meanwhile yield gain of up to +10\% for sorghum and yams, +24\% for cotton, and +39\% for rice are expected. Over the time period 2001 - 2050, on average the future yield changes range between -3\% and -13\% under REMO SRES-B1 (GHG)+LCC, -2\% and -11\% under REMO SRES-A1B (GHG only),and -3\% and -14\% under REMO SRES-A1B (GHG)+LCC for pineapple, maize, sorghum, groundnuts, cowpeas and cassava. In the meantime for yams, cotton and rice, the average yield gains lie in interval of about +2\% to +7\% under REMO SRES-B1 (GHG)+LCC, +0.1\% and +12\% under REMO SRES-A1B (GHG only), and +3\% and +10\% under REMO SRES-A1B (GHG)+LCC. For sorghum, although the long-term average future yield depicts a reduction there are tendencies towards increasing yields in the future. The results also reveal that the increases in mean air temperature more than the changes in precipitation patterns are responsible for the projected yield changes. As well the results suggest that the reductions in pineapple yields cannot be attributed to the land cover/land use changes across sub-Saharan Africa. The production of groundnuts and in particular yams and cotton will profit from the on-going land use/land cover changes while the other crops will face detrimental effects. Henceforth, policymakers should take effective measures to limit the on-going land degradation processes and all other anthropogenic actions responsible for temperature increase. Biotechnological improvement of the cultivated crop varieties towards development of set of seed varieties adapted to hotter and dry conditions should be included in the breeding pipeline programs. Amongst other solutions, application of appropriate climate-smart agricultural practices and conservation agriculture are also required to offset the negative impacts of climate change in agriculture.}, subject = {Benin}, language = {en} } @article{AyanuConradJentschetal.2015, author = {Ayanu, Yohannes and Conrad, Christopher and Jentsch, Anke and Koellner, Thomas}, title = {Unveiling undercover cropland inside forests using landscape variables: a supplement to remote sensing image classification}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0130079}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151686}, pages = {e0130079}, year = {2015}, abstract = {The worldwide demand for food has been increasing due to the rapidly growing global population, and agricultural lands have increased in extent to produce more food crops. The pattern of cropland varies among different regions depending on the traditional knowledge of farmers and availability of uncultivated land. Satellite images can be used to map cropland in open areas but have limitations for detecting undergrowth inside forests. Classification results are often biased and need to be supplemented with field observations. Undercover cropland inside forests in the Bale Mountains of Ethiopia was assessed using field observed percentage cover of land use/land cover classes, and topographic and location parameters. The most influential factors were identified using Boosted Regression Trees and used to map undercover cropland area. Elevation, slope, easterly aspect, distance to settlements, and distance to national park were found to be the most influential factors determining undercover cropland area. When there is very high demand for growing food crops, constrained under restricted rights for clearing forest, cultivation could take place within forests as an undercover. Further research on the impact of undercover cropland on ecosystem services and challenges in sustainable management is thus essential.}, language = {en} } @phdthesis{Bachschmidt2015, author = {Bachschmidt, Theresa}, title = {Magnetic Resonance Imaging in Proximity to Metal Implants at 3 Tesla}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135690}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Magnetic resonance imaging is derogated by the presence of metal implants and image quality is impaired. Artifacts are categorized according to their sources, the differences in susceptibility between metal and tissue and the modulation of the magnetic radiofrequency (RF) transmit field. Generally, these artifacts are intensified at higher field strength. The purpose of this work is to analyze the efficiency of current methods used for metal artifact reduction at 3T and to investigate improvements. The impact of high-bandwidth RF pulses on susceptibility-induced artifacts is tested. In addition, the benefit of a two-channel transmit system with respect to shading close to total hip replacements and other elongated metal structures in parallel to the magnetic field is analyzed. Local transmit/receive coils feature a higher peak B1 amplitude than conventional body coils and thus enable high-bandwidth RF pulses. Susceptibility-induced through-plane distortion relates reciprocally to the RF bandwidth, which is evaluated in vitro for a total knee arthroplasty. Clinically relevant sequences (TSE and SEMAC) with conventional and high RF pulse bandwidths and different contrasts are tested on eight patients with different types of knee implants. Distortion is rated by two radiologists. An additional analysis assesses the capability of a local spine transmit coil. Furthermore, B1 effects close to elongated metal structures are described by an analytical model comprising a water cylinder and a metal rod, which is verified numerically and experimentally. The dependence of the optimal polarization of the transmit B1 field, creating minimum shading, on the position of the metal is analyzed. In addition, the optimal polarization is determined for two patients; its benefit compared to circular polarization is assessed. Phantom experiments confirm the relation of the RF bandwidth and the through-plane distortion, which can be reduced by up to 79\% by exploitation of a commercial local transmit/receive knee coil at 3T. On average, artifacts are rated "hardly visible" for patients with joint arthroplasties, when high-bandwidth RF pulses and SEMAC are used, and for patients with titanium fixtures, when high-bandwidth RF pulses are used in combination with TSE. The benefits of the local spine transmit coil are less compared to the knee coil, but enable a bandwidth 3.9 times as high as the body coil. The modulation of B1 due to metal is approximated well by the model presented and the position of the metal has strong influence on this effect. The optimal polarization can mitigate shading substantially. In conclusion, through-plane distortion and related artifacts can be reduced significantly by the application of high-bandwidth RF pulses by local transmit coils at 3T. Parallel transmission offers an option to substantially reduce shading close to long metal structures aligned with the magnetic field. Effective techniques dedicated for metal implant imaging at 3T are introduced in this work.}, subject = {Kernspintomografie}, language = {en} } @article{BahnikStuchlik2015, author = {Bahn{\´i}k, Štěp{\´a}n and Stuchl{\´i}k, Aleš}, title = {Temporal and spatial strategies in an active place avoidance task on Carousel: a study of effects of stability of arena rotation speed in rats}, series = {PeerJ}, volume = {3}, journal = {PeerJ}, number = {e1257}, doi = {10.7717/peerj.1257}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141931}, year = {2015}, abstract = {The active place avoidance task is a dry-arena task used to assess spatial navigation and memory in rodents. In this task, a subject is put on a rotating circular arena and avoids an invisible sector that is stable in relation to the room. Rotation of the arena means that the subject's avoidancemust be active, otherwise the subject will be moved in the to-be-avoided sector by the rotation of the arena and a slight electric shock will be administered. The present experiment explored the effect of variable arena rotation speed on the ability to avoid the to-be-avoided sector. Subjects in a group with variable arena rotation speed learned to avoid the sector with the same speed and attained the same avoidance ability as rats in a group with a stable arena rotation speed. Only a slight difference in preferred position within the room was found between the two groups. No difference was found between the two groups in the dark phase, where subjects could not use orientation cues in the room. Only one rat was able to learn the avoidance of the to-be-avoided sector in this phase. The results of the experiment suggest that idiothetic orientation and interval timing are not crucial for learning avoidance of the to-be-avoided sector. However, idiothetic orientation might be sufficient for avoiding the sector in the dark.}, language = {en} } @phdthesis{Bakhtiari2015, author = {Bakhtiari, Giti}, title = {The Role of Fluency in Oral Approach and Avoidance}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118666}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Names of, for instance, children or companies are often chosen very carefully. They should sound and feel good. Therefore, many companies try to choose artificially created names that can easily be pronounced in various languages. A wide range of psychological research has demonstrated that easy processing (high processing fluency) is intrinsically experienced as positive. Due to this positive feeling, easy processing can have profound influences on preferences for names. Topolinski, Maschmann, Pecher, and Winkielman (2014) have introduced a different mechanism that influences the perception of words. Across several experiments they found that words featuring consonantal inward wanderings (inward words) were preferred over words featuring consonantal outward wanderings (outward words). They argued that this was due to the fact that approach and avoidance motivations are activated by articulating inward and outward words, because the pronunciation resembles approach and avoidance behaviors of swallowing and spitting, respectively. They suggested this close link as an underlying mechanism for the so-called in-out effect, but did not test this assumption directly. In the current work, I tested an alternative fluency account of the in-out effect. Specifically, I hypothesized that processing fluency might play a critical role instead of motivational states of approach and avoidance being necessarily activated. In Chapter 1, I introduce the general topic of my dissertation, followed by a detailed introduction of the research area of approach and avoidance motivations in Chapter 2. In Chapter 3, I narrow the topic down to orally induced approach and avoidance motivations, which is the main topic of my dissertation. In Chapter 4, I introduce the research area of ecological influences on psychological processes. This chapter builds the base for the idea that human language might serve as a source of processing fluency in the in-out effect. In the following Chapter 5, I elaborate the research area of processing fluency, for which I examined whether it plays a role in the in-out effect. After an overview of my empirical work in Chapter 6, the empirical part starts with Study 1a and Study 1b (Chapter 7) that aimed to show that two languages (Eng. \& Ger.) in which the in-out effect has originally been found might feature a source of higher processing fluency for inward over outward words. The results showed that higher frequencies of inward dynamics compared to outward dynamics were found in both languages. This can lead to higher pronunciation fluency for inward compared to outward words which might in turn lay the ground for higher preferences found for inward over outward words. In Chapter 8, the assumption that inward compared to outward dynamics might be more efficient to process was tested directly in experiments that examined objective as well as subjective processing fluency of artificially constructed non-words featuring pure inward or outward dynamics. Studies 2a-4b found an objective as well as subjective processing advantage for inward over outward words. In Chapter 9, the causal role of objective and subjective pronunciation fluency in the in-out effect was examined. In Study 5 mediational analyses on item-level and across studies were conducted using objective and subjective fluency as possible mediating variables. In Study 6 mediation analyses were conducted with data on subject- and trial-level from a within-subject design. Overall, the data of the item-based, subject-based and trial-based mediation analyses provide rather mixed results. Therefore, an experimental manipulation of fluency was implemented in the last two studies. In Chapter 10, Study 7 and Study 8 demonstrate that manipulating fluency experimentally does indeed modulate the attitudinal impact of consonantal articulation direction. Articulation ease was induced by letting participants train inward or outward kinematics before the actual evaluation phase. Additionally, the simulation training was intensified in Study 8 in order to examine whether a stronger modulation of the in-out effect could be found. Training outward words led to an attenuation and, after more extensive training, even to a reversal of the in-out effect, whereas training inward words led to an enhancement of the in-out effect. This hints at my overall hypothesis that the explicit preferences of inward and outward words are, at least partially, driven by processing fluency. Almost all studies of my dissertation, except for one analysis of the item-based mediation study, speak in favor of the hypothesis that inward words compared to outward words are objectively and subjectively easier to articulate. This possibly contributes partially to a higher preference of inward over outward words. The results are discussed in Chapter 11 with respect to processing fluency and to the role of language as an ecological factor. Finally, future research ideas are elaborated.}, subject = {Sozialpsychologie}, language = {en} } @phdthesis{Balk2015, author = {Balk, Anja}, title = {Ionic liquids of active pharmaceutical ingredients: A novel platform addressing solubility challenges of poorly water soluble drugs}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121925}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Starting in the late 1990s ionic liquids (ILs) gained momentum both in academia as well as industry. ILs are defined as organic salts with a melting point below 100 °C. Active pharmaceutical ingredients (APIs) may be transferred into ILs by creating salts with a bulky counterion with a soft electron density. ILs have demonstrated the potential to tune important pharmaceutical features such as the solubility and the dissolution rate, particularly addressing the challenge of poor water soluble drugs (PWSD). Due to the tunability of ILs, modification of physico-chemical properties of APIs may be envisioned without any modifications of the chemical structure. In the first chapter the potential as well as the limitation of ILs are discussed. The chapter commences with an overview of preparation and characterization of API-ILs. Moreover, examples for pharmaceutical parameters are presented which may be affected by IL formation, including the dissolution rate, kinetic solubility or hygroscopicity as well as biopharmaceutical performance and toxicology. The impact of IL formation on those pharmaceutically relevant features is highlighted, resulting in a blueprint for a novel formulation concept to overcome PWSD challenges without the need for structural changes of the API. Within the second chapter the IL concept is detailed for one specific API - counterion combination. A poorly water soluble acidic API against migraine attacks was transformed into an IL in an effort to minimize the time to maximum plasma concentration (tmax) and optimize the overall bioavailability. These studies were conducted in parallel to a prodrug of the API for comparison of the IL strategy versus a strategy involving modification of the API's structure. A significantly longer duration of API supersaturation and a 700 fold faster dissolution rate of the IL in comparison to the free acid were obtained and the underlying mechanism was elucidated. The transepithelial absorption was determined using Caco-2 cell layers. For the IL about 3 times more substance was transported in comparison to the prodrug when substances were applied as suspensions, despite the higher permeability of the prodrug, as increased solubility of the IL exceeded this effect. Cytotoxicity of the counterion was assessed in hepatic, renal and macrophage cell lines, respectively, and IC50 values were in the upper µM / lower mM range. The outcome of the study suggested the IL approach instrumental for tuning biopharmaceutical properties, without structural changes of the API as required for preparation of prodrugs. Thus the toolbox for formulation strategies of poorly water soluble drugs could be extended by an efficient concept. The third chapter focuses on the effect of different counterions on the physico-chemical properties of an API-IL, in particular to overcome the challenge of poor water solubility. Therefore, the same poorly water soluble acidic API against migraine attacks mentioned above was combined with 36 counterions resulting in ILs and low lattice enthalpy salts (LLES). Depending on the counterions, different dissolution rates, durations of supersaturation and hygroscopicities were obtained and release profiles could be tailored from immediate to sustained release. Besides, in vitro the cytotoxicity of the counterions was assessed in three cell lines. Using molecular descriptors such as the number of hydrophobic atoms, the graph theoretical diameter and the number of positive charges of the counterion, the dissolution rate, supersaturation and hygroscopicity as well as the cytotoxicity of counterions could be adequately modeled, rendering it possible to predict properties of new LLESs. Within the forth chapter different poorly water soluble APIs were combined with the counterion tetrabutylphosphonium (TBP) studying the impact on the pharmaceutical and physical properties of the APIs. TBP-ILs and low lattice enthalpy salts were prepared of the acidic APIs Diclofenac, Ibuprofen, Ketoprofen, Naproxen, Sulfadiazine, Sulfamethoxazole and Tolbutamide. NMR and IR spectroscopy, DSC, XRPD, DVS and dissolution rate measurements, release profiles and saturation concentration measurements were used to characterize the free acids and TBP salts as compared to the corresponding sodium salts. The TBP salts as compared to the free acids displayed lower melting points and glass transition temperatures and up to 1000 times higher dissolution rates. The increase in the dissolution rate directly correlated with the salts' hygroscopicity, an aspect which is critically discussed in terms of pharmaceutical translation challenges. In summary TBP ILs of solid salts were proved instrumental to approach the challenge of poor water solubility. The outcome profiled tailor-made counterions as a powerful formulation strategy to address poor water solubility, hence bioavailability and ultimately therapeutic potential of challenging APIs. In summary, a plethora of ILs and LLESs were prepared by combination of different acidic APIs and counterions. The IL and LLESs concept was compared to conventional salt and prodrug strategies. By choice of the counterion, biopharmaceutical relevant parameters were deliberately modified and release profiles were tuned ranging from immediate to prolonged release. The impact of distinct structural counterion features controlling the dissolution, supersaturation, hygroscopicity and counterion cytotoxicity were identified, correlations were presented and predictive models were built. ILs and LLESs could be proven to be a powerful concept for the formulation of poorly water soluble acidic APIs.}, subject = {Arzneimittel}, language = {en} } @article{BarejSchmitzPenneretal.2015, author = {Barej, Michael F. and Schmitz, Andreas and Penner, Johannes and Doumbia, Joseph and Sandberger-Loua, Laura and Hirschfeld, Mareike and Brede, Christian and Emmrich, Mike and Kouam{\´e}, N'Goran Germain and Hillers, Annika and Gonwouo, Nono L. and Nopper, Joachim and Adeba, Patrick Jo{\"e}l and Bangoura, Mohamed A. and Gage, Ceri and Anderson, Gail and R{\"o}del, Mark-Oliver}, title = {Life in the spray zone - overlooked diversity in West African torrent-frogs (Anura, Odontobatrachidae, Odontobatrachus)}, series = {Zoosystematics and Evolution}, volume = {91}, journal = {Zoosystematics and Evolution}, number = {2}, doi = {10.3897/zse.91.5127}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144254}, pages = {115-149}, year = {2015}, abstract = {West African torrent-frogs of the genus Odontobatrachus currently belong to a single species: Odontobatrachus natator (Boulenger, 1905). Recently, molecular results and biogeographic separation led to the recognition of five Operational Taxonomic Units (OTUs) thus identifying a species-complex. Based on these insights, morphological analyses on more than 150 adult specimens, covering the entire distribution of the family and all OTUs, were carried out. Despite strong morphological congruence, combinations of morphological characters made the differentiation of OTUs successful and allowed the recognition of five distinct species: Odontobatrachus natator, and four species new to science: Odontobatrachus arndti sp. n., O. fouta sp. n., O. smithi sp. n. and O. ziama sp. n. All species occur in parapatry: Odontobatrachus natator is known from western Guinea to eastern Liberia, O. ziama sp. n. from eastern Guinea, O. smithi sp. n. and O. fouta sp. n. from western Guinea, O. arndti sp. n. from the border triangle Guinea-Liberia-Cote d'Ivoire. In addition, for the first time the advertisement call of a West African torrent-frog (O. arndti sp. n.) is described.}, language = {en} } @article{BarteitHoepffnerHuwendieketal.2015, author = {Barteit, Sandra and Hoepffner, Philip and Huwendiek, S{\"o}ren and Karamagi, Angela and Munthali, Charles and Theurer, Antje and Neuhann, Florian}, title = {Self-directed e-learning at a tertiary hospital in Malawi - a qualitative evaluation and lessons learnt}, series = {GMS Journal for Medical Education}, volume = {32}, journal = {GMS Journal for Medical Education}, number = {1}, doi = {10.3205/zma000949}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150208}, pages = {Doc7}, year = {2015}, abstract = {Background: Malawi faces a severe lack of health workers. Despite initiatives to address this problem, a critical shortage of health care staff remains. This lack challenges the education and training of junior medical staff, especially medical interns in their final and crucial training year before they independently work as medical doctors. Project description: We have introduced an e-learning platform in the medical department of the Kamuzu Central Hospital (KCH) in Malawi. With the support of computer-assisted instruction, we aimed to improve the quality of medical training and education, as well as access to current medical materials, in particular for interns. Method: From March to April 2012, we conducted a qualitative evaluation to assess relevance and appropriateness of the e-learning platform. Data was collected via face-to-face interviews, a guided group discussion and a checklist based observation log. Evaluation data was recorded and coded using content analysis, interviewees were chosen via purposive sampling. Results: E-learning proved to be technically feasible in this setting. Users considered the e-learning platform to be relevant and appropriate. Concerns were raised about sustainability, accessibility and technical infrastructure, as well as limited involvement and responsibilities of Malawian partners. Interest in e-learning was high, yet, awareness of and knowledge about the e-learning platform among potential users was low. Evaluation results indicated that further adaptions to local needs are necessary to increase usage and accessibility. Conclusions: Interview results and our project experiences showed that, in the given setting, e-learning requires commitment from local stakeholders, adequate technical infrastructure, identification and assignation of responsibilities, as well as specific adaption to local needs.}, language = {en} } @article{BassetCizekCuenoudetal.2015, author = {Basset, Yves and Cizek, Lukas and Cu{\´e}noud, Philippe and Didham, Raphael K. and Novotny, Vojtech and {\O}degaard, Frode and Roslin, Tomas and Tishechkin, Alexey K. and Schmidl, J{\"u}rgen and Winchester, Neville N. and Roubik, David W. and Aberlenc, Henri-Pierre and Bail, Johannes and Barrios, Hector and Bridle, Jonathan R. and Casta{\~n}o-Meneses, Gabriela and Corbara, Bruno and Curletti, Gianfranco and da Rocha, Wesley Duarte and De Bakker, Domir and Delabie, Jacques H. C. and Dejean, Alain and Fagan, Laura L. and Floren, Andreas and Kitching, Roger L. and Medianero, Enrique and de Oliveira, Evandro Gama and Orivel, Jerome and Pollet, Marc and Rapp, Mathieu and Ribeiro, Servio P. and Roisin, Yves and Schmidt, Jesper B. and S{\o}rensen, Line and Lewinsohn, Thomas M. and Leponce, Maurice}, title = {Arthropod Distribution in a Tropical Rainforest: Tackling a Four Dimensional Puzzle}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {12}, doi = {10.1371/journal.pone.0144110}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-136393}, pages = {e0144110}, year = {2015}, abstract = {Quantifying the spatio-temporal distribution of arthropods in tropical rainforests represents a first step towards scrutinizing the global distribution of biodiversity on Earth. To date most studies have focused on narrow taxonomic groups or lack a design that allows partitioning of the components of diversity. Here, we consider an exceptionally large dataset (113,952 individuals representing 5,858 species), obtained from the San Lorenzo forest in Panama, where the phylogenetic breadth of arthropod taxa was surveyed using 14 protocols targeting the soil, litter, understory, lower and upper canopy habitats, replicated across seasons in 2003 and 2004. This dataset is used to explore the relative influence of horizontal, vertical and seasonal drivers of arthropod distribution in this forest. We considered arthropod abundance, observed and estimated species richness, additive decomposition of species richness, multiplicative partitioning of species diversity, variation in species composition, species turnover and guild structure as components of diversity. At the scale of our study (2km of distance, 40m in height and 400 days), the effects related to the vertical and seasonal dimensions were most important. Most adult arthropods were collected from the soil/litter or the upper canopy and species richness was highest in the canopy. We compared the distribution of arthropods and trees within our study system. Effects related to the seasonal dimension were stronger for arthropods than for trees. We conclude that: (1) models of beta diversity developed for tropical trees are unlikely to be applicable to tropical arthropods; (2) it is imperative that estimates of global biodiversity derived from mass collecting of arthropods in tropical rainforests embrace the strong vertical and seasonal partitioning observed here; and (3) given the high species turnover observed between seasons, global climate change may have severe consequences for rainforest arthropods.