Die Frühgeburtlichkeit ist ein weltweites Problem und betrifft etwa 10-20% der neugeborenen Kinder und ist die häufigste Todesursache bei Kindern unter 5 Jahren. In Deutschland kommt etwa jedes zehnte Kind zu früh auf die Welt, davon etwa 12% mit einem Geburtsgewicht unter 1500 g. Ein geringes Geburtsgewicht und postnatale Komplikationen korrelieren dabei mit einem erhöhten Risiko für Mortalität und Morbidität. Präventive und therapeutische Interventionen haben in den letzten Jahrzehnten die Überlebensrate verbessert, jedoch ist weiterhin insbesondere bei Kindern mit einem Geburtsgewicht unter 1500 g eine hohe Morbiditätsrate zu beklagen. Abgesehen von der systemischen und organischen Unreife des zu früh geborenen Kindes, gibt es eine Vielzahl an exogenen Noxen, die in der Pathogenese frühgeburtlicher Erkrankungen eine Rolle spielen können. Neben der Sauerstofftoxizität, resultierend aus den unphysiologisch hohen Sauerstoffkonzentrationen, denen Frühgeborene aufgrund der Geburt und notwendiger Sauerstoffsupplementierung ausgesetzt sind, sind medikamentöse Insulte, wie Anästhetika, als ebenso kausal anzusehen. Die Unreife bedingt dabei ein Ungleichgewicht physiologischer Prozesse, wie des respiratorischen Systems und des anti-oxidativen Abwehrsysteme. In dieser redox-instabilen Situation können zahlreiche medizinisch notwendige medikamentöse oder therapeutische Insulte modulierend wirken und sind mit Nebenwirkungen für die Kurz- und Langzeitentwicklung behaftet. Oxidativer Stress spielt bei der Pathogenese vieler Erkrankungen der Frühgeborenen eine entscheidende Rolle, wobei die kausalen Pathologien bisher unvollständig verstanden sind. Neben der Klärung der pathologischen Prozesse, ist die Identifizierung möglicher therapeutischer Strategien Ziel der neonatologischen Forschung. Klinische Studien belegen bereits die protektive Wirkung von Koffein, einem in der Neonatologie eingesetztem Medikament zur Behandlung und Prävention von Frühgeborenen-Apnoen, für das Langzeit-Outcome von Frühgeborenen und auch die möglichen neuroprotektiven Effekte von Dexmedetomidin, einem Sedativa mit vielseitigen pharmakologischen Wirkungen, da aber subtile Störungen der neurologischen Entwicklung im Umfeld von Frühgeburtlichkeit, neonatalen Adaptationsstörungen und intensivmedizinische Maßnahmen Einfluss nehmen können, können standardisierte Tierversuche dazu beitragen, potentiell protektive Effekte von Koffein und Dexmedetomidin im sich entwickelnden Gehirn und/oder der unreifen Lunge zu identifizieren. Dazu wurden Untersuchungen der infantilen Ratte, einem neonatalen entwicklungsadäquaten Tiermodell, in einem akuten Hyperoxie-Schädigungsmodell durchgeführt. Ziel der Untersuchungen war, ob die Präkonditionierung mit Koffein oder Dexmedetomidin unter postnataler, akuter Hyperoxie (6, 24 und/oder 48 Stunden), die durch oxidativen Stress assoziierten, zellulären Veränderungen reduzieren kann. Oxidativer Stress im akuten Sauerstoffschädigungsmodell im unreifen Gehirn der Ratte beeinträchtigte die hippocampale Neurogenese und induzierte die oxidativen Stress-Kaskade mit daraus resultierender Neuroinflammation und Neurodegeneration. Des Weiteren scheint die anti-oxidative Abwehrkapazität während der Exposition gegenüber Hyperoxie vermindert zu sein. Eine Präkonditionierung mit einer Einzeldosis Koffein (10 mg/kg KGW) vor dem hyperoxischem Insult verringerte die durch oxidativen Stress ausgelöste Neuroinflammation und Neurodegeneration und verstärkte die anti-oxidative Stressantwort. Anti-inflammatorische Effekte zeigte Koffein auch in der unreifen Lunge mit einer adäquaten Inhibierung der Immunzellinfiltration, einer Reduktion der pro-inflammtorischen Antwort und Verminderung der Chemokin-Expression. Neben der unselektiven Antagonisierung der Adenosinrezeptoren, scheint Koffein per se anti-oxidative Eigenschaften zu vermitteln. Das zur Präkonditionierung eingesetzte Dexmedetomidin (1, 5 und 10 µg/kg KGW) zeigte neuroprotektive Eigenschaften in unserem Modell der oxidativen Stress-Schädigung im sich entwickelnden Rattenhirn, wobei apoptotischer Zelltod und pro-inflammatorische Zytokininsulte inhibiert und die postnatale Neurogenese und neuronale Plastizität erhalten wurden. Dexmedetomidin erhöhte die Proliferationskapazität von mitotischen Zellen, was letztlich zu höheren Zellzahlen von reifen Neuronen führte, ohne die Apoptoserate bei Kontrolltieren zu beeinflussen. Die anti-oxidativen und anti-inflammatorischen Eigenschaften von Dexmedetomidin über die 2-Adrenorezeptor-Agonisierung scheint eine potente Möglichkeit der Neuroprotektion darzustellen. Weiterführende Untersuchungen zu protektiven Medikamenten mit anti-oxidativen Eigenschaften, die bereits in der neonatalen Intensivversorgung als Medikament zugelassen sind, sollten weiterhin im Fokus klinischer und experimenteller Studien stehen, um pharmakokinetische und molekulare Mechanismen besser verstehen zu können und die Effektivität und Sicherheit beim klinischen Einsatz zu erhöhen, um nicht-vermeidbare medizinisch-induzierte Maßnahmen mit einem verbessertem Outcome für frühgeborene Kinder in Einklang zu bringen.

