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Continuously increasing energy prices have considerably influenced the cost of living over the last decades. At the same time increasingly extreme weather conditions, drought-filled summers as well as autumns and winters with heavier rainfall and worsening storms have been reported. These are possibly the harbingers of the expected approaching global climate change. Considering the depletability of fossil energy sources and a rising distrust in nuclear power, investigations into new and innovative renewable energy sources are necessary to prepare for the coming future.
In addition to wind, hydro and biomass technologies, electricity generated by the direct conversion of incident sunlight is one of the most promising approaches. Since the syntheses and detailed studies of organic semiconducting polymers and fullerenes were intensified, a new kind of solar cell fabrication became conceivable. In addition to classical vacuum deposition techniques, organic cells were now also able to be processed from a solution, even on flexible substrates like plastic, fabric or paper.
An organic solar cell represents a complex electrical device influenced for instance by light interference for charge carrier generation. Also charge carrier recombination and transport mechanisms are important to its performance. In accordance to Coulomb interaction, this results in a specific distribution of the charge carriers and the electric field, which finally yield the measured current-voltage characteristics. Changes of certain parameters result in a complex response in the investigated device due to interactions between the physical processes. Consequently, it is necessary to find a way to generally predict the response of such a device to temperature changes for example.
In this work, a numerical, one-dimensional simulation has been developed based on the drift-diffusion equations for electrons, holes and excitons. The generation and recombination rates of the single species are defined according to a detailed balance approach. The Coulomb interaction between the single charge carriers is considered through the Poisson equation. An analytically non-solvable differential equation system is consequently set-up. With numerical approaches, valid solutions describing the macroscopic processes in organic solar cells can be found. An additional optical simulation is used to determine the spatially resolved charge carrier generation rates due to interference.
Concepts regarding organic semiconductors and solar cells are introduced in the first part of this work. All chapters are based on previous ones and logically outline the basic physics, device architectures, models of charge carrier generation and recombination as well as the mathematic and numerical approaches to obtain valid simulation results.
In the second part, the simulation is used to elaborate issues of current interest in organic solar cell research. This includes a basic understanding of how the open circuit voltage is generated and which processes limit its value. S-shaped current-voltage characteristics are explained assigning finite surface recombination velocities at metal electrodes piling-up local space charges. The power conversion efficiency is identified as a trade-off between charge carrier accumulation and charge extraction. This leads to an optimum of the power conversion efficiency at moderate to high charge carrier mobilities. Differences between recombination rates determined by different interpretations of identical experimental results are assigned to a spatially inhomogeneous recombination, relevant for almost all low mobility semiconductor devices.
Learning and memory is considered to require synaptic plasticity at presynaptic specializations of neurons. Kenyon cells are the intrinsic neurons of the primary olfactory learning center in the brain of arthropods – the mushroom body neuropils. An olfactory mushroom body memory trace is supposed to be located at the presynapses of Kenyon cells. In the calyx, a sub-compartment of the mushroom bodies, Kenyon cell dendrites receive olfactory input provided via projection neurons. Their output synapses, however, were thought to reside exclusively along their axonal projections outside the calyx, in the mushroom body lobes. By means of high-resolution imaging and with novel transgenic tools, we showed that the calyx of the fruit fly Drosophila melanogaster also comprised Kenyon cell presynapses. At these presynapses, synaptic vesicles were present, which were capable of neurotransmitter release upon stimulation. In addition, the newly identified Kenyon cell presynapses shared similarities with most other presynapses: their active zones, the sites of vesicle fusion, contained the proteins Bruchpilot and Syd-1. These proteins are part of the cytomatrix at the active zone, a scaffold controlling synaptic vesicle endo- and exocytosis. Kenyon cell presynapses were present in γ- and α/β-type KCs but not in α/β-type Kenyon cells.
The newly identified Kenyon cell derived presynapses in the calyx are candidate sites for an olfactory associative memory trace. We hypothesize that, as in mammals, recurrent neuronal activity might operate for memory retrieval in the fly olfactory system.
