Disagreement among and within individuals is not unusual. If there is, however, only one correct answer to a particular question, disagreement can lead to serious problems. Take, for example, a patient who consults with different doctors (or the same doctor on different occasions) about the malignancy of a mass in her mammogram and hears different diagnoses. Not to know which diagnosis is correct and whether the prescribed treatment is appropriate can endanger a patient’s health and understandably raises concerns about the judge’s competence. However, in such disagreement can lie hidden potential, a source of wisdom that becomes visible only when taking a step back to observe the disagreeing “crowd” from a distance. Such crowds often possess a fragmented and probably noisy encyclopedia of information, which is distributed over the individual members in the group. How should this fragmented knowledge be assembled into a meaningful and accurate judgment? Is there one superior strategy that consistently outperforms competing strategies? Or does the performance of each strategy depend on the statistical properties of the environment?

In the first chapter, I introduce the elementary concepts on which this dissertation draws. Crowds can be understood in many ways, of which two are relevant in this dissertation. First, a crowd can be several individuals forming a group of people, for example, a group of radiologists diagnosing the malignancy of a tumor. Second, one can think of the different opinions existing within an individual’s mind as an inner crowd. For example, a single radiologist might assess the same mammogram multiple times and give different diagnoses. The main empirical body covers work on the wisdom of the inner crowd, that is, methods to harness the wisdom within an individual. In Chapter 2, I compare theoretically and empirically the performance of two strategies to improve confidence judgments of associated decisions. In the case of inconsistent judgments, should one choose the higher confidence judgment or average them? Averaging two confidence judgments consistently improves their accuracy, whereas always choosing the higher confidence judgment is risky: It can substantially harm the accuracy of confidence judgments and begins to outperform averaging only in environments where the probability of making a correct judgment is 60% or higher. Therefore, when one lacks insight into the statistical properties of an environment, the results of the presented studies suggest that averaging—due to its robustness—should be the default strategy to harness one’s conflicting judgments. In the third chapter, I investigate the relationship between inconsistency in decisions, confidence judgments, and the statistical environment within expert decisions. I seek to understand when physicians change their mind, and I offer advice for people relying on expert decisions. In short, when an expert disagrees with herself, the results of this study suggest to choose the more confident decision—since the probability of making a correct decision is often 60% or higher in expert decisions. In Chapter 4, I extend the wisdom of the inner crowd to sequential diagnostic decision making and investigate cognitive dependencies between successive decisions. Existing literature suggests that gains from aggregating judgments are larger the more independent judgments are. The results so far show that the statistical properties of the environment moderate the extent of cognitive dependency processes. Future studies should investigate how such dependencies influence the accuracy of the final diagnosis. In Chapter 5, my colleagues and I review four judgment-aggregation strategies through an ecological lens. I show that there are a variety of ways to reduce uncertainty, each successful under distinct statistical properties of the environment. If such statistical properties cannot be known, I suggest adopting two principles: (a) aggregate more judgments than fewer, and (b) use experience to adapt to the environment. Finally, in Chapter 6 I summarize the key results and point to new ideas for future research.

Taken together, the results suggest that judgment-aggregation strategies offer great potential to reduce judgment uncertainty, yet the process of doing so involves dealing with another type of uncertainty: What strategy to select in a particular environment? To investigate this and further questions I use analytical methods, computer simulations and empirical studies in different domains, ranging from mere perceptual tasks to general knowledge questions to diagnostic decisions. This work extends previous research in that it adapts and compares previous strategies and investigates them in the context of expert decisions. All in all, this sheds a different light on judgment inconsistency and shows how and when disagreement among and within individuals can be turned into a benefit.

In this work, a new method to produce nanographene was identified. The comparably high yield, scalability of a wet chemistry approach, and good quality of produced nG – defined in this case as narrow distributions of lateral size, low levels of sp3 defects, and low number of layers – all provide significant benefits as compared to previously reported methodologies. The functionalization of these nG materials via [2+1] cycloaddition with Trz was carried out, and the resulting nGTrz material characterized in detail. nGTrz was found to exhibit behavior analogous to heteroatom doped graphene, namely p-type doping effects, whereby conductivity was increased. Combined with theoretical simulations, a new structure was proposed for the nitrene cycloaddition product of Trz with nG, with extensive supporting evidence in the form of statistical Raman and SFM-TM analysis.

The nGTrz platform was put into use by post-functionalization with short perfluoroalkanes, yielding a photothermally active fluorinated solid. The applications of this nGTrz-PF nanoconjugate for fluorous biphasic catalysis were explored and successfully demonstrated with fTPP in a modified regenerative Appel reaction, whereby alcohols could be chlorinated and the fTPP catalyst successfully reused with only minimal losses in efficacy over a minimum of 10 reactions.

Going forward, one of the primary benefits of nG is the small and very narrow size range of the sheets. For biological applications, especially drug delivery, this could be particularly relevant as the sheets can benefit from the EPR effect for tumor targeting. [8,123-124] Simultaneously, biomedical nanomaterials require very defined architectures for both consistent practical effect and regulatory approval – another area where nG could be advantageous compared to typical routes for producing graphenic materials.

The modified nGTrz system is more intriguing still, especially with the demonstrated electronic effects of Trz conjugation. The possibility of graphene’s superaromatic network being able to incorporate at least the nitrogen bridge at the conjugation site, and perhaps the entire Trz moiety, raises a number of avenues for further exploration. Trz conjugation could prove to be a powerful method for band gap tuning of conductive or semi-conductive carbon nanomaterials, offering new routes for nanoelectronics. If the entire Trz ring is also incorporated into the electronic structure of nGTrz, vast possibilities arise for conductive networked materials. nGTrz crosslinked with aromatic moieties could yield 3D graphene composites with high isotropic conductivities. Similarly, conductive polymers with end groups targeting specific cells, pathogens, or molecules could be attached to nGTrz to produce highly sensitive graphene-based sensors.

Fluorous chemistry could also be explored further with nGTrz-PF. It will be worthwhile to investigate additional and potentially more powerful fluorinated catalysts as payloads, and also to explore the properties and potential new applications of similar nanosystems with higher degrees of functionalization. Increasing fluorine content is known to impact a range of material properties, including electronic properties and interfacial chemistry or interactions. Heavily fluorinated nG platforms could enable the production of photo-controllable superhydrophobic and lipophobic coatings, for instance, whereby a film of nG with more dense coverage of Trz and PF should be prepared. Given the temperature sensitive interfacial forces between fluorinated chains and other liquids, the photothermal heating of the nG component could allow controlled, temporary wettability.

