No description available.

This work presents the application of spiroligomers as inhibitors of protein-protein interactions. After the discovery of an acyl-transfer coupling reaction by Dr. Zachary Brown, a previous graduate student of Schafmeister group, the synthesis of highly functionalized spiroligomers that mimic the helical domain of p53 was undertaken before each molecule was tested for binding to HDM2, a natural binding partner of p53. A library of molecules was synthesized on solid support that altered the stereochemistry along the spiroligomer as well as the presented functional groups. It was determined that spiroligomers enter human liver cancer cells through passive diffusion and induces a biological response in both a dose- and time-dependent manner. The synthesis of additional spiroligomer analogues achieved low micromolar to high nanomolar range activity during screening in direct and competitive binding assays. In parallel to the project above, a series of spiroligomers that mimic the side chains of the leucine zipper region of Max were synthesized in an effort to disrupt the interaction of the protein with c-Myc. The series of compounds contained various stereocenter combinations and different functional groups as before but were made in solution before testing for inhibition. Initial binding assays resulted in low micromolar activity, however, secondary assays (ELISA and cellular assays) did not confirm the inhibitory effect of spiroligomers on the c-Myc/Max heterodimer. In summary, this work illustrates that spiroligomers are capable mimics of helical peptides and can induce a biological response. / Chemistry

Relying on the perspectives of critical disability studies and mad studies, this graduate thesis seeks to uncover the experiences of youth with undiagnosed mental health issues who have been streamed into alternative education. Guided by methodological principles of interpretive phenomenological analysis and arts-informed inquiry, the 5 participants in this study were invited to a focus group where they could engage in an arts-based activity, meant to provide the opportunity to reflect on their experience, build rapport with the researcher, express themselves through alternative means, and connect with peers who have shared experience. Participants were then invited to discuss their experiences with the topic in a one-on-one, semi-structured interview. This study reveals the ways in which the system of education, school communities, teachers, and social workers can support youth who are not diagnosed with a mental illness but still experience mental health challenges that impede on their school experience. Supported by mad studies, this study reveals how peer support has become the method of mental health response and treatment through which students feel is most effective. This study also challenges medical hegemony and the ways in which access to services is dependent on medical diagnoses. Finally, this study reminds stakeholders of the value of building trusting and empathic relationships between school staff and students. School communities and school boards are challenged to think about the structuring of their systems, and the ways in which they may present barriers to the success of all students regardless of ability and/or need. / Thesis / Master of Social Work (MSW)

