Le carcinome hépatocellulaire (CHC) et le cholangiocarcinome (CCA) sont 2 types de cancer primitif du foie. Le CHC est le plus fréquent, cependant l’incidence du CCA augmente partout dans le monde avec un diagnostic difficile, un mauvais pronostic et des thérapies très limitées. Ce travail avait pour objectif d'identifier des cibles pour le diagnostic et la thérapeutique du CCA. Il est basé sur l'étude de la septine 9 et des phosphoinositides (PIs). La septine 9 appartient à une famille de GTPases qui participent à l’organisation des microtubules et du cytosquelette d’actine. Les septines sont impliquées dans la cytokinèse, le trafic vésiculaire et la polarité cellulaire, elles sont aussi des partenaires importantes des PIs. Pour déterminer le rôle de la septine 9 dans le CCA nous nous sommes intéressés à son interaction avec les PIs et avec l’inhibiteur de l’inducteur et activateur de la transcription 1 (PIAS1) qui a été décrite comme une protéine pouvant agir comme une SUMO ligase pour les septines. Nous avons étudié l’expression de la septine 9 et de PIAS1 dans le CCA et le CHC. Nous avons mis en évidence un mécanisme original par lequel, la production du PtdIns5P (Phosphatidylinositol -5-phosphate) permet un recrutement de la septine 9, la stabilisation des microtubules et le transport de PIAS1 du cytoplasme vers le noyau. Il démontre un rôle important des septines en association avec les PIs dans le trafic. De plus, nous avons montré que la septine 9 est un régulateur de la signalisation de l’interféron γ qui agit au niveau de la phosphorylation de STAT1 et l’entrée de PIAS1 dans le noyau. Ce travail peut constituer une nouvelle piste pour la recherche des thérapies ciblées en immunothérapie dans le traitement de ce cancer. / Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are two types of primary liver cancer. HCC is the most frequent, however the incidence of CCA increases throughout the world with a difficult diagnosis, poor prognosis and very limited therapies. The objective of this work was to identify targets for the diagnosis and treatment of CCA. It is based on the study of septin 9 and phosphoinositides (PIs). Septin 9 belongs to a family of GTPases that participate in the organization of microtubules and the actin cytoskeleton. Septins are involved in cytokinesis, vesicular trafficking and cellular polarity and are also important partners of PIs. To determine the role of septin 9 in the CCA, we investigated its interaction with PIs and with Protein inhibitory of activated STAT1 (PIAS1), which has been described as a SUMO ligase for septins. We studied the expression of septin 9 and PIAS1 in CCA and CHC. We have demonstrated an original mechanism by which la production of PtdIns5P allows the recruitment of septin 9, the stabilization of microtubules and the transport of PIAS1 from the cytoplasm to the nucleus. It demonstrates an important role of the septins in association with the PIs in trafficking. Besides, we have shown that septin 9 is a regulator of interferon γ signaling which acts at the level of the phosphorylation of STAT1 and the entry of PIAS1 into the nucleus. This work can constitute a new avenue for the research of targeted immunotherapy for this cancer.

