Dissertationen zum Thema „Mạc family“

The proto-oncogene c-myc is encoded by a transcript in which the 5' UTR contains a potent internal ribosome entry segment (IRES). The N-myc gene shows considerable homology to c-myc and also possesses a 5' UTR that is long and structured. Thus, the potential for internal ribosome entry within this UTR was examined. N-myc was found to contain an IRES that was of comparable activity to that of c-myc in non-neuronal cells, but was specifically activated relative to the c-myc IRES in neuronal cells in which the N-myc transcription is expressed. Furthermore, the activity of the N-myc IRES was specifically inhibited during neuronal differentiation, when N-myc expression is reduced. The trans-acting factor requirements for N-myc IRES function were examined and a candidate protein was found, although not characterised. An IRES was also identified in the 5' UTR of the third well-studied member of the myc gene family, L-myc. An alternative form of the UTR exists in which an intron is retained, but it was not possible to draw any definite conclusions on the IRES activity of this UTR. Translation of both c- and N-myc mRNAs can occur by both cap-dependent and IRES-dependent mechanisms, so the existence of IRESs within these transcripts was intriguing. c-Myc protein levels were analysed during apoptosis and were maintained, despite the apoptotic inhibition of protein synthesis and the short half-life of c-Myc. The activity of the c-myc IRES was maintained during apoptosis and was responsible for this effect. The c-myc IRES was also shown to lie downstream of the p38 mitogen-activated protein kinase signalling pathway.

One of the most exciting frontiers of expanding pharmacopeia to combat currently untreatable diseases is achieving specifically and potently disruption of unwanted protein-protein interactions where traditional small molecule drugs tend to fall short. Our laboratory has developed the methodology of peptide stapling and pioneered successful applications in multiple disease models since its induction over a decade ago. One common feature of past applications is the use of a single stapled peptide in helical form, derived from the natural binding interface of target proteins. This dissertation ventures into protein interactions that involve multiple components and sites and explores the extended use of stapled peptides in these volatile settings.
Chemistry and Chemical Biology

Criminal gang membership is growing, which corresponds to a continued breakdown of the family unit in the United States. Most of the young people who form gangs come from broken families or single-parent-headed households. This study explored the role of family hierarchy on gang membership. A qualitative case study approach was used to gather information on what motivates young people to join criminal gangs. A random sampling technique was used to recruit seven former members of the Mac Baller Brim gang. Ethical concerns were addressed to minimize the risks to the participants. The collected data from interviews were analyzed using an interpretive research philosophy to determine the contribution of family hierarchy on motivating the participants to join gangs. Interpretive research philosophy indicates that reality can only be understood by subjective interpretation and intervention. An action research strategy was also used in an attempt to provide a practical solution for the people studied while adding to existing theories. The findings of the study indicated that there are 5 reasons why young people join gangs: protection, respect, money, fun, and because a friend was in the gang. This study may contribute to social change by identifying factors that lead to gang membership to aid policy and program interventions that lower the likelihood of youth joining gangs.

To make a comprehensive assessment of the incidence, nature and significance of MYC gene family amplification in medulloblastoma, we first developed a quantitative real-time PCR (qPCR) assay to identify MYCC, MYCN and MYCL amplification in a large patient cohort (n=292), which included 178 children entered into the SIOP/UKCCSG PNET3 clinical trial. MYCC, MYCN and MYCL copy number elevation was identified in 6% (17/292), 6% (18/292), and 1% (3/292) of medulloblastomas, respectively. No evidence of co-incident copy number elevation of more than one MYC family member was identified in any sample. The transcript expression of genes frequently harboured within the MYCC and MYCN amplicons was assessed and a correlation was identified between gene copy number and transcript expression of four genes (TRIB2, DDX1, NESE2 and AK093424) neighbouring the MYCC and MYCN loci, suggesting that these genes may represent amplification targets and play a role in medulloblastoma. In cases where RNA was available (n=60), a correlation was identified between MYCC copy number elevation (n=8) and elevated expression of its transcript; however the relationship between MYCN copy number and transcript expression was less clear. MYCL expression was assessed in a smaller number (n=18) of medulloblastoma primary tumours and was found to be significantly overexpressed in cases with MYCL amplification (n=2). All three MYC family members were more highly expressed in medulloblastomas with a deregulated Shh- or Wnt- signalling pathway, suggesting that these pathways also play a role in the regulation of MYC family member expression in medulloblastoma. Comprehensive assessment of the clinico-histopathological significance of MYCC and MYCN amplification (HCN ≥5.00) identified an association with the large cell anaplastic (LCA) medulloblastoma and all tumours with an elevated copy number of MYCC (n=17) and MYCN (n=18) were derived from patients greater than three years of age. Log-rank tests identified MYCC or MYCN amplifications as a marker of poor prognosis and Cox proportional hazards models revealed that MYCC and MYCN amplification had similar hazard ratios (hazard ratio (HR); 299) to establish markers fo disease risk (Metastatic (M) stage ≥2 (HR; 3.33) and the LCA subtype (HR; 3.63)). Multivariate analyses identified MYCC or MYCN amplification as independent markers of poor prognosis and together with LCA histology and M stage ≥2, formed a combined high risk group of patients with a significantly poorer prognosis (29.4% (75/255); p<0.0001).

The c-Myc oncoprotein (or Myc) is a transcription factor of the basic-Helix-Loop-Helix Leucine-zipper (bHLH-LZ) family, whose transcriptional activity depends on dimerization with the bHLH-LZ partner Max and DNA binding, mediated by the basic regions of both proteins. Myc/Max dimers bind preferentially to the hexanucleotide motif CACGTG (known as E-box) and variants thereof. The ability of Myc to bind DNA in vivo, however, is not stringently regulated by the presence of the E-box, since many genomic sites targeted by Myc do not contain this motif. Hence, we still need to fully comprehend how Myc recognizes its genomic targets and to what extent sequence-specific DNA binding contributes to this process. Based on the crystal structure of the DNA-bound Myc/Max dimer, we generated a Myc mutant in which two basic region residues engaged in sequence-specific contacts (H359 and E363) were mutated to Alanine (Myc HEA), and compared this with a mutant in which three Arginine residues involved in DNA backbone interactions were mutated to Alanine (Myc RA). While both mutants showed impaired E-box recognition in vitro, their over-expression in murine fibroblasts revealed very different genome-interaction profiles, Myc RA showing no detectable DNA binding, and Myc HEA retaining about half of the binding sites seen with Myc wt. The analysis of the binding intensity of Myc wt and Myc HEA at their binding sites revealed that, as expected, Myc wt bound more strongly the sites containing the E-box, while Myc HEA bound the sites with an E-box as well as the sites without it, confirming that the mutant lost the sequence-specific recognition ability. The interactions retained by the Myc HEA were dramatically reduced with the protein expressed from the endogenous c-myc locus, though genome engineering. Thus, unlike Myc RA, the Myc HEA mutant retained non-specific interactions with genomic DNA (detectable at elevated protein levels) but failed to engage more stably through sequence-specific DNA contacts. In spite of this residual DNA-binding activity, Myc HEA was profoundly impaired in its biological function, undistinguishable from Myc RA: in particular, neither mutant could substitute for wild-type Myc in supporting cell proliferation in murine fibroblasts, whether at normal or supra-physiological levels. While the assessment of transcriptional activities is still ongoing, we conclude that E-box recognition is essential for Myc’s biological function.

