Esta pesquisa teve por objetivo verificar como é que o aluno consegue por si próprio manipular os recursos, tais como gráficos disponibilizados pelo software GeoGebra, para auxiliar nas práticas diárias de sala de aula, mais especificamente no que tange a construir a conexão entre as progressões aritméticas e as funções afins, bem como entre as progressões geométricas e as funções exponenciais. Este software possibilita fazer análises a partir de diferentes registros tais como: gráficos, tabelas e registros algébricos, seguindo a teoria dos registros semióticos de Duval. Como metodologia, desenvolvemos roteiros de atividades com duas turmas do 2º ano do Ensino Médio do Colégio Estadual Visconde de Bom Retiro. Os alunos foram convidados a construir, verificar e interpretar seus próprios resultados, refletindo e analisando estratégias para responder à questão: Quais relações os alunos conseguem evidenciar, através da comparação entre gráficos (obtidos com o GeoGebra) de funções afins e exponenciais, com progressões aritméticas e geométricas, respectivamente? Ao final da pesquisa, os registros coletados possibilitaram a validação qualitativa da proposta, mostrando que os alunos avançaram na compreensão dos conteúdos abordados. / The aim of this research was to verify how the student can himself manipulate the resources, such as plots made available by the GeoGebra software, to aid in the daily classroom practices, specifically in the construction of the connection between arithmetic progressions and linear functions, as well as between geometric progressions and exponential functions. This software makes possible to analyze from different registers such as: plots, tables and algebraic records, following the theory of semiotic records of Duval. Our methodology consisted in developing activity scripts with students of two classes of the 2nd year of the High School of Visconde de Bom Retiro State College. More specifically, they were asked to build, verify and interpret their own results, speculating and analyzing strategies to answer the question: What relations are the students able to highlight through comparing plots (obtained with GeoGebra) of linear and exponential functions, with arithmetic progressions and geometric, respectively? At the end of the research, the collected records made possible the qualitative validation of the proposal, showing that the students improved their understanding of the focused contents.

Un des défis majeurs de l’immunologie antitumorale repose sur l’induction efficace et prolongée de laphase effectrice de la réponse immune antitumorale. Une meilleure compréhension des mécanismesimpliqués dans la potentialisation de l’activité antitumorale des effecteurs immunitaires, en particulier lesCTL infiltrant la tumeur représente donc un enjeu considérable dans le développement de nouvellesapproches d’immunothérapie visant à induire une réponse immunitaire spécifique efficace contre latumeur. Dans ce contexte, nous nous sommes particulièrement intéressés à étudier le rôle de CD5 dans lecontrôle de la progression tumorale, en particulier dans la potentialisation de l’activité T cytotoxique desCTL infiltrant le mélanome B16 in vivo. Nos résultats ont montré un ralentissement significatif de lacroissance tumorale chez des souris déficientes pour l’expression de CD5 comparées à leurs équivalentessauvages. Le contrôle de la progression de la tumeur chez les souris CD5-/- ne semble pas corréler avec unrecrutement plus important de lymphocytes T, mais avec une efficacité accrue de leur réactivité vis-à-visdu mélanome B16. Nous avons montré aussi que cette réponse est transitoire et qu’un échappementtumoral au système immunitaire ait lieu à un stade plus tardif de la progression de la tumeur. Cetéchappement tumoral semble être associé à une augmentation de la mort par AICD des TIL CD8+/CD5-par rapport aux TIL CD8+/CD5+ et ce par induction de FasL à la surface des TIL. La modulation de la voieFas/FasL in vivo avec un adénovirus Fas-Fc protège les lymphocytes T CD8+/CD5- infiltrant la tumeur dela mort par apoptose et empêche ainsi l’échappement tumoral. De plus, l’analyse du répertoirelymphocytaire T spécifique du mélanome B16 dans les souris CD5-/- suggère que le contrôle de laprogression de la tumeur serait lié à une meilleure prolifération de lymphocytes T CD5-/- spécifiques insitu. Nos résultats montrent aussi que l’immunisation des souris CD5-/- en utilisant des Ag tumorauxassociés au mélanome B16 contribue à la potentialisation de la réponse immunitaire antitumorale.L’ensemble de nos résultats soulignent un intérêt particulier du ciblage de CD5 pour améliorer lesapproches d’immunothérapie antitumorale actuelles. / A major