Made available in DSpace on 2014-06-11T19:32:58Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-08-12Bitstream added on 2014-06-13T21:05:25Z : No. of bitstreams: 1 ricardo_ha_dr_botfmvz.pdf: 511383 bytes, checksum: c1c678a5f609d7e8b161335091d3395e (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Universidade Estadual Paulista (UNESP) / Noventa e seis ovinos foram agrupados em cinco classes de Tipo Ovino (TO): TO1 – cordeiros com peso de abate (PA) até 30 kg (n=16); TO2 – cordeiros com PA entre 30 e 35 kg (n=20); TO3 – cordeiros com PA entre 35 e 40 kg (n=22); TO4 – cordeiros com PA acima de 40 kg (n=23); TO5 – ovino com pelo menos um par de dentes incisivos permanentes (n=15). Foi avaliado o efeito do TO sobre o PA, escore de condição corporal (ECC), caracaterísticas da carcaça e morfometria. As carcaças também foram avaliadas pelo sistema EUROP de classificação. Houve influência do TO sobre o PA, com maior valor para o TO5, sendo que esta classe não se diferenciou do TO4, enquanto que o ECC não se diferenciou entre os TO. Não houve diferença para o peso de carcaça quente (PCQ) e de carcaça fria (PCF) entre o TO5 e TO4, que apresentaram os maiores valores, sendo que o TO1 e TO2 não se diferenciaram quanto ao PCQ mas apresentaram diferença para PCF. A maior perda de peso no resfriamento (PPR) foi observada para as carcaças do TO1 enquanto que o TO3 foi a classe que perdeu menos peso. Os maiores valores para o comprimento externo da carcaça (CEC) foram obtidos para o TO4 e TO5, sendo que o TO5 apresentou a maior largura e perímetro da garupa (LG e PG), e largura e profundidade do tórax (LT e PT) dentre os TO. Não houve diferença para o perímetro da perna (PP) entre TO4 e TO5, com o TO1 apresentando o menor valor para esta medida morfométrica. Pelo sistema EUROP, 54% das carcaças pesadas apresentaram classe de conformação boa e somente uma carcaça foi classificada com classe de conformação excelente. Para as classes de camada de gordura, nenhuma carcaça obteve as classes 4 e 5, apenas 9% das carcaças de ovinos com menos de doze meses de idade foram classificadas com classe de camada de gordura 3, enquanto que 43% obtiveram classe 1 e 48% classe 2. Com base na dentição dos animais... / Noventa e seis ovinos foram agrupados em cinco classes de Tipo Ovino (TO): TO1 – cordeiros com peso de abate (PA) até 30 kg (n=16); TO2 – cordeiros com PA entre 30 e 35 kg (n=20); TO3 – cordeiros com PA entre 35 e 40 kg (n=22); TO4 – cordeiros com PA acima de 40 kg (n=23); TO5 – ovino com pelo menos um par de dentes incisivos permanentes (n=15). Foi avaliado o efeito do TO sobre o PA, escore de condição corporal (ECC), caracaterísticas da carcaça e morfometria. As carcaças também foram avaliadas pelo sistema EUROP de classificação. Houve influência do TO sobre o PA, com maior valor para o TO5, sendo que esta classe não se diferenciou do TO4, enquanto que o ECC não se diferenciou entre os TO. Não houve diferença para o peso de carcaça quente (PCQ) e de carcaça fria (PCF) entre o TO5 e TO4, que apresentaram os maiores valores, sendo que o TO1 e TO2 não se diferenciaram quanto ao PCQ mas apresentaram diferença para PCF. A maior perda de peso no resfriamento (PPR) foi observada para as carcaças do TO1 enquanto que o TO3 foi a classe que perdeu menos peso. Os maiores valores para o comprimento externo da carcaça (CEC) foram obtidos para o TO4 e TO5, sendo que o TO5 apresentou a maior largura e perímetro da garupa (LG e PG), e largura e profundidade do tórax (LT e PT) dentre os TO. Não houve diferença para o perímetro da perna (PP) entre TO4 e TO5, com o TO1 apresentando o menor valor para esta medida morfométrica. Pelo sistema EUROP, 54% das carcaças pesadas apresentaram classe de conformação boa e somente uma carcaça foi classificada com classe de conformação excelente. Para as classes de camada de gordura, nenhuma carcaça obteve as classes 4 e 5, apenas 9% das carcaças de ovinos com menos de doze meses de idade foram classificadas com classe de camada de gordura 3, enquanto que 43% obtiveram classe 1 e 48% classe 2. Com base na dentição... (Complete abstract click electronic access below)

Crystallising large, flexible molecules, which are becoming more common in pharmaceutical development, often presents significant challenges for chemists and particle scientists. These difficulties are sometimes attributed to the flexibility of the molecule, and the existence of multiple conformers in solution. Structurally related impurities, frequently present when crystallising these materials, can also impact on growth and habit, and both these aspects are considered in this thesis. This work considers two pharmaceutical compounds, a relatively small but nonetheless flexible molecule, ethenzamide, and a precursor of Amprenavir, a much larger molecule. Both compounds typically grow as thin needles in a wide variety of solvents, and effort was required to grow suitable crystals for structure determination. Ethenzamide has an unusual