A pesquisa Famílias no museu de arte: lazer e conhecimento um estudo sobre o programa educativo Interar-te do MAC USP teve como objetivo investigar as motivações dos adultos que optam por proporcionar a crianças e jovens, nos momentos de lazer de sua família, atividades de cunho cultural e educativo e, com isso, observar os desdobramentos destas iniciativas na formação e na criação do hábito de frequentação de museus de arte de todos os envolvidos. Foi selecionado para estudo de caso o programa Interar-te do Museu de Arte Contemporânea da Universidade de São Paulo. Este programa uma das ações de extensão universitária da Divisão Técnico-Científica de Educação e Arte do MAC USP tem como público-alvo famílias e é realizado aos sábados, uma vez ao mês, entre janeiro e novembro; foi criado a partir de uma demanda institucional para a sede do Museu no Parque Ibirapuera, que é muito frequentado aos finais de semana pelas opções de lazer que oferece. Para compreensão do contexto da pesquisa, foram delimitados os conceitos de lazer e de família e abordados princípios sobre educação em museus de arte. Utilizou-se metodologias de análise qualitativa de pesquisa e outras informações complementares foram obtidas através de instrumentos quantitativos direcionados à amostra selecionada para estudo. Constatou-se que há influências da família de origem sobre os adultos na criação de seus hábitos de frequentação de programações artístico-culturais, assim como destes sobre suas próprias famílias, considerando-se a delimitação do perfil que a amostra representa; e, ainda, que o programa educativo Interar-te do MAC USP promove ensino e aprendizagem em artes visuais a diferentes faixas etárias e promove integração entre os membros das famílias que o frequentam.
The research Families in the museum of art: leisure and knowledge a study about the Interar-te Educational Program from MAC USP aims to investigate the motivation of adults who provide their children with cultural and educational activities during their families leisure time, in order to observe the impact of these initiatives on the habit of attending museums of art among these family members. A program called Interar-te, which is developed by the Museum of Contemporary Art of the University of São Paulo (MAC USP), was chosen for this case study. This Program, whose target audience is directed to parents and their children, is held once a month, on Saturdays, between January and November, and is one of the university extension activities provided by the Technical-Scientific Division of Education and Art of MAC USP. It was created to supply an institutional demand of the Museums headquarters, located at Ibirapuera Park, which is a park that receives lots of visitors on weekends because of the leisure options it offers. The concepts of leisure and family were approached, and the principles related to education in art museums were approached in order to provide a better comprehension of the research context. The research was based on methodologies for qualitative research analysis, and other complementary information was collected by using quantitative tools, which were directed to the sample selected for the study. Considering the delimitation of the sample profile, we verified that families play an influential role on adults in relation to the construction of their habits of attending cultural-artistic programs, and that these habits also influence their own families. We also concluded that the Interar-te Educational Program of MAC USP promotes teaching and learning concerning visual arts for people of different ages and promotes integration among the family members who visit the Museum.

This thesis bridges ideas from both international business (IB) and institutional perspectives and offers a holistic view of the organizational, cognitive and political concerns characterizing the headquarter (HQ)-subsidiary relationships. The relevance of specific national institutional contexts for multinational corporations (MNCs) is highlighted. Particularly, the HQ-subsidiary perception gap - the difference in perception between subsidiary and HQ managers regarding the subsidiary’s role - is one of the key challenges faced by MNCs. Both IB and institutional approaches, however, have neglected this topic, and, especially, its institutional derivation and political dynamics. In this thesis I investigate the emergence and evolution of an HQ-subsidiary perception gap and its metamorphosis into a politically laden phenomenon. The single case research design with embedded multiple units of analysis draws on qualitative, longitudinal data referring to a process of cross-border, post-acquisition integration. The findings suggest that the emergence of an HQ-subsidiary perception gap is explained by the organizational and institutional distance existing between the two actors of the dyad. Moreover, this relationship is moderated by the status differential between the HQ and the acquired subsidiary, and between the countries in which the actors are located. Once emerged, the perception gap evolves through three different process loops - stabilizing, polarizing and neutralizing of the HQ-subsidiary interactions and of the quality of the HQ-subsidiary relationship - and becomes an instrument of political contention. Beyond the phenomenon of HQ-subsidiary perception gap, this thesis explores the meso level of subsidiaries’ organizational design, a topic that has been hitherto overlooked by institutional scholars. Through a longitudinal and comparative analysis of subsidiaries’ organizational configurations and boards of directors composition, I bring attention to the enduring relevance of societal specific logics. Overall, this thesis portrays MNCs as places in which institutional-bound organizational, cognitive and political issues dynamically coexist and interact.

L'objet de cette these est la correction d'echos longs pour les signaux de television. Les signaux consideres sont des signaux analogiques pour l'image de television de qualite amelioree de type mac/paquets. Pour ces signaux de television, les echos sont tres genants et produisent une image fantome qu'il faut corriger. La difficulte principale reside dans le fait que les frequences d'echantillonnage sont tres elevees. Par des methodes classiques, le filtrage necessiterait plusieurs centaines de coefficients, et donc de multiplieurs, ce qui n'est pas realisable. La solution proposee consiste a decoreller l'algorithme de calcul des coefficients, du filtrage proprement dit, de sorte que seul ce dernier est realise en temps reel. Nous montrons que le filtrage le moins complexe est realise dans le domaine frequentiel en utilisant plusieurs sous-filtres en parallele, ce qui permet de realiser des tfr (transformee de fourier rapide) de petites dimensions. Une caracteristique importante est la selection des sous-filtres, car on sait que la reponse impulsionnelle du canal n'est pas perturbee sur tout le support temporel considere. Il en resulte une simplification importante qui rend le filtrage realisable. Les sous-filtres se deduisent, par decimation frequentielle, de la reponse en frequence du canal. Celle-ci est obtenue par des methodes d'identification utilisant ou non un signal de reference. Nous presentons trois methodes differentes d'identification du canal. Les deux methodes utilisant un signal de reference donnent de tres bons resultats et permettent dans tous les cas consideres de reduire les echos residuels en dessous du seuil de visibilite. La derniere methode fonctionnant en aveugle donne des resultats sous-optimaux mais a l'avantage d'etre applicable a tous types de signaux. Nous avons propose une solution de correction d'echos, dans le domaine frequentiel, realisable dans un environnement grand public. Cette solution tres generale, peut etre appliquee a d'autres types de signaux notamment aux modulations numeriques qui sont actuellement a l'etude pour diffuser la television numerique. Dans ce contexte, un circuit integre, reprenant les principes developpes dans cette these, sera realise dans les mois prochains