challenge in tumor immunology is based on effective and prolonged induction of the effectorphase of antitumor immune response. A better understanding of the mechanisms involved in potentiatingthe antitumor activity of immune effectors, particularly the CTL infiltrating the tumor represents aconsiderable challenge in developing new approaches to immunotherapy. In this context we areparticularly interested in studying the role of CD5 in the control of tumor progression, particularly inpotentiating the cytotoxic activity of CTLs infiltrating B16 melanoma. Our results showed a significantdelay in tumor growth in CD5-/- mice as compared with wild type mice. The control of tumor growth inCD5-/- mice does not seem to correlate with a higher recruitment of T cells, but with increased cytotoxicityof infiltrating T cells against B16 cells. We have also shown that this response is transient and that thetumor escape from immune system takes place at a later stage of tumor progression. This tumor escapeappears to be associated with increased death by AICD of TIL CD8+ from CD5-/- mice as compared withTIL CD8+ from wild type mice wich correlated with the induction of FasL on the surface of TIL. In vivomodulation of Fas/FasL with an adenovirus AdFas-Fc protects tumor infiltrating T CD8+/CD5- fromapoptosis and thereby prevents the tumor escape. In addition, analysis of specific T lymphocyte repertoirein CD5-/- mice suggests that the control of tumor progression could be linked to a greater in situproliferation of specific CD5- T lymphocytes. Our results also show that immunization of CD5-/- miceusing different melanoma associated antigens contributes to the potentiation of antitumor immuneresponse. All these results highlight a particular interest in targeting of CD5 to improve currentapproaches to tumor immunotherapy.

Neste trabalho são apresentadas duas propostas de sequências didáticas para ensino de logaritmos. A primeira delas é destinada ao aperfeiçoamento de professores de Matemática e a outra, para alunos de Ensino Médio. Tais sequências foram desenvolvidas com base em pesquisas realizadas pelo Prof. João Pedro da Ponte sobre o processo de investigação matemática. A sequência didática para professores foi aplicada no Centro de Aperfeiçoamento do Ensino de Matemática do Instituto de Matemática e Estatística da Universidade de São Paulo (CAEM IME USP). Já a sequência para alunos foi aplicada em uma escola da rede estadual situada no município de São Paulo. Ambas foram analisadas sob os pontos de vista da eficiência e adequação, bem como da clareza das ideias apresentadas. As sequências didáticas têm como ponto de partida a observação das propriedades comuns a várias tabelas, cada uma contendo uma progressão geométrica ao lado de uma progressão aritmética. Tais propriedades caracterizam o que virá a ser definido como logaritmo. Essa introdução ao conceito de logaritmo é diferente da usual, que se baseia na solução de uma equação exponencial. O processo de investigação matemática visa a um aprendizado eficaz por parte do aluno, proporcionado por atividades que conduzam o aluno, de forma gradual, a fazer descobertas, formular conjecturas e buscar validações. Tais investigações são coordenadas e supervisionadas pelo professor, cujo papel é fundamental no processo de construção do conhecimento. / This dissertation presents two didactic sequences for teaching and learning logarithms. One of them aims at Mathematics teachers and is designed for improving their knowledge. The other sequence is meant to be used on high school students. Both didactic sequences were developed based upon research carried out by Professor João Pedro da Ponte on Mathematical Investigations. The didactic sequence for teachers was applied at CAEM IME USP. The one for students was applied at a state school in the city of São Paulo. They were analysed from the points of view of efficiency and of adequacy, as well as of the clarity of the presented ideas. The didactic sequences start with the observation of properties common to multiple tables, each containing a geometric progression side by side with an arithmetic progression. The observed properties characterize what will be later defined as logarithm. Such introduction to the concept of logarithm is different from the usual, which is based on the solution of an exponential equation. The Mathematical Investigation process aims at an effective learning by the students, which is provided by activities that lead the student to gradually make discoveries, formulate conjectures, and search for validations. These investigations are coordinated and supervised by the teacher, whose role in the knowledge construction process is fundamental.