Chronisch-inflammatorische Hauterkrankungen sind häufig mit einer gestörten Permeabilitätsbarriere der Haut assoziiert, welche für ein Eindringen von Pathogenen prädestiniert. Tatsächlich sind verschiedene Dermatosen wie atopische Dermatitis (AD), Acne inversa (AI) und Mycosis fungoides (MF) mit einem erhöhten Risiko für Hautinfektionen verbunden. In seltenen Fällen einer systemischen Ausbreitung können diese für die Betroffenen sogar lebensbedrohlich werden (Ekzema herpeticatum bei AD und MF, bakterielle Sepsis im Spätstadium der MF). Durch die immunstimulierenden Effekte mikrobieller/viraler Bestandteile spielen Infektionen außerdem vielfach eine pathogenetische Rolle bei den Hauterkrankungen. Interessanterweise zeigt jedoch eine weitere Hauterkrankung, die Psoriasis, sehr geringe Hautinfektionsraten, welche mit denen gesunder Probanden vergleichbar sind, und nimmt somit in Hinblick auf die hier scheinbar adäquate antimikrobielle/antivirale Kompetenz der Haut eine Sonderstellung ein. Vorangegangene Studien zu den Ursachen der bakteriellen Infektionsresistenz der psoriatischen Haut demonstrierten eine im Vergleich zur erkrankten Haut von AD-Patienten massive lokale Produktion antimikrobieller Proteine (AMPs). Über die Ursachen der viralen Infektionsresistenz der psoriatischen Haut war bislang nichts bekannt. Vor diesem Hintergrund entstand die vorliegende Arbeit, welche die Charakterisierung der kutanen Produktion von sowohl AMPs als auch antiviralen Proteinen (AVP) bei chronisch-entzündlichen Dermatosen und die Aufklärung deren Regulierung durch Inflammationsmediatoren (Zytokine) zum Ziel hatte. Bei der vergleichenden Untersuchung der verschiedenen Patientengruppen stellten wir fest, dass obgleich die läsionale Haut von Patienten mit AD, AI und MF gegenüber der Haut gesunder Probanden eine klar gesteigerte AMP-Expression zeigte, diese Steigerung im Vergleich zur psoriatischen Haut stark limitiert war. Besonders deutlich war dieses Phänomen bei der AI und der MF ausgeprägt. Als essentiellen Induktor der kutanen AMP-Expression identifizierten wir das – wie wir heute wissen - von TH22- und TH1-Zellen sowie lymphoiden Zellen des angeborenen Immunsystems (ILC3) gebildete Zytokin IL-22. IL-22 zeigte hohe Expressionslevel in psoriatischer Haut, welche mit der Stärke der jeweiligen AMP-Expression korrelierten. Tatsächlich war IL-22 in der Lage, die Expression verschiedener AMPs wie beta-Defensine und S100A-Proteine in den als IL-22-Zielzellen identifizierten Keratinozyten zu induzieren. Zusätzlich zu seiner direkten Wirkung beobachteten wir die Induktion eines sehr ähnlich wirkenden Mediators in den Keratinozyten, dem IL-20, der somit potentiell die IL-22-Wirkung unterstützt. Passend zu seiner Funktion als AMP-Induktor demonstrierten weitere Untersuchungen, dass IL-22 im Körper vornehmlich auf Epithelzellen an Barriereorganen wirkt. Dagegen waren Immunzellen überraschenderweise nicht durch IL-22 beeinflussbar, was strikt genommen diesen Mediator als ‚Interleukin‘ disqualifiziert. Vergleichende Expressionsstudien bei unterschiedlichen Dermatosen zeigten, dass AI-Patienten gegenüber Psoriasispatienten tatsächlich geringe kutane Level an IL-22 und seines downstream Mediators IL-20 produzieren, während die Expression anderer AMP-Induktoren vergleichbar war. AI-Patienten zeigten außerdem eine verminderte läsionale Expression der zellulären IL-22/IL-20-Rezeptorkomponenten bei gleichzeitig erhöhter Expression des natürlichen IL-22-Inhibitors, dem IL-22BP. Somit scheint bei der AI nicht nur die kutane Produktion sondern auch die Wirksamkeit von IL-22 selektiv eingeschränkt. Im Gegensatz zur AI waren jedoch die IL-22-Level der läsionalen Haut von Patienten mit AD und MF mit denen von Psoriasispatienten durchaus vergleichbar, was andere Ursachen der unzureichenden kutanen AMP-Produktion dieser Patienten nahelegte. Tatsächlich konnten wir für diese beiden Erkrankungen stattdessen eine relative Defizienz des TH17-Zell/ILC3-Mediators und AMP-Induktors IL-17 aufzeigen. Ähnlich IL-22 war IL-17 in der Lage, die keratinozytäre Expression verschiedener AMPs massiv zu induzieren. Daneben war die läsionale Expression des TH2-Zytokins IL-13, welches bekanntermaßen in der Lage ist, die epitheliale AMP-Expression zu hemmen, bei AD- und MF-Patienten erhöht. Die Daten zeigen somit, dass die starke antimikrobielle Kompetenz der psoriatischen Haut mit einer massiven Expression einer Reihe von AMP-Induktoren inklusive IL-22 und IL-17 assoziiert ist. Dagegen fand sich bei Patienten mit AD, AI und MF eine unzureichende Produktion von entweder IL-22/IL-20 (AI) oder von IL-17 bei gleichzeitig deutlicher IL-4/IL-13-Produktion (AD, MF). Dieses deutet klar darauf hin, dass trotz der Redundanz verschiedener AMP-induzierender Zytokine, einzelnen dieser Mediatoren eine essentielle Rolle bei der Sicherung einer ausreichenden antimikrobiellen Kompetenz bei chronischer Hautinflammation zukommt. Dieses Konzept ließ sich durch in vitro-Studien untermauern, welche zeigten, dass bei Stimulierung isolierter Keratinozyten durch ein Gemisch verschiedener AMP-induzierender Zytokine die resultierende AMP-Induktion jeweils bei Wegfall von IL-17 oder IL-22 zusammenbricht. Bei der Suche nach den Ursachen der unzureichenden Produktion von IL-22 (AI) bzw. IL-17 (AD und MF) stießen wir auf Hinweise, die gegen eine reduzierte Anzahl IL-22- bzw. IL-17-produziernder Lymphozyten in der Haut dieser Patienten gegenüber der von Psoriatikern sprachen. Stattdessen entdeckten wir eine Rolle von IL-4/IL-13 und IL-10: IL-10, dessen starke Expression wir in AI aufzeigen konnten, hemmte die lymphozytäre Produktion von IL-22. Demgegenüber waren die für AD und MF prototypischen TH2-Zell-Zytokine IL-4 und IL-13 in der Lage, die IL-17-Produktion der TH17-Zellen zu reduzieren. Neben der Aufklärung der Regulation der mikrobiellen Infektionsabwehr widmeten wir uns der antiviralen Kompetenz der Haut der Patienten mit chronischer Hautentzündung. In Expressionsstudien fanden wir massive epidermale Level von AVPs in der läsionalen Haut der Psoriasispatienten im Vergleich zur Haut gesunder Spender als auch im Vergleich zur Haut von AD-Patienten. Als der die AVP-Produktion der psoriatischen Haut verursachende Stimulus wurde IL-29 identifiziert. Während IL-29 deutlich in der psoriatischen Haut exprimiert war und als einziger Mediator eine überzeugende Korrelation mit den AVP-Expressionen zeigte, war dieses Zytokin in der Haut der AD-Patienten nicht nachweisbar. Stimulationsexperimente in vitro zeigten die potente AVP-Induktion von IL-29 in Keratinozyten, welche mit dem Schutz der Zellen vor einer Herpes-simplex-Virus-Infektion einherging. Weiterhin ließ sich durch IL-29-Neutralisierung eine Reduktion der AVP-Expression in Proben der den Psoriasispatienten entnommenen läsionalen Haut erzielen. Im Gegensatz zu IL-29 waren Typ-1-IFNs, welche als klassische AVP-Induktoren bekannt sind, in den psoriatischen Läsionen nicht nachweisbar, was eine ursächliche Beteiligung dieser Zytokine ausschließt. Für das Verständnis der IL-29-Rolle wurde nach weiteren Zielzellen des Zytokins gesucht. Unter den verschiedenen Gewebszellen der Haut zeigten neben Keratinozyten auch Melanozyten eine Reaktion auf IL-29-Exposition. Die Analyse verschiedener Immunzelltypen demonstrierte überraschenderweise, dass diese trotz Expressionsnachweis des spezifischen IL-29-Rezeptors nicht durch das Zytokin beeinflussbar waren, was möglicherweise mit deren Expression einer inhibitorischen Rezeptorvariante im Zusammenhang steht. Weitere Untersuchungen identifizierten TH17-Zellen als wichtige Produzenten von IL-29 in psoriatischer Haut. Die starke Fähigkeit der TH17-Zellen zur IL-29-Produktion, AVP-Induktion und anti-viralen Abwehr konnte in vitro bestätigt werden und enthüllte somit eine völlig neue Funktion dieser Zellen. Wie die IL-17-Produktion dieser Zellen, so war auch ihre IL-29-Produktion durch die für AD und MF relevanten Zytokine IL-4/IL-13 hemmbar, währenddessen diese Zytokine keinen direkten Einfluss auf die keratinozytäre AVP-Produktion ausübten. Weitere Studien sind notwendig, die antivirale Kompetenz in der Haut von Patienten mit AI und MF und die Rolle von ILCs bei der IL-29-Produktion zu charakterisieren. Zusammenfassend lässt sich festhalten, dass bei der epidermalen Produktion der AMPs und AVPs spezifischen TH-Zell/ILC-Zytokinen eine essentielle Rolle zukommt, und die unzureichende Produktion dieser Zytokine mit einem erhöhten kutanen Infektionsrisiko bei entzündlichen Dermatosen assoziiert ist. Die Erkenntnisse bilden somit einen Meilenstein im Verständnis der first-line Infektionsabwehr der Epidermis und ebnen nicht nur den Weg für die Entwicklung therapeutischer Ansätze mit hohem Sicherheitsprofil, sondern auch für die Charakterisierung der Prozesse an anderen Barriereorganen.

