Chicken feathers are the most abundant keratinous biomass in the world. Disposal of thehuge and increasing volume of waste feathers presents as a major concern for poultryindustry. On the other hand, energy and material recovery of this valuable protein sourceis an important issue for organic solid waste treatment and bioenergy generation.Anaerobic digestion is an environmentally and economically promising alternativeprocess for biogas production of waste feathers.In this study in order to enhance the methane potential of batch anaerobic digestion ofchicken feathers this waste was treated by various kinds of pretreatments includingthermal, thermo-chemical, enzymatic, thermo-enzymatic and chemo-enzymatic methods.Also the effect of different treatment conditions on the methane yield was investigated.As a whole, thermo-chemical pretreatment with lime (Ca(OH)2) rendered the mostsignificant effect on enhancement of the chicken feathers methane potential. In particularlime treated triplicate samples under treatment condition of 40g TS feather/l water, 0.1gCa (OH)2 /g TS feather, 100°C and 30 min produced the highest amount of methane (anaverage maximum volume of 480 Nml/g VS, which is about 96.8% of the theoreticalmethane potential of protein), during 50 days of anaerobic incubation. Increasing theoperational parameters such as feather concentration, lime loading, temperature andreaction time improved the feathers solublisation resulting in a higher soluble chemicaloxygen demand (SCOD) concentration of the samples but inserted negative impacts onthe anaerobic digestion performance. Although other pretreatment methods improved theSCOD concentrations of the feathers too, compared to the lime treatment those methodsdidn’t show considerable effects on the enhancement of methane yield from the chickenfeathers. Thermo-enzymatic, enzymatic, and thermal pretreated triplicate samplesproduced an average maximum of 185 Nml/g VS, 154 Nml/g VS, and 143 Nml/g VS(37.3%, 31%, 28.8% of the theoretical methane potential) respectively, during 33 days of50 days of anaerobic incubation. Especially, chemo-enzymatic pretreated sample showednegative methane potential of only 41 Nml/g VS, i.e. 8% of the theoretical methanepotential. Consequently, lime pretreatment under the above recommended conditions canbe suggested for hydrolysis of chicken feathers to achieve significant enhancement of itsmethane potential.

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La sélection de sous-ensembles de molécules diverses est un enjeu très important de la recherche pharmaceutique. En effet, de la qualité de cette sélection, dépendra la découverte efficace d'un médicament. De nombreuses méthodes existent pour répondre à cette demande. Certaines sont basées sur la création de groupes de molécules, d'autres sur le principe de dissimilarité inter-moléculaire. Nous proposons dans ce travail, une nouvelle technique à la croisée de ces méthodes, qui permet d'obtenir des sous-ensembles à la fois divers dans l'espace et représentatifs de l'ensemble initial duquel ils sont extraits. Pour créer cette méthode de sélection, nous avons tout d'abord défini et formalisé mathématiquement un critère de diversité, puis nous nous sommes appuyés sur des heuristiques connues en apprentissage artificiel pour concevoir l'algorithme. Celui-ci a été comparé à d'autres types de sélections de diversité couramment utilisées en chémoinformatique telles que les k-medoïds, Maximum-Dissimilarity, Sphere-Exclusion. La formalisation du critère de diversité nous a enfin permis de proposer un nouveau critère d'évaluation de la qualité des sélections. La méthode et le critère présentés dans ce travail donnent des échantillons divers et représentatifs d'un espace chimique.

