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Martin, Franck. "Structural and functional studies of chromatin remodeling complex mamalian SWI / SNF". Electronic Thesis or Diss., Strasbourg, 2024. http://www.theses.fr/2024STRAJ044.
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La chromatine est une structure dynamique régulée par différents mécanismes épigénétiques parmi lesquels le remodelage de la chromatine dépendant de l’ATP comme le SWI/SNF. Leur importance est telle que les mutations des protéines de remodelage de la chromatine sont fortement associées à plusieurs maladies dont le cancer. Par exemple les protéines BCL7, qui sont de nouvelles sous unité centrales récemment identifié du complexe SWI/SNF des mammifère, sont associées à différents types de cancers comme dans le Diffuse Large B-cell Lymphoma (DLBCL). Les informations sur les protéines BCL7 sont à ce jour très limitées. En utilisant des approches biochimiques et structurelles, ce projet vise à mieux comprendre la structure et la fonction de ces sous unités auxiliaires. Nous rapportons ici que les protéines se lient à l’acidique patch du nucleosome avec sa regions N-terminal qui comprend un motif d’ancrage arginines et que la mutation de l’une de ces arginines impacte directement la liaison au nucleosome. Nous apportons aussi une hypothèse sur la position au sein du complexe SWI/SNF de BCL7 qui interagit avec le module ARP et plus particulièrement avec ACTB par l'intermédiaire d'un motif 2W, et qu’elles sont directement des partenaires de liaisons avec BAF47. Nous avons aussi pu identifier qu’une fois sur les nucléosomes c’est BAF47 qui prend place sur l’acidique patch et l’hélice de BCL7A est déplacéChromatin is a dynamic structure regulated by various epigenetic mechanisms, including ATP-dependent chromatin remodeling such as SWI/SNF. Their importance is such that mutations in chromatin remodeling proteins are strongly associated with several diseases, including cancer. For example, BCL7 proteins, which are newly identified core subunits of the mammalian SWI/SNF complex, are associated with different types of cancer, such as Diffuse Large B-cell Lymphoma (DLBCL). To date, information on BCL7 proteins is very limited. Using biochemical and structural approaches, this project aims to better understand the structure and function of these auxiliary subunits. We report here that the proteins bind to the nucleosome with its N-terminal regions, which include an arginine anchoring motif, and that mutation of one of these arginines directly impacts binding to the nucleosome. We also hypothesize that the position within the SWI/SNF complex of BCL7, which interacts with the ARP module and more specifically with ACTB via a 2W motif, is directly linked to BAF47. We were also able to identify that once on the nucleosomes, BAF47 takes its place on the acidic patch and the BCL7A helix is displaced
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Barrans, Sharon Louise. "Immunophenotypic and molecular approaches to the classification of diffuse large B cell lymphoma". Thesis, Manchester Metropolitan University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366169.
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Li, Yue. "Investigating Selected Mechanisms of Modulation of BECN1-mediated Autophagy". Diss., North Dakota State University, 2019. https://hdl.handle.net/10365/29775.
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Autophagy is a lysosomal degradation pathway wherein cytoplasmic components not needed by or harmful to the cell are degraded and recycled. BECN homologs are key autophagy proteins consisting of an intrinsically disordered region (IDR), flexible helical domain (FHD), coiled-coil domain (CCD) and β-α repeated, autophagy-specific domain (BARAD). Diverse proteins modulate autophagy by binding BECN1. Understanding the mechanisms by which these proteins regulate BECN1-mediated autophagy is important for developing therapeutics targeting these proteins. Toward this goal, we have developed purification protocols for multi-domain BECN1 fragments to explore the conformational flexibility and interactions. We show that a BECN1 helix transitions between mutually exclusive packing states, wherein it either forms part of the CCD homodimer or packs against the BARAD, but predominantly packs against the BARAD. The same set of residues on this helix contribute to the CCD homodimer or packing with the BARAD, and mutation of these residues abrogates starvation-induced up-regulation of autophagy. Next, we show the equatorial groove of GAPR-1 may be responsible for binding BECN1. The five conserved residues lining the GAPR-1 equatorial groove are essential for the interaction, as mutation of these residues disrupts GAPR-1:BECN1 interaction. We also solved the structure of this pentad mutant, which indicates the changes in the equatorial groove and the improved dimerization of pentad mutant likely abrogates BECN1-binding. We then show that BH3D is not required for BECN1 to up-regulate autophagy, though it is required for binding BCL2 homologs. Therefore, we investigated the interactions between BH3D-containing BECN1 fragments and the BCL2 homolog, M11. BECN1 regions outside the BH3D increase binding to M11 by 5-10 fold. In addition, M11-binding increases flexibility of the nuclear export sequence (NES). Further, homodimerization and thermostability of BECN1 BH3D-FHD-CCD increases upon M11-binding. Lastly, the M11:BH3D-FHD-CCD complex appears to fluctuate between two major types of conformations, which may be mediated by the increased flexibility of BECN1 NES upon binding M11. Lastly, we investigated the interactions between BH3D-containing BECN1 fragments and Bcl-XL. Our results indicate that BECN1 regions outside the BH3D do not affect BECN1 interaction with Bcl-XL. Together, these studies are important for better understanding how proteins down-regulate BECN1-mediate autophagy.NIH: RO3 NS090939, R15 GM122035, P20 RR015566, and R21 AI078198 (S.S). R15 GM113227, P30 GM103332-01, P41 GM103622, and P41 GM103403.; NSF: MCB-1413525 (S.S.); ND Dept. of Commerce: Award #14-11-J1-73 (S.S.)
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Thompson, Brian M. "Amino-terminal sequences of the bacillus anthracis exosporium proteins BCLA and BCLB important for localization and attachment to the spore surface". Diss., Columbia, Mo. : University of Missouri-Columbia, 2008. http://hdl.handle.net/10355/5700.
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Thesis (M.S.)--University of Missouri-Columbia, 2008.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. "August 2008" Includes bibliographical references.
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Kunze, Doreen. "Small interfering RNA-vermittelte Hemmung der Apoptoseinhibitoren BCL2, BCL-XL, XIAP und Survivin in Zellkultur- und Mausmodellen des humanen Harnblasenkarzinoms". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-81888.
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Das Harnblasenkarzinom (BCa) stellt in Deutschland die vierthäufigste Tumorneuerkrankung und die zehnthäufigste krebsbedingte Todesursache bei Männern dar. Nichtmuskelinvasive BCa werden organerhaltend aus der Blasenwand entfernt und zur Rezidiv- und Progressionsprophylaxe mittels intravesikaler Chemo- oder Immuntherapien behandelt. Trotz dieser adjuvanten Therapien, die mit starken Nebenwirkungen verbunden sein können, ist nur eine bedingte Minimierung des Rezidivrisikos möglich. Besonders im fortgeschrittenen Stadium weisen Harnblasenkarzinome eine schlechte Prognose auf. Obwohl das BCa eine chemosensitive Erkrankung darstellt, wird das Ansprechen auf lokale oder systemische Chemotherapien häufig durch auftretende Resistenzmechanismen limitiert. Daher stehen sowohl die Verbesserung konventioneller Chemotherapien als auch die Suche nach neuartigen Behandlungsstrategien im Fokus der experimentellen BCa-Forschung.
Die Apoptose, eine Form des programmierten Zelltodes, ist ein essenzieller, streng regulierter biologischer Prozess, welcher der Aufrechterhaltung der Gewebshomöostase und der gezielten, entzündungsfreien Eliminierung geschädigter Zellen dient. Fehlregulationen in den Apoptosesignalwegen stellen ein zentrales Ereignis in der Tumorgenese dar und tragen außerdem zur Entstehung von Chemo- und Radiotherapieresistenzen bei. Eine wichtige Rolle in der Apoptoseregulation spielen die Mitglieder der BCL2- und der Inhibitor of Apoptosis Protein (IAP)-Familien, deren wichtigste antiapoptotische Vertreter BCL2, BCL-XL, XIAP und Survivin häufig in Tumoren, einschließlich des BCa, überexprimiert sind.
Unter Verwendung von small interfering RNAs (siRNAs), synthetischen Nukleinsäurekonstrukten zur selektiven Geninhibition, wurde im Rahmen der Arbeit in vitro und in vivo untersucht, ob die Hemmung der Apoptoseinhibitoren BCL2, BCL-XL, XIAP und Survivin – allein und in Kombination mit Chemotherapie – eine Therapieoption zur Behandlung des BCa darstellen könnte. Da zur Tumorentstehung und -progression eine Vielzahl von genetischen Veränderungen beitragen, erscheint der Angriff eines einzelnen Zielgens unzureichend für eine effektive Tumortherapie. Aufgrund dessen wurde untersucht, ob durch simultane Reduktion der ausgewählten Apoptoseinhibitoren in BCa-Zellen stärkere wachstumsinhibitorische Effekte erzielt werden können.
In der vorliegenden Arbeit wurde gezeigt, dass insbesondere die siRNA-vermittelte Hemmung von BCL-XL und Survivin in den BCa-Zelllinien EJ28 und J82 antiproliferative Effekte hervorruft und diese Tumorzellen gegenüber einer nachgeschalteten Chemotherapie mit Mitomycin C oder Cisplatin sensitiviert. Hingegen bewirkte sowohl die transiente als auch die stabile RNAi-induzierte Hemmung von BCL2 und XIAP in den untersuchten BCa-Monolayerzellkulturen, möglicherweise infolge kontinuierlicher Versorgung der Tumorzellen mit Sauerstoff und Nährstoffen, keine Reduktion des Tumorwachstums.
Eine gegenüber den Einzelbehandlungen deutliche Verstärkung der antitumoralen und insbesondere der chemosensitivierenden Effekte in den BCa-Zelllinien wurde durch simultane Hemmung von BCL-XL und Survivin erzielt. Beispielsweise stieg der Anteil apoptotischer Zellen von 64 % nach Survivin-siRNA+Cisplatin-Behandlung auf 94 % nach gleichzeitiger BCL-XL+Survivin-Inhibition in Kombination mit Cisplatin. Folglich stellt die simultane Inhibition von BCL-XL und Survivin in Kombination mit Chemotherapeutika eine äußert viel versprechende BCa-Therapieoption dar. Tierexperimentelle Studien belegen die wachstumsinhibitorische Wirkung der Survivin-Reduktion und der kombinierten BCL-XL-siRNA+Chemotherapie-Behandlung, so wurde das Tumorendvolumen im Vergleich zur Kontrollbehandlung um 43 % bzw. um 48 % reduziert.
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Mahn, Friederike Marie [Verfasser]. "Bruchereignisse in den Onkogenorten BCL2, BCL6 und MYC bei aggressiven B-Zell-Lymphomen im Kindesalter : molekularzytogenetische Analysen im Rahmen der NHL-BFM-Studie / Friederike Maria Mahn". Kiel : Universitätsbibliothek Kiel, 2010. http://d-nb.info/101998337X/34.
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Viant, Charlotte. "Régulation du développement et de la fonction des cellules innées lymphoïdes NKp46+". Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4018/document.
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Il existe différents groupes de cellules lymphoïdes innées (ILC) qui ont été caractérisées en fonction des facteurs de transcriptions indispensables à leur différenciation et des cytokines qu’elles sécrètent. Les ILC1, dont font partie les cellules Natural Killer (NK), expriment T-bet et produisent de l’IFN-γ. Les ILC2 sont caractérisées par GATA-3 et sécrètent de l’IL-5 et de l’IL-13. Quant aux ILC3, elles ont été identifiées par leur sécrétion d’IL-17 et d’IL-22 ainsi que par l’expression de RORγt.Mon travail de thèse m’a amené à étudier différents aspects de la biologie des cellules NK et ILC3 : leur tolérance, leur homéostasie et leur plasticité.Les cellules NK jouent un rôle dans l’élimination de cellules cancéreuses et des cellules infectées par des bactéries et des virus. J’ai mis en évidence le rôle de la phosphatase SHP-1 (Src homology region 2 domain-containing phosphatase-1) dans les mécanismes de tolérance et d’activation des cellules NK. J’ai également montré que la protéine anti-apoptotique Bcl2 (B-cell lymphoma 2) est importante pour l’homéostasie des cellules NK. Seules les cellules en cycle cellulaire peuvent compenser l’absence de Bcl2, notamment du fait de l’augmentation de l’expression d’une autre protéine anti-apoptotique, Mcl1 (Myeloid Cell Leukemia 1). Les ILC3 sont des cellules principalement localisées dans l’intestin et qui peuvent être classées en différents groupes en fonction des marqueurs qu’elles expriment. J’ai montré qu’il existe une plasticité entre les différentes populations d’ILC3, et que cette plasticité est régulée par des facteurs environnementaux tel que le TGF-β et le ligand de Notch, DL1There are three groups of innate lymphoid cells (ILC), defined notably by the transcriptions factors essential to their differentiation and their cytokines secretion. ILC1, including natural killer (NK) cells, express T-bet and secrete IFN-γ. ILC2 are characterized by GATA3 expression and the production of IL-5 and IL-13. ILC3 secrete IL-17 and IL-22 and express RORγt.My PhD work dealt with different aspects of NK cells and ILC3: their tolerance, homeostasis and plasticity.NK cell are involved in killing tumor cells and bacteria- or virus-infected cells. I found that the phosphatase SHP-1 (Src homology region 2 domain-containing phosphatase-1) has a role in NK cell tolerance and activation.I also showed that the anti-apoptotic Bcl2 protein (B-cell lymphoma 2) is important for NK cell homeostasis. Only cycling NK cells could compensate the Bcl2 deficiency, due to the increase expression of another anti-apoptotic protein, Mcl1 (Myeloid Cell Leukemia 1).ILC3 are mainly located in the gut and are classified in different groups, depending on the markers that they expressed. I showed that there is plasticity between ILC3 populations and that this plasticity is regulated by environmental factors, including TGF-β and the Notch ligand, DL1
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Hakert, James Damian. "The crosstalk between notch1 and BCL6". Tallahassee, Fla. : Florida State University, 2010. http://purl.fcla.edu/fsu/lib/digcoll/undergraduate/honors-theses/2181936.