Novel photovoltaic materials have to be developed at an increasing pace to keep up with the progress of established solar cell technologies and to fit into the limited funding periods of science. Such a speed-up can be realized by the characterization of photovoltaic materials with time-resolved terahertz spectroscopy (TRTS) which can reveal the limits and losses of photovoltaic materials and thereby guides their further development. First, TRTS was advanced and validated in this work for the characterization of charge carrier lifetime and mobility in photovoltaic materials. Publication [3] shows that TRTS can measure charge carrier mobilities in thin films on metal substrates, which are the prevalent architecture of photovoltaic thin-film samples. Further, publication [5] shows that the individual mobilities of electrons and holes are derived by combining TRTS transients and the usually derived TRTS sum mobility. Such distinction is especially important for photovoltaics because the charge transport in solar cells is usually limited by the minority charge carriers. Second, an in-depth characterization of a Cu2ZnSnSe4 thin film was conducted. This thin film was deposited during my stay at the national renewable energy laboratory (NREL) at similar conditions as their record Cu2ZnSnSe4 solar cell. The charge carrier dynamics, including cooling, trapping, localization, recombination, and transport, were probed and integrated into one narrative. The recombination of the photo-excited charge carriers is characterized by a bulk charge carrier lifetime of 4.4 ns and by a surface recombination velocity of 6*104 cm/s [5]. The transport is described by an electron mobility of 127 cm2/Vs ±25 % and a hole mobility of 7 cm2/Vs ±50 % [5]. These mobilities are limited by localization on a length scale of ~11nm and correspond to the transport within the ~1 µm sized grains the polycrystalline Cu2ZnSnSe4 [4]. However, the mobility in Cu2ZnSnSe4 is relatively high in comparison to 15 other photovoltaic materials that I probed [7-17]. The Cu-Zn disorder has no impact on mobility and lifetime in Cu2ZnSnSe4 [6]. Third, the relatively low efficiency of the Cu2ZnSnSe4 solar cell of 7.2 % compared to its Shockley-Queisser limit of 31.4 % and to competing photovoltaic materials, was mostly attributed to charge carrier recombination, which reduces the voltage by ~239 meV and the current by ~8.5 mA/cm2. Band tails, which are often regarded as the main limitation, affect the performance only to a minor degree. We found a tenfold reduction of the mobility and a loss in the voltage by ~105 meV. An impact on the lifetime and recombination could not be proven. The charge carrier mobility, absorption and bandgap energy of Cu2ZnSnSe4 are in principle suited for high efficiencies.

Plate tectonics shapes the face of the earth and subduction and collision zones are among the most important features on Earth. Here, crustal material is recycled into the mantle or integrated into growing orogens. However, the processes active at depth cannot be studied directly and we thus rely on geophysical imaging methods to visualize the geometries that result from the ongoing processes. Additionally, these processes can be studied in fossil subduction and collision zones. However, the scales at which observations from geophysical imaging are made are orders of magnitude larger than those made in field-based studies of fossil subduction and collision zones. This thesis provides insight into how eclogitization modifies the physical properties of deeply buried rocks and what influence the resulting lithologies and their geometrical configuration have on geophysical imaging. In an interdisciplinary approach, I show how structures that are likely representative for those present at depth in subduction and collision zones develop and what their geometries at depth will be. I then derive their petrophysical properties and show how these are modified on various scales, and how this influences the detectability of such associations using geophysical imaging techniques. To do so, the island of Holsnøy in western Norway serves as a natural laboratory that is ideal to study eclogitization of crustal material. Geological mapping on Holsnøy constrains the geometric framework of the constituting lithologies and the scales at which such structures could be expected to establish. Previously, several authors have shown that many of the eclogite occurrences on Holsnøy are produced contemporaneously with ductile deformation forming shear zones at various scales. Our geological mapping aided by photogrammetry using drone images reveals that large parts of this exposed continental sliver were eclogitized statically without associated ductile deformation. This shows that even in domains with ongoing regional deformation, low-strain domains develop within the descending crustal material. Nevertheless, even the major shear zones that are exposed are only a few hundred meters thick, and thus far below the scale that is detectable by geophysical imaging techniques. However, geological mapping of the area suggests that the exposed structures are, at least in a qualitative sense, scale independent, suggesting that the same structural framework could be present at a larger scale in active subduction and collision zones. Measurements of P and S wave velocities of the exposed granulitic protolith and eclogites suggest that eclogitization of the lower crust causes three major changes of the petrophysical properties: (1) increased P and S wave velocities, (2) an increase of the seismic anisotropy, and (3) a decrease of the VP/VS ratio, suggesting distinct variations in the geophysical signal when the descending material is partially eclogitized. Additionally, testing the signal that the exposed shear zones would give in reflection seismic and receiver function studies reveals that the variations in shear zone structure indeed produces variations in the retrieved waveforms. Nevertheless, as the exposed structures are too small for geophysical imaging, the finite element method is used to calculate the effective properties of representative structures acting as an effective medium. The results show that the geometrical configuration of the constituting lithologies only has a minor impact on the P wave velocities and anisotropies of the resulting effective medium. Furthermore, our effective medium calculations on the kilometer scale show that eclogitization of crustal material can indeed produce significant seismic anisotropy. In this case, the calculated anisotropy reaches ~5%, which would produce a dependence of the retrieved signal in, for example, receiver function studies on the backazimuth of the sampled rays. Such backazimuthal dependence is indeed observed in active collision zones such as the Himalaya-Tibet collision system and the results presented here can thus be used to constrain the lithologies at depth, suggesting that the lower crust of India below the Himalaya is partially eclogitized along shear zones similar to those exposed on Holsnøy.

The analysis of the structural and the dynamical behavior of biomolecules is very important to under- stand their biological function, stability or physico-chemical properties. In this thesis, it is highlighted how different theoretical methods to characterize the aforementioned structural and dynamical properties can be used and combined, to obtain kinetic information or to detect biomolecule-ligand interactions. The basis for most of the analyses, performed in the course of this work, are molecular dynamics sim- ulations sampling the conformational space of the biomolecule of interest. Using molecular dynamics simulations, the remarkable stable water-soluble-binding-protein is examined first. On a theoretical ba- sis, structural modifications that can influence the stability of the protein are discussed. Additionally, by combining the simulations with a QM/MM optimization scheme and quantum chemical calculations, spectroscopical properties can be investigated. Markov State Models are applied frequently to capture the slow dynamics within simulation trajectories. They are based on a discretization of the conformational space. This discretization, however, introduces an error in the outcome of the analysis. The application of a core-set discretization can reduce this error. In this thesis, it is discussed how density-based cluster algorithms can be used to determine these core sets, and the application on linear and cyclic peptides is highlighted. The performance of a promising cluster algorithm is investigated and error sources in the construction of the Markov models are discussed. Finally, it is shown how molecular docking combined with molecular dynamics simulations can be used to determine the binding behavior of ligands towards biomolecules. In this context, the important in- teractions within the active site of an enzyme, and different binding modes of DNA intercalators are identified.