Mud crabs of the genus Scylla are widely exploited for aquaculture in the Asia- Pacific region. In the current study, a series of in vivo experiments were carried to assess the protein requirement, protein sparing effects of starch and the capacity of Scylla serrata to digest diets that contained different animal and plant-based feed meals and different levels and types of starch. Results from a protein requirement study indicated that juvenile S. serrata fed diets containing 45% or 55% protein demonstrated significantly higher growth responses than those fed the diet containing 25% protein. The subsequent study was carried out to determine if responses to dietary protein could be influenced by using purified wheat, potato, rice or corn starch to manipulate the gross energy level of fishmeal- based diets (18 or 15.5 MJ kg-1), i.e., to see if starch had a protein sparing effect in these animals. Overall, growth responses in this study appeared to be positively correlated with the level of protein in the diet with the highest growth rates achieved using diets containing 45% protein, regardless of the energy level of the diet. In addition, at a dietary protein level of 40% there was no evidence that the source of starch had any significant impact on growth performance or feed utilisation suggesting it had no protein sparing effect. By contrast, it was found that growth of juvenile S. serrata was strongly correlated with the intake of digestible dietary protein. The investigation of the capacity of sub-adult S. serrata to digest different animal and plant- based feed meals showed that apparent dry matter digestibility (ADMD) and apparent gross energy digestibility (AGED) values were not significant different for most selected feed meals (cotton seed, poultry, canola, fishmeal, soybean, and lupin meal). Apparent crude protein digestibility (ACPD) for all test feed meals were relatively high (86-96%). A subsequent study was carried out to determine if purified starch from different sources influenced the digestibility of fishmeal based diets. Overall, most diets containing starch were readily digested by mud crabs. In particular, there were no negative impacts on the digestibility of major nutrients (e.g. protein) observed following the inclusion of wheat, rice or corn starch in formulated feeds. Nevertheless, the apparent starch digestibility (ASD) of wheat starch decreased significantly as the inclusion level was increased from 15% to 60%, although there was no significant effect on ACPD values. At a 30% inclusion level, the ASD of diets containing different starches decreased in the order corn > wheat > potato = rice. Moreover, ACPD values were significantly higher for diets containing corn or rice starch than for those containing wheat or potato starch. The capacity of another species of mud crab commonly exploited for aquaculture in South East Asia, S. paramamosain, to digest the local plant-based ingredients (defatted soybean meal, rice bran, cassava and corn flour) was also conducted in Vietnam. Overall, the findings of this study showed that at a 30% inclusion level diets containing soybean meal or rice bran were well digested by mud crabs. In particular, the ACPD and AGED values for all diets containing soybean meal were not significantly different from the fishmeal based reference diet. Likewise, all digestibility values for the diet containing 30% rice bran were relatively high and not significantly different from the reference diet. By contrast, diets containing cassava flour appeared to be poorly utilised since their digestibility values for all parameters were lower than those from other testingredients. In summary, the apparent digestibility of dry matter, protein and energy was in the following order (from most to least digestible) soybean meal ~ rice bran > corn flour > cassava flour. In the next study the effects of attractants in diets (chicken meal, betaine, tuna oil and bait enhancer), temperature (26.5oC, 28.5oC and 30.5oC), sex (female and male) and size (small, medium and large) on feeding responses of S. serrata were investigated. Significant differences were observed in the behavioral responses of mud crabs to diets containing different attractants. Specifically, consumption of diets with chicken meal or betaine was significantly higher than for other treatments. With the exception of betaine, no significant difference in food consumption was observed when attractant inclusion levels were raised from 2% to 5%. Overall, small crabs consumed significantly more of the ration (as a percentage of body weight) than larger crabs. Temperature showed a significant impact on most behaviour of mud crabs, excepting continuation response and there was some evidence that females were significantly more active than males. Light intensity was considered as a main factor effect to crab response since there were extremely high percentage time of crab spent in half-shaded of the Y –maze which valued at 95.6%, 93.8 and 94.4% (corresponded to small, medium and large size respectively) in comparison to those of crabs spent in the unshaded side. Overall, the findings from these studies demonstrated that mud crabs have a high capacity to digest a range of plant based feed ingredients. In particular, soybean meal appeared to be well digested by both species of mud crabs examined. It was also shown that a range of purified starches were well digested by S. serrata although starch inclusion in diets did not appear to reduce the requirement for protein to promote growth. Subsequent attractant studies demonstrated that chicken meal and betaine produced significantly elevated feeding responses and food consumption when added to diets. Based on these results we propose that these ingredients can be utilised to increase the attractiveness and consumption of artificial mud crab feeds.

