A cada dia convive-se com novas tecnologias da informação. As novas gerações estão sendo chamadas de “nativos digitais”, ou seja, nascem envolvidas no mundo informatizado. As distâncias estão tornando-se cada vez mais curtas e o mundo cada vez mais globalizado. O uso das novas tecnologias da informação e comunicação (NTIC´s) é um desafio para a humanidade quando o foco é a educação. Este trabalho representa a tentativa de submeter as NTIC´s no ensino superior como forma de flexibilizar a aprendizagem para cursos das áreas científicotecnológicas. Cada vez mais percebe-se a evasão nos cursos de engenharia, principalmente devido às disciplinas de exatas. Esta tese apresenta o desenvolvimento de uma plataforma tecnológica para dar suporte ao ensino presencial através de um ambiente de aprendizado virtual 3D. Este ambiente, baseado em software gratuito, simula a realidade de uma sala de aula e pode ser uma nova fronteira para o aluno do século XXI. O conceito de imersão é aplicado. Além disto, integrado a este ambiente virtual 3D, tem-se acoplado um experimento remoto que permite ao acadêmico realizar as atividades práticas do módulo de elasticidade envolvendo conceitos fundamentais da conformação mecânica. Com a realização da tese um laboratório de experimentação remota foi montado, diversos recursos tecnológicos utilizados como: servidor Linux, redes de computadores integradas, internet, microservidores (MSW), interfaces eletrônicas, motor de passo, software como OpenSimulador, SLOODLE e MOODLE. Para consolidar o trabalho, uma proposta de avaliação foi aplicada correlacionando as habilidades cognitivas dos acadêmicos (questionário VARK), questionário de avaliação da satisfação do estudante (QASE) e o histórico escolar de cada acadêmico quando eles foram envolvidos nas aulas virtuais e experimentação remota. / Everyday we are living with new information of technology. The new generation are being called “digital natives”, this means that they were born embedded a high tech world. The distances each day shorter and world each day more “globalized”. The use of New Information and Communication Technology (ICT´s) is a challenge to the humanity when the goal is education. This paper represents a try to submit the ICT´s in the university studies as a way to flexible the learning to scientific and technologic areas. Once more we are living with the evasion in engineering courses, mainly because the math subjects. This thesis shows the developing of a technologic framework to support the classroom learning through 3D virtual learning environment. This environment based in a free software, simulates the reality of a classroom and can be the new frontier XXI century student. The concept of immersion is applied. Beyond this, integrated in this 3D virtual environment, we have coupled a remote experiment that allows the student perform the practical activities of elasticity module involving fundamental concepts of mechanical conformation. To the accomplishment of this thesis a remote experimentation lab was build and many technologies resources was used, such as: linux server, integrated compute network, microservers (MSW), electronic interfaces, step motors, software like opensimulator, sloodle and moodle. To consolidate the work, proposal evaluation was applied correlating the cognitive abilities of the students (VARK questionnaire), questionnaire for assessing student satisfaction and the student score when they were involved in virtual class and remote experimentation.

Este trabalho procura avaliar o retorno elástico em aços avançados de alta resistência utilizados em processo de dobramento. Para isso, foram usadas chapas de aço bifásico DP 600 e DP 800, ambas revestidas. Foram empregados dois métodos de medição a fim de abordar e avaliar o retorno elástico. O primeiro método abordado foi à conformação de tiras em U e o segundo método foi à realização do ensaio Dobramento Sob Tensão, aos quais possibilitaram a coleta de dados para aplicação em cálculo de coeficiente de atrito no processo de dobramento. Em ambas as avaliações foram utilizadas duas diferentes condições de lubrificação para o processo de dobramento, visando variar a condição de atrito no processo. A primeira foi à aplicação de um lubrificante em forma de pasta, de nome comercial Clarus Desmoldax DCP 35 e a segunda foi à aplicação em forma líquida, denominado Clarus Desmoldax DCP 35X. Para analisar o retorno elástico, foram utilizadas como critério de avaliação as medições de abertura da parede da tira conformada, permitindo desta forma considerar o atrito por intermédio da variação do tipo lubrificante. As análises realizadas nos corpos de prova conformados em formato U evidenciaram um retorno elástico menor para as amostras do aço DP 600, se comparadas com as amostras do aço DP 800. Não existiu relevância na variação dos lubrificantes quanto ao retorno elástico nas amostras de um mesmo tipo de aço. As análises realizadas nos corpos de prova submetidos ao ensaio de dobramento sob tensão, também evidenciaram um retorno elástico menor para as amostras do aço DP 600 se comparadas com as amostras do aço DP 800. Comparando as amostras com base nos dados coletados e aplicados ao cálculo de coeficiente de atrito, percebeu-se que as amostras que tiveram um retorno elástico menor, também possuíam coeficientes de atrito menor, constatando assim que quanto menor o coeficiente de atrito, menor é o retorno elástico. / This piece of work seeks to evaluate the springback effect on advanced high strength steel used in the bending process. For this, biphasic steel plates DP 600 and DP 800, both coated, were used. Two methods of measurement were used to approach and asses the springback effect. The first method approached was the conformation of strips in U and the second method was the preformance of the Bending Under Tension test, which enabled the data collect for the application in calculation of the friction coefficient in the bending process. In both assessments two different lubricant conditions for the bending process were used with the aim of varying the condition of friction in the process. The first one was the application of a paste lubricant, with the brand name Clarus Desmoldax DCP 35 and the second one was the application of a liquid lubricant, called Clarus Desmoldax DCP 35X. To analyze the springback effect the measurements of the opening of the wall of the conformed strip were used, thus allowing to consider the friction through the variation of the type of lubricant. The assessments carried out in the specimens in U shape showed a smaller springback effect for the steel samples DP 600 in comparison with the DP 800 ones. There was no relevance in the range of lubricants as the springback effect in the samples of the same type of steel. The analyzes carried out in the specimens subjected to bending under pressure test also showed a smaller springback effect for the steel samples DP 600 compared with the DP 800 ones. Comparing the samples based on the data collected and applied to the calculation of the friction coefficient, it was noticed that the samples that had a smaller springback effect also had lower friction coefficients, therefore verifying that the lower the friction coefficient is, the lower the springback effect.