No description available.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Xylopia nitida and Xylopia sericea are commonly known as âembira-brancaâ and âpimenta do sertÃoâ, respectively, belonging to Annonaceae family. The chromatographic analysis of X. nitida roots allowed isolation of a trachlyobane diterpene, ent-trachlyoban-18,19-diol and its acetylated product, ent-18,19-diacetoxy-trachylobane, a kaurene diterpene, ent-kaur-16-en-18,19-diol, two aporphinic alkaloids, 5,6,6a,7-tetrahydro-1-methoxy-(6aS)-4H-benzo[de][1,3]benzodioxolo[5,6-g]quinoline e xylopine, and a glucoside, named 1-O-ethyl-β-D-glucopiranose. Also using chromatographic analysis of X. sericea fruits were obtained a kaurane diterpene, kauran-16β-ol and a diterpenes mixture, ent-kaur-16-en-19-oic acid and beyer-15-19-oic acid. The structures of these compounds were elucidated by spectroscopic studies (IR, MS and NMR). In the second part of this work, has been showed the diffusion-ordered spectroscopy (DOSY) as a powerful tool in natural product mixture analysis. The assignment of NMR signals to specific components in a mixture is a challenging task. DOSY has provided important progress in this area, allowing the signals originating from individual components of different molecular sizes to be distinguished. However, when the sizes of the compounds are similar and/or the spectra are overlapped, signal assignment can easily become intractable. The use of a co-solute in a matrix-assisted DOSY (MAD) experiment can be a useful solution, improving diffusional (and sometimes spectral) resolution by exploiting selective binding to the matrix. The challenge is to apply MAD to molecules with high structural similarity, for example in natural product mixtures. Various surfactants, including SDS, AOT and CTAB have previously been shown to be effective in MAD analysis. Here we present an important addition, the Brij family of nonionic surfactants. We demonstrate the use of Brij micelles and other systems in mixed solvents with a variety of mixtures relevant to natural products. / Xylopia nitida e X. sericea, conhecidas popularmente como embira-branca e pimenta do sertÃo, respectivamente, sÃo espÃcies pertencentes à famÃlia Annonaceae. A anÃlise cromatogrÃfica dos extratos hexÃnico e etanÃlico das raÃzes de X. nitida possibilitou o isolamento de um diterpeno de esqueleto traquilobano, ent-traquiloban-18,19-diol e seu derivado acetilado, ent-18,19-diacetÃxi-traquilobano, um diterpeno de esqueleto caureno, ent-caur-16-en-18,19-diol, dois alcalÃides aporfÃnicos, 5,6,6a,7-tetraidro-1-metoxi-(6aS)-4H-benzo[de][1,3]benzodioxolo[5,6-g]quinolina e xylopina e um glicosÃdeo, 1-O-etil-β-D-glicopiranose, todos de carÃter inÃdito na literatura, exceto os dois Ãltimos. AtravÃs da anÃlise cromatogrÃfica do extrato hexÃnico dos frutos de X. sericea foi possÃvel obter um diterpeno de esqueleto caurano denominado cauran-16β-ol e uma mistura de diterpenos, Ãcido ent-caur-16-en-19-Ãico e Ãcido beier-15-en-19-Ãico. O isolamento dos constituintes quÃmicos presentes nos extratos da raiz e frutos de X. nitida e X. sericea, respectivamente, foi realizada por mÃtodos cromatogrÃficos convencionais e a determinaÃÃo estrutural das substÃncias isoladas foi realizada a partir de mÃtodos espectromÃtricos como: IV, EM, RMN 1H, 13C e DEPT 135 incluindo tÃcnicas bidimensionais como, COSY, HSQC e HMBC. A primeira parte deste trabalho relata o estudo quÃmico das raÃzes de X. nitida e dos frutos de X. sericea. A espectroscopia ordenada por difusÃo ou DOSY (Diffusion Ordered Spectroscopy) provà um meio para uma âseparaÃÃo virtualâ de compostos, atravÃs de um mapa bidimensional onde em um eixo temos o deslocamento quÃmico e em outro observamos o coeficiente de difusÃo (D) das molÃculas na mistura. A separaÃÃo de sinais somente à possÃvel quando espÃcies difundem a diferentes velocidades. Na quÃmica de produtos naturais, frequentemente nos deparamos com misturas de compostos quimicamente semelhantes e de tamanhos muito similares, o que torna limitado o experimento DOSY tradicional. Entretanto, o coeficiente de difusÃo das substÃncias pode ser modificado pela adiÃÃo de co-solutos e/ou co-solventes, surgindo a partir daà a espectroscopia ordenada por difusÃo assistida por matriz (matrix-assisted DOSY ou MAD). VÃrios surfactantes, incluindo SDS, AOT e CTAB tÃm se mostrado efetivos em anÃlises por MAD. Neste trabalho, experimentos MAD foram realizados com algumas misturas de produtos naturais com similaridades estruturais utilizando o Ãcido perfluoro-octanÃico (PFOA), polivinilpirrolidona (PVP) e os surfactantes Brij 78 e 98, que por sua vez, ainda nÃo haviam sido utilizados para esse propÃsito. NÃs tambÃm demonstramos a formaÃÃo de micelas de Brij 78 e 98 em misturas dos solventes DMSO-d6 e D2O.