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Thesis (Honors paper)--Florida State University, 2010.Advisor: Dr. Yoichi Kato, Florida State University, College of Arts and Sciences, Dept. of Chemistry and Biochemistry. Includes bibliographical references.
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Warner, Andrew. "Borylative cyclisation of alkynes using BCl3". Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/borylative-cyclisation-of-alkynes-using-bcl3(7a4e56f3-e8c6-4c68-97ec-4596ef5e0ce2).html.
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Boron trichloride, a cheap and commercially available Lewis acid, has been demonstrated to activate alkynes possessing appropriate nucleophiles, facilitating borylative cyclisation. This reaction furnishes polycyclic compounds possessing a new C(sp2)-B bond externally to the newly formed ring (through concomitant C-C and C-B bond formation). The RBCl2 intermediates generated from cyclisation were esterified with pinacol to furnish air/moisture stable boronic esters. This methodology has been applied to the following classes of starting materials: 1,4-disubstituted but-1-ynes (including N- and O- linked analogues), 2-alkynylanisoles, 2-alkynylthioanisoles and 1,2-bis(alkynyl)benzenes. Thus, borylated scaffolds such as dihydronaphthalenes, dihydroquinolines, 2H-chromenes, benzofurans, benzothiophenes, dibenzopentalenes and benzofulvenes have been synthesised. A variety of functionalities (e.g. amines, esters, nitriles) were tolerated by the reaction, with a number of substrates cyclised on either a gram scale, or under ambient conditions, demonstrating the robust nature of this methodology. An oxidation reaction with [Ph3C][BF4] was carried out on some of the borylated dihydronaphthalene compounds to obtain borylated naphthalenes. Suzuki-Miyaura cross-coupling reactions were carried out on certain borylated cycles to furnish new C-C bonds and generate analogues of established pharmaceuticals such as Nafoxidine or Raloxifene, demonstrating the synthetic value of these borylated cycles. Additionally, a one-pot borylative cyclisation/Suzuki-Miyaura cross-coupling reaction was also developed. Throughout this investigation, alternative reactivity has been observed when using BCl3 to activate certain alkynes, including intermolecular 1,2-trans-carboboration and a rare example of N- and O-directed 1,2-trans-haloboration. Additionally, multiple borylative cyclisations have been carried out on an appropriate alkyne to obtain a B-doped polyaromatic hydrocarbon (PAH), which has potential material-based applications.
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Leal, Cristina Tavares. "Identificação da família BCL2 como alvo terapêutico no tratamento das neoplasias mieloproliferativas associadas à mutação da JAK2V617F". Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17154/tde-06042018-114114/.
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As neoplasias mieloproliferativas (NMPs) negativas para o rearranjo t(9;22)/BCRABL1, incluindo Policitemia Vera (PV), Trombocitemia Essencial (TE) e Mielofibrose Primária (MFP), são doenças hematopoéticas clonais e estão frequentemente associadas à mutação JAK2V617F. Apesar dos avanços no conhecimento da fisiopatologia após a descoberta da mutação JAK2V617F e do desenvolvimento de inibidores da JAK2, o tratamento permanece não curativo. Sabe-se que as célulastronco mais primitivas nas NMPs são responsáveis pela iniciação da doença e que a expansão dos precursores mieloeritróides contribui para o fenótipo clínico. Dados recentes obtidos com ensaios in vitro mostram que as proteínas da família BCL2, reguladoras da apoptose mitocondrial, desempenham um papel relevante na patogênese das NMPs. Acreditamos que a expressão anômala de BCL2 nas células progenitoras hematopoéticas (CPH) das NMPs pode contribuir para a patogênese desse grupo de doenças. Avaliamos a expressão gênica, por meio de PCR em Tempo Real, da família BCL2 (genes antiapoptóticos BCL-xL e BCL2 e o pró-apoptótico BIM) nas diferentes subpopulações de progenitores hematopoéticos murinos (de um modelo condicional knockin de expressão heterozigótica condicional da Jak2V617F) e de pacientes portadores de NMPs bem como sua contribuição para o fenótipo da doença e resposta ao inibidores da JAK2 (com a droga ruxolitinibe) e/ou inibição da família BCL2 (com o inibidor de BCL2 obatoclax). Não encontramos diferença de expressão basal dos genes BCL2, BCL-xL e BIM nas células CD34+ bem como nas subpopulações de células CD34+38-/+ de pacientes com NMPs, independente da presença da mutação JAK2V617F, em relação às células CD34+ e subpopulações CD34+38-/+ dos controles (p>0.05). Nas células CD34+ de pacientes com TE encontramos aumento de expressão de BCL2 em relação às células CD34+ pacientes com MFP (p=0.03). No modelo transgênico de camundongos Jak2 wt/VF (que apresentam uma NMP semelhante à PV) e Jak2 wt/wt (controles), comparamos a expressão diferencial dos genes da família Bcl2 em precursores hematopoéticos imaturos (LSKs) e progenitores mieloides mais maduros (MPs). A expressão do BclxL em MPs de camundongos wt/VF foi maior em relação à subpopulação de células LSKs e em relação as duas subpopulações de células dos controles (p=0.0011). Não houve diferença significativa de expressão do Bcl2 nas subpopulações de células LSKs e MPs de animais wt/VF e wt/wt (p=0.12). Observou-se menor expressão de Bim em LSKs em relação às células MPs dos animais mutados (p=0.026), diferença essa não observada entre os controles Jak2 wt/wt. O tratamento isolado com inibidor de JAK2 ou de BCL2 resultou em aumento de expressão do Bim nas CPH (LSKs e MPs) de camungongos Jak2 wt/VF em relação aos animais Jak2 wt/wt. Este aumento da expressão de Bim foi ainda mais evidente após o tratamento das células com a combinação das duas drogas quando comparadas às células não tratadas ou tratadas com um dos dois inibidores, sendo maior em animais doentes do que em animais controles (p<0.0001). A análise do efeito do tratamento com os inibidores de JAK2 e BCL2 na indução de apoptose por meio de citometria de fluxo (marcação com anexina/7-AAD) revelou que as células LSKs foram mais resistentes à apoptose tardia do que as células MPs independentemente da mutação da JAK2 (p<0.05). O tratamento com obatoclax resultou em indução de apoptose diferentemente do que foi observado com o tratamento com ruxolitinibe (p=0.594) nas células MPs de animais Jak2 wt/VF. Ademais, o tratamento combinado com ruxolitinibe e obatoclax resultou no aumento da apoptose nas células MPs dos animais com fenótipo de PV (Jak2 wt/VF) em relação aos animais Jak2 wt/wt (p=0.05). Em conclusão, demonstramos que a resistência à apoptose nas NMPs ocorre desde as CPH iniciadoras da doença. Nossos resultados sugerem que a modulação da apoptose mitocondrial pode ser uma nova estratégia terapêutica para pacientes com NMP em combinação aos inibidores de JAK2, na medida em que atua tanto nas CPH que iniciam a doença como nos MPs, responsáveis pelos sinais e sintomas de mieloproliferação.Myeloproliferative Neoplasms (MPNs) negative for t(9;22)/BCR-ABL1 rearrangement, including Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF), are clonal hematopoietic diseases and are often associated with the JAK2V617F mutation. Despite advances in the pathophysiology knowledge after the discovery of the JAK2V617F mutation and the development of JAK2 inhibitors, treatment remains non-curative. It is known that MPN primitive stem cells are essential for the initiation of the disease and that the expansion of the myeloeritroid precursors contributes to the clinical phenotype. Recent data, obtained with in vitro assays, showed that BCL2 family proteins, regulators of mitochondrial apoptosis, play a relevant role in the pathogenesis of MPNs. We believe that the anomalous expression of BCL2 in hematopoietic progenitor cells (HPCs) of MPNs may contribute to their pathogenesis. We evaluated BCL2 family (antiapoptotic genes BCL-xL and BCL2 and the pro-apoptotic BIM) gene expression by real-time PCR in different subpopulations of hematopoietic progenitors from a conditional Jak2V617F knockin murine model and from patients with MPNs as well as their contribution to the disease phenotype and response to JAK2 inhibitors (with ruxolitinib) and/or to the inhibition of the BCL2 family (with the BH3-mimetic obatoclax). We found no difference in the basal expression of the BCL2, BCL-xL and BIM in CD34+ cells as well as in subpopulations of CD34+ 38-/+ cells from patients with MPNs, regardless of the presence of the JAK2V617F mutation. In CD34+ cells obtained from patients with ET, we found an increase of BCL2 expression when compared to CD34+ cells with PMF (p=0.03). In the Jak2 wt/VF transgenic mice (that develop a MPN similar to PV) and Jak2 wt/wt controls, we compared the differential expression of Bcl2 family genes in immature hematopoietic precursors (LSKs) and more mature myeloid progenitors (MPs). Expression of Bcl-xL in MPs of wt/VF mice was greater when compared to LSKs and to the two progenitor subpopulations of control cells (p=0.0011). There was no significant difference in Bcl2 expression between the subpopulations of LSKs and MPs from wt/VF and wt/wt animals (p=0.12). Lower Bim expression in LSKs than in MPs was observed in samples from JAK2-mutated animals (p=0.026). Such difference was not observed between the Jak2 wt/wt subpopulations. Treatment with JAK2 or BCL2 inhibitors alone resulted in increased Bim expression in LSKs and MPs of the Jak2 wt/VF mice when compared to Jak2 wt/wt animals. This increase in Bim expression was even more evident when these cells were treated with the combination of the two drugs as compared to single treatment with one of the two inhibitors, being higher in mutaded than control animals (p<0.0001). The analysis of apoptosis by flow cytometry (annexin / 7-AAD labeling) revealed that LSK cells were more resistant to late apoptosis than MP cells regardless of the JAK2 mutation (p<0.05). Treatment with obatoclax resulted in greater apoptosis induction than it was observed with ruxolitinib treatment (p=0.594) on MP cells of Jak2 wt/VF animals. In addition, the combined treatment with ruxolitinib and obatoclax resulted in increased apoptosis in MP cells of animals with the PV phenotype (Jak2 wt/VF) as compared to the Jak2 wt/wt animals (p=0.05). In conclusion, we demonstrated that resistance to apoptosis in MPNs occurs at the level of the hematopoietic progenitors that initiate the disease. Our results suggest that modulation of mitochondrial apoptosis may be a new therapeutic strategy for MPN patients in combination with JAK2 inhibitors, as it acts on both the disease initiating and more mature progenitors, responsible for the clinical findings of myeloproliferation.
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Kurata, Masayuki. "Characterization of t(3;6)(q27;p21) breakpoints in B-cell non-Hodgkin's lymphoma and construction of the histone H4/BCL6 fusion gene, leading to altered expression of Bcl-6". Kyoto University, 2003. http://hdl.handle.net/2433/149369.
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Xavier, Flavia Dias. "Padrão de expressão e significado prognóstico dos genes BCL2, BCL6, CCND2, FN1, LMO2 e SCYA3 pela técnica de PCR em tempo real com linfoma difuso de grandes células B tratado com rituximabe". Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5167/tde-24062013-114437/.
