Die Dissertation hat sich zum Ziel gesetzt, das Motiv des Vorübergehens, das George und Hofmannsthal während ihrer Auseinandersetzungen mit Baudelaires Sonett „À une passante“ transformiert und sich angeeignet haben, als Strukturphänomen in ihren Werken herauszuarbeiten, das sich in drei Elementen niederschlägt, nämlich „Ennui“, „Epiphanie“ und „Mnemopoesie“. Nach diesem Modell werden unter anderem das sogenannte Maximin-Erlebnis Georges und die Auffassung Hofmannsthals über die Kunstproduktion erläutert. Im Grunde lässt sich das Vorübergehen als ein poetischer Augenblick der Moderne begreifen. Die Zeit wird dabei als Kairos statt Chronos aufgefasst. Anstelle von Gott oder Muse ist der Dichter selbstgekrönt und verdankt sein Werk der Introspektion. Und aus einer Erinnerung, die sich als Verdichtung und Verinnerlichung erweist, ist die Kunst geboren.

Die juvenile idiopathische Arthritis ist eine chronische Erkrankung mit Beginn im Kindes- und Jugendalter. Bei mehr als 50% der Patienten persistiert die JIA bis in das Erwachsenenalter. Vor diesem Hintergrund sind die Kontrolle der Entzündung der Gelenke bzw. der Krankheitsaktivität, das Erreichen einer Remission, Verhinderung von Gelenkschäden und langfristiger Behinderungen, sowie das Erreichen der bestmöglichen Lebensqualität die wichtigsten Therapieziele bei der Behandlung der JIA. Die Krankheitslast der JIA hat sich in den letzten Jahren deutlich verringert. Die Versorgungssituation der Patienten, ein schnellerer Zugang zu spezialisierten multidisziplinären Behandlungszentren, der Einzug von konsentierten Therapieempfehlungen und deren Umsetzung in der Routineversorgung, sowie der breite Einsatz von konventionellen DMARDs und die Einführung der Biologika in der Behandlung der JIA haben einen entscheidenden Anteil an dieser Entwicklung. Das Therapieziel einer inaktiven Erkrankung wird heutzutage bei bis zu 75% der Patienten erreicht, wobei die Raten zwischen den Studien stark variieren, abhängig von der Definition der inaktiven Erkrankung, der Kohorte, der Erkrankungsdauer und dem Beobachtungszeitraum. Das Erreichen einer optimalen Lebensqualität für den Patienten gewinnt neben anderen vom Patienten berichteten Parametern als Therapieziel zunehmend an Bedeutung, da die JIA alle Bereiche des Lebens des Kindes und seiner Familie beeinflusst. Bisherige Studien zeigen weiterhin im Mittel eine signifikant niedrigere Lebensqualität der JIA Patienten im Vergleich zu gesunden Kontrollen. Es gibt aber auch Hinweise, dass Patienten mit einer inaktiven JIA in ihrer Lebensqualität das Niveau einer gesunden Kontrollkohorte erreichen können. Daten aus dem Biologika Register JuMBO zeigten, dass sich die Lebensqualität der Patienten seit der Einführung der biologischen Medikamente kontinuierlich verbesserte. Der Grad der Funktionseinschränkung ist ein wesentlicher Einflussfaktor für die subjektiv erreichte Lebensqualität. In der Kinderkerndokumentation (2000 bis 2015) kann man eine stetige Zunahme des Anteiles der Patienten ohne Funktionseinschränkungen beobachten. Dieser Trend wird begleitet von der immer früheren und intensiveren Therapie mit csDMARDs und bDMARDs in diesem Patientenkollektiv. Mit dem Blick auf die potentiell lange Exposition der schwerer betroffenen JIA Patienten mit csDMARDs und bDMARDs rückt die Therapiesicherheit und damit vor allem auch die fatalen Outcomes einer malignen Erkrankung oder die Mortalität in den Blick. Der derzeitige Kenntnisstand bezüglich des Zusammenhanges zwischen dem Auftreten von malignen Erkrankungen und einer DMARD Therapie lässt keinen endgültigen Schluss zu. Die Beurteilung des Malignomrisikos bei JIA Patienten gestaltet sich aus mehreren Gründen als schwierig. Gründe sind das seltene Auftreten maligner Erkrankungen im Kindes- und Jugendalter, die möglicherweise lange Latenzzeit nach Exposition bis zum Auftritt und das Zuordnungsproblem bei Exposition mit mehreren immunsupprimierenden Substanzen im Krankheitsverlauf. Allgemein akzeptiert ist das 3-fach erhöhte Malignomrisiko bei JIA Patienten im Vergleich zur Allgemeinbevölkerung. Die Therapie mit MTX, Etanercept und Adalimumab scheint das Malignomrisiko nur marginal zu erhöhen. Die Mortalität bei JIA-Patienten ist in den letzten 30 Jahren deutlich zurückgegangen. Im Vergleich zur Allgemeinbevölkerung ist die Mortalitätsrate bei Patienten mit einer JIA aber weiterhin erhöht. Die geschätzte Letalität bei Kindern und Jugendlichen mit einer JIA lag bei 4% vor 1980 und 0,4% im Jahr 2016. Die langfristige Beobachtung der JIA Patienten in Registern wie BiKeR und JuMBO ist eine wichtige Aufgabe der Kinder und Jugendrheumatologie, um die Sicherheit der eingesetzten Substanzen im Hinblick auf das Auftreten von seltenen Erkrankungen und Erkrankungen mit einer langen Latenzzeit beurteilen zu können.

