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The role of human Ephrin receptor tyrosine kinase A2 (EphA2) in Chlamydia trachomatis infection
(2015)
Chlamydia trachomatis (Ctr), an obligate intracellular gram negative human pathogen, causes sexually transmitted diseases and acquired blindness in developing countries. The infectious elementary bodies (EB) of Ctr involved in adherence and invasion processes are critical for chlamydial infectivity and subsequent pathogenesis which requires cooperative interaction of several host cell factors. Few receptors have been known for this early event, yet the molecular mechanism of these receptors involvement throughout Ctr infection is not known. Chlamydial inclusion membrane serves as a signaling platform that coordinates Chlamydia-host cell interaction which encouraged me to look for host cell factors that associates with the inclusion membrane, using proteome analysis. The role of these factors in chlamydial replication was analyzed by RNA interference (RNAi) (in collaboration with AG Thomas Meyer). Interestingly, EphrinA2 receptor (EphA2), a cell surface tyrosine kinase receptor, implicated in many cancers, was identified as one of the potential candidates. Due to the presence of EphA2 in the Ctr inclusion proteome data, I investigated the role of EphA2 in Ctr infection. EphA2 was identified as a direct interacting receptor for adherence and entry of C. trachomatis. Pre-incubation of Ctr-EB with recombinant human EphA2, knockdown of EphA2 by siRNA, pretreatment of cells with anti-EphA2 antibodies or the tyrosine kinase inhibitor dasatinib significantly reduced Ctr infection. This marked reduction of Ctr infection was seen with both epithelial and endothelial cells used in this study. Ctr activates EphA2 upon infection and invades the cell together with the activated EphA2 receptor that interacts and activates PI3K survival signal, promoting chlamydial replication. EphA2 upregulation during infection is associated with Ctr inclusion membrane inside the cell and are prevented being translocated to the cell surface. Ephrins are natural ligands for Ephrin receptors that repress the activation of the PI3K/Akt pathway in a process called reverse signaling. Purified Ephrin-A1, a ligand of EphA2, strongly interferes with chlamydial infection and normal development, supporting the central role of these receptors in Chlamydia infection. Overexpression of full length EphA2, but not the mutant form lacking the intracellular cytoplasmic domain, enhanced PI3K activation and Ctr infection. Ctr infection induces EphA2 upregulation and is mediated by activation of ERK signaling pathway. Interfering with EphA2 upregulation sensitizes Ctr-infected cells to apoptosis induced by tumor necrosis factor-alpha (TNF-α) suggesting the importance of intracellular EphA2 signaling.
Collectively, these results revealed the first Ephrin receptor “EphA2” that functions in promoting chlamydial infection. In addition, the engagement of a cell surface receptor at the inclusion membrane is a new mechanism how Chlamydia subverts the host cell and induces apoptosis resistance. By applying the natural ligand Ephrin-A1 and targeting EphA2 offers a promising new approach to interfere with Chlamydia infection. Thus, the work provides the evidence for a host cell surface tyrosine kinase receptor that is exploited for invasion as well as for receptor-mediated intracellular signaling to facilitate the chlamydial replication.
Knowledge-based systems (KBS) face an ever-increasing interest in various disciplines and contexts. Yet, the former aim to construct the ’perfect intelligent software’ continuously shifts to user-centered, participative solutions. Such systems enable users to contribute their personal knowledge to the problem solving process for increased efficiency and an ameliorated user experience. More precisely, we define non-functional key requirements of participative KBS as: Transparency (encompassing KBS status mediation), configurability (user adaptability, degree of user control/exploration), quality of the KB and UI, and evolvability (enabling the KBS to grow mature with their users). Many of those requirements depend on the respective target users, thus calling for a more user-centered development. Often, also highly expertise domains are targeted — inducing highly complex KBs — which requires a more careful and considerate UI/interaction design. Still, current KBS engineering (KBSE) approaches mostly focus on knowledge acquisition (KA) This often leads to non-optimal, little reusable, and non/little evaluated KBS front-end solutions.
In this thesis we propose a more encompassing KBSE approach. Due to the strong mutual influences between KB and UI, we suggest a novel form of intertwined UI and KB development. We base the approach on three core components for encompassing KBSE:
(1) Extensible prototyping, a tailored form of evolutionary prototyping; this builds on mature UI prototypes and offers two extension steps for the anytime creation of core KBS prototypes (KB + core UI) and fully productive KBS (core KBS prototype + common framing functionality). (2) KBS UI patterns, that define reusable solutions for the core KBS UI/interaction; we provide a basic collection of such patterns in this work. (3) Suitable usability instruments for the assessment of the KBS artifacts. Therewith, we do not strive for ’yet another’ self-contained KBS engineering methodology. Rather, we motivate to extend existing approaches by the proposed key components. We demonstrate this based on an agile KBSE model.
For practical support, we introduce the tailored KBSE tool ProKEt. ProKEt offers a basic selection of KBS core UI patterns and corresponding configuration options out of the box; their further adaption/extension is possible on various levels of expertise. For practical usability support, ProKEt offers facilities for quantitative and qualitative data collection. ProKEt explicitly fosters the suggested, intertwined development of UI and KB. For seamlessly integrating KA activities, it provides extension points for two selected external KA tools: For KnowOF, a standard office based KA environment. And for KnowWE, a semantic wiki for collaborative KA. Therewith, ProKEt offers powerful support for encompassing, user-centered KBSE.
Finally, based on the approach and the tool, we also developed a novel KBS type: Clarification KBS as a mashup of consultation and justification KBS modules. Those denote a specifically suitable realization for participative KBS in highly expertise contexts and consequently require a specific design. In this thesis, apart from more common UI solutions, we particularly also introduce KBS UI patterns especially tailored towards Clarification KBS.
At the center of the Internet’s protocol stack stands the Internet Protocol (IP) as a common denominator that enables all communication. To make routing efficient, resilient, and scalable, several aspects must be considered. Care must be taken that traffic is well balanced to make efficient use of the existing network resources, both in failure free operation and in failure scenarios.