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Introdução: O linfoma difuso de grandes células B é o mais freqüente grupo de linfoma não- Hodgkin, perfazendo quase 50% dos casos no serviço de hematologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e Instituto do Câncer do Estado de São Paulo. Possui heterogeneidade clínica e biológica traduzida em mais de vinte subtipos na Organização Mundial da Saúde. Sua terapêutica se baseia na associação do anticorpo monoclonal anti-CD20 e quimioterapia com antracíclico, esquema que resulta em 43,5% de sobrevida global em 10 anos. Determinantes de prognóstico clínico como o Índice Internacional de Prognóstico e o Índice Internacional de Prognóstico Revisado carecem de acurácia, pois até 20% dos pacientes de baixo risco falecerão da doença e 60% dos pacientes de alto risco estarão vivos em quatro anos. Essas discrepâncias podem, em parte, ser atribuídas a fatores genéticos. A assinatura gênica do linfoma difuso de grandes células B tipo centro germinativo apresenta sobrevida global superior ao tipo células B ativadas (76% versus 16%, p=0,01), contudo o perfil de expressão gênica por microarray ainda não está disponível na prática clínica. Entretanto, o escore preditivo de mortalidade para linfoma difuso de grandes células B baseado no valor prognóstico da expressão dos genes BCL2, BCL6, CCND2, FN1, LMO2 e SCYA3 por PCR em tempo real quantitativa mostrou-se independente do Índice Internacional de Prognóstico na era pré-rituximabe. Mas não foi significante em pacientes de alto risco clínico tratados com R-CHOP. Os genes BCL2, CCND2 e SCYA3 integram a assinatura de células B ativadas, BCL6 e LMO2 a do centro germinativo e FN1 a linfonodal. Objetivo: Avaliar o impacto da expressão absoluta dos genes BCL2, BCL6, CCND2, FN1, LMO2 e SCYA3 em população brasileira com linfoma difuso de grandes células B tratada com R-CHOP em relação à resposta global, sobrevida livre de doença, sobrevida livre de progressão e sobrevida global. Métodos: A expressão gênica foi analisada por PCR em tempo real quantitativa de RNA extraído de amostras parafinadas de 63 pacientes, porém foi avaliável em 42. Seus valores foram normatizados pelo gene endógeno ABL e transformados em escala logarítmica na base 2 para posterior correlação com variáveis clínicas e de desfecho. Resultados: Com mediana de seguimento de 29 meses, as sobrevidas global, livre de doença e livre de progressão foram, respectivamente, 82,8%, 97,14% e 87,53%, enquanto a resposta completa foi 82,5%. A expressão de LMO2>3logs e BCL6>3,5logs definiu um grupo de maior sobrevida global (91% versus 64,3%, p=0,040) e sobrevida livre de doença (95,5% versus 70,7%, p=0,03), independentemente do Índice Internacional de Prognóstico (p=0,010 e p=0,042) e com significativa hiperexpressão do SCYA3 (p=0,046). Não se observou associação entre escore preditivo de mortalidade baseado nos seis genes e prognóstico. Assim, foi criado novo escore genético prognóstico baseado no poder da expressão concomitante de LMO2 e CCND2, definindo-se grupos de baixo risco (<2,5) e alto risco (>=2,5) com distintas sobrevidas global (92,4% versus 57,1%, p=0,011) e livre de progressão (96,2% versus 66,7%, p=0,013), independentes do IPI. Conclusão: Em pacientes com linfoma difuso de grandes células B tratados com R-CHOP, a hiperexpressão de BCL6, LMO2 e SCYA3 correlacionou-se com melhor prognóstico. O novo escore genético prognóstico definido por LMO2 e CCND2 estratificou grupos de risco de prognósticos distintos independentes do Índice Internacional de PrognósticoIntroduction: Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma; which accounts for almost 50% of the cases at the Hematology Department of Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo. Its clinical and biological heterogeneity results in more than twenty subtypes according to the World Health Organization classification. Its treatment is based on a combination of anti-CD20 monoclonal antibody and antracycline-based chemotherapy, with a 10-year overall survival of 43.5%. Clinical prognostic determinants such as the International Prognostic Index and the Revised International Prognostic Index lack accuracy, since up to 20% of low-risk patients will die from the disease and up to 60% of high-risk patients will be alive within four years. Such discrepancies can partially be attributed to genetic factors. Diffuse large B-cell lymphoma germinal center gene signature shows superior overall survival compared to activated B-cell signature (76% versus 16%, p=0.01), however microarray gene expression profile is not yet available in clinical practice. Nonetheless, the Mortality Predictor Score for diffuse large B-cell lymphoma based on the prognostic value of BCL2, BCL6, CCND2, FN1, LMO2 and SCYA3 gene expression by quantitative real-time PCR has proved to be independent from the International Prognostic Index in the pre-rituximab era. But it was not significant in high clinical risk patients treated with R-CHOP. The genes BCL2, CCND2 and SCYA3 compose activated B-cell signature, whereas BCL6 and LMO2 compose the germinal center signature and FN1 the lymph-node signature. Objective: Evaluate the impact of BCL2, BCL6, CCND2, FN1, LMO2 and SCYA3 absolute gene expression in Brazilian population diagnosed with diffuse large B-cell lymphoma and treated with R-CHOP, with respect to overall response, disease free survival, progression free survival and overall survival. Methods: Gene expression was analyzed by quantitative real-time PCR of RNA extracted from paraffin-embedded samples of 63 patients, although evaluable in 42. Their values were normalized by endogenous gene ABL and log- transformed on a base 2 scale for subsequent correlation with clinical and outcome variables. Results: With a median follow-up of 29 months, overall survival, disease free survival and progression free survival accounted for 82.8%, 97.14% and 87.53% respectively, while complete response was 82.5%. The expression of LMO2>3logs and BCL6>3.5logs defined a group with higher overall survival (91% versus 64.3%, p=0.040) and progression free survival (95.5% versus 70.7%, p=0.03), independent of International Prognostic Index (p=0.010 and p=0.042) and with significant overexpression of SCYA3 (p=0.046). It was not identified any association between six gene Mortality Predictor Score and prognosis. As a result, we developed the New Genetic Prognostic Score based on the power of concomitant expression of LMO2 and CCND2, defining low-risk (<2.5) and high-risk (>=2.5) groups with distinct overall survival (92.4% versus 57.1%, p=0.011) and progression free survival (96.2% versus 66.7%, p=0.013), independent of International Prognostic Index. Conclusion: In patients with diffuse large B-cell lymphoma treated with R-CHOP, hyperexpression of BCL6, LMO2 and SCYA3 was correlated with a better prognosis. The New Genetic Prognostic Score, defined by LMO2 and CCND2, stratified risk groups with different prognosis, independent of International Prognostic Index
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Ng, Florence Wai Hung. "Identification and characterization of Bcl-2/Bcl-X¦L interacting protein, p28Bap31". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0015/NQ44531.pdf.
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Piedfer, Marion. "Identification de nouvelles cibles pro-apoptotiques dans les leucémies aiguës myéloblastiques". Phd thesis, Université René Descartes - Paris V, 2012. http://tel.archives-ouvertes.fr/tel-00781221.
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Les leucémies aiguës myéloblastiques (LAM) sont des maladies hématopoïétiques caractérisées par une prolifération incontrôlée de précurseurs myéloïdes bloqués à divers stades de différenciation. Le pronostic des LAM reste sombre à cause de la résistance aux traitements et des rechutes après rémission. En conséquence, des thérapies moins intensives et mieux tolérées doivent être développées ; ceci nécessite le développement de stratégies combinatoires associant des molécules avec des modes d'action différents pour augmenter l'efficacité des traitements. Plusieurs approches sont en cours d'étude préclinique et clinique [inhibiteurs des voies de signalisation PI3K/Akt/mTOR, anticorps monoclonaux couplés à une drogue (Mylotarg®), inhibiteurs du protéasome (bortezomib)...] Des travaux récents ont relancé l'intérêt de l'étude des molécules d'origine naturelle pour le traitement des cancers. Ainsi, l'acide flavone-8-acétique (FAA) a suscité de nombreux espoirs au vu de son action sur les tumeurs greffées chez la souris ; il s'est néanmoins révélé inactif chez l'homme du fait d'une métabolisation différente de celle de la souris. L'objectif de ma thèse a été d'étudier les effets d'anticorps monoclonaux dirigés contre l'antigène tumoral CD13 (aminopeptidase-N) et de deux dérivés de FAA, la 2',3-Dinitroflavone-8-acétique (DNFAA ; inhibiteur de l'activité enzymatique de CD13) et la 3,3'-Diamino-4'-méthoxyflavone (DD1) dans les LAM. Mon étude a montré que DNFAA n'affecte ni la prolifération ni la survie des cellules de LAM (lignées et cellules primaires). Cependant, le traitement de ces cellules par les anticorps anti-CD13, (MY7, SJ1D1, WM15 ; reconnaissant ou non le site enzymatique) induit l'apoptose en activant les voies extrinsèque et intrinsèque. Dans la voie intrinsèque, les anti-CD13 régulent négativement l'expression des protéines anti-apoptotiques Bcl-2 et Mcl-1 et positivement l'expression de la protéine pro-apoptotique Bax. De plus, l'activation de la voie PI3K/Akt apparaît associée au processus apoptotique. Mon étude sur les effets du 3,3'-Diamino-4'-méthoxyflavone dans les cellules de LAM montre une induction d'apoptose résultant de la convergence de l'inhibition du protéasome et de l'activation des voies extrinsèque et intrinsèque. Les cibles de DD1 sont le protéasome, la kinase p70S6K (kinase en aval de mTOR), et les protéines pro-apoptotiques Bad et Bax. De plus, j'ai mis en évidence la dégradation de p70S6K sous l'action de la caspase 3, par le traitement avec DD1, nouvelle propriété partagée par DD1 et le bortezomib. En conclusion, mon travail a permis de mettre en évidence les capacités à induire in vitro des voies d'apoptose déficientes dans les cellules de LAM, d'anticorps monoclonaux anti-CD13 et de la flavone originale, 3,3'-Diamino-4'-methoxyflavone, en tant que nouvel inhibiteur du protéasome. Les propriétés de ces agents pro-apoptotiques méritent d'être analysées de façon plus approfondie.
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Szostek, Joanna M. "Russia in the news of its neighbours : cross border media influence in Ukraine and Belarus". Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:ae3ece7b-32ad-41e5-bce7-5f7ddeb28490.
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This thesis investigates the nature and impact of Russian influence on Russian-language print and broadcast news in Ukraine and Belarus. TV channels and publications with shareholders or partners in Russia are widely available in both the countries studied; existing literature suggests that such ‘Russian’ media are a source of regional power for the Kremlin. To shed light on how Russian partners and shareholders affect editorial treatment of Russia, the thesis compares content samples from 27 TV news bulletins and newspapers available in Ukraine or Belarus, some of which have Russian partners or shareholders while others do not. It also draws on in-depth interviews with 46 journalists and other media professionals. The thesis then compares the cases of Ukraine and Belarus to explain how political and economic conditions in a ‘target’ state affect the Russian authorities’ scope for communicating messages to mass audiences abroad via pro-Kremlin broadcasters. The findings of the thesis serve as a basis for assessing whether Russian news exports might contribute to Russian foreign policy success in the way envisaged by the literature on soft power. This research reveals complexities which have previously been overlooked in discussions about Russia’s media influence in the post-Soviet region. The news providers in Ukraine and Belarus which have Russian partners or shareholders are diverse and often vulnerable to constraints within their operating environment. Their utility as a source of soft power for the Kremlin is questionable, because the association between media and soft power is premised on public sentiments swaying foreign policy decisions. This premise is problematic, particularly in authoritarian Belarus. Pro-Kremlin Russian news exporters undoubtedly play a role in Moscow’s relations with Minsk and Kiev. However, their significance may lie at least as much in their capacity to provoke as their capacity to ‘softly’ attract and persuade a mass audience.
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Charlton, Andrew. "Towards the development of direct methodology to enantioenriched α-alkylated aldehydes". Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:bcfe43bb-1497-4f94-bcc7-6f7c2ae0b3a1.
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Enantiopure α-alkyl-substituted aldehydes are widely recognised as important building blocks in synthesis. Despite this, methods to prepare such substrates are limited. Strategically, asymmetric intermolecular SN2 α-alkylation represents a highly straightforward transformation, but still remains an elusive feat. This thesis describes efforts to address this challenge, with attempted access to enantioenriched α-alkyl aldehydes by way of C-alkylation of chiral, non-racemic, hindered aldenamines using simple alkyl halides. Enamines derived from four types of auxiliary (a tropane, an oxazolidine, a pyrrolidine and a homotropane) have been prepared, and their alkylation profile examined. While the desired levels of asymmetric induction were not attained, use of the tropane and homotropane auxiliaries, which differ only by a single methylene group, interestingly, gave complimentary diastereocontrol during alkylation with EtI. The observed stereoselectivity is supported by density functional studies performed for ethylation of both enamines. Additionally, in the course of preparing the homotropane a highly efficient asymmetric synthesis of a homotropinone bearing gem-α-substitution has been developed.
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Pitidol, Thorn. "The limits of community participation : examining the roles of discourse, institutions, and agency in the promotion of community participation in Thailand". Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:c6588478-750c-4d54-bc57-7b06ef220f7a.
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This thesis is a study of how community participation is understood, enacted, produced and governed in the context of an organization that promotes community participation. The contribution of this thesis is to shed light on the frequently found gap between the expectations and the reality of community participation. In examining how community participation is promoted, the thesis focuses in particular on actors such as community leaders and development workers, and the interactions between them. The thesis applies a multi-disciplinary theoretical framework, which is built through combining theoretical approaches that include discourse analysis, institutional analysis, and the actor-oriented approach. The framework accommodates the examination of the roles of various types of social factors in shaping the workings of community participation. These include the idea of community, social relations in communities, and the agency of actors who are promoting the approach. This thesis conducts a case study of the Council of Community Organisations (CCO) programme in Thailand, which is a large-scale promotion of community participation in development and governance. The case study examines the operation of the programme from national to local level, and explores several localities where the programme is being implemented. The exploration of the CCO programme illuminates pathways through which the approach’s inner mechanisms can constrain it from fulfilling the expectations. The thesis identifies how the idea of community, through its association with the sense of collective identity, tends to distort community participation from achieving empowerment. Moreover, the social relations in communities, generally characterised by inequality and diversity of interests, frequently constrain the approach from achieving effective mobilisation of collective action. Such a constraint is often accentuated by adverse incentives that community leaders face when they become part of development interventions. Finally, it is found that the deficiencies of community participation are likely to persist. This is because the actors who are promoting the approach usually manoeuvre to gain advantages from their roles in ways that reinforce the influence of the aforementioned factors.
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Linguraru, Marius George. "Feature detection in mammographic image analysis". Thesis, University of Oxford, 2004. http://ora.ox.ac.uk/objects/uuid:b92185f0-c7bf-40e1-bc17-bf71065f001f.
