Investigating the motion of electrons in atoms, molecules and solids on attosecond timescales is of widespread current research interest. In recent years, attosecond transient absorption spectroscopy (ATAS), has emerged as a versatile tool to study these dynamics. In ATAS the modification of absorption of an attosecond pulse in the extreme ultraviolet (XUV) wavelength region by a phase-locked infrared pulse (IR) is explored, revealing the dynamics of electronic coherences and light-induced couplings on attosecond timescales. To resolve the light-induced coupling of molecular valence and Rydberg states on the timescales of the cycle of the IR laser lightfield, an ATAS study on iodomethane is presented in the first part of this thesis. For the first time, ATAS is extended from atoms and homo-nuclear molecules to a polyatomic molecule, as well as to core-to-valence and core-to-Rydberg transitions in the XUV to soft X-ray spectral regimes that allow a site-specific insight into the molecular light-induced dynamics. The impact of symmetry on the observable coupling pathways in ATAS is unraveled and the possibility to obtain additional information from polar and chiral molecules in future experiments is discussed.

In the second part of this thesis, XUV refractive optics are developed using a dense gas jet. Refractive optics have so far been absent in the XUV region, due to a lack of materials with suitable properties. An XUV prism is introduced as the first demonstration of XUV refractive optics, based on the utilization of an inhomogeneous, dense gas jet. In a second application of XUV refractive optics, an XUV gas lens is constructed: A dense gas jet matching the XUV beam diameter is used to focus an XUV beam similar to the way conventional cylindrical lenses focus beams. Exploring the behavior of refractive indices in the XUV spectral domain a novel phase-matching concept is introduced that allows to efficiently modify and control the spectral bandwidth of an XUV source. The concept is experimentally demonstrated by means of XUV bandwidth compression in a krypton gas jet.

The results of the work reported in this thesis show how the complex transient dipole spectrum of atoms and molecules can be experimentally observed and theoretically understood from a transient absorption or refraction measurement and used to unravel dynamics on the attosecond timescale. The developed tools allow for a more versatile application of XUV spectroscopy in the future.

In dieser Arbeit wird der Einfluss von Nanostrukturen auf die Elektronendynamik in organischen und anorganischen Halbleitern mittels zeitauflösender Zwei-Photonen-Photoemission (2PPE) untersucht.

Im ersten Teil werden dünne Schichten des organischen Halbleiters a-Sexithiophen (alpha-6T) auf einem Au(1 1 1)-Substrat untersucht. Aufbauend auf vorangegangenen 2PPE-Untersuchungen an diesem Probensystem [1–3] stehen in dieser Arbeit die Bildungs- und Zerfallsdynamik von Exzitonen bei einer optischen Anregung 130 meV oberhalb des Exzitonenbandbodens im Zentrum der Betrachtungen. Dadurch soll geklärt werden, wie sich vibronische Anregungen auf die Exzitonendynamik auswirken. Dünne Schichten alpha-6T auf Au(1 1 1) wachsen bei Raumtemperatur in einem Stranski- Krastanov-Modus mit einer Benetzungsschicht von 2ML und anschließender Kristallitbildung. Thermische Desorptionsspektroskopie (TDS) ergibt, dass die in direktem Kontakt zum Metall stehende erste Lage eine Moleküldichte von 0,56 Moleküle/nm^{2} aufweist und nicht molekular desorbiert. Während a-6T auf einer Quarzoberfläche ein stark gekoppeltes H-Aggregat aus senkrecht stehenden Molekülen bildet, adsorbieren die Moleküle auf Au(1 1 1) mit der langen Achse überwiegend parallel zur Oberfläche. Differenzielle Reflexionsspektren im Energiebereich der S1-Bande von a-6T zeigen bei Multilagenbedeckungen charakteristische Merkmale eines HJ-Aggregates mit Kopplung an Vibrationsmoden. In den 2PPE-Messungen werden Exzitonen nur bei Bedeckungen beobachtet, die die Benetzungsschicht übersteigen. Sie entstehen durch direkte Photonenanregung im alpha-6TFilm. Die Evolution der asymmetrischen Peakform im 2PPE-Spektrum erlaubt Rückschlüsse auf die dynamische Entwicklung der Exzitonen. Die optisch angeregte Exzitonenpopulation relaxiert mit einer Zeitkonstanten von 70 fs zum Exzitonenbandboden. Die Entwicklung auf einer längeren Zeitskala von 1 ps wird einer zunehmenden Lokalisierung der Exzitonen und damit einhergehender Änderung der Kopplung an ihre lokale Umgebung zugeschrieben. Die Exzitonenpopulation zerfällt nach der optischen Anregung auf einer Zeitskala von über 100 ps und zeigt dabei ein nicht-exponentielles Verhalten. Die Rekombination an der Molekül/Substrat-Grenzschicht stellt den dominanten Zerfallskanal dar.

Der zweite Teil dieser Arbeit befasst sich mit dem Einfluss von Goldnanostrukturen auf die Elektronendynamik an der Ge(0 0 1)-Oberfläche. Selbst bei nominellen Goldbedeckungen von mehreren Monolagen bleiben die charakteristischen Germaniumoberflächenzustände erhalten. Die Populations- und Zerfallsraten der Germaniumzustände erhöhen sich jedoch deutlich. Dies wird dem großen Streuquerschnitt der Goldatome für angeregte Ladungsträger zugeschrieben. Weiterhin induziert die Adsorption von Gold die Bildung von eindimensionalen Nanodrähten auf der Ge(0 0 1)-Oberfläche. In Photoemissionsmessungen zeigen die Nanodrähte parabelförmige Elektronenbänder symmetrisch zum Gamma-Punkt bei k_{||} = 0,2Å^{−1} [4]. Durch Messungen mit einer Photonenenergie von 6,23 eV können die Elektronenbänder in direkter Photoemission durch Differenzmessungen von Au/Ge(0 0 1)- und Ge(0 0 1)-Proben sichtbar gemacht werden. Die Elektronenbänder zeigen die aus der Literatur bekannten Eigenschaften [5]. Da n- und p-dotierte Proben ähnliche Signale aufweisen, müssen die durch das Gold induzierten Zustände die Fermi-Energie 130 meV über dem Valenzbandmaximum pinnen. Die Untersuchung der Ladungsträgerdynamik in diesen Elektronenbändern zeigt unterschiedliche Elektron- und Lochlebensdauern: Im Vergleich zu Messungen bei 300K haben Löcher bei 160K nahe der Fermi-Energie eine deutlich höhere Lebensdauer als Elektronen. Dies beweist den eindimensionalen Charakter des Elektronensystems auf dieser Oberfläche [6].