In this thesis we consider closed, embedded, smooth curves in the plane whose local total curvature does not lie below -\pi and study their behaviour under the area preserving curve shortening flow (APCSF) and the length preserving curve flow (LPCF). For the APCSF, we show that under the above initial condition, the flow does not develop any singularities in finite time but exists for all times and converges smoothly and exponentially to a round circle after becoming convex in finite time. For the LPCF, we prove that under the above initial condition, the flow does not develop collapsed singularities and if it exists for all positive times, it converges smoothly and exponentially to a round circle after becoming convex in finite time. For these results, the above initial condition on the local total curvature is sharp. To exclude singularities, we introduce a distance comparison principle and a monotonicity formula and use methods from the theory of curve shortening flow.

Immune evasion represents an important hallmark of cancer progression. In this context, the induction of tumor-specific cytotoxic T cell immunity to overcome immunological tolerance has become a focal point of cancer immunotherapy. Langerhans cells (LCs) constitute a dendritic cell (DC) subset residing in the epidermis of the human skin. They have been recognized for their capacity to endocytose and cross-present exogenous antigens via MHC-I to efficiently prime naïve CD8+ T cells. Langerin, an endocytic C-type lectin receptor (CLR) involved in the Ca2+-dependent recognition of both pathogen- and self-associated glycans, displays an expression profile highly restricted to LCs. Hence, the targeted delivery of tumor-associated antigens (TAAs) to Langerin represents an intriguing approach to develop novel vaccination strategies. Over the last decades, liposomes have emerged as versatile delivery platforms that can be targeted to LCs via the conjugation to Langerin ligands. As glycan interactions with CLRs are typically weak and highly promiscuous, liposomal targeting required the discovery of potent and specific glycomimetic ligands. However, the onerous synthesis of carbohydrate analogs as well as the hydrophilicity and high solvent exposure of carbohydrate binding sites render glycomimetic ligand design challenging. The structure-based in silico analysis of 21 X-ray structures presented in this dissertation corroborated the classification of CLRs as undruggable or challenging targets. Druggable secondary binding pockets adjacent to the carbohydrate binding site were exclusively identified for CLRs of limited therapeutic relevance. Several strategies were employed to address the challenges outlined above and to discover potent carbohydrate analogs for Langerin. The structure-based in silico screening of substituents in C2 of the mannose (Man) scaffold served to design an initial focused glycomimetic library. The structure-activity relationship (SAR) of this scaffold was further elucidated via determination of affinities for an existing library of Man analogs derivatized in C1 and C6. Alternatively, a structure-based design strategy guided the exploration of substituents in C2 of glucsoamine-2-sulfate (GlcNS). These investigations ultimately led to the discovery of potent Man (KI = 0.25±0.07 mM) and GlcNS (KI = 0.24±0.03 mM) analogs displaying a 40- to 42-fold affinity increase over naturally occurring carbohydrate ligands. The multivalent organization of carbohydrates or their synthetic analogs to match the geometry of the Langerin trimer represents an attractive strategy to optimize their specificity and potency. The GlcNS analog was conjugated to nucleic acid scaffolds to design divalent glycomimetics (IC50 = 23±2 µM) resulting in an additional distance-dependent 12-fold avidity increase. In an alternative approach, trivalent Man-bearing glycoclusters (IC50 = 0.20±0.08 mM) displayed an 80-fold avidity increase over naturally occurring carbohydrate ligands. The development of a sensitive 19F R2-filtered nuclear magnetic resonance (NMR) assay enabled the determination of KI and IC50 values for Langerin. Importantly, the optimization of the assay setup with respect to throughput and material consumption proved instrumental for the discovery of potent carbohydrate analogs and multivalent glycomimetics. Moreover, the implementation of an explorative 19F R2-filtered NMR fragment screening led to the identification of the first non-carbohydrate inhibitor reported for Langerin. The assay was successfully transferred to the CLR DC-SIGN to evaluate the specificity of designed carbohydrate analogs. While 19F R2-filtered NMR experiments served as the primary screening and characterization assay, affinities were validated via saturation transfer difference and 15N heteronuclear single quantum coherence NMR. Furthermore, an integrated strategy combining these NMR experiments with molecular docking studies was implemented to analyze the Ca2+-dependent binding mode of the designed Man and GlcNS analogs. These investigations enabled the development of suitable conjugation strategies for liposomal formulations. The GlcNS analog displayed remarkable specificity against DC-SIGN in 19F R2-filtered NMR experiments and was thus utilized for the preparation of targeted liposomes. Flow cytometry studies were employed to optimize liposomal formulations and to validate the binding of these liposomes to Langerin+ model cells in vitro. Finally, ex vivo experiments demonstrated their capacity to specifically target LCs in the human skin. The liposomes were efficiently endocytosed and thus represent a promising TAA delivery platform. In conclusion, the integration of carbohydrate chemistry, structure-based in silico methods and NMR experiments enabled the discovery of carbohydrate analogs and multivalent glycomimetics as potent and specific ligands of the endocytic CLR Langerin. These ligands were demonstrated to specifically target liposomes to LCs in the human skin and to promote endocytosis. Consequently, the findings presented in this dissertation constitute an important advancement for the research field of DC immunology and the development of novel cancer immunotherapies.

The main objective of this thesis is to develop a numerical method, known as the SASLDG method, that solves the compressible linear advection equation in a semi-analytical way using a semi-Lagrangian approach and applying ideas from the discontinuous Galerkin (DG) methods. In order to achieve physically meaningful solutions, mass conservation is required. For the same reason, the option of slope limiting and thus positivity preservation are also necessary. Furthermore, high-order accuracy and no time step restriction are required.

First, the basic methods underpinning the SASLDG method are introduced. We describe a method developed independently by Prather and van Leer. This so-called second-order moments method is a preliminary stage of the SASLDG method. Both methods are equivalent for CFL numbers less than or equal to one and with constant velocity. We then introduce DG methods to generalize the concept of high-order accuracy of numerical solutions using a polynomial representation for each grid cell. One drawback of this class of methods is the strict time step restriction. In contrast, semi-Lagrangian methods allow time steps of arbitrary size without violating stability properties. We also introduce and analyze the numerical scheme multidimensional positive definite advection transport algorithm (MPDATA).

Following the semi-Lagrangian notion, the advected quantity is tracked analytically along the trajectories. It is represented as piecewise polynomials of degree two. A condition for this approach is the restriction of the given velocity field to a piecewise linear distribution. This enables the derivation of the exact solution, which is in general not in polynomial form. Therefore, much like with DG methods, a projection onto the polynomial space is carried out. A deviation from the solution only occurs in the projection step. The SASLDG method involves rigorously computing every step of the solution to the linear advection equation analytically. However, this concept places many conditions on the algorithm, which require the application of different branches of the SASLDG method. To prevent the cancellation of significant digits, further exceptions have to be made and resolved by alternative computations.

A thorough analysis of the SASLDG method proves its consistency and stability. Third-order accuracy for advection with constant velocity and second-order accuracy for variable velocity is demonstrated analytically and confirmed by numerical convergence tests.

Test cases in one- and two- space dimensions are conducted to show the performance of the SASLDG method. High accuracy is shown in tests using smooth and discontinuous initial values. The method’s ability to handle an irregular grid and arbitrary CFL numbers is assessed. Tests in 1D show that an increase of the CFL number results in smaller maximum- and $l_1$-errors. This feature cannot be transferred to the 2D case since the extension is done via operator splitting, where accuracy increases with decreasing time step sizes. Numerous physical phenomena, e.g.\ in the dynamics of the atmosphere or the ocean, can occur on different scales of the space dimensions. This can lead to computational grids with higher resolution and grid cells sizes in the vertical direction than in the horizontal direction. To address this scenario, we develop a hybrid method which employs MPDATA and a modified version of the SASLDG method. This scheme can compute the solution to the advection equation on grids with high aspect ratio without strict time step restrictions in the vertical direction. Overall, the SASLDG method shows promising results and is worthy of further development.

