In vitro generation and characterization of acute myeloid leukemia-reactive CD8 + cytotoxic T-lymphocyte clones from healthy donors

Donor-derived CD8+ cytotoxic T lymphocytes (CTLs) eliminating host leukemic cells mediate curative graft-versus-leukemia (GVL) reactions after allogeneic hematopoietic stem cell transplantation (HSCT). The leukemia-reactive CTLs recognize hematopoiesis-restricted or broadly expressed minor histocompatibility and leukemia-associated peptide antigens that are presented by human leukocyte antigen (HLA) class I molecules on recipient cells. The development of allogeneic CTL therapy in acute myeloid leukemia (AML) is hampered by the poor efficiency of current techniques for generating leukemia-reactive CTLs from unprimed healthy donors in vitro. In this work, a novel allogeneic mini-mixed lymphocyte/leukemia culture (mini-MLLC) approach was established by stimulating CD8+ T cells isolated from peripheral blood of healthy donors at comparably low numbers (i.e. 10e4/well) with HLA class I-matched primary AML blasts in 96-well microtiter plates. Before culture, CD8+ T cells were immunomagnetically separated into CD62L(high)+ and CD62L(low)+/neg subsets enriched for naive/central memory and effector memory cells, respectively. The application of 96-well microtiter plates aimed at creating multiple different responder-stimulator cell compositions in order to provide for the growth of leukemia-reactive CTLs optimized culture conditions by chance. The culture medium was supplemented with interleukin (IL)-7, IL-12, and IL-15. On day 14, IL-12 was replaced by IL-2. In eight different related and unrelated donor/AML pairs with complete HLA class I match, numerous CTL populations were isolated that specifically lysed myeloid leukemias in association with various HLA-A, -B, or -C alleles. These CTLs recognized neither lymphoblastoid B cell lines of donor and patient origin nor primary B cell leukemias expressing the corresponding HLA restriction element. CTLs expressed T cell receptors of single V-beta chain families, indicating their clonality. The vast majority of CTL clones were obtained from mini-MLLCs initiated with CD8+ CD62L(high)+ cells. Using antigen-specific stimulation, multiple CTL populations were amplified to 10e8-10e10 cells within six to eight weeks. The capability of mini-MLLC derived AML-reactive CTL clones to inhibit the engraftment of human primary AML blasts was investigated in the immunodeficient nonobese diabetic/severe combined immune deficient IL-2 receptor common γ-chain deficient (NOD/SCID IL2Rγnull) mouse model. The leukemic engraftment in NOD/SCID IL2Rγnull was specifically prevented if inoculated AML blasts had been pre-incubated in vitro with AML-reactive CTLs, but not with anti-melanoma control CTLs. These results demonstrate that myeloid leukemia-specific CTL clones capable of preventing AML engraftment in mice can be rapidly isolated from CD8+ CD62L(high)+ T cells of healthy donors in vitro. The efficient generation and expansion of these CTLs by the newly established mini-MLLC approach opens the door for several potential applications. First, CTLs can be used within T cell-driven antigen identification strategies to extend the panel of molecularly defined AML antigens that are recognizable by T cells of healthy donors. Second, because these CTLs can be isolated from the stem cell donor by mini-MLLC prior to transplantation, they could be infused into AML patients as a part of the stem cell allograft, or early after transplantation when the leukemia burden is low. The capability of these T cells to expand and function in vivo might require the simultaneous administration of AML-reactive CD4+ T cells generated by a similar in vitro strategy or, less complex, the co-transfer of CD8-depleted donor lymphocytes. To prepare clinical testing, the mini-MLLC approach should now be translated into a protocol that is compatible with good manufacturing practice guidelines.

