@article{KonteTerpitzPlemenitaš2016, author = {Konte, Tilen and Terpitz, Ulrich and Plemenitaš, Ana}, title = {Reconstruction of the High-Osmolarity Glycerol (HOG) Signaling Pathway from the Halophilic Fungus Wallemia ichthyophaga in Saccharomyces cerevisiae}, series = {Frontiers in Microbiology}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2016.00901}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165214}, year = {2016}, abstract = {The basidiomycetous fungus Wallemia ichthyophaga grows between 1.7 and 5.1 M NaCl and is the most halophilic eukaryote described to date. Like other fungi, W. ichthyophaga detects changes in environmental salinity mainly by the evolutionarily conserved high-osmolarity glycerol (HOG) signaling pathway. In Saccharomyces cerevisiae, the HOG pathway has been extensively studied in connection to osmotic regulation, with a valuable knock-out strain collection established. In the present study, we reconstructed the architecture of the HOG pathway of W. ichthyophaga in suitable S. cerevisiae knock-out strains, through heterologous expression of the W. ichthyophaga HOG pathway proteins. Compared to S. cerevisiae, where the Pbs2 (ScPbs2) kinase of the HOG pathway is activated via the SHO1 and SLN1 branches, the interactions between the W. ichthyophaga Pbs2 (WiPbs2) kinase and the W. ichthyophaga SHO1 branch orthologs are not conserved: as well as evidence of poor interactions between the WiSho1 Src-homology 3 (SH3) domain and the WiPbs2 proline-rich motif, the absence of a considerable part of the osmosensing apparatus in the genome of W. ichthyophaga suggests that the SHO1 branch components are not involved in HOG signaling in this halophilic fungus. In contrast, the conserved activation of WiPbs2 by the S. cerevisiae ScSsk2/ScSsk22 kinase and the sensitivity of W. ichthyophaga cells to fludioxonil, emphasize the significance of two-component (SLN1-like) signaling via Group III histidine kinase. Combined with protein modeling data, our study reveals conserved and non-conserved protein interactions in the HOG signaling pathway of W. ichthyophaga and therefore significantly improves the knowledge of hyperosmotic signal processing in this halophilic fungus.}, language = {en} } @article{ContarinoSmitvandenDooletal.2016, author = {Contarino, Maria Fiorella and Smit, Marenka and van den Dool, Joost and Volkmann, Jens and Tijssen, Marina A. J.}, title = {Unmet Needs in the Management of Cervical Dystonia}, series = {Frontiers in Neurology}, volume = {7}, journal = {Frontiers in Neurology}, number = {165}, doi = {10.3389/fneur.2016.00165}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165225}, year = {2016}, abstract = {Cervical dystonia (CD) is a movement disorder which affects daily living of many patients. In clinical practice, several unmet treatment needs remain open. This article focuses on the four main aspects of treatment. We describe existing and emerging treatment approaches for CD, including botulinum toxin injections, surgical therapy, management of non-motor symptoms, and rehabilitation strategies. The unsolved issues regarding each of these treatments are identified and discussed, and possible future approaches and research lines are proposed.}, language = {en} } @article{ArimanyNardiMinuesaPastorAngladaetal.2016, author = {Arimany-Nardi, Cristina and Minuesa, Gerard and Pastor-Anglada, Mar{\c{c}}al and Keller, Thorsten and Erkizia, Itziar and Koepsell, Hermann and Martinez-Picado, Javier}, title = {Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions}, series = {Frontiers in Pharmacology}, volume = {7}, journal = {Frontiers in Pharmacology}, number = {175}, doi = {10.3389/fphar.2016.00175}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165236}, year = {2016}, abstract = {Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level.}, language = {en} } @article{ProppingLorenzMicheletal.2016, author = {Propping, Stefan and Lorenz, Kristina and Michel, Martin C. and Wirth, Manfred P. and Ravens, Ursula}, title = {beta-Adrenoceptor-mediated Relaxation of Urinary Bladder Muscle in beta 2-Adrenoceptor Knockout Mice}, series = {Frontiers in Pharmacology}, volume = {7}, journal = {Frontiers in Pharmacology}, number = {118}, doi = {10.3389/fphar.2016.00118}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165245}, year = {2016}, abstract = {Background and Objective: In order to characterize the β-adrenoceptor (AR) subtypes involved in agonist-stimulated relaxation of murine urinary bladder we studied the effects of (-)-isoprenaline and CL 316,243 on tonic contraction and spontaneous contractions in detrusor strips of wild-type (WT) and β2-AR knockout (β2-AR KO) mice. Materials and Methods: Urinary bladders were isolated from male WT and β2-AR KO mice. β-AR subtype expression was determined with quantitative real-time PCR. Intact muscle strips pre-contracted with KCl (40 mM) were exposed to cumulatively increasing concentrations of (-)-isoprenaline or β3-AR agonist CL 316,243 in the presence and absence of the subtype-selective β-AR blockers CGP 20712A (β1-ARs), ICI 118,551 (β2-ARs), and L748,337 (β3-ARs). Results: Quantitative real-time PCR confirmed lack of β2-AR expression in bladder tissue from β2-AR KO mice. In isolated detrusor strips, pre-contraction with KCl increased basal tone and enhanced spontaneous activity significantly more in β2-AR KO than in WT. (-)-Isoprenaline relaxed tonic tension and attenuated spontaneous activity with similar potency, but the concentrations required were two orders of magnitude higher in β2-AR KO than WT. The concentration-response curves (CRCs) for relaxation were not affected by CGP 20712A (300 nM), but were shifted to the right by ICI 118,551 (50 nM) and L748,337 (10 μM). The -logEC50 values for (-)-isoprenaline in WT and β2-AR KO tissue were 7.98 and 6.00, respectively, suggesting a large receptor reserve of β2-AR. (-)-CL 316,243 relaxed detrusor and attenuated spontaneous contractions from WT and β2-AR KO mice with a potency corresponding to the drug's affinity for β3-AR. L743,337 shifted the CRCs to the right. Conclusion: Our findings in β2-AR KO mice suggest that there is a large receptor reserve for β2-AR in WT mice so that this β-AR subtype will mediate relaxation of tone and attenuation of spontaneous activity under physiological conditions. Nevertheless, upon removal of this reserve, β3-AR can also mediate murine detrusor relaxation.}, language = {en} } @article{ZinnerMoralesAlamoOrtenbladetal.2016, author = {Zinner, Christoph and Morales-Alamo, David and {\O}rtenblad, Niels and Larsen, Filip J. and Schiffer, Tomas A. and Willis, Sarah J. and Gelabert-Rebato, Miriam and Perez-Valera, Mario and Boushel, Robert and Calbet, Jose A. L. and Holmberg, Hans-Christer}, title = {The Physiological Mechanisms of Performance Enhancement with Sprint Interval Training Differ between the Upper and Lower Extremities in Humans}, series = {Frontiers in Physiology}, volume = {7}, journal = {Frontiers in Physiology}, number = {426}, doi = {10.3389/fphys.2016.00426}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165257}, year = {2016}, abstract = {To elucidate the mechanisms underlying the differences in adaptation of arm and leg muscles to sprint training, over a period of 11 days 16 untrained men performed six sessions of 4-6 × 30-s all-out sprints (SIT) with the legs and arms, separately, with a 1-h interval of recovery. Limb-specific VO2peak, sprint performance (two 30-s Wingate tests with 4-min recovery), muscle efficiency and time-trial performance (TT, 5-min all-out) were assessed and biopsies from the m. vastus lateralis and m. triceps brachii taken before and after training. VO2peak and Wmax increased 3-11\% after training, with a more pronounced change in the arms (P < 0.05). Gross efficiency improved for the arms (+8.8\%, P < 0.05), but not the legs (-0.6\%). Wingate peak and mean power outputs improved similarly for the arms and legs, as did TT performance. After training, VO2 during the two Wingate tests was increased by 52 and 6\% for the arms and legs, respectively (P < 0.001). In the case of the arms, VO2 was higher during the first than second Wingate test (64 vs. 44\%, P < 0.05). During the TT, relative exercise intensity, HR, VO2, VCO2, VE, and Vt were all lower during arm-cranking than leg-pedaling, and oxidation of fat was minimal, remaining so after training. Despite the higher relative intensity, fat oxidation was 70\% greater during leg-pedaling (P = 0.017). The aerobic energy contribution in the legs was larger than for the arms during the Wingate tests, although VO2 for the arms was enhanced more by training, reducing the O2 deficit after SIT. The levels of muscle glycogen, as well as the myosin heavy chain composition were unchanged in both cases, while the activities of 3-hydroxyacyl-CoA-dehydrogenase and citrate synthase were elevated only in the legs and capillarization enhanced in both limbs. Multiple regression analysis demonstrated that the variables that predict TT performance differ for the arms and legs. The primary mechanism of adaptation to SIT by both the arms and legs is enhancement of aerobic energy production. However, with their higher proportion of fast muscle fibers, the arms exhibit greater plasticity.}, language = {en} } @article{NyssenVanNieulandVandenbergheetal.2016, author = {Nyssen, Jan and Van Nieuland, Jasper and Vandenberghe, Dimitri and Juilleret, J{\´e}r{\^o}me and Terhorst, Birgit}, title = {Gr{\`e}zes lit{\´e}es and their genesis: the site of Enscherange in the Rhenish-Ardennes Massif as a case study}, series = {Die Erde : Journal of the Geographical Society of Berlin}, volume = {147}, journal = {Die Erde : Journal of the Geographical Society of Berlin}, number = {1}, doi = {10.12854/erde-147-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165032}, year = {2016}, abstract = {The freeze-thaw cycles in periglacial areas during the Quaternary glacials increased frost weathering, leading to a disintegration of rock formations. Transported downslope, clasts allowed in some areas the formation of stratified slope deposits known as "gr{\`e}zes lit{\´e}es". This study reviews the existing theories and investigates the gr{\`e}zes lit{\´e}es deposits of Enscherange and Rodershausen in Luxembourg. This process was reinforced by the lithostructural control of the parent material expressed by the dip of schistosity (66°) and its orientation parallel to the main slopes in the area. This gave opportunities to activate the frost-weathering process on top of the ridge where the parent material outcropped. As the stratified slope deposits have a dip of 23° and as there is no significant lateral variation in rock fragment size, slope processes that involve only gravity are excluded and transportation in solifluction lobes with significant slopewash and sorting processes is hypothesized. The Enscherange formation, the biggest known outcrop of gr{\`e}zes lit{\´e}es in north-western Europe, shows evidence of clear layering over the whole profile depth. A palaeolandscape reconstruction shows that ridges must have been tens of metres higher than presently. The investigation of the matrix composition shows Laacher See tephra in the overlying periglacial cover bed with infiltrations of the minerals in the reworked upper layer of the gr{\`e}zes lit{\´e}es deposit. Chronostratigraphic approaches using the underlying cryoturbation zone and Laacher See heavy minerals in the overlying topsoil place the formation of gr{\`e}zes lit{\´e}es deposits in the Late Pleistocene.}, language = {en} } @article{BechtleCamargoMolinaDeschetal.2016, author = {Bechtle, Philip and Camargo-Molina, Jos{\´e} Eliel and Desch, Klaus and Dreiner, Herbert K. and Hamer, Matthias and Kr{\"a}mer, Michael and O'Leary, Ben and Porod, Werner and Sarrazin, Bj{\"o}rn and Stefaniak, Tim and Uhlenbrock, Mathias and Wienemann, Peter}, title = {Killing the cMSSM softly}, series = {The European Physical Journal C}, volume = {76}, journal = {The European Physical Journal C}, number = {96}, doi = {10.1140/epjc/s10052-015-3864-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165045}, year = {2016}, abstract = {We investigate the constrained Minimal Supersymmetric Standard Model (cMSSM) in the light of constraining experimental and observational data from precision measurements, astrophysics, direct supersymmetry searches at the LHC and measurements of the properties of the Higgs boson, by means of a global fit using the program Fittino. As in previous studies, we find rather poor agreement of the best fit point with the global data. We also investigate the stability of the electro-weak vacuum in the preferred region of parameter space around the best fit point. We find that the vacuum is metastable, with a lifetime significantly longer than the age of the Universe. For the first time in a global fit of supersymmetry, we employ a consistent methodology to evaluate the goodness-of-fit of the cMSSM in a frequentist approach by deriving p values from large sets of toy experiments. We analyse analytically and quantitatively the impact of the choice of the observable set on the p value, and in particular its dilution when confronting the model with a large number of barely constraining measurements. Finally, for the preferred sets of observables, we obtain p values for the cMSSM below 10 \%, i.e. we exclude the cMSSM as a model at the 90 \% confidence level.}, language = {en} } @article{BoettcherPrifertWeissbrichetal.2016, author = {B{\"o}ttcher, S. and Prifert, C. and Weißbrich, B. and Adams, O. and Aldabbagh, S. and Eis-H{\"u}binger, A. M. and Diedrich, S.}, title = {Detection of enterovirus D68 in patients hospitalised in three tertiary university hospitals in Germany, 2013 to 2014}, series = {Eurosurveillance}, volume = {21}, journal = {Eurosurveillance}, number = {19}, doi = {10.2807/1560-7917.ES.2016.21.19.30227}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165068}, pages = {pii=30227}, year = {2016}, abstract = {Enterovirus D68 (EV-D68) has been recognised as a worldwide emerging pathogen associated with severe respiratory symptoms since 2009. We here report EV-D68 detection in hospitalised patients with acute respiratory infection admitted to three tertiary hospitals in Germany between January 2013 and December 2014. From a total of 14,838 respiratory samples obtained during the study period, 246 (1.7\%) tested enterovirus-positive and, among these, 39 (15.9\%) were identified as EV-D68. Infection was observed in children and teenagers (0-19 years; n=31), the majority (n=22) being under five years-old, as well as in adults > 50 years of age (n=8). No significant difference in prevalence was observed between the 2013 and 2014 seasons. Phylogenetic analyses based on viral protein 1 (VP1) sequences showed co-circulation of different EV-D68 lineages in Germany. Sequence data encompassing the entire capsid region of the genome were analysed to gain information on amino acid changes possibly relevant for immunogenicity and revealed mutations in two recently described pleconaril binding sites.}, language = {en} } @article{HeldBerzHensgenetal.2016, author = {Held, Martina and Berz, Annuska and Hensgen, Ronja and Muenz, Thomas S. and Scholl, Christina and R{\"o}ssler, Wolfgang and Homberg, Uwe and Pfeiffer, Keram}, title = {Microglomerular Synaptic Complexes in the Sky-Compass Network of the Honeybee Connect Parallel Pathways from the Anterior Optic Tubercle to the Central Complex}, series = {Frontiers in Behavioral Neuroscience}, volume = {10}, journal = {Frontiers in Behavioral Neuroscience}, number = {186}, doi = {10.3389/fnbeh.2016.00186}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165080}, year = {2016}, abstract = {While the ability of honeybees to navigate relying on sky-compass information has been investigated in a large number of behavioral studies, the underlying neuronal system has so far received less attention. The sky-compass pathway has recently been described from its input region, the dorsal rim area (DRA) of the compound eye, to the anterior optic tubercle (AOTU). The aim of this study is to reveal the connection from the AOTU to the central complex (CX). For this purpose, we investigated the anatomy of large microglomerular synaptic complexes in the medial and lateral bulbs (MBUs/LBUs) of the lateral complex (LX). The synaptic complexes are formed by tubercle-lateral accessory lobe neuron 1 (TuLAL1) neurons of the AOTU and GABAergic tangential neurons of the central body's (CB) lower division (TL neurons). Both TuLAL1 and TL neurons strongly resemble neurons forming these complexes in other insect species. We further investigated the ultrastructure of these synaptic complexes using transmission electron microscopy. We found that single large presynaptic terminals of TuLAL1 neurons enclose many small profiles (SPs) of TL neurons. The synaptic connections between these neurons are established by two types of synapses: divergent dyads and divergent tetrads. Our data support the assumption that these complexes are a highly conserved feature in the insect brain and play an important role in reliable signal transmission within the sky-compass pathway.}, language = {en} } @article{MeyerRichterSchreiberetal.2016, author = {Meyer, Neele and Richter, S. Helene and Schreiber, Rebecca S. and Kloke, Vanessa and Kaiser, Sylvia and Lesch, Klaus-Peter and Sachser, Norbert}, title = {The Unexpected Effects of Beneficial and Adverse Social Experiences during Adolescence on Anxiety and Aggression and Their Modulation by Genotype}, series = {Frontiers in Behavioral Neuroscience}, volume = {10}, journal = {Frontiers in Behavioral Neuroscience}, number = {97}, doi = {10.3389/fnbeh.2016.00097}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165090}, year = {2016}, abstract = {Anxiety and aggression are part of the behavioral repertoire of humans and animals. However, in their exaggerated form both can become maladaptive and result in psychiatric disorders. On the one hand, genetic predisposition has been shown to play a crucial modulatory role in anxiety and aggression. On the other hand, social experiences have been implicated in the modulation of these traits. However, so far, mainly experiences in early life phases have been considered crucial for shaping anxiety-like and aggressive behavior, while the phase of adolescence has largely been neglected. Therefore, the aim of the present study was to elucidate how levels of anxiety-like and aggressive behavior are shaped by social experiences during adolescence and serotonin transporter (5-HTT) genotype. For this purpose, male mice of a 5-HTT knockout mouse model including all three genotypes (wildtype, heterozygous and homozygous 5-HTT knockout mice) were either exposed to an adverse social situation or a beneficial social environment during adolescence. This was accomplished in a custom-made cage system where mice experiencing the adverse environment were repeatedly introduced to the territory of a dominant opponent but had the possibility to escape to a refuge cage. Mice encountering beneficial social conditions had free access to a female mating partner. Afterwards, anxiety-like and aggressive behavior was assessed in a battery of tests. Surprisingly, unfavorable conditions during adolescence led to a decrease in anxiety-like behavior and an increase in exploratory locomotion. Additionally, aggressive behavior was augmented in animals that experienced social adversity. Concerning genotype, homozygous 5-HTT knockout mice were more anxious and less aggressive than heterozygous 5-HTT knockout and wildtype mice. In summary, adolescence is clearly an important phase in which anxiety-like and aggressive behavior can be shaped. Furthermore, it seems that having to cope with challenge during adolescence instead of experiencing throughout beneficial social conditions leads to reduced levels of anxiety-like behavior.}, language = {en} } @article{ZhouAllisonKuebleretal.2016, author = {Zhou, Sijie and Allison, Brendan Z. and K{\"u}bler, Andrea and Cichocki, Andrzej and Wang, Xingyu and Jin, Jing}, title = {Effects of Background Music on Objective and Subjective Performance Measures in an Auditory BCI}, series = {Frontiers in Computational Neuroscience}, volume = {10}, journal = {Frontiers in Computational Neuroscience}, number = {105}, doi = {10.3389/fncom.2016.00105}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165101}, year = {2016}, abstract = {Several studies have explored brain computer interface (BCI) systems based on auditory stimuli, which could help patients with visual impairments. Usability and user satisfaction are important considerations in any BCI. Although background music can influence emotion and performance in other task environments, and many users may wish to listen to music while using a BCI, auditory, and other BCIs are typically studied without background music. Some work has explored the possibility of using polyphonic music in auditory BCI systems. However, this approach requires users with good musical skills, and has not been explored in online experiments. Our hypothesis was that an auditory BCI with background music would be preferred by subjects over a similar BCI without background music, without any difference in BCI performance. We introduce a simple paradigm (which does not require musical skill) using percussion instrument sound stimuli and background music, and evaluated it in both offline and online experiments. The result showed that subjects preferred the auditory BCI with background music. Different performance measures did not reveal any significant performance effect when comparing background music vs. no background. Since the addition of background music does not impair BCI performance but is preferred by users, auditory (and perhaps other) BCIs should consider including it. Our study also indicates that auditory BCIs can be effective even if the auditory channel is simultaneously otherwise engaged.}, language = {en} } @article{WiedenmannBocquillonDeaconetal.2016, author = {Wiedenmann, J. and Bocquillon, E. and Deacon, R.S. and Hartinger, S. and Herrmann, O. and Klapwijk, T.M. and Maier, L. and Ames, C. and Br{\"u}ne, C. and Gould, C. and Oiwa, A. and Ishibashi, K. and Tarucha, S. and Buhmann, H. and Molenkamp, L.W.}, title = {4π-periodic Josephson supercurrent in HgTe-based topological Josephson junctions}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, doi = {10.1038/ncomms10303}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175353}, year = {2016}, abstract = {The Josephson effect describes the generic appearance of a supercurrent in a weak link between two superconductors. Its exact physical nature deeply influences the properties of the supercurrent. In recent years, considerable efforts have focused on the coupling of superconductors to the surface states of a three-dimensional topological insulator. In such a material, an unconventional induced p-wave superconductivity should occur, with a doublet of topologically protected gapless Andreev bound states, whose energies vary 4π-periodically with the superconducting phase difference across the junction. In this article, we report the observation of an anomalous response to rf irradiation in a Josephson junction made of a HgTe weak link. The response is understood as due to a 4π-periodic contribution to the supercurrent, and its amplitude is compatible with the expected contribution of a gapless Andreev doublet. Our work opens the way to more elaborate experiments to investigate the induced superconductivity in a three-dimensional insulator.}, language = {en} } @article{FroehlichHanekePapenfortetal.2016, author = {Fr{\"o}hlich, Kathrin S. and Haneke, Katharina and Papenfort, Kai and Vogel, J{\"o}rg}, title = {The target spectrum of SdsR small RNA in Salmonella}, series = {Nucleic Acids Research}, volume = {44}, journal = {Nucleic Acids Research}, number = {21}, doi = {10.1093/nar/gkw632}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175365}, pages = {10406-10422}, year = {2016}, abstract = {Model enteric bacteria such as Escherichia coli and Salmonella enterica express hundreds of small non-coding RNAs (sRNAs), targets for most of which are yet unknown. Some sRNAs are remarkably well conserved, indicating that they serve cellular functions that go beyond the necessities of a single species. One of these 'core sRNAs' of largely unknown function is the abundant ∼100-nucleotide SdsR sRNA which is transcribed by the general stress σ-factor, σ\(^{S}\) and accumulates in stationary phase. In Salmonella, SdsR was known to inhibit the synthesis of the species-specific porin, OmpD. However, sdsR genes are present in almost all enterobacterial genomes, suggesting that additional, conserved targets of this sRNA must exist. Here, we have combined SdsR pulse-expression with whole genome transcriptomics to discover 20 previously unknown candidate targets of SdsR which include mRNAs coding for physiologically important regulators such as the carbon utilization regulator, CRP, the nucleoid-associated chaperone, StpA and the antibiotic resistance transporter, TolC. Processing of SdsR by RNase E results in two cellular SdsR variants with distinct target spectra. While the overall physiological role of this orphan core sRNA remains to be fully understood, the new SdsR targets present valuable leads to determine sRNA functions in resting bacteria.}, language = {en} } @phdthesis{Forster2016, author = {Forster, Johannes}, title = {Variational Approach to the Modeling and Analysis of Magnetoelastic Materials}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147226}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {This doctoral thesis is concerned with the mathematical modeling of magnetoelastic materials and the analysis of PDE systems describing these materials and obtained from a variational approach. The purpose is to capture the behavior of elastic particles that are not only magnetic but exhibit a magnetic domain structure which is well described by the micromagnetic energy and the Landau-Lifshitz-Gilbert equation of the magnetization. The equation of motion for the material's velocity is derived in a continuum mechanical setting from an energy ansatz. In the modeling process, the focus is on the interplay between Lagrangian and Eulerian coordinate systems to combine elasticity and magnetism in one model without the assumption of small deformations. The resulting general PDE system is simplified using special assumptions. Existence of weak solutions is proved for two variants of the PDE system, one including gradient flow dynamics on the magnetization, and the other featuring the Landau-Lifshitz-Gilbert equation. The proof is based on a Galerkin method and a fixed point argument. The analysis of the PDE system with the Landau-Lifshitz-Gilbert equation uses a more involved approach to obtain weak solutions based on G. Carbou and P. Fabrie 2001.}, subject = {Magnetoelastizit{\"a}t}, language = {en} } @article{KunzLiangNillaetal.2016, author = {Kunz, Meik and Liang, Chunguang and Nilla, Santosh and Cecil, Alexander and Dandekar, Thomas}, title = {The drug-minded protein interaction database (DrumPID) for efficient target analysis and drug development}, series = {Database}, volume = {2016}, journal = {Database}, doi = {10.1093/database/baw041}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147369}, pages = {baw041}, year = {2016}, abstract = {The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure-activity relationships.}, language = {en} } @article{StrekalovaMarkovaShevtsovaetal.2016, author = {Strekalova, Tatyana and Markova, Nataliia and Shevtsova, Elena and Zubareva, Olga and Bakhmet, Anastassia and Steinbusch, Harry M. and Bachurin, Sergey and Lesch, Klaus-Peter}, title = {Individual Differences in Behavioural Despair Predict Brain GSK-3beta Expression in Mice: The Power of a Modified Swim Test}, series = {Neural Plasticity}, volume = {2016}, journal = {Neural Plasticity}, doi = {10.1155/2016/5098591}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147379}, pages = {5098591}, year = {2016}, abstract = {While deficient brain plasticity is a well-established pathophysiologic feature of depression, little is known about disorder-associated enhanced cognitive processing. Here, we studied a novel mouse paradigm that potentially models augmented learning of adverse memories during development of a depressive-like state. We used a modification of the classic two-day protocol of a mouse Porsolt test with an additional session occurring on Day 5 following the initial exposure. Unexpectedly, floating behaviour and brain glycogen synthase kinase-3 beta (GSK-3beta) mRNA levels, a factor of synaptic plasticity as well as a marker of distress and depression, were increased during the additional swimming session that was prevented by imipramine. Observed increases of GSK-3beta mRNA in prefrontal cortex during delayed testing session correlated with individual parameters of behavioural despair that was not found in the classic Porsolt test. Repeated swim exposure was accompanied by a lower pGSK-3beta/GSK-3beta ratio. A replacement of the second or the final swim sessions with exposure to the context of testing resulted in increased GSK-3beta mRNA level similar to the effects of swimming, while exclusion of the second testing prevented these changes. Together, our findings implicate the activation of brain GSK-3beta expression in enhanced contextual conditioning of adverse memories, which is associated with an individual susceptibility to a depressive syndrome.