Hintergrund/ Fragestellung: Schmerz wird peripher von Nozizeptoren detektiert und ins zentrale Nervensystem weitergeleitet. Hier kommt es zur Wahrnehmung, Lokalisation und Bewertung des Schmerzes. Wiederkehrender Schmerz führt zur Chronifizierung. Chronische Schmerzen führen zu spezifischen Veränderungen sowohl im zentralen als auch im peripheren Nervensystem. Ziel war es zu untersuchen, ob der Motorkortex einen Einfluss besitzt, um die Schmerzwahrnehmung bei Gesunden und Schmerzpatienten zu verändern. Zusätzlich wurde getestet, ob der Motorkortex eine geeignete Zielstruktur darstellt, um eine Einschätzung über Krankheitsstadien bei zwei Modell-Erkrankungen (Patienten mit chronischen Schmerzen oder einer Enzephalitis) zu treffen. Methoden: Eine mentale Aufgabe sowie die transkranielle Gleichstromstimulation (tDCS) wurden auf Veränderungen in der Druckschmerzschwelle und der kortikalen Exzitabilität (mittels transkranieller Magnetstimulation (TMS)) bzw. der funktionellen Konnektivität (mittels Magnetresonanztomographie (MRT)) getestet. Es wurden gesunde Probanden und Schmerzpatienten mit einer chronisch entzündlichen Darmerkrankung (CED) und chronisch myofaszialen Schmerzen untersucht. Weiter wurde geprüft, ob neurophysio-logische TMS-Parameter des Motorkortex mit klinischen Skalen für Krankheitsstadien (Schmerz-Katastrophisieren-Skala oder modifizierte Rankin-Skala) korrelieren. Ergebnisse: Die Arbeiten zeigen, dass die Aktivierung des Motorkortex im Zusammen-hang mit der Schmerzwahrnehmung steht. Dabei erscheint eine gesteigerte Motorkortex-Exzitabilität mit einer Schmerzreduktion einherzugehen und umgekehrt eine reduzierte Exzitabilität mit einer Schmerzsteigerung. Die tDCS-Therapie, die die Motorkortexaktivität steigert, führte bei CED-Patienten mit chronischen Schmerzen zu einer signifikanten Schmerzreduktion. Dies war von einer Veränderung in der Ruhezustands-MRT im Sinne einer gesteigerten funktionellen Konnektivität in verschiedenen Gehirnnetzwerken begleitet. Zudem zeigten sich signifikante Assoziationen zwischen verschiedenen TMS-Parametern der Motorkortex-Exzitabilität und den gewählten klinischen Skalen. Schlussfolgerungen: Der Motorkortex und dessen Aktivitätssteigerung haben einen bedeutenden Einfluss auf die Schmerzreduktion bzw. vermitteln diese. Die gewonnenen Erkenntnisse können für eine neue, multimodale Schmerztherapie genutzt werden. Darüber hinaus bietet der Motorkortex eine mögliche Zielstruktur, um nicht-invasiv eine Einschätzung der Erkrankungsschwere bei bestimmten Krankheiten zu treffen.

Non-biodegradability, low loading capacity, non-specific interaction with drugs, and low yield synthetic protocols are four main challenges that prevent many biomedical applications of polyglycerol derivatives. In this study we tried to address and solve these problems. We also showed the advantages of the synthesized materials for the biomedical applications exemplified by dermal delivery of known therapeutic agents. In the first project, new nanogel-peptide conjugates for the specific interactions with m-THPC, as targeted therapeutic agent, were synthesized and their ability to delivery this drug through the skin was evaluated. Loading capacity of nanogels was improved 16-fold compared to the nanogels without peptide segments. Furthermore, nanogel-peptide conjugates specifically loaded the targeted drug in a complex media. Our results show that peptide segments, which were synthesized and selected because they combined well, are very effective bioligands for specific interaction with the target molecules. Conjugation of these bioligands to the surface of nanocarriers, in this case, polyglycerol nanogels improved their specific biointeraction, loading capacity, and bioavailability. In the second project, short poly(lactide) segments were incorporated in the backbone of polyglycerol to obtain biodegradable polyglycerol derivatives. Due to the one-pot and straightforward synthesis, poly(lactide-co-glycerol) was synthesized on a gram scale. This copolymer was freely soluble in water and showed loading capacity as high as 14.5% w/w for tacrolimus (TAC), because of the hydrophobic poly(lactide) segments in its backbone. Skin penetration tests on human skin showed that the synthesized copolymer was able to efficiently deposit Nile red and TAC into the stratum corneum and viable epidermis. The cutaneous biodistribution profile of cargo of poly(lactide-co-glycerol), TAC, showed that 80%, 16%, and 4% of the cutaneous drug level was deposited in the stratum corneum, viable epidermis, and upper dermis, respectively. The delivered TAC efficiently suppressed the IL-2 and TSLP expressions in human skin models. One of the main goals of this project was to synthesize a biodegradable polyglycerol derivative. In order to investigate the biodegradability of the synthesized copolymer, it was incubated with skin lysates. It was found that poly(lactide-co-glycerol) efficiently is broken down to small segments. Results of this project showed that a short-chain polylactides could be incorporated in the backbone of polyglycerol; the reaction can be performed in one step and on gram scale. In spite of considerable molar ratio of poly(lactide) segments, poly(lactide-co-glycerol) are highly soluble in aqueous solutions. This is due to the fact that poly(lactide) segments are incorporated in the backbone of copolymer and they are surrounded by polyglycerol segments. Increasing the hydrophobicity of polyglycerol backbone resulted in the highest known loading capacity for a very hydrophobic drug, i.e., TAC. Biodegradability of poly(lactide-co-glycerol) in a skin-mimicked media decreased the risk of toxicity, which is very promising for future dermal delivery. In the third project, succinic acid was copolymerized with glycidol using two different catalysts, Sn(Oct)2 and novozyme. It was found that both catalysts were able to copolymerize these monomers. Interestingly, copolymerization in the presence of novozyme resulted in nanogels, because this enzyme showed a dual role including activation of monomers and catalyzing esterification of the produced copolymers. Succinic anhydride is a cheap and commercially available compound and the one-pot copolymerization with glycidol resulted in nanogels in gram quantities. To the best of our knowledge, this is the first protocol for a gram-scale synthesis of polyglycerol nanogels. The synthesized nanogels showed a high ability for loading of hydrophobic drugs such as m-THPC and TAC. Different experiments showed that poly(glycerol-succinic anhydride) nanogels were able to efficiently improve the skin penetration of their cargos. Straightforward and gram-scale synthesis, high loading capacity, skin penetration, and biodegradability of poly(glycerol-succinic anhydride) nanogels make them fascinating candidates for dermal delivery application with a minimal health risk. In the fourth project, similar to the second project, glycidol was copolymerized ε-caprolactone and biodegradable poly(glycerol-caprolactone) with the ability of loading and transport TAC through the skin. Poly(glycerol-caprolactone) was degraded by skin lysate efficiently, but it showed much lower loading capacities for TAC in comparison with poly(lactide-co-glycerol). The lower loading capacity for poly(glycerol-caprolactone) could be due to the flexibility of poly(caprolactone) segments. High biocompatibility, water solubility, biodegradability, and the ability to improve the skin penetration of its cargo show that this copolymer is a promising candidate for topical drug delivery applications. In the final project, supramolecular nanogels compromised of pillar[5]arene and guest alkyl chains were produced and used for the dermal delivery of dexamethasone. Owing to their supramolecular nature, such nanogels were able to efficiently diffuse into skin and improve the skin penetration of their cargo. This project showed that supramolecular systems are very efficient alternatives for the dermal delivery of therapeutic agents. They could be more promising when both host and guest segments are natural compounds. In summary, incorporation of ester linkages in the backbone of polyglycerols by gram scale one-pot copolymerization of glycidol with the known cyclic monomers resulted in biodegradable polyglycerols or nanogels with a high ability to load and transfer therapeutic agents into the skin.