This thesis deals with the development of an organocatalytic [3,3]-sigmatropic rearrangement of divinylcyclopropanes to cycloheptadienes. The reactive motif was formed in situ by condensation of α,β-unsaturated aldehydes with secondary amines.

After optimisation of the reaction, a variety of cycloheptadienes with diverse substituents was obtained in high yields and with excellent diastereoselectivities. Furthermore, the reaction was demonstrated to be stereospecific and proceeded under mild conditions. Hereby, the synthesis of a broad substrate library posed a formidable challenge. A synthetic strategy was devised in which the key transformation was the late-stage introduction of diversity in the final step by C–C cross coupling followed by one-pot deprotection. This strategy allowed most substrates to be derived from one common precursor. Individual substrates could be obtained by nickel catalysed reductive cross-coupling in a step efficient manner.

Intermediates of the substrate synthesis were applied to the selective modification of proteinogenic lysine residues.

This dissertation consists of three essays that investigate the effects and transmission mechanisms of monetary policy to the macroeconomy, and the role of financial frictions in modeling the business cycle. The first essay focuses on the question of how to include financial sector dynamics into macroeconomic models in order to improve their efficacy for macroeconomic policy analysis. We augment a standard New Keynesian model with a financial accelerator mechanism and show that financial frictions generate large state-dependent amplification effects. We fit the model to US data and show that the nonlinear model produces much stronger propagation of shocks than the linear model, particularly when shocks drive the model far away from the steady state. We document that these amplification effects are due to endogenous variation in financial conditions and not due to other nonlinearities in the model. Motivated by these findings, we propose a regime-switching DSGE framework where financial frictions endogenously fluctuate between moderate (low risk) and severe (high risk) depending on the state of the economy. This framework allows for efficient estimation with many state variables and improves fit with respect to the linear model. The second essay focuses on the following question: does monetary policy effectiveness in influencing the economy depend on households' balance sheets in the US economy? We investigate the interrelation between household balance sheets, collateral constraints, and monetary policy. We estimate a monetary DSGE model with financial frictions and occasionally binding borrowing constraints. The model implies stronger effects of monetary policy interventions when the borrowing constraint is binding compared to situations when it turns slack. In a prediction analysis we find that, out of a set of alternative plausible endogenous model variables, the level of household net worth is the single best predictor of the tightness of the borrowing constraint, which implies that monetary policy is more effective when household net worth is low. We test this model prediction in the data and provide robust empirical evidence on asymmetric effects of monetary policy across the household net worth cycle that validates the model predictions. A contractionary monetary policy shock leads to a large and significant fall in economic activity during periods of low household net worth. By contrast, monetary policy shocks have only small and mostly insignificant effects when net worth is high. The third essay focuses on the following question: how do credit constraints affect households' consumption response to monetary policy in the US economy? Combining detailed survey data on household portfolios, loan rejections, and consumption, I estimate the consumption response to exogenous changes in interest rates at the household level. I find large and statistically significant heterogeneity in the consumption responses across households, with constrained households being significantly less responsive. Specifically, the consumption response of unconstrained households to a monetary policy shock is between two to three times larger than the average response across all households. Using a New Keynesian model with heterogeneous households, I argue that this empirical finding is consistent with a model where financially constrained households have a low direct sensitivity to interest rates and indirect effects of monetary policy take time to materialize.

This thesis seeks to understand the repercussions of increasing ecological constraints and of the imperative of “greening” for the future of global capitalism. It engages in depth with the Green Economy (or green growth) approach developed by major international institutions (OECD, World Bank and UNEP) and focuses on the centrality, conditions, feasibility and by-effects of systemic accumulation in a green-capitalist economy. To theorize these, a conceptual framework is developed that distinguishes between political-economic and structural-economic constraints and comprises a set of functional and normative criteria for “green” capitalism (economic, ecological and social), potentially available “green” systemic accumulation strategies and empirically observable green-capitalist macro-strategies. This framework draws on a wide range of critical theory, including Marxian economics, regulation theory, world-systems analysis, Jason W. Moore’s world-ecology approach and further writings in political ecology.

It is found that a combination of political-economic and structural-economic constraints renders the market-oriented Green Economy approach largely ineffectual with respect to its declared intentions. Its non-confrontational politics are too passive even to realize a minimal “passive revolution” in the Gramscian sense. Instead, the “actually emerging” Green Economy assumes the form of an Economy of Additionality that leaves the fossil-fueled infrastructure of global capitalism in place and develops little transformative power. Prevalent “green” strategies partially internalize socio-ecological costs only to re-externalize these to vulnerable populations and ecosystems, in violation of the Green Economy’s normative standards and “win-win-win” promise.