}, language = {en} } @article{RieplMusselOsinskyetal.2016, author = {Riepl, Korbinian and Mussel, Patrick and Osinsky, Roman and Hewig, Johannes}, title = {Influences of State and Trait Affect on Behavior, Feedback-Related Negativity, and P3b in the Ultimatum Game}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {11}, doi = {10.1371/journal.pone.0146358}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147386}, pages = {e0146358}, year = {2016}, abstract = {The present study investigates how different emotions can alter social bargaining behavior. An important paradigm to study social bargaining is the Ultimatum Game. There, a proposer gets a pot of money and has to offer part of it to a responder. If the responder accepts, both players get the money as proposed by the proposer. If he rejects, none of the players gets anything. Rational choice models would predict that responders accept all offers above 0. However, evidence shows that responders typically reject a large proportion of all unfair offers. We analyzed participants' behavior when they played the Ultimatum Game as responders and simultaneously collected electroencephalogram data in order to quantify the feedback-related negativity and P3b components. We induced state affect (momentarily emotions unrelated to the task) via short movie clips and measured trait affect (longer-lasting emotional dispositions) via questionnaires. State happiness led to increased acceptance rates of very unfair offers. Regarding neurophysiology, we found that unfair offers elicited larger feedback-related negativity amplitudes than fair offers. Additionally, an interaction of state and trait affect occurred: high trait negative affect (subsuming a variety of aversive mood states) led to increased feedback-related negativity amplitudes when participants were in an angry mood, but not if they currently experienced fear or happiness. We discuss that increased rumination might be responsible for this result, which might not occur, however, when people experience happiness or fear. Apart from that, we found that fair offers elicited larger P3b components than unfair offers, which might reflect increased pleasure in response to fair offers. Moreover, high trait negative affect was associated with decreased P3b amplitudes, potentially reflecting decreased motivation to engage in activities. We discuss implications of our results in the light of theories and research on depression and anxiety.}, language = {en} } @article{KoesslerHermannWeberetal.2016, author = {Koessler, Juergen and Hermann, Stephanie and Weber, Katja and Koessler, Angela and Kuhn, Sabine and Boeck, Markus and Kobsar, Anna}, title = {Role of Purinergic Receptor Expression and Function for Reduced Responsiveness to Adenosine Diphosphate in Washed Human Platelets}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {1}, doi = {10.1371/journal.pone.0147370}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146400}, pages = {e0147370}, year = {2016}, abstract = {Background Washing of platelets is an important procedure commonly used for experimental studies, e.g. in cardiovascular research. As a known phenomenon, responsiveness to adenosine diphosphate (ADP) is reduced in washed platelets, although underlying molecular mechanisms—potentially interfering with experimental results—have not been thoroughly studied. Objectives Since ADP mediates its effects via three purinergic receptors P2Y1, P2X1 and P2Y12, their surface expression and function were investigated in washed platelets and, for comparison, in platelet-rich-plasma (PRP) at different time points for up to 2 hours after preparation. Results In contrast to PRP, flow cytometric analysis of surface expression in washed platelets revealed an increase of all receptors during the first 60 minutes after preparation followed by a significant reduction, which points to an initial preactivation of platelets and consecutive degeneration. The activity of the P2X1 receptor (measured by selectively induced calcium flux) was substantially maintained in both PRP and washed platelets. P2Y12 function (determined by flow cytometry as platelet reactivity index) was partially reduced after platelet washing compared to PRP, but remained stable in course of ongoing storage. However, the function of the P2Y1 receptor (measured by selectively induced calcium flux) continuously declined after preparation of washed platelets. Conclusion In conclusion, decreasing ADP responsiveness in washed platelets is particularly caused by impaired activity of the P2Y1 receptor associated with disturbed calcium regulation, which has to be considered in the design of experimental studies addressing ADP mediated platelet function.}, language = {en} } @article{FehrholzGlaserSeidenspinneretal.2016, author = {Fehrholz, Markus and Glaser, Kirsten and Seidenspinner, Silvia and Ottensmeier, Barbara and Curstedt, Tore and Speer, Christian P. and Kunzmann, Steffen}, title = {Impact of the New Generation Reconstituted Surfactant CHF5633 on Human CD4\(^+\) Lymphocytes}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {4}, doi = {10.1371/journal.pone.0153578}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146419}, pages = {e0153578}, year = {2016}, abstract = {Background Natural surfactant preparations, commonly isolated from porcine or bovine lungs, are used to treat respiratory distress syndrome in preterm infants. Besides biophysical effectiveness, several studies have documented additional immunomodulatory properties. Within the near future, synthetic surfactant preparations may be a promising alternative. CHF5633 is a new generation reconstituted synthetic surfactant preparation with defined composition, containing dipalmitoyl-phosphatidylcholine, palmitoyl-oleoyl-phosphatidylglycerol and synthetic analogs of surfactant protein (SP-) B and SP-C. While its biophysical effectiveness has been demonstrated in vitro and in vivo, possible immunomodulatory abilities are currently unknown. Aim The aim of the current study was to define a potential impact of CHF5633 and its single components on pro- and anti-inflammatory cytokine responses in human CD4\(^+\) lymphocytes. Methods Purified human CD4\(^+\) T cells were activated using anti CD3/CD28 antibodies and exposed to CHF5633, its components, or to the well-known animal-derived surfactant Poractant alfa (Curosurf®). Proliferative response and cell viability were assessed using flow cytometry and a methylthiazolyldiphenyltetrazolium bromide colorimetric assay. The mRNA expression of IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 was measured by quantitative PCR, while intracellular protein expression was assessed by means of flow cytometry. Results Neither CHF5633 nor any of its phospholipid components with or without SP-B or SP-C analogs had any influence on proliferative ability and viability of CD4\(^+\) lymphocytes under the given conditions. IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 mRNA as well as IFNγ, IL-2, IL-4 and IL-10 protein levels were unaffected in both non-activated and activated CD4+ lymphocytes after exposure to CHF5633 or its constituents compared to non-exposed controls. However, in comparison to Curosurf®, expression levels of anti-inflammatory IL-4 and IL-10 mRNA were significantly increased in CHF5633 exposed CD4\(^+\) lymphocytes. Conclusion For the first time, the immunomodulatory capacity of CHF5633 on CD4\(^+\) lymphocytes was evaluated. CHF5633 did not show any cytotoxicity on CD4\(^+\) cells. Moreover, our in vitro data indicate that CHF5633 does not exert unintended pro-inflammatory effects on non-activated and activated CD4+ T cells. As far as anti-inflammatory cytokines are concerned, it might lack an overall reductive ability in comparison to animal-derived surfactants, potentially leaving pro- and anti-inflammatory cytokine response in balance.}, language = {en} } @article{BuschBuschScholzetal.2016, author = {Busch, Albert and Busch, Martin and Scholz, Claus-J{\"u}rgen and Kellersmann, Richard and Otto, Christoph and Chernogubova, Ekaterina and Maegdefessel, Lars and Zernecke, Alma and Lorenz, Udo}, title = {Aneurysm miRNA Signature Differs, Depending on Disease Localization and Morphology}, series = {International Journal of Molecular Science}, volume = {17}, journal = {International Journal of Molecular Science}, number = {1}, issn = {International Journal of Molecular Science}, doi = {10.3390/ijms17010081}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146422}, pages = {81}, year = {2016}, abstract = {Limited comprehension of aneurysm pathology has led to inconclusive results from clinical trials. miRNAs are key regulators of post-translational gene modification and are useful tools in elucidating key features of aneurysm pathogenesis in distinct entities of abdominal and popliteal aneurysms. Here, surgically harvested specimens from 19 abdominal aortic aneurysm (AAA) and 8 popliteal artery aneurysm (PAA) patients were analyzed for miRNA expression and histologically classified regarding extracellular matrix (ECM) remodeling and inflammation. DIANA-based computational target prediction and pathway enrichment analysis verified our results, as well as previous ones. miRNA-362, -19b-1, -194, -769, -21 and -550 were significantly down-regulated in AAA samples depending on degree of inflammation. Similar or inverse regulation was found for miR-769, 19b-1 and miR-550, -21, whereas miR-194 and -362 were unaltered in PAA. In situ hybridization verified higher expression of miR-550 and -21 in PAA compared to AAA and computational analysis for target genes and pathway enrichment affirmed signal transduction, cell-cell-interaction and cell degradation pathways, in line with previous results. Despite the vague role of miRNAs for potential diagnostic and treatment purposes, the number of candidates from tissue signature studies is increasing. Tissue morphology influences subsequent research, yet comparison of distinct entities of aneurysm disease can unravel core pathways.}, language = {en} } @article{SchmittLindner2016, author = {Schmitt, Joachim and Lindner, Nathalie}, title = {A 3-week multimodal intervention involving high-intensity interval training in female cancer survivors: a randomized controlled trial}, series = {Physiological Reports}, volume = {4}, journal = {Physiological Reports}, number = {3}, doi = {10.14814/phy2.12693}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146455}, pages = {e12693}, year = {2016}, abstract = {To compare the effects of a 3-week multimodal rehabilitation involving supervised high-intensity interval training (HIIT) on female breast cancer survivors with respect to key variables of aerobic fitness, body composition, energy expenditure, cancer-related fatigue, and quality of life to those of a standard multimodal rehabilitation program. A randomized controlled trial design was administered. Twenty-eight women, who had been treated for cancer were randomly assigned to either a group performing exercise of low-to-moderate intensity (LMIE; n = 14) or a group performing high-intensity interval training (HIIT; n = 14) as part of a 3-week multimodal rehabilitation program. No adverse events related to the exercise were reported. Work economy improved following both HIIT and LMIE, with improved peak oxygen uptake following LMIE. HIIT reduced mean total body fat mass with no change in body mass, muscle or fat-free mass (best P < 0.06). LMIE increased muscle and total fat-free body mass. Total energy expenditure (P = 0.45) did not change between the groups, whereas both improved quality of life to a similar high extent and lessened cancer-related fatigue. This randomized controlled study demonstrates that HIIT can be performed by female cancer survivors without adverse health effects. Here, HIIT and LMIE both improved work economy, quality of life and cancer-related fatigue, body composition or energy expenditure. Since the outcomes were similar, but HIIT takes less time, this may be a time-efficient strategy for improving certain aspects of the health of female cancer survivors.}, language = {en} } @article{KasangKalluvyaMajingeetal.2016, author = {Kasang, Christa and Kalluvya, Samuel and Majinge, Charles and Kongola, Gilbert and Mlewa, Mathias and Massawe, Irene and Kabyemera, Rogatus and Magambo, Kinanga and Ulmer, Albrecht and Klinker, Hartwig and Gschmack, Eva and Horn, Anne and Koutsilieri, Eleni and Preiser, Wolfgang and Hofmann, Daniela and Hain, Johannes and M{\"u}ller, Andreas and D{\"o}lken, Lars and Weissbrich, Benedikt and Rethwilm, Axel and Stich, August and Scheller, Carsten}, title = {Effects of Prednisolone on Disease Progression in Antiretroviral-Untreated HIV Infection: A 2-Year Randomized, Double-Blind Placebo-Controlled Clinical Trial}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {1}, doi = {10.1371/journal.pone.0146678}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146479}, pages = {e0146678}, year = {2016}, abstract = {Background HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients. Methods Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-na{\"i}ve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl. Results No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men. Conclusions This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection.}, language = {en} } @article{HerrmannBeierSimonsetal.2016, author = {Herrmann, Martin J. and Beier, Jennifer S. and Simons, Bibiane and Polak, Thomas}, title = {Transcranial Direct Current Stimulation (tDCS) of the Right Inferior Frontal Gyrus Attenuates Skin Conductance Responses to Unpredictable Threat Conditions}, series = {Frontiers in Human Neuroscience}, volume = {10}, journal = {Frontiers in Human Neuroscience}, number = {352}, doi = {10.3389/fnhum.2016.00352}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146486}, year = {2016}, abstract = {Patients with panic and post-traumatic stress disorders seem to show increased psychophysiological reactions to conditions of unpredictable (U) threat, which has been discussed as a neurobiological marker of elevated levels of sustained fear in these disorders. Interestingly, a recent study found that the right inferior frontal gyrus (rIFG) is correlated to the successful regulation of sustained fear during U threat. Therefore this study aimed to examine the potential use of non-invasive brain stimulation to foster the rIFG by means of anodal transcranial direct current stimulation (tDCS) in order to reduce psychophysiological reactions to U threat. Twenty six participants were randomly assigned into an anodal and sham stimulation group in a double-blinded manner. Anodal and cathodal electrodes (7 * 5 cm) were positioned right frontal to target the rIFG. Stimulation intensity was I = 2 mA applied for 20 min during a task including U threat conditions (NPU-task). The effects of the NPU paradigm were measured by assessing the emotional startle modulation and the skin conductance response (SCR) at the outset of the different conditions. We found a significant interaction effect of condition × tDCS for the SCR (F(2,48) = 6.3, p < 0.01) without main effects of condition and tDCS. Post hoc tests revealed that the increase in SCR from neutral (N) to U condition was significantly reduced in verum compared to the sham tDCS group (t(24) = 3.84, p < 0.001). Our results emphasize the causal role of rIFG for emotional regulation and the potential use of tDCS to reduce apprehension during U threat conditions and therefore as a treatment for anxiety disorders.}, language = {en} } @article{ZlamyAlmanzarParsonetal.2016, author = {Zlamy, Manuela and Almanzar, Giovanni and Parson, Walther and Schmidt, Christian and Leierer, Johannes and Weinberger, Birgit and Jeller, Verena and Unsinn, Karin and Eyrich, Matthias and W{\"u}rzner, Reinhard and Prelog, Martina}, title = {Efforts of the human immune system to maintain the peripheral CD8+ T cell compartment after childhood thymectomy}, series = {Immunity \& Ageing}, volume = {13}, journal = {Immunity \& Ageing}, number = {3}, doi = {10.1186/s12979-016-0058-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146497}, year = {2016}, abstract = {Background Homeostatic mechanisms to maintain the T cell compartment diversity indicate an ongoing process of thymic activity and peripheral T cell renewal during human life. These processes are expected to be accelerated after childhood thymectomy and by the influence of cytomegalovirus (CMV) inducing a prematurely aged immune system. The study aimed to investigate proportional changes and replicative history of CD8+ T cells, of recent thymic emigrants (RTEs) and CD103+ T cells (mostly gut-experienced) and the role of Interleukin-(IL)-7 and IL-7 receptor (CD127)-expressing T cells in thymectomized patients compared to young and old healthy controls. Results Decreased proportions of naive and CD31 + CD8+ T cells were demonstrated after thymectomy, with higher proliferative activity of CD127-expressing T cells and significantly shorter relative telomere lengths (RTLs) and lower T cell receptor excision circles (TRECs). Increased circulating CD103+ T cells and a skewed T cell receptor (TCR) repertoire were found after thymectomy similar to elderly persons. Naive T cells were influenced by age at thymectomy and further decreased by CMV. Conclusions After childhood thymectomy, the immune system demonstrated constant efforts of the peripheral CD8+ T cell compartment to maintain homeostasis. Supposedly it tries to fill the void of RTEs by peripheral T cell proliferation, by at least partly IL-7-mediated mechanisms and by proportional increase of circulating CD103+ T cells, reminiscent of immune aging in elderly. Although other findings were less significant compared to healthy elderly, early thymectomy demonstrated immunological alterations of CD8+ T cells which mimic features of premature immunosenescence in humans.}, language = {en} } @article{BeckerKucharskiRoessleretal.2016, author = {Becker, Nils and Kucharski, Robert and R{\"o}ssler, Wolfgang and Maleszka, Ryszard}, title = {Age-dependent transcriptional and epigenomic responses to light exposure in the honey bee brain}, series = {FEBS Open Bio}, volume = {6}, journal = {FEBS Open Bio}, number = {7}, doi = {10.1002/2211-5463.12084}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147080}, pages = {622-639}, year = {2016}, abstract = {Light is a powerful environmental stimulus of special importance in social honey bees that undergo a behavioral transition from in-hive to outdoor foraging duties. Our previous work has shown that light exposure induces structural neuronal plasticity in the mushroom bodies (MBs), a brain center implicated in processing inputs from sensory modalities. Here, we extended these analyses to the molecular level to unravel light-induced transcriptomic and epigenomic changes in the honey bee brain. We have compared gene expression in brain compartments of 1- and 7-day-old light-exposed honey bees with age-matched dark-kept individuals. We have found a number of differentially expressed genes (DEGs), both novel and conserved, including several genes with reported roles in neuronal plasticity. Most of the DEGs show age-related changes in the amplitude of light-induced expression and are likely to be both developmentally and environmentally regulated. Some of the DEGs are either known to be methylated or are implicated in epigenetic processes suggesting that responses to light exposure are at least partly regulated at the epigenome level. Consistent with this idea light alters the DNA methylation pattern of bgm, one of the DEGs affected by light exposure, and the expression of microRNA miR-932. This confirms the usefulness of our approach to identify candidate genes for neuronal plasticity and provides evidence for the role of epigenetic processes in driving the molecular responses to visual stimulation.}, language = {en} } @phdthesis{Koch2016, author = {Koch, Julia Diana}, title = {Value Ranges for Schlicht Functions}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144978}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {This thesis deals with value sets, i.e. the question of what the set of values that a set of functions can take in a prescribed point looks like. Interest in such problems has been around for a long time; a first answer was given by the Schwarz lemma in the 19th century, and soon various refinements were proven. Since the 1930s, a powerful method for solving such problems has been developed, namely Loewner theory. We make extensive use of this tool, as well as variation methods which go back to Schiffer to examine the following questions: We describe the set of values a schlicht normalised function on the unit disc with prescribed derivative at the origin can take by applying Pontryagin's maximum principle to the radial Loewner equation. We then determine the value ranges for the set of holomorphic, normalised, and bounded functions that have only real coefficients in their power series expansion around 0, and for the smaller set of functions which are additionally typically real. Furthermore, we describe the values a univalent self-mapping of the upper half-plane with hydrodynamical normalization which is symmetric with respect to the imaginary axis can take. Lastly, we give a necessary condition for a schlicht bounded function f on the unit disc to have extremal derivative in a point z where its value f(z) is fixed by using variation methods.}, subject = {Pontrjagin-Maximumprinzip}, language = {en} } @article{LukasczikWolfGerlichetal.2016, author = {Lukasczik, Matthias and Wolf, Hans-Dieter and Gerlich, Christian and K{\"u}ffner, Roland and Vogel, Heiner and Neuderth, Silke}, title = {Addressing Work-Related Issues in Medical Rehabilitation: Revision of an Online Information Tool for Healthcare Professionals}, series = {Rehabilitation Research and Practice}, volume = {2016}, journal = {Rehabilitation Research and Practice}, doi = {10.1155/2016/7621690}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146911}, pages = {7621690}, year = {2016}, abstract = {Background. Medical rehabilitation increasingly considers occupational issues as determinants of health and work ability. Information on work-related rehabilitation concepts should therefore be made available to healthcare professionals. Objective. To revise a website providing healthcare professionals in medical rehabilitation facilities with information on work-related concepts in terms of updating existing information and including new topics, based on recommendations from implementation research. Method. The modification process included a questionnaire survey of medical rehabilitation centers (n=28); two workshops with experts from rehabilitation centers, health payers, and research institutions (n=14); the selection of new topics and revision of existing text modules based on expert consensus; and an update of good practice descriptions of work-related measures. Results. Health payers' requirements, workplace descriptions, and practical implementation aids were added as new topics. The database of good practice examples was extended to 63 descriptions. Information on introductory concepts was rewritten and supplemented by current data. Diagnostic tools were updated by including additional assessments. Conclusions. Recommendations from implementation research such as assessing user needs and including expert knowledge may serve as a useful starting point for the dissemination of information on work-related medical rehabilitation into practice. Web-based information tools such as the website presented here can be quickly adapted to current evidence and changes in medicolegal regulations.}, language = {en} } @article{WunschHohmannMillesetal.2016, author = {Wunsch, Marie and Hohmann, Christopher and Milles, Bianca and Rostermund, Christina and Lehmann, Paul V. and Schroeter, Michael and Bayas, Antonios and Ulzheimer, Jochen and M{\"a}urer, Mathias and Erg{\"u}n, S{\"u}leyman and Kuerten, Stefanie}, title = {The Correlation between the Virus- and Brain Antigen-Specific B Cell Response in the Blood of Patients with Multiple Sclerosis}, series = {Viruses}, volume = {8}, journal = {Viruses}, number = {4}, doi = {10.3390/v8040105}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146946}, pages = {105}, year = {2016}, abstract = {There is a largely divergent body of literature regarding the relationship between Epstein-Barr virus (EBV) infection and brain inflammation in multiple sclerosis (MS). Here, we tested MS patients during relapse (n = 11) and in remission (n = 19) in addition to n = 22 healthy controls to study the correlation between the EBV- and brain-specific B cell response in the blood by enzyme-linked immunospot (ELISPOT) and enzyme-linked immunosorbent assay (ELISA). Cytomegalovirus (CMV) was used as a control antigen tested in n = 16 MS patients during relapse and in n = 35 patients in remission. Over the course of the study, n = 16 patients were untreated, while n = 33 patients received immunomodulatory therapy. The data show that there was a moderate correlation between the frequencies of EBV- and brain-reactive B cells in MS patients in remission. In addition we could detect a correlation between the B cell response to EBV and disease activity. There was no evidence of an EBV reactivation. Interestingly, there was also a correlation between the frequencies of CMV- and brain-specific B cells in MS patients experiencing an acute relapse and an elevated B cell response to CMV was associated with higher disease activity. The trend remained when excluding seronegative subjects but was non-significant. These data underline that viral infections might impact the immunopathology of MS, but the exact link between the two entities remains subject of controversy.}, language = {en} } @article{MusselUlrichAllenetal.2016, author = {Mussel, Patrick and Ulrich, Nathalie and Allen, John J. B. and Osinsky, Roman and Hewig, Johannes}, title = {Patterns of theta oscillation reflect the neural basis of individual differences in epistemic motivation}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, doi = {10.1038/srep29245}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146957}, pages = {29245}, year = {2016}, abstract = {Theta oscillations in the EEG have been shown to reflect ongoing cognitive processes related to mental effort. Here, we show that the pattern of theta oscillation in response to varying cognitive demands reflects stable individual differences in the personality trait epistemic motivation: Individuals with high levels of epistemic motivation recruit relatively more cognitive resources in response to situations possessing high, compared to low, cognitive demand; individuals with low levels do not show such a specific response. Our results provide direct evidence for the theory of the construct need for cognition and add to our understanding of the neural processes underlying theta oscillations. More generally, we provide an explanation how individual differences in personality traits might be represented on a neural level.}, language = {en} } @article{DotterweichTowerBrandletal.2016, author = {Dotterweich, Julia and Tower, Robert J. and Brandl, Andreas and M{\"u}ller, Marc and Hofbauer, Lorenz C. and Beilhack, Andreas and Ebert, Regina and Gl{\"u}er, Claus C. and Tiwari, Sanjay and Sch{\"u}tze, Norbert and Jakob, Franz}, title = {The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {5}, doi = {10.1371/journal.pone.0155087}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146960}, pages = {e0155087}, year = {2016}, abstract = {Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R), a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs) and osteoprogenitor cells (OPCs) when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment.}, language = {en} } @article{BankogluTschoppSchmittetal.2016, author = {Bankoglu, Ezgi Eyluel and Tschopp, Oliver and Schmitt, Johannes and Burkard, Philipp and Jahn, Daniel and Geier, Andreas and Stopper, Helga}, title = {Role of PTEN in Oxidative Stress and DNA Damage in the Liver of Whole-Body Pten Haplodeficient Mice}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {11}, doi = {10.1371/journal.pone.0166956}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146970}, pages = {e0166956}, year = {2016}, abstract = {Type 2 diabetes (T2DM) and obesity are frequently associated with non-alcoholic fatty liver disease (NAFLD) and with an elevated cancer incidence. The molecular mechanisms of carcinogenesis in this context are only partially understood. High blood insulin levels are typical in early T2DM and excessive insulin can cause elevated reactive oxygen species (ROS) production and genomic instability. ROS are important for various cellular functions in signaling and host defense. However, elevated ROS formation is thought to be involved in cancer induction. In the molecular events from insulin receptor binding to genomic damage, some signaling steps have been identified, pointing at the PI3K/AKT pathway. For further elucidation Phosphatase and Tensin homolog (Pten), a tumour suppressor phosphatase that plays a role in insulin signaling by negative regulation of PI3K/AKT and its downstream targets, was investigated here. Dihydroethidium (DHE) staining was used to detect ROS formation in immortalized human hepatocytes. Comet assay and micronucleus test were performed to investigate genomic damage in vitro. In liver samples, DHE staining and western blot detection of HSP70 and HO-1 were performed to evaluate oxidative stress response. DNA double strand breaks (DSBs) were detected by immunohistostaining. Inhibition of PTEN with the pharmacologic inhibitor VO-OHpic resulted in increased ROS production and genomic damage in a liver cell line. Knockdown of Pten in a mouse model yielded increased oxidative stress levels, detected by ROS levels and expression of the two stress-proteins HSP70 and HO-1 and elevated genomic damage in the liver, which was significant in mice fed with a high fat diet. We conclude that PTEN is involved in oxidative stress and genomic damage induction in vitro and that this may also explain the in vivo observations. This further supports the hypothesis that the PI3K/AKT pathway is responsible for damaging effects of high levels of insulin.}, language = {en} } @article{BrunetVolffSchartl2016, author = {Brunet, Fr{\´e}d{\´e}ric G. and Volff, Jean-Nicolas and Schartl, Manfred}, title = {Whole Genome Duplications Shaped the Receptor Tyrosine Kinase Repertoire of Jawed Vertebrates}, series = {Genome Biology Evolution}, volume = {8}, journal = {Genome Biology Evolution}, number = {15}, doi = {10.1093/gbe/evw103}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146988}, pages = {1600-1613}, year = {2016}, abstract = {The receptor tyrosine kinase (RTK) gene family, involved primarily in cell growth and differentiation, comprises proteins with a common enzymatic tyrosine kinase intracellular domain adjacent to a transmembrane region. The amino-terminal portion of RTKs is extracellular and made of different domains, the combination of which characterizes each of the 20 RTK subfamilies among mammals. We analyzed a total of 7,376 RTK sequences among 143 vertebrate species to provide here the first comprehensive census of the jawed vertebrate repertoire. We ascertained the 58 genes previously described in the human and mouse genomes and established their phylogenetic relationships. We also identified five additional RTKs amounting to a total of 63 genes in jawed vertebrates. We found that the vertebrate RTK gene family has been shaped by the two successive rounds of whole genome duplications (WGD) called 1R and 2R (1R/2R) that occurred at the base of the vertebrates. In addition, the Vegfr and Ephrin receptor subfamilies were expanded by single gene duplications. In teleost fish, 23 additional RTK genes have been retained after another expansion through the fish-specific third round (3R) of WGD. Several lineage-specific gene losses were observed. For instance, birds have lost three RTKs, and different genes are missing in several fish sublineages. The RTK gene family presents an unusual high gene retention rate from the vertebrate WGDs (58.75\% after 1R/2R, 64.4\% after 3R), resulting in an expansion that might be correlated with the evolution of complexity of vertebrate cellular communication and intracellular signaling.