Thesis (Ph.D.)--University of Kansas, 1997. / Co-Chairs: Chu-tsing Li; Marsha Weidner. Includes bibliographical references.

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La résonance magnétique nucléaire est une technique de choix pour étudier la dynamique de l'échange dans des composés à portée thérapeutique. Cependant, les spectres acquis avec les méthodes 1D et 2D classiques présentent souvent des recouvrements importants, ce qui rend l'attribution de chaque espèce en échange difficile. Le développement méthodologique d'une approche pure shift permettrait donc d'améliorer la résolution de ces données. Au cours de cette thèse, nous avons effectué une série de développements méthodologiques des expériences de type EXSY dans lesquelles nous avons mis en œuvre différentes méthodes de découplage homonucléaire. En particulier, deux approches ont été testées: la méthode PSYCHE appliqué aux dimensions F1 et F2 des cartes EXSY, et la méthode Zangger-Sterk en F2. Ces approches ont toutes mené à une amélioration significative de la résolution qui nous a permis de caractériser les deux conformères s-cis/s-trans du Trandolapril. Nous avons également étudié l’intérêt de la technique d'échantillonnage non-uniforme (NUS) du signal pour réduire le temps d'analyse. Cette approche nous a permis de gagner en temps d'analyse, mais la présence d'artefacts à certaines températures suggère que d'autres développements seront encore nécessaires. Ces résultats ouvrent la voie vers une analyse plus fine du processus d’échange dans des composés présentant un spectre RMN complexe. / Nuclear magnetic resonance is a technique of choice for studying chemical exchange in therapeutic compounds. However, spectra acquired with standard 1D and 2D methods often show spectra with overlapping signals, which makes the assignment of each species difficult. Methodological development of a pure shift approach would therefore make it possible to improve the resolution of these data. During this thesis, we carried out a series of developments of the EXSY type experiments in which we implemented different homonuclear decoupling methods. Two approaches were tested: the PSYCHE method applied to the F1 and F2 dimensions of EXSY maps, and the Zangger-Sterk method in F2. These approaches all led to a significant resolution improvements allowing us to characterize the s-cis/ s-trans conformers in Trandolapril. We have also studied the interest of the non-uniform sampling (NUS) technique to reduce the analysis time. This approach allowed us to accelerate the experiment, but the presence of artifacts at various temperatures suggests that further developments will still be needed. These results pave the way for more analysis of the exchange process in compounds with complex NMR spectrum.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

The aim of this master thesis is to analyze the role of the concept of pure intentional object in aesthetics of Roman Ingarden. This analysis allows to avoid the problem of traditional aesthetical intepretations of Ingarden's maybe most important aesthetical work called The Literary Work of Art, in which this important work become a rupture in the whole of Ingarden's work.

O principal problema desta tese é a aplicação da teoria psicoacústica sobre percepção de dissonância em novas ferramentas de computação musical em tempo real. Os objetivos e contribuições incluem: Prover uma revisão critica do Estado da Arte em teoria psicoacústica de modelos de dissonância, projetar trabalhos futuros; Explorar um potencial criativo negligenciado de modelos psicoacústicos de dissonância em Eletrônica ao Vivo; Desenvolver novas ferramentas computacionais baseadas na teoria; Investigar o potencial e limitações da teoria e técnicas. Discutir sua pertinência e impacto; Tornar a teoria e técnicas mais acessíveis a músicos por meio deste texto e as ferramentas desenvolvidas. A percepção de Dissonância é um fenômeno complexo em que a abordagem psicoacústica cobre apenas uma porção. Além disso, ainda há muito debate na área da psicoacústica sobre o desenvolvimento de modelos de dissonância. Portanto, a tese apresenta uma revisão crítica do Estado da Arte da teoria psicoacústica, apontando pontos fracos e fortes do atual conhecimento, e futuros desenvolvimentos no campo. Um teste perceptivo também foi elaborado para gerar ponderações relevantes. Os modelos foram implementados em Pure Data, e uma série de patches foi desenvolvida para testar o potencial criativo em eletrônica ao vivo. Esse processo culminou em um sistema desenvolvido em Pure Data que agrega diversas das técnicas baseadas nos modelos psicoacústicos. Suas possibilidades incluem, por exemplo, encontrar intervalos consonantes de acordo com um espectro, ou alterar componentes espectrais para que estejam de acordo com uma escala musical ou afinação particular. Essas ferramentas foram empregadas em um duo de improvisação livre com o autor e um saxofonista. O autor também compôs uma peça orquestral que utilizou o sistema desenvolvido na parte de eletrônica ao vivo. / The problem of this research is to apply the state of the art in psychoacoustic theories about dissonance perception in the development of novel creative computer music tools for composition and live electronics. Goals and contributions include: To provide a critical review of the State of the Art in Psychoacoustic theory regarding dissonance modeling, project further work; To explore neglected creative potential of psychoacoustic dissonance models in Live Electronics; To develop novel computer music tools based on the theory; To investigate the potential and limitations of the theory and techniques; To discuss its creative musical impact and pertinence; To make the theory and techniques more accessible to musicians through the text and the free developed tools. The perception of Dissonance is a complex phenomenon in which the psychoacoustical approach covers just a portion thereof. Not only that, but psychoacoustic theory is still in debate about the development of dissonance models. Therefore, the thesis provides a critical review of the state of the art in psychoacoustic theory, pointing out weaknesses and strong points of the current knowledge, and future developments in the field. A perceptual test was also designed to generate data for relevant insights. Apart from the theoretical review, the models were implemented in Pure Data, and a series of patches was developed in order to test their creative potential in Live Electronics. This culminated in a system developed as a Pure Data Patch that aggregates several techniques based on the psychoacoustic models. Their possibilities include, for example, finding consonant intervals according to a spectrum, or altering spectral components so they are in accordance to musical intervals and particular tunings. These tools were used in a Free Improvisation duo with the author and a sax player, and the author also composed an orchestral piece that applied the developed system in the Live Electronics section.