Generally, most “greening” measures do not contribute positively to systemic accumulation but merely attempt, by rationalizing the maintenance of capital’s conditions of (re)production, to reduce the drag on accumulation exerted by ecological degradation and resource depletion. Against this background, the pressure for a “green-tech revolution” to resolve the fundamental capital—ecology contradiction is enormous, but the unprecedented absolute decoupling of systemic accumulation from environmental consumption remains physically and politically extremely unlikely, and “green” capitalism’s dependence on its realization is a very risky wager. These structural constraints equally apply to more politically balanced alternative green-capitalist projects such as neo-Keynesian proposals for a Green New Deal, suggesting systemic limits to the “greening” of capitalism. The hypothetical full internalization of socio-ecological costs, while not precisely quantifiable, might well render further systemic accumulation impossible by pushing down profit rates. Global capitalism is approaching planetary limits, the potential for the appropriation of “cheap nature” is increasingly exhausted – and “win-win-win” scenarios for nature, society and capital are not on the horizon.

Group B Streptococcus (GBS) is a major neonatal pathogen and a leading cause of infant mortality worldwide. Management of GBS infection relies on the prophylactic and therapeutic use of antibiotics. This approach has limited efficiency and increases antibiotic resistance. Carbohydrate conjugate vaccines are consensually regarded as the best possible alternative and several formulations have been and are now in clinical trials. In general, carbohydrate vaccine development suffers from shortfalls associated with the availability oligosaccharide libraries. Chemically pure glycans enable the prosecution of structure-immunogenicity studies that elucidate minimal epitopes and the intermolecular interactions responsible for recognition and immunity. One of the most promising methodologys to produce libraries of glycans is Automated Glycan Assembly (AGA). In this work, glycans from GBS are produced by AGA using the commercial synthesizer Glyconeer. The entire process is optimized since the production of building blocks to the automated oligosaccharide synthesis process. Ready-to-use building blocks (BBs) are required in bulk to do automated experiments in a continuous way. The synthesis of BBs can be achieved with a variety of different methods and the choice is usually based on the chemist preference and experience. This work optimizes and streamlines the strategies for the synthesis of building blocks for AGA bearing a thiolate aglycon as a leaving group. The synthetic schemes are completed and upscaled with minimal column purifications. This thesis goes on to describing the optimization of elongation cycles that introduce each BB in the growing oligosaccharide chain during AGA. The first target is GBS type IV capsular polysaccharide. In the synthesis of GBS type IV, the major bottleneck was the assembly of the Glc-α-1,4-Gal cis linkage. A trisaccharide containing this linkage was successfully synthesized. However, the low yields obtained rendered the elongation of the chain unsuccessful. The other target structures were related with GBS type III. With only three different BBs, four different GBS type III fragments were assembled. A sialic acid moiety present in the native polysaccharide was introduced enzymatically, proving that the combination of enzymatic sialylation with AGA is an expeditious approach to the preparation of complex glycans for vaccine development. Overall, the work in this thesis is a contribution to the standardization of the chemical work involved in AGA and a steppingstone for the fast and cheap production of GBS related glycans.

Implant-associated infections are devastating complications. The implant surface is very easy to be colonized by bacteria, which then form a biofilm. The biofilm on the implant surface is difficult to eradicate. Therefore, the prevention procedures for an implant surface are of crucial importance. Prevention of the implants begins with knowledge of the factors that cause the risk of infection, which can lead to the development of infection in different stages: preoperatively, intraoperatively, or postoperatively. The systemically injected antibiotic spreads through the entire body. As a result, the concentration, which arrives at the infection site is mainly sublethal. The insufficient dosage of such antimicrobials leads to unresolved infection because it often does not reach the infected site. Therefore, there is a critical need for a novel solution, either one, which allows the drug to reach the infection with high concentration and improve the biofilm penetration or the one, which helps the implant surface hinder bacteria colonization. In this PhD work few strategies for biofilm-based infections were introduced: prodrug antibiotic local delivery based on biorthogonal chemistry, antimicrobial coating against S.aureus utilizing the inverse-electron demand Diels-Alder reaction and MI-dPG polymer, antifungal impregnated PMMA bone cement against Candida spp. biofilms and electro-responsive hydrogels with photosensitizer curcumin release against MRSA.

Bone diseases in horses constitute a major and persistent problem in equine industry. Hypogonadism in other species and in men leads to osteoporosis and osteopenia. On this basis, we hypothesized that castration in two to three year old stallions and stallions older than six years have significant influences on their hormone and bone metabolism. To test this hypothesis, a field study was carried out: A comparison of 2-3 years old and stallions older than six years should be castrated and compared to each peers. (However, a sufficiently large group of older castrates could not be collected during period of the study.) In order to avoid compromising the test horses' well-being, non-invasive methods were applied. Stallions were divided into four groups (field A: two years old castrati, field B: three years old castrati, field C: two year old stallions, field D: stallions older than 6 years). Blood samples were taken from all probands between 7.30 to 10.30 a.m., at T-4D (four days before castration), T0D (day of castration), T+4W to T+20W (five times each in the four-week intervals) and T+36W (36 weeks after). Finally, the levels of osteocalcin (OC), bone alkaline phosphatase (BALP), c-terminal telopeptide of type I collagen (CTX-I), testosterone (T) and estradiol (E2) could be measured in 263 blood samples: OC was examined with a horse-specific RIA. To determine the BALP, the samples were analyzed using a commercially available ELISA kit. CTX-I was determined using a commercially available, automated elektrochemiluminiscent sandwich assay (ECLIA) in the Elecsys 2010 analyzer. Determination of E2 was carried out by “Biocontrol” laboratory. This test based on modified ultra-sensitive-estradiol-RIA kit from Diagnostic Systems Laboratories. T levels were determinated via ECLIA (Elecsys testosterone immunoassay) with the Elecsys 2010 analyzer.