Organisationskrisen stellen eine Bedrohung für die betroffenen Unternehmen dar, insbesondere im Hinblick auf ihre Unternehmensreputation. Die Krisenkommunikationsforschung zu Organisationskrisen - besonders die Situational Crisis Communication Theory (SCCT) - hat sich bislang vor allem mit der Frage beschäftigt, wie Unternehmen mit angemessenen Kommunikationsstrategien auf die betreffende Krise reagieren und darüber die Wahrnehmung ihrer Unternehmensreputation durch Stakeholder positiv beeinflussen können. Kaum untersucht wurde hingegen, wie sich Kommunikationsstrategien in den Massenmedien auswirken, über deren Rezeption die Reputationswahrnehmung der Stakeholder oft maßgeblich geprägt wird, da sie von Krisen in der Regel aus den Medien erfahren. Vor diesem Hintergrund befasst sich die vorliegende Arbeit mit der Fragestellung ‚Welchen Einfluss haben Kommunikationsstrategien von Unternehmen bei Krisen auf die Bewertungen der Unternehmen in Medien-Beiträgen über diese Krisen?‘. Die Forschungsfrage wird anhand des sozial relevanten Beispiels von Lebensmittelskandalen untersucht, bei denen die betroffenen Unternehmen sowie die gesamte Branche mit erheblichen Beschädigungen ihrer Unternehmensreputation konfrontiert sind. Methodisch wird der Einfluss der Kommunikationsstrategien von Unternehmen bei Krisen auf deren Bewertung in Medien-Beiträgen über diese Krisen über eine Determinationsanalyse ermittelt. Diese erfolgt über eine zweistufige qualitativ-quantitative Inhaltsanalyse von PR-Statements marktführender Lebensmittelunternehmen in Deutschland zu Lebensmittelskandalen und der Medien-Beiträge zu zwei großen Lebensmittelskandalen der vergangenen Jahre (Pferdefleischskandal 2013, EHEC-Skandal 2011) in überregionalen Leitmedien der Tages- und Wochenpresse. Wie die Ergebnisse zeigen, können die Kommunikationsstrategien von Unternehmen deren Bewertungen in der Medienberichterstattung positiv beeinflussen. In welchem Maße dies gelingt, hängt von den Faktoren ‚Thematisierung der Kommunikationsstrategien in Medien-Beiträgen‘, ‚Übernahme von Bewertungen aus den PR-Quellen zu den Kommunikationsstrategien in die Medien-Beiträge (Tendenzinduktionen)‘, ‚Strategie- und Krisentyp‘, ‚Medien-Frames in den Medien-Beiträgen‘, ‚Medium der Medien-Beiträge‘ und ‚Berichterstattungsmuster der Medien-Beiträge‘ ab. Dies wird theoretisch in einem Modell dargestellt, das den Einfluss der Kommunikationsstrategien von Unternehmen bei Krisen auf ihre Bewertungen in Medien-Beiträgen über diese Krisen erklärt. Das Modell eignet sich somit dazu, die situative Krisenkommunikationstheorie (SCCT) um den Aspekt der Medien zu ergänzen.

The subject of this thesis is the development of theoretical and computational methods to allow for the search of new superconductors via High-Throughput Methods (HTMs)

HTMs test thousands of materials for a desired property. Each test on a material is performed by computational simulation; hence the computational cost of each individual simulation has a strong impact on the global performance of a HTM. While first-principle methods exist and allow for in-depth studies of single superconducting materials, such methods are far too expensive to be applied directly in HTMs.

In order to predict superconductors, one needs to address primarily three challenges, namely the accelerated prediction (i) of new crystalline systems that are thermodynamically or at least dynamically stable and are yet to be synthesized, (ii) of basic electronic properties such as the metallicity and absence of magnetic instabilities, (iii) of the strength of the pairing interaction and hence the possibility of having a high superconducting transition temperature Tc within this work, we consider conventional electron-phonon superconductivity.}

At the core of this work, we focus on challenge (iii) by introducing Descriptors of Superconductivity, that, while accessible at low computational cost, convey sufficient information to select candidate materials for in-depth investigation. Our approach to develop such descriptors is based both on theoretical knowledge and on empirical data, while connections between the former and the latter are demonstrated by models. We implement the Descriptors numerically on the basis of Kohn-Sham Density Functional Theory (DFT). We perform a high-throughput search, evaluating our Descriptors of Superconductivity on a library of known materials, and identify promising candidate superconductors. For a subset sample of those candidates, we perform expensive full-scale ab initio calculations, validating our Descriptors.

We address challenge (ii) by developing machine learning (ML) methods with the goal to further accelerate the process by predicting electronic properties directly from the crystal structure of a given material. For this purpose, we introduce a new representation of crystal structures for ML, which takes important symmetries of periodic systems into account. These ML methods are evaluated with the help of the data generated in our high-throughput search.

Finally, we develop a strategy for challenge (i), which allows to predict new crystalline systems via element substitution. By means of statistical analysis performed on a large library of materials, we introduce a new measure for the similarity between chemical elements.

Escherichia coli (E. coli) is both, a facultative commensal of the gut microbiota and an important bacterial cause of human as well as animal diseases. Due to the high genetic plasticity, gene transfer allows those bacteria to colonize different sites in the host acting as pathogens, being responsible for a wide range of infections [1, 67]. For toxins alone, variants have been described with respect to functional changes [44, 70, 132]. Based on of phylogenetic differences, the hypothesis of this thesis is that allelic variants of toxins differ in their biological effect with regard to their toxicity. Therefore, in silico analyses were performed to unravel sequence differences for all known toxins encoded in several E. coli and Shigella genomes. The gene sequence research of all currently published toxins until June 2016 revealed a total set of 39 toxin genes being present in the genome of E. coli and Shigella spp. To test the hypothesis, the selected reference toxin sequences were used as templates to screen the NCBI database as well as an internal database using the BLAST algorithm. The internal database consists of 423 whole genome sequences of the “ECore” dataset [140] and 69 Shiga-Toxin-producing E. coli whole genome sequences [31]. To identify genetic variations of each toxin gene, the software Geneious was used, providing alignments and phylogenetic trees. After identification of allelic variations, the gene sequences were translated into their protein sequences. Finally, the resulting secondary and three-dimensional protein structures were predicted in order to receive indications of potentially functional changes. Detected allelic protein structures were modelled via the open source platform I-Tasser and visualised by the python based software PyMol. The results show that genetic variations of all 39 toxin genes are available in both databases. The effector protein EspH and the metalloprotease YghJ were analyzed for the first time by their three-dimensional structures, with regard to possible functional changes for their resulting protein variants. Different variants of the Subtilase Cytotoxin SubAB were predicted and analyzed with regard to a different pathogenic potential and toxicity as was shown for the different Shiga-Toxin variants. Furthermore, the three-dimensional protein variants of the serine protease autotransporter of Enterobacteriaceae (SPATEs), indicate that the SPATE members are already allelic variations by name and split into two known functionally different classes [132]. The inclusion of the Shiga-Toxin variants [44, 111] revealed the same results, indicating that the chosen bioinformatics methods are sound and comparable. All the other identified allelic variations of toxins in the genome of E. coli and Shigella spp. due to in silico analyses had no impact on the resulting three-dimensional protein models, indicating a conserved function as in the case of EspF. This thesis gives a first overview about the occurrence and impact of toxin variants in the genome of E. coli and Shigella spp. on the basis of bioinformatics analysis. The “toxome” allows the screening of all currently known toxin genes and its variants in the whole genome sequence of the mentioned bacteria with a BLASTn algorithm.

