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1
Grisham, Tom, and tgrisham@tampabay rr com. "Cross cultural leadership." RMIT University. Property, Construction and Project Management, 2006. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20061116.125205.
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Global markets are increasingly taking advantage of the strength and economic advantages of a diverse global workforce. It is common on international projects to find multi-cultural teams located in multiple countries. It is also common to find such projects led by Project Managers who come from many different countries. So having a person raised in India managing a project in China, with a design team in the USA, procurement procurement teams in Japan and Mexico, and a drafting team in Albania is not unusual. Even in historically monolithic markets like the USA, it is far more common to have mulit-cultural teams and foreign competition. In addition, the pressure on the industry to increase productivity and reduce costs is unrelenting. This leads to flatter project structures, and the need for leadership at multiple levels. My experience in such markets, and the glaring need for a Cross-Cultural Leadership model that could be used to improve leadership skills in international markets were the reasons for undertaking this thesis. The hypothesis of this thesis is that there are of cross-cultural leadership dimensions that are effective and essential, regardless of culture. Those dimensions are Trust, Empathy, Transformation, Power, and Communication. The thesis first explores the cultural and leadership aspects of Cross-Cultural Leadership through a review of the published literature. The literature research was then subjected to an exegetical review of the themes that emerged, and used to construct the Descriptors, and Sub-Descriptors for each of the leadership dimensions. The thesis also explored the transfer of cultural knowledge with metaphors and storytelling. In a fast paced business environment, developing a richer understanding and sensitivity to other coulters, in general and specific, is a skill that Leaders must possess. Lastly, the thesis explored the connections between conflict management and Cross-Cultural Leadership. Conflict management skills are becoming ever more important due to the rapid changes that are common in the current business environment. Change, cultural mis-information, scarce resources, poor communication skills, contractual ambiguity and complexity are but a few of the reasons that managing conflict is a critical skill for leaders. IV The design of the testing protocols was bifurcated. One track evaluated the hypothesis, the other track evaluated the connection between the Leadership Dimensions hypothesized, and the GLOBE survey. The GLOBE survey was utilized to investigate if a viable connection existed between the Leadership Dimensions and a broad based international survey of cultural dimensions. The testing of the hypothesis was performed using a Delphi panel of experts in international cross-cultural leadership, through two sessions of questions with feedback after the end of the first session. Subsequently, the results were analyzed, studied, and evaluated with an eye toward my practical experience in the field - sense making. The results were that the hypothesis was confirmed, and the connection to the GLOBE Survey cultural dimensions was also confirmed. A model is presented to summarize the findings of the thesis, called the Cross-Cultural Leadership Intelligence (XLQ) Model. As discussed in the thesis, Project Management has not emphasized leadership in the current body of knowledge (PMBOK), and it only makes general reference to cultural considerations. Recognizing this, The Project Management Institute (PMI) has funded a study that recommends more research in the area of cross-cultural leadership, and a new grant to study the question of how global the PMBOK really is. Both of these issues are addressed by this thesis. The XLQ model provides a framework for assessing and training Project Managers in cross-cultural leadership skills. The model is a global one that can be used across cultures, business models, and markets. The model also points towards the need for further research into metrics, education, training techniques, and of course, further empirical testing of the model itself.
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Horn, Peter Christian. "Charakterisierung des XIAP-Gens bei zwei Familien mit X-chromosomalem lymphoproliferativem Syndrom." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-179636.
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Dissertation zur Erlangung des akademischen Grades Dr. med.
Charakterisierung des XIAP-Gens bei zwei Familien mit X-chromosomalem lymphoproliferativem Syndrom
Eingereicht von:
Peter Christian Horn
geboren am 04.08.1982 in Freiburg
Angefertigt an:
Der Universitätsklinik und Poliklinik für Kinder und Jugendliche Leipzig und dem Zentrum für familiären Brust- und Eierstockkrebs der technischen Universität München
Betreuer:
Prof. Dr. med. Volker Schuster (Universität Leipzig) Prof. Dr. rer. nat. Alfons Meindl (TU München)
Eingereicht im Dezember 2014
Das X-linked-inhibitor-of-apoptosis Protein XIAP nimmt eine zentrale Rolle in der Hemmung von Apoptoseprozessen beim Menschen ein. In Abwesenheit von XIAP kann eine defekte Immunabwehr gegenüber viralen Infektionen beobachtet werden. In Folge können lebensbedrohliche Immunreaktionen wie hämophagozytäre Lymphhistiozytose, aplastische Anämie und persistierende Hypogammaglobulinämie auftreten.
Im Rahmen dieser Arbeit wurde untersucht, ob bei einem Patientenkollektiv mit lymphoproliferativem Syndrom Mutationen im XIAP-Gen Auslöser der Erkrankung sind. Es wurde eine molekulargenetische Sequenzierung und Auswertung des XIAP-
5 Zusammenfassung der Arbeit 53
Gens bei 36 Verdachtsfällen eines X-chromosomal vererbten lymphoproliferativen Syndroms durchgeführt. In allen Fällen wurde der gesamte exonische Abschnitt des Gens sequenziert und auf Polymorphismen und Mutationen untersucht. Bei zwei Proben wurden Mutationen im XIAP-Gen gefunden. Weiter konnten Mutter und Bruder eines der Betroffenen untersucht werden, so dass insgesamt drei Knaben mit XIAP-Gendefekt sowie eine heterozygote Konduktorin identifiziert wurden.
Nach der Identifikation der Mutationsträger erfolgte eine Auswertung der Krankenge- schichte und ein Vergleich mit den verfügbaren Beschreibungen von XIAP-Defizienz. Die beiden neu identifizierten Mutationen verursachen ein Krankheitsbild, das mit den wenigen verfügbaren Beschreibungen von XIAP-Defizienz vereinbar ist. Die Auswer- tung der Klinik der drei Betroffenen unterstützt die Hypothese, dass bei XIAP- Defizienz keine Lymphome auftreten.
Die Therapieentscheidung bei XIAP-Defizienz ist einzelfallabhängig. Die Arbeit ver- gleicht den Krankheitsverlauf der neu beschriebenen Patienten mit der Literatur und unterstreicht, dass die Entscheidung zu einer Knochenmarkstransplantation gut begrün- det werden muss. Es sind inzwischen mehr Patienten bekannt, die ohne Therapie oder unter IVIG-Gabe asymptomatisch sind, als solche, die eine Knochenmarkstransplantati- on überlebt haben. Alle hier beschriebenen Patienten konnten ohne Transplantation be- handelt werden. Eine Stammzelltransplantation kann jedoch erfolgreich sein. Bei kon- servativ behandelten Patienten können Rezidive auftreten.
Kritisch zu sehen sind im Licht der Erfahrung mit den XIAP-defizenten Patienten An- strengungen, XIAP-Inhibitoren zur Tumortherapie am Menschen zu entwickeln – dies könnte als Nebenwirkung paradoxe Folgen wie Lymphoproliferation oder HLH haben.
Die in der Arbeit beschriebenen Patienten waren die ersten Patienten mit XIAP- Defizienz, die im deutschsprachigen Raum identifiziert wurden. Die beiden Mutationen die bei den Familien gefunden wurden, waren bisher nicht beschrieben.
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Lam, Wai-Yeung. "XCQ : a framework for XML compression and querying /." View abstract or full-text, 2003. http://library.ust.hk/cgi/db/thesis.pl?COMP%202003%20LAM.
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Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2003.Includes bibliographical references (leaves 142-147). Also available in electronic version. Access restricted to campus users.
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AL, MOHAINI MOHAMMED. "XLF-Dependent Nonhomologous End Joining of Complex DNA Double-Strand Breaks with Proximal Thymine Glycol and Screening for XRCC4-XLF Interaction Inhibitors." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3988.
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DNA double-strand breaks induced by ionizing radiation are often accompanied by ancillary oxidative base damage that may prevent or delay their repair. In order to better define the features that make some DSBs repair-resistant, XLF-dependent nonhomologous end joining of blunt-ended DSB substrates having the oxidatively modified nonplanar base thymine glycol (Tg) at the first (Tg1) , second (Tg2), third (Tg3) or fifth (Tg5) positions from one 3’ terminus was examined in human whole-cell extracts. Tg at the third position had little effect on end-joining even when present on both ends of the break. However, Tg as the terminal or penultimate base was a major barrier to end joining (>10-fold reduction in ligated products) and an absolute barrier when present at both ends. Dideoxy trapping of base excision repair intermediates indicated that Tg was excised from Tg1, Tg2 and Tg3 largely if not exclusively after DSB ligation. However, Tg was rapidly excised from the Tg5 substrate, resulting in a reduced level of DSB ligation, as well as slow concomitant resection of the opposite strand. XLFL115D mutant completely eliminates ligation of all five substrates and previous X‑ray crystallography shows that XLF binds to XRCC4 via a “leucine lock” motif wherein L115 of XLF slips into a hydrophobic pocket in XRCC4. This makes the XRCC4-XLF interaction a good target to develop peptide inhibitors in order to radiosensitize breast tumor cells that are dependent on NHEJ to repair their DSBs after ionizing radiation exposure. Using mRNA display, we created a diverse library of 870 billion unique peptide sequences. After seven rounds of in vitro selection, the eluted fusions were cloned and sequenced. The results showed homology of sequences of five main families. We have selected representative peptides from those families (Pep 7.1-7.5), and several were chemically synthesized. However, none of these significantly inhibited XLF-dependent end joining in whole-cell extracts. Overall, the results suggest that promoting ligation of DSBs with proximal base damage may be an important function of XLF, but that Tg can still be a major impediment to repair, being relatively resistant to both trimming and ligation. The effectiveness of XLF-XLRCC4 inhibitors in blocking nonhomologous end joining remains to be determined.
5
Spencer, Stefan. "W XLV : structural and collisional atomic generation for fusion." Thesis, Queen's University Belfast, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.711906.
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Bacigalupo, Luis Eduardo. "Bernardo contra Abelardo: Moral y política en el siglo XlI." Pontificia Universidad Católica del Perú, 2012. http://repositorio.pucp.edu.pe/index/handle/123456789/119318.
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Una de las más célebres contiendas de la Edad Media es la que enfrentó en Sens (1140) a Pedro Abelardo y Bernardo de Claraval. El primero llegó a esa localidad como acusado; el segundo había reunido el concilio como acusador.
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DZWONKOWSKI, PIOTR. "Micro-generateur electrochimique li/b#2o#3+xli#2o/inse." Paris 6, 1990. http://www.theses.fr/1990PA066124.
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Des micro-generateurs en couches minces ont ete realises et etudies. Les structures sont constituees par l'empilement de couches minces: de lithium, d'electrolyte solide vitreux et d'inse. Les micro-generateurs ont une tension de l'ordre de 1. 5-2 v, un courant d'echange sur l'interface de l'ordre de 5. 10##9 a/cm#2. La valeur de coefficient de diffusion chimique du lithium dans la cathode est estimee a se situer entre 10##1#4-10##1#5 cm#2/s. Differents electrolytes solides du systeme b-o-li, b-o-li-cl et b-o-li-s ont ete envisages et les caracteristiques des micro-generateurs ont ete etudiees en fonction de la composition de l'electrolyte. La structure de l'electrolyte a ete etudiee par la spectroscopie d'absorption infrarouge. Une etude complete de l'impedance complexe des couches minces des verres alcalins a ete menee
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Santos, AndrÃa Feitosa dos. "Uma gramÃtica LFG-XLE para o processamento sintÃtico profunda do portuguÃs." Universidade Federal do CearÃ, 2014. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=13867.
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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel SuperiorA presente tese descreve a elaboraÃÃo de uma gramÃtica da frase do PortuguÃs Brasileiro, desenvolvida no quadro de um modelo teÃrico de sofisticado formalismo computacional, a Lexical Functional Grammar (LFG) e implementada no sistema que constitui o estado da arte em ambiente de processamento sintÃtico profundo no modelo gerativo da LFG, o robusto Xerox Linguistic Environment (XLE). A principal caracterÃstica da gramÃtica à que adota o sistema de anotaÃÃo do ParGram e a metodologia convencionada por desenvolvedores de gramÃtica XLE. No fragmento de gramÃtica estÃo modelados diversificados elementos da sintaxe frasal. Em nossa gramÃtica, foram modelados constituintes oracionais como IP e CP, elementos que encabeÃam as sentenÃas do portuguÃs. TambÃm foram modelados determinados aspectos da subcategorizaÃÃo verbal e da estrutura argumental. Dos elementos verbais, nossa gramÃtica contempla alguns casos de complexos verbais constituÃdos de verbos modais e verbos de controle. Os elementos nominais tratados na gramÃtica, de modo central, foram os pronomes expletivos e reflexivos, e os casos de sintagmas nominais e determinantes com pronomes demonstrativos e interrogativos. Os demais aspectos modelados na gramÃtica sÃo os sintagmas preposicionados, cuja complexidade se dà na distinÃÃo entre preposiÃÃes semÃnticas e nÃo semÃnticas; os sintagmas adjetivais, cuja projeÃÃo na sentenÃa pode ocorrer a partir de formas adjetivais atributivas, de formas ordinais ou cardinais e na forma de intensificadores; e os sintagmas adverbiais, cuja estrutura interna foi modelada levando-se em consideraÃÃo tanto advÃrbios intransitivos quanto transitivos com complemento PP. A nossa avaliaÃÃo demonstra que das 40 sentenÃas testadas, a nossa gramÃtica atribui, para todas elas, anÃlises consistentes e bem fundamentadas, ao passo que o parser Palavras, o atual estado da arte em processamento sintÃtico profundo do portuguÃs, atribui, a 9 sentenÃas, anÃlises incorretas. Uma outra avaliaÃÃo demonstra que, das 20 sentenÃas agramaticais testadas tanto em nossa gramÃtica, quanto no Palavras, somente 2 receberam anÃlises por parte de nossa gramÃtica, enquanto o Palavras fornece anÃlises para 19 sentenÃas. O trabalho tem, essencialmente, o objetivo de fazer uma descriÃÃo formal e fundamentada de um amplo leque de fenÃmenos do portuguÃs brasileiro, mas, sobretudo, tem o objetivo de contribuir com uma gramÃtica nÃo trivial da frase do portuguÃs no formalismo LFG-XLE, disponibilizando efetivamente um recurso gramatical do portuguÃs voltado para o processamento de linguagem natural.