Next-generation sequencing (NGS), in particular Illumina sequencing, is the current stateof- the-art DNA sequencing technology. However, when it comes to time-critical analysis, Illumina sequencing lacks sufficiently short turnaround times due to the sequential paradigm of data acquisition and analysis. For clinical application and infectious disease outbreaks, a significant reduction of time needed from sample arrival to analysis outcome is crucial to optimally treat patients and to prevent further spread of disease. At the same time, nucleotidelevel analysis is required to enable (sub-)species level classification and determination of organism-specific properties such as, for example, antimicrobial resistances. To accelerate the generation of NGS analysis results, the real-time read aligner HiLive was developed that performs read alignment while sequencing. Still, HiLive delivers results only at the end of the sequencing process and lacks sufficient resolution and scalability. In this thesis, a novel real-time alignment algorithm is introduced that was implemented in HiLive2. Unlike its predecessor, HiLive2 provides results at any desired stage of sequencing at full nucleotide-level resolution. The novel approach is based on an FM-index and is more scalable with respect to reference database size and sample size. HiLive2 enables high-quality downstream analysis as shown by performing variant calling based on realtime alignments of human sequencing data. Further, PathoLive is presented, a pipeline for real-time pathogen identification from metagenomic datasets. Based on the output of HiLive2, PathoLive performs a weighted ranking of identified species. Thereby, sequences that typically do not occur in samples from non-infected human individuals are assumed to be of high clinical significance and therefore highlighted in the results. PathoLive also provides an intuitive and interactive visualization that significantly facilitates the interpretation of results. In a case study of a real-world sample from Sudan, PathoLive enables the correct identification of Crimean–Congo hemorrhagic fever virus based on only a few dozen related reads. Besides analytical challenges, samples from human individuals are problematic with respect to data protection as reads from a human host can be used for the identification of the patient. To address this issue, PriLive was developed that enables the irrevocable removal of human sequences from Illumina sequencing data during the ongoing sequencing process. This enables a much higher level of data protection than conventional post hoc host removal approaches as the human sequences are at no time available in full length.

Die kognitive Leistungsfähigkeit, wie z.B. auch die Arbeitsgedächtnisleistung, nimmt mit zunehmendem Alter ab (Dobbs & Rule, 1989). Damit einhergehend nehmen subjektive kognitive Beschwerden zu (Ponds, Van Boxtel, & Jolles, 2000). Allerdings kann diese Aussage nicht auf alle älteren Personen übertragen werden. So wurden hinsichtlich der tatsächlichen kognitiven Leistung inter-individuelle Leistungsverläufe sichtbar (z.B. Daffner et al., 2010). Auf Seiten der subjektiven kognitiven Beschwerden ist der Zusammenhang zur tatsächlichen Leistungsfähigkeit umstritten, sodass vor allem der Einfluss anderer Faktoren, wie beispielsweise eine depressive Stimmungslage, als auschlaggebend für das Ausmaß subjektiver kognitiver Beschwerden diskutiert wurde (Jessen et al., 2014). Das Ziel der vorliegenden Arbeit bestand darin, objektive und subjektive Altersveränderungen mit Hinblick auf inter-individuelle Leistungsunterschiede und Subgruppen zu betrachten, um genaueren Aufschluss über zugrundeliegende Prozesse zu gewinnen. Auf objektiver Seite wurde dazu zunächst überprüft, ob eine Abnahme der Arbeitsgedächtnisleistung im Alter sichtbar wurde. Von Interesse waren dann insbesondere diejenigen Älteren, die keine Leistungsabnahme aufwiesen und ob sich bei diesen funktionelle Prozesse abbilden ließen, die hierfür verantwortlich waren. Auch hinsichtlich der subjektiven kognitiven Beschwerden wurden verschiedene Subgruppen überprüft. Im Fokus standen verschiedene Beschwerdetypen und die Frage, hinsichtlich welcher psychosozialen Variablen, insbesondere der depressiven Stimmung, sich diese unterscheiden. Von weiterem Interesse war darüber hinaus auch der Einfluss der kognitiven Leistungsfähigkeit auf subjektive kognitive Beschwerden sowie mögliche Wirkrichtungen zwischen diesen Faktoren. Insgesamt wurde deutlich, dass eine objektive Abnahme der Arbeitsgedächtnisleistung nicht zwingend eintreten muss, wofür vor allem erhaltene Prozesse der exekutiven Aufmerksamkeit relevant waren. Auch hinsichtlich subjektiver kognitiver Beschwerden zeigte sich, dass diese nicht generell mit dem Alter zunahmen, sondern dass Personen mit Beschwerden der exekutiven Funktionen eher jünger waren und dies zudem mit einer depressiven Stimmung einherging. Letztere kann zudem zu einer tatsächlichen Leistungsabnahme in höheren Aufmerksamkeitsfunktionen führen, was wiederum die subjektiven kognitiven Beschwerden erklären kann. Insgesamt verdeutlichen die Ergebnisse die Notwendigkeit der Berücksichtigung inter-individuelle Leistungsunterschiede sowie Subgruppen in weiterer Forschung sowie klinischer Anwendung, da die Ergebnisse Hinweise auf mögliche Interventionen liefern.

As a major cause of infectious diarrheal diseases, non-typhoidal Salmonella (NTS), such as S. enterica subsp. enterica serovar Typhimurium, are of global health concern for both human and veterinary medicine. Besides causing usually self-limiting gastroenteritis in immunocompetent adult individuals, infection of neonates with this pathogen can induce invasive and potentially life-threatening conditions. Invasive infection caused by NTS are predominantly observed in developing countries with poor hygiene standards, where the pathogen is frequently isolated from cases of neonatal sepsis and meningitis. The pathogenicity of Salmonella is conferred by certain virulence factors encoded on chromosomal regions acquired by horizontal gene transfer, called Salmonella pathogenicity islands (SPIs). Delivery of effector proteins of SPI-1 and SPI-2 into the host cell is enabled via own type three secretion systems (T3SSs). The role of SPI effectors in host-pathogen interactions has been extensively studied in vitro and it is widely accepted that SPI-2 is crucial for the establishment of an intracellular compartment, the Salmonella-containing vacuole (SCV), which allows the bacteria to survive and replicate inside the host cell. Besides this, the translocated effector proteins allow the pathogen to modulate and manipulate the host cell system in various respects. Knowledge about effector contribution and their distinct role in pathogenesis of invasive NTS infections in vivo is rather scant. Therefore, we applied the neonate mouse model, which, in contrast to the commonly used streptomycin adult mouse infection model, allows the formation of SCVs inside infected enterocytes, followed by mucosal barrier penetration and subsequent bacterial dissemination without previous antibiotic depletion of the resident gut microbiota. In this study, we used this infection model to extend our knowledge on the role of individual SPI-2 effector proteins in establishment and progression of systemic Salmonella infections in the neonate host. Oral infection of neonates with wildtype and ΔSPI-2 Salmonella resulted in similar bacterial loads of the gastrointestinal tract, but re-isolation rates of SPI-2-deficient mutants from systemic organs, such as liver and spleen, and expression of pro-inflammatory cytokines were significantly decreased. Interestingly, in contrast to the general understanding of SPI-2 as prerequisite for SCV formation in vitro, mutants were able to establish and maintain SCVs in neonatal intestinal enterocytes. In fact, SPI-2-deficient bacteria grow to high numbers inside SCVs, nonetheless, like in the adult host, are attenuated in virulence and hampered in disease progression. The establishment of an SCV is not only feasible in the absence of the SPI-2 effector protein subset, but also without the host adaptor protein myeloid differentiation primary response 88 (MYD88). The observation of enlarged SCV formation in the absence of SPI-2, however, is strictly limited to the neonatal period. This is due to the immature intestinal tract constituting a unique environment with pending epithelial renewal on the one hand, whereas constant nutrient supply is ensured by fusion of the bacterial vacuole with transport vesicles on the other hand. By evaluating isogenic single SPI-2 effector protein mutants, we detected that SPI-2 effectors enabling interaction with the host cell microtubule network and positioning of the SCV inside the host cell partly phenocopy the SPI-2 dependent phenotype in vivo. Results achieved in this study suggest that depletion of SPI-2 effectors involved in the interaction with the host cell transport machinery still allows bacterial replication in the neonate intestine. However, the absence of these effectors prevents SCV transmigration from the apical to the basolateral side of the enterocytes. Mutants are therefore “stuck” inside their SCVs, which ultimately diminishes systemic spread to liver and spleen and complete pathogenesis of Salmonella in vivo. Thereby, SPI-2 effector proteins are needless in terms of early steps in NTS pathogenesis in the neonate host, but become urgent for the pathogen in order to overcome the epithelial barrier and achieve systemic dissemination.