Moreover, we present evidence for structural synaptic plasticity in the mushroom body calyx. This is the first demonstration of synaptic plasticity in the central nervous system of Drosophila melanogaster. The volume of the mushroom body calyx can change according to changes in the environment. Also size and numbers of microglomeruli - sub-structures of the calyx, at which projection neurons contact Kenyon cells – can change. We investigated the synapses within the microglomeruli in detail by using new transgenic tools for visualizing presynaptic active zones and postsynaptic densities. Here, we could show, by disruption of the projection neuron - Kenyon cell circuit, that synapses of microglomeruli were subject to activity-dependent synaptic plasticity. Projection neurons that could not generate action potentials compensated their functional limitation by increasing the number of active zones per microglomerulus. Moreover, they built more and enlarged microglomeruli. Our data provide clear evidence for an activity-induced, structural synaptic plasticity as well as for the activity-induced reorganization of the olfactory circuitry in the mushroom body calyx.
Frequent acquisition activities in high-technology industries are due to the intense competition, driven by short product life cycles, more complex products/services and prevalent network effects. This dissertation theoretically analyzes the circumstances leading to technology-driven acquisitions and empirically tests these within a clearly defined market scenario.
Large-scale anatomical and functional analyses of the connectivity in both invertebrate and mammalian brains have gained intense attention in recent years. At the same time, the understanding of synapses on a molecular level still lacks behind. We have only begun to unravel the basic mechanisms of how the most important synaptic proteins regulate release and reception of neurotransmitter molecules, as well as changes of synaptic strength. Furthermore, little is known regarding the stoichiometry of presynaptic proteins at different synapses within an organism. An assessment of these characteristics would certainly promote our comprehension of the properties of different synapse types. Presynaptic proteins directly influence, for example, the probability of neurotransmitter release as well as mechanisms for short-term plasticity. We have examined the strength of expression of several presynaptic proteins at different synapse types in the central nervous system of Drosophila melanogaster using immunohistochemistry. Clear differences in the relative abundances of the proteins were obvious on different levels: variations in staining intensities appeared from the neuropil to the synaptic level. In order to quantify these differences, we have developed a ratiometric analysis of antibody stainings. By application of this ratiometric method, we could assign average ratios of presynaptic proteins to different synapse populations in two central relays of the olfactory pathway. In this manner, synapse types could be characterized by distinct fingerprints of presynaptic protein ratios. Subsequently, we used the method for the analysis of aberrant situations: we reduced levels of Bruchpilot, a major presynaptic protein, and ablated different synapse or cell types. Evoked changes of ratio fingerprints were proportional to the modifications we had induced in the system. Thus, such ratio signatures are well suited for the characterization of synapses. In order to contribute to our understanding of both the molecular composition and the function of synapses, we also characterized a novel synaptic protein. This protein, Drep-2, is a member of the Dff family of regulators of apoptosis. We generated drep-2 mutants, which did not show an obvious misregulation of apoptosis. By contrast, Drep-2 was found to be a neuronal protein, highly enriched for example at postsynaptic receptor fields of the input synapses of the major learning centre of insects, the mushroom bodies. Flies mutant for drep-2 were viable but lived shorter than wildtypes. Basic synaptic transmission at both peripheral and central synapses was in normal ranges. However, drep-2 mutants showed a number of deficiencies in adaptive behaviours: adult flies were locomotor hyperactive and hypersensitive towards ethanol-induced sedation. Moreover, the mutant animals were heavily impaired in associative learning. In aversive olfactory conditioning, drep-2 mutants formed neither short-term nor anaesthesia-sensitive memories. We could demonstrate that Drep-2 is required in mushroom body intrinsic neurons for normal olfactory learning. Furthermore, odour-evoked calcium transients in these neurons, a prerequisite for learning, were reduced in drep-2 mutants. The impairment of the mutants in olfactory learning could be fully rescued by pharmacological application of an agonist to metabotropic glutamate receptors (mGluRs). Quantitative mass spectrometry of Drep-2 complexes revealed that the protein is associated with a large number of translational repressors, among them the fragile X mental retardation protein FMRP. FMRP inhibits mGluR-mediated protein synthesis. Lack of this protein causes the fragile X syndrome, which constitutes the most frequent monogenic cause of autism. Examination of the performance of drep-2 mutants in courtship conditioning showed that the animals were deficient in both short- and long-term memory. Drep-2 mutants share these phenotypes with fmrp and mGluR mutants. Interestingly, drep-2; fmrp double mutants exhibited normal memory. Thus, we propose a model in which Drep-2 antagonizes FMRP in the regulation of mGluR-dependent protein synthesis. Our hypothesis is supported by the observation that impairments in synaptic plasticity can arise if mGluR signalling is imbalanced in either direction. We suggest that Drep-2 helps in establishing this balance.