}, language = {en} } @phdthesis{Jung2016, author = {Jung, Lisa Anna}, title = {Targeting MYC Function as a Strategy for Tumor Therapy}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146993}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {A large fraction of human tumors exhibits aberrant expression of the oncoprotein MYC. As a transcription factor regulating various cellular processes, MYC is also crucially involved in normal development. Direct targeting of MYC has been a major challenge for molecular cancer drug discovery. The proof of principle that its inhibition is nevertheless feasible came from in vivo studies using a dominant-negative allele of MYC termed OmoMYC. Systemic expression of OmoMYC triggered long-term tumor regression with mild and fully reversible side effects on normal tissues. In this study, OmoMYC's mode of action was investigated combining methods of structural biology and functional genomics to elucidate how it is able to preferentially affect oncogenic functions of MYC. The crystal structure of the OmoMYC homodimer, both in the free and the E-box-bound state, was determined, which revealed that OmoMYC forms a stable homodimer, and as such, recognizes DNA via the same base-specific DNA contacts as the MYC/MAX heterodimer. OmoMYC binds DNA with an equally high affinity as MYC/MAX complexes. RNA-sequencing showed that OmoMYC blunts both MYC-dependent transcriptional activation and repression. Genome-wide DNA-binding studies using chromatin immunoprecipitation followed by high-throughput sequencing revealed that OmoMYC competes with MYC/MAX complexes on chromatin, thereby reducing their occupancy at consensus DNA binding sites. The most prominent decrease in MYC binding was seen at low-affinity promoters, which were invaded by MYC at oncogenic levels. Strikingly, gene set enrichment analyses using OmoMYC-regulated genes enabled the identification of tumor subgroups with high MYC levels in multiple tumor entities. Together with a targeted shRNA screen, this identified novel targets for the eradication of MYC-driven tumors, such as ATAD3A, BOP1, and ADRM1. In summary, the findings suggest that OmoMYC specifically inhibits tumor cell growth by attenuating the expression of rate-limiting proteins in cellular processes that respond to elevated levels of MYC protein using a DNA-competitive mechanism. This opens up novel strategies to target oncogenic MYC functions for tumor therapy.}, subject = {Myc}, language = {en} } @article{KamawalSteinertHolzapfeletal.2016, author = {Kamawal, Yama and Steinert, Andre F and Holzapfel, Boris M and Rudert, Maximilian and Barthel, Thomas}, title = {Case report - calcification of the medial collateral ligament of the knee with simultaneous calcifying tendinitis of the rotator cuff}, series = {BMC Muscoskeletal Disorders}, volume = {17}, journal = {BMC Muscoskeletal Disorders}, number = {283}, doi = {10.1186/s12891-016-1147-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147669}, year = {2016}, abstract = {Calcification of the medial collateral ligament (MCL) of the knee is a very rare disease. We report on a case of a patient with a calcifying lesion within the MCL and simultaneous calcifying tendinitis of the rotator cuff in both shoulders. Case presentation: Calcification of the MCL was diagnosed both via x-ray and magnetic resonance imaging (MRI) and was successfully treated surgically. Calcifying tendinitis of the rotator cuff was successfully treated applying conservative methods. Conclusion: This is the first case report of a patient suffering from both a calcifying lesion within the medial collateral ligament and calcifying tendinitis of the rotator cuff in both shoulders. Clinical symptoms, radio-morphological characteristics and macroscopic features were very similar and therefore it can be postulated that the underlying pathophysiology is the same in both diseases. Our experience suggests that magnetic resonance imaging and x-ray are invaluable tools for the diagnosis of this inflammatory calcifying disease of the ligament, and that surgical repair provides a good outcome if conservative treatment fails. It seems that calcification of the MCL is more likely to require surgery than calcifying tendinitis of the rotator cuff. However, the exact reason for this remains unclear to date.}, language = {en} } @article{RichterPolatLawrenzetal.2016, author = {Richter, Anne and Polat, B{\"u}lent and Lawrenz, Ingulf and Weick, Stefan and Sauer, Otto and Flentje, Michael and Mantel, Frederick}, title = {Initial results for patient setup verification using transperineal ultrasound and cone beam CT in external beam radiation therapy of prostate cancer}, series = {Radiation Oncology}, volume = {11}, journal = {Radiation Oncology}, number = {147}, doi = {10.1186/s13014-016-0722-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147677}, year = {2016}, abstract = {Evaluation of set up error detection by a transperineal ultrasound in comparison with a cone beam CT (CBCT) based system in external beam radiation therapy (EBRT) of prostate cancer. Methods: Setup verification was performed with transperineal ultrasound (TPUS) and CBCT for 10 patients treated with EBRT for prostate cancer. In total, 150 ultrasound and CBCT scans were acquired in rapid succession and analyzed for setup errors. The deviation between setup errors of the two modalities was evaluated separately for each dimension. Results: A moderate correlation in lateral, vertical and longitudinal direction was observed comparing the setup errors. Mean differences between TPUS and CBCT were (-2.7 ± 2.3) mm, (3.0 ± 2.4) mm and (3.2 ± 2.7) mm in lateral, vertical and longitudinal direction, respectively. The mean Euclidean difference between TPUS and CBCT was (6.0 ± 3.1) mm. Differences up to 19.2 mm were observed between the two imaging modalities. Discrepancies between TPUS and CBCT of at least 5 mm occurred in 58 \% of monitored treatment sessions. Conclusion: Setup differences between TPUS and CBCT are 6 mm on average. Although the correlation of the setup errors determined by the two different image modalities is rather week, the combination of setup verification by CBCT and intrafraction motion monitoring by TPUS imaging can use the benefits of both imaging modalities.}, language = {en} } @article{SiminSoltamovPoshakinskiyetal.2016, author = {Simin, D. and Soltamov, V. A. and Poshakinskiy, A. V. and Anisimov, A. N. and Babunts, R. A. and Tolmachev, D. O. and Mokhov, E. N. and Trupke, M. and Tarasenko, S. A. and Sperlich, A. and Baranov, P. G. and Dyakonov, V. and Astakhov, G. V.}, title = {All-Optical dc Nanotesla Magnetometry Using Silicon Vacancy Fine Structure in Isotopically Purified Silicon Carbide}, series = {Physical Review X}, volume = {6}, journal = {Physical Review X}, doi = {10.1103/PhysRevX.6.031014}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147682}, pages = {031014}, year = {2016}, abstract = {We uncover the fine structure of a silicon vacancy in isotopically purified silicon carbide (4H-\(^{28}\)SiC) and reveal not yet considered terms in the spin Hamiltonian, originated from the trigonal pyramidal symmetry of this spin-3/2 color center. These terms give rise to additional spin transitions, which would be otherwise forbidden, and lead to a level anticrossing in an external magnetic field. We observe a sharp variation of the photoluminescence intensity in the vicinity of this level anticrossing, which can be used for a purely all-optical sensing of the magnetic field. We achieve dc magnetic field sensitivity better than 100  nT/√Hz within a volume of 3×10\(^{-7}\)mm\(^3\) at room temperature and demonstrate that this contactless method is robust at high temperatures up to at least 500 K. As our approach does not require application of radio-frequency fields, it is scalable to much larger volumes. For an optimized light-trapping waveguide of 3  mm\(^3\), the projection noise limit is below 100  fT/√Hz.}, language = {en} } @article{RovitusoSchefflerWunschetal.2016, author = {Rovituso, Damiano M. and Scheffler, Laura and Wunsch, Marie and Kleinschnitz, Christoph and D{\"o}rck, Sebastian and Ulzheimer, Jochen and Bayas, Antonios and Steinman, Lawrence and Erg{\"u}n, S{\"u}leyman and Kuerten, Stefanie}, title = {CEACAM1 mediates B cell aggregation in central nervous system autoimmunity}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, doi = {10.1038/srep29847}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147690}, pages = {29847}, year = {2016}, abstract = {B cell aggregates in the central nervous system (CNS) have been associated with rapid disease progression in patients with multiple sclerosis (MS). Here we demonstrate a key role of carcinoembryogenic antigen-related cell adhesion molecule1 (CEACAM1) in B cell aggregate formation in MS patients and a B cell-dependent mouse model of MS. CEACAM1 expression was increased on peripheral blood B cells and CEACAM1\(^+\) B cells were present in brain infiltrates of MS patients. Administration of the anti-CEACAM1 antibody T84.1 was efficient in blocking aggregation of B cells derived from MS patients. Along these lines, application of the monoclonal anti-CEACAM1 antibody mCC1 was able to inhibit CNS B cell aggregate formation and significantly attenuated established MS-like disease in mice in the absence of any adverse effects. CEACAM1 was co-expressed with the regulator molecule T cell immunoglobulin and mucin domain -3 (TIM-3) on B cells, a novel molecule that has recently been described to induce anergy in T cells. Interestingly, elevated coexpression on B cells coincided with an autoreactive T helper cell phenotype in MS patients. Overall, these data identify CEACAM1 as a clinically highly interesting target in MS pathogenesis and open new therapeutic avenues for the treatment of the disease.}, language = {en} } @article{FalibeneRocesRoessleretal.2016, author = {Falibene, Augustine and Roces, Flavio and R{\"o}ssler, Wolfgang and Groh, Claudia}, title = {Daily Thermal Fluctuations Experienced by Pupae via Rhythmic Nursing Behavior Increase Numbers of Mushroom Body Microglomeruli in the Adult Ant Brain}, series = {Frontiers in Behavioral Neuroscience}, volume = {10}, journal = {Frontiers in Behavioral Neuroscience}, number = {73}, doi = {10.3389/fnbeh.2016.00073}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146711}, year = {2016}, abstract = {Social insects control brood development by using different thermoregulatory strategies. Camponotus mus ants expose their brood to daily temperature fluctuations by translocating them inside the nest following a circadian rhythm of thermal preferences. At the middle of the photophase brood is moved to locations at 30.8°C; 8 h later, during the night, the brood is transferred back to locations at 27.5°C. We investigated whether daily thermal fluctuations experienced by developing pupae affect the neuroarchitecture in the adult brain, in particular in sensory input regions of the mushroom bodies (MB calyces). The complexity of synaptic microcircuits was estimated by quantifying MB-calyx volumes together with densities of presynaptic boutons of microglomeruli (MG) in the olfactory lip and visual collar regions. We compared young adult workers that were reared either under controlled daily thermal fluctuations of different amplitudes, or at different constant temperatures. Thermal regimes significantly affected the large (non-dense) olfactory lip region of the adult MB calyx, while changes in the dense lip and the visual collar were less evident. Thermal fluctuations mimicking the amplitudes of natural temperature fluctuations via circadian rhythmic translocation of pupae by nurses (amplitude 3.3°C) lead to higher numbers of MG in the MB calyces compared to those in pupae reared at smaller or larger thermal amplitudes (0.0, 1.5, 9.6°C), or at constant temperatures (25.4, 35.0°C). We conclude that rhythmic control of brood temperature by nursing ants optimizes brain development by increasing MG densities and numbers in specific brain areas. Resulting differences in synaptic microcircuits are expected to affect sensory processing and learning abilities in adult ants, and may also promote interindividual behavioral variability within colonies.}, language = {en} } @phdthesis{Ziegler2016, author = {Ziegler, Christiane}, title = {Epigenetic Mechanisms in the Pathogenesis and Therapy of Anxiety Disorders}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146815}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Anxiety disorders (AD) are common, disabling mental disorders, which constitute the most prevalent mental health condition conveying a high individual and socioeconomic burden. Social anxiety disorder (SAD), i.e. fear in social situations particularly when subjectively scrutinized by others, is the second most common anxiety disorder with a life time prevalence of 10\%. Panic disorder (PD) has a life time prevalence of 2-5\% and is characterized by recurrent and abrupt surges of intense fear and anticipatory anxiety, i.e. panic attacks, occurring suddenly and unexpected without an apparent cue. In recent years, psychiatric research increasingly focused on epigenetic mechanisms such as DNA methylation as a possible solution for the problem of the so-called "hidden heritability", which conceptualizes the fact that the genetic risk variants identified so far only explain a small part of the estimated heritability of mental disorders. In the first part of this thesis, oxytocin receptor (OXTR) gene methylation was investigated regarding its role in the pathogenesis of social anxiety disorder. In summary, OXTR methylation patterns were implicated in different phenotypes of social anxiety disorder on a categorical, neuropsychological, neuroendocrinological as well as on a neural network level. The results point towards a multilevel role of OXTR gene hypomethylation particularly at one CpG site (CpG3, Chr3: 8 809 437) within the protein coding region of the gene in SAD. The second part of the thesis investigated monoamine oxidase A (MAOA) gene methylation regarding its role in the pathogenesis of panic disorder as well as - applying a psychotherapy-epigenetic approach - its dynamic regulation during the course of cognitive behavioural therapy (CBT) in PD patients. First, MAOA hypomethylation was shown to be associated with panic disorder as well as with panic disorder severity. Second, in patients responding to treatment MAOA hypomethylation was shown to be reversible up to the level of methylation in healthy controls after the course of CBT. This increase in MAOA methylation along with successful psychotherapeutic treatment was furthermore shown to be associated with symptom improvement regarding agoraphobic avoidance in an independent replication sample of non-medicated patients with PD. Taken together, in the future the presently identified epigenetic patterns might contribute to establishing targeted preventive interventions and personalized treatment options for social anxiety disorder or panic disorder, respectively.}, subject = {Angst}, language = {en} } @article{WalperWeisteMuelleretal.2016, author = {Walper, Elisabeth and Weiste, Christoph and Mueller, Martin J. and Hamberg, Mats and Dr{\"o}ge-Laser, Wolfgang}, title = {Screen Identifying Arabidopsis Transcription Factors Involved in the Response to 9-Lipoxygenase-Derived Oxylipins}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {4}, doi = {10.1371/journal.pone.0153216}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146857}, pages = {e0153216}, year = {2016}, abstract = {13-Lipoxygenase-derived oxylipins, such as jasmonates act as potent signaling molecules in plants. Although experimental evidence supports the impact of oxylipins generated by the 9-Lipoxygenase (9-LOX) pathway in root development and pathogen defense, their signaling function in plants remains largely elusive. Based on the root growth inhibiting properties of the 9-LOX-oxylipin 9-HOT (9-hydroxy-10,12,15-octadecatrienoic acid), we established a screening approach aiming at identifying transcription factors (TFs) involved in signaling and/or metabolism of this oxylipin. Making use of the AtTORF-Ex (Arabidopsis thaliana Transcription Factor Open Reading Frame Expression) collection of plant lines overexpressing TF genes, we screened for those TFs which restore root growth on 9-HOT. Out of 6,000 lines, eight TFs were recovered at least three times and were therefore selected for detailed analysis. Overexpression of the basic leucine Zipper (bZIP) TF TGA5 and its target, the monoxygenase CYP81D11 reduced the effect of added 9-HOT, presumably due to activation of a detoxification pathway. The highly related ETHYLENE RESPONSE FACTORs ERF106 and ERF107 induce a broad detoxification response towards 9-LOX-oxylipins and xenobiotic compounds. From a set of 18 related group S-bZIP factors isolated in the screen, bZIP11 is known to participate in auxin-mediated root growth and may connect oxylipins to root meristem function. The TF candidates isolated in this screen provide starting points for further attempts to dissect putative signaling pathways involving 9-LOX-derived oxylipins.}, language = {en} } @article{BornZinnerDuekingetal.2016, author = {Born, Dennis-Peter and Zinner, Christoph and D{\"u}king, Peter and Sperlich, Billy}, title = {Multi-Directional Sprint Training Improves Change-Of-Direction Speed and Reactive Agility in Young Highly Trained Soccer Players}, series = {Journal of Sports Science and Medicine}, volume = {15}, journal = {Journal of Sports Science and Medicine}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146866}, pages = {314-319}, year = {2016}, abstract = {The aim of this study was to evaluate the effect of a repeated sprint training with multi-directional change-of-direction (COD) movements (RSmulti) compared to repeated shuttle sprints (RSS) on variables related to COD speed and reactive agility. Nineteen highly-trained male U15 soccer players were assigned into two groups performing either RSmulti or RSS. For both groups, each training session involved 20 repeated 15 s sprints interspersed with 30 s recovery. With RSmulti the COD movements were randomized and performed in response to a visual stimulus, while the RSS involved predefined 180° COD movements. Before and following the six training sessions, performance in the Illinois agility test (IAT), COD speed in response to a visual stimulus, 20 m linear sprint time and vertical jumping height were assessed. Both groups improved their performance in the IAT (p < 0.01, ES = 1.13; p = 0.01, ES = 0.55). The COD speed in response to a visual stimulus improved with the RSmulti (p < 0.01, ES = 1.03), but not the RSS (p = 0.46, ES = 0.28). No differences were found for 20 m sprint time (P=0.73, ES = 0.07; p = 0.14, ES = 0.28) or vertical jumping height (p = 0.46, ES = 0.11; p = 0.29, ES = 0.12) for the RSmulti and RSS, respectively. In conclusion, performance in the IAT improved with the RSmulti as well as RSS. With the RSmulti however, the COD movements are performed in response to a visual stimulus, which may result in specific adaptations that improve COD speed and reactive agility in young highly trained soccer players.}, language = {en} } @article{FuchsHartmannErnestusetal.2016, author = {Fuchs, Andreas and Hartmann, Stefan and Ernestus, Karen and Mutzbauer, Grit and Linz, Christian and Brands, Roman C. and K{\"u}bler, Alexander C. and M{\"u}ller-Richter, Urs D. A.}, title = {Mandibular intraosseous pseudocarcinomatous hyperplasia: a case report}, series = {Journal of Medical Case Reports}, volume = {16}, journal = {Journal of Medical Case Reports}, number = {268}, doi = {10.1186/s13256-016-1052-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146873}, year = {2016}, abstract = {Background Mandibular pseudocarcinomatous hyperplasia is a rare and generally benign pathology. We report on one of these rare cases. Case presentation The case history of a 73-year-old white man stated that he had a carcinoma of the oropharynx, which was primarily treated with radiotherapy and chemotherapy 4 years prior. As a result of radiotherapy he developed an osteoradionecrosis of his mandible and a consecutive pathological fracture of his left mandibular angle. Subsequent osteosynthesis was performed with a reconstruction plate. When we first saw him, his reconstruction plate was partially exposed with intraoral and extraoral fistulation. The resected bone of his defect-bordering jaw showed the typical pathohistological findings of an intraosseous mandibular pseudocarcinomatous hyperplasia. After a first reconstruction attempt with an iliac crest graft failed, definitive reconstruction of his mandible with a microvascular anastomosed fibula graft was achieved. Conclusions Intraosseous pseudocarcinomatous hyperplasia of the mandible is a rare differential diagnosis in maxillofacial surgery. Besides other benign epithelial neoplasms, such as calcifying epithelial odontogenic tumor, squamous odontogenic tumor, or different forms of ameloblastoma, the far more frequent invasive squamous cell carcinoma needs to be excluded. A misinterpretation of pseudocarcinomatous hyperplasia as squamous cell carcinoma must be avoided because it can lead to a massive overtreatment.}, language = {en} } @article{BeykanDamEberleinetal.2016, author = {Beykan, Seval and Dam, Jan S. and Eberlein, Uta and Kaufmann, Jens and Kj{\ae}rgaard, Benedict and J{\o}dal, Lars and Bouterfa, Hakim and Bejot, Romain and Lassmann, Michael and Jensen, Svend Borup}, title = {\(^{177}\)Lu-OPS201 targeting somatostatin receptors: in vivo biodistribution and dosimetry in a pig model}, series = {EJNMMI Research}, volume = {6}, journal = {EJNMMI Research}, number = {50}, doi = {10.1186/s13550-016-0204-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146888}, year = {2016}, abstract = {Background \(^{177}\)Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of \(^{177}\)Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications. Results \(^{177}\)Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/μg. Prior to administration, the radiochemical purity was measured as s > 99.7 \% in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 \% of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq \(^{177}\)Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of 177Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels. Conclusions The \(^{177}\)Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range.}, language = {en} } @article{KaltdorfSrivastavaGuptaetal.2016, author = {Kaltdorf, Martin and Srivastava, Mugdha and Gupta, Shishir K. and Liang, Chunguang and Binder, Jasmin and Dietl, Anna-Maria and Meir, Zohar and Haas, Hubertus and Osherov, Nir and Krappmann, Sven and Dandekar, Thomas}, title = {Systematic Identification of Anti-Fungal Drug Targets by a Metabolic Network Approach}, series = {Frontiers in Molecular Bioscience}, volume = {3}, journal = {Frontiers in Molecular Bioscience}, doi = {10.3389/fmolb.2016.00022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147396}, pages = {22}, year = {2016}, abstract = {New antimycotic drugs are challenging to find, as potential target proteins may have close human orthologs. We here focus on identifying metabolic targets that are critical for fungal growth and have minimal similarity to targets among human proteins. We compare and combine here: (I) direct metabolic network modeling using elementary mode analysis and flux estimates approximations using expression data, (II) targeting metabolic genes by transcriptome analysis of condition-specific highly expressed enzymes, and (III) analysis of enzyme structure, enzyme interconnectedness ("hubs"), and identification of pathogen-specific enzymes using orthology relations. We have identified 64 targets including metabolic enzymes involved in vitamin synthesis, lipid, and amino acid biosynthesis including 18 targets validated from the literature, two validated and five currently examined in own genetic experiments, and 38 further promising novel target proteins which are non-orthologous to human proteins, involved in metabolism and are highly ranked drug targets from these pipelines.}, language = {en} } @article{WernerLueckerathSchmidetal.2016, author = {Werner, R. A. and L{\"u}ckerath, K. and Schmid, J. S. and Higuchi, T. and Kreissl, M. C. and Grelle, I. and Reiners, C. and Buck, A. K. and Lapa, C.}, title = {Thyroglobulin fluctuations in patients with iodine-refractory differentiated thyroid carcinoma on lenvatinib treatment - initial experience}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, doi = {10.1038/srep28081}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147407}, pages = {28081}, year = {2016}, abstract = {Tyrosine kinase inhibitors (TKI) have shown clinical effectiveness in iodine-refractory differentiated thyroid cancer (DTC). The corresponding role of serum thyroglobulin (Tg) in iodine-refractory DTC has not been investigated yet. 9 patients (3 female, 61 ± 8y) with progressive iodine-refractory DTC starting on lenvatinib were considered. Tumor restaging was performed every 2-3 months including contrast-enhanced computed tomography (CT, RECIST 1.1). Serum Tg was measured and compared to imaging findings. After treatment initiation, serum Tg levels dropped in all patients with a median reduction of 86.2\%. During long-term follow-up (median, 25.2 months), fluctuations in Tg could be observed in 8/9 subjects. According to RECIST, 6/9 subjects achieved a partial response or stable disease with the remaining 3/9 experiencing progressive disease (2/3 with Tg levels rising above baseline). All of the patients with disease progression presented with a preceding continuous rise in serum Tg, whereas tumor marker oscillations in the subjects with controlled disease were only intermittent. Initiation of lenvatinib in iodine-refractory DTC patients is associated with a significant reduction in serum Tg levels as a marker of treatment response. In the course of treatment, transient Tg oscillations are a frequent phenomenon that may not necessarily reflect morphologic tumor progression.}, language = {en} } @article{KrausHeiberVaethetal.2016, author = {Kraus, Hannes and Heiber, Michael C. and V{\"a}th, Stefan and Kern, Julia and Deibel, Carsten and Sperlich, Andreas and Dyakonov, Vladimir}, title = {Analysis of Triplet Exciton Loss Pathways in PTB7:PC\(_{71}\)BM Bulk Heterojunction Solar Cells}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, number = {29158}, doi = {10.1038/srep29158}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147413}, year = {2016}, abstract = {A strategy for increasing the conversion efficiency of organic photovoltaics has been to increase the VOC by tuning the energy levels of donor and acceptor components. However, this opens up a new loss pathway from an interfacial charge transfer state to a triplet exciton (TE) state called electron back transfer (EBT), which is detrimental to device performance. To test this hypothesis, we study triplet formation in the high performing PTB7:PC\(_{71}\)BM blend system and determine the impact of the morphology-optimizing additive 1,8-diiodoctane (DIO). Using photoluminescence and spin-sensitive optically detected magnetic resonance (ODMR) measurements at low temperature, we find that TEs form on PC\(_{71}\)BM via intersystem crossing from singlet excitons and on PTB7 via EBT mechanism. For DIO blends with smaller fullerene domains, an increased density of PTB7 TEs is observed. The EBT process is found to be significant only at very low temperature. At 300 K, no triplets are detected via ODMR, and electrically detected magnetic resonance on optimized solar cells indicates that TEs are only present on the fullerenes. We conclude that in PTB7:PC\(_{71}\)BM devices, TE formation via EBT is impacted by fullerene domain size at low temperature, but at room temperature, EBT does not represent a dominant loss pathway.}, language = {en} } @article{BiehlMerzDresleretal.2016, author = {Biehl, Stefanie C. and Merz, Christian J. and Dresler, Thomas and Heupel, Julia and Reichert, Susanne and Jacob, Christian P. and Deckert, J{\"u}rgen and Herrmann, Martin J.}, title = {Increase or Decrease of fMRI Activity in Adult Attention Deficit/ Hyperactivity Disorder: Does It Depend on Task Difficulty?}, series = {International Journal of Neuropsychopharmacology}, volume = {19}, journal = {International Journal of Neuropsychopharmacology}, number = {10}, doi = {10.1093/ijnp/pyw049}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147551}, pages = {pyw049}, year = {2016}, abstract = {Background: Attention deficit/hyperactivity disorder has been shown to affect working memory, and fMRI studies in children and adolescents with attention deficit/hyperactivity disorder report hypoactivation in task-related attentional networks. However, studies with adult attention deficit/hyperactivity disorder patients addressing this issue as well as the effects of clinically valid methylphenidate treatment are scarce. This study contributes to closing this gap. Methods: Thirty-five adult patients were randomized to 6 weeks of double-blind placebo or methylphenidate treatment. Patients completed an fMRI n-back working memory task both before and after the assigned treatment, and matched healthy controls were tested and compared to the untreated patients. Results: There were no whole-brain differences between any of the groups. However, when specified regions of interest were investigated, the patient group showed enhanced BOLD responses in dorsal and ventral areas before treatment. This increase was correlated with performance across all participants and with attention deficit/hyperactivity disorder symptoms in the patient group. Furthermore, we found an effect of treatment in the right superior frontal gyrus, with methylphenidate-treated patients exhibiting increased activation, which was absent in the placebo-treated patients. Conclusions: Our results indicate distinct activation differences between untreated adult attention deficit/hyperactivity disorder patients and matched healthy controls during a working memory task. These differences might reflect compensatory efforts by the patients, who are performing at the same level as the healthy controls. We furthermore found a positive effect of methylphenidate on the activation of a frontal region of interest. These observations contribute to a more thorough understanding of adult attention deficit/hyperactivity disorder and provide impulses for the evaluation of therapy-related changes.