As some of the most abundant minerals on earth, aluminium hydroxides, oxohydroxides and oxides are used in a variety of applications ranging from catalysis to ion adsorption from water and usage in cement and anti-corrosive coatings and even in anti-cancer treatments. In all these applications, their performance highly depends on interactions with water. Therefore, different fields of application can be broached by tackling the complex processes involved in the assembly or dissolution of macroscopic structures via nanostructures in water while simultaneously influencing those processes by incorporating defects. Within this work, nanostructures are modelled with a bulk-like core and a flat surface-like shell. Periodic density functional theory is used to investigate different aluminium hydroxides and oxohydroxides as core materials and α-aluminium oxide surfaces as shell representatives. The bulk calculations with fluoride ions as dopants not only show their influence on the stability of the concerned systems, but also that the aluminium hydroxides thermodynamically favour the uptake of fluoride ions, which makes them more suitable candidates for fluoride removal from water in comparison to the aluminium oxohydroxides. Doping the α-aluminium oxide surfaces with various amounts of fluoride shows in general no reconstruction of the surface. This in turn highlights their robustness during the fluorination. The adsorption strength of water on these surfaces decreases with an increasing amount of surface fluoride ions. Although the hydrogen bonds to terminal fluoride ions are stronger than to terminal hydroxide groups, this verifies the water repellent effect of fluoride ions even in ionic compounds. Based on this observation, it is assumed that fluorinated aluminium oxides are less likely to dissolve and that the corresponding fluorinated nanostructures are more likely to assemble themselves into macroscopic structures. Due to the comparably high amount of water molecules per surface area, the water molecules are able to form different structural motifs. The obtained different arrangements of water molecules are compared to known structure motifs in various ice phases. In many cases, the adsorbed water structure motifs resemble ones found in ice-I h or ice-I c , which leads to a potential application of certain modified surfaces to grow specifically ice-I c on them. For a better and easier collaboration of theory and experiments, NMR shifts as well as OH stretch wavenumbers are calculated and result in a good accordance of both fields. Thus, the findings can also be used to verify, assign, and mutually check the findings of experimental studies and draw conclusions about the structure at hand.

Recently, lithium(Li)-based batteries have attracted significant attention due to their applications in electric vehicles and many new kinds of portable electronic devices such as cell phones. However, such batteries still need more research and improvement in order to meet the market demands for low cost and high-rate performance. Lithium-sulfur (Li-S) batteries with their high theoretical energy density, and all-solid-state Li-ion batteries (ASSLB) with their increased safety and design flexibility are among the most promising energy-storage systems. The focus of current dissertation is set on the important materials in these two kinds of batteries. The common cathode materials for Li-S batteries are S8 or Li2S. Intermediate Li-polysulfides are also formed at the cathode during the charge/discharge process. Moreover, carbon-based materials are added to sulfur cathodes in order to increase their electronic conductivity. In Li-S batteries, the Li-polysulfides migrate through the electrolyte, and their reductions and oxidations on both electrodes result in excessive utilization of the active material and self discharging. To inhibit this process, traping of Li-polysulfides in the cathode has been proposed. Here, we have investigated the ability of graphene (pristine and defective) as part of sulfur cathode to trap the Li-polysulfides. To this end, binding energies and Gibbs free energies for adsorption process of Li2Sx onto the graphene are calculated using Density Functional Theory (DFT) with PBE-D2 method. To calculate the Gibbs free energies, vibrational and configurational entropies are evaluated. It is found that the interaction of the Li-polysulfides and graphene is mostly dominated by the dispersion interactions, and pristine as well as defective graphene cannot immobilize the Li-polysulfides. Although during the adsorption of Li2Sx on monovacant graphene, one S atom is chemically attached to the defect site, the resulting S-doped graphene cannot hinder the Li-polysulfide migration either. In the next step, Li2S, which is one of the promising cathode materials in Li-S batteries, has been investigated. Similar to S8 , Li2S has a low electronic conductivity. Moreover, Li-ion conductivity of Li2S at room temperature is low, but this crystal possesses a high ionic conductivity at high temperatures. Although many experiments have been performed to study the ionic conductivity of Li2S, it has not been studied theoretically so far. In this thesis, we have studied ionic conductivity of Li2S as well as the origin of its superionic phase transition which has been reported by experimentalists. To achieve this aim, we have applied DFT and ab initio molecular dynamics (AIMD). Through AIMD simulations at different temperatures, diffusion coefficients are evaluated. Additionally, concentration of the Li ions is calculated from thermodynamics of defects as well as using the detailed balance condition. Finally, the Li-ion conductivity is obtained for various temperatures which shows the superionic phase transition for temperatures above T = 900K, in good agreement with the experimental reports. In the case of ASSLBs, although the solid electrolyte has a high ionic conductivity and a high stability, such systems do not possess a high energy density compared to the conventional cells, which is due to a large interfacial resistance at electrolyte/electrode interface. Therefore, it is of crucial importance to know the atomic and electronic structures of these interfaces. In this work, an important electrolyte/cathode interface for ASSLBs, namely Li7La3Zr2O12 /LiCoO2, has been investigated. Although several experimental researches have synthesized and studied this interface, its complex structure makes it difficult to investigate theoretically. Here, for the first time, we have modeled and studied this interface using DFT (PBE+U method) by focusing on Li7La3Zr2O12(001)/LiCoO2(10-14). To consider the effect of lattice mismatch between the two surfaces, three models with different lattice parameters for the interface have been applied. Therefore, different magnitudes of biaxial compressive and tensile strains are applied on the interface. It is shown that during the interface optimization, a Li ion moves from the surface of LiCoO2 to Li7La3Zr2O12. This ion migration is accompanied by electron transfer in the same direction attempting to neutralize the system. The electron transfer also results in the formation of certain gap states at the interface. In the next step, the possibility of cation interchange (Co↔Zr or Co↔La) has been studied at the Li7La3Zr2O12(001)/LiCoO2(10-14) interface. By calculating the energy difference between interface with interchanged cations and pristine interface, it is found that this process is possible only under a large stress along the interface normal direction. In addition, to minimize the strain on such systems during the cation interchange, the bulk models of Li7La3Zr2O12 and LiCoO2 have been considered, and the full optimization has been carried out for these bulk structures. Moreover, to increase the accuracy, HSE06 hybrid functional has been applied. Comparing with pristine Li7La3Zr2O12 and LiCoO2 bulks, the structures with Co↔Zr or Co↔La cation interchange are unfavorable. As a result, these structures can only form under a large stress which is consistent with experimental observations, showing the cation interchange during the cathode annealing at high temperatures. In the case of Li-S batteries, our findings show that pristine and even vacant graphene in sulfur cathode do not have the ability to catch the Li-polysulfides. Therefore, another way to trap the Li-polysulfides should be proposed. According to the experimental results, doping of graphene by certain dopants such as nitrogen or phosphorus can immobilize the Li2Sx molecules, and improve the performance of sulfur cathode. This process should be studied theoretically in detail, similar to what we have done for pristine and defective graphene. In order to study the Li-ion conductivity, the approach that has been used in Li2S can be applied to model superionic phase transition in ionic crystals. In addition, at Li7La3Zr2O12(001)/LiCoO2(10-14) interface, our calculations enable us to have a better understanding of processes at such interfaces which will eventually lead to fabricate the more efficient ASSLB.

This cumulative dissertation explores the contestation of global norms. It seeks to shed light on the discursive strategies behind those struggles about meaning and asks about their relation to normative change on the international level. To do so, I accept the empirical ambiguity and contestedness of normative meaning as a starting point, not an analytical problem to be overcome. Rather than isolating ‘pure’ and unambiguous norms that can be neatly traced, the articles in this dissertation seek to shed light on those ambiguities, contradictions and tensions: First, how can be conceptualize them and capture them analytically? Second, what do actors do with those ambiguities and contradictions? How do they leverage them? How are they bound by normative struc-tures and, simultaneously, how do they engage and seek to transform them? How do actors use norms and normative context in struggles over meaning, for example by exploiting, resisting, subverting, stabilizing or de-stabilizing them? What agency lies in gaining power over definition and meaning? And third, what does this teach us about the process of normative change on the international level? This dissertation consists of four separate articles. First, Political Steering: How the EU Employs Power in its Neighbourhood Policy towards Morocco, was published in Mediterranean Politics and co-authored with David Remmert. It explores the European Union’s promotion of the rule of law and human rights norms and conceptualizes this as a form of discursive power. Second, Appropriation and the Dualism of Human Rights: Understanding the Contradictory Impact of Gender Norms in Nigeria was published in Third World Quar-terly. It conceptualizes appropriation as a form of local agency in norm promotion pro-cesses. Third, Friction, not Erosion: Assassination Norms at the Fault Line between Sovereignty and Liberal Values was published in Contemporary Security Policy. It shifts the focus towards the conundrum of weakening norms and explores the role of normative context in it, stressing normative change as slow and incremental. Fourth, Talking ‘Heads’: The Language of Decapitation and the Targeting of Individuals in U.S. Security Policy is an unpublished manuscript. It addresses the domestic side of targeted killing norms and highlights the gradual nature of normative change in U.S. security discourses and targeting paradigms

