La découverte et le développement d'un médicament est un processus long et très coûteux. Pour améliorer ce processus, une nouvelle approche de criblage et de conception rationnelle de nouveaux ligands est apparue durant la dernière décennie. Elle se base sur le criblage par des techniques de biophysique structurale, de petites molécules organiques appelées "fragments". Ces fragments sont caractérisés par une faible affinité pour la cible mais par une grande efficacité de liaison. Cette approche a été mise en place au CBS et appliquée à la découverte de nouveaux inhibiteurs des cyclophilines humaines. Les cyclophilines (Cyps) sont des protéines ubiquitaires chez l'Homme. Elles possèdent une activité peptidyl-prolyl cis-trans isomèrase et aident au repliement des protéines. Il a été montré que le développement d'inhibiteurs de ces protéines pourrait déboucher sur de nouveaux traitements pour des pathologies telles que le VIH, le VHC, certains cancers ou Alzheimer. Nous avons découvert, par un criblage RMN puis une validation par cristallographie aux rayons X, 14 fragments-touches millimolaires sur les Cyps. Ces fragments-touches ont permis de déterminer une nouvelle famille chimique d'inhibiteurs des Cyps. Le meilleur inhibiteur possède une activité 1-10 µM sur CypA, B et D, et de la dizaine de micromolaires sur la réplication du VHC dans les cellules. Un brevet a été déposé sur cette famille chimique. / Drug discovery and development is a long and expensive process. To improve this process, a new approach of creening and rational drug design appeared during the last decade. This approach is based on screening of small organic compounds called "fragments" by structural biophysic techniques. These fragments are characterized by low affinity for the target but high ligand efficiency. This approach was implemented at the CBS and applied to find new human cyclophilin inhibitors. Cyclophilins (Cyps) are ubiquitous proteins in Human. They have a peptidyl-prolyl cis-transisomerase activity and help protein folding. It was shown that development of inhibitors for these proteins could lead to new treatments against HIV, HCV, cancers or Alzheimer diseases for example. We discovered 14 fragment hits in the millimolar range on the Cyps by NMR screening and further validation by X-ray crystallography. With these fragment hits, we identified a new family of chemical inhibitors of the Cyps. The best inhibitor has 1-10 µM activity on CypA, B and D, and around 10 micromolar activity on HCV replication in cells. A patent has been deposited for this family of chemical inhibitors.

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In his work A Literary Review, Kierkegaard bemoans much about "the present age" and in the text he presents an extremely bleak picture of the potential for one to live an authentically religious life. However, he also makes it clear that he believes the present age is in a uniquely superior position because a religious leap remains possible. The purpose of this thesis is to determine why Kierkegaard believes that a religious leap is possible in the present age. I attempt to understand one promising method of achieving a religious leap by appealing to another work by Kierkegaard entitled Philosophical Fragments. It is my position that, given a particular interpretation, Philosophical Fragments places some readers in a position where a religious leap emerges as a possibility.

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An ambient odour of anise was used in a context-dependent memory study with three different memory tasks targeting both declarative and non-declarative memory functions. Declarative memory was assessed by means of two episodic memory tests; recall of a prose text and a complex figure. Priming was used to assess the non-declarative memory with word fragment completion. Memory was tested immediately and after 48 hours. The results showed a significant main effect of context (odour or not) for all three tests in favour of the olfactory context. In addition, a significant main effect of time was observed for all three tests and a significant interaction effect between context and time for the priming test were observed. This interaction showed that the priming effect was equal in size across both conditions at immediate testing, although when the odour was reinstated at the delayed test the results showed larger priming relative the control condition.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Building upon C.P. Cavafy’s overall poetics with which the existing scholarship has dealt, this dissertation attempts to further define the Alexandrian poet’s art of making poetry by locating its ever-increasing global appeal in the notion of the “fragment” as a performance genre. The concept of the fragment repositions and redefines Cavafy’s poetry as a text that “does things” and as a result, it opens the gateway to performativity. Thus, through fragmentation Cavafy’s poems cease to be proper texts and are endowed with the potential of political acts. The interaction of poetry with music is indeed the key to understanding the fluidity of the Cavafean poetry and its subsequent undeniable appeal worldwide, which the interaction of poetry with music makes visible. Viewed as a sonorous envelope, a fantasy space, a psychotextual discourse or an activity based upon musico-textual mechanisms, music opens the way to being viewed as a socio-cultural site of subjectivity formation that ignores all kinds of boundaries, both temporal and spatial. This dissertation thus argues for a sui generis Cavafean poetics of fragmentation in both thematic and stylistic terms that allows for ample experimentation and freedom not only on the poet’s behalf, but also in terms of its reception. Moreover, this project further tests the validity of such an argument at the intersection of poetry and music when one fuses into another in the form of the art song. By scrutinizing how Cavafy’s poetry has been put into music by various composers by means of a variety of approaches, including music analysis (e.g., melodic, harmonic, textural, semiotic, music psychology), psychoanalysis, and cultural theory, it aims to shape a “map” of various musical receptions of such a highly fragmented oeuvre as the Cavafean. To this end, it focuses on several case studies of music renditions ranging from that of the composer Dimitri Mitropoulos during the days of High Modernism (publicly presented in 1927 in Athens, Greece) through Peter Schat’s For Lenny at 70 (for tenor and piano, 1988), Lou Harrison’s Scenes from Cavafy (a work composed for gamelan orchestra, 1992), Yannis Papaioannou’s The Funeral of Sarpedon (2000), Ned Rorem’s Another Sleep: Waiting for the Barbarians (2002) and John Tavener’s Tribute to Cavafy (first performed in 2005 at Birmingham, UK), to the contemporary composer Kostas Rekleitis’ Cavafy Cycle (2012). By entering the deep, almost invisible territories where one art fuses with another, this thesis aspires to contribute to a better understanding of such a complex poetry as the Cavafean one, by offering a fresh perspective and mode of investigation onto an overlooked dimension of Cavafy’s work. It thus ultimately calls for a renewed interest for further interdisciplinary explorations, not only in the reception of Cavafy in music, but also of Cavafy in more complex artistic settings and forms, especially, that of performance.