Ces travaux de thèse portent sur la conception par voie chimio-enzymatique de polymères amphiphiles issus de glycolipides, capables de s’auto-assembler en phase aqueuse et susceptibles de répondre à des applications de vectorisation de principes actifs. Après une étude préalable des paramètres influents lors de la synthèse enzymatique, huit monomères glycolipidiques porteurs de fonctions esters vinyliques,méthacrylate ou [alpha]-méthylstyrène ont été synthétisés à partir de dérivés d’huile de ricin et de glucose. Les monomères porteurs d’une fonction ester vinylique comme groupement polymérisable ont été copolymérisés en présence d’acétate de vinyle mais les copolymères ainsi formés n’ont pas montré de capacité à s’autoassembler. Les monomères fonctionnalisés par un groupement méthacrylate, ont été copolymérisés en présence de méthacrylate de méthyle ; trois gammes de copolymères ont ainsi été synthétisées par polymérisation radicalaire, les deux premières selon un mécanisme non contrôlé en présence d’un agent de transfert thiolé ou pas et la troisième selon la méthodologie RAFT. Dans tous les cas, des nanoparticules bien définies et stables pendant plusieurs mois ont été obtenues par auto-assemblage de ces trois gammes de copolymères en phase aqueuse. Le Rouge de Nil a été piégé au sein de ces nanoparticules puis relargué par ajout de chlorure de sodium, laissant entrevoir des applications de stabilisation et de vectorisation de principes actifs pour ces nouveaux copolymères. / The aim of this thesis was the conception of amphiphilic polymers able to self-assembly in water forpotential drug delivery applications, from glycolipidic monomers synthesized by a chemo-enzymatic pathway.After a preliminary study of the influent parameters on glycolipid synthesis via enzymatic catalysis, eightmonomers bearing either vinyl ester, methacrylate or a-methylstyrene groups have been synthesized fromglucose and castor oil derivatives. The vinyl ester-bearing monomers have been copolymerized with vinylacetate. Unfortunately, the resulting copolymers did not show interesting self-assembly properties in water.Three families of copolymers were synthesized from the methacrylate-bearing monomers and methylmethacrylate, either by free radical polymerization in the presence or not of a transfer agent or by reversibleaddition-fragmentation polymerization (RAFT). Well-defined and stablenanoparticles were obtained from allthose copolymers. Nile Red was successfully trapped into those nanoparticles and released by adding sodiumchloride, allowing perspectives as potential drug delivery applications for those new copolymers.

Les ADN topoisomérases de type 2 (Top2) sont des protéines universelles et essentielles à la vie cellulaire. Elles ont pour fonction de réguler de manière fine l’équilibre topologique de l’ADN. Chez l’homme, les Top2 (HsTop2) sont des cibles thérapeutiques de première importance en oncologie. Des molécules telles que l’étoposide et la doxorubicine font partie des traitements anticancéreux les plus utilisés en clinique à l’heure actuelle, elles agissent en stabilisant les complexes Top2/ADN/inhibiteurs qui sont transformés en lésions permanentes dont l’accumulation entraîne la mort cellulaire. Mon travail de thèse porte sur la caractérisation fonctionnelle et structurale des isoformes des HsTop2 entières en complexe avec des composés thérapeutiques. Mon projet de thèse comporte trois axes principaux et complémentaires : (i) La production et la caractérisation fonctionnelle in vitro des isoformes recombinantes. Nous avons optimisé et simplifié les protocoles de surexpression des deux isoformes dans la levure et avons également mis au point leur expression dans les cellules de mammifère. (ii) une étude structurale par cryo-microscopie électronique sur les HsTop2 entières en complexe avec des composés thérapeutiques et des oligonucléotides. Ces premiers travaux ont permis l’obtention d’une carte tridimensionnelle de l’enzyme entière qui servira de base pour l’étude de l’architecture des HsTop2 au sein de complexes protéiques de plus grande taille. (iii) des expériences de protéomique chimique permettant de mettre à jour les cibles secondaires potentielles de l’étoposide et de la doxorubicine dans des extraits cellulaires de lignées cancéreuses. / The type 2 DNA topoisomerases are universal proteins essential for cell survival. These enzyme fine tune the topological equilibrium of the DNA in cells. The human proteins are major targets of therapeutics drugs used in oncology. Molecules like etoposide and doxorubicin are among the most effective anticancer drugs used in chemotherapy treatments; they form stable Top2/DNA/drugs complexes which are then transformed in permanent DNA damages. This thesis project focuses on the functional and structural characterization of these complexes using 3 main strategies:(i) the production and the in vitro functional characterization of the recombinant isoforms. We optimized and simplified the production and purification procedures and overexpressed both isoforms in mammalian cells. (ii) a structural study by cryoelectron microscopy on the full enzyme complex with DNA and therapeutic drugs. We obtained a 3D density map that will be used for further studies on the architecture of large HsTop2 associated complexes. (iii) ChemoProteomic experiments on cancer cell lines to highlight the potential etoposide and doxorubicin secondary targets.