This dissertation introduces two new remote sensing retrieval methods for snow and ice characteristics and phytoplankton properties. A synergistic usage might be a promising advanced application to investigate ice algae in high latitudes. The retrievals exploit the discrimination power of emissivity and phytoplankton absorption, scattering, and fluorescence due to specific dependency of the properties on object and wavelength. The cryospheric algorithm sorts three surface emissivities, which are converted from remotely sensed thermal infra-red (TIR) brightness temperatures from Advanced Along-Track Spectro-Radiometer (AATSR) 11 μm and 12 μm bands in nadir and forward view, in a classification scheme. The scheme is based on measurements of Hori et al. (2006) and discriminates between fine, medium, coarse grained snow and suncrust and ice. Depending on the physical surface temperature wet areas are detected. Invalid pixels mostly occur at topographically complex areas and due to collocation of the two views. Scenes in Antarctica and Greenland exhibit classified pixels between 60% to 90%. Phytoplankton is characterized with Total Algae Peak Integration Retrieval (TAPIR) linking the local reflectance maximum in the chlorophyll-a fluorescence domain from 650 nm to 730 nm with the local chlorophyll-a absorption maximum at 670 nm a670. Radiative transfer simulations show high sensitivity on chlorophyll-a absorption, phytoplankton scattering and chlorophylla fluorescence, which are combined in a670 in TAPIR. The peak’s shape, magnitude and spectral location is mainly influenced from those properties which are considered by a spectral peak integration in the retrieval. TAPIR functions are retrieved for several hyper-spectral instruments such as Environmental Mapping and Analysis Program (EnMAP) and can be applied to multi-spectral sensors, e.g. Ocean and Land Colour Imager (OLCI), with a fitting function. An application of both algorithms to Lake Erie at the Canadian/American border reveals good performance of TAPIR for high algae concentrations but insufficient results for low phytoplankton amount. A qualitative comparison between classification of snow and ice with meteorological quantities show good agreement. Therefore, the cryospheric algorithm qualifies for detection of snow types and TAPIR for medium to high chlorophyll-a concentration with promising potential to retrieve phytoplankton species and fluorescence.

Das Ziel der Studie war es, den Einfluss von variierenden Gehalten von Protein, Calcium und Phosphor im Futter auf die Leistung, Nährstoffverdaulichkeit und Ganzkörperzusammensetzung von männlichen Lohmann Dual Hühnern zu untersuchen.

Im Rahmen dieser Studie wurde der Einfluss von Protein, Calcium und Phosphor im Futter auf die Leistung, Nährstoffverdaulichkeit und Ganzkörperzusammensetzung in zwei aufeinander folgenden Untersuchungen getestet. Es wurden jeweils 480 bzw. 460 männliche Lohmann Dual Hühner eingestallt und für 77 bzw. 63 Tage in drei bzw. vier Fütterungsgruppen gemästet. Während der gesamten Zeit wurden die Tiere täglich tierärztlich inspiziert und wöchentlich gewogen. Die Körpermasse wurde sowohl als Gruppenmittel als auch als Individualkörpermasse erfasst. Zusätzlich erfasste Leistungsparameter waren die Futteraufnahme sowie der Futteraufwand. Am Ende der Mastperiode wurden Proben entnommen, um die Nährstoffverdaulichkeit und Ganzkörperzusammensetzung zu ermitteln.

Die Ergebnisse beider Untersuchungsdurchgänge zeigten, dass die Reduktion von Protein, Calcium und Phosphor keinen Einfluss auf die Leistung sowie die Ganzkörperzusammensetzung im ersten Durchgang hatte. Lediglich in der Mastphase des ersten Durchganges wurden temporär höhere Körpermassen und Körpermassezunahmen erreicht, wenn die Tiere das Kontrollfutter bzw. eine moderate Proteinrestriktion erhielten. Die Futteraufnahme war am höchsten in der Kontrollgruppe. Im zweiten Versuchsdurchgang wurde der Futteraufwand während der Mastphase durch die unterschiedlichen Versuchsdiäten beeinflusst. Hier wurde der günstigste Futteraufwand erreicht bei Tieren deren Ration zwar im Calcium- und Phosphorgehalt, nicht aber im Proteingehalt reduziert war. Die Ganzkörperzusammensetzung wurde im zweiten Durchgang durch die starke Proteinreduktion negativ beeinflusst. Alle temporären Leistungsunterschiede zwischen den Gruppen konnten sich nicht auf die Gesamtleistung nach 77 bzw. 63 Tagen auswirken. Im ersten Untersuchungsdurchgang war die Nährstoffverdaulichkeit ähnlich zwischen den Gruppen, höhere Verdaulichkeiten wurden bei Fütterung der proteinreduzierten Rationen ermittelt. Unterschiede traten zwischen der Kontrollgruppe und beiden proteinreduziert gefütterten Gruppen auf, letztere unterschieden sich lediglich in der totalen Verdaulichkeit von Rohprotein. Im zweiten Versuchsdurchgang konnten keine Unterschiede durch variierenden Proteingehalt zwischen den Versuchsdiäten in der ilealen scheinbaren Verdaulichkeit sowie in der Gesamtverdaulichkeit von Rohasche, Rohprotein und Calcium festgestellt werden. Die ileale Phosphorverdaulichkeit wurde negativ durch proteinreduzierte Fütterung beeinflusst. Unterschiede ergaben sich für alle getesten ilealen Nährstoffverdaulichkeiten, sowie für die Gesamtverdaulichkeit von Calcium durch unterschiedliche Calcium- und Phosphorgehalte. Die Gesamtverdaulichkeit von Rohprotein und Phosphor wurde durch die Veränderung aller drei Nährstoffe beeinflusst. Die Ausscheidung von Stickstoff wurde durch die unterschiedlichen Proteingehalte im Futter nicht beeinflusst. Die Phosphorausscheidung wurde niedrigere Proteingehalte negativ beeinflusst, wohingegen eine Variation aller drei Nährstoffe keinen Einfluss auf die Ausscheidung hatte. Die Stickstoffausscheidung wurde durch eine gemeinsame Reduktion von Protein, Calcium und Phosphor verändert. Im Rahmen dieser Studie konnten in den Fütterungsversuchen keine negativen Effekte durch Reduktion von Protein, Calcium und Phosphor auf die Leistung und Nährstoffverdaulichkeit der Broiler ermittelt werden, sodass davon ausgegangen werden kann, dass deren Bedarfswerte deutlich unter denen von konventionellen Broilern liegen. Die Ganzkörperzusammensetzung wurde durch zu starke Reduktion der Proteingehalte negativ beeinflusst. Um konkretere Aussagen zu den Nährstoffbedürfnissen der Lohmann Dual Hühner treffen zu können, sollten weitere Versuche durchgeführt werden, welche die Ganzkörperzusammensetzung zu verschiedenen Zeitpunkten untersuchen, um genauere Empfehlungen zur Fütterung für die jeweiligen Mastphasen geben zu können.

Diese Einzelfallstudie stellt – auf der Grundlage einer Durchsicht ausgewählter Literatur in den Bereichen empirisch-analytische Erziehungswissenschaft, Betriebswirtschaftslehre, Soziologie und Psychologie – den verschiedenen Herausforderungen an eine Berliner Sekundarschule sowie ausgewählter Wege zur gelingenden Organisationsentwicklung die Handlungen eines Schulleiters in einem pragmatischen Analyseraster gegenüber und versucht theoriebasiert, an zwei Schlüsselpunkten Reaktionen des Systems auf seine Steuerimpulse nachzuvollziehen. Um die Komplexität des Systems zumindest partiell abzubilden, werden die Methoden trianguliert. Der Schwerpunkt der Untersuchung liegt auf der Einschätzung der Veränderungen in den basalen kulturellen Rationalitätsannahmen des „mittleren Managements“ der Schule und der damit einhergehenden Akzeptanz eines neuen Rollenverständnisses der Akteure in der Schule. Die Arbeit schließt mit einer Einschätzung der Nachhaltigkeit der Veränderungen.