The present thesis describes the development of a Brazilian Portuguese sentence grammar, developed in the framework of a sophisticated computational formalism, named Lexical Functional Grammar, and implemented on a system that is state of the art in deep parsing environment in LFG generative model, the robust XLE. The main feature of the grammar is that it adopts the ParGram annotation system and the methodology agreed by XLE grammar developers. In the grammar fragment are modeled diverse elements of phrasal syntax. In our grammar were modeled constituents as IP and CP, elements that are head the sentences of the Portuguese. Also were modeled certain aspects of verbal subcategorization and argument structure. In terms of verbal elements, our grammar includes some cases of verbal complex made up of modal verbs and control verbs. The nominal elements treated in grammar, centrally, were the expletives and reflexive pronouns, and cases of nominal and determiners phrases with demonstrative pronouns and interrogative. The other aspects modeled in the grammar are PPs, whose complexity is given the distinction between semantic and nonstandard prepositions; the adjectival phrases, whose projection in the sentence can occur from attributive adjectival forms of ordinal or cardinal forms and as intensifiers; and adverbial phrases, whose internal structure was modeled taking into account both adverbs as intransitive and as transitive, with PP complement. Our evaluation shows that of the 40 tested sentences, our grammar assigns, for all of them, consistent and well-founded analysis, while the parser Palavras, the current state of the art in deep syntactic processing of Portuguese, assigns incorrect analysis for 9 sentences. Another evaluation shows that, of the 20 ungrammatical sentences tested both in our grammar, as in Palavras, only 2 received analysis by our grammar, while the Palavras provides analysis to 19 sentences. The work has essentially the goal of making a formal and grounded description in a broad range of phenomena in Brazilian Portuguese, but mainly aims to collaborate with a not trivial grammar of the sentence in the LFG-XLE formalism, effectively contributing to a grammatical resource turned to the natural language processing.
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Sharifi, G. "Cellular studies on the pathogenesis of X-linked lymphoproliferative (XLP) syndrome." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1445057/.
Full textAbstract:
X-linked lymphoproliferative (XLP) disease is a severe primary immunodeficiency. Immunodysregulatory phenomena are observed following EBV infection suggesting that defects exist in these effector populations. The gene defective in XLP is SAP (SLAM-associated protein), an intracellular adaptor protein that mediates signals through SLAM and other immunoglobulin superfamily receptors including 2B4. Cytotoxic T cells (CTLs) and natural killer (NK) cells play a major role in the normal immune response to Epstein-Barr virus (EBV) infection. EBV specific T cell lines (EBV-T cell lines) were generated from normal individuals and XLP patients and examined for CTL function in response to different stimuli. It has been shown that XLP patients can generate EBV-T cell lines that are phenotypically similar to those from unaffected individuals. XLP patient derived EBV-T cell lines showed a significant decrease in interferon-gamma (IFN-gamma) production in response to 2B4 and autologous EBV transformed lymphoblastoid cell line (LCL) stimulation but not in response to SLAM. Furthermore, XLP EBV-T cell lines demonstrated markedly decreased cytotoxic activity against autologous LCLs. By retroviral gene transfer of the SAP gene into XLP patient derived EBV-T cell lines, reconstitution of EFN-gamma production and cytotoxic activity has been shown, confirming the defects are SAP dependent. These studies demonstrate that in XLP the lack of SAP affects specific signalling pathways resulting in severe disruption of CTL function. In addition, SLAM and 2B4 expression on immune cell lineages has been investigated, the results suggest a wider range of 2B4 expression and deserve further investigation in relation to XLP molecular and cellular pathogenesis.
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Groh, Stefan. "Die Insula XLI von Flavia Solva : Ergebnisse der Grabungen 1959 und 1989 bis 1992 /." Wien : Eingenverl. der Österreichischen Archäologischen Institutes, 1996. http://catalogue.bnf.fr/ark:/12148/cb39234694c.
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Santos, Andréa Feitosa dos. "Uma gramática LFG-XLE para o processamento sintático profundo da frase do português brasileiro." www.teses.ufc.br, 2014. http://www.repositorio.ufc.br/handle/riufc/11367.
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SANTOS, Andréa Feitosa dos. Uma gramática LFG-XLE para o processamento sintático profundo da frase do português brasileiro. 2014. 181f. – Tese (Doutorado) – Universidade Federal do Ceará, Departamento de Letras Vernáculas, Programa de Pós-graduação em Linguística, Fortaleza (CE), 2014.Submitted by Márcia Araújo (marcia_m_bezerra@yahoo.com.br) on 2015-04-14T14:40:19Z No. of bitstreams: 1 2014_tese_afsantos.pdf: 4829005 bytes, checksum: ec110a9d0e7e0a67af100a1ae610369c (MD5)
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The present thesis describes the development of a Brazilian Portuguese sentence grammar, developed in the framework of a sophisticated computational formalism, named Lexical Functional Grammar, and implemented on a system that is state of the art in deep parsing environment in LFG generative model, the robust XLE. The main feature of the grammar is that it adopts the ParGram annotation system and the methodology agreed by XLE grammar developers. In the grammar fragment are modeled diverse elements of phrasal syntax. In our grammar were modeled constituents as IP and CP, elements that are head the sentences of the Portuguese. Also were modeled certain aspects of verbal subcategorization and argument structure. In terms of verbal elements, our grammar includes some cases of verbal complex made up of modal verbs and control verbs. The nominal elements treated in grammar, centrally, were the expletives and reflexive pronouns, and cases of nominal and determiners phrases with demonstrative pronouns and interrogative. The other aspects modeled in the grammar are PPs, whose complexity is given the distinction between semantic and nonstandard prepositions; the adjectival phrases, whose projection in the sentence can occur from attributive adjectival forms of ordinal or cardinal forms and as intensifiers; and adverbial phrases, whose internal structure was modeled taking into account both adverbs as intransitive and as transitive, with PP complement. Our evaluation shows that of the 40 tested sentences, our grammar assigns, for all of them, consistent and well-founded analysis, while the parser Palavras, the current state of the art in deep syntactic processing of Portuguese, assigns incorrect analysis for 9 sentences. Another evaluation shows that, of the 20 ungrammatical sentences tested both in our grammar, as in Palavras, only 2 received analysis by our grammar, while the Palavras provides analysis to 19 sentences. The work has essentially the goal of making a formal and grounded description in a broad range of phenomena in Brazilian Portuguese, but mainly aims to collaborate with a not trivial grammar of the sentence in the LFG-XLE formalism, effectively contributing to a grammatical resource turned to the natural language processing.
A presente tese descreve a elaboração de uma gramática da frase do Português Brasileiro, desenvolvida no quadro de um modelo teórico de sofisticado formalismo computacional, a Lexical Functional Grammar (LFG) e implementada no sistema que constitui o estado da arte em ambiente de processamento sintático profundo no modelo gerativo da LFG, o robusto Xerox Linguistic Environment (XLE). A principal característica da gramática é que adota o sistema de anotação do ParGram e a metodologia convencionada por desenvolvedores de gramática XLE. No fragmento de gramática estão modelados diversificados elementos da sintaxe frasal. Em nossa gramática, foram modelados constituintes oracionais como IP e CP, elementos que encabeçam as sentenças do português. Também foram modelados determinados aspectos da subcategorização verbal e da estrutura argumental. Dos elementos verbais, nossa gramática contempla alguns casos de complexos verbais constituídos de verbos modais e verbos de controle. Os elementos nominais tratados na gramática, de modo central, foram os pronomes expletivos e reflexivos, e os casos de sintagmas nominais e determinantes com pronomes demonstrativos e interrogativos. Os demais aspectos modelados na gramática são os sintagmas preposicionados, cuja complexidade se dá na distinção entre preposições semânticas e não semânticas; os sintagmas adjetivais, cuja projeção na sentença pode ocorrer a partir de formas adjetivais atributivas, de formas ordinais ou cardinais e na forma de intensificadores; e os sintagmas adverbiais, cuja estrutura interna foi modelada levando-se em consideração tanto advérbios intransitivos quanto transitivos com complemento PP. A nossa avaliação demonstra que das 40 sentenças testadas, a nossa gramática atribui, para todas elas, análises consistentes e bem fundamentadas, ao passo que o parser Palavras, o atual estado da arte em processamento sintático profundo do português, atribui, a 9 sentenças, análises incorretas. Uma outra avaliação demonstra que, das 20 sentenças agramaticais testadas tanto em nossa gramática, quanto no Palavras, somente 2 receberam análises por parte de nossa gramática, enquanto o Palavras fornece análises para 19 sentenças. O trabalho tem, essencialmente, o objetivo de fazer uma descrição formal e fundamentada de um amplo leque de fenômenos do português brasileiro, mas, sobretudo, tem o objetivo de contribuir com uma gramática não trivial da frase do português no formalismo LFG-XLE, disponibilizando efetivamente um recurso gramatical do português voltado para o processamento de linguagem natural.
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FARSSI, YAHYA. "Etude dielectrique et acoustique des verres dipolaires de k#1#-#xli#xtao#3 (klt)." Paris 6, 1995. http://www.theses.fr/1995PA066317.
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Dans les cristaux de tantalate de potassium et de lithium k#1#-#xli#xtao#3 (klt), les ions lithium se repartissent au hasard et se mettent en position hors-centre suivant l'une des six directions 100 en creant ainsi des moments dipolaires electriques et quadrupolaires elastiques aleatoires. L'interaction entre ces moments donne lieu, a basse temperature, une transition de phase vers un etat dont la nature est encore tres controversee (verre dipolaire ou ferroelectrique desordonne ?). Nous avons effectue des mesures de constantes dielectrique et elastique en fonction de la temperature et de la frequence dans des echantillons de klt de differentes concentrations. Un de nos resultats les plus marquants est la forme tres particuliere des diagrammes d'argand ou cole-cole, pour des temperatures superieures a la temperature de transition: ils ont des pentes infinies vers les hautes frequences et finies vers les basses frequences. Nous avons elabore un modele pour expliquer ces diagrammes. Nous sommes partis d'un modele de glauber utilise initialement pour les verres de spins et nous avons introduit un parametre lie au champ de reaction. Nous avons obtenu l'expression de la constante dielectrique en fonction de la distribution spectrale des interactions. La distribution choisie de type beta donne des resultats tres satisfaisants: les diagrammes d'argand sont bien reproduits. Une discussion sur la variation des differents parametres en fonction de la temperature et de la concentration est exposee. Nous esperons que ce travail contribuera a la comprehension de ces materiaux ainsi que d'autres systemes presentant des interactions aleatoires
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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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Levchenko, Kirill. "XL a communication-efficient routing algorithm /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p3320168.
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Thesis (Ph. D.)--University of California, San Diego, 2008.Title from first page of PDF file (viewed September 22, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 63-67).
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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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Yariz, Kemal Oral. "The Chronicles of X-Linked Spinal Muscular Atrophy: The Linkage, The Gene and The SMN Complex." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/115.