Invasion biology is a relatively young sub-discipline of biology. Despite the fact that the idea was established in Charles Darwin’s book ‘On the origin of species’, the field was only founded a hundred years later with Charles Elton. Since the middle of the 1990s, the field has substantially grown in size. Accordingly, the number of hypotheses and concepts about biological invasions has substantially increased, and some of them are similar to each other, others are not supported by empirical evidence. The aim of this work was to develop and apply methods to create networks of hypotheses and concepts that visualize the field of invasion biology. The thesis contains four different methods and their resulting networks. Due to the nature of the topic, this work is interdisciplinary. The topics range from biology and its way to find categories (chapter 2), over social science (chapters 3 & 5) to bibliometrics (chapter 4). Also, this work had to overcome challenges in visualizing the emerging networks (see chapter 6.1). The method presented and applied in chapter 2 is a straightforward possibility to structure hypotheses based on their traits and characteristics. This method resulted in a hypothesis network with several clusters of hypotheses. For chapter 3, a survey approach was applied to create hypothesis networks. The participants of the survey were experts in the field of invasion biology. Surprisingly, the results showed that experts in invasion biology seem to have no consistent idea of their research field and therefore no clear, consistent inner map of invasion biology. With additional analyses, however, we were able to create networks of the best-known hypotheses and concepts in invasion biology seen by the participating experts. In chapter 4, we looked at co-citations of the key papers related to the major invasion hypotheses. This approach led to two clear maps of the field (one for each of the two applied analysis methods). Finally, in chapter 5, we created a hypothesis network based on a workshop we held in Berlin. This network emerged from a Delphi-based consensus approach that we developed. We also applied an advanced cluster-finding algorithm here that clusters links between nodes in the network instead of clustering nodes which is done by traditional cluster-finding algorithms. The advanced algorithm thus allows nodes to be in more than one cluster. This network based on the consensus approach and analyzed with the link-clustering algorithm has a better resolution and provides more information than the other networks presented in this thesis. I conclude this thesis with a discussion of the benefits and drawbacks of each network and its underlying approach. It seems that the best approaches to create a useful hypothesis network of a research field are those presented in chapters 4 and 5, i.e. the co-citation and consensus approaches. A co- 6 citation based network reveals how a research field such as invasion biology is seen by scientists who work in the field and how they cite publications. But there are no strict rules for citation and therefore this approach is based on trust in scientifically correct citations. The risk of a strong bias is reduced in case of the consensus approach, as the resulting network is based on the combined perspective of a sizeable number of experts. This seems to be the best way to structure existing hypotheses of invasion biology right now. A future important step is to apply this and possibly other approaches in other research fields.

LRP2 is an endocytic receptor of the LDL receptor gene family expressed on the apical surface of absorptive epithelia in the embryonic and the adult mammalian organisms. Binding a functionally diverse array of ligands, including morphogens, this receptor plays a crucial role not only in endocytosis but also in regulation of signal transduction in various cell types during embryonic development and in adulthood. LRP2 is best known for its ability to mediate cellular uptake of the morphogens sonic hedgehog (SHH) and bone morphogenetic protein (BMP) 4, an activity required to establish SHH and BMP signaling centers in the embryonic neural tube. Loss of receptor expression in gene targeted mice or in patients with inheritable LRP2 gene defect (Donnai Barrow syndrome) results in disturbances in neural tube neurogenesis and in malformation of the embryonic forebrain.

Intriguingly, expression of LRP2 persists in ependyma cells of adult mammalian brain. Ependymal cells are part of the neurogenic niche of the subventricular zone (SVZ), one of two regions of the adult mammalian brain capable of sustained neurogenesis. A possible role for LRP2 in adult neurogenesis was supported by earlier work documenting a decreased proliferative capacity in the SVZ of adult receptor mutant mice. Still, the molecular details of receptor function in adult neurogenesis remained obscure. I addressed this important question by performing detailed investigations of the adult neurogenesis and relevant ependymal cell functions in wild-type and LRP2-deficient mouse models as well as in brain explants and primary ependymal cell lines derived thereof.

In my studies, I uncovered defects in SHH signaling in LRP2-deficient mice in the rostral but not the caudal regions of the SVZ. A region-specific impact of receptor deficiency in the SVZ was also observed for other morphogen pathways, including BMP and WNT, as well as for mTOR activtity in this niche. The region-specific alterations in morphogen signaling in the SVZ coincided with a loss of the neural stem cell population and with impaired neurogenesis in the rostral but not the caudal region of the LRP2-deficient SVZ. Finally, the regional specificity in LRP2 action in the adult brain was substantiated by documenting aberrant accumulation of SHH in the caudal SVZ. Jointly, the above findings argued for a global effect of LRP2 activity on spatial control of adult neurogenesis in the mouse brain. This hypothesis received experimental support by documenting a defect in coordination of motile cilia beating in ependymal cells of LRP2 deficient mice. Because coordination of cilia beating is essential to control the flow of the cerebrospinal fluid (CSF) in a caudal to rostral direction, these findings suggested disturbed CSF flow and, hence, faulty distribution of morphogens to underlie the region-specific impact of receptor deficiency on morphogen signaling and adult neurogenesis in the SVZ. The molecular mechanism of LRP2 action in motile cilia function still remains to be fully established. However, my observations of the localization of LRP2 to the endocytically active ciliary pocket and of an altered distribution of endocytic markers in motile cilia from receptor mutant cells supports a role for LRP2 in controlling endocytic processes that safeguard coordinated cilia beating and thereby proper morphogen distribution in the neurogenic niche of the SVZ.

This thesis describes the successful first total synthesis of the biofilm-penetrating anti-MRSA agent (+)-darwinolide. The synthesis of this rearranged diterpenoid was achieved via a convergent strategy. One fragment was synthesized from (S)-isophorol using an Ireland-Claisen rearrangement as the key step. The synthesis of the second fragment featured a highly enantioselective organocatalytic desymmetrization of a meso-diol. Fragment coupling was achieved by Aldol addition and the central seven-membered ring was closed by olefin-metathesis. In the second project of this thesis, a concise semisynthetic access to the renal cancer inhibitor (−)-englerin A was achieved. The starting material, guaia-6,10(14)-diene was obtained by synthetic biology and was also used for the syntheses of (−)-oxyphyllol and (+)-orientalol E. Furthermore, seven new analogs of englerin A were synthesized, and their structure-activity relationship was studied.

