Resonant Multi-Photon Ionization Experiments on Neon Monomers and Dimers Augmented by Pulse Intensity and Wavelength Diagnostics

This thesis deals with experiments on resonant multi-photon double ionization of Neon monomers and dimers. Experiments were carried out at the reaction microscope beamline of the XUV free-electron laser FLASH2. Employing the variable gap undulators of FLASH2, the photon energy was scanned over the 2s-2p resonance in ionic Ne+ at 26:9 eV, where resonance-enhanced sequential ionization and single-photon laser-enabled Auger decay (spLEAD) is expected for monomers and Interatomic Coulombic Decay (ICD) for dimers. As FLASH2 operates in SASE mode, which leads to large statistical fluctuations, post-analysis of single-shot diagnostics was developed and performed. The pulse energy was monitored through a photocurrent on the final focusing mirror and the photon energy with an electron spectrometer. Through single-shot analysis of the pulse-energy better insight into the power scaling of the ionization rates could be gained

Structural Exploration of Different Binding Pockets Suitable to Affect Protein Kinases CK2α and CK2α’ With Peptides and Small Molecules

The eukaryotic protein kinase CK2, previously known as casein kinase 2, is a ubiquitously expressed, acidophilic serine/threonine kinase belonging to a branch of the group of CMGC kinases. The enzyme features several peculiarities, one of which is its extraordinary pleiotropic character. A plethora of biological substrates have been described for CK2 to date and these are, among others, involved in cell proliferation, angiogenesis, apoptotic processes, viral infections, and DNA-damage repair. Several of these substrates play key roles in the development and progression of a diverse spectrum of diseases. The ubiquitous presence of CK2, combined with its unusual constitutive activity, presents a highly interesting pharmacological profile as a promising drug target. In particular, neoplastic diseases are significantly driven by high levels of CK2 and the importance of the search for suitable molecules to alter the enzymatic properties of CK2 is therefore evident and a subject of current research. This thesis also contributes to this field, focusing primarily on the investigation of the structural aspects of various protein-ligand interactions at different binding sites of the enzyme. An important role in these structural studies is accounted by CK2α’, a paralog of the catalytic subunit CK2α. Although the two paralogs are highly similar in many respects, CK2α’ has been neglected in CK2 research over the past decades due to its poor biochemical handleability and its insufficient crystallization properties. Therefore, in this work, for the first time, a crystallization protocol was developed that reliably yields CK2α structures with an atomic resolution of 1.0 Å and thereby outperforming all previously existing CK2α structures to date. This protocol has proven to be an extremely valuable crystallographic tool to study the precise binding mode of a wide variety of CK2 inhibitors from different substance classes, including high and low-affinity compounds. As an example, the exact binding site and binding mode of different 2 aminothiazole derivatives could be elucidated. These compounds belong to a class of CK2 inhibitors that were erroneously assumed to bind outside the cosubstrate pocket. In addition to crystallographic studies, organic syntheses were also conducted as part of the research for this thesis. This includes the synthesis of halogenated cyclic peptides which address the α/β interface area of the catalytic subunits, interfering with CK2β binding and thus with the tetrameric holoenzyme assembly. Furthermore, by conjugating with the cell-penetrating peptide sC18, it was possible to investigate the impact of some of these compounds on different cell lines. Moreover, different 4,5,6,7 tetrabromobenzimidazole derivatives were synthesized and studied. In particular, the bivalent inhibitor KN2, which simultaneously occupies the cosubstrate binding pocket as well as the recently discovered αD binding pocket, proved to be exceptionally high in affinity and outstandingly selective. The aspect of selectivity has always been a particular challenge for kinase inhibitors due to the high degree of conservation of the cosubstrate binding region among eukaryotic protein kinases. The inclusion of the αD binding pocket is currently one of the most promising approaches to overcome this challenge since the high plasticity in this region has exclusively been described for CK2. In this thesis, it was shown for the first time that this is not only true for CK2α, but rather for both paralogs. Finally, the crystallization successes with CK2α’ and an eight-month desalting procedure led to the discovery of a novel binding site, located close to the N-terminus. However, the suitability of this cryptic site for the design of future generations of CK2 inhibitors requires further studies

