Cette thèse traite de la résistance du VIH-1 aux antirétroviraux, en particulier de l'activité antivirale de plusieurs inhibiteurs non nucléosidiques de la transcriptase inverse (INNTI) ainsi que des inhibiteurs de protéase (IP). Nous avons exploré l’émergence et la spécificité des voies de mutations qui confèrent la résistance contre plusieurs nouveaux INNTI (étravirine (ETR) et rilpivirine (RPV)) (chapitres 2 et 3). En outre, le profil de résistance et le potentiel antirétroviral d'un nouvel IP, PL-100, est présenté dans les chapitres 4 et 5. Pour le premier projet, nous avons utilisé des sous-types B et non-B du VIH-1 pour sélectionner des virus résistants à ETR, et ainsi montré que ETR favorise l’émergence des mutations V90I, K101Q, E138K, V179D/E/F, Y181C, V189I, G190E, H221H/Y et M230L, et ce, en 18 semaines. Fait intéressant, E138K a été la première mutation à émerger dans la plupart des cas. Les clones viraux contenant E138K ont montré un faible niveau de résistance phénotypique à ETR (3,8 fois) et une diminution modeste de la capacité de réplication (2 fois) par rapport au virus de type sauvage. Nous avons également examiné les profils de résistance à ETR et RPV dans les virus contenant des mutations de résistance aux INNTI au début de la sélection. Dans le cas du virus de type sauvage et du virus contenant la mutation unique K103N, les premières mutations à apparaître en présence d’ETR ou de RPV ont été E138K ou E138G suivies d’autres mutations de résistance aux INNTI. À l’inverse, dans les mêmes conditions, le virus avec la mutation Y181C a évolué pour produire les mutations V179I/F ou A62V/A, mais pas E138K/G. L'ajout de mutations à la position 138 en présence de Y181C n'augmente pas les niveaux de résistance à ETR ou RPV. Nous avons également observé que la combinaison de Y181C et E138K peut conduire à un virus moins adapté par rapport au virus contenant uniquement Y181C. Sur la base de ces résultats, nous suggérons que les mutations Y181C et E138K peuvent être antagonistes. L’analyse de la résistance au PL-100 des virus de sous-type C et CRF01_AE dans les cellules en culture est décrite dans le chapitre 4. Le PL-100 sélectionne pour des mutations de résistance utilisant deux voies distinctes, l'une avec les mutations V82A et L90M et l'autre avec T80I, suivi de l’addition des mutations M46I/L, I54M, K55R, L76F, P81S et I85V. Une accumulation d'au moins trois mutations dans le rabat protéique et dans le site actif est requise dans chaque cas pour qu’un haut niveau de résistance soit atteint, ce qui démontre que le PL-100 dispose d'une barrière génétique élevée contre le développement de la résistance. Dans le chapitre 5, nous avons évalué le potentiel du PL-100 en tant qu’inhibiteur de protéase de deuxième génération. Les virus résistants au PL-100 émergent en 8-48 semaines alors qu’aucune mutation n’apparaît avec le darunavir (DRV) sur une période de 40 semaines. La modélisation moléculaire montre que la haute barrière génétique du DRV est due à de multiples interactions avec la protéase dont des liaison hydrogènes entre les groupes di-tétrahydrofuranne (THF) et les atomes d'oxygène des acides aminés A28, D29 et D30, tandis que la liaison de PL-100 est principalement basée sur des interactions polaires et hydrophobes délocalisées à travers ses groupes diphényle. Nos données suggèrent que les contacts de liaison hydrogène et le groupe di-THF dans le DRV, ainsi que le caractère hydrophobe du PL-100, contribuent à la liaison à la protéase ainsi qu’à la haute barrière génétique contre la résistance et que la refonte de la structure de PL-100 pour inclure un groupe di-THF pourrait améliorer l’activité antivirale et le profil de résistance. / This thesis focuses on HIV-1 drug resistance and on the antiviral activity of several non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). We have explored the mutational pathways and resistance patterns of several new NNRTIs (etravirine (ETR) and rilpivirine (RPV)) (Chapters 2 and 3). In addition, the drug resistance profile and potential of a novel protease inhibitor (PI) PL-100 is presented in Chapters 4 and 5. In the first project, we used both B and non-B subtypes of HIV-1 to select for ETR resistance and showed that ETR selected for mutations at positions V90I, K101Q, E138K, V179D/E/F, Y181C, V189I, G190E, H221H/Y and M230L within 18 weeks of commencing drug pressure. Interestingly, E138K was the first mutation to emerge in most instances. Viral clones containing E138K displayed low-level phenotypic