structure, the amide group being out-of-plane relative to the ring, while in all known co-crystals of the compound, including three new co-crystal structures determined in this work, it has a planar structure with an intramolecular hydrogen bond not seen in the single component crystal. Theoretical structure generation calculations suggest a second polymorph with a planar conformation may exist, though a screen has not found any further solid phases. ab initio work suggests the planar conformation is the stable arrangement in vacuo. Several structures for the Amprenavir intermediate have been determined, as an ethanol solvate, a methanol solvate and a hydrate. A phase diagram has been measured in the industrial solvent mix, and the nucleation and growth properties of this molecule, both pure and in the presence of several structurally related impurities, have been measured. The Cambridge Structural Database has been searched for similar structures, and conformational searches have been carried out for both molecules, using vacuum phase ab initio energy calculations. Infrared spectroscopy has been used to investigate solution phase structure. These theoretical and practical studies will try to relate conformational properties to crystallisation behaviour.

Les pièces mécaniques fabriquées tel que les feuilles de métal et les pièces à paroi mince, ont souvent des différences géométriques significatives par rapport à leurs modèles CAD nominaux car ils ont une forme considérablement différente dans une condition d’état libre en raison de la gravité et/ou la tension résiduelle. Par conséquence, les fixtures de conformation coûteux sont traditionnellement utilisés pendant les opérations d’inspection géométriques à la phase de contrôle de qualité. L’objective de cette étude est de développer les méthodes d’inspection géométriques automatisées des pièces flexibles qui ne nécessiteraient pas d’utilisation des fixtures. / In manufacturing, quality control (QC) is an essential phase of a product’s lifecycle management (PLM) as it ensures customers receive parts within permissible tolerance ranges and free from defects. Given that all manufactured parts often have geometrical differences compared to their nominal computer-aided design (CAD) models, performing geometrical inspections becomes critical during the QC phase. Nowadays, actual measurements and defect identification during geometrical inspections have been semi-automated through the use of computer-aided inspection (CAI) software. Such software can simplify the inspection into a data acquisition task (contact-based probing or non-contact scanning of the part) followed by semi-automated procedures in a software environment. Despite their growing popularity and practicality, currently available CAI software assume the input acquired data are from a rigid part. This assumption is a major limitation given that not all manufactured parts are rigid, and in some sectors such as the aeronautical industries a considerable percentage of all manufactured components (35 to 40 percent) possess some nonrigid behavior. In other words, CAI software can only be used when a part maintains its shape in both free-state and state-of-use positions. Free-state shape is that which a part has without inspection fixture support and/or before assembly, whilst state-of-use shape is that which is defined in the nominal CAD. Although free-state and state-of-use positions are the same for rigid parts, some mechanical parts such as sheet metals and skins (thin-wall featured parts) often have significantly large geometric deviations in a free-state position compared to their nominal CAD models due to the effects of gravity and residual stress. Referring to such parts as flexible, the aforementioned deviations force the QC technicians to traditionally use a variety of inspection fixtures and conformation jigs in order to maintain flexible parts in their state-of-use position before using conventional CAI software. Without fixation, the free-state elastic geometric deviation of flexible parts would be mistaken by CAI software as plastic deformations and as a result identified as defects. With fixation, the aforementioned free-state deviations are removed before data acquisition, and whatever deviations remain can be inspected as potential defects. However, multiple disadvantages exist in using fixtures including: time consuming set-up process (e.g. 60+ hours for a skin panel in the aerospace industry), considerable purchase and operating expenses, limitations of standard fixture kits in some scenarios, big errors in CAI analysis if fixation has not been conducted correctly, etc. Such disadvantages have recently led researchers to:1) try to circumvent use of fixtures by digitally deforming (or better called registering) the acquired free-state pointcloud/mesh data of a flexible part until it superimposes onto the part’s corresponding nominal CAD model, thereby elastically deforming the data to obtain an