Submitted by (edna.saturno@ufrpe.br) on 2017-04-27T12:16:30Z No. of bitstreams: 1 Geovergue Rodrigues Medeiros.pdf: 480577 bytes, checksum: 3b1d1e16fcbb4a13fb43c241f0ba7d9e (MD5) / Made available in DSpace on 2017-04-27T12:16:30Z (GMT). No. of bitstreams: 1 Geovergue Rodrigues Medeiros.pdf: 480577 bytes, checksum: 3b1d1e16fcbb4a13fb43c241f0ba7d9e (MD5) Previous issue date: 2006-03-24 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / The study was conducted at Sheep and Goats Sector of the Departament of Animal Science of the Federal Rural University, Recife – Pernambuco – Brazil. Were evaluate performance, nutrients intake and digestibility, carcass characteristics and non carcass components in thirty two males castrate Morada Nova hair sheep breed, in feedlot, feeding with differents levels of concentrate in the diet 20, 40, 60 and 80%. The age and initial live weight was 8,11 ± 1,15 and 19,67 ± 2,97 kg, respectively, and slaughter weight of 30,0 kg. A blocks randomized design, with eight replicates, was used. The concentrate level above 60% of concentrate increasing performance of the Morada Nova hair sheep in feedlot, with elevation of daily weight gain and decreasing of time for reach slaughter, that to change from 52,50 to 123,37 days. Diets above 40% of concentrate increasing the digestibility index, however ether extract digestibility decreasing to start 61,45%, while nonfibrous carbohydrates to start 73,15% of the concentrate level in the diet. In relation to carcass characteristics, the concentrate levels increasing empty body weight, weight and yield cold carcass, but the shoulder, loin, leg cuts and body and carcass measurements were relationed with slaughter weight. The lows weights and yields of carcass were because of the high components non carcass weights. The weight slaughter was representative for organs, viscera and by-products weights in relation to concentrate levels, except liver, omasum, small intestines, blood and paws. Independet of the concentrate levels, the yields and weights of the non carcass components were high, with values that reflect in less yields and weights of carcass of the feedlot Morada Nova hair sheep. / O trabalho foi desenvolvido no Setor de Caprino-ovinocultura do Departamento de Zootecnia da Universidade Federal Rural de Pernambuco, objetivando avaliar o desempenho, consumo e digestibilidade dos nutrientes, as características de carcaça e componentes não carcaça em 32 ovinos da raça Morada Nova, castrados, confinados, recebendo dietas contendo 20, 40, 60 e 80% de concentrado. Os animais tinham 8,11 ± 1,15 meses de idade, peso inicial de 19,67 ± 2,97 kg e ao abate (PVA) 30,0 kg. Utilizou-se um delineamento experimental em blocos casualizados, com quatro tratamentos e oito repetições. O número de dias em confinamento variou de 52,50 a 123,37. O consumo de matéria seca/dia de 0,089 a 0,224 kg; o ganho de peso diário, a conversão e eficiência alimentar melhoraram com o aumento dos níveis de concentrado na dieta. Dietas acima de 40% de concentrado melhoraram os índices de digestibilidade, porém a do extrato etéreo diminuiu a partir do nível de 61,45%, enquanto que para os carboidratos não fibrosos a partir de 73,15% de concentrado. O aumento dos níveis de concentrado elevou o peso do corpo vazio, peso e rendimento da carcaça fria, além de reduzir o período de permanência dos animais no confinamento, mas os cortes da paleta, lombo, perna e as medidas corporais e da carcaça foram mais relacionados com o peso ao abate. O critério de peso adotado para o abate, foi mais representativo para os pesos dos órgãos, vísceras e subprodutos do que os níveis de concentrado utilizados, exceto para o fígado, omaso, intestino delgado, sangue e patas. Independente dos níveis de concentrado, os pesos e rendimentos dos componentes não carcaça foram altos, com valores que refletem menores pesos e rendimentos da carcaça dos ovinos Morada Nova confinados.