resistance to ETR (3.8-fold) and modestly impaired replication capacity (2-fold) compared to wild-type virus. We also examined resistance patterns to ETR and RPV in viruses containing NNRTI mutations at baseline. In wild-type (wt) viruses and viruses containing K103N alone, E138K or E138G mutations were observed in the presence of either ETR or RPV drug pressure followed by the appearance of other NNRTI resistance mutations. Alternatively, subtype B viruses containing Y181C generated V179I/F or A62V/A on exposure to ETR or RPV drug pressure, respectively, but not E138K. The addition of mutations at position 138 to Y181C did not significantly enhance levels of resistance to ETR or RPV. We also observed that the combination of Y181C and E138K may lead to a less fit virus compared to virus containing Y181C alone. Based on these findings, we suggest that Y181C may be antagonistic to E138K. The tissue culture drug resistance analysis of PL-100 in subtype C and CRF01_AE viruses is described in Chapter 4. PL-100 selected for PI resistance mutations along either of two distinct pathways, one of which involved resistance mutations at positions V82A and L90M while the other involved a mutation at position T80I, with other mutations being observed at positions M46I/L, I54M, K55R, L76F, P81S and I85V. An accumulation of at least three mutations in the protease flap and enzyme active sites were required in each case for high-level resistance to occur, demonstrating that PL-100 has a high genetic barrier against the development of drug resistance. In Chapter 5, we evaluated the potential of PL-100 as a second generation HIV-1 protease inhibitor. PL-100 resistant variants emerged within 8-48 weeks while darunavir (DRV) did not select for resistance mutations over a period of 40 weeks. Structural modeling demonstrated that the high genetic barrier of DRV is due to numerous interactions with protease that include hydrogen-bonding to PR backbone oxygens at amino acid positions A28, D29 and D30 via di-tetrahydrofuran (THF) groups, while binding of PL-100 was predominantly based on polar interactions and delocalized hydrophobic interactions through its diphenyl groups. Our data suggest that hydrogen bonding contacts and the di-THF group in DRV, as well as the hydrophobic nature of PL-100, contribute to PI binding and a high genetic barrier for resistance and that redesigning the structure of PL-100 to include a di-THF group might improve it antiviral potency and drug resistance profile.

The morbidity and societal burden of youth bipolar spectrum disorders (BSD) are high. These disorders are multisystemic in that adult populations there are clear interactions with inflammatory processes and steroidal physiological systems. There are much less data concerning these areas of study in youth populations with BSD. This is surprising given the association of youth-onset BSD with puberty and its associated physiological changes. In this mini-review, we overview the theoretical role of inflammatory processes and steroidal physiological systems in youth BSD, describe the greater literature in adult populations, detail the literature in youth populations when available, and overview current proposed molecular mechanistic pathways and interaction effects based on the available data. We also attend to the interplay of this complex system with body composition and weight gain, an especially important consideration in relation to the role of second generation antipsychotics as the first line treatment for youth with BSD in major clinical guidelines. A developmental model of early onset BSD for boys is hypothesized with pubertal hormonal changes increasing risk for first (hypo-)manic/depressive episode. The dramatic androgen rise during puberty might be relevant for first onset of BSD in boys. A shift from general hypercortisolism driven by glucocorticoid resistance to hypocortisolism with further disease progression is assumed, while increased levels of inflammation are functionally associated with endocrine dysregulation. The interacting role of overweight body habitus and obesity in youth with BSD further indicates leptin resistance to be a central moderator of the dynamic neurobiology of BSD in youth. The intent of this mini-review is to advance our knowledge of youth BSD as multisystemic disorders with important contributions from endocrinology and immunology based on a developmental perspective. This knowledge can influence current clinical care and more importantly inform future research.