Finding the optimal routing in a network is an NP-complete problem. Therefore, routing optimization is usually performed using heuristics. This dissertation shows that a routing optimized with one objective function is often not good when looking at other objective functions. It can even be worse than unoptimized routing with respect to that objective function. After looking at failure-free routing and traffic distribution in different failure scenarios, the analysis is extended to include the loop-free alternate (LFA) IP fast reroute mechanism. Different application scenarios of LFAs are examined and a special focus is set on the fact that LFAs usually cannot protect all traffic in a network even against single link failures. Thus, the routing optimization for LFAs is targeted on both link utilization and failure coverage. Finally, the pre-congestion notification mechanism PCN for network admission control and overload protection is analyzed and optimized. Different design options for implementing the protocol are compared, before algorithms are developed for the calculation and optimization of protocol parameters and PCN-based routing.
The second part of the thesis tackles a routing problem that can only be resolved on a global scale. The scalability of the Internet is at risk since a major and intensifying growth of the interdomain routing tables has been observed. Several protocols and architectures are analyzed that can be used to make interdomain routing more scalable. The most promising approach is the locator/identifier (Loc/ID) split architecture which separates routing from host identification. This way, changes in connectivity, mobility of end hosts, or traffic-engineering activities are hidden from the routing in the core of the Internet and the routing tables can be kept much smaller. All of the currently proposed Loc/ID split approaches have their downsides. In particular, the fact that most architectures use the ID for routing outside the Internet’s core is a poor design, which inhibits many of the possible features of a new routing architecture. To better understand the problems and to provide a solution for a scalable routing design that implements a true Loc/ID split, the new GLI-Split protocol is developed in this thesis, which provides separation of global and local routing and uses an ID that is independent from any routing decisions.
Besides GLI-Split, several other new routing architectures implementing Loc/ID split have been proposed for the Internet. Most of them assume that a mapping system is queried for EID-to-RLOC mappings by an intermediate node at the border of an edge network. When the mapping system is queried by an intermediate node, packets are already on their way towards their destination, and therefore, the mapping system must be fast, scalable, secure, resilient, and should be able to relay packets without locators to nodes that can forward them to the correct destination. The dissertation develops a classification for all proposed mapping system architectures and shows their similarities and differences. Finally, the fast two-level mapping system FIRMS is developed. It includes security and resilience features as well as a relay service for initial packets of a flow when intermediate nodes encounter a cache miss for the EID-to-RLOC mapping.
A simple test setup has been developed at Institute of Aerospace Information Technology, University of Würzburg, Germany to realize basic functionalities for formation flight of quadrocopters. The test environment is planned to be utilized for developing and validating the algorithms for formation flying capability in real environment as well as for education purpose. An already existing test bed for single quadrocopter was extended with necessary inter-communication and distributed control mechanism to test the algorithms for formation flights in 2 degrees of freedom (roll / pitch). This study encompasses the domain of communication, control engineering and embedded systems programming. Bluetooth protocol has been used for inter-communication between two quadrocopters. A simple approach of PID control in combination with Kalman filter has been exploited. MATLAB Instrument Control Toolbox has been used for data display, plotting and analysis. Plots can be drawn in real-time and received information can also be stored in the form of files for later use and analysis. The test setup has been developed indigenously and at considerably low cost. Emphasis has been placed on simplicity to facilitate students learning process. Several lessons have been learnt during the course of development of this setup. Proposed setup is quite flexible that can be modified as per changing requirements.
Microbial species (bacteria and archaea) in the gut are important for human health in various ways. Not only does the species composition vary considerably within the human population, but each individual also appears to have its own strains of a given species. While it is known from studies of bacterial pan-genomes, that genetic variation between strains can differ considerably, such as in Escherichia coli, the extent of genetic variation of strains for abundant gut species has not been surveyed in a natural habitat. This is mainly due to the fact that most of these species cannot be cultured in the laboratory. Genetic variation can range from microscale genomic rearrangements such as small nucleotide polymorphism (SNP) to macroscale large genomic rearrangements like structural variations. Metagenomics offers an alternative solution to study genetic variation in prokaryotes, as it involves DNA sequencing of the whole community directly from the environment. However, most metagenomic studies to date only focus on variation in gene abundance and hence are not able to characterize genetic variation (in terms of presence or absence of SNPs and genes) of gut microbial strains of individuals.
The aim of my doctorate studies was therefore to study the extent of genetic variation in the genomic sequence of gut prokaryotic species and its phenotypic effects based on: (1) the impact of SNP variation in gut bacterial species, by focusing on genes under selective pressure and (2) the gene content variation (as a proxy for structural variation) and their effect on microbial species and the phenotypic traits of their human host.
In the first part of my doctorate studies, I was involved in a project in which we created a catalogue of 10.3 million SNPs in gut prokaryotic species, based on metagenomes. I used this to perform the first SNP-based comparative study of prokaryotic species evolution in a natural habitat. Here, I found that strains of gut microbial species in different individuals evolve at more similar rates than the strains within an individual. In addition, I found that gene evolution can be uncoupled from the evolution of its originating species, and that this could be related to selective pressure such as diet, exemplified by galactokinase gene (galK). Despite the individuality (i.e. uniqueness of each individual within the studied metagenomic dataset) in the SNP profile of the gut microbiota that we found, for most cases it is not possible to link SNPs with phenotypic differences. For this reason I also used gene content as a proxy to study structural variation in metagenomes.
In the second part of my doctorate studies, I developed a methodology to characterize the variability of gene content in gut bacterial species, using metagenomes. My approach is based on gene deletions, and was applied to abundant species (demonstrated using a set of 11 species). The method is sufficiently robust as it captures a similar range of gene content variability as has been detected in completely sequenced genomes. Using this procedure I found individuals differ by an average of 13% in their gene content of gut bacterial strains within the same species. Interestingly no two individuals shared the same gene content across bacterial species. However, this variation corresponds to a lower limit, as it is only accounts for gene deletion and not insertions. This large variation in the gene content of gut strain was found to affect important functions, such as polysaccharide utilization loci (PULs) and capsular polysaccharide synthesis (CPS), which are related with digestion of dietary fibers.
In summary, I have shown that metagenomics based approaches can be robust in characterizing genetic variation in gut bacterial species. I also illustrated, using examples both for SNPs and gene content (galK, PULs and CPS), that this genetic variation can be used to predict the phenotypic characteristics of the microbial species, as well as predicting the phenotype of their human host (for example, their capacity to digest different food components). Overall, the results of my thesis highlight the importance of characterizing the strains in the gut microbiome analogous to the emerging variability and importance of human genomics.