Mass transport deposits form a significant portion of the rock record in both modern and ancient basins. Their geometry, composition, distribution and genesis are poorly understood, making it difficult to predict anything about these deposits in assessing subsurface basin stratigraphy or modern seafloor hazards. A tremendous effort has been made in the last few years to characterize and better understand seafloor failures in numerous margins of the world. These mass failures have triggered the interests of geologists, particularly in the oil and gas industry, as they can form prominent seals and reservoirs. To increase our knowledge base of mass transport complexes (MTCs), the characteristics of 259 siliciclastic deposits worldwide, were analyzed in terms of their volume, area, length, thickness, lithology, and tectonic settings. In some instances, MTCs were geo-referenced and digitized into ArcGIS and their dimensions were calculated. These data reveal several interesting points and suggest a number of statistically significant predictive relationships. Sand-rich mass transport deposits show a propensity to be short and thick. Muddy MTCs show a propensity to be longer and thinner. The highest number and largest volume of clastic mass transport deposits occur along passive margins. These mega-MTCs are typically muddy with lengths up to 800 km and volumes up to 5000 km3. Sandy and gravelly Quaternary-age MTCs show maximum lengths of less than 300 km and with volumes less than 2000 km3. Pre-Quaternary MTCs are systematically under-documented in literature, but known occurrences are found in passive, active and convergent margins. The largest (30,000 to 40,000 sq km) occur along the older Tertiary margin of West Africa. To date, 41 separate mass transport deposits composed dominantly of carbonate material have been identified in literature. The most extensive and voluminous (7000 km3) carbonate mass transport complexes occur in the Citronens Fjord, Offshore Greenland. They are 200m thick, Silurian-age mega-breccias that were deposited in a convergent margin setting. On comparison carbonate MTCs tend to show longer flows with coarser grain sizes, while clastics show coarser grained deposits to be of more limited length. The Mad Dog area, Gulf of Mexico is a region of active salt tectonics and mass transport processes. Consequently, it was selected to form a focus study area to test the relationships developed during this project. MTCs in this region were grouped into four main types based on their size, geomorphology and internal structure. Their geometries indicate they are comparable to MTCs found offshore Oregon and New Jersey and are most likely muddy in nature. / text

This thesis is about Ibn Taymiyya's thinking on jihād and baghy. It aims to make an important contribution to the study of early Islamic political thought. It considers how the terms jihād and baghy have developed and been expanded from the structure established by the Qur'an and hadith. It also examines the relationship between jihād and baghy in Islamic law and reveals the pivotal role of the imām in politics. The main focus of this study is Ibn Taymiyya's thinking on jihād and the fatwās that resulted from it, using hitherto overlooked printed materials. It also seeks to explain why Ibn Taymiyya upheld jihād against the Mongols, the Franks and the heretic Shī'a. The thesis is divided into four chapters and structured as follows. The first chapter deals with the life of Ibn Taymiyya. This chapter moves beyond conventional biography to relate the story of Ibn Taymiyya's life to the main events that occurred during the Mongols' incursion. The second chapter identifies what Meccan and Medinan Qur'anic texts say about jihād, and examines whether jihād is a mechanism of self defense or an act of aggression; it also explains the relationship between jihād and the establishment of dār al-Islām, dār al-ḥarb and dār al-'ahd. The third chapter considers Ibn Taymiyya's view on jihād. The fourth chapter analyses Ibn Taymiyya's view on baghy, and aims to arrive at a clearer picture of the relationship between Ibn Taymiyya's concepts of jihād and baghy.

Pour résoudre de novo la structure de protéines par cristallographie, il est nécessaire de calculer les phases des facteurs de structure à partir des intensités des rayons X diffractés. Pour ce but, les méthodes SAD et MAD se servent de la diffusion anomale d'atomes présents dans le cristal de la protéine. L'introduction de ces diffuseurs anomaux dans les cristaux est une des étapes clés de la résolution de structure des protéines.<br />Nous avons étudié une classe de huit complexes de gadolinium servant à insérer les diffuseurs anomaux dans les cristaux de protéine. Le gadolinium présente une forte diffusion anomale et avec le rayonnement X d'un générateur de laboratoire et dans son seuil d'absorption LIII.<br />Une étude cristallographique menée avec cette classe de complexes et avec huit protéines différentes a permis de démontrer le potentiel élevé des complexes pour la préparation de dérivés à fort pouvoir de phasage. En effet, pour un grand nombre des dérivés testés, les phases expérimentales calculées ont mené à des cartes de densité expérimentale d'excellente qualité, permettant la construction aisée du modèle de la protéine.<br />L'affinement de la structure des complexes liés à la protéine a permis de comprendre l'interaction des différents complexes avec les protéines.<br />L'utilisation des complexes a permis de résoudre la structure de quatre nouvelles protéines.<br />Nous avons également étudié des méthodes physico-chimiques alternatives à la cristallographie dans le dessein de détecter la fixation d'un complexe sur une protéine en tenant compte de la particularité de l'interaction qui est caractérisée par une constante de d'association faible.