Recent years have seen an expansion beyond the more druggable biological targets into novel areas of biological space. However, drug discovery campaigns against these challenging targets have been afflicted with low hit rates during screening campaigns and high levels of candidate attrition during clinical trials. Subsequent studies have looked to explore the underlying factors to these challenges and have identified the lack of scaffold diversity and poor physicochemical properties in screening libraries as the leading causes. In an attempt to address this issue drug discovery strategies such as fragment-based drug discovery and lead-oriented synthesis have been developed which control and direct the compound properties within screening libraries towards relevant areas of chemical space. In addition, strategies such as diversity oriented synthesis aim to synthesise structurally complex and diverse compounds, expanding screening collections into previously under-explored areas of chemical space. This thesis reports the development of a step-efficient, modular and highly adaptable synthetic route for the synthesis of partially saturated bicyclic heteroaromatic scffolds (Figure i). The designed route takes advantage of the large chiral pool provided by amino acids, with each scaffold synthesised in just 4-6 steps from these readily available enantiopure starting materials. The mild conditions allow for excellent functional group tolerance, thus enabling the incorporation of growth vectors for chemical elaboration from the outset, a strong advantage in the drug discovery process. Overall, 29 partially saturated bicyclic heteroaromatic compounds were synthesised based around 7 different scaffolds. These demonstrated a number of possible areas for diversifation both on and around the scaffold, including variation of functional groups (Figure i, red), double (cis-diastereoisomers) and single (R2- and R3-positions) substitution patterns, variation of the 5-membered heterocycle (Figure i, green) and increased size of the saturated ring (Figure i, blue). Furthermore, careful selection of the substituents, heterocycle and size of the saturated ring would enable the synthesis of screening libraries within the constraints of fragment-like, lead-like or drug-like structures. The final library has been incorporated into the Diamond XChem high-throughput crystallography program and initial screening has identified a weakly binding hit for Activin A.

Icing can pose problems due to both accretions on aircraft aerodynamic surfaces as well as through shedding of large ice particles from aircraft surfaces. The shed ice causes damage by impacting downstream aerodynamic surfaces and on ingestion by aft mounted engines. Present ice trajectory simulation tools have limited capabilities due to the lack of experimental aerodynamic force and moment data for ice fragments and the large number of variables that can affect the trajectories of ice particles in the aircraft flowfield like the particle shape, size, mass, initial velocity, particle shedding location and orientation during shedding. A comprehensive literature review of experimental studies related to "random-shape" bluff body aerodynamics was conducted to support the development of a list of ice fragments for consideration in this research effort. Recommendations were also obtained from aircraft engine manufacturers and industry partners in developing the ice fragment list. Fifteen ice shapes were identified for aerodynamic testing and they were prioritized based on input from industry. The top three were selected for the present wind tunnel study. The ice fragments selected included a rectangular slab, a semicircular shell and a hemispherical shell. The literature review of experimental studies yielded a variety of methods employed by other investigators in obtaining force and moment data for randomshape bodies. However, in most previous experimental investigations force and moment data were obtained for infinite aspect ratio (2D) fragments. The research described in this thesis was performed to establish 3D six degree of freedom experimental force and moment data in the WSU 7-ft by 10-ft wind tunnel facility. The data obtained will be used in the probabilistic trajectory simulation methods of "random-shape" ice fragments employed at WSU. Experimental results are presented for five ice fragment configurations and include lift, drag and side force coefficients. In certain cases, the pitching, yawing and rolling moment coefficients are also provided. The data was reduced from the balance body axis system to the wind axis system. Transformations were developed to obtain the force and moment data at the model resolving center from the balance virtual center. The forces and moments were resolved by the WSU external balance at the virtual center. Detailed discussions are provided on the effects on the aerodynamic force and moment data due to the test mount, test section wall, model-mount interference, aspect-ratio, ice fragment shape and the associated Reynolds number. Moreover, the flowfield about selected ice fragments was computed using simulation tools like FLUENT (a Navier-Stokes solver) and GAMBIT (meshing preprocessor) to elucidate flow behavior and sting-model interference effects. Results from the computational effort are presented and include pressure coefficient contours and velocity colored streamlines. / Thesis (M.S.)--Wichita State University, College of Engineering, Dept. of Aerospace Engineering. / "December 2006." / Includes bibliographic references (leaves 134-140)