Protein kinases as targets for the development of novel drugs against alveolar echinococcosis
(2015)
The metacestode larval stage of the fox tapeworm Echinococcus multilocularis is the causative agent of alveolar echinococcosis (AE), one of the most lethal zoonosis of the northern hemisphere. The development of metacestode vesicles by asexual multiplication and the almost unrestricted infiltrative growth within the host organs is ensured from a population of undifferentiated, proliferative cells, so-called germinative cells. AE treatment options include surgery, if possible, as well as Benzimidazole-based chemotherapy (BZ). Given that the cellular targets of BZs, the -tubulins, are highly conserved between cestodes and humans, the chemotherapy is associated with considerable side-effects. Therefore, BZ can only be applied in parasitostatic doses and has to be given lifelong. Furthermore, the current anti-AE chemotherapy is ineffective in eliminating the germinative cell population of the parasite, which leads to remission of parasite growth as soon as therapy is discontinued.
This work focuses on protein kinases involved in the proliferation and development of the parasite with the intention of developing novel anti-AE therapies. Polo-like kinases (Plks) are important regulators of the eukaryotic cell cycle and are involved in the regulation and formation of the mitotic spindles during the M-phase of the cell cycle. Plks have already been shown to be associated with deregulated cellular growth in human cancers and have been investigated as novel drug targets in the flatworm parasite Schistosoma mansoni. In the first part of this work, the characterisation of a novel and druggable parasite enzyme, EmPlk1, which is homologous to the polo-like kinase 1 (Plk1) of humans and S. mansoni (SmPlk1), is presented. Through in situ hybridisation, it could be demonstrated that emplk1 is specifically expressed in the Echinococcus germinative cells. Upon heterologous expression in the Xenopus oocyte system, EmPlk1 induced germinal vesicle breakdown, thus indicating that it is an active kinase. Furthermore, BI 2536, a compound originally designed to inhibit the human ortholog of EmPlk1, inhibited the EmPlk1 activity at a concentration of 25 nM. In vitro treatment of parasite vesicles with similar concentrations of BI 2536 led to the elimination of the germinative cells from Echinococcus larvae, thus preventing the growth and further development of the parasite. In in vitro cultivation systems for parasite primary cells, BI 2536 effectively inhibited the formation of new metacestode vesicles from germinative cells. Thus, BI 2536 has profound anti-parasitic activities in vitro at concentrations well within the range of plasma levels measured after the administration of safe dosages to patients (50 nM after 24 h). This implies that EmPlk1 is a promising new drug target for the development of novel anti-AE drugs that would specifically affect the parasite’s stem cell population, namely the only parasite cells capable of proliferation. In addition to the chemotherapeutic aspects of this work, the inhibitor BI 2536 could be further used to study the function of stem cells in this model organism, utilising a method of injection of parasite stem cells into metacestode vesicles, for instance, as has been developed in this work.
In the second part of this work, a novel receptor tyrosine kinase, the Venus flytrap kinase receptor (EmVKR) of E. multilocularis has been characterised. Members of this class of single-pass transmembrane receptors have recently been discovered in the related trematode S. mansoni and are associated with the growth and differentiation of sporocyst germinal cells and ovocytes. The ortholog receptor in EmVKR is characterised by an unusual domain composition of an extracellular Venus flytrap module (VFT), which shows significant similarity to GABA receptors, such as the GABAB receptor (γ-amino butyric acid type B) and is linked through a single transmembrane domain to an intracellular tyrosine kinase domain with similarities to the kinase domains of human insulin receptors. Based upon the size (5112bp) of emvkr and nucleotide sequence specificities, efforts have been made to isolate the gene from cell culture samples to study the ligand for the activation of this receptor type in Xenopus oocytes. To date, this type of receptor has only been described in invertebrates, thus making it an attractive target for drug screening. In a first trial, the ATP competitive inhibitor AG 1024 was tested in our in vitro cell culture.
In conclusion, the EmVKR represents a novel receptor tyrosine kinase in E. multilocularis. Further efforts have to be made to identify the activating ligand of the receptor and its cellular function, which might strengthen the case for EmVKR as a potential drug target. The successful depletion of stem cells in the metacestode vesicle by the Plk1 inhibitor BI 2536 gives rise to optimising the chemical component for EmPlk1 as a new potential drug target. Furthermore, this inhibitor opens a new cell culture technique with high potential to study the cellular behaviour and influencing factors of stem cells in vitro.
Several aspects of the stability analysis of large-scale discrete-time systems are considered. An important feature is that the right-hand side does not have have to be continuous.
In particular, constructive approaches to compute Lyapunov functions are derived and applied to several system classes.
For large-scale systems, which are considered as an interconnection of smaller subsystems, we derive a new class of small-gain results, which do not require the subsystems to be robust in some sense. Moreover, we do not only study sufficiency of the conditions, but rather state an assumption under which these conditions are also necessary.
Moreover, gain construction methods are derived for several types of aggregation, quantifying how large a prescribed set of interconnection gains can be in order that a small-gain condition holds.
One of the most popular extensions of the SM is Supersymmetry (SUSY). It is a symmetry relating fermions and bosons and also the only feasible extension to the symmetries of spacetime. With SUSY it is then possible to explain some of the open questions left by the SM while at the same time opening the possibility of gauge unification at a high scale. SUSY theories require the addition of new particles, in particular an extra Higgs doublet and at least as many new scalars as fermions in the SM. Much in the same way that the Higgs boson breaks SU (2)L symmetry, these new scalars can break any symmetry for which they carry a charge through spontaneous symmetry breaking.
Let us assume there is a local minimum of the potential that reproduces the correct phenomenol- ogy for a parameter point of a given model. By exploring whether there are other deeper minima with VEVs that break symmetries we want to conserve, like SU (3)C or U (1)EM , it is possible to exclude regions of parameter space where that happens. The local minimum with the correct phenomenology might still be metastable, so it is also necessary to calculate the probability of tunneling between minima.
In this work we propose and apply a framework to constrain the parameter space of models with many scalars through the minimization of the one-loop eff e potential and the calculation of tunneling times at zero and non zero temperature.After a brief discussion about the shortcomings of the SM and an introduction of the basics of SUSY, we introduce the theory and numerical methods needed for a successful vacuum stability analysis. We then present Vevacious, a public code where we have implemented our proposed framework. Afterwards we go on to analyze three interesting examples.
