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A completely revised and enhanced version of the water balance model MODBIL of the regional water balance dynamics of Cyprus was developed for this study. The model is based on a physical, process-oriented, spatially distributed concept and is applied for the calculation of all important water balance components of the island for the time period of 1961-2004. The calibrated results are statistically analysed and visualised for the whole island area, and evaluated with respect to the renewability of natural water resources. Climate variability and changes of the past decades are analysed with regard to their influence on water balances. A further part of the study focusses on the simulation of impacts of potential climate change. The water balances are simulated under changing climatic conditions on the base of theoretical precipitation, temperature and relative humidity changes and the revealed impacts on the water balances and renewable resources are discussed. Furthermore, a first principal water balance scenario is developed for the assessment of the regional hydrological changes expected for Cyprus by the end of the 21st century. The scenarios are based on recently calculated climate change assessments for this part of the Mediterranean, under an assumed further increase of greenhouse gasses in the atmosphere.
The voltage –gated calcium channel, Cav1.2, and the plasma membrane calcium ATPase, PMCA4b, play important roles in excitable and non-excitable cells. The central function of Cav1.2 is to regulate the calcium entry into cells upon depolarization, while PMCA4b is responsible for calcium extrusion and has an influence on cellular calcium homeostasis. Both proteins control fundamental functions in the heart and brain, but the specific functions and the precise mechanisms are still investigated. In order to identify new interaction partners that may regulate the activities of the Cav1.2 and the PMCA4b, we used three independent assays and co-localization studies. The assays, which were used are PDZ domain arrays (testing 124 different PDZ domains), GST pull-downs, and conventional immunoprecipitation assays. In the PDZ arrays, strongest interactions with Cav1.2 and PMCA4b were found for the PDZ domains of MAST-205, MAGI-1, MAGI-2, MAGI-3, and ZO-1. Additionally, we established interactions between Cav1.2 and the PDZ domains of NHERF1/2, Mint-2, and CASK. PMCA4b was observed to interact with Mint-2, and its interactions with Chapsyn-110 and CASK were confirmed. Furthermore, we validated interaction of Cav1.2 and PMCA4b with NHERF1, CASK, MAST-205 and MAGI-3 via immunoprecipitation. We also demonstrated direct interaction of the C-terminus of Cav1.2 and the PDZ domain of nNOS. We assumed that nNOS overexpression would reduce Ca2+ influx through Cav1.2. To address this question, we measured Ca2+ currents in stably transfected HEK 293 cells expressing the Cav1.2 (α1b and β2a subunit of the smooth muscle L-type calcium channel) and nNOS. It has been shown that NO modulates ion channel activity by nitrosylation of sulfhydryl groups on the channel protein. So we propose that the interaction between the C-terminus of Cav1.2 and the PDZ domain of nNOS inhibits the currents by an S-nitrosylation of the channel protein. All these interactions connect both proteins to signaling networks involved in signal transmission, cell adhesion, and apoptosis, which may help provide new hints about the physiological functions of Cav1.2 and PMCA4b in intra- and intercellular signaling.