The following results were obtained: 1. After castration of the stallions levels of T dropped below detection limit. Levels of E2 decreased slight above detection limit. In contrast, rising concentrations were recorded for the adolescent stallions (field C). 2. BALP increased after castration compared to the peer group (field C) from time T+4W to T+36W. At T+36W the difference was statistically significant (P ≤ 0.05). The OC showed until T+12W steady concentrations, and then rose in comparison to the peer group (field C) up to T+36W. At T+36W the difference could be safeguarded statistically significant (p ≤ 0.05). The concentration of CTX-I rose from T+12W to T+16W at levels above field C. Then the values of field C dropped below the value of field A. At T+8W and T+12W, differences of CTX-I concentrations between field A and C was statistical significant (p ≤ 0.05). 3. All selected bone markers exhibited lower activity respectively lower concentrations in non-castrated horses with increasing age. OC and age correlated with rP = 0.437 (p ≤ 0.001) in field D. 4. All measured concentrations and activities of the bone markers and steroid hormones correspond to scientific context. It was shown that within 36 weeks after the castration of the stallions bone metabolism changes towards bone loss and increased turnover in comparing to the stallion group.

We have designed two new experimental approaches to overcome limitations of previously established methods. Their usefulness, however, turned out to be limited and we were unable to provide a reliable improvement to existing methodologies. Secondly, we provided an extensive atlas of the transcriptional landscape of MCF-7 cells during the DDR. We employed three different high-throughput RNA sequencing approaches to provide a comprehensive analysis of the transcriptome. Our efforts led to identification of differentially expressed transcripts regardless of their polyadenylation or stability, or towards their presence in existing genome annotations. We have provided a foundation for future functional studies of lncRNAs potentially involved in DDR and investigated four lncRNAs upregulated in this condition in more detail. Thirdly, we have provided a new important insight into regulatory mechanism of DDX3 – a protein, which has been previously reported to associate with lncRNAs and is implicated in both DDR and tumorigenesis. We have described the nature of DDX3-lncRNAs interactions on a transcriptome-wide scale and furthered our understanding of DDX3 mediated regulation of translation. We have determined the global effects of DDX3 depletion on the abundance of mRNAs and their translation efficiency. In combination with the analysis of DDX3-mRNA binding specificity those results show that the protein is required for translation initiation on subset of mRNAs harboring structured 5’ UTRs.

Perfluorinated compounds are found in a wide array of technical applications associated with modern society. For instance, perfluorinated compounds are used as various surfactants, or as cooling agents in the production of electronics. The Simons process is applied in industry for the synthesis of such compounds. The experimental setup consists of a Ni anode, a cathode (often Ni or Fe) and anhydrous hydrogen fluoride (HF) as fluorine source and solvent, in which organic substrates are dissolved. A cell potential of around 4.5-6.0 V is applied, which drives the fluorination reaction. Despite the prevalence in industrial applications, the chemical mechanism of the Simons process has still not been fully understood. There is evidence that the electrochemistry only involves the oxidation of the Ni anode and subsequent binding of fluoride ions from the solvent, leading to a reactive nickel fluoride film (NixFy) forming at the anode. The film is of unknown structure and chemical composition, although it is believed to include highly oxidized Ni3+ or Ni4+ centers. In this thesis, the structure and formation of the NixFy film is considered. Using a model system involving Ni(111) surfaces and layers of explicit solvent molecules, results from DFT calculations indicate that a metallic Ni anode is easily oxidized at very low cell potentials. Furthermore, the work contains studies on the interface of a Ni(111) surface and a single HF molecule, in order to gain knowledge of the adsorption mechanism of the molecule in a non-electrochemical environment. A good starting point for models of NixFy films are the already known binary nickel fluorides. Particularly NiF3 is of interest because of its strongly oxidizing properties and proposed role in the Simons process. The series of magnetic 3d metal trifluorides from TiF3 to NiF3 is considered with hybrid DFT and DFT+U methods. NiF3 is characterized as an antiferromagnetic wide-bandgap (3.3 eV) semiconductor. Hence, the compound is expected to be less electrically insulating than the Mott-Hubbard insulator NiF2 (bandgap 5 eV). Anodes are typically passivized at cell potentials below ca. 3 V, due to the formation of an insulating NiF2 film. In this thesis, the anode is structurally modeled as different NiF2 surfaces. Using hybrid DFT calculations and thermodynamical considerations for the cell potential, the oxidation of surface Ni2+ to Ni3+ is calculated to proceed at potentials around 3.1 V, which is in good agreement with oxidation features in cyclic voltammetry experiments.

Opioid analgesics constitute the most effective treatment of severe pain, but they also cause adverse and often fatal side effects. Selective targeting of peripheral opioid receptors in injured tissue is a promising strategy to convey analgesia devoid of severe adverse effects. Drug targeting to injured tissue can be achieved by exploiting the acidic pH associated with inflammation. Yet, little is known on ligand recognition and signaling of opioid receptors at acidic pH. In the present study, I demonstrate that at acidic pH, μ-opioid receptor (MOR) responses are modulated depending on a specific structural property of bound ligands. In radioligand binding experiments, acidic pH reduced binding of naloxone (NLX) and [D-Ala2,N-Me- Phe4,Gly5-ol]-enkephalin (DAMGO), ligands that form hydrogen bond networks to histidine residue H297/6.52 within the receptor binding pocket. Furthermore, I observed impaired DAMGO-induced G-protein activation (as assessed by [35S]-GTPγS binding) and naloxone modulation of cAMP levels at acidic pH. In contrast, acidic pH did not alter G-protein activation and cAMP responses induced by fentanyl, a ligand that is unable to form hydrogen bonds to MOR residue H297/6.52. The exchange of residue H297/6.52 by alanine (A) abolished high-affinity binding of [3H]-NLX and [3H]-DAMGO, as well as DAMGO-induced G-protein activation. This mutation did not significantly alter fentanyl-induced Gprotein activation, but reduced cAMP responses to fentanyl. I conclude that H297/6.52A is crucial to effective binding of DAMGO and NLX to the MOR, while this residue contributes less to the binding of fentanyl. Overall, these findings indicate that acidic pH selectively impairs binding and consequent signaling of ligands that strongly depend on hydrogen bond formation to H297/6.52. To ensure maximum MOR binding and signaling in inflamed tissue, I suggest that opioid ligands should bind largely independent of H297/6.52.