L'expression de c-Myc, Max, Mad1 et Mxi1 d'une part, de Bcl-2 et Bax d'autre part, a été recherchée par immunocytochimie en microscopie optique et électronique dans les chondrocytes du cartilage de croissance de jeunes rats au sevrage supplémentes, ou carences, en vitamine d. Les quantités de c-Myc, de son partenaire de dimérisation Max et de ses inhibiteurs compétitifs Mad1 et Mxi1 sont élevées dans le noyau des chondrocytes prolifératifs ; seul Mxi1 est présent dans le cytoplasme. Les quantités de c-Myc, Max, et Mad1 diminuent avec l'arrêt de la prolifération des chondrocytes, alors que mxi1 demeure présent tout au long de la différenciation terminale des chondrocytes et dans le noyau et dans le cytoplasme une intense sur-expression de c-Myc a lieu dans les chondrocytes parvenus au stade terminal de leur differenciation. L'absence du partenaire commun de dimérisation, Max, dans le cytoplasme de tous les chondrocytes et dans le noyau des chondrocytes hypertrophiques parvenus en fin de differenciation, implique l'existence de partenaires de dimerisation de c-Myc et de Mxi1 inconnus à ce jour. L'initiateur du programme de mort cellulaire, Bax, est présent dans tous les chondrocytes, alors que intensité d'expression de son inhibiteur, Bcl-2, est élevée dans les chondrocytes prolifératifs, puis décroit progressivement jusqu'a devenir presque nulle dans les chondrocytes parvenus au dernier stade de leur différenciation. Le programme de mort des chondrocytes comporte donc deux des caracteristiques de l'apoptose : la surexpression de c-Myc et la diminution d'expression de Bcl-2. L'expression de toutes ces protéines protooncog7nes dans tous les chondrocytes des rats carences en vitamine d.

A temática da educação rural e/ou do campo, mesmo ainda sendo carente de pesquisas, tem aparecido de forma crescente nos debates e estudos sobre a agricultura familiar brasileira nas últimas décadas. Isso se deve ao reconhecimento da contribuição do ensino para o desenvolvimento rural. Se por um lado o Estado vem recuperar a sua responsabilidade para com este aspecto social, de outra parte, movimentos sociais atuam em conjunto ou paralelos às ações do Estado, lutando para que seu direito educacional seja de qualidade equânime àquela ofertada às demais classes. Num recorte a esta temática apresenta-se aqui uma análise do Programa Escola Ativa no processo educacional rural brasileiro no atendimento ao povo do campo. O PEA, inspirado no modelo colombiano Escuela Nueva – Escuela Activa, foi implantado no Brasil pelo Ministério da Educação, oficialmente em 1997. Este foi considerado o primeiro programa governamental em atendimento às especificidades do povo do campo com filhos em turmas multisseriadas. Em 2008, ele teve sua expansão para todo o Brasil, sendo implantado no município de Salinas/MG em 2009. Este estudo propôs-se, conforme indica o objetivo geral, a analisar a implementação do PEA/MEC/SALINAS-MG, em seus aspectos de formação e prática pedagógica docente, verificando como são consideradas as características socioeconômicas, culturais e as condições de vida dos agricultores familiares da região de abrangência das escolas do PEA/SALINAS. Através de abordagem qualitativa, procedeu-se à investigação buscando compreender como as dimensões de formação e práticas docentes consideram a realidade local dos filhos destes agricultores, possibilitando a eles melhores condições de vida. Como conteúdo, a tese contextualiza o processo histórico da evolução das políticas públicas para a educação rural, paralela à atuação dos movimentos sociais com ações reivindicatórias e propositivas por uma educação do campo conforme seus interesses. Apresenta, ainda, conteúdos teóricos de análises sociais e educacionais dedicados às condições de vida e à educação no meio rural. Interpõem-se também posições de debates sobre o PEA refletindo o novo momento em que se dá o ensino para os cidadãos do campo e sobre as possibilidades de sua contribuição para o desenvolvimento rural. Orientado por este arcabouço de conteúdos reflexivos e analíticos, procedeu-se à caracterização e à análise do PEA no município de Salinas, MG. Os resultados alcançados indicam alguns progressos, mas também a contestação da hipótese original, isto é, a não efetivação da consideração das variáveis socioeconômicas e culturais e das condições de vida no processo educacional do PEA em Salinas, MG.
The issue of rural education and/or farm, though still lacking of research, has been increasing in the discussions and studies on Brazilian family farming over the recent decades. This is due to the recognition of the contribution of education to rural development. If, on the one hand, the State has the responsibility to recover this social aspect, on the other, social movements work together or in parallel with the actions of the State's struggle for their right to equitable quality education to which offers to other social classes. In this thematic approach, an analysis of the Active School (Escola Ativa) Program (EAP) provides the educational process of the Brazilian rural services. The EAP, based on the Colombian Escuela Nueva – Escuela Activa was officially implemented in Brazil by the Ministry of Education and Culture in 1997. This program has been considered as the first government system geared to the needs of the rural population with the children in the multi-seriated school system. In 2008, the program was expanded throughout Brazil and it was implemented in the city of Salinas, State of Minas Gerais in 2009. The Main Objective of this study is to analyze the implementation of the EAP/MEC/SALINAS - State of Minas Gerais, in terms of teacher training and pedagogical practice to check the socioeconomic, cultural and conditions of life of farmers in the region covered by EAP/SALINAS schools. A qualitative research approach has been carried out to understand how the dimensions of training and teaching take into account the local situation of the children of farmers, in order to improve their living conditions. In this context, the thesis defines the historical process of the development of public policies for rural education in parallel with the role of social movements in the claims and proposals for agricultural education based on their interests. It also shows the theoretical content of social analysis and education dedicated to the living conditions and education in rural areas. Discussions also on the EAP filing reflects the new time should be given to the teaching of the agricultural population and the possibility of the contribution of education to rural development. The characterization and analysis of the EAP in the city of Salinas has guided this framework of reflective and analytical content. The results show some progress, but also contesting the original hypothesis, i.e., consideration of the ineffectiveness of the variables and the socioeconomic and cultural conditions of life in the educational process of the EAP in the city of Salinas, State of Minas Gerais.
El tema de la educación rural y/o del campo, aunque todavía carece de investigaciones, ha ido en aumento en los debates y estudios sobre la agricultura familiar brasileña en las últimas décadas. Esto se debe al reconocimiento de la contribución de la educación al desarrollo rural. Si, por un lado, el Estado tiene la responsabilidad de recuperar este aspecto social, por el otro, los movimientos sociales funcionan en conjunto o en paralelo con las acciones de la lucha del Estado de su derecho a la educación de calidad equitativa a la que ofrece para otras clases. En este enfoque temático, un análisis del Programa Escuela Activa, (PEA) contiene el proceso educativo de los servicios rurales brasileños. El PEA, basado en la colombiana Escuela Nueva - Escuela Activa, se puso en práctica oficialmente en Brasil por el Ministerio de Educación y Cultura en 1997. Este programa ha sido considerado como el primer sistema de gobierno dirigido a las necesidades de la población rural con los niños en el sistema de escuelas multigrado. En 2008, el programa se extendió por todo Brasil y fue ejecutado en la ciudad de Salinas, Estado de Minas Gerais en 2009. El Objetivo Principal de este estudio es analizar la implementación del PEA/MEC/SALINAS - Estado de Minas Gerais, en términos de formación de profesores y la práctica pedagógica, para comprobar las condiciones socioeconómicas, culturales y de vida de los agricultores de la región cubierta por las escuelas PEA de Salinas. Un enfoque de investigación cualitativa se ha llevado a cabo para entender cómo las dimensiones de la formación y la enseñanza tienen en cuenta la situación local de los hijos de los agricultores, con el fin de mejorar sus condiciones de vida. En este contexto, la tesis define el proceso histórico del desarrollo de políticas públicas para la educación rural en paralelo con el papel de los movimientos sociales en las reivindicaciones y propuestas para una educación agrícola en función de sus intereses. También muestra los contenidos teóricos de análisis social y la educación dedicados a las condiciones de vida y la educación en las zonas rurales. Las discusiones interponiendo también en el PEA refleja el nuevo tiempo que se debe dar a la enseñanza de los ciudadanos agrícolas y las posibilidades de la contribución de la educación para el desarrollo rural. La caracterización y el análisis del PEA en el municipio de Salinas ha guiado este marco de contenido reflexivo y analítico. Los resultados obtenidos indican un cierto progreso, pero también la contestatión de la hipótesis original, es decir, la consideración de la ineficacia de las variables y las condiciones socioeconómicas y culturales de la vida en el proceso educativo del PEA en la ciudad de Salinas, Estado de Minas Gerais.