Charge generation and recombination in hybrid organic,inorganic solar cells

This thesis deals with the investigation of exciton and charge dynamics in hybrid solar cells by time-resolved optical spectroscopy. Quasi-steady-state and transient absorption spectroscopy, as well as time-resolved photoluminescence spectroscopy, were employed to study charge generation and recombination in solid-state organic dye-sensitized solar cells, where the commonly used liquid electrolyte is replaced by an organic solid hole transporter, namely 2,2′7,7′-tetrakis-(N,N-di-p-methoxyphenyl-amine)-9,9′-spirobifluorene (spiro-MeOTAD), and polymer-metal oxide bulk heterojunction solar cells, where the commonly used fullerene acceptor [6,6]-phenyl C61 butyric acid methyl ester (PCBM) is replaced by zinc oxide (ZnO) nanoparticles. By correlating the spectroscopic results with the photovoltaic performance, efficiency-limiting processes and processes leading to photocurrent generation in the investigated systems are revealed. rnIt is shown that the charge generation from several all-organic donor-π-bridge-acceptor dyes, specifically perylene monoimide derivatives, employed in solid-state dye-sensitized solar cells, is strongly dependent on the presence of a commonly used additive lithium bis(trifluoromethanesulphonyl)imide salt (Li-TFSI) at the interface. rnMoreover, it is shown that charges can not only be generated by electron injection from the excited dye into the TiO2 acceptor and subsequent regeneration of the dye cation by the hole transporter, but also by an alternative mechanism, called preceding hole transfer (or reductive quenching). Here, the excited dye is first reduced by the hole transporter and the thereby formed anion subsequently injects an electron into the titania. This additional charge generation process, which is only possible for solid hole transporters, helps to overcome injection problems. rnHowever, a severe disadvantage of solid-state dye-sensitized solar cells is re-vealed by monitoring the transient Stark effect on dye molecules at the inter-face induced by the electric field between electrons and holes. The attraction between the negative image charge present in TiO2, which is induced by the positive charge carrier in the hole transporter due to the dielectric contrast between the organic spiro-MeOTAD and inorganic titania, is sufficient to at-tract the hole back to the interface, thereby increasing recombination and suppressing the extraction of free charges.rnBy investigating the effect of different dye structures and physical properties on charge generation and recombination, design rules and guidelines for the further advancement of solid-state dye-sensitized solar cells are proposed.rnFinally, a spectroscopic study on polymer:ZnO bulk heterojunction hybrid solar cells, employing different surfactants attached to the metal oxide nanoparticles, was performed to understand the effect of surfactants upon photovoltaic behavior. By applying a parallel pool analysis on the transient absorption data, it is shown that suppressing fast recombination while simultaneously maintaining the exciton splitting efficiency by the right choice of surfactants leads to better photovoltaic performances. Suppressing the fast recombination completely, whilst maintaining the exciton splitting, could lead to a doubling of the power conversion efficiency of this type of solar cell.

Generation and characterisation of acute myeloid leukaemia-reactive CD4 + T cells and their potential to eliminate human leukaemia blasts in NSG mice