The continuing epidemic of overweight and obesity faces a lack of appropriate pharmaceutical treatment options to support health care systems. Although studied for decades, currently available drugs only show low efficacy but serious or at least unpleasant side effects. Multi-target drugs hold promise to overcome the limitations of traditional pharmaceutics by modulating several nodes of the disease-relevant biological network. In this thesis, the multi-target concept was applied to macromolecular targets involved in obesity. In order to identify target pairs useful as starting points for multi-target drug design, we applied a systematic data mining approach employing publicly available bioactivity data of small molecules binding to targets involved in obesity. The target pair with the highest molecular similarity among known active ligands was found to comprise of histamine H3 receptor (H3R) and melanin-concentrating hormone receptor 1 (MCHR1). Both proteins are part of the G-protein coupled receptor (GPCR) family and were extensively studied as potential obesity targets. Although antagonizing either receptor was efficient in rodent models of obesity, drug candidates failed to proof efficacy in clinical studies. To test the potential of H3R and MCHR1 in multi-target drug development, a shape-based virtual screening campaign was conducted resulting in the selection of three small molecules. A subsequent in vitro evaluation revealed nanomolar affinity for all three molecules at both receptors. Lead optimization against multiple targets can dramatically benefit from integration of structural data. Since H3R and MCHR1 lack experimental structural data for structure-based drug design, two novel methods were developed that support drug design campaigns based on homology models. H3R is part of the aminergic family of GPCRs, which share a conserved charged interaction between ligand and protein. This crucial interaction was incorporated into a ligand-guided homology modeling campaign revealing valuable insights into side chain conformations critical for appropriate ligand placement in H3R. A subsequent virtual screening campaign followed by in vitro validation revealed two novel ligands with nanomolar affinity at H3R. MCHR1 is less well characterized and was found to contain several highly flexible residues in the ligand binding pocket, which hindered the translation of the ligand-guided homology modeling strategy to MCHR1. To include the high flexibility of binding site residues, the protein environment of water molecules in molecular dynamics simulations was analyzed to derive 3D pharmacophores for virtual screening. Generated 3D pharmacophores were highly successful in a retrospective virtual screening campaign in discriminating active MCHR1 ligands from decoys. This method was translated into a Python package (PyRod), where the source code was released publicly. The results and methods developed in this thesis provide valuable tools to support the development of more efficient and safe anti-obesity medications. We show that the simultaneous inhibition of H3R and MCHR1 with a single high affinity binder is possible. We developed novel computational methods to support structure-based virtual screening campaigns against both receptors.

The need to consider groundwater and surface water as a single resource has fostered the interest of the scientific community on the interactions between surface water and groundwater. The region below and alongside rivers where surface hydrology and subsurface hydrology concur is the hyporheic zone. This is the region where water exchange determines many biogeochemical and ecological processes of great impact on the functioning of rivers. However, the complex processes taking place in the hyporheic zone require a multidisciplinary approach.

The combination of innovative point and distributed techniques originally developed in separated disciplines is of great advantage for the indirect identification of water exchange in the hyporheic zone. Distributed techniques using temperature as a tracer such as fiber-optic distributed temperature sensing can identify the different components of groundwater-surface water interactions based on their spatial and temporal thermal patterns at the sediment-water interface. In particular, groundwater, interflow discharge and local hyporheic exchange flows can be differentiated based on the distinct size, duration and sign of the temperature anomalies. The scale range and resolution of fiber-optic distributed temperature sensing are well complemented by geophysics providing subsurface structures with a similar resolution and scale. Thus, the use of fiber-optic distributed temperature sensing to trace flux patterns supported by the exploration of subsurface structures with geophysics enables spatial and temporal investigation of groundwater-surface water interactions with an unprecedented level of accuracy and resolution.

In contrast to the aforementioned methods that can be used for pattern identification at the interface, other methods such as point techniques are required to quantify hyporheic exchange fluxes. In the present PhD thesis, point methods based on hydraulic gradients and thermal profiles are used to quantify hyporheic exchange flows. However, both methods are one-dimensional methods and assume that only vertical flow occurs while the reality is much more complex. The study evaluates the accuracy of the available methods and the factors that impact their reliability. The applied methods allow not only to quantify hyporheic exchange flows but they are also the basis for an interpretation of the sediment layering in the hyporheic zone. For upscaling of the previous results three-dimensional modelling of flow and heat transport in the hyporheic zone combines pattern identification and quantification of fluxes into a single framework. Modelling can evaluate the influence of factors governing groundwater-surface water interactions as well as assess the impact of multiple aspects of model design and calibration of high impact on the reliability of the simulations. But more importantly, this modelling approach enables accurate estimation of water exchange at any location of the domain with unparalleled resolution. Despite the challenges in 3D modelling of the hyporheic zone and in the integration of point and distributed data in models, the benefits should encourage the hyporheic community to adopt an integrative approach comprising from the measurement to the upscaling of hyporheic processes.