}, language = {en} } @article{UeceylerBikoHoseetal.2016, author = {{\"U}{\c{c}}eyler, Nurcan and Biko, Lydia and Hose, Dorothea and Hoffmann, Lukas and Sommer, Claudia}, title = {Comprehensive and differential long-term characterization of the alpha-galactosidase A deficient mouse model of Fabry disease focusing on the sensory system and pain development}, series = {Molecular Pain}, volume = {12}, journal = {Molecular Pain}, number = {1744806916646370}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147562}, year = {2016}, abstract = {Fabry disease is an X-linked lysosomal storage disorder due to impaired activity of alpha-galactosidase A with intracellular accumulation of globotriaosylceramide. Associated small fiber pathology leads to characteristic pain in Fabry disease. We systematically assessed sensory system, physical activity, metabolic parameters, and morphology of male and female mice with alpha-galactosidase A deficiency (Fabry ko) from 2 to 27 months of age and compared results with those of age- and gender-matched wild-type littermates of C57Bl/6J background. Results From the age of two months, male and female Fabry mice showed mechanical hypersensitivity (p < 0.001 each) compared to wild-type littermates. Young Fabry ko mice of both genders were hypersensitive to heat stimulation (p < 0.01) and developed heat hyposensitivity with aging (p < 0.05), while cold hyposensitivity was present constantly in young (p < 0.01) and old (p < 0.05) Fabry ko mice compared to wild-type littermates. Stride angle increased only in male Fabry ko mice with aging (p < 0.01) in comparison to wild-type littermates. Except for young female mice, male (p < 0.05) and female (p < 0.01) Fabry ko mice had a higher body weight than wild-type littermates. Old male Fabry ko mice were physically less active than their wild-type littermates (p < 0.05), had lower chow intake (p < 0.001), and lost more weight (p < 0.001) in a one-week treadmill experiment than wild-type littermates. Also, Fabry ko mice showed spontaneous pain protective behavior and developed orofacial dysmorphism resembling patients with Fabry disease. Conclusions. Mice with alpha-galactosidase A deficiency show age-dependent and distinct deficits of the sensory system. alpha-galactosidase A-deficient mice seem to model human Fabry disease and may be helpful when studying the pathophysiology of Fabry-associated pain.}, language = {en} } @phdthesis{Ruf2016, author = {Ruf, Franziska}, title = {The circadian regulation of eclosion in \(Drosophila\) \(melanogaster\)}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146265}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Eclosion is the emergence of an adult insect from the pupal case at the end of development. In the fruit fly Drosophila melanogaster, eclosion is a circadian clock-gated event and is regulated by various peptides. When studied on the population level, eclosion reveals a clear rhythmicity with a peak at the beginning of the light-phase that persists also under constant conditions. It is a long standing hypothesis that eclosion gating to the morning hours with more humid conditions is an adaption to reduce water loss and increase the survival. Eclosion behavior, including the motor pattern required for the fly to hatch out of the puparium, is orchestrated by a well-characterized cascade of peptides. The main components are ecdysis-triggering hormone (ETH), eclosion hormone (EH) and crustacean cardioactive peptide (CCAP). The molt is initiated by a peak level and pupal ecdysis by a subsequent decline of the ecdysteroid ecdysone. Ecdysteroids are produced by the prothoracic gland (PG), an endocrine tissue that contains a peripheral clock and degenerates shortly after eclosion. Production and release of ecdysteroids are regulated by the prothoracicotropic hormone (PTTH). Although many aspects of the circadian clock and the peptidergic control of the eclosion behavior are known, it still remains unclear how both systems are interconnected. The aim of this dissertation research was to dissect this connection and evaluate the importance of different Zeitgebers on eclosion rhythmicity under natural conditions. Potential interactions between the central clock and the peptides regulating ecdysis motor behavior were evaluated by analyzing the influence of CCAP on eclosion rhythmicity. Ablation and silencing of CCAP neurons, as well as CCAP null-mutation did not affect eclosion rhythmicity under either light or temperature entrainment nor under natural conditions. To dissect the connection between the central and the peripheral clock, PTTH neurons were ablated. Monitoring eclosion under light and temperature entrainment revealed that eclosion became arrhythmic under constant conditions. However, qPCR expression analysis revealed no evidence for cycling of Ptth mRNA in pharate flies. To test for a connection with pigment-dispersing factor (PDF)-expressing neurons, the PDF receptor (PDFR) and short neuropeptide F receptor (sNPFR) were knocked down in the PTTH neurons. Knockdown of sNPFR, but not PDFR, resulted in arrhythmic eclosion under constant darkness conditions. PCR analysis of the PTTH receptor, Torso, revealed its expression in the PG and the gonads, but not in the brain or eyes, of pharate flies. Knockdown of torso in the PG lead to arrhythmicity under constant conditions, which provides strong evidence for the specific effect of PTTH on the PG. These results suggest connections from the PDF positive lateral neurons to the PTTH neurons via sNPF signaling, and to the PG via PTTH and Torso. This interaction presumably couples the period of the peripheral clock in the PG to that of the central clock in the brain. To identify a starting signal for eclosion and possible further candidates in the regulation of eclosion behavior, chemically defined peptidergic and aminergic neurons were optogenetically activated in pharate pupae via ChR2-XXL. This screen approach revealed two candidates for the regulation of eclosion behavior: Dromyosuppressin (DMS) and myo-inhibitory peptides (MIP). However, ablation of DMS neurons did not affect eclosion rhythmicity or success and the exact function of MIP must be evaluated in future studies. To assess the importance of the clock and of possible Zeitgebers in nature, eclosion of the wildtype Canton S and the clock mutant per01 and the PDF signaling mutants pdf01 and han5304 was monitored under natural conditions. For this purpose, the W{\"u}rzburg eclosion monitor (WEclMon) was developed, which is a new open monitoring system that allows direct exposure of pupae to the environment. A general decline of rhythmicity under natural conditions compared to laboratory conditions was observed in all tested strains. While the wildtype and the pdf01 and han5304 mutants stayed weakly rhythmic, the per01 mutant flies eclosed mostly arrhythmic. PDF and its receptor (PDFR encoded by han) are required for the synchronization of the clock network and functional loss can obviously be compensated by a persisting synchronization to external Zeitgebers. The loss of the central clock protein PER, however, lead to a non-functional clock and revealed the absolute importance of the clock for eclosion rhythmicity. To quantitatively analyze the effect of the clock and abiotic factors on eclosion rhythmicity, a statistical model was developed in cooperation with Oliver Mitesser and Thomas Hovestadt. The modelling results confirmed the clock as the most important factor for eclosion rhythmicity. Moreover, temperature was found to have the strongest effect on the actual shape of the daily emergence pattern, while light has only minor effects. Relative humidity could be excluded as Zeitgeber for eclosion and therefore was not further analyzed. Taken together, the present dissertation identified the so far unknown connection between the central and peripheral clock regulating eclosion. Furthermore, a new method for the analysis of eclosion rhythms under natural conditions was established and the necessity of a functional clock for rhythmic eclosion even in the presence of multiple Zeitgebers was shown.}, subject = {Taufliege}, language = {en} } @article{DejungSubotaBuceriusetal.2016, author = {Dejung, Mario and Subota, Ines and Bucerius, Ferdinand and Dindar, G{\"u}lcin and Freiwald, Anja and Engstler, Markus and Boshart, Michael and Butter, Falk and Janzen, Chistian J.}, title = {Quantitative proteomics uncovers novel factors involved in developmental differentiation of Trypanosoma brucei}, series = {PLoS Pathogens}, volume = {12}, journal = {PLoS Pathogens}, number = {2}, doi = {10.1371/journal.ppat.1005439}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146362}, pages = {e1005439}, year = {2016}, abstract = {Developmental differentiation is a universal biological process that allows cells to adapt to different environments to perform specific functions. African trypanosomes progress through a tightly regulated life cycle in order to survive in different host environments when they shuttle between an insect vector and a vertebrate host. Transcriptomics has been useful to gain insight into RNA changes during stage transitions; however, RNA levels are only a moderate proxy for protein abundance in trypanosomes. We quantified 4270 protein groups during stage differentiation from the mammalian-infective to the insect form and provide classification for their expression profiles during development. Our label-free quantitative proteomics study revealed previously unknown components of the differentiation machinery that are involved in essential biological processes such as signaling, posttranslational protein modifications, trafficking and nuclear transport. Furthermore, guided by our proteomic survey, we identified the cause of the previously observed differentiation impairment in the histone methyltransferase DOT1B knock-out strain as it is required for accurate karyokinesis in the first cell division during differentiation. This epigenetic regulator is likely involved in essential chromatin restructuring during developmental differentiation, which might also be important for differentiation in higher eukaryotic cells. Our proteome dataset will serve as a resource for detailed investigations of cell differentiation to shed more light on the molecular mechanisms of this process in trypanosomes and other eukaryotes.}, language = {en} } @article{LiuHuNordbecketal.2016, author = {Liu, Dan and Hu, Kai and Nordbeck, Peter and Ertl, Georg and St{\"o}rk, Stefan and Weidemann, Frank}, title = {Longitudinal strain bull's eye plot patterns in patients with cardiomyopathy and concentric left ventricular hypertrophy}, series = {European Journal of Medical Research}, volume = {21}, journal = {European Journal of Medical Research}, number = {21}, doi = {10.1186/s40001-016-0216-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146373}, year = {2016}, abstract = {Despite substantial advances in the imaging techniques and pathophysiological understanding over the last decades, identification of the underlying causes of left ventricular hypertrophy by means of echocardiographic examination remains a challenge in current clinical practice. The longitudinal strain bull's eye plot derived from 2D speckle tracking imaging offers an intuitive visual overview of the global and regional left ventricular myocardial function in a single diagram. The bull's eye mapping is clinically feasible and the plot patterns could provide clues to the etiology of cardiomyopathies. The present review summarizes the longitudinal strain, bull's eye plot features in patients with various cardiomyopathies and concentric left ventricular hypertrophy and the bull's eye plot features might serve as one of the cardiac workup steps on evaluating patients with left ventricular hypertrophy.}, language = {en} } @article{WestermaierLinsenmannHomolaetal.2016, author = {Westermaier, Thomas and Linsenmann, Thomas and Homola, Gy{\"o}rgy A. and Loehr, Mario and Stetter, Christian and Willner, Nadine and Ernestus, Ralf-Ingo and Soymosi, Laszlo and Vince, Giles H.}, title = {3D rotational fluoroscopy for intraoperative clip control in patients with intracranial aneurysms - assessment of feasibility and image quality}, series = {BMC Medical Imaging}, volume = {16}, journal = {BMC Medical Imaging}, number = {30}, doi = {10.1186/s12880-016-0133-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146381}, year = {2016}, abstract = {Background Mobile 3D fluoroscopes have become increasingly available in neurosurgical operating rooms. In this series, the image quality and value of intraoperative 3D fluoroscopy with intravenous contrast agent for the evaluation of aneurysm occlusion and vessel patency after clip placement was assessed in patients who underwent surgery for intracranial aneurysms. Materials and methods Twelve patients were included in this retrospective analysis. Prior to surgery, a 360° rotational fluoroscopy scan was performed without contrast agent followed by another scan with 50 ml of intravenous iodine contrast agent. The image files of both scans were transferred to an Apple PowerMac® workstation, subtracted and reconstructed using OsiriX® free software. The procedure was repeated after clip placement. Both image sets were compared for assessment of aneurysm occlusion and vessel patency. Results Image acquisition and contrast administration caused no adverse effects. Image quality was sufficient to follow the patency of the vessels distal to the clip. Metal artifacts reduce the assessability of the immediate vicinity of the clip. Precise image subtraction and post-processing can reduce metal artifacts and make the clip-site assessable and depict larger neck-remnants. Conclusion This technique quickly supplies images at adequate quality to evaluate distal vessel patency after aneurysm clipping. Significant aneurysm remnants may be depicted as well. As it does not require visual control of all vessels that are supposed to be evaluated intraoperatively, this technique may be complementary to other intraoperative tools like indocyanine green videoangiography and micro-Doppler, especially for the assessment of larger aneurysms. At the momentary state of this technology, it cannot replace postoperative conventional angiography. However, 3D fluoroscopy and image post-processing are young technologies. Further technical developments are likely to result in improved image quality.}, language = {en} } @article{WolfBraunHainingetal.2016, author = {Wolf, Karen and Braun, Attila and Haining, Elizabeth J. and Tseng, Yu-Lun and Kraft, Peter and Schuhmann, Michael K. and Gotru, Sanjeev K. and Chen, Wenchun and Hermanns, Heike M. and Stoll, Guido and Lesch, Klaus-Peter and Nieswandt, Bernhard}, title = {Partially Defective Store Operated Calcium Entry and Hem(ITAM) Signaling in Platelets of Serotonin Transporter Deficient Mice}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {1}, doi = {10.1371/journal.pone.0147664}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146399}, pages = {e0147664}, year = {2016}, abstract = {Background Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation. Objective To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt\(^{-/-}\)) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke. Results In 5Htt\(^{-/-}\) platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca\(^{2+}\) entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt\(^{-/-}\) platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt\(^{-/-}\) mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt\(^{-/-}\) mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice. Conclusion Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization.}, language = {en} } @phdthesis{Schmitz2016, author = {Schmitz, Tobias}, title = {Functional coatings by physical vapor deposition (PVD) for biomedical applications}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144825}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Metals are the most used materials for implant devices, especially in orthopedics, but despite their long history of application issues such as material failure through wear and corrosion remain unsolved leading to a certain number of revision surgeries. Apart from the problems associated with insufficient material properties, another serious issue is an implant associated infection due to the formation of a biofilm on the surface of the material after implantation. Thus, improvements in implant technology are demanded, especially since there is a projected rise of implants needed in the future. Surface modification methods such as physical vapour deposition (PVD), oxygen diffusion hardening and electrochemical anodization have shown to be efficient methods to improve the surfaces of metallic bulk materials regarding biomedical issues. This thesis was focused on the development of functional PVD coatings that are suitable for further treatment with surface modification techniques originally developed for bulk metals. The aim was to precisely adjust the surface properties of the implant according to the targeted application to prevent possible failure mechanisms such as coating delamination, wear or the occurrence of post-operative infections. Initially,  tantalum layers with approx 5 µm thickness were deposited at elevated substrate temperatures on cp Ti by RF magnetron sputtering. Due to the high affinity of tantalum to oxygen, these coatings are known to provide a self healing capacity since the rapid oxide formation is known to close surface cracks. Here, the work aimed to reduce the abrupt change of mechanical properties between the hard and brittle coating and the ductile substrate by creating an oxygen diffusion zone. It was found that the hardness and adhesion could be significantly increased when the coatings were treated afterwards by oxygen diffusion hardening in a two step process. Firstly, the surface was oxidized at a pressure of 6.7•10-3 mbar at 350 450 °C, followed by 1-2 h annealing in oxygen-free atmosphere at the same temperature leading to a diffusion of oxygen atoms into deeper parts of the substrate as proved by X-ray diffraction (XRD) analysis. The hereby caused mechanical stress in the crystal lattice led to an increase in Vickers hardness of the Ta layers from 570 HV to over 900 HV. Investigations into the adhesion of oxygen diffusion treated samples by Rockwell measurements demonstrated an increase of critical force for coating delamination from 12 N for untreated samples up to 25 N for diffusion treated samples. In a second approach, the development of modular targets aimed to produce functional coatings by metallic doping of titanium with biologically active agents. This was demonstrated by the fabrication of antimicrobial Ti(Ag) coatings using a single magnetron sputtering source equipped with a titanium target containing implemented silver modules under variation of bias voltage and substrate temperature. The deposition of both Ti and Ag was confirmed by X-ray diffraction and a clear correlation between the applied sputtering parameters and the silver content of the coatings was demonstrated by ICP-MS and EDX. Surface-sensitive XPS measurements revealed that higher substrate temperatures led to an accumulation of Ag in the near-surface region, while the application of a bias voltage had the opposite effect. SEM and AFM microscopy revealed that substrate heating during film deposition supported the formation of even and dense surface layers with small roughness values, which could even be enforced by applying a substrate bias voltage. Additional elution measurements using ICP-MS showed that the release kinetics depended on the amount of silver located at the film surface and hence could be tailored by variation of the sputter parameters. In a final step, the applied Ti and Ti(Ag) coatings deposited on cp Ti, stainless steel (316L) and glass substrates were subsequently nanostructured using a self-ordering process induced by electrochemical anodization in aqueous fluoride containing electrolytes. SEM analysis showed that nanotube arrays could be grown from the Ti and Ti(Ag) coatings deposited at elevated temperatures on any substrate, whereby no influence of the substrate on nanotube morphology could be observed. EDX measurements indicated that the anodization process led to the selective etching of Ti from Ti(Ag) coating. Further experiments on coatings deposited on glass surfaces revealed that moderate substrate temperatures during deposition resulting in smooth Ti layers as determined by AFM measurements, are favorable for the generation of highly ordered nanotube arrays. Such arrays exhibited superhydrophilic behavior as proved by contact angle measurements. XRD analysis revealed that the nanostructured coatings were amorphous after anodization but could be crystallized to anatase structure by thermal treatment at temperatures of 450°C.}, subject = {PVD-Verfahren}, language = {en} } @phdthesis{Cicova2016, author = {Cicova, Zdenka}, title = {Characterization of a novel putative factor involved in host adaptation in Trypanosoma brucei}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142462}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Trypanosomes are masters of adaptation to different host environments during their complex life cycle. Large-scale proteomic approaches provide information on changes at the cellular level in a systematic way. However, a detailed work on single components is necessary to understand the adaptation mechanisms on a molecular level. Here we have performed a detailed characterization of a bloodstream form (BSF) stage-specific putative flagellar host adaptation factor (Tb927.11.2400) identified previously in a SILAC-based comparative proteome study. Tb927.11.2400 shares 38\% amino acid identity with TbFlabarin (Tb927.11.2410), a procyclic form (PCF) stage specific flagellar BAR domain protein. We named Tb927.11.2400 TbFlabarin like (TbFlabarinL) and demonstrate that it is a result of a gene duplication event, which occurred in African trypanosomes. TbFlabarinL is not essential for growth of the parasites under cell culture conditions and it is dispensable for developmental differentiation from BSF to the PCF in vitro. We generated a TbFlabarinL-specific antibody and showed that it localizes in the flagellum. The co-immunoprecipitation experiment together with a biochemical cell fractionation indicated a dual association of TbFlabarinL with the flagellar membrane and the components of the paraflagellar rod.}, subject = {Trypanosoma brucei}, language = {en} } @unpublished{ArrowsmithBoehnkeBraunschweigetal.2016, author = {Arrowsmith, Merle and B{\"o}hnke, Julian and Braunschweig, Holger and Celik, Mehmet and Claes, Christina and Ewing, William and Krummenacher, Ivo and Lubitz, Katharina and Schneider, Christoph}, title = {Neutral Diboron Analogues of Archetypal Aromatic Species by Spontaneous Cycloaddition}, doi = {10.1002/anie.201602384}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142500}, pages = {4}, year = {2016}, abstract = {Among the numerous routes organic chemists have developed to synthesize benzene derivatives and heteroaro- matic compounds, transition-metal-catalyzed cycloaddition reactions are the most elegant. In contrast, cycloaddition reactions of heavier alkene and alkyne analogues, though limited in scope, proceed uncatalyzed. In this work we present the first spontaneous cycloaddition reactions of lighter alkene and alkyne analogues. Selective addition of unactivated alkynes to boron-boron multiple bonds under ambient con- ditions yielded diborocarbon equivalents of simple aromatic hydrocarbons, including the first neutral 6p-aromatic dibora- benzene compound, a 2 p-aromatic triplet biradical 1,3-dibor- ete, and a phosphine-stabilized 2 p-homoaromatic 1,3-dihydro- 1,3-diborete. DFT calculations suggest that all three com- pounds are aromatic and show frontier molecular orbitals matching those of the related aromatic hydrocarbons, C6H6 and C4H42+, and homoaromatic C4H5+.}, subject = {Diborane}, language = {en} } @phdthesis{Kupper2016, author = {Kupper, Maria}, title = {The immune transcriptome and proteome of the ant Camponotus floridanus and vertical transmission of its bacterial endosymbiont Blochmannia floridanus}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142534}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {The evolutionary success of insects is believed to be at least partially facilitated by symbioses between insects and prokaryotes. Bacterial endosymbionts confer various fitness advantages to their hosts, for example by providing nutrients lacking from the insects' diet thereby enabling the inhabitation of new ecological niches. The Florida carpenter ant Camponotus floridanus harbours endosymbiotic bacteria of the genus Blochmannia. These primary endosymbionts mainly reside in the cytoplasm of bacteriocytes, specialised cells interspersed into the midgut tissue, but they were also found in oocytes which allows their vertical transmission. The social lifestyle of C. floridanus may facilitate the rapid spread of infections amongst genetically closely related animals living in huge colonies. Therefore, the ants require an immune system to efficiently combat infections while maintaining a "chronic" infection with their endosymbionts. In order to investigate the immune repertoire of the ants, the Illumina sequencing method was used. The previously published genome sequence of C. floridanus was functionally re-annotated and 0.53\% of C. floridanus proteins were assigned to the gene ontology (GO) term subcategory "immune system process". Based on homology analyses, genes encoding 510 proteins with possible immune function were identified. These genes are involved in microbial recognition and immune signalling pathways but also in cellular defence mechanisms, such as phagocytosis and melanisation. The components of the major signalling pathways appear to be highly conserved and the analysis revealed an overall broad immune repertoire of the ants though the number of identified genes encoding pattern recognition receptors (PRRs) and antimicrobial peptides (AMPs) is comparatively low. Besides three genes coding for homologs of thioester-containing proteins (TEPs), which have been shown to act as opsonins promoting phagocytosis in other insects, six genes encoding the AMPs defesin-1 and defensin-2, hymenoptaecin, two tachystatin-like peptides and one crustin-like peptide are present in the ant genome. Although the low number of known AMPs in comparison to 13 AMPs in the honey bee Apis mellifera and 46 AMPs in the wasp Nasonia vitripennis may indicate a less potent immune system, measures summarised as external or social immunity may enhance the immune repertoire of C. floridanus, as it was discussed for other social insects. Also, the hymenoptaecin multipeptide precursor protein may be processed to yield seven possibly bioactive peptides. In this work, two hymenoptaecin derived peptides were heterologously expressed and purified. The preliminary antimicrobial activity assays indicate varying bacteriostatic effects of different hymenoptaecin derived peptides against Escherichia coli D31 and Staphylococcus aureus which suggests a functional amplification of the immune response further increasing the antimicrobial potency of the ants. Furthermore, 257 genes were differentially expressed upon immune challenge of C. floridanus and most of the immune genes showing differential expression are involved in recognition of microbes or encode immune effectors rather than signalling components. Additionally, genes coding for proteins involved in storage and metabolism were downregulated upon immune challenge suggesting a trade-off between two energy-intensive processes in order to enhance effectiveness of the immune response. The analysis of gene expression via qRT-PCR was used for validation of the transcriptome data and revealed stage-specific immune gene regulation. Though the same tendencies of regulation were observed in larvae and adults, expression of several immune-related genes was generally more strongly induced in larvae. Immune gene expression levels depending on the developmental stage of C. floridanus are in agreement with observations in other insects and might suggest that animals from different stages revert to individual combinations of external and internal immunity upon infection. The haemolymph proteome of immune-challenged ants further established the immune-relevance of several proteins involved in classical immune signalling pathways, e.g. PRRs, extracellularly active proteases of the Toll signalling pathway and effector molecules such as AMPs, lysozymes and TEPs. Additionally, non-canonical proteins with putative immune function were enriched in immune-challenged haemolymph, e.g. Vitellogenins, NPC2-like proteins and Hemocytin. As known from previous studies, septic wounding also leads to the upregulation of genes involved in stress responses. In the haemolymph, proteins implicated in protein stabilisation and in the protection against oxidative stress and insecticides were enriched upon immune challenge. In order to identify additional putative immune effectors, haemolymph peptide samples from immune-challenged larvae and adults were analysed. The analysis in this work focussed on the identification of putative peptides produced via the secretory pathway as previously described for neuropeptides of C. floridanus. 