Este trabalho busca avaliar a ductilidade de ligas metálicas utilizando como ferramenta a teoria da mecânica do dano proposta por Kachanov e desenvolvida por Lemaitre, a qual é apresentada desde as hipóteses básicas até as equações que modelam a deterioração de um material em regime de fratura dúctil. Como o enfoque do trabalho é a predição de trincas em processos de conformação mecânica, em especial estampagem de chapas, o mecanismo de formação destes defeitos é revisado, buscando na literatura o entendimento de como os parâmetros microestruturais influenciam na fratura dúctil. Ensaios de tração foram efetuados em corpos de prova retirados de chapas de aço SAE 1050 em duas condições microestruturais, cementita esferoidizada em matriz ferrítica e ferritaperlita, e em duas direções em relação à laminação da chapa original, paralelo e transversal. A evolução do dano foi medida de maneira indireta por meio da variação do módulo elástico e as propriedades mecânicas necessárias para utilização do modelo de Lemaitre foram calculadas. Por meio de difração de raios X, efetuamos o estudo da evolução da textura cristalográfica, apresentado na forma de figuras de distribuição de orientação e análise da intensidade das principais fibras encontradas em aços laminados a quente. Não foi observada influência significativa do tipo de microestrutura e da direção de deformação na evolução da textura. Por fim, o modelo de evolução de dano de Lemaitre foi transformado em um algoritmo numérico e implementado no código comercial Abaqus, em sua versão explícita, por meio do uso da subrotina VUMAT. Resultados foram obtidos e comparados com os experimentos, validando a aplicação do modelo. A evolução do dano para o aço SAE 1050 também foi comparada com resultados para outros aços ao manganês encontrados na literatura. Relações empíricas entre o teor de carbono e parâmetros como a deformação limite para início do dano, resistência à evolução do dano e dano máximo suportado foram desenvolvidas e apresentadas, com o intuito de funcionar como guias gerais para cálculo sem a necessidade de uma bateria de ensaios dedicados, facilitando a utilização da teoria da mecânica do dano em condições industriais. / The aim of the present work is to evaluate the ductility of metallic alloys employing the theory of damage mechanics as suggested by Kachanov and developed by Lemaitre, which is presented since its basic hypothesis until the equation that model the material deterioration under a regime of ductile fracture. As the focus of the work is the fracture prediction during mechanical working processes (mainly sheet metal stamping), the mechanism of formation of these defects is revised, based upon literature data, aiming at the understanding of how the material microstructural parameters influence ductile fracture. Tensile tests have been performed on samples obtained from SAE 1050 steel sheets for two microstructural conditions namely spheroidized cementite and regular ferrite-perlite for two rolling directions (rolling and transverse directions). In those tests, damage evolution has been measured indirectly through the materials variation in the Young modulus with strain, obtaining the mechanical properties, needed to be used in the calculation of Lemaitres model. Through X-ray diffraction measurements, the crystallographic texture evolution, presented in the form of orientation distribution functions and the associated fiber intensities observed for both microstructural conditions, has been evaluated. No major influence has been observed in this texture evolution, for the tested conditions. Finally, the Lemaitre damage evolution model has been transformed into a numerical algorithm and implemented in the Abaqus commercial code, in its explicit form, through the VUMAT sub-routine. Results have been obtained and compared with the experimental values, validating the suggested model. Damage evolution for the SAE 1050 steel has been also compared with results from literature for other C-Mn steels. Empirical relationships between C level and damage parameters such as limit strain for damage initiation, resistance to damage evolution and maximum allowable damage, have been developed and presented, envisaging their application as general guidelines, without requiring a sequence of dedicated tests, making easier the usage of damage mechanics under industrial conditions.