Scientific surveys provide sufficient evidence that anxiety disorders are one of the most common psy-chiatric disorders in the world. The lifetime prevalence rate of anxiety disorder is 28.8% (Kessler, et al., 2005). The most widely studied anxiety disorders are as follows panic disorder (PD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), social phobia (or social anxiety disorder), specific phobias, and generalized anxiety disorder (GAD). (NIMH Article, 2009). Classical conditioning is the stable paradigm used from the last one century to understand the neurobi-ology of fear learning. Neurobiological mechanism of fear learning is well documented with the condi-tioning studies. In the therapy of anxiety disorders, exposure based therapies are known to be the most effective approaches. Flooding is a form of exposure therapy in which a participant is exposed to the fear situation and kept in that situation until their fear dissipates. The exposure therapy is based on the phenomena of extinction; this means that a conditioned response diminishes if the conditioned stimulus (CS) is repeatedly presented without an unconditioned stimulus (UCS). One problem with extinction as well as with exposure-based therapy is the problem of fear return (for e.g. renewal, spontaneous recov-ery and reinstatement) after successful extinction. Therefore, extinction does not delete the fear memory trace. It has been well documented that memory processes can be modulated or disrupted using several sci-entific paradigms such as behavioral (for e.g. exposure therapy), pharmacological (for e.g. drug manipu-lation), non-invasive stimulation (for e.g. non-invasive stimulation such as electroconvulsive shock (ECS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), etc. However, modulation of memory processes after reactivation or via non-invasive stimulation is still not clear, which is the focus of the current study. In addition, study of genetic variant suggests that genetic differences play a vital role in the psychiatric disorder especially in fear learning. Hence, it is also one of the concerns of the current dissertation to investigate the interaction between gene and reconsolidation of memory. With respect to fear-conditioning, there are three findings in the current dissertation, which are as fol-lows: (i) In the first study we investigated that non-invasive weak electrical stimulation interferes with the consolidation process and disrupts the fear consolidation to attain stable form. This might offer an effective treatment in the pathological memories, for e.g. PTSD, PD, etc. (ii) In the second study we demonstrated whether a brief single presentation of the CS will inhibit the fear recovery. Like earlier studies we also found that reactivation followed by reconsolidation douses fear return. Attenuation of fear recovery was observed in the reminder group compared to the no-reminder group. (iii) Finally, in our third study we found a statistically significant role of brain derived neurotrophic factor (BDNF) polymorphism in reconsolidation. Results of the third study affirm the involvement of BDNF variants (Met vs. Val) in the modulation of conditioned fear memory after its reactivation. In summary, we were able to show in the current thesis modulation of associative learning and recon-solidation via transcranial direct current stimulation and genetic polymorphism.