La dissémination métastatique est associée à de faibles chances de survie dans les cas de mélanomes humains, comme pour d’autres cancers. Le développement de métastases est un processus qui se fait en plusieurs étapes et nécessite la réorganisation du cytosquelette d’actine pour permettre la migration et l’invasion cellulaire. La protéine Nck2 est un adaptateur protéique principalement impliqué dans la réorganisation du cytosquelette. Une étude préliminaire réalisée dans notre laboratoire avait révélé que les niveaux de la protéine Nck2 et de son ARNm sont augmentés dans les lignées de mélanome métastatiques en comparaison aux lignées primaires. Le but de la présente recherche était donc d’étudier le rôle de l’adaptateur Nck2 dans la progression métastatique. Les résultats obtenus confirment que l’expression de Nck2 augmente de façon marquée au cours de la progression métastatique du mélanome humain. Cette étude révèle en plus que l’expression de hauts niveaux de Nck2 dans les cellules de mélanome primaire stimule la prolifération cellulaire et la migration, n’affecte pas l’invasion d’une matrice de collagène de type I, mais semble affaiblir les contacts cellule-cellule et l’adhésion au substrat. Une étude préliminaire effectuée in vivo révèle que ces phénomènes se traduisent par une légère augmentation de la tumorigenèse et de la croissance tumorale. Dans l’ensemble, les résultats obtenus suggèrent que Nck2 pourrait effectivement jouer un rôle dans la progression métastatique du mélanome en favorisant la prolifération des cellules tumorales et en facilitant leur détachement de la tumeur primaire, les rendant plus aptes à se disperser dans l’organisme et à établir des colonies métastatiques. Au niveau moléculaire, nous proposons que Nck2 est recruté dans les invadopodes pour favoriser la formation de complexes protéiques qui stimulent l’invasion. La mobilisation de Nck2 dans ces structures membranaires diminuerait sa disponibilité pour l’établissent d’autres complexes protéiques, entre autres dans les complexes d’adhésion focaux (FAs) et dans les jonctions adhérentes, diminuant ainsi les contacts des cellules cancéreuses avec la matrice extracellulaire et les cellules avoisinantes. / The metastatic process is highly fatal in many cancers, including human melanoma. Metastatic progression is a multistep process in which cytoskeletal organization allows migration and invasion of cancer cells. Nck2 is an adaptor protein mainly associated with cytoskeletal organization. A preliminary study carried out in our laboratory has shown that Nck2 protein and mRNA levels are increased in metastatic melanoma cell lines compared to primary cell lines. In this study, the role of Nck2 in metastatic progression was further investigated. Results confirmed that Nck2 levels are increased in metastatic melanoma compared to primary cell lines. Nck2 overexpression in primary melanoma induced migration and cell proliferation, did not affect invasion in type I collagen matrix, but decreased cell-cell and cell-substrate adhesion. In addition, a preliminary in vivo study suggested that Nck2 overexpression slightly increased tumorigenesis and tumor growth in primary melanoma. All together, these results indicate that Nck2 may effectively influence metastatic progression of melanoma by increasing cancer cell proliferation and detachment from the primary tumor, allowing them to enter the blood circulation and form distant colonies. At the molecular level, we propose that Nck2 is recruited to invadopodia in order to form molecular complexes that increase cell invasion, and this may results in a decrease in Nck2 levels available to form other molecular complexes in others cell compartments, such as focal adhesions (FA) and adherent cell junctions.