}, language = {en} } @phdthesis{Bauer2015, author = {Bauer, Andreas}, title = {Argumentieren mit multiplen und dynamischen Repr{\"a}sentationen}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, isbn = {978-3-95826-022-1 (print)}, doi = {10.25972/WUP-978-3-95826-023-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112114}, school = {W{\"u}rzburg University Press}, pages = {132}, year = {2015}, abstract = {Der Einzug des Rechners in den Mathematikunterricht hat eine Vielzahl neuer M{\"o}glichkeiten der Darstellung mit sich gebracht, darunter auch multiple, dynamisch verbundene Repr{\"a}sentationen mathematischer Probleme. Die Arbeit beantwortet die Frage, ob und wie diese Repr{\"a}sentationsarten von Sch{\"u}lerinnen und Sch{\"u}ler in Argumentationen genutzt werden. In der empirischen Untersuchung wurde dabei einerseits quantitativ erforscht, wie groß der Einfluss der in der Aufgabenstellung gegebenen Repr{\"a}sentationsform auf die schriftliche Argumentationen der Sch{\"u}lerinnen und Sch{\"u}ler ist. Andererseits wurden durch eine qualitative Analyse spezifische Nutzungsweisen identifiziert und mittels Toulmins Argumentationsmodell beschrieben. Diese Erkenntnisse wurden genutzt, um Konsequenzen bez{\"u}glich der Verwendung von multiplen und/oder dynamischen Repr{\"a}sentationen im Mathematikunterricht der Sekundarstufe zu formulieren.}, subject = {Argumentation}, language = {de} } @article{BauerGoebelerWeissbrichetal.2015, author = {Bauer, Boris and Goebeler, Matthias and Weissbrich, Benedikt and Kerstan, Andreas}, title = {Kerinokeratosis papulosa of childhood}, series = {Dermatology}, volume = {231}, journal = {Dermatology}, number = {1}, issn = {1018-8665}, doi = {10.1159/000381539}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-198997}, pages = {1 -- 4}, year = {2015}, abstract = {Background: Kerinokeratosis papulosa (KP) is considered an extremely rare genodermatosis presenting usually as waxy papules on the trunk in childhood. Objective: To describe and analyze the clinical, histological and potential etiopathological aspects of KP. Methods: The dermatoscopic features of a new case of KP of childhood are investigated. The presence of human papillomavirus (HPV) DNA in lesional skin was studied by polymerase chain reaction. Furthermore, all cases of KP of childhood reported so far were reviewed. Results: As a diagnostic tool, we describe for the first time a dermatoscopic feature, namely a cribriform pattern of KP, in an 11-year-old boy. In addition, we detected HPV (type 57) in his KP lesions. Conclusions: Dermatoscopic examination might be a useful tool to distinguish KP from other skin lesions, e.g. common warts. The detection of HPV type 57 might hint to an etiological role of HPV for KP.}, language = {en} } @phdthesis{Bauer2015, author = {Bauer, Ulrich Josef}, title = {Conformal Mappings onto Simply and Multiply Connected Circular Arc Polygon Domains}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123914}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {The goal of this thesis is to investigate conformal mappings onto circular arc polygon domains, i.e. domains that are bounded by polygons consisting of circular arcs instead of line segments. Conformal mappings onto circular arc polygon domains contain parameters in addition to the classical parameters of the Schwarz-Christoffel transformation. To contribute to the parameter problem of conformal mappings from the unit disk onto circular arc polygon domains, we investigate two special cases of these mappings. In the first case we can describe the additional parameters if the bounding circular arc polygon is a polygon with straight sides. In the second case we provide an approximation for the additional parameters if the circular arc polygon domain satisfies some symmetry conditions. These results allow us to draw conclusions on the connection between these additional parameters and the classical parameters of the mapping. For conformal mappings onto multiply connected circular arc polygon domains, we provide an alternative construction of the mapping formula without using the Schottky-Klein prime function. In the process of constructing our main result, mappings for domains of connectivity three or greater, we also provide a formula for conformal mappings onto doubly connected circular arc polygon domains. The comparison of these mapping formulas with already known mappings allows us to provide values for some of the parameters of the mappings onto doubly connected circular arc polygon domains if the image domain is a polygonal domain. The different components of the mapping formula are constructed by using a slightly modified variant of the Poincar{\´e} theta series. This construction includes the design of a function to remove unwanted poles and of different versions of functions that are analytic on the domain of definition of the mapping functions and satisfy some special functional equations. We also provide the necessary concepts to numerically evaluate the conformal mappings onto multiply connected circular arc polygon domains. As the evaluation of such a map requires the solution of a differential equation, we provide a possible configuration of curves inside the preimage domain to solve the equation along them in addition to a description of the procedure for computing either the formula for the doubly connected case or the case of connectivity three or greater. We also describe the procedures for solving the parameter problem for multiply connected circular arc polygon domains.}, subject = {Konforme Abbildungen}, language = {en} } @phdthesis{Baunach2015, author = {Baunach, Gregor Ludwig Viktor}, title = {Dentale Auswirkungen bei der chirurgisch unterst{\"u}tzten Gaumennahterweiterung durch skelettal verankerte Apparaturen im Vergleich zur Anwendung dental verankerter Apparaturen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134658}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Ziele: Das Ziel der vorliegenden Untersuchung war es, die dentalen Auswirkungen einer chirurgisch unterst{\"u}tzten Gaumennahterweiterung unter Anwendung einer skelettal verankerten Apparatur (TPD) im Vergleich zur Anwendung einer dental verankerten Apparatur (GNE) mit Hilfe eines dreidimensionalen Modellscanners zu analysieren. Patienten und Methode: 28 erwachsene Patienten (Durchschnittsalter: 27,4 ± 9,1 Jahre) wurden mit einer chirurgisch unterst{\"u}tzten transversalen Erweiterung des Oberkiefers therapiert. Die Erweiterung erfolgte bei 16 Patienten mit einem skelettal verankerten transpalatinalen Distraktor (TPD-Gruppe) und bei 12 Patienten mit einer dental abgest{\"u}tzten GNE-Apparatur (Hyrax-Gruppe). Innerhalb beider Patientengruppen wurde eine subtotale Le-Fort-I-Osteotomie mit Schw{\"a}chung der Sutura pterygomaxillaris durchgef{\"u}hrt. Bei allen Patienten wurden sowohl vor Einsetzten der Apparaturen als auch nach erfolgter Erweiterung des Oberkiefers Situationsmodelle erstellt. Nach Generierung virtueller Modelle mittels des optischen Sensors R 700 (3Shape A/S, Kopenhagen, D{\"a}nemark), wurde eine dreidimensionale Analyse mit Hilfe der OrthoAnalyzer Software (3Shape A/S, Kopenhagen, D{\"a}nemark) zur Berechnung der Zahnstellungs{\"a}nderungen durchgef{\"u}hrt. Ergebnisse: Bei der SARME findet unabh{\"a}ngig von der verwendeten Appartur eine signifikante Erweiterung des Oberkiefers statt. Beim Einsatz einer skelettal verankerten Apparatur tritt eine geringere Bukkalkippung der Seitenz{\"a}hne auf als beim Einsatz einer dental verankerten Apparatur. Intrusionen bzw. Extrusionen finden nur in klinisch irrelevantem Maß statt. Schlussfolgerung: Die Therapie der hypoplastischen Maxilla durch eine SARME bei adulten Patienten ist sowohl mittels Hyrax-Apparatur als auch mittels TPD m{\"o}glich. Das Behandlerteam aus Kieferorthop{\"a}den und Kieferchirurgen kann durch das Wissen {\"u}ber die unterschiedliche Reaktion beider Apparaturen bereits in der pr{\"a}therapeutischen Phase die Bewegungsmuster der Kiefersegmente planen: • Bei Anwendung einer Hyrax-Apparatur ist mit einer ann{\"a}hernd parallelen Erweiterung des Zahnbogens mit Zuwachs in der Pr{\"a}molarenregion zu rechnen. • Bei Anwendung eines TPD ist eher mit einer V-f{\"o}rmigen erweiterung des Zahnbogens mit gr{\"o}ßtem Zuwachs im anterioren Bereich zu rechnen. Durch die Option der variablen Positionierung der Dehnschraube weiter anterior oder posterior der Pr{\"a}molarenregion bei Einsatz des TPDs und dem daraus ver{\"a}nderten Modus der Erweiterung resultiert eine Erweiterung des kieferorthop{\"a}dischen und kieferchirurgischen Spektrums.}, subject = {Gaumennahterweiterung}, language = {de} } @article{BaurSchedelbeckPulzeretal.2015, author = {Baur, Johannes and Schedelbeck, Ulla and Pulzer, Alina and Bluemel, Christina and Wild, Vanessa and Fassnacht, Martin and Steger, U.}, title = {A case report of a solitary pancreatic metastasis of an adrenocortical carcinoma}, series = {BMC Surgery}, volume = {15}, journal = {BMC Surgery}, number = {93}, doi = {10.1186/s12893-015-0076-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126130}, year = {2015}, abstract = {Background Solitary metastases to the pancreas are rare. Therefore the value of resection in curative intention remains unclear. In the literature there are several promising reports about resection of solitary metastasis to the pancreas mainly of renal origin. Case presentation Here we report for the first time on the surgical therapy of a 1.5 cm solitary pancreatic metastasis of an adrenocortical carcinoma. The metastasis occurred almost 6 years after resection of the primary tumor. A partial pancreatoduodenectomy was performed and postoperatively adjuvant mitotane treatment was initiated. During the follow-up of 3 years after surgery no evidence of tumor recurrence occurred. Conclusion Resection of pancreatic tumors should be considered, even if the mass is suspicious for metastatic disease including recurrence of adrenocortical cancer.}, language = {en} } @phdthesis{Bechmann2015, author = {Bechmann, Cornelius}, title = {Behandlungsergebnisse der konservativen Therapie ausgedehnter kn{\"o}cherner Brustwandverletzungen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135005}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Zielsetzung: Der klinische Stellenwert der operativen Stabilisierung komplexer kn{\"o}cherner Brustwandverletzungen - insbesondere bei Mehrfachverletzten - ist weiterhin unklar. Studienergebnisse aus anderen Gesundheitssystemen weisen einen Vorteil der Rippenosteosynthese gegen{\"u}ber konservativen Therapieans{\"a}tzen aus. Die {\"U}bertragung dieser Ergebnisse auf die deutsche Versorgungssituation ist jedoch problematisch. Methode: Retrospektive Analyse aller Patienten, die im Zeitraum von 2011 bis 2013 in einem {\"u}berregionalen Traumazentrum der Deutschen Gesellschaft f{\"u}r Unfallchirurgie mit einem schweren Thoraxtrauma behandelt wurden. Einschlusskriterium in diese Analyse war der Nachweis einer ein- oder beidseitigen Rippenserienfraktur in dem bei Patientenaufnahme durchgef{\"u}hrten Trauma CT. Die thorakalen Begleitverletzungen und die Ergebnisse der Therapie wurden erfasst. Ergebnis: Im Untersuchungszeitraum wurden in dem Studienzentrum 2801 Polytraumata versorgt. Von diesen hatten 251 Patienten eine ein- oder beidseitge Rippenserienfraktur (links=111; rechts=87; beidseits=45). Traumaursachen waren St{\"u}rze (37,9\%), PKW- (32,9\%) und Motorradunf{\"a}lle (14,4\%). Die Verletzungen wurden bei 243 Patienten konservativ versorgt. 110 Patienten (45,3\%) erhielten wegen thorakaler Begleitverletzungen eine Thoraxdrainage. 119 Patienten wurden beatmet. Die durchschnittliche Beatmungsdauer, Intensiv- und Krankenhausaufenthaltsdauern waren 118,1 Stunden und 7,4 bzw. 15,4 Tage. Die Krankenhaus-Mortalit{\"a}t war 13,2\%. Patienten mit isolierten Thoraxtraumata hatten g{\"u}nstigere Behandlungsverl{\"a}ufe. Die von uns ermittelten Behandlungskennzahlen sind damit zumeist besser als die in internationalen Therapie-Studien publizierten Ergebnisse. Schlussfolgerung: Die Osteosynthese komplexer kn{\"o}cherner Brustwandverletzungen stellt eine vielversprechende Behandlungsoption f{\"u}r Traumapatienten dar. F{\"u}r eine Bewertung des tats{\"a}chlichen zus{\"a}tzlichen klinischen Nutzens ist jedoch eine genaue Charakterisierung des behandelten Patientenkollektivs erforderlich.}, subject = {Thoraxchirurgie}, language = {de} } @phdthesis{BeckgebKnoll2015, author = {Beck [geb. Knoll], Carolin}, title = {Die polyklonale Aktivierung regulatorischer T-Zellen durch einen CD28-spezifischen superagonistischen monoklonalen Antik{\"o}rper reduziert die Arteriosklerose in \(T_{reg}\) defizienten ApoEko-M{\"a}usen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122633}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Die Arteriosklerose ist ein chronisch entz{\"u}ndlicher Prozess der Gef{\"a}ßwand, in dem CD4+CD25+FoxP3+ regulatorische T-Zellen („\(T_{reg}\)") eine atheroprotektive Rolle spielen. Durch exogenen \(T_{reg}\)-Transfer konnten andere Gruppen eine Reduktion der Arteriosklerose nachweisen. In der vorliegenden Arbeit wurde die Aktivit{\"a}t der endogenen Treg durch spezielle Antik{\"o}rper modifiziert, ihr Einfluss auf die Entwicklung arteriosklerotischer Plaques in ApoEko-M{\"a}usen untersucht sowie eine m{\"o}gliche Abh{\"a}ngigkeit dieser Wirkung vom zellul{\"a}ren Immunstatus des Wirts gepr{\"u}ft. Im Abstand von 28 Tagen wurde weiblichen ApoEko-M{\"a}usen zweimal der CD28-spezifische superagonistische monoklonale Antik{\"o}rper D665 injiziert, um eine polyklonale Vermehrung ihrer \(T_{reg}\) anzuregen. In einer zweiten Versuchsreihe wurden endogene \(T_{reg}\) zweimal im Abstand von 28 Tagen durch Gabe eines CD25-spezifischen Antik{\"o}rpers (PC61) zun{\"a}chst depletiert und jeweils 7 Tage sp{\"a}ter durch D665 geboostert, um den Effekt der \(T_{reg}\) auf ein initial Treg defizientes Tiermodell zu testen. Verglichen wurde mit der alleinigen Treg-Depletion durch PC61 sowie mit einem Kontrollantik{\"o}rper (Isotyp-IgG, MOPC). Die Quantifizierung der Arterioskleroseentwicklung erfolgte mittels Planimetrie der Plaquefl{\"a}che der Aorta. Die Wirksamkeit der Antik{\"o}rper auf die \(T_{reg}\)-Konzentrationen wurde mittels FACS-Analysen aus Blut und Milz untersucht. Nach alleiniger \(T_{reg}\)-Amplifikation durch D665-Injektion zeigte sich kein Unterschied in der prozentualen Plaquefl{\"a}che im Vergleich zur Kontrollgruppe. Auch eine alleinige Depletion mit PC61 zeigte keine Ver{\"a}nderungen in der L{\"a}sionsfl{\"a}che. Durch Kombination beider Antik{\"o}rper jedoch kam es nach Treg-Depletion mittels PC61, gefolgt von Treg-stimulierender D665-Behandlung, zu einer signifikanten Verminderung der prozentualen Plaquefl{\"a}che der Aorta um 32,02\% im Vergleich zur MOPC Kontrolle und um 28,73\% im Vergleich zur alleinigen \(T_{reg}\)-Depletion mit PC61+MOPC. Die FACS-Analysen best{\"a}tigten eine signifikante Depletion durch PC61-Injektion sowie eine signifikante Zunahme der Treg eine Woche nach D665-Injektion. Die Stimulation regulatorischer T-Zellen in einem Treg-defizienten arteriosklerotischen Tiermodell reduzierte die aortale arteriosklerotische L{\"a}sionsfl{\"a}che signifikant. In der immunkompetenten ApoEko Maus jedoch bewirkte die alleinige Vermehrung oder die alleinige Depletion regulatorischer T-Zellen keine messbare Ver{\"a}nderung in der Plaqueentwicklung. Diese Arbeit zeigt, dass ein Zusammenhang zwischen der Wirksamkeit regulatorischer T-Zellen und der inflammatorischen Ver{\"a}nderung der Gef{\"a}ßwand besteht.}, language = {de} } @article{BeckTitzeHuebneretal.2015, author = {Beck, Hanna and Titze, Stephanie I. and H{\"u}bner, Silvia and Busch, Martin and Schlieper, Georg and Schultheiss, Ulla T. and Wanner, Christoph and Kronenberg, Florian and Krane, Vera and Eckardt, Kai-Uwe and K{\"o}ttgen, Anna}, title = {Heart Failure in a Cohort of Patients with Chronic Kidney Disease: The GCKD Study}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {4}, doi = {10.1371/journal.pone.0122552}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143315}, pages = {e0122552}, year = {2015}, abstract = {Background and Aims Chronic kidney disease (CKD) is a risk factor for development and progression of heart failure (HF). CKD and HF share common risk factors, but few data exist on the prevalence, signs and symptoms as well as correlates of HF in populations with CKD of moderate severity. We therefore aimed to examine the prevalence and correlates of HF in the German Chronic Kidney Disease (GCKD) study, a large observational prospective study. Methods and Results We analyzed data from 5,015 GCKD patients aged 18-74 years with an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73m\(^{2}\) or with an eGFR >= 60 and overt proteinuria (>500 mg/d). We evaluated a definition of HF based on the Gothenburg score, a clinical HF score used in epidemiological studies (Gothenburg HF), and self-reported HF. Factors associated with HF were identified using multivariable adjusted logistic regression. The prevalence of Gothenburg HF was 43\% (ranging from 24\% in those with eGFR >90 to 59\% in those with eGFR<30 ml/min/1.73m2). The corresponding estimate for self-reported HF was 18\% (range 5\%-24\%). Lower eGFR was significantly and independently associated with the Gothenburg definition of HF (p-trend <0.001). Additional significantly associated correlates included older age, female gender, higher BMI, hypertension, diabetes mellitus, valvular heart disease, anemia, sleep apnea, and lower educational status. Conclusions The burden of self-reported and Gothenburg HF among patients with CKD is high. The proportion of patients who meet the criteria for Gothenburg HF in a European cohort of patients with moderate CKD is more than twice as high as the prevalence of self-reported HF. However, because of the shared signs, symptoms and medications of HF and CKD, the Gothenburg score cannot be used to reliably define HF in CKD patients. Our results emphasize the need for early screening for HF in patients with CKD.}, language = {en} } @article{BeckEhmannAndlaueretal.2015, author = {Beck, Katherina and Ehmann, Nadine and Andlauer, Till F. M. and Ljaschenko, Dmitrij and Strecker, Katrin and Fischer, Matthias and Kittel, Robert J. and Raabe, Thomas}, title = {Loss of the Coffin-Lowry syndrome-associated gene RSK2 alters ERK activity, synaptic function and axonal transport in Drosophila motoneurons}, series = {Disease Models \& Mechanisms}, volume = {8}, journal = {Disease Models \& Mechanisms}, doi = {10.1242/dmm.021246}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145185}, pages = {1389-1400}, year = {2015}, abstract = {Plastic changes in synaptic properties are considered as fundamental for adaptive behaviors. Extracellular-signal-regulated kinase (ERK)-mediated signaling has been implicated in regulation of synaptic plasticity. Ribosomal S6 kinase 2 (RSK2) acts as a regulator and downstream effector of ERK. In the brain, RSK2 is predominantly expressed in regions required for learning and memory. Loss-of-function mutations in human RSK2 cause Coffin-Lowry syndrome, which is characterized by severe mental retardation and low IQ scores in affected males. Knockout of RSK2 in mice or the RSK ortholog in Drosophila results in a variety of learning and memory defects. However, overall brain structure in these animals is not affected, leaving open the question of the pathophysiological consequences. Using the fly neuromuscular system as a model for excitatory glutamatergic synapses, we show that removal of RSK function causes distinct defects in motoneurons and at the neuromuscular junction. Based on histochemical and electrophysiological analyses, we conclude that RSK is required for normal synaptic morphology and function. Furthermore, loss of RSK function interferes with ERK signaling at different levels. Elevated ERK activity was evident in the somata of motoneurons, whereas decreased ERK activity was observed in axons and the presynapse. In addition, we uncovered a novel function of RSK in anterograde axonal transport. Our results emphasize the importance of fine-tuning ERK activity in neuronal processes underlying higher brain functions. In this context, RSK acts as a modulator of ERK signaling.}, language = {en} } @article{Beck2015, author = {Beck, Lukas}, title = {Kein K{\"o}nig von Mallorca mehr}, series = {JURA - Juristische Ausbildung}, volume = {37}, journal = {JURA - Juristische Ausbildung}, number = {4}, issn = {1612-7021}, doi = {10.1515/jura-2015-0070}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-194158}, pages = {383 -- 395}, year = {2015}, abstract = {Kein Abstract verf{\"u}gbar.}, language = {de} } @phdthesis{Becker2015, author = {Becker, Johannes}, title = {Development and implementation of new simulation possibilities in the CAST program package}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132032}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {The aim of the present work is the development and implementation of new simulation possibilities for the CAST program package. Development included, among other things, the partial parallelization of the already existing force fields, extension of the treatment of electrostatic interactions and implementation of molecular dynamics and free energy algorithms. The most time consuming part of force field calculations is the evaluation of the nonbonded interactions. The calculation of these interactions has been parallelized and it could be shown to yield a significant speed up for multi-core calculations compared to the serial execution on only one CPU. For both, simple energy/gradient as well as molecular dynamics simulations the computational time could be significantly reduced. To further increase the performance of calculations employing a cutoff radius, a linkedcell algorithm was implemented which is able to build up the non-bonded interaction list up to 7 times faster than the original algorithm. To provide access to dynamic properties based on the natural time evolution of a system, a molecular dynamics code has been implemented. The MD implementation features two integration schemes for the equations of motion which are able to generate stable trajectories. The basic MD algorithm as described in Section 1.2 leads to the sampling in the microcanonical (NVE) ensemble. The practical use of NVE simulations is limited though because it does not correspond to any experimentally realistic situation. More realistic simulation conditions are found in the isothermal (NVT) and isothermalisobaric (NPT) ensembles. To generate those ensembles, temperature and pressure control has been implemented. The temperature can be controlled in two ways: by direct velocity scaling and by a Nose-Hoover thermostat which produces a real canonical ensemble. The pressure coupling is realized by implementation of a Berendsen barostat. The pressure coupling can be used for isotropic or anisotropic box dimensions with the restriction that the angles of the box need to be 90� . A crucial simulation parameter in MD simulations is the length of the timestep. The timestep is usually in the rang of 1fs. Increasing the timestep beyond 1fs can lead to unstable trajectories since the fastest motion in the system, usually the H-X stretch vibration can not be sampled anymore. A way to allow for bigger timesteps is the use of a constraint algorithm which constrains the H-X bonds to the equilibrium distance. For this the RATTLE algorithm has been implemented in the CAST program. The velocity Verlet algorithm in combination with the RATTLE algorithm has been shown to yield stable trajectories for an arbitrary length of simulation time. In a first application the MD implementation is used in conjunction with the MOPAC interface for the investigation of PBI sidechains and their rigidity. The theoretical investigations show a nice agreement with experimentally obtained results. Based on the MD techniques two algorithms for the determination of free energy differences have been implemented. The umbrella sampling algorithm can be used to determine the free energy change along a reaction coordinate based on distances or dihedral angles. The implementation was tested on the stretching of a deca-L-alanine and the rotation barrier of butane in vacuum. The results are in nearly perfect agreement with literature values. For the FEP implementation calculations were performed for a zero-sum transformation of ethane in explicit solvent, the charging of a sodium ion in explicit solvent and the transformations of a tripeptide in explicit solvent. All results are in agreement with benchmark calculations of the NAMD program as well as literature values. The FEP formalism was then applied to determine the relative binding free energies between two inhibitors in an inhibitor-protein complex. Next to force fields, ab-initio methods can be used for simulations and global optimizations. Since the performance of such methods is usually significantly poorer than force field applications, the use for global optimizations is limited. Nevertheless significant progress has been made by porting these codes to GPUs. In order to make use of these developments a MPI interface has been implemented into CAST for communication with the DFT code TeraChem. The CAST/TeraChem combination has been tested on the \$H_2 O_{10}\$ cluster as well as the polypeptide met-Enkephalin. The pure ab-initio calculations showed a superior behavior compared to the standard procedure where the force field results are usually refined using quantum chemical methods.