Os objetivos deste trabalho foram avaliar diferentes modelos de seleção com base nos efeitos aleatórios maternos considerados para características de crescimento e perímetro escrotal, estimar parâmetros genéticos para pesos do nascimento aos 12 meses (pesos ao nascer, a desmama e aos 12 meses de idade); perímetro escrotal aos 12 meses e correlações genéticas entre as características para bovinos compostos Montana Tropical, em análises uni, bicaracterísticas. Estimar parâmetros genéticos para as características categóricas de musculosidade, precocidade e conformação aos 12 meses em modelos uni e bicaracterísticas utilizando diferentes metodologias para análise (modelos mistos, modelos thresholds bayesianos e modelos lineares generalizados mistos) e compará-los. Nas análises feitas para as características de crescimento e perímetro escrotal os efeitos maternos influenciaram os pesos do nascimento aos 12 meses de idade. As estimativas de herdabilidade direta obtidas das análises bicaracterísticas foram superiores àquelas obtidas das análises unicaracterísticas e as estimativas pela análise bicaracterística para as herdabilidades foram 0,27 para peso ao nascer; 0,18 para peso à desmama; 0,20 para peso aos 12 meses; e 0,19 para perímetro escrotal aos 12 meses. As correlações genéticas estimadas entre pesos obtidos em idades jovens com peso ao ano foram moderadas a baixas (< 0,60). A correlação genética obtida entre perímetro escrotal e características de crescimento foram 0,04, e <0,01 com peso a desmama indicando baixa associação entre as características e de 0,38 com peso aos 12 meses o que pode ao longo do tempo gerar animais mais pesados aos 12 meses. A seleção com base em características de crescimento em qualquer idade pode promover ganhos genéticos moderados no peso corporal de animais do composto Montana Tropical. É importante considerar nas análises os pesos prévios à seleção para estimar parâmetros genéticos para pesos após a seleção. Para as características morfológicas as estimativas de herdabilidade foram de baixas a moderadas e houve diferença entre o modelo linear e o de limiar e o modelo linear generalizado misto, na obtenção de estimativas de herdabilidades e correlações genéticas, de características categóricas morfológicas multinomiais. As estimativas dos parâmetros genéticos obtidas por modelo de limiar foram superiores aos demais métodos avaliados, com valores de 0,42; 0,37 e 0,25 para musculosidade, precocidade e conformação aos 12 meses, e as correlações genéticas estimadas em conjunto com peso a desmama para musculosidade, precocidade e conformação aos 12 meses foram 0,89; 0,22 e 0,83 respectivamente. Os escores visuais de conformação, precocidade e musculatura aos 12 meses podem responder rapidamente à seleção individual. / The objectives this study were to evaluate different models of selection based on maternal random effects considered for growth traits and scrotal circumference; to estimate genetic parameters for weights from birth to 12 months (birth weight, weaning and 12 months old), scrotal circumference at 12 months and to estimate genetic correlations between traits for cattle composite Montana Tropical, by univariate and two-trait analysis. To estimate genetic parameters for categorical traits of muscling, precocity and conformation at 12 months in uni-and two-trait models using different methodologies for analysis (mixed models, Bayesian models thresholds and generalized linear mixed models) and compare them. In the analysis made for growth traits and scrotal circumference, maternal effects influenced the weights from birth to 12 months of age. Direct heritability estimates obtained from two-trait analyzes were higher than those obtained using univariate models, and the estimates of heritability for the two traits analysis were 0.27 for birth weight, 0.18 for weaning weight, 0.20 for weight at 12 months , and 0.19 for scrotal circumference at 12 months. The genetic correlation obtained between weights at young ages and yearling weight were moderate to low ( < 0.60). Genetic correlation obtained between scrotal circumference and growth traits were 0.04, and < 0.01 with weaning weight indicating a low correlation between the traits and 0.38 from weight at 12 months which may over time provide heavier animals at 12 months. Selection based on growth traits at any age can provide moderate genetic gains in body weight of animals of the composite Montana Tropical. It is important to consider in the analysis to selecting the prior weights to estimate genetic parameters for weights after selection. For the morphological traits, heritability estimates were low to moderate and there was a difference between the threshold and linear model and generalized linear mixed model, for estimates of heritability and genetic correlations of morphological multinomial categorical traits. Estimates of genetic parameters by the threshold model were higher than the other methods evaluated, with values of 0.42, 0.37 and 0.25 for muscling, precocity, and conformation at 12 months, and the genetic correlations estimated in with weaning weight for muscling, precocity and conformation at 12 months were 0.89, 0.22 and 0.83 respectively. The visual scores of conformation, precocity and muscling at 12 months can respond quickly to individual selection.

No description available.

