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1
Gonçalves, Maia Maria João. "Le syndrome Xeroderma Pigmentosum : Un nouveau modèle pour l’étude du rôle des fibroblastes dans la modulation de la réponse immunitaire innée contre les cellules cutanées cancéreuses." Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2019. http://www.theses.fr/2019AZUR4037.
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L’étiologie des cancers cutanées est liée à des mutations génétiques résultant de l’exposition aux rayonnements ultraviolets (UV) émis par le soleil. La propagation des cellules cancéreuses dépend aussi des interactions avec les cellules présentes dans le microenvironnement circulant, notamment des fibroblastes associés au cancer (FAC) et des cellules immunitaires. Xeroderma pigmentosum (XP) est une maladie génétique qui comprend 7 groupes de complémentation génétique (XP-A à XP-G). Les patients XP présentent une déficience du mécanisme de réparation des lésions de l’ADN provoquées par les UV. Ces patients sont susceptibles au développement précoce de très nombreux cancers cutanées. XP-C est le groupe de complémentation le plus représenté en Europe. Chez ces patients, les carcinomes spino-cellularies (CSC) sont plus fréquents que les carcinomes baso-cellulaires (CBC) (taux 5 : 1). Les CSC ont un potentiel métastatique plus élevé que les CBC. Des travaux précédents ont suggéré que la réponse immunitaire chez les patients XP pouvait être altérée, incluant un déficit de l’activité cytolytique des cellules Natural Killer (NK) et une diminution du nombre des lymphocytes T circulants.L’objectif central de cette thèse était, d’identifier des facteurs du microenvironnement impliqués dans la progression des cancer cutanées agressifs, en prenant comme modèle de susceptibilité au cancer, des cellules de patients XP-C. Une analyse transcriptomique comparant les fibroblastes WT et des patients XP-C a permis d’identifier que CLEC2A, un ligand activateur du récepteur NKp65 des cellules NK, est exprimé par les fibroblastes WT mais pas par les fibroblastes XP-C. Nos travaux ont pu montrer une diminution du niveau d’expression de CLEC2A au cours de la sénescence réplicative ; une absence dans les FAC et dans les CSC et que, des facteurs solubles secrétés para les CSC diminuent l’expression de CLEC2A. Ces résultats suggèrent que la perte de CLEC2A peut induire un déficit d’activation des cellules NK au sein du microenvironnement tumoral et dans les dermes des patients XP-C. Par la suite, nous avons élaboré un modèle de culture de peau 3D, dans lequel nous avons introduit des cellules NK, en présence ou absence d’anticorps bloquants CLEC2A. Ce modèle nous a permis de montrer que l’interaction CLEC2A/NKp65 régule l’invasion des CSC via un dialogue entre fibroblastes et cellules NK. Nos résultats suggèrent que l’expression de CLEC2A dans les fibroblastes WT contribue à la surveillance immunitaire dans la peau et que son absence, par des facteurs encore inconnus, favorise le développement des cancers agressifs chez les patients XP-C. CLEC2A peut être une cible dans le combat contre la progression des CSCSkin cancer etiology is related to genetic mutations arising after ultraviolet (UV) sun exposure. The propagation of cancer cells is also dependent of a crosstalk with cells present in the surrounding microenvironment, mainly cancer associated fibroblasts (CAF) and immune cells. Xeroderma pigmentosum (XP) is a genetic disease that comprises seven groups of genetic complementation (XP-A to XP-G). XP patients present a default in the mechanism responsible for the repair of UV-induced DNA lesions. They are prone to develop skin cancers with high frequencies early in their life. XP-C is the most represented complementation group in Europe and in XP-C patients squamous cell carcinoma (SCC) are more frequent than basal cell carcinoma (BCC) (ratio 5:1). SCC have high metastatic potential compared to BCC. Previous studies suggested that the immune responses in XP patients could be altered with defects in their NK lytic activity and a decrease in the levels of circulating T lymphocytes. The main objective of this thesis was to identify microenvironment factors that could contribute to the progression of aggressive skin cancers using XP-C disease cells as a model of skin cancer susceptibility. Comparative transcriptomic analysis of WT and XP-C dermal patient’s fibroblasts revealed that CLEC2A, a ligand of the activating NK receptor NKp65 implicated in the activation of the innate immune system, is expressed in WT fibroblasts and absent in XP-C fibroblasts. Additional work showed that CLEC2A level is decreased in WT fibroblasts during replicative senescence, is absent in CAF and SCC, and is down regulated by soluble factors secreted by SCC cells. These results suggest that the loss of CLEC2A may induce a deficit of NK cell activation in the tumor microenvironment of SCC and in the dermis of XP-C patients. Elaboration of 3D skin culture models including NK cells and, in the presence or absence of blocking anti-CLEC2A antibody, allowed us to show that CLEC2A/NKp65 interaction regulates SCC cells invasion through a crosstalk between fibroblasts and NK cells. Our results suggest that the expression of CLEC2A in fibroblasts contributes to skin immune surveillance while, conversely, its absence under yet unidentified factors, favors the development of aggressive cancers in XP-C patients. CLEC2A could be a potential target in the fight against SCC progression
2
Haddad, Yacine. "Rôle de Clec9a dans l'athérosclérose." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB099/document.