For the constrained MSSM (CMSSM) we explore the existence of charge- and color- breaking (CCB) minima and see how it constraints the phenomenological relevant region of its parameter space at T = 0. We show that the regions reproducing the correct Higgs mass and the correct relic density for dark matter all overlap with regions suffering from deeper CCB minima.
Inspired by the results for the CMSSM, we then consider the natural MSSM and check the region of parameter space consistent with the correct Higgs mass against CCB minima at T /= 0. We find that regions of parameter space with CCB minima overlap significantly with that reproducing the correct Higgs mass. When thermal eff are considered the majority of such points are then found to have a desired symmetry breaking minimum with very low survival probability. In both these studies we find that analytical conditions presented in the literature fail in dis- criminating regions of parameter space with CCB minima. We also present a way of adapting our framework so that it runs quickly enough for use with parameter fit studies.
Lastly we show a different example of using vacuum stability in a phenomenological study. For the BLSSM we investigate the violation of R-parity through sneutrino VEVs and where in parameter space does this happen. We find that previous analyses in literature fail to identify regions with R-parity conservation by comparing their results to our full numerical analysis.
The learned helplessness phenomenon is a specific animal behavior induced by prior exposure to uncontrollable aversive stimuli. It was first found by Seligman and Maier (1967) in dogs and then has been reported in many other species, e.g. in rats (Vollmayr and Henn, 2001), in goldfishes (Padilla, 1970), in cockroaches (Brown, 1988) and also in fruit flies (Brown, 1996; Bertolucci, 2008). However, the learned helplessness effect in fruit flies (Drosophila melanogaster) has not been studied in detail. Thus, in this doctoral study, we investigated systematically learned helplessness behavior of Drosophila for the first time.
Three groups of flies were tested in heatbox. Control group was in the chambers experiencing constant, mild temperature. Second group, master flies were punished in their chambers by being heated if they stopped walking for 0.9s. The heat pulses ended as soon as they resumed walking again. A third group, the yoked fly, was in their chambers at the same time. However, their behavior didn’t affect anything: yoked flies were heated whenever master flies did, with same timing and durations. After certain amount of heating events, yoked flies associated their own behavior with the uncontrollability of the environment. They suppressed their innate responses such as reducing their walking time and walking speed; making longer escape latencies and less turning around behavior under heat pulses. Even after the conditioning phase, yoked flies showed lower activity level than master and control flies. Interestingly, we have also observed sex dimorphisms in flies. Male flies expressed learned helplessness not like female flies. Differences between master and yoked flies were smaller in male than in female flies. Another interesting finding was that prolonged or even repetition of training phases didn’t enhance learned helplessness effect in flies.
Furthermore, we investigated serotonergic and dopaminergic nervous systems in learned helplessness. Using genetic and pharmacological manipulations, we altered the levels of serotonin and dopamine in flies’ central nervous system. Female flies with reduced serotonin concentration didn’t show helpless behavior, while the learned helplessness effect in male flies seems not to be affected by a reduction of serotonin. Flies with lower dopamine level do not display the learned helplessness effect in the test phase, suggesting that with low dopamine the motivational change in learned helplessness in Drosophila may decline faster than with a normal dopamine level.
The focus of this work was the investigation of energy transfer between charge transfer states. For this purpose the multidimensional chromophores HAB-S, HAB-A, B1 and B2 were synthesised, each consisting of three electron donor and three electron acceptor redox centres linked symmetrically or asymmetrically by the hexaarylbenzene framework. Triarylamines represent in all these compounds the electron donors, whereas the electron poor centres were triarylboranes in B1 and B2 and PCTM centres in HAB-S and HAB-A, respectively. The hexaarylbenzenes were obtained by cobalt catalysed cyclotrimerisation of the respective tolan precursors. In addition, Star was synthesised, which consists of a central PCTM linked to three triarylamin centres by tolan bridging units in a star-like configuration. The hexaarylbenzene S1a/b substituted with six squaraine chromophores could not be realised. It is assumed that the cyclotrimerisation catalyst Co2(CO)8 does not tolerate the essential hydroxyl groups in the tolan precursor S2a. The alternative reaction pathway to execute the cyclotrimerisation reaction first and introduce the hydroxyl groups thereafter failed as well, because the required hexaarylbenzene substituted by six semisquaric acid moieties could not be synthesised. However, energy transfer interactions could be investigated in the tolan precursor S2a with two squaraine units to obtain information about the electronic coupling provided by the tolan bridge. For all multidimensional compounds model molecules were synthesised with only a single donor-acceptor pair (B3, Star-Model and HAB-Model). This allows a separate consideration of energy and charge transfer processes. It has to be stressed that in all before mentioned multidimensional compounds the “through bond” energy transfer interaction between neighbouring IV-CT states is identical to a transfer of a single electron between two redox centres of the same kind (e.g. TAA -> TAA+). The latter can be analysed by electron transfer theory. This situation is observed when the two IV-CT states transferring energy share one redox centre.
All compounds containing PCTM centres were characterised by paramagnetic resonance spectroscopy. Thereby, a weak interaction between the three PCTM units in HAB-S and HAB-A was observed. In addition, when oxidising Star-Model, a strongly interacting singlet or triplet state was obtained. In contrast, signals corresponding to a weakly interacting biradical were obtained for HAB-Model+. This indicates a strong electronic coupling between the redox centres provided by the tolan bridge and a weak coupling when linked by the hexaarylbenzene. This trend is supported by UV/Vis/NIR absorption measurements. The analysis of the observed IV-CT absorption bands by electron transfer theory reveals a weak electronic coupling of V = 340 cm-1 in HAB-Model and a distinctly stronger coupling of V = 1190-2900 cm-1 in Star-Model. In the oxidised HAB-S+, Star+ and Star-Model+ a charge transfer reversed from that of the neutral species, that is, from the PCTM radical to the electron poorer cationic TAA centre, was observed by spectroelectrochemistry. The temporal evolution of the excited states was monitored by ultrafast transient absorption measurements. Within the first picosecond stabilisation of the charge transfer state was observed, induced by solvent rotation. Anisotropic transient absorption measurements revealed that within the lifetime of the excited state (tau = 1-4 ps) energy transfer does not occur in the HABs whereas in the star-like system ultrafast and possibly coherent energy redistribution is observed. Taken this information together the identity between energy transfer and electron transfer in the specific systems were made apparent. It has to be remarked that neither energy transfer nor charge transfer theory can account for the very fast energy transfer in Star.