Controlling conformation of macromolecules, both in solution and solid state, has remained an exciting challenge till date as it confronts the entropy driven random coil conformation. Folded forms of biomacromolecules, like proteins and nucleic acids, have served as role-models to the scientists in terms of designing synthetic foldamers. The folded functional forms of proteins and nucleic acids have been shown to rely heavily on various factors, like directional hydrogen bonding, intrinsic conformational preferences of the backbone, solvation (e.g. hydrophobic effects), coulombic interactions, charge-transfer interactions, metal-ion complexation, etc. Chapter-1 discusses various designs of synthetic polymers explored by research groups world-over to emulate the exquisite conformational control exercised by biomacromolecular systems. Our laboratory has been extensively involved since 2004 in designing charge-transfer complexation induced folding of flexible donor-acceptor (DA) polymeric systems, such as those shown in Scheme 1. It was observed that such polymers adopt a folded conformation in polar solvents, like methanol, in the presence of an excess of an appropriate alkali metal ion. To explore folding in the solid state, Jonas and co-workers recently showed that a polyethylene-like polyester with long alkylene segments containing periodically located pendant propyl group forms a semicrystalline morphology with alternating crystalline and amorphous regions primarily because of the periodic folding of the backbone due to the steric exclusion of the propyl branches from the crystalline domains. In order to explore immiscibility-driven folding of polyethylene-like polyesters, Roy et al. designed a periodically grafted amphiphilic copolymer (PGAC) containing long alkylene segments (mimicking polyethylene) and pendant oligoethyleneglycol chains at periodic intervals (Scheme 2). Scheme 2: Proposed folding of a periodically grafted amphiphilic copolymer It was demonstrated that immiscibility between the hydrocarbon backbone and pendant PEG segments drives the polymer to adopt a folded zigzag conformation as shown in Scheme 2. The above synthetic strategy, however, does not permit easy structural variation of the side chain segments because the side-chain segment is covalently linked to the malonate monomer. In Chapter-2, a more general strategy to prepare periodically grafted copolymers has been described. In an effort to do so, we designed a series of clickable polyesters carrying propargyl/allyl functionality at regular intervals along the polymer backbone, as shown in Scheme 3. Scheme 3: Periodically clickable polyesters for the preparation of periodically grafted copolymers The polyesters were prepared by reacting either 2-propargyl-1,3-propanediol, 2,2-dipropargyl-1,3-propanediol or 2-allyl-2-propargyl-1,3-propanediol with an alkylene diacid chloride, namely 1,20-eicosanedioic acid chloride, under solution polycondensation conditions. Since these polyesters carry either, one propargyl, two propargyls or one propargyl and one allyl group on every repeat unit, it provides us an opportunity to synthesise exact graft copolymers with one side chain, two side chains or even two dissimilar side chains per repeat unit. In Chapter-3, the periodically clickable polyesters were reacted with MPEG-350 (PEG 350 monomethyl ether) azides using Cu(I) catalyzed azide-yne click reaction to generate periodically grafted amphiphilic copolymers (PGAC) carrying crystallizable hydrophobic backbone and pendant hydrophilic MPEG-350 side-chains (Scheme 4). Since the PGACs carry either one or two pendant MPEG-350 chains on every repeat unit, it allowed us to examine the effect of steric crowding on the crystallization propensity of the central alkylene segment. Scheme 4: Functionalization of periodically clickable polyesters with MPEG 350 azide by azide-yne click reaction From DSC studies, it was observed that increase in steric crowding at junctions resulting from increased side-chain volume hinders effective packing of the hydrocarbon backbone. As a result, both transition temperatures and the enthalpies associated with these transitions decreases. SAXS and AFM studies revealed the formation of lamellar morphology with alternate domains of PEG and hydrocarbon. Based on these observations, we proposed that self-segregation between hydrophobic backbone and hydrophilic side-chains induce the backbone to adopt a folded zigzag conformation (Scheme 5). Scheme 5: Schematic depiction of self-segregation induced folding of PGAC and their assembly on mica surface (AFM image) In order to study the effect of solvent polarity on conformational evolution of the periodically grafted amphiphilic copolymers, we randomly incorporated pyrene in the backbone of the polymer by reacting a small fraction (~ 5 mole %) of the propargyl groups with pyrene azide. Fluorescence study of the pyrene labelled polymer showed that increase in solvent polarity increases the intensity of the excimer band dramatically; this suggests the possible collapse of the polymer chain to the folded zigzag form. In an extension of this work, the PGAC was further used as template to synthesise layered silicates that appears to replicate the lamellar periodicity seen in the polymer. In order to study the effect of reversing the amphiphilicity on self-segregation, in Chapter-4, we synthesised a series of clickable polyesters carrying PEG segments of varying lengths, namely PEG 300, PEG 600 and PEG 1000, along the polymer backbone. The polymers were prepared by trans-esterification of 2-propargyl dihexylmalonate with different PEG-diols. These polyesters were then clicked with docosyl (C22) azide using Cu(I) catalyzed azide-yne click reaction to generate the desired periodically grafted amphiphilic polymers carrying crystallizable hydrophobic pendant chains at periodic intervals; the periodicity in this case was governed by