In recent years, there has been increasing concern that gender bias has prevented women from advancing as rapidly and as frequently as men into management positions. Although the number of women managers has increased, they may experience difficulty moving into upper management positions. The purpose of our research was to study employee gender perception of key variables of women and the positions held in high technology companies. In this research, phenomenological research method was chosen, because the aim of it is to determine what the experience means for the people who have experienced it. Based on the collected data, answers and experiences, structural analysis was done in order to find out the major phenomena of gender perceptions. A number of variables uncover the perception of aspects of policy and gender and barriers that may affect female employees' opportunities for advancement. Using a sample of 30 full-time employees from Company A, the results indicated that position held was significantly different for male and female employees. The results also indicated that neither male nor female employees appeared to notice the apparent perceptions apparently as a glass ceiling within their company and the Implications discussed and recommendations provided. With reference to the Empirical research, this paper increases the knowledge about women’s career development and provides recommendations how to deal with it. It is also expected that this thesis will be helpful to all women who are in the labour market for their career development and advancement.

The use of environmentally friendly products increased the interest in renewable resources as alternatives to petrochemical products. Polyhydroxyalkanoates (PHAs) are examples of such promising products, as they are biodegradable polymers with numerous potential applications. PHA production approach consists of using an open mixed microbial culture (MMC) and inexpensive feedstocks (waste or industry byproducts feedstock). The PHA process generally comprises three stages: (1) acidogenic fermentation (AF) stage (conversion of organic carbon into fermentation products); (2) culture selection stage (enrichment in PHA-storing organisms by applying Feast and Famine regime); and (3) PHA production stage (PHA accumulation up to the culture’s maximum capacity). AF of protein-rich residues results in ammonia-rich fermented streams, which can be presented as a challenge for the PHA production stage. The presence of ammonia during this stage may induce organisms to grow instead of producing PHAs. For this reason, the assessment of the effect of a high content of ammonia on PHA production it is the utmost importance. The main goal of the current project is to select a MMC enriched in PHA-accumulating organisms in conditions of high ammonia content and to evaluate the effects of ammonia presence during PHA accumulation. The culture was selected applying the Feast & Famine strategy, and fed, firstly, using a synthetic mixture of VFAs and later using a fermented stream obtained from the fermentation of protein-rich raw materials. The selected culture could accumulate up to 24% PHA per VSS with the synthetic mixture of VFAs and up to 29% for the real fermented stream. The PHA accumulation resulted in different production in the presence and absence of ammonia. Regarding to the synthetic feed, 59%wt. PHA (VSS basis) in the absence of ammonia, and 55%wt. (VSS basis) in the presence, were obtained. For the real feed, the PHA content was about 40%wt. (VSS basis) in both reactors.

Dissertação para obtenção do Grau de Mestre em Engenharia Química e Bioquímica
Polyhydroxyalkanoates (PHAs) are polyesters of hydroxyl fatty acids, which are accumulated in microbial cells as carbon/energy reserves. PHAs are bio-based and biodegradable and display a wide range of thermoplastic properties, being a promising alternative to conventional plastics. Presently, industrial PHA production was primarily based on pure microbial cultures. Although this process has high PHA production efficiency, it presents high costs associated with the use of chemically-defined feedstocks, and to the need for sterility. An attractive feature of mixed microbial cultures (MMCs) PHAs production is the ability to use waste/surplus feedstocks. Many industrial wastes are seasonally produced making it necessary find the best method of utilization of this feedstock on PHA production process. Two different approaches might be taken account: (1) stock of industrial wastes during their production for their use throughout the year. However, the high fermentability of these agro-industrial wastes makes them susceptible to degradation during storage period; (2) the use of different feedstocks over the year according its availability. It is thus important to study MMC’s response to different feedstocks. The aim of this work is study how MMC PHA production process is affected by a feedstock shift, using cheese whey (CW) and sugar cane molasses (SCM) as model feedstocks. The use of waste based feedstock by MMCs requires a previous conversion of sugars to organic acids (OAs), which is achieved through anaerobic fermentation. In this study, a three-stage MMC PHA process was used, comprising: (1) anaerobic fermentation of surplus feedstocks to produce OAs in a membrane bioreactor (AnMBR); (2) PHA accumulating culture selection in a sequencing batch reactor (SBR) under feast and famine conditions using fermented feedstocks; and (3) PHA production using the selected cultures and the OAs produced in the earlier stages. Initially the effect of both feedstocks (CW and, SCM) in the acidogenic fermentation (stage 1) was assessed. Firstly, the AnMBR was operated under steady state with CW. When the feedstock was changed to SCM an adaption period of about 10 to 15 days was observed. When SCM was replaced by CW a faster adaptation response, approximately 7 days, was observed. The AnMBR reached similar OAs profiles in both phases when CW was fed (% g-COD HAA/g-COD OAs): 65% acetate, 10% propionate, 22% butyrate, 2% valerate, and 1% lactate. These results demonstrate that the system’s performance is reproducible. On the other hand, the anaerobic fermentation of a different feedstock, SCM, resulted in a different OAs profile (%g-COD HAA/g-COD OAs): 24% acetate, 38% propionate, 19% butyrate, and 19% valerate. In a second phase, different fermented feedstocks were used in the selection of PHA-storing organisms under a feast and famine regime in a SBR (stage 2). Initially the SBR was fed with a synthetic OAs solution; then fermented SCM (fSCM) and fermented CW (fCW) were subsequently fed as they were produced in the AnMBR. The adaption of the MMC to fSCM was faster than the adaptation to fCW. Whenever steady state was reached, PHA accumulation tests were performed using the enriched MMC fed with the corresponding feedstock (stage 3), namely synthetic OAs solution, fSCM, and fCW. Storage yields of 0.74, 0.49, and 0.73 C-mol PHA/ C-mol OAs were obtained with synthetic OAs solution, fermented molasses, and fermented CW, respectively. The culture reached a maximum PHA content of 60%, 56% and 65%, when feedstock fed were synthetic OAs solution, fSCM and fCW, respectively. A direct relation between the used feedstock and the polymers composition was observed, which was related with the different OAs profile. Even though, the shift of complex feedstock in three-stage MMC PHA process is still at a very early stage of development, this work illustrates the advantage of favoring the selection of cultures with the capacity to adapt its metabolism to different feedstocks. This will offer the possibility of using numerous substrates and improving strategies to optimize acidogenic fermentation, culture selection and polymer production.