At any given moment, information reaches us via our different sensory systems. In order to navigate this multitude of information, associated information needs to be integrated to a coherent percept. In recent years, the hypothesis that synchronous neural oscillations play a prominent role in unisensory and multisensory processing has received substantial support. Current findings further convey the idea that local oscillations and functional connectivity reflect bottom-up as well as top-down processes during multisensory integration and perception. In the current work, I review recent findings on the role of neural oscillations for conscious multisensory perception. Subsequently, I present an integrative network model for multisensory integration that describes the cortical correlates of conscious multisensory perception, the influence of fluctuations of oscillatory neural activity on subsequent perception, and the influence of cognitive processes on neural oscillations and perception. I propose that neural oscillations in distinct, coexisting frequencies reflect the various processing steps underlying multisensory perception.

Violent loss (i.e. homicide, suicide, accident) is associated with high levels of prolonged grief disorder (PGD), a condition defined as a maladaptive reaction to loss. PGD is a disorder marked by persistent yearning for the deceased, feelings of emptiness, and difficulties in accepting the loss for a period of at least six months. No meta-analytic evidence yet exists that identified specific risk factors for PGD after violent loss. Violent loss is particularly common in conflict-affected regions. Losses in warfare are often intertwined with traumatic experiences and high comorbidities between PGD and posttraumatic stress disorder (PTSD) are reported. Research has yet to determine how PGD and PTSD manifest in these populations. A further particular characteristic of violent loss in the context of warfare is the loss of a significant other to disappearance, which leaves relatives wondering about the fate of the missing person. Despite the large number of persons globally affected by the disappearance of a loved one, the scientific evidence about the psychological consequences among relatives of missing persons remains limited. This thesis followed several aims to address the above-mentioned research gaps. The first study provided a systematic review and meta-analytic evidence on risk factors for PGD among individuals exposed to a violent loss. Across 36 eligible studies (N=5911), 29 potential risk factors were identified. Large effect sizes were found for other psychological disorders, suicidality and rumination, while medium effect sizes were found for exposure to traumatic events and factors associated with the relationship to the deceased. Small effect sizes emerged for sociodemographic characteristics, multiple loss, physical symptoms and religious beliefs. Ten variables did not show a significant association with PGD. Heterogeneity was observed among several risk factors, however, subgroup analyses could not explain the heterogeneity. The meta-analysis identified, among other results, a high association between PGD and PTSD after violent loss. The second study subsequently addressed how PGD and PTSD manifest in the aftermath of warfare. The results revealed that clinical manifestations of PGD and PTSD among survivors of armed conflict may be characterized by four classes of symptom profiles: A resilient class, a PTSD class, a predominately PGD class, and a high distress class with overall high values of PGD and PTSD. Relative to the resilient class, participants in the high-distress class were more likely to be female, to have lost a close relative, to have been exposed to a higher number of traumatic events, and to perceive less social support. Compared to the PTSD class, the PGD class was marked by less time since the loss had occurred and a higher likelihood to have had lost a close relative. The third and fourth article addressed the psychological and psychosocial consequences of the loss of a significant other to disappearance by providing an overview about the current state of research (paper III) and by contributing a comparative study of relatives of disappeared persons and bereaved individuals (paper IV). The overview indicated that depression, PTSD and PGD are common consequences among relatives of disappeared persons. While three of the reviewed studies found that relatives of disappeared persons had higher levels of psychopathology than bereaved individuals, paper IV did not indicate significant differences in PGD, depression, or PTSD symptom severity between the two groups. Results of paper IV furthermore indicated that the extent to which relatives of disappeared persons hoped that their loved one was still alive was significantly associated with the severity of PGD symptoms. To conclude, prolonged grief disorder is an important psychological disorder that can emerge in response to the violent loss of a significant other. This dissertation contributes significantly to the knowledge on risk factors and clinical manifestations of PGD among violent loss survivors. This is especially relevant in the light of inclusion of PGD in the forthcoming International Classification of Diseases (ICD-11) as it will be important for clinicians to identify bereaved individuals at risk for PGD. This dissertation furthermore added important knowledge on psychological consequences and their risk factors to the under-researched field of psychological distress among relatives of disappeared persons.

In thirteen years, infrared observations from the Visual and Infrared Mapping Spectrometer (VIMS) onboard the Cassini orbiter have provided significant hints about the spectral and geological diversity on Titan's surface, the largest moon of Saturn. The analysis of the infrared signature of spectral units enables constraining the surface composition, which is essential to understand the possible interactions between Titan's interior, surface and atmosphere and to constrain the hydrocarbon cycle existing on the moon. Here, a selection of areas are investigated in the equatorial regions of the moon, imaged by Cassini's remote sensing instruments, which exhibit an apparent transition from the VIMS IR-bright to the IR-blue and IR-brown units. These spectral units are named as such owing to their appearance in false-color composites at infrared wavelengths (red: 1.57/1.27 µm, green: 2.01/1.27 µm, and blue: 1.27/1.08 µm). By applying an updated radiative transfer model, the surface albedo was extracted for each of the infrared units identified in these regions. Surface albedo was then compared with synthetic spectra of binary mixtures of the two most expected components of Titan's surface, namely water ice and laboratory tholins. Water ice is supposed to primarily form Titan's substratum, while the tholins are analogous to the aerosols photochemically produced in the atmosphere. This compositional analysis allows to reconnect the derived surface composition and grain size information to the geomorphology retrieved from RADAR's SAR swaths. Hence, IR-bright units are interpreted as hills and plains coated by organic material and incised by fluvial networks. The erosion products are transported downstream to areas where IR-blue units are seen near the IR-bright units. These areas, enriched in water ice, are most likely outwash plains hosting icy and organic debris from fluvial erosion. Farther away from the IR-bright units, the IR-brown units are dominantly made of organics with varied grain sizes ranging from dust- to sand-sized particles that form the dunes fields. The transition areas therefore exhibit trends in terms of water ice content and grain size supported by geomorphological observations.

Seit der Entdeckung der RIPs und der Aufklärung der enzymatischen Aktivität dieser Proteine sind einige Reviews veröffentlicht worden. Jedoch kam es im Laufe der Zeit zu Unstimmigkeiten bezüglich der Nomenklatur und Definition mancher RIPs. Für diese Arbeit wurde eine Übersichtstabelle erstellt, die diese Unstimmigkeiten beseitigen sollte und es konnte gezeigt werden, dass aktuell 193 Typ 1 RIPs und 88 Typ 2 RIPs existieren. Daneben existieren Proteine, die den klassischen RIPs sehr ähnlich sind, aber aufgrund struktureller oder funktioneller Unterschiede nicht als solche klassifiziert werden können und dementsprechend wurde ein Vorschlag unterbreitet wie diese Proteine klassifiziert und benannt werden könnten. Durch eine Affinitätschromatographie, bei der aufgereinigte Antikörper verwendet wurden, konnte ein Protein aus Agrostemma githago isoliert werden, welches in einer Echtzeit-Untersuchung eine gewisse Toxizität zeigte, die in Kombination mit dem Saponin SO1861 verstärkt wurde. Die Aminosäuresequenzen von fünf Peptidfragmenten wurden durch MALDI-TOF-MS erhalten. Dadurch war zum einen die Produktion von anti-Peptid Antikörpern möglich, mit deren Hilfe eine größere Menge Protein isoliert werden konnte. Zum anderen konnte eine Datenbank kreiert werden, um die Rohdaten der RNA-Seq auszuwerten. Darüber hinaus konnte die Masse des isolierten Proteins von 26963 Da ermittelt werden und aufgrund des Spektrums wurde die Vermutung aufgestellt, dass es sich bei dem isolierten Protein um drei Isoformen handeln könnte. Nach der bioinformatischen Auswertung der RNA-Seq-Rohdaten wurde eine erste Konsen-sussequenz erhalten, die eine Länge von 247 Aminosäuren und eine theoretische Masse von 27140 Da aufzeigte. Anhand dieser Sequenz konnten fünf weitere Peptidfragmente der MALDI-TOF-MS Untersuchung sequenziert werden. Durch einen Vergleich der MALDI-TOF-MS-Sequenzen mit der Konsensussequenz wurde aufgrund von Sequenzunterschieden einzelner Aminosäuren der Verdacht bestätigt, dass es sich bei dem isolierten Protein um drei Isoformen handeln musste. Außerdem wurde die erste Konsensussequenz revidiert und es wurde eine zweite Konsensussequenz erhalten mit einer Länge von 290 Aminosäuren und einer theoretischen Masse von 31900 Da. Durch in silico Untersuchungen konnte ein N-terminales Signalpeptid ausfindig gemacht werden, jedoch konnte die Massedifferenz der zweiten Konsensussequenz und des isolierten Proteins nicht im Detail erklärt werden und stattdessen wurde lediglich der Verdacht aufgestellt, dass bei der Isolierung des Proteins ein Peptid proteolytisch abgespalten wurde. Durch Vergleich der zweiten Konsensussequenz mit den Aminosäuresequenzen von anderen RIPs konnte gezeigt werden, dass die Konsensussequenz die konservierten Aminosäuren enthält, die für die enzymatische N-Glykosidase Aktivität verantwortlich sind. Damit wurde endgültig geklärt, dass es sich bei dem isolierten Protein um das Typ 1 RIP Agrostin handeln musste. Durch eine RACE-PCR konnte gezeigt werden, dass die mRNA für das Agrostin nicht nur in silico durch Auswertung der RNA-Seq-Rohdaten aufgezeigt werden konnte, sondern auch in vitro. Abschließend wurde für zukünftige Untersuchungen nicht nur die zweite, sondern auch die erste Konsensussequenz so weit präpariert, um eine Fremdexpression durchführen zu können. Dadurch soll unter anderem untersucht werden, ob es sich bei der ersten Konsensusse-quenz um eine Isoform des Agrostins handeln könnte.