Acute myeloid leukaemia (AML) is a cancer of the haematopoietic system, which can in many cases only be cured by haematopoietic stem cell transplantation (HSCT) and donor lymphocyte infusion (DLI) (Burnett et al., 2011). This therapy is associated with the beneficial graft-versus-leukaemia (GvL) effect mediated by transplanted donor T and NK cells that either recognise mismatch HLA molecules or polymorphic peptides, so-called minor histocompatibility antigens, leukaemia-associated or leukaemia-specific antigens in the patient and thus eliminate remaining leukaemic blasts. Nevertheless, the mature donor-derived cells often trigger graft-versus-host disease (GvHD), leading to severe damages in patients’ epithelial tissue, mainly skin, liver and intestine (Bleakley & Riddell, 2004). Therefore, approaches for the selective mediation of strong GvL effects are needed, also in order to prevent relapse after transplantation. One promising opportunity is the in vitro generation of AML-reactive CD4+ T cells for adoptive transfer. CD4+ T cells are advantageous compared to CD8+ T cells, as HLA class II molecules are under non-inflammatory conditions only expressed on haematopoietic cells; a fact that would minimise GvHD (Klein & Sato, 2000). In this study, naive CD4+ T cells were isolated from healthy donors and were successfully stimulated against primary AML blasts in mini-mixed lymphocyte/leukaemia cell cultures (mini-MLLC) in eight patient/donor pairs. After three to seven weekly restimulations, T cells were shown to produce TH1 type cytokines and to be partially of monoclonal origin according to their TCR Vβ chain usage. Furthermore, they exhibited lytic activity towards AML blasts, which was mediated by the release of granzymes A and B and perforin. The patient/donor pairs used in this study were fully HLA-class I matched, except for one pair, and also matched for HLA-DR and -DQ, whereas -DP was mismatched in one or both alleles, reflecting the actual donor selection procedure in the clinic (Begovich et al., 1992). Antibody blocking experiments suggested that the generated CD4+ T cells were directed against the HLA-DP mismatches, which could be confirmed by the recognition of donor-derived lymphoblastoid cell lines (LCLs) electroporated with the mismatched DP alleles. Under non-inflammatory conditions primary fibroblasts did not express HLA-DP and were thus not recognised, supporting the idea of a safer application of CD4+ T cells regarding induction of GvHD. For the assessment of the biological significance of these T cells, they were adoptively transferred into NSG mice engrafted with human AML blasts, where they migrated to the bone marrow and lymphoid tissue and succeeded in eliminating the leukaemic burden after only one week. Therefore, AML-reactive CD4+ T cells expanded from the naive compartment by in vitro stimulation with primary leukaemia blasts appear to be a potent tool for DLI in HSCT patients and promise to mediate specific GvL effects without causing GvHD.

Charge generation and recombination in solid-state dye-sensitized solar cells

Diese Doktorarbeit befasst sich mit Ladungsgeneration und – rekombination in Feststoff-Farbstoffsolarzellen, die spiro-OMeTAD als Lochleiter verwenden. Die vorliegende Arbeit ist in drei Fallstudien unterteilt: i.) Kern-erweiterte Rylen-Farbstoffe, ii.) ein Perylenmonoimid-Farbstoff und iii.) Donor-π verbrückte (Cyclopentadithiophen)-Akzeptor-Farbstoffe. Trotz ihres hohen molaren Extinktionskoeffizienten und der hohen Absorbanz der sensibilisierten Filme, zeigen einige dieser Farbstoffmoleküle nur geringe photovoltaischen Effizienzen. Um den Ursprung des geringen Wirkungsgrades herauszufinden, wurde breitbandige, ultraschnelle transiente Absorptionsspektroskopie an Solarzellen durchgeführt.rnInsbesondere die Auswirkungen verschiedender Ankergruppen, Dipolmomente, Photolumineszenzlebenszeiten, Lithium-Kationensensitivität und Ladungsträgerdynamik, die alle einen großen Einfluss auf den Wirkungsgrad der Solarzelle besitzen, wurden untersucht. In der ersten Fallstudie zeigte ein kurzer Rylen-Farbstoff aufgrund deutlich verlängerter Lebenszeiten die beste Effizienz im Vergleich zu größeren Kern-erweiterten Rylen-Farbstoffen. Die Lebenszeit wurde weiter reduziert, wenn Maleinsäure als Ankergruppe unter einer Ringöffnungsreaktion an die mesoporöse Oberfläche des Metalloxid-Halbleiters adsorbierte. Dies konnte mit Hilfe von Berechnungen mittels der Dichtefunktionaltheorie (DFT, B3LYP) auf die Differenz des Dipolmoments zwischen Grundzustand und angeregtem Zustand zurückgeführt werden. Die Berechnungen bekräftigen die unvorteilhafte Injektion von Ladungen durch die Änderung der Richtung des Dipolmoments, wenn eine Ringöffnung der Anhydridgruppe stattfindet. In der zweiten Studie zeigte das Perylenmonoimid-Derivat ID889 einen Wirkungsgrad von 4.5% in Feststoff-Farbstoffsolarzellen, wobei ID889 sogar ohne Zuhilfenahme eines Additivs in der Lage ist langlebige Farbstoffkationen zu bilden. Die Verwendung von Lithium-Kationen stabilisiert jedoch sowohl den Prozess der Ladungsgeneration als auch den der Ladungsregeneration. Des Weiteren wurde in ID889-sensitivierten Bauteilen kein reduktives Löschen beobachtet. Dabei wurde die Dynamik der Exzitonen mittels einer soft-modelling Methode Kurvenanalyse aus den Daten der transienten Absorptionsspektroskopie gewonnen. Zuletzt wurden Strukturen mit Cyclopentadithiophen(CPDT)-Baustein untersucht, die eine typische D-π-A Molekülstruktur bilden. FPH224 und 233 zeigten dabei eine bessere Effizienz als FPH231 und 303 aufgrund einer großen Injektionseffizienz (IE) und längerer Lebenszeit der angeregten Zustände. Dies kann auf reduktives Löschen in FPH231 und 303 zurückgeführt werden, wohingegen FPH224 und 233 einen moderaten Zerfall des Spirokationensignals zeigten.