The work described in this thesis aims at facilitating the design and im- plementation of web-based editors, driven by speech or natural language input, with a focus on editing mathematics. First, a taxonomy for system architectures of speech-based applications is given. This classification is based on the location of the speech recognition, the speech, and application logic and the resulting flow of data between client and server components. This contribution extends existing system architecture approaches to take into account the characteristics of speech- based systems. We then show, using statistical language modelling techniques, that math- ematics, either spoken or typed, is more predictable than everyday natu- ral languages. We illustrate how these models, in combination with error correction algorithms, can be used to successfully assist the process of cre- ating mathematical expressions within electronic documents using speech. We have successfully implemented systems to demonstrate our findings, which have also been evaluated using standard language modelling evalua- tion techniques. This work is novel as applying statistical language models to the recognition of spoken mathematics has not been evaluated to this extent prior to our work. We create a parsing framework for spoken mathematics, based on mixfix operators, operator precedences and non-deterministic parsing techniques. This framework can significantly improve the design and parsing of spoken command languages such as spoken mathematics. A novel robust error recovery method for an adaptation of the XGLR parsing approach to our operator precedence setting is presented. This greatly enhances the range of spoken or typed mathematics that can be parsed. The novel parsing framework, algorithms and error recovery that we have designed are suitable for more general structured spoken command languages, as well. The algorithms devised in this thesis have been implemented and integrated in a research prototype system called TalkMaths. We evaluate our contri- butions to the new version of this system by comparing the power of our parser with that contained in previous versions, and by conducting a field study where students engage with our system in a real classroom-based environment. We show that using TalkMaths, rather than a conventional mathematics editor, had a positive impact on the learning and understand- ing of mathematical concepts of the participants.

Tryptases are trypsin-like enzymes found in mast cell granules. Although in vivo substrates have not been positively identified, tryptases cleave a limited number of potential physiological substrates in vitro, including high molecular weight kininogen (HMWK) and vasoactive intestinal peptide (VIP). Purified human lung mast cell tryptase (HLT) apparently exists as a tetramer with an M$\sb{\rm r}$ of 135-144 kDa by gel filtration, whereas SDS-PAGE yielded two bands of M$\sb{\rm r}$ 29 Kda and 33 Kda. Tryptases are resistant to inhibition by most natural trypsin inhibitors and display some affinity for heparin. The existence of tryptase isozymes has been implied from the cloning of two tryptase cDNAs from human lung tissue, but distinct isozymes have not been isolated and characterized. This knowledge gap has been filled by isolating and characterizing two electrophoretically different forms of human lung mast cell tryptase, designated high-HLT (high molecular weight HLT) and low-HLT (low molecular weight HLT). These two forms of HLT have been separated by chromatography on a cellulose phosphate column, with the high M$\sb{\rm r}$ form eluting with 10 $\mu$M heparin and the low M$\sb{\rm r}$ form subsequently eluting with 1 M NaCl. Using HMWK and VIP as substrates, these two forms of HLT were found to differ with regard to specificity and rate of cleavage. High-HLT initially cleaved HMWK at a single Arg residue, whereas low-HLT cleaved HMWK simultaneously at multiple sites. Both isozymes cleaved VIP at multiple sites, but differed with regard to the preferential site of cleavage. Low-HLT was, on an active site basis, 25 and 2 times more active than high-HLT on HMWK and VIP, respectively. In addition, gel filtration of the isozymes yielded M$\sb{\rm r}$s of 125 Kda for high-HLT and 28 kDa for low-HLT, indicating tetrameric and monomeric quaternary structures, respectively. Both isozymes were inhibited by human secretory leukocyte proteinase inhibitor (SLPI), but not by other trypsin inhibitors tested. This work provides the first evidence for the existence of distinct tryptase isozymes, with supposedly different in vivo functions, and identification of an inhibitor that may control tryptase activity in vivo.