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Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease. SMA is associated with homozygous mutations in the Survival of Motor Neuron gene I (SMN1). SMN protein does not appear to exist in cells in isolation but associates with several proteins to form a large multi-protein complex. The functions of SMN complex include assembly, metabolism and transport of diverse classes of ribonucleoproteins. X- Linked Spinal Muscular Atrophy is a rare congenital disorder characterized by multiple joint contractures. It is associated with hypotonia, areflexia, chest deformities and congenital joint contractures. A candidate interval was defined for XL-SMA in Xp11.3-Xq11.2 in 1995. The purpose of this study was to refine the XL-SMA gene region and discover the XL-SMA gene. In addition to that, the gene product was investigated to delineate the genotype-phenotype correlation. My studies were focused on single nucleotide polymorphism (SNP) analysis. The candidate gene interval was refined by studying 14 SNPs in the three largest families. This analysis revealed a recombination event which allowed elimination of the NDP gene. Significantly positive LOD scores were obtained from these SNP studies. The exons and exon-intron boundaries of 12 genes were screened. No mutations were found in these genes in affected male samples. In late 2006, UBE1 (Ubiquitin activating enzyme 1) was discovered as the XL-SMA gene. UBE1 protein is responsible for the first step of ubiquitination of proteins in a cell. To investigate a possible common molecular mechanism between SMA and XL-SMA, proteins in the SMN Complex in XL-SMA patient cell lines were studied. SMN and Gemin3 protein levels were found to be consistently lower in XL-SMA patient cell lines (lymphoblasts) compared to healthy cell line. These results imply that there may be a common disease mechanism. To understand if the SMN and Gemin3 RNA levels decrease. RNA expression studies were performed. These studies confirmed that there is no difference of RNA expression of SMN and Gemin3 in XL-SMA cell lines when compared to healthy cell lines. As for UBE1, the same experimental procedure for SMN Complex proteins were repeated with antibodies to UBE1 to determine if there is any decline of UBE1 protein levels in XL-SMA patient cell lines compared to a healthy cell line. There was a decline in protein levels of UBE1 in XL-SMA patients. Two possible models are proposed for a molecular mechanism in XL-SMA: 1) UBE1 involves in degradation of a protein which downregulates SMN Complex (or a protein which stabilizes SMN Complex). When UBE1 is mutated, the protein in question is not degraded and this results in excess downregulation of SMN Complex (maybe via a pathway involving SMN-Gemin3 interaction). 2) UBE1 and UBA6 interact with the proteins of SMN Complex as they monoubiquinate them for different cellular processes. When UBE1 is mutated, UBA6 cannot compensate the deficiency of UBE1, which in turn disrupts normal cellular RNA metabolism required for motor neuron development and survival.
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AL, MOHAINI MOHAMMED. "Development of Natural Cyclic Peptide Inhibitors of XRCC4/XLF Interaction for Radio-Sensitization of Breast Tumor Cells." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/384.
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Breast cancer is the second leading cause of cancer death in women according to the American Cancer Society. The standard treatment regimen for breast cancer involves ionizing radiation combined with surgery and chemotherapy. Ionizing radiation induces a complex signaling response in cells resulting in either growth arrest, senescence or cell death, and the cell killing after exposure to radiation results largely from DNA double-strand breaks (DSBs). There are two main mechanisms in mammalian cells responsible for repairing the DSBs; the primary mechanism is non-homologous end joining (NHEJ) and the secondary mechanism is homologous recombination (HRR). Previous studies showed that breast tumor cells depend mainly on NHEJ for repairing induced DNA damage. XRCC4 and XLF are two essential proteins in the NHEJ process. The interaction between XRCC4 and XLF (also called Cernunnos) is responsible for stimulating ligase IV for rejoining DNA ends. A single mutation on the XLF-binding interface of XRCC4 at M61, F106, M59 or D58 has been shown to disrupt its interaction with XLF and thus inhibiting NHEJ. Therefore, it is proposed that small natural cyclic peptides that bind to the XLF interface of XRCC4 near M61 and F106 can be identified through an mRNA display in vitro selection, and these peptides will inhibit NHEJ and thereby radiosensitize breast tumor cells. We have synthesized five DNA libraries that produced mRNA-peptide fusions containing a trillion unique peptide sequences that will be used for the selection of peptide inhibitors of the XRCC4/XLF interaction, and we have verified their randomness. Tagged wild-type and mutant versions of the head domain of XRCC4 protein, containing the XLF binding site, were successfully purified, and the wild-type version was applied to initial stages of selection of inhibitory peptides by mRNA display. The percentage of the mRNA-peptide fusions that bound to the XRCC4157 after the first round was 2.1%. The recovery after the second and third rounds was 1.14% and 2%, respectively. Results obtained thus far, although preliminary, suggest that the mRNA display method can be successfully applied to the XLF/XRCC4 interaction.
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Zhao, Rui. "Bcl-xL deamidation in oncogenic tyrosine kinase signalling." Thesis, Anglia Ruskin University, 2011. http://arro.anglia.ac.uk/213610/.
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I have been interested in the molecular mechanisms of Haematopoietic malignant diseases such as leukaemia and lymphoma, especially those involving oncogenic tyrosine kinases. About 30 of the 90 tyrosine kinases in the human genome have been implicated in cancer (Blume-Jensen P, 2001). The oncogenic tyrosine kinases (OTKs), such as Bcr-Abl (product of chromosomal translocations of two genes bcr and abl) in Chronic Myelogenous Leukaemia, and Erythroblastic leukaemia viral oncogene homolog 2(Erb-B2) in mammary and other cancers, mediate their transforming effects via a diverse array of signalling pathways involved in DNA damage, cell survival and cell cycle regulation (Deutsch E, 2001; Skorski T, 2002; Kumar R, 1996). My work has been centred around the analysis of a mouse cancer model that is driven by an oncogenic tyrosine kinase – p56 Lck-F505 expressed on CD45 knock- out background (Baker M, 2000). The investigation of this mouse model has revealed that oncogenic inhibition of deamidation of the Bcl-xL survival protein plays a critical role in protecting thymocytes from DNA-damage induced apoptosis. Cells that would normally be eliminated due to accumulating DNA damage are instead preserved with an increasing load of double-stranded breaks, leading to genomic instability, chromosomal abnormalities and transformation. This work was published in Cancer Cell (An oncogenic tyrosine kinase inhibits DNA repair and DNA-damage-induced BclxL deamidation in T cell transformation. Zhao R, 2004). Following that I have tried to elucidate the different roles of the two deamidated species of Bcl-xL in apoptosis, and also the molecular mechanisms of DNA damage- induced Bcl-xL deamidation in order to understand the inhibition of Bcl-xL deamidation by oncogenic tyrosine kinases. Recently I have shown that Bcl-xL deamidation, whereby two critical Asn residues are converted to iso-Asp, cripples the ability of the protein to sequester pro-apoptotic BH3-only proteins such as Bim and p53- upregulated modulator of apoptosis (PUMA), thereby explaining its loss of pro-survival functionality. In vivo, DNA damage causes intracellular alkalinisation that is both necessary and sufficient to deamidate Bcl-xL, promoting apoptosis: no enzyme is necessary for this process. In pre-tumourigenic thymocytes alkalinisation is blocked, so preserving Bcl-xL in its pro-survival mode. Furthermore murine tumours are protected from genotoxic attack by native Bcl-xL, but enforced alkalinisation and consequent Bcl-xL deamidation promotes apoptosis. This part of work was published in Plos Biology (DNA damage-induced Bcl-xL deamidation is mediated by NHE-1 antiport regulated intracellular pH. Zhao R, 2007). Through collaboration with Prof AR Green’s research group at the Department of Haematology of the University of Cambridge, I have also analysed the Bcl-xL deamidation pathway in human myeloproliferative disorders, e.g. Polycythemia vera(PV) and Chronic Myelogenous Leukaemia (CML). We found that the oncogenic tyrosine kinases involved in these disorders, i.e. Jak2V617F and Bcr-Abl also inhibit the Bcl-xL deamidation pathway in DNA damage responses. These findings shed light on potential therapeutic application of the Bcl-xL deamidation pathway in human malignancies. This piece of work was recently published in the New England Journal of Medicine (Inhibition of the Bcl-xL deamidation pathway in myeloproliferative disorders. Zhao R, 2008). Overall the cited work has led to several important new insights into the molecular mechanisms involved in oncogenesis: first, that Bcl-xL deamidation is important in the cascade of events leading from DNA damage to apoptosis; second, that oncogenic tyrosine kinases inhibit these events in both the murine and human context; third, that up-regulation of the NHE-1 antiport and consequent intracellular alkalinisation are critical events in this DNA damage-induced cascade leading to apoptosis. In the process I have demonstrated the first in vivo mechanism for the deamidation of an internal protein Asn. Essentially, a completely new and unexpected signalling pathway has been uncovered that seems to pertain to all murine and human haematopoietic cell lineages that have been investigated so far.
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Chalasani, Sri Lakshmi. "RESOLUTION OF PROXIMAL OXIDATIVE BASE DAMAGE AND 3′-PHOSPHATE TERMINI FOR NONHOMOLOGOUS END JOINING OF FREE RADICAL-MEDIATED DNA DOUBLE-STRAND BREAKS." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5237.
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Clustered damage to DNA is a signature mark of radiation-induced damage, which involves damage to the nucleobases and/or DNA backbone. Double-strand breaks created by damaging agents are detrimental to cell survival leading to chromosomal translocations. Normal cells employ Non-homologous end-joining because of its faster kinetics, to suppress chromosomal translocations. However, the presence of complex DNA ends constitutes a significant challenge to NHEJ. Location of Thymine glycol (Tg) at DSB ends was a potential hindrance to end joining. The substrate with Tg at the third position (Tg3) from the DSB joined better than when present at the fifth position (Tg5). However, hNTH1 assay showed Tg5 to be a better substrate than Tg3 for BER, potentially explaining the increased Tg removal and decreased end joining of Tg5 in extracts. Nonetheless, there appeared to be no preference in the susceptibility of 5’-Tg substrates with Tg at the second and third positions from DSB ends.
Polynucleotide kinase phosphatase is crucial in restoring the 3′ hydroxyl, and 5′ phosphate ends at strand breaks. No other enzyme is known to possess PNKP’s activity in mammalian cells at DSBs. Experiments done with PNKP knockout cells have shown some activity similar to PNKP, which appeared to be a part of NHEJ and was not pharmacologically inhibited by PNKP inhibitor. Additionally, core NHEJ factors XRCC4 and XLF influenced the activities of PNKP.
Overall, these experiments suggest that Tg repair is dependent on the position from DSB and an alternative enzyme processes 3′- PO, and 5′-OH ends.
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Coffey, Alison Jane. "Physical mapping on the human X chromosome and its application to the positional cloning of the XLP gene." Thesis, King's College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327181.
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Ramalho, Vanessa Domingues 1985. "Mutações no gene da tirosina quinase de Bruton (Btk) de pacientes brasileiros com agamaglobulinemia ligada ao X (XLA)." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311072.
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Orientador: Maria Marluce dos Santos VilelaDissertação (mestrado) - Universidade Estadual de Campinas. Faculdade de Ciencias Medicas
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Resumo: A agamaglobulinemia ligada ao X (XLA; OMIM#300755) é uma imunodeficiência primária humoral caracterizada por um bloqueio na diferenciação dos linfócitos B na medula óssea, levando à profunda hipogamaglobulinemia e reduzido número ou ausência de células B periféricas. Os pacientes com XLA são susceptíveis a infecções recorrentes por bactérias encapsuladas e enterovírus devido à deficiência de anticorpos. Mutações no gene codificante da tirosina quinase de Bruton (Btk) são responsáveis pela doença. Btk é uma tirosina quinase citoplasmática da família Tec importante no desenvolvimento, na diferenciação e na sinalização dos linfócitos B. A detecção de mutações no gene btk possibilita o diagnóstico definitivo de XLA. O objetivo deste estudo foi identificar e caracterizar mutações em btk. Foram incluídos 6 pacientes conforme os critérios do PAGID e ESID: indivíduos do sexo masculino com menos de 2% de linfócitos B periféricos, hipogamaglobulinemia e história de infecções bacterianas de repetição. A triagem de mutações foi realizada com a técnica de SSCP e possíveis mutações foram confirmadas por seqüenciamento. A expressão de Btk nos pacientes e mães foi avaliada em monócitos por citometria de fluxo. Dentre os pacientes analisados as principais manifestações clínicas foram as infecções do trato respiratório. Todos tiveram início dos sintomas durante o primeiro ano de vida, linfócitos B periféricos abaixo de 2% e hipogamaglobulinemia anterior ao início da terapia de reposição de imunoglobulinas. Foram identificadas cinco mutações em btk, três novas (p.Ala347fsX55, p.I355T e p.Thr324fsX24) e duas já descritas na literatura (p.Q196X e p.E441X). A detecção das mutações nos pacientes permitiu a análise mutacional de mães, avós e tias maternas. Três mães e uma avó foram confirmadas portadoras de XLA. Em adição, os valores de expressão de Btk obtidos mostraram deficiência da proteína (4,5% a 65,2%) nos pacientes e um padrão bimodal de expressão de Btk foi observado nas mães, indicando o estado de portadora de XLA. Em um dos pacientes não foi identificada mutação, entretanto a expressão de Btk mostrou-se reduzida. O uso combinado da análise genética e da avaliação da expressão de Btk por citometria de fluxo possibilitou o diagnóstico definitivo de XLA e a identificação de portadoras da doença.