Après 25 ans de recherche intensive, aucun vaccin ou traitement définitif contre le SIDA n'existe, et les mécanismes moléculaires de pathogenèse de l'infection VIH-1 ne sont pas clairement élucidés. Les avancées technologiques permettent de comparer des sujets malades avec des sujets contrôles sur tout le génome. Il est ainsi possible d’identifier sans a priori des gènes potentiellement impliqués dans le développement de la maladie avec pour conséquence le développement rationnel de nouvelles stratégies diagnostiques ou thérapeutiques. Durant ma thèse, j’ai réalisé deux études d’association ‘génome entier’ dans le SIDA, en comparant les 275 non-progresseurs à long terme ou les 85 progresseurs rapides de la cohorte GRIV avec une cohorte de contrôles séronégatifs. J’ai réalisé une troisième analyse en exploitant les données issues de trois études ‘génome entier’ internationales dont la nôtre (France, Pays-Bas, USA), ciblant plus particulièrement les SNPs de fréquence faible (fréquence de l’allèle mineur, MAF<5%). Ces approches ‘génome entier’ ont réaffirmé le rôle central du HLA dans la progression vers le SIDA, mais aussi dévoilé de nouveaux gènes candidats très pertinents donnant une nouvelle lumière sur les mécanismes moléculaires de la maladie. / After 25 years of intensive research, no vaccine or cure exists against AIDS, and the molecular mechanisms of pathogenesis of HIV-1 infection are not clearly understood. Technological progress has made possible to compare cases versus controls over the whole genome. It is thus possible to identify genes potentially involved in disease development with no a priori, and consequently develop rationally new diagnostic or therapeutic strategies. During my PhD, I have completed two genome-wide association studies (GWAS) in AIDS, comparing 275 long term non-progressors or the 85 rapid progressors from the GRIV cohort with a cohort of seronegative controls. I have also completed a third analysis exploiting data from three international GWAS including ours (France, Netherlands, USA), targeting particularly low frequency SNPs (minor allele frequency, MAF <5%). These GWAS approaches have reaffirmed the central role of HLA for progression towards AIDS, but also revealed new relevant candidate genes, shedding a new light on the molecular mechanisms of disease progression.

Les cancers broncho-pulmonaires à petites cellules (CBPPC), tumeurs endocrines représentant 20% des cancers pulmonaires, sont fortement associés au tabagisme. Ils sont très agressifs en raison de leur progression rapide et de la présence de métastases souvent présentes au moment du diagnostic. Moins de 10% des patients sont opérables et la plupart des échantillons de tumeurs sont recueillis par endoscopie bronchique ou par médiastinoscopie. Dans ce travail de thèse, nous avons montré que l’expression du TFPI-2, un gène suppresseur de tumeur, était diminué dans 65% des cas de CBPPC. Afin d’étudier l’impact du TFPI-2 sur la progression tumorale, nous avons préalablement développé un modèle orthotopique murin de CBPPC qui mime le développement de ce type de cancer pulmonaire. Des cellules NCI-H209, n’exprimant pas le TFPI-2, ont été préalablement transfectées pour exprimer la luciférase et la croissance tumorale a été suivie par imagerie de bioluminescence. L’expression du TFPI-2 a ensuite été restaurée dans ces cellules et nous avons montré que la croissance tumorale était alors réduite. Cet effet peut s’expliquer par une diminution de la prolifération des cellules exprimant le TFPI-2, associée à un arrêt du cycle cellulaire en phase G1/S dû à l’expression de p15 et de p27 et à une induction de l’apoptose. Nous avons aussi démontré que lorsque le TFPI-2 est surexprimé, les transcrits et les protéines MMP-1 et -3 sont diminuées, tout comme la phosphorylation des protéines de la voie des MAP Kinases impliquées dans l’induction des transcrits de ces MMP. Cette corrélation entre l’expression du TFPI-2 et la diminution de celle de la MMP-1 a été retrouvée dans 35% des échantillons de CBPPC humains. Ces résultats suggèrent que l’inactivation du TFPI-2 dans les CBPPC peut favoriser le développement de ce cancer. Enfin, nous avons également démontré, pour la première fois que le TFPI-2 peut aussi inhiber la kallicréine 12, une protéase à sérine potentiellement anti-angiogénique. L’ensemble de ces données suggèrent que le TFPI-2 peut être un potentiel biomédicament capable de limiter la progression des carcinomes pulmonaires à petites cellules. / Small Cell Lung Cancer (SCLC) is the most common neuroendocrine tumour of the lung (15% of cases) and is strongly associated with smoking. It is characterised by tumours that grow rapidly with early metastases. Less than 10% of patients with SCLC have a resectable tumour, thus surgical specimens are scarce and most tumour samples come from small biopsies obtained during bronchial endoscopy or mediastinoscopy. In this study, low levels of TFPI-2 expression were found in 65% of patients with SCLC. To study the impact of TFPI-2 in tumour progression, we first developed a clinically relevant animal model that resembles various stages of human SCLC. NCI-H209 cells, not expressing TFPI-2, were genetically modified to express firefly luciferase and the growth of the tumour was sensitively followed by bioluminescence imaging. TFPI-2 was then overexpressed in these cells and we showed that TFPI-2 inhibited lung tumour growth. Such inhibition could be explained in vitro by a decrease in tumour cell proliferation, blockade of G1/S phase cell cycle transition due to p15 and p27 expression, and an increase in apoptosis shown in NCI-H209 cells expressing TFPI-2. We also demonstrated that TFPI-2 upregulation in NCI-H209 cells decreased MMP expression, particularly by downregulating MMP-1 and MMP-3. Moreover, TFPI-2 inhibited phosphorylation of the MAPK signalling pathway proteins involved in the induction of MMP transcripts, among which MMP-1 was predominant in SCLC tissues and was inversely expressed with TFPI-2 in 35% of cases. These results suggest that downregulation of TFPI-2 expression could favour the development of SCLC. Finally, we also demonstrated for the first time that TFPI-2 could inhibit the kallikrein 12, an anti-angiogenic serine proteinase. Altogether, these results suggest that TFPI-2 could be a new potent therapeutic agent to control SCLC tumour progression in SCLC.