567 regulated peptides derived from 39 proteins were identified in the larval haemolymph, whereas 342 regulated peptides derived from 13 proteins were found in the adult haemolymph. Most of the peptides are derived from hymenoptaecin or from putative uncharacterised proteins. One haemolymph peptide of immune-challenged larvae comprises the complete amino acid sequence of a predicted peptide derived from a Vitellogenin. Though the identified peptide lacks similarities to any known immune-related peptide, it is a suitable candidate for further functional analysis. To establish a stable infection with the endosymbionts, the bacteria have to be transmitted to the next generation of the ants. The vertical transmission of B. floridanus is guaranteed by bacterial infestation of oocytes. This work presents the first comprehensive and detailed description of the localisation of the bacterial endosymbionts in C. floridanus ovaries during oogenesis. Whereas the most apical part of the germarium, which contains the germ-line stem cells, is not infected by the bacteria, small somatic cells in the outer layers of each ovariole were found to be infected in the lower germarium. Only with the beginning of cystocyte differentiation, endosymbionts are exclusively transported from follicle cells into the growing oocytes, while nurse cells were never infected with B. floridanus. This infestation of the oocytes by bacteria very likely involves exocytosis-endocytosis processes between follicle cells and the oocytes. A previous study suggested a down-modulation of the immune response in the midgut tissue which may promote endosymbiont tolerance. Therefore, the expression of several potentially relevant immune genes was analysed in the ovarial tissue by qRT-PCR. The relatively low expression of genes involved in Toll and IMD signalling, and the high expression of genes encoding negative immune regulators, such as PGRP-LB, PGRP-SC2, and tollip, strongly suggest that a down-modulation of the immune response may also facilitate endosymbiont tolerance in the ovaries and thereby contribute to their vertical transmission. Overall, the present thesis improves the knowledge about the immune repertoire of C. floridanus and provides new candidates for further functional analyses. Moreover, the involvement of the host immune system in maintaining a "chronic" infection with symbiotic bacteria was confirmed and extended to the ovaries.}, subject = {Camponotus floridanus}, language = {en} } @phdthesis{Wanzek2016, author = {Wanzek, Katharina}, title = {The investigation of the function of repair proteins at G-quadruplex structures in \(Saccharomyces\) \(cerevisiae\) revealed that Mms1 promotes genome stability}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142547}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {G-quadruplex structures are highly stable alternative DNA structures that can, when not properly regulated, impede replication fork progression and cause genome instability (Castillo Bosch et al, 2014; Crabbe et al, 2004; Koole et al, 2014; Kruisselbrink et al, 2008; London et al, 2008; Lopes et al, 2011; Paeschke et al, 2013; Paeschke et al, 2011; Piazza et al, 2015; Piazza et al, 2010; Piazza et al, 2012; Ribeyre et al, 2009; Sabouri et al, 2014; Sarkies et al, 2012; Sarkies et al, 2010; Schiavone et al, 2014; Wu \& Spies, 2016; Zimmer et al, 2016). The aim of this thesis was to identify novel G-quadruplex interacting proteins in Saccharomyces cerevisiae and to unravel their regulatory function at these structures to maintain genome integrity. Mms1 and Rtt101 were identified as G-quadruplex binding proteins in vitro via a pull-down experiment with subsequent mass spectrometry analysis. Rtt101, Mms1 and Mms22, which are all components of an ubiquitin ligase (Rtt101Mms1/Mms22), are important for the progression of the replication fork following fork stalling (Luke et al, 2006; Vaisica et al, 2011; Zaidi et al, 2008). The in vivo binding of endogenously tagged Mms1 to its target regions was analyzed genome-wide using chromatin-immunoprecipitation followed by deep-sequencing. Interestingly, Mms1 bound independently of Mms22 and Rtt101 to G-rich regions that have the potential to form G-quadruplex structures. In vitro, formation of G-quadruplex structures could be shown for the G-rich regions Mms1 bound to. This binding was observed throughout the cell cycle. Furthermore, the deletion of MMS1 caused replication fork stalling as evidenced by increased association of DNA Polymerase 2 at Mms1 dependent sites. A gross chromosomal rearrangement assay revealed that deletion of MMS1 results in a significantly increased genome instability at G-quadruplex motifs compared to G-rich or non-G-rich regions. Additionally, binding of the helicase Pif1, which unwinds G4 structures in vitro (Paeschke et al, 2013; Ribeyre et al, 2009; Sanders, 2010; Wallgren et al, 2016), to Mms1 binding sites was reduced in mms1 cells. The data presented in this thesis, together with published data, suggests a novel mechanistic model in which Mms1 binds to G-quadruplex structures and enables Pif1 association. This allows for replication fork progression and genome integrity.}, subject = {Quadruplex-DNS}, language = {en} } @phdthesis{Maurus2016, author = {Maurus, Katja}, title = {Melanoma Maintenance by the AP1 Transcription Factor FOSL1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142995}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Identifying novel driver genes in cancer remains a crucial step towards development of new therapeutic approaches and the basic understanding of the disease. This work describes the impact of the AP1 transcription activator component FOSL1 on melanoma maintenance. FOSL1 is strongly upregulated during the progression of melanoma and the protein abundance is highest in metastases. I found that the regulation of FOSL1 is strongly dependent on ERK1/2- and PI3K- signaling, two pathways frequently activated in melanoma. Moreover, the involvement of p53 in FOSL1 regulation in melanoma was investigated. Elevated levels of the tumor suppressor led to decreased FOSL1 protein levels in a miR34a/miR34c- dependent manner. The benefit of elevated FOSL1 amounts in human melanoma cell lines was analyzed by overexpression of FOSL1 in cell lines with low endogenous FOSL1 levels. Enhanced levels of FOSL1 had several pro-tumorigenic effects in human melanoma cell lines. Besides increased proliferation and migration rates, FOSL1 overexpression induced the colony forming ability of the cells. Additionally, FOSL1 was necessary for anchorage independent growth in 3D cell cultures. Microarray analyses revealed novel downstream effectors of FOSL1. On the one hand, FOSL1 was able to induce the transcription of different neuron-related genes, such as NEFL, NRP1 and TUBB3. On the other hand, FOSL1 influenced the transcription of DCT, a melanocyte specific gene, in dependence of the differentiation of the melanoma cell line, indicating dedifferentiation. Furthermore, FOSL1 induced the transcription of HMGA1, a chromatin remodeling protein with reprogramming ability, which is characteristic for stem cells. Consequently, the influence of HMGA1 on melanoma maintenance was investigated. In addition to decreased proliferation and reduced anoikis resistance, HMGA1 knockdown reduced melanoma cell survival. Interestingly, the FOSL1 induced pro-tumorigenic effects were demonstrated to be dependent on the HMGA1 level. HMGA1 manipulation reversed FOSL1 induced proliferation and colony forming ability, as well as the anchorage independent growth effect. In conclusion, I could show that additional FOSL1 confers a clear growth benefit to melanoma cells. This benefit is attributed to the induction of stem cell determinants, but can be blocked by the inhibition of the ERK1/2 or PI3K signaling pathways.}, subject = {Melanom}, language = {en} } @phdthesis{Erle2016, author = {Erle, Thorsten Michael}, title = {A Grounded Approach to Psychological Perspective-Taking}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143247}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {„Perspektiven{\"u}bernahme" bezeichnet die F{\"a}higkeit des Menschen, sich in die Lage eines anderen hineinzuversetzen. In der psychologischen Forschung unterscheidet man drei Arten der Perspektiven{\"u}bernahme, n{\"a}mlich perzeptuelle (visuo-spatiale), affektive (Empathie) und kognitive (Theory of Mind). Die letztgenannten Arten der Perspektiven{\"u}bernahme werden oft als „psychologische Perspektiven{\"u}bernahme" zusammengefasst. Diese Dissertation befasst sich mit der Frage, ob diese verschiedenen Arten der Perspektiven{\"u}bernahme als theoretisch unterscheidbare Konstrukte oder lediglich als Facetten ein und desselben Konstrukts angesehen werden sollten. Die Befundlage in der psychologischen Fachliteratur ist diesbez{\"u}glich nicht eindeutig. W{\"a}hrend einige Autoren Korrelationen zwischen verschiedenen Arten der Perspektiven{\"u}bernahme f{\"u}r zu gering erachten, um ein einheitliches Konstrukt zu konstatieren, bewerten andere Autoren Korrelationen derselben Gr{\"o}ße als Evidenz hierf{\"u}r. Ein weniger arbitr{\"a}res Vorgehen w{\"a}re es, experimentalpsychologisch zugrunde liegende Mechanismen zu identifizieren, die allen Arten der Perspektiven{\"u}bernahme gemein sind, und zu untersuchen, ob eine Manipulation dieser Mechanismen abh{\"a}ngige Maße affektiver, kognitiver und perzeptueller Perspektiven{\"u}bernahme gleichermaßen beeinflusst. Diesem Ansatz folgend macht die vorliegende Arbeit die Annahme, dass die mentale Selbstrotation des K{\"o}rperschemas in die Position einer anderen Person, der zentrale Mechanismus visuo-spatialer Perspektiven{\"u}bernahme, ein gemeinsamer Mechanismus aller Arten der Perspektiven{\"u}bernahme ist. Entgegen fr{\"u}herer Ans{\"a}tze wird diese Einheit somit nicht nur {\"u}ber die zentrale gemeinsame Funktionalit{\"a}t aller Arten von Perspektiven{\"u}bernahme, also dem Verlassen des egozentrischen Referenzrahmens zugunsten einer (visuellen, affektiven oder kognitiven) Fremdperspektive, gerechtfertigt, sondern mit der Annahme eines gemeinsamen zugrundeliegenden Mechanismus. Daraus wird die einfache Hypothese abgeleitet, dass visuo-spatiale Perspektiven{\"u}bernahme zu psychologischen Konsequenzen f{\"u}hren kann. Dies wurde in 6 Experimenten getestet. In diesen Experimenten mussten die Probanden zun{\"a}chst immer die visuelle Perspektive einer anderen Person einnehmen. Hierzu sahen die Probanden eine Person, die mit zwei Objekten an einem Tisch sitzt. In jedem Durchgang mussten die Probanden sich entscheiden, mit welcher Hand diese Person eines der beiden Objekte greifen w{\"u}rde. Dabei wurde die Position der Zielperson so manipuliert, dass sie in der H{\"a}lfte der F{\"a}lle im selben visuo-spatialen Referenzrahmen wie der Proband saß, was Perspektiven{\"u}bernahme zur L{\"o}sung der Aufgabe obsolet machte, w{\"a}hrend sie sich in den verbleibenden Durchg{\"a}ngen in einem anderen visuo-spatialen Referenzrahmen befand, so dass die Probanden die visuelle Perspektive der Zielperson {\"u}bernehmen mussten um die Aufgabe korrekt zu l{\"o}sen. Nach jedem Durchgang wurde dem Ziel dieser visuo-spatialen Aufgabe eine psychologische Eigenschaft zugeschrieben. Dies geschah im Rahmen eines abgewandelten Paradigmas zur Untersuchung der Ankerheuristik. Hierzu wurde den Probanden nach jedem Durchgang der visuo-spatialen Aufgabe eine Sch{\"a}tzfrage gestellt. Zeitgleich wurde die Antwort des Ziels bekannt gegeben. Entsprechend der Haupthypothese, dass visuo-spatiale Perspektiven{\"u}bernahme psychologische Konsequenzen erzeugen kann, konnte gezeigt werden, dass die Probanden nach visuo-spatialer Perspektiven{\"u}bernahme in h{\"o}herem Maße die Gedanken der Zielperson {\"u}bernahmen. Dies konnte sowohl anhand der absoluten Gr{\"o}ße des Ankereffekts, als auch anhand der Differenz zwischen den Urteilen der Probanden und der Zielperson, gezeigt werden. Weitere Experimente schlossen Stichprobeneigenschaften, die verwendeten Stimuli oder die Aufgabenschwierigkeit als Alternativerkl{\"a}rungen f{\"u}r diese Effekte aus. Die beiden letzten Experimente zeigten zudem, dass dieser Effekt spezifisch f{\"u}r alle Konstellationen ist, in denen eine mentale Selbstrotation in die Zielperspektive notwendig war und dass die {\"U}bernahme fremder Gedanken mit einem Gef{\"u}hl von {\"A}hnlichkeit assoziiert war. Zusammengenommen unterst{\"u}tzen die Ergebnisse dieser Arbeit die theoretisch abgeleitete Sicht eines einheitlichen Perspektiven{\"u}bernahme-Konstrukts und grenzen dieses zus{\"a}tzlich von verwandten Konstrukten ab. In der abschließenden Diskussion werden die Bedeutung dieser Befunde f{\"u}r die Forschung in den Bereichen Empathie, Theory of Mind, und Perspektiven{\"u}bernahme und ebenfalls praktische Implikationen der Ergebnisse aufgezeigt.}, subject = {Perspektiven{\"u}bernahme}, language = {en} } @phdthesis{Backhaus2016, author = {Backhaus, Philipp}, title = {Effects of Transgenic Expression of Botulinum Toxins in Drosophila}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143279}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Clostridial neurotoxins (botulinum toxins and tetanus toxin) disrupt neurotransmitter release by cleaving neuronal SNARE proteins. We generated transgenic flies allowing for conditional expression of different botulinum toxins and evaluated their potential as tools for the analysis of synaptic and neuronal network function in Drosophila melanogaster by applying biochemical assays and behavioral analysis. On the biochemical level, cleavage assays in cultured Drosophila S2 cells were performed and the cleavage efficiency was assessed via western blot analysis. We found that each botulinum toxin cleaves its Drosophila SNARE substrate but with variable efficiency. To investigate the cleavage efficiency in vivo, we examined lethality, larval peristaltic movements and vision dependent motion behavior of adult Drosophila after tissue-specific conditional botulinum toxin expression. Our results show that botulinum toxin type B and botulinum toxin type C represent effective alternatives to established transgenic effectors, i.e. tetanus toxin, interfering with neuronal and non-neuronal cell function in Drosophila and constitute valuable tools for the analysis of synaptic and network function.}, subject = {Botulinustoxin}, language = {en} } @phdthesis{Rodrigues2016, author = {Rodrigues, Johannes}, title = {Let me change your mind… Frontal brain activity in a virtual T-maze}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143280}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Frontal asymmetry, a construct invented by Richard Davidson, linking positive and negative valence as well as approach and withdrawal motivation to lateralized frontal brain activation has been investigated for over thirty years. The frontal activation patterns described as relevant were measured via alpha-band frequency activity (8-13 Hz) as a measurement of deactivation in electroencephalography (EEG) for homologous electrode pairs, especially for the electrode position F4/ F3 to account for the frontal relative lateralized brain activation. Three different theories about frontal activation patterns linked to motivational states were investigated in two studies. The valence theory of Davidson (1984; 1998a; 1998b) and its extension to the motivational direction theory by Harmon-Jones and Allen (1998) refers to the approach motivation with relative left frontal brain activity (indicated by relative right frontal alpha activity) and to withdrawal motivation with relative right frontal brain activation (indicated by relative left frontal alpha activity). The second theory proposed by Hewig and colleagues (2004; 2005; 2006) integrates the findings of Davidson and Harmon - Jones and Allen with the reinforcement sensitivity theory of Jeffrey A. Gray (1982, 1991). Hewig sees the lateralized frontal approach system and withdrawal system proposed by Davidson as subsystems of the behavioral activation system proposed by Gray and bilateral frontal activation as a biological marker for the behavioral activation system. The third theory investigated in the present studies is the theory from Wacker and colleagues (2003; 2008; 2010) where the frontal asymmetrical brain activation patterns are linked to the revised reinforcement sensitivity theory of Gray and McNaughton (2000). Here, right frontal brain activity (indicated by lower relative right frontal alpha activity) accounts for conflict, behavioral inhibition and activity of the revised behavioral inhibition system, while left frontal brain activation (indicated by lower relative left frontal alpha activity) stands for active behavior and the activity of the revised behavioral activation system as well as the activation of the revised flight fight freezing system. In order to investigate these three theories, a virtual reality T-maze paradigm was introduced to evoke motivational states in the participants, offering the opportunity to measure frontal brain activation patterns via EEG and behavior simultaneously in the first study. In the second study the virtual reality paradigm was additionally compared to mental imagery and a movie paradigm, two well-known state inducing paradigms in the research field of frontal asymmetry. In the two studies, there was confirming evidence for the theory of Hewig and colleages (2004; 2005; 2006), showing higher bilateral frontal activation for active behavior and lateralized frontal activation patterns for approach (left frontal brain activation) and avoidance (right frontal brain activation) behavior. Additionally a limitation for the capability model of anterior brain asymmetry proposed by Coan and colleagues (2006), where the frontal asymmetry should be dependent on the relevant traits driving the frontal asymmetry pattern if a relevant situation occurs, could be found. As the very intense virtual reality paradigm did not lead to a difference of frontal brain activation patterns compared to the mental imagery paradigm or the movie paradigm for the traits of the participants, the trait dependency of the frontal asymmetry in a relevant situation might not be given, if the intensity of the situation exceeds a certain level. Nevertheless there was an influence of the traits in the virtual reality T-maze paradigm, because the shown behavior in the maze was trait-dependent. The implications of the findings are multifarious, leading from possible objective personality testing via diversification of the virtual reality paradigm to even clinical implications for depression treatments based on changes in the lateralized frontal brain activation patterns for changes in the motivational aspects, but also for changes in bilateral frontal brain activation when it comes to the drive and preparedness for action in patients. Finally, with the limitation of the capability model, additional variance in the different findings about frontal asymmetry can be explained by taking the intensity of a state manipulation into account.}, subject = {Electroencephalographie}, language = {en} } @phdthesis{Pieczykolan2016, author = {Pieczykolan, Aleksandra}, title = {Cross-Modal Action Control}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142356}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Multitasking als allgegenw{\"a}rtiges Ph{\"a}nomen wird heutzutage in verschiedenen wissenschaftlichen Disziplinen diskutiert. In der vorliegenden Arbeit wird Multitasking aus der Perspektive der kognitiven Verhaltenswissenschaften beleuchtet mit dem Fokus auf der Rolle von Konfliktl{\"o}sungs- prozessen bei der Verarbeitung von Mehrfacht{\"a}tigkeiten. Insbesondere liegt der Fokus auf kognitiven Mechanismen der crossmodalen Handlungskontrolle, d.h. der Kontrolle von zwei Handlungen in verschiedenen Effektorsystemen. Mit dem Ziel, den bisherigen Umfang derjenigen Handlungsmodalit{\"a}ten zu erweitern, die {\"u}blicherweise in Studien eingesetzt wurden, wurden okulomotorische Reaktionen (d.h. Sakkaden), die bisher als Handlungsmodalit{\"a}t in der Forschung vernachl{\"a}ssigt wurden, in Kombination mit Reaktionen in anderen Efffektorsystemen untersucht (d.h. mit manuellen und vokalen Reaktionen). Weiterhin wurde beabsichtigt, Mechanismen von Crosstalk zu spezifizieren, welches ein Erkl{\"a}rungskonzept darstellt, das sich auf den Aufgabeninhalt bezieht. Crosstalk erscheint besonders relevant f{\"u}r crossmodale Handlungen, da sich Handlungsmodalit{\"a}ten vor allem bez{\"u}glich ihrer Reaktionsmerkmale unterscheiden. In der vorliegenden Arbeit werden vier Studien berichtet, die auf jeweils zwei oder drei Experimenten beruhen. In Studie A wurden crossmodale Doppelreaktionen auf einen einzelnen Stimulus untersucht mit der Fragestellung, wie sich das Zusammenspiel des Vorhandenseins von Reaktionsalternativen und der Kompatibilit{\"a}t zwischen Reaktionen (also dem Crosstalkpotential) auswirkt. In drei Experimenten zeigte sich, dass Crosstalk in mehrere Komponenten dissoziiert werden kann, n{\"a}mlich eine Komponente, die auf der aktuellen Konfliktst{\"a}rke (Online-Crosstalk) basiert, und eine ged{\"a}chtnisbasierte Komponente, die entweder durch Restaktivit{\"a}t vergangener Handlungsanforderungen bestimmt wird (retrospektiver Crosstalk), oder durch Vorbereitung auf zuk{\"u}nftige Handlungsanforderungen (prospektiver Crosstalk). Studie B lieferte Evidenz daf{\"u}r, dass okulomotorische Reaktionen sowohl struktureller als auch inhaltsbasierte Interferenz unterliegen. In drei Experimenten wurde das Paradigma zeitlich {\"u}berlappender Aufgaben verwendet, bei dem zwei Stimuli mit zeitlichem Versatz pr{\"a}sentiert wurden, auf die jeweils mit einer okulomotorischen und einer manuellen Handlung reagiert werden musste. Dabei wurden sowohl Hinweise auf einen seriellen als auch auf einen parallelen Verarbeitungsmodus gefunden. Weiterhin deuteten die Ergebnisse darauf hin, dass abh{\"a}ngig von der Aufgabenkompatibilit{\"a}t zwischen diesen Verarbeitungsmodi gewechselt wurde, d.h. zu eher paralleler Verarbeitung bei kompatiblen Aufgabenanforderungen und zu eher serieller Verarbeitung bei inkompatiblen Aufgabenanforderungen. In Studie C wurden Verarbeitungspriorit{\"a}ten zwischen Effektorsystemen untersucht. In zwei Experimenten zeigte sich, dass das zuvor berichtete Verarbeitungsdominanzmuster repliziert werden konnte, bei der okulomotorische Reaktionen vokale Reaktionen dominieren und diese wiederum manuelle Reaktionen dominieren. Die relative St{\"a}rke der Dominanz konnte allerdings bei vorhandenem Reaktionskonflikt angepasst werden. Die Verarbeitungspriorit{\"a}ten wurden hierbei zum Teil in Richtung derjenigen Reaktion verschoben, in der bereits ein Konflikt im Bezug auf die Kompatibilit{\"a}t zwischen Stimulus und Reaktion gel{\"o}st werden musste. Dieses Ergebnis zeigt, dass Verarbeitungspriorit{\"a}ten flexibel an die spezifischen Handlungsanforderungen angepasst werden k{\"o}nnen. Studie D besch{\"a}ftigte sich mit einem bisher weitgehend vernachl{\"a}ssigten Bereich innerhalb der Doppelaufgabenforschung, n{\"a}mlich der Kontrolle der zeitlichen Reaktionsreihenfolge. In einer drei Experimente umfassenden Untersuchung wurden mehrere Faktoren variiert, die sich in fr{\"u}heren Studien bereits als relevant f{\"u}r Mechanismen der Doppelaufgabeninterferenz gezeigt haben. In der vorliegenden Studie wurde gezeigt, dass die finale Reaktionsreihenfolge in einem Handlungsdurchgang das Ergebnis eines kontinuierlichen Anpassungsprozesses ist, welcher auf dem Zusammenspiel mehrerer top-down-Faktoren, z.B. der Antizipation von Reaktionsmerkmalen, und mehrerer bottom-up-Faktoren, wie z.B. der Stimulusreihenfolge oder der Aufgabenkompatibilit{\"a}t, basiert. Die vorliegende Arbeit liefert somit einen wichtigen Beitrag zum Fortschritt des Verst{\"a}ndnisses der Verarbeitung komplexer Handlungsanforderungen aus der Perspektive crossmodaler Handlungen. Insbesondere wurden Spezifikationen f{\"u}r Mechanismen der Effektorpriorisierung und der Kontrolle der Reaktionsreihenfolge als auch eine neuartige Taxonomie von Crosstalk vorgestellt, welche als umfassende Rahmenvorstellung zur Erkl{\"a}rung von Interferenzmechanismen bei Kontrollprozessen von Mehrfachanforderungen dienlich sein kann.}, subject = {Kognition}, language = {en} } @phdthesis{Schweinlin2016, author = {Schweinlin, Matthias Oliver}, title = {Development of advanced human intestinal in vitro models}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142571}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {The main function of the small intestine is the absorption of essential nutrients, water and vitamins. Moreover, it constitutes a barrier protecting us from toxic xenobiotics and pathogens. For a better understanding of these processes, the development of intestinal in vitro models is of great interest to the study of pharmacological and pathological issues such as transport mechanisms and barrier function. Depending on the scientific questions, models of different complexity can be applied. In vitro Transwell® systems based on a porous PET-membrane enable the standardized study of transport mechanisms across the intestinal barrier as well as the investigation of the influence of target substances on barrier integrity. However, this artificial setup reflects only limited aspects of the physiology of the native small intestine and can pose an additional physical barrier. Hence, the applications of this model for tissue engineering are limited. Previously, tissue models based on a biological decellularized scaffold derived from porcine gut tissue were demonstrated to be a good alternative to the commonly used Transwell® system. This study showed that preserved biological extracellular matrix components like collagen and elastin provide a natural environment for the epithelial cells, promoting cell adhesion and growth. Intestinal epithelial cells such as Caco-2 cultured on such a scaffold showed a confluent, tight monolayer on the apical surface. Additionally, myofibroblasts were able to migrate into the scaffold supporting intestinal barrier formation. In this thesis, dendritic cells were additionally introduced to this model mimicking an important component of the immune system. This co-culture model was then successfully proven to be suitable for the screening of particle formulations developed as delivery system for cancer antigens in peroral vaccination studies. In particular, nanoparticles based on PLGA, PEG-PAGE-PLGA, Mannose-PEG-PAGE-PLGA and Chitosan were tested. Uptake studies revealed only slight differences in the transcellular transport rate among the different particles. Dendritic cells were shown to phagocytose the particles after they have passed the intestinal barrier. The particles demonstrated to be an effective carrier system to transport peptides across the intestinal barrier and therefore present a useful tool for the development of novel drugs. Furthermore, to mimic the complex structure and physiology of the gut including the presence of multiple different cell types, the Caco-2 cell line was replaced by primary intestinal cells to set up a de novo tissue model. To that end, intestinal crypts including undifferentiated stem cells and progenitor cells were isolated from human small intestinal tissue samples (jejunum) and expanded in vitro in organoid cultures. Cells were cultured on the decellularized porcine gut matrix in co-culture with intestinal myofibroblasts. These novel tissue models were maintained under either static or dynamic conditions. Primary intestinal epithelial cells formed a confluent monolayer including the major differentiated cell types positive for mucin (goblet cells), villin (enterocytes), chromogranin A (enteroendocrine cells) and lysozyme (paneth cells). Electron microscopy images depicted essential functional units of an intact epithelium, such as microvilli and tight junctions. FITC-dextran permeability and TEER measurements were used to assess tightness of the cell layer. Models showed characteristic transport activity for several reference substances. Mechanical stimulation of the cells by a dynamic culture system had a great impact on barrier integrity and transporter activity resulting in a tighter barrier and a higher efflux transporter activity. In Summary, the use of primary human intestinal cells combined with a biological decellularized scaffold offers a new and promising way to setup more physiological intestinal in vitro models. Maintenance of primary intestinal stem cells with their proliferation and differentiation potential together with adjusted culture protocols might help further improve the models. In particular, dynamic culture systems and co culture models proofed to be a first crucial steps towards a more physiological model. Such tissue models might be useful to improve the predictive power of in vitro models and in vitro in vivo correlation (IVIVC) studies. Moreover, these tissue models will be useful tools in preclinical studies to test pharmaceutical substances, probiotic active organisms, human pathogenic germs and could even be used to build up patient-specific tissue model for personalized medicine.}, subject = {Tissue Engineering}, language = {en} } @phdthesis{Karl2016, author = {Karl, Stefan}, title = {Control Centrality in Non-Linear Biological Networks}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150838}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Biological systems such as cells or whole organisms are governed by complex regulatory networks of transcription factors, hormones and other regulators which determine the behavior of the system depending on internal and external stimuli. In mathematical models of these networks, genes are represented by interacting "nodes" whose "value" represents the activity of the gene. Control processes in these regulatory networks are challenging to elucidate and quantify. Previous control centrality metrics, which aim to mathematically capture the ability of individual nodes to control biological systems, have been found to suffer from problems regarding biological plausibility. This thesis presents a new approach to control centrality in biological networks. Three types of network control are distinguished: Total control centrality quantifies the impact of gene mutations and identifies potential pharmacological targets such as genes involved in oncogenesis (e.g. zinc finger protein GLI2 or bone morphogenetic proteins in chondrocytes). Dynamic control centrality describes relaying functions as observed in signaling cascades (e.g control in mouse colon stem cells). Value control centrality measures the direct influence of the value of the node on the network (e.g. Indian hedgehog as an essential regulator of proliferation in chondrocytes). Well-defined network manipulations define all three centralities not only for nodes, but also for the interactions between them, enabling detailed insights into network pathways. The calculation of the new metrics is made possible by substantial computational improvements in the simulation algorithms for several widely used mathematical modeling paradigms for genetic regulatory networks, which are implemented in the regulatory network simulation framework Jimena created for this thesis. Applying the new metrics to biological networks and artificial random networks shows how these mathematical concepts correspond to experimentally verified gene functions and signaling pathways in immunity and cell differentiation. In contrast to controversial previous results even from the Barab{\´a}si group, all results indicate that the ability to control biological networks resides in only few driver nodes characterized by a high number of connections to the rest of the network. Autoregulatory loops strongly increase the controllability of the network, i.e. its ability to control itself, and biological networks are characterized by high controllability in conjunction with high robustness against mutations, a combination that can be achieved best in sparsely connected networks with densities (i.e. connections to nodes ratios) around 2.0 - 3.0. The new concepts are thus considerably narrowing the gap between network science and biology and can be used in various areas such as system modeling, plausibility trials and system analyses. Medical applications discussed in this thesis include the search for oncogenes and pharmacological targets, as well their functional characterization.