}, subject = {Molekulardynamik}, language = {en} } @article{BeckerRauSchmittetal.2015, author = {Becker, Philip P. and Rau, Monika and Schmitt, Johannes and Malsch, Carolin and Hammer, Christian and Bantel, Heike and M{\"u}llhaupt, Beat and Geier, Andreas}, title = {Performance of serum microRNAs -122, -192 and -21 as biomarkers in patients with non-alcoholic steatohepatitis}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0142661}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145147}, pages = {e0142661}, year = {2015}, abstract = {Objectives Liver biopsies are the current gold standard in non-alcoholic steatohepatitis (NASH) diagnosis. Their invasive nature, however, still carries an increased risk for patients' health. The development of non-invasive diagnostic tools to differentiate between bland steatosis (NAFL) and NASH remains crucial. The aim of this study is the evaluation of investigated circulating microRNAs in combination with new targets in order to optimize the discrimination of NASH patients by non-invasive serum biomarkers. Methods Serum profiles of four microRNAs were evaluated in two cohorts consisting of 137 NAFLD patients and 61 healthy controls. In a binary logistic regression model microRNAs of relevance were detected. Correlation of microRNA appearance with known biomarkers like ALT and CK18-Asp396 was evaluated. A simplified scoring model was developed, combining the levels of microRNA in circulation and CK18-Asp396 fragments. Receiver operating characteristics were used to evaluate the potential of discriminating NASH. Results The new finding of our study is the different profile of circulating miR-21 in NASH patients (p<0.0001). Also, it validates recently published results of miR-122 and miR-192 to be differentially regulated in NAFL and NASH. Combined microRNA expression profiles with CK18-Asp396 fragment level scoring model had a higher potential of NASH prediction compared to other risk biomarkers (AUROC = 0.83, 95\% CI = 0.754-0.908; p<0.001). Evaluation of score model for NAFL (Score = 0) and NASH (Score = 4) had shown high rates of sensitivity (91\%) and specificity (83\%). Conclusions Our study defines candidates for a combined model of miRNAs and CK18-Asp396 levels relevant as a promising expansion for diagnosis and in turn treatment of NASH.}, language = {en} } @article{BeissSpiegelBoesetal.2015, author = {Beiss, Veronique and Spiegel, Holger and Boes, Alexander and Scheuermayer, Matthias and Reimann, Andreas and Schillberg, Stefan and Fischer, Rainer}, title = {Plant expression and characterization of the transmission-blocking vaccine candidate PfGAP50}, series = {BMC Biotechnology}, volume = {15}, journal = {BMC Biotechnology}, number = {108}, doi = {10.1186/s12896-015-0225-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137327}, year = {2015}, abstract = {Background: Despite the limited success after decades of intensive research and development efforts, vaccination still represents the most promising strategy to significantly reduce the disease burden in malaria endemic regions. Besides the ultimate goal of inducing sterile protection in vaccinated individuals, the prevention of transmission by so-called transmission blocking vaccines (TBVs) is being regarded as an important feature of an efficient malaria eradication strategy. Recently, Plasmodium falciparum GAP50 (PfGAP50), a 44.6 kDa transmembrane protein that forms an essential part of the invasion machinery (glideosome) multi-protein complex, has been proposed as novel potential transmission-blocking candidate. Plant-based expression systems combine the advantages of eukaryotic expression with a up-scaling potential and a good product safety profile suitable for vaccine production. In this study we investigated the feasibility to use the transient plant expression to produce PfGAP50 suitable for the induction of parasite specific inhibitory antibodies. Results: We performed the transient expression of recombinant PfGAP50 in Nicotiana benthamiana leaves using endoplasmatic reticulum (ER) and plastid targeting. After IMAC-purification the protein yield and integrity was investigated by SDS-PAGE and Western Blot. Rabbit immune IgG derived by the immunization with the plastidtargeted variant of PfGAP50 was analyzed by immune fluorescence assay (IFA) and zygote inhibition assay (ZIA). PfGAP50 could be produced in both subcellular compartments at different yields IMAC (Immobilized Metal Affinity Chromatography) purification from extract yielded up to 4.1 mu g/g recombinant protein per fresh leaf material for ER-retarded and 16.2 mu g/g recombinant protein per fresh leave material for plasmid targeted PfGAP50, respectively. IgG from rabbit sera generated by immunization with the recombinant protein specifically recognized different parasite stages in immunofluorescence assay. Furthermore up to 55 \% inhibition in an in vitro zygote inhibition assay could be achieved using PfGAP50-specific rabbit immune IgG. Conclusions: The results of this study demonstrate that the plant-produced PfGAP50 is functional regarding the presentation of inhibitory epitopes and could be considered as component of a transmission-blocking malaria vaccine formulation.}, language = {en} } @phdthesis{BeitzenHeineke2015, author = {Beitzen-Heineke, Antonia}, title = {Invariant Natural Killer T cells possess immune-modulating functions during \(Aspergillus\) \(fumigatus\) infection}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144966}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Aspergillus fumigatus is the most common cause for invasive fungal infections, a disease associated with high mortality in immune-compromised patients. CD1d-restricted invariant Natural Killer T (iNKT) cells compose a small subset of T cells known to impact the immune response towards various infectious pathogens. To investigate the role of human iNKT cells during A. fumigatus infection, we studied their activation as determined by CD69 expression and cytokine production in response to distinct fungal morphotypes in the presence of different CD1d⁺ antigen presenting cells using flow cytometry and multiplex ELISA. Among CD1d⁺ subpopulations, CD1d⁺CD1c⁺ mDCs showed the highest potential to activate iNKT cells on a per cell basis. The presence of A. fumigatus decreased this effect of CD1d⁺CD1c⁺ mDCs on iNKT cells and led to reduced secretion of TNF-α, G-CSF and RANTES. Production of other Th1 and Th2 cytokines was not affected by the fungus, suggesting an immune-modulating function for human iNKT cells during A. fumigatus infection.}, subject = {Aspergillus fumigatus}, language = {en} } @phdthesis{Bellwon2015, author = {Bellwon, Patricia}, title = {Kinetic assessment by in vitro approaches - A contribution to reduce animals in toxicity testing}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122693}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {The adoption of directives and regulations by the EU requires the development of alternative testing strategies as opposed to animal testing for risk assessment of xenobiotics. Additionally, high attrition rates of drugs late in the discovery phase demand improvement of current test batteries applied in the preclinical phase within the pharmaceutical area. These issues were taken up by the EU founded 7th Framework Program "Predict-IV"; with the overall goal to improve the predictability of safety of an investigational product, after repeated exposure, by integration of "omics" technologies applied on well established in vitro approaches. Three major target organs for drug-induced toxicity were in focus: liver, kidney and central nervous system. To relate obtained dynamic data with the in vivo situation, kinetics of the test compounds have to be evaluated and extrapolated by physiologically based pharmacokinetic modeling. This thesis assessed in vitro kinetics of the selected test compounds (cyclosporine A, adefovir dipivoxil and cisplatinum) regarding their reliability and relevance to respective in vivo pharmacokinetics. Cells were exposed daily or every other day to the test compounds at two concentration levels (toxic and non-toxic) for up to 14 days. Concentrations of the test compounds or their major biotransformation products were determined by LC-MS/MS or ICP-MS in vehicle, media, cells and plastic adsorption samples generated at five different time-points on the first and the last treatment day. Cyclosporine A bioaccumulation was evident in primary rat hepatocytes (PRH) at the high concentration, while efficient biotransformation mediated by CYP3A4 and CYP3A5 was determined in primary human hepatocytes (PHH) and HepaRG cells. The lower biotransformation in PRH is in accordance with observation made in vivo with the rat being a poor model for CYP3A biotransformation. Further, inter-assay variability was noticed in PHH caused by biological variability in CYP3A4 and CYP3A5 activity in human donors. The inter-assay variability observed for PRH and HepaRG cells was a result of differences between vehicles regarding their cyclosporine A content. Cyclosporine A biotransformation was more prominent in HepaRG cells due to stable and high CYP3A4 and CYP3A5 activity. In addition, in vitro clearances were calculated and scaled to in vivo. All scaled in vitro clearances were overestimated (PRH: 10-fold, PHH: 2-fold, HepaRG cells: 2-fold). These results should be proven by physiologically-based pharmacokinetic modeling and additional experiments, in order to verify that these overestimations are constant for each system and subsequently can be diminished by implementation of further scaling factors. Brain cell cultures, primary neuronal culture of mouse cortex cells and primary aggregating rat brain cells, revealed fast achieved steady state levels of cyclosporine A. This indicates a chemical distribution of cyclosporine A between the aqueous and organic phases and only minor involvement of biological processes such as active transport and biotransformation. Hence, cyclosporine A uptake into cells is presumably transport mediated, supported by findings of transporter experiments performed on a parallel artificial membrane and Caco-2 cells. Plastic adsorption of cyclosporine A was significant, but different for each model, and should be considered by physiologically based pharmacokinetic modeling. Kinetics of adefovir dipivoxil highlights the limits of in vitro approaches. Active transporters are required for adefovir uptake, but were not functional in RPTECT/TERT1. Therefore, adefovir uptake was limited to passive diffusion of adefovir dipivoxil, which itself degrades time-dependently under culture conditions. Cisplatinum kinetics, studied in RPTEC/TERT1 cells, indicated intracellular enrichment of platinum, while significant bioaccumulation was not noted. This could be due to cisplatinum not reaching steady state levels within 14 days repeated exposure. As shown in vivo, active transport occurred from the basolateral to apical side, but with lower velocity. Hence, obtained data need to be modeled to estimate cellular processes, which can be scaled and compared to in vivo. Repeated daily exposure to two different drug concentrations makes it possible to account for bioaccumulation at toxic concentrations or biotransformation/extrusion at non-toxic concentrations. Potential errors leading to misinterpretation of data were reduced by analyses of the vehicles as the applied drug concentrations do not necessarily correspond to the nominal concentrations. Finally, analyses of separate compartments (medium, cells, plastic) give insights into a compound's distribution, reduce misprediction of cellular processes, e.g. biotransformation, and help to interpret kinetic data. On the other hand, the limits of in vitro approaches have also been pointed out. For correct extrapolation to in vivo, it is essential that the studied in vitro system exhibits the functionality of proteins, which play a key role in the specific drug induced toxicity. Considering the benefits and limitations, it is worth to validate this long-term treatment experimental set-up and expand it on co-culture systems and on organs-on-chips with regard to alternative toxicity testing strategies for repeated dose toxicity studies.}, subject = {Zellkultur}, language = {en} } @phdthesis{Benkert2015, author = {Benkert, Thomas}, title = {Neue Steady-State-Techniken in der Magnetresonanztomographie}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115381}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Die bSSFP-Sequenz kombiniert kurze Akquisitionszeiten mit einem hohen Signal-zu-Rausch-Verh{\"a}ltnis, was sie zu einer vielversprechenden Bildgebungsmethode macht. Im klinischen Alltag ist diese Technik jedoch bisher - abgesehen von vereinzelten Anwendungen - kaum etabliert. Die Hauptgr{\"u}nde hierf{\"u}r sind Signalausl{\"o}schungen in Form von Bandingartefakten sowie der erzielte T2/T1-gewichtete Mischkontrast. Das Ziel dieser Dissertation war die Entwicklung von Methoden zur L{\"o}sung der beiden genannten Limitationen, um so eine umfassendere Verwendung von bSSFP f{\"u}r die MR-Diagnostik zu erm{\"o}glichen. Magnetfeldinhomogenit{\"a}ten, die im Wesentlichen durch Suszeptibilit{\"a}tsunterschiede oder Imperfektionen seitens der Scannerhardware hervorgerufen werden, {\"a}ußern sich bei der bSSFP-Bildgebung in Form von Bandingartefakten. Mit DYPR-SSFP (DYnamically Phase-cycled Radial bSSFP) wurde ein Verfahren vorgestellt, um diese Signalausl{\"o}schungen effizient zu entfernen. W{\"a}hrend f{\"u}r bereits existierende Methoden mehrere separate bSSFP-Bilder akquiriert und anschließend kombiniert werden m{\"u}ssen, ist f{\"u}r die Bandingentfernung mittels DYPR-SSFP lediglich die Aufnahme eines einzelnen Bildes notwendig. Dies wird durch die neuartige Kombination eines dynamischen Phasenzyklus mit einer radialen Trajektorie mit quasizuf{\"a}lligem Abtastschema erm{\"o}glicht. Die notwendigen Bestandteile k{\"o}nnen mit geringem Aufwand implementiert werden. Des Weiteren ist kein spezielles Rekonstruktionsschema notwendig, was die breite Anwendbarkeit des entwickelten Ansatzes erm{\"o}glicht. Konventionelle Methoden zur Entfernung von Bandingartefakten werden sowohl bez{\"u}glich ihrer Robustheit als auch bez{\"u}glich der notwendigen Messzeit {\"u}bertroffen. Um die Anwendbarkeit von DYPR-SSFP auch jenseits der gew{\"o}hnlichen Bildgebung zu demonstrieren, wurde die Methode mit der Fett-Wasser-Separation kombiniert. Basierend auf der Dixon-Technik konnten so hochaufgel{\"o}ste Fett- sowie Wasserbilder erzeugt werden. Aufgrund der Bewegungsinsensitiv{\"a}t der zugrunde liegenden radialen Trajektorie konnten die Messungen unter freier Atmung durchgef{\"u}hrt werden, ohne dass nennenswerte Beeintr{\"a}chtigungen der Bildqualit{\"a}t auftraten. Die erzielten Ergebnisse am Abdomen zeigten weder Fehlzuordnungen von Fett- und Wasserpixeln noch verbleibende Bandingartefakte. Ein Nachteil der gew{\"o}hnlichen Dixon-basierten Fett-Wasser-Separation ist es, dass mehrere separate Bilder zu verschiedenen Echozeiten ben{\"o}tigt werden. Dies f{\"u}hrt zu einer entsprechenden Verl{\"a}ngerung der zugeh{\"o}rigen Messzeit. Abhilfe schafft hier die Verwendung einer Multiecho-Sequenz. Wie gezeigt werden konnte, erm{\"o}glicht eine derartige Kombination die robuste, bandingfreie Fett-Wasser-Separation in klinisch akzeptablen Messzeiten. DYPR-SSFP erlaubt die Entfernung von Bandingartefakten selbst bei starken Magnetfeldinhomogenit{\"a}ten. Dennoch ist es m{\"o}glich, dass Signalausl{\"o}schungen aufgrund des Effekts der Intravoxeldephasierung verbleiben. Dieses Problem tritt prim{\"a}r bei der Bildgebung von Implantaten oder am Ultrahochfeld auf. Als Abhilfe hierf{\"u}r wurde die Kombination von DYPR-SSFP mit der sogenannten z-Shim-Technik untersucht, was die Entfernung dieser Artefakte auf Kosten einer erh{\"o}hten Messzeit erm{\"o}glichte. Die mit DYPR-SSFP akquirierten radialen Projektionen weisen aufgrund des angewendeten dynamischen Phasenzyklus leicht verschiedene Signallevel und Phasen auf. Diese Tatsache zeigt sich durch inkoh{\"a}rente Bildartefakte, die sich jedoch durch eine Erh{\"o}hung der Projektionsanzahl effektiv reduzieren lassen. Folglich bietet es sich in diesem Kontext an, Anwendungen zu w{\"a}hlen, bei denen bereits intrinsisch eine verh{\"a}ltnism{\"a}ßig hohe Anzahl von Projektionen ben{\"o}tigt wird. Hierbei hat sich gezeigt, dass neben der hochaufgel{\"o}sten Bildgebung die Wahl einer 3D radialen Trajektorie eine aussichtsreiche Kombination darstellt. Die in der vorliegenden Arbeit vorgestellte 3D DYPR-SSFP-Technik erlaubte so die isotrope bandingfreie bSSFP-Bildgebung, wobei die Messzeit im Vergleich zu einer gew{\"o}hnlichen bSSFP-Akquisition konstant gehalten werden konnte. Verbleibende, durch den dynamischen Phasenzyklus hervorgerufene Artefakte konnten effektiv mit einem Rauschunterdr{\"u}ckungsalgorithmus reduziert werden. Anhand Probandenmessungen wurde gezeigt, dass 3D DYPR-SSFP einen aussichtsreichen Kandidaten f{\"u}r die Bildgebung von Hirnnerven sowie des Bewegungsapparats darstellt. W{\"a}hrend die DYPR-SSFP-Methode sowie die darauf beruhenden Weiterentwicklungen effiziente L{\"o}sungen f{\"u}r das Problem der Bandingartefakte bei der bSSFP-Bildgebung darstellen, adressiert die vorgestellte RA-TOSSI-Technik (RAdial T-One sensitive and insensitive Steady-State Imaging) das Problem des bSSFP-Mischkontrasts. Die M{\"o}glichkeit der Generierung von T2-Kontrasten basierend auf der bSSFP-Sequenz konnte bereits in vorausgehenden Arbeiten gezeigt werden. Hierbei wurde die Tatsache ausgenutzt, dass der T1-Anteil des Signalverlaufs nach Beginn einer bSSFP-Akquisition durch das Einf{\"u}gen von Inversionspulsen in ungleichm{\"a}ßigen Abst{\"a}nden aufgehoben werden kann. Ein so akquiriertes Bild weist folglich einen reinen, klinisch relevanten T2-Kontrast auf. Die im Rahmen dieser Arbeit vorgestellte Methode basiert auf dem gleichen Prinzip, jedoch wurde anstelle einer gew{\"o}hnlichen kartesischen Trajektorie eine radiale Trajektorie in Kombination mit einer KWIC-Filter-Rekonstruktion verwendet. Somit k{\"o}nnen bei gleichbleibender oder sogar verbesserter Bildqualit{\"a}t aus einem einzelnen, mit RA-TOSSI akquirierten Datensatz verschiedene T2-Wichtungen als auch gew{\"o}hnliche T2/T1-Wichtungen generiert werden. Mittels Variation der Anzahl der eingef{\"u}gten Inversionspulse konnte ferner gezeigt werden, dass es neben den besagten Wichtungen m{\"o}glich ist, zus{\"a}tzliche Kontraste zu generieren, bei denen verschiedene Substanzen im Bild ausgel{\"o}scht sind. Diese Substanzen k{\"o}nnen am Beispiel der Gehirnbildgebung Fett, graue Masse, weiße Masse oder CSF umfassen und zeichnen sich neben den reinen T2-Kontrasten durch eine {\"a}hnlich hohe klinische Relevanz aus. Die m{\"o}gliche Bedeutung der vorgestellten Methode f{\"u}r die klinische Verwendung wurde durch Messungen an einer Gehirntumorpatientin demonstriert. Zusammenfassend l{\"a}sst sich sagen, dass die im Rahmen dieser Dissertation entwickelten Techniken einen wertvollen Beitrag zur L{\"o}sung der eingangs beschriebenen Probleme der bSSFP-Bildgebung darstellen. Mit DYPR-SSFP akquirierte Bilder sind bereits mit bestehender, kommerzieller Rekonstruktionssoftware direkt am Scanner rekonstruierbar. Die Software f{\"u}r die Rekonstruktion von RA-TOSSI-Datens{\"a}tzen wurde f{\"u}r Siemens Scanner implementiert. Folglich sind beide Methoden f{\"u}r klinische Studien einsetzbar, was gleichzeitig den Ausblick dieser Arbeit darstellt.}, subject = {Kernspintomografie}, language = {de} } @article{BenoitGoebeler2015, author = {Benoit, Sandrine and Goebeler, Matthias}, title = {Mepacrine in recalcitrant cutaneous lupus erythematosus: old-fashioned or still useful?}, series = {Acta Dermato-Venereologica}, volume = {95}, journal = {Acta Dermato-Venereologica}, doi = {10.2340/00015555-2031}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149181}, pages = {596-599}, year = {2015}, abstract = {Treatment of recalcitrant cutaneous lupus erythematosus (CLE) is challenging. In situations where conventional treatment approaches fail mepacrine - an antimalarial/antiinfiammatory drug that has fallen into oblivion in the last decades might still be a promising option. We retrospectively analysed medical records of 10 patients with refractory CLE that were treated with mepacrine (100-200 mg/day) as mono- or combination therapy for various time intervals between 2001 and 2013 at the University Hospital Wurzburg. Mepacrine was generally well tolerated. Side effects were mild and usually resolved after reduction or cessation. Over 50\% of the patients experienced amelioration of their symptoms despite a previously recalcitrant clinical course. Altogether, our data demonstrate that mepacrine still remains a useful and effective therapeutic option for otherwise treatment-resistant CLE.}, language = {en} } @phdthesis{Benthin2015, author = {Benthin, Heiko}, title = {Ist die Anwendung lungenprotektiver Beatmungsmuster mit Tidalvolumina von 6 ml/kg K{\"o}rpergewicht bei mehr als 90\% aller beatmeten Patienten Fakt oder Fiktion?}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117951}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Zusammenfassung Hintergrund Das akute Atemnotsyndrom des Erwachsenen (ARDS = Acute respiratory distress Syndrome) hat bei einer Inzidenz von 60 F{\"a}llen auf 100.000 Einwohner eine Letalit{\"a}t von 27-45\%. Außer der Behandlung der zum ARDS f{\"u}hrenden Grunderkrankung und der lungenprotektiven Beatmung gibt es bisher keine bahnbrechenden Neuerungen in der Therapie. Ziel der Arbeit Mehr als 90\% aller beatmeten Patienten eines privaten Klinikkonzerns sollten lungenprotektiv beatmet werden und die Ergebnisse {\"u}ber drei Monate protokolliert werden. Material und Methoden Die {\"a}rztlichen und pflegerischen Mitarbeiter aller beteiligten Intensivstationen wurden in der Anwendung der lungenprotektiven Beatmung geschult. Im Anschluss wurden {\"u}ber einen Zeitraum von drei Monaten die biometrischen Daten, sowie die Beatmungsparameter aller beatmeten Patienten erfasst. Ergebnisse Es wurden 851 Patienten mit 4346 Beatmungsstunden auf 24 Intensivstationen in die Studie eingeschlossen. Abweichungen von den vorgegebenen Beatmungsparametern gab es an 38,4\% der Beatmungstage, f{\"u}hrend als Ursache f{\"u}r eine Abweichung waren Spontanatmung, Patienten mit chronisch obstruktiven Atemwegserkrankungen oder erh{\"o}htem intrakraniellem Druck. Die t{\"a}gliche Selbsteinsch{\"a}tzung {\"u}ber die korrekte Einhaltung der Beatmungsparameter und die objektive Beurteilung der Einstellungen deckten sich nicht. Von den Patienten im Weaning gab es nur bei 0,2\% der Patienten keinen Grund f{\"u}r eine weitere Beatmung. Schlussfolgerung Das Ziel mehr als 90\% aller Patienten lungenprotektiv zu beatmen wurde nicht erreicht. Das Ziel ist erreichbar, wenn nur die invasiv beatmeten Patienten eingeschlossen werden. Als Fazit bleiben zwei wesentliche Aussagen: Die wichtigste Therapie des ARDS ist die Therapie der zur respiratorischen Insuffizienz f{\"u}hrenden Grunderkrankung. Der wichtigste Faktor f{\"u}r die Anwendung der lungenprotektiven Beatmung ist die Schulung und die Kontrolle der Anwender.}, subject = {Assistierte Beatmung}, language = {de} } @article{BenzJonesYounasetal.2015, author = {Benz, Roland and Jones, Michael D. and Younas, Farhan and Maier, Elke and Modi, Niraj and Mentele, Reinhard and Lottspeich, Friedrich and Kleinekath{\"o}fer, Ulrich and Smit, John}, title = {OmpW of Caulobacter crescentus functions as an outer membrane channel for cations}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0143557}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145114}, pages = {e0143557}, year = {2015}, abstract = {Caulobacter crescentus is an oligotrophic bacterium that lives in dilute organic environments such as soil and freshwater. This bacterium represents an interesting model for cellular differentiation and regulation because daughter cells after division have different forms: one is motile while the other is non-motile and can adhere to surfaces. Interestingly, the known genome of C. crescentus does not contain genes predicted to code for outer membrane porins of the OmpF/C general diffusion type present in enteric bacteria or those coding for specific porins selective for classes of substrates. Instead, genes coding for 67 TonB-dependent outer membrane receptors have been identified, suggesting that active transport of specific nutrients may be the norm. Here, we report that high channel-forming activity was observed with crude outer membrane extracts of C. crescentus in lipid bilayer experiments, indicating that the outer membrane of C. crescentus contained an ion-permeable channel with a single-channel conductance of about 120 pS in 1M KCl. The channel-forming protein with an apparent molecular mass of about 20 kDa was purified to homogeneity. Partial protein sequencing of the protein indicated it was a member of the OmpW family of outer membrane proteins from Gram-negative bacteria. This channel was not observed in reconstitution experiments with crude outer membrane extracts of an OmpW deficient C. crescentus mutant. Biophysical analysis of the C. crescentus OmpW suggested that it has features that are special for general diffusion porins of Gram-negative outer membranes because it was not a wide aqueous channel. Furthermore, OmpW of C. crescentus seems to be different to known OmpW porins and has a preference for ions, in particular cations. A putative model for OmpW of C. crescentus was built on the basis of the known 3D-structures of OmpW of Escherichia coli and OprG of Pseudomonas aeruginosa using homology modeling. A comparison of the two known structures with the model of OmpW of C. crescentus suggested that it has a more hydrophilic interior and possibly a larger diameter.