Polyhydroxyalkanoates (PHA) are biodegradable polyesters with comparable properties to some petroleum-based polyolefins. Within the context of the B-PLAS process, the PHA production is integrated with a wastewater treatment process aimed at recovering energy and C through platform molecules such as volatile fatty acids (VFAs). Eventually, selected mixed microbial cultures (MMCs) are provided with a fermentation broth under an aerobic dynamic feeding regime to produce PHA-enriched biomass. In this study, an anoxic/aerobic selection and accumulation process has been explored and compared on a bench scale with the standard and most studied full aerobic alternative. A final setup for both the bench-scale experiments and the B-PLAS pilot plant has also been proposed, allowing to achieve, on-demand, a higher dried biomass PHA content (>50%) compared to the analogous aerobic setup. In addition, the selected population has been proven to respond positively to reduced oxygenation conditions, opening new possibilities to maximise the production of the pilot plant while reducing the oxygenation-related costs and streamlining the process scheme.

Les hypersensibilités allergiques médicamenteuses sont des pathologies mettant en jeu le système immunitaire et induites par la prise de médicaments. Notre travail s’est décomposé en quatre étapes successives : 1- Nous avons classé les β-lactamines en fonction de leurs champs moléculaires, et obtenons un dendrogramme de 4 familles, validé par les données cliniques. Nous avons également réalisé une étude de 3D-QSAR visant à connaître les parties du médicament impliquées dans la pathologie, et à prédire l’allergénicité des β-lactamines. 2- Partant de l’hypothèse que les β-lactamines sont des haptènes, nous avons étudié leur réactivité vis-à-vis d’acides aminés de type lysine et sérine. Nous avons ensuite réalisé des expériences de « docking » afin de définir les interactions entre le médicament et l’albumine sérique humaine. Nous concluons que les sites des lysines 190 et 212 sont les plus adaptés pour la fixation covalente de la drogue et avons validé cette analyse par des méthodes mixtes QM/MM. Enfin, grâce à notre logiciel SuMo, nous avons déterminé d’autres protéines candidates pour l’hapténisation. 3- S’agissant des HyperSensibilités Allergiques Immédiates, nous avons modélisé les différents partenaires que sont les IgE, la β-lactamine portée ou non par une protéine. Nous avons envisagé plusieurs modes de reconnaissance. D’autre part, nous avons analysé les modifications de la protéine, induites par la fixation de la drogue. 4- Concernant les HSA retardées, nous avons émis plusieurs scénarios de reconnaissance de la β-lactamine par le TCR. Nous avons modélisé différents complexes impliquant le TCR, le peptide hapténisé par le médicament, un ion éventuel, ainsi que le CMH, et les soumettons à des dynamiques moléculaires afin d’en étudier la pertinence. D’autre part, nous avons déterminé plusieurs peptides, issus des protéines d’hapténisation et susceptibles de présenter le médicament au TCR, via le CMH. L’ensemble des résultats obtenus est ou sera validé par des expériences in vitro et in vivo
Drug hypersensitivity is an immune-mediated reaction to a drug. Our work was divided into four stages: 1 - We have classified β-lactam antibiotics based on their molecular fields, and obtained a dendrogram of 4 families, validated by clinical data. We also conducted a 3D-QSAR study to determine what parts of the drug are involved in the pathology and to predict the allergenicity of β- lactams. 2 - Under the assumption that β-lactam antibiotics are haptens, we studied their reactivity in comparison with lysine and serine. We then conducted "docking" experiments to define the interactions between the drug and human serum albumin. We conclude that lysine 190 and 212 are the most suitable sites for the covalent binding of the drugs. We validate this analysis by mixed QM / MM methods. Finally, thanks to our software SuMo, we have found other candidate proteins for haptenization. 3 - Regarding immediate hypersensitivity reactions, we modeled the IgE, the β-lactam and the haptenized protein. We considered several modes of recognition. Secondly, we analyzed the structural changes of the protein induced by the binding of the drug. 4 - Concerning delayed reactions, we considered different scenarios for the recognition of β-lactam by the TCR. We modeled complexes involving the TCR, the peptide haptenized by the β-lactam, a possible ion, and the MHC. We investigated them with molecular dynamics to study their relevance. On the other hand, we have identified many peptides derived from haptenization proteins and able to present the drug to the TCR through the MHC. The validity of the obtained results is or will be confirmed using experiments in vitro and in vivo

Les molécules du CMH de classe I « like » MICA jouent un rôle important dans l'activation de cellules effectrices de l'immunité innée et adaptative, principalement comme ligands du récepteur activateur NKG2D. Le gène MICA est polymorphe (102 allèles décrits) ; ce polymorphisme favorise l'induction d'une réponse humorale participant au rejet en transplantation. Cependant la contribution des différents allèles à une diversité de protéines MICA reste mal connue. Notre étude montre que les allèles MICA*015 et MICA*017 codent pour un panel de 5 isoformes MICA-A, MICA-B1, MICA-B2, MICA-C et MICA-D correspondant à des protéines MICA délétées des domaines α3 et pour certaines α2. Ces protéines résultent d'un épissage alternatif issu d'une délétion dans l'intron 4 observée pour ces deux allèles. Trois isoformes (MICA-B1, MICAB2 et MICA-D) possèdent une affinité, modeste, pour NKG2D. MICA-B2 est un nouveau ligand agoniste capable d'activer NKG2D. MICA-D est capable de lier NKG2D sans induire ni modulation ni activation du récepteur mais possède un effet antagoniste/inhibiteur pour l'activation de NKG2D par un ligand agoniste. Ces travaux apportent de nouvelles données sur la relation structure/fonction des protéines MICA et en particulier sur l'importance du domaine α3 et des sites de Nglycosylation pour l'interaction et l'activation de NKG2D. Ce travail décrit aussi l'expression restreinte et localisée de MICA dans les cellules épithéliales des tubules proximaux et distaux et les cellules de l'endothélium micro- et macrovasculaire du rein. Ces cellules sont les cibles privilégiées du BK virus suggérant un rôle spécifique de MICA dans l'infection ou le contrôle de l'infection par ce virus qui reste à explorer
Functionnal and morphological alterations of the enteric neuro-glio-epithelial unit (NGEU) have been consistently reported in digestive disorders such as irritable bowel syndrome or inflammatory bowel disease. There is mounting evidence that Parkinson's disease (PD) is not only a brain disease but also a gut disorder. Gastrointestinal involvement is a frequent and early event in the course of PD, and it may be critically involved in the early development of the disease. As in PD the enteric neurons accumulate a-synuclein, and thus are showing PD specific pathological features, we undertook the present PhD work to investigate whether the enteric glia in PD become reactive by assessing the expression and phosphorylation levels of GFAP protein in colonic biopsies. In parallel we investigated whether changes in the intestinal epithelial barrier (IEB) function and/or morphology occur in PD by measuring the para- and transcellular permeabilities in colonic biopsies and by assessing the expression and localization of the two tight junctions protein ZO-1 and occludin. As compared to control subjects, patients with PD had significant higher enteric GFAP expression levels whereas the phosphorylation at serine 13 was significantly lower. The para- and transcellular permeabilities were not different between PD patients and controls. The expression of occludin, but not ZO-1, was significantly lower in colonic samples from PD patients as compared to controls and the cellular distribution of both proteins was altered in PD patients. Our findings provides evidence that the NGEU is altered in PD via accumulation of a- synuclein in enteric neurons, enteric glial reaction and IEB morphological impairments. This PhD work further reinforce the potential role of the gastrointestinal tract in the initiation and/or the progression of the disease