The electrochemical and photophysical properties of B1 and B2 were investigated by cyclic voltammetry, absorption and fluorescence measurements and were compared to B3 with only one neighbouring donor-acceptor pair. For the asymmetric B2 CV measurements show three oxidations as well as three reduction peaks whose peak separation is greatly influenced by the conducting salt due to ion-pairing and shielding effects. Consequently, peak separations cannot be interpreted in terms of electronic couplings in the generated mixed valence species. Transient absorption, fluorescence solvatochromism and absorption spectra show that charge transfer states from the amine to the boron centres are generated after optical excitation. The electronic donor-acceptor interaction is weak though as the charge transfer has to occur predominantly through space. The electronic coupling could not be quantified as the CT absorption band is superimposed by pi-pi* transitions localised at the amine and borane centres. However, this trend is in good agreement to the weak coupling measured for HAB-Model. Both transient absorption and fluorescence upconversion measurements indicate an ultrafast stabilisation of the charge transfer state in B1- B3 similar to the corresponding observations in HAB-S and Star. Moreover, the excitation energy of the localised excited charge transfer states can be redistributed between the aryl substituents of these multidimensional chromophores within fluorescence lifetime (ca. 60 ns). This was proved by steady state fluorescence anisotropy measurements, which further indicate a symmetry breaking in the superficially symmetric HAB. Anisotropic fluorescence upconversion measurements confirm this finding and reveal a time constant of tau = 2-3 ps for the energy transfer in B1 and B2. It has to be stressed that, although the geometric structures of B1 and HAB-S are both based on the same framework and furthermore the neighbouring CT states show in both cases similar Coulomb couplings and negligible “through bond” couplings, very fast energy transfer is observed in B1 whereas in HAB-S the energy is not redistributed within the excited state lifetime. To explain this, it has to be kept in mind that the energy transfer and the relaxation of the CT state are competing processes. The latter is influenced moreover by the solvent viscosity. Hence, it is assumed that this discrepancy in energy transfer behaviour is caused by monitoring the excited state in solvents of varying viscosity. Adding fluoride ions causes the boron centres to lose their acceptor ability due to complexation. Consequently, the charge transfer character in the donor-acceptor chromophores vanishes which could be observed in both the absorption and fluorescence spectra. However, the fluoride sensor ability of the boron centre is influenced strongly by the moisture content of the solvent possibly due to hydrogen bonding of water to the fluoride anions.
UV/Vis/NIR absorption measurements of S2a show a red-shift by 1800 cm-1 of the characteristic squarain band compared to the model compound S20. From exciton theory a Coulomb coupling of V = 410 cm-1 is calculated which cannot account for this strong spectral shift. Consequently, “through-bond” interactions have to contribute to the strong communication between the two squaraine chromophores in S2a. This is in accordance with the strong charge transfer coupling calculated for the tolan spacer in Star-Model.
The aim of this thesis is to examine the competition patterns that exist between originators and generics by focusing on the articulations between regulation and incentives to innovate.
Once the characteristics of regulation in pharmaceutical markets is reviewed in the first chapter and an analysis of some current challenges related to cost-containment measures and innovation issues is performed, then in the second chapter, an empirical study is performed to investigate substitution patterns. Based on the EC´s merger decisions in the pharmaceutical sector from 1989 to 2011, this study stresses the key criteria to define the scope of the relevant product market based on substitution patterns and shows the trend towards a narrower market in time.
Chapters three and four aim to analyse in depth two widespread measures, the internal reference pricing system in off-patent markets, and risk-sharing schemes in patent-protected markets. By taking into account informational advantages of originators over generics, the third chapter shows the extent to which the implementation of a reference price for off-patent markets can contribute in promoting innovation.
Finally, in the fourth chapter, the modeling of risk-sharing schemes explains how such schemes can help in solving moral hazard and adverse selection issues by continuously giving pharmaceutical companies incentives to innovate and supplying medicinal products of a higher quality.
Bereits seit Anfang der 1990er Jahre wird jungen Wissenschaftlern im Vorfeld der Tagung "Wirtschaftsinformatik" ein Doctoral Consortium als unterstützendes Forum angeboten. Diese Einrichtung wurde auch zur größten Internationalen Konferenz der Wirtschaftsinformatik, der WI 2015 in Osnabrück fortgeführt. Dieser Band fasst die zum Vortag ausgewählten Beiträge zusammen.
Division of labor represents a major advantage of social insect communities that accounts for their enormous ecological success. In colonies of the honeybee, Apis mellifera, division of labor comprises different tasks of fertile queens and drones (males) and, in general, sterile female workers. Division of labor also occurs among workers in form of an age-related polyethism. This helps them to deal with the great variety of tasks within the colony. After adult eclosion, workers spend around three weeks with various duties inside the hive such as tending the brood or cleaning and building cells. After this period workers switch to outdoor tasks and become foragers collecting nectar, pollen and water. With this behavioral transition, workers face tremendous changes in their sensory environment. In particular, visual sensory stimuli become important, but also the olfactory world changes. Foragers have to perform a completely new behavioral repertoire ranging from long distance navigation based on landmark orientation and polarized-skylight information to learning and memory tasks associated with finding profitable food sources. However, behavioral maturation is not a purely age-related internal program associated with a change, for example, in juvenile hormone titers. External factors such as primer pheromones like the brood pheromone or queen mandibular pheromone can modulate the timing of this transition. In this way colonies are able to flexibly adjust their work force distribution between indoor and outdoor tasks depending on the actual needs of the colony. Besides certain physiological changes, mainly affecting glandular tissue, the transition from indoor to outdoor tasks requires significant adaptations in sensory and higher-order integration centers of the brain.
The mushroom bodies integrate olfactory, visual, gustatory and mechanosensory information. Furthermore, they play important roles in learning and memory processes. It is therefore not surprising that the mushroom bodies, in particular their main input region, the calyx, undergo volumetric neuronal plasticity. Similar to behavioral maturation, plastic changes of the mushroom bodies are associated with age, but are also to be affected by modulating factors such as task and experience.