the length of the PEG diols (Scheme 6). Scheme 6: PGACs carrying hydrophilic PEG backbone and crystallizable hydrophobic pendant docosyl chains Varying the average periodicity of grafting provided an opportunity to examine its consequences on the self-segregation behavior. Given the strong tendency of the pendant docosyl segments to crystallize, DSC studies proved useful to analyse the self-segregation; DOCOPEG 300 clearly exhibited the most effective self-segregation, whereas both DOCOPEG 600 and DOCOPEG 1000 showed weaker segregation. Based on the observations from DSC studies, we proposed that the PEG backbone adopts a hairpin like conformation (Scheme 7). Scheme 7: Proposed self-segregation through hairpin like conformation of backbone PEG segments In order to confirm the bulk morphology, we carried out small angle X-ray scattering (SAXS) and atomic force microscopic (AFM) studies. The SAXS profiles confirmed the observations from DSC studies, and only DOCOPEG 300 exhibited well-defined lamellar ordering. Thus, it is clear that the length of the backbone PEG segment (volume-fraction) strongly influences the morphology of the PGACs. Based on the inter-lamellar spacing from SAXS and the height measurements from AFM studies (Scheme 8), we proposed that these polymers form lamellar morphology through inter-digitation of the pendant docosyl side-chains. The observations from Chapters 3 and 4 suggested that the crystallization of the backbone has a dramatic effect on the conformation of the polymer backbone. In order to explore the possibility of independent crystallization of both backbone and pendant side-chains, the periodically clickable polyesters, described in Chapter-2, were quantitatively reacted with a fluoroalkyl azide, namely CF3(CF2)7CH2CH2N3 using Cu(I) catalyzed azide-yne click reaction; Chapter-5 describes these polyesters carrying long chain alkylene segments along the backbone and either one or two perfluoroalkyl segments located at periodic intervals along the polymer chain (Scheme 9). DSC thermograms of two of the samples showed two distinct endotherms associated with the melting of the individual domains, while the WAXS patterns confirm the existence of two separate peaks corresponding to the inter-chain distances within the crystalline lattices of the hydrocarbon (HC) and fluorocarbon (FC) domains; this confirmed the occurrence of independent crystallization of both the backbone and side chains. Scheme 10: Left-variation of SAXS profile of all three polymers as a function of temperature, Right- molecular modelling of representative FC-HC-FC triblock structures. Interestingly, a smectic-type liquid crystalline phase was observed at temperatures between the two melting transitions. SAXS data, on the other hand, revealed the formation of an extended lamellar morphology with alternating domains of HC and FC (Scheme 10). The inter-lamellar spacing calculated from SAXS matches reasonably well with those estimated from TEM images. Based on these observations, we proposed that the FC modified polymers adopt a folded zigzag conformation whereby the backbone alkylene (HC) segment becomes colocated at the center and is flanked by the perfluoroalkyl (FC) groups on either side, as depicted in Scheme 11. Melting of alternate HC domains first leads to the formation of a smectic-type liquid crystalline mesophase, wherein the crystalline FC domains retain the smectic ordering; this was confirmed by polarizing light microscopic observations. Scheme 11: Schematic presentation of self-segregation induced folding of polymer chains; and hence crystallization assisted assembly of these singly folded chains to form lamellar structure One interesting challenge would be to create unsymmetrical folded structures, wherein the top and bottom segments of the zigzag folded form would be occupied by two different segments, such as PEG and FC, whereas the backbone alkylene segment would form the central domain; this would lead to the possible formation of consecutive domains of PEG, HC and FC through immiscibility driven self-segregation process. In Chapter-6, several approaches to access such systems have been described; one such design that could have resulted in the successful synthesis of a periodically clickable polymer carrying orthogonally clickable propargyl and allyl groups along the backbone in an alternating fashion is depicted in (Scheme 12). The parent polyester was successfully synthesized and the propargyl group was first clicked with the FC-azide to yield the FC-clicked polyester; however, several attempts to click MPEG-SH onto the allyl groups using thiol-ene click reaction failed. Scheme 12: Scheme for the synthesis of alternating orthogonally clickable polymer In order to accomplish our final objective, we chose to first prepare the FC-clicked diacid chloride and polymerize it with an azide-alkyne clickable macro-diol, as depicted in Scheme 13; this approach was successful and yielded the desired clickable polyester bearing the FC segments at every alternate location. This polymer was then clicked with PEG-750 azide to yield the final targeted polymer that carries mutually immiscible FC and PEG-750 segments at alternating positions along the polymer backbone. The occurrence of self-segregation of FC, PEG-750 and the alkylene backbone (HC) was first examined by DSC studies, which appeared to suggest the presence of three peaks, although these were not very well-resolved. Scheme 13: Schematic for the synthesis of the polymer carrying FC and PEG 750 alternatingly along the backbone A schematic depiction of the anticipated organization of such unsymmetric folded macromolecules is shown in Scheme 15; it is evident that because of mutual immiscibility, the layers will be organized such that the FC domains of adjacent layers will be together and similarly the PEG domains of adjacent layers will also be together. Such an organization would lead to an