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In modern society, cancer has become one of the most terrifying diseases because of its high and increasing death rate. The disease's deep impact demands extensive research to detect and eradicate it in all its forms. Breast cancer is one of the most common forms of cancer, and approximately one in nine women in the Western world will develop it over the course of their lives. Screening programmes have been shown to reduce the mortality rate, but they introduce an enormous amount of information that must be processed by radiologists on a daily basis. Computer Aided Diagnosis (CAD) systems aim to assist clinicians in their decision-making process, by acting as a second opinion and helping improve the detection and classification ratios by spotting very difficult and subtle cases. Although the field of cancer detection is rapidly developing and crosses over imaging modalities, X-ray mammography remains the principal tool to detect the first signs of breast cancer in population screening. The advantages and disadvantages of other imaging modalities for breast cancer detection are discussed along with the improvements and difficulties encountered in screening programmes. Remarkable achievements to date in breast CAD are equally presented. This thesis introduces original results for the detection of features from mammographic image analysis to improve the effectiveness of early cancer screening programmes. The detection of early signs of breast cancer is vital in managing such a fast developing disease with poor survival rates. Some of the earliest signs of cancer in the breast are the clusters of microcalcifications. The proposed method is based on image filtering comprising partial differential equations (PDE) for image enhancement. Subsequently, microcalcifications are segmented using characteristics of the human visual system, based on the superior qualities of the human eye to depict localised changes of intensity and appearance in an image. Parameters are set according to the image characteristics, which makes the method fully automated. The detection of breast masses in temporal mammographic pairs is also investigated as part of the development of a complete breast cancer detection tool. The design of this latter algorithm is based on the detection sequence used by radiologists in clinical routine. To support the classification of masses into benign or malignant, novel tumour features are introduced. Image normalisation is another key concept discussed in this thesis along with its benefits for cancer detection.
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Choi, Yoonjoo. "Protein loop structure prediction". Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:bd5c1b9b-89ba-4225-bc17-85d3f5067e58.
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This dissertation concerns the study and prediction of loops in protein structures. Proteins perform crucial functions in living organisms. Despite their importance, we are currently unable to predict their three dimensional structure accurately. Loops are segments that connect regular secondary structures of proteins. They tend to be located on the surface of proteins and often interact with other biological agents. As loops are generally subject to more frequent mutations than the rest of the protein, their sequences and structural conformations can vary significantly even within the same protein family. Although homology modelling is the most accurate computational method for protein structure prediction, difficulties still arise in predicting protein loops. Protein loop structure prediction is therefore a bottleneck in solving the protein structure prediction problem. Reflecting on the success of homology modelling, I implement an improved version of a database search method, FREAD. I show how sequence similarity as quantified by environment specific substitution scores can be used to significantly improve loop prediction. FREAD performs appreciably better for an identifiable subset of loops (two thirds of shorter loops and half of the longer loops tested) than ab initio methods; FREAD's predictive ability is length independent. In general, it produces results within 2Å root mean square deviation (RMSD) from the native conformations, compared to an average of over 10Å for loop length 20 for any of the other tested ab initio methods. I then examine FREAD’s predictive ability on a specific type of loops called complementarity determining regions (CDRs) in antibodies. CDRs consist of six hypervariable loops and form the majority of the antigen binding site. I examine CDR loop structure prediction as a general case of loop structure prediction problem. FREAD achieves accuracy similar to specific CDR predictors. However, it fails to accurately predict CDR-H3, which is known to be the most challenging CDR. Various FREAD versions including FREAD with contact information (ConFREAD) are examined. The FREAD variants improve predictions for CDR-H3 on homology models and docked structures. Lastly, I focus on the local properties of protein loops and demonstrate that the protein loop structure prediction problem is a local protein folding problem. The end-to-end distance of loops (loop span) follows a distinctive frequency distribution, regardless of secondary structure elements connected or the number of residues in the loop. I show that the loop span distribution follows a Maxwell-Boltzmann distribution. Based on my research, I propose future directions in protein loop structure prediction including estimating experimentally undetermined local structures using FREAD, multiple loop structure prediction using contact information and a novel ab initio method which makes use of loop stretch.
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Meyer, Thomas George. "Global human rights and contextualised civic learning : a case study of human rights education in Japan". Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:f073a51d-20b8-4610-bc37-84370d4700a5.
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While global human rights knowledge has become a central facet of curricula used to shape multicultural societies and develop cosmopolitan citizenry, such knowledge is shaped by sociopolitical context. Japan has a long history of incorporating human rights concepts into its citizenship curriculum; however, this curriculum is produced in a political context where there is resistance to extending rights to minorities and the disadvantaged, and where there are renewed attempts to emphasise traditional Japanese cultural values through education. Potential tensions have been recognised, yet little has been written about educational knowledge as end product, or its role in informing learner and teacher understanding of human rights. Intentions to promote inclusivity and new communal identities notwithstanding, this work establishes that the recontextualising discourse of human rights within Japan's school curriculum, as a discourse that regulates identity and citizenship, portrays the rights of marginalised and non-Japanese identities as privileges extending beyond the norm of society, while at the same time implicitly denying ethnic Japanese individuals full access to rights language. Thus, while learners regard human rights of value, many are less receptive and empathetic to rights claims made by non-like others, and are likely to consider society as incapable of embracing diversity. Human rights concepts possess symbolic value and weight; however, their symbolic importance can be easily embedded within particularistic notions of identity and nationality to ends contrary to multiculturalism and cosmopolitanism, which for this research was witnessed in their transformation into tools for cultural and political legitimacy by the Japanese State. This research arrives at these conclusions through a systemic, holistic analysis of human rights learning in Japan that ties official knowledge to instructional and learning outcomes. This research is first a mixed-method policy sociology utilising computer-based analytical techniques to examine the structure and content of human rights knowledge within upper-secondary social studies textbooks representing Japan's official curriculum. This is followed by a comparative case study of two upper-secondary institutional sites of human rights learning, an academic, public coeducational western Japan senior high school, and a private Tokyo girls' senior high school, the primary differentiation being that the western Japan school is an explicit site of human rights learning, applying its own content and pedagogic practice as part of a specialised human rights curriculum designed to supplement the official curriculum. This research not only has implications for Japan in yielding a greater understanding of how the curriculum engages and reproduces identities and to what end, but also potentially to understand how similar tensions and contradictions between universal and particular play out in other national, State-sponsored education contexts.
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O'Loughlin, Aisling. "Towards extracellular vesicle based gene therapy for Huntington's disease". Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:d44d4535-aeb2-4bc0-bc27-15ce9ef4e37e.
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Huntington's disease (HD) can be regarded as a model neurodegenerative disorder to screen potential genetic based therapeutics and their carriers. It is an autosomal dominant disorder caused by a mutation in a single gene that leads to progressive neurodegeneration caused in part by protein misfolding. The mutation codes for an expanded polyglutamine tract within the Huntingtin gene (HTT) which leads to neuronal loss through a pathological cascade of events. Current treatment strategies include symptom management but no disease-modifying therapies exist. Research has shown that nucleic acid based therapeutics aimed at decreasing HTT expression can prevent, or reverse, the phenotype. Translating such therapies to the clinic is hindered by the blood brain barrier (BBB) and the lack of an easily administrable, non-toxic, immunologically inert delivery vehicle capable of bypassing the BBB. This study examines a range of nucleic acid based therapeutics for their potency and toxicity, and evaluates extracellular vesicles (EVs) as a delivery vehicle through investigation of the biodistribution of brain targeted EVs and an analysis of EV loading. A small interfering RNA (siRNA) targeting a region upstream of the repeat induced potent non-toxic silencing of HTT. In examining EVs as a carrier for therapeutics for neurological diseases including HD, it was found that targeting can increase brain accumulation of EVs but that the physiological characteristics of EVs which make them susceptible to clearance by the reticuloendothelial system (RES) must be further evaluated to bioengineer modified EVs to avoid fast clearance. Lastly, loading by electroporation was found to induce siRNA aggregation which can lead to overestimation of loading by increasing siRNA content in an ultracentrifugation pellet, but cholesterol-conjugated siRNA mixed with EVs was capable of generating silencing in vitro. This thesis examined EV based treatment for HD through the selection of a nucleic acid cargo to silence HTT, and examination of EVs as a delivery vehicle via biodistribution and loading studies. If the loading can be optimised and fast clearance avoided, there is promise in the use of EVs as a carrier of siRNA for HD.
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Laghezza, Gianluca. "Lattice Boltzmann study of evaporation phenomena". Thesis, University of Oxford, 2016. http://ora.ox.ac.uk/objects/uuid:ddab7a63-09d8-4fa7-bc87-577be6333091.
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Evaporation phenomena are having a resurgent interest in the recent years thanks to new techniques that allow for better flow visualization and microfabrication techniques of surfaces with interesting wetting properties. From the theoretical point of view the development of simulation techniques for evaporation phenomena is a challenging work due to the presence of moving interfaces and multiphase flows. Thanks to its mesoscopic nature, the Lattice Boltzmann method is an ideal candidate for the simulation of evaporation phenomena. Here we present a Lattice Boltzmann algorithm capable to correctly reproduce the diffusion-limited evaporation dynamics. We apply this numerical method to study the dynamics of multiple droplets evaporating together and we compare the results with experimental measures. We show that the presence of other droplets can dramatically increase the evaporation lifetime compared to the single droplet case; we also investigate the competition between convection and collective effects. We then develop a theory to predict the instability behaviour of liquid fronts in two dimensional confined geometries and we consider the interplay between capillary forces, wettability gradients and phase changes. We use LB simulations to investigate the effect of a three dimensional geometry that cannot be taken into account in the analytical theory. Finally we investigate the effect of flows on droplet evaporation. We consider both buoyancy induced and external flows. We show that even when diffusion is the dominant mechanism, flow effects are not negligible.
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Abed, Shahla. "Läkemedel mot Bcl-2 överuttryckande resistenta Prostatatumörer : Läkemedel mot Bcl-2 överuttryckande resistenta Prostatatumörer". Thesis, Umeå universitet, Kemiska institutionen, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-106293.
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Barrezueta, Luis Fernando Mesias [UNIFESP]. "Imuno-expressão das proteínas da família BCL-2 (BCL-2. BCL-XL, BAX, BAK, BAD) em câncer gátrico, preparados em arranjo em matriz (TMA)". Universidade Federal de São Paulo (UNIFESP), 2009. http://repositorio.unifesp.br/handle/11600/9724.
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Previous issue date: 2009-01-28Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Em casos de carcinoma gástrico, para contribuir ao conhecimento do processo de carcinogênese: Objetivo: Estudar a expressão das proteínas da família Bcl-2 (BcI-2, Bcl-xl, Bak, Bad, Bax). Correlacionar a expressão destas proteínas com 0 índice apoptótico mediante a expressão da proteína Caspase 3 clivada, com 0 índice mit6tico mediante a expressão da proteína Ki-67 e com a expressão da proteína p53. Método: Técnica de arranjo em matriz de amostras teciduais (TMA): em 87 amostras de adenocarcinomas gástricos (grupo teste) e de mucosa gástrica não tumoral (grupo controle) foi avaliada a imuno-expressão das proteínas da família BcI-2 (BeI-2, Bcl-xl, Bak, Bad, Bax), da proteína p53, da proteína caspase 3 e da proteína Ki-67. Resultados: Todas as proteínas examinadas foram observadas nos adenocarcinomas e mucosa não tumoral, porem com diferenças de expressão em relação à porcentagem de positividade e intensidade. Observamos: i) Houve associação entre 0 tamanho do tumor e a proteína p53. ii) Houve associação da proteína Bad no adenocarcinoma com a idade dos pacientes. iii) Associação das proteínas Bax, Bad e Ki-67 com 0 adenocarcinoma de tipo intestinal. iv) As proteínas Bcl-xl, Bak, Bad, p53 e Ki-67 apresentaram diferenças estatisticamente significantes entre a imuno-expressão no tumor e na mucosa não tumoral. v) Associação das proteínas Bax, Bak e Bad na mucosa não tumoral. vi) Não houve correlação da imunoexpressão das proteínas com a sobrevida dos pacientes. Conclusão: A expressão aumentada da proteína Bcl-xl nos adenocarcinomas, com evidente diferença de expressão entre 0 grupo teste e 0 grupo controle, esta relacionada com 0 efeito anti-apoptótico da proteína. A expressão reduzida das proteínas Bak e Bad e a expressão aumentada das proteínas p53 e Ki-67 nos adenocarcinomas demonstram 0 desequilíbrio entre morte e proliferação celular, permitindo 0 crescimento descontrolado das células neoplásicas.
Purpose: To study the immunoexpression of Bcl-2 family proteins (Bcl-2, Bcl-xl, Bax, Bak, Bad) and to evaluate the correlation between the immunoexpression of these proteins with the cleaved caspases 3, Ki-67 and p53 immuno-expression. Methods: A TMA paraffin block was constructed with gastric carcinoma tissue (test group) and normal gastric adjoining mucosa (control group) of 87 patients. The TMA block was submitted to immunohistochemistry for Bcl-2, Bcl-xl, Bax, Bak, Bad, p53 and-cleaved Caspase 3. Results: All studied proteins were present in tumor and normal gastric adjoining mucosa, but with different intensity and amount of positive cells. i) There was an association between tumor size and p53 expression. ii) association between Bad expression in the tumor and patient’s age. iii) Intestinal type adenocarcinoma was positively correlated with the expression of Bax, Bad and Ki-67. iv) The protein Bcl-xl, Bak, Bad, p53 and Ki-67 showed statistically significant differences between the immuno-expression in tumor and normal gastric adjoining mucosa. v) There was an association between the proteins Bax, Bak and Bad expression in the normal gastric adjoining mucosa. vi) No correlation between patient’s survival rates and the expression of the proteins was observed. Conclusions: The higher expression of Bcl-xl protein in adenocarcinoma, the difference of Bcl-xl expression between test group and control group, might be related with the anti-apoptotic effect of this protein. The lower expression of Bak and Bad and the increased expression of p53 protein and Ki-67 protein in adenocarcinomas demonstrate the imbalance between death and cellular proliferation, which allows the uncontrolled tumor cell proliferation.