}, language = {en} } @article{BerenikeHerrmannvanDalenOskamSchoech2015, author = {Berenike Herrmann, J. and van Dalen-Oskam, Karina and Sch{\"o}ch, Christof}, title = {Revisiting Style, a Key Concept in Literary Studies}, series = {Journal of Literary Theory}, volume = {9}, journal = {Journal of Literary Theory}, number = {1}, issn = {1862-8990}, doi = {10.1515/jlt-2015-0003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-194349}, pages = {25-52}, year = {2015}, abstract = {Language and literary studies have studied style for centuries, and even since the advent of ›stylistics‹ as a discipline at the beginning of the twentieth century, definitions of ›style‹ have varied heavily across time, space and fields. Today, with increasingly large collections of literary texts being made available in digital form, computational approaches to literary style are proliferating. New methods from disciplines such as corpus linguistics and computer science are being adopted and adapted in interrelated fields such as computational stylistics and corpus stylistics, and are facilitating new approaches to literary style. The relation between definitions of style in established linguistic or literary stylistics, and definitions of style in computational or corpus stylistics has not, however, been systematically assessed. This contribution aims to respond to the need to redefine style in the light of this new situation and to establish a clearer perception of both the overlap and the boundaries between ›mainstream‹ and ›computational‹ and/or ›empirical‹ literary stylistics. While stylistic studies of non-literary texts are currently flourishing, our contribution deliberately centers on those approaches relevant to ›literary stylistics‹. It concludes by proposing an operational definition of style that we hope can act as a common ground for diverse approaches to literary style, fostering transdisciplinary research. The focus of this contribution is on literary style in linguistics and literary studies (rather than in art history, musicology or fashion), on textual aspects of style (rather than production- or reception-oriented theories of style), and on a descriptive perspective (rather than a prescriptive or didactic one). Even within these limits, however, it appears necessary to build on a broad understanding of the various perspectives on style that have been adopted at different times and in different traditions. For this reason, the contribution first traces the development of the notion of style in three different traditions, those of German, Dutch and French language and literary studies. Despite the numerous links between each other, and between each of them to the British and American traditions, these three traditions each have their proper dynamics, especially with regard to the convergence and/or confrontation between mainstream and computational stylistics. For reasons of space and coherence, the contribution is limited to theoretical developments occurring since 1945. The contribution begins by briefly outlining the range of definitions of style that can be encountered across traditions today: style as revealing a higher-order aesthetic value, as the holistic ›gestalt‹ of single texts, as an expression of the individuality of an author, as an artifact presupposing choice among alternatives, as a deviation from a norm or reference, or as any formal property of a text. The contribution then traces the development of definitions of style in each of the three traditions mentioned, with the aim of giving a concise account of how, in each tradition, definitions of style have evolved over time, with special regard to the way such definitions relate to empirical, quantitative or otherwise computational approaches to style in literary texts. It will become apparent how, in each of the three traditions, foundational texts continue to influence current discussions on literary style, but also how stylistics has continuously reacted to broader developments in cultural and literary theory, and how empirical, quantitative or computational approaches have long ­existed, usually in parallel to or at the margins of mainstream stylistics. The review will also reflect the lines of discussion around style as a property of literary texts - or of any textual entity in general. The perspective on three stylistic traditions is accompanied by a more systematic perspective. The rationale is to work towards a common ground for literary scholars and linguists when talking about (literary) style, across traditions of stylistics, with respect for established definitions of style, but also in light of the digital paradigm. Here, we first show to what extent, at similar or different moments in time, the three traditions have developed comparable positions on style, and which definitions out of the range of possible definitions have been proposed or promoted by which authors in each of the three traditions. On the basis of this synthesis, we then conclude by proposing an operational definition of style that is an attempt to provide a common ground for both mainstream and computational literary stylistics. This definition is discussed in some detail in order to explain not only what is meant by each term in the definition, but also how it relates to computational analyses of style - and how this definition aims to avoid some of the pitfalls that can be perceived in earlier definitions of style. Our definition, we hope, will be put to use by a new generation of computational, quantitative, and empirical studies of style in literary texts.}, language = {en} } @article{BergSchellingHailuetal.2015, author = {Berg, Stefan and Schelling, Esther and Hailu, Elena and Firdessa, Rebuma and Gumi, Balako and Erenso, Girume and Gadisa, Endalamaw and Mengistu, Araya and Habtamu, Meseret and Hussein, Jemal and Kiros, Teklu and Bekele, Shiferaw and Mekonnen, Wondale and Derese, Yohannes and Zinsstag, Jakob and Ameni, Gobena and Gagneux, Sebastien and Robertson, Brian D and Tschopp, Rea and Hewinson, Glyn and Yamuah, Lawrence and Gordon, Stephen V and Aseffa, Abraham}, title = {Investigation of the high rates of extrapulmonary tuberculosis in Ethiopia reveals no single driving factor and minimal evidence for zoonotic transmission of Mycobacterium bovis infection}, series = {BMC Infectious Diseases}, volume = {15}, journal = {BMC Infectious Diseases}, number = {112}, doi = {10.1186/s12879-015-0846-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143935}, year = {2015}, abstract = {Background: Ethiopia, a high tuberculosis (TB) burden country, reports one of the highest incidence rates of extra-pulmonary TB dominated by cervical lymphadenitis (TBLN). Infection with Mycobacterium bovis has previously been excluded as the main reason for the high rate of extra-pulmonary TB in Ethiopia. Methods: Here we examined demographic and clinical characteristics of 953 pulmonary (PTB) and 1198 TBLN patients visiting 11 health facilities in distinct geographic areas of Ethiopia. Clinical characteristics were also correlated with genotypes of the causative agent, Mycobacterium tuberculosis. Results: No major patient or bacterial strain factor could be identified as being responsible for the high rate of TBLN, and there was no association with HIV infection. However, analysis of the demographic data of involved patients showed that having regular and direct contact with live animals was more associated with TBLN than with PTB, although no M. bovis was isolated from patients with TBLN. Among PTB patients, those infected with Lineage 4 reported "contact with other TB patient" more often than patients infected with Lineage 3 did (OR = 1.6, CI 95\% 1.0-2.7; p = 0.064). High fever, in contrast to low and moderate fever, was significantly associated with Lineage 4 (OR = 2.3; p = 0.024). On the other hand, TBLN cases infected with Lineage 4 tended to get milder symptoms overall for the constitutional symptoms than those infected with Lineage 3. Conclusions: The study suggests a complex role for multiple interacting factors in the epidemiology of extra-pulmonary TB in Ethiopia, including factors that can only be derived from population-based studies, which may prove to be significant for TB control in Ethiopia.}, language = {en} } @phdthesis{Bergler2015, author = {Bergler, Felix}, title = {Photolumineszenzbasierte Untersuchung der Struktur und der thermodynamischen Bildungsparameter mizellar stabilisierter (6,5)-Kohlenstoffnanor{\"o}hren}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123586}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {In dieser Arbeit werden die Wechselwirkungen zwischen der Oberfl{\"a}che von Kohlenstoffnanor{\"o}hren und verschiedenen Dispergierreagenzien anhand der Photolumineszenz (PL) der (6,5)-Nanor{\"o}hren untersucht. Um den Einfluss der verschiedenen Reagenzien auf die exzitonischen Eigenschaften und die PL-Emission zu quantifizieren, wurden die Dispergierreagenzien ausgetauscht, die Temperaturabh{\"a}ngigkeit bestimmt und die Konzentration der Reagenzien variiert. Die Dispergierreagenzien eines immobilisierten, SC-stabilisierten (6,5)-SWNT-Ensembles wurden im Mikrofluidikkanal ausgetauscht. Wird der Kanal mit Wasser gesp{\"u}lt, verringern sich die PL-Intensit{\"a}t und die Emissionsenergie, da der Wasserfluss die Tensidmolek{\"u}le von der Oberfl{\"a}che entfernt. Beim Austausch einer DOC-Umgebung gegen Wasser nimmt die PL-Intensit{\"a}t ebenfalls ab und die PL-Emissionsenergie verringert sich. Die Austauschexperimente verlaufen reversibel und der instantane Anstieg der Emissionsenergie bei der Tensidadsorption weist auf eine kooperative Anlagerung hin. Deshalb ist anzunehmen, dass sich Tensid-SWNT-Heteromizellen ausbilden. Anschließend werden die Emissionsenergie und die PL-Intensit{\"a}t in verschiedenen Dispergierreagenzien und in Wasser verglichen. Die gr{\"o}ßte Emissionsenergie und PL-Intensit{\"a}t werden w{\"a}hrend des Wechsels von einer SDS- zu einer (GT)16-L{\"o}sung gemessen. Dies kann auf die l{\"u}ckenlose Bedeckung der SWNT-Oberfl{\"a}che mit einer heterogenen Schicht aus SDS-Molek{\"u}len und (GT)16-Str{\"a}ngen zur{\"u}ckgef{\"u}hrt werden. In reiner SDS-Umgebung emittieren die Nanor{\"o}hren Licht mit der zweith{\"o}chsten Energie, aber die PL-Intensit{\"a}t liegt unter der in einer SC-Umgebung. Die Emissionsenergie in der SC-Umgebung ist geringer und davon abh{\"a}ngig, ob die SWNTs bereits mit (GT)16-Str{\"a}ngen stabilisiert waren, da dies eine permanente Rotverschiebung der Emissionsenergie in der SC-Umgebung sowie eine verringerte PL-Intensit{\"a}t verursacht. In w{\"a}ssriger Umgebung verringert sich nach erfolgtem (GT)16-Kontakt die PL-Intensit{\"a}t dauerhaft. Danach wurde die Anlagerung von Tensidmolek{\"u}len an die (6,5)-SWNT-Oberfl{\"a}che in Suspensionen mit der Temperatursprungmethode untersucht. Die Temperatur im Mikrofluidikkanal wurde anhand der linearen Abnahme der Emissionsenergie SC- und DOC-stabilisierter SWNTs mit steigender Temperatur bestimmt. Die Suspensionstemperatur ist in den verschiedenen Temperatursprungexperimenten unabh{\"a}ngig von der Messposition im Mikrofluidikkanal und wird durch die absolute Position auf den Peltier-Elementen bestimmt. Zudem stimmen die im Kanal gemessenen Temperaturen f{\"u}r SC- und DOC-stabilisierte (6,5)-SWNTs {\"u}berein, weshalb in diesem Experiment nicht die erwartete Einstellung eines Gleichgewichts wie in einem Temperatursprungexperiment der Fall, sondern die Momentantemperatur gemessen wird. Die schnelle Gleichgewichtseinstellung zwischen freien und auf der SWNT-Oberfl{\"a}che adsorbierten Tensidmolek{\"u}len beim Temperatursprung zeigt, dass die SC- und DOC-(6,5)-SWNT-Suspensionen thermochrome Farbstoffe sind. Wegen der Temperaturabh{\"a}ngigkeit der Emissionsenergie ist es bei wissenschaftlichen Arbeiten wichtig, neben dem verwendeten Dispergierreagenz auch die Temperatur der SWNT-Suspension anzugeben. Abschließend wurden die kritischen Mizellenkonzentrationen von Tensid-SWNT-Suspensionen in Verd{\"u}nnungsexperimenten und daraus die thermodynamischen Bildungsparameter der Tensid-SWNT-Heteromizellen ermittelt. In der temperaturabh{\"a}ngigen Analyse der SC-SWNT-Mizellenbildung wird ein konstanter Hill-Koeffizient erhalten, der die Mizellenbildung als positiv kooperativ klassifiziert. F{\"u}r die Bestimmung der Freien Mizellierungsenthalpie wurden nur die CMCs aus den Verd{\"u}nnungsexperimenten verwendet, da die Mizellenbildung bei der Aufkonzentration teils kinetisch gehemmt ist. Da die Freie Mizellierungsenthalpie bei allen Temperaturen negativ ist, stabilisiert die Bildung der Heteromizellen das System. Die Triebkraft f{\"u}r die Mizellenbildung ist {\"u}ber 322 K die Enthalpie, w{\"a}hrend unterhalb von 316 K der Entropiegewinn dominiert. Die Verd{\"u}nnung einer DOC-SWNT-Suspension zeigt keine {\"A}nderung der Emissionsenergie, obwohl dabei sowohl die prim{\"a}re als auch die sekund{\"a}re CMC von DOC unterschritten werden. Zuletzt wurden die Verd{\"u}nnungsexperimente mit einer SDS-SWNT-Suspension durchgef{\"u}hrt und die thermodynamischen Parameter der Mizellenbildung bestimmt. Da auf die Aufl{\"o}sung der Mizellenstruktur direkt die Aggregation der SWNTs folgt, wurde f{\"u}r die Ermittlung der CMC n{\"a}herungsweise die Konzentration am Maximum der Emissionsenergie verwendet. Daraus ergibt sich bei jeder Temperatur eine negative Freie Mizellierungsenthalpie, deren Beitr{\"a}ge analog zu SC bei kleineren Temperaturen als 323 K entropisch und bei h{\"o}heren Temperaturen enthalpisch dominiert werden. Somit erm{\"o}glichen die Experimente mit SC- und SDS-SWNT-Suspensionen die temperaturabh{\"a}ngige Bestimmung der CMC und damit die Berechnung der Freien Mizellierungsenthalpie sowie der zugeh{\"o}rigen enthalpischen und entropischen Beitr{\"a}ge.}, subject = {Kohlenstoff-Nanor{\"o}hre}, language = {de} } @phdthesis{Berner2015, author = {Berner, G{\"o}tz}, title = {Funktionelle oxidische Heterostrukturen aus dem Blickwinkel der Spektroskopie}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121721}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {In oxidischen Heterostrukturen rufen Neuordnung von Ladung und Spin eine Vielzahl von unerwarteten physikalischen Eigenschaften hervor. Die M{\"o}glichkeit, Leitf{\"a}higkeit, Magnetismus oder auch Hochtemperatur-Supraleitung zu kontrollieren, machen diese k{\"u}nstlich hergestellten Materialien vor allem in Hinblick auf eine zuk{\"u}nftige Anwendung in der Mikroelektronik {\"a}ußerst interessant. Dies erfordert jedoch ein grunds{\"a}tzliches Verst{\"a}ndnis f{\"u}r die zugrunde liegenden Mechanismen. Die vorliegende Doktorarbeit befasst sich mit photonengest{\"u}tzter Spektroskopie, die einen direkten Zugang zur elektronischen Struktur dieser Heterostruktursysteme erm{\"o}glicht. Ein weiteres Ziel ist es, geeignete spektroskopische Methoden zur Charakterisierung der vergrabenen Schichten zu etablieren. Zwei prototypische oxidische Mehrschichtsysteme stehen im Zentrum der hier vorgestellten Untersuchungen. Das LaAlO3/SrTiO3-Heterostruktursystem weist ab einer kritischen LaAlO3-Filmdicke an der Grenzfl{\"a}che ein zweidimensionales Elektronensystem mit hochmobilen Ladungstr{\"a}gern auf. Als treibender Mechanismus wird die elektronische Rekonstruktion diskutiert. Im Rahmen dieser Arbeit wurde dieses zweidimensionale Elektronensystem mithilfe der Photoelektronenspektroskopie und der resonanten inelastischen R{\"o}ntgenstreuung charakterisiert. Die daraus bestimmten Ladungstr{\"a}gerdichten weisen im Vergleich mit Daten aus Transportmessungen auf eine Koexistenz von lokalisierten und mobilen Ladungstr{\"a}gern an der Grenzfl{\"a}che hin. Die Analyse von Rumpfniveau- und Valenzbandspektren zeigt, dass man zur Erkl{\"a}rung der experimentellen Resultate ein modifiziertes Bild der elektronischen Rekonstruktion ben{\"o}tigt, bei der Sauerstofffehlstellen an der LaAlO3-Oberfl{\"a}che als Ladungsreservoir dienen k{\"o}nnten. Mithilfe der resonanten Photoelektronenspektroskopie war es m{\"o}glich, die metallischen Zust{\"a}nde am chemischen Potential impulsaufgel{\"o}st zu spektroskopieren. So gelang es erstmals, die vergrabene Fermi-Fl{\"a}che einer oxidischen Heterostruktur zu vermessen. Außerdem konnten Titan-artige Zust{\"a}nde identifiziert werden, die h{\"o}chstwahrscheinlich durch Sauerstofffehlstellen im SrTiO3 lokalisiert sind. Diese werden als m{\"o}gliche Quelle f{\"u}r den Ferromagnetismus interpretiert, der mit der supraleitenden Phase in der LaAlO3/SrTiO3-Heterostruktur koexistiert. Bei dem anderen hier untersuchten Mehrschichtsystem handelt es sich um die LaNiO3-LaAlO3-{\"U}bergitterstruktur. Der Einbau des metallischen LaNiO3 in eine Heterostruktur ist aufgrund seiner N{\"a}he zu einer korrelationsinduzierten isolierenden Phase hinsichtlich einer kontrollierten Ausbildung von neuartigen Phasen besonders interessant. In der Tat beobachtet man unterhalb einer LaNiO3-Schichtdicke von vier Einheitszellen einen kontinuierlichen Metall-Isolator-{\"U}bergang, der sich in den Valenzbandspektren durch einen Verlust an Quasiteilchenkoh{\"a}renz {\"a}ußert. Auch wenn die impulsaufgel{\"o}sten Daten am Fermi-Niveau durch Photoelektronenbeugung beeinflusst sind, so l{\"a}sst sich dennoch eine Fermi-Fl{\"a}che identifizieren. Ihre Topologie bietet die M{\"o}glichkeit eines Fermi-Fl{\"a}chen-Nestings mit der Ausbildung einer Spindichtewelle. Die Resultate unterst{\"u}tzen die Hinweise auf eine magnetische Ordnung im zweidimensionalen Grundzustand.}, subject = {Heterostruktur}, language = {de} } @article{BiegstraatenArngrimssonBarbeyetal.2015, author = {Biegstraaten, Marieke and Arngr{\´i}msson, Reynir and Barbey, Frederic and Boks, Lut and Cecchi, Franco and Deegan, Patrick B and Feldt-Rasmussen, Ulla and Geberhiwot, Tarekegn and Germain, Dominique P and Hendriksz, Chris and Hughes, Derralynn A and Kantola, Ilkka and Karabul, Nesrin and Lavery, Christine and Linthorst, Gabor E and Mehta, Atul and van de Mheen, Erica and Oliveira, Jo{\~a}o P and Parini, Rossella and Ramaswami, Uma and Rudnicki, Michael and Serra, Andreas and Sommer, Claudia and Sunder-Plassmann, Gere and Svarstad, Einar and Sweeb, Annelies and Terryn, Wim and Tylki-Szymanska, Anna and T{\o}ndel, Camilla and Vujkovac, Bojan and Weidemann, Frank and Wijburg, Frits A and Woolfson, Peter and Hollak, Carla EM}, title = {Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document}, series = {Orphanet Journal of Rare Diseases}, volume = {10}, journal = {Orphanet Journal of Rare Diseases}, number = {36}, doi = {10.1186/s13023-015-0253-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175374}, year = {2015}, abstract = {Introduction: Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD. Methods: A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75\% agreement and no disagreement. Results: For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m\(^{2}\)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped. Conclusion: The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.}, language = {en} } @phdthesis{Bieker2015, author = {Bieker, Steffen}, title = {Time and Spatially Resolved Photoluminescence Spectroscopy of Hot Excitons in Gallium Arsenide}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134419}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {The present thesis investigates the impact of hot exciton effects on the low-temperature time and spatially resolved photoluminescence (PL) response of free excitons in high-purity gallium arsenide (GaAs). The work at hand extends available studies of hot carrier effects, which in bulk GaAs have up to now focused on hot electron populations. In crucial distinction from previous work, we extensively study the free exciton second LO-phonon replica. The benefit of this approach is twofold. First, the two LO phonon-assisted radiative recombination allows to circumvent the inherent interpretation ambiguities of the previously investigated free exciton zero-phonon line. Second, the recombination line shape of the second LO-phonon replica provides direct experimental access to the exciton temperature, thereby enabling the quantitative assessment of hot exciton effects. In the first part of the thesis, we address the influence of transient cooling on the time evolution of an initially hot photocarrier ensemble. To this end, we investigate time-resolved photoluminescence (TRPL) signals detected on the free exciton second LO-phonon replica. Settling a long-standing question, we show by comparison with TRPL transients of the free exciton zero-phonon line that the slow free exciton photoluminescence rise following pulsed optical excitation is dominated by the slow buildup of a free exciton population and not by the relaxation of large K-vector excitons to the Brillouin zone center. To establish a quantitative picture of the delayed photoluminescence onset, we determine the cooling dynamics of the initially hot photocarrier cloud from a time-resolved line shape analysis of the second LO-phonon replica. We demonstrate that the Saha equation, which fundamentally describes the thermodynamic population balance between free excitons and the uncorrelated electron-hole plasma, directly translates the experimentally derived cooling curves into the time-dependent conversion of unbound electron-hole pairs into free excitons. In the second part of the thesis, we establish the impact of hot exciton effects on low-temperature spatially resolved photoluminescence (SRPL) studies. Such experiments are widely used to investigate charge carrier and free exciton diffusion in semiconductors and semiconductor nanostructures. By SRPL spectroscopy of the second LO-phonon replica, we show that above-band gap focused laser excitation inevitably causes local heating in the carrier system, which crucially affects the diffusive expansion of a locally excited exciton packet. Undistorted free exciton diffusion profiles, which are correctly described by the commonly used formulation of the photocarrier diffusion equation, are only observed in the absence of spatial temperature gradients. At low sample temperatures, the reliable determination of free exciton diffusion coefficients from both continuous-wave and time-resolved SRPL spectroscopy requires strictly resonant optical excitation. Using resonant laser excitation, we observe the dimensional crossover of free exciton diffusion in etched wire structures of a thin, effectively two-dimensional GaAs epilayer. When the lateral wire width falls below the diffusion length, the sample geometry becomes effectively one-dimensional. The exciton diffusion profile along the wire stripe is then consistently reproduced by the steady-state solution to the one-dimensional diffusion equation. Finally, we demonstrate the formation of macroscopic free and bound exciton photoluminescence rings in bulk GaAs around a focused laser excitation spot. Both ring formation effects are due to pump-induced local heating in the exciton system. For a quantitative assessment of the mechanism underlying the free exciton ring formation, we directly determine the exciton temperature gradient from a spatially resolved line shape analysis of the free exciton second LO-phonon replica. We demonstrate that a pump-induced hot spot locally modifies the thermodynamic population balance between free excitons and unbound electron-hole pairs described by the Saha equation, which naturally explains the emergence of macroscopic free exciton ring structures. In summary, we demonstrate that quantitative consideration of hot exciton effects provides a coherent picture both of the time-domain free exciton luminescence kinetics and of the distinct spatially resolved photoluminescence patterns developing under the influence of spatial photocarrier diffusion.}, subject = {Exziton}, language = {en} } @article{BiernackaSangkuhlJenkinsetal.2015, author = {Biernacka, J. M. and Sangkuhl, K. and Jenkins, G. and Whaley, R. M. and Barman, P. and Batzler, A. and Altman, R. B. and Arolt, V. and Brockm{\"o}ller, J. and Chen, C. H. and Domschke, K. and Hall-Flavin, D. K. and Hong, C. J. and Illi, A. and Ji, Y. and Kampman, O. and Kinoshita, T. and Leinonen, E. and Liou, Y. J. and Mushiroda, T. and Nonen, S. and Skime, M. K. and Wang, L. and Baune, B. T. and Kato, M. and Liu, Y. L. and Praphanphoj, V. and Stingl, J. C. and Tsai, S. J. and Kubo, M. and Klein, T. E. and Weinshilboum, R.}, title = {The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response}, series = {Translational Psychiatry}, volume = {5}, journal = {Translational Psychiatry}, number = {e553}, doi = {10.1038/tp.2015.47}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143223}, year = {2015}, abstract = {Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50\% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N = 2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P = 5.03E - 08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.}, language = {en} } @article{BittnerBobakHofmannetal.2015, author = {Bittner, Stefan and Bobak, Nicole and Hofmann, Majella-Sophie and Schuhmann, Michael K. and Ruck, Tobias and G{\"o}bel, Kerstin and Br{\"u}ck, Wolfgang and Wiendl, Heinz and Meuth, Sven G.}, title = {Murine K\(_{2P}\)5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K\(_{2P}\)3.1-and K\(_{V}\)1.3-Dependent Mechanisms}, series = {International Journal of Molecular Sciences}, volume = {16}, journal = {International Journal of Molecular Sciences}, doi = {10.3390/ijms160816880}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151454}, pages = {16880 -- 16896}, year = {2015}, abstract = {Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K\(_{2P}\)5.1(TASK2; KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T lymphocytes in patients with multiple sclerosis and rheumatoid arthritis. In humans, K\(_{2P}\)5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K\(_{2P}\)5.1 is currently hampered by a lack of highly selective inhibitors, making it necessary to evaluate the impact of KCNK5 in established preclinical animal disease models. We here demonstrate that K\(_{2P}\)5.1 knockout (K\(_{2P}\)5.1\(^{-/-}\) mice display no significant alterations concerning T cell cytokine production, proliferation rates, surface marker molecules or signaling pathways. In an experimental model of autoimmune neuroinflammation, K\(_{2P}\)5.1\(^{-/-}\) mice show a comparable disease course to wild-type animals and no major changes in the peripheral immune system or CNS compartment. A compensatory upregulation of the potassium channels K\(_{2P}\)3.1 and K\(_{V}\)1.3 seems to counterbalance the deletion of K\(_{2P}\)5.1. As an alternative model mimicking autoimmune neuroinflammation, experimental autoimmune encephalomyelitis in the common marmoset has been proposed, especially for testing the efficacy of new potential drugs. Initial experiments show that K\(_{2P}\)5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K\(_{2P}\)5.1-targeting drugs.