Existe la creencia de que los investigadores españoles no han tenido particular interés en profundizar acerca del conocimiento de África y que, por tanto, la bibliografía generada en nuestro país sobre este continente es minúscula, sobre todo si la comparamos con la de otros países europeos. Un estudio en profundidad de los fondos bibliográficos existentes en las bibliotecas permite advertir la existencia de este africanismo español, que tuvo personalidades descollantes y se ha mantenido, con una sucesiva transformación de su discurso, hasta nuestros días. Esto es particularmente evidente en lo que respecta al Sáhara occidental. La peripecia de su frustrada descolonización, que ha devenido en un serio problema internacional aún no resuelto, ha dado lugar a que el interés sobre el Sáhara no sólo no decayese, sino que aumentase, con el resultado de una actividad investigadora y bibliográfica de notable importancia. En consecuencia, el investigador que suscribe se ha propuesto realizar un análisis concienzudo de la literatura precolonial, colonial y poscolonial española referida en concreto al tema del Sáhara occidental y, a través ella, tratar de interpretar el discurso que subyace en este patrimonio documental. / There is a belief that Spanish researchers have not had particular interest in deepening their knowledge of Africa and that, moreover, the bibliography generated in our country regarding that continent is minuscule, above all if we compare it with that of other European countries. An in-depth study of the existing bibliographic sources in the libraries makes it possible to report the existence of this Spanish interest in Africa, which includes outstanding personalities and has continued, with successive transformation of its discourse, until our time. This is particularly evident with respect to the Western Sahara. The drama of its unsuccessful decolonisation, which has become a serious and still unresolved international problem, has meant that interest in the Sahara has not only not dwindled, but has actually increased, with notably important research and bibliographical activity as the result. Consequently, the researcher who takes up this option has to carry out a conscientious analysis of the precolonial, colonial and postcolonial Spanish literature referring specifically to the subject of the Western Sahara and, through this, to interpret the underlying discussion in this documentary patrimony.

Le remodelage maladaptif du ventricule gauche (VG) peut conduire au développement d’une insuffisance cardiaque (IC) après un infarctus du myocarde (IM). Il est lié à l’activité de la métalloprotéinase matricielle (MMP)-9. L'adénosine (Ado) est connue pour ses propriétés cardioprotectrices, toutefois son rôle dans le remodelage du VG est mal défini. Notre hypothèse est que l’Ado pourrait avoir un effet sur la MMP-9. Après IM, 2 vagues de cellules inflammatoires infiltrent séquentiellement le cœur : les neutrophiles puis les monocytes-macrophages. Nous avons montré que l’Ado inhibe la sécrétion de MMP-9 par les neutrophiles primaires humains activés via la stimulation du récepteur à l’adénosine A2a. Nous avons ensuite utilisé des monocytes primaires humains différenciés en macrophages in vitro. Contrairement aux résultats obtenus avec les neutrophiles, l'Ado augmente la sécrétion de MMP-9 par les macrophages. Cette augmentation semble passer via le récepteur à l’adénosine A3. Nos résultats suggèrent également que l’Ado améliore la capacité migratoire des monocytes via la stimulation de l'activité MMP-9. Enfin, des expériences préliminaires semblent indiquer que l’Ado inhiberait l’apoptose des monocytes primaires humains. Ces travaux ont contribué à la caractérisation des effets de l’Ado sur certains processus clefs dans le remodelage du VG, notamment la dégradation de la matrice extracellulaire et l’apoptose des cellules inflammatoires. Ils mettent en exergue la notion de fenêtre thérapeutique temporelle et pourraient avoir d’importantes implications lors de stratégies thérapeutiques utilisant l’Ado et/ou ses récepteurs dans le traitement de l'IM et la prévention de l’IC. / Maladaptive remodeling of the left ventricle (LV) is a leading cause of heart failure (HF) after myocardial infarction (MI). It is associated with matrix metalloproteinase (MMP)-9. Although adenosine (Ado) is known to have cardioprotective properties, its role in LV remodeling is still unclear. We hypothesized that Ado could be involved in the regulation of MMP-9. Two waves of inflammatory cells successively infiltrate the heart after MI: first neutrophils then monocytes-macrophages. On the one hand, we have shown that Ado inhibits the secretion of MMP-9 by activated primary human neutrophils. This effect is mediated by the activation of the adenosine-A2a receptor. On the other hand, we cultured human primary macrophages differentiated in vitro from blood monocytes. In sharp contrast to our previous observations with neutrophils, we have shown that Ado enhanced MMP-9 secretion by macrophages. This increase is probably mediated by the adenosine-A3 receptor. We have also shown that Ado improves monocytes migratory capacity and that this effect seems to be consecutive to the stimulation of MMP-9 activity. Finally, preliminary experiments suggest that Ado could have an anti-apoptotic effect on human primary monocytes. These observations thus contributed to the characterization of the effects of Ado on some key processes involved in LV remodeling, including extracellular matrix degradation and inflammatory cells apoptosis. They bring arguments for a paradigm of temporal therapeutic window and could have important implications for therapeutic strategies using Ado and/or its receptors in the treatment of MI and in the prevention of HF.