Energy and Charge Transfer in Dimers and Trimers of Xenon

The goal of this thesis is the investigation of decay processes in innershell ionised xenon dimers and trimers. To this end, the small clusters were ionised using 100 eV photons from a Free-Electron Laser and the momenta of the created ion fragments and electrons were measured using the Reaction Microscope at FLASH2. Employing an XUV/XUV pump-probe scheme, the timescale to distribute energy or charge throughout the cluster following local excitation was determined to below (186+-6) fs for dimers decaying into Xe^{1+} / Xe^{2+} and (84+-13) fs for trimers decaying into Xe^{1+}/Xe^{1+}/Xe^{1+}. The kinetic energy distributions yield clear evidence that Xe_2^{2+} decays by a slow CT process after bond contraction and Xe_3^{2+*} decays by ETMD(3) before the nuclei can move. Furthermore, we see signatures of frustrated ionisation in Xe_2 dimers

Trau, SCHAU, wem? - V-IDS oder eine andere Sicht der Dinge

Die ständig wachsende Flut der in einem Netzwerk anfallenden sicherheitsrelevanten Daten macht in zunehmendem Maße neue Darstellungsformen notwendig. Nur so können diese Daten ausreichend schnell und in angemessenem Umfang erfassbar und beherrschbar bleiben. Wesentlich schneller und intuitiver als reinen Text können wir den Inhalt von Bildern erfassen, grafische Darstellungen machen Geschehnisse in der Regel leichter erfassbar. Informationen können zusätzlich stärker verdichtet dargestellt werden, ohne dass der transportierte Inhalt darunter leidet. Die Darstellung von Sicherheitsdaten in grafischer Form steht derzeit noch sehr am Anfang, es gibt wenig Erfahrung, welche Darstellungen mehr und welche weniger geeignet sind. V-IDS soll Grundlagen legen für eine dynamische, dreidimensionale Darstellung solcher Daten. Es soll ein einfaches Experimentieren mit verschiedenen und neuartigen Darstellungen ermöglichen. Damit können dann vorhandene und zukünftige Ideen einfach und ohne längere Entwicklungszeit prototypisch umgesetzt und bewertet werden

"Wet-to-Dry" Conformational Transition of Polymer Layers Grafted to Nanoparticles in Nanocomposite

The present communication reports the first direct measurement of the conformation of a polymer corona grafted around silica nano-particles dispersed inside a nanocomposite, a matrix of the same polymer. This measurement constitutes an experimental breakthrough based on a refined combination of chemical synthesis, which permits to match the contribution of the neutron silica signal inside the composite, and the use of complementary scattering methods SANS and SAXS to extract the grafted polymer layer form factor from the inter-particles silica structure factor. The modelization of the signal of the grafted polymer on nanoparticles inside the matrix and the direct comparison with the form factor of the same particles in solution show a clear-cut change of the polymer conformation from bulk to the nanocomposite: a transition from a stretched and swollen form in solution to a Gaussian conformation in the matrix followed with a compression of a factor two of the grafted corona. In the probed range, increasing the interactions between the grafted particles (by increasing the particle volume fraction) or between the grafted and the free matrix chains (decreasing the grafted-free chain length ratio) does not influence the amplitude of the grafted brush compression. This is the first direct observation of the wet-to-dry conformational transition theoretically expected to minimize the free energy of swelling of grafted chains in interaction with free matrix chains, illustrating the competition between the mixing entropy of grafted and free chains, and the elastic deformation of the grafted chains. In addition to the experimental validation of the theoretical prediction, this result constitutes a new insight for the nderstanding of the general problem of dispersion of nanoparticles inside a polymer matrix for the design of new nanocomposites materials

A Hybrid Evolutionary Search Concept for Data-based Generation of Relevant Fuzzy Rules in High Dimensional Spaces

In this paper we propose a hybrid fuzzy-evolutionary system for fuzzy modelling in high dimensional spaces. The system architecture is based on a Michigan-style approach (one individual represents one fuzzy rule). The design of the evolutionary algorithm makes use of a distance measure in the search space that in turn reflects some heuristic assumptions about the fitness landscape. Additionally, strategy parameters are dynamically adapted by means of a fuzzy controller. The approach is successfully applied to a complex benchmark problem as well as to several real-world modelling tasks such as the cancellation behaviour of insurance clients and the classification of automatic gearboxes