}, language = {en} } @article{BlancoKuchenbaeckerCuadrasetal.2015, author = {Blanco, Ignacio and Kuchenbaecker, Karoline and Cuadras, Daniel and Wang, Xianshu and Barrowdale, Daniel and Ruiz de Garibay, Gorka and Librado, Pablo and Sanchez-Gracia, Alejandro and Rozas, Julio and Bonifaci, N{\´u}ria and McGuffog, Lesley and Pankratz, Vernon S. and Islam, Abul and Mateo, Francesca and Berenguer, Antoni and Petit, Anna and Catal{\`a}, Isabel and Brunet, Joan and Feliubadal{\´o}, Lidia and Tornero, Eva and Ben{\´i}tez, Javier and Osorio, Ana and Ram{\´o}n y Cajal, Teresa and Nevanlinna, Heli and Aittom{\"a}ki, Kristina and Arun, Banu K. and Toland, Amanda E. and Karlan, Beth Y. and Walsh, Christine and Lester, Jenny and Greene, Mark H. and Mai, Phuong L. and Nussbaum, Robert L. and Andrulis, Irene L. and Domchek, Susan M. and Nathanson, Katherine L. and Rebbeck, Timothy R. and Barkardottir, Rosa B. and Jakubowska, Anna and Lubinski, Jan and Durda, Katarzyna and Jaworska-Bieniek, Katarzyna and Claes, Kathleen and Van Maerken, Tom and D{\´i}ez, Orland and Hansen, Thomas V. and J{\o}nson, Lars and Gerdes, Anne-Marie and Ejlertsen, Bent and De la Hoya, Miguel and Cald{\´e}s, Trinidad and Dunning, Alison M. and Oliver, Clare and Fineberg, Elena and Cook, Margaret and Peock, Susan and McCann, Emma and Murray, Alex and Jacobs, Chris and Pichert, Gabriella and Lalloo, Fiona and Chu, Carol and Dorkins, Huw and Paterson, Joan and Ong, Kai-Ren and Teixeira, Manuel R. and Hogervorst, Frans B. L. and Van der Hout, Annemarie H. and Seynaeve, Caroline and Van der Luijt, Rob B. and Ligtenberg, Marjolijn J. L. and Devilee, Peter and Wijnen, Juul T. and Rookus, Matti A. and Meijers-Heijboer, Hanne E. J. and Blok, Marinus J. and Van den Ouweland, Ans M. W. and Aalfs, Cora M. and Rodriguez, Gustavo C. and Phillips, Kelly-Anne A. and Piedmonte, Marion and Nerenstone, Stacy R. and Bae-Jump, Victoria L. and O'Malley, David M. and Schmutzler, Rita K. and Wappenschmidt, Barbara and Rhiem, Kerstin and Engel, Christoph and Meindl, Alfons and Ditsch, Nina and Arnold, Norbert and Plendl, Hansjoerg J. and Niederacher, Dieter and Sutter, Christian and Wang-Gohrke, Shan and Steinemann, Doris and Preisler-Adams, Sabine and Kast, Karin and Varon-Mateeva, Raymonda and Gehrig, Andrea and Bojesen, Anders and Pedersen, Inge Sokilde and Sunde, Lone and Birk Jensen, Uffe and Thomassen, Mads and Kruse, Torben A. and Foretova, Lenka and Peterlongo, Paolo and Bernard, Loris and Peissel, Bernard and Scuvera, Giulietta and Manoukian, Siranoush and Radice, Paolo and Ottini, Laura and Montagna, Marco and Agata, Simona and Maugard, Christine and Simard, Jacques and Soucy, Penny and Berger, Andreas and Fink-Retter, Anneliese and Singer, Christian F. and Rappaport, Christine and Geschwantler-Kaulich, Daphne and Tea, Muy-Kheng and Pfeiler, Georg and John, Esther M. and Miron, Alex and Neuhausen, Susan L. and Terry, Mary Beth and Chung, Wendy K. and Daly, Mary B. and Goldgar, David E. and Janavicius, Ramunas and Dorfling, Cecilia M. and Van Rensburg, Elisabeth J. and Fostira, Florentia and Konstantopoulou, Irene and Garber, Judy and Godwin, Andrew K. and Olah, Edith and Narod, Steven A. and Rennert, Gad and Paluch, Shani Shimon and Laitman, Yael and Friedman, Eitan and Liljegren, Annelie and Rantala, Johanna and Stenmark-Askmalm, Marie and Loman, Niklas and Imyanitov, Evgeny N. and Hamann, Ute and Spurdle, Amanda B. and Healey, Sue and Weitzel, Jeffrey N. and Herzog, Josef and Margileth, David and Gorrini, Chiara and Esteller, Manel and G{\´o}mez, Antonio and Sayols, Sergi and Vidal, Enrique and Heyn, Holger and Stoppa-Lyonnet, Dominique and L{\´e}on{\´e}, Melanie and Barjhoux, Laure and Fassy-Colcombet, Marion and Pauw, Antoine de and Lasset, Christine and Fert Ferrer, Sandra and Castera, Laurent and Berthet, Pascaline and Cornelis, Fran{\c{c}}ois and Bignon, Yves-Jean and Damiola, Francesca and Mazoyer, Sylvie and Sinilnikova, Olga M. and Maxwell, Christopher A. and Vijai, Joseph and Robson, Mark and Kauff, Noah and Corines, Marina J. and Villano, Danylko and Cunningham, Julie and Lee, Adam and Lindor, Noralane and L{\´a}zaro, Conxi and Easton, Douglas F. and Offit, Kenneth and Chenevix-Trench, Georgia and Couch, Fergus J. and Antoniou, Antonis C. and Pujana, Miguel Angel}, title = {Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {4}, doi = {10.1371/journal.pone.0120020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143469}, pages = {e0120020}, year = {2015}, abstract = {While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95\% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10\(^{-4}\) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95\% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p\(_{interaction}\) values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.}, language = {en} } @phdthesis{Blankenbach2015, author = {Blankenbach, Margareta}, title = {Phasic und Sustained Fear im Startle Versuch}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126826}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {In der vorliegenden Studie sollten Phasic und Sustained Fear Zust{\"a}nde hervorgerufen und durch Messung des Akustischen Startle Reflexes erfasst werden. Dazu wurde ein Instructed Fear Paradigma eingesetzt, bei dem 37 gesunde Probanden durch visuelle Darstellung {\"u}ber die M{\"o}glichkeit eines aversiven Stimulus (weiblicher Schrei) in der sogenannten Schreckbedingung informiert wurden. Zum Vergleich wurde eine neutrale, sichere Versuchsbedingung geschaltet. Beide Bedingungen wurden {\"u}ber drei verschiedene L{\"a}ngen (kurz, mittel, lang) in mehreren Wiederholungen pr{\"a}sentiert. Bei zunehmender Dauer einer Versuchsphase sollte durch zunehmende Unvorhersehbarkeit die Sustained Fear Reaktion gesteigert werden. Außerdem war beabsichtigt, antizipatorische Angst (Erwartungsangst) durch die Vorschaltung einer kurzen, ereignislosen Antizipationsphase vor jede Versuchsphase auszul{\"o}sen. Die Ergebnisse zeigten, dass die Schreckbedingungen zu erh{\"o}hten Startle Reaktionen f{\"u}hrten, welche sich als sichere Zeichen einer Angstreaktion deuten lassen. In der kurzen Dauer der Versuchsbedingung (4-8 s) l{\"a}sst sich aufgrund des unmittelbar einsetzenden Schreckreizes eine Phasic Fear Reaktion detektieren. F{\"u}r die mittlere Dauer (10-18 s) kommt eine Sustained Fear Reaktion in Betracht, da der Hinweis auf die Gefahr in keinem engen zeitlichen Zusammenhang mit dem Schreckreiz steht und weniger vorhersehbar ist. In der langen Dauer (30-50 s) zeigte sich invers zu unserer Annahme, eine starke Abnahme der Startle Amplituden. Dieses Ph{\"a}nomen ist mit dem Eingreifen kognitiver emotionsregulatorischer Mechanismen erkl{\"a}rbar. Die postexperimentelle Befragung der Teilnehmer weist darauf hin, dass es zu einer Umdeutung der angstausl{\"o}senden Situation in eine zunehmend langweilige Situation kam. Somit k{\"o}nnte diese Neuinterpretation zur Verringerung der Startle Amplituden gef{\"u}hrt haben. Die Antizipationsphase ergab einen antizipatorischen Effekt, obwohl die Versuchsteilnehmer nicht {\"u}ber diese vorgeschaltete Phase informiert waren. Allerdings ließ sich keine unterschiedliche Auswirkung durch die Aussicht auf verschieden lange, d.h. unterschiedlich vorhersehbare Versuchsbedingungen feststellen. Daher ist nicht mit Sicherheit davon auszugehen, ob tats{\"a}chlich antizipatorische Angst ausgel{\"o}st wurde, oder ob es sich aufgrund der kurzen Zeit nicht eher um eine Phasic Fear Reaktion handeln k{\"o}nnte. Des Weiteren bleibt zu hinterfragen, inwiefern die nicht gekennzeichnete Antizipationsphase zu einer Verschiebung des Zeitrasters der Versuchsdauern gef{\"u}hrt haben k{\"o}nnten. Dies l{\"a}sst sich im Nachhinein nicht eindeutig kl{\"a}ren. Daher ist die vermutete Phasic Fear Reaktion in der kurzen L{\"a}nge kritisch zu betrachten, und eventuell als beginnende Sustained Fear zu interpretieren. Die Bewertung der Bedingungen ist mit den Startle Daten dahingehend konsistent, dass die Schreckbedingung als aufregender eingestuft wird. Es ergab sich kein Unterschied in der Bewertung der verschiedenen Versuchsdauern innerhalb der Schreckbedingung. Damit konnte kein Effekt der gr{\"o}ßeren Unvorhersehbarkeit auf die subjektive Einsch{\"a}tzung festgestellt werden. Auch die emotionsregulatorischen Prozesse spiegeln sich nicht in der Bewertung wider. Abschließend l{\"a}sst sich sagen, dass verschiedene Entit{\"a}ten der Angst, wie phasische, anhaltende und antizipatorische Angst, hervorgerufen werden konnten, welche sich {\"u}ber die Zeit ver{\"a}ndern. Dauert die Angst l{\"a}nger an, wird sie schließlich durch Eingreifen corticaler Regulationsmechanismen unterdr{\"u}ckt. Weitere Untersuchungen, z.B. mit fMRT, k{\"o}nnten dieses Ph{\"a}nomen genauer entschl{\"u}sseln.}, subject = {Angst}, language = {de} } @article{BleinBardelDanjeanetal.2015, author = {Blein, Sophie and Bardel, Claire and Danjean, Vincent and McGuffog, Lesley and Healay, Sue and Barrowdale, Daniel and Lee, Andrew and Dennis, Joe and Kuchenbaecker, Karoline B. and Soucy, Penny and Terry, Mary Beth and Chung, Wendy K. and Goldgar, David E. and Buys, Saundra S. and Janavicius, Ramunas and Tihomirova, Laima and Tung, Nadine and Dorfling, Cecilia M. and van Rensburg, Elizabeth J. and Neuhausen, Susan L. and Ding, Yuan Chun and Gerdes, Anne-Marie and Ejlertsen, Bent and Nielsen, Finn C. and Hansen, Thomas V. O. and Osorio, Ana and Benitez, Javier and Andreas Conejero, Raquel and Segota, Ena and Weitzel, Jeffrey N. and Thelander, Margo and Peterlongo, Paolo and Radice, Paolo and Pensotti, Valeria and Dolcetti, Riccardo and Bonanni, Bernardo and Peissel, Bernard and Zaffaroni, Daniela and Scuvera, Giulietta and Manoukian, Siranoush and Varesco, Liliana and Capone, Gabriele L. and Papi, Laura and Ottini, Laura and Yannoukakos, Drakoulis and Konstantopoulou, Irene and Garber, Judy and Hamann, Ute and Donaldson, Alan and Brady, Angela and Brewer, Carole and Foo, Claire and Evans, D. Gareth and Frost, Debra and Eccles, Diana and Douglas, Fiona and Cook, Jackie and Adlard, Julian and Barwell, Julian and Walker, Lisa and Izatt, Louise and Side, Lucy E. and Kennedy, M. John and Tischkowitz, Marc and Rogers, Mark T. and Porteous, Mary E. and Morrison, Patrick J. and Platte, Radka and Eeles, Ros and Davidson, Rosemarie and Hodgson, Shirley and Cole, Trevor and Godwin, Andrew K and Isaacs, Claudine and Claes, Kathleen and De Leeneer, Kim and Meindl, Alfons and Gehrig, Andrea and Wappenschmidt, Barbara and Sutter, Christian and Engel, Christoph and Niederacher, Dieter and Steinemann, Doris and Plendl, Hansjoerg and Kast, Karin and Rhiem, Kerstin and Ditsch, Nina and Arnold, Norbert and Varon-Mateeva, Raymonda and Schmutzler, Rita K. and Preisler-Adams, Sabine and Markov, Nadja Bogdanova and Wang-Gohrke, Shan and de Pauw, Antoine and Lefol, Cedrick and Lasset, Christine and Leroux, Dominique and Rouleau, Etienne and Damiola, Francesca and Dreyfus, Helene and Barjhoux, Laure and Golmard, Lisa and Uhrhammer, Nancy and Bonadona, Valerie and Sornin, Valerie and Bignon, Yves-Jean and Carter, Jonathan and Van Le, Linda and Piedmonte, Marion and DiSilvestro, Paul A. and de la Hoya, Miguel and Caldes, Trinidad and Nevanlinna, Heli and Aittom{\"a}ki, Kristiina and Jager, Agnes and van den Ouweland, Ans M. W. and Kets, Carolien M. and Aalfs, Cora M. and van Leeuwen, Flora E. and Hogervorst, Frans B. L. and Meijers-Heijboer, Hanne E. J. and Oosterwijk, Jan C. and van Roozendaal, Kees E. P. and Rookus, Matti A. and Devilee, Peter and van der Luijt, Rob B. and Olah, Edith and Diez, Orland and Teule, Alex and Lazaro, Conxi and Blanco, Ignacio and Del Valle, Jesus and Jakubowska, Anna and Sukiennicki, Grzegorz and Gronwald, Jacek and Spurdle, Amanda B. and Foulkes, William and Olswold, Curtis and Lindor, Noralene M. and Pankratz, Vernon S. and Szabo, Csilla I. and Lincoln, Anne and Jacobs, Lauren and Corines, Marina and Robson, Mark and Vijai, Joseph and Berger, Andreas and Fink-Retter, Anneliese and Singer, Christian F. and Rappaport, Christine and Geschwantler Kaulich, Daphne and Pfeiler, Georg and Tea, Muy-Kheng and Greene, Mark H. and Mai, Phuong L. and Rennert, Gad and Imyanitov, Evgeny N. and Mulligan, Anna Marie and Glendon, Gord and Andrulis, Irene L. and Tchatchou, Andrine and Toland, Amanda Ewart and Pedersen, Inge Sokilde and Thomassen, Mads and Kruse, Torben A. and Jensen, Uffe Birk and Caligo, Maria A. and Friedman, Eitan and Zidan, Jamal and Laitman, Yael and Lindblom, Annika and Melin, Beatrice and Arver, Brita and Loman, Niklas and Rosenquist, Richard and Olopade, Olufunmilayo I. and Nussbaum, Robert L. and Ramus, Susan J. and Nathanson, Katherine L. and Domchek, Susan M. and Rebbeck, Timothy R. and Arun, Banu K. and Mitchell, Gillian and Karlan, Bethy Y. and Lester, Jenny and Orsulic, Sandra and Stoppa-Lyonnet, Dominique and Thomas, Gilles and Simard, Jacques and Couch, Fergus J. and Offit, Kenenth and Easton, Douglas F. and Chenevix-Trench, Georgia and Antoniou, Antonis C. and Mazoyer, Sylvie and Phelan, Catherine M. and Sinilnikova, Olga M. and Cox, David G.}, title = {An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers}, series = {Breast Cancer Research}, volume = {17}, journal = {Breast Cancer Research}, number = {61}, doi = {10.1186/s13058-015-0567-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145458}, year = {2015}, abstract = {Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95\% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95\% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.}, language = {en} } @article{BoddenRichterSchreiberetal.2015, author = {Bodden, Carina and Richter, S. Helene and Schreiber, Rebecca S. and Kloke, Vanessa and Gerß, Joachim and Palme, Rupert and Lesch, Klaus-Peter and Lewejohann, Lars and Kaiser, Sylvia and Sachser, Norbert}, title = {Benefits of adversity?! How life history affects the behavioral profile of mice varying in serotonin transporter genotype}, series = {Frontiers in Behavioral Neuroscience}, volume = {9}, journal = {Frontiers in Behavioral Neuroscience}, number = {47}, doi = {10.3389/fnbeh.2015.00047}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143723}, year = {2015}, abstract = {Behavioral profiles are influenced by both positive and negative experiences as well as the genetic disposition. Traditionally, accumulating adversity over lifetime is considered to predict increased anxiety like behavior ("allostatic load"). The alternative "mismatch hypothesis" suggests increased levels of anxiety if the early environment differs from the later-life environment. Thus, there is a need for a whole-life history approach to gain a deeper understanding of how behavioral profiles are shaped. The aim of this study was to elucidate the effects of life history on the behavioral profile of mice varying in serotonin transporter (5-HIT) genotype, an established mouse model of increased anxiety-like behavior. For this purpose, mice grew up under either adverse or beneficial conditions during early phases of life. In adulthood, they were further subdivided so as to face a situation that either matched or mismatched the condition experienced so far, resulting in four different life histories. Subsequently, mice were tested for their anxiety-like and exploratory behavior. The main results were: (1) Life history profoundly modulated the behavioral profile. Surprisingly, mice that experienced early beneficial and later escapable adverse conditions showed less anxiety-like and more exploratory behavior compared to mice of other life histories. (2) Genotype significantly influenced the behavioral profile, with homozygous 5-HTT knockout mice displaying highest levels of anxiety-like and lowest levels of exploratory behavior. Our findings concerning life history indicate that the absence of adversity does not necessarily cause lower levels of anxiety than accumulating adversity. Rather, some adversity may be beneficial, particularly when following positive events. Altogether, we conclude that for an understanding of behavioral profiles, it is not sufficient to look at experiences during single phases of life, but the whole life history has to be considered.}, language = {en} } @article{BoehmeRitterTefikowetal.2015, author = {Boehme, Stephanie and Ritter, Viktoria and Tefikow, Susan and Stangier, Ulrich and Strauss, Bernhard and Miltner, Wolfgang H. R. and Straube, Thomas}, title = {Neural correlates of emotional interference in social anxiety disorder}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0128608}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148534}, pages = {e0128608}, year = {2015}, abstract = {Disorder-relevant but task-unrelated stimuli impair cognitive performance in social anxiety disorder (SAD); however, time course and neural correlates of emotional interference are unknown. The present study investigated time course and neural basis of emotional interference in SAD using event-related functional magnetic resonance imaging (fMRI). Patients with SAD and healthy controls performed an emotional stroop task which allowed examining interference effects on the current and the succeeding trial. Reaction time data showed an emotional interference effect in the current trial, but not the succeeding trial, specifically in SAD. FMRI data showed greater activation in the left amygdala, bilateral insula, medial prefrontal cortex (mPFC), dorsal anterior cingulate cortex (ACC), and left opercular part of the inferior frontal gyrus during emotional interference of the current trial in SAD patients. Furthermore, we found a positive correlation between patients' interference scores and activation in the mPFC, dorsal ACC and left angular/supramarginal gyrus. Taken together, results indicate a network of brain regions comprising amygdala, insula, mPFC, ACC, and areas strongly involved in language processing during the processing of task-unrelated threat in SAD. However, specifically the activation in mPFC, dorsal ACC, and left angular/supramarginal gyrus is associated with the strength of the interference effect, suggesting a cognitive network model of attentional bias in SAD. This probably comprises exceeded allocation of attentional resources to disorder-related information of the presented stimuli and increased self-referential and semantic processing of threat words in SAD.}, language = {en} } @article{BoelchJansenMeffertetal.2015, author = {Boelch, S. P. and Jansen, H. and Meffert, R. H. and Frey, S. P.}, title = {Six Sesamoid Bones on Both Feet: Report of a Rare Case}, series = {Journal of Clinical and Diagnostic Research}, volume = {9}, journal = {Journal of Clinical and Diagnostic Research}, number = {8}, doi = {10.7860/JCDR/2015/12842.6394}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126073}, pages = {RD04-RD05}, year = {2015}, abstract = {There is a variation of the total number of distinct bones in the human in the literature. This difference is mainly caused by the variable existence of sesamoid bones. Sesamoid bones at the first MTP are seen regularly. In contrast additional sesamoid bones at the divond to fifth MTP are rare. We report a case of additional sesamoid bones at every metatarsophalangeal joint (MTP) of both feet. A 22-year-old female Caucasian presented with weight-dependent pain of the divond MTP of the left foot. In the radiographs of both feet additional sesamoid bones at every MTP could be seen. This case reports a very rare variation in human anatomy. A similar case has not been displayed to the academic society and therefore should be acknowledged.}, language = {en} } @article{BoelchBarthelGoebeletal.2015, author = {Boelch, Sebastian Philipp and Barthel, Thomas and Goebel, Sascha and Rudert, Maximilian and Plumhoff, Piet}, title = {Calcinosis universalis - a rare case with classical presentation}, series = {Case Reports in Orthopedics}, volume = {2015}, journal = {Case Reports in Orthopedics}, doi = {10.1155/2015/505420}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126300}, pages = {505420}, year = {2015}, abstract = {Juvenile Dermatomyositis (JDM) is a rare autoimmune disease in children and adolescents. In these patients calcinosis might be the most characteristic symptom. However there are only few reported cases of intramuscular calcinosis in Dermatomyositis. We report a case of calcinosis universalis (CU) of the elbow in JDM successfully treated with broaching. The patient, a 24-year-old woman, suffered from a long history of JDM. On examination she presented with a fistula lateral to the olecranon and pain of the right elbow joint. Plain X-rays displayed a diffuse pattern of multiple periarticular, subcutaneous, and intramuscular calcifications. The patient underwent surgery for histological and microbiological sampling as well as broaching. Intraoperatively sinus formation and subfascial hard calcium deposition were found. Due to the risk of collateral tissue damage, incomplete broaching was performed. A local infection with Staphylococcus was diagnosed and treated with antibiotics. On six-week and 30-month follow-up the patient was free of pain and had very good function. Calcifications on standard radiographs had almost resolved entirely. This case report gives a summary on calcinosis in Dermatomyositis and adds a new case of recalcitrant CU to the literature. Broaching surgery proved to be a reliable treatment option in symptomatic calcinosis.}, language = {en} } @article{BoesSpiegelVoepeletal.2015, author = {Boes, Alexander and Spiegel, Holger and Voepel, Nadja and Edgue, Gueven and Beiss, Veronique and Kapelski, Stephanie and Fendel, Rolf and Scheuermayer, Matthias and Pradel, Gabriele and Bolscher, Judith M. and Behet, Marije C. and Dechering, Koen J. and Hermsen, Cornelus C. and Sauerwein, Robert W. and Schillberg, Stefan and Reimann, Andreas and Fischer, Rainer}, title = {Analysis of a multi-component multi-stage malaria vaccine candidate—tackling the cocktail challenge}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {7}, doi = {10.1371/journal.pone.0131456}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173092}, pages = {e0131456}, year = {2015}, abstract = {Combining key antigens from the different stages of the P. falciparum life cycle in the context of a multi-stage-specific cocktail offers a promising approach towards the development of a malaria vaccine ideally capable of preventing initial infection, the clinical manifestation as well as the transmission of the disease. To investigate the potential of such an approach we combined proteins and domains (11 in total) from the pre-erythrocytic, blood and sexual stages of P. falciparum into a cocktail of four different components recombinantly produced in plants. After immunization of rabbits we determined the domain-specific antibody titers as well as component-specific antibody concentrations and correlated them with stage specific in vitro efficacy. Using purified rabbit immune IgG we observed strong inhibition in functional in vitro assays addressing the pre-erythrocytic (up to 80\%), blood (up to 90\%) and sexual parasite stages (100\%). Based on the component-specific antibody concentrations we calculated the IC50 values for the pre-erythrocytic stage (17-25 μg/ml), the blood stage (40-60 μg/ml) and the sexual stage (1.75 μg/ml). While the results underline the feasibility of a multi-stage vaccine cocktail, the analysis of component-specific efficacy indicates significant differences in IC50 requirements for stage-specific antibody concentrations providing valuable insights into this complex scenario and will thereby improve future approaches towards malaria vaccine cocktail development regarding the selection of suitable antigens and the ratios of components, to fine tune overall and stage-specific efficacy.}, language = {en} } @article{BoivinBeyersdorfPalmetal.2015, author = {Boivin, Val{\´e}rie and Beyersdorf, Niklas and Palm, Dieter and Nikolaev, Viacheslav O. and Schlipp, Angela and M{\"u}ller, Justus and Schmidt, Doris and Kocoski, Vladimir and Kerkau, Thomas and H{\"u}nig, Thomas and Ertl, Georg and Lohse, Martin J. and Jahns, Roland}, title = {Novel Receptor-Derived Cyclopeptides to Treat Heart Failure Caused by \(Anti-β_1-Adrenoceptor\) Antibodies in a Human-Analogous Rat Model}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {2}, doi = {10.1371/journal.pone.0117589}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126028}, pages = {e0117589}, year = {2015}, abstract = {Despite recent therapeutic advances the prognosis of heart failure remains poor. Recent research suggests that heart failure is a heterogeneous syndrome and that many patients have stimulating auto-antibodies directed against the second extracellular loop of the \(β_1\) adrenergic receptor \((β_1EC2)\). In a human-analogous rat model such antibodies cause myocyte damage and heart failure. Here we used this model to test a novel antibody-directed strategy aiming to prevent and/or treat antibody-induced cardiomyopathy. To generate heart failure, we immunised n = 76/114 rats with a fusion protein containing the human β1EC2 (amino-acids 195-225) every 4 weeks; n = 38/114 rats were control-injected with 0.9\% NaCl. Intravenous application of a novel cyclic peptide mimicking \(β_1EC2\) (\(β_1EC2-CP\), 1.0 mg/kg every 4 weeks) or administration of the \(β_1-blocker\) bisoprolol (15 mg/kg/day orally) was initiated either 6 weeks (cardiac function still normal, prevention-study, n = 24 (16 treated vs. 8 untreated)) or 8.5 months after the 1st immunisation (onset of cardiomyopathy, therapy-study, n = 52 (40 treated vs. 12 untreated)); n = 8/52 rats from the therapy-study received \(β_1EC2-CP/bisoprolol\) co-treatment. We found that \(β_1EC2-CP\) prevented and (alone or as add-on drug) treated antibody-induced cardiac damage in the rat, and that its efficacy was superior to mono-treatment with bisoprolol, a standard drug in heart failure. While bisoprolol mono-therapy was able to stop disease-progression, \(β_1EC2-CP\) mono-therapy -or as an add-on to bisoprolol- almost fully reversed antibody-induced cardiac damage. The cyclo¬peptide acted both by scavenging free \(anti-β_1EC2-antibodies\) and by targeting \(β_1EC2\)-specific memory B-cells involved in antibody-production. Our model provides the basis for the clinical translation of a novel double-acting therapeutic strategy that scavenges harmful \(anti-β_1EC2-antibodies\) and also selectively depletes memory B-cells involved in the production of such antibodies. Treatment with immuno-modulating cyclopeptides alone or as an add-on to \(β_1\)-blockade represents a promising new therapeutic option in immune-mediated heart failure.