Abstract: X-linked agammaglobulinemia (XLA; OMIM# 300755) is a primary humoral immunodeficiency characterized by a block in early B cell differentiation, leading to profound hypogammaglobulinemia and few or no circulating B cells. Patients with XLA are susceptible to recurrent infections by encapsulated bacteria and enteroviruses due to antibody deficiency. Mutations in the Bruton tyrosine kinase (Btk) gene have been identified as responsible for XLA. Btk is a cytoplasmic tyrosine kinase of the Tec family important in B-lymphocyte development, differentiation, and signaling. Detection of a btk mutation allows definitive diagnosis of XLA. The aim of this study was to identify and characterize mutations in btk. Six patients were included according to the criteria of PAGID and ESID: males with less than 2% of circulating B cells, hypogammaglobulinemia and a history of recurrent bacterial infections. Mutation screening was performed with SSCP technique and possible mutations were confirmed by sequencing. Expression of Btk protein in patients and mothers was assessed in monocytes by flow cytometry. The major clinical manifestations among patients were respiratory tract infections. All had onset of symptoms during the first year of life, circulating B cells below 2% and hypogammaglobulinemia before the start of immunoglobulin replacement therapy. We identified five mutations in btk, three novel (p.Ala347fsX55, p.I355T and p.Thr324fsX24) and two recurrent mutations (p.Q196X and p.E441X). The btk mutations detection in patients enabled the screening of mothers, grandmothers and maternal aunts. Three mothers and one grandmother were confirmed XLA carriers. In addition, flow cytometric evaluation of Btk expression in monocytes revealed that Btk deficiency (4,5% a 65,2%) was present in patients and a bimodal pattern of Btk expression was observed in mothers, indicating that they were XLA carriers. In one patient no mutation was identified, but his Btk expression was reduced. The combined use of genetic analysis and flow cytometric assay of Btk protein expression allowed the definitive diagnosis of XLA and its carriers detection.
Mestrado
Saude da Criança e do Adolescente
Mestre em Saude da Criança e do Adolescente
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Lamartine, Jérôme. "Cartographie physique de la région du syndrome lymphoprolifératif lié au chromosome X (XLP) et recherche de gènes candidats." Lyon 1, 1996. http://www.theses.fr/1996LYO1T213.
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Manupipatpong, Worapong. "XS architecture versus XL furniture : the scale in-between." Thesis, Konstfack, Inredningsarkitektur & Möbeldesign, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:konstfack:diva-2732.
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The manipulation of space, materials and issues about shape, color, texture and gravity are common to architecture and furniture. For my degree project, I examine the three-dimensional territories of architecture and furniture. I investigate how the notion of architecture can influence furniture design, or the other way around. Many times, architects cross the boundary from building to furniture design to try and challenge themselves with different scale as same as designer. With my project, I don’t want to cross the border between them, but rather seek the space in-between the two territories, where design and architecture are blended. I’m intrigued by particular spaces and things when they can’t be classified exactly; something in-between. It leaves me with curiosity, inspiration and space for imagination. My project can be seen as something in-between because it is hard to define. Whether it is extra small architecture or an extra large piece of furniture, it is somewhere in-between these aspects of scale and function.Master / InSpace 2009
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Oliver, Vila Irene. "Paper del receptor CD84 en l' activació mastocitària." Doctoral thesis, Universitat de Barcelona, 2009. http://hdl.handle.net/10803/924.
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TESI:L'objecte d'estudi d'aquesta tesi és el receptor CD84, que pertany a la Família del CD150, alhora englobada dins la superfamília de les immunoglobulines. La família del CD150 està composta per nou receptors que comparteixen una elevada homologia estructural, i que poden presentar interacció homotípica o heterotípica. Sis dels membres d'aquesta família presenten a la seva cua citoplasmàtica almenys un motiu d'unió a les proteïnes adaptadores SAP i EAT-2. La deficiència del gen que codifica per la proteïna SAP (SH2D1A), és la causant de l'aparició d'una immunodeficiència lligada al cromosoma X, la Síndrome XLP, corresponent a un desordre de baixa incidència, que es caracteritza per una elevada susceptibilitat al virus del Epstein-Barr. El CD84 es troba àmpliament expressat a la superfície dels leucòcits i és l'únic membre de la família que es troba expressat a nivells elevats en mastòcits en estat basal. Els mastòcits són les principals cèl·lules efectores de les reaccions al·lèrgiques, tot i que es troben implicats en molts altres processos, inclosos la immunitat innata i l'autoimmunitat. La via clàssica d'activació dels mastòcits s'inicia amb la unió de la IgE al receptor d'alta afinitat per la IgE (FcepsilonRI) i dóna lloc a l'alliberació d'histamina i molts altres mediadors. Les respostes mastocitàries requereixen una regulació molt precisa que està mitjançada per un ampli ventall de factors i molècules. L'objectiu d'estudi d'aquesta tesi ha estat determinar la funció del receptor CD84 en l'activació mastocitària, donada l'elevada expressió d'aquest immunoreceptor en mastòcits, i les implicacions d'aquest tipus cel·lular en la regulació de les respostes del sistema immunitari.
Mitjançant estudis de sobre-expressió del receptor CD84 en una línia mastocitària de rata, RBL-2H3, vam caracteritzar el CD84 com un nou receptor inhibidor de la cascada de senyalització iniciada pel receptor d'alta afinitat per la IgE. Vam demostrar que el receptor CD84 inhibeix tant esdeveniments primerencs (com la senyalització de calci, la reorganització del citoesquelet, la desgranulació i la fosforilació de MAPKs), com esdeveniments tardans (síntesi de citocines), mitjançant la interacció homotípica, on el receptor actua com el seu propi lligand. Mitjançant la generació de mutants puntuals per a les quatre tirosines que el receptor CD84 presenta a la seva cua citoplasmàtica, vam disseccionar la implicació de cadascuna d'elles en el mecanisme inhibitori del CD84, i vam comprovar que les tirosines responsables de la inhibició del CD84 són les que es troben a les posicions 279 i 324. Per altra banda, les tirosines 262 i 299, que es troben englobades en motius d'unió a les proteïnes adaptadores SAP i EAT-2, no participen en el mecanisme inhibitori del CD84, determinant que la funció negativa del receptor és independent de SAP. Mitjançant estudis bioquímics, vam determinar que les molècules adaptadores c-CBL i DOK-1 participen en el mecanisme inhibitori del CD84. Vam fer també estudis de transfecció en cèl·lules COS, amb la finalitat d'establir les cinases implicades en la fosforilació del receptor CD84 i vam determinar LYN i FPS/FES com les cinases principals en la fosforilació de les tirosines 279 i 324, respectivament. Finalment, vam utilitzar una línia mastocitària humana, LAD-2, que ens ha permès corroborar els efectes observats amb la línia RBL-2H3 en un sistema fisiològicament més proper a l'humà. Vam comprovar que l'efecte inhibitori del CD84, es manté en els esdeveniments primerencs estudiats en LAD-2, i vam confirmar també, en aquesta línia cel·lular, la implicació de DOK-1 en la senyalització negativa del CD84. Les dades obtingudes en aquesta tesi perfilen el receptor CD84 com un molècula important en la funció dels mastòcits i una possible diana terapèutica en al·lèrgies inflamatòries.
CD84 belongs to the CD150 family of receptors. This family is a subset of the CD2 cell-surface receptor Ig superfamily and it is defined by its binding to the cytoplasmic adaptors SAP and EAT-2. SAP/SH2D1A is the product of the gene mutation in X-linked lymphoproliferative disease (XLP), a rare immune disorder commonly triggered by Epstein-Barr virus. CD84 is a homophilic adhesion molecule expressed in a broad range of leukocytes. The CD84 is the only member of the CD150 family expressed in resting mast cells. Mast cells are currently recognized as effector cells in many settings other than mere allergic reactions, including innate immunity and autoimmunity. The classic and most studied activation pathway of these cells starts with the binding of IgE to the high-affinity Fc receptor for IgE (FcepsilonRI); and the release of histamine and other mediators after crosslinking of surface-bound IgE by allergen. Appropriate activation and fine tuning of mast cell responses is mediated by a complex array of factors and molecules. The aim of this work was to determine the function of CD84 in mast cells.
The CD84 receptor was transfected and overexpressed in the rat mast cell line RBL-2H3. We found that this receptor has an inhibitory effect in early events (degranulation, cytoskeleton arrangement, calcium influx, MAPKs phosphorylation and PI3K phosphorylation) and late events (cytokines synthesis). Generation of mutants for each of the four tyrosines present in the cytoplasmic tail of the CD84, demonstrates that this inhibitory effect is related with Y279 and Y324. Interestingly, Y262 and Y299, which are part of a consensus motif for SAP or EAT-2 binding, do not participate in CD84-mediated inhibition. Thus, we postulate that the inhibitory effect of the CD84 is not mediated by SAP or EAT-2 in mast cells. We performed transfection studies with COS cells and we determined that LYN and FPS/FES kinases are the main kinases in Y279 and Y324 phosphorylation, respectively. Finally we used a human mast cell line, LAD-2, to corroborate the effects observed in RBL-2H3. We found that CD84 receptor has also an inhibitory effect in IgE-dependent early events in LAD-2, whereas no inhibitory effect was seen using non-immunological stimuli. These data suggest that CD84 may play a role in modulating FcepsilonRI-mediated signaling in mast cells and it could have a protective role against undesired allergic and inflammatory responses.
25
Beaumatin, Florian. "Étude des fonctions de survie de l'oncogène Bcl xL : rôles de la déamidation de Bcl xL et de l'interaction avec la protéine Rab7." Thesis, Bordeaux 2, 2012. http://www.theses.fr/2012BOR22012/document.
Full textAbstract:
La protéine Bcl xL, membre de la famille de Bcl 2, est essentiellement décrite pour son rôle dans l'inhibition de la mort des cellules. Récemment, un nouveau rôle lui a été attribué dans la régulation de la macro-autophagie, processus principalement décrit pour promouvoir la survie des cellules. Bcl xL exerce donc ses fonctions de survie à travers la régulation d'au moins deux processus différents.Si les fonctions anti-apoptotiques de Bcl xL ne sont plus à démontrer, ses fonctions dans la régulation de l'autophagie sont davantage débattues. Ainsi, nous avons centré ce travail sur la caractérisation des fonctions pro-autophagiques de Bcl xL afin de mieux comprendre ses fonctions de survie. Nos résultats suggèrent que Bcl xL subit in vivo et dans des cellules en culture une modification de type déamidation. Nous montrons que cette modification renforce les fonctions pro-autophagiques de Bcl xL sans affecter ses fonctions anti-apoptotiques. Par ailleurs, nous nous sommes intéressés à l'interaction entre Bcl xL et la petite GTPase Rab7, une protéine essentielle au processus autophagique et endocytique. Nous avons généré, et analysé d'un point de vue fonctionnel, des mutants de Bcl xL de type perte ou gain d'interaction avec Rab7. Notre principale conclusion est que Bcl xL stimule le trafic des vésicules médié par Rab7, et nous proposons que les fonctions pro-autophagiques de Bcl xL sont majoritairement dépendantes de son interaction avec Rab7. Cette étude contribue ainsi à mieux définir les fonctions pro-autophagiques de Bcl xL ainsi que les processus qui les régulent. Par ailleurs, elle approfondit nos connaissances des fonctions oncogéniques de Bcl xL en intégrant la composante supplémentaire de ses fonctions pro-autophagiques, et ouvre ainsi des perspectives pour l'élaboration de nouvelles stratégies thérapeutiques anti-cancéreuses notammentBcl xL, a member of the Bcl-2 family, is mainly described for its role in the inhibition of cell death. Recently, Bcl xL was attributed a new role in the regulation of macro-autophagy, a process described mainly for its contribution to cell survival. Hence, Bcl xL wields its survival functions through the regulation of at least two different processes. If the anti-apoptotic functions of Bcl xL are now well established, its role in the regulation of autophagy is more debated. Therefore we focused this work on the characterization of Bcl xL pro-autophagic functions in order to get a better understanding of its survival functions. Our results suggest that Bcl xL undergoes in vivo and in cultured cells a modification called deamidation. We show that this modification enhances its pro-autophagic functions without affecting its anti-apoptotic functions. In addition, we characterized an interaction between Bcl xL and the small GTPase Rab7 which is essential for autophagy and endocytosis. We generated mutants of Bcl xL either gaining or loosing interaction with Rab7. The functional analysis of these mutants suggested that Bcl xL stimulates the vesicle trafficking mediated by Rab7, and prompts us to hypothesize that Bcl xL pro-autophagic functions are mainly dependent on its interaction with Rab7. This study helps to better define the pro-autophagic functions of Bcl xL and the processes regulating them. It provides further insights in the oncogenic functions of Bcl xL by implementing additional component of its pro-autophagic functions, and opens perspectives for the development of new therapeutic strategies against cancer progression
26
Proust, Richard. "Régulation des voies de signalisation des lymphocytes T par la protéine SAP et ses partenaires." Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00914177.
