Partial Supergravity Breaking and the Effective Action of Consistent Truncations

We study vacua of N = 4 half-maximal gauged supergravity in five dimensions and determine crucial properties of the effective theory around the vacuum. The main focus is on configurations with exactly two broken supersymmetries, since they frequently appear in consistent truncations of string theory and supergravity. Evaluating one-loop corrections to the Chern-Simons terms we find necessary conditions to ensure that a consistent truncation also gives rise to a proper effective action of an underlying more fundamental theory. To obtain concrete examples, we determine the N=4 action of M-theory on six-dimensional SU(2)-structure manifolds with background fluxes. Calabi-Yau threefolds with vanishing Euler number are examples of SU(2)-structure manifolds that yield N=2 Minkowski vacua. We find that that one-loop corrections to the Chern-Simons terms vanish trivially and thus do not impose constraints on identifying effective theories. This result is traced back to the absence of isometries on these geometries. Examples with isometries arise from type IIB supergravity on squashed Sasaki-Einstein manifolds. In this case the one-loop gauge Chern-Simons terms vanish due to non-trivial cancellations, while the one-loop gravitational Chern-Simons terms are non-zero.Comment: 44 pages, v2: minor changes, references adde

In-Line Quality Assurance for the Manufacturing of Carbon Fiber Reinforced Aircraft Structures

Carbon fiber reinforced polymers are playing a key role for future aircraft structure design concepts as the newest technical developments for aircraft models B787 and A350 are showing. Due to the specific mechanical properties of this composite material and the novel manufacturing and machining techniques for large-scale CFRP made aircraft structures, it is necessary to establish an adequate process integrated quality assurance system that enables a cost-effective automated manufacturing route. Beside upcoming releases of numerous new reference guidelines based on well defined technical tolerances, it is necessary to look for non-destructive test techniques that are capable to monitor the different manufacturing steps and to detect defects and tolerance deviations within the processing route. For choosing reliable NDE techniques some key criteria as for example non-contact measurement, imaging options, penetration depth, scanning speed, the maximum possible coverage area and others have to be considered. The decisive step for applying new NDE methods is the scale up from laboratory conditions to large component testing in an automated manufacturing environment. Beside the ability to find and evaluate small microstructural features within a large CFRP structure component, it is also necessary to establish an intelligent software infrastructure which allows to exchange, compare and merge data sets of different non-destructive scanning techniques in terms of a reliable signal interpretation and evaluation

The Manifold Fruits of Digitalization - Determining the Literal Value Behind

As digitalization is rewriting the rules of competition, companies need to adapt to external changes or they will be left behind. Indeed, digitalization bears a lot of economic potential and is undoubted to have tremendous impacts on the economy. Many companies already launched digital initiatives. However, most of them lack an understanding of the value digitalization can create. They often neither know the organizational value created, nor define accountability measures or specify targets. Therefore, as a first step this paper aims to provide clarity by relating digital benefits listed in literature and highlighting the underlying value drivers. Our results help companies to identify digital business value, but also lower the hurdles that prevent them from scaling up their digital effort

Die Effekte der Augmentationstherapie auf systemische sowie pulmonale Inflammationsmarker beim hereditären alpha1-Antitrypsinmangel

