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Diese Dissertation führt den Beweis, dass Sprechaktbezug nicht anaphorischer, sondern deiktischer Natur ist, und stellt ein formales Modell für denselben vor. Korpusdaten in gesprochenem Deutsch und Daten aus Fernseh-Talkshows zeigen, dass man sich nur mit demonstrativen Ausdrücken auf Sprechakte beziehen kann. Zusätzlich unterstützen zwei Experimente die Beobachtung, dass Sprechaktbezüge nicht mit Personalpronomen getätigt werden. Nur selten lassen Muttersprachler des Deutschen ein gegebenes Personalpronomen auf einen Sprechakt referieren, und nur selten wählen sie das Personalpronomen, um sich auf einen gegebenen Sprechaktreferenten zu beziehen. Die klare Präferenz liegt beim Demonstrativum. Um auf Entitäten außerhalb des Diskurses zu referieren, nutzt man im Deutschen Demonstrativ-, nicht aber Personalpronomen. Dementsprechend sollten Sprechakte als Ereignisse im Äußerungskontext und nicht als Teil von sprachlicher Form und Bedeutung aufgefasst werden. Bestehenden Diskurstheorien mangelt es an einer Unterscheidung zwischen Anaphern und Deixis, während umgekehrt Theorien über sprachliche Bezüge sich nicht mit Sprechakten beschäftigen. Segmented Discourse Representation Theory (SDRT) integriert nicht-sprachliche Objekte als Diskursreferenten in die Diskursstruktur, was auch für Sprechakte gilt. Dieser Umstand erlaubt allerdings Anaphern auf Sprechakte. Da sich schwach referentielle Ausdrücke wie Personalpronomen nicht auf Sprechakte beziehen können, muss die Ontologie von Sprechakten in SDRT überdacht werden. Hier wird eine SDRT-Variante vorgestellt, die als Diskursmodell zwei Informationsquellen umfasst, nämlich a) semantische Äußerungsinhalte und b) die physische Umgebung der Gesprächsteilnehmer (d.h. ihre "joint attention"), dargestellt als zwei DRSen. Das Modell unterscheidet systematisch zwischen anaphorischem und deiktischem Bezug und dadurch auch zwischen Bezug auf sprachlichen Inhalt und auf sprachliche "Behältnisse": Sprechakte. / This dissertation provides evidence that reference to speech acts is deictic, not anaphoric, and furthermore introduces a formal model of speech act reference. Corpus data from spoken German as well as observed data from German TV talk shows demonstrates that speech acts are exclusively referred to by demonstrative expressions. Additionally, new experimental evidence supports this observation and shows that speech acts are not referred to by personal pronouns. German native speakers rarely make given personal pronouns refer to a speech act, nor do they decide for a personal pronoun to refer to a given speech act referent when forced to choose between personal and demonstrative pronouns. Demonstratives are strongly preferred. In German, demonstrative pronouns rather than personal pronouns are used to refer to objects external to the discourse. Consequently, speech acts should be modeled as events in the utterance context rather than as parts of linguistic form and meaning. Existing theories of discourse structure lack a distinction between anaphora and deixis, while theories of reference do not integrate the concept of a speech act. Segmented Discourse Representation Theory (SDRT) introduces non-linguistic entities in discourse structure. This includes speech acts, which are introduced as discourse referents, which in return predicts anaphoric reference to speech acts. Since reference to speech acts with weak expressions like personal pronouns does not occur, the status of speech acts in SDRT must be redefined. As variant of SDRT, I propose a discourse model that comprises the two information sources of a) semantic content of utterances and b) immediate physical environment of the interlocutors (i.e. their joint attention), which are represented as a pair of DRSs. This model systematically distinguishes between anaphora and deixis, and therefore between reference to linguistic content and reference to linguistic containers: speech acts.

Taxol (1) was first isolated from the bark of the Pacific yew about 35 years ago by Drs. Wall and Wani. Although its development as an anticancer agent was delayed by numerous reasons, including its scarcity and insolubility, the discovery of its tubulin-assembly activity and other factors motivated oncologists to overcome these problems. It has since become one of the most important current drugs for the treatment of several cancers, including breast and ovarian cancers. Like almost all anticancer drugs taxol does have some toxic side effects and many tumors also show significant resistance to therapy with taxol. Drug targeting studies aimed at improving its selectivity and efficacy is described. Two targeting methods, the estrogen receptor (ER) directed targeting and colloidal gold (cAu)directed targeting, were used in our research. In this dissertation, a series of estradiol-taxol conjugates (ETCs) were synthesized. They were active in four cytotoxicity assays and tubulin polymerization assay, but less active than taxol. One of them showed the desired selectivity for ER positive cancer cells. Recently, several studies have attempted to elucidate the bioactive binding conformation of taxol on microtubules. Three models have been proposed for this conformation. The T-taxol conformation was proposed by Dr. Snyder based on electron crystallographic density and molecular modeling. In this dessertation, a series of cyclopropyl-containing taxol analogs and macrocyclic taxol lactones were synthesized. The bioassay results showed they are less active than taxol. The molecular modeling studies suggested that the cyclopropyl-containing taxol analogs could not adopt the T-taxol conformation, which would result in the loss of bioactivities. It is an indirect evidence to support T-taxol conformation. As for macrocyclic taxol lactones, it is proposed that they would have a close contact between the ester moiety on the C-3' phenyl ring and Phe272 of the β-tubulin protein when they adopt T-taxol conformation. It will push the macrocyclics out of the binding pocket and lead to the lost of bioactivities. / Ph. D.