No description available.

The Holocaust represented humanities first confrontation with unparalleled destruction and evil unchecked. It continues to impact upon the lives of survivors, their children- the second generation- and generations thereafter. The study aimed to provide the second generation with a voice. Their roles within their respective family systems and the impact of the Holocaust upon them are explored. The theoretical framework is social constructionism. One-on-one in-depth interviews were conducted with three adults whose parent/s are survivors. The manner of analysis was `Hermeneutic.' The participants' narratives took the form of interview transcripts. These were analysed and themed by the researcher. Themes that repeated themselves were elaborated upon and later linked with the available literature. The researcher hopes that the dissertation will contribute to existing research on the multigenerational effects of trauma in relation to familial and individual roles and memory. / Psychology / M. A. (Clinical Psychology)

Submitted by Caroline Periotto (carol@ufscar.br) on 2016-09-21T20:12:40Z No. of bitstreams: 1 TeseFFF.pdf: 5653411 bytes, checksum: 875bb8d2ed23313c792c9c246e285a85 (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-09-23T18:31:05Z (GMT) No. of bitstreams: 1 TeseFFF.pdf: 5653411 bytes, checksum: 875bb8d2ed23313c792c9c246e285a85 (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-09-23T18:31:11Z (GMT) No. of bitstreams: 1 TeseFFF.pdf: 5653411 bytes, checksum: 875bb8d2ed23313c792c9c246e285a85 (MD5) / Made available in DSpace on 2016-09-23T18:31:20Z (GMT). No. of bitstreams: 1 TeseFFF.pdf: 5653411 bytes, checksum: 875bb8d2ed23313c792c9c246e285a85 (MD5) Previous issue date: 2016-03-18 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Lignocellulosic ethanol, also called second generation ethanol, is a promising alternative for decreasing fossil fuel dependency globally. Nevertheless, its production process still needs further improvements in order to achieve industrial feasibility. Despite the massive experimental effort in this area, threshold values to be pursued in order to attain an economically feasible process are still missing. In this context, this study focused on constructing a methodology for economic evaluation of early-stage developing processes, such as second generation ethanol, aiming to show the R&D area directions to be followed for a successful industrial implementation of the process. The systematic procedure integrates bioprocess systems engineering (PSE) and economic engineering tools to perform a “retro” tecno-economic analysis. This analysis is able to identify the main process variables that influence the economic feasibility of the process and their target values. Initially, the methodology was tested on a case study involving the production of succinic acid from sucrose by fermentation. The methodology was able to eliminate one of the variables initially considered (sucrose conversion), due to its low influence on the process feasibility. Additionally, target values were obtained for the succinic acid concentration in the fermenter as a function of the selectivity and the specific productivity (the process variables chosen). Finally, the integrated production of ethanol from sugarcane juice and bagasse (first and second generation ethanol, respectively) was assessed. The three variables with the highest effect on the economic feasibility of the process were: the biocatalyst yield, the sucrose conversion and the solid mass fraction, both in the hydrolysis reactor. The reactor productivity, on the other hand, had little impact on the process feasibility. Besides, the experimental results already achieved the values needed for this variable. In general, the methodology was able to yield important information about both case studies required improvements for achieving economic feasibility. Although used in biochemical processes, the methodology is general, applying to all types of chemical processes. / A produção de etanol lignocelulósico, o chamado etanol de segunda geração, é uma alternativa promissora para diminuir a dependência energética global dos combustíveis fósseis. Entretanto, um desenvolvimento maior de seu processo de produção ainda é necessário para sua efetiva implementação industrial. Apesar do grande esforço experimental na área, ainda não existem informações