Bone Morphogenetic Proteins (BMPs) are key regulators for a lot of diverse cellular processes. During embryonic development these proteins act as morphogens and play a crucial role particularly in organogenesis. BMPs have a direct impact on distinct cellular fates by means of concentration-gradients in the developing embryos. Using the diverse signaling input information within the embryo due to the gradient, the cells transduce the varying extracellular information into distinct gene expression profiles and cell fate decisions. Furthermore, BMP proteins bear important functions in adult organisms like tissue homeostasis or regeneration. In contrast to TGF-ß signaling, currently only little is known about how cells decode and quantify incoming BMP signals. There is poor knowledge about the quantitative relationships between signal input, transducing molecules, their states and location, and finally their ability to incorporate graded systemic inputs and produce qualitative responses. A key requirement for efficient pathway modulation is the complete comprehension of this signaling network on a quantitative level as the BMP signaling pathway, just like many other signaling pathways, is a major target for medicative interference. I therefore at first studied the subcellular distribution of Smad1, which is the main signal transducing protein of the BMP signaling pathway, in a quantitative manner and in response to various types and levels of stimuli in murine c2c12 cells. Results indicate that the subcellular localization of Smad1 is not dependent on the initial BMP input. Surprisingly, only the phospho-Smad1 level is proportionally associated to ligand concentration. Furthermore, the activated transducer proteins were entirely located in the nucleus. Besides the subcellular localization of Smad1, I have analyzed the gene expression profile induced by BMP signaling. Therefore, I examined two endogenous immediate early BMP targets as well as the expression of the stably transgenic Gaussia Luciferase. Interestingly, the results of these independent experimental setups and read-outs suggest oscillating target gene expression. The amplitudes of the oscillations showed a precise concentration-dependence for continuous and transient stimulation. Additionally, even short-time stimulation of 15’ activates oscillating gene-expression pulses that are detectable for at least 30h post-stimulation. Only treatment with a BMP type I receptor kinase inhibitor leads to the complete abolishment of the target gene expression. This indicated that target gene expression oscillations depend directly on BMP type I receptor kinase activity.
Polycomb group (PcG) proteins are chromatin modifiers involved in heritable gene repression. Two main PcG complexes have been characterized: Polycomb repressive complex (PRC) 2 is involved in the initiation of gene silencing, whereas PRC1 participates in the stable maintenance of gene repression. Pcgf4 (Polycomb group protein, Bmi1) is one of the most studied PRC1 members with essential functions for embryonic development and adult stem cell self renewal. In embryonic stem cells (ES cells), Pcgf4 is poorly expressed while its paralogs (Pcgf1, Pcgf2, Pcgf3, Pcgf5 and Pcgf6) are expressed at higher levels. The relevance of the Pcgf paralog Pcgf6 for the maintenance of ESC pluripotency has not been addressed so far. My analyses revealed that Pcgf6 was the most expressed Pcgf paralog in undifferentiated ES cells. When ES cells differentiated, gene expression of Pcgf6 strongly declined. To investigate the functions of Pcgf6 in ES cells, we established a doxycycline (dox) inducible shRNA-targeted knockdown system according to publications by Seibler et al. (Seibler et al. 2005; Seibler et al. 2007). Following dox-induced knockdown (KD) of Pcgf6, we observed decreased ES cell colony formation. In parallel, gene expression of pluripotency markers Oct4, Nanog and Sox2 was reduced upon dox-treatment, wheras the expression of mesoderm genes such as T (Brachyury) were up-regulated. Further, microarray analysis revealed de-repression of several spermatogenesis-specic genes upon Pcgf6-KD, suggesting that Pcgf6 may play a role during spermatogenesis. Upon in vitro differentiation, Pcgf6-KD ES cells showed increased hemangioblast formation, paralleled by increased hematopoietic development. In summary, results of this study suggest that Pcgf6 is involved in maintaining ES cell identity by repressing lineage-specific gene expression in undifferentiated ES cells.