}, language = {en} } @phdthesis{Bok2015, author = {Bok, Thomas}, title = {Frontotemporale Hirnoxygenierung w{\"a}hrend Wortfl{\"u}ssigkeit bei entgifteten Patienten mit Alkoholabh{\"a}ngigkeit: Eine Untersuchung mit Nah-Infrarot Spektroskopie und Elektromyographie des Musculus temporalis}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117124}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Einf{\"u}hrung. In der vorliegenden Studie untersuchten wir durch funktionelle Nahinfrarotspektroskopie (fNIRS) pr{\"a}frontale Hirnoxygenierung w{\"a}hrend Ableistung von Sprachaufgaben. FNIRS weist {\"u}ber Bestimmung von Konzentrationsunterschieden von sauerstoffbeladenes (OxyHb) und sauerstofffreies H{\"a}moglobin (DeoxyHb) regionale Blutfluss{\"a}nderungen nach und l{\"a}sst somit validen R{\"u}ckschluss auf Hirnaktivit{\"a}t zu. Bereits in fr{\"u}heren Studien konnte nachgewiesen werden, dass Patienten mit Alkoholkrankheit verminderte pr{\"a}frontale Hirnaktivit{\"a}t zeigen. Teil 2 der Studie untersucht den im Untersuchungsgebiet liegenden Schl{\"a}fenmuskel (musculus temporalis) auf Einfl{\"u}sse auf die Methode fNIRS. Methoden. Wir verglichen 15 entgiftete Patienten mit Alkoholkrankheit (Patientengruppe, PG) mit passenden 15 gesunden Kontrollprobanden (Kontrollgruppe, KG)bez{\"u}glich deren Hirn- und Muskelaktivit{\"a}t w{\"a}hrend Ableistung Wortfl{\"u}ssigkeitsaufgabe (VFT; engl. Verbal Fluency Task). Bestimmte, insbesondere pr{\"a}frontale Hirnareale wurden durch phonologische und semantische Testsaufgaben (TA´s), ebenso durch eine Kontrollaufgabe (KA), (Wochentag aufz{\"a}hlen) aktiviert. Durch EMG wurde w{\"a}hrend Durchf{\"u}hrung der Aufgabe die Aktivit{\"a}t des musculus temporalis gemessen. Wir verwendeten zur Datenanalyse sowohl von fNIRS wie auch EMG eine 2x2x2x6 Varianzanalyse (ANOVA) mit Zwischensubjektfaktor „Gruppe" und Innersubjektfaktoren „Bedingung", „Seite" und „Zeit", gerechnet wurde dies f{\"u}r jeweils Oxy- und DeoxyHb sowie den phonologischen sowie semantischen Teil. Ergebnisse. Beide Gruppen lieferten eine vergleichbare Menge an Worten, Hirnaktivierung zeigte sich bei beiden Gruppen signifikant h{\"o}her in den Testaufgaben (phonologisch > semantisch). Die PG zeigte verminderte Hirnaktivierung pr{\"a}frontal im phonologischen, vergleichbare Hirnaktivit{\"a}t im semantischen Teil. Beide Gruppen zeigten vergleichbare Muskelaktivit{\"a}t, jeweils signifikant h{\"o}her in den jeweiligen Testaufgaben. Es zeigten sich keine systematischen Assoziationen (Korrelation nach Pearson) zwischen fNIRS und EMG. Schlussfolgerungen. Insgesamt konnten vorherige Studien mit Nachweis niedrigerer pr{\"a}frontaler Hirnoxygenierung bei entgifteten Patienten mit Alkoholkrankheit gegen{\"u}ber gesunden Kontrollen best{\"a}tigt werden. Die Mehraktivierung beider Gruppen w{\"a}hrend phonologischer Aufgabe gr{\"u}ndet in dem h{\"o}heren intelektuellen Anspruch der Aufgabe, dies erkl{\"a}rt auch den Gruppenunterschied in speziell dieser Aufgabe. Durch eine vergleichbare Muskelaktivit{\"a}t der beiden Gruppen sowie fehlende Assoziationen zwischen fNIRS und EMG sehen wir keinen Einfluss von Muskelaktivit{\"a}t auf die Hirnaktivit{\"a}tsmessung durch fNIRS. Auch eine valide Untersuchung von psychiatrisch kranken Probandengruppen wie Patienten mit Alkoholkrankheit ist hierdurch gut m{\"o}glich. Die Studie bef{\"u}rwortet den k{\"u}nftigen Einsatz und weitere methodische Untersuchungen zur Messung mit fNIRS, einem validen, artefaktunempfindlichen, handlichen und relativ g{\"u}nstigen Messinstrument.}, subject = {fNIRS}, language = {de} } @article{Borgards2015, author = {Borgards, Roland}, title = {Introduction: Cultural and Literary Animal Studies}, series = {Journal of Literary Theory}, volume = {9}, journal = {Journal of Literary Theory}, number = {2}, issn = {1862-8990}, doi = {10.1515/jlt-2015-0008}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195123}, pages = {155-160}, year = {2015}, abstract = {No abstract available.}, language = {en} } @phdthesis{Born2015, author = {Born, Dennis Peter}, title = {Effekte von Kompressionsbekleidung in Training und Wettkampf - Analyse zugrunde liegender physiologischer und biomechanischer Mechanismen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121872}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Einleitung: Es konnte gezeigt werden, dass die Applikation von Kompressionsbekleidung zu einem erh{\"o}hten Blutfluss bei Patienten mit ven{\"o}ser Insuffizienz f{\"u}hrt und das Thromboserisiko bei bettl{\"a}gerigen und postoperativen Patienten reduziert. Davon ausgehend, dass Kompressionsbekleidung auch bei gesunden und trainierten Athlet/innen zu einer verbesserten H{\"a}mdynamik f{\"u}hrt, wurde eine Vielzahl an Studien durchgef{\"u}hrt, die nach einer Leistungssteigerung durch das Tragen von Kompressionsbekleidung w{\"a}hrend sportlicher Belastung gesucht haben. Die Ergebnisse der bisher ver{\"o}ffentlichten Studien widersprechen sich jedoch h{\"a}ufig und lassen kein abschließendes Fazit bez{\"u}glich ergogener Effekte von Kompressionsbekleidung auf die Leistung w{\"a}hrend k{\"o}rperlicher Belastung zu. Auch ist unklar, welche physiologischen und/oder biomechanischen Mechanismen bei gesunden und trainierten Athlet/innen zu einer potentiellen Leistungssteigerung f{\"u}hren k{\"o}nnten. Ziel der vorliegenden Arbeit war es daher: 1) Belastungsarten und -intensit{\"a}ten zu identifizieren, bei denen das Tragen von Kompressionsbekleidung leistungssteigernde Effekte verspricht, 2) die identifizierten Potentiale anhand empirischer Datenerhebung zu evaluieren und 3) die physiologischen und biomechanischen Mechanismen zu untersuchen, die einer m{\"o}glichen Leistungssteigerung mit Kompressionsbekleidung bei gesunden und trainierten Athlet/innen zugrunde liegen k{\"o}nnten. Methodik: Mittels eines {\"U}bersichtsartikels und Berechnung von Effektst{\"a}rken wurden verschiedene Belastungsarten und -intensit{\"a}ten identifiziert, bei denen das Tragen von Kompressionsbekleidung leistungssteigernde Effekte verspricht (Studie 1). Auch wurden die m{\"o}glichen Mechanismen zusammengetragen, die einer Leistungssteigerung zugrunde liegen k{\"o}nnten. Basierend auf diesen Ergebnissen wurden die Untersuchungsprotokolle f{\"u}r die weiteren Studien entwickelt. In Studie 2 absolvierten hoch-trainierte Eisschnelll{\"a}ufer/innen eine 3000 m Wettkampfsimulation mit und ohne Kompressionsbekleidung in randomisierter Reihenfolge. Physiologische Daten wurden mittels mobiler Spirometrie und Nahinfrarotspektroskopie (NIRS) erhoben. Des Weiteren wurden Athletinnen aus Mannschaftssport und Leichtathletik einer intermittierenden Sprintbelastung mit dreißig 30 m Sprints und einer Abgangszeit von einer Minute mit und ohne Kompressionsbekleidung in randomisierter Reihenfolge unterzogen (Studie 3). Neben mobiler Spirometrie und NIRS wurden biomechanische Daten mittels kinematischer Bewegungsanalyse und Elektromyographie erhoben. Ergebnisse:Studie 1 zeigte ein leistungssteigerndes Potential mit der Applikation von Kompressionsbekleidung bei hoch-intensiver und weniger bei submaximaler Belastungsintensit{\"a}t. Insbesondere hoch-intensive Ausdauer- (> 3 Minuten), Sprint- und Sprungbelastung als auch die Erholungsf{\"a}higkeit von Kraft- und Schnellkraft scheinen durch Kompressionsbekleidung verbessert. Die Ergebnisse zeigen auch, dass bisher nur wenige Daten bei weiblichen Sportlern erhoben wurden. Auch evaluierten nur wenige Studien die Effekte von Kompressionsbekleidung bei Athlet/innen auf h{\"o}chstem Leistungsniveau. In Studie 2 zeigte die Applikation von Kompressionsbekleidung w{\"a}hrend der 3000 m Wettkampfsimulation bei hoch-trainierten Eisschnelll{\"a}ufer/innen keinen Effekt auf die Laufleistung. Auch blieben mittels NIRS gemessenes Blutvolumen und Muskeloxygenierung im m. quadrizeps femoris sowie alle weiteren kardio-respiratorischen, metabolischen und subjektiven Parameter unbeeinflusst. Dagegen war die Laufleistung w{\"a}hrend eines intermittierenden (30 x 30 m) Sprintprotokolls mit Kompressionsbekleidung signifikant verbessert (Studie 3). Auch in dieser Untersuchung blieben alle gemessenen h{\"a}modynamischen, kardio-respiratorischen und metabolischen Parameter unbeeinflusst. Die kinematische Bewegungsanalyse zeigte jedoch, dass Kompressionsbekleidung zu ver{\"a}nderter Lauftechnik f{\"u}hrt und die Schrittl{\"a}nge bei gleichbleibender Schrittfrequenz vergr{\"o}ßert. Auch wurde die Sprintbelastung lokal an der Oberschenkelmuskulatur subjektiv weniger anstrengend empfunden. Zusammenfassung und Fazit: Die Applikation von Kompressionsbekleidung zeigte keine generelle leistungssteigernde Wirkung w{\"a}hrend k{\"o}rperlicher Belastung bei gesunden und trainierten Athlet/innen. Abh{\"a}ngig von Belastungsart und -intensit{\"a}t manifestieren sich ergogene Effekte w{\"a}hrend hoch-intensiver Lauf- insbesondere intermittierender Sprintbelastungen. Im Zusammenhang mit weiteren Untersuchungen scheinen die ergogenen Effekte jedoch nicht auf ver{\"a}nderter H{\"a}modynamik zu basieren. Der blutflusssteigernde Effekt von Kompressionsbekleidung, der in klinischen Studien bei Patienten mit ven{\"o}ser Insuffizienz gezeigt wurde, l{\"a}sst sich nicht in gleichem Maße bei gesunden und trainierten Athlet/innen nachweisen. Vielmehr scheinen kinematische und subjektive Parameter, wie eine ver{\"a}nderte Lauftechnik und verringertes Belastungsempfinden, die intermittierende Sprintleistung verbessert zu haben.}, subject = {Kompression}, language = {de} } @phdthesis{Boyer2015, author = {Boyer, Sonja}, title = {Morphologische und spektroskopische Untersuchungen von Supernova-{\"U}berresten}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119108}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Bis heute ist nicht bekannt, in welcher Umgebung die schwersten Elemente durch Neutroneneinfangprozesse entstehen. Es gibt zwei m{\"o}gliche Szenarien, die in der Literatur diskutiert werden: Supernova-Explosionen und Neutronensternverschmelzungen. Beide tragen zur Elementproduktion bei. Welches Szenario aber die dominierende Umgebung ist, bleibt umstritten. Mehrere Fakten sprechen f{\"u}r Supernova-Explosionen als Entstehungsorte: Wenn ein massereicher Stern kollabiert und anschließend explodiert, sind die Temperatur und die Dichte so hoch, dass Neutronen von den bereits bestehenden Elementen eingefangen und angelagert werden k{\"o}nnen. Obwohl in Simulationen mit kugelsymmetrischen Modellen nur protonen- reiche Ausw{\"u}rfe entstehen, kann es in asymmetrischen Explosionen aufgrund der Rotation und der Magnetfelder vermutlich zu einem neutronenreichen Auswurf kommen. Dieser ist hoch genug, dass der schnelle Neutroneneinfang auftreten kann. In dieser Arbeit habe ich daher die {\"U}berreste solcher Explosionen untersucht, um nach Asymmetrien und ihren m{\"o}glichen Auswirkungen auf die Element-Entstehung und Verteilung zu suchen. Daf{\"u}r wurden die beiden Supernova-{\"U}berreste CTB 109 und RCW 103 ausgew{\"a}hlt. CTB 109 besitzt im Zentrum einen anomale R{\"o}ntgenpulsar, also einen Neutronenstern mit hohem Magnetfeld und starker Rotation, die durch Asymmetrien hervorgerufen worden sein k{\"o}nnten. Auch RCW 103 hat vermutlich einen solchen Pulsar als zentrale Quelle. Beide {\"U}berreste sind noch recht jung und befinden sich in ihrer Sedov-Taylor Phase. Die Distanz zur Erde betr{\"a}gt f{\"u}r beide {\"U}berreste ungef{\"a}hr 3 kpc, womit sie in der n{\"a}heren Umgebung der Erde zu finden sind. Die Elemente bis zur Eisengruppe haben ihre bekanntesten Linien im Bereich der R{\"o}ntgenstrahlung. Deswegen wurden f{\"u}r diese Arbeit archivierte Daten des Satelliten XMM-Newton ausgew{\"a}hlt und die Spektren in definierten Regionen in den bei- den Supernova-{\"U}berresten mit den EPIC MOS-Kameras ausgewertet. Die heutigen R{\"o}ntgensatelliten haben jedoch keine ausreichende Sensitivit{\"a}t, um die schwersten Elemente zu detektieren. In den Spektren der beiden {\"U}berreste wurden deshalb vorwiegend die Elemente Silizium und Magnesium gefunden, in CTB 109 auch Neon. Elemente mit h{\"o}heren Massezahlen konnten leider nicht signifikant aus dem Hintergrund herausgefiltert werden. Deutlich sind die Peaks der drei Elementen sichtbar, aber auch Schwefel ist in den Regionen mit hohen Z{\"a}hlraten zu entdecken. F{\"u}r bei- de Supernova-{\"U}berreste wurde der beste Fit mit dem Modell vpshock gefunden. In diesem Modell wird ein Plasma angenommen, das bei konstanter Temperatur plan-parallel geschockt wird. Um diesen Fit zu erzielen wurden die Parameter f{\"u}r die Elemente Fe, S, Si, Mg, O und Ne variiert. Die restlichen Elemente wurden auf die solare H{\"a}ufigkeit festgelegt. Bei CTB 109 befinden sich die Temperaturen (kT) in den Regionen mit hohen Z{\"a}hlraten im Bereich zwischen 0.6 und 0.7 keV und liegen damit im selben Bereich, der bereits mit anderen Teleskopen f{\"u}r CTB 109 gefunden wurde. In den Regionen mit niedrigen Z{\"a}hlraten liegen die Temperaturen etwas tiefer mit 0.3-0.4 keV. Im Supernova-{\"U}berrest RCW 103 wurde nur eine Region mit hoher Z{\"a}hlrate analysiert und eine Temperatur von 0.57 keV gefunden, w{\"a}hrend in der Region mit niedriger Z{\"a}hlrate die Temperatur kT = 0.36 ± 0.08 keV betr{\"a}gt. Beide Werte passen zu den Werten in CTB 109. Die einzelnen Elementlinien wurden zus{\"a}tzlich mit einer Gauß-Verteilung angepasst und die Fl{\"u}sse ermittelt. Diese wurden in Intensit{\"a}tskarten aufgetragen, in denen die unterschiedlichen Verteilungen der Elemente {\"u}ber den Supernova-{\"U}berrest zu sehen sind. W{\"a}hrend Silizium in einigen wenigen Regionen geklumpt auftritt, ist Magnesium {\"u}ber die {\"U}berreste verteilt und hat in einigen Regionen h{\"o}here Werte als Silizium. Das l{\"a}sst den Schluss zu, dass die beiden Elemente auf unterschiedliche Weise aus der Explosion herausgeschleudert wurden. Die Verteilung ist hier durchaus asymmetrisch, es ist jedoch nicht m{\"o}glich dies auf eine asymmetrische Explosion der Supernova zur{\"u}ckzuf{\"u}hren. Daf{\"u}r m{\"u}ssen mehr als zwei Supernova-{\"U}berreste mit dieser Methode untersucht werden und mit einer noch nicht vorhandenen Theorie zur Verteilung der Elemente in {\"U}berresten verglichen werden. Im direkten Vergleich der beiden bisher untersuchten Supernova-{\"U}berreste CTB 109 und RCW 103 sieht man, dass die beiden {\"U}berreste sich sehr in der Temperatur und der Verteilung der Elemente {\"a}hneln. Das l{\"a}sst auf eine einheitliche Ausbreitung der Elemente innerhalb der Supernova-{\"U}berreste schließen. Silizium wird aufgrund der Explosion in fingerartigen Strukturen, die Rayleigh-Taylor-Instabilit{\"a}ten, nach außen transportiert. Dabei bildet es Klumpen, die mit den weiter außen liegenden Schalen reagieren. Magnesium und Neon hingegen werden haupts{\"a}chlich in den Brennphasen vor der Explosion und in den {\"a}ußeren Schichten des Sterns, der Zwiebelschalenstruktur, produziert. Dadurch ist eine ausgedehnte Verteilung zu er- warten. Diese Verteilungen der drei Elemente ist in dieser Arbeit best{\"a}tigt worden. W{\"a}hrend Magnesium und Neon {\"u}ber den gesamten {\"U}berrest hohe Fl{\"u}sse aufweisen, ist Silizium sehr lokal im Lobe von CTB 109 und im hellen S{\"u}den von RCW 103 zu finden. Mit zuk{\"u}nftigen R{\"o}ntgenteleskopen, die eine h{\"o}here r{\"a}umliche Aufl{\"o}sung erm{\"o}glichen, k{\"o}nnten die beobachteten Zusammenh{\"a}nge zwischen der asymmetrischen Elementverteilung im Supernova{\"u}berrest und den Mechanismen der Elemententstehung in der Supernova weiter untersucht werden.}, subject = {Supernova{\"u}berrest}, language = {de} } @phdthesis{Brand2015, author = {Brand, Johannes}, title = {Darstellung und Untersuchung von niederkoordinierten Platinimino-, Platinoxo- und Platinalkylidenborylkomplexen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112306}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Diese Dissertation handelt von der Darstellung, Charakterisierung und Reaktivit{\"a}tsuntersuchungen von neuartigen Platinalkylidenborylkomplexen und eines heteroleptischen Platiniminoborylkomplexes. Außerdem wurden Reaktivit{\"a}tsuntersuchungen an einem Platinoxoborylkomplex durchgef{\"u}hrt und die erhaltenen Produkte wurden genau untersucht und charakterisiert.}, subject = {Dreifachbindung}, language = {de} } @article{BratengeierHolubyev2015, author = {Bratengeier, Klaus and Holubyev, Kostyantyn}, title = {Characteristics of non-coplanar IMRT in the presence of target-embedded organs at risk}, series = {Radiation Oncology}, volume = {10}, journal = {Radiation Oncology}, number = {207}, doi = {10.1186/s13014-015-0494-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125292}, year = {2015}, abstract = {Background The aim is to analyze characteristics and to study the potentials of non-coplanar intensity modulated radiation therapy (IMRT) techniques. The planning study applies to generalized organ at risk (OAR) - planning target volume (PTV) geometries. Methods The authors focus on OARs embedded in the PTV. The OAR shapes are spherically symmetric (A), cylindrical (B), and bended (C). Several IMRT techniques are used for the planning study: a) non-coplanar quasi-isotropic; b) two sets of equidistant coplanar beams, half of beams incident in a plane perpendicular to the principal plane; c) coplanar equidistant (reference); d) coplanar plus one orthogonal beam. The number of beam directions varies from 9 to 16. The orientation of the beam sets is systematically changed; dose distributions resulting from optimal fluence are explored. A selection of plans is optimized with direct machine parameter optimization (DMPO) allowing 120 and 64 segments. The overall plan quality, PTV coverage, and OAR sparing are evaluated. Results For all fluence based techniques in cases A and C, plan quality increased considerably if more irradiation directions were used. For the cylindrically symmetric case B, however, only a weak beam number dependence was observed for the best beam set orientation, for which non-coplanar directions could be found where OAR- and PTV-projections did not overlap. IMRT plans using quasi-isotropical distributed non-coplanar beams showed stable results for all topologies A, B, C, as long as 16 beams were chosen; also the most unfavorable beam arrangement created results of similar quality as the optimally oriented coplanar configuration. For smaller number of beams or application in the trunk, a coplanar technique with additional orthogonal beam could be recommended. Techniques using 120 segments created by DMPO could qualitatively reproduce the fluence based results. However, for a reduced number of segments the beam number dependence declined or even reversed for the used planning system and the plan quality degraded substantially. Conclusions Topologies with targets encompassing sensitive OAR require sufficient number of beams of 15 or more. For the subgroup of topologies where beam incidences are possible which cover the whole PTV without direct OAR irradiation, the quality dependence on the number of beams is much less pronounced above 9 beams. However, these special non-coplanar beam directions have to be found. On the basis of this work the non-coplanar IMRT techniques can be chosen for further clinical planning studies.}, language = {en} } @phdthesis{Bregenzer2015, author = {Bregenzer, J{\"u}rgen}, title = {Effizienter Einsatz von Multicore-Architekturen in der Steuerungstechnik}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, isbn = {978-3-95826-010-8 (Print)}, doi = {10.25972/WUP-978-3-95826-011-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-106239}, school = {W{\"u}rzburg University Press}, pages = {185}, year = {2015}, abstract = {Der Einsatz von Multicore-Prozessoren in der industriellen Steuerungstechnik birgt sowohl Chancen als auch Risiken. Die vorliegende Dissertation entwickelt und bewertet aus diesem Grund generische Strategien zur Nutzung dieser Prozessorarchitektur unter Ber{\"u}cksichtigung der spezifischen Rahmenbedingungen und Anforderungen dieser Dom{\"a}ne. Multicore-Prozessoren bieten die Chance zur Konsolidierung derzeit auf dedizierter Hardware ausgef{\"u}hrter heterogener Steuerungssubsysteme unter einer bisher nicht erreichbaren temporalen Isolation. In diesem Kontext definiert die vorliegende Dissertation die spezifischen Anforderungen, die eine integrierte Ausf{\"u}hrung in der Dom{\"a}ne der industriellen Automatisierung erf{\"u}llen muss. Eine Vorbedingung f{\"u}r ein derartiges Szenario stellt allerdings der Einsatz einer geeigneten Konsolidierungsl{\"o}sung dar. Mit einem virtualisierten und einem hybriden Konsolidierungsansatz werden deshalb zwei repr{\"a}sentative L{\"o}sungen f{\"u}r die Dom{\"a}ne eingebetteter Systeme vorgestellt, die schließlich hinsichtlich der zuvor definierten Kriterien evaluiert werden. Da die Taktraten von Prozessoren physikalische Grenzen erreicht haben, werden sich in der Steuerungstechnik signifikante Performanzsteigerungen zuk{\"u}nftig nur durch den Einsatz von Multicore-Prozessoren erzielen lassen. Dies hat zur Vorbedingung, dass die Firmware die Parallelit{\"a}t dieser Prozessorarchitektur in geeigneter Weise zu nutzen vermag. Leider entstehen bei der Parallelisierung eines komplexen Systems wie einer Automatisierungs-Firmware im Allgemeinen signifikante Aufw{\"a}nde. Infolgedessen sollten diesbez{\"u}gliche Entscheidungen nur auf Basis einer objektiven Abw{\"a}gung potentieller Alternativen getroffen werden. Allerdings macht die Systemkomplexit{\"a}t eine Absch{\"a}tzung der durch eine spezifische parallele Firmware-Architektur zu erwartenden Performanz zu einer anspruchsvollen Aufgabe. Dies gilt vor allem, da eine Parallelisierung gefordert wird, die f{\"u}r eine Vielzahl von Lastszenarien in Form gesteuerter Maschinen geeignet ist. Aus diesem Grund spezifiziert die vorliegende Dissertation eine anwendungsorientierte Methode zur Unterst{\"u}tzung von Entwurfsentscheidungen, die bei der Migration einer bestehenden Singlecore-Firmware auf eine homogene Multicore-Architektur zu treffen sind. Dies wird erreicht, indem in automatisierter Weise geeignete Firmware-Modelle auf Basis von dynamischem Profiling der Firmware unter mehreren repr{\"a}sentativen Lastszenarien erstellt werden. Im Anschluss daran werden diese Modelle um das Expertenwissen von Firmware-Entwicklern erweitert, bevor mittels multikriterieller genetischer Algorithmen der Entwurfsraum der Parallelisierungsalternativen exploriert wird. Schließlich kann eine spezifische L{\"o}sung der auf diese Weise hergeleiteten Pareto-Front auf Basis ihrer Bewertungsmetriken zur Implementierung durch einen Entwickler ausgew{\"a}hlt werden. Die vorliegende Arbeit schließt mit einer Fallstudie, welche die zuvor beschriebene Methode auf eine numerische Steuerungs-Firmware anwendet und dabei deren Potential f{\"u}r eine umfassende Unterst{\"u}tzung einer Firmware-Parallelisierung aufzeigt.}, subject = {Mehrkernprozessor}, language = {de} } @phdthesis{BreuergebHemberger2015, author = {Breuer [geb. Hemberger], Kathrin R. F.}, title = {Effiziente 3D Magnetresonanzbildgebung schnell abfallender Signale}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150750}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {In der vorliegenden Arbeit wird die Rotated-Cone-UTE-Sequenz (RC-UTE), eine 3D k-Raum-Auslesetechnik mit homogener Verteilung der Abtastdichte, vorgestellt. Diese 3D MR-Messtechnik erm{\"o}glicht die f{\"u}r die Detektion von schnell abfallenden Signalen notwendigen kurzen Echozeiten und weist eine h{\"o}here SNR-Effizienz als konventionelle radiale Pulssequenzen auf. Die Abtastdichte ist dabei in radialer und azimutaler Richtung angepasst. Simulationen und Messungen in vivo zeigen, dass die radiale Anpassung das T2-Blurring reduziert und die SNR-Effizienz erh{\"o}ht. Die Drehung der Trajektorie in azimutale Richtung erm{\"o}glicht die Reduzierung der Unterabtastung bei gleicher Messzeit bzw. eine Reduzierung der Messzeit ohne Aufl{\"o}sungsverlust. Die RC-UTE-Sequenz wurde erfolgreich f{\"u}r die Bildgebung des Signals des kortikalen Knochens und der Lunge in vivo angewendet. Im Vergleich mit der grundlegenden UTE-Sequenz wurden die Vorteile von RC-UTE in allen Anwendungsbeispielen aufgezeigt. Die transversalen Relaxationszeit T2* des kortikalen Knochen bei einer Feldst{\"a}rke von 3.0T und der Lunge bei 1.5T und 3.0T wurde in 3D isotroper Aufl{\"o}sung gemessen. Außerdem wurde die Kombination von RC-UTE-Sequenz mit Methoden der Magnetisierungspr{\"a}paration zur besseren Kontrasterzeugung gezeigt. Dabei wurden die Doppel-Echo-Methode, die Unterdr{\"u}ckung von Komponenten mit langer Relaxationszeit T2 durch Inversionspulse und der Magnetisierungstransfer-Kontrast angewendet. Die Verwendung der RC-UTE-Sequenz f{\"u}r die 3D funktionelle Lungenbildgebung wird ebenfalls vorgestellt. Mit dem Ziel der umfassenden Charakterisierung der Lungenfunktion in 3D wurde die simultane Messung T1-gewichteter Bilder und quantitativer T2*-Karten f{\"u}r verschiedene Atemzust{\"a}nde an sechs Probanden durchgef{\"u}hrt. Mit der hier vorgestellten Methode kann die Lungenfunktion in 3D {\"u}ber T1-Wichtung, quantitative T2*-Messung und Rekonstruktion verschiedener Atemzust{\"a}nde durch Darstellung von Ventilation, Sauerstofftransport und Volumen{\"a}nderung beurteilt werden.}, subject = {Kernspintomografie}, language = {de} } @article{BrieseSaalAppenzelleretal.2015, author = {Briese, Michael and Saal, Lena and Appenzeller, Silke and Moradi, Mehri and Baluapuri, Apoorva and Sendtner, Michael}, title = {Whole transcriptome profiling reveals the RNA content of motor axons}, series = {Nucleic Acids Research}, journal = {Nucleic Acids Research}, doi = {10.1093/nar/gkv1027}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126800}, year = {2015}, abstract = {Most RNAs within polarized cells such as neurons are sorted subcellularly in a coordinated manner. Despite advances in the development of methods for profiling polyadenylated RNAs from small amounts of input RNA, techniques for profiling coding and non-coding RNAs simultaneously are not well established. Here, we optimized a transcriptome profiling method based on double-random priming and applied it to serially diluted total RNA down to 10 pg. Read counts of expressed genes were robustly correlated between replicates, indicating that the method is both reproducible and scalable. Our transcriptome profiling method detected both coding and long non-coding RNAs sized >300 bases. Compared to total RNAseq using a conventional approach our protocol detected 70\% more genes due to reduced capture of ribosomal RNAs. We used our method to analyze the RNA composition of compartmentalized motoneurons. The somatodendritic compartment was enriched for transcripts with post-synaptic functions as well as for certain nuclear non-coding RNAs such as 7SK. In axons, transcripts related to translation were enriched including the cytoplasmic non-coding RNA 7SL. Our profiling method can be applied to a wide range of investigations including perturbations of subcellular transcriptomes in neurodegenerative diseases and investigations of microdissected tissue samples such as anatomically defined fiber tracts.