optimal state-of-use shape whilst avoiding neutralization of any existing manufacturing defects2) and to try to introduce dedicated defect identification modules with higher degrees of automation (compared to conventional semi-automated CAI tools)In this thesis the same two goals are pursued. A bi-criterion registration method (and two algorithms/demos based upon it) is proposed to achieve the first goal, thereby enabling defect identification of flexible parts in conventional CAI software without the use of fixtures. This is followed by introducing an automated method for fast approximation of defect amplitudes (and an algorithm/demo based upon it) to achieve the second goal. Validation was conducted against a number of virtual (simulated) and experimental industrial case studies. Obtained satisfactory results reflect the effectiveness and utility of the proposed methods.

In recent years a great deal of research has focussed on understanding and exploiting self assembling peptides as they form fibrillar hydrogels for use in a variety of different applications, such as tissue engineering and drug delivery. A particular class of such peptide systems are ionic-complementary peptides, composed of alternating hydrophobic and hydrophilic amino acids. Their simple structure is generally seen to assemble into β sheet rich fibrils, and easy modification of the primary structure is possible to allow the inclusion of recognition motifs tailored for a specific use. This can be done simply via physical mixing. To maximise the potential of such systems it is important to understand the interactions that govern the self-assembly behaviour. Here a variety of different peptides have been studied to elucidate control of peptide conformation and fibril morphology. The ability to easily tune the mechanical strength of the hydrogel has been explored by mixing peptide systems. The peptide FEFEFKFK (FEKII) was seen to assemble into β sheet rich fibrils of ~3 nm in diameter. Control of pH and hence the charge state of the E and K side chains altered sample properties. Gelation at pH 2.8 occurred at a concentration between 20 30 mg ml 1. At pH 4, 5 and 10 where the peptide has a lower net charge gelation was lowered to ~10 mg ml 1. Mechanical properties varied with G' values of 20-1200 Pa as pH was altered. Stronger gels were formed with lower net peptide charge. Hierarchical fibre assembly was observed for positively charged peptides, with fibres forming from lateral association of fibrils. Negatively charged peptides at pH 10 showed no such hierarchical assembly, and lower fibril persistence length. This was related to the change in charge along the fibril structure. At pH 7, where the peptide has no net charge, precipitation occurred. This showed a net charge was required on the peptide to disperse fibrils and prevent aggregation. The work showed the importance of ionic-interactions in determining both network morphology and bulk properties, and also elucidated control of such behaviour. AEAEAKAK (AEKII) was shown to assemble into α helix fibres. Alanine (A) is less hydrophobic than F, and is a known helix former. The role of F and A in assembly was assessed by the design of peptides FEAEFKAK (FAIEKII) and FEFEAKAK (FAIIEKII). Mixing A with F disrupted the peptides' ability to form a β sheet network by lowering the driving force for assembly given by the F residues. Trace amounts of β sheet were observed at low concentration, but at a critical concentration β sheet content increased and gelation occurred. This was found to be pH dependent. FAIEKII formed β-sheet fibrils at a lower concentration than FAIIEKII. While FAIEKII was able to assemble into different fibril structures, FAIIEKII showed no specific aggregation. This not only highlighted the importance of Hydrophobicity as a key driving force to assembly but also how the grouping of these amino acids in the primary sequence can determine the overall assembly characteristics of the peptide. The peptides FEFEFKFKGGFEFEFKFK (FEKII18-1) and FEFEFKFKGGFKFKFEFE (FEKII18-2) were designed to co-assemble with FEKII. Individually both peptides were seen to assemble into β sheet fibrils. FEKII18-1 formed fibrils of 2.3 3.1 nm in size, a result of folding along the chain caused by intra molecular attractive ionic interactions. FEKII18-2 formed larger fibrils of 4.4 5.2 nm from a straightened peptide chain given by the change in charge distribution. When co assembled with FEKII mechanical properties were enhanced, with G' increasing from 40 Pa at 20 mg ml 1 to 2400 Pa, depending on the concentration of FEKII18-1/FEKII18-2 added to the system. This was a result of these peptides providing fibril connections acting as cross links. This work has detailed control over the assembly process via peptide conformation and fibril interactions and the effect this has on overall macroscopic sample properties. This is vital in determining the viability of such systems in various biomedical applications.