In biological and other non-isolated systems, an environment is typically coupled to a collective variable that characterizes the physical process of interest. Therefore, effective models are necessary for the description of the collective variable, which is also called the reaction coordinate. If there is no separation of time scales between the dynamics of reaction coordinate and environment, memory effects are present. This thesis investigates several systems in the realm of biological physics where memory effects are relevant. In the first part, we study cyclization kinetics of linear polymers via Langevin simulations of different backbone models, and phantom as well as self-avoiding collapsed chains. We find that while details of bonded interactions do not influence the end-to-end distance dynamics qualitatively, self-avoidance does. All memory kernels for the end-to-end distance and cyclization times extracted from our simulations are explained by scaling arguments based on Flory theory. In the second part, we study the mean first-passage time for barrier crossing for non-Markovian dynamics using Langevin simulations. For single-exponential memory, we recover known asymptotic scalings and identify a new parameter regime where memory effects accelerate barrier crossing. These numerical results are supplemented by a theoretical analysis. We present a heuristic formula for calculating the mean first-passage time and use it to globally characterize the dependence of the barrier crossing time on the system parameters. For bi-exponential memory, we find that the mean first-passage time can be calculated using the single-exponential heuristic formula with effective parameters, which are dominated by the shorter of the two memory times. This dominance is corroborated by an analytical calculation. In the third part, we consider surface waves. We study linear surface waves on a viscoelastic medium bounded by a viscoelastic interface, including the effects of gravitation. We investigate in which parameter regimes the classical Rayleigh, capillary-gravity and Lucassen surface waves exist and how they are related, and identify an additional wave solution which exists on a pure air-water interface. We subsequently derive the nonlinear fractional wave equation that governs compression waves at an elastic interface that is coupled to a viscous bulk medium. The fractional character of the equation constitutes a memory effect and comes from the frequency-dependent effective thickness of the bulk layer that is coupled to the interface. The nonlinearity arises from the dependence of the interface compressibility on the local compression. Numerical solutions of our theory reproduce experimental key features of surface waves in phospholipid monolayers at the air-water interface without freely adjustable fitting parameters.

The mind’s ability to create a picture of the world requires the continual processing and integration of huge amounts of different sensory stimuli at every moment. The aim of the present work was to examine the interplay of experiential, neurophysiological, and neurochemical aspects of brain function and to investigate potential differences in the processes between healthy controls (HC) and individuals with schizophrenia (SCZ). In the first study the relationship between multisensory integration in the audiovisual Sound Induced Flash Illusion (SIFI) paradigm, high frequency neural oscillations and the neurotransmitters gamma-aminobutyric acid (GABA) and glutamate were examined. Neurophysiology was assessed by using electroencephalography, and neurotransmitter concentrations were obtained by using proton magnetic resonance spectroscopy. It could be shown that GABA concentration in the superior temporal sulcus (STS) mediates gamma band oscillation power and perception in the SIFI. Furthermore, in the second study the relationship between multisensory processing in the SIFI and event-related potentials (ERPs), as well as beta/gamma band oscillatory activity was assessed. Results did not reveal any behavioral differences in the SIFI illusion rate between SCZ and HC. In the ERPs SCZ compared to HC showed reduced amplitudes and diminished ERP differences between illusion and no-illusion trials. Furthermore, time-frequency representations of oscillatory activity in SCZ revealed a lack of 25-35 Hz oscillatory power enhancement over occipital electrodes. The results suggest that there are multisensory processing alterations in SCZ, however they do not translate on the behavioral level. The third study was focused on the interplay between experiential and neurochemical aspects and examined the relationship between the neurotransmitter glutamate in the STS and occipital cortex and personality traits in SCZ and HC, measured by the NEO-Five Factory Inventory. The results revealed higher neuroticism and lower extraversion scores and higher STS glutamate concentrations in SCZ compared to HC. Furthermore, data suggested an inverse relationship between STS glutamate concentrations and neuroticism scores in SCZ. Glutamate could hereby be a compensatory mechanism for otherwise enhanced neuroticism trait scores. In summary, in HC a three-fold relationship between the three aspects (experiential, neurophysiological, neurochemical) could be found, whereas in SCZ, only parts of the interactions between the different aspects could be confirmed. The results of this work further the understanding of basic principles of multisensory processing and aims to connect the interplay between different aspects that are present in cortical activity in SCZ and HC.

Protein glycosylation is an important co- and post-translational modification that is critical for many protein functions and biological processes. Glycan biosynthesis is a non-template driven cellular process, which gives rise to glycan structural heterogeneity. Glycome modulations coincide with the development of a number of diseases including cancer as well as inflammatory diseases. Therefore, such alterations are of diagnostic relevance to monitor remission and relapse. Immunoglobulin G (IgG), the most abundant serum glycoprotein, plays a vital role in the humoral immune response by recognizing and eliminating harmful antigens as well as pathogens. N-Glycosylation of the constant IgG Fc portion is altered during pathological or changed physiological conditions that modulates antibody effector functions. In a first article, the human N-glycome was investigated in detail by CE-LIF. Glycome modulations of serum proteins in the course of diseases had so far only been identified for the 12 most abundant glycan isomers. Reference glycoproteins as well as an exoglycosidase digestion array were used to identify linkage and positional isomers of desialylated N-glycans from human serum by CE-LIF. It was possible to assign and quantify 34 N-glycan isomers in the serum of epithelial ovarian cancer (EOC) patients. It could be confirmed that the levels of diantennary structures and of high-mannose 5 were significantly lower in patients with EOC than in healthy controls. The hallmark of cancer modulation, namely elevated branching as well as increased antennary fucosylation, was also detected in EOC patients. In addition, low abundant but biologically significant core-fucosylated tri- and tetraantennary N-glycan structures were identified, which resulted in an improvement of N-glycome analysis when compared with earlier studies. This could also lead to novel glycan biomarkers for EOC. The second aim of this work was the optimization of N-glycan analysis using capillary electrophoresis coupled with laser-induced fluorescence (CE-LIF). CE-LIF is currently one of the most popular methods for separating IgG N-glycan isomers. To date, the measurement of sialylated N-glycans using this instrument was challenging. Due to their negative charge sialic acids have short migration times, which results in peak co-migration and reduced resolution. A protocol was developed in this work to enhance N-glycan resolution by methylating the negative charge of carboxylic groups of sialic acids. The migration times of sialylated N-glycans are then delayed, which results in improved resolution and better quantification of N-glycan isomers by CE-LIF. To evaluate this new method, Fc-glycosylation of IgG isolated from EOC patients and healthy controls was analyzed using the conventional and the methylation method. With both methods, an increase of agalactosylated structures was measured. However, due to the superior resolution of the methylation method, an increase of an afucosylated truncated structure could be also detected. IgG hypogalactosylation has been widely recognized for its association with inflammatory disease activity in rheumatoid arthritis (RA) and its dependence on activation of humoral immunity. It was therefore examined in a third article whether the correlation between IgG agalactosylation and inflammation depends on the presence of anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), or HLA-DRB1 shared epitope (SE). Furthermore, it was investigated whether IgG glycosylation is related to inflammation in axial spondyloarthritis (axSpA). IgG-Fc N-glycosylation analysis was carried out using CE-LIF to compare the serum of RA patients, axSpA patients, and healthy controls. Differences in IgG-Fc galactosylation were assessed in relation to C-reactive protein (CRP) concentrations. The relation between IgG hypogalactosylation and disease activity markers (CRP, erythrocyte sedimentation rate, DAS28) was studied in RA stratified by HLA-DRB1 SE, ACPA, or RF. Aberrant galactosylation of IgG was found to be strongly dependent on inflammatory activity in RA, but was missing in non-humoral autoimmune processes like axSpA. In RA, IgG galactosylation was present in SE-negative/ACPA-negative individuals and was comparable to galacosylation levels of axSpA patients and healthy controls, indicating humoral activation with a different specificity in this subset. Assessing the correlation between IgG hypogalactosylation and disease activity markers, a significant heterogeneity between strata defined by SE as well as RF but no difference between both ACPA-strata was found. This finding sheds novel light on the relation between SE, ACPA and RF in RA.