}, subject = {Bioinformatik}, language = {en} } @phdthesis{Muenchow2016, author = {M{\"u}nchow, Hannes}, title = {I feel, therefore I learn - Effectiveness of affect induction interventions and possible covariates on learning outcomes}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148432}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Affective states in the context of learning and achievement can influence the learning process essentially. The impact of affective states can be both directly on the learning performance and indirectly mediated via, for example, motivational processes. Positive activating affect is often associated with increased memory skills as well as advantages in creative problem solving. Negative activating affect on the other hand is regarded to impair learning outcomes because of promoting task-irrelevant thinking. While these relationships were found to be relatively stable in correlation studies, causal relationships have been examined rarely so far. This dissertation aims to investigate the effects of positive and negative affective states in multimedia learning settings and to identify potential moderating factors. Therefore, three experimental empirical studies on university students were conducted. In Experiment 1, N = 57 university students were randomly allocated to either a positive or negative affect induction group. Affects were elicited using short film clips. After a 20-minute learning phase in a hypertext-based multimedia learning environment on "functional neuroanatomy" the learners' knowledge as well as transfer performance were measured. It was assumed that inducing positive activating affect should enhance learning performance. Eliciting negative activating affect on the other hand should impair learning performance. However, it was found that the induction of negative activating affect prior to the learning phase resulted in slight deteriorations in knowledge. Contrary to the assumptions, inducing positive activating affect before the learning phase did not improve learning performance. Experiment 2 induced positive activating affect directly during learning. To induce affective states during the entire duration of the learning phase, Experiment 2 used an emotional design paradigm. Therefore, N = 111 university students were randomly assigned to learn either in an affect inducing multimedia learning environment (use of warm colours and round shapes) or an affectively neutral counterpart (using shades of grey and angular shapes) on the same topic as in Experiment 1. Again, knowledge as well as transfer performance were measured after learning for 20 minutes. In addition, positive and negative affective states were measured before and after learning. Complex interaction patterns between the treatment and initial affective states were found. Specifically, learners with high levels of positive affect before learning showed better transfer performance when they learned in the affect inducing learning environment. Regarding knowledge, those participants who reported high levels of negative activating affect prior to the learning period performed worse. However, the effect on knowledge did not occur for those students learning in the affect inducing learning environment. For knowledge, the treatment therefore protected against poorer performance due to high levels of negative affective states. Results of Experiment 2 showed that the induction of positive activating affect influenced learning performance positively when taking into account affective states prior to the learning phase. In order to confirm these interaction effects, a conceptual replication of the previous experiment was conducted in Experiment 3. Experiment 3 largely retained the former study design, but changed the learning materials and tests used. Analogous to Experiment 2, N = 145 university students learning for 20 minutes in either an affect inducing or an affectively neutral multimedia learning environment on "eukaryotic cell". To strengthen the treatment, Experiment 3 also used anthropomorphic design elements to induce affective states next to warm colours and round shapes. Moreover, in order to assess the change in affective states more exactly, an additional measurement of positive and negative affective states after half of the learning time was inserted. Knowledge and transfer were assessed again to measure learning performance. The learners' memory skills were used as an additional learning outcome. To control the influence of potential confounding variables, the participants' general and current achievement motivation as well as interest, and emotion regulation skills were measured. Contrary to the assumptions, Experiment 3 could not confirm the interaction effects of Experiment 2. Instead, there was a significant impact of positive activating affect prior to the learning phase on transfer, irrespective of the learners' group affiliation. This effect was further independent of the control variables that were measured. Nevertheless, the results of Experiment 3 fit into the picture of findings regarding "emotional design" in hypermedia learning settings. To date, the few publications that have used this approach propose heterogeneous results, even when using identical materials and procedures.}, subject = {Affekt}, language = {en} } @article{ZhuShabalaCuinetal.2016, author = {Zhu, Min and Shabala, Lana and Cuin, Tracey A and Huang, Xin and Zhou, Meixue and Munns, Rana and Shabala, Sergey}, title = {Nax loci affect SOS1-like Na\(^{+}\)/H\(^{+}\) exchanger expression and activity in wheat}, series = {Journal of Experimental Botany}, volume = {67}, journal = {Journal of Experimental Botany}, number = {3}, doi = {10.1093/jxb/erv493}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150236}, pages = {835-844}, year = {2016}, abstract = {Salinity stress tolerance in durum wheat is strongly associated with a plant's ability to control Na\(^{+}\) delivery to the shoot. Two loci, termed Nax1 and Nax2, were recently identified as being critical for this process and the sodium transporters HKT1;4 and HKT1;5 were identified as the respective candidate genes. These transporters retrieve Na\(^{+}\) from the xylem, thus limiting the rates of Na\(^{+}\) transport from the root to the shoot. In this work, we show that the Nax loci also affect activity and expression levels of the SOS1-like Na\(^{+}\)/H\(^{+}\) exchanger in both root cortical and stelar tissues. Net Na\(^{+}\) efflux measured in isolated steles from salt-treated plants, using the non-invasive ion flux measuring MIFE technique, decreased in the sequence: Tamaroi (parental line)>Nax1=Nax2>Nax1:Nax2 lines. This efflux was sensitive to amiloride (a known inhibitor of the Na\(^{+}\)/H\(^{+}\) exchanger) and was mirrored by net H\(^{+}\) flux changes. TdSOS1 relative transcript levels were 6-10-fold lower in Nax lines compared with Tamaroi. Thus, it appears that Nax loci confer two highly complementary mechanisms, both of which contribute towards reducing the xylem Na\(^{+}\) content. One enhances the retrieval of Na\(^{+}\) back into the root stele via HKT1;4 or HKT1;5, whilst the other reduces the rate of Na\(^{+}\) loading into the xylem via SOS1. It is suggested that such duality plays an important adaptive role with greater versatility for responding to a changing environment and controlling Na\(^{+}\) delivery to the shoot.}, language = {en} } @article{NeuderthSchwarzGerlichetal.2016, author = {Neuderth, Silke and Schwarz, Betje and Gerlich, Christian and Schuler, Michael and Markus, Miriam and Bethge, Matthias}, title = {Work-related medical rehabilitation in patients with musculoskeletal disorders: the protocol of a propensity score matched effectiveness study (EVA-WMR, DRKS00009780)}, series = {BMC Public Health}, volume = {16}, journal = {BMC Public Health}, number = {804}, doi = {10.1186/s12889-016-3437-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150015}, year = {2016}, abstract = {Background Musculoskeletal disorders are one of the most important causes of work disability. Various rehabilitation services and return-to-work programs have been developed in order to reduce sickness absence and increase sustainable return-to-work. As the effects of conventional medical rehabilitation programs on sickness absence duration were shown to be slight, work-related medical rehabilitation programs have been developed and tested. While such studies proved the efficacy of work-related medical rehabilitation compared with conventional medical rehabilitation in well-conducted randomized controlled trials, its effectiveness under real-life conditions has yet to be proved. Methods/Design The cohort study will be performed under real-life conditions with two parallel groups. Participants will receive either a conventional or a work-related medical rehabilitation program. Propensity score matching will be used to identify controls that are comparable to treated work-related medical rehabilitation patients. Over a period of three months, about 18,000 insured patients with permission to undergo a musculoskeletal rehabilitation program will be contacted. Of these, 15,000 will receive a conventional and 3,000 a work-related medical rehabilitation. We expect a participation rate of 40 \% at baseline. Patients will be aged 18 to 65 years and have chronic musculoskeletal disorders, usually back pain. The control group will receive a conventional medical rehabilitation program without any explicit focus on work, work ability and return to work in diagnostics and therapy. The intervention group will receive a work-related medical rehabilitation program that in addition to common rehabilitation treatments contains 11 to 25 h of work-related treatment modules. Follow-up data will be assessed three and ten months after patients' discharge from the rehabilitation center. Additionally, department characteristics will be assessed and administrative data records used. The primary outcomes are sick leave duration, stable return to work and subjective work ability. Secondary outcomes cover several dimensions of health, functioning and coping strategies. Discussion This study will determine the relative effectiveness of a complex, newly implemented work-related rehabilitation strategy for patients with musculoskeletal disorders.}, language = {en} } @phdthesis{Pfeuffer2016, author = {Pfeuffer, Rebekka Christina}, title = {Growth and characterization of II-VI semiconductor nanowires grown by Au catalyst assisted molecular beam epitaxy}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141385}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {In the present PhD thesis the control of the morphology, such as the diameter, the length, the orientation, the density, and the crystalline quality of 1D ZnSe NWs grown by MBE for optical and transport applications has been achieved.}, subject = {Zinkselenid}, language = {en} } @phdthesis{Hennighausen2016, author = {Hennighausen, Anna Christine}, title = {Costly signaling with mobile devices: An evolutionary psychological perspective on smartphones}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141049}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {In the last decade, mobile device ownership has largely increased. In particular, smartphone ownership is constantly rising (A. Smith, 2015; Statista, 2016a), and there is a real hype for luxury brand smartphones (Griffin, 2015). These observations raise the question of which functions smartphones serve in addition to their original purposes of making and receiving calls, searching for information, and organizing. Beyond these obvious functions, studies suggest that smartphones express fashion, lifestyle, and one's economic status (e.g., B{\o}dker et al., 2009; Statista, 2016b; Vanden Abeele, Antheunis, \& Schouten, 2014). Specifically, individuals seem to purchase and use conspicuous luxury brand smartphones to display and enhance status (D. Kim et al., 2014; M{\"u}ller-Lietzkow et al., 2014; Suki, 2013). But how does owning a conspicuous, high-status smartphone contribute to status, and which benefits may these status boosts provide to their owners? From an evolutionary perspective, status carries a lot of advantages, particularly for males; high status grants them priority access to resources and correlates with their mating success (van Vugt \& Tybur, 2016). In this sense, research suggests that men conspicuously display their cell phones to attract mates and to distinguish themselves from rivals (Lycett \& Dunbar, 2000). In a similar vein, evolutionarily informed studies on conspicuous consumption indicate that the purchase and display of conspicuous luxuries (including mobile phones and smartphones) relate to a man's interest in uncommitted sexual relationships and enhance his desirability as a short-term mate (Hennighausen \& Schwab, 2014; Saad, 2013; Sundie et al., 2011). Drawing on these findings, this doctoral dissertation investigated how a man is perceived given that he is an owner of a high-status (vs. nonconspicuous, low-status) smartphone as a romantic partner and male rival. This was done in three experiments. In addition, it was examined how male conspicuous consumption of smartphones interacted with further traits that signal a man's mate quality, namely facial attractiveness (Studies 1 and 2) and social dominance (Study 3). Study 1 revealed that men and women perceived a male owner of a conspicuous smartphone as a less desirable long-term mate and as more inclined toward short-term mating. Study 2 replicated these results and showed that men and women assigned traits that are associated with short-term mating (e.g., low loyalty, interest in flirts, availability of tangible resources) to a male owner of a conspicuous smartphone and perceived him as a stronger male rival and mate poacher, and less as a friend. The results of Study 2 further suggested that specifically more attractive men might benefit from owning a conspicuous smartphone in a short-term mating context and might be hence considered as stronger male rivals. Study 3 partially replicated the findings of Studies 1 and 2 pertaining to the effects of owning a conspicuous smartphone. Study 3 did not show different effects of conspicuous consumption of smartphones on perceptions of a man dependent on the level of his social dominance. To conclude, the findings of this doctoral dissertation suggest that owning a conspicuous, high-status smartphone might not only serve proximate functions (e.g., making and receiving calls, organization) but also ultimate functions, which relate to mating and reproduction. The results indicate that owning a conspicuous smartphone might yield benefits for men in a short-term rather than in a long-term mating context. Furthermore, more attractive men appear to benefit more from owning a conspicuous smartphone than less attractive men. These findings provide further insights into the motivations that underlie men's purchases and displays of conspicuous, high-status smartphones from luxury brands that reach beyond the proximate causes frequently described in media and consumer psychological research. By applying an evolutionary perspective, this doctoral dissertation demonstrates the power and utility of this research paradigm for media psychological research and shows how combining a proximate and ultimate perspective adds to a more profound understanding of smartphone phenomena.}, subject = {Verbraucher}, language = {en} } @phdthesis{Milenkoski2016, author = {Milenkoski, Aleksandar}, title = {Evaluation of Intrusion Detection Systems in Virtualized Environments}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141846}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Virtualization allows the creation of virtual instances of physical devices, such as network and processing units. In a virtualized system, governed by a hypervisor, resources are shared among virtual machines (VMs). Virtualization has been receiving increasing interest as away to reduce costs through server consolidation and to enhance the flexibility of physical infrastructures. Although virtualization provides many benefits, it introduces new security challenges; that is, the introduction of a hypervisor introduces threats since hypervisors expose new attack surfaces. Intrusion detection is a common cyber security mechanism whose task is to detect malicious activities in host and/or network environments. This enables timely reaction in order to stop an on-going attack, or to mitigate the impact of a security breach. The wide adoption of virtualization has resulted in the increasingly common practice of deploying conventional intrusion detection systems (IDSs), for example, hardware IDS appliances or common software-based IDSs, in designated VMs as virtual network functions (VNFs). In addition, the research and industrial communities have developed IDSs specifically designed to operate in virtualized environments (i.e., hypervisorbased IDSs), with components both inside the hypervisor and in a designated VM. The latter are becoming increasingly common with the growing proliferation of virtualized data centers and the adoption of the cloud computing paradigm, for which virtualization is as a key enabling technology. To minimize the risk of security breaches, methods and techniques for evaluating IDSs in an accurate manner are essential. For instance, one may compare different IDSs in terms of their attack detection accuracy in order to identify and deploy the IDS that operates optimally in a given environment, thereby reducing the risks of a security breach. However, methods and techniques for realistic and accurate evaluation of the attack detection accuracy of IDSs in virtualized environments (i.e., IDSs deployed as VNFs or hypervisor-based IDSs) are lacking. That is, workloads that exercise the sensors of an evaluated IDS and contain attacks targeting hypervisors are needed. Attacks targeting hypervisors are of high severity since they may result in, for example, altering the hypervisors's memory and thus enabling the execution of malicious code with hypervisor privileges. In addition, there are no metrics and measurement methodologies for accurately quantifying the attack detection accuracy of IDSs in virtualized environments with elastic resource provisioning (i.e., on-demand allocation or deallocation of virtualized hardware resources to VMs). Modern hypervisors allow for hotplugging virtual CPUs and memory on the designated VM where the intrusion detection engine of hypervisor-based IDSs, as well as of IDSs deployed as VNFs, typically operates. Resource hotplugging may have a significant impact on the attack detection accuracy of an evaluated IDS, which is not taken into account by existing metrics for quantifying IDS attack detection accuracy. This may lead to inaccurate measurements, which, in turn, may result in the deployment of misconfigured or ill-performing IDSs, increasing the risk of security breaches. This thesis presents contributions that span the standard components of any system evaluation scenario: workloads, metrics, and measurement methodologies. The scientific contributions of this thesis are: A comprehensive systematization of the common practices and the state-of-theart on IDS evaluation. This includes: (i) a definition of an IDS evaluation design space allowing to put existing practical and theoretical work into a common context in a systematic manner; (ii) an overview of common practices in IDS evaluation reviewing evaluation approaches and methods related to each part of the design space; (iii) and a set of case studies demonstrating how different IDS evaluation approaches are applied in practice. Given the significant amount of existing practical and theoretical work related to IDS evaluation, the presented systematization is beneficial for improving the general understanding of the topic by providing an overview of the current state of the field. In addition, it is beneficial for identifying and contrasting advantages and disadvantages of different IDS evaluation methods and practices, while also helping to identify specific requirements and best practices for evaluating current and future IDSs. An in-depth analysis of common vulnerabilities of modern hypervisors as well as a set of attack models capturing the activities of attackers triggering these vulnerabilities. The analysis includes 35 representative vulnerabilities of hypercall handlers (i.e., hypercall vulnerabilities). Hypercalls are software traps from a kernel of a VM to the hypervisor. The hypercall interface of hypervisors, among device drivers and VM exit events, is one of the attack surfaces that hypervisors expose. Triggering a hypercall vulnerability may lead to a crash of the hypervisor or to altering the hypervisor's memory. We analyze the origins of the considered hypercall vulnerabilities, demonstrate and analyze possible attacks that trigger them (i.e., hypercall attacks), develop hypercall attack models(i.e., systematized activities of attackers targeting the hypercall interface), and discuss future research directions focusing on approaches for securing hypercall interfaces. A novel approach for evaluating IDSs enabling the generation of workloads that contain attacks targeting hypervisors, that is, hypercall attacks. We propose an approach for evaluating IDSs using attack injection (i.e., controlled execution of attacks during regular operation of the environment where an IDS under test is deployed). The injection of attacks is performed based on attack models that capture realistic attack scenarios. We use the hypercall attack models developed as part of this thesis for injecting hypercall attacks. A novel metric and measurement methodology for quantifying the attack detection accuracy of IDSs in virtualized environments that feature elastic resource provisioning. We demonstrate how the elasticity of resource allocations in such environments may impact the IDS attack detection accuracy and show that using existing metrics in such environments may lead to practically challenging and inaccurate measurements. We also demonstrate the practical use of the metric we propose through a set of case studies, where we evaluate common conventional IDSs deployed as VNFs. In summary, this thesis presents the first systematization of the state-of-the-art on IDS evaluation, considering workloads, metrics and measurement methodologies as integral parts of every IDS evaluation approach. In addition, we are the first to examine the hypercall attack surface of hypervisors in detail and to propose an approach using attack injection for evaluating IDSs in virtualized environments. Finally, this thesis presents the first metric and measurement methodology for quantifying the attack detection accuracy of IDSs in virtualized environments that feature elastic resource provisioning. From a technical perspective, as part of the proposed approach for evaluating IDSsthis thesis presents hInjector, a tool for injecting hypercall attacks. We designed hInjector to enable the rigorous, representative, and practically feasible evaluation of IDSs using attack injection. We demonstrate the application and practical usefulness of hInjector, as well as of the proposed approach, by evaluating a representative hypervisor-based IDS designed to detect hypercall attacks. While we focus on evaluating the capabilities of IDSs to detect hypercall attacks, the proposed IDS evaluation approach can be generalized and applied in a broader context. For example, it may be directly used to also evaluate security mechanisms of hypervisors, such as hypercall access control (AC) mechanisms. It may also be applied to evaluate the capabilities of IDSs to detect attacks involving operations that are functionally similar to hypercalls, for example, the input/output control (ioctl) calls that the Kernel-based Virtual Machine (KVM) hypervisor supports. For IDSs in virtualized environments featuring elastic resource provisioning, our approach for injecting hypercall attacks can be applied in combination with the attack detection accuracy metric and measurement methodology we propose. Our approach for injecting hypercall attacks, and our metric and measurement methodology, can also be applied independently beyond the scenarios considered in this thesis. The wide spectrum of security mechanisms in virtualized environments whose evaluation can directly benefit from the contributions of this thesis (e.g., hypervisor-based IDSs, IDSs deployed as VNFs, and AC mechanisms) reflects the practical implication of the thesis.}, subject = {Eindringerkennung}, language = {en} } @phdthesis{Vaeth2016, author = {V{\"a}th, Stefan Kilian}, title = {On the Role of Spin States in Organic Semiconductor Devices}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141894}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {The present work addressed the influence of spins on fundamental processes in organic semiconductors. In most cases, the role of spins in the conversion of sun light into electricity was of particular interest. However, also the reversed process, an electric current creating luminescence, was investigated by means of spin sensitive measurements. In this work, many material systems were probed with a variety of innovative detection techniques based on electron paramagnetic resonance spectroscopy. More precisely, the observable could be customized which resulted in the experimental techniques photoluminescence detected magnetic resonance (PLDMR), electrically detected magnetic resonance (EDMR), and electroluminescence detected magnetic resonance (ELDMR). Besides the commonly used continuous wave EPR spectroscopy, this selection of measurement methods yielded an access to almost all intermediate steps occurring in organic semiconductors during the conversion of light into electricity and vice versa. Special attention was paid to the fact that all results were applicable to realistic working conditions of the investigated devices, i.e. room temperature application and realistic illumination conditions.}, subject = {Organischer Halbleiter}, language = {en} } @phdthesis{Sivadasan2016, author = {Sivadasan, Rajeeve}, title = {The role of RNA binding proteins in motoneuron diseases}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141907}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Motoneuron diseases form a heterogeneous group of pathologies characterized by the progressive degeneration of motoneurons. More and more genetic factors associated with motoneuron diseases encode proteins that have a function in RNA metabolism, suggesting that disturbed RNA metabolism could be a common underlying problem in several, perhaps all, forms of motoneuron diseases. Recent results suggest that SMN interacts with hnRNP R and TDP-43 in neuronal processes, which are not part of the classical SMN complex. This point to an additional function of SMN, which could contribute to the high vulnerability of spinal motoneurons in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). The current study elucidates functional links between SMN, the causative factor of SMA (spinal muscular atrophy), hnRNP R, and TDP-43, a genetic factor in ALS (amyotrophic lateral sclerosis). In order to characterize the functional interaction of SMN with hnRNP R and TDP-43, we produced recombinant proteins and investigated their interaction by co-immunoprecipitation. These proteins bind directly to each other, indicating that no other co-factors are needed for this interaction. SMN potentiates the ability of hnRNP R and TDP-43 to bind to ß-actin mRNA. Depletion of SMN alters the subcellular distribution of hnRNP R in motoneurons both in SMN-knockdown motoneurons and SMA mutant mouse (delta7 SMA). These data point to functions of SMN beyond snRNP assembly which could be crucial for recruitment and transport of RNA particles into axons and axon terminals, a mechanism which may contribute to SMA pathogenesis and ALS. ALS and FTLD (frontotemporal lobar degeneration) are linked by several lines of evidence with respect to clinical and pathological characteristics. Both sporadic and familial forms are a feature of the ALS-FTLD spectrum, with numerous genes having been associated with these pathological conditions. Both diseases are characterized by the pathological cellular aggregation of proteins. Interestingly, some of these proteins such as TDP-43 and FUS have also common relations not only with ALS-FTLD but also with SMA. Intronic hexanucleotide expansions in C9ORF72 are common in ALS and FTLD but it is unknown whether loss of function, toxicity by the expanded RNA or dipeptides from non ATG-initiated translation is responsible for the pathophysiology. This study tries to characterize the cellular function of C9ORF72 protein. To address this, lentiviral based knockdown and overexpression of C9ORF72 was used in isolated mouse motoneurons. The results clearly show that survival of these motoneurons was not affected by altered C9ORF72 levels, whereas adverse effects on axon growth and growth cone size became apparent after C9ORF72 suppression. Determining the protein interactome revealed several proteins in complexes with C9ORF72. Interestingly, C9ORF72 is present in a complex with cofilin and other actin binding proteins that modulate actin dynamics. These interactions were confirmed both by co-precipitation analyses and in particular by functional studies showing altered actin dynamics in motoneurons with reduced levels of C9ORF72. Importantly, the phosphorylation of cofilin is enhanced in C9ORF72 depleted motoneurons and patient derived lymphoblastoid cells with reduced C9ORF72 levels. These findings indicate that C9ORF72 regulates axonal actin dynamics and the loss of this function could contribute to disease pathomechanisms in ALS and FTLD.