Les erreurs humaines et les interruptions sont des phénomènes courants mais négligés, voire ignorés, dans le processus de développement des systèmes interactifs. En outre, leur automatisation massive n'a pas éliminé erreurs et interruptions, mais en a accentué le caractère critique. Ce mémoire a pour objet l'amélioration de la fiabilité des systèmes homme-machine par la prise en compte explicite des erreurs et des interruptions dans la pratique de l'Ingénierie de l'Interaction Homme-Machine. Nous appliquons notre étude au cas exigeant des systèmes critiques automatisés et notamment aux systèmes aéronautiques, pour lesquels les erreurs humaines et les interruptions ont une importance décisive. Dans la première partie du mémoire, dédiée aux concepts, nous présentons une revue des recherches sur l'automatisation et sur l'analyse des erreurs humaines telle que l'envisage la psychologie cognitive. A notre tour, nous proposons le concept de singularité comme notion pivot aux phénomènes d'erreur et d'interruption. Nous en fournissons un modèle qui explicite les activités mentales en relation avec la détection et la correction de singularité. La seconde partie du mémoire a trait à l'expression formelle des singularités dans le processus de développement d'un système interactif. Après une revue des formalismes et des notations utilisés en Interaction Homme-Machine, nous retenons MAD, UAN et les réseaux de Petri pour leurs qualités et leur usage complémentaires. Pour chacun, nous proposons les extensions nécessaires à l'expression des singularités. Nous fournissons également les règles de traduction de ces extensions entre les trois formalismes retenus, évitant ainsi la perte de conformité au cours du processus de développement d'un système.

<p>Glycosidases hydrolyse the glycosidic bond in carbohydrates. Structural studies of three glycosidases with different substrate specificities are presented in this work.</p><p>Dextranase catalyzes the hydrolysis of <i>α</i>-1,6-glycosidic linkage in dextran polymers. The structure of dextranase, Dex49A, from <i>Penicillium minioluteum</i> was solved in the apo-enzyme (1.8 Å resolution) and product-bound (1.65 Å resolution) forms. The main domain of the enzyme is a right-handed β-helix, which is connected to a β-sandwich domain at the N-terminus. Using NMR spectroscopy the reaction course was shown to occur with net inversion at the anomeric carbon. A new clan is suggested that links glycoside hydrolase (GH) families 28 and 49.</p><p>Endo-<i>β</i>-1,4-D-mannanase catalyzes the depolymerization of <i>β</i>-1,4-mannan polymers. The structure of endo-1,4-<i>β</i>-mannanase Man5A from blue mussel <i>Mytilus edulis</i> has been determined at 1.6 Å resolution. Kinetic analysis of Man5A revealed that the enzyme requires at least 6 subsites for efficient hydrolysis. The architecture of the catalytic cleft differs significantly from other GH 5 enzyme structures. We therefore suggest that Man5A represents a new subfamily in GH 5. </p><p>Both the Dex49A and the Man5A structures were determined by multiple-wavelength anomalous diffraction using the selenium <i>K</i>-edge with selenomethionyl enzymes expressed in the yeast <i>Pichia pastoris</i>.</p><p>Endoglucanase Cel6A from <i>Thermobifida fusca</i> hydrolyzes the <i>β</i>-1,4 linkages in cellulose. The structure of the catalytic domain of Cel6A from <i>T. fusca</i> in complex with a non-hydrolysable substrate analogue has been determined to 1.5 Å resolution. The glycosyl unit in subsite –1 was sterically hindered by Tyr73 and forced into a distorted ²S_O conformation. In the enzyme where Tyr73 was mutated to a serine residue the hindrance was removed and the glycosyl unit in subsite –1 had a relaxed ⁴C₁ chair conformation.</p>