Charge generation, transport and recombination in organic solar cells

This thesis presents a study of the charge generation, transport, and recombination processes in organic solar cells performed with time-resolved experimental techniques. Organic solar cells based on polymers can be solution-processed on large areas and thus promise to become an inexpensive source of renewable energy. Despite significant improvements of the power conversion efficiency over the last decade, the fundamental working principles of organic solar cells are still not fully understood. It is the aim of this thesis to clarify the role of different performance limiting processes in organic solar cells and to correlate them with the molecular structure of the studied materials, i.e. poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl C61 butyric acid methyl ester (PCBM). By combining time-of-flight charge transport measurements, transient absorption spectroscopy, a newly developed experimental technique called time delayed double pulse experiment and drift-diffusion simulations a comprehensive analysis of the working principles of P3HT:PCBM solar cells could be performed. It was found that the molecular structure of P3HT (i.e. the regioregularity) has a pronounced influence on the morphology of thin films of pristine P3HT and of blends of P3HT with PCBM. This morphology in turn affected the charge transport properties as well as the charge generation and recombination kinetics. Well-ordered regioregular P3HT was found to be characterized by a high charge carrier mobility, efficient charge generation and low but field-dependent (non-geminate) recombination. Importantly, the charge generation yield was found to be independent of temperature and applied electric field as opposed to the expectations of the Onsager-Braun model that is commonly applied to describe the temperature and field dependence of charge generation in organic solar cells. These properties resulted in a reasonably good power conversion efficiency. In contrast to this, amorphous regiorandom P3HT was found to show poor charge generation, transport and recombination properties that combine to a much lower power conversion efficiency.

1-, 2- and 3-dimensional phenylene-based materials for optoelectronic applications