Les parois des cellules végétales sont des structures formées de divers polymères polysaccharidiques et de nombreuses protéines. Ces structures possèdent un fort dynamisme assuré par l'action spécifique des protéines pariétales (CWP). Parmi ces CWP, se situent les peroxydases de classe III (CIII Prx) formant une famille multigénique de 73 membres chez la plante modèle Arabidospis thaliana. Les CIII Prxs assurent de nombreux rôles dans le développement et les interactions avec l'environnement mais seuls de rares études ont pu attribuer une fonction précise à un membre individuel de la famille. Ceci est probablement du à la faible spécificité de ces enzymes in vitro et à la possible redondance fonctionnelle obligeant à considérer des études in situ-in vivo et l'utilisation de mutants multiples. Dans ce contexte, le premier objectif de cette thèse était d'établir un atlas d'expression spatiotemporelle par hybridation in situ (HIS) utilisant le développement de la graine d'A. thaliana comme modèle. Ce travail s'est appuyé sur une étude de micro-transcriptomique récemment publiée, permettant d'établir des comparaisons avec nos résultats d'HIS. Ils ont montré une complémentarité entre les deux approches et permis (1) d'établir des seuils de valeurs de transcriptomiques compatibles avec la sensibilité de l'HIS et (2) de définir des candidats d'intérêt présentant des profils d'expression spatiotemporelle suggérant des fonctions précises. Le deuxième objectif de cette thèse a été de caractériser fonctionnellement l'un de ces candidats (AtPRX36). Nous avons pu démontrer le rôle de cette protéine dans le contrôle du relargage du mucilage polysaccharidique lors de l'imbibition de la graine. Nos résultats suggèrent que l'ancrage localisé de cette protéine est assuré par un microdomaine pectique d'homogalacturonane globalement méthylestérifié formé par l'action d'un inhibiteur de une pectine méthylestérase (PMEI6), et permet un rôle d'AtPRX36 dans le relâchement polarisé de la paroi au niveau de ce microdomaine délimitant la zone de rupture des graines lors de l'imbibition
Plant cell walls are complex structures, mainly composed of a large number of polysaccharides and proteins. The cell wall (CW) is a highly dynamic compartment which is remodeled by specific cell wall proteins (CWP). Among these CWP, the plant specific class III peroxidases (CIII Prxs) are a multigenic family of 73 members in Arabidopsis thaliana. CIII Prxs are involved in plant development but also in the interaction of the plant with its environment. However, only a few studies describing the exact function of individual members of this multigenic family have been published. This can be due to the weak in vitro substrate specificity of these enzymes and their possible functional redundancy, forcing to characterize their function in situ-in vivo and the use of multiple mutants. In this context, the first goal of my thesis was to establish the fine cellular spatio-temporal expression atlas of CIII Prxs throughout the seed development of Arabidopsis thaliana with an in situ hybridization (ISH) approach. This expression work (ISH) was partially permitted thanks to a recent published micro-transcriptomic study which allowed to compare both expression results (ISH vs micro-transcriptomic). This comparison showed that both techniques are complementary and it allowed to; (1) set a threshold for the ISH detection limit based on micro-transcriptomic expression values, and (2) to define specific spatio-temporal expression pattern that helps to select CIII Prx candidates for functional study. The second objective was to characterize the function of one of these CIII Prxs candidates (AtPRX36). We were able to determine the role of AtPRX36 during mucilage extrusion of imbibed seeds.Our results suggest that AtPRX36 is anchored within a globally methylesterified pectins CW micro-domain, putatively formed by the action of a pectin methylesterase inhibitor (PMEI6). This CW micro-domain is needed for the CW loosening action of AtPRX36 to permit CW polarized rupture during seed imbibition

Des lésions de l’ADN sont impliquées dans les mécanismes de l’oncogenèse. De plus, la prolifération incontrôlée des cellules tumorales induit l’accumulation d’aberrations géniques. En réponse à ce stress génotoxique, les cellules en transformation expriment les ligands NKG2D MICA et MICB, molécules du CMH de classe I non conventionnelles qui activent une réponse cytotoxique T et NK contre cette transformation. Dans les syndromes lymphoprolifératifs chroniques, les mécanismes de la leucémogenèse reposent essentiellement sur une stimulation antigénique ou une activation des voies du récepteur à l’antigène (BCR) qui induit la prolifération cellulaire. De plus, les ligands MICA/B ne sont pas retrouvés à la surface de ces cellules. Les objectifs de cette thèse sont (i) rechercher si l’activation de la prolifération lymphocytaire peut induire l’expression de MICA/B et (ii) étudier les mécanismes induisant cette expression et leurs liens avec les voies de lésions/réparations de l’ADN. Pour cela, nous avons mis en place des conditions d’activation du récepteur à l’antigène permettant d’obtenir une prolifération (objectivée après marquage par CFSE) de lymphocytes B sains et de lymphocytes issus de patients porteurs de leucémie lymphoïde chronique (LLC), la plus fréquente des leucémie de l’adulte. L’expression des ligands MICA et MICB a ensuite été évaluée par qPCR, cytométrie en flux, western blots et ELISA. L’implication des différentes voies de signalisation en aval du récepteur à l’antigène a été analysée, ainsi que la cinétique d’apparition des lésions de l’ADN durant ce processus. Mes résultats montrent que MICA/B ne sont pas exprimés à la surface des lymphocytes B issus de donneurs sains ou de patients porteurs de LLC. Cependant, l’activation de la prolifération lymphocytaire induit une activation transcriptionnnelle de MICA ainsi que son expression à la surface de ces cellules. Cette expression est induite par différentes voies du récepteur à l’antigène ainsi que par la voie JAK/STAT et est indépendante des lésions de l’ADN qui surviennent plus tardivement dans la cellule. Au total, l’activation du récepteur à l’antigène qui induit la prolifération lymphocytaire induit également l’expression du ligand MICA (et non MICB) à la surface des lymphocytes sains et cette capacité d’expression est conservée dans les cellules de LLC qui ne l’expriment pas. Ces résultats suggèrent que MICA pourrait jouer un rôle crucial aux stades précoces de l’immunité anti-proliférative, ce qui ouvre la voie à de potentielles applications thérapeutiques
Tumor cell’s uncontrolled proliferation induces an accumulation of genetic aberrations. In response to this genotoxic stress, most cells in transformation express NKG2D ligands (not expressed on resting cells), including MICA and MICB, which are non-conventional MHC class I molecules that could induce a cytotoxic T and NK response against the transformed cell. In chronic lymphoproliferative conditions, leukemogenic mechanisms rely in part on antigenic stimulations and/or activation of the B cell antigen receptor (BCR) pathways that induce cell proliferation. My thesis aims at studying : (i) the induction of MICA/B expression during lymphocyte proliferation and (ii) the mechanisms inducing this expression and their relationship with the DNA damage/repair pathways.I did generate BCR activation conditions to obtain B cells proliferation from healthy control individuals and from patients suffreing from chronic lymphocytic leukemia (CLL), the most common leukemia in adults. MICA and MICB expression was assessed by quantitative PCR, flow cytometry, Western blotting and ELISA after activation of B-cell proliferation. The different signaling pathways downstream BCR were analyzed, as were the kinetics of the DNA damage during this process. The results show that MICA/B aren’t expressed on cell surface of B cells from healthy control individuals or CLL patients before activation. Lymphoproliferative stimulation however up-regulates both MICA mRNA and surface protein in these same cells. This expression was induced by several BCR and by JAK/STAT pathways and seems to be indpendant of DNA damage. In conclusion, antigen receptor activation that induces lymphocyte proliferation also induces MICA expression (but not MICB) on B cells surface from healthy control individuals and this expression capacity is conserved in B cells from patients suffering from CLL. These results suggest that MICA may play a crucial role in the early stages of anti-proliferative immunity, which opens the avenue for therapeutic interventions