Any attractive system for efficient light-driven water splitting needs to involve water-oxidation catalysts, which ideally are based on earth-abundant chemical elements only. Prime candidates are oxides of first-row transition metals, in particular the elements manganese to copper. In 2008, Kanan and Nocera described electrodeposition of an amorphous cobalt-based oxide film (CoCat) in phosphate buffer, which promotes water oxidation in the neutral pH regime and excels by self-healing properties. In this thesis, stability and self-healing of a cobalt catalyst (CoCat), a nickel catalyst (NiCat) and a nickel-iron catalyst (NiFeCat) were investigated at various electrochemical potentials. Cyclic voltammograms were measured every 30 min, to diagnose the catalytic activity and loss in redox-active cobalt ions. Furthermore, X-ray absorption spectroscopy is used for assessment of structural changes at the atomic level. The optimal electric potential window for having a comparably stable (> 80 %) CoCat sample is 1.1 < V vs. NHE < 1.35, where reasonable activity (> 65 %) is maintained after 24 hours operation in Co-free phosphate buffer (0.1 M KPi, pH 7). On the other hand, operation in Co-containing buffer results in an almost stable performance (in terms of current density per geometrical surface area), but the film thickness is growing significantly. Thus, self-assembly of CoCat is not well described as self-healing. Structural analysis of CoCat operated in 20 μmol L-1 Co-containing KPi buffer for 24 hours at catalytic potential (1.3 V vs. NHE) exhibit small, but significant changes in EXAFS spectra because long time operation results in increasingly ordered structure or enhanced CoCat fragment size, which cause a drop in the activity of the CoCat. XAS In-situ measurements show a slowdown of redox kinetics of the CoCat after being operated for 24 hours. This finding can be attributed to charge transport limitations in the thicker film, operated for 24 hours, and a different kinetic response of the Co-oxide fragment. One-week operation of NiCat in Ni-free buffer at non-catalytic and catalytic potentials in glass container reveals that the redox charge drastically decreases within the first day of operation and then reaches a stable condition. However, the catalytic current has a different behavior, means that first it drops and reach a minimum amount and then continuously increased. The steady increase of catalytic current is related to Fe contamination of glassware because operation in a plastic container or Fe-containing buffer confirmed that. TXRF result also confirmed that the ratio Fe:Ni increases after the operation. The Tafel slope of NiCat after one-week operation is lower than as-deposited sample, meaning that lower over-potential is needed for operated sample to increase the reaction rate. XAS measurements show that the minimum catalytic activity of NiCat operated at non-catalytic potentials (0.8 and 0.9 V vs. NHE, 11 hours) is related to a rather ordered amorphous nickel-oxide. However, after 48 hours of operation at these potentials, the catalyst is more disordered. On the other hand, operation at catalytic potential (1.4 V vs. NHE) induces a structure similar to γ-NiOOH, which is majorly stable over electrolysis time. Furthermore, long-time operation of a NiCat results in a shift of the edge position towards higher energies, which corresponds to higher oxidation state. XAS In-situ measurements show that the derivative of the CVs fluorescence data matches very closely to the reductive wave of the CV, meaning that mostly related to redox and structural changes of the Ni metal centers and not to changes in other species (no formation of peroxides or superoxides for example).

Die gestörte Frakturheilung stellt nach wie vor aufgrund der limitierten Behandlungsoptionen eine große klinische Herausforderung dar. Vor diesem Hintergrund ist das klinische Phänomen bedeutsam, dass ein Schädelhirntrauma die Frakturheilung positiv beeinflusst. Mithilfe eines standardisierten und reproduzierbaren experimentellen Ansatzes konnten wir bislang zeigen, dass die Frakturheilung in operierten Mäusen mit kombiniertem Schädel-Hirn-Trauma (Controlled Cortical Impact Injury) und Femurfraktur mit Fixateur externe ebenfalls erhöht ist. Nach der Etablierung des Tiermodells konnten wir eine Reihe von in-vivo- und ex-vivo-radiologischen (Mikro-CT) und biomechanischen Experimenten durchführen, um den Effekt des SHT auf die Frakturheilung von WT-Mäusen zu untersuchen. Die radiologische Untersuchung zeigte eine erhöhte Kallusformation in den Tieren mit dem kombinierten Verletzungsmuster bereits 2 Wochen posttraumatisch sowie eine erhöhte Tendenz zur beschleunigten Frakturüberbrückung. Diese Ergebnisse waren entscheidend für die nächsten Schritte, denn die initiale Hypothese wurde bestätigt und beweist das Vorliegen des Phänomens auch in Tieren. Die konsekutive biomechanische Testung der Femora zeigte zusätzlich eine biomechanische Überlegenheit der Frakturen in der Gruppe der kombinierten Verletzung im Vergleich zu der Gruppe mit der isolierten Fraktur. Dieser Befund impliziert eine normale Kallusformation, die schlussendlich zu den beobachteten biomechanischen Eigenschaften führt. Nachfolgend wurde das Experiment mit leptin-defizienten Mäusen wiederholt, um den Effekt vom Leptin, als zentrales Hormon der Homöostase, auf das Phänomen zu untersuchen. Interessanterweise konnten die vorherigen Ergebnisse der erhöhten Kallusbildung nicht reproduziert werden. Die hohe Pseudarthroserate weist auf die wichtige Rolle von Leptin im Rahmen der Frakturheilung und der ossären Homöostase hin. Des Weiteren konnten diese Ergebnisse histologisch bestätigt werden. Die weitere Etablierung eines Polytrauma-Modells mit hämorrhagischem Schock und die beobachtete Stimulation der Frakturheilung bestätigen die Komplexität des Phänomens und die vielfältigen steuernden Mechanismen. Nachdem die zugrundeliegenden Mechanismen weiterhin unklar sind, sollen in zukünftigen Studien die zellulären und molekularen Grundlagen des beobachtenden Phänomens aufgedeckt werden. Wir werden umfassende Analysen der Genexpression, histologische und FACS-Untersuchungen neben Serum- und Urinmessungen durchführen, um die entscheidenden Zielorgane, Zellen und Signaltransduktionswege zu identifizieren, die an der gesteigerten Frakturheilung nach einem SHT beteiligt sind. Abhängig von diesen Ergebnissen werden vielversprechende Kandidaten und Signaltransduktionswege anhand von Zellkulturexperimenten mit Primärzellen oder Zelllinien näher charakterisiert. Abschließend erfolgt die Verifizierung der Funktion etablierter Kandidaten durch pharmakologische und/oder genetische Proof-of-Principle-Experimente. Die zelluläre und molekulare Charakterisierung der gesteigerten Frakturheilung vervollständigt die Erforschung der gestörten Knochenheilung und ist die Grundlage zum grundlegenden Verständnis der Knochenregeneration und zur Entwicklung jeglicher neuartiger Therapieformen für betroffene Patienten.