claras sobre os valores limites a serem alcançados nas diversas etapas de processo para que esse se torne economicamente viável. Nesse contexto, o objetivo deste trabalho foi construir uma metodologia para avaliação econômica de processos em estágio inicial de desenvolvimento, como é o caso do etanol de segunda geração, indicando à área de P&D direções a serem seguidas para sua viável implementação industrial. Tal procedimento sistemático integra ferramentas de engenharia de bioprocessos e sistemas e engenharia econômica para realizar uma análise tecno-econômica “reversa”, que permite obter as variáveis que mais influenciam a viabilidade do processo, bem como seus valores limites para que tal viabilidade seja alcançada. Inicialmente, a metodologia proposta foi testada em um estudo de caso envolvendo o processo de produção de ácido succínico a partir da sacarose por rota fermentativa. Nesse processo, a metodologia conseguiu eliminar uma das variáveis inicialmente consideradas (a conversão da sacarose), devido a sua baixa influência. Além disso, foram obtidos valores mínimos para a concentração de ácido succínico no fermentador em função da seletividade e da produtividade específica (as variáveis de processo escolhidas). Em seguida, considerou-se a produção integrada de etanol a partir do caldo e do bagaço de cana-de-açúcar, etanol de primeira e segunda geração, respectivamente. As três variáveis com maior impacto na viabilidade econômica do processo foram: o rendimento do biocatalisador, a conversão da celulose no reator de hidrólise e a fração de sólidos nesse reator. A produtividade do reator, por outro lado apresentou baixo impacto na viabilidade, além de os resultados experimentais já estarem no patamar necessário para essa variável. De modo geral, a metodologia foi aplicada com sucesso aos estudos de caso escolhidos, produzindo dados importantes quanto às melhorias necessárias para que os processos alcancem a viabilidade econômica. Apesar de ter sido aplicada a bioprocessos, a metodologia é geral, sendo adequada ao estudo econômico de qualquer processo químico.

This research is an attempt to understand the living experiences of young adult Muslim SGIs, in Britain. This research advocates to understand their living experiences from the perspective of social identity approach which discusses multiple dimensions of identity, unlike acculturation theory which focuses on a mono dimension of identity. This research introduced a multiple social identity model for Muslim SGIs. Contrary to the previous literature, the first study, the interview study, revealed that they explained their conflicts with their non-Muslim British peers and with their parents on the basis of non-shared identity. With their non-Muslim British peers they shared cultural (national) identity, therefore, they explained their conflicts in terms of different religious values (practices); with their parents they shared religious identity, therefore they explained their conflicts in terms of different cultural (ethnic) values and practices. They argued that their parents practise various cultural practices in the name of Islam, and Muslim SGIs distinguished Islam from their parents' culture, and identified with the former, not the latter, and attributed their conflicts to their parents' cultural values. In addition, they explained that their religious identity enables them to deal with conflicts with peers and parents. The second study, the focus group, successfully validated the findings of the first study, and it broadened the understanding of the fact that SGIs and their parents both explained their religion in their own cultural context. Their religious (Muslim) identity also promotes their relationships with their non-Muslim British peers and parents, which contributes positively towards their British identity, and more specifically they define themselves as British Muslims. In the third study, the survey study, the hypotheses were developed on the bases of the qualitative studies. It was expected and found that British and Muslim identities were positively correlated; they had non-significant identity differences with the Muslim identity and significant identity difference with British and ethnic identities from their parents. Ethnic identity difference from their parents was the only found predictor of their attribution of their conflicts to their parents' cultural values.