estimated spacing that would correspond to a bilayer of the folded structures. Interestingly, SAXS study (Scheme 14) reveals the formation of lamellar morphology with a d-spacing of 14.6 nm. Scheme 14: Figure 6.10: SAXS profile of the polymer PE-FC-PEG 750 In order to gain an estimate of the expected inter-lamellar spacing, the end-to-end distance of a model repeat-unit was computed to be ~ 9.4 nm. It is, therefore, evident that the inter-lamellar spacing of 14.6 nm seen in the SAXS is significantly larger and must represent a bilayer type organization (Scheme 15). In this regard it is important to say that the organization of these alternatingly functionalized folded chains should give a variety of d-spacings. Because of highest electron density contrast of FC among PEG, HC and FC, we proposed that the d-spacing calculated from the SAXS profile corresponds to ‘d4’ in Scheme 15. This first demonstration of the formation of zigzag folded unsymmetric entities bearing dissimilar segments on either side of the folded chain holds exciting potential for a variety of different applications and beckons further investigations. Scheme 15: Schematic for the proposed self-assembly of the singly folded polymer chains

Des décennies d'études ont montré que la structure de la chromatine est étroitement liée aux processus métaboliques de l'ADN. Une bonne organisation des chromosomes tout au long du cycle cellulaire est particulièrement importante pour assurer le maintien de l'intégrité de l'ADN. Le but de mon projet de doctorat était de caractériser dans quelle mesure la réorganisation de la chromatine pendant le cycle cellulaire pourrait influencer la stabilité des chromosomes. Pour ce faire, nous avons d'abord effectué une étude complète de la réorganisation des chromosomes de la levure modèle Saccharomyces cerevisiae pendant tout un cycle cellulaire. Ce travail, en plus de récapituler les caractéristiques chromosomiques attendues, a conduit à la caractérisation de structures chromosomiques particulières, telle qu'une boucle d'ADN reliant l'ADNr et les centromères. Le rôle des complexes SMC et des microtubules a été étudié en profondeur. Une deuxième partie de mon travail a porté sur la description de l'organisation de la chromatine de cellules qui ont quitté le cycle cellulaire prolifératif et sont entrées en quiescence. Nous avons ainsi caractérisé le statut dense de l'hétérochromatine silencieuse dans des loci spécifiques tels que les télomères. Enfin, nous avons essayé de mieux comprendre l'interaction fonctionnelle entre la stabilité chromosomique et l'architecture 3D du génome durant la réplication en étudiant la stabilité génomique à des sites de pause de réplication. Nos résultats indiquent une adaptabilité frappante des structures de réplication sous différentes contraintes. Le travail futur vise à cartographier les réarrangements chromosomiques dépendants de la réplication. / Decades of studies showed that chromatin structure is tightly linked to DNA related metabolic processes, through the dynamic regulation of a myriad of molecular factors. The proper organization of chromosomes is notably important to ensure the maintenance of DNA integrity during cell cycle progression. Using the model S. cerevisiae, the aim of my PhD project was to characterize to which extent chromatin reorganization during the cell cycle may influence chromosome stability. To do so, we first generated a comprehensive genome-wide study of the reorganization of yeast’s chromosomes during an entire cell cycle. This work, besides recapitulating expected chromosomal features of the replication and mitotic stages, led to the characterization of peculiar chromosome structures such as a DNA loop bridging the rDNA and the centromeres. The role of structural maintenance of chromosomes (SMC) complexes and of microtubules were thoroughly investigated. A second part of my work focused on describing features of the chromatin organization of cells that exited the proliferative cell cycle and entered into quiescence. We characterized the dense status of silenced heterochromatin at specific loci, such as telomeres, in relation to the silent information regulators (SIRs). Finally, we tried to achieve a better understanding of the functional interplay between chromosome stability and the 3D genome architecture during replication, by investigating the genomic stability at replication pausing sites. Overall, our results point at a striking plasticity of replication structures to different stresses. Future work aims to map replication-dependent chromosomal rearrangements on the genomic maps.

Le travail décrit dans ce manuscrit est consacré à la synthèse et à la caractérisation structurale d'une nouvelle famille de γ-amino acides hétérocycliques contraints, les ATCs (acides 4-Amino-(méthyl)-1,3-Thiazole-5-Carboxyliques). Ces monomères sont construits autour d'un noyau thiazole inséré entre les carbones Cα-Cβ permettant de limiter la valeur de l'angle dièdre ζ à 0°. La présence de deux points de substitution, sur le carbone γ asymétrique et en position 2 du noyau aromatique, autorise une large diversification structurale des ATCs. Des séries d'oligomères, i.e. dimères, tétramères et hexamères solubles dans les solvants organiques halogénés, dans les alcools et dans l'eau ont été synthétisées par couplages peptidiques. La conformation adoptée par ces séquences a été déterminée en solution par RMN 1D et 2D associées à des techniques de modélisation sous contraintes RMN. Nous avons montré que les oligomères d'ATCs s'arrangeaient en hélices 39 droites, présentant un pas de 11,8 Å. La conformation hélicoïdale est stabilisée par un réseau de liaisons hydrogène de type CO(i)…NH(i+2) s'établissant tout au long de la séquence, faisant entrer les oligomères d'ATCs dans le monde des foldamères. Des mesures de dichroïsme circulaire ont permis d'apprécier la stabilité conformationnelle des édifices et l'analyse à l'état