}, subject = {Motoneuron}, language = {en} } @unpublished{BraunschweigKrummenacherLichtenbergetal.2016, author = {Braunschweig, Holger and Krummenacher, Ivo and Lichtenberg, Crispin and Mattock, James and Sch{\"a}fer, Marius and Schmidt, Uwe and Schneider, Christoph and Steffenhagen, Thomas and Ullrich, Stefan and Vargas, Alfredo}, title = {Dibora[2]ferrocenophane: A Carbene-Stabilized Diborene in a Strained cis-Configuration}, series = {Angewandte Chemie, International Edition}, journal = {Angewandte Chemie, International Edition}, doi = {10.1002/anie.201609601}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141981}, pages = {9}, year = {2016}, abstract = {Unsaturated bridges that link the two cyclopentadienyl ligands together in strained ansa metallocenes are rare and limited to carbon-carbon double bonds. The synthesis and isolation of a strained ferrocenophane containing an unsaturated two-boron bridge, isoelectronic with a C=C double bond, was achieved by reduction of a carbene-stabilized 1,1'-bis(dihaloboryl)ferrocene. A combination of spectroscopic and electrochemical measurements as well as density functional theory (DFT) calculations was used to assess the influence of the unprecedented strained cis configuration on the optical and electrochemical properties of the carbene-stabilized diborene unit. Initial reactivity studies show that the dibora[2]ferrocenophane is prone to boron-boron double bond cleavage reactions.}, subject = {Metallocene}, language = {en} } @phdthesis{Reinhold2016, author = {Reinhold, Ann-Kristin}, title = {New players in neuropathic pain? microRNA expression in dorsal root ganglia and differential transcriptional profiling in primary sensory neurons}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140314}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Neuropathic pain, caused by neuronal damage, is a severely impairing mostly chronic condition. Its underlying molecular mechanisms have not yet been thoroughly understood in their variety. In this doctoral thesis, I investigated the role of microRNAs (miRNAs) in a murine model of peripheral neuropathic pain. MiRNAs are small, non-coding RNAs known to play a crucial role in post-transcriptional gene regulation, mainly in cell proliferation and differentiation. Initially, expression patterns in affected dorsal root ganglia (DRG) at different time points after setting a peripheral nerve lesion were studied. DRG showed an increasingly differential expression pattern over the course of one week. Interestingly, a similar effect, albeit to a smaller extent, was observed in corresponding contralateral ganglia. Five miRNA (miR-124, miR-137, miR-183, miR-27b, and miR-505) were further analysed. qPCR, in situ hybridization, and bioinformatical analysis point towards a role for miR-137 and -183 in neuropathic pain as both were downregulated. Furthermore, miR-137 is shown to be specific for non-peptidergic non-myelinated nociceptors (C fibres) in DRG. As the ganglia consist of highly heterocellular tissue, I also developed a neuron-specific approach. Primarily damaged neurons were separated from intact adjacent neurons using fluorescence-activated cell-sorting and their gene expression pattern was analysed using a microarray. Thereby, not only were information obtained about mRNA expression in both groups but, by bioinformatical tools, also inferences on miRNA involvement. The general expression pattern was consistent with previous findings. Still, several genes were found differentially expressed that had not been described in this context before. Among these are corticoliberin or cation-regulating proteins like Otopetrin1. Bioinformatical data conformed, in part, to results from whole DRG, e.g. they implied a down-regulation of miR-124, -137, and -183. However, these results were not significant. In summary, I found that a) miRNA expression in DRG is influenced by nerve lesions typical of neuropathic pain and that b) these changes develop simultaneously to over-expression of galanin, a marker for neuronal damage. Furthermore, several miRNAs (miR-183, -137) exhibit distinct expression patterns in whole-DRG as well as in neuron-specific approaches. Therefore, further investigation of their possible role in initiation and maintenance of neuropathic pain seems promising. Finally, the differential expression of genes like Corticoliberin or Otopetrin 1, previously not described in neuropathic pain, has already resulted in follow-up projects.}, subject = {Schmerzforschung}, language = {en} } @phdthesis{Baur2016, author = {Baur, Ramona}, title = {Adult Attention-Deficit/Hyperactivity Disorder (ADHD), Emotion Processing, and Emotion Regulation in Virtual Reality}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142064}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by symptoms of inattentiveness and hyperactivity/impulsivity. Besides, increasing evidence points to ADHD patients showing emotional dysfunctions and concomitant problems in social life. However, systematic research on emotional dysfunctions in ADHD is still rare, and to date most studies lack conceptual differentiation between emotion processing and emotion regulation. The aim of this thesis was to systematically investigate emotion processing and emotion regulation in adult ADHD in a virtual reality paradigm implementing social interaction. Emotional reactions were assessed on experiential, physiological, and behavioral levels. Experiment 1 was conducted to develop a virtual penalty kicking paradigm implying social feedback and to test it in a healthy sample. This paradigm should then be applied in ADHD patients later on. Pleasant and unpleasant trials in this paradigm consisted of hits respectively misses and subsequent feedback from a virtual coach. In neutral trials, participants were teleported to different spots of the virtual stadium. Results indicated increased positive affectivity (higher valence and arousal ratings, higher zygomaticus activations, and higher expression rates of positive emotional behavior) in response to pleasant compared to neutral trials. Reactions to unpleasant trials were contradictory, indicating increased levels of both positive and negative affectivity, compared to neutral trials. Unpleasant vs. neutral trials revealed lower valence ratings, higher arousal ratings, higher zygomaticus activations, slightly lower corrugator activations, and higher expression rates of both positive and negative emotional behavior. The intensity of emotional reactions correlated with experienced presence in the virtual reality. To better understand the impact of hits or misses per se vs. hits or misses with coach feedback healthy participants' emotional reactions, only 50\% of all shots were followed by coach feedback in experiment 2. Neutral trials consisted of shots over the free soccer field which were followed by coach feedback in 50 \% of all trials. Shots and feedback evoked more extreme valence and arousal ratings, higher zygomaticus activations, lower corrugator activations, and higher skin conductance responses than shots alone across emotional conditions. Again, results speak for the induction of positive emotions in pleasant trials whereas the induction of negative emotions in unpleasant trials seems ambiguous. Technical improvements of the virtual reality were reflected in higher presence ratings than in experiment 1. Experiment 3 investigated emotional reactions of adult ADHD patients and healthy controls after emotion processing and response-focused emotion regulation. Participants successively went through an ostensible online ball-tossing game (cyber ball) inducing negative emotions, and an adapted version of the virtual penalty kicking game. Throughout cyber ball, participants were included or ostracized by two other players in different experimental blocks. Participants were instructed to explicitly show, not regulate, or hide their emotions in different experimental blocks. Results provided some evidence for deficient processing of positive emotions in ADHD. Patients reported slightly lower positive affect than controls during cyber ball, gave lower valence ratings than controls in response to pleasant penalty kicking trials, and showed lower zygomaticus activations than controls especially during penalty kicking. Patients in comparison with controls showed slightly increased processing of unpleasant events during cyber ball (higher ratings of negative affect, especially in response to ostracism), but not during penalty kicking. Patients showed lower baseline skin conductance levels than controls, and impaired skin conductance modulations. Compared to controls, patients showed slight over-expression of positive as well as negative emotional behavior. Emotion regulation analyses revealed no major difficulties of ADHD vs. controls in altering their emotional reactions through deliberate response modulation. Moreover, patients reported to habitually apply adaptive emotion regulation strategies even more frequently than controls. The analyses of genetic high-risk vs. low-risk groups for ADHD across the whole sample revealed similar results as analyses for patients vs. controls for zygomaticus modulations during emotion processing, and for modulations of emotional reactions due to emotion regulation. To sum up, the virtual penalty kicking paradigm proved to be successful for the induction of positive, but not negative emotions. The importance of presence in virtual reality for the intensity of induced emotions could be replicated. ADHD patients showed impaired processing of primarily positive emotions. Aberrations in negative emotional responding were less clear and need further investigation. Results point to adult ADHD in comparison to healthy controls suffering from baseline deficits in autonomic arousal and deficits in arousal modulation. Deficits of ADHD in the deliberate application of response-focused emotion regulation could not be found.}, subject = {Aufmerksamkeitsdefizit-Syndrom}, language = {en} } @phdthesis{Riano2016, author = {Ria{\~n}o, Rub{\´e}n Felipe}, title = {BTN3A1 in the immune response of Vγ9Vδ2 T cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142084}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Human Vγ9Vδ2 T cells are the main γδ T cell subset in the circulation, accounting for up to 5\% of the total peripheral blood lymphocyte population. They have been suggested to be important in response to tumors and infections. Their immune mechanisms encompass cell killing via cytotoxicity and secretion of pro-inflammatory cytokines such as IFNγ and tumor necrosis factor (TNF). The main stimulators of Vγ9Vδ2 T cells are isopentenyl pyrophosphate (IPP) and (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), denominated phosphoantigens (PAg). A major advance in the understanding of PAg detection and Vγ9Vδ2 T cell activation has been the identification of the butyrophlin 3A (BTN3A) proteins as key mediators in these processes. In humans, three isoforms constitute the BTN3A family: BTN3A1, BTN3A2, and BTN3A3; and their genes are localized on the short arm of chromosome 6. The role of BTN3A1 has been highlighted by BTN3A-specific monoclonal antibody 20.1 (mAb 20.1), which has an agonist effect and causes proliferation, expansion, and activation of primary human Vγ9Vδ2 T cells. On the other hand, BTN3A-specific monoclonal antibody 103.2 (mAb 103.2) is antagonistic, inhibiting the Vγ9Vδ2 T cell response. The actual mechanism underlying both PAg- and mAb 20.1-mediated activation is not completely elucidated, but the importance of BTN3A1 is clear. The main objective of this dissertation was to characterize the role of BTN3A1 in the PAg-dependent and PAg-independent Vγ9Vδ2 T cell activation and to evaluate its contribution in the response to influeza A virus infected cells. This research work demonstrated, by using Vγ9Vδ2 TCR MOP-transduced murine cells (reporter cells), that human chromosome 6 (Chr6) is mandatory for PAg-induced stimulation, but not for stimulation with mAb 20.1. The reporter cells responded to mAb 20.1 in cultures with BTN3A1-transduced Chinese hamster ovary cells (CHO BTN3A1) as antigen presenting cells. Nevertheless, for PAg-dependent activation the presence of Chr6 in CHO BTN3A1 was mandatory. Although reporter cells expressing clonotypically different Vγ9Vδ2 TCRs showed similar PAg response, they clearly differed in the mAb 20.1 response. The reporter cell line transduced with Vγ9Vδ2 TCR D1C55 demonstrated essentially no response to mAb 20.1 compared to Vγ9Vδ2 TCR MOP cells. These findings were further supported by experiments performed with human PBMCs-derived Vγ9Vδ2 T cell clones. The results indicate heterogeneity in the PAg- and 20.1-dependent responses, in terms of CD25 and CD69 expression, among three different Vγ9Vδ2 T cells clones. Co-cultures of reporter cells with Raji RT1BI and PAg plus mAb 20.1 or single chain antibody 20.1 (sc 20.1) revealed no additive or synergistic activating effects. In contrast, mAb 20.1 or sc 20.1 inhibited the PAg-mediated activation of the reporter cells. The comparison of the relative contribution of the isoforms BTN3A2 and BTN3A3, in the activation of Vγ9Vδ2 T cells, was undertaken by overexpression of these isoforms in CHO cells. The results showed that BTN3A2 contributes to both PAg- and mAb-induced Vγ9Vδ2 T cell activation. On the contrary, BTN3A3 does not support PAg-mediated γδ T cell response. Additionally, mutations in the proposed PAg- and mAb 20.1-binding sites of the extracellular BTN3A1 domain were generated by means of site-directed mutagenesis. These mutations revoked the mAb 20.1-induced Vγ9Vδ2 T cell activation, but not that induced by PAg. Finally, co-cultures of Vγ9Vδ2 TCR MOP-transduced murine reporter cells with influenza A/PR/8/34-infected cells, or infection of PBMCs with this virus strain indicated that BTN3A1 might be dispensable for the Vγ9Vδ2 T cell response against influenza A. The data of this research work points out that: i) in addition to BTN3A1, other Chr6-encoded genes are necessary for Vγ9Vδ2 T cell activation with PAg; ii) clonotypical (CDR3) differences influence the PAg- and mAb 20.1-mediated Vγ9Vδ2 T cell activation; iii) the PAg- and mAb 20.1-induced responses are not synergistic and interfere with each other; iv) BTN3A2 and BTN3A3 isoforms differ in the ability to support PAg- or mAb 20.1-dependent Vγ9Vδ2 T cell activation; v) the importance of the intracellular B30.2 domain of BTN3A1, in the Vγ9Vδ2 T cell activation, might be higher than that of the extracellular domain; and vi) in spite of the importance of BTN3A1 in the activation of Vγ9Vδ2 T cells, it is possible that many molecules with redundant functions are involved in the elimination of influenza virus infection by these cells. In summary, it is possible to hypothesize a model in which BTN3A1 detects prenyl pyrophosphates in the cytoplasm via its B30.2 domain and in association with another protein(s). The binding of PAg to this domain induces a multimerization of BTN3A1 or a conformational change of its extracellular domain (mimicked by mAb 20.1). These modifications might be recognized by the Vγ9Vδ2 TCR or by an associated T cell protein. In the case that the TCR directly recognizes BTN3A1, the intensity of the response will depend on the Vγ9Vδ2 TCR clonotype. Future research will allow to gain a better understanding of BTN3A1, its interaction with other proteins, its actual role in the activation of Vγ9Vδ2 T cells, and its importance in specific models of cancer or infection. This knowledge will be necessary to transform these cells into effective tools in the clinic.}, subject = {T-Lymphozyt}, language = {en} } @phdthesis{Schreyeck2016, author = {Schreyeck, Steffen}, title = {Molecular Beam Epitaxy and Characterization of Bi-Based V\(_2\)VI\(_3\) Topological Insulators}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145812}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {The present thesis is addressed to the growth and characterization of Bi-based V2VI3 topological insulators (TIs). The TIs were grown by molecular beam epitaxy (MBE) on differently passivated Si(111) substrates, as well as InP(111) substrates. This allows the study of the influence of the substrate on the structural and electrical properties of the TIs. The Bi2Se3 layers show a change of mosaicity-tilt and -twist for growth on the differently prepared Si(111) substrates, as well as a significant increase of crystalline quality for growth on the lateral nearly lattice matched InP(111). The rocking curve FWHMs observed for thick layers grown on InP are comparable to these of common zincblende layers, which are close to the resolution limit of standard high resolution X-ray diffraction (HRXRD) setups. The unexpected high structural crystalline quality achieved in this material system is remarkable due to the presence of weak van der Waals bonds between every block of five atomic layers, i.e. a quintuple layer (QL), in growth direction. In addition to the mosaicity also twin domains, present in films of the V2VI3 material system, are studied. The twin defects are observed in Bi2Se3 layers grown on Si(111) and lattice matched InP(111) suggesting that the two dimensional surface lattice of the substrates can not determine the stacking order ABCABC... or ACBACB... in locally separated growth seeds. Therefore the growth on misoriented and rough InP(111) is analyzed. The rough InP(111) with its facets within a hollow exceeding the height of a QL is able to provide its stacking information to the five atomic layers within a QL. By varying the roughness of the InP substrate surface, due to thermal annealing, the influence on the twinning within the layer is confirmed resulting in a complete suppression of twin domains on rough InP(111). Focusing on the electrical properties of the Bi2Se3 films, the increased structural quality for films grown on lattice matched flat InP(111)B results in a marginal reduction of carrier density by about 10\% compared to the layers grown on H-passivated Si(111), whereas the suppression of twin domains for growth on rough InP(111)B resulted in a reduction of carrier density by an order of magnitude. This implies, that the twin domains are a main crystal defect responsible for the high carrier density in the presented Bi2Se3 thin films. Besides the binary Bi2Se3 also alloys with Sb and Te are fabricated to examine the influence of the compound specific point defects on the carrier density. Therefore growth series of the ternary materials Bi2Te(3-y)Se(y), Bi(2-x)Sb(x)Se3, and Bi(2-x)Sb(x)Te3, as well as the quaternary Bi(2-x)Sb(x)Te(3-y)Se(y) are studied. To further reduce the carrier density of twin free Bi2Se3 layers grown on InP(111)B:Fe a series of Bi(2-x)Sb(x)Se3 alloys were grown under comparable growth conditions. This results in a reduction of the carrier density with a minimum in the composition range of about x=0.9-1.0. The Bi(2-x)Sb(x)Te3 alloys exhibit a pn-transition, due to the dominating n-type and p-type point defects in its binary compounds, which is determined to reduce the bulk carrier density enabling the study the TI surface states. This pn-transition plays a significant role in realizing predicted applications and exotic effects, such as the quantum anomalous Hall effect. The magnetic doping of topological insulators with transition metals is studied by incorporating Cr and V in the alloy Bi(2-x)Sb(x)Te3 by codeposition. The preferential incorporation of Cr on group-V sites is confirmed by EDX and XRD, whereas the incorporation of Cr reduces the crystalline quality of the layer. Magnetotransport measurements of the Cr-doped TIs display an anomalous Hall effect confirming the realization of a magnetic TI thin film. The quantum anomalous Hall effect is observed in V-doped Bi(2-x)Sb(x)Te3, where the V-doping results in higher Curie temperatures, as well as higher coercive fields compared to the Cr-doping of the TIs. Moreover the present thesis contributes to the understanding of the role of the substrate concerning the crystalline quality of van der Waals bonded layers, such as the V2VI3 TIs, MoS2 and WoTe2. Furthermore, the fabrication of the thin film TIs Bi(2-x)Sb(x)Te(3-y)Se(y) in high crystalline quality serves as basis to explore the physics of topological insulators.}, subject = {Bismutverbindungen}, language = {en} } @article{SchindeleBorzi2016, author = {Schindele, Andreas and Borz{\`i}, Alfio}, title = {Proximal Methods for Elliptic Optimal Control Problems with Sparsity Cost Functional}, series = {Applied Mathematics}, volume = {7}, journal = {Applied Mathematics}, number = {9}, doi = {10.4236/am.2016.79086}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145850}, pages = {967-992}, year = {2016}, abstract = {First-order proximal methods that solve linear and bilinear elliptic optimal control problems with a sparsity cost functional are discussed. In particular, fast convergence of these methods is proved. For benchmarking purposes, inexact proximal schemes are compared to an inexact semismooth Newton method. Results of numerical experiments are presented to demonstrate the computational effectiveness of proximal schemes applied to infinite-dimensional elliptic optimal control problems and to validate the theoretical estimates.}, language = {en} } @article{DietlSchwinnDietletal.2016, author = {Dietl, Sebastian and Schwinn, Stefanie and Dietl, Susanne and Riedl, Simone and Deinlein, Frank and Rutkowski, Stefan and von Bueren, Andre O. and Krauss, J{\"u}rgen and Schweitzer, Tilmann and Vince, Giles H. and Picard, Daniel and Eyrich, Matthias and Rosenwald, Andreas and Ramaswamy, Vijay and Taylor, Michael D. and Remke, Marc and Monoranu, Camelia M. and Beilhack, Andreas and Schlegel, Paul G. and W{\"o}lfl, Matthias}, title = {MB3W1 is an orthotopic xenograft model for anaplastic medulloblastoma displaying cancer stem cell- and Group 3-properties}, series = {BMC Cancer}, volume = {16}, journal = {BMC Cancer}, number = {115}, doi = {10.1186/s12885-016-2170-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145877}, year = {2016}, abstract = {Background Medulloblastoma is the most common malignant brain tumor in children and can be divided in different molecular subgroups. Patients whose tumor is classified as a Group 3 tumor have a dismal prognosis. However only very few tumor models are available for this subgroup. Methods We established a robust orthotopic xenograft model with a cell line derived from the malignant pleural effusions of a child suffering from a Group 3 medulloblastoma. Results Besides classical characteristics of this tumor subgroup, the cells display cancer stem cell characteristics including neurosphere formation, multilineage differentiation, CD133/CD15 expression, high ALDH-activity and high tumorigenicity in immunocompromised mice with xenografts exactly recapitulating the original tumor architecture. Conclusions This model using unmanipulated, human medulloblastoma cells will enable translational research, specifically focused on Group 3 medulloblastoma.}, language = {en} } @article{PeckSchugZhangetal.2016, author = {Peck, Barrie and Schug, Zachary T. and Zhang, Qifeng and Dankworth, Beatrice and Jones, Dylan T. and Smethurst, Elizabeth and Patel, Rachana and Mason, Susan and Jian, Ming and Saunders, Rebecca and Howell, Michael and Mitter, Richard and Spencer-Dene, Bradley and Stamp, Gordon and McGarry, Lynn and James, Daniel and Shanks, Emma and Aboagye, Eric O. and Critchlow, Susan E. and Leung, Hing Y. and Harris, Adrian L. and Wakelam, Michael J. O. and Gottlieb, Eyal and Schulze, Almut}, title = {Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments}, series = {Cancer \& Metabolism}, volume = {4}, journal = {Cancer \& Metabolism}, number = {6}, doi = {10.1186/s40170-016-0146-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145905}, year = {2016}, abstract = {Background Enhanced macromolecule biosynthesis is integral to growth and proliferation of cancer cells. Lipid biosynthesis has been predicted to be an essential process in cancer cells. However, it is unclear which enzymes within this pathway offer the best selectivity for cancer cells and could be suitable therapeutic targets. Results Using functional genomics, we identified stearoyl-CoA desaturase (SCD), an enzyme that controls synthesis of unsaturated fatty acids, as essential in breast and prostate cancer cells. SCD inhibition altered cellular lipid composition and impeded cell viability in the absence of exogenous lipids. SCD inhibition also altered cardiolipin composition, leading to the release of cytochrome C and induction of apoptosis. Furthermore, SCD was required for the generation of poly-unsaturated lipids in cancer cells grown in spheroid cultures, which resemble those found in tumour tissue. We also found that SCD mRNA and protein expression is elevated in human breast cancers and predicts poor survival in high-grade tumours. Finally, silencing of SCD in prostate orthografts efficiently blocked tumour growth and significantly increased animal survival. Conclusions Our data implicate lipid desaturation as an essential process for cancer cell survival and suggest that targeting SCD could efficiently limit tumour expansion, especially under the metabolically compromised conditions of the tumour microenvironment.}, language = {en} } @phdthesis{Kessel2016, author = {Kessel, Maximilian}, title = {HgTe shells on CdTe nanowires: A low-dimensional topological insulator from crystal growth to quantum transport}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149069}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {A novel growth method has been developed, allowing for the growth of strained HgTe shells on CdTe nanowires (NWs). The growth of CdTe-HgTe core-shell NWs required high attention in controlling basic parameters like substrate temperature and the intensity of supplied material fluxes. The difficulties in finding optimized growth conditions have been successfully overcome in this work. We found the lateral redistribution of liquid growth seeds with a ZnTe growth start to be crucial to trigger vertical CdTe NW growth. Single crystalline zinc blende CdTe NWs grew, oriented along [111]B. The substrate temperature was the most critical parameter to achieve straight and long wires. In order to adjust it, the growth was monitored by reflection high-energy electron diffraction, which was used for fine tuning of the temperature over time in each growth run individually. For optimized growth conditions, a periodic diffraction pattern allowed for the detailed analysis of atomic arrangement on the surfaces and in the bulk. The ability to do so reflected the high crystal quality and ensemble uniformity of our CdTe NWs. The NW sides were formed by twelve stable, low-index crystalline facets. We observed two types stepped and polar sides, separated by in total six flat and non-polar facets. The high crystalline quality of the cores allowed to grow epitaxial HgTe shells around. We reported on two different heterostructure geometries. In the first one, the CdTe NWs exhibit a closed HgTe shell, while for the second one, the CdTe NWs are overgrown mainly on one side. Scanning electron microscopy and scanning transmission electron microscopy confirmed, that many of the core-shell NWs are single crystalline zinc blende and have a high uniformity. The symmetry of the zinc blende unit cell was reduced by residual lattice strain. We used high-resolution X-ray diffraction to reveal the strain level caused by the small lattice mismatch in the heterostructures. Shear strain has been induced by the stepped hetero-interface, thereby stretching the lattice of the HgTe shell by 0.06 \% along a direction oriented with an angle of 35 ° to the interface. The different heterostructures obtained, were the base for further investigation of quasi-one-dimensional crystallites of HgTe. We therefore developed methods to reliably manipulate, align, localize and contact individual NWs, in order to characterize the charge transport in our samples. Bare CdTe cores were insulating, while the HgTe shells were conducting. At low temperature we found the mean free path of charge carriers to be smaller, but the phase coherence length to be larger than the sample size of several hundred nanometers. We observed universal conductance fluctuations and therefore drew the conclusion, that the trajectories of charge carriers are defined by elastic backscattering at randomly distributed scattering sites. When contacted with superconducting leads, we saw induced superconductivity, multiple Andreev reflections and the associated excess current. Thus, we achieved HgTe/superconductor interfaces with high interfacial transparency. In addition, we reported on the appearance of peaks in differential resistance at Delta/e for HgTe-NW/superconductor and 2*Delta/e for superconductor/HgTe-NW/superconductor junctions, which is possibly related to unconventional pairing at the HgTe/superconductor interface. We noticed that the great advantage of our self-organized growth is the possibility to employ the metallic droplet, formerly seeding the NW growth, as a superconducting contact. The insulating wire cores with a metallic droplet at the tip have been overgrown with HgTe in a fully in-situ process. A very high interface quality was achieved in this case.