}, language = {en} } @phdthesis{BrillgebSchubert2015, author = {Brill [geb. Schubert], Sabine}, title = {Blutzuckerverlauf, hormonelle Gegenregulation und kognitive Leistungsf{\"a}higkeit unter definierter k{\"o}rperlicher Belastung bei Patienten mit Morbus Addison und Diabetes mellitus Typ 1 CANDI - Studie: Counterregulatory Hormone Production in Adrenal Insufficiency and Diabetes Type I}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142646}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Spiroergometrische Dauerbelastung von Probanden mit Morbus Addison, Diabetes mellitus Typ 1, Polyglandul{\"a}rem Autoimmunsyndrom Typ 2 (erkrankt sowohl an Mb. Addison als auch an Diabetes mellitus Typ1) und gesunden Kontrollen. Blutzuckerverlauf, hormonelle Gegenregulation und kognitive Leistungsf{\"a}higkeit vor und nach Belastung wurden gemessen. W{\"a}hrend einer spiroergometrischen Dauerbelastung von 23 Minuten zeigte sich bei keinem der 10 Probanden mit ausschließlich Morbus Addison eine Neigung zur Hypoglyk{\"a}mie trotz fehlender Einnahme der mitt{\"a}glichen Glukokortikoiddosis. Die Blutzucker blieben bei s{\"a}mtlichen Probanden stabil und es zeigte sich sogar ein leichter Anstieg in der der Ergometrie anschließenden Nachbeobachtungsphase, eventuell als Hinweis auf eine m{\"o}gliche Entwicklung einer Inulin-Resistenz. Auf die erwartungsgem{\"a}ße Mindersekretion von Adrenalin zeigte sich eine ame ehesten kompensatorisch leicht h{\"o}here Sekretion von Noradrenalin als bei den nebennierengesunden Gruppen. Die {\"u}brige Sekretion gegenregulatorischer Hormone entsprach den Vergleichsgruppen. Die geleistete Arbeit am Fahrradergometer war bei den Probandengruppen mit Morbus Addison und APS 2 nahezu identisch, die Morbus Addison - Probanden traten sogar minimal weniger Ergometerwiderstand {\"u}ber die 15 Minuten Dauerbelastung. Dennoch zeigten die Probanden mit ausschließlich M. Addison einen ad{\"a}quaten Anstieg der gegenregulatorischen Hormone ohne starke Schwankungen der Plasmaglukose, wohingegen es bei den Probanden mit APS 2, zu einem deutlichen Abfall der Plasmaglukose kam trotz deutlich niedrigerer Insulinkonzentrationen im Vergleich zur Probandengruppe mit ausschließlich Diabetes mellitus Typ 1. Die unzureichende Sekretion von Adrenalin, sowie der geringste Konzentrationsanstieg von Noradrenalin und dieser Untersuchung auch Wachstumshormon aller Probandengruppen verhinderte einen ad{\"a}quaten Wiederanstieg des Blutzuckers. Die Probanden mit Nebennierenrindeninsuffizienz verzeichneten teils signifikant schlechtere Ergebnisse bei einem Konzentrations- und einem Kurzzeitged{\"a}chtnistest im direkten Anschluss an die Ergometrie im Vergleich mit den anderen Probandengruppen. Es gab keine relevanten Unterschiede der Testergebnisse in Ruhe. Die nebenniereninsuffizienten Probanden verbesserten sich jedoch signifikant weniger nach der Ergometrie bzw. zeigten nach dem Dauertest teils sogar schlechtere Leistungen. Die Probandengruppen mit Diabetes mellitus Typ 1 und die Kontrollgruppe zeigten eine erwartungsgem{\"a}ße Verbesserung ihrer Leistung als Reaktion auf die vorherige k{\"o}rperliche Aktivit{\"a}t. Die Unterschiede in der kognitiven Performance sind am ehesten mit der unzureichenden Adrenalinsekretion und einem fehlenden akuten Cortisolanstieg der nebenniereninsuffizienten Probanden zu erkl{\"a}ren. Die Probanden mit Nebennierenrindeninsuffizienz wurden mit signifikant niedrigeren Widerst{\"a}nden am Fahrradergometer belastet als die nebennierengesunden Probanden. Ein m{\"o}glicher Erkl{\"a}rungsansatz hierf{\"u}r k{\"o}nnte eine gewisse cortisonbedingte Myopathie sein. Dies verdeutlicht nochmals die Notwendigkeit der Optimierung der Glukokortikoidsubstitutionstherapie. Neue Substitutionsregime sollten m{\"o}glichst die physiologische circadiane Sekretionsrhythmik besser imitieren und im Optimalfall die Tagesdosis an Hydrocortison reduzieren, um glukokortikoidbedingte Nebenwirkungen wie Myopathie und Insulin-Resistenz zu reduzieren. Die Probanden mit polyglandul{\"a}rem Autoimmunsyndrom Typ 2, welche sowohl an Morbus Addison als auch an Diabetes mellitus Typ 1 leiden, m{\"u}ssen im Rahmen von Patientenschulungen besonders auf das Risiko von Hypoglyk{\"a}mien bei vermehrter k{\"o}rperlicher Aktivit{\"a}t hingewiesen werden. Patienten mit Insulinpumpe sollten das Ausschalten w{\"a}hrenddessen erw{\"a}gen und dar{\"u}ber hinaus besondere Aufmerksamkeit auf die Einnahme einer zus{\"a}tzlichen Kohlenhydrateinheit f{\"u}r den Sport walten lassen. Eine zus{\"a}tzliche Einnahme des Glukokortikoids ist in diesem Zusammenhang nicht sinnvoll. [31] Ein vor dem Sport beispielsweise inhalativ appliziertes Epinephrinpr{\"a}parat w{\"a}re eine m{\"o}gliche Strategie zur Verbesserung des Plasmaglukose-Outcomes nach sportlicher Bet{\"a}tigung auf moderatem bzw. hohem Anstrengungslevel bei Patienten mit Morbus Addison und Diabetes mellitus Typ 1 und sollte Gegenstand weiterf{\"u}hrender Studien sein.}, language = {de} } @article{BrillMeyerRoessler2015, author = {Brill, Martin F. and Meyer, Anneke and Roessler, Wolfgang}, title = {It takes two—coincidence coding within the dual olfactory pathway of the honeybee}, series = {Frontiers in Physiology}, volume = {6}, journal = {Frontiers in Physiology}, number = {208}, doi = {10.3389/fphys.2015.00208}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126179}, year = {2015}, abstract = {To rapidly process biologically relevant stimuli, sensory systems have developed a broad variety of coding mechanisms like parallel processing and coincidence detection. Parallel processing (e.g., in the visual system), increases both computational capacity and processing speed by simultaneously coding different aspects of the same stimulus. Coincidence detection is an efficient way to integrate information from different sources. Coincidence has been shown to promote associative learning and memory or stimulus feature detection (e.g., in auditory delay lines). Within the dual olfactory pathway of the honeybee both of these mechanisms might be implemented by uniglomerular projection neurons (PNs) that transfer information from the primary olfactory centers, the antennal lobe (AL), to a multimodal integration center, the mushroom body (MB). PNs from anatomically distinct tracts respond to the same stimulus space, but have different physiological properties, characteristics that are prerequisites for parallel processing of different stimulus aspects. However, the PN pathways also display mirror-imaged like anatomical trajectories that resemble neuronal coincidence detectors as known from auditory delay lines. To investigate temporal processing of olfactory information, we recorded PN odor responses simultaneously from both tracts and measured coincident activity of PNs within and between tracts. Our results show that coincidence levels are different within each of the two tracts. Coincidence also occurs between tracts, but to a minor extent compared to coincidence within tracts. Taken together our findings support the relevance of spike timing in coding of olfactory information (temporal code).}, language = {en} } @article{Brinktrine2015, author = {Brinktrine, Ralf}, title = {Konkurrentenstreitverfahren im Beamtenrecht}, series = {JURA - Juristische Ausbildung}, volume = {37}, journal = {JURA - Juristische Ausbildung}, number = {11}, issn = {1612-7021}, doi = {10.1515/jura-2015-0237}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-194866}, pages = {1192-1205}, year = {2015}, abstract = {Kein Abstract verf{\"u}gbar.}, language = {de} } @phdthesis{Brockmann2015, author = {Brockmann, Markus}, title = {Inhibition von Aurora-A als neue Therapiestrategie gegen MYCN-amplifizierte Neuroblastome}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135951}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Im Neuroblastom ist die Amplifikation des MYCN-Gens, das f{\"u}r den Transkriptionsfaktor N-Myc kodiert, der klinisch bedeutendste Faktor f{\"u}r eine schlechte Prognose. Als Mitglied der onkogenen Myc-Familie induziert N-Myc die Expression von Genen, die in vielen biologischen Prozessen wie Metabolismus, Zellzyklusprogression, Zellwachstum und Apoptose eine wichtige Rolle spielen. Die Deregulation der MYCN-Expression f{\"u}hrt zu einem charakteristischen Genexpressionsprofil und einem aggressiven Phenotyp in den Tumorzellen. In normalen neuronalen Vorl{\"a}uferzellen wird N-Myc gew{\"o}hnlich sehr schnell proteasomal abgebaut. W{\"a}hrend der Mitose wird N-Myc an Serin 62 phosphoryliert. Diese Phosphorylierung dient als Erkennungssignal f{\"u}r die Kinase GSK3β, die die Phosphorylierung an Threonin 58 katalysiert. Das Phosphodegron wird von Fbxw7, einer Komponente des E3-Ubiquitinligase-Komplex SCFFbxw7, erkannt. Die anschließende Ubiquitinierung induziert den proteasomalen Abbau des Proteins. Die Reduktion der N-Myc-Proteinlevel erm{\"o}glicht den neuronalen Vorl{\"a}uferzellen den Austritt aus dem Zellzyklus und f{\"u}hrt zu einer terminalen Differenzierung. In einem shRNA Screen konnte AURKA als essentielles Gen f{\"u}r die Proliferation MYCN-amplifizierter Neuroblastomzellen identifiziert werden. Eine Aurora-A-Depletion hatte jedoch keinen Einfluss auf das Wachstum nicht-amplifizierter Zellen. W{\"a}hrend dieser Doktorarbeit konnte gezeigt werden, dass Aurora-A speziell den Fbxw7-vermittelten Abbau verhindert und dadurch N-Myc stabilisiert. F{\"u}r die Stabilisierung ist zwar die Interaktion der beiden Proteine von entscheidender Bedeutung, {\"u}berraschenderweise spielt die Kinaseaktivit{\"a}t von Aurora-A jedoch keine Rolle. Zwei spezifische Aurora-A-Inhibitoren, MLN8054 und MLN8237, sind allerdings in der Lage, nicht nur die Kinaseaktivit{\"a}t zu hemmen, sondern auch die N-Myc-Proteinlevel zu reduzieren. Beide Molek{\"u}le induzieren eine Konformations{\"a}nderung in der Kinasedom{\"a}ne von Aurora-A. Diese ungew{\"o}hnliche strukturelle Ver{\"a}nderung hat zur Folge, dass der N-Myc/Aurora-A-Komplex dissoziiert und N-Myc mit Hilfe von Fbxw7 proteasomal abgebaut werden kann. In MYCN-amplifizierten Zellen f{\"u}hrt diese Reduktion an N-Myc zu einem Zellzyklusarrest in der G1-Phase. Die in vitro Daten konnten in einem transgenen Maus-Modell f{\"u}r das MYCN-amplifizierte Neuroblastom best{\"a}tigt werden. Die Behandlung mit MLN8054 und MLN8237 f{\"u}hrte in den Tumoren ebenfalls zu einer N-Myc-Reduktion. Dar{\"u}ber hinaus konnte ein prozentualer Anstieg an differenzierten Zellen, die vollst{\"a}ndige Tumorregression in der Mehrzahl der Neuroblastome und eine gesteigerte Lebenserwartung beobachtet werden. Insgesamt zeigen die in vitro und in vivo Daten, dass die spezifischen Aurora-A-Inhibitoren ein hohes therapeutisches Potential gegen das MYCN-amplifizierte Neuroblastom besitzen.}, subject = {N-Myc}, language = {de} } @phdthesis{Brugger2015, author = {Brugger, J{\"u}rgen}, title = {Die Rolle der Mangansuperoxiddismutase bei der Kohlenstoffmonoxid vermittelten Protektion in der systemischen Inflammation im murinen Maustiermodell}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137410}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Fragestellung: Die Leberdysfunktion im Rahmen einer systemischen Inflammation stellt einen der wichtigsten Faktoren dar, welcher die Letalit{\"a}t erh{\"o}ht. Sauerstoffradikale (ROS) sind zytotoxisch und wichtige Mediatoren in der Pathophysiologie der entz{\"u}ndlichen Lebersch{\"a}digung. Dies war bereits Gegenstand vieler Arbeiten. Kohlenstoffmonoxid (CO), ein Produkt der Katalyse von H{\"a}m via H{\"a}moxygenase (HO), wirkt zytoprotektiv gegen entz{\"u}ndliche Prozesse. In der vorliegenden Studie untersuchten wir in der Leber die Wirkungsweise von CO auf das Antioxidans Mangan-Superoxiddismutase (MnSOD) in einem Tiermodell der systemischen Entz{\"u}ndungsreaktion. Methodik: Nach Einverst{\"a}ndnis der Tierschutzkommission wurden m{\"a}nnliche M{\"a}use (C57/BL6) mit Isoflurane narkotisiert und zur Messung des mittleren arteriellen Blutdruck (MAP) instrumentiert. Ein normotensives SIRS wurde mit Hilfe einer beidseitigen Isch{\"a}mie der Hinterl{\"a}ufe f{\"u}r 60 Minuten und nachfolgender Reperfusion (I/R) f{\"u}r 3 Stunden induziert. Die H{\"a}moxygenaseaktivit{\"a}t wurde mit Haem induziert und mittels Chromium Mesoporphyrin (CrMP) kompetetiv gehemmt. Ein Teil der Tiere inhalierte CO (250 ppm) nach Beginn der Reperfusion oder erhielt Methylenchlorid (MC, i.p.) zur Induktion der endogenen hepatischen CO Produktion. Die Fetts{\"a}urenoxidation (Malondialdehyde, MDA) und die Gewebespiegel f{\"u}r Glutathione (GSH) wurden mittels spezifischen Enzymessays bestimmt. ROS-Bildung konnte mittels intravitaler Fluoreszenzmikroskopie und dem Farbstoff Dihydrorhodamine (DHR) quantifiziert werden. Das Lebergewebe wurde in sinusoidale und parenchymale Zellfraktionen aufgetrennt. Die Mangan-Superoxiddismutase (MnSOD) Aktivit{\"a}t und Proteinmenge wurde in der sinusoidalen und parenchymalen Zellfraktion mittels Western Blot analysiert. Die Karbonylierung ist eine inaktivierende oxidative Proteinmodifikation. Das Ausmaß der Karbonylierung von MnSOD in den Zellfraktionen wurde mittels Immuno-Blot (OxyBlot; Chemicon) untersucht. Die statistische Testung erfolgte mittels Kruskal-Wallis Test, wobei p<0,05 signifikant war. Ergebnisse: I/R Tiere zeigten signifikant mehr DHR-Fluoreszenz, mehr MDA-Bildung und weniger GSH als Sham Tiere (p<0.02). I/R+CrMP Behandlung hatte signifikant am meisten oxidativen Stress im Vergleich zu allen Behandlungsgruppen zur Folge. Die Inhalation von CO oder die Injektion von MC nach I/R reduzierte die DHR-Fluoreszenz, MDA-Bildung und normalisierte die GSH Spiegel im Vergleich zu I/R Tieren. I/R+CrMP+CO Behandlung zeigte die gleichen Ergebnisse wie I/R+CO Behandlung. Die parenchymale Zellfraktion der Leber zeigte keine Ver{\"a}nderung der MnSOD. In der sinusoidalen Zellfraktion fand sich keine Ver{\"a}nderung der MnSOD Proteinmenge. Jedoch reduzierte sich die sinusoidale MnSOD Aktivit{\"a}t signifikant nach I/R (p<0.02), erholte sich aber nach I/R+CO Behandlung wieder auf Sham Niveau. Die Karbonylierung von MnSOD nach I/R war signifikant erh{\"o}ht in der sinusoidalen Zellfraktion. Nach I/R+CO konnte eine Reduktion der Karbonylierung von MnSOD auf das Sham Niveau nachgewiesen werden. Interpretation: CO reduziert signifikant den hepatischen oxidativen Stress in der systemischen Inflammation. CO induziert die Aktivit{\"a}t der MnSOD in den sinusoidalen, nicht jedoch in den parenchymalen Zellen der Leber. Es konnte in der systemischen Entz{\"u}ndungsreaktion gezeigt werden, dass CO die antioxidative Wirkung von MnSOD durch eine Hemmung der Karbonylierung in den sinusoidalen Zellen der Leber induziert. Diese Ergebnisse zeigen erstmals, {\"u}ber die Karbonylierung von MnSOD, einen indirekten antioxidativen Effekt von CO. Welche weiteren Enzymsysteme von CO auf diese Weise beeinflusst werden, m{\"u}ssen weitere Untersuchungen zeigen.}, subject = {Entz{\"u}ndung}, language = {de} } @phdthesis{Brunecker2015, author = {Brunecker, Frank}, title = {Kohlenstoffnanorohr-Komplexe - Adsorption und Desorption von (Bio-)Polymeren}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113485}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Zur Charakterisierung der Wechselwirkungen zwischen organischen Dispergiermitteln und nanoskaligen Oberfl{\"a}chen stellen Komplexe aus Kohlenstoffnanor{\"o}hren und (Bio-)Polymeren aufgrund der großen Oberfl{\"a}che der Nanor{\"o}hren und der kommerziellen Verf{\"u}gbarkeit fluoreszenzmarkierter DNA-Oligomere unterschiedlicher L{\"a}nge sowie intrinsisch fluoreszierender Polymere ein vielversprechendes Modellsystem dar. Im Rahmen der vorliegenden Dissertation wurden verschiedene Methoden evaluiert, um die Stabilit{\"a}t derartiger Komplexe zu untersuchen und dadurch R{\"u}ckschl{\"u}sse auf das Adsorptionsverhalten der (Bio-)Polymere zu ziehen. Dabei konnte gezeigt werden, dass das publizierte helikale Adsorptionsmodell der DNA auf Kohlenstoffnanor{\"o}hren die Resultate der durchgef{\"u}hrten Experimente nur unzureichend beschreiben kann und stattdessen andere Adsorptionskonformationen in Erw{\"a}gung gezogen werden m{\"u}ssen.}, subject = {Kohlenstoff-Nanor{\"o}hre}, language = {de} } @incollection{Brunner2015, author = {Brunner, Alexandra}, title = {Die Fragilit{\"a}t der Identit{\"a}tsentw{\"u}rfe im Zeichen einer Krise der Repr{\"a}sentation im (post-)modernen Roman Lateinamerikas}, series = {Kommunikation und Repr{\"a}sentation in den romanischen Kulturen. Festschrift f{\"u}r Gerhard Penzkofer}, booktitle = {Kommunikation und Repr{\"a}sentation in den romanischen Kulturen. Festschrift f{\"u}r Gerhard Penzkofer}, editor = {Hornung, Christoph and Lambrecht, Gabriella-Maria and Sendner, Annika}, publisher = {AVM.edition}, address = {M{\"u}nchen}, isbn = {9783954770557}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-152280}, publisher = {Universit{\"a}t W{\"u}rzburg}, pages = {379-396}, year = {2015}, abstract = {No abstract available.}, subject = {Roman}, language = {de} } @phdthesis{Bruno2015, author = {Bruno, Raphael Romano}, title = {Auswirkung von Infusionsl{\"o}sungen mit Hydroxyethylst{\"a}rke (HES) auf humane proximale Tubulusepithelzellen der Niere in vitro}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123278}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Die Volumentherapie durch Infusionsl{\"o}sungen spielt eine herausragende Rolle im klinischen Alltag von Intensivmedizin, perioperativer Medizin und Notfallmedizin. F{\"u}r diesen Zweck stehen verschiedene kristalloide und kolloidale Infusionsl{\"o}sungen zur Verf{\"u}gung. Das in Deutschland am h{\"a}ufigsten eingesetzte Kolloid ist die Hydroxyethylst{\"a}rke (HES). Dessen Stellenwert ist stark umstritten. Insbesondere die Wirkung von Hydroxyethylst{\"a}rke auf die f{\"u}r den kritisch Kranken eine zentrale Rolle spielende Niere gilt als zentrales Problem. Die vorliegende Arbeit untersuchte aufbauend auf die in vivo-Versuche von Schick et al. die Auswirkungen klinisch relevanter Dosierungen von Hydroxyethylst{\"a}rke und anderen Infusionsl{\"o}sungen (Gelatine, Humanalbumin, 0,9\% NaCl, Sterofundin® ISO) auf die Viabilit{\"a}t von immortalisierten humanen proximalen Tubulusepithelzellen (HK-2). Im Anschluss wurde die Relevanz des pH - Wertes, der Osmolalit{\"a}t, der Tr{\"a}gerl{\"o}sung, des Molek{\"u}lursprungs, der Molek{\"u}lgr{\"o}ße, der HES - Generation und der Inkubationsdauer auf die von HES ausgel{\"o}sten Effekte gepr{\"u}ft. Danach wurde gezeigt, ob der beobachtete Effekt reversibel war, ob es sich um ein direkt zytotoxisches Ph{\"a}nomen handelte, ob die HES _ Wirkung durch proinflammatorische Stimuli verst{\"a}rkt und ob HES selbst eine Inflammation auf mRNA - Ebene induzieren konnte. HES bewirkte keine proinflammatorische Stimulation der Zellen und wird durch die Anwesenheit proinflammatorischer Stimuli in seiner sch{\"a}digenden Wirkung nicht verst{\"a}rkt. Die mitochondriale Leistungsf{\"a}higkeit als Schl{\"u}sselaspekt des kritisch Kranken wurde durch den EZ4U („Viabilit{\"a}t") bestimmt. Ein Messartefakt konnte nicht identifiziert werden. HES reduziert mit steigender Dosis die Viabilit{\"a}t der HK - 2 Zellen in deutlichem Ausmaß, obwohl die Zellen immortalisiert und nicht vorgesch{\"a}digt waren. Diese Reduktion erfolgte durch alle untersuchten HES - Pr{\"a}parate. Dabei war niedermolekulares HES leicht weniger sch{\"a}dlich als hochmolekulares HES. Der HES - Effekt war unmittelbar nach Beginn der Inkubation nachweisbar. Der Viabilit{\"a}tsreduktion stand eine verz{\"o}gert einsetzende Zytoxoxizit{\"a}t gegen{\"u}ber. Der HES - Effekt war auch nach einer „Regenerationsphase" der Zellen nachweisbar und somit in vitro nur partiell reversibel. Gelatine erwies sich im Vergleich als ebenso bis schlechter vertr{\"a}glich. Gelatine war deutlich zytotoxischer. Humanalbumin zeigte in niedrigen Dosierungen protektive, in hohen Dosierungen ebenfalls negative Einfluss auf Zellviabilit{\"a}t und war in h{\"o}heren Dosierungen zytotoxisch. Die balancierte Vollelektrolytl{\"o}sung Sterofundin® ISO war gr{\"o}ßtenteils inert, in seiner Wirkung auf die mRNA im Vergleich zur 0,9\% NaCl Kontrolll{\"o}sung protektiv. Zusammenfassend konnte eine {\"U}bergelegenheit des HES der „3. Generation" gegen{\"u}ber anderen HES - Pr{\"a}paraten nicht gefunden werden. Alles deutete darauf hin, dass ausschließlich die applizierte Gesamtmasse von HES ausschlaggebend ist. Synthetische Kolloide sind in vitro nephrotoxisch und beeintr{\"a}chtigen die mitochondriale Funktionsf {\"a}higkeit deutlich. Diese Beobachtungen entsprechen denen großer klinischer Studien. Die Ursache dieses Ph{\"a}nomens bleibt unklar. Weitere Grundlagenforschung ist notwendig, um den zugrundeliegenden Pathomechanimus aufzukl{\"a}ren.}, subject = {Hydroxy{\"a}thylst{\"a}rke}, language = {de} } @phdthesis{Bruns2015, author = {Bruns, Constanze}, title = {Der Einfluss von Laktobazillen auf Oberfl{\"a}che und Eigenschaften von verschiedenen Nahtmaterialien}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132982}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Hintergrund: Nach oralchirurgischen Eingriffen empfiehlt der Operateur allgemein die Vermeidung von Milchprodukten in Hinblick auf eine bessere Heilung im Wundgebiet. Dies st{\"u}tzt sich u.a. auf die Annahme, dass Laktobazillen und ihre Stoffwechselprodukte (z.B. Milchs{\"a}ure) Nahtmaterial angreifen k{\"o}nnen. Der Aufbau dieser Studie zielte darauf ab, diesen Sachverhalt in Frage zu stellen und Funktionsverluste bei Milchs{\"a}ureexposition sowie Besieldungsverhalten der Bakterien zu charakterisieren. Material und Methoden: Polyamid (PA), Polyester/Polyethylenterephtalat (PET), Polypropylen (PP), Polyvinylidenfluorid (PVDF), Seide, Polyglycols{\"a}ure (PGA bzw. PGACL), teilweise mit Polylactid (PLA), Polydioxanon (PDO) und Polytetrafluorethylen (PTFE) kamen zur Anwendung. Die F{\"a}den wurden mit L.acidophilus (LAC) beimpft, inkubiert und anschließen im Tensiometer mit verschiedenen Knotenvarianten getestet. F{\"u}r die Keimbesiedlung (CFU) wurden die F{\"a}den beimpft, inkubiert und das Keimmaterial anschließend mit Ultraschall- Vortex- Verfahren vom Faden abgel{\"o}st und ausgez{\"a}hlt. Dieses Verfahren wurde durch REM- Aufnahmen zus{\"a}tzlich bewertet. Ergebnisse: Reißfestigkeiten waren stets im Rahmen der Herstellerangaben bzw. dar{\"u}ber zu verzeichnen. Alle resorbierbaren F{\"a}den hatten h{\"o}here Ausgangsreißkr{\"a}fte als die nichtresorbierbaren Produkte. Die Applikation eines Knotens minderte ausschlaggebend f{\"u}r alle Produkte die maximale Reißfestigkeit eines Materials. Die Knotenhaltbarkeiten konnten sich w{\"a}hrend der Liegezeit im sauren w{\"a}ssrigen Milieu ver{\"a}ndern. Die f{\"u}r klinische Anwendungen besten Ergebnisse verzeichneten PA als nichtresorbierbare, monofiles PDO und polyfiles PGA/PLA + CHX als resorbierbare Vertreter. Eine erh{\"o}hte CFU-Zahl auf polyfilen F{\"a}den im Vergleich zu monofilen F{\"a}den wurde best{\"a}tigt. Seide (polyfil, nicht resorbierbar) hatte mit Abstand die h{\"o}chsten CFU, gefolgt von PGACL (polyfil, resorbierbar). PVDF (monofil, nichtresorbierbar) hatte die niedrigsten CFU- Werte. Im Schnitt war die CFU-Zahl von PGA/PLA+CHX (polyfil, resorbierbar) {\"a}hnlich hoch wie die von monofilen Produkten. Diskussion: Die Annahme, dass eine Kontamination mit LAC den Heilungserfolg beeinflussen kann, wurde im Hinblick auf Materialerm{\"u}dung durch S{\"a}ureexposition aus Stoffwechselprodukten des Bakteriums entkr{\"a}ftet. Die f{\"u}r klinische Anwendungen besten Ergebnisse verzeichneten PA als nichtresorbierbare, polyfiles PGA/PLA + CHX als resorbierbare Vertreter. Alle getesteten Produkte entsprachen trotz LAC- Einwirkungen den Herstellerangaben und haben somit die materiellen Voraussetzungen einer vorhersagbaren Nahthaltbarkeit erbracht.}, subject = {Lactobacillus acidophilus}, language = {de} } @phdthesis{Bruttel2015, author = {Bruttel, Valentin Stefan}, title = {Soluble HLA-G binds to dendritic cells which likely suppresses anti-tumour immune responses in regional lymph nodes in ovarian carcinoma}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127252}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Zusammenfassung Einleitung HLA-G, ein nicht-klassisches HLA bzw. MHC Klasse Ib Molek{\"u}l, kann sowohl als membrangebundenes als auch als l{\"o}sliches Molek{\"u}l verschiedenste Immunzellpopulationen effektiv inhibieren. Unter physiologischen Bedingungen wird HLA-G vor allem in der Plazenta exprimiert, wo es dazu beitr{\"a}gt den semiallogenen Embryo vor einer Abstoßung durch das m{\"u}tterliche Immunsystem zu besch{\"u}tzen. Außerdem wird HLA-G in einer Vielzahl von Tumoren wie zum Beispiel in Ovarialkarzinomen {\"u}berexprimiert. Ziel dieser Arbeit war es besonders die Rolle von l{\"o}slichem HLA-G im Ovarialkarzinom und die Expression von HLA-G in verschiedenen Subtypen des Ovarialkarzinoms genauer zu untersuchen. Ergebnisse Anhand eines Tissue Microarrays wurde best{\"a}tigt dass HLA-G unter physiologischen Bedingungen nur in sehr wenigen Geweben wie Plazenta oder Testes exprimiert wird. Außerdem wurden erstmals auch im Nebennierenmark hohe Expressionslevel detektiert. Im Gegensatz zur physiologischen Expression wurde HLA-G in ser{\"o}sen, muzin{\"o}sen, endometrioiden und Klarzellkarzinomen und somit in Tumoren aller untersuchten Subtypen des Ovarialkarzinoms detektiert. Am h{\"a}ufigsten war HLA-G in hochgradigen ser{\"o}sen Karzinomen {\"u}berexprimiert. Hier konnte gezeigt werden dass auf Genexpressionslevel in Ovarialkarzinomen die Expression des immunsuppressiven HLA-G mit der Expression von klassischen MHC Molek{\"u}len wie HLA-A, -B oder -C hochsignifikant korreliert. Außerdem konnte in Aszitesproben von Patientinnen mit Ovarialkarzinomen hohe Konzentrationen von l{\"o}slichem HLA-G nachgewiesen werden. Auch auf metastasierten Tumorzellen in regionalen Lymphknoten war HLA-G nachweisbar. {\"U}berraschenderweise wurde aber besonders viel HLA-G auf Dendritischen Zellen in Lymphknoten detektiert. Da in Monozyten und Dendritischen Zellen von gesunden Spendern durch IL-4 oder IL-10 im Gegensatz zu Literatur keine Expression von HLA-G induzierbar war, untersuchten wir ob Dendritische Zellen l{\"o}sliches HLA-G binden. Es konnte gezeigt werden, dass besonders Dendritische Zellen die in Gegenwart von IL-4, IL-10 und GM-CSF aus Monozyten generiert wurden (DC-10) effektiv l{\"o}sliches HLA-G {\"u}ber ILT Rezeptoren binden. In Abh{\"a}ngigkeit von ihrer Beladung mit HLA-G hemmen auch fixierte DC-10 Zellen noch die Proliferation von zytotoxischen CD8+ T Zellen. Zudem wurden regulatorische T Zellen induziert. Schlussfolgerungen Besonders in den am h{\"a}ufigsten diagnostizierten hochgradigen ser{\"o}sen Ovarialkarzinomen ist HLA-G in den meisten F{\"a}llen {\"u}berexprimiert. Durch die Expression immunsuppressiver MHC Klasse Ib Molek{\"u}le wie HLA-G k{\"o}nnen wahrscheinlich auch Tumore wachsen, die noch klassische MHC Molek{\"u}le exprimieren und aufgrund ihrer Mutationslast eigentlich vom Immunsystem erkannt und eliminiert werden m{\"u}ssten. L{\"o}sliches HLA-G k{\"o}nnte zudem lokal Immunantworten gegen Tumorantigene unterdr{\"u}cken indem es an Dendritische Zellen in regionalen Lymphknoten bindet. Diese Zellen pr{\"a}sentieren nomalerweise zytotoxischen T Zellen Tumorantigene und spielen daher eine entscheidende Rolle in der Entstehung von protektiven Immunantworten. Mit l{\"o}slichem HLA-G beladene Dendritische Zellen hemmen jedoch die Proliferation von CD8+ T Zellen und induzieren regulatorische T Zellen. Dadurch k{\"o}nnten Ovarialkarzinome "aus der Ferne" auch in metastasenfreien Lymphknoten die Entstehung von gegen den Tumor gerichteten Immunantworten unterdr{\"u}cken. Dieser erstmals beschriebene Mechanismus k{\"o}nnte auch in anderen malignen Erkrankungen eine Rolle spielen, da l{\"o}sliches HLA-G in einer Vielzahl von Tumorindikationen nachgewiesen wurde.