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L’athérosclérose est une maladie inflammatoire chronique. L’une des caractéristiques des lésions d’athérosclérose est l’accumulation anormale de corps apoptotiques et nécrotiques, due à un défaut d’efferocytose, ceci entraînant la formation du cœur nécrotique. L’évolution de ce cœur nécrotique est également associée à une augmentation de l’inflammation et de la taille des plaques d’athérosclérose, mais aussi dans la survenue de complications telle que la rupture de plaque. Clec9a est un récepteur transmembranaire de type lectine C, majoritairement exprimé par une sous population de cellules dendritiques les DC-CD8α+. Il est capable de reconnaître un ligand spécifiquement exprimé par les corps nécrotiques, l’actine F. L’objectif de notre travail a été de savoir si Clec9a, qui est capable de reconnaître les corps nécrotiques, pouvait être impliqué dans la modulation de l’inflammation observée au cours du développement de l’athérosclérose. Au cours de cette étude, nous avons montré, in vivo partir de deux modèles murins (ApoE-/- et LDLr-/-), que la délétion de Clec9a entraîne une diminution significative de la taille des lésions dans un contexte d’hypercholestérolémie modérée. Cette athéro-protection observée en l’absence de Clec9a, est associée à une augmentation de l’expression de l’IL-10, qui est une interleukine anti-athérogène et anti-inflammatoire. Cet effet athéroprotecteur de l’absence de Clec9a n’est plus observé lorsque l’IL-10 est totalement invalidée. De plus, nous avons montré que l’invalidation de Clec9a spécifiquement dans les DC-CD8α+ entraîne, in vivo, une diminution de l’infiltration des macrophages et des lymphocytes T dans les lésions, ainsi qu’une augmentation de l’expression de l’IL-10, favorisant une diminution de la taille des lésions. La compréhension des mécanismes inflammatoires dans l’athérosclérose constitue un enjeu majeur pour prévenir les risques de complications comme la rupture de plaque ou la thrombose. Ainsi, ce travail met en évidence un nouveau rôle de Clec9a dans la régulation de l’inflammation dans l’athérosclérose et pourrait donc représenter une cible thérapeutique potentielleAtherosclerosis is a chronic inflammatory disease. One of the characteristics of atherosclerotic lesions is the abnormal accumulation of apoptotic and necrotic cells, due to a deficiency of efferocytosis, which leads to the formation of the necrotic heart. The evolution of this necrotic core is also associated with an increase in inflammation and lesions of atherosclerosis, but also in the occurrence of complications such as plaque rupture. Clec9a is a C type lectin receptor, mainly expressed by a subpopulation of dendritic cells, which are the CD8α+ dendritic cells. This receptor is able to recognize a ligand expressed by necrotic cells, the actin F. The aim of our work was to find out if Clec9a, which can sense necrotic cells, could be involved in modulating the inflammation observed during the development of atherosclerosis. In this study, we have shown, in vivo with two mouse models (ApoE - / - and LDLr - / -), that the deletion of Clec9a leads to a significant decrease in the incidence of moderate hypercholesterolemia. This athero-protection observed in the absence of Clec9a, is associated with an increase in the expression of IL-10, which is an anti-atherogenic and anti-inflammatory cytokine. This athero-protective effect of the absence of Clec9a is abolished after total invalidation of IL-10. Furthermore, we report that specific knockdown of Clec9a in CD8α+-DC, in vivo, leads to a decrease in macrophage and lymphocyte infiltration in lesions, as well as an increase in IL-1 expression. 10, which promotes a decrease in lesions size. Understanding of inflammatory mechanisms in atherosclerosis is a major challenge to prevent the risk of complications such as plaque rupture or thrombosis. Thus, this work highlights a new role of Clec9a in the regulation of inflammation in atherosclerosis and could be therefore a potential therapeutic target
3
Lodhia, Puja. "Investigating the intracellular interactions of CLEC14A and the characterisation of monoclonal antibodies targeting CLEC14A." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/7014/.