In my thesis, I analyzed in detail the neuronal processes underlying volumetric plasticity in the mushroom body. Immunohistochemical labeling of synaptic proteins combined with quantitative 3D confocal imaging revealed that the volume increase of the mushroom body calyx is largely caused by the growth of the Kenyon cell dendritic network. This outgrowth is accompanied by changes in the synaptic architecture of the mushroom body calyx, which is organized in a distinct pattern of synaptic complexes, so called microglomeruli. During the first week of natural adult maturation microglomeruli remain constant in total number. With subsequent behavioral transition from indoor duties to foraging, microglomeruli are pruned while the Kenyon cell dendritic network is still growing. As a result of these processes, the mushroom body calyx neuropil volume enlarges while the total number of microgloumeruli becomes reduced in foragers compared to indoor workers. In the visual subcompartments (calyx collar) this process is induced by visual sensory stimuli as the beginning of pruning correlates with the time window when workers start their first orientation flights. The high level of analysis of cellular and subcellular process underlying structural plasticity of the mushroom body calyx during natural maturation will serve as a framework for future investigations of behavioral plasticity in the honeybee.
The transition to foraging is not purely age-dependent, but gets modulated, for example, by the presence of foragers. Ethyl oleate, a primer pheromone that is present only in foragers, was shown to delay the onset of foraging in nurse bees. Using artificial application of additional ethyl oleate in triple cohort colonies, I tested whether it directly affects adult neuronal plasticity in the visual input region of the mushroom body calyx. As the pheromonal treatment failed to induce a clear behavioral phenotype (delayed onset of foraging) it was not possible to show a direct link between the exposure to additional ethyl oleate and neuronal plasticity in mushroom body calyx. However, the general results on synaptic maturation confirmed my data of natural maturation processes in the mushroom body calyx.
Given the result that dendritic plasticity is a major contributor to neuronal plasticity in the mushroom body calyx associated with division of labor, the question arose which proteins could be involved in mediating these effects. Calcium/calmodulin-dependent protein kinase II (CaMKII) especially in mammals, but also in insects (Drosophila, Cockroach), was shown to be involved in facilitating learning and memory processes like long-term synaptic potentiation. In addition to presynaptic effects, the protein was also revealed to directly interact with cytoskeleton elements in the postsynapse. It therefore is a likely candidate to mediate structural synaptic plasticity. As part of my thesis, the presence and distribution of CaMKII was analyzed, and the results showed that the protein is highly concentrated in a distinct subpopulation of the mushroom body intrinsic neurons, the noncompact Kenyon cells. The dendritic network of this population arborizes in two calyx subregions: one receiving mainly olfactory input – the lip – and the collar receiving visual input. This distribution pattern did not change with age or task. The high concentration of CaMKII in dendritic spines and its overlap with f-actin indicates that CaMKII could be a key player inducing structural neuronal plasticity associated with learning and memory formation and/or behavioral transitions related to division of labor. Interestingly CaMKII immunoreactivity was absent in the basal ring, another subregion of the mushroom body calyx formed almost exclusively by the inner compact Kenyon cells and known to receive combined visual and olfactory input. This indicates differences of this mushroom body subregion regarding the molecular mechanisms controlling plastic changes in corresponding Kenyon cells.
How is timing of behavioral and neuronal plasticity regulated? The primer pheromone ethyl oleate was found in high concentrations on foragers and was shown to influence behavioral maturation by delaying the onset of foraging when artificially applied in elevated concentrations. But how is ethyl oleate transferred and how does it shift the work force distribution between indoor and outdoor tasks? Previous work showed that ethyl oleate concentrations are highest in the honeycrop of foragers and suggested that it is transferred and communicated inside the colony via trophallaxis. The results of this thesis however clearly show, that ethyl oleate was not present inside the honey crop or the regurgitate, but rather in the surrounding tissue of the honey crop. As additionally the second highest concentration of ethyl oleate was measured on the surface of the cuticle of forgers, trophallaxis was ruled out as a mode of transmission. Neurophysiological measurements at the level of the antennae (electroantennogram recordings) and the first olfactory neuropil (calcium imaging of activity in the antennal lobe) revealed that the primer pheromone ethyl oleate is received and processed as an olfactory stimulus. Appetitive olfactory conditioning using the proboscis extension response as a behavioral paradigm showed that ethyl oleate can be associated with a sugar reward. This indicates that workers are able to perceive, learn and memorize the presence of this pheromone. As ethyl oleate had to be presented by a heated stimulation device at close range, it can be concluded that this primer pheromone acts via close range/contact chemoreception through the olfactory system. This is also supported by previous behavioral observations.
Taken together, the findings presented in this thesis revealed structural changes in the synaptic architecture of the mushroom body calyx associated with division of labor. For the primer pheromone ethyl oleate, which modulates the transition from nursing to foraging, the results clearly showed that it is received via the olfactory system and presumably acts via this pathway. However, manipulation experiments did not indicate a direct effect of ethyl oleate on synaptic plasticity. At the molecular level, CaMKII is a prime candidate to mediate structural synaptic plasticity in the mushroom body calyx. Future combined structural and functional experiments are needed to finally link the activity of primer pheromones like ethyl oleate to the molecular pathways mediating behavioral and synaptic plasticity associated with division of labor in Apis mellifera. The here identified underlying processes will serve as excellent models for a general understanding of fundamental mechanisms promoting behavioral plasticity.
Performance Assessment of Resource Management Strategies for Cellular and Wireless Mesh Networks
(2015)
The rapid growth in the field of communication networks has been truly amazing in the last decades. We are currently experiencing a continuation thereof with an increase in traffic and the emergence of new fields of application. In particular, the latter is interesting since due to advances in the networks and new devices, such as smartphones, tablet PCs, and all kinds of Internet-connected devices, new additional applications arise from different areas. What applies for all these services is that they come from very different directions and belong to different user groups. This results in a very heterogeneous application mix with different requirements and needs on the access networks.
The applications within these networks typically use the network technology as a matter of course, and expect that it works in all situations and for all sorts of purposes without any further intervention. Mobile TV, for example, assumes that the cellular networks support the streaming of video data. Likewise, mobile-connected electricity meters rely on the timely transmission of accounting data for electricity billing. From the perspective of the communication networks, this requires not only the technical realization for the individual case, but a broad consideration of all circumstances and all requirements of special devices and applications of the users.