Full textAbstract:
Une réponse immunitaire adéquate nécessite la participation coordonnée de plusieurs populations de cellules immunitaires, comme les lymphocytes T et B, les macrophages, les cellules dendritiques ou les cellules NK. L'activation de ces types cellulaires est modulée par différents récepteurs membranaires dont la fonction est de déclencher une cascade de signalisation.L'activation des lymphocytes T, acteurs cruciaux de la mise en place de la réponse immunitaire adaptative, s'initie par l'engagement du récepteur T (TCR). Plusieurs autres types de récepteurs participent à la modulation des réponses cellulaires. Ainsi, les récepteurs aux facteurs de croissance, aux cytokines et aux chimiokines ainsi que les molécules d'adhésion et les récepteurs de la famille SLAM (pour Signaling Lymphocyte Activation Molecule) influencent l'activation cellulaire. Des travaux récents ont montré que l'activation des récepteurs SLAM induit leur association avec les membres de la famille SAP et est nécessaire à l'induction d'une réponse humorale, au développement des cellules NKT ainsi qu'à la cytotoxicité médiée par les lymphocytes T CD8 et les cellules NK. L'altération du gène sh2d1a codant pour SAP conduit à l'apparition du syndrome lymphoprolifératif lié à l'X-1 (XLP-1). Les patients atteints de ce syndrome développent trois principaux phénotypes cliniques qui sont une mononucléose infectieuse fulminante, une dysgammaglobulinémie, et des désordres lymphoprolifératifs.L'objectif de mon travail de thèse a été d'étudier les étapes précoces d'activation des lymphocytes T et de comprendre comment la protéine SAP, associée à d'autres protéines ou domaines protéiques intracellulaires, est impliquée dans la régulation de ces mécanismes d'activation. Mon travail s'est donc orienté vers l'identification de nouveaux partenaires de SAP, autres que les récepteurs SLAM, et qui nous permettraient de mieux définir la fonction de SAP dans la signalisation T. Par une approche de biochimie, mon travail a permis de démontrer que SAP s'associe directement à la chaîne CD3 du complexe TCR-CD3, régule la signalisation induite par l'activation du récepteur T et permet la sécrétion de cytokines. Enfin, par une approche de double hybride, nous avons identifié Pecam-1 comme nouveau partenaire de SAP. Nous avons par la suite observé que l'association de SAP avec Pecam-1 régule l'adhérence des lymphocytes T. Par ces deux études, mon travail de thèse a permis de démontrer l'implication de SAP dans de nouvelles voies de signalisation et permet de mieux comprendre les mécanismes dérégulés lors de l'absence de SAP.
27
Al-Emam, Ahmed Mohamed Ahmed. "Genetic analyses of XLF and KU and their functional impacts on DNA-double strand break repair in human cells." Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/3110/.
Full textAbstract:
XRCC4-like factor (XLF) is the most recently discovered core member of the nonhomologous end joining (NHEJ) machinery. XLF enhances ligation of DNA ends by DNA ligase IV (LIG4) and functionally interacts with KU70. Previous results showed that some polymorphic changes in LIG4 impact on the efficiency of double strand breaks (DSBs) repair. A random Caucasian population sample was screened for XLF polymorphic mutations with similar functional impact. This analysis identified two novel noncoding single nucleotide polymorphisms (SNPs). To address the regulation of XLF and KU70, the acetylation status of both proteins were analysed. It has been found that XLF undergoes acetylation both in vitro and in vivo and the acetylation sites were mapped in vitro by mass spectrometry. Preliminary analysis has indicated that XLF deacetylation might be histone-deacetylase (HDAC3) dependent. For KU70, it has been found that lysine residues K317, K331 and K338 are critical for NHEJ. Cells overexpressing aceto-mimicking or aceto-blocking mutants of these residues are radiosensitive and defective in DSBs repair (DSBR). This indicates that the dynamic regulation of the acetylation/deacetylation status of these residues is critical for DSBR in response to ionizing radiation. These findings establish the importance of non-histone repair protein acetylation in the regulation of NHEJ and define new possible therapeutic targets for cancer treatment.
28
Gérart, Stéphane. "Identification d’un nouveau mécanisme de contrôle de l’homéostasie des lymphocytes T iNKT et MAIT." Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05TO22/document.
Full textAbstract:
Les cellules Invariant Natural Killer T (iNKT) représentent une sous-population particulière de cellules T qui se distingue par son développement, ses fonctions et les ligands qu’elle reconnaît. Chez l’homme, les cellules iNKT expriment le réarrangement Vα24-Jα18/Vβ11 et reconnaissent des glycosphingolipides présentés par la molécule monomorphe du CMH de classe I CD1d. De plus, elles produisent rapidement de grandes quantités de cytokines, et sont ainsi considérées comme des cellules T ayant des caractéristiques innées. Les mécanismes moléculaires qui régulent l’homéostasie descellules iNKT ne sont pas complètement compris. La protéine XIAP (X-linked Inhibitor of Apoptosis) est un inhibiteur physiologique des caspases 3, 7 et 9. Des mutations du gène XIAP sont à l’origine du syndrome lymphoprolifératif lié à l’X de type 2 (XLP-2), un déficit immunitaire primitif (DIP) caractérisé par une susceptibilité accrue à l’infection par le virus Epstein Barr (EBV). Les patients souffrant du XLP-2 présentent une forte réduction de leur nombre de cellules iNKT dans le sang. Au cours de mon travail de thèse, j’ai montré que XIAP est requis pour la survie des cellules iNKT humaines. Cette fonction de XIAP corrèle avec un phénotype pro-apoptotique des cellules iNKT qui n’est pas retrouvé dans les cellules T conventionnelles. La susceptibilité accrue à l’apoptose des cellules iNKT est observée en utilisant des stimuli de la voie intrinsèque ou extrinsèque de l’apoptose. Les cellules iNKT, contrairement aux cellules T conventionnelles expriment des quantités élevées de protéines pro-apoptotiques comme les caspases 3 ou 7 ou Bid. Ce phénotype proapoptotique est acquis de manière précoce, puisqu’il est déjà présent dans des cellules iNKT de thymus ou de sang de cordon. L’extinction de XIAP dans des cellules iNKT et l’analyse de patients déficients en XIAP indiquent que XIAP est un inhibiteur efficace de l’apoptose dans les cellules iNKT alors qu’il n’a qu’un effet modéré dans les cellules T conventionnelles. J’ai ensuite montré que le phénotype pro-apoptotique des cellules iNKT est dépendant de l’expression du facteur de transcription PLZF. Celui-ci est déjà connu comme étant nécessaire à l’acquisition des fonctions effectrices de cescellules. De manière concordante, la surexpression de PLZF dans des cellules T conventionnelles conduit à un phénotype pro-apoptotique et à une augmentation de l’expression de la caspase 3. Récemment, une deuxième population de cellules T invariantes, les cellules MAIT (Mucosal Associated Invariant T) a été décrite. Ces cellules expriment un TCR semi-invariant Vα7.2-Jα33 et partagent avec les cellules iNKT certaines caractéristiques qui en font des cellules T innées comme les cellules iNKT. De la même manière que les cellules iNKT, les cellules MAIT ont un phénotype proapoptotiqueet sont diminuées dans le sang des patients déficients en XIAP. Ce phénotype proapoptotique est aussi dépendant de PLZF. De manière intéressante, un patient déficient en XIAP et ayant un nombre normal de cellules iNKT a été identifié. Ce patient n’a pas encore rencontré l’EBV, suggérant que la diminution des cellules iNKT chez les patients déficients en XIAP est due à une apoptose augmentée dans un contexte d’infection par l’EBV. Enfin, j’ai obtenu des données préliminaires suggérant que l’EBV utilise un mécanisme d’échappement aux cellules iNKT en diminuant l’expression de CD1d à la surface des cellules B. Mon travail de thèse a donc permis d’identifier une voie de régulation inconnue des lymphocytes T innés qui dépend de XIAP et de PLZF. PLZF est donc un facteur clé pour la différentiation et l’homéostasie des cellules T innées en régulant l’acquisition de leurs fonctions effectrices et en limitant leur survie. Ces observations ont aussi permis d’identifier le premier DIP associé à un déficit en cellules MAIT. Enfin, ces résultats suggèrent un rôle des cellules iNKT dans le contrôle de l’infection par l’EBVInvariant natural killer T (iNKT) lymphocytes represent a peculiar T cell-lineage that differs from conventional T cells by its development, function, and ligands it recognizes. In humans, iNKT cells express an invariant TCR made of the V?24-J?18/V?11 rearrangement, which recognizes glycosphingolipids presented by the MHC class I monomorphic molecule CD1d. Moreover, they rapidly produce high amounts of cytokines when stimulated and are thus considered as innate-like T cells. The molecular mechanisms that control the homeostasis of iNKT are poorly understood. XIAP (X-linked Inhibitor of Apoptosis) is a physiological inhibitor of caspases 3, 7 and 9 and is mutated in the X-linked lymphoproliferation syndrome 2 (XLP-2), a rare primary immunodeficiency (PID) characterized by a peculiar susceptibility to Epstein-Barr virus (EBV) infection. Patients with a XIAP deficiency exhibit a strong reduction of their iNKT cells in blood. Here, I report that XIAP is required for the survival of iNKT cells in humans. The requirement of XIAP correlates with a pro-apoptotic phenotype of iNKT cells that is not observed in conventional T cells. The increased susceptibility to apoptosis of iNKT cells was observed upon stimuli that trigger either extrinsic or intrinsic apoptosis pathways. iNKT cells by contrast to conventional T cells express elevated amounts of pro-apoptotic molecules including caspases 3 or 7 and Bid. The pro-apoptotic phenotype of iNKT cells is early acquired since iNKT cells from cord blood and thymus display a similar pro-apoptotic phenotype. Knock-down of XIAP in iNKT cells and analysis of XIAP-deficient humans indicate that XIAP is a potent inhibitor of apoptosis in iNKT cells while it has only a moderate effect in conventional T cells. I also show that this pro-apoptotic phenotype of iNKT cells is dependent of the expression of the transcription factor PLZF. This factor is already known to be necessary for the acquisition of the effector functions of these cells. Conversely, over expression of PLZF in conventional T cells leads to a pro-apoptotic phenotype and to an increased expression of caspase 3. Recently, a second invariant T cell subpopulation, the mucosal associated invariant T (MAIT) cells was identified both in humans and mice. These cells express a semi-invariant TCR made of V?7.2-J?33 rearrangements and share with iNKT cells a number of developmental, functional and phenotypical features that lead to consider MAIT cells as innate-like T cells like iNKT cells. Similarly, MAIT cells also exhibit a pro-apoptotic phenotype and are decreased in XIAP-deficient humans. The pro-apoptotic phenotype of MAIT cells is also dependent on PLZF. Interestingly, one XIAP-deficient patient with normal iNKT cell number was identified. This patient has not yet encountered EBV, suggesting that reduction of iNKT cells in XIAP-deficient patients is likely due to increased apoptosis in the context of EBV infection. I also show that EBV might have an escape mechanism from iNKT cells by down-regulating the expression of CD1d on the surface of B cells. My thesis works identify a previously unknown pathway controlling innate T cell homeostasis depending on XIAP and PLZF. PLZF is thus a key factor involved in the differentiation and the homeostasis of innate T cells by regulating the acquisition of their effector functions and their survival. I also identified the first PID associated with a defect in MAIT cells. Finally, these results provide evidences that iNKT cells might play a role against EBV infection
29
Ng, Florence Wai Hung. "Identification and characterization of Bcl-2Bcl-XL interacting protein p28Bap31." Thesis, McGill University, 1998. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=35027.
Full textAbstract:
Programmed cell death (apoptosis) is a fundamental process in multicellular organisms. The human proto-oncogene bcl-2 functions to suppress apoptosis and promote cell survival. It is the-most studied apoptotic regulator, yet the mechanism of action of this protein remains elusive.We have identified p28Bap31 as a Bcl-2 associating protein which also interacts with Bcl-XL. p28Bap31 is a polytopic integral membrane protein which resides primarily in the endoplasmic reticulum with an N lumen-Ccyto orientation. This orientation exposes the COOH-terminal leucine zipper overlapping with a weak death effector domain, flanked on either side by caspase cleavage sites, to the cytosol.
In the absence of Bcl-2, p28Bap31 is cleaved during apoptosis mediated by E1A generating a 20kDa product, p20Bap31. On the contrary, expression of Bcl-2 suppresses cell death and blocks the proteolytic cleavage of p28Bap31. In vitro cleavage studies suggested that p28Bap31 is a substrate for caspase-8, an initiator caspase, but not for effector caspases such as caspase-3. Although it is not known whether the cleavage of p28Bap31 contributes to the cell death program, ectopic expression of p20 can trigger apoptosis which can be rescued by co-expression of Bcl-2. To date, it is not clear how p20 induces apoptosis. However, it is possible that it does so by amplification of the caspase cascade, or by activation of a parallel pathway.