A subject of this diploma paper is to follow practise of putting children into alternative family care. The key method of finding answers is analysis of interviews with social workers and a worker of socially legal protection of children, and content analysis of texts and documents connected with the issue of alternative family care. The paper examines the role of social workers in the process of putting applicants into register for any form of alternative family care and workers' influence in forming such a process. The aim is to focus on social workers' activity analysis and to discover in which moments and in which ways ideological and normative settings of social workers might affect practice of putting children into alternative family care. One of the points of activity analysis is description of social workers' fulfilment of a concept - the best interest of a child and family. The paper is looking for the answer to what extent and in which moments normative ideas of family and topics family related might affect putting or not putting a child into a particular applicant's care.

Le carcinome hépatocellulaire (CHC) est la première néoplasie létale du foie, représentant 80 à 90% des cas. Actuellement, la majeure partie des patients bénéficient de solutions thérapeutiques avec des efficacités très modestes. La haute variété étiologique, l’hétérogénéité des tumeurs ainsi que l’absence de médiateurs oncogéniques clés connus dans le développement de cette pathologie sont responsables du manque d’options thérapeutiques. À partir d’un crible génétique du kinome humain, nous avons identifié la tyrosine kinase Yes comme un acteur majeur de la prolifération des cellules de CHC. Yes appartient à la famille des kinases Src qui contrôlent de nombreux processus cellulaires notamment la prolifération, la motilité et la survie. La sur-expression ou activation anormale de Yes est retrouvée dans de nombreux cancers et est souvent associée à un mauvais pronostic. Nous avons démontré par des expériences in vitro et in vivo l’activité pro-proliférative de Yes ainsi que son potentiel oncogénique. Notamment, dans un modèle murin de carcinogenèse hépatique induit par le diéthylnitrosamine, la déplétion génétique de Yes abolit totalement la formation de tumeurs. Grâce aux profils transcriptionnels obtenus dans plusieurs modèles cellulaires de CHC, nous avons découvert que l’activité de Yes est associée à une augmentation des signatures géniques des régulateurs transcriptionnels YAP et TAZ ainsi que du facteur transcriptionnel c-Myc. Ces observations ont abouti à identifier YAP, TAZ et c-Myc comme des nouveaux substrats de la tyrosine kinase Yes. Nous avons montré que la phosphorylation par Yes de YAP et TAZ médie leur recrutement dans le noyau ce qui conduit à une hausse de leur activité transcriptionnelle. Nous avons d’ailleurs confirmé l’importance de YAP et TAZ dans les propriétés prolifératives de Yes, notamment dans différents modèles murins de carcinogenèse hépatique. De manière intéressante, nous avons observé que près de 50% de CHCs humains présentent une activation anormale des kinases Src qui corrèle avec la phosphorylation et activation de YAP. Enfin, nous avons observé in vitro et in vivo que Yes stabilise c-Myc. En effet, l’expression transgénique de Yes constitutivement actif dans des hépatocytes entraine la stabilisation de c-Myc à des stades précoces du développement tumoral et une induction de plusieurs de ses gènes cibles à des stades plus tardifs. En plus de leur synergie d’action, cette étude propose que la tyrosine Yes intervient dans les propriétés oncogéniques de c-Myc. Finalement, nous avons découvert que la kinase Yes joue un rôle dans la progression de la stéatose hépatique. En effet, la progression de la pathologie est abolie à la suite de la déplétion de Yes ou suivant l’inhibition pharmacologique des kinases Src. De plus, la survie des cellules tumorales face à leur élimination par le système immunitaire semble être favorisé par la signalisation Yes qui induit l’expression des points de contrôle immuns PD-L1/2. En conclusion nous avons découvert et caractérisé trois nouveaux effecteurs clés de la signalisation oncogénique de la tyrosine kinase Yes dans le CHC. D’ailleurs, la signature génique induite par Yes permet de prédire la survie des patients atteints de CHC. Ces données fournissent de robustes évidences qui placent la tyrosine kinase Yes comme une cible thérapeutique de choix pour la maladie du CHC.
Hepatocellular carcinoma (HCC) is the first lethal neoplasia of the liver, representing 80 to 90% of cases. Currently, for most patients the therapeutic option only provides modest efficiencies. The high etiological variety and heterogeneity of the tumors as well as the absence of known key oncogenic mediator in the development of this pathology is mainly responsible for the lack of therapeutic option. Based on a genetic screen of the human kinome, we identified the tyrosine kinase Yes as a major player in the proliferation of HCC cells. Yes belongs to the family of Src kinases which control many cellular processes including proliferation, motility and survival. The over-expression or abnormal activation of Yes is detected in many cancers and is often associated with poor prognosis. We have demonstrated in vitro and in vivo the pro-proliferative activity of Yes as well as its oncogenic potential. In particular, in a mouse model of hepatic carcinogenesis induced by diethylnitrosamine, the genetic depletion of Yes completely abolishes the formation of tumors. Thanks to the transcriptional profiles obtained in several cellular models of CHC, we discovered that the activity of Yes is associated with an increase in the gene signatures of the transcriptional regulators YAP and TAZ as well as of the transcriptional factor c-Myc. These observations led to the identification of YAP, TAZ and c-Myc as new substrates for the tyrosine kinase Yes. We have shown that the phosphorylation of YAP and TAZ by Yes mediates their recruitment into the nucleus associated with an increase in their transcriptional activity. We have also confirmed the importance of YAP and TAZ in the proliferative properties of Yes in various mouse models of hepatocarcinogenesis. Interestingly, we observed that nearly 50% of human CHCs exhibit an abnormal activation of Src kinases that correlates with phosphorylation and activation of YAP. Moreover, in vitro and in vivo experiments revealed that Yes stabilizes c-Myc. Indeed, the transgenic expression of constitutively active Yes into hepatocytes leads to the accumulation of c-Myc protein at early stages of tumor development and to the induction of several of its target genes at later stages. In addition to their synergistic action, this study suggests that Yes is involved in the oncogenic properties of c-Myc. Finally, we discovered that Yes kinase plays a role in the progression of fatty liver diseases. Indeed, the progression of the pathology is abolished following the depletion of Yes or the pharmacological inhibition of Src kinases. In addition, the survival of Yes-active tumor cells is associated with the induction of PD-L1/2 immune checkpoints that protect cells from immune elimination. In conclusion, we have discovered and characterized three new key effectors of the oncogenic tyrosine kinase Yes in HCC. Interestingly, the gene signature induced by Yes can predict the survival of patients with HCC. These data provide strong evidence for targeting the tyrosine kinase Yes in HCC.