In this thesis the electronic, structural, and magnetic properties of metal complexes are studied, with a focus on the different properties that arise from their interaction with a variety of substrates. The thermal-activated ring-closure reaction that transforms octaethylporphyrin (OEP) metal complexes into tetrabenzoporphyrin (TBP) ones is investigated with x-ray absorption spectroscopy (XAS) and x-ray magnetic circular dichroism (XMCD) for different molecules composed of one of two metal centers, Fe or Co. The changes to the magnetic properties of the complexes are discussed as a result of their interaction with the different substrates (Au(111), Au(100), Cu(111), Cu(100), and graphene on Ni/W(110)). Spin- Hamiltonian formalism is applied in order to obtain further magnetic information about the ion and a comparison to density functional theory (DFT) is also done. The magnetic measurements, performed usually at a temperature T = 4K and external field B = 6T, evidenced clear modifications to the uniaxial anisotropy and magnetic moments of the molecules before and after the ring-closure reaction, as well as among the different substrates. The FeOEP uniaxial anisotropy changes from D = 1.72 meV to D = 0.39 meV within the plane of the molecules after the ring-closure reaction on Au(111), while the magnetic moment remains constant. In the CoOEP molecule the change is even more striking, with the spin magnetic moment being completely quenched after ring closure on the Cu(100) substrate. No spin moment is observed for either Co molecule when deposited on Cu(111). The same techniques are applied to the study of another set of metal complexes, based on lanthanides. Two tris(tetramethylheptanedionate) ((TMHD)3) molecules, with Dy and Er as lanthanide metal centers, were investigated. Sharp variation in the direction and intensity of the uniaxial magnetic anisotropy of the two molecules were identified on different substrates (graphene/Ir(111), graphene/Ni/W(110), HOPG (highly ordered pyrolytic graphite), and Au(111)), with no substantial variation in their magnetic moments. The flexibility of these molecules enables the quantization axis of their 4f orbitals to be rotated, depending on the substrate, so that the Dy molecule exhibits a quantization axis that lays parallel to the substrate when it is deposited on graphene/Ir(111), but rests at an intermediary position on the HOPG substrate, not fully parallel or perpendicular to it. For the Er molecule a similar situation is observed, this time with the substrates graphene/Ni/W(110) and Au(111).

Internet connectivity forms the basis of the digitally networked society. About twenty-five years after the onset of the commercial internet, this thesis explores the economics of internet interconnection. It explores the question of how network operators worldwide overcome the tension between cooperation and competition and jointly provide internet connectivity. For this purpose, this dissertation develops a cross-disciplinary research perspective. It puts the architecture of the internet, economic coordination and community structures between internet engineers into relation. Conceptually, the study draws on approaches from science and technology studies, economics of convention, and heterodox economics. Empirically, the study is based on interviews with network operators worldwide. Taken together, it can be shown that when it comes to internet connectivity economics, network operators are exposed to architectural uncertainties, which in turn induce the coexistence of market coordination (transit) and cooperative co-production (peering). In the co-production of connectivity economic equivalence is established without the medium of money. This explains to a large extent why product-centered quality conventions play a pivotal role in interconnection negotiations. The community of networkers forms an arena in which these quality conventions are negotiated and tested. This thesis also contributes a new order of worth to the economics of convention tradition. It is the quality convention of connectivity, in which internet connectivity is regarded as a commons worth protecting, whose provision serves the common good.

The structure and function of proteins depend on the protonation states of amino acids; ergo, the pKa values of titratable residues in proteins and the influence of protein environment on these pKa values are of great interest in biochemistry. In this work, the method for pKa computations is improved. More importantly, electrostatic energy and pKa computations are used to shed light on the function of a prominent enzyme in energy metabolism, namely cytochrome c oxidase. Karlsberg2+ is a modular software used for pKa computations of proteins with known structure, using an implementation of the established protocol from its preceding version. The pKa values are obtained by solving the linearized Poisson-Boltzmann equation. To adapt the protein conformation to different pH ranges, local conformational changes are modeled, i.e. salt-bridges are perturbed. The slow modeling procedure from the software predecessor is improved, accelerating the computation 16 times on the average. The software was tested on the extensive benchmark set of 194 experimental pKa values, however, computation accuracy remains unchanged. The important elements of cytochrome c oxidase (CcO) function are elucidated. CcO is a terminal enzyme of the electron transport chain in mitochondria and some aerobic bacteria. It is reducing the molecular oxygen and using the released energy to pump protons across the membrane against the electrochemical gradient. With each electron from cytochrome c, one proton is pumped and one is spent in the chemical reaction (chemical proton) at the binuclear center (BNC). In total, four pumped and two chemical protons are translocated via the D-channel and remaining two chemical protons via the K-channel. The proton loading site (PLS) is a molecular group whose pKa increases upon reduction of BNC and temporarily store a pumped proton. The arrival of the chemical proton in the BNC and possibly the next upcoming pumped proton lowers the pKa of the PLS, pumping proton to the other side of the membrane. The required difference in the pKa values should approximately be 5 pH units. In this study, potential PLS candidates are identified and studied. The propionates D- and A- of heme a3 (PRDa3 and PRAa3, respectively) can act as the PLS, when the salt-bridge, blocking the protonation of PRDa3, is open and when PRAa3 is not involved in hydrogen bonding. Coupled with charge changes at the BNC, the pKa change of PRDa3 is 2.24 and of PRAa3 is 1.36, suggesting that other changes in the environment of the PLS may take place in order to fully explain its function. Propionates of heme a are excluded as PLS candidates. Loading and unloading schemes of the PLS involving propionates of heme a3 and His ligand of CuB are postulated. K-channel is active in the reductive part of the CcO redox cycle. In this study, pioneering work, which combines molecular dynamics (MD) simulations and pKa computations with site-directed fluorescence labelling experiments, explains some aspects of the K-channel activity. His73 is proposed as the K-channel proton entry point, possibly serving as a proton shuttle. The direct electrostatic influence of redox changes at the BNC on pKa values of residues at the CcO surface close to the K-channel entry is marginal. As a consequence, it is implied that in the reductive part of the CcO cycle, subtle conformational changes take place, namely rearrangements of hydrogen-bond networks, possibly affecting some secondary structural elements.