In cotransfected 293T cells, p28Bap31 associates simultaneously with both BCl-XL and procaspase-8, presumably depending on the presence of a Ced-4-like adaptor molecule. The direct interaction between p28Bap31 and C. elegans Ced-4 suggests that a mammalian Ced-4-like molecule may be a normal constituent of the p28Bap31 protein complex in the ER. It also further supports the idea that p28Bap31 plays a role in the regulation of apoptosis. Moreover, the function of this protein complex may be analogous to the Fas/TNFR1 death-inducing signaling complexes by providing an intracellular site for the recruitment of procaspase-8. The presence of Bcl-2-like proteins may act to prevent the processing and activation of the initiator caspase, thereby inhibiting downstream events culminating in cell death.
30
Durie, Danielle. "RNA Binding Protein HuR Regulates the Expression of Bcl-xL." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23206.
Full textAbstract:
The RNA-binding protein HuR controls key cellular processes by binding target
mRNAs and regulating them at
various
post-transcriptional levels. HuR
can function as
an
Internal
Ribosome
Entry
Site (IRES)
trans-acting factor
that
regulates the IRES-mediated
translation of XIAP.
Since
XIAP and Bcl-xL
expression was reported to be co-regulated, we
investigated whether
HuR
is also a
regulat
or of Bcl-xL expression. We found that HuR binds
the 3’end of the Bcl-xL 5’UTR
in-vitro. In U2OS cells, we showed that loss of HuR by
siRNA significantly increased Bcl-xL protein expression
while
Bcl-2 and Mcl-1 levels
remained unchanged. We found that
the HuR-dependent
Bcl-xL
increase was
through
translation,
shown by polysome
profiling.
Possible transcriptional, stability
and splicing
changes were eliminated.
At the physiological level HuR levels did not impact cell survival
but altered mitochondrial morphology,
partially through Bcl-xL.
Thus, HuR may be involved
in maintaining proper mitochondrial
function
by controlling Bcl-xL expression.
31
Molina, Contreras Jaime. "Modos de fallas predominantes en perfiles XL de acero estructural." Tesis, Universidad de Chile, 2014. http://www.repositorio.uchile.cl/handle/2250/129830.
Full textAbstract:
Ingeniero CivilPara determinar el modo de falla y la carga crítica asociada, se realizaron tres tipos de análisis. Bajo el criterio descrito por la norma de diseño AISC, según las fórmulas desarrolladas por Marsh (1997) en su trabajo Design of Single and Multiple Angle Columns and Beams y mediante un análisis no lineal a través del programa de elementos finitos ANSYS, en el cual se realiza un estudio estático tipo Push-Over. La metodología utilizada consistió en calcular la carga crítica y modo de falla dada por cada método de análisis. Además, con los modelos de elementos finitos se determinaron las solicitaciones sobre las placas de conexión de los arriostramientos, tanto su magnitud como la distribución sobre las caras de las placas. Para el desarrollo de la investigación se utilizó una gama de perfiles XL de dimensiones comúnmente utilizadas en la práctica y largos totales de 1.5, 2.5, 5 y 10 metros. Con los resultados obtenidos se generó una clasificación de la falla predominante en los perfiles XL y se definió que la tendencia de los perfiles a fallar por torsión se encuentra relacionada con la razón entre la esbeltez global y local menor a 5.5. Por el otro lado, los elementos que superan este valor muestran fallar por pandeo flexural. Finalmente, para los elementos que fallen por flexión, se recomienda diseñar la conexión de cada cara de la placa para la carga total obtenida. Mientras que para los elementos con falla torsional es posible utilizar la mitad de la carga para cada conexión.
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Cunha, Carlos Otoniel Pacheco da. "“Moço, intelligente e médico de competência notável”: antecedentes da trajetória política republicana de Carlos Barbosa Gonçalves (segunda metade do século XlX)." Universidade do Vale do Rio dos Sinos, 2018. http://www.repositorio.jesuita.org.br/handle/UNISINOS/7342.
Full textAbstract:
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CNPQ – Conselho Nacional de Desenvolvimento Científico e Tecnológico
O médico e político Carlos Barbosa Gonçalves experienciou uma carreira política de relevo durante a Primeira República. Neste período, ocupou os cargos de deputado estadual, vice-presidente e presidente do estado e senador. No entanto, acreditamos que o sucesso político experimentado durante o período republicano só foi possível pela ascensão do Partido Republicano Rio-grandense (PRR) ao poder – ocasionada pela Proclamação da República – e também porque Barbosa possuía os requisitos necessários para tanto. Sendo assim, o objetivo deste trabalho é investigar quais recursos (econômicos, políticos, sociais e simbólicos) Barbosa herdou e empenhou-se em adquirir para que pudesse ocupar a posição de líder político local de Jaguarão, bem como ter sucesso em outras esferas políticas durante o período republicano. Para que isso fosse possível, analisamos – através de inúmeros tipos de fontes – diferentes momentos, tanto dos Gonçalves da Silva, quanto de Barbosa. Com relação aos antecedentes familiares, investigamos as relações da família com Jaguarão e a Guerra dos Farrapos, como também a situação econômica familiar. Quando tratamos especificamente de Barbosa, o acompanhamos nos estudos realizados no Rio de Janeiro, na propaganda republicana em Jaguarão e também a atuação médica.
The doctor and politician Carlos Barbosa Gonçalves experienced a political career of relief during the First Republic. During this period, he held the positions of state deputy, state president and senator. However, we believe that the political success experienced during the republican period was only possible by the rise of the Rio-grandense Republican Party (PRR) to power – occasioned by the Proclamation of the Republic – and also because Barbosa had the necessary requirements for it. Thus, the objective of this work is to investigate which resources (economic, political, social and symbolic) Barbosa inherited and committed himself to acquire so that he could occupy the position of local political leader of Jaguarão, as well as to succeed in other political spheres during the republican period. For this to be possible, we analyzed – through many types of sources – different moments, both from Gonçalves da Silva and Barbosa. Regarding the family history, we investigated the family's relations with Jaguarão and the Farrapos War, as well as the familiar economic situation. When we deal specifically with Barbosa, we accompany him in his studies in Rio de Janeiro, in republican propaganda in Jaguarão, and also in medical practice.
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Lilja, Fredrik. "Evaluation of the Prostar XL vascular closuredevice used in EVAR procedures." Thesis, Uppsala universitet, Medicinska fakulteten, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-210469.
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Rudys, Saulius. "Plačiajuostės dielektrinės spektroskopijos metodų tobulinimas, tiriant (1-x)(Na1/2 Bi1/2)TiO3 - xLa(Mg1/2 Ti1/2)O3 ir kitas medžiagas." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2012. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2012~D_20121001_093621-49513.
Full textAbstract:
Šiame darbe nagrinėjamos galimybės patobulinti plačiajuostės dielektrinės spektroskopijos metodus naudojant skaitmeninius ir analitinius daugelio modų dielektrinės skvarbos skaičiavimo metodus, tiriami (1-x)(Na1/2 Bi1/2)TiO3 - xLa(Mg1/2 Ti1/2)O3 (NBT-LMT) keramikų grupės laidumo ypatumai. Nagrinėjama galimybė pritaikyti HFSS skaitmeninio modeliavimo programą dielektrinės spektroskopijos tikslams. Naudojant šią programinę įrangą, apskaičiuojama dielektrinė ir magnetinė skvarbos komplikuotiems mikrojuostelinės linijos ir dalinai užpildyto bangolaidžio matavimo grandinių atvejams. Pateikiami patobulinti kondensatoriaus koaksialinėje linijoje ir ribotų matmenų atviro galo koaksialinės linijos matematiniai modeliai. Šie modeliai patikrinami skaitmeniniu metodu. Naudojant daugiamodį kondensatoriaus modelį, atsižvelgus į magnetinio lauko pasiskirstymą koaksialinėje matavimo grandinėje, pasiūlomas būdas pamatuoti mažai bandinio magnetinei skvarbai, kai dielektrinė skvarba didelė (dešimtim ar šimtais kartų didesnė už magnetinę skvarbą). Atviro galo koaksialinei linijai siūloma keletas kalibravimo būdų, įrenginys bandiniui prispausti prie linijos. Bešvinė NBT-LMT keramika buvo tyrinėjama dielektrinės spektroskopijos metodais. Gauti rezultatai rodo, kad NBT-LMT keramikų grupėje elektriniam laidumui galioja Maerio-Neldelio taisyklė.One of the basic problems in measurements of the electrical properties of materials is finding relations between measured electrical values and characteristics of the material, especially when the field distribution in the device under test with a sample inside is complex. Commercial electromagnetic simulation software was used in unconventional way to calculate materials' electrical properties. Because the software is not adopted for this task, built-in optimisation option was used. In this way dielectric and magnetic properties of materials in very complex shape were calculated. The method was tested by calculation of complex dielectric permittivity of Bi1.5ZnNb1.5O7-xF2 pyrochlore ceramics as well as by calculation of both complex dielectric permittivity and complex dielectric permeability of carbon-coated capsules of Ni embedded into polyurethane matrix from experimental results. Due to the fact that using numerical methods is time consuming, a mathematical model on mode matching approach of rectangular rod in a waveguide and a new model of multimode capacitor were developed. Models were checked by numerical methods. On a high frequency, when electric field in the sample is inhomogeneous, the magnetic field in the sample is much stronger than in the transmission line. Thus, the magnetic permeability of the sample will affect scattering parameters. Based on this circumstance, the method to measure small magnetic permeability using capacitor like in coaxial line when... [to full text]
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Wu, Qian. "Structural studies of human DNA double-strand breaks repair non-homologous end joining protein complex XLF-XRCC4 : dance in a helical way." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610376.
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Renault, Thibaud. "Régulations de la protéine proapoptotique Bax : rôle des kinases Akt et GSK-3β et de la protéine antiapoptotique Bcl-xL." Thesis, Bordeaux 2, 2010. http://www.theses.fr/2010BOR21794/document.
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La protéine proapoptotique Bax joue un rôle fondamental au cours de la voie intrinsèque de l’apoptose. Elle participe au déclenchement de la mort en permettant la libération de facteurs apoptogéniques mitochondriaux vers le cytosol. Un des points-clé de la fonction de Bax est son activation, caractérisée par la transition entre une forme cytosolique, globulaire et inactive de la protéine et une conformation mitochondriale, membranaire et active. Les différentes étapes de l’activation de Bax sont relativement bien connues, toutefois un grand nombre de questions reste en suspens quant-à leur régulation.Ce travail s’est focalisé sur la régulation de l’activation de Bax par les kinases Akt et GSK-3β ainsi que par la protéine antiapoptotique Bcl-xL . Ces régulations ont été caractérisées en exprimant la protéine Bax humaine chez la levure Saccharomyces cerevisiae, un paradigme d’étude simplifié qui permet d’accéder aux composantes individuelles des mécanismes d’activation de Bax.Les données obtenues suggèrent qu’il existe deux étapes régulées indépendamment au cours de l’activation de Bax. Nous avons montré que la protéine kinase GSK-3β favorise l’adressage de Bax vers la mitochondrie mais qu’elle n’entraîne pas un changement de conformation suffisant à son activation complète et à la perméabilisation de la membrane mitochondriale externe. Des changements de conformations complémentaires de Bax sont requis pour conduire à une forme capable d’entraîner la libération des facteurs apoptogéniques mitochondriaux. La protéine kinase Akt est impliquée dans le contrôle de Bax via la phosphorylation de la sérine 184 et participe à l’inhibition de l’apoptose. Nous avons mis en évidence qu’une mutation phosphomimétique de la sérine 184 ou l’expression d’Akt, en l’absence de partenaires antiapoptotiques, stimulent un changement de conformation de Bax vers une forme active. Akt semble donc plus jouer un rôle sur la conformation de Bax qu’entraîner une inhibition directe. La présence de protéines antiapoptotiques serait ainsi requise pour l’inhibition de Bax en présence d’Akt.D’autre part, nous nous sommmes intéressés aux mécanismes d’action de la protéine antiapoptotique Bcl-xL . Nous avons déterminé que Bcl-xL pouvait favoriser l’adressage de Bax vers la membrane mitochondriale tout en exerçant un rôle antiapoptotique. Ceci suggère que Bcl-xL intervienne dans le contrôle des étapes tardives de l’activation de Bax. Ce contrôle est dépendant d’une interaction stable entre les deux protéines. Inversement, un variant de Bcl-xL n’interagissant que de façon transitoire avec Bax (Bcl-xL ∆C) entraîne l’activation de Bax. Cette observation est en faveur d’un modèle d’activation indirecte de Bax consécutive à la rupture de l’interaction avec Bcl-xL et dans lequel les protéines à BH3-seulement telles que Bad joueraient un rôle crucialProapoptotic protein Bax plays a major role during apoptosis intrinsic pathway. Bax promotes cell death by inducing the release of apoptogenic factors from mitochondria to cytosol. Bax activation is a key step of its function which involves a change from a globular, cytosolic and inactive conformation to an active mitochondrial, membrane inserted conformation. Bax activation substeps are rather well known, however their regulation remains to be characterized.This work focuses on the study of the regulation of Bax activation by kinases Akt and GSK-3β and by antiapoptotic protein Bcl-xL . Human Bax regulations have been studied by expressing the protein in yeast Saccharomyces cerevisiae which represents a simplified paradigm for the understanding of the individual components of Bax activation mecha- nisms.Our data suggest that there are two independently regulated steps during Bax activation. We showed that GSK-3β expression led to Bax addressing to mitochondria but was not sufficent to promote a complete activation and mitochondrial outer membrane premeabilization. Further conformational changes are required to promote Bax full activation and the release of mitochondrial apoptotic factors. Protein kinase Akt is involved in Bax activation control through the phosphorylation of serine 184 and contributes to apoptosis inhibition. We observed that either a phosphomimetic mutation of serine 184 or coexpression of Akt, in the absence of antiapoptotic partners, were responsible of Bax conformational change into an active form. By itself Akt did not inhibit Bax but appeared more likely to control its conformational change. Thus, implication of antiapoptotic proteins seems to be critical in a model of Bax inhibition by Akt.Furthermore, we tried to understand the molecular mechanisms of antiapoptotic protein Bcl-xL inhibition on Bax. We determined that Bcl-xL could increase Bax mitochondrial localization while leading to its inhibition suggesting that Bcl-xL controled Bax late activation steps. Bax inhibition was dependent on a stable interaction with Bcl-xL . Conversely, a variant of Bcl-xL having a transitory interaction with Bax (Bcl-xL ∆C) was able to promote Bax activation. This supports a model of Bax indirect activation following the rupture of interaction with Bcl-xL in which BH3-only proteins like Bad would play an important role
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Voigt, Gesina [Verfasser], Charlotte [Akademischer Betreuer] Niemeyer, and Christine [Akademischer Betreuer] Dierks. "Transient apoptosis inhibition by Bcl-xL overexpression during hematopoietic stem cell transplantation." Freiburg : Universität, 2015. http://d-nb.info/1119452066/34.