La liaison peptidique au sein d’un peptide ou d’une protéine est d’ordinaire plane et en conformation trans pour la majorité des acides aminés. La situation est un peu différente en amont d’une proline : la barrière thermodynamique qui s’oppose à la rotation de la liaison amide est plus faible et la tendance de la liaison à rester plane est un peu moins grande. Cette liaison AA-Pro peut donc adopter une conformation cis, entraînant la formation d’un coude prononcé dans une chaîne peptidique à son niveau. Ce travail décrit la synthèse et la réactivité chimique de nouveaux analogues bis-azotés de la proline en solution permettant de favoriser la conformation cis d’une liaison AA-ΨPro. L’impact conformationnel que peut engendrer ces résidus au sein de pseudopeptides est également exposé. Dans un premier temps, une nouvelle voie d’accès à la α-azaproline énantiomériquement pure et orthogonalement protégée a été mise au point en exploitant des travaux antérieurs concernant la synthèse d’α-hydrazinoesters et de N-aminodipeptides. L’étude de la réactivité de cette pseudoproline a permis de définir les meilleures conditions de formations de pseudotripeptides de formule P1-AA1-δ-azaPro-AA3-P3. Elle a également orienté les travaux, dans un second temps, vers la synthèse de pseudopeptides incorporant un motif acide pyrazolique. Enfin, la structure des composés préparés a été analysée par RMN, IR et par modélisation moléculaire. L’examen des P1-AA1-δ-azaPro(Boc)-AA3-P3 a révélé la formation par liaison hydrogène d’un pseudocycle en C7, favorisant la conformation trans de la liaison AA1-δ-azaPro, alors que l’absence de la fonction Boc favorise la conformation cis de cette liaison. / The peptidic bond in a peptide or a protein is usually flat and in trans conformation for the majority of amino acids. The situation is a little bit different upstream the proline: the thermodynamic barrier which opposes the rotation of the amide bond is weaker and the tendency of the bond to remain flat is lesser. So, this AA-Pro bond can adopt a cis conformation, leading to the formation of a turn in the peptidic chain. This work describes the synthesis and the chemical reactivity of new bis-nitrogen analogous of proline in solution to facilitate the cis conformation of a AA-PΨPro bond. The conformational impact that these residues may generate in pseudopeptides is also exposed.Initially, a new access road to the orthogonally protected and enantiomerically pure δ-azaproline has been developed by exploiting previous work on the synthesis of α- hydrazinoesters and N-aminodipeptides. The study of the reactivity of this pseudoproline helped define the best conditions for forming pseudotripeptides of formula P1-AA1--δ-azaPro-AA3-P3. It also guided the work, in a second step, towards the synthesis of pseudopeptide incorporating a pyrazole acid motif. Finally, the structure of the prepared compounds was analyzed by NMR, IR and molecular modeling. Examination of the P1-AA1-δ-azaPro(Boc)-AA3-P3 revealed the formation of a pseudocycle C7 by a Hydrogen bond, favoring the trans conformation of the AA1-δ-azaPro bond, while the absence of Boc function seems to favor the cis conformation of this bond.