Physiological Role of Fatty Acid Desaturation in Agrobacterium-induced Arabidopsis Crown Galls
(2011)
Crown gall development is accompanied by hypoxia, drought and oxidative stress. These abiotic stress factors are known to have an impact on fatty acid (FA) desaturation. Thus, an alteration in the lipid profile of plant tumors was expected. A comprehensive lipid analysis of Arabidopsis thaliana crown galls induced by Agrobacterium tumefaciens showed an increase in the degree of FA desaturation. The poly unsaturated fatty acid (PUFA) linolenic acid (18:3) of endoplasmic reticulum (ER) derived phospholipids was especially affected. The increased levels of desaturated FAs were reflected by a strong induction of two genes encoding desaturases, FAD3 and SAD6. In contrast to FAD3, which encodes the ER membrane bound fatty acid desaturase enzyme that synthesizes 18:3 PUFAs in the ER, the function of SAD6 is unknown. The ability of SAD6 to complement the extreme dwarf growth phenotype of the ssi2-2 mutant allele suggests that SAD6 is a functional stearoyl-acyl-carrier-protein delta-9 desaturase (SAD) which catalyzes the first step in FA desaturation and forms stearic acid (18:1). Overexpression of the SAD6 gene in Arabidopsis (SAD6-OE) to a similar degree as in tumors resulted in a light-dependent chlorosis phenotype and caused a similar shift in the lipid profile towards unsaturated phospholipids. Posttranscriptional down-regulation of SAD6 overexpression by RNA reverted the chlorosis phenotype and the changes in the lipid profile, showing that SAD6 overexpression forms the unsaturated FA profile and the phenotype in SAD6-OE. The subcellular localization of the SAD6 protein in chloroplasts, which is obligatory for SAD function was demonstrated. SSI2, which encodes the major contributor to the 18:1 FA levels in Arabidopsis is down-regulated in crown galls pointing to a replacement of SSI2 function by SAD6 in the tumor. SAD6 transcripts were almost undetectable in Arabidopsis under normal growth condition, whereas under hypoxia the gene was strongly activated. In the tumor hypoxia most likely caused the very high transcription of SAD6. Hypoxia is known to limit FA desaturation and it is associated with an elevated reactive oxygen species (ROS) production which is detrimental for unsaturated FAs. Thus, up-regulation of SAD6 in the crown gall, most likely serves as an adaptive mechanism to activate desaturation under low oxygen concentrations and to maintain the levels of unsaturated FA under oxidative stress. The ER localized FAD3 most likely is responsible for the rise in 18:3 of the phospholipid class to cope with drought stress in crown galls. This hypothesis was supported by the loss of function mutant, fad3-2, which developed significantly smaller tumors as the wild type under low relative humidity.Taken together, this study suggests that the induction of SAD6 and FAD3 shapes the tumor lipid profile by increasing the levels of unsaturated FAs. Unsaturated fatty acids prepare the crown gall to cope with ongoing hypoxia, drought and oxidative stress during growth and development.
Effective T cell immunity was believed to occur by mature DC, whereas tolerogenicity was attributed strictly to immature DC phenotypes. However, intermediate DC maturation stages were identified conditioned by inflammatory mediators like TNF. Furthermore, the T cell tolerance mechanisms are dependent on distinct modes and intensities of co-stimulation. Therefore, in this study it was addressed how distinct DC maturation signatures instruct CD4+ T cell tolerance mechanisms. DC acquire antigens from apoptotic cells for self-peptide-MHC presentation and functionally adapt presumed tolerogenic DC phenotypes. Here, immature murine bone-marrow derived DC representing both inflammatory and conventional DC subsets adapted a maturationresistant DC signature upon apoptotic cell recognition but no additional tolerogenic features. Immature DC instruct CD4+ FoxP3+ regulatory T cells in a TGF-β prone micro-environment or generate anergic CD4+ T cells hampered in the TCR-induced proliferation and IL-2 secretion. Secondary stimulation of such anergic CD4+ T cells by immature DC increased primarily IL-10 production and conferred regulatory function. These IL-10+ regulatory T cells expressed high levels of CTLA-4, which is potently induced by immature DC in particular. Data in this work showed that anergic T cells can be re-programmed to become IL-10+ regulatory T cells upon ligation of CTLA-4 and CD28 signalling cascades by B7 costimulatory ligands on immature DC. In contrast, semi-mature DC phenotypes conditioned by the inflammatory mediator TNF prevented autoimmune disorders by induction of IL-10+ Th2 responses as demonstrated previously. Here, it was shown that TNF as an endogenous maturation stimulus and pathogenic Trypanosoma brucei variant-specific surface glycoproteins (VSG) induced highly similar DC gene expression signatures which instructed default effector Th2 responses. Repetitive administration of the differentially conditioned semi-mature DC effectively skewed T cell immunity to IL-10+ Th2 cells, mediating immune deviation and suppression. Collectively, the data presented in this work provide novel insights how immature and partially mature DC phenotypes generate T cell tolerance mechanisms in vitro, which has important implications for the design of effective DC-targeted vaccines. Unravelling the DC maturation signatures is central to the long-standing quest to break tolerance mimicked by malignant tumours or re-establish immune homeostasis in allergic or autoimmune disorders.