A series of oligo-phenylene dendronised conjugated polymers was prepared. The divergent synthetic approach adopted allowed for the facile synthesis of a range of dendronised monomers from a common intermediate, e.g. first and second generation fluorene. Only the polymerisation of the first generation and alkylarylamine substituted dendronised fluorene monomers yielded high molecular weight materials, attributed to the low solubility of the remaining dendronised monomers. The alkylarylamine substituted dendronised poly(fluorene) was incorporated into an organic light emitting diode (OLED) and exhibited an increased colour stability in air compared to other poly(fluorenes). The concept of dendronisation was extended to poly(fluorenone), a previously insoluble material. The synthesis of the first soluble poly(fluorenone) was achieved by the incorporation of oligo-phenylene dendrons at the 4-position of fluorenone. The dendronisation of fluorenone allowed for a polymer with an Mn of 4.1 x 104 gmol-1 to be prepared. Cyclic voltammetry of the dendronised poly(fluorenone) showed that the electron affinity of the polymer was high and that the polymer is a promising n-type material. A dimer and trimer of indenofluorene (IF) were prepared from the monobromo IF. These oligomers were investigated by 2-dimensional wide angle x-ray spectroscopy (2D-WAXS), polarised optical microscopy (POM) and dielectric spectroscopy, and found to form highly ordered smetic phases. By attaching perylene dye as the end-capper on the IF oligomers, molecules that exhibited efficient Förster energy transfer were obtained. Indenofluorene monoketone, a potential defect structure for IF based OLED’s, was synthesised. The synthesis of this model defect structure allowed for the long wavelength emission in OLED’s to be identified as ketone defects. The long wavelength emission from the indenofluorene monoketone was found to be concentration dependent, and suggests that aggregate formation is occurring. An IF linked hexa-peri-hexabenzocoronene (HBC) dimer was synthesised. The 2D-WAXS images of this HBC dimer demonstrate that the molecule exhibits intercolumnar organisation perpendicular to the extrusion direction. POM images of mixtures of the HBC dimer mixed with an HBC with a low isotropic temperature demonstrated that the HBC dimer is mixing with the isotropic HBC.

Electrostatic supramolecular assembly of charged dendritic polymers and their biological application

The aim of this study was the development of functional multilayer films through electrostatic layer by layer (LbL) assembly of dendritic macromolecules, the investigation of the fundamental properties of these multilalyered films and the study of their biological applications. rnThe synthesis of the anionic hyperbranched polyglycerols (hbPG) and the preparation of multilayers made of hbPG/phosphorus dendrimer as well as the influences of deposition conditions on multilayers were reported. The thicknesses of multilayer films increase with a decrease of molecular weight of anionic hbPGs. The multilayer films fabricated by low molecular weight hbPGs grow less regularly due to the less charged carboxylic acid groups providing the relative weaker electrostatic forces for the deposition. The thicknesses of multilayer films are reduced with increasing pH values and decreasing the concentration of NaCl. The observed changes of multilayer thickness and surface morphology could be interpreted with the aid of theories regarding the charge density and conformation of the anionic hbPG chains in solution. rnBesides the study of fundamental properties of hbPG/phosphorus multilayer films, antifouling thin films derived from hbPG layers were developed. The antifouling properties of hbPG layers were found to correlate with factors of the molecular weight of anionic hbPG and the film thickness. It was demonstrated that anionic hbPG single layer with highest molecular weight can reduce non specific protein adsorption more efficiently than single layer with lower molecular weight and all the hbPG bilayers possessed excellent property of antifouling. rnPhosphorus dendrimer multilayers were successfully prepared as the platforms to detect DNA immobilization and hybridization. The effect of NaCl concentration on the multilayer film thickness was evaluated to obtain the optimized film thickness. Making use of the multilayer deposited at the optimized condition as a substrate, a high loading of DNA probes was achieved through covalent coupling of probe DNA with the as-formed multilayer films. The hybridization of target DNA with immobilized probe DNA was then carried out and studied by SPFS. The limit of detection upon hybridization was estimated on various dendrimer multilayer platforms. The minimum detection concentration for DNA hybridization is in the same order of magnitude compared with other neutral phosphorus dendrimer systems. Furthermore, the LbL deposition of phosphorus dendrimer multilayers provided a mild and simple way to prepare platforms as DNA microarrays. rnBased on the phosphorus dendrimer multilayer systems, dendritic star polymers were employed which have more reactive groups than that phosphorus dendrimers. The as-assembled dendritic star polymer multilayer films exhibited such distinct morphology characteristics that they underwent extensive structural reorganization upon post-treatment under different pH conditions. Kinetic binding of probe DNA molecules on the outermost negatively charged dendritic surface was studied by SPR as well. The binding capacities of probe DNA on the multilayer surfaces fabricated from the first-generation and the second-generation of dendritic star polymers were compared. The improved binding capacity was achieved from the second-generation of dendritic star polymer multilayer films due to their more reactive groups. DNA hybridization reaction on dendritic multilayer films was investigated by SPFS. The similar hybridization behaviors were found on both multilayer surfaces. Meanwhile, the hybridization kinetic affinities were compared with that of phosphorus dendrimer multilayer surfaces and showed improved detection sensitivity than phosphorus dendrimer multilayer films.rn