Nitrogen dioxide (NO$\sb2$), an air pollutant produced by burning fossil fuels and a component of cigarette smoke, is thought to contribute to the pathogenesis of pulmonary diseases, such as emphysema. To gain information on the mechanism by which NO$\sb2$ damages the lung, in vitro exposures of $\alpha\sb1$-proteinase inhibitor ($\alpha\sb1$-PI), elastin, bovine serum albumin (BSA), human serum albumin (HSA) and synthetic poly-L-lysine were performed. A genetic deficiency of $\alpha\sb1$-PI predisposes humans to emphysema and NO$\sb2$ has been hypothesized to damage $\alpha\sb1$-PI, which would leave proteases such as human neutrophil elastase, (HNE) free to attack lung structural proteins. The ability of $\alpha\sb1$-PI to inhibit HNE declined with exposure to 50% of the control value at molar ratios of NO$\sb2$:$\alpha\sb1$-PI of 400:1 and greater. Exposure of $\alpha\sb1$-PI to NO$\sb2$ resulted in a 50% loss of immunoreactivity with either monoclonal or polyclonal antibodies in an enzyme-linked immunosorbent assay at molar ratios of NO$\sb2$:$\alpha\sb1$-PI of essentially 100:1 and greater. The mechanisms of these effects were investigated via ultraviolet-visible spectroscopy and amino acid analysis. The remaining target molecules were labeled by reductive methylation of amino groups with $\sp3$H-HCHO prior to treatment with NO$\sb2$ in aqueous solutions at physiological pH. Time course exposure of 5 mg $\sp3$H-insoluble bovine ligamentum nuchae elastin suspensions with up to 120 $\mu$moles of NO$\sb2$ resulted in 90% solubilization of the label. Amino acid analysis of the soluble and insoluble fractions from these exposures confirmed that 80% of the $\sp3$H-dimethyllysine residues were in the soluble fraction. Since these results suggested a specific reactivity of NO$\sb2$ with lysine residues, 400 $\mu$g $\sp3$H-poly-L-lysine was exposed to 120 $\mu$moles NO$\sb2$. Gel filtration chromatography revealed that the 50,000 M$\sb{\rm r}$ $\sp3$H-poly-L-lysine had been degraded to small peptides of 1-3,000 M$\sb{\rm r}$. Similar exposures were conducted using $\sp3$H-BSA and $\sp3$H-HSA, followed by gel filtration chromatography and SDS-PAGE with fluorography. The results suggest that NO$\sb2$ preferentially reacts with Lys-Lys or other specific sequences, resulting in peptide bond cleavage. Under the conditions used, 23% of the BSA tyrosine residues were nitrated and aggregates of HSA indicative of bityrosine cross-link formation were observed. These findings are the first indication that NO$\sb2$ can cause protein fragmentation and provide additional data on the potential of NO$\sb2$ to damage lung proteins, such as elastin.

A novel 0.6 kb LINE family in human DNA, designated L2Hs, has been described (Musich and Dykes 1986). Studies employing clone N6.4, containing three 0.6 kb segments of this family, indicate that these sequences are interspersed and moderately repetitive. Two additional variant sequences of the L2Hs family, N6.1 and N6.3, have been identified. Restriction mapping of each cloned segment indicates similarities among N6.4, N6.3 and N6.1. When the cloned DNAs were cleaved with restriction enzymes and subjected to cross-hybridization, each cloned insert produced a pattern indicating that the sequences contained in N6.1 and N6.3 are represented in at least one of the three 0.6 kb segments within the clone N6.4. Hybridization of human genomic DNA digested with KpnI or KpnI+AccI reveals differences in nuclear organization for these segments. For any particular human DNA, the hybridization patterns for each of the three probes overlap. However, these differences indicate that the inserts in N6.1 and N6.3 and one of the N6.4 inserts each represents a subset of the L2Hs LINE family. Sequence analysis of N6.1 indicates that the probability of a functional translation product from N6.1 transcript is not high. The sequence contains stop and nonsense codons in all reading frames. However, the DNA has properties suggesting a structural, non-coding role. The N6.1 sequence contains 11 regions of alternating purine and pyrimidines which can affect the three dimensional structure and, therefore, the structural behavior of the molecule. In addition, putative binding regions for microtubule-associated proteins have been identified. A cloned variant of the XbaI family of repetitive DNAs, PuHu7, was identified. Studies of its genomic organization showed a tandem arrangement similar to other, previously described members of this family. The genomic organization of a previously undescribed repetitive DNA family is also reported. This family descriptor is the clone PuHu26. Hybridization of genomic DNA digested with HindIII showed that sequences homologous to PuHu26 are tandemly organized. Genomic DNA cleaved with EcoRI revealed that a subpopulation of the PuHu26 family contains EcoRI restriction sites spaced at multiples of approximately 172 bp.