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CLEC14A is a tumour endothelial marker known to regulate sprouting angiogenesis. While the extracellular interactions of CLEC14A have previously been studied, the intracellular interactions of CLEC14A are unknown. Fascin was identified as a binding partner for the cytoplasmic tail of CLEC14A using a yeast two hybrid screen. Interaction of CLEC14A with fascin was confirmed by proximity ligation and co-localisation was observed in HUVEC filopodia. This data indicated that interaction of CLEC14A and fascin may be important for filopodia formation during sprouting angiogenesis. Binding studies with domain deletion mutants of fascin revealed the CLEC14A binding site to be located within a highly conserved region of the β-trefoil 3 domain between amino acids 323 and 384. In addition, phosphorylation of S274 was found to regulate this interaction. Five monoclonal antibodies against CLEC14A had the potential to be developed into anti-angiogenic cancer therapeutics. The functional properties of these antibodies were explored in in vitro assays. Clones 1 and 3 were found to inhibit cell migration while clone 4 disrupted tubule formation. Clones 3 and 4 were developed into antibody drug conjugates (ADCs). These ADCs demonstrated potent cytotoxicity localised to the tumour endothelium in vivo. These results indicate that targeting CLEC14A could be an effective strategy to disrupt the tumour vasculature.
4
Huysamen, Cristal. "The characterization of a novel C-type lectin-like receptor, CLEC9A." Doctoral thesis, University of Cape Town, 2008. http://hdl.handle.net/11427/3060.
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Messerer, Denise [Verfasser], and Sven [Akademischer Betreuer] Reese. "Bedeutung Clec9a-abhängiger Immunzellen in kardialen Entzündungsprozessen / Denise Messerer ; Betreuer: Sven Reese." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1215499965/34.
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Teng, Ooiean, and 丁瑋嫣. "Identification of CLEC5A in modulating host immune response after influenza A virus infection." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208615.
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Human infections with influenza A virus (IAV) exhibit mild to severe clinical outcomes as a result of differential virus-host interactions. C-type lectin receptors (CLRs) are pattern recognition receptors that may sense carbohydrates, proteins, or lipids derived from infected hosts or the invading microbes including bacteria, viruses, fungi, or parasites. CLR-viral interaction may lead to increased viral entry and spread; furthermore, their interactions have been reported to trigger downstream signaling that further modulates host’s innate immune responses through the induction of pro-inflammatory cytokines. To date, DC-SIGN and DC-SIGNR have been shown to mediate IAV entry; however, the potential interactions between other human transmembrane CLRs with IAV have not yet been systematically investigated. We utilized lentiviral-based pseudoparticles expressing influenza hemagglutinin (HA) to examine the binding potential between HA and a panel of human CLRs expressed in soluble form. CLEC5A was identified as a potential interacting target with the HA proteins derived from a highly pathogenic avian H5N1 virus A/VN/1203/04 (VN1203) or a human seasonal H1N1 virus A/HK/54/98 (HK5498), albeit at different binding intensity. Applying siRNA gene silencing, we confirmed that CLEC5A did not enhance influenza entry in human monocytic U937 cells that constitutively express CLEC5A or in the lentiviral-transduced stable CHO and CHO-Lec2 cells that overly expressed CLEC5A. To investigate downstream signaling upon engagement of CLEC5A to influenza virus, M-CSF or GM-CSF differentiated human macrophages with high expression levels of CLEC5A and DAP12, a known adaptor protein for CLEC5A upon phosphorylation to initiate signal transduction, was subjected to CLEC5A siRNA gene silencing followed by infection with recombinant A/PR/8/34 virus expressing HA and NA derived from either VN1203 (H5N1) or HK5498 (H1N1) viruses. RG-PR8xVN1203HA,NA (H5N1) exhibited a higher infectivity and induced higher levels of pro-inflammatory cytokines (TNF-( and IFN-α) and chemokines (IP-10, MCP-1, MIG and MIP-1α) secretion in M-CSF or GM-CSF differentiated macrophages while compared to that of the RG-PR8xHK5498HA,NA (H1N1) virus. Knocking-down CLEC5A in macrophages led to a universal reduction of cytokines and chemokines secretion after infection with either the RG-PR8xVN1203HA,NA, RG-PR8xHK5498HA,NA, RG-A/VN/1203/04 (H5N1) or A/Shanghai/2/2014 (H7N9) viruses, suggesting that CLEC5A plays a role as cytokine and chemokine amplifier after influenza infection. Since DAP12 phosphorylation is known to activate downstream signaling via Spleen tyrosine kinase (Syk), pre-incubation of M-CSF macrophages with a Syk inhibitor (Bay 61-3606) also lead to a significant reduction of TNF-α and IP-10 in infected macrophages. A higher mortality was observed in CLEC5A-/- mice while compared to the wild-type C57BL/6 mice after challenged with a lethal dose of RG-A/VN/1203/04 (H5N1) influenza virus suggesting that CLEC5A as a host innate response amplifier play a protective role upon influenza infection. In conclusion, we have identified CLEC5A as a novel host factor for influenza pathogenesis by modulating host innate inflammatory response.published_or_final_version
Public Health
Doctoral
Doctor of Philosophy
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Van, Blijswijk J. M. "Mouse models to deplete or label dendritic cells via genetic manipulation of the Clec9a locus." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1472681/.