Chapter 1: The Impact of Culture on the Second-Generation Immigrants’ Level of Trust in Canada Trust is one of the main elements of social capital; it determines the extent to which an individual cooperates with others. In this chapter, I assess whether cultural factors influence the level of trust in the population of second-generation immigrants in Canada. This paper is related to two strands of empirical literature. The first analyses the determinants of trust and the second studies the cultural transmission of values, attitudes and beliefs. I follow closely the literature on the cultural transmission and use an epidemiological approach to assess whether trust of second-generation immigrants is affected by their cultural heritage. This approach consists of comparing information about the outcomes of second-generation immigrants with that of the country of origin of their ancestry. We apply this approach using the Ethnic Diversity Survey (EDS), the World Value Survey (WVS) and the European Value Survey (EVS). Estimation results show that the average level of trust in the countries of origin of the ancestors of the second-generation immigrants has a strong significant impact on their level of trust. Thus, individual whose country of ancestry displays a high level of trust, tend to have a high level of trust. This provides evidence that individuals’ level of trust is not only explained by their personal experiences, characteristics, and the environment in which they live; but also by the culture in their country of ancestry. This means that culture does matter! I find that the results remain robust even if certain key countries are omitted or a different data set is used. Chapter 2: Decomposing Health Achievement and Socioeconomic Health Inequalities in Presence of Multiple Categorical Information This chapter presents a decomposition of the health achievement and the socioeconomic health inequality indices by multiple categorical variables and by regions. I adopt Makdissi and Yazbeck's (2014) counting approach to deal with the ordinal nature of the data of the United States National Health Interview Survey 2010. The findings suggest that the attributes that contribute the most to the deviation from perfect health in the United States are: anxiety, depression and exhaustion. Also, I find that the attributes that contribute the most to the total socioeconomic health inequality are ambulation, depression and pain. The regional decomposition results suggest that, if the aversion to socioeconomic health inequality is high enough, socioeconomic health inequalities between regions are the main contributors to the total socioeconomic health inequality in the United States. Chapter 3: Accounting for Freedom and Economic Resources in the Assessment of Changes in Women Poverty in Sub-Saharan Africa This chapter assesses the importance of freedom in women’s wellbeing in twelve Sub-Saharan Africa countries by using data from Demographic Health Surveys. This paper presents a poverty comparison by using the stochastic dominance approach and relies on the economic resources and freedom as the two aspects of wellbeing which evokes the multidimensionality of poverty. This study is related to the following three pieces of literature: the sequential stochastic dominance, the multidimensional poverty, the Sen’s capability approach which is based on freedom. This paper is built on Makdissi et al. (2014) but differs from it in a number of respects. First, it focuses on poverty instead of welfare. Secondly, it applies the Shapley decomposition to determine the contributions of the economic resource distribution and the incidence of the threat of domestic violence to poverty changes over time. Consistent with previous work on the importance of freedom, I find that more freedom, i.e. less threat of domestic violence, affects women’s wellbeing positively since it decreases women’s poverty. The results indicate that women’s wellbeing has improved in Burkina Faso, Ghana, Kenya, Lesotho, Madagascar, Malawi, Rwanda, Senegal, and Zimbabwe and deteriorated in Ethiopia, Nigeria and Tanzania.

Dans ce travail, nous proposons de suivre une approche multi-échelles pour simuler des propriétés spatiales des réservoirs, permettant d'intégrer des données directes (observation de puits) ou indirectes (sismique et données de production) de résolutions différentes. Deux paramétrisations sont utilisées pour résoudre ce problème: les ondelettes et les pyramides gaussiennes. A l'aide de ces paramétrisations, nous démontrons les avantages de l'approche multi-échelles sur deux types de problèmes d'estimations des incertitudes basés sur la minimisation d'une distance. Le premier problème traite de la simulation de propriétés à partir d'un algorithme de géostatistique multipoints. Il est montré que l'approche multi-échelles basée sur les pyramides gaussiennes améliore la qualité des réalisations générées, respecte davantage les données et réduit les temps de calculs par rapport à l'approche standard. Le second problème traite de la préservation des modèles a priori lors de l'assimilation des données d'historique de production. Pour re-paramétriser le problème, nous développons une transformée en ondelette 3D applicable à des grilles stratigraphiques complexes de réservoir, possédant des cellules mortes ou de volume négligeable. Afin d'estimer les incertitudes liées à l'aspect mal posé du problème inverse, une méthode d'optimisation basée ensemble est intégrée dans l'approche multi-échelles de calage historique. A l'aide de plusieurs exemples d'applications, nous montrons que l'inversion multi-échelles permet de mieux préserver les modèles a priori et est moins assujettie au bruit que les approches standards, tout en respectant aussi bien les données de conditionnement. / In this work, we propose to follow a multi-scale approach for spatial reservoir properties characterization using direct (well observations) and indirect (seismic and production history) data at different resolutions. Two decompositions are used to parameterize the problem: the wavelets and the Gaussian pyramids. Using these parameterizations, we show the advantages of the multi-scale approach with two uncertainty quantification problems based on minimization. The first one concerns the simulation of property fields from a multiple points geostatistics algorithm. It is shown that the multi-scale approach based on Gaussian pyramids improves the quality of the output realizations, the match of the conditioning data and the computational time compared to the standard approach. The second problem concerns the preservation of the prior models during the assimilation of the production history. In order to re-parameterize the problem, we develop a new 3D grid adaptive wavelet transform, which can be used on complex reservoir grids containing dead or zero volume cells. An ensemble-based optimization method is integrated in the multi-scale history matching approach, so that an estimation of the uncertainty is obtained at the end of the optimization. This method is applied on several application examples where we observe that the final realizations better preserve the spatial distribution of the prior models and are less noisy than the realizations updated using a standard approach, while matching the production data equally well.