Next to unconsciousness, the suppression of nociception – i. e. the neuronal processing of noxious stimuli – is a central component of general anaesthesia. While unconsciousness can be monitored fairly accurately using electroencephalography (EEG)-derived measures, there is no reliable measure that allows quantifying the level of nociception in unconscious humans available to this day.

Therefore, this dissertation aimed at developing a multimodal measure of nociceptive processing in humans and applying this measure to investigate the spinal and cerebral processing of innocuous and noxious somatosensory stimuli during general anaesthesia. Using a setup that combined functional magnetic resonance imaging (fMRI) with simultaneous EEG and spinal nociceptive reflex monitoring, we were able for the first time to (i) concurrently investigate spinal and cerebral effects of general anaesthetics on the processing of somatosensory stimuli and to (ii) investigate intense noxious stimuli at intensities comparable to surgical stimuli.

During unconsciousness, we found an anaesthetic dose-dependent change of nociceptive processing in a variety of brain regions including higher-order association cortices. The changes in processing were accompanied by changes in functional connectivity between nociceptive brain regions, in accordance with the notion that general anaesthetics induce unconsciousness by altering the information transfer patterns in the brain. We found that profound spinal and cerebral nociceptive-evoked activation persisted even at levels of general anaesthesia that are deeper than applied in clinical practice. Currently used clinical indicators of analgesic efficacy (e. g. haemodynamic responses to noxious stimuli) were absent at far lower levels of general anaesthesia, demonstrating that the absence of these clinical responses is not indicative of absent nociceptive processing.

Due to the unavailability of reliable measures of intraoperative nociception, it is not known whether persisting nociception during general anaesthesia contributes to adverse effects on patient outcomes such as pain chronification. We therefore supplemented the primary experimental research of this dissertation by a clinical study, in which we showed that the level of intraoperative analgesia was related to persistent postoperative pain. As the analgesic dosings were in the range in which we found profound persistent nociceptive processing in our experimental studies, these results suggest that persistent nociception during currently used levels of intraoperative analgesia indeed contributes to long-term harm on patient outcomes.

This thesis presents a systematic study of charge-transport and -recombination mechanisms via paramagnetic states in hydrogenated amorphous silicon (a-Si:H). The structural disorder of this prototypical amorphous semiconductor induces localized states within the band gap that act as traps and recombination centers for charge carriers, detrimentally influencing the electronic material properties. Gaining insight into the nature of such loss mechanisms is thus crucial to develop a better understanding of the relation between structural and electronic properties of amorphous semiconductors in general, and of the functioning of a-Si-based technological applications like photovoltaic devices in particular.

The tool of choice to study the influence of localized states on the electronic material properties is electrically detected magnetic resonance (EDMR). This technique combines the power of electron paramagnetic resonance (EPR) to identify and characterize paramagnetic species on a microscopic level with current detection, providing selectivity to those species involved in electronic transitions. Due to its high sensitivity, EDMR further allows to probe current-limiting spin-dependent processes in fully processed devices. This capability will be exploited to conduct EDMR experiments on both the bulk a-Si:H film samples and operating a-Si:H solar cells.

Using a combinination of EDMR and EPR techniques, we directly probe the fundamental charge-separation mechanism in a-Si:H. For the first time, we conclusively prove the existence of both EDMR and EPR fingerprints of strongly localized light-generated excitonic states in a-Si:H. We will investigate their impact on electronic properties and provide evidence for their key role in the separation process of light-generated charge carriers, which is of central importance for the operation of photovoltaic devices.

In the scope of this work, we also describe and develop EDMR methodology, which is not only limited to a-Si:H, but can be applied to all kinds of organic and inorganic materials that exhibit spin-dependent conductivity. In particular, we present a novel EDMR detection scheme that can be used to separate the resonances of different paramagnetic species based on their spin state.

This work has to be seen in the context of a vast amount of previous research in the field of disordered solids in general and a-Si:H in particular. We will review results of earlier studies in light of our new findings and thereby will be able to give answers to long-standing questions concerning the microscopic nature of transport and recombination channels in a-Si:H. Since many of the structural and electronic properties of a-Si:H are universal features of disordered solids, our results do not only concern technological applications of a-Si:H, but are also of basic scientific interest regarding current-limiting processes in amorphous semiconductors.

This thesis concerns with the investigation of two closely-related spin-crossover molecules (SCMs)—[Fe(H2B(pz)2)bipy] (pz = pyrazole; bipy = 2,2’-bipyridine) and [Fe(H2B(pz)2)phen] (phen = 1,10-phenanthroline)—and their derivatives in submonolayers and in ultra-thin films deposited mainly on a highly-oriented graphite (HOPG) substrate (apart from Au(111) and Bi(111) substrates) with the aim of gaining insight into the fundamental processes governing the spin switching in such systems, using x-ray absorption spectroscopy (XAS). In a submonolayer of the SCM [Fe(H2B(pz)2)bipy] deposited on an HOPG substrate, x-ray-induced HS→LS transition, termed as reverse-SOXIESST, is observed at 5K for the first time—apart from the observation of soft x-ray-induced excited spin-state trapping (SOXIESST) already reported in the literature for the bulk material. The switching rates are found to be highly dependent upon the photon fluxes. This observation is rationalized as the spin switching processes being essentially caused by the interaction between the x-ray-induced secondary electrons and the molecules. The observed SOXIESST and reverse-SOXIESST phenomenon is analogous to light- and electron-induced spin switching reported in the literature. Both thermal- and light-induced spin transition of [Fe(H2B(pz)2)bipy] deposited on an HOPG substrate in coverage ranging from submonolayers to multilayers (of up to 10 monolayers (ML)) is systematically probed for cooperative effects and its evolution. In the thermal-induced spin transitions, the submonolayers exhibit an apparent anticooperativity, while a free-molecule-like behaviour is indicated at the monolayer; yet, the multilayers, starting from the double-layer, evidenced cooperativity in their spin-transition processes, with the interaction energy increasing to about 60% of the reported bulk value for the 10-ML sample. The light-induced spin transitions—albeit highly efficient—are free from cooperative effects. The photo-induced metastable HS state of the submonolayers at low temperatures is highly unstable, and showed a clear departure in the mode of spin relaxation from the bulk material. The SCM [Fe(H2B(pz)2)phen] is methylated with two ([Fe(H2B(pz)2)2(phen–me2)]) and four ([Fe(H2B(pz)2)2(phen–me4)]) methyl compounds at the phen ligand. The daughter molecules exhibit spin-crossover behaviour entirely different from the parent molecule upon contact with an HOPG surface; while [Fe(H2B(pz)2)phen] is found to undergo complete spin transition with light and temperature, about 50% of [Fe(H2B(pz)2)2(phen–me2)] molecules are trapped in the HS state within the accessible temperature range; [Fe(H2B(pz)2)2(phen–me4)] molecules lose their spin-crossover behaviour altogether upon contact with the HOPG surface. Similar spin-crossover behaviour is exhibited by the parent and the daughter molecule [Fe(H2B(pz)2)2(phen–me2)] on Au(111) and Bi(111) substrates: both the molecules undergo decomposition, resulting in the loss of spin-crossover on Au(111), while just about 50% of both types of molecules retain their spin-crossover on Bi(111) substrate.