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Dendritic cells (DCs) play important roles at the interface between innate and adaptive immunity by priming and directing T cell responses. Much of our current knowledge of DC biology has come from mouse models in which DCs can be genetically manipulated, labelled or ablated. Here, novel models are presented using a strategy that targets DC precursors via genetic editing of the Clec9a locus. While validating a novel mouse model to inducibly deplete DCs using diphtheria toxin receptor (DTR) expression driven by Clec9a, it became clear that these Clec9a+/CreROSAiDTR mice suffer from unexpected lymph node (LN) hypocellularity and reduced frequencies of DCs in LNs, even in the absence of diphtheria toxin (DT) injection. This phenotype turned out to be a common feature of other mouse models in which DTR is expressed on DCs (e.g. CD11c-DTR and Langerin-DTR mice) and raises questions about the interpretation of results obtained with such animals. Therefore, in an alternative approach, mice were developed to constitutively lack DCs by expressing the diphtheria toxin alpha (DTA) subunit under control of the Clec9a locus. Unfortunately, these mice still harboured DCs and only showed partial reduction of one DC subset. Finally, seeding of tissues by DC precursors was examined. Clec9a+/CreROSA+/confetti mice were generated in which DC precursors stochastically express one of four fluorescent proteins, which is inherited by its daughter cells. 8- Colour microscopy of tissue sections and histo-cytometry analysis of the images was developed to analyse these mice. This approach will be used to determine how many daughter cells are produced when a single DC precursor seeds the small intestine (clonal burst size), whether these daughters are found among different DC subsets and whether seeding changes during inflammation. In summary, manipulation of the Clec9a locus proves to be an excellent way to study the DC lineage and DC precursor behaviour in the mouse.
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Sormani, Laura. "Identification d’un nouveau gène dans la pigmentation cutanée - CLEC12B." Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2019. http://theses.univ-cotedazur.fr/2019AZUR6037.
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La mélanogenèse est un processus complexe et étroitement régulé. Une étude transcriptomique à large échelle a été réalisée sur des peaux lésionnelles de patients atteints de vitiligo (dépourvues de mélanocytes et donc de pigmentation) comparées à des peaux non lésionnelles et des peaux de sujets sains. L’analyse différentielle des transcrits a permis la découverte d’un nouveau gène dont l’expression est significativement régulée négativement, dans les peaux lésionnelles, en comparaison avec les peaux non lésionnelles ou saines : CLEC12B. Le degré de régulation de CLEC12B était similaire à ceux observés pour les enzymes clefs de la mélanogenèse (TYR, TYRP1 ou DCT) suggérant que CLEC12B pourrait être un gène mélanocytaire important et jouer un rôle, jusqu’ici inconnu, dans la pigmentation cutanée. CLEC12B est membre de la famille des lectines de type C, qui sont des récepteurs transmembranaires possédant un domaine ITIM capable de recruter et d’activer SHP1 et SHP2. Ces phosphatases régulent de nombreuses voies de signalisation cellulaire impliquées dans des processus biologiques importants. À ce jour, très peu de données sont disponibles dans la littérature concernant CLEC12B qui a uniquement été rapporté dans les cellules myéloïdes. Son ligand, ainsi que les voies de signalisation en aval, n’ont toujours pas été identifiés et aucun lien n’a été rapporté entre CLEC12B et la pigmentation cutanée. Nous avons montré, pour la première fois, que CLEC12B est exprimé par les mélanocytes humains normaux (NHM) et que son expression dépend du phototype de la peau. La modulation de l’expression de CLEC12B par shRNA induit une augmentation significative de la production de mélanines dans les NHMs. Au contraire, la surexpression de CLEC12B entraîne une diminution significative de la pigmentation. Ces résultats ont été confirmés à l'aide d'un modèle d'épiderme humain reconstruit. L’utilisation d’un mutant du domaine ITIM de CLEC12B nous a permis de montrer que CLEC12B recrute et active directement les phosphatases