The release of porcine endogenous retrovirus (PERV) particles from pig cells is a potential risk factor during xenotransplantation by way of productively infecting the human transplant recipient. Potential countermeasures against PERV replication are restriction factors, such as SAMHD1, that block retroviral replication. SAMHD1 is a triphosphohydrolase that depletes the cellular pool of dNTPs in non-cycling cells preventing retroviral reverse transcription. Restriction factors and innate immune responses are the first line of defense against invading pathogens. Sensing of viruses in a cell usually results in the production of type I IFNs that lead to the activation of IFN-stimulated genes. The first part of this study focuses on the analysis of the antiviral activity of SAMHD1 against PERV-A/C in human immune cells. To study that, PERV-A/Cs originating from activated porcine PBMCs was used to infect human primary cells from healthy human donors. In parallel, primary cells were transduced with virus-like particles (VLPs) lacking or containing the Vpx protein from SIVmac239. The result showed that SAMHD1 potently restricts PERV-A/C reverse transcription in human monocytes, monocyte-derived dendritic cells (MDDC), macrophages (MDM) or resting-CD4+ T-cells and in monocytic THP-1 cells. Degradation of SAMHD1 by SIVmac Vpx or CRISPR/Cas9 knock-out of SAMHD1 allowed for PERV reverse transcription. Addition of deoxynucleosides alleviated the SAMHD1-mediated restriction suggesting that SAMHD1-mediated degradation of dNTPs restricts PERV replication in these human immune cells. The aims in the second part of this study were to investigate the IFN response by monitoring induction of IFN stimulated genes following infection by PERV-A/Cs, and to identify the signaling pathways, which play a role in the type I IFNs response. The results showed that PERV-A/C increased (over 100-fold) CXCL-10 production in human MDDCs, monocytes and MDMs compared with non-infected cells or heat-inactivated virus. Treatment with VLP+Vpx or empty VLP did not cause more CXCL-10 induction compared with untreatment. The JAK-inhibitor (AT9283) reduced the CXCL-10 induction in infected cells indicating that the JAK/STAT pathway is activated by PERV-A/C infection of primary human myeloid cells. In conclusion, the findings in this work highlight SAMHD1 as a potential barrier to PERV-A/C transmission from pig transplants to human recipients during xenotransplantation.

Primary cardiomyopathies (CMPs) are genetically heterogeneous disorders with a large number of disease-causing genes. The underlying genetic mechanisms and early pathological events of children with primary CMP are poorly characterized. This work aimed to identify genetic causes of childhood CMP, and to understand the development of early-onset and severe heart muscle disease. Mutation of PR/SET domain 16 (PRDM16) was shown to be associated with two types of CMP, dilated CMP (DCM) and left ventricular non-compaction CMP (LVNC). PRDM16 encodes for a transcriptional regulator with a previously unknown function in the heart. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel-based next generation sequencing (NGS) approach of 89 genes. Adverse events such as heart transplantation (HTX) and death were higher for individuals affected by DCM and restrictive CMP than for other types of CMP. Patients with a higher number of variants of interest (VOI) had an increased risk to experience an adverse event. At least one pathogenic or likely pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently VOI in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of troponin I3, cardiac type (TNNI3) revealed that the TNNI3 protein was absent and associated with upregulation of the fetal isoform troponin I1, slow skeletal type (TNNI1). These observations support the clinical importance of sarcomeric mutation in primary CMP. TNNI3 is the third most important disease gene in pediatric CMP. The mutational spectrum of PRDM16 in an extended cohort of 285 patients with different types of heart muscle diseases revealed 16 VOI in total. These alterations occurred in six different cardiac diseases and comprised missense, splice site, frame shift, and stop gain variants. Pathogenic PRDM16 variants were only found in LVNC patients, confirming the important role of PRDM16 in LVNC pathogenesis. By prediction of posttranslational modification sites, structural features and functional interaction sites of the PRDM16 protein were identified. Functional and biochemical characterization of PRDM16 showed different subcellular localization of CMP variants and the influence of CMP variants on the protein stability of PRDM16. Patient specific CMP variants altered the cellular distribution of PRDM16, with condensed signals differing between the cytoplasm and the nucleus. In conclusion, the spectrum and number of genetic alteration in pediatric primary CMP determine clinical outcome. PDRM16 is a frequent CMP gene and translational approaches for potential therapies need to be developed.