}, subject = {Quecksilbertellurid}, language = {en} } @phdthesis{Dagvadorj2016, author = {Dagvadorj, Nergui}, title = {Improvement of T-cell response against WT1-overexpressing leukemia by newly developed anti-hDEC205-WT1 antibody fusion proteins}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149098}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Wilms tumor protein 1 (WT1) is a suitable target to develop an immunotherapeutic approach against high risk acute myeloid leukemia (AML), particularly their relapse after allogeneic hematopoietic stem cell transplantation (HSCT). As an intracellular protein traversing between nucleus and cytoplasm, recombinant expression of WT1 is difficult. Therefore, an induction of WT1-specific T-cell responses is mostly based on peptide vaccination as well as dendritic cell (DC) electroporation with mRNA encoding full-length protein to mount WT1-derived peptide variations presented to T cells. Alternatively, the WT1 peptide presentation could be broadened by forcing receptor-mediated endocytosis of DCs. In this study, antibody fusion proteins consisting of an antibody specific to the human DEC205 endocytic receptor and various fragments of WT1 (anti-hDEC205-WT1) were generated for a potential DC-targeted recombinant WT1 vaccine. Anti-hDEC205-WT1 antibody fusion proteins containing full-length or major parts of WT1 were not efficiently expressed and secreted due to their poor solubility and secretory capacity. However, small fragment-containing variants: anti-hDEC205-WT110-35, anti-hDEC205-WT191-138, anti-hDEC205-WT1223-273, and anti-hDEC205-WT1324-371 were obtained in good yields. Since three of these fusion proteins contain the most of the known immunogenic epitopes in their sequences, the anti-hDEC205-WT191-138, anti-hDEC205-WT1223-273, and anti-hDEC205-WT1324-371 were tested for their T-cell stimulatory capacities. Mature monocyte-derived DCs loaded with anti-hDEC205-WT191-138 could induce ex vivo T-cell responses in 12 of 16 blood samples collected from either healthy or HSC transplanted individuals compared to included controls (P < 0.01). Furthermore, these T cells could kill WT1-overexpressing THP-1 leukemia cells in vitro after expansion. In conclusion, alongside proving the difficulty in expression and purification of intracellular WT1 as a vaccine protein, our results from this work introduce an alternative therapeutic vaccine approach to improve an anti-leukemia immune response in the context of allogeneic HSCT and potentially beyond.}, subject = {Akute myeloische Leuk{\"a}mie}, language = {en} } @article{SchuberthHenselerDijkstra2016, author = {Schuberth, Florian and Henseler, J{\"o}rg and Dijkstra, Theo K.}, title = {Partial least squares path modeling using ordinal categorical indicators}, series = {Quality \& Quantity}, journal = {Quality \& Quantity}, doi = {10.1007/s11135-016-0401-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144016}, year = {2016}, abstract = {This article introduces a new consistent variance-based estimator called ordinal consistent partial least squares (OrdPLSc). OrdPLSc completes the family of variance-based estimators consisting of PLS, PLSc, and OrdPLS and permits to estimate structural equation models of composites and common factors if some or all indicators are measured on an ordinal categorical scale. A Monte Carlo simulation (N =500) with different population models shows that OrdPLSc provides almost unbiased estimates. If all constructs are modeled as common factors, OrdPLSc yields estimates close to those of its covariance-based counterpart, WLSMV, but is less efficient. If some constructs are modeled as composites, OrdPLSc is virtually without competition.}, language = {en} } @phdthesis{Sickel2016, author = {Sickel, Wiebke}, title = {High-throughput biodiversity assessment - Powers and limitations of meta-barcoding}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144573}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Traditional species identification based on morphological characters is laborious and requires expert knowledge. It is further complicated in the case of species assemblages or degraded and processed material. DNA-barcoding, species identification based on genetic data, has become a suitable alternative, yet species assemblages are still difficult to study. In the past decade meta-barcoding has widely been adopted for the study of species communities, due to technological advances in modern sequencing platforms and because manual separation of individual specimen is not required. Here, meta-barcoding is put into context and applied to the study of bee-collected pollen as well as bacterial communities. These studies provide the basis for a critical evaluation of the powers and limitations of meta-barcoding. Advantages identified include species identification without the need for expert knowledge as well as the high throughput of samples and sequences. In microbiology, meta-barcoding can facilitate directed cultivation of taxa of interest identified with meta-barcoding data. Disadvantages include insufficient species resolution due to short read lengths and incomplete reference databases, as well as limitations in abundance estimation of taxa and functional profiling. Despite these, meta-barcoding is a powerful method for the analysis of species communities and holds high potential especially for automated biomonitoring.}, subject = {Biodiversit{\"a}t}, language = {en} } @phdthesis{Sawatzky2016, author = {Sawatzky, Edgar}, title = {Design und Synthese selektiver Butyrylcholinesterase (BChE) Inhibitoren zur Entwicklung von Radiopharmazeutika zur Erforschung der Alzheimer Erkrankung}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144037}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Although the physiological roles of BChE are not yet determined to date, the importance of this enzyme is continuously increasing as it was found to be associated with several disorders like diabetes mellitus type 2, cardiovascular diseases, obesity and especially with Alzheimer's disease (AD). In consequence, for investigations of BChE's pathological role in these diseases and to find new medication strategies, the development of selective and potent inhibitors is necessary. For this purpose, the current work progresses in five chapters on the exploration of the chemical, physical and biochemical properties of tetrahydroquinazoline based carbamates which were previously reported to be selective BChE inhibitors with potency in the low nanomolar range. 1) A Novel Way to Radiolabel Human Butyrylcholinesterase for PET through Irreversible Transfer of the Radiolabeled Moiety: PET-radiotracers represent an innovative tool to determine the distribution and the expression of a biological target in vivo. BChE lacks to a large degree of such tracers with a few exceptions. In this work, methods were developed to incorporate the radioisotopes 11C and 18F into the carbamate moiety of an tetrahydroquinazoline based inhibitor. In contrast to reversibly acting PET-probes, the described radiotracers were proven by kinetic studies to transfer the radioisotope covalently onto the active site of BChE, thus labeling the enzyme directly and permanently. 2) Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode: To investigate the role of the tetrahydroquinazoline carrier scaffold on BChE inhibition, carbamate based inhibitors were synthesized. These compounds were successively used to perform kinetic investigations to determine their inhibition mode. Based on these data, a plausible binding model was postulated explaining the influence of the tetrahydroquinazoline carrier scaffold for binding at BChE's active site just before carbamate transfer takes place. Additionally, these compounds feature neuroprotective properties and prevent oxidative stress induced cell death in their carbamate form as well as after the release of the tetrahydroquinazoline carrier scaffold. 3) Dual Addressing of Butyrylcholinesterase by Targeting the Catalytic Active Site (CAS) and the Peripheral Anionic Site (PAS): Compounds which are dual-targeting the CAS and the PAS of BChE are the most potent and selective BChE inhibitors to date with inhibition values in the picomolar range. In this work, a strategy is described how to turn tetrahydroquinazoline based carbamates into dual binding BChE inhibitors. These inhibitors feature a carbamate moiety which is covalently transferred onto the CAS of BChE, and in addition provide a second pharmacophore connected via a linker to the carbamate moiety which is proposed to target the PAS. Preliminary results reveal a high tolerance of BChE towards different linker lengths without decrease in affinity. 4) Investigation into Selective Debenzylation and Ring Cleavage of Quinazoline based Heterocycles: The tetrahydroquinazoline system is well investigated in terms of its synthesis and its selective oxidation. To explore the reactivity of this system, a tetracyclic tetrahydroquinazoline was exposed to common reduction agents. These experiments revealed a high sensitivity of the tetrahydroquinazoline core towards several reduction conditions 5) Experimental and Theoretical Investigation into the Stability of Cyclic Aminals: Tetrahydroquinazolines are known to degrade in acidic media through hydrolysis of their aminal system; but literature is lacking of a systematic investigation into this behavior. Therefore, different tetrahydroquinazolines were synthesized and exposed to phosphate buffered systems with defined pH-values. A clear increase of the hydrolysis rate of the aminal system was determined in dependency of an increasing acidic media. Computational studies predicted and experimental studies proved that hydrolysis takes place in an acidic environment while the condensation of this system is preferred in neutral or basic aqueous media.}, subject = {Cholinesterase}, language = {en} } @phdthesis{Bahnik2016, author = {Bahn{\´i}k, Štěp{\´a}n}, title = {Processing fluency and judgment}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144656}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {To simplify a judgment, people often base it on easily accessible information. One cue that is usually readily available is processing fluency - a metacognitive feeling of ease of cognitive processing. Consequently, processing fluency is used as a cue for many different types of judgment, such as judgment of truth, confidence, and novelty. The present work describes results of three studies investigating various aspects of processing fluency effects on judgment. Processing fluency has been sometimes equated with speed of a cognitive process. Therefore, response times have been used for evaluation of processing fluency. However, response times in experimental tasks often do not encompass only the time needed for a given process, but also the time needed for a decision based on the resulting information. The study described in Chapter II uses a novel experimental method that enables separation of reading and decision times. The results show that people make a decision about liking of pseudowords faster when the pseudowords are hard-to-pronounce (i.e., disfluent) than when they are moderate in pronounceability. This suggests that response times cannot be used as a proxy for processing fluency when they include the time needed to make a decision. One of the studies of judgmental effects of processing fluency showed that food additives with easier pronounceable names are judged to be less harmful than those with hard-to-pronounce names. While people encounter food additives that are safe more often, this environmental association may be in the opposite direction for some categories of objects. For example, people are more likely to see names of especially dangerous criminals in the news. Chapter III describes a study which initially tested whether the fluency-safety association may be in the opposite direction for some categories of objects as a consequence of this selective exposure to especially dangerous exemplars. The results did not show support for this hypothesis. Furthermore, subsequent studies suggest that the previously found association between fluency and safety is replicable with the original stimuli used in the previous research, but not with newly constructed stimuli. Chapter IV describes a study which applied a finding from the processing fluency literature to a positive psychology exercise in order to increase its effectiveness. Namely, the experiment manipulated the number of good things that participants listed daily for two weeks as part of the exercise. While listing more things was considered harder, the number of things listed each day had no effect on effectiveness of the exercise.}, subject = {Urteilen}, language = {en} } @phdthesis{Koepke2016, author = {Koepke, Robin}, title = {Capital Flows and Financial Stability in Emerging Markets: the Role of U.S. Monetary Policy}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140524}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Die Dissertation besch{\"a}ftigt sich mit den Triebkr{\"a}ften der internationalen Kapitalstr{\"o}me in Schwellenl{\"a}nder sowie den Determinanten von Krisen in Schwellenl{\"a}ndern. Besonderes Augenmerk liegt dabei auf der Rolle der Geldpolitik in den USA. Die Dissertation besteht aus drei eigenst{\"a}ndigen Kapiteln. Kapitel 1 nimmt eine Bestandsaufnahme der umfangreichen empirischen Literatur zu den Triebkr{\"a}ften von Kapitalstr{\"o}men in Schwellenl{\"a}nder vor. Die empirische Evidenz hinsichtlich dieser Triebkr{\"a}fte ist entlang mehrer Dimensionen strukturiert. So werden die Triebkr{\"a}fte entsprechend des etablierten Paradigmas eingeordnet, nachdem zwischen externen Faktoren (z.B. US-Geldpolitik) und internen Faktoren (z.B. Wachstum in Schwellenl{\"a}ndern) unterschieden wird (Calvo et al. 1993). Eine umfassende Auswertung der empirischen Literatur zeigt, dass externe Faktoren Portfolioinvestitionen am meisten beeinflussen, gefolgt von Zufl{\"u}ssen von Banken. F{\"u}r Direktinvestitionen hingegen ist die empirische Evidenz hinsichtlich einer Reihe externer Faktoren nicht eindeutig. Interne Faktoren sind f{\"u}r alle drei Arten von Kapitalstr{\"o}men von erheblicher Bedeutung, insbesondere f{\"u}r Zufl{\"u}sse von Banken. Dar{\"u}ber hinaus unterscheidet die vorliegende Studie zwischen zyklischen und strukturellen Faktoren, die Kapitalstr{\"o}me beeinflussen. Eine historische Analyse deutet darauf hin, dass die Literatur die Bedeutung von zyklischen Faktoren zulasten l{\"a}ngerfristiger struktureller Trends {\"u}berbewertet hat. Kapitel 2 nimmt eine empirische Analyse der Triebkr{\"a}fte von Portfolioinvestitionen in Schwellenl{\"a}ndern vor, mit besonderem Fokus auf die Rolle der Geldpolitik der US-Zentralbank. Dabei werden zwei unterschiedliche Datens{\"a}tze zu hochfrequenten Portfolioinvestitionen mit Hilfe eines Zeitreihenmodells analysiert. Die empirische Analyse zeigt, dass Portfolioinvestitionen erheblich vom {\"U}berraschungsmoment der US-Geldpolitik getrieben werden. Wenn Marktteilnehmer ihre Erwartungen bez{\"u}glich des k{\"u}nftigen Pfades der Leitzinsen ver{\"a}ndern, dann hat dies direkte Auswirkungen auf das Verhalten von Portfolio-Kapitalstr{\"o}men. Eine Verschiebung der erwarteten Leitzinsen nach unten [nach oben] erh{\"o}ht [vermindert] die Portfoliozufl{\"u}sse in Schwellenl{\"a}nder. Dieses Ergebnis legt eine neue Interpretation der Rolle der US-Geldpolitik nahe. In der gegenw{\"a}rtigen Literatur besteht die zentrale {\"U}berzeugung hinsichtlich der Rolle der US-Geldpolitik darin, dass sich eine Erh{\"o}hung der Leitzinsen negativ auf Kapitalfl{\"u}sse in Schwellenl{\"a}nder auswirkt, unabh{\"a}ngig davon wie schnell die Leitzinsen erh{\"o}ht werden (z.B. Fernandez-Arias 1996). Die Ergebnisse der vorliegenden Arbeit hingegen deuten darauf hin, dass eine Straffung der US-Geldpolitik sich nicht notwendigerweise negativ auf Portfolioinvestitionen auswirkt. Negative Effekte bleiben insbesondere dann aus, wenn eine Zinserh{\"o}hung von den Marktteilnehmern bereits erwartetet und somit eingepreist war. Eine Erh{\"o}hung der Leitzinsen kann sogar mit positiven Effekten auf Kapitalstr{\"o}me einhergehen, n{\"a}mlich dann, wenn sie von einer Abw{\"a}rtsbewegung im erwarteten Pfad der Leitzinsen begleitet ist (zum Beispiel weil die Zentralbank signalisiert, dass weitere Zinserh{\"o}hungen nicht zu erwarten sind). Umgekehrt kann die US-Geldpolitik Portfolioinvestitionen auch ohne eine Erh{\"o}hung der Leitzinsen beeintr{\"a}chtigen, n{\"a}mlich dann, wenn Marktteilnehmer ihre Erwartungen hinsichtlich der k{\"u}nftigen Leitzinsen nach oben revidieren. Kapitel 3 untersucht die Rolle der US-Geldpolitik hinsichtlich ihres Einflusses auf das Auftreten von Krisen in Schwellenl{\"a}ndern. Es werden ein negativ-binomisches Z{\"a}hlmodell und ein Panel-Logitmodell {\"o}konometrisch gesch{\"a}tzt, um die Determinanten von W{\"a}hrungskrisen, Bankenkrisen und Staatsbankrotten in 27 Schwellenl{\"a}ndern zu analysieren. Die Sch{\"a}tzergebnisse deuten darauf hin, dass die Wahrscheinlichkeit von Krisen wesentlich h{\"o}her ist, (1) wenn die US-Leitzinsen {\"u}ber ihrem nat{\"u}rlichen Niveau liegen, (2) w{\"a}hrend Zinsanhebungszyklen, und (3) wenn Marktteilnehmer von Signalen {\"u}berrascht werden, dass die US-Zentralbank die Leitzinsen schneller als erwartet anheben wird. Diese Ergebnisse stehen im Gegensatz zur bestehenden Literatur, die interne Faktoren in Schwellenl{\"a}ndern als die dominante Ursache von Krisen ansieht (z.B. Gourinchas und Obstfeld 2012). Die Ergebnisse dieser Studie weisen auch auf ein erh{\"o}htes Risiko von Krisen in Schwellenl{\"a}ndern in den kommenden Jahren hin, wenn die US-Zentralbank wie erwartet die Leitzinsen weiterhin graduell anheben wird.}, subject = {Internationale Kapitalbewegung}, language = {en} } @phdthesis{MuellerLeisse2016, author = {M{\"u}ller-Leisse, Johanna}, title = {Influence of myeloid-derived suppressor cells and neutrophil granulocytes on natural killer cell homeostasis and function}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140734}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Polymorphonuclear neutrophils (PMNs) are phagocytic cells of the innate immune system that efficiently kill bacteria. However, they also have regulatory effects on other immune cells and contribute to immunosuppression in cancer, which worsens the outcome. In particular, this has been demonstrated for a subset of granulocytic cells called myeloid- derived suppressor cells (MDSCs), but its distinction from PMNs is controversial. Most authors have explored the suppressive effects of MDSCs on T cells, but recent data suggest that NK cells are also affected. NK cells are crucial for the combat of tumor cells, in particular leukemic cells. There is hardly data available on the interaction between NK cells and suppressive granulocytic cells. Therefore, the aim of this thesis was to explore the effects of MDSCs and PMNs on the NK cell function against the leukemia cell line K562. In co-culture experiments, I demonstrate that granulocytic MDSCs and PMNs had similar effects on NK cell function and homeostasis. On the one hand, they positively influenced the survival and maturation of NK cells. On the other, they inhibited the activation, cytotoxicity and cytokine production of NK cells, both IFNγ and TNFα, in response to K562 target cells. Furthermore, I show a down-regulation of the activating receptor NKp30 on NK cells in the presence of MDSCs or PMNs, which may form part of the underlying suppressive mechanisms. However, there is also evidence for the involvement of other molecules. Further investigations are needed to confirm a relevant suppression of NK cells by granulocytic cells in cancer patients, and to identify therapeutic targets. The recognition that regular PMNs have similar effects on NK cells as MDSCs could simplify future experiments, since MDSCs are heterogeneous and laborious to isolate and identify. NKcells and granulocytes are among the first immune cells to reconstitute after hematopoietic stem cell transplantation, and NK cells may be particularly exposed to suppressive effects of granulocytes this scenario. Modulating these suppressive effects of granulocytes on NK cells therapeutically may yield a better NK cell function and an improved cancer prognosis. }, subject = {Nat{\"u}rliche Killerzelle}, language = {en} } @article{WalterCollenburgJaptoketal.2016, author = {Walter, T. and Collenburg, L. and Japtok, L. and Kleuser, B. and Schneider-Schaulies, S. and M{\"u}ller, N. and Becam, J. and Schubert-Unkmeir, A. and Kong, J. N. and Bieberich, E. and Seibel, J.}, title = {Incorporation and visualization of azido-functionalized N-oleoyl serinol in Jurkat cells, mouse brain astrocytes, 3T3 fibroblasts and human brain microvascular endothelial cells}, series = {Chemical Communications}, volume = {52}, journal = {Chemical Communications}, number = {55}, doi = {10.1039/c6cc02879a}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191263}, pages = {8612-8614}, year = {2016}, abstract = {The synthesis and biological evaluation of azido-N-oleoyl serinol is reported. It mimicks biofunctional lipid ceramides and has shown to be capable of click reactions for cell membrane imaging in Jurkat and human brain microvascular endothelial cells.}, language = {en} } @article{FleglerSchneiderPrieschletal.2016, author = {Flegler, Andreas and Schneider, Michael and Prieschl, Johannes and Stevens, Ralph and Vinnay, Thomas and Mandel, Karl}, title = {Continuous flow synthesis and cleaning of nano layered double hydroxides and the potential of the route to adjust round or platelet nanoparticle morphology}, series = {RSC Advances}, volume = {6}, journal = {RSC Advances}, number = {62}, doi = {10.1039/c6ra09553d}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191305}, pages = {57236-57244}, year = {2016}, abstract = {Here, we report a continuous flow synthesis of nano LDH, comprising a continuous precipitation process using static mixers and followed by an immediate cleaning process via a semi-continuous centrifuge to obtain the final product in one-go. Via this synthesis setup, it is possible to independently vary the concentrations of the reactants during precipitation and at the same time ensure constant reaction conditions and an immediate "quenching" of the precipitate due to "on the flow"-washing. We found that this paves the way to adjust the synthesis parameters in a way that the final morphology of the nano-LDH particles can be controlled to be either round or platelet-like.}, language = {en} } @article{EmmertWitzelHeinrich2016, author = {Emmert, M. and Witzel, P. and Heinrich, D.}, title = {Challenges in tissue engineering - towards cell control inside artificial scaffolds}, series = {Soft Matter}, volume = {12}, journal = {Soft Matter}, number = {19}, doi = {10.1039/c5sm02844b}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191341}, pages = {4287-4294}, year = {2016}, abstract = {Control of living cells is vital for the survival of organisms. Each cell inside an organism is exposed to diverse external mechano-chemical cues, all coordinated in a spatio-temporal pattern triggering individual cell functions. This complex interplay between external chemical cues and mechanical 3D environments is translated into intracellular signaling loops. Here, we describe how external mechano-chemical cues control cell functions, especially cell migration, and influence intracellular information transport. In particular, this work focuses on the quantitative analysis of (1) intracellular vesicle transport to understand intracellular state changes in response to external cues, (2) cellular sensing of external chemotactic cues, and (3) the cells' ability to migrate in 3D structured environments, artificially fabricated to mimic the 3D environment of tissue in the human body.}, language = {en} } @misc{Karremann2016, author = {Karremann, Isabel}, title = {Hans-Peter Wagner. An Introduction to British and Irish Fiction: Renaissance to Romanticism. Trier: Wissenschaftlicher Verlag Trier, 2014, 262 pp., 60 illustr., € 29.50.}, series = {Anglia}, volume = {134}, journal = {Anglia}, number = {4}, issn = {1865-8938}, doi = {10.1515/ang-2016-0078}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-194309}, pages = {711-715}, year = {2016}, abstract = {No abstract available.}, language = {en} } @misc{Nord2016, author = {Nord, Ilona}, title = {Jan Peter Grevel, Mit Gott im Gr{\"u}nen. Eine Praktische Theologie der Naturerfahrung (Research in Contemporary Religion, Vol. 17), G{\"o}ttingen (Vandenhoeck \& Ruprecht) 2015, 357 pp, ISBN 9783525604519, Eur (D) 110.}, series = {International Journal of Practical Theology}, volume = {20}, journal = {International Journal of Practical Theology}, number = {2}, issn = {1612-9768}, doi = {10.1515/ijpt-2016-0039}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-194900}, pages = {282-284}, year = {2016}, abstract = {No abstract available.}, language = {en} } @article{Froehlich2016, author = {Fr{\"o}hlich, Andrea}, title = {Discussion Report: Formation of Companies}, series = {European Company and Financial Law Review}, volume = {13}, journal = {European Company and Financial Law Review}, number = {2}, issn = {1613-2556}, doi = {10.1515/ecfr-2016-0373}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-194468}, pages = {373-374}, year = {2016}, abstract = {No abstract available.}, language = {en} } @article{Schmidt2016, author = {Schmidt, Lena}, title = {Discussions Report: Reorganization of Companies}, series = {European Company and Financial Law Review}, volume = {13}, journal = {European Company and Financial Law Review}, number = {2}, issn = {1613-2556}, doi = {10.1515/ecfr-2016-0370}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-194479}, pages = {370-372}, year = {2016}, abstract = {No abstract available.}, language = {en} } @article{Teichmann2016, author = {Teichmann, Christoph}, title = {Corporate Restructuring under the EMCA}, series = {European Company and Financial Law Review}, volume = {13}, journal = {European Company and Financial Law Review}, number = {2}, issn = {1613-2556}, doi = {10.1515/ecfr-2016-0277}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-194488}, pages = {277 -- 300}, year = {2016}, abstract = {No abstract available.}, language = {en} } @article{ClaussYanKuenzer2016, author = {Clauss, Kersten and Yan, Huimin and Kuenzer, Claudia}, title = {Mapping Paddy Rice in China in 2002, 2005, 2010 and 2014 with MODIS Time Series}, series = {Remote Sensing}, volume = {8}, journal = {Remote Sensing}, number = {5}, doi = {10.3390/rs8050434}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180557}, year = {2016}, abstract = {Rice is an important food crop and a large producer of green-house relevant methane. Accurate and timely maps of paddy fields are most important in the context of food security and greenhouse gas emission modelling. During their life-cycle, rice plants undergo a phenological development that influences their interaction with waves in the visible light and infrared spectrum. Rice growth has a distinctive signature in time series of remotely-sensed data. We used time series of MODIS (Moderate Resolution Imaging Spectroradiometer) products MOD13Q1 and MYD13Q1 and a one-class support vector machine to detect these signatures and classify paddy rice areas in continental China. Based on these classifications, we present a novel product for continental China that shows rice areas for the years 2002, 2005, 2010 and 2014 at 250-m resolution. Our classification has an overall accuracy of 0.90 and a kappa coefficient of 0.77 compared to our own reference dataset for 2014 and correlates highly with rice area statistics from China's Statistical Yearbooks (R2 of 0.92 for 2010, 0.92 for 2005 and 0.90 for 2002). Moderate resolution time series analysis allows accurate and timely mapping of rice paddies over large areas with diverse cropping schemes.}, language = {en} } @article{WaechtlerKuebelBarthelmesetal.2016, author = {W{\"a}chtler, Maria and K{\"u}bel, Joachim and Barthelmes, Kevin and Winter, Andreas and Schmiedel, Alexander and Pascher, Torbj{\"o}rn and Lambert, Christoph and Schubert, Ulrich S. and Dietzek, Benjamin}, title = {Energy transfer and formation of long-lived \(^3\)MLCT states in multimetallic complexes with extended highly conjugated bis-terpyridyl ligands}, series = {Physical Chemistry Chemical Physics}, volume = {18}, journal = {Physical Chemistry Chemical Physics}, number = {4}, doi = {10.1039/c5cp04447b}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191041}, pages = {2350-2360}, year = {2016}, abstract = {Multimetallic complexes with extended and highly conjugated bis-2,2':6',2''-terpyridyl bridging ligands, which present building blocks for coordination polymers, are investigated with respect to their ability to act as light-harvesting antennae. The investigated species combine Ru(II)- with Os(II)- and Fe(II)-terpyridyl chromophores, the latter acting as energy sinks. Due to the extended conjugated system the ligands are able to prolong the lifetime of the \(^3\)MLCT states compared to unsubstituted terpyridyl species by delocalization and energetic stabilization of the \(^3\)MLCT states. This concept is applied for the first time to Fe(II) terpyridyl species and results in an exceptionally long lifetime of 23 ps for the Fe(II) \(^3\)MLCT state. While partial energy (>80\%) transfer is observed between the Ru(II) and Fe(II) centers with a time-constant of 15 ps, excitation energy is transferred completely from the Ru(II) to the Os(II) center within the first 200 fs after excitation.}, language = {en} } @article{GrimmKleinKopeketal.2016, author = {Grimm, Jonathan B. and Klein, Teresa and Kopek, Benjamin G. and Shtengel, Gleb and Hess, Harald F. and Sauer, Markus and Lavis, Luke D.}, title = {Synthesis of a far-red photoactivatable silicon-containing rhodamine for super-resolution microscopy}, series = {Angewandte Chemie International Edition}, volume = {55}, journal = {Angewandte Chemie International Edition}, number = {5}, doi = {10.1002/anie.201509649}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191069}, pages = {1723-1727}, year = {2016}, abstract = {The rhodamine system is a flexible framework for building small-molecule fluorescent probes. Changing N-substitution patterns and replacing the xanthene oxygen with a dimethylsilicon moiety can shift the absorption and fluorescence emission maxima of rhodamine dyes to longer wavelengths. Acylation of the rhodamine nitrogen atoms forces the molecule to adopt a nonfluorescent lactone form, providing a convenient method to make fluorogenic compounds. Herein, we take advantage of all of these structural manipulations and describe a novel photoactivatable fluorophore based on a Si-containing analogue of Q-rhodamine. This probe is the first example of a "caged" Si-rhodamine, exhibits higher photon counts compared to established localization microscopy dyes, and is sufficiently red-shifted to allow multicolor imaging. The dye is a useful label for super-resolution imaging and constitutes a new scaffold for far-red fluorogenic molecules.}, language = {en} }