The transcription factor NFATc1 has been shown to regulate the activation and differentiation of T-cells and B-cells, of DCs and megakaryocytes. Dysregulation of NFAT signaling was shown to be associated with the generation of autoimmune diseases, malignant transformation and the development of cancer [71]. The primary goal of this work was to gain insights on Nfatc1 induction and regulation in lymphocytes and to find new direct NFATc1 target genes. Three new BAC -transgenic reporter mouse strains (tgNfatc1/Egfp, tgNfatc1/DE1 and tgNfatc1/DE2) were applied to analyze Nfatc1 induction and regulation in primary murine B- and T-cells. As a result, we were able to show the persistent requirement of immunoreceptor-signaling for constant Nfatc1 induction, particularly, for NFATc1/αA expression. Furthermore, we showed that NF-κB inducing agents, such as LPS, CpG or CD40 receptor engagement, in combination with primary receptor-signals, positively contributed to Nfact1 induction in B-cells [137]. We sought to establish a new system which could help to identify direct NFATc1 target genes by means of ChIP and NGS in genom-wide approaches. We were able to successfully generate a new BAC-transgene encoding a biotinylatable short isoform of NFATc1, which is currently injected into mice oocyte at the TFM in Mainz. In addition, in vivo biotinylatable NFATc1–isoforms were cloned and stably expressed in the murine B-cell lymphoma line WEHI-231. The successful use of these cells stably overexpressing either the short NFATc1/αA or the long NFATc1/βC isoform along with the bacterial BirA biotin ligase was confirmed by intracellular stainings, FACS analysis, confocal microscopy and protein IP. By NGS, we detected 2185 genes which are specifically controlled by NFATc1/αA, and 1306 genes which are exclusively controlled by NFATc1/βC. This shows that the Nfatc1 locus encodes “two genes” which exhibit alternate, in part opposite functions. Studies on the induction of apoptosis and cell-death revealed opposed roles for the highly inducible short isoform NFATc1/αA and the constantly expressed long isoform NFATc1/βC. These findings were confirmed by whole transcriptome-sequencing performed with cells overexpressing NFATc1/αA and NFATc1/βC. Several thousand genes were found to be significantly altered in their expression profile, preferentially genes involved in apoptosis and PCD for NFATc1/βC or genes involved in transcriptional regulation and cell-cycle processes for NFATc1/αA. In addition we were able to perform ChIP-seq for NFATc1/αA and NFATc1/βC in an ab-independent approach. We found potential new target-sites, but further studies will have to address this ambitious goal in the future. In individual ChIP assays, we showed direct binding of NFATc1/αA and NFATc1/βC to the Prdm1 and Aicda promoter regions which are individually controlled by the NFATc1 isoforms.
KasA is a key enzyme which plays an essential part in the biosynthetic pathway of mycolic acids, the building block of cell wall in Mycobacterium tuberculosis. Its importance was demonstrated by the finding that the depletion of KasA leads to the cell lysis of Mycobacterium tuberculosis. Since Mycobacterium tuberculosis is a pathogen of tuberculosis, the second leading cause of death from an infectious disease worldwide, KasA has drawn attention as one of the attractive drug targets against tuberculosis. Due to the emergence of extensively drug-resistant strains which make most of the known antibiotics for treating tuberculosis ineffective, it became an urgent issue to develop new drugs against tuberculosis. In chapter 3.1, the protonation state of the catalytic residues in the resting state was mainly addressed. The FEP computation and MD simulations were employed for this investigation, and the results showed that the zwitterionic state is most probable. To underpin this conclusion with more solid data, The PESs for the proton transfer between the neutral and zwitterionic state were computed in the context of QM/MM. However, due to the strong dependency of the QM/MM optimization on the initial structure, it was not possible to obtain consistent results from these computations. To circumvent this problem, QM/MM based umbrella sampling was carried out with a semi-empirical method (RM1), and the resulting PMF surface indicated that the zwitterionic state is more stable than the neutral state. In chapter 3.2, the protonation state of significant residues in the acyl-enzyme state was investigated. Unlike other catalytic residues, the protonation state of His311 is ambiguous in the acyl-enzyme state, and different decarboxylation mechanisms can be derived depending on the