Network-based feature selection methods on omics data have been developed in recent years. Their performance gain, however, is shown to be affected by the datasets, networks, and evaluation metrics. The reproducibility and robustness of biomarkers await to be improved. In this endeavor, one of the major challenges is the curse of dimensionality.

To mitigate this issue, we proposed the Phenotype Relevant Network-based Feature Selection (PRNFS) framework. By employing a much smaller but phenotype relevant network, we could avoid irrelevant information and select robust molecular signatures. The advantages of PRNFS were demonstrated with the application of lung cancer prognosis prediction. Specifically, we constructed epithelial mesenchymal transition (EMT) networks and employed them for feature selection. We mapped multiple types of omics data on it alternatively to select single-omics signatures and further integrated them into multi-omics signatures. Then we introduced a multiplex network-based feature selection method to directly select multi-omics signatures. Both single-omics and multi-omics EMT signatures were evaluated on TCGA data as well as an independent multi-omics dataset.

The results showed that EMT signatures achieved significant performance gain, although EMT networks covered less than 2.5% of the original data dimensions. Frequently selected EMT features achieved average AUC values of 0.83 on TCGA data. Employing EMT signatures on the independent dataset stratified the patients into significantly different prognostic groups. Multi-omics features showed superior performance over single-omics features on both TCGA data and the independent data.

Additionally, we tested the performance of a few relational and non-relational databases for storing and retrieving omics data. Since biological data have large volume, high velocity, and wide varieties, it is necessary to have database systems that meet the need of integrative omics data analysis. Based on the results, we provided a few advices on building scalable omics data infrastructures.

The signal-to-noise ratio of MAS NMR signals can be enhanced via dynamic nuclear polarization (DNP) by several orders of magnitude. DNP can provide new perspectives in structural biology, metabolomics studies and material science. At cryogenic temperatures (100 K) stable water-soluble nitroxide biradicals are added to the investigated samples as polarizing agents. The large polarization of the biradical electrons can be transferred to the analytes under continuous microwave irradiation via the so-called cross effect (CE). Hence, the use of DNP enables MAS NMR experiments that suffer from inherent low sensitivity and would not have been executed normally due to the excessively long experimental time required for signal averaging. The current challenge in DNP MAS NMR is the homogeneous and heterogeneous line broadening and the temperature dependence of the CE. In this work, experimental conditions, parameters and aspects that determine the CE efficiency were investigated. Novel polarizing agents were tested for the first time, the methodology further developed and the new insights applied to biomolecular projects. The amino acid proline and the 62 amino acid long protein SH3 in microcrystalline form were used as model systems. Four CD3-TOTAPOL isotopologues were investigated and compared to already established biradicals such as TOTAPOL and AMUPol in the course of this work. Their CE efficiency was assessed by comparing enhancement values and the signal-to-noise ratio per 10 min (10minSNR) for 1D hC (1H- 13C CP) experiments in a temperature range between 100 and 200 K at 9.4 T. Signal-to-noise ratio were analyzed and compared with a newly devised procedure. The deuteration of the methyl groups of 1H-TOTAPOL led to larger signal enhancements compared to 1H-TOTAPOL. The effect of deuteration of 1H-TOTAPOL did not influence the electron relaxation parameter as initially hypothesized and are not the reason for increased CE efficiency of the polarizing agent. Highest signal enhancements were obtained for the isotopologue CD3-TOTAPOL-0 that has deuterated methyl groups but protonated 3 and 5 positions of the TEMPO ring. The results highlight the importance of protons that are at close proximity to the radical center, presumably involved in the initial polarization buildup. In addition, the new polarizing agent bcTol, designed for biological applications was tested for the first time in the course of this work. The maximum signal enhancement that could be obtained was e ~ 248 for a sample containing microcrystalline SH3 at 110 K. The bcTol biradical showed unprecedented solubility in water, GDH and [D8]-glycerol. Measurements of signal-to-noise per unit time suggest a comparable DNP performance of bcTol at 110 K to that of AMUPol.Furthermore, a 10minSNR study was conducted to investigate the influence of electron relaxation parameters and the radical linker. Therefore, the novel polarizing agents and cyolyl-TOTAPOL and bcTol-M were investigated for the first time. bcTol-M is similar to bcTol but with methyl groups on the nitrogen atoms showed greater 10minSNR ratio than bcTol. The maximum signal enhancement that could be measured with this radical was e ~ 302 on a proline sample in a 3.2 mm sapphire rotor at 110 K. The superior performance compared to bcTol and AMUPol can be mainly attributed to the shorter 1H-T1 times. The presence of the methyl groups on the linkage presumably promotes nuclear relaxation. Given the simplified handling of the radical and its good performance in hC cross polarization experiments, bcTol-M constitutes an ideal polarizing agent for biomolecular DNP MAS NMR studies. The three urea-based radicals AMUPol, bcTol und bcTol-M show a considerable higher enhancement and SNR compared to 1H-TOTAPol and cyolyl-TOTAPol. Among the urea based radicals, the enhancement values do not differ to a large extent but the values for the SNR do. Furthermore, the electron relaxation times that were measured at the same field as the NMR spectra (9.4 T) for the radicals 1H- TOTAPOL, cyolyl-TOTAPOL, bcTol, AMUPol, and bcTol-M do not dominate the performance of the radicals at 110 K, 8 kHz MAS and 9.4 T. The different performance correlates with the chosen type of linker and the degree of alkylation, affecting the size of the effective electron-electron dipolar coupling and the nuclear relaxation times. A sample preparation protocol for the SH3 samples was developed in order to get reliable and reproducible results. 2D 13C-13C DARR spectra were recorded under DNP conditions for each radical. The best resolution was obtained for the samples containing AMUPol as polarizing agent. The signal-to-noise ratio at 200 K on SH3 standard samples is 15 times larger compared to a sample without polarizing agent. 2D and 3D NCACX/NCOCX spectra were recorded at 200 K within 1 and 13 hours respectively. The obtained resolution allows for some spectral assignment of amino acid side chains. For the novel nitroxide biradical bcTol the signal-to-noise per unit time were higher compared to AMUPol at 181 K. 2D spectra of the SH3 domain sample recorded at 181 K gave a signal enhancement of e ~ 40 and show sufficient resolution for structural studies. In the final sections of this thesis, the power of these new insights and developments were demonstrated on diverse biological problems.