This work analyses the American family in context of society and its demands. It focuses on the cannonical works of the Modern American drama, namely plays of Tennessee Williams, Arthur Miller, Edward Albee, Sam Shepard and David Mamet. The playwrights are analysed in two distinctive groups according to similar themes they share. Tennessee Williams and Arthur Miller depict the family under increasing pressure from the outside as well from the inside. The unit disintegrates, members of the family escape and thus the unit loses its funtions. The pressure is imposed by the tenets of the American mythology that governs the society, which, in turn, influences the family. The common theme of the first group of playwrights is the feeling of loss. This comprises of two dimensions - spatial and tempoval. The second group of playwrights share the same theme of loss with its spatial and temporal implications. They are characteristic by their distinctive use of language that depicts the prevalent sense of doom, apocalypse, futility and sterility. The search for identity is also implied by the restlessness of characters. The detrimental effect of harsh business environment on the family is explored with regards to masculinity. The work shows the family in the context of the 1950s, an era when the family was elevated to...

This thesis focuses on harmonisation of work and family life of female university graduates at beginning of their careers and at the time when they were taking care of babies up to five years of age. I have chosen this topic not only because it is rather an actual topic but also because I'm personally attached to it. My feminist research analysis is based on the theory of power and knowledge as is it described by Foucault and Butler. I was interested in original families of my communication partners where they grew up and where they adopted their social habits and behaviour. In the light of this social process, I have analysed what powers they had to face in their original families in terms of usage of gender stereotypes based on patriarchal layout of our society and preferential existence of one gender over the other. I have also focused on current families of my communication partners and on power relationships on the basis of which the process of harmonisation of professional and family life of my communication partners takes place, both in their private and public space. I have also analysed how social habits and behaviour gained during their childhood are implemented. It was very important for the interviews and for my feminist research to approach my communication partners as subjects, and...

Dissertação de mestrado em Educação Especial (área de especialização em Dificuldades de Aprendizagem Específicas)
Este estudo teve como finalidade conhecer a perceção dos alunos sobre as suas experiências de leitura em contextos familiares e comunitários, no âmbito da primeira fase do modelo de resposta à intervenção. Estudamos a população de 1432 alunos do 3.º ano de escolaridade de 12 Agrupamentos de Escolas do Concelho de Braga, num total de 85 turmas. Para este estudo foi utilizado um questionário denominado “Ler: A voz dos alunos”. Para a seleção de alunos em risco e alunos não em risco foram utilizados os dados recolhidos através uma prova de Monitorização com Base no Currículo (MBC) - compreensão (MBC-MAZE). Os resultados permitiram concluir que: a) as experiências de leitura em contextos familiares e comunitários não são diferentes entre rapazes ou raparigas, no que respeita ao gosto pela leitura, ao conhecimento das letras do alfabeto aquando da entrada para a escola do 1.º Ciclo do Ensino Básico e à consciência sobre a sua prestação na leitura; b) as experiências de leitura em contextos familiares e comunitários são diferentes entre rapazes ou raparigas, no que respeita à visita a bibiotecas ou livrarias, à realização de jogos de rimas, ao diálogo com um adulto sobre palavras desconhecidas, ao hábito de ler sozinho, ao hábito de ler acompanhado por um adulto, à correção, por parte de um adulto, das palavras que o aluno não lê bem, ao diálogo com um adulto sobre o que leram e ao hábito de ver adultos a ler; c) o gosto pela leitura é diferente nos alunos em risco e nos alunos não em risco de apresentaram dificuldades de aprendizagem específica na leitura; d) o número de vezes que visitam bibliotecas e livrarias é diferente nos alunos em risco e nos alunos não em risco; e) o hábito de fazer jogos de rimas é diferente nos alunos em risco e nos alunos não em risco; f) o conhecimento das letras do alfabeto aquando da entrada na escola do 1.º ciclo do Ensino Básico é diferente nos alunos em risco e nos alunos não em risco; g) o hábito de ler sozinho é diferente nos alunos em risco e nos alunos não em risco; h) o hábito de ler acompanhado por um adulto é diferente nos alunos em risco e nos alunos não em risco; i) a correção, por parte de um adulto, das palavras que o aluno não lê bem apresenta diferenças entre os alunos em risco e os alunos não em risco; j) o hábito de ver adultos a ler apresenta diferenças entre os alunos em risco e os alunos não em risco; k) a consciência sobre a sua prestação na leitura é diferente nos alunos em risco e nos alunos não em risco; l) o valor do Alfa de Cronbach para o inquérito foi de 0,585.
This study aimed to understand the students' perceptions about their reading experiences in family and community contexts, within the first phase of the response to intervention model. It was used a sample of 1432 students enrolled in the 3rd grade of 12 school clusters in the Municipy of Braga, in a total of 85 classes. For this study it was used a questionnaire called “ Reading: the voice of the students”. Data was collected through a curriculum-based-measurement probe (CBMMAZE) for the selection of at risk students and students not at risk. The results showed that: a) reading experiences in family and community contexts are not different between boys and girls, as regards to the pleasure of reading, to the knowledge of the alphabet letters on entry to 1st grade and the awareness on their performance in reading; b) reading experiences in family and community contexts are are different between boys and girls, as regards to the visits to libraries or bookstores, conducting rhyming games, to the dialogue with an adult about unknown words, to the habit of reading alone, to the habit of reading with an adult, to correction of the words that the student does not read well by an adult, to the dialogue with an adult about what they read and to the habit of seeing adults reading; c) the pleasure of reading is different for students at risk and students not at risk for specific learning difficulties in reading; d) the number of times they visit libraries and bookstores is different for students at risk and not at risk students; e) the habit of conducting rhyming games is different for students at risk and not at risk students; f) the knowledge of alphabet letters when entry to 1st grade is different for students at risk and not at risk students; g) the habit of reading alone is different for students at risk and not at risk students; h) the habit of reading with an adult is different for students at risk and not at risk students; i) the correction of the words that student doesn’t read well, by an adult, is different between at risk students and students not at risk; j) the habit of seeing adults reading is different at risk students and students not at risk; k) the awareness about his performance in reading is different in at risk students and students not at risk; l) the value of Cronbach's alpha for the survey was 0,585.