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Geny, Charlotte. "Recherche d'inhibiteurs naturels des protéines anti-apoptotiques Bcl-xL et Mcl-1." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA114833/document.
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Dans le but de rechercher des inhibiteurs naturels des protéines anti-Apoptotiques Bcl-XL et Mcl-1, deux essais biologiques ont été mis au point sur Bcl-XL/Bak-CF et Mcl-1/Bid-CF. Ces deux tests utilisent la polarisation de fluorescence et sont basés sur la liaison d’un peptide pro-Apoptotique marqué à la fluorescéine (Bak-CF ou Bid-CF) avec une protéine anti-Apoptotique (Bcl-XL ou Mcl-1). Au total, près de 600 extraits de pantes, provenant de diverses régions du monde, ont été criblés sur les deux protéines Bcl-XL et Mcl-1 permettant de sélectionner les extraits acétate d’éthyle des écorces de Knema hookeriana (Myristicaceae) et de Fissistigma latifolium (Annonaceae). L’analyse chimique des constituants des écorces de K. hookeriana a conduit à l’isolement de 12 lipides phénoliques dont 6 n’avaient jamais été isolés d’un organisme vivant. Seuls les acides anacardiques ont révélé de très fortes inhibitions de l’interaction Bcl-XL/Bak-CF et Mcl-1/Bid-CF dans les essais par polarisation de fluorescence. Une étude plus approfondie des interactions entre le plus actif des produits et les protéines (Bcl-XL, Mcl-1, Bak et Bid) par RMN, a montré que la modulation des interactions Bcl-XL/Bak et Mcl-1/Bid n’est pas liée à l’affinité de l’acide anacardique pour les protéines Bcl-XL et Mcl-1 mais a une forte affinité pour les peptides Bid et Bak. Le fractionnement bioguidé de l’extrait AcOEt des écorces de F. latifolium a conduit à l’isolement d’une nouvelle chalcone prénylée, la (±)-Écarlottone possédant une dual activité sur les protéines, Bcl-XL et Mcl-1. Par la suite, le fractionnement "RMN-Guidé" a mené à l’isolement de 6 analoguesIn order to search for natural inhibitors of anti-Apoptotic protein Bcl-XL and Mcl-1, two bioassays were developed on Bcl-XL/Bak-CF and Mcl-1/Bid-CF. Both assays use fluorescent polarisation, and are based on binding of a fluorescein labeled pro-Apoptotic peptide (Bak-CF or-CF Bid) with an anti-Apoptotic protein (Bcl-XL or Mcl-1). Nearly 600 extracts from various parts of the world were screened on both Bcl-XL and Mcl-1 proteins to select the ethyl acetate bark extracts of Knema hookeriana (Myristicaceae) and Fissistigma latifolium (Annonaceae). The chemical analysis of the constituents of K. hookeriana has led to the isolation of 12 phenolic lipids. 6 of them were never isolated from a living organism. Only anacardic acids showed very strong inhibition of the interaction Bcl-XL/Bak-CF and Mcl-1/Bid-CF in fluorescent polarisation assays. Further study of the interactions between the most active anacardic acid and proteins (Bcl-XL, Mcl-1, Bak and Bid) by NMR showed that the modulation of Bcl-XL/Bak and Mcl-1/Bid is not related to the affinity of the compoun to the anti-Apoptotic proteins, Bcl-XL and Mcl-1 but to its affinity for peptides, Bid and Bak. The bioguided fractionation of the AcOEt bark extract of F. latifolium led to the isolation of a novel prenylated chalcone, (±)-Écarlottone having a dual activity on protein, Bcl-XL and Mcl-1. Subsequently, fractionation "NMR-Guided" led to the isolation of 6 new analogs
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Aguilar, Velazco Melany Renata, Ramos Diana Cimith Cueva, Hurtado Andrea Samanta Espinoza, Huaraz Yasmin Areliz Pizarro, and Guando José Inocencio Quiroz. "Tienda virtual de ropa para perros de raza grande: XL DOG SHOP." Bachelor's thesis, Universidad Peruana de Ciencias Aplicadas (UPC), 2021. http://hdl.handle.net/10757/655427.
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El presente trabajo tiene finalidad sustentar el modelo de negocio enfocado en la venta de ropa para perros en las tallas 7 y 8. ¿Cómo se surgió? Los participantes de este proyecto tenemos perros de diferentes razas, lo cual identificamos por medio de nuestras conversaciones y con otras personas, que son pocas las empresas que se enfocan en este segmento. La idea inicial, fue plantear y realizar las entrevistas para determinar el problema de muchos dueños que poseen perros de raza grande al momento de comprar una prenda para su engreído en talla grande. En base a la información recopilada se encontró que el problema es: el precio elevado en las prendas de tallas grandes, la poca producción de estas prendas en tallas grandes y la falta de diseños de estos. Asimismo, se realizó el prototipo, se creó las redes sociales y se publicaron las prendas para incrementar seguidores, también se identificó a 8 posibles compradores que interactuaban en nuestras publicaciones, lo cual se les envió el prototipo para recibir un feedback del producto. Después, con los comentarios de los entrevistados se mejoró el prototipo y se lanzó a la venta en nuestras redes sociales. Las nuevas prendas fueron confeccionadas por Ana Flores, la confeccionista escogida por la calidad de sus prendas y fueron publicadas tanto en Facebook como en Instagram y en Tik Tok. Finalmente, con los resultados de las ventas se hicieron los estados financieros, los flujos de caja y las proyecciones de ventas a 3 añosThe purpose of this work is to support the business model focused on the sale of clothes for dogs in sizes 7 and 8. How did it come about? The participants of this project have dogs of different breeds, which we identify through our conversations and with other people, that few companies focus on this segment. The initial idea was to raise and conduct interviews to determine the problem of many owners who own large breed dogs when buying a garment for their cocky in large size. Based on the information collected, it was found that the problem is: the high price of large-size garments, the low production of these garments in large sizes and the lack of designs of these. Likewise, the prototype was made, social networks were created, and the garments were published to increase followers, 8 possible buyers who interacted in our publications were also identified, which were sent the prototype to receive feedback on the product. Later, with the comments of the interviewees, the prototype was improved, and it was launched for sale on our social networks. The new garments were made by Ana Flores, the garment maker chosen for the quality of her garments and were published on Facebook, Instagram and Tik Tok. Finally, with the sales results, the financial statements, the cash flows and the 3-year sales projections were made.
Trabajo de investigación
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Wilder, Elisabeth. ""Game Over" for the Climate: The Keystone XL Pipeline on TV News." PDXScholar, 2013. https://pdxscholar.library.pdx.edu/open_access_etds/1438.
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The overwhelming consensus of the world's climate scientists is that we must rapidly reduce our greenhouse emissions if we are to avoid catastrophic and irreversible climate change. Yet the proposed Keystone XL pipeline, which would carry tar sands oil that emits three to four times the carbon emissions of conventional gasoline across the U.S., is supported by a solid majority of Americans. This level of support for a project a proposal that would dramatically increase greenhouse gas emissions, pollute sensitive lands and water sources, and threaten the health and safety of communities along the way begs the question: what kind of information have Americans received about the pipeline?
Relying on theoretical perspectives developed by scholars who examine power structures, ideology, and the political economy of the mass media, I analyze 177 national network and cable news broadcasts in order to determine what kind of information leading media sources provide to the public about the Keystone XL pipeline proposal and the context in which this information is presented. Content analysis of broadcast transcripts reveals that television news stations exhibit biased coverage that encourages viewers to support pipeline construction. Furthermore, television news stations marginalize environmental and social concerns and disproportionately rely on business and government sources for information. Finally, the dominant frame employed by the news media is informed by neoliberal ideology and offers no challenge to the preferences of corporate and government elites--including the continued dominance of the fossil fuel industry. This type of coverage affords viewers a very limited basis for understanding the environmental and ultimately social threats posed by Keystone XL.
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Souihli, Asma. "Interrogation des bases de données XML probabilistes." Thesis, Paris, ENST, 2012. http://www.theses.fr/2012ENST0046/document.
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XML probabiliste est un modèle probabiliste pour les bases de données incertaines semi-structurées, avec des applications telles que l'intégration incertaine de données, l'extraction d'informations ou le contrôle probabiliste de versions. Nous explorons dans cette thèse une solution efficace pour l'évaluation des requêtes tree-pattern avec jointures sur ces documents, ou, plus précisément, pour l'approximation de la probabilité d'une requête booléenne sur un document probabiliste. L'approche repose sur, d'une part, la production de la provenance probabiliste de la requête posée, et, d'autre part, la recherche d'une stratégie optimale pour estimer la probabilité de cette provenance. Cette deuxième partie s'inspire des approches des optimiseurs de requêtes: l'exploration de différents plans d'évaluation pour différentes parties de la formule et l'estimation du coût de chaque plan, suivant un modèle de coût établi pour les algorithmes de calcul utilisés. Nous démontrons l'efficacité de cette approche sur des jeux de données utilisés dans des travaux précédents sur l'interrogation des bases de données XML probabilistes, ainsi que sur des données synthétiquesProbabilistic XML is a probabilistic model for uncertain tree-structured data, with applications to data integration, information extraction, or uncertain version control. We explore in this dissertation efficient algorithms for evaluating tree-pattern queries with joins over probabilistic XML or, more specifically, for approximating the probability of each item of a query result. The approach relies on, first, extracting the query lineage over the probabilistic XML document, and, second, looking for an optimal strategy to approximate the probability of the propositional lineage formula. ProApproX is the probabilistic query manager for probabilistic XML presented in this thesis. The system allows users to query uncertain tree-structured data in the form of probabilistic XML documents. It integrates a query engine that searches for an optimal strategy to evaluate the probability of the query lineage. ProApproX relies on a query-optimizer--like approach: exploring different evaluation plans for different parts of the formula and predicting the cost of each plan, using a cost model for the various evaluation algorithms. We demonstrate the efficiency of this approach on datasets used in a number of most popular previous probabilistic XML querying works, as well as on synthetic data. An early version of the system was demonstrated at the ACM SIGMOD 2011 conference. First steps towards the new query solution were discussed in an EDBT/ICDT PhD Workshop paper (2011). A fully redesigned version that implements the techniques and studies shared in the present thesis, is published as a demonstration at CIKM 2012. Our contributions are also part of an IEEE ICDE
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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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Rivière, Étienne. "Implication de la protéine Bcl-xL dans la mégacaryopoïèse humaine normale et dans le purpura thrombopénique immunologique chronique." Thesis, Bordeaux, 2015. http://www.theses.fr/2015BORD0148/document.