Geothermal energy is one of the cleanest renewable alternatives to reduce the dependency on fossil fuel. Despite its promising future, its implementation faces various challenges, one of them being corrosion processes. To implement this energy, hot fluids are pumped from a geothermal well. These hot fluids originate from deep within the earth, so consist of different ionic species and gases in a wide range of temperatures, which lead to their corrosive nature. In terms of geothermal energy resources, Indonesia is at the forefront, with the highest preserved geothermal energy in the world of about 29 GWe and 312 potential geothermal locations. Geothermal wells in Sibayak (North Sumatera), Indonesia, belong to young stratovolcanoes and have operating temperatures varying from 36 °C at the near ground surface to 310 °C at the bottom of the well, which is liquid-dominated with acidic and saline properties. Therefore, this geothermal fluid creates an aggressive environment that is conducive to corrosion of the powerplant infrastructure. Parts of the geothermal powerplant infrastructure, such as pipelines and heat exchangers, are commonly made of metals, e.g. carbon steel and stainless steel. Consequently, they may undergo corrosion and scaling when exposed to the geothermal fluid, especially for carbon steel. To ensure the safety and longevity of a geothermal powerplant, the infrastructure is constructed of expensive corrosion resistant alloys, e.g., titanium and Ni-Cr based alloys, or carbon steel which needs to be protected by coatings or inhibitors. To address the corrosion of carbon steel in the geothermal environment, artificial geothermal water was used to simulate a geothermal well in Sibayak, Indonesia, with pH 4 and a saline composition of 1,500 mg/l Cl-, 20 mg/l SO42-, 15 mg/l HCO3-, 200 mg/l Ca2+, 250 mg/l K+, and 600 mg/l Na+. Carbon steel underwent the most severe corrosion at 150°C in an oxygen-containing solution with a corrosion rate of 0.34 mm/year, which is approximately ten times higher than that in the absence of dissolved oxygen. In all conditions, pitting corrosion was observed, which necessitate a protection strategy on carbon steel. In order to promote a cost effective and locally available option, this work focused on an easily applicable coating which utilized local resources. Toward developing such protective coating based on the locally available resources in Indonesia which can yield good corrosion resistance and thermal stability in geothermal environment, two additional components, i.e. polyaniline (PANI) and silicon dioxide, were used to modify an alkyd-based commercial coating. The selection of the alkyd-based coating as a matrix focused on the industrial convenience basis, where the coating application procedure should be simple and easy to apply within reasonable costs. The alkyd-based coating underwent severe blistering when exposed to the artificial geothermal water at 70 and 150°C due to the reaction between CaCO3 (as one of its components) and the artificial geothermal water, as well as a possible alkyd hydrolysis in the initial stage of exposure. In the oxygen-free solution, the degradation was controlled by chemical and thermal reactions, whereas in the aerated condition, oxidization at the coating surface further accelerated polymer degradation. PANI was chosen as one of the anticorrosion pigments which was widely developed over the past decades. To investigate the interaction between PANI and the artificial geothermal water, PANI film was electrochemically deposited on the carbon steel surface and exposed to the artificial geothermal water. Electrochemically synthesized oxalate-doped PANI was protective against corrosion of carbon steel in artificial geothermal water at room temperature. The mechanism involved an exchange of electroactive species within the coating layer, as confirmed by electrochemical impedance spectra. Interaction of ionic species, such as Cl , Na+, Ca2+ from the artificial geothermal water, with the outer layer of PANI is suggested both at 25°C and 150°C, based on the EDX spectra of the coating surface after exposure to the artificial geothermal water. Thus, the protection mechanism of PANI is not solely based on the physical barrier layer properties, but rather associated with the redox mediated properties of PANI, which selectively allow ionic species intrusion from the electrolyte into the PANI layer. Although PANI is a promising candidate as an anticorrosion coating, its morphological characterization reveals that electrochemically deposited PANI is not stable for an application at 150°C. Therefore, another approach was used to promote better protective behavior of PANI by dispersing chemically synthesized PANI in the alkyd-based coating. To enhance the thermal stability of the coating, silicon dioxide (SiO2) was added, which was able to prolong the sustainability of coated metals until 28 days compared to the unmodified alkyd-based coating, which underwent a change in color to brown/orange only within 7 days of exposure. This improvement might be associated with the role of SiO2 to proportionate the thermal expansion coefficient of the coating system to be compatible with that of carbon steel. Although the coating is thermally enhanced, the electrolyte might still intrude through the coating resulting in the change of coating color after 28 days of exposure in the artificial geothermal water. When PANI was added, the coating system provided an active corrosion protection on the carbon steel surface. The chemical and morphological characterization of the PANI-alkyd and SiO2-alkyd coating system showed that coatings were improved, and no blisters were observed, albeit the degradation continued. Based on the results of exposure tests, the combined coating system was further investigated. The combinational coating of PANI/SiO2-alkyd was used with 2 wt% of PANI and 15 wt% of SiO2. Electrochemical tests indicated cathodic protection at 150°C, as the Ecorr of PANI/SiO2 remained approximately 400 mV lower than the carbon steel potential. The impedance spectra of the combinational coating of PANI/SiO2 showed a continuous decrease in the absolute impedance value over time. A significant decrease was observed within one day of exposure, followed by a slow gradual decrease, which might be associated with water absorption in the coating. FTIR spectra revealed that several peaks associated with the organic portion of the coatings were reduced after the specimens were exposed for 6 months. However, the absorption peaks related to the inorganic portion of the coatings remained stable until 6 months. Morphological characterization of the combinational coating of PANI/SiO2 showed that there were no blisters or significant discoloration of coatings after long-term exposure for 6 months in artificial geothermal water at 150°C, indicating that the chemical degradation does not significantly affect the functionality of the coating. This clearly shows the durability of PANI/SiO2 coating in the geothermal condition, suggesting that this coating can be used for such geothermal application. However, further testing of this coating should be conducted in a real geothermal environment on-site to ensure safety and viability.

Expansion microscopy (ExM) was introduced since 2015 and has been fast developed since then. This technique, via physical enlargement of fluorescence carried biological samples, can resolve structures of tens of nanometers with conventional microscopes. Here I discussed the current methods in ExM and influences of different fixation, protease digestion and labelling methods used in ExM. Validation of ExM was also carried out in the work using image registration of microtubule cytoskeletons and the 190 nm periodic structures of β-spectrin ring structures in neurons. Next, the combination of ExM with other super-resolution techniques, e.g. stimulated emission depletion (STED) microscopy was proposed. The centrosome protein CEP152, the primary cilium and microtubule were resolved using expansion STED (ExSTED) microscopy. With the optimized ExSTED microscopy, a sub-10 nm 2D and a sub-50 nm 3D resolution was achieved. Structured illumination microscopy (SIM) was also attempted to image the expanded hydrogels, but severe artifacts were observed. Finally, a tri-functional fluorescent probe was proposed, where a fluorescent dye was linked with a benzyl-guanine and an acrylic acid group. The probe was used to stain a SNAP-tagged nuclear pore protein in cells and used to crosslink proteins to acrylamide-based hydrogel in ExM.