protonation state of His311 in the acyl-enzyme state. Therefore, FEP computations were carried out to find most probable protonation state of His311 in terms of free energy, and the results showed that the pKa value at Nδ is considerably lowered by the enzyme environment while that of Nε is not. Additionally, the PMF profiles for the proton transfer between Lys340 and Glu354 were computed using QM/MM based umbrellas sampling method, and the results showed that the property of the Lys340/Glu354 pair is neutral rather than ionic when His311 is protonated at Nε. Moreover, a relatively larger ionic character of the Lys340/Glu354 pair when His311 is doubly protonated provides a valuable insight into how the Lys340/Glu354 pair plays a role in shifting the protonated state from Nδ to Nε in His311 after the acyl-transfer step. Overall, the results demonstrated that His311 is neutral and protonated at Nε, and the Lys340/Glu354 pair is also neutral in the acyl-enzyme state. Those computational results lead to the conclusion that the decarboxylation reaction is facilitated by an oxyanion hole which is comprised of two catalytic histidines. In chapter 3.3, the protonation state of catalytic residues in the resting state was revisited because a recent benchmark study showed that the employed semi-empirical method (RM1) in chapter 3.1 tends to overestimate the stabilization of the zwitterionic state. Furthermore, the Lys340/Glu354 pair was considered as purely ionic in chapter 3.1, while it actually has a mixed neutral and ionic character as demonstrated in chapter 3.2. The new investigations employed a larger QM region including the Lys340/Glu354 pair with the BLYP/6-31G** approach, which was proven to be accurate enough for the present purpose by benchmark computations. The new results from the QM/MM MD and FEP computations indicated the catalytic residues to be neutral most probably in the resting state, and this in turn brought up the question how KasA can be activated to initiate the catalytic reaction. On the basis of the results from the MD simulations and FEP computations for the His311Ala mutant in chapter 3.1, we hypothesized that the open conformation of Phe404 would trigger the activation of the catalytic residues by the formation of a strong hydrogen bond. The QM/MM MD simulation proved that the activation of the catalytic residues can indeed be accomplished by the open conformation of Phe404 we suggested, and the corresponding force field based PMF profile also indicated that this conformational change is energetically feasible. The distribution of hydrophilic and hydrophobic residues in the malonyl binding pocket in conjunction with our computational results further provided a valuable insight into the detailed process how the catalytic residues is activated upon the substrate entering.
In the context of this thesis, the novel method soft X-ray energy-dispersive NEXAFS spectroscopy was explored and utilized to investigate intermolecular coupling and post-growth processes with a temporal resolution of seconds. 1,4,5,8- naphthalene tetracarboxylic acid dianhydride (NTCDA)multilayer films were the chosen model system for these investigations. The core hole-electron correlation in coherently coupled molecules was studied by means of energy-dispersive near-edge X-ray absorption fine-structure spectroscopy. A transient phase was found which exists during the transition between a disordered condensed phase and the bulk structure. This phase is characterized by distinct changes in the spectral line shape and energetic position of the X-ray absorption signal at the C K-edge. The findings were explained with the help of theoretical models based on the coupling of transition dipole moments, which are well established for optically excited systems. In consequence, the experimental results provides evidence for a core hole-electron pair delocalized over several molecules. Furthermore, the structure formation of NTCDA multilayer films on Ag(111) surfaces was investigated. With time-resolved and energy-dispersive NEXAFS experiments the intensity evolution in s- and p-polarization showed a very characteristic behavior. By combining these findings with the results of time-dependent photoemission measurements, several sub-processes were identified in the post- growth behavior. Upon annealing, the amorphous but preferentially flat-lying molecules flip into an upright orientation. After that follows a phase characterized by strong intermolecular coupling. Finally, three-dimensional islands are established. Employing the Kolmogorov-Johnson-Mehl-Avrami model, the activation energies of the sub-processes were determined.