solide par diffraction des rayons X a confirmé l'arrangement observé par RMN. Dans une seconde partie nous avons étudié le rôle structurant d'un motif ATC placé au sein d'une petite séquence peptidique. Nous montrons au travers d'expériences RMN et de calculs théoriques que la configuration du monomère d'ATC conditionne la conformation de peptides hybrides αγαα en solution. En termes d'application nous décrivons l'utilisation du motif ATC comme mime de coude pour concevoir un analogue fonctionnel de la gramicidine S, un cyclodécapeptide symétrique antibactérien. La dernière partie de ce travail concerne nos efforts pour développer, à partir des connaissances acquises quant à la structure tridimensionnelle des oligomères d'ATCs, des inhibiteurs de l'interaction protéine-protéine STAT6-NCoA-1. / The work described herein is devoted to the synthesis and the structural characterization of a new family of heterocyclic constrained γ-amino acids, named ATCs (4-Amino-(methyl)-1,3-Thiazole-5-Carboxylic acids). These building-blocks are built around a thiazole ring inserted between the Cα-Cβ carbons allowing the limitation of the ζ dihedral angle value to 0°. The presence of two diversification points both on the γ asymmetric carbon and on the position 2 of the aromatic ring, allows a large structural diversification of the ATCs. Series of oligomers consisting in dimers, tetramers and hexamers soluble in halogenated solvents, alcools and water have been synthesized according to peptide chemistry. The conformations of the sequences have been studied by various NMR experiments associated to modelling studies led under NMR constraints. The ATC oligomers adopt a right 39 helical shape, owning a pitch of 11.8 Å which has been confirmed by crystallography. The helix is stabilized by a conserved hydrogen bond pattern between CO(i)…NH(i+2) occurring all along the sequence axis. Circular dichroism measures have been done to check the conformational stability of the architectures. In the second part of the manuscript, we demonstrate by NMR and theoretical computing that when included in a short peptide sequence, ATCs could act as turns. The derived application consists in optimizing the biological behaviour of the ATC moiety as a turn mimetic thanks to the design and the antibacterial evaluation of a gramicidin S analogue. Based on our knowledge about the three-dimensional structure of ATC oligomers, the last part of this work deals with our efforts to develop inhibitors of protein-protein interaction STAT6-NCoA-1.

Un important dispositif de détection de QTL caprin laitier basé sur 2 254 chèvres génotypées sur puce SNP 50K et issues de 20 mâles d'IA séquencés a été mis en place. Des QTL avaient déjà été détectés pour de nombreux caractères laitiers ou de morphologie. Un certain nombre de caractères restait néanmoins à étudier ou à approfondir. Dans un premier temps, une analyse de type GWAS a été réalisée sur cinq caractères. Pour deux d'entre eux, les trayons surnuméraires et le débit de traite, nos résultats sont en faveur d'un déterminisme polygénique. Pour deux phénotypes de coloration indésirables en race Saanen et la présence de pampilles, une région du génome a été trouvée comme très significativement associée au phénotype (chromosomes 11, 13 et 10 respectivement). Le gène ASIP est un candidat fonctionnel et positionnel très prometteur pour le QTL du chromosome 13 qui agit sur la coloration rose des animaux Saanen. En revanche, malgré une analyse plus poussée des deux autres zones via l'analyse de séquences et des génotypages, aucune mutation causale candidate n'a pu être identifiée. Enfin, nous avons étudié deux mutations associées à des différences de taux butyreux qui avaient été précédemment identifiées dans le gène DGAT1 caprin. Après avoir produit in vitro les différentes versions de la protéine en système " baculovirus/cellules de lépidoptère ", l'activité enzymatique des différents variants a été testée sur le diglycéride DAG 10 :10. Nos résultats confirment l'effet délétère des mutations sur la production de triglycérides et signent ainsi la causalité de ces mutations. Ces travaux ont permis de mettre en évidence de nouvelles régions du génome impliquées dans le contrôle de caractères d'intérêt pour la filière et ont prouvé la causalité de deux mutations. L'ensemble de ces résultats pourra aider la filière à mieux gérer ces phénotypes dans le schéma. / A large daughter design based on 2 254 genotyped dairy goats genotyped on a 50K SNP chip and their 20 sequenced fathers was carried out for mapping traits of interest in French dairy goats and QTL have been detected for some dairy and morphologic traits. However, in-depth studies were needed and some unstudied traits remained. A GWAS analysis was performed on five different traits. For two of them: supernumerary teats and milk flow, results showed a polygenic determinism. For the three others: two undesired coat color in the Saanen breed and the presence of wattles, a genome region was very significantly associated with each of these phenotypes (chromosomes 11, 13 and 10 respectively). The ASIP gene is a strong functional and positional candidate for the QTL on chromosome 13 for the pink coat trait. Despite in-depth analyses for the two other regions using sequences data and genotyping, no candidate causal mutation has been identified. Finally, two mutations previously identified in the DGAT1 gene and statistically associated with differences of milk fat content have been investigated. After in vitro production of the different version of the protein by a baculovius system, the enzymatic activity was assessed on diglyceride DAG 10:10. The results attest the deleterious effect of these mutations on triglyceride production and prove the causality of the mutations. This work lead to the identification of new genome regions associated with traits of interest and will be useful for the breeding organization.