DNA hybrid materials consisting of oligonucleotides and organic molecules: synthesis, characterization and applications

The goal of this thesis was to increase the functionality of pristine DNA scaffolds by functionalizing them with fluorescent dyes and hydrophobic moieties. Two important steps were necessary to realize this aim successfully. First, nucleic acids needed to be synthesized making use of multidisciplinary toolbox for the generation and manipulation of polynucleic acids. The most important techniques were the solid phase synthesis involving the incorporation of standard and modified phosphoramidite building blocks as well as molecular biology procedures like the polymerase chain reaction, the bacterial amplification of plasmids and the enzymatic digestion of circular vectors. Second, and evenly important, was the characterization of the novel bioorganic hybrid structures by a multitude of techniques, especially optical measurements. For studying DNA-dye conjugates methods like UV/Vis and photoluminescence spectroscopy as well as time resolved luminescence spectroscopy were utilized. While these measurements characterized the bulk behavior of an ensemble of DNA-dye hybrids it was necessary for a complete understanding of the systems to look at single structures. This was done by single-molecule fluorescence spectroscopy and fluorescence correlation spectroscopy. For complete analysis the optical experiments were complemented by direct visualization techniques, i.e. high resolution transmission electron microscopy and scanning force microscopy.

Quantifying and modeling financial market fluctuations

Die Entstehung eines Marktpreises für einen Vermögenswert kann als Superposition der einzelnen Aktionen der Marktteilnehmer aufgefasst werden, die damit kumulativ Angebot und Nachfrage erzeugen. Dies ist in der statistischen Physik mit der Entstehung makroskopischer Eigenschaften vergleichbar, die von mikroskopischen Wechselwirkungen zwischen den beteiligten Systemkomponenten hervorgerufen werden. Die Verteilung der Preisänderungen an Finanzmärkten unterscheidet sich deutlich von einer Gaußverteilung. Dies führt zu empirischen Besonderheiten des Preisprozesses, zu denen neben dem Skalierungsverhalten nicht-triviale Korrelationsfunktionen und zeitlich gehäufte Volatilität zählen. In der vorliegenden Arbeit liegt der Fokus auf der Analyse von Finanzmarktzeitreihen und den darin enthaltenen Korrelationen. Es wird ein neues Verfahren zur Quantifizierung von Muster-basierten komplexen Korrelationen einer Zeitreihe entwickelt. Mit dieser Methodik werden signifikante Anzeichen dafür gefunden, dass sich typische Verhaltensmuster von Finanzmarktteilnehmern auf kurzen Zeitskalen manifestieren, dass also die Reaktion auf einen gegebenen Preisverlauf nicht rein zufällig ist, sondern vielmehr ähnliche Preisverläufe auch ähnliche Reaktionen hervorrufen. Ausgehend von der Untersuchung der komplexen Korrelationen in Finanzmarktzeitreihen wird die Frage behandelt, welche Eigenschaften sich beim Wechsel von einem positiven Trend zu einem negativen Trend verändern. Eine empirische Quantifizierung mittels Reskalierung liefert das Resultat, dass unabhängig von der betrachteten Zeitskala neue Preisextrema mit einem Anstieg des Transaktionsvolumens und einer Reduktion der Zeitintervalle zwischen Transaktionen einhergehen. Diese Abhängigkeiten weisen Charakteristika auf, die man auch in anderen komplexen Systemen in der Natur und speziell in physikalischen Systemen vorfindet. Über 9 Größenordnungen in der Zeit sind diese Eigenschaften auch unabhängig vom analysierten Markt - Trends, die nur für Sekunden bestehen, zeigen die gleiche Charakteristik wie Trends auf Zeitskalen von Monaten. Dies eröffnet die Möglichkeit, mehr über Finanzmarktblasen und deren Zusammenbrüche zu lernen, da Trends auf kleinen Zeitskalen viel häufiger auftreten. Zusätzlich wird eine Monte Carlo-basierte Simulation des Finanzmarktes analysiert und erweitert, um die empirischen Eigenschaften zu reproduzieren und Einblicke in deren Ursachen zu erhalten, die zum einen in der Finanzmarktmikrostruktur und andererseits in der Risikoaversion der Handelsteilnehmer zu suchen sind. Für die rechenzeitintensiven Verfahren kann mittels Parallelisierung auf einer Graphikkartenarchitektur eine deutliche Rechenzeitreduktion erreicht werden. Um das weite Spektrum an Einsatzbereichen von Graphikkarten zu aufzuzeigen, wird auch ein Standardmodell der statistischen Physik - das Ising-Modell - auf die Graphikkarte mit signifikanten Laufzeitvorteilen portiert. Teilresultate der Arbeit sind publiziert in [PGPS07, PPS08, Pre11, PVPS09b, PVPS09a, PS09, PS10a, SBF+10, BVP10, Pre10, PS10b, PSS10, SBF+11, PB10].