The current thesis studies the RNA processing dynamics in a high-resolution time scale manner. The method used, called BrU Chase Seq, determined the processing kinetics of pri-miRNAs within intact cells over time using a pulse-chase approach to obtain nascent RNA within a 1-hour window after transcription. Further analysis showed that primiRNAs exhibit different processing kinetics ranging from fast over intermediate to slow processing. In addition, polycistronic pri-miRNAs show differential processing. The second part of the thesis describes for the first time the role of m6A RNA modification impact on RNA splicing kinetics. Two techniques have been developed namely TNT-Seq and qTNT-Chase Seq. These techniques provide the first time-resolved high-resolution assessment of m6A on nascent RNA transcripts and unveil its importance for the control of RNA splicing kinetics. More specifically, the early co-transcriptional m6A deposition near splice junctions promotes fast splicing, while m6A modifications in introns are associated with long, slowly processed introns and alternative splicing events. In conclusion, the early m6A deposition specifies the fate of transcripts regarding splicing kinetics and alternative splicing.

Beside 5’-capping and 3’-polyadenylation, splicing is one of the essential steps in the processing of most protein-coding genes in higher eukaryotes. It is catalyzed by the spliceosome, a large and dynamic RNA-protein molecular machine that encompasses five core components, the U1, U2, U4, U5 and U6 snRNPs. For each splicing reaction, a spliceosome is assembled anew in a stepwise manner. Spliceosomes must accurately recognize each splice site, as a single mistake can result in the production of a non-functional and potentially toxic protein. The crucial step of exon definition is facilitated by the U1 and U2 snRNP during early splicing. Cryo electron microscopy structures of early spliceosomal complexes in yeast have shown that the Prp39/Prp42 heterodimer is a crucial scaffolding subcomplex. It acts as a hub for multiple protein-protein interactions for example the contact between the U1 and the U2 snRNP, indicating that the Prp39/Prp42 heterodimer is important for the precise spatial positioning of the U1 and U2 snRNPs relative to each other. Interestingly there is no homolog for Prp42 in higher eukaryotes. PRPF39 is largely unstudied in higher eukaryotes and came to our attention because it is alternatively spliced in a differential manner in murine naïve vs. memory T-cells. I could show that an alternative exon is included in a differential manner. This can control PRPF39 expression by NMD in a tissue- and activation-dependent manner in mice and human, suggesting a role in adapting splicing efficiency to cell type specific requirements. Furthermore, I solved the crystal structure of murine PRPF39 at 3.3 Å resolution. The protein is largely α-helical and the structure shows the protein to be organized as a homodimer. Dimerization in solution could be confirmed with further biophysical assays. The mode of PRPF39 homodimerization is strikingly similar to heterodimerization of Prp39 and Prp42 in yeast. Structure guided point mutations could completely abolish dimerization and by using the monomeric PRPF39 mutants I could show that the monomer has a detrimental effect on splicing in vitro. Based on a structural comparison of murine PRPF39 and the yeast heterodimer, we performed a phylogenetic analysis showing, that organisms with a Prp39 homodimer have a substantially shortened U1 snRNA compared to organisms with a Prp39/Prp42 heterodimer. Our analysis indicates that a shortened U1 snRNA accompanied by a PRPF39 homodimer was crucial in the evolutionary development of more complex splicing. This observation is unexpected, as fewer splicing factors usually mirror lower splicing complexity and not the opposite. Taken together, my results reveal the structural and functional implications of murine PRPF39 on splicing. The data suggests, that a PRPF39 homodimer acts to substitute the Prp39/Prp42 heterodimer observed in yeast. Additionally, the reduction in RNA and protein complexity of the U1 snRNP may have been crucial in allowing highly complex and sophisticated splicing regulation across species.