Memoria para optar al Título Profesional de Médico Veterinario / El Factor de Crecimiento Diferencial 9 (GDF9) cumple un rol esencial en el desarrollo ovocitario de los mamíferos, sin embargo, en ovocitos caninos se desconoce su presencia y participación durante la maduración. En este estudio, se evaluó la presencia de GDF9 en ovocitos de perra madurados in vitro (MIV) y su relación con la expansión del cúmulo, para lo cual complejos cúmulo ovocito (COC’s) se cultivaron por 0, 48, 72 y 96 h. Posteriormente, algunos COC’s fueron desprendidos del cúmulo. De este modo, ovocitos sin células del cúmulo y COC’s se procesaron para su evaluación a través de Inmunofluorescencia Indirecta y Western blot con el anticuerpo anti GDF9 humano. Con ambas técnicas, la proteína se detectó principalmente en el ovocito y en menor proporción en las células del cúmulo. Además, en ambos tipos celulares, la detección de GDF9 disminuyó a medida que progresó el tiempo de cultivo. En ovocitos denudados y COC’s, se detectó una banda de ~56 kDa correspondiente a la pro-proteína en todos los tiempos de maduración. Sin embargo, sólo en COC’s no madurados y MIV por 48 h se detectaron dos bandas de proteína madura de ~18 y 19 kDa. Finalmente, se observó una relación inversa entre la expansión del cúmulo durante la MIV y la detección de GDF9 por Western blot. Por consiguiente, GDF9 está presente en ovocitos de perra y tendría participación en los procesos iniciales del crecimiento y desarrollo ovocitario / Financiamiento: Proyecto Fondecyt 1110265

Basierend auf die vorangegangene Studie der Abteilung für Neuropathologie des Pathologischen Instituts der Universität Würzburg, in der genetische Aberrationen auf dem Chromosom 9 in Ependymome beschrieben wurden, sollte eine Screeninguntersuchung des gesamten Chromosoms sowie eine verfeinerte Analyse der zuvor auffälligen Regionen erfolgen. Ziel der vorliegenden Arbeit war es, mögliche Tumorsuppressorgene oder Onkogene, die mit der Entstehung oder Progression von Ependymome verbunden sind, zu definieren. Weiterhin sollte eine Korrelation zu den klinischen Daten erfolgen. Dabei konnte bei erwachsenen Patienten gezeigt werden, dass Aberrationen auf Chromosom 9 die Prognose verbessern. Speziell der Marker D9S1872 bei DCR1 (DBCCR1) zeigte einen Trend zu einem Überlebensvorteil bei Erwachsenen. Deshalb könnte er in Zukunft zur prognostischen Einteilung von Ependymompatienten in der Klinik beitragen. Des Weiteren konnten bei Kindern in supratentoriellen Tumoren signifikant mehr Aberrationen gefunden wurden als in infratentoriellen. Dies deutet darauf hin, dass Ependymome zumindest bei Kindern abhängig von der Lokalisation unterschiedliche Entstehungswege haben. Es konnten zwei Regionen identifiziert werden, in denen sich häufig Aberrationen fanden: 9p21.1-22.3 und 9q31.3-33.3. Weiterhin konnten Lokalisation und Resektionsausmaß als unabhängige Prognosefaktoren bestätigt werden. / Based on a former study of the departmentof neuropathology of the pathologic instisute of the university of Wuerzburg, in which aberrations on chromosome 9 in ependymomas had been described, the whole chromosome should be screened and a finer analysis of previously aberrated regions should be carried out. The aim of the thesis was defining possible tumor suppressor genes or oncogenes being involved in the development and progression of ependymomas. Moreover there should be a correlation to the clinical data. Adults with ependymomas harboring aberrations on chromosome 9 showed significantly longer overall survival than patients of the same group without this aberration, irrespective of the extent of resection in multivariate analysis. Aberrations of chromosome 9, and particularly of DCR1 (DBCCR1), may play a role in the prognostic evaluation for ependymomas in adults in the future. In pediatric patients, genetic aberrations were found significantly more often in supratentorial tumors than in tumors with infratentorial location. Two common regions of deletions were identified (9p21.1 approximately p22.3 and 9q31.3 approximately q33.2). Localization and extend of resection could be confirmed as prognostic factors.