XPD is a 5‘-3‘ helicase of the superfamily 2. As part of the transcription factor IIH it functions in transcription initiation and nucleotide excision repair. This work focus on the role of XPD in nucleotide excision repair. NER is a DNA repair pathway unique for its broad substrate range. In placental mammals NER is the only repair mechanism able to remove lesions induced by UV-light. NER can be divided into four different steps that are conserved between pro- and eukaryotes. Step 1 consists of the initial damage recognition, during step 2 the putative damage is verified, in step 3 the verified damage is excised and in the 4th and final step the resulting gap in the DNA is refilled. XPD was shown to be involved in the damage verification step. It was possible to solve the first apo XPD structure by a MAD approach using only the endogenous iron from the iron sulfur cluster. Based on the apo XPD structure several questions arise: where is DNA bound? Where is DNA separated? How is damage verification achieved? What is the role of the FeS cluster? These questions were addressed in this work. Hypothesis driven structure based functional mutagenesis was employed and combined with detailed biochemical characterization of the variants. The variants were analyzed by thermal unfolding studies to exclude the possibility that the overall stability could be affected by the point mutation. DNA binding assays, ATPase assays and helicase assays were performed to delineate amino acid residues important for DNA binding, helicase activity and damage recognition. A structure of XPD containing a four base pair DNA fragment was solved by molecular replacement. This structure displays the polarity of the translocated strand with respect to the helicase framework. Moreover the properties of the FeS cluster were studied by electron paramagnetic resonance to get insights into the role of the FeS cluster. Furthermore XPD from Ferroplasma acidarmanus was investigated since it was shown that it is stalled at CPD containing lesions. The data provide the first detailed insight into the translocation mechanism of a SF2B helicase and reveal how polarity is achieved. This provides a basis for further anlayses understanding the combined action of the helicase and the 4Fe4S cluster to accomplish damage verification within the NER cascade.
The technology of organic photovoltaics offers the possibility of low-cost devices due to easy fabrication procedures and low material consumption and at the same time high flexibility concerning the applied substrates or design features such as the color palette. Owing to these benefits, this research field is highly active, being reflected by the continuously rising number of publications. Chapter 1 gives an extensive overview of a part of these reports, namely the field of solution-processed BHJ organic solar cells using small molecules as electron-donating materials. In the early years of this research area (2006-2008), well known hole transporting materials such as triphenylamine based chromophores, oligothiophenes and polyaromatic hydrocarbons were applied. However, many of these dyes lacked absorption at longer wavelengths and were therefore limited in their light harvesting qualities. Later, chromophores based on low band gap systems consisting of electron-donating and electron-accepting units showing internal charge transfer overcame this handicap. Today, donor-substituted diketopyrrolopyrroles (D-A-D chromophores), squaraines (D-A-D chromophores) and acceptor substituted oligothiophenes (A-D-A chromophores) are among the most promising dyes for small molecule based organic solar cells with PCEs of 4-5%. This work is based on the findings of the groups of Würthner and Meerholz, which tested merocyanine dyes for the first time in organic BHJ solar cells.4 According to the Bässler theory85, the high dipolarity of these dyes should hamper the charge transport, but the obtained first results with PCE of 1.7% proved the potenital of this class of dyes for this application. Merocyanine dyes offer the advantages of facile synthesis and purification, high tinctorial strength and monodispersity. Additionally, the electronic structure of the dyes, namely the absorption as well as the electrochemical properties, can be adjusted by using the right combination of donor and acceptor units. For these reasons, this class of dye is highly interesting for the application in organic solar cells. It was the aim of the thesis to build more knowledge about the potential and limitations of merocyanines in BHJ photovoltaic devices. By screening a variety of donor and acceptor groups a comprehensive data set both for the molecular materials as well as for the respective solar devices was generated and analyzed. As one focus, the arrangement of the chromophores in the solid state was investigated to gain insight about the packing in the solar cells and its relevance for the performance of the latter. To do so, X-ray single crystal analyses were performed for selected molecules. By means of correlations between molecular properties and the characteristics of the corresponding solar cells, several design rules to generate efficient chromophores for organic photovoltaics were developed. The different donor and acceptor moieties applied in this work are depicted in the following ...