Das Ziel dieser Arbeit war die durchflusszytometrische Untersuchung der Fremdkörperantwort (FBR) nach Implantation von reinem Magnesium (Mg) im Vergleich zu den permanenten Biomaterialien Polyetheretherketon (PEEK) und Polystyrol (PS). Es sollte erstmals die FBR auf reines Magnesium im zeitlichen Verlauf beschrieben und detailliert dargestellt werden, wobei der Einfluss der In-vivo-Korrosion auf die lokale Immunantwort zu berücksichtigen war. Hierfür wurden die Aufarbeitung und die durchflusszytometrische Analyse der Fremdkörperkapsel im Tiermodell Ratte etabliert. Zusätzlich sollten systemische Effekte nach Implantation der Materialien mittels Durchflusszytometrie in Blut und Milz untersucht werden. In 108 weibliche Lewis Ratten wurden unter Allgemeinanästhesie jeweils vier zylindri-sche Implantate (Durchmesser 8 mm, Höhe 2 mm) eines Materials (PEEK, PS, Mg) nach einer präoperativen Blutentnahme implantiert. Dabei erhielt jedes Tier zwei subkutane und zwei intramuskuläre Implantate. Am 1., 3., 7., 14., 21. und 28. post-operativen Tag erfolgte unter erneuter Allgemeinanästhesie eine finale Blutentnahme mit anschließender Euthanasie der Tiere (n = 6 je Material und Zeitpunkt). Danach wurden die Milz sowie die Implantate mit der umgebenden Fremdkörperkapsel entnommen. Zusätzlich wurden Gewebeproben aus der unmittelbaren Umgebung der Fremdkörperkapseln zum Ausschluss einer bakteriellen Kontamination mittels quantitativer Echtzeit-Polymerase-Kettenreaktion (RTQ-PCR) asserviert. Für die durchflusszytometrische Untersuchung wurden aus Milz, Fremdkörperkapsel sowie den präoperativen und finalen Blutproben vitale Einzelzellsuspensionen gewonnen und mit Fluorochrom-gekoppelten Antikörpern gefärbt. Es wurde jeweils ein spezifisches Antikörper-Panel für Blut/Milz und Fremdkörperkapsel etabliert und verwendet. Die Validierung der durchflusszytometrischen Analyse erfolgte mittels Zellsortierung, Zytozentrifugation und histologischer Färbung. Für die Mg-Implantate wurde nach Entfernen der Korrosionsprodukte die In-vivo-Korrosionsgeschwindigkeit anhand des Masseverlustes bestimmt. Die statistische Analyse der Zeitpunkt- und Materialgrup-penvergleiche in Blut, Milz und Fremdkörperkapsel umfasste eine zweifaktorielle Varianzanalyse, paarweise Vergleiche und eine Bonferroni-Holm-Prozedur. Mithilfe der etablierten durchflusszytometrischen Analyse konnten die charakteristischen Leukozytenpopulationen der FBR in der Fremdkörperkapsel identifiziert und quantifiziert werden. Es zeigte sich der typische zeitliche Verlauf der FBR für alle drei Biomaterialien mit einer initialen Dominanz von neutrophilen Granulozyten begleitet von einer zunehmenden Rekrutierung von Monozyten/Makrophagen in die Implantatumgebung. Während der chronischen Entzündungsreaktion und der Fremdkörperreaktion dominierten ein- und mehrkernige Makrophagen sowie T-Lymphozyten in der Fremdkörperkapsel. Signifikante Unterschiede zwischen Mg und den permanenten Polymeren wurden ausschließlich nach subkutaner Implantation und nur für folgende Zellpopulationen aufgefunden: erhöhter Anteil der CD4-negativen Monozyten/Makrophagen an der Gesamtleukozytenzahl (Tag 1 und 3), erhöhter Anteil der Mastzellen/NK-Zellen an den lebenden Leukozyten (Tag 7 und 14) sowie verringerter Anteil der späten ein- und mehrkernigen Makrophagen an der Gesamtleukozytenzahl (Tag 14 und 28). Die analysierten Zellpopulationen in den finalen Blutproben befanden sich nach Implantation von PEEK, PS und Mg über den gesamten Untersuchungszeitraum jeweils innerhalb des studieninternen Referenzbereiches (präoperative Blutproben). Die Materialgruppenvergleiche der Blutproben ergaben keine Unterschiede. In der Milz zeigten sich für die untersuchten Leukozytenpopulationen keine wesentlichen Unterschiede zwischen den Zeitpunkten und den Implantatmaterialien. Während der ersten vier Wochen nach Implantation korrodierte Mg in vivo mit einer niedrigen Korrosionsgeschwindigkeit begleitet von einer klinisch nicht relevanten Gasansammlung an der Implantationsstelle. Eine bakterielle Kontamination der Kapselproben wurde durch die RTQ-PCR ausgeschlossen. Zusammenfassend riefen die drei Implantatmaterialien PEEK, PS und Mg eine ver-gleichbare, milde lokale Immunantwort im untersuchten Zeitraum an beiden Implantat-lokalisationen hervor. Die subkutan aufgefundenen materialspezifischen Effekte der Mg-Implantate besaßen nur eine geringe Relevanz. Eine systemische Immunantwort infolge der Implantation konnte ausgeschlossen werden. Folglich hatte die In-vivo- Korrosion der Mg-Implantate im Vergleich zu PEEK und PS keinen verstärkenden Einfluss auf die FBR und verursachte keine systemische Immunantwort. Insgesamt legte die durchflusszytometrische Beurteilung der lokalen und systemischen Effekte nach Implantation eine gute Biokompatibilität von PEEK, PS und Mg nahe. Hierbei stellte die etablierte durchflusszytometrische Analyse ein geeignetes Werkzeug zur Untersuchung der Kinetik der systemischen und lokalen Immunantwort in den ersten vier Wochen nach Implantation von Mg, PEEK und PS im Rattenmodell dar.

Scintigraphy of the processus spinosi is a standard procedure for the evaluation of horses with back pain. The scintigraphic evaluation is based on a subjective or semi-quantitative analysis of areas with increased radiopharmaceutical uptake. The first part of this retrospective, analytical thesis aimed to compare subjective and semi-quantitative methods for the evaluation of scintigraphic images of the processus spinosi in the equine thoracic spine. Additionally, a new modified semi-quantitative evaluation method was developed and analysed for inter- and intraobserver agreement. The second aim was to investigate the agreement between the modified semi-quantitative scintigraphic evaluation technique and other established scintigraphic evaluation methods. Subsequently the agreement of scintigraphic evaluation techniques with clinical and radiological findings was analysed. Scintigraphic images of the thoracic processus spinosi of 20 Warmblood horses were subjectively assessed by eleven veterinary surgeons using red-green-blue (RGB) scale and greyscales for entire scintigraphic images or masked images. For semi-quantitative assessment, the observers placed "regions of interest" (ROIs) across each processus spinosus of the 13th to 18th thoracic vertebrae. The radiopharmaceutical uptake of each processus spinosus was determined in comparison with a reference ROI. Subsequently, a modified semi-quantitative calculation was developed in which only the highest counts per pixel for a given number of pixels were included in the calculation. The inter- and intraobserver agreement was determined using intraclass correlation coefficients (ICCs). Inter- and intraobserver ICCs were 41.65% and 71.39%, respectively, for the subjective image scoring. A correlation between intraobserver agreement, experience of the operator and scintigraphic greyscale images was identified. Inter- and intraobserver agreement was significantly increased using the semi-quantitative analysis (97.35%, 98.36%) or modified semi-quantitative calculation (98.61%, 98.82%). For the second part of the study, 223 Warmblood horses underwent scintigraphic, radiographic and clinical examination of the thoracic spine and were included in a retrospective study. Scintigraphic images were assessed using subjective, semi-quantitative and the newly developed modified semi-quantitative techniques. Radiographs were evaluated subjectively (grade 0-7). The analysed horses were assigned to one of two groups, including horses with or without thoracolumbar pain. The total radiographic and total (subjective) scintigraphic grades were significantly higher in horses with thoracolumbar pain than in horses without thoracolumbar pain (p < 0.05). Semi-quantitative and modified semi-quantitative radiopharmaceutical uptake ratios did not differ significantly in horses with or without thoracolumbar pain. The calculation of kappa agreement between scintigraphic evaluation methods revealed a substantial agreement between the modified semi-quantitative and the semi-quantitative scintigraphic evaluation technique. The agreement between subjective scintigraphic and modified semi-quantitative scintigraphic image analysis was fair. There was slight agreement between all scintigraphic techniques and the radiographic findings. In summary, the modified semi-quantitative scintigraphic image scoring has provided results that are comparable with the established scintigraphic evaluation methods but with a significant increase in inter- and intraobserver agreement. However, an association between results obtained with semi-quantitative scintigraphic image evaluation techniques and clinical signs of thoracolumbar pain could not be observed. More factors may need to be added to semi-quantitative radiopharmaceutical uptake ratio calculations to improve the clinical significance of these methods.