FAPESP: 04/09932-4
FAPESP: 06/54187-0
TEDE
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Bah, Nourdine. "Contrôle du déclenchement de l'apoptose pendant l'arrêt mitotique par l'homologue de Bcl-2, Bcl-xL". Nantes, 2013. http://archive.bu.univ-nantes.fr/pollux/show.action?id=d6222d04-bb86-43e6-810b-21a673a07295.
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Les poisons des microtubules, comme le paclitaxel, sont des composés qui modifient la dynamique des microtubules, et bloquent les cellules en mitose par non-satisfaction du point de contrôle mitotique. La principale cible du point de contrôle mitotique est l'APC/C, une ligase E3 qui régule la dégradation de protéines importantes pour la progression de la mitose. Un de ces substrats est la cycline BI, le cofacteur essentiel à l'activité de Cdk1 , et par conséquent essentiel pour le maintien de la mitose. Sous paclitaxel, le point de contrôle mitotique est actif, et cela aboutit à un blocage en mitose du à l'inhibition d'APC/C via la séquestration de Cdc20. Cet arrêt mitotique peut aboutir à plusieurs devenirs cellulaires, notamment la mort mitotique et l'échappement à l'arrêt mitotique. Nous nous sommes intéressés au rôle de Bcl-xl, dans la réponse cellulaire à l'arrêt mitotique induit par le paclitaxel, et l'extinction de Cdc20, dans des lignées de cancer du sein. Il apparaît que la mort mitotique induite par le paclitaxel ou l'extinction de Cdc20 n'est pas dépendante des caspases, ni de Bax et Bak. L'extinction de Bcl-xl , ou le traitement par l'ABT-737, pendant l'arrêt mitotique induit une conversion de la mort mitotique en une apoptose classique dépendante des caspases et de Bax. Ce « switch » dans l'activité de Bcl-xl (protection/induction de l'apoptose par libération de Bax) est dépendant de sa phosphorylation sur la sérine 62, au cours de l'arrêt mitotique, phosphorylation qui module sa capacité à interagir avec Bax. L'exploitation clinique de ces données (en accord avec d'autres récemment publiées) suggère d'associer ABT-737 (inhibition de Bcl-xl ) et taxanes pour favoriser la réponse des cellules tumorales aux antimitotiques vers une mort mitotique majoritaireAntimitotic agents such as microtubule inhibitors (paclitaxel) are widely used in cancer therapy while new agents blocking mitosis onset are currently in development. All these agents impose a prolonged mitotic arrest in cancer cells that relies on sustained activation of the spindle assembly checkpoint and may lead to subsequent cell death by incompletely understood molecular events. We have investigated the role played by anti-apoptotic Bcl-2 family members in the fate of mitotically arrested mammary tumor cells treated with paclitaxel, or depleted in Cdc20, the activator of the anaphase promoting complex. Under these conditions, a weak and delayed mitotic cell death occurs that is caspase- and Bax/Bak-independent. Moreover, BH3 profiling assays indicate that viable cells during mitotic arrest are primed to die by apoptosis and that Bcl-xL is required to maintain mitochondrial integrity. Consistently, Bcl-xL depletion, or treatment with its inhibitor ABT-737 (but not with the specific Bcl-2 inhibitor ABT-199), during mitotic arrest converts cell response to antimitotics to efficient caspase and Bax-dependent apoptosis. Apoptotic priming under conditions of mitotic arrest relies, at least in part, on the phosphorylation on serine 62 of Bcl- xL, which modulates its interaction with Bax and its sensitivity to ABT-737. The phospho-mimetic S62D-Bcl-xL mutant is indeed less efficient than the corresponding phospho-deficient S62A-Bcl-xL mutant in sequestrating Bax and in protecting cancer cells from mitotic cell death or yeast cells from Bax-induced growth inhibition. Our results provide a rationale for combining Bcl-xL targeting to antimitotic agents to improve clinical efficacy of antimitotic strategy in cancer therapy
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Pécot, Jessie. "Dépendance des cellules cancéreuses à BCL-xL : ciblage thérapeutique du réseau d'interactions PUMA, BAX et BCL-xL : effets oncogéniques non canoniques de l'interaction RAS / BCL-xL". Nantes, 2015. https://archive.bu.univ-nantes.fr/pollux/show/show?id=57dfe09c-18e6-4d60-a1e1-cbc567f5cda6.
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La protéine BCL-xL fréquemment surexprimée dans les cancers est impliquée dans la résistance aux chimiothérapies. De nouvelles molécules ciblant cette protéine ont ainsi été développées. Le travail présenté dans le cadre de cette thèse montre que, malgré une spécificité de plus en plus grande de ces molécules, elles restent inefficaces à antagoniser certaines interactions impliquant BCL-xL. Ainsi un traitement au WEHI-539 (ciblant spécifiquement BCL-xL) ne sensibilise pas des cellules surexprimant BCL-xL à une mort dépendante de PUMA, une protéine interagissant avec BCL-xL qui joue un rôle essentiel dans le déclenchement de l'apoptose. Alors que les interactions BAX/BCL-xL répondent au WEHI-539, nos résultats montrent que les interactions PUMA/BCL-xL n'y sont sensibles qu'en dessous d'un certain seuil d'expression de BCL-xL, au-delà duquel la survie des cellules est maintenue par des complexes PUMA/BCL-xL résistants aux BH3-mimétiques. Ces données soulignent l'importance de la compréhension du rôle joué par ce réseau d'interactions impliquant les membres de la famille de BCL-2, en particulier BCL-xL, dans le contexte du développement tumoral. L'autre partie de ce travail est ainsi consacrée à l'étude des conséquences fonctionnelles de l'interaction entre BCL-xL et l'oncogène RAS qui demeurent largement inconnues bien que des travaux lui attribuent des effets oncogéniques. Pour ce faire, nous avons développé des approches de BRET et de pep-scan en vue de mieux caractériser cette interaction d'un point de vue structurel et fonctionnelBCL-xL plays a role in chemoresistance that needs to be overcome. We show here that currently available BH3-mimetics do not efficiently derepress BCL-xL inhibition of BAX-mediated cell death induced by PUMA, a major pro-apoptotic effector of chemotherapy. Live cell measurements of protein-protein interactions reveal that BH3-mimetics readily inhibit BAX interactions with BCL-xL and the effects of BCL-xL on BAX oligomerization but that PUMA interactions with BCL-xL are highly resistant. Thus, PUMA only favors BAX oligomerization/activation and induction of cell death in response to BH3-mimetics when BCL-xL expression is limiting. Mutagenesis studies show that the robustness of PUMA/BCL-xL interactions is due to the avidity of the PUMA BH3 domain for mitochondrial BCL-xL. This has important consequences for the design of strategies combining PUMA-inducing genotoxics and BCL-xL inhibitors, and argues that mitochondrial membranes per se influence treatment outcome. BCL-xL does not only function as guardian of mitochondrial permeability. Non-canonical effects and functions of this protein have been described, as its interaction with the RAS oncogene. Some studies suggest the oncogenic effects of the BCL-xL/RAS interaction. However, its functional consequences remain unknown. So we have used BRET and pep-scan assays in order to structurally and functionally characterize this interaction
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Dawes, Joanna Camilla. "Modelling Crebbp loss in BCL2 driven non-Hodgkin's lymphoma". Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/58194.
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Non-Hodgkin’s lymphomas (NHL) are a spectrum of hematopoietic cancer accounting for 4% of new cancer diagnoses each year. Approximately 95% of all NHL are of B-cell origin; diffuse large B-cell lymphomas (DLBCL) and follicular lymphoma (FL) accounting for 30-40% and 20% of B-NHL respectively. Recent human mutation profiling and resequencing studies have shown that CREBBP and BCL2 are frequently mutated, early events in B-NHL that are often are concurrent. This thesis presents a study of their role in oncogenesis by generating a novel model of B-NHL overexpressing BCL2 in the haematopoetic compartment combined with the conditional heterozygous loss of Crebbp in the germinal centre B-cells. Loss of Crebbp significantly accelerated BCL2 driven lymphomagenesis. Characterisation of these lymphomas by flow cytometry demonstrated that they were phenotypically similar to mature human B-cell lymphomas of germinal centre origin. Additionally an insertional mutagenesis screen was performed in mice sensitised to B-NHL. Somatic MoMuLV caused mutations interact with the sensitising mutations, facilitating tumourigenesis and recapitulating the stepwise and accumulative progression of human disease. Provirus insertions were detected using a novel method of insertion site cloning called UMI-LM-PCR which amplifies the region flanking the provirus. Insertions were then mapped to the mouse genome flagging genes with a putative role in tumourigenesis. This method represents the highest throughput method to date and its applicability to Illumina sequencing permits the most comprehensive quantitative survey of subclonal mutations. This work confirms Crebbp is a tumour suppressor gene and that its loss cooperates with overexpression of BCL2 to accelerate lymphomagenesis. Through insertional mutagenesis screening of this model hundreds of putative cancer genes have been identified including Pou2f2 and Tfrc which have a propensity for mutation specifically in B-cell lymphomas deficient in Crebbp and overexpressing BCL2. These candidates now need to be validated to better characterise their role in B-cell lymphoma.
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Webster, Philip. "The genetics and kinetics of BCL2 driven lymphoid malignancies". Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/45406.
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Introduction: Non-Hodgkin Lymphoma (NHL) is rising in incidence. Treatment of this genetically heterogeneous disease has toxic side effects and significant numbers of relapsers / non-responders. BCL2, an anti-apoptotic protein, is commonly overexpressed in NHL as a result of the t(14;18) translocation. A number of BCL2 inhibitors have shown success in clinical trials but variable efficacy has meant that none have been licenced for use. Methods: Retroviral insertional mutagenesis (RIM), using Moloney Murine Leukaemia Virus (MoMuLV) in transgenic mice overexpressing BCL2, was used to identify putative target genes deregulated alongside BCL2 in lymphomagenesis. This project aimed to update MoMuLV integration site identification and sequencing, allowing quantification of integration site clonal abundance. Cohorts of mice were sacrificed at time points prior to disease onset in order to interrogate integration site kinetics. To test the oncogenic potential of candidate genes, C57BL/6 Vav-BCL2 p53+/- mouse B cells were retrovirally transduced with genes of interest and transplanted into mice to study the speed of lymphoma onset. Results & Conclusions: A novel, high throughput, quantitative library preparation and sequencing protocol compatible with an Illumina platform was validated. RIM screening in BCL2 transgenic and wild-type mice identified different insertion sites profiles, detecting known oncogenes and tumour suppressor genes as well as novel candidate genes involved in pathways of lymphoid organ development, B-cell activation and differentiation. Study of insertion kinetics over time showed three patterns of clonal abundance and also allowed the study of specific gene deregulation prior to disease onset. Overexpression of Cd86 slowed disease onset whilst Ildr1 expedited disease onset suggesting the former is a tumour suppressor gene and the latter an oncogene. Discovering genes mutated with BCL2 in lymphoma may help to explain the lack of efficacy of BCL2 inhibitors and also identify novel therapeutic targets.
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Приступа, Людмила Никодимівна, Людмила Никодимовна Приступа, Liudmyla Nykodymivna Prystupa, Владислава Володимирівна Кмита, Владислава Владимировна Кмыта, Vladyslava Volodymyrivna Kmyta, М. М. Фендик e Л. О. Свириденко. "Bcl1 поліморфізм як одна із генетичних детермінант нікотинової залежності". Thesis, Сумський державний університет, 2014. http://essuir.sumdu.edu.ua/handle/123456789/35697.
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Згідно останніх даних куріння є причиною смерті близько п'яти мільйонів людей щороку, оскільки збільшує ризик розвитку багатьох захворювань, у першу чергу – легень і серцево-судинної системи, а також – онкопаталогії. Давно відомо щодо стимулюючого впливу ряду факторів зовнішнього середовища на формування даної пагубної звички. Тим не менш, в останні роки, з’являється велика кількість досліджень щодо ролі генетичних факторів у розвитку нікотинової залежності. Система досліджень у популяціях близнюків та окремих сімей показала, що існує не один конкретний ген, який визначає розвиток схильності до куріння, а швидше низка певних генів, котрі обумовлюють вищу сприйнятливість до нікотинової залежності. Ці гени відповідають за продукцію та метаболізацію нейромедіаторів, кількість сприйнятливих рецепторів та окремої здатності індивідуумів до швидкості метаболізування нікотину. Згідно літературних даних одним із таких генетичних чинників є Bcl1 поліморфізм гена глюкокортикоїдного рецептора (ГР).
При цитуванні документа, використовуйте посилання http://essuir.sumdu.edu.ua/handle/123456789/35697
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Rabbitte, Deirdre. "The translational control of Bcl-2". Thesis, University of Nottingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430650.
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Fukuda, Nobutaka. "Fertility decline in Japan since the 1970s : socio-ecomic factors or attitudinal factors?" Thesis, University of Oxford, 1997. http://ora.ox.ac.uk/objects/uuid:8303e991-71bf-4198-bc87-d2090c0415d6.