Cannabinoid CB1 receptor in the regulation of sociability, stress coping, and its interaction with the serotonergic system

Cannabinerge Substanzen können das Verhalten in einer dosisabhängigen, aber biphasischen Weise beeinflussen. Eine Erklärung für diese Art der Effekte könnte die Verteilung des CB1 Rezeptors auf verschiedenen Neuronentypen sein. CB1 Rezeptoren in glutamatergen und GABAergen Neuronen sind hier besonders wichtig, da die entsprechenden Neurotransmitter als Gegenspieler die neuronale Erregung kontrollieren. Spezifische Deletion des CB1 Rezeptor-Gens von einer der beiden Populationen führte zu gegensätzlichen Phenotypen, genauer gesagt, einem erniedrigten, bzw. einem gesteigerten Interaktiondrang. Tiere, bei denen der CB1 Rezeptor ausschließlich in striatalen, GABAergen „Medium Spiny“ Neuronen deletiert wurde, zeigten keinen veränderten Phänotyp. Dies legt nahe, dass der CB1 Rezeptor in kortikalen glutamatergen und GABAergen Neuronen für einen ausgeglichenen Interaktionsdrang entscheidend ist (siehe Kapitel 3).rnDiese dosisabhängigen, biphasischen Effekte auf das Verhalten können auch im „Forced Swim Test“ (FST) beobachtet werden. Ein möglicher Mechanismus, durch den Cannabinoide das Stressverhalten beeinflussen können, wäre die Regulierung der Monoaminausschüttung. Um die Abhängigkeit der Cannabinoideffekte von der Serotonintransmission zu untersuchen, wurden Dosen von CB1 Rezeptoragonisten und –antagonisten mit antidepressiv-induzierenden Eigenschaften bei gleichzeitiger Inhibition der Serotonintransmission im FST getestet. Die Ergebnisse zeigten, dass lediglich der Agonisteffekt durch die Inhibition der Serotoninauschüttung beeinflusst wird. Zusätzlich konnte die Abhängigkeit des Antagonisteneffekts von funktionsfähigen GABAergen CB1 Rezeptoren nachweisen werden. Interessanter Weise konnte der durch die Deletion von glutamatergen CB1 Rezeptoren induzierte Phänotyp durch Inhibition der Serotoninausschüttung blockiert werden (siehe Kapitel 4).rnEin indirekter Einfluss auf Serotoninausschüttung scheint also wahrscheinlich zu sein. Bis jetzt blieb jedoch unklar, inwieweit cannabinerge Substanzen direkt auf serotonerge Neuronen wirken können. Im Jahr 2007 konnte unsere Gruppe die Expression des CB1 Rezeptors in serotonergen Neuronen auf mRNA- und Proteinebene nachweisen. Die Züchtung und Analyse einer mutanten Mauslinie, in welcher der CB1-Rezeptor spezifisch in serotonergen Neuronen ausgeschaltet wurde, zeigte bei männlichen Tieren eine schwache, aber signifikante Verhaltensänderungen, die durch soziale Stimuli und lebensbedrohlichen Situationen ausgelöst wurde. So ist es erstmals gelungen nachzuweisen, dass serotonerge CB1-Rezeptoren eine physiologische Relevanz besitzen (siehe Kapitel 5).rn