Transcriptional regulation of gene expression is a central topic in biological research. The DNA sequencing methodology ChIP-seq is used to infer binding sites of transcription factors and histone proteins in a genome-wide fashion. The ChIP-nexus protocol is a further development of ChIP-seq that allows to predict binding sites with much greater accuracy. This thesis is about the primary analysis of ChIP-seq and ChIP-nexus data. The first part provides an application example in which ChIP-seq was used to elucidate the pathomechanism underlying the phenotype of a patient with severe hand and foot malformations carrying a mutation of the gene encoding for the transcription factor HOXD13.

In the second part, the ChIP-seq peak caller Q is introduced that addresses shortcomings of the recommended software identified in the course of practical applications. Improvements regarding efficiency and reproducibility were verified within the framework of the ENCODE standards using 38 publicly available datasets. Furthermore, Q was used to characterize a signature of RNA polymerase II and histone modification H3K4me3 peaks that is consistent with the concept of paused open promoters. In the final part, the first bespoke software package Q-nexus for the analysis of ChIP-nexus data is presented. The ChIP-seq caller Q was extended by additional modules that are required for the analysis of ChIP-nexus data. The software makes use of the random barcodes introduced with the ChIP-nexus protocol and was used to characterize specific binding patterns of transcription factors at binding sites. Finally, Q-nexus was compared to two other peak callers with respect to reproducibility of peak calling.

Zusammenfassend weisen die Lebertransplantation und die Leberteilresektion verschiedene Vor- und Nachteile auf, die einen differenzierten Einsatz beider Verfahren für die kurative Therapie des HCC begründen. Ein hohes Alter ist per se keine Kontraindikation für eine Lebertransplantation. In der Tat ist die Lebensqualität älterer Organempfänger nach Lebertransplantation vergleichbar mit der junger Organempfänger. Für die immunsuppressive Therapie nach Lebertransplantation ist es entscheidend, das Alter des Organspenders und des Organempfängers zur berücksichtigen, da die Immunseneszenz zu einer veränderten allogenen Immunantwort führt. Die laparoskopische Leberteilresektion kann als konkurrierendes Verfahren zur Lebertransplantation für die Therapie des HCC eingesetzt werden. Der Vorteil der Leberteilresektion besteht in der hohen Verfügbarkeit in den jeweiligen spezialisierten Zentren, da in Zeiten des ubiquitären Organmangels kein passender Spender gefunden werden muss. Auffallend ist, dass die onkologischen Ergebnisse nach Leberteilresektion in den letzten Jahren deutlich verbessert worden sind und die revolutionierenden laparokopischen Techniken die chirurgischen Standards der Leberteilresektion neu definieren.

Periodontitis (PD) is a bacterially induced disease of the oral cavity and, in the long term, can lead to tooth loss due to the inflammatory degradation of the alveolar bone. For the severe forms of PD, there is a prevalence rate of 11% worldwide, making it one of the most common inflammatory diseases. Aggressive periodontitis (AgP) is an early (<35 years) and particularly severe clinical form of PD, whereas chronic periodontitis (CP) usually has a slow and more moderate course. The estimated heritability of PD is 50%. Twin studies and examples where individuals share the same environment and lifestyle yet have different risk for disease, illustrate the strong influence of hereditary factors on the pathogenesis of PD. Several randomized clinical trials have demonstrated a relationship between PD and coronary artery disease (CAD), with an epidemiological relationship between the two disease to be independent of smoking as a common risk factor. CAD is a complex disease of the arteries with a strong inflammatory component. Plaque formation in the arteries can impair the blood supply, which can trigger a heart attack. Previous studies have identified genetic risk variants at several loci in the human genome that predispose to PD. The gene locus GLT6D1 is associated with AgP at genome-wide significance. Furthermore, common genetic risk variants of PD and CAD were identified for the gene sites ANRIL, Plasminogen and VAMP3. However, the known genetic risk factors explain only a small fraction of the heritability of PD. Indeed the underlying genetic risk factors remain largely unknown. The identification of yet unknown genetic risk factors can significantly contribute to a better understanding of the causes and molecular mechanisms of PD as well as the genetic and molecular relationship to CAD and to the improvement of diagnosis and treatment of PD. In my thesis, I carried out genome-wide association studies and meta-analyses with the aim of systematically identifying further risk genes. I had access to the, to date, world's largest AgP sample with 851 cases and 6,580 controls of Dutch and German descents. In addition, I used a non-genotyped AgP sample with 220 cases and 560 controls of Turkish descent which were used to confirm single genetic variants. For CP samples I had a total of 4,244 cases and 3,328 controls of German and European-American descent which were also taken into account. I could identify new risk variants of PD that either reached genome-wide significance levels (P < 5 x 10^-8) or could be independently validated. These variants are located proximal to the genes DEFA1A3, SIGLEC5, LOC107964137, MTND1P5, VAMP8, PF4/PPBP/CXCL5, IL37. In silico functional characterization of these loci points to specific processes that play a role in wound healing and in bacterial immune defense. A pleiotropic variant at VAMP8 also increases susceptibility to CAD and suggests a possible molecular mechanism underlying the epidemiological link between PD and CAD. The results confirm that the relationship between PD and CAD cannot be explained solely by shared lifestyle factors. However, the SNP-gene relationships shown in this work require further experimental studies.