京都大学 / 新制・課程博士 / 博士(工学) / 甲第23224号 / 工博第4868号 / 新制||工||1760(附属図書館) / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 辻井 敬亘, 教授 秋吉 一成, 教授 竹中 幹人 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Proteins are made of vast chains of amino acids that twist and fold into intricate designs. These structures are held in place by networks of noncovalent interactions. One of these, the hydrogen bond, forms bridges between adjacent pieces of the protein chain and is one of the most important contributors to the shape and stability of proteins. Hydrogen bonds come in all shapes and sizes and a full understanding of these not only aids in our understanding of proteins in general but can bridge the gap to finding cures to many protein-related diseases, such as sickle-cell anemia. The primary aim of this thesis is to discover if a specific type of hydrogen bond, the N-H···N bond, occurs within proteins and if so, if it contributes to the structure and stability of proteins.

Les protéines et acides ribonucléiques sont les principaux acteurs de nombreux processus cellulaires.Comprendre leurs fonctions, structures et interactions est un challenge important.Les méthodes expérimentales fournissent des informations sur la structure et la dynamique des molécules.Cependant les méthodes expérimentales sont limitées par le nombre de molécules qu'elles peuvent observer et les moyens qu'elles requièrent.Les méthodes de prédiction permettent d'obtenir des informations structurelles de façon quasi-automatique.Pour s'assurer de leur fiabilité, elles sont testées sur des données expérimentales.Nous présentons une procédure basée sur la cinétique inverse pour trouver une transition entre deux conformations d'un ARN tout en conservant sa structure secondaire.Nous obtenons des résultats comparables à l'état de l'art, ce qui montre que notre sélection des degrés de liberté est pertinente.De plus, nous utilisons des données partielles, ce qui permet d'utiliser différents types de résultats expérimentaux.Nous abordons aussi le problème du repliement protéique par une approche de théorie des jeux.Nous représentons une protéine par un jeu où les joueurs sont les acides aminés et les stratégies, les angles dièdres.La prédiction de structure peut alors être vue comme la recherche d'un équilibre dans un jeu multi-joueur où les fonctions d'utilité correspondent à la qualité du repliement.Nous montrons que l'algorithme de non-regret, appelé Hedge, garantit l'élimination des stratégies dominées et la convergence locale vers un équilibre de Nash.Puis, en limitant notre analyse aux jeux de potentiel, nous montrons qu'une classe plus large d'algorithmes, les algorithmes de régularisation, convergent vers un équilibre de Nash presque surement. / Proteins and Ribonucleic Acids are the workhorses of many cellular processes.Understanding their functions, structures and interactions is an important challenge.Experimental methods provide actual information on structure and dynamics of molecules.However they have limitations : they cannot be applied to all molecules, and they need a lot of resources.Prediction methods are almost automatic ways of obtaining structural information.They are tested on experimental data to attest their reliability.We present, here, approaches tackling different problems.We develop a kinematics-based procedure to morph a RNA molecule between conformations while preserving its secondary structure.We obtain results comparable to state of the art methods showing that our selection of degrees of freedom is efficient.Furthermore we only use sparse information allowing for various kinds of experimental inputs.We also look at the protein structure prediction problem from a game theory angle.We represent the protein dynamics as a game, in which players are amino acids and strategies are dihedrals angles.The structure prediction can thus be seen as finding equilibrium in a multi-players game where all players have utility functions corresponding to the quality of the protein structure.We showed that a well-known no-regret algorithm, called Hedge, guarantees dominated strategies to vanish and a local convergence toward Nash equilibria.Furthermore restricting our analysis to potential games we showed that dual-averaging regularized learning algorithms converge toward a Nash equilibrium almost surely.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第20388号 / 工博第4325号 / 新制||工||1670(附属図書館) / 京都大学大学院工学研究科材料化学専攻 / (主査)教授 松原 誠二郎, 教授 吉田 潤一, 教授 中尾 佳亮 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

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