Hintergrund: α1-Antitrypsin (AAT), auch als α1-Proteinase-Inhibitor oder SERPINA1 bezeichnet, ist ein im menschlichen Blutplasma vorkommendes Protein, welches eine wichtige Funktion im Proteasen-Antiproteasen Verhältnis erfüllt. Bei entsprechender genetischer Voraussetzung kommt es zu verminderter AAT Sekretion der Leber und damit zu einem Mangel an AAT im Plasma. Der AAT-Mangel (AATM) prädisponiert zu einer früh einsetzenden und schnell voranschreitenden chronisch obstruktiven Lungenerkrankung (COPD) mit Lungenemphysem und entzündlichen Lebererkrankungen. Die einzige spezifische Therapie für den AATM stellt die Substitution mit humanem AAT dar. Der Nutzen der Substitutionstherapie ist mangels eindeutigen Nachweises der Wirksamkeit in prospektiv randomisierten Studien weiterhin Gegenstand der Diskussion. Sowohl die immunmodulatorische Funktion des AAT wie auch die Rolle der bei an AATM erkrankten Patienten vermehrt auftretenden AAT-Polymere sind bisher nur unzureichend verstanden. Ziel: Ziel dieser Arbeit war es systemische sowie lokale Inflammationsmarker bei Patienten mit hereditärem AATM in vivo als auch in vitro zu evaluieren und deren Reaktion auf die Substitution mit AAT zu untersuchen. Hierdurch sollten die antiinflammatorischen sowie die immunologischen Effekte des AAT untersucht werden. Zudem sollte der Einfluss der Substitutionstherapie mit der kommerziell erhältlichen Form Prolastin™ auf die Bildung von AAT-Polymeren erfasst und deren potentiell proinflammatorische Effekte in vitro evaluiert werden. Methoden: Es wurden 24 AATM Patienten mit nachgewiesenem PiZZ Genotyp in die Studie eingeschlossen. 12 Patienten erhielten eine wöchentliche Substitutionstherapie mit humanem AAT und 12 erhielten keine Substitution mit AAT. Serum und EBC Proben wurden vor Substitution, 2 Stunden danach und an Tag 3 nach Substitution mit AAT bei den augmentierten Patienten gewonnen. Es erfolgte die Bestimmung des totalen sowie polymeren AAT im Serum und der Zytokine/Chemokine und des C-reaktiven Proteins (CRP) im Serum und Atemwegskondensat (Exhaled Breath Condensate, EBC). Für die in vitro Versuche wurden neutrophile Granulozyten von 12 PiZZ homozygoten Spendern sowie primäre humane Bronchialepithelzellen mit den verschiedenen AAT-Fraktionen stimuliert und die Zytokine/Chemokine bestimmt. Ergebnisse: Die gemessenen AAT Spiegel sind nach Substitution von AAT signifikant höher als vor Substitution. Die AAT Konzentrationen fallen an Tag 3 nach Substitution, bleiben jedoch signifikant höher als vor Substitution. Nicht substituierte Patienten haben signifikant niedrigere AAT Spiegel als substituierte Patienten. Bei substituierten Patienten sind die Polymerkonzentrationen nach Substitution signifikant höher. IL-8 und MCP-1, aber auch IL-6, TNF und VEGF zeigen im Serum nach Substitution signifikante Schwankungen. Bei nicht augmentierten Patienten werden höhere IL-8 und niedrigere MCP-1 Werte beobachtet. Im EBC werden signifikant höhere CRP Konzentrationen bei den nicht substituierten Patienten gemessen. Im Zellversuch zeigt sich nach Stimulation mit Prolastin™ und Polymeren eine signifikant niedrigere IL-8 Sekretion der NG im Vergleich zu Monomeren. Die gemessenen IL-8 Konzentrationen nach Stimulation mit Monomer sind signifikant höher als die der Kontrolle. Bei der Stimulation der primären humanen Bronchialepithelzellen zeigen die verschiedenen Fraktionen des AAT keine unterschiedlichen Effekte auf die Sekretion von IL-6, IL-8 und MCP-1. Schlussfolgerung: Neben seiner Funktion im Proteasen-Antiproteasen Verhältnis zeigt AAT auch eine Funktion in der Regulation des Immunsystems. Der Einfluss des substituierten AAT auf die Zytokine IL-8 und MCP-1 lässt auf eine Funktion bei der Rekrutierung von neutrophilen Granulozyten und Monozyten schließen. Im Vergleich der nicht substituierten mit den substituierten Patienten deuten die gemessenen höheren CRP Spiegel im EBC als auch die IL-8 Konzentrationen im Serum auf einen antiinflammatorischen Effekt des augmentierten AAT hin. Im Zuge der Substitution kommt es zu einem Anstieg der AAT-Polymere im Serum. Bei Stimulation der NG mit den verschiedenen AAT-Fraktionen zeigen sich unterschiedliche Wirkungen, wobei sich die nachweisbare Wirkung der hochmolekularen AAT Fraktion ähnlich wie Prolastin™ verhält. Eine toxische Wirkung von nicht modifizierten AAT-Polymeren auf humane Bronchialepithelzellen konnte in dieser Arbeit nicht nachgewiesen werden