The need for new designs of biomaterials for existing challenges in biomedical applications has led to the fabrication of three different polymeric hydrogels using dendritic polyglycerol and polyethylene glycol. These polymers were used for their bio-inertness, the possibility of a large varieties of functionalization and the ability to adapt the mechanical properties of the resulting material to the desired applications. In the first project, the aim was to build a bioactive material specific for antibody detection where specific peptides were immobilized in the matrix as capture ligands. The challenge was to immobilize these molecules of recognition without altering their biological functions, without any change of conformation nor denaturation and without any leaching out of the system overtime. The easy and fast crosslinking biorthogonal approach to build the hydrogels was therefore well suited for the biosensing applications since they were also customizable to the desired application. The main reason for the use of hydrogels was to enhance the capability of 3D structures to improve biosensing strategies in terms of sensitivity, high loading capacity, and stability of the biomolecules, which prevents errors in the sensing method. Another aspect was the possibility of miniaturization of the system by using, for example, microarrays. All these aspects lack in existing 2D systems, which are however used in current biosensors. The strategy was thus to improve these existing 2D systems by using the advantages offered by a 3D hydrogel approach. To predict the biosensing ability of our systems, we first characterized in depth the hydrogels in nano- and micro-scales, varying the molecular weights of the linkers. The linkers would influence the mechanical properties and morphology of the hydrogel networks. Regarding the physical properties of the networks, a remarkable swelling of the hydrogels (up to 100 their dry weight) was reached with an increasing swelling as a function of the molecular weights of the linkers. For the biosensing characterization, we obtained a specific and selective detection. Besides, a higher loading capacity was obtained with seven times higher than the one of 2D arrays. The sensitivity increased by 20% compared to the 2D detection method, the obtained limit of detection being 27 pg/mL. In the second project, we proposed a patterned soft nanocomposite hydrogel as a soft cell culture scaffold. Directing stem cells to a specific lineage and keeping their pluripotency is challenging. And yet, in soft tissue engineering, soft tissue reconstruction to restore deficient tissues underneath the skin remains a hard endeavor. Recent studies have shown that culturing hMSCs on typical TCPS or glass (hard substrates) has damaged the intrinsic function of these cells which has led to loss of stemness as the number of passages increased. In addition, they lost their adipogenesis differentiation potential. Stemness is defined as the mechano-sensing ability, immunophenotyping, and differentiation potential of a cell. To retain these properties of the stem cell, we produced a tissue mimicking cell responsive platform by tuning the mechanical, biological, and morphological characteristics of the nanocomposite fabricated in a biorthogonal click strategy and Au-S chemistry. We obtained nanocomposites with stiffness in the range of liver tissues (elastic moduli < 2 kPa). To correctly predict the effect of the matrix on hMSCs, we studied their mechanical properties as a function of two different molecular weights of PEG linkers. The locomotion of hMSCs was first investigated on two different surfaces with patterns (wrinkles or creases) and the strong attachment of the cells on the nanocomposites was assessed. Stemness and differentiation potential were observed with an influence of the mechanical characteristics and the presence of adhesive peptides (RGD) and their spatial organization. We hypothesized that such system would influence the cells’ behavior and morphology. In addition, they would keep their stemness compared to on bare TCPS or glass (hard surfaces). The studies have shown that a cell culture on these hydrogels preserved the immunophenotyping and mechano-sensibility of the hMSCs but lost on hard surfaces. This suggested that these polymeric networks had a positive influence on the hMSCs’ fate by keeping their pluripotency. Finally, the soft substrates allowed exclusively the differentiation into a specific lineage, yielding adipocytes. In the third project, a hybrid hydrogel has been established using both inorganic and organic materials to produce a nanocomposite. The hydrogel was virus responsive giving a double response, both an optical and a mechanical response to Influenza virus. We combined the use of gold nanoparticles for their optical properties, polysaccharides (sialic acid) for their specificity to Influenza virus and polyols for their ability to produce a highly swellable hydrogel. Besides the unique optical properties of gold nanoparticles displaying a color change visible by naked eyes, they also offer the possibility to anchor multiple molecules and biomolecules preventing at the same time any leaching out of the network and a better stability. The polyols (polyethylene glycol and dendritic polyglycerol) produced a bio-orthogonal hydrogel by strain-promoted azide-alkyne cycloaddition, which represents a suitable environment for biospecies by preventing their denaturation and any unspecific interaction. In addition, to enhance the specificity of the system, we used a bioimprinting procedure and used the virus as a template to create specific recognition sites. Specific recognition of macro-biomolecules such as virus represents a challenge and a responsive system giving a double response to viruses is unique to this date. We present here a proof-of-principle that any virus and more generally any multivalent molecule can be recognized in a responsive polymer network by responding with a color change and shrinkage detectable by eyes. Given the specific molecules and imprint technique, these hydrogel features make it a customizable network for the desired application.

Patienten mit hämorrhagischem Schlaganfall erwartet ein hohes Maß an Morbidität und Mortalität. Die vorliegende Arbeit hatte zum Ziel, zum Verständnis von Zusammenhängen zwischen klinischen Variablen und Langzeit-Ergebnis beizutragen. In den vorgestellten Arbeiten wurden Schwerpunkte auf Identifikation, Charakterisierung bzw. Therapie solcher Variablen gelegt. In den Studien zur spontanen intrazerebralen Blutung (ICB) (Originalarbeiten 1 und 2) wurden die intraventrikuläre Blutungskomponente (IVB) und das perihämorrhagische Ödem (PHE) untersucht. Für beide wurde gezeigt, dass ihr Vorhandensein bzw. ihre Ausdehnung zeitabhängig sind, und das Blutungsstadium widerspiegeln. Für die IVB wurde gezeigt, dass sie ein Indikator für eine fortgeschrittene und schwere ICB darstellt und dass der verspätete Ventrikeleinbruch, vormals als häufiges Phänomen postuliert, selten ist. Für das PHE wurde konklusiv gezeigt, dass Statine als Hausmedikation keinen Einfluss auf seine Größe im Aufnahme-CT haben. Periodische EEG-Entladungen (PDs) nach spontaner Subarachnoidalblutung (SAB) gehen, abhängig von der Entladungs-Frequenz, mit Veränderungen von Sauerstoffpartialdruck und regionalem Blutfluß des Hirngewebes einher (Originalarbeit 3). Oberhalb einer PD-Frequenz von 2 Hertz stellt sich Hypoxie ein und die Veränderungen gleichen dann solchen, wie sie vormals während elektrographischer Anfälle nachgewiesen wurden. Die Studienergebnisse suggerieren, dass die antikonvulsive Behandlung hoch-frequenter PDs prospektiv untersucht werden sollte. Originalarbeit 4 beschreibt erstmals ein multimodales Prädiktions-Modell für Patienten mit SAB, welches in einer externen Patientenkohorte validiert wurde. Mit dem Modell können Behinderung, Kognition und Lebensqualität nach SAB prognostiziert werden. Die epidemiologische Originalarbeit 5 zeigt hohe Inzidenzen von Vorhofflimmern/-flattern bei Patienten nach Hospitalisierung im Rahmen eines hämorrhagischen Schlaganfalls, nahezu vergleichbar mit den Inzidenzen in den Kontrollgruppen (Patienten mit ischämischem Schlaganfall bzw. Hospitalisierte ohne Schlaganfall). Es besteht Bedarf, die Bedeutung intermittierenden VHF genauer zu charakterisieren, um Antikoagulations-Bedarf bei Patienten nach hämorrhagischem Schlaganfall zu definieren. Die vorgestellten Arbeiten charakterisieren Prädiktoren und Verschlechterungs-Mechanismen nach intrakraniellen Blutungen während der Hospitalisierungs- und Langzeit Follow-up Phase. Sie definieren somit Studien-Subpopulationen und neue Therapieziele, die nun prospektiv untersucht werden können.