La prédiction précise du comportement à long et court terme des structures en béton dans le domaine nucléaire est essentielle pour assurer des performances optimales (intégrité, capacité de confinement) pendant leur durée de vie. Dans le cas particulier des structures massives en béton, la chaleur produite au jeune âge par les processus d'hydratation ne peut pas s’évacuer rapidement, si bien que des températures élevées peuvent être atteintes et les gradients de température qui en résultent peuvent conduire à la fissuration, en fonction des conditions aux limites et contraintes internes auxquelles ces structures sont soumises. Les objectifs de cette étude sont (1) d'effectuer des simulations numériques afin de décrire et prédire le comportement thermo-chimio-mécanique au jeune âge d'une structure massive en béton dédiée au stockage de déchets en surface, et (2) de développer et appliquer des outils de changement d'échelle pour estimer rigoureusement, à partir de la composition du matériau, les propriétés physiques du béton nécessaires à une analyse au jeune âge. Une étude chimio-thermique visant à déterminer l'influence de la convection, du rayonnement solaire, du re-rayonnement et de la chaleur d'hydratation sur la réponse thermique de la structure est tout d’abord menée. Des recommandations pratiques concernant les températures de bétonnage sont fournies afin de limiter la température maximale atteinte au sein de la structure. Ensuite, au moyen d'une analyse mécanique, des stratégies de modélisation simplifiées et plus complexes (prenant en compte l’endommagement couplé au fluage) sont mises en œuvre pour évaluer des scénarios intégrant différentes conditions aux limites issues de l'analyse chimio-thermique précédente. Dans un second temps, une étude prenant en compte le caractère multi-échelle du béton est réalisée. Un modèle simplifié de cinétique d'hydratation du ciment est proposé. Les évolutions des fractions volumiques des différentes phases au niveau de la pâte de ciment peuvent être alors estimées. Par la suite des outils d’homogénéisation analytiques et numériques développés dans un cadre vieillissant sont présentés et appliqués pour estimer les propriétés mécaniques et thermiques des matériaux cimentaires. Les données d’entrée utilisées dans l'analyse structurelle sont finalement comparées avec les estimations obtenues dans l'analyse multiéchelle. Pour conclure, la stratégie proposée dans cette thèse vise à prédire le comportement des structures massives en béton à partir de la composition du béton au moyen d'une approche séquentielle: le comportement du béton est estimé via les outils de changement d’échelle, fournissant ainsi les données d'entrée pour l'analyse phénoménologique à l’échelle de la structure. / The accurate prediction of the long and short-term behaviour of concrete structures in the nuclear domain is essential to ensure optimal performances (integrity, containment roperties) during their service life. In the particular case of massive concrete structures, at early age the heat produced by hydration reactions cannot be evacuated fast enough so that high temperatures may be reached and the resulting gradients of temperature might lead to cracking according to the external and internal restraints to which the structures are subjected. The goals of this study are (1) to perform numerical simulations in order to describe and predict the thermo-chemo-mechanical behaviour at early-age of a massive concrete structure devoted to nuclear waste disposal on surface, and (2) to develop and apply upscaling tools to estimate rigorously the key properties of concrete needed in an early-age analysis from the composition of the material. Firstly, a chemo-thermal analysis aims at determining the influence of convection, solar radiation, reradiation and hydration heat on the thermal response of the structure. Practical recommendations regarding concreting temperatures are provided in order to limit the maximum temperature reached within the structure. Then, by means of a mechanical analysis, simplified and more complex (i.e. accounting for coupled creep and damage) modelling strategies are used to assess scenarios involving different boundary conditions defined from the previous chemo-thermal analysis. Secondly, a study accounting for the multiscale character of concrete is performed. A simplified model of cement hydration kinetics is proposed. The evolution of the different phases at the cement paste level can be estimated. Then, analytical and numerical tools to upscale the ageing properties are presented and applied to estimate the mechanical and thermal properties of cementbased materials. Finally, the input data used in the structural analysis are compared with the estimations obtained in the multiscale analysis. To conclude, the entire strategy proposed in this thesis aims at predicting the behaviour of massive concrete structures from the composition of the concrete by means of a sequenced approach: concrete behaviour is estimated using the upscaling tools, providing then the input data to the phenomenological analysis at the structure level.