Computers for chemistry and chemistry for computers: From computational prediction of reaction selectivities to novel molecular wires for electrical devices

Taking advantage of cutting-edge technologies in computational and experimental chemistry, my Ph. D. research aimed to bridge both of these chemical subdivisions. Therefore, while part I of this dissertation focuses on new structure-based computational methodologies to predict selectivities of organic and enzymatic reactions, part II is concerned with the design, the synthesis and the electrical properties of novel, single molecular wires. These single molecule technologies described in part II are likely to contribute to more powerful computer chips in the future, which will in turn lead to faster and more accurate computational predictions for chemical problems. Part I: Computers for Chemistry: Progress towards the design of accurate computational tools to predict the selectivity of chemical reactions. The first fully quantum mechanical study to predict enantioselectivities for a large dataset of organic reactions has been reported. Enantioselectivities were calculated for a diverse set of 46 dioxirane catalyzed epoxidation reactions. Comparison to experiments showed that our methodology is able to accurately predict the free energy differences between transition states leading to enantiomeric products. To further improve the predictive performance, we have also developed a new correction scheme, which increases the accuracy of density functional theory (DFT) for non-covalent interactions. Our new correction scheme accurately estimates interaction energies of non-covalent complexes not only with large, but also with small basis sets at lower computational cost. The improved enantioselectivity prediction protocol containing our latest non-covalent corrections has now been fully automated in a user-friendly fashion. We are currently testing its accuracy for other asymmetric reactions, such as CBS reductions and are also trying to use our methodology to design new asymmetric organocatalysts. In collaboration with Dr. Jianing Li, a structure based computational methodology to predict sites of metabolism of organic substrates with P450 enzymes has also been developed, which is highly relevant for structure-based drug discovery. Part II: Chemistry for Computers: From novel antiaromatic and pi-pi-stacked molecular wires to highly conducting link groups with direct Au-C bonds. Part II of this dissertation describes studies of antiaromatic and pi-pi-stacked molecular wires as well as new direct ways to connect them to gold electrodes. At the beginning, the first successful single molecule conductance measurements ever on partially antiaromatic molecular wires are described. These wires, based on a biphenylene backbone, were synthesized via a highly regioselective cyclization enabled by the antiaromaticity. Then, two new ways to connect single molecules to gold electrodes with direct Au-C links are presented. The first methodology is based on strained arene rings in [2.2]-paracyclophanes, which were found to directly contact gold electrodes with their pi-systems. The second methodology employs tin based precursors, which get replaced in situ by gold electrodes to also form direct Au-C bonds with very low resistance. The direct Au-C bonds observed with strained paracyclophanes enabled us to study, for the first time, single molecule conductance through multiple layers of stacked benzene rings. Further single molecule conductance studies with less strained stacked benzene rings are currently under way and will provide additional valuable evidence about electron transport in stacked pi-systems

Long-term in vivo imaging of fibrillar tau in the retina of P301S transgenic mice.

Tauopathies are widespread neurodegenerative disorders characterised by the intracellular accumulation of hyperphosphorylated tau. Especially in Alzheimer's disease, pathological alterations in the retina are discussed as potential biomarkers to improve early diagnosis of the disease. Using mice expressing human mutant P301S tau, we demonstrate for the first time a straightforward optical approach for the in vivo detection of fibrillar tau in the retina. Longitudinal examinations of individual animals revealed the fate of single cells containing fibrillar tau and the progression of tau pathology over several months. This technique is most suitable to monitor therapeutic interventions aimed at reducing the accumulation of fibrillar tau. In order to evaluate if this approach can be translated to human diagnosis, we tried to detect fibrillar protein aggregates in the post-mortem retinas of patients that had suffered from Alzheimer's disease or Progressive Supranuclear Palsy. Even though we could detect hyperphosphorylated tau, we did not observe any fibrillar tau or Aß aggregates. In contradiction to previous studies, our observations do not support the notion that Aβ or tau in the retina are of diagnostic value in Alzheimer's disease