Charge separation and recombination in novel polymeric absorber materials for organic solar cells : a photophysical study

In dieser Dissertation wird die Ladungsträgergeneration und -rekombination in neuen polymeren Absorbermaterialien für organische Solarzellen untersucht. Das Verständnis dieser Prozesse ist wesentlich für die Entwicklung neuer photoaktiver Materialsysteme, die hohe Effizienzen erzielen und organische Solarzellen konkurrenzfähig im Bereich der erneuerbaren Energien machen. Experimentell verwendet diese Arbeit hauptsächlich die Methode der transienten Absorptionsspektroskopie, die sich für die Untersuchung photophysikalischer Prozesse auf einer Zeitskala von 100 fs bis 1 ms als sehr leistungsfähig erweist. Des Weiteren wird eine soft-modeling Methode vorgestellt, die es ermöglicht, photophysikalische Prozesse aus einer gemessenen transienten Absorptions-Datenmatrix zu bestimmen, wenn wenig a priori Kenntnisse der Reaktionskinetiken vorhanden sind. Drei unterschiedliche Donor:Akzeptor-Systeme werden untersucht; jedes dieser Systeme stellt eine andere Herangehensweise zur Optimierung der Materialien dar in Bezug auf Lichtabsorption über einen breiten Wellenlängenbereich, effiziente Ladungstrennung und schnellen Ladungstransport. Zuerst wird ein Terpolymer untersucht, das aus unterschiedlichen Einheiten für die Lichtabsorption und den Ladungstransport besteht. Es wird gezeigt, dass es möglich ist, den Fluss angeregter Zustände vom Chromophor auf die Transporteinheit zu leiten. Im zweiten Teil wird der Einfluss von Kristallinität auf die freie Ladungsträgergeneration mit einer Folge von ternären Mischungen, die unterschiedliche Anteile an amorphem und semi-kristallinem Polymer enthalten, untersucht. Dabei zeigt es sich, dass mit steigendem amorphen Polymeranteil sowohl der Anteil der geminalen Ladungsträgerrekombination erhöht als auch die nicht-geminale Rekombination schneller ist. Schlussendlich wird ein System untersucht, in dem sowohl Donor als auch Akzeptor Polymere sind, was zu verbesserten Absorptionseigenschaften führt. Die Rekombination von Ladungstransferzuständen auf der unter 100 ps Zeitskala stellt hier den hauptsächliche Verlustkanal dar, da freie Ladungsträger nur an Grenzflächen erzeugt werden können, an denen Donor und Akzeptor face-to-face zueinander orientiert sind. Darüber hinaus wird festgestellt, dass weitere 40-50% der Ladungsträger durch die Rekombination von Grenzflächenzuständen verloren gehen, die aus mobilen Ladungsträgern geminal gebildet werden.