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This study investigates the influence of socio-economic and attitudinal factors on recent changes in marriage and fertility in Japan. Using macroand micro-data (collected especially for this research), the study examines the validity of three main theories: (1) the New Home Economics theory; (2) Easterlin's theory; and (3) the ideational (or attitudinal) theory in detemining Japanese marriage and fertility behaviour. The findings of this study show that socio-economic factors exert a substantial effect on Japanese marriage and fertility behaviour. More specifically, an increase in women's earning capacity raised their marriage age, lowered the level of their fertility, and lengthened their birth intervals. This evidence is in agreement with the New Home Economics theory. On the other hand, relative economic status also affected Japanese marriage and fertility behaviour. An improvement in the economic situation of young adults encouraged them to marry earlier, and to have more children. These findings support Easterlin's theory. However, comparing the two theories, the longitudinal trend of marriage and fertility pattern in Japan is better explained by the New Home Economics theory than Easterlin's theory. The level of women's wages had a relatively stronger impact on these patterns than their relative economic status. The findings also reveal that attitudinal factors play a significant role in determining Japanese marriage and fertility behaviour. As women became less committed to traditional norms and values, they married later, had fewer children and lengthened their birth intervals. Likewise, the reinforcement of women's individualistic attitudes raised their marriage age, lowered the level of their fertility, and delayed their entry to parenthood. This evidence indicates that marriage and fertility pattern in Japan cannot be due entirely to socio-economic factors. Comparing socio-economic and attitudinal factors, the former had a greater influence on marriage and fertility behaviour than the latter. We conclude from the findings of this study that Japanese marriage and fertility behaviour are affected both by socio-economic and attitudinal (ideational) factors, but the influence of the latter is secondary.
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Keykhah, Mojdeh. "The shape of uncertainty : insurance underwriting in the face of catastrophe". Thesis, University of Oxford, 2000. http://ora.ox.ac.uk/objects/uuid:850ace8c-da6d-4c9a-bce7-8f7495ba7357.
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In this thesis I study the nature of decision making under uncertainty in the case of natural catastrophes and reinsurance underwriting at Lloyd's of London. I begin by describing the broad context of natural catastrophes and society, which forms the basis for a market in catastrophe reinsurance. I then proceed to a review of literatures in risk, uncertainty, philosophy, and probability as a prelude to an analysis of decision making under catastrophic risk. According to the early 20th century philosopher-economist Frank Knight, risk specified those cases in which a frequency probability could be assigned, while situations of uncertainty do not allow a frequency probability since they are unique instances. In the thesis, I make the additional argument that risk and uncertainty are not solely categories of probability, but rather categories of probability and causality. The second main strand of the thesis refers to J.M. Keynes' work on probability which while related to frequency probability, is different in its emphasis on judgment and the assessment of information. I propose a causal framework to Keynes' weight of argument approach in terms of J.L. Mackie's causal field. With these two main ideas on probability and the addition of the causal field, the thesis presents the theoretical basis of its model of decision making. The last component of the model is developed through a review and critique of the economic literature on decision making under uncertainty. As the literature is founded upon frequency probability definitions of risk, the thesis argues through its theoretical investigations that this approach neglects the causal element of decision making, and that uncertainty requires a broader conceptualization than simply lack of probability. This final component, decision making routines, combines both individual and organizational elements. The empirical investigation of catastrophe risk underwriting at Lloyd's is organized into categories of decision making within a situated market context. I investigate the dominant categories and find that capital capacity and relationships drive reinsurance praxis. As an integration of its theoretical and empirical components, the thesis applies its risk decision making model. This model has implications for economic geography studies of the firm, in that it provides an epistemic and organizational basis for the formalization of tacit knowledge. The model also holds consequences for economic decision making theory, in that it integrates causal assessment in the purely probability based economic paradigm.
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Paddon, Emily. "Taking sides : impartiality, norm contestation and the politics of UN peacekeeping". Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:1dda63f4-5e19-4c98-bc57-3d0902dd80f6.
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Impartiality has long been a core norm of United Nations peacekeeping. However, since 2000 the dominant conception of impartiality has changed, leading to more coercive forms of peacekeeping. Claims to impartial authority are no longer based exclusively on terms to which all parties consent. Instead, they are premised on a more ambitious and expansive set of norms related to human rights, around which consensus is presumed but not always affirmed. This dissertation critically examines the change in both the conception and practice of impartiality, which, it argues, is an integral part of the emergence of a more assertive liberal internationalism. In doing so, it challenges dominant constructivist approaches within IR that conceive of norms as linear and static. It advances a framework for a multi-level analysis of impartiality as a “composite” and “contested” norm. Through this framework it elucidates the macro-level politics surrounding the norm’s institutionalisation at the UN, as well as the micro-level politics surrounding its implementation in the specific case of the UN mission in Congo (MONUC). The analysis of the processes of both institutionalisation and implementation reveals an absence of consensus over the norm itself, and over the purposes of and actions involved in contemporary peacekeeping. This contestation, together with varying expectations and incentives created by the norm amongst local actors, frequently results in unintended consequences, which are contrary to the norm’s original intent. And yet, despite these consequences, the very nature of assertive impartiality makes it difficult for those who claim such authority to change course. Given that the legitimacy of peacekeeping derives both from whether it is seen to reflect and promote shared values, as from the degree to which it is actually effective, this difficulty raises troubling questions for peacekeeping itself and for the UN, the institution to which it has become so symbolically linked. This dissertation argues that, ultimately, the UN’s role may be to reflect, rather than to resolve, the differences of normative interpretation among its member states. It concludes that a more practical and prudent conception of impartiality – one which recognises that impartiality is necessarily and inextricably political – will be necessary if scholars and practitioners alike are to navigate the normative tensions inherent to a more assertive liberal international order.
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Messenger, Gregory. "The development of WTO law in light of transnational influences : the merits of a causal approach". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:2b2214c2-6e83-44cd-bc07-bd0bf2999dc8.
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The WTO is one piece in a complex network of international, regional and domestic legal systems and regulatory frameworks. The influences on the development of WTO law extend far beyond its own Members and institutions: domestic legal instruments have provided the inspiration for numerous WTO obligations while the rights and obligations under the covered agreements are frequently incorporated into the legal systems of the Membership. The WTO is home to numerous committees and working groups that also engage with other international bodies and their domestic counterparts. Transnational actors seek to take advantage of these networks, encouraging WTO law to develop in their favour. The interactions involved, however, are highly complex and unpredictable. By drawing on different models of causal explanation, it is possible to offer a perspective on the development of WTO law that accepts its role as part of a larger globalized process. Three different causal influences are identified: instrumental, systemic and constitutive. Together, they offer a prism through which to examine the development of WTO law as it responds to the behaviour of transnational actors, bridging gaps between international relations and law and, it is hoped, offering a convincing explanatory rationale for the way in which WTO law develops.
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Drenas, Andrew J. G. "'The Standard-bearer of the Roman Church' : Lorenzo da Brindisi (1559-1619) and Capuchin Missions in the Holy Roman Empire". Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:74703f2b-5da1-4a5c-bc77-923f006781f3.
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This thesis examines the missionary work of the Italian Capuchin Lorenzo da Brindisi. Renowned in his own day as a preacher, Bible scholar, missionary, chaplain, and diplomat, as well as vicar general of his Order, Lorenzo led the first organised, papally-commissioned Capuchin mission among the non-Catholics of Bohemia in the Holy Roman Empire from 1599 to 1602, and returned there, again under papal mandate, from 1606 to 1613. This thesis examines Lorenzo’s evangelistic and polemical activities in Central Europe in order to shed light on some of the ways the Capuchins laboured in religiously divided territories to confirm Catholics in their faith and to win over heretics. The introduction explains, principally, the thesis’s purpose and the historiographical background. Chapter one provides a brief biographical sketch of Lorenzo’s life followed by details of his afterlife. Chapter two examines his leading role in establishing the Capuchins’ new Commissariate of Bohemia-Austria-Styria in 1600, and specifically its first three friaries in Prague, Vienna, and Graz. Chapter three treats his preaching against heresy. Chapter four focuses on how Lorenzo, while in Prague, involved himself directly in theological disputations with two different Lutheran preachers. The first dispute, with Polykarp Leyser, took place in July 1607, and dealt with good works and justification. The second, with a Lutheran whose name is not known for certain, and which occurred in August 1610, concerned Catholic veneration of the Virgin Mary. Chapter five analyses the Lutheranismi hypotyposis, Lorenzo’s literary refutation of Lutheranism following additional contact with Polykarp Leyser in 1607. The conclusion considers briefly the effectiveness of Lorenzo’s apostolate and closes with a review of the thesis as a whole.
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Johnston, Jean-Michel. "The moods of modernity : Germany in the age of telegraphy, c.1830-c.1880". Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:2054eff2-ca29-4326-bc27-a79396f6de6a.
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This thesis investigates the origins and impact of electrical telegraphy in Germany between 1830 and 1880, situating them within the context of long-term transformations in the theory and practice of communication. It uses the development of telegraphy as an analytical lens through which to explore the connections between actors at the heart of the socio-economic transformations taking place in Germany during the period. Both as an innovation and as a tool of communication, this thesis argues, the telegraph epitomised the simultaneously growing interdependence and differentiation between people and places which was a defining characteristic of modernity. By exploring the motivations and interactions of scientists, entrepreneurs, state officials, and ordinary users who engaged with the technology, this thesis highlights the diverse expectations which were placed upon telegraphy, and the many different directions in which its development was pulled. In doing so, it reveals the ties between the âmodernisingâ processes with which the technology has been associated. It challenges linear narratives of technological innovation which focus exclusively upon individual or state actors, emphasising the cooperation and collaboration across society which was necessary to produce the telegraph. It similarly questions triumphalist interpretations of the 'communications revolution' so often attributed to the nineteenth century, emphasising instead the tensions and divisions which it also generated. Revisiting the themes of industrialisation, capitalism, community and bourgeois class-formation in nineteenth-century Germany in this light, this thesis emphasises their intrinsic interdependence, and the inevitable mixture of hopes and anxieties, expectations and frustrations, which it produced.
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Mohran, Hossnia Saber. "Analytical and thermodynamic studies on some halogenated benzenoid compounds". Thesis, Royal Holloway, University of London, 1986. http://repository.royalholloway.ac.uk/items/6eed7444-a22e-47ac-bcc7-850e50d14fbb/1/.
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The bromination of 2-fluorophenol, 3-fluorophenol, 4-fluorophenol, 2-fluoroaniline, 3-fluoroaniline and 4-fluoroaniline was carried out inaqueous medium using an acidified mixture of potassium bromate andpotassium bromide as a source of bromine. The chlorination of thesecompounds was carried out using sulphuryl chloride as a chlorinatingagent in chloroform or diethyl ether. Anhydrous aluminium chloridewas used as a catalyst in the chlorination of the fluoroanilines. All the reaction products obtained were analyzed by fluorine-19 nuclear magnetic resonance spectroscopy (F n.m.r. spectroscopy), gas liquid chromatography (GLC) and high-performance liquid chromatography (HPLC).The identification and the structure of these products were established by comparison with the authentic compounds. For the thermodynamic studies:-(a) The enthalpies of solution (at saturation) of 2,4,6-tribromophenol (Br3C6H2OH), 4-bromoani1ine (BrC6H4NH2), 2,6-dibromoaniline (Br2C6H3NH2) and 2,4,6-tribromoaniline (Br3C6H2NH2) in toluene and n-propanol were determined from solubility measurements. ASO1H (Br3C6H2OH) in Toluene = 33.90 kJ mol -1Aso/ (Br3C6H2OH) in n-Propanol = 24.01 kJ mol-1AS0/ (BrC6H4NH2) in Toluene = 65.94 kJ mol -1Aso1H° (BrC6H4NH2) in n-Propanol = 61.95 kJ mol -1A SO1 H0 (Br2C6H3NH2) in Toluene = 46.65 kJ mol -1 sol ' 2 6 3 2'2AgQ-jH"0 (Br2C6H3NH2) in n-Propanol = 44.93 kj mol -1Aso1H° (Br3C6H2NH2) in Toluene = 28.09 kj mol -1Aso1H° (Br3C6H2NH2) in n-Propanol = 20.22 kJ mol -1Entropies of solution, enthalpies of transfer, free energies of transfer and the entropies of transfer between the two solvents were also calculated. (b) Enthalpies of reaction of the bromination of 2-chloroaniline, 4-bromo-2-chloroaniline and 4-chloroaniline in aqueous medium (perchloric acid/sodium bromide) with aqueous bromine (sodium bromide/sodium bromate) were found using reaction calorimetry. arH0θ (2-chloroaniline. + bromine. aq) = -207.84 - 0.63 kj mol-1r aqArH° (4-bromo-2-chloroaniline,c + bromine,aq ) = -91.29 - 0.96 kJ mol -1 ArH° (4-chloroaniline,c + bromine, aq) = -189.61 - 0.90 kJ mol-1.(c) A titration calorimetric technique was used to determine the enthalpies of bromination of 2-nitroaniline and 4-nitroanle in aqueous medium (perchloric acid/sodium bromide) with aqueous bromine (sodium bromide/sodium bromate).
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Carter, Jason W. "First principles in Aristotle's psychology : the science of soul in De Anima 1". Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:5321c889-bce7-4e4f-a3f8-860b286c3380.
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This thesis analyses the method, purpose, and results of Aristotle's treatment of a select number of Presocratic and Platonic theses about the soul within the context of De Anima 1. Contrary to a prevalent interpretation of De Anima 1 which sees Aristotle's treatment of his predecessors' psychological views as dialectical, I argue that Aristotle treats his predecessors as having offered potentially viable hypotheses about the nature of the soul, and that these hypotheses are treated as attempts to explain the soul's basic powers. I further show that, in order to test the explanatory limits of these theories, Aristotle uses a version of the scientific method of inquiry advertised in the Prior and Posterior Analytics, which consists in setting out the basic psychological phenomena which psychology should explain, and then testing the extent to which his predecessors' definitions of the soul are able to accomplish this task. This thesis argues that, by demonstrating where his predecessors' first principles fall short, Aristotle is able to make theoretical progress towards establishing his own 'hylomorphic' first principle of soul, that soul is the 'first fulfilment of a natural instrumental body', and towards the idea that soul operates in the body of living beings as a formal, final, and efficient cause.