Esta pesquisa teve por objetivo verificar como é que o aluno consegue por si próprio manipular os recursos, tais como gráficos disponibilizados pelo software GeoGebra, para auxiliar nas práticas diárias de sala de aula, mais especificamente no que tange a construir a conexão entre as progressões aritméticas e as funções afins, bem como entre as progressões geométricas e as funções exponenciais. Este software possibilita fazer análises a partir de diferentes registros tais como: gráficos, tabelas e registros algébricos, seguindo a teoria dos registros semióticos de Duval. Como metodologia, desenvolvemos roteiros de atividades com duas turmas do 2º ano do Ensino Médio do Colégio Estadual Visconde de Bom Retiro. Os alunos foram convidados a construir, verificar e interpretar seus próprios resultados, refletindo e analisando estratégias para responder à questão: Quais relações os alunos conseguem evidenciar, através da comparação entre gráficos (obtidos com o GeoGebra) de funções afins e exponenciais, com progressões aritméticas e geométricas, respectivamente? Ao final da pesquisa, os registros coletados possibilitaram a validação qualitativa da proposta, mostrando que os alunos avançaram na compreensão dos conteúdos abordados. / The aim of this research was to verify how the student can himself manipulate the resources, such as plots made available by the GeoGebra software, to aid in the daily classroom practices, specifically in the construction of the connection between arithmetic progressions and linear functions, as well as between geometric progressions and exponential functions. This software makes possible to analyze from different registers such as: plots, tables and algebraic records, following the theory of semiotic records of Duval. Our methodology consisted in developing activity scripts with students of two classes of the 2nd year of the High School of Visconde de Bom Retiro State College. More specifically, they were asked to build, verify and interpret their own results, speculating and analyzing strategies to answer the question: What relations are the students able to highlight through comparing plots (obtained with GeoGebra) of linear and exponential functions, with arithmetic progressions and geometric, respectively? At the end of the research, the collected records made possible the qualitative validation of the proposal, showing that the students improved their understanding of the focused contents.

Esta pesquisa teve por objetivo verificar como é que o aluno consegue por si próprio manipular os recursos, tais como gráficos disponibilizados pelo software GeoGebra, para auxiliar nas práticas diárias de sala de aula, mais especificamente no que tange a construir a conexão entre as progressões aritméticas e as funções afins, bem como entre as progressões geométricas e as funções exponenciais. Este software possibilita fazer análises a partir de diferentes registros tais como: gráficos, tabelas e registros algébricos, seguindo a teoria dos registros semióticos de Duval. Como metodologia, desenvolvemos roteiros de atividades com duas turmas do 2º ano do Ensino Médio do Colégio Estadual Visconde de Bom Retiro. Os alunos foram convidados a construir, verificar e interpretar seus próprios resultados, refletindo e analisando estratégias para responder à questão: Quais relações os alunos conseguem evidenciar, através da comparação entre gráficos (obtidos com o GeoGebra) de funções afins e exponenciais, com progressões aritméticas e geométricas, respectivamente? Ao final da pesquisa, os registros coletados possibilitaram a validação qualitativa da proposta, mostrando que os alunos avançaram na compreensão dos conteúdos abordados. / The aim of this research was to verify how the student can himself manipulate the resources, such as plots made available by the GeoGebra software, to aid in the daily classroom practices, specifically in the construction of the connection between arithmetic progressions and linear functions, as well as between geometric progressions and exponential functions. This software makes possible to analyze from different registers such as: plots, tables and algebraic records, following the theory of semiotic records of Duval. Our methodology consisted in developing activity scripts with students of two classes of the 2nd year of the High School of Visconde de Bom Retiro State College. More specifically, they were asked to build, verify and interpret their own results, speculating and analyzing strategies to answer the question: What relations are the students able to highlight through comparing plots (obtained with GeoGebra) of linear and exponential functions, with arithmetic progressions and geometric, respectively? At the end of the research, the collected records made possible the qualitative validation of the proposal, showing that the students improved their understanding of the focused contents.