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La protéine Bcl-xL fait partie de la famille des protéines anti-apoptotiques Bcl-2. Il a été montré que cette protéine avait un rôle majeur dans la formation des plaquettes chez la souris (mégacaryopoïèse). Une dérégulation de cette protéine pourrait aboutir à une altération de la mégacaryopoïèse et donner des pathologies humaines comme des thrombopénies chroniques. Une des causes de thrombopénies chroniques est le purpura thrombopénique immunologique (ou PTI), qui associe deux mécanismes physiopathologiques : une destruction auto-immune des plaquettes et une insuffisance de leur production par la moelle osseuse. Le PTI est un diagnostic d’exclusion par élimination de toutes les causes connues de thrombopénie. Au sein de notre cohorte de patients suivis en médecine interne pour cette maladie, nous avons identifié certains patients qui présentaient un profil non-immunologique, c’est-à-dire l’absence d’auto-immunité et une non réponse à tous les traitements immunomodulateurs, ou pas d’indication à un traitement compte tenu d’un taux de plaquettes suffisant. Nous montrons dans ce travail de thèse que Bcl-xL est nécessaire pour la survie du mégacaryocyte humain pendant toute la mégacaryopoïèse, à la différence de la souris. Par ailleurs, certains patients ont une altération intrinsèque de la formation des proplaquettes, et certains d’entre eux ont également une diminution de l’ARN messager et de la protéine Bcl-xL dans leurs plaquettes. Ces observations nouvelles suggèrent l’implication de Bcl-xL dans la physiopathologie de leur maladie et ouvrent la voie à l’identification d’une potentielle nouvelle cause de thrombopénie chroniqueThe Bcl-xL protein is a member of Bcl-2 anti-apoptotic proteins. It has been shown in mouse that this protein had a major role in platelet production (megakaryopoiesis). Bcl-xL deregulation could lead to megakaryopoiesis impairement and explain some human diseases such as chronic thrombocytopenias. One cause of chronic thrombocytopenia is immune thrombocytopenia (ITP) that associates 2 pathophysiological mechanisms: an immune-mediated platelet destruction and an insufficient production from the bone marrow cells. ITP is a diagnosis of exclusion when all known causes of thrombocytopenia have been ruled out by diagnosis work-up. In ITP cohort of patients followed in our internal medicine department, we have identified some patients with a haematological profile of their disease, ie absence of overt features of auto-immunity, and absence of response to immunomudulatory treatments, or no indication to such treatment because of sufficient platelet count. We demonstrate in this study that Bcl-xL is necessary for megakaryocyte survival during all megakaryopoiesis, contrary to what was found in mouse. Moreover, some patients have an intrinsically impaired proplatelet formation, and some of them also have a decrease of Bcl-xL mRNA and protein in their platelets. These novel observations suggest that a deregulation of Bcl-xL is a possible cause of their disease and lead the way to the identification of a potentially new cause of chronic thrombocytopenia in human
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Schouten, Shane Michael. "Complete CFD analysis of a Velocity XL-5 RG with flight-test verification." Texas A&M University, 2008. http://hdl.handle.net/1969.1/85894.
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The Texas A&M Flight Research Laboratory (FRL) recently received delivery of its
newest aircraft, the Velocity XL-5 RG. The Velocity can fly faster than the other aircraft
owned by the FRL and does not have a propeller in the front of the aircraft to disrupt the
air flow. These are definite advantages that make the Velocity an attractive addition to
the FRL inventory to be used in boundary-layer stability and transition control. Possible
mounting locations built into the aircraft for future projects include hard points in the
wings and roof of the fuselage. One of the drawbacks of the aircraft is that it has a
canard ahead of the main wing that could disrupt the incoming flow for a wing glove or
research requiring test pieces mounted to the hard point in the wing. Therefore, it is
necessary to understand the influence the canard and the impact of its wake on the wing
of the aircraft before any in-depth aerodynamic research could be completed on the
aircraft.
A combination of in-flight measurements of the canard wake and Computational
Fluid Dynamics (CFD) were used to provide a clear picture of the flowfield around the
aircraft. The first step of the project consisted of making a 3-D CAD model of the
aircraft. This model was then used for the CFD simulations in Fluent. 2-D, 3-D, inviscid,
and viscous simulations were preformed on the aircraft. A pressure rake was designed to
house a 5-hole probe and 18 Pitot probes that extended forward of the main wing to
measure the location and strength of the canard wake at various flight conditions. There
were five primary test points that were recorded at multiple times over the course of three flights. Once all of the data were collected from the flights, the freestream
conditions became the inputs into the final, 3-D CFD simulations on the aircraft.
The good agreement between the CFD results and the in-flight measurements
provided the necessary verification of the CFD model of the aircraft. These results can
be used in the future planning and execution of experiments involving the Velocity XL-5
RG.
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Siegel, Eric Mitchell. "Reading the public comment : the keystone XL pipeline and future of environmental writing." Thesis, University of Iowa, 2014. https://ir.uiowa.edu/etd/4754.
Full textAbstract:
In the lead up to the 2011 official U.S. State Department decision on the proposed Keystone XL pipeline--running from the Alberta, Canada Tar Sands to the Gulf of Mexico--the Department held nine public meetings in Fall 2011 in the six U.S. states through which the proposed Keystone XL pipeline project would pass (the Department rejected the proposal; however, a new proposal is under consideration as of this writing). The transcripts of these public meetings are publicly accessible.
Understanding the pipeline as a project of trans-national trade and the global circulation of petrochemicals--including global emissions of carbon dioxide--this paper hones in on one region within one U.S. state: the Nebraskan Sandhills, a cattle ranching region of grass-stabilized sand dunes and inter-dunal valleys stretching 20,000-square miles across the north-central part of the state, under which rests a vast hydrological network, including the largest freshwater aquifer in the world - the Ogallala Aquifer.
This essay argues that we can read the Public Comments as a form of poetic expression, paying attention to the ways the State Department transcription process formatted the oral testimonies into an "official" and sanctioned public document -- instituting line-breaks and other syntactical procedures. Using the tools of literary-critical analysis, this paper makes a case that we can read the Comments as a form of documentary poetry - in the tradition of such American modernist poets as Charles Reznikoff, Muriel Rukeyser, and George Oppen - that explore ecological questions while experimenting with lyric structures. The Comments reveal competing environmental stakeholders' stances - on such topics as Prairie systems ecology and the neoliberal economics of private-public capital markets. In doing so, they subsequently express citizens' various understandings of themselves in relation to landscape, ecology, technology, and geo-politics.
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Bloch-Queyrat, Coralie. "Activation et inhibition de la réponse cytotoxique des cellules NK par le récepteur 2B4 : rôle de l'adaptateur SAP." Paris 6, 2007. http://www.theses.fr/2007PA066012.
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Fokwa, Tsinde Boniface Polequin. "Synthesen, Kristallstrukturen und Eigenschaften der Verbindungen LnSeTe2, YSe1,85, Ln1-xLn`xSe2[-delta] und Ln2O2Te1-xSex (Ln = La, Ce, Pr, Nd, Sm; Ln` = Y, Gd)." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2003. http://nbn-resolving.de/urn:nbn:de:swb:14-1070535105546-49794.
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Yang, Chih-Cheng. "Stragegies to overcome progression of androgen refractory prostate cancer – targeting BCL-XL and androgen receptor." The Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1165358220.
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ALLENET-LE, PAGE BENEDICTE, and Jean-François Bach. "Etude de l'expression des proteines xlr (x-linked lymphocyte regulated) dans les lignees lymphoide et germinale chez la souris et identification d'un equivalent chez l'homme." Paris 6, 1993. http://www.theses.fr/1993PA066292.
Full textAbstract:
La demarche de genetique inverse initiee par m. Davis, dont nous presentons ici les developpements, avait pour but d'identifier, chez la souris, des genes dont la fonction est essentielle dans l'ontogenese et la physiologie du systeme immunitaire et dont les homologues pourraient etre impliques dans les deficits immunitaires lies au chromosome x, chez l'homme. Cette demarche a permis d'identifier la famille des genes xlr (x-chromosome linked, lymphocyte regulated). Nous avons etudie l'expression de xlr, non plus seulement dans des cellules en lignee, mais aussi chez des souris saines, ex vivo. Au moins deux proteines xlr apparentees sont exprimees de maniere etroitement regulee, la premiere dans les cellules t en voie de differenciation dans le thymus ftal, la deuxieme dans les cellules germinales males au cours de la meiose. Les similitudes que partagent les deux systemes de differenciation cellulaire permettent de formuler de nouvelles hypotheses sur la fonction possible des proteines xlr. Enfin, bien que les sondes nucleiques de la souris ne montrent pas de reaction croisee avec l'adn humain, nous avons identifie et caracterise une proteine nucleaire humaine exprimee dans des cellules en lignee ou dans les meiocytes, grace a des anticorps monoclonaux. Les caracteristiques physiques et d'expression de cette proteine suggerent qu'elle represente l'equivalent humain de xlr
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Vera, Gabriella. "Défauts de la réparation de l’ADN et développement lymphoïde : Analyse de situations pathologiques chez l’homme et la souris." Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05T028/document.
Full textAbstract:
Au cours de leur développement, les cellules du système hématopoïétique sont très exposées aux dommages à l’ADN qui peuvent avoir une origine exogène ou endogène. Les organismes vivants ont développé de nombreux mécanismes de réparation pour y faire face, et leur dysfonctionnement est responsable de maladies rares mais sévères chez l’Homme. Un des deux mécanismes de réparation des cassures double-brin (CDB) de l’ADN joue un rôle prépondérant dans le développement du système immunitaire (SI) des mammifères. Il s’agit de la voie de réparation des extrémités non-homologues (NHEJ) qui est absolument essentiel au bon déroulement de la recombinaison V(D)J dans les progéniteurs lymphocytaires de la moelle osseuse et du thymus. En effet, la formation de CDB de l’ADN est une étape clé de ce remaniement. De même, bien que dans une moindre mesure, le NHEJ intervient pour réparer les cassures induites par AID lors de la commutation de classe des immunoglobulines (Ig- CSR). Notre équipe a précédemment identifié un nouveau facteur du NHEJ, Cernunnos (ou XLF), responsable chez l’Homme de déficit immunitaire combiné sévère (DCIS) associé à une sensibilité aux rayonnements ionisants (RI) et à une microcéphalie. Afin de mieux comprendre le rôle de Cernunnos dans le système hématopoïétique et dans le développement des lymphocytes en particulier, nous avons créé un modèle murin invalidé pour ce gène. De façon surprenante, le développement lymphocytaire se fait quasi normalement dans ces souris, le seul défaut observé est une diminution du nombre de lymphocytes. Cependant, l’analyse fine du répertoire des cellules T a permis de mettre en évidence un biais dans l’utilisation des segments variables V et J de la chaîne α du récepteur (TCRα). Ce serait là la signature d’un défaut de survie des thymocytes, passant par une activation chronique de la voie de l’apoptose dépendante de p53 en réponse à l’accumulation de dommages de l’ADN. Certaines sous- populations de lymphocytes T, comme les iNKTs et les MAITs, seraient ainsi affectées. Par ailleurs, notre équipe poursuit la caractérisation génétique et fonctionnelle de pathologies chez des patients dont le tableau clinique laisse penser qu’il existe un déficit immunitaire ou hématologique primaire associé à un défaut de réparation de l’ADN. Nous nous sommes intéressés à un patient dont le tableau clinique combinant déficit hématopoïétique et instabilité génomique suggère une origine génétique forte. Grâce aux techniques de séquençage haut- débit et à l’étude de ségrégation au sein de la famille nous avons pu isoler plusieurs mutations dont une nous a interpellé plus particulièrementThroughout their development, hematopoietic cells are exposed to many DNA damages of either exogenous or endogenous origin. Living organisms evolved a variety of DNA repair mechanisms in order to face those threats, and their impairment leads to rare but severe diseases in human. Of the two mechanisms involved in the repair of DNA double-strand break (DSB) repair, one plays a major role in mammal’s Immune System (IS). The non-homologous end joining (NHEJ) pathway is essential for the correct proceeding of V(D)J recombination in lymphocyte progenitors from bone marrow and thymus. Indeed, the formation of DNA DSB is a key step of the rearrangement. In similar fashion, though to a lesser degree, NHEJ is involved in repair of AID induced breaks during immunoglobulin class switch recombination (Ig-CSR). Our team previously identified a new NHEJ factor, Cernunnos (or XLF), as being responsible for a human syndrome of severe combined immunodeficiency (SCID) associated with ionizing radiation (IR) sensitivity (RS-SCID) and microcephaly. To better understand Cernunnos role in the hematopoietic system and particularly in lymphocyte development, we engineered a knock-out (KO) mouse model for this gene. Surprisingly, lymphocyte development is almost normal in these mice, the only defect observed being a decrease of lymphocyte number. However, a refined analysis of T cell repertoire allowed us to uncover a bias in the use of V and J segments from the receptor’s α chain (TCRα). This is the signature of a survival defect in thymocytes, caused by chronic activation of the p53 dependent apoptosis pathway in response to DNA damage. Some discrete T cell populations, such as iNKTs and MAITS, would be affected. In the meantime, our team pursues the uncovering of genetic diseases and their functional description in patients showing signs of immune or hematopoietic deficiency combined to impaired DNA repair. We focused on a patient harboring clinical signs of genomic instability and hematopoietic defects with strong evidence for genetic cause. Thanks to high-throughput DNA sequencing technology and whole genome association study (WGAS), we identified several mutations, one of them striking us as pertinent