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Pearse, Jane Elizabeth. "Factors that impede the adoption of TQM in Professional Scientific Organisations". Thesis, University of Brighton, 1997. https://research.brighton.ac.uk/en/studentTheses/46f01eeb-8cc0-48c3-bc37-6dcbeb2eba18.
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This thesis reports on the implementation of TQM in the unusual environment of two Professional Scientific Organisations. An action research case study was concluded in the first organisation which had implemented an unconventional form of TQM. A corroborating case study was conducted in the other which had implemented "traditional" TQM.
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Green, Laura. "Assessing the nature of early farming in Neolithic western Asia : a functional ecological approach to emerging arable weeds". Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:09a905ab-e375-4d45-bc27-d12cc21e9451.
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Research on the origins of agriculture in western Asia has placed great emphasis on the location and pace of domestication. However, much less attention has been given to reconstructing the specific nature and social implications of early cultivation practices across the agricultural transition, and to the potentially varied land management strategies involved. By employing a functional ecological approach to the interpretation of arable 'weed' taxa associated with early cultivars, this research addresses this gap in archaeobotancial research by enabling detailed analysis of the growing conditions and farming methods involved in early plant cultivation in western Asia. The core methodology analyses the functional ecological attributes (e.g. leaf area and thickness; canopy dimensions; stomatal density and distribution) of the relevant arable weed taxa isolated from archaeological contexts to determine the specific growing conditions of early crops and hence the nature of management practices. Functional attributes are morphological or behavioural characteristics that predict species' potential in relation to major environmental variables, such as soil productivity, disturbance and moisture. Statistical analysis incorporating these attributes is used to explore variation amongst early cultivation contexts and compare them with weed survey data from contrasting (semi-)arid modern regimes, including a recent study of traditional cereal farming in Morocco. Ecological 'signatures' were determined using the isolated weed dataset from four well documented and contextually rich Pre-Pottery and Pottery Neolithic sites, which were strategically selected to explore agricultural strategies from its initial stages through to the established Neolithic, as well as to exploit detailed sample-by-sample data and extensive in situ deposits. The sites investigated are PPNA Jerf el-Ahmar and PPNA/EPPNB Dja'de in northern Syria, PPNB Tell Aswad in southern Syria, and PPN-PN Çatalhöyük in Central Anatolia. Refined identification of selected weed genera at these sites enabled more accurate indications of their arable ecologies. The results generated suggest that early farming practices were highly variable within sites, reflecting the specific affordances of local climate and surrounding landscapes, but relatively labour-intensive in comparison with later urban agrosystems. Furthermore, there are indications for greater cultivation intensity over time, as households became more autonomous.
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Bessou, Margaux. "Contribution de la forme mitochondriale de Bcl-xL dans le contrôle de la migration cellulaire". Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1104/document.
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Les protéines de la famille Bcl-2 sont les principaux régulateurs de la mort cellulaire par apoptose. Au sein de cette famille, la protéine Bcl-xL appartient au sous-groupe des anti-apoptotiques et contribue à maintenir la survie cellulaire. Cependant, des données récentes suggèrent que les membres de la famille Bcl-2, et en particulier Bcl-xL, ont également d'autres fonctions.Dans le contexte pathologique du cancer du sein, la surexpression du gène Bcl-x n'affecterait pas la taille de la tumeur initiale mais favoriserait plutôt l'invasion ganglionnaire et la formation de métastases. La capacité des tumeurs à former des métastases repose notamment sur le potentiel migratoire et invasif des cellules cancéreuses, et de ce fait nous avons cherché à savoir si Bcl-xL pouvait contrôler ces processus. En lien avec les données cliniques, nous montrons que la perte d'expression de Bcl-xL réduit la capacité migratoire de cellules cancéreuses mammaires. De plus, le contrôle de la migration exercé par Bcl-xL est indépendant de son activité anti-apoptotique. Ainsi, l'inhibition de la poche hydrophobe de Bcl-xL par des composés BH3-mimétiques n'a pas d'effet sur la migration des cellules. Nous avons alors recherché le mécanisme par lequel Bcl-xL agit sur la migration. Nous observons que la fraction mitochondriale de Bcl-xL régule la migration cellulaire, et non la protéine localisée au réticulum endoplasmique. Au niveau de la mitochondrie, nous proposons que Bcl-xL contrôle la migration par l'intermédiaire de son domaine BH4, domaine modulant l'activité du canal mitochondrial VDACProteins of the Bcl-2 family are the main regulators of apoptosis. Among the family, the Bcl-xL protein belongs to the anti-apoptotic subgroup and favors cell survival. However, increasing evidence suggest that Bcl-2 proteins, and in particular Bcl-xL, exert other functions in the cells.In the pathological context of breast cancer, Bcl-x gene overexpression seems to have only little impact on primary tumor growth but instead increases lymph nodes invasion and metastasis. Metastasis formation mainly relies on tumor cells’ ability to migrate and invade surrounding tissues. Therefore, we wondered wether Bcl-xL could control these processes.In line with clinical data, we show that Bcl-xL complete or partial loss of expression reduces cell migration of mammary cancer cell lines. Furthermore, we find that Bcl-xL control of cell migration is independent of its anti-apoptotic activity. Indeed, treatments with BH3-mimetics that bind to and inhibit Bcl-xL hydrophobic pocket have no effect on cell migration. Since Bcl-xL regulation of cell migration seems to be independent of interactions with other Bcl-2 family members, we investigated alternative mechanisms. We observe that mitochondrial Bcl-xL, but not the ER-targeted Bcl-xL, is involved in cell migration. At the mitochondria, we propose that Bcl-xL controls cell migration through its BH4 domain, by modulating the activity of mitochondrial VDAC channel
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EL, Dhaybi Mohamad. "Déterminants moléculaires non-apoptotiques de l'activité oncogénique de Bcl-xL : rôle de la monodéamidation de Bcl-xL". Thesis, Limoges, 2017. http://www.theses.fr/2017LIMO0034/document.
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Bcl-xL est un oncogène surexprimé dans plusieurs types de cancers et qui joue un rôle important dans la survie cellulaire en régulant deux processus: l'apoptose et l'autophagie. Récemment, nous avons identifié l'existence d'une nouvelle forme de Bcl-xL qui subit une simple déamidation sur le résidu Asn52. Cette forme monodéamidée est exprimée en conditions contrôles et apparaît spontanément in vitro et in vivo. La déamidation de Bcl-xL produit un mélange de protéines contenant en position 52 soit un résidu Asp, soit un résidu isoAsp. L'objectif de cette thèse est de caractériser les fonctions de ces deux espèces protéiques, et de déterminer comment la monodéamidation de Bcl-xL modifie les fonctions de survie de cet oncogène. Nous avons montré que le mutant déamido-mimétique Bcl-xL N52DN66A conserve la même fonction anti-apoptotique que Bcl-xL native, mais présente une activité autophagique plus grande, et des propriétés oncogéniques et tumorigéniques altérées in vitro, ex vivo et in vivo. Nous avons étudié certains des mécanismes impliqués dans la régulation de l'autophagie et les propriétés oncogéniques comme la voie mTor, les voies de signalisation médiées par l'oncogène Ras, ainsi que l'activité métabolique et l'état souche des cellules. D'autre part, nous avons aussi développé des tests in vitro pour analyser les interactions établies par les formes déamidées de Bcl-xL comportant un isoAsp. L'ensemble de nos données permet de suggérer une régulation des fonctions de Bcl-xL par des mécanismes indépendants de l'apoptose, et renforce l'importance d'explorer les fonctions non apoptotiques de cette protéine pour mettre en évidence sa capacité à promouvoir la survie cellulaire et entraîner la progression du cancerBcl-xL is an oncogene overexpressed in many types of cancer and which promotes cell survival by regulating two cellular processes : apoptosis and autophagy. We have recently identified a new form of this oncogene, which results from the deamidation of Asn52. This monodeamidated form is expressed under control conditions and is ubiquitously found in vitro and in vivo. Bcl-xL monodeamidation produces a mixture of proteins containing either an Asp residue or an IsoAsp residue in position 52. Our goal is to caracterise the functions of both species, and to determine how Bcl-xL monodeamidation modifies the survival functions of this oncogene. We have shown that the deamidomimetic mutant Bcl-xL N52DN66A retains the same anti-apoptotic function as the native protein, but exhibits enhanced autophagic activity and impaired clonogenic and tumorigenic properties in vitro, ex-vivo, and in vivo. We have studied certain of the mechanisms which can be involved in the regulation of autophagy and oncogenic properties of Bcl-xL such as mTor, Ras oncogene signaling pathway, metabolic activity measurement and stemness. We also implement in vitro assays to analyse the interactions established by isoAsp containing forms of Bcl-xL. Altogether our results support the view that deamidation regulates Bcl-xL oncogenic properties through apoptosis-independent mechanisms, and reinforce the importance of deciphering the non apoptotic functions of this protein to tackle its ability to sustain cell survival and drivecancer progression
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Kunze, Doreen [Verfasser], Pée Karl-Heinz [Akademischer Betreuer] van e Manfred P. [Akademischer Betreuer] Wirth. "Small interfering RNA-vermittelte Hemmung der Apoptoseinhibitoren BCL2, BCL-XL, XIAP und Survivin in Zellkultur- und Mausmodellen des humanen Harnblasenkarzinoms / Doreen Kunze. Gutachter: Karl-Heinz van Pée ; Manfred P. Wirth. Betreuer: Karl-Heinz van Pée". Dresden : Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2012. http://d-nb.info/1067729836/34.
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Sonntag, Christina. "Charakterisierung der humoralen Immunantwort nach Phagenidiotypvakzinierung im murinen BCL1-Lymphommodell". Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-80058.
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Heath-Engel, Hannah. "Novel roles for Bcl2 family proteins at the endoplasmic reticulum". Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96894.
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The Bcl2 family proteins are central regulators of apoptosis; the primary form of physiological cell death. Furthermore, inappropriate activation or silencing of Bcl2 family members has been associated with cancer development and treatment resistance. These proteins therefore represent attractive therapeutic targets, and, in consequence, an increased understanding of the roles played by Bcl2 proteins will be important for the development and implementation of targeted therapies. Although best characterized with respect to their role at the mitochondria, it is now evident that Bcl2 proteins also function at the endoplasmic reticulum (ER). The focus of this thesis is on the role of Bcl2 proteins at the ER, specifically with respect to cell death initiated by the ER localized proteins Bik and p20Bap31. Bik and p20Bap31 were previously shown to initiate similar proapoptotic pathways, characterized by an early release of ER calcium stores, and inhibitable by Bcl2. The results of the current study are two-fold: first, using ER-targeted Bak and Bcl2 (Bakb5 and Bcl2b5) in a Bak/Bax deficient background, I have shown that Bik can disrupt an interaction between Bak and Bcl2 at the ER. Furthermore, Bik could overcome the protective effect of Bcl2b5 with respect to Bakb5. This finding provides the first direct evidence for regulation of cell death via binary interactions between Bcl2 family members at the ER. The second part of this study was designed to determine the roles of Bax/Bak and ER-restricted Bcl2 in the p20Bap31-initiated pathway. Using E1A/DNp53 transformed wild-type and Bax/Bak double knockout baby mouse kidney epithelial cells, I have shown that ectopic expression of p20Bap31, but not of Bik, can initiate a paraptosis-like form of non-apoptotic, Bax/Bak independent, cell death. Of particular importance, cell death could be delayed by Bcl2b5, in the absence of Bax/Bak; pointing to a novel, Bax/Bak independent, prosurvival role for Bcl2 at the ER. In summary, this study demonstrates the ability of Bcl2 family members to regulate cell death through binary interactions at the ER, and of Bcl2 to inhibit cell death in a Bax/Bak independent manner. Furthermore, a novel non-apoptotic cell death pathway initiated by p20Bap31 expression is identified.La famille de protéines Bcl2 a une importance fondamentale dans le contrôle de l'apoptose; la forme principale de mort cellulaire physiologique. De plus, le développement de cancers et la résistance aux thérapies sont associés à l'activation ou la suppression de membres de la famille Bcl2. Cette famille de protéines représente une cible thérapeutique intéressante et par conséquent, une connaissance approfondie des rôles des protéines Bcl2 sera important pour amener et exécuter des thérapies ciblées. Tandis que le rôle de ces protéines à la mitochondrie est bien caractérisé, une fonction des protéines Bcl2 au niveau du réticulum endoplasmique (RE) est maintenant évidente. Cette thèse porte sur le rôle des protéines Bcl2 au niveau du RE, particulièrement concernant l'apoptose initiée par Bik et p20Bap31, deux protéines qui sont localisés au RE. Les voies de signalisation proapoptotique qui sont initiées par Bik et p20Bap31 sont caractérisées par une libération précoce d'une réserve de calcium du RE et sont inhibées par Bcl2. Les résultats de l'étude présente portent sur deux domaines: premièrement, en empruntant des formes de Bak et Bcl2 qui sont ciblées au RE (Bakb5 et Bcl2b5) sur un fond déficient en Bak et Bax, je démontre que Bik est capable de perturber l'interaction entre Bak et Bcl2 au RE. En outre, Bik peut surmonter l'effet protectrice contre l'apoptose de Bcl2b5 par rapport à Bakb5. Ce sont les premières évidences qu'une interaction binaire entre des membres de la famille Bcl2 au RE peut contrôler la mort cellulaire. La deuxième partie de cette étude était conçu pour déterminer le rôle de Bax/Bak et Bcl2 localisé uniquement au RE, dans la voie de signalisation initiée par p20Bap31. En utilisant des cellules provenant de l'épithélium rénale de souris nouveau-nés transformées par E1A/DNp53, soit de souche sauvage ou avec double knockout des gènes Bax et Bak, je démontre que l'expression ectopique de p20Bap31, mais non pas de Bik, peut initier une forme de mort cellulaire non-apoptotique indépendante de Bax/Bak qui ressemble la paraptose. Un résultat d'importance primordiale est qu'un délai de mort cellulaire attribué à Bcl2b5 s'avère dans l'absence de Bax et Bak, ce qui suggère un rôle pro-survie inattendu de Bcl2 au RE indépendant de Bax/Bak. Cette étude démontre une capacité de contrôler la mort cellulaire des membres de la famille Bcl2 par des interactions binaires au RE et une fonction inhibitrice de Bcl2 sur la mort cellulaire indépendante de Bax/Bak. De plus, une nouvelle voie de signalisation de mort cellulaire non-apoptotique initiée par p20Bap31 est identifiée.