Such a comprehensive consideration of all eventualities can only be achieved by a dynamic, customized, and intelligent management of the transmission resources. This management requires to exploit the theoretical capacity as much as possible while also taking system and network architecture as well as user and application demands into account. Hence, for a high level of customer satisfaction, all requirements of the customers and the applications need to be considered, which requires a multi-faceted resource management.
The prerequisite for supporting all devices and applications is consequently a holistic resource management at different levels. At the physical level, the technical possibilities provided by different access technologies, e.g., more transmission antennas, modulation and coding of data, possible cooperation between network elements, etc., need to be exploited on the one hand. On the other hand, interference and changing network conditions have to be counteracted at physical level. On the application and user level, the focus should be on the customer demands due to the currently increasing amount of different devices and diverse applications (medical, hobby, entertainment, business, civil protection, etc.).
The intention of this thesis is the development, investigation, and evaluation of a holistic resource management with respect to new application use cases and requirements for the networks. Therefore, different communication layers are investigated and corresponding approaches are developed using simulative methods as well as practical emulation in testbeds. The new approaches are designed with respect to different complexity and implementation levels in order to cover the design space of resource management in a systematic way. Since the approaches cannot be evaluated generally for all types of access networks, network-specific use cases and evaluations are finally carried out in addition to the conceptual design and the modeling of the scenario.
The first part is concerned with management of resources at physical layer. We study distributed resource allocation approaches under different settings. Due to the ambiguous performance objectives, a high spectrum reuse is conducted in current cellular networks. This results in possible interference between cells that transmit on the same frequencies. The focus is on the identification of approaches that are able to mitigate such interference.
Due to the heterogeneity of the applications in the networks, increasingly different application-specific requirements are experienced by the networks. Consequently, the focus is shifted in the second part from optimization of network parameters to consideration and integration of the application and user needs by adjusting network parameters. Therefore, application-aware resource management is introduced to enable efficient and customized access networks.
As indicated before, approaches cannot be evaluated generally for all types of access networks. Consequently, the third contribution is the definition and realization of the application-aware paradigm in different access networks. First, we address multi-hop wireless mesh networks. Finally, we focus with the fourth contribution on cellular networks. Application-aware resource management is applied here to the air interface between user device and the base station. Especially in cellular networks, the intensive cost-driven competition among the different operators facilitates the usage of such a resource management to provide cost-efficient and customized networks with respect to the running applications.
The propagation of the genetic information into proteins is mediated by messenger- RNA (mRNA) intermediates. In eukaryotes mRNAs are synthesized by RNA- Polymerase II and subjected to translation after various processing steps. Earlier it was suspected that the regulation of gene expression occurs primarily on the level of transcription. In the meantime it became evident that the contribution of post- transcriptional events is at least equally important. Apart from non-coding RNAs and metabolites, this process is in particular controlled by RNA-binding proteins, which assemble on mRNAs in various combinations to establish the so-called “mRNP- code”.
In this thesis a so far unknown component of the mRNP-code was identified and characterized. It constitutes a hetero-trimeric complex composed of the Tudor domain-containing protein 3 (TDRD3), the fragile X mental retardation protein (FMRP) and the Topoisomerase III beta (TOP3β) and was termed TTF (TOP3β-TDRD3-FMRP) -complex according to its composition.
The presented results also demonstrate that all components of the TTF-complex shuttle between the nucleus and the cytoplasm, but are predominantly located in the latter compartment under steady state conditions. Apart from that, an association of the TTF-complex with fully processed mRNAs, not yet engaged in productive translation, was detected. Hence, the TTF-complex is a component of „early“ mRNPs.
The defined recruitment of the TTF-complex to these mRNPs is not based on binding to distinct mRNA sequence-elements in cis, but rather on an interaction with the so-called exon junction complex (EJC), which is loaded onto the mRNA during the process of pre-mRNA splicing. In this context TDRD3 functions as an adapter, linking EJC, FMRP and TOP3β on the mRNP. Moreover, preliminary results suggest that epigenetic marks within gene promoter regions predetermine the transfer of the TTF-complex onto its target mRNAs.
Besides, the observation that TOP3β is able to catalytically convert RNA-substrates disclosed potential activities of the TTF-complex in mRNA metabolism. In combination with the already known functions of FMRP, this finding primarily suggests that the TTF-complex controls the translation of bound mRNAs.
In addition to its role in mRNA metabolism, the TTF-complex is interesting from a human genetics perspective as well. It was demonstrated in collaboration with researchers from Finland and the US that apart from FMRP, which was previously linked to neurocognitive diseases, also TOP3β is associated with neurodevelopmental disorders. Understanding the function of the TTF-complex in mRNA metabolism might hence provide important insight into the etiology of these diseases.
In this thesis, I present a model system for carbohydrate interactions with single-crystalline Ru surfaces. Geometric and electronic properties of copper phthalocyanine (CuPc) on top of graphene on hexagonal Ru(0001), rectangular Ru(10-10) and vicinal Ru(1,1,-2,10) surfaces have been studied. First, the Fermi surfaces and band structures of the three Ru surfaces were investigated by high-resolution angle-resolved photoemission spectroscopy. The experimental data and theoretical calculations allow to derive detailed information about the momentum-resolved electronic structure. The results can be used as a reference to understand the chemical and catalytic properties of Ru surfaces. Second, graphene layers were prepared on the three different Ru surfaces. Using low-energy electron diffraction and scanning tunneling microscopy, it was found that graphene can be grown in well-ordered structures on all three surfaces, hexagonal Ru(0001), rectangular Ru(10-10) and vicinal Ru(1,1,-2,10), although they have different surface symmetries. Evidence for a strong interaction between graphene and Ru surfaces is a 1.3-1.7e V increase in the graphene pi-bands binding energy with respect to free-standing graphene sheets. This energy variation is due to the hybridization between the graphene pi bands and the Ru 4d electrons, while the lattice mismatch does not play an important role in the bonding between graphene and Ru surfaces. Finally, the geometric and electronic structures of CuPc on Ru(10-10), graphene/Ru(10-10), and graphene/Ru(0001) have been studied in detail. CuPc molecules can be grown well-ordered on Ru(10-10) but not on Ru(0001). The growth of CuPc on graphene/Ru(10-10) and Ru(0001) is dominated by the Moire pattern of graphene. CuPc molecules form well-ordered structures with rectangular unit cells on graphene/Ru(10-10) and Ru(0001). The distance of adjacent CuPc molecules is 1.5 and 1.3 nm on graphene/Ru(0001) and 1.54 and 1.37 nm on graphene/Ru(10-10). This indicates that the molecule-substrate interaction dominates over the intermolecular interaction for CuPc molecules on graphene/Ru(10-10) and graphene/Ru(0001).