Transgenesis is a process of introducing foreign genetic material into the genomes of living organisms. One of the tools for transgenesis are the transposable elements (TEs), which include transposons. Transposons are naturally occurring sequences of DNA which are recognised, excised and inserted into a new location by a single enzyme – transposase. Here we show studies of the biophysical properties and activities of two highly related eukaryotic TEs of the mariner family: Mos1 from Drosophila mauritiana and Mboumar-9 (Mbo9) from Messor bouviery. Using biochemical and molecular methods we examined the properties of transposases in vitro and in vivo. Recombinant transposases were expressed in E.coli and purified using HPLC. Each protein’s activity was assayed for cleavage, integration and the whole transposition reaction. We used a modelling approach to predict the structure of the complex of Mbo9 transposase bound to the specific terminal sequences of the transposon, the paired end complex (PEC), based on the published crystal structure of Mos1 PEC. We have found that both transposases are elongated dimers in solution and that the first helix-turn-helix domain is involved in the protein dimerization. Moreover we show that mariner transposases cut one of the imperfect inverted repeats more efficiently than the other. The terminal nucleotide of the inverted repeat is important for integration of the transposon into a new target DNA, while having no effect at the stage of cleavage. Previously, neither Mos1 nor Mbo9 had been shown to have significant activity in mammalian cells. We have developed a new assay that allows chromosomal integration of the desired DNA sequence in vivo in bacterial, yeast and mammalian cells without the use of helper plasmids or mRNA injection. We found the optimal combination of inverted repeats for each of the transposons and have enhanced the transposition efficiency of Mbo9 by changing the sequence of its inverted repeat DNA. This study is a foundation for improving mariner TEs for transgenesis.

Includes bibliography. / xv, 257 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines the role of polymorphisms in immunoregularatory genes in conferring susceptibility to common variable immunodeficiency. / Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1998?

<p>Uppsatsen behandlar några av de faktorer som påverkar högstadieelevers övergång från</p><p>grundskolan till gymnasieskolan. Undersökningen är genomförd med hjälp av intervjuer och med en enkät, intervjuerna riktades till elever och enkäten besvarades av dessas lärare. De studien undersökta ungdomarna trivs på sin skola på grund av den närhet de upplever till varandra och till sina lärare, den fysiska miljön spelar bara en underordnad roll, är en av de slutsatser uppsatsen mynnar ut i.</p>

Policies under consideration within the Climate Convention would impose CO₂ controls on only a subset of nations. A model of economic growth and emissions, coupled to an analysis of the climate system, is used to explore the consequences of a sample proposal of this type. The results show how economic burdens are likely to be distributed among nations, how carbon "leakage" may counteract the reductions attained, and how policy costs may be influenced by emissions trading. We explore the sensitivity of results to uncertainty in key underlying assumptions, including the influence on economic impacts and on the policy contribution to long-term climate goals. / Includes bibliographical references (p. 16). / Abstract in HTML and technical report in HTML and PDF available on the Massachusetts Institute of Technology Joint Program on the Science and Policy of Global Change website (http://mit.edu/globalchange/www/).

Uppsatsen behandlar några av de faktorer som påverkar högstadieelevers övergång från grundskolan till gymnasieskolan. Undersökningen är genomförd med hjälp av intervjuer och med en enkät, intervjuerna riktades till elever och enkäten besvarades av dessas lärare. De studien undersökta ungdomarna trivs på sin skola på grund av den närhet de upplever till varandra och till sina lärare, den fysiska miljön spelar bara en underordnad roll, är en av de slutsatser uppsatsen mynnar ut i.