Meandering rivers across the globe present a striking similarity in their alignment, and this pattern has intrigued scientific curiosity for almost a century. However, still very little is known about ‘unconventional’ river meanders with a “zigzagging” planform appearance, but which occur in rivers from the temperate to the tropic regions. In order to compare the characteristics of flow, morphology and morphodynamics of conventional (‘round’ and ‘fat’) and unconventional (‘sharp’ and ‘angular’) river bends, I studied the Prut (Romania/Moldova), one of the last remaining freely meandering lowland rivers of Europe. The Prut is a clay-bed river that meanders for about 585 km of channel length in its lower section, with an average discharge of c. 90 m3 s-1 and channel width ranging from 39-84 m. For the analysis of long-term channel dynamics (chapter 2), bend morphometry, morphodynamics and temporal trajectories were determined for a section of Prut that included multiple replicates of each bend type. Data were extracted from historical maps and imagery for a c. 250 km long section of the Prut River spread over a 90-year period (1915-2005). For that, I used a geographical information system (GIS) and state-of-the-art software PyRIS to derive measures of bend-scale morphometry and migration features for a total of 118 simple and back-traceable river bends, after exclusion of compound bends and bends that cut-off during those 90 years. Normalized bend curvatures (CmaxB) ranged from 0.01 to 1.44 (as for 2005). Sharp bends were distinguished from round bends and angular bends from fat bend geometries by width normalized bend curvature, CmaxB threshold (round < 0.5 and sharp > 0.5) and the maximum to mean bend curvature ratio, Cr threshold (fat < 3 and angular > 3), respectively. Over the 90 year period, studied bends (N=118) displayed a gradual narrowing and homogenization of channel width (median= 72 m and interquartile range (IQR)= 63-86 m in 1915; median = 52 m and IQR = 50-57 m in 2005), a reduction of migration rates (mean= 0.038 widths/yr, SD=0.028 in 1915-1960 to mean= 0.015 widths/yr, SD = 0.011 in 1980-2005) and a slightly increase of sinuosity (from 1.41 to 1.63). Sharp and angular bends tended to stabilize over longer periods (20-90 years), and concomitantly displayed more unchanged shape transitions (for sharp bends: 1915-1960= 49%; 1960-1980= 61%; 1980-2005= 57%, N=49) compared to their conventional counterparts (for round bends: 1915-1960= 37%; 1960-1980= 22%; 1980-2005= 22%, N=49). These results provide new insights into the formation and maintenance of unconventional bends (sharp and angular), which on the Prut are mainly due to autogenic processes. In unconventional bends, special patterns of erosion and deposition create features like deeper pools or zones of flow separation, with fallen trees possibly acting as additional allogenic factor. These interrelationships among bend form, flow and river bed features in unconventional meanders were then investigated in detail fora set of 14 bends (chapter 3). Boat operated ADCP (Acoustic Doppler Current Profiler) field surveys enabled detailed records of 3-D velocity and depth distribution along these bends.This dataset enabled for the first time to systematically compare flow characteristics of unconventional with that in conventional meanders under field conditions. The studied set of bends comprised at least 2 bends of each simple bend shape types (see chapter 2) i.e. angular, sharp, round and fat bend shapes. A significant linear increase in the lateral extent of the Inner-Bank Flow Separation zone (IBFS) at the bend apex with increasing bend curvature was recorded (IBFS = 6.1+ 45.8 CmaxB + 8.2; R2= 0.55; p < 0.001; N=14). In angular bends, hydraulics was influenced by a locally eroded point bar and a steep sloping upstream riffle to pool transition. This was reflected by the significant increase in depth ratio (ratio of apex pool depth to upstream riffle depth) with stronger bend angularity, as defined by curvature ratio (ratio of maximum to mean of bend curvature) (Hratio = 0.83 + 0.41 Cr; R2 = 0.44; p < 0.005; N=14). These morphological features influenced the extent of the horizontal recirculation occurring within the IBFS zones at the bend apex, and were further associated with the formation of two separate IBFS zones in fat bends compared to a singular zone in angular bends. Pool depth (Hp) displayed an increasing trend with higher curvature but then to stabilize at bend curvatures greater than c. 0.5, suggesting the existence of a negative autogenic feedback at high bend curvature, as pool depth is also weakly related to the IBFS size (IBFS = -14+ 10.3 Hp + 10.2; R2= 0.30; p<0.02; N=14). The observed interdependence between flow patterns and planform shape inangular and fat bends partially explains their different morphodynamics, too. While fat bends are prone to develop multilobing or a delayed cut-offs, angular bends may display increased temporal stability and even inward migration. Hence, this thesis demonstrates for the first time the different characteristics of conventional and unconventional meanders in terms of their morphometry and hydraulic geometry based on the study of bends from a real meandering river, and complemented by documentation of the long-term morphological trajectories of these meander types during a nearly centennial period. Thus, this thesis provides new insights into the so far poorly explored linkages between forms and processes of river bends, and indicates field-based explanations on the formation and relative stability of unconventional bend forms over extended time periods.

This thesis proposes the application of various economic theories and analytical techniques from the fields of energy economics, environmental economics, comparative economic systems and, development economics in the regional context of South and Central Asia. Applying IV estimation in essay one leads to the conclusion that ethnolinguistic diversity instrumented by diversity of ancient civilizations/empires is strongly linked with contemporary development in Afghanistan. Ethnolinguistic diversity induces higher levels of trust and lower levels of individualism. Moreover, it is associated with higher levels of income and lower levels of violence or crime. A robust regression discontinuity design has been used to estimate the impact of historical ethnolinguistic borders on the contemporary economic development of Afghanistan. Pashtuns have the clear advantage over the other ethnolinguistic groups in Afghanistan in terms of level of income and provision of public goods such as safe drinking water and electricity. The Pashtun belt has suffered more violence and crime due to foreign interference in the Pashtun areas. The ethnolinguistic division in Afghanistan in terms of political preferences is obvious by the fact that support for Ashraf Ghani declines significantly when crossing the ethnic and linguistic border into the non-Pashtun areas. Structural equation modeling results reveal that the empires of Achaemenids, Parthians, and, most prominently, Sasanians, categorized as Old Persian, and the empires of Turkic origin left a positive and persistent impact on the contemporary economic development of Afghanistan. Essay 2 and essay 3 of the dissertation deal with the economics of electricity and sustainable energy. Electricity generation from the use of fossil fuels is one of the largest sources of man-made carbon dioxide emissions in the world. Switching the power industry to the use of renewables such as hydro, solar, and wind energy is an option to deal with the issue of climate change. There are various challenges confronting the world and particularly South Asia in this energy transition towards renewable energy resources. Therefore, there is a necessity to take policy measures that enable electric utilities operating on fossil fuels to reach a technically efficient point where considerable savings in terms of costs and carbon emissions can be made. This has been estimated in the case of Pakistan in essay 2, with a possible reduction of about 34% of carbon emissions and 26% of the cost of power generation from fossil fuels with the use of technically efficient inputs. In essay 3, this thesis explores factors that are impediments to growth of the renewable energy sector by using pooled mean group autoregressive distributed lag (PMG ARDL) and the time series autoregressive distributed lag model, as well as by using the analytical tool of SWOT methodology to identify the strengths, weaknesses, opportunities, and threats in relation to the internal and external environment of development of the renewable energy sector in South Asia. Empirical results suggest that poor economic growth and the depreciating exchange rate are the major barriers to the development of the renewable energy sector of South Asia. SWOT analysis suggests that credit institutions’ lack of interest in financing for renewable energy projects, the poor financial situation of the distribution companies, and inadequate research in the sustainable energy sector are the main obstacles to this development.