Analysis of discretization schemes for Fokker-Planck equations and related optimality systems
(2015)
The Fokker-Planck (FP) equation is a fundamental model in thermodynamic kinetic theories and
statistical mechanics.
In general, the FP equation appears in a number of different fields in natural sciences, for instance in solid-state physics, quantum optics, chemical physics, theoretical biology, and circuit theory. These equations also provide a powerful mean to define
robust control strategies for random models. The FP equations are partial differential equations (PDE) describing the time evolution of the probability density function (PDF) of stochastic processes.
These equations are of different types depending on the underlying stochastic process.
In particular, they are parabolic PDEs for the PDF of Ito processes, and hyperbolic PDEs for piecewise deterministic processes (PDP).
A fundamental axiom of probability calculus requires that the integral of the PDF over all the allowable state space must be equal to one, for all time. Therefore, for the purpose of accurate numerical simulation, a discretized FP equation must guarantee conservativeness of the total probability. Furthermore, since the
solution of the FP equation represents a probability density, any numerical scheme that approximates the FP equation is required to guarantee the positivity of the solution. In addition, an approximation scheme must be accurate and stable.
For these purposes, for parabolic FP equations on bounded domains, we investigate the Chang-Cooper (CC) scheme for space discretization and first- and
second-order backward time differencing. We prove that the resulting
space-time discretization schemes are accurate, conditionally stable, conservative, and preserve positivity.
Further, we discuss a finite difference discretization for the FP system corresponding to a PDP process in a bounded domain.
Next, we discuss FP equations in unbounded domains.
In this case, finite-difference or finite-element methods cannot be applied. By employing a suitable set of basis functions, spectral methods allow to treat unbounded domains. Since FP solutions decay exponentially at infinity, we consider Hermite functions as basis functions, which are Hermite polynomials multiplied by a Gaussian.
To this end, the Hermite spectral discretization is applied
to two different FP equations; the parabolic PDE corresponding to Ito processes, and the system of hyperbolic PDEs corresponding to a PDP process. The resulting discretized schemes are analyzed. Stability and spectral accuracy of the Hermite spectral discretization of the FP problems is proved. Furthermore, we investigate the conservativity of the solutions of FP equations discretized with the Hermite spectral scheme.
In the last part of this thesis, we discuss optimal control problems governed by FP equations on the characterization of their solution by optimality systems. We then investigate the Hermite spectral discretization of FP optimality systems in unbounded domains.
Within the framework of Hermite discretization, we obtain sparse-band systems of ordinary differential equations. We analyze the accuracy of the discretization schemes by showing spectral convergence in approximating the state, the adjoint, and the control variables that appear in the FP optimality systems.
To validate our theoretical estimates, we present results of numerical experiments.
Based on the results of a 3-day workshop at the Brown University (2012) this white paper tries to sum up important topics and problems which came up in the presentations and discussions and to outline some general aspects of data modeling in digital humanities. Starting with an attempt to define data modeling it introduces distinctions like curation-driven vs. research-driven for a more general description of data modeling. The second part discusses specific problems and challenges of data modeling in the Humanities, while the third part outlines practical aspects, like the creation of data models or their evaluation.
The article presents a proposal for the assessment of the quality of democracy. After elaborating on the methodological strategy, a definition of democracy is proposed, which entails the construction of the matrix of democracy based on three dimensions (political freedom, political equality, and political and judicial control) and five institutions. The methodological application of this measuring tool is then explained. This conception guarantees an appropriate measurement in different cultural contexts, enables the characterization of democratic profiles, and allows for the identification of deficiencies in democracies. Before the conclusion, three examples of the measurement (USA, Russia, and Italy) illustrate how the matrix works.
Context-specific Consistencies in Information Extraction: Rule-based and Probabilistic Approaches
(2015)
Large amounts of communication, documentation as well as knowledge and information are stored in textual documents. Most often, these texts like webpages, books, tweets or reports are only available in an unstructured representation since they are created and interpreted by humans. In order to take advantage of this huge amount of concealed information and to include it in analytic processes, it needs to be transformed into a structured representation. Information extraction considers exactly this task. It tries to identify well-defined entities and relations in unstructured data and especially in textual documents.
Interesting entities are often consistently structured within a certain context, especially in semi-structured texts. However, their actual composition varies and is possibly inconsistent among different contexts. Information extraction models stay behind their potential and return inferior results if they do not consider these consistencies during processing. This work presents a selection of practical and novel approaches for exploiting these context-specific consistencies in information extraction tasks. The approaches direct their attention not only to one technique, but are based on handcrafted rules as well as probabilistic models.
A new rule-based system called UIMA Ruta has been developed in order to provide optimal conditions for rule engineers. This system consists of a compact rule language with a high expressiveness and strong development support. Both elements facilitate rapid development of information extraction applications and improve the general engineering experience, which reduces the necessary efforts and costs when specifying rules.
The advantages and applicability of UIMA Ruta for exploiting context-specific consistencies are illustrated in three case studies. They utilize different engineering approaches for including the consistencies in the information extraction task. Either the recall is increased by finding additional entities with similar composition, or the precision is improved by filtering inconsistent entities. Furthermore, another case study highlights how transformation-based approaches are able to correct preliminary entities using the knowledge about the occurring consistencies.
The approaches of this work based on machine learning rely on Conditional Random Fields, popular probabilistic graphical models for sequence labeling. They take advantage of a consistency model, which is automatically induced during processing the document. The approach based on stacked graphical models utilizes the learnt descriptions as feature functions that have a static meaning for the model, but change their actual function for each document. The other two models extend the graph structure with additional factors dependent on the learnt model of consistency. They include feature functions for consistent and inconsistent entities as well as for additional positions that fulfill the consistencies.
The presented approaches are evaluated in three real-world domains: segmentation of scientific references, template extraction in curricula vitae, and identification and categorization of sections in clinical discharge letters. They are able to achieve remarkable results and provide an error reduction of up to 30% compared to usually applied techniques.