The difference between the positions of the maximum peak of the carrier wave of a laser pulse and the maximum of its intensity envelope is termed carrier-envelope phase (CEP). In the last decades, the control and stabilization of this parameter has greatly improved, which enables many applications in research fields that rely on CEP-stable pulses such as attosecond science and optical frequency metrology. Further progress in these fields depends strongly on minimizing the CEP noise that restricts stabilization performance. While the CEP of most high repetition-rate low-energy laser oscillators has been stabilized to a remarkable precision, some types of oscillators show extensive noise that inhibits precise stabilization. The CEP stabilization performance of low repetition-rate high peak-power amplified laser systems also remains limited by noise, which is believed to stem mainly from the CEP detection process. In this thesis, the origins of the CEP noise within four oscillators as well as the noise induced by the measurement of the CEP of amplified pulses are investigated. In the first part, the properties of the CEP noise of one Ti:sapphire oscillator and three different fiber oscillators are extracted by analyzing the unstabilized CEP traces by means of time-resolved correlation analysis of carrier-envelope amplitude and phase noise as well as by methods that reveal the underlying statistical noise properties. In the second part, investigations into the origin of CEP noise induced by the measurement of the CEP of amplified pulses are conducted by comparing several different CEP detection designs that are based on f -2 f interferometry. These detection setups differ in the employed sources of spectral broadening as well as frequency doubling media, both necessary steps to measure the CEP. The results in both parts of this thesis show that white quantum noise dominates most CEP measurements. In one particular fiber oscillator, the strong white noise is found to be a result of a correlating mechanism within the employed SESAM. During amplifier CEP detection, the CEP noise is found to be originating only to a marginal degree from the number of photons that are detected during the measurement, which excludes shot noise as a limiting source. Instead, the analysis reveals that the origin of the observed strong white noise can be interpreted as a loss of coherence during detection. This type of coherence is termed here intra-pulse coherence and describes the phase transfer within f -2 f interferometry. Its degradation is a result of amplitude-to-phase coupling during the spectral broadening process that leads to pulse-to-pulse fluctuations of the phases at the edges of the extended spectrum. Numerical simulations support the concept of intra-pulse coherence degradation and show that the degradation is substantially stronger during plasma-driven spectral broadening as compared to self-phase modulation-dominated spectral broadening. This difference in degradation also explains the much stronger CEP noise typically observed in amplified systems as compared to oscillators, as the former typically rely on filamentation-based and hence plasma-dominated spectral broadening for CEP detection. The concept of intra-pulse coherence constitutes a novel measure to assess the suitability of a spectral broadening mechanism for application in active as well as in passive CEP stabilization schemes and provides new strategies to reduce the impact of the CEP detection on the overall stabilization performance of most lasers.

The temporal contrast of optical pulses produced by high-peak power laser systems is important for laser-matter applications, such as table-top particle accelerators and sources of attosecond pulses in the extreme ultraviolet and X-ray ranges. Currently available laser technologies cannot provide a temporal shape of an ultra-short pulse at high energy which is absolutely pre-pulse free. This work is dedicated to issues of the temporal shape of light pulses generated by Chirped Pulse Amplifcation (CPA) lasers based on the widely-used Ti:Sapphire technology. This analysis is performed at the low picoseconds time scale around the main pulse and in a dynamic range of intensity > 10¹⁰. An overview of the current state of the problem is presented as well as a detailed discussion of the many related aspects including the characterization of laser pulses over a high dynamic range and the technologies for nonlinear temporal fltering that are required for the suppression of pre-pulses and improvement of the leading front of the laser pulse.

The most commonly used diagnostics for characterization of laser pulses over a high dynamic range, including third-order cross-correlators, have been considered in detail. It has been shown that this method can introduce artefacts into the measured traces. An improvement to the optical scheme of the commercial Sequoia cross-correlator has been suggested. A method to indicate coherent parts of laser pulses has also been proposed.

Commonly used schemes for optical stretchers and compressors with di erent dispersive optics have been compared and investigated. It was shown and proved, for the first time that the nonlinear processes occurring during propagation of a stretched pulse result in the generation of a ragged pre-pedestal from the post-pedestal which is coherent to the main pulse. The key role of the ragged post-pedestal as well as its coherence have also been highlighted for the first time in this work. An explanation for the observed phenomena is given. It has also been shown that the post-pedestal is the key limiting factor of the picosecond temporal contrast in CPA Ti:Sapphire-based laser technology.

Highly effcient nonlinear fltering technology based on rotation of the polarization ellipse in gases and a post-compression technique have been combined to to improve the temporal shape of laser pulses on the femtosecond and picosecond time scales.

Die vorliegende Dissertation widmet sich der Analyse der ältesten bekannten Monumentalarchitektur der Menschheit. Diese Bauten wurden in der Tükei, in Nordsyrien und in Jordanien entdeckt und werden ungefähr in die Zeit um 10.000 v. Chr. (akeramisches Neolithikum) datiert. Sie unterscheiden sich insbesondere durch ihre Monumentalität von normalen Wohnhäusern. In der Literatur wird für diese Bauten üblicherweise der Terminus Sondergebäude verwendet. Die entdeckten Befunde und Funde der akeramisch neolithischen Siedlungen im vorderasiatischen Raum verweisen auf eine komplexe Sozialstruktur. Ihr spezifischer Charakter ließ Archäologen wie Hauptmann (1993), Rollefson (2005) und Schmidt (2006) nach der Entstehung von Kultbauten während der Zeit des akeramischen Neolithikums fragen – aber diese Frage blieb bislang unbeantwortet. In den letzten zehn Jahren hat insbesondere die spektakuläre Entdeckung der monumentalen und kommunalen Strukturen in den akeramisch neolithischen Siedlungen des 10.–8. Jahrtausends v. Chr. in Nordsyrien, Jordanien und vor allem in der Südosttürkei diese Frage erneut aufgeworfen. Die Berichte der Ausgrabungen von Jerf el-Ahmar, Mureybet, Nevalı Çori, Göbekli Tepe, Aşıklı Höyük, Çayönü und ‘Ain Ghazal ermöglichen es uns, der Entwicklung allgemeiner Grundsätze bei der Errichtung von Kultstrukturen dieser frühen Siedlungen auf die Spur zu kommen. Einer der Hauptpfeiler der Dissertation ist daher die Sammlung aller relevanten Daten aus den publizierten Berichten in einem Katalog, der die Grundlage für die Beschreibung der Fundorte, ihrer Architektur und Funde bildet. Im Anschluss daran wird eine vergleichende Analyse zwischen den Sondergebäuden und den Wohnhäusern innerhalb einer Siedlung und zwischen den Sondergebäuden verschiedener Siedlungen durchgeführt. Ziel dieser Analysen ist es, zu Aussagen über eine mögliche sakrale oder profane Funktion zu kommen. Daher werden die in der Literatur eingeführten Bezeichnungen als Tempel oder Sondergebäude zwar verwendet, aber bis zur Auswertung und Neubeurteilung über den Status der Gebäude durch Kursivschrift gekennzeichnet.