Immigration is a common phenomenon in contemporary society and results in challenges withmaintaining cultural identity while integrating with a new culture. This is particularlyimportant in the family unit, where first-generation immigrant communities may havedifferent levels of experience and cultural values compared to their offspring (Secondgeneration immigrants). Integration in second-generation immigrants is often related tobilingualism and the concept of a dual social identity, embracing elements of host and nativeculture. The aim of this study was to explore the perspective of parents on the role ofbilingualism on integration and identity in their children. A sample of five families, originallyfrom Afghanistan and now living in Sweden, was purposively selected to complete semistructured interviews exploring bilingualism, social identity and integration. The findings ofthese interviews revealed three key themes relating to the adoption of Swedish identity bychildren, the loss of Afghani identity, and the role of the school and society in facilitatingthese identities.Overall, the interview data suggested that children living in Sweden identified as Swedish andengaged in cultural and social activities consistent with integration. Bilingualism was animportant aspect of holding a largely Swedish identity, although parents valued dual identityof children. Often, immersion in Swedish culture and limited opportunities to socialise as anAfghani cultural unit were viewed as threats to maintaining or developing a clear Afghaniidentity. The role of schools, parents and society in general is considered important in theseprocesses, particularly with regards to supporting cultural and religious values of the familyunit, while promoting successful integration. Bilingualism was universally viewed as apositive tool that could facilitate integration and dual identity, where suitable opportunitiesarose. / <p>Grade A</p>

The morbidity and societal burden of youth bipolar spectrum disorders (BSD) are high. These disorders are multisystemic in that adult populations there are clear interactions with inflammatory processes and steroidal physiological systems. There are much less data concerning these areas of study in youth populations with BSD. This is surprising given the association of youth-onset BSD with puberty and its associated physiological changes. In this mini-review, we overview the theoretical role of inflammatory processes and steroidal physiological systems in youth BSD, describe the greater literature in adult populations, detail the literature in youth populations when available, and overview current proposed molecular mechanistic pathways and interaction effects based on the available data. We also attend to the interplay of this complex system with body composition and weight gain, an especially important consideration in relation to the role of second generation antipsychotics as the first line treatment for youth with BSD in major clinical guidelines. A developmental model of early onset BSD for boys is hypothesized with pubertal hormonal changes increasing risk for first (hypo-)manic/depressive episode. The dramatic androgen rise during puberty might be relevant for first onset of BSD in boys. A shift from general hypercortisolism driven by glucocorticoid resistance to hypocortisolism with further disease progression is assumed, while increased levels of inflammation are functionally associated with endocrine dysregulation. The interacting role of overweight body habitus and obesity in youth with BSD further indicates leptin resistance to be a central moderator of the dynamic neurobiology of BSD in youth. The intent of this mini-review is to advance our knowledge of youth BSD as multisystemic disorders with important contributions from endocrinology and immunology based on a developmental perspective. This knowledge can influence current clinical care and more importantly inform future research.