Just do it! Guilt as a moral intuition to cooperate - A parallel constraint satisfaction approach
(2011)
After a long dominance of rational models of judgment and decision-making in moral psychology (e.g. Kohlberg, 1969) there is now a strong interest in how intuitions and emotions influence moral judgments and decisions (e.g. Greene, 2007; Haidt, 2001; Monin, Pizarro, & Beer, 2007). In the literature, the influence of emotions on moral decisions is explained by heuristic or non-compensatory information processing (e.g. Sinnott-Armstrong, Young, & Cushman, 2010; Sunstein, 2005; Tobler, Kalis, & Kalenscher, 2008). However, the process of emotion elicitation is ignored. Appraisal theories postulate that emotion elicitation is due to the incoherence (or discrepancy) of behavioral representations like goals and actions (Moors, 2009). Emotion elicitation and intuitive decision-making can be combined if both processes apply a connectionist information processing structure (e.g. Barnes & Thagard, 1996). The current work contrasts both perspectives of intuitive-emotional decision-making with respect to guilt and cooperation.
This thesis investigated the potential of Compressed Sensing (CS) applied to Magnetic Resonance Imaging (MRI). CS is a novel image reconstruction method that emerged from the field of information theory. The framework of CS was first published in technical reports in 2004 by Candès and Donoho. Two years later, the theory of CS was published in a conference abstract and two papers. Candès and Donoho proved that it is possible, with overwhelming probability, to reconstruct a noise-free sparse signal from incomplete frequency samples (e.g., Fourier coefficients). Hereby, it is assumed a priori that the desired signal for reconstruction is sparse. A signal is considered “sparse“ when the number of non-zero elements is significantly smaller than the number of all elements. Sparsity is the most important foundation of CS. When an ideal noise-free signal with few non-zero elements is given, it should be understandably possible to obtain the relevant information from fewer Fourier coefficients than dictated by the Nyquist-Shannon criterion. The theory of CS is based on noise-free sparse signals. As soon as noise is introduced, no exact sparsity can be specified since all elements have signal intensities that are non-zero. However, with the addition of little or moderate noise, an approximate sparsity that can be exploited using the CS framework will still be given. The ability to reconstruct noisy undersampled sparse MRI data using CS has been extensively demonstrated. Although most MR datasets are not sparse in image space, they can be efficiently sparsified by a sparsifying transform. In this thesis, the data are either sparse in the image domain, after Discrete Gradient transformation, or after subtraction of a temporally averaged dataset from the data to be reconstructed (dynamic imaging). The aim of this thesis was to identify possible applications of CS to MRI. Two different algorithms were considered for reconstructing the undersampled sparse data with the CS concept. The Nonlinear Conjugate Gradient based technique with a relaxed data consistency constraint as suggested by Lustig et al. is termed Relaxed DC method. An alternative represents the Gradient or Steepest Descent algorithm with strict data consistency and is, therefore, termed the Strict DC method. Chapter 3 presents simulations illustrating which of these two reconstruction algorithms is best suited to recover undersampled sparse MR datasets. The results lead to the decision for the Strict DC method as reconstruction technique in this thesis. After these simulations, different applications and extensions of CS are demonstrated. Chapter 4 shows how CS benefits spectroscopic 19F imaging at 7 T, allowing a significant reduction of measurement times during in vivo experiments. Furthermore, it allows highly resolved spectroscopic 3D imaging in acceptable measurement times for in vivo applications. Chapter 5 introduces an extension of the Strict DC method called CS-CC (CS on Combined Coils), which allows efficient processing of sparse undersampled multi-coil data. It takes advantage of a concept named “Joint Sparsity“, which exploits the fact that all channels of a coil array detect the same sparse object weighted with the coil sensitivity profiles. The practical use of this