Essays on prices and price convergence

This thesis looks at prices in two different markets. The first one is the market for food products in Europe. With the introduction of the common market in 1992, most European markets have been integrated. When 10 more countries joined the EU in 2004, another round of integration took place and the common market was extended to these countries as well. We analyse if retail prices for food products have converged in the time after this "shock" of the EU enlargement. While there exists an extensive literature on convergence in general, this chapter is the first to be able to look at retail price convergence within the European Union at a micro-data level. By decomposing price convergence into within sub-groups and between sub-groups of countries convergence, we add further insight to the literature on what causes the strong price convergence within the enlarged EU. The second market this thesis looks at is the one for internet facilitated sexual services in Germany. Sex work and the advertisement thereof is legal in Germany, which has led to a range of internet platforms concerned with selling sexual services. While many platforms only contain advertisements, one of these platforms gives sex workers the opportunity to sell their services either as an auction or at a fixed price. This has allowed us to create a dataset on sex work with information based on actual concluded contracts, which is a very unique feature in this kind of literature. Furthermore, each data point is geo- and time-referenced. This dataset is used to show that 1) offering unprotected sexual services is endogenous, 2) local events influence the supply, demand and price of sexual services, and 3) regional effects influence local prices and habits

Systemic hypothermia increases PAI-1 expression and accelerates microvascular thrombus formation in endotoxemic mice

INTRODUCTION: Hypothermia during sepsis significantly impairs patient outcome in clinical practice. Severe sepsis is closely linked to activation of the coagulation system, resulting in microthrombosis and subsequent organ failure. Herein, we studied whether systemic hypothermia accelerates microvascular thrombus formation during lipopolysacharide (LPS)-induced endotoxemia in vivo, and characterized the low temperature-induced endothelial and platelet dysfunctions. METHODS: Ferric-chloride induced microvascular thrombus formation was analyzed in cremaster muscles of hypothermic endotoxemic mice. Flow cytometry, ELISA and immunohistochemistry were used to evaluate the effect of hypothermia on endothelial and platelet function. RESULTS: Control animals at 37°C revealed complete occlusion of arterioles and venules after 759 ± 115 s and 744 ± 112 s, respectively. Endotoxemia significantly (p < 0.05) accelerated arteriolar and venular occlusion in 37°C animals (255 ± 35 s and 238 ± 58 s, respectively). This was associated with an increase of circulating endothelial activation markers, agonist-induced platelet reactivity, and endothelial P-selectin and plasminogen activator inhibitor (PAI)-1 expression. Systemic hypothermia of 34°C revealed a slight but not significant reduction of arteriolar (224 ± 35 s) and venular (183 ± 35 s) occlusion times. Cooling of the endotoxemic animals to 31°C core body temperature, however, resulted in a further acceleration of microvascular thrombus formation, in particular in arterioles (127 ± 29 s, p < 0.05 versus 37°C endotoxemic animals). Of interest, hypothermia did not affect endothelial receptor expression and platelet reactivity, but increased endothelial PAI-1 expression and, in particular, soluble PAI-1 antigen (sPAI-Ag) plasma levels. CONCLUSION: LPS-induced endotoxemia accelerates microvascular thrombus formation in vivo, most probably by generalized endothelial activation and increased platelet reactivity. Systemic hypothermia further enhances microthrombosis in endotoxemia. This effect is associated with increased endothelial PAI-1 expression and sPAI-Ag in the systemic circulation rather than further endothelial activation or modulation of platelet reactivity

Compression of the lateral femoral cutaneous nerve by a fibrous sartorius strand in a professional female soccer player

Meralgia paraesthetica represents a neuropathy involving pain, burning, tingling, and numbness in the distribution of the lateral femoral cutaneous nerve (LFCN) of the thigh, which is commonly due to nerve entrapment under the inguinal ligament. We report an unusual case of compression of the LFCN at the anterior surface of the sartorius muscle in a professional female soccer player. Intraoperatively, the LCFN was found to pass without major compression under the inguinal ligament, but was strained over a fibrous thickening of the superficial thigh fascia and the anterior medial border of the sartorius muscle 8cm caudal of the inguinal ligament. Excision of the fibrous tissue completely resolved the symptoms. In professional athletes, the LFCN should be explored along its entire course on the anterior thigh during operative decompression to rule out a distal muscular compression site. Level of evidence: Level V, therapeutic stud