The aim of the study was to compare the wording of assignments in two textbooks in Swedish with the focus on their level of linguistic difficulty. The textbooks are intended for grade 3 and grade 4 respectively. The comparison considers factors that affect the difficulty of a text, and the study is based on the following analytical categories: parts of speech, word length, compound words, sentence length, noun quota, and readability index. The results of the study indicate that the assignment descriptions in grade 4 are at a textually higher level of difficulty in five of six analytical categories, since the assignment descriptions in grade 3 can be perceived as more colloquial, with a lower readability index and a lower density of information than the textbook for grade 4. However, the analysis of compound words shows that the assignment descriptions for grade 3 contain a larger proportion of compounds; unlike the other factors, this does not suggest a textual progression from grade 3 to grade 4. Despite this discrepant result, one can observe a linguistic progression between the assignment descriptions in the textbooks based on the other categories, and from the factors that have been studied it may be assumed that the assignment descriptions in the textbook for grade 4 are at a higher level of linguistic difficulty. / Studiens syfte är att jämföra uppgiftsformuleringar i två läroböcker i svenska med fokus på deras språkliga svårighetsnivå. Läroböckerna är avsedda för årskurs 3 respektive årskurs 4. Jämförelsen sker utifrån faktorer som påverkar en texts svårighetsgrad och de analyskategorier som studien baseras på är ordklasser, ordlängd, sammansatta ord, meningslängd, nominalkvot och läsbarhetsindex. Studiens resultat tyder på att uppgiftsformuleringarna i årskurs 4 har en textuellt högre svårighetsnivå i fem av sex analyskategorier eftersom uppgiftsformuleringarna i årskurs 3 kan upplevas mer talspråkliga, har ett lägre läsbarhetsindex samt har en lägre informationstäthet jämfört med läroboken för årskurs 4. Dock visar analysen av sammansatta ord att uppgiftsformuleringarna för årskurs 3 innehåller en större andel sammansatta ord, vilket till skillnad från de övriga faktorerna inte talar för en textuell progression från årskurs 3 till årskurs 4. Trots det avvikande resultatet kan en språklig progression mellan uppgiftsformuleringarna i läroböckerna konstateras utifrån de övriga kategorierna och det kan, utifrån de faktorer som undersökts, antas att uppgiftsformuleringarna i läroboken för årskurs 4 har en högre språklig svårighetsnivå.

Redan idag är närmare var tredje medarbetare i Försvarsmakten civilanställd och den andelen förväntas öka. Trots det har få studier gjorts kring vad som driver dessa människor. Den modell vi tagit fram visar att civilanställda i Försvarsmakten känner en stark samhörighet och ser sig som en del av den gemensamma identiteten. De påverkas dock av en upplevd otydlighet och byråkratisering, precis som sina militära kollegor. Dock med en stor skillnad – att byta arbetsgivare ligger närmare till hands än för en Officer. Vår studie utgår från workshops med civilanställda vid två krigsförband. Urvalet av deltagare har gett oss en inblick i såväl administrativa roller som roller burna av specialister inom kärnverksamheten. Vi har valt att analysera vår empiri utifrån perspektiv som Försvarsmakten kan påverka. Den här studien handlar inte om motivationsteori utan vad arbetsgivaren kan och bör göra för att säkra både rekrytering och bibehållande av individer som är avgörande för organisationens framtid. Det enskilt viktigaste Försvarsmakten kan göra för att behålla kompetensen hos dessa medarbetare är att ge dem trovärdiga karriärvägar, likt de Officerskåren har.