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Wakefield, Alison. "Role of Bcl3 in the normal and neoplastic mammary gland". Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/55135/.
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The NF-kB family of transcription factors have previously been shown to be elevated in many malignant diseases including breast cancer. NF-kB activation is strongly associated with signalling downstream of the epidermal growth factor (EGF) family of receptors in both aggressive EGFR-positive and ERBB2-positive breast cancer subtypes. These observations have led to much interest in the use of NF-kB inhibitors to suppress tumour progression in breast cancer patients. However, as NF-kB controls numerous functions in homeostasis there are significant risks associated with sustained global inhibition of NF-kB signalling. This investigation therefore aimed to determine whether inhibition of the NF-kB co-factor, B-Cell Lymphoma 3 (BCL3), would block the pro-tumourigenic function of NF-kB, while allowing it to retain its physiological functions in normal tissues. Deletion of BCL3 had no effect on the gross morphology or function of the mammary gland during the pregnancy cycle, although a subtle BCL3 dose-dependent effect was observed during involution whereby 8c/3+/" mice had increased apoptotic bodies in comparison with both 6c/3+/+ and Bcl3'h mice. Loss of BCL3 in the context of ERBB2-driven murine mammary carcinogenesis resulted in a significant delay in both the initiation and metastatic progression of mammary adenocarcinomas. Further in vitro investigation revealed that Bcl3 suppression by SiRNA in a murine mammary ERBB2- positive cell line reduced both the migratory and invasive capacity of cells, indicating that BCL3 was able, at least in part, to exert a pro-metastatic effect in a cell autonomous manner. In addition, SiRNA suppression of BCL3 reduced both the proliferative and migratory capacity of both ERBB2-positive and EGFR-positive human breast cancer cell lines. Collectively, these results suggest that targeting BCL3 may be an effective therapeutic strategy in the treatment of both ERBB2- and EGFR-positive breast cancers.
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Cartlidge, Rachael Charlotte. "The Epstein-Barr virus BCL-2 homologues : interactions with cellular BCL-2 proteins and their role in apoptosis". Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/5898/.
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Epstein-Barr virus (EBV) encodes two viral BCL-2 homologues, BHRF1 and BALF1. BHRF1 is expressed in a subset of EBV-positive Burkitt’s lymphoma (BL) tumours; as BHRF1 is highly anti-apoptotic, expression could result in treatment-resistant BL. Little is known about BALF1, including whether BALF1 is pro- or anti-apoptotic. Interactions between BHRF1 and cellular BCL-2 homologues have not been fully characterised, but previous studies have focused on BIM as a key binding partner. We stably expressed wild-type or mutant vBCL-2s in EBV-negative BL lines to investigate interactions between BHRF1 and cellular BCL-2 homologues. The ability to bind BIM, whilst well documented, had no impact on BHRF1-mediated protection. Our data suggests that BHRF1’s protective ability may be mediated through binding to BID and BAK. This work also identified two amino acids, located in the binding groove of BHRF1, which are highly important for protein function. We detected BALF1 expression, at potentially functionally relevant levels, in a wide variety of EBV-associated tumour lines. BALF1 mRNA was detectable in lines with highly varied patterns of viral gene expression, indicating that expression is not restricted to one part of the viral life-cycle. In BL, BALF1 was found to be anti-apoptotic, and co-operated with, rather than antagonized, BHRF1.
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Dupont, Salomé. "Développement d’un modèle préclinique de leucémogénèse expérimentale chez la souris humanisée". Thesis, Paris Sciences et Lettres (ComUE), 2017. http://www.theses.fr/2017PSLEP057/document.
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Les modèles animaux actuellement disponibles pour l’étude des leucémies humaines ne sont pas adaptés pour le développement optimal de nouvelles thérapies ciblées. Au cours de ce projet, qui s’inscrit dans une double perspective fondamentale et industrielle, nous avons cherché à générer un modèle versatile de leucémogénèse humaine chez la souris humanisée BRGS (BALB/c Rag2-/- IL-2Rγc-/- SIRPα.NOD). Les animaux sont greffés avec des progéniteurs hématopoïétiques transduits par des vecteurs lentiviraux surexprimant les oncogènes MYC et BCL2 et placés sous le contrôle d’un promoteur ubiquitaire (EF1α ou SFFV). Le suivi longitudinal des animaux sur une période de 5 mois montre que seule la construction SFFV/Myc-T2A-Bcl2 entraîne la transformation des progéniteurs hématopoïétiques. Entre 12 à 14 semaines post-greffe, >90% des animaux développent des lympho-proliférations de type pro-B (CD19+CD10+CD9+CD20-cytIgM-) infiltrant principalement la rate et la moelle osseuse, et circulant en abondance dans le sang. Le caractère transmissible des tumeurs est validé par des greffes secondaires de tumeurs spléniques. Les cultures in vitro de progéniteurs hématopoïétiques suggèrent que l’émergence des blastes est liée à la réactivation d’un programme B latent dans les précurseurs T, dont le développement est bloqué. Nous avons développé en parallèle un modèle de tumeur autologue. L’ensemble de ces résultats valide le modèle de leucémogénèse humaine développé chez la souris humanisée BRGS et ouvre des perspectives pour la caractérisation fonctionnelle des mécanismes de leucémogénèse, et la validation préclinique de nouvelles stratégies anti-tumoralesExisting animal models for the study of human leukemia are not accurate for the proper development of innovative, targeted therapies. The aim of this project, which contains both a fundamental and an industrial perspective, therefore was to develop a new, versatile model of human leukemogenesis in the BRGS (BALB/c Rag2-/- IL-2Rγc-/- SIRPα.NOD) humanized mouse. Animals are grafted with hematopoietic progenitors transduced with lentivirals vectors to allow overexpression of MYC and BCL2 proteins under the control of an ubiquitous promotor (EF1α or SFFV). Longitudinal monitoring of the animals over five months shows that only the SFFV/Myc-T2A-Bcl2 construction induces the transformation of humans hematopoietics progenitors. Between 12 and 14 weeks post-transplantation, more than 90% of the animals develop pro-B lympho-proliferations (CD19+CD10+CD9+CD20-cytIgM-), with tumor cells being mainly found in the spleen, the bone marrow and in blood. Tumor transferability is achievable through secondary transplantation in immunodeficient mouse recipients. In vitro culture of bone marrow T cell progenitors suggest that the blasts arise from these cells after reactivation of a latent B cell program with blockade of their T cell development. In parallel, we have also developed an autologous tumor model. Altogether, these results validate the human leukemogenesis model constructed here in humanized BRGS mice and provide attractive prospects regarding the functional characterization of leukemogenesis and a preclinical validation of new anti-tumor strategies
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Charlé, Christoph. "Kontrolle der Expression des Apoptoseregulatorgens bcl-x". [S.l.] : [s.n.], 1999. http://www.diss.fu-berlin.de/2000/106/index.html.
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Abou, samra Alma. "Conception, synthèse et évaluation biologique d’inhibiteurs des protéines anti-apoptotiques de la famille Bcl-2". Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS390/document.
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La mitochondrie joue un rôle capital dans la mort cellulaire programmée ou apoptose par l’intermédiaire des protéines de la famille Bcl-2. Le dérèglement de l'apoptose dans de nombreux cancers fait de cette voie et des protéines de la famille Bcl-2 des cibles prometteuses pour la thérapie anti-cancéreuse. Le développement de petites molécules ciblant les protéines de la famille Bcl-2 s’est toutefois révélé être un grand défi, et peu d’entre elles ont atteint des études de phase clinique. Cependant, depuis une quinzaine d’années, grâce à des approches variées et souvent innovantes, des composés très actifs ont été développés. Plusieurs composés sont actuellement en essais clinique et une molécule, le venetoclax, a obtenu la première autorisation de mise sur le marché en avril 2016. Ce succès thérapeutique démontre que les protéines de la famille de Bcl-2 sont des cibles potentielles pour la thérapie anticancéreuse.Les substances naturelles sont une source importante de nouvelles molécules à structures originales, et de nombreux médicaments utilisés actuellement en chimiothérapie sont d’origine naturelle. La meiogynine A est un triterpène dimère qui a été isolé et synthétisé dans notre équipe. Ce composé possède une activité inhibitrice duale des protéines anti-apoptotiques Bcl-xL et Mcl-1. Des analogues de première et deuxième génération ont été élaborés par la suite, parmi lesquels, certains présentent une activité duale sub-micromolaire. Contrairement aux analogues de première génération, ces composés ne sont cependant pas cytotoxiques, probablement en raison de la présence d’une fonction ester sur la chaine latérale qui peut s’hydrolyser en un métabolite inactif.Mon projet de thèse vise à élaborer des analogues de troisième génération de la meiogynine A possédant une activité inhibitrice multiple sub-micromolaire des protéines anti-apoptotiques Bcl-xL, Mcl-1, Bcl-2 et cytotoxiques sur des lignées cellulaires surexprimant ces mêmes protéines. Pour cela, un essai biologique de mesure d’inhibition de l’interaction Bcl-2/Bim a été mis en place et robotisé afin d’évaluer l’activité biologique des composés synthétisés. De plus, la voie de synthèse bioinspirée d’un précurseur commun des nouveaux analogues a été mise au point à l’échelle de plusieurs grammes. Ce précurseur a permis d’élaborer différents analogues de troisième génération de la meiogynine A en réalisant des pharmacomodulations sur la chaîne latérale afin de remplacer la fonction ester des analogues de deuxième génération par un groupement stable et résistant in cellulo. Différentes séries ont été envisagées (alcènes, amines, amides, carbamates et triazoles). L’activité biologique des composés synthétisés a été évaluée sur les trois cibles in vitro. Finalement, des analyses de cytotoxicité pour les analogues les plus actifs ont été réalisées par nos collaborateurs à l’Institut Gustave RoussyApoptosis is used by multicellular organisms to regulate tissue homeostasis through the elimination of useless or potentially harmful cells. The key players of apoptosis are caspases, a family of proteases whose activation is induced by two major signalling pathways. One of these pathways (the intrinsic pathway) is regulated by the Bcl-2 family of proteins. In recent years, numerous studies have shown that overexpression of the antiapoptotic Bcl-2, Bcl-xL or Mcl-1 proteins is involved in the development of many kinds of cancers or confers resistance to apoptosis induced by standard anticancer therapies. Consequently, targeting this family of proteins is a highly promising strategy for tumour treatment.The feasibility of disrupting protein-protein interactions between anti- and pro-apoptotic members of the Bcl-2 family, using small-molecule inhibitors has been successfully established, and venetoclax was the first to obtain the FDA authorisation in April 2016 as an inhibitor of anti-apoptotic proteins of Bcl-2.Natural products are still playing a significant role in drug discovery and development process. Thus, from the 1940’s to date, 75% of the 175 small molecules used in cancer therapy, are either natural products or derivatives of natural compounds. Screening of plant extracts, marine organisms or microorganisms can provide highly original and functionalized bioactive molecules that are unlikely obtained by screening synthetic libraries. In fact, structural complexity is often a criterion of specificity for biological target.Meiogynin A is an original molecule isolated from a Malaysian Annonaceae and synthesized in our team in 2009. It exhibited a promising inhibitory activity of Bcl-2, Bcl-xL and Mcl-1, three anti-apoptotic proteins of Bcl-2 family whose overexpression is correlated with many cancers. 1st- and 2nd-generation analogs were further elaborated. Despite their remarkable affinity towards target proteins, 2nd-generation analogs lacked cytotoxicity, probably due to the presence of an ester linker that could undergo competitive hydrolysis in cellulo, leading to an inactive metabolite.We aim to develop 3rd-generation analogues of meiogynine A exhibiting high affinity towards multiple anti-apoptotic members of Bcl-2 family as well as cytotoxicity on cancer cells that overexpress these proteins. For this, a new fluorescence polarization inhibition test for Bcl-2/Bim interaction has been implemented, and meiogynine A and its analogues have been tested against the new interaction. In addition to Bcl-xL/Bak and Mcl-1/Bid interaction inhibition, these molecules showed an ability to inhibit Bcl-2/Bim interaction. Thus, they are considered multiple inhibitors.3rd-generation analogues of meiogynine A were obtained by pharmacomodulation of a common precursor that was synthesized on a gram-scale through a bioinspired Diels-Alder reaction. Several functional groups that have better stability in vivo than the ester group were anticipated, such as the amines, amides, carbamates and triazoles. Biological activity of the synthesized analogues was evaluated, and those presenting the best inhibitory profile were evaluated in cellulo by our collaborators in the Institut Gustave Roussy