Cornichon (CNI) proteins are a conserved family of proteins among eukaryotes, from Erv14 in the yeast Saccharomyces cerevisiae to CNI homologs (CNIHs) in mammals and plants. Erv14 functions as a cargo receptor of coat protein complex II (COPII) for protein trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus, en route to their final destinations. By interacting with specific cargo proteins, CNI proteins regulate key steps of embryo polarity in Drosophila, budding in yeast, and synaptic transmission in the mammalian brain. However, we have very limited understanding of plant CNIHs. Positive-strand RNA viruses assemble their viral replication complexes (VRCs) at specific host organelle membranes. With a better understanding of host factors involved in targeting viral replication proteins to the preferred organelles, we expect to block trafficking of viral replication proteins and thus, viral infection, by manipulating the required host proteins. Brome mosaic virus (BMV) is a model of positive-strand RNA viruses and its replication can be recapitulated in yeast. Importantly, BMV replication protein 1a is the only required viral protein to form VRCs at the perinuclear ER membrane in yeast. I demonstrate that Erv14 and COPII coat proteins are required for targeting BMV 1a to the perinuclear ER in yeast, suggesting a novel function of COPII vesicles in protein trafficking to the perinuclear ER membrane and in the BMV VRC formation. As for cellular functions, I show that plant CNIHs complement the defective distribution of BMV 1a in yeast mutant lacking Erv14. Taking advantage of Arabidopsis thaliana knockout mutants and knockdown of gene expression in Nicotiana benthamina, I also discover that CNIHs unexpectedly play crucial roles in pollen development, infection of a bacterial pathogen, and maintenance of ER tubules. I further confirm that CNI proteins are also required for maintaining ER tubules in yeast, suggesting a novel and conserved role in shaping ER morphology. Therefore, these findings indicate the functional diversity and redundancy of CNI proteins in key cellular processes and suggest a novel strategy to control plant pathogenic viruses and bacteria by manipulating plant CNIHs. / Ph. D.

Das Wortlernen begleitet unser Leben von der Kindheit bis ins Alter. Kleinkinder lernen ihre Muttersprache(n), aber auch Erwachsene lernen neue Wörter, z.B. beim Fremdspracherwerb. Unter gewissen Umständen muss eine neue Sprache wieder erlernen werden, wie z.B. nach einer Gehirnläsion. Wie meistert unser Gehirn diese herausfordernden Wortlernsituationen? Um die Neuroplastizität des Wortlernens zu untersuchen, wurden unterschiedliche neurowissenschaftliche Methoden (Elektroenzephalographie, funktionelle Nahinfrarotspektroskopie, voxel-basierte Läsion-Verhalten/EEG Mapping), teilweise in Kombination, bei Kleinkindern, Kindern und Erwachsenen sowie Patienten mit einer Gehirnläsion im Vergleich zu älteren Kontrollprobanden angewendet. 5 Experimente untersuchten die neuronale Verarbeitung von Pseudowörtern, welche mutter- und fremdsprachlichen phonotaktischen Regeln (d.h. die Kombination von verschiedenen Phonemen) folgten, in unterschiedlichen Lernsettings bei monolingualen Teilnehmern. Gesunde Erwachsene aber auch 6monatige und ältere Teilnehmer und Patienten konnten diese Regeln differenzieren. Beteiligte Gehirnareale umfassten ein links-hemisphärisches fronto-temporales Netzwerk. Die Verarbeitung universeller Spracheigenschaften, andererseits, zeigte sich in parietalen Regionen. Während Erwachsene eine klare Dominanz der linken Hemisphäre aufwiesen, nutzten 6monatige noch beide Gehirnhälften. Unterschiedliche Sprachtrainings (semantische Trainings oder Passives Zuhören) an drei aufeinanderfolgenden Tagen veränderten auch die Gehirnaktivität der Kleinkinder und der Erwachsenen und wiesen auf eine erhöhte Lernflexibilität hin. Im 6. Experiment lernten 5jährige bilinguale Kinder anhand pragmatischer Eigenschaften neue Adjektive und zeigten effizientere neuronale Mechanismen als Monolinguale. Die Ergebnisse unterstreichen die Wichtigkeit multi-methodologischer Ansätze, um genauere Einblicke in die komplexen Mechanismen der Neuroplastizität zu erlangen. / Word learning accompanies our everyday life from infancy to advanced age. Infants have to learn the native language(s) but also during adulthood word learning can take place, for example if we learn a new foreign language. Sometimes people are confronted with a situation in which they have to re-learn a language because of a brain lesion. How does the brain master these challenging word learning settings? To assess neuroplasticity of word learning several neuroscientific methods (electroencephalography, functional near-infrared spectroscopy, voxel-based lesion-behavior/EEG mapping), partially in combination, were used in infants, children, and adults as well as in patients suffering from a brain lesion compared to matched elderly controls. In 5 experiments neuronal processing of pseudowords corresponding to native and non-native phonotactic rules (i.e., the combination of different phonemes) was investigated under different learning conditions in monolingual participants. Healthy adults but also 6-month-old infants and elderly subjects and patients were able to differentiate these rules. Involved brain areas included a left-hemispheric network of fronto-temporal regions. When processing universal linguistic features, however, more parietal regions were involved. While adults revealed a clear left-dominant network, 6-month-olds still recruited bilateral brain areas. Differential language trainings (semantic or passive listening trainings) over three consecutive days also modulated brain activation in both infants and adults suggesting a high flexibility for learning native and non-native linguistic regularities. In a 6th experiment, bilingual 5-year-old children learned novel adjectives by means of pragmatic cues and revealed more efficient neuronal mechanisms compared to monolingual children. Findings underline the importance of multi-methodological approaches to get clearer insights into the complex machinery of neuroplasticity.