}, subject = {HLA-G}, language = {en} } @article{BuechnerMaitiDrohatetal.2015, author = {Buechner, Claudia N. and Maiti, Atanu and Drohat, Alexander C. and Tessmer, Ingrid}, title = {Lesion search and recognition by thymine DNA glycosylase revealed by single molecule imaging}, series = {Nucleic Acids Research}, volume = {43}, journal = {Nucleic Acids Research}, number = {5}, doi = {10.1093/nar/gkv139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148795}, pages = {2716-2729}, year = {2015}, abstract = {The ability of DNA glycosylases to rapidly and efficiently detect lesions among a vast excess of nondamaged DNA bases is vitally important in base excision repair (BER). Here, we use singlemolecule imaging by atomic force microscopy (AFM) supported by a 2-aminopurine fluorescence base flipping assay to study damage search by human thymine DNA glycosylase (hTDG), which initiates BER of mutagenic and cytotoxic G:T and G:U mispairs in DNA. Our data reveal an equilibrium between two conformational states of hTDG-DNA complexes, assigned as search complex (SC) and interrogation complex (IC), both at target lesions and undamaged DNA sites. Notably, for both hTDG and a second glycosylase, hOGG1, which recognizes structurally different 8-oxoguanine lesions, the conformation of the DNA in the SC mirrors innate structural properties of their respective target sites. In the IC, the DNA is sharply bent, as seen in crystal structures of hTDG lesion recognition complexes, which likely supports the base flipping required for lesion identification. Our results support a potentially general concept of sculpting of glycosylases to their targets, allowing them to exploit the energetic cost of DNA bending for initial lesion sensing, coupled with continuous (extrahelical) base interrogation during lesion search by DNA glycosylases.}, language = {en} } @article{BurgsdorfSlabyHandleyetal.2015, author = {Burgsdorf, Ilia and Slaby, Beate M. and Handley, Kim M. and Haber, Markus and Blom, Jochen and Marshall, Christopher W. and Gilbert, Jack A. and Hentschel, Ute and Steindler, Laura}, title = {Lifestyle Evolution in Cyanobacterial Symbionts of Sponges}, series = {mBio}, volume = {6}, journal = {mBio}, number = {3}, doi = {10.1128/mBio.00391-15}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143117}, pages = {e00391-15}, year = {2015}, abstract = {The "Candidatus Synechococcus spongiarum" group includes different clades of cyanobacteria with high 16S rRNA sequence identity (~99\%) and is the most abundant and widespread cyanobacterial symbiont of marine sponges. The first draft genome of a "Ca. Synechococcus spongiarum" group member was recently published, providing evidence of genome reduction by loss of genes involved in several nonessential functions. However, "Ca. Synechococcus spongiarum" includes a variety of clades that may differ widely in genomic repertoire and consequently in physiology and symbiotic function. Here, we present three additional draft genomes of "Ca. Synechococcus spongiarum," each from a different clade. By comparing all four symbiont genomes to those of free-living cyanobacteria, we revealed general adaptations to life inside sponges and specific adaptations of each phylotype. Symbiont genomes shared about half of their total number of coding genes. Common traits of "Ca. Synechococcus spongiarum" members were a high abundance of DNA modification and recombination genes and a reduction in genes involved in inorganic ion transport and metabolism, cell wall biogenesis, and signal transduction mechanisms. Moreover, these symbionts were characterized by a reduced number of antioxidant enzymes and low-weight peptides of photosystem II compared to their free-living relatives. Variability within the "Ca. Synechococcus spongiarum" group was mostly related to immune system features, potential for siderophore-mediated iron transport, and dependency on methionine from external sources. The common absence of genes involved in synthesis of residues, typical of the O antigen of free-living Synechococcus species, suggests a novel mechanism utilized by these symbionts to avoid sponge predation and phage attack. IMPORTANCE While the Synechococcus/Prochlorococcus-type cyanobacteria are widely distributed in the world's oceans, a subgroup has established its niche within marine sponge tissues. Recently, the first genome of sponge-associated cyanobacteria, " Candidatus Synechococcus spongiarum," was described. The sequencing of three representatives of different clades within this cyanobacterial group has enabled us to investigate intraspecies diversity, as well as to give a more comprehensive understanding of the common symbiotic features that adapt "Ca. Synechococcus spongiarum" to its life within the sponge host.}, language = {en} } @incollection{Burrichter2015, author = {Burrichter, Brigitte}, title = {Die Frage der Ehre. Ehre und Schande in den Romanen Chr{\´e}tiens de Troyes}, series = {Kommunikation und Repr{\"a}sentation in den romanischen Kulturen. Festschrift f{\"u}r Gerhard Penzkofer}, booktitle = {Kommunikation und Repr{\"a}sentation in den romanischen Kulturen. Festschrift f{\"u}r Gerhard Penzkofer}, editor = {Hornung, Christoph and Lambrecht, Gabriella-Maria and Sendner, Annika}, publisher = {AVM.edition}, address = {M{\"u}nchen}, isbn = {9783954770557}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-152061}, publisher = {Universit{\"a}t W{\"u}rzburg}, pages = {33-48}, year = {2015}, abstract = {No abstract available.}, subject = {Ehre }, language = {de} } @phdthesis{Buschmann2015, author = {Buschmann, Peter}, title = {Anbindung von Katalysatoren an Nanodiamantpartikel mit Hilfe starrer Linker}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132966}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Das Ziel dieser Arbeit war die Herstellung von Diamantmaterialien, deren Oberfl{\"a}chen mit Alkinen, Aziden oder Aldehyden modifiziert waren. Diese funktionellen Gruppen sollten die einfache Anbindung verschiedener katalytisch aktiver Systeme mit Hilfe der 1,3-dipolaren Cycloaddition nach Huisgen bzw. Iminbildung ermg{\"o}glich. Da in einer vorangegangenen Arbeit Hinweise darauf gefunden wurde, dass die hochgradig funktionalisierte Oberfl{\"a}che von Detonationsnanodiamant dazu in der Lage ist, die Aktivit{\"a}t von immobilisierten Katalysatoren zu behindern. Darum wurde in dieser Arbeit verglichen, ob die Verwendung von starren Linkern auf Tolanbasis einen Vorteil gegen{\"u}ber ihren flexiblen Gegenst{\"u}cken liefert. Dazu wurde f{\"u}r jede der oben genannten Funktionalisierungsarten je ein Diamantmaterial mit flexibler sowie mindestens eines mit unbiegsamer Verbindungseinheit hergestellt und getestet. Dadurch konnte das Konzept der starren Linker f{\"u}r Enzyme best{\"a}tigt werden und es wurde eine signifikant h{\"o}here Aktivit{\"a}t erhalten, als wenn flexible Anbindungsbr{\"u}cken verwendet wurden. Bei Organokatalysatoren und metallorganischen Systemen konnten jedoch keine erfolgreichen Katalysen durchgef{\"u}hrt werden.}, subject = {Nanopartikel}, language = {de} } @phdthesis{Boehm2015, author = {B{\"o}hm, Christoph}, title = {Loewner equations in multiply connected domains}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129903}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {The first goal of this thesis is to generalize Loewner's famous differential equation to multiply connected domains. The resulting differential equations are known as Komatu--Loewner differential equations. We discuss Komatu--Loewner equations for canonical domains (circular slit disks, circular slit annuli and parallel slit half-planes). Additionally, we give a generalisation to several slits and discuss parametrisations that lead to constant coefficients. Moreover, we compare Komatu--Loewner equations with several slits to single slit Loewner equations. Finally we generalise Komatu--Loewner equations to hulls satisfying a local growth property.}, subject = {Biholomorphe Abbildung}, language = {en} } @phdthesis{Boehm2015, author = {B{\"o}hm, Jennifer}, title = {Die N{\"a}hrstoffresorption in den Fallen von Dionaea muscipula weist Parallelen zur N{\"a}hrsalzaufnahme in Wurzeln auf}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123958}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Die Venusfliegenfalle, Dionaea muscipula, weckte aufgrund ihrer karnivoren Lebensweise schon sehr fr{\"u}h das Interesse vieler Wissenschaftler. F{\"u}r karnivore Pflanzen, die auf N{\"a}hrstoff-armen B{\"o}den wachsen, spielen Insekten als Beute und somit als N{\"a}hrstofflieferant eine entscheidende Rolle. So k{\"o}nnen die Pflanzen durch die Verdauung der Beute mit wichtigen Makro- und Mikron{\"a}hrstoffen, wie Stickstoff, Phosphat, Kalium oder Natrium versorgt werden. Aus diesem Grund sollte im Rahmen meiner Arbeit ein besonderes Augenmerk auf die molekularen Mechanismen der Kationenaufnahme w{\"a}hrend der N{\"a}hrstoffresorption gerichtet werden. Insbesondere die aus dem Insekt stammenden N{\"a}hrstoffe Kalium und Natrium waren dabei von großem Interesse. Im Allgemeinen sind Kaliumionen f{\"u}r Pflanzen eine essentielle anorganische Substanz und von großer physiologischer Bedeutung f{\"u}r die Entwicklung, den Metabolismus, die Osmoregulation, das Membranpotential und viele zellul{\"a}re Prozesse. Analysen der Kaliumaufnahme an Wurzeln von Modellpflanzen wie Arabidopsis thaliana und Reis zeigten, dass die Aufnahme von K+ ein Zusammenspiel von hoch-affinen K+-Transportern der HAK5-Familie und nieder-affinen Kaliumkan{\"a}len (AKT1/AtKC1) erfordert, die in ein komplexes (De-)Phosphorylierungsnetzwerk eingebunden sind. In der vorliegenden Arbeit war es mir m{\"o}glich das Netzwerk zur Kaliumaufnahme in den Dr{\"u}sen der Venusfliegenfalle zu entschl{\"u}sseln. Es konnten Orthologe zum Kaliumtransporter HAK5 aus Arabidopsis (DmHAK5) und zum Kaliumkanal AKT1 (DmKT1) identifiziert und im heterologen Expressionssystem der Xenopus laevis Oozyten elektrophysiologisch charakterisiert werden. Dabei zeigte sich, das DmKT1 durch einen Ca2+-Sensor/Kinase-Komplex aus der CBL/CIPK-Familie phosphoryliert und somit aktiviert wird. Phylogenetische Analysen von DmKT1 best{\"a}tigten die Eingruppierung dieses Kaliumkanals in die Gruppe der pflanzlichen Shaker-Kaliumkan{\"a}le des AKT1-Typs. Die Transporteigenschaften zeigten zudem, dass DmKT1 bei hyperpolarisierenden Membranpotentialen aktiviert wird und einen K+-selektiven Einw{\"a}rtsstrom vermittelt. In Oozyten konnte eine Kaliumaufnahme bis zu einer externen Konzentration von ≥1 mM beobachtet werden. DmKT1 repr{\"a}sentiert also einen Kaliumkanal mit einer hohen Transportkapazit{\"a}t, der die nieder-affine Kaliumaufnahme in die Dr{\"u}senzellen der Venusfliegenfalle vermitteln kann. Unterhalb einer externen Kaliumkonzentration von 1 mM w{\"u}rde der anliegende elektrochemische Kaliumgradient einen Kaliumausstrom und somit einen Verlust von Kalium favorisieren. Hoch-affine K+/H+-Symporter k{\"o}nnen durch die Ausnutzung des Protonengradienten eine Kaliumaufnahme im mikromolaren Bereich gew{\"a}hrleisten. In Wurzelhaaren von Arabidopsis vermittelt der Transporter AtHAK5 die Kaliumaufnahme unter Kaliummangelbedingungen. DmHAK5, ein Ortholog zu AtHAK5, ist in Dionaea Dr{\"u}sen exprimiert und konnte zum ersten Mal im heterologen Expressionssystem der Xenopus Oozyten im Detail charakterisiert werden. Interessanterweise zeigte sich, dass DmHAK5 wie der K+-Kanal DmKT1 durch denselben CBL/CIPK-Komplex posttranslational reguliert und aktiviert wird. Die Transporteigenschaften von DmHAK5 wiesen auf einen Transporter mit einer breiten Substratspezifit{\"a}t hin, sodass sich DmHAK5 neben Kalium auch f{\"u}r Ammonium permeabel zeigte. Affinit{\"a}tsuntersuchungen von DmHAK5 zu seinem Substrat Kalium klassifizierten das Protein als einen hoch-affinen Kaliumtransporter, der im Symport mit Protonen die Kaliumaufnahme im mikromolaren Konzentrationsbereich vermitteln kann. Das Kaliumtransportmodul besteht also aus dem K+-selektiven Kanal DmKT1 und dem K+/H+-Symporter DmHAK5, die die hoch- und nieder-affine Kaliumaufnahme in den Dr{\"u}senzellen w{\"a}hrend der Beuteverdauung in Dionaea muscipula Fallen erm{\"o}glichen. Beide Transportmodule werden Kalzium-abh{\"a}ngig durch die Kinase CIPK23 und den Ca2+-Sensor CBL9 auf posttranslationaler Ebene reguliert. Zusammenfassend gelang es in dieser Arbeit Einblicke in die Kationenaufnahme w{\"a}hrend der N{\"a}hrstoffresorptionsphase der Venusfliegenfalle, Dionaea muscipula, zu gewinnen. Dabei wurde klar, dass Dionaea muscipula im Laufe ihrer Evolution zu einer karnivoren Pflanze, nicht neue Transportmodule zur N{\"a}hrstoffresorption aus der Beute entwickelte, sondern bekannte aus Wurzeln stammende Transportmodule umfunktionierte. Auf molekularer Ebene konnten die biophysikalischen Charakteristika der K+- und Na+-Transportproteine, sowie ihre Regulation entschl{\"u}sselt werden. Diese Erkenntnisse wurden schließlich in den Kontext des Beutefangs der Venusfliegenfalle gebracht und diskutiert.}, subject = {Venusfliegenfalle}, language = {de} } @phdthesis{CamargoMolina2015, author = {Camargo Molina, Jos{\´e} Eliel}, title = {Vacuum stability of models with many scalars}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112755}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {One of the most popular extensions of the SM is Supersymmetry (SUSY). It is a symmetry relating fermions and bosons and also the only feasible extension to the symmetries of spacetime. With SUSY it is then possible to explain some of the open questions left by the SM while at the same time opening the possibility of gauge unification at a high scale. SUSY theories require the addition of new particles, in particular an extra Higgs doublet and at least as many new scalars as fermions in the SM. Much in the same way that the Higgs boson breaks SU (2)L symmetry, these new scalars can break any symmetry for which they carry a charge through spontaneous symmetry breaking. Let us assume there is a local minimum of the potential that reproduces the correct phenomenol- ogy for a parameter point of a given model. By exploring whether there are other deeper minima with VEVs that break symmetries we want to conserve, like SU (3)C or U (1)EM , it is possible to exclude regions of parameter space where that happens. The local minimum with the correct phenomenology might still be metastable, so it is also necessary to calculate the probability of tunneling between minima. In this work we propose and apply a framework to constrain the parameter space of models with many scalars through the minimization of the one-loop eff e potential and the calculation of tunneling times at zero and non zero temperature.After a brief discussion about the shortcomings of the SM and an introduction of the basics of SUSY, we introduce the theory and numerical methods needed for a successful vacuum stability analysis. We then present Vevacious, a public code where we have implemented our proposed framework. Afterwards we go on to analyze three interesting examples. For the constrained MSSM (CMSSM) we explore the existence of charge- and color- breaking (CCB) minima and see how it constraints the phenomenological relevant region of its parameter space at T = 0. We show that the regions reproducing the correct Higgs mass and the correct relic density for dark matter all overlap with regions suffering from deeper CCB minima. Inspired by the results for the CMSSM, we then consider the natural MSSM and check the region of parameter space consistent with the correct Higgs mass against CCB minima at T /= 0. We find that regions of parameter space with CCB minima overlap significantly with that reproducing the correct Higgs mass. When thermal eff are considered the majority of such points are then found to have a desired symmetry breaking minimum with very low survival probability. In both these studies we find that analytical conditions presented in the literature fail in dis- criminating regions of parameter space with CCB minima. We also present a way of adapting our framework so that it runs quickly enough for use with parameter fit studies. Lastly we show a different example of using vacuum stability in a phenomenological study. For the BLSSM we investigate the violation of R-parity through sneutrino VEVs and where in parameter space does this happen. We find that previous analyses in literature fail to identify regions with R-parity conservation by comparing their results to our full numerical analysis.}, subject = {Supersymmetry}, language = {en} } @phdthesis{Campbell2015, author = {Campbell, Marlen Jamie-Lee}, title = {Organizational cultures' impact on employees' corruption}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123251}, school = {Universit{\"a}t W{\"u}rzburg}, pages = {197}, year = {2015}, abstract = {Although many researchers refer to organizational culture as the key to explain employees' organizational corruption (= corruption on behalf of the organization), literature lacks systematic empirical evidence. Through a mixed-method approach this research tries to shed some first lights on this issue with the questions: what characteristics describe an organizational culture that promotes employees' corruption? Does a certain type of organizational culture shape a positive attitude towards organizational corruption? Does organizational culture differ in its impact on different types of corruption? Does organizational culture interact with employees' sex to promote employees' corruption? And, is there a main effect of sex on corruption? A qualitative study investigates the characteristics of a corrupt organizational culture in both general and in particular for managers and employees (Study 1). 14 experts of different occupations were asked about underlying assumptions, values, and norms of a corrupt organizational culture coding the frequency and relationship of their answers. The results showed specific underlying assumptions, values, and norms that were shared by the interviewees and provide first insights into their interrelatedness. In addition, the quantitative field survey (Study 2) analyzed if a corrupt organizational culture shapes a positive attitude towards organizational corruption and if both tangible rewards and lax control mechanism mediate this impact. 131 participants answered questionnaires about their perceived competition in their industry, tangible rewards, lax control mechanism, and their attitude towards both gifting and bribery. Results showed that lax control mechanism (and for gifting also tangible rewards) mediated the positive impact of a corrupt organizational culture on organizational corruption. In addition, men and women did not differ in their attitude towards organizational corruption in a corrupt organizational culture. Finally a web-based experiment investigates if organizational culture shapes employees' corruption (Study 3). In addition this approach also covers if the impact of organizational culture on corruption depends on the type of corruption (organizational corruption vs. counterproductive), and if employees' sex influence corruption and if there is an interaction of organizational culture and sex on employees' corruption. 563 participants had to decide whether they engage in corruption. Although a corrupt organizational culture raises both types of corruption, there was neither a notable main effect of sex nor a high impact interaction effect of both on both types of corruption. Thus, aspects of a corrupt organizational culture seem to influence employees' corruption.}, subject = {Korruption}, language = {en} } @phdthesis{Campion2015, author = {Campion, Marie-Genevi{\`e}ve}, title = {Competition between Originators and Generics: Public Regulation and Incentives to Innovate}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111701}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {The aim of this thesis is to examine the competition patterns that exist between originators and generics by focusing on the articulations between regulation and incentives to innovate. Once the characteristics of regulation in pharmaceutical markets is reviewed in the first chapter and an analysis of some current challenges related to cost-containment measures and innovation issues is performed, then in the second chapter, an empirical study is performed to investigate substitution patterns. Based on the EC´s merger decisions in the pharmaceutical sector from 1989 to 2011, this study stresses the key criteria to define the scope of the relevant product market based on substitution patterns and shows the trend towards a narrower market in time. Chapters three and four aim to analyse in depth two widespread measures, the internal reference pricing system in off-patent markets, and risk-sharing schemes in patent-protected markets. By taking into account informational advantages of originators over generics, the third chapter shows the extent to which the implementation of a reference price for off-patent markets can contribute in promoting innovation. Finally, in the fourth chapter, the modeling of risk-sharing schemes explains how such schemes can help in solving moral hazard and adverse selection issues by continuously giving pharmaceutical companies incentives to innovate and supplying medicinal products of a higher quality.}, subject = {Pharmazeutische Industrie}, language = {en} } @phdthesis{CarmonaArana2015, author = {Carmona Arana, Jos{\´e} Antonio}, title = {Regulation Tumornekrosefaktor (TNF) Rezeptor assoziierter Signalwege durch das Adapterprotein TRAF1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128735}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {TWEAK ist ein zu der TNF-Superfamilie (Tumor Necrosis Factor) zugeh{\"o}riges Zytokin, welches in Form l{\"o}slicher und membranst{\"a}ndiger Molek{\"u}le vorkommt. Beide Formen des Liganden k{\"o}nnen an den Rezeptor (Fn14) binden. Viele verschiedene intrazellul{\"a}re Signalwege werden durch den Fn14 aktiviert, beispielweise Erk1/2, JNK, Jun und STAT3, vor allem jedoch das NFkB. L{\"o}sliches und membranst{\"a}ndiges TWEAK zeigen eine {\"a}hnliche Aktivierungseffizienz bez{\"u}glich des alternativen NFkB-Signalwegs, wohingegen membranst{\"a}ndiges TWEAK weit besser als l{\"o}sliches TWEAK den klassischen NFkB-Signalweg aktiviert. In der vorliegenden Arbeit wurde zun{\"a}chst die TWEAK-vermittelte Induzierbarkeit von verschiedenen Zielgenen des NFkB-Systems untersucht. L{\"o}sliches TWEAK zeigte einen weit schw{\"a}cheren aktivierenden Effekt auf den klassischen NFkB-Signalweg als TNF, das ein sehr guter Aktivator des klassischen NFkB-Systems ist (Abb. 5, 6). Nichtsdestotrotz war TWEAK imstande eine st{\"a}rkere TRAF1-Induktion als TNF herbeizuf{\"u}hren (Abbildung 7, 8). TRAF1 ist ein durch NFkB-System stark reguliertes Gen. Um posttranskriptionelle TRAF1-Modifikationen als Ursache f{\"u}r die unerwartet gute TRAF1-Induktion durch l{\"o}sliches TWEAK auszuschließen, wurde die TRAF1-Expression nach Proteasom- und Caspasen-Inhibition untersucht (Abbildung 9). Dies ergab keinen Hinweis auf einen Einfluss dieser Prozessen auf der TRAF1-Expression. Mittels des IKK2-spezifischen Inhibitor TPCA-1 wurde die TWEAK-vermittelte TRAF1-Induktion Zelltyp-abh{\"a}ngig gehemmt, wohingegen die TNF-vermittelte Induktion von TRAF1 in allen Zelllinien vollst{\"a}ndig inhibiert wurde (Abbildung 13). Versuche mit dem NEDD8-aktivierenden Enzym (NAE) Inhibitor MLN4924, resultierten in einer totalen Inhibition der TRAF1-Expression in allen TWEAK- und TNF-stimulierten Zellen (Abbildung 14). Diese Befunde sprechen daf{\"u}r, dass bei der TWEAK-vermittelten TRAF1-Expression beide Zweige des NFkB-Signalwegs Zelltyp-abh{\"a}ngig beteiligt sind. Die Oligomerisierung der Liganden der TNF-Familie verst{\"a}rkt oft ihre Aktivit{\"a}t. Oligomerisiertes TWEAK imitiert die biologische Aktivit{\"a}t von membranst{\"a}ndigem TWEAK. L{\"o}sliches TWEAK wurde mit einem anti-Flag Antik{\"o}rper oligomerisiert und die TRAF1-Induktion durch den alternativen NFkB-Signalweg wurde analysiert Oligomerisiertes TWEAK aktivierte Zelltyp-unabh{\"a}ngig den klassischen NFkB-Signalweg st{\"a}rker als l{\"o}sliches TWEAK, wohingegen kein Effekt auf die TRAF1-Induktion oder auf die Aktivierung den alternativen NFkB-Signalweg festgestellt wurde (Abbildung 11, 12). TWEAK ist imstande die TRAF2-vermittelte CD40-Induktion des klassischen NFkB-Signalwegs zu hemmen (Abbildung 16, 17). Um den Beitrag von TWEAK-Induziertem TRAF1 zur CD40-Inhibition zu herauszufinden, wurden TRAF1-stabil transfizierte 786O- und U2OS-Zellen hergestellt (Abbildung 19). Die CD40-Induzierte IkBa-Degradation und IL8/6 Produktion war in den TRAF1-Transfektanten als auch in mit l{\"o}slichem TWEAK vorbehandelte Zellen stark inhibiert (Abbildung 21, 22), wobei die CD40-Expression und CD40/CD40L-Interaktion unver{\"a}ndert blieb (Abbildung 20). Diese Ergebnisse sprechen f{\"u}r einen wichtigen Beitrag des Adaptorprotein TRAF1 in der TWEAK-vermittelte Inhibition der CD40-induzierte Aktivierung des klassischen NFkB-Signalwegs.}, subject = {Antigen CD40}, language = {de} }