Error-free DNA replication is paramount to maintaining genomic integrity. Despite being highly regulated, the process of DNA replication is often challenged by various intrinsic and extrinsic sources of replication stress. Failure to maintain the DNA replication quality reduces genomic stability, cell survival and results in diseases, such as cancer. Thus, cells rely on the replication stress response that detects perturbations in DNA replication and pauses or arrests cellular replication. Similar to other intrinsic replication obstacles, oncogene expression also induces the replication stress response that acts as a barrier to cancer, thereby mystifying how cancer develops. Here, we demonstrate that oncogene expression, similar to other replication stress inducing agents, induces single-stranded DNA (ssDNA) gaps that reduce cell fitness unless counteracted by translesion synthesis (TLS). Moreover, we find that TLS subverts the replication stress response in a wide range of cancer cell lines indicating that TLS is a previously unappreciated and unique cancer vulnerability. Mechanistically, we reveal that upon replication stress, TLS restricts replication fork slowing, reversal, and fork degradation, while maintaining continuous replication. Furthermore, we demonstrate that a small molecule inhibitor targeting the TLS factor, REV1, not only disrupts DNA replication and cancer cell fitness, but also synergizes with other therapies that induce replication gaps. Thus, our study places TLS at the center of cancer cell fitness as a necessary adaptation to overcome replication stress.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第18933号 / 工博第3975号 / 新制||工||1612(附属図書館) / 31884 / 京都大学大学院工学研究科社会基盤工学専攻 / (主査)教授 木村 亮, 教授 勝見 武, 准教授 木元 小百合 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Dans ce travail prospectif, nous proposons une modélisation intégrant un couplage thermo-chimio-mécanique pour les élastomères chargés et dissipatifs. En se basant sur les résultats et les observations de la littérature, nous avons développé un cadre thermodynamique général et proposé trois modèles phénoménologiques de comportement. Nos outils principaux sont la thermodynamique des processus irréversibles, la notion d'états intermédiaires, les matériaux standards généralisés. Une variable interne correspondant au degré de réticulation est introduite. L'évolution de cette variable prend en compte une influence thermique et mécanique à travers la pression hydrostatique. Il s'agit d'une des originalités de cette approche. Ce travail se place dans le cadre général des grandes transformations. Un schéma numérique de résolution monolithique des équations bilan par éléments finis est proposé. Ce schéma tient compte de l'hypothèse de faible compressibilité du matériau par un choix judicieux de relations faibles entre inconnues et par le choix des approximations pour ces dernières. La résolution en temps est traitée par un schéma d'Euler implicite associé à une technique de linéarisation de Newton-Raphson. Un modèle orienté objet du matériau thermo-chimio-mécanique est proposé et implémenté en langage Java dans le code FEMJava. Quelques exemples de simulation illustrent le potentiel de ces modèles en reproduisant de manière qualitative des observations expérimentales. / In this prospective study, we propose a new thermo-chemo-mechanical coupled model for dissipative filled rubber. This work is based on experimental observations and results from the literature. In this context, we have developed three phenomenological constitutive laws within a generic thermodynamical framework. The models enters the category of the thermodynamics of irreversible processes. Intermediate states are taken into account in the model which is build within the generalized standard materials framework. The degree of cure is introduced as an internal variable. The evolution of this variable takes into account the thermal influence and the mechanical influence via the hydrostatic pressure. This is one of the features making this model original. A finite strains approach is considered. A finite element model is applied to the global problem. A monolithic solution scheme is built based on an implicit Euler scheme associated to a of Newton-Raphson linearization technique. This scheme takes into account the weak compressibility of the material condition through, first, a judicious choice of weak relations between unknowns, and second, an adequate choice of approximations for the unknowns of problem to enforce the stability of the numerical scheme. An object-oriented model for the constitutive equations of the thermo-chemo-mechanical model is proposed and is implemented in Java into the FEMJava code. Some simulations illustrate the high potential of these models in qualitatively reproducing these experimental observations.