new algorithm is demonstrated in dynamic radial cardiac imaging. Accurate reconstructions of cardiac motion in free breathing without ECG triggering were obtained for high undersampling factors. An Iterative GRAPPA algorithm is introduced in Chapter 6 that can recover undersampled data from arbitrary (Non-Cartesian) trajectories and works solely in the Cartesian plane. This characteristic makes the proposed Iterative GRAPPA computationally more efficient than SPIRiT. Iterative GRAPPA was developed in a preceding step to combine parallel imaging with CS. Optimal parameters for Iterative GRAPPA (e.g. number of iterations, GRAPPA kernel size) were determined in phantom experiments and verified by retrospectively undersampling and reconstructing a radial cardiac cine dataset. The synergistic combination of the coil-by-coil Strict DC CS method and Iterative GRAPPA called CS-GRAPPA is presented in Chapter 7. CS-GRAPPA allows accurate reconstruction of undersampled data from even higher acceleration factors than each individual method. It is a formulation equivalent to L1-SPIRiT but computationally more efficient. Additionally, a comparison with CS-CC is given. Interestingly, exploiting joint sparsity in CS-CC is slightly more efficient than the proposed CS-GRAPPA, a hybrid of parallel imaging and CS. The last chapter of this thesis concludes the findings presented in this dissertation. Future applications expected to benefit from CS are discussed and possible synergistic combinations with other existing MR methodologies for accelerated imaging are also contemplated.
This work deals with nonlinear optics with wavefront controlled ultra-short laser pulses. The effects studied are self-phase modulation due to filamentation of ultra-short laser pulses and high-order harmonic generation in a jet of noble gas. Additionally, a way to optimize the spectral brilliance of the high-order harmonic source is studied by measuring the spectrum and wavefront of the generated XUV beam.
Magnetic resonance imaging (MRI) is a medical imaging method that involves no ionizing radiation and can be used non-invasively. Another important - if not the most important - reason for the widespread and increasing use of MRI in clinical practice is its interesting and highly flexible image contrast, especially of biological tissue. The main disadvantages of MRI, compared to other widespread imaging modalities like computed tomography (CT), are long measurement times and the directly resulting high costs. In the first part of this work, a new technique for accelerated MRI parameter mapping using a radial IR TrueFISP sequence is presented. IR TrueFISP is a very fast method for the simultaneous quantification of proton density, the longitudinal relaxation time T1, and the transverse relaxation time T2. Chapter 2 presents speed improvements to the original IR TrueFISP method. Using a radial view-sharing technique, it was possible to obtain a full set of relaxometry data in under 6 s per slice. Furthermore, chapter 3 presents the investigation and correction of two major sources of error of the IR TrueFISP method, namely magnetization transfer and imperfect slice profiles. In the second part of this work, a new MRI thermometry method is presented that can be used in MRI-safety investigations of medical implants, e.g. cardiac pacemakers and implantable cardioverter-defibrillators (ICDs). One of the major safety risks associated with MRI examinations of pacemaker and ICD patients is RF induced heating of the pacing electrodes. The design of MRI-safe (or MRI-conditional) pacing electrodes requires elaborate testing. In a first step, many different electrode shapes, electrode positions and sequence parameters are tested in a gel phantom with its geometry and conductivity matched to a human body. The resulting temperature increase is typically observed using temperature probes that are placed at various positions in the gel phantom. An alternative to this local thermometry approach is to use MRI for the temperature measurement. Chapter 5 describes a new approach for MRI thermometry that allows MRI thermometry during RF heating caused by the MRI sequence itself. Specifically, a proton resonance frequency (PRF) shift MRI thermometry method was combined with an MR heating sequence. The method was validated in a gel phantom, with a copper wire serving as a simple model for a medical implant.