In the first chapter, a Q-switched fiber laser that is capable of generating transform-limited pulses based on single-frequency fiber laser seeded ring cavity is demonstrated. The output pulse width can be tuned from hundreds of nanoseconds to several microseconds. This Q-switched ring cavity fiber laser can operate over the whole C-band. In addition, a theoretical model is developed to numerically study the pulse characteristics, and the numerical results are in good agreements with the experimental results. In the next chapter, a Raman fiber laser is developed for generating signal at 1480 nm. Initial experimental results has demonstrated generating of Raman laser at 1175 nm, 1240 nm, 1315 nm, and 1395 nm wavelength. Finally, a free space fiber amplifier is studied both theoretically and experimentally. The experimental work has demonstrated signal coupling efficiency up to 90% in the NP highly Er/Yb co-doped phosphate fiber.

Cytochrome P450 enzymes (P450s) are involved in cancer development and treatment due to their roles in the oxidative metabolism of various endogenous (e.g. oestrogen) and exogenous (e.g. tamoxifen) compounds. It is well-known that intermediate P450 metabolites derived from oestrogen metabolism are associated with breast carcinogenesis. The main aim of this project was to profile the cytochrome P450 and P450-regulatory nuclear receptor mRNAs in a series of breast cancer cell lines (BCCs) and compare this profile with normal breast cells. This study used the qualitative reverse transcriptasepolymerase chain reaction (RT-PCR) to detect mRNA expression of target genes. Results showed CYP1B1, CYP2D6, CYP2J2, CYP2R1, CYP2U1 and CYP4X1 mRNA to be present in all cell lines. CYP2A6, CYP2C8, CYP2C18, CYP2F1 and CYP4Z1 mRNA were expressed in oestrogen receptor (ER)-positiveCaucasian and ER-negative Afro- Caribbean BCCs. Although no differences in P450 mRNA were observed between the different ethnic groups, these preliminary findings suggest potential similarities in the ERpositive Caucasian and ER-negative Afro-Caribbean BCCs which warrant further investigation The CYP4Z1 PCR product was identified as two distinct bands. Specific primer sets were used to demonstrate potential intron retention in CYP4Z1. Using established in vitro models for the study of regulatory mechanisms of CYP4Z1, T47D and ZR-75-1 breast cancer cell lines were used to determine the appropriate nuclear receptors (i.e. progesterone receptor, glucocorticoid receptor or peroxisome proliferator-activated receptor alpha ). These findings suggest that there may be an alternative receptor mechanism involved in CYP4Z1 mRNA induction in these cells. In conjunction, pre-treatment of these two cell lines with the RNA synthesis inhibitor actinomycin D followed by the agonists showed a significant reduction (p < 0.05) of CYP4Z1 mRNA levels and inhibited CYP4Z1 induction by either progesterone, dexamethasone or pirinixic acid, indicating that these agonists have effects on CYP4Z1 mRNA transcription or stability. In contrast, cycloheximide differentially affected the level of CYP4Z1 mRNA induction by these agonists. Taken together, these results suggest that CYP4Z1 mRNA induction in T47D and ZR-75-1 is mediated through differential cell type specific regulatory mechanisms and there is evidence for differential regulation of the splice variants.