Der überwiegende Teil der Krankenversorgung in Deutschland findet in fragmentierten Strukturen statt. Getrennte Leistungssektoren, zu denen die ambulante und stationäre Krankenversorgung zählen, gehen mit funktionalen Brüchen in der Zusammenarbeit der Gesundheitsprofessionen einher. Schon seit Längerem zielen Gesundheitsreformen auf eine Überwindung der Fragmentierung, diese erweist sich jedoch als äußerst beharrlich. In der vorliegenden Arbeit wird nach Gründen der Beharrung gesucht. Dabei wird auf einen eher diskreten Gegenstand fokussiert. In einer historischen Rückschau, die bis vor die Gründungsjahre der Gesetzlichen Krankenversicherung reicht, wird der Entwicklungsprozess sogenannter Praktiken untersucht, mit denen ärztliche Leistungserbringer in der ambulanten Krankenversorgung ihre Zusammenarbeit organisieren und regulieren. Dazu zählen Überweisungspraktiken genauso wie Zuständigkeitsregelungen in der Krankenversorgung. Diese Regulationspraktiken entwickelten sich im Wechselspiel zwischen entstehenden Versorgungsstrukturen und den Handlungsvollzügen der Leistungserbringer sowie relevanter professions- und gesundheitspolitischer Akteure. Es wird gezeigt, wie sich in deren Zusammenarbeit Pfadabhängigkeit ausbilden konnte und wie den Akteuren trotz vorhandener Alternativen die Fähigkeit zur integrierten Leistungserbringung sukzessive verloren ging. Vor diesem Hintergrund und am Beispiel von Ärztenetzwerken wird als nächstes gezeigt, dass der historisch gewachsene Pfad der fragmentierten Leistungserbringung gebrochen werden kann. Beispielhaft werden jene von den Ärztenetzwerken geschaffenen Versorgungsstrukturen und Handlungsvollzüge herausgearbeitet, die zur Integration der Krankenversorgung auf Ebene der Regulationspraktiken beitragen. Schließlich werden Empfehlungen für ein Netzwerkmanagement gegeben, das den Übergang von der fragmentierten zur integrierten Leistungserbringung unterstützt.

The interplay of magnetism and superconductivity leads to a variety of phenomena whose fundamental understanding is still under research.

In this thesis we investigate the properties of the iron-porphine (FeP) molecules on a Pb(111) surface with scanning tunneling microscopy (STM), scanning tunneling spectroscopy (STS) and atomic force microscopy (AFM). A special focus is placed on how their electronic and magnetic properties are affected by their environment and on how to modify these properties by the presence of an STM tip and molecular neighborhood.

First, we characterize the molecular self-assembly of FeP-Cl molecules after sublimation on a Pb(111) surface. We show that by adjusting the sample temperature during and after evaporation one can tune the FeP/Cl ratio on the surface. This leads to the formation of different molecular phases in which the electronic and magnetic properties of the molecules are affected in various ways.

We first focus on the electronic properties of the molecules. We demonstrate that the presence of Cl adatoms leads to the appearance of two different molecular types that have different charge distributions and thereby electronic properties. Interestingly, some molecules display a peculiar feature that can be related to a local gating induced by the tip's electric field. This gating effect is attributed to modifications of image potential states and underlines their importance when considering the energy level alignment at interfaces.

The rest of the thesis is devoted to the study of magnetism and superconductivity. Focusing first on single impurities we demonstrate that by approaching the tip toward a FeP molecule it is possible to modify the magnetic coupling to the substrate and therefore the energy of a Yu-Shiba-Rusinov (YSR) state, allowing for an identification of the nature of the many-body ground state of the system. Furthermore, we tune the system through the quantum phase transition (QPT) on the single impurity level and identify its hallmark characteristics in STS. Finally, this experiment also allows for an identification of the various transport processes that happen through the junction as its conductance increases.

Another aspect of the YSR state is then investigated: the variation of its asymmetry across a molecule. This variation is identical to the one of the phase factor of the Kondo resonance when the substrate is in its normal state. We explain these with local modulations of the electron-hole asymmetry of the scattering of electrons at the impurity level caused by the spatial variations of the frontier orbitals.

Finally we study the coupling of YSR states within a Kagome lattice. By investigating building blocks of this lattice we show the YSR hybridization and discuss its possible origin. Molecular self-assembly is thus a promising alternative to atomic or molecular manipulation in order to engineer well-defined and large systems of coupled impurities. The conditions for the formation of a Kondo lattice in this Kagome arrangement are also discussed.

Marketingaktivitäten werden in Business-to-Business Unternehmen typischerweise nicht nur in der Marketingabteilung, sondern von mehreren Akteuren entlang der Wertschöpfungskette durchgeführt. Die vorliegende Arbeit thematisiert fünf Aspekte dieses Phänomens mithilfe eines Mixed-Methods-Forschungsdesigns. Es geht dabei zunächst darum zu verstehen, was genau Marketingaktivitäten in Business-to-Business Unternehmen sind und wie diese strukturell verankert sind. Der zweite Fokus liegt auf der Messung des Grads der Dispersion von Marketingaktivitäten. Hierzu wurde ein Messinstrument entwickelt, das neben der Messung des aggregierten Dispersionsgrads pro Unternehmen große Unterschiede der zwölf untersuchten Marketingaktivitätsbündel aufzeigen konnte. Einflussfaktoren und Auswirkungen des Grads der Dispersion von Marketingaktivitäten stellen den dritten Forschungskomplex dar. Auf Basis der Ergebnisse konnten sieben interne bzw. externe Einflussfaktoren sowie sieben Outcome-Dimensionen nach Effizienz und Effektivität identifiziert werden. Die Rolle der Informalität ist das vierte Themengebiet der Arbeit. Der fünfte Themenblock der Arbeit ist auf das Zusammenspiel zwischen der Dispersion von Marketingaktivitäten und Informationsmanagement gerichtet, das eine der Outcome-Dimensionen ist. Hierbei ging es insbesondere darum abteilungsübergreifende Informationsakquise sowie -distribution genauer zu untersuchen. Diese fünf Forschungsthemen waren in drei empirischen Sequenzen des Mixed-Methods-Designs eingebettet: die erste Sequenz stellt eine branchenübergreifende Interviewstudie dar, die zweite Sequenz ist eine qualitative Fallstudie und die dritte Studie ist eine rein quantitative Fragebogenerhebung.