SHP1 et SHP2 dans les mélanocytes. Ceci conduit à la régulation négative des facteurs de transcription CREB et MITF ainsi que des enzymes de la mélanogenèse (TYR, TYRP1 et DCT).Ce nouvel apport dans la compréhension de la physiologie de la pigmentation cutanée pourrait permettre, in fine, à l’identification de nouvelles cibles thérapeutiques et aboutir un jour au développement d’agents dans le traitement clinique et cosmétique des troubles pigmentairesMelanogenesis is a complex and tightly regulated process. A transcriptome analysis in lesional and non-lesional skin of vitligo patients compared to healthy controls allowed us to identify a new gene CLEC12B, which is only expressed in controls and in non lesional skin of vitiligo patients. The decreased expression of CLEC12B in lesional skin of vitiligo patients is comparable to the one observed for key melanocytic genes such as TYR, TYRP1 or DCT suggesting that CLEC12B could be an important melanocytic gene. CLEC12B is a member of the C-type lectin family, which are transmembrane receptors that possess an ITIM domain which can recruit phosphatases. So far, only few data are available on this gene that is essentially reported in myeloid cells. Ligand and downstream signaling of CLEC12B are unknown and to date, no link has been reported between CLEC12B and pigmentation. We demonstrated that CLEC12B is selectively expressed in melanocytes, and that its expression is decreased in highly pigmented skin compared to white skin. Silencing of CLEC12B in normal human melanocytes (NHM) by short hairpin RNA induced a significant increase in melanin production. On the contrary, CLEC12B overexpression using lentiviral vector resulted in significant loss of pigmentation in NHM. These results were confirmed using a reconstructed human epidermis model. Using a mutant of the ITIM domain of CLEC12B, we showed that CLEC12B directly recruits and activate SHP2, leading to the negative regulation of CREB, MITF and melanogenesis enzymes such as tyrosinase and DCT accordingly to the pigmentary phenotypes observed. These results provide novel insights not only for the development of melanogenic agents in the clinical and cosmetic fields, but also for a better understanding of the melanocyte biology and regulation of melanogenesis
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Köhler, Arnaud. "Rôle des cellules dendritiques pre-CD8α Clec9A+ dans la protection contre Listeria monocytogenes en début de vie." Doctoral thesis, Universite Libre de Bruxelles, 2016. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/235619.
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Selon un rapport de l’OMS, les maladies infectieuses figurent parmi les 3 causes les plus fréquentes de mortalité en début de vie. En effet, les nouveau-nés présentent une sensibilité particulièrement importante aux infections, de par leur système immunitaire toujours en développement et donc immature. Parmi les particularités de l’immunité néonatale, l’absence de cDCs CD11chigh CD8α+ durant la 1ère semaine de vie rend compte de l’incapacité du nouveau-né à développer des réponses de type Th1 et T CD8+ cytotoxiques, essentielles à la protection contre certains pathogènes comme Listeria monocytogenes (Lm). Mon travail de thèse a porté sur l’ontogénie des DCs conventionnelles CD11chigh CD8α+ et plus particulièrement sur la fonction de cette lignée de DCs en début de vie lors d’une infection par Lm. Au cours de cette étude, nous avons identifié, chez le nouveau-né, une population splénique de cDCs CD11chigh qui expriment les marqueurs CD24, CD205 et Clec9A mais pas le CD8α. Cette population, qui dépend du facteur de transcription Batf3, acquière le CD8α une fois transférée dans une souris adulte. Ces DCs néonatales, que nous nommerons DCs pre-CD8α Clec9A+, constituent donc les précurseurs des DCs CD8α+. L’étude fonctionnelle de ces DCs pre-CD8α Clec9A+ a montré qu’elles étaient capables de phagocyter Lm et de générer des réponses T CD8+ contre cette bactérie. De plus, ces cellules sécrètent de l’IL-12p40 et de manière unique de l’IL-10 en réponse à une stimulation par Lm. Par contre, contrairement aux cDCs CD8α+ adultes, nous n’avons observé aucune production d’IL-12p70 par les DCs pre-CD8α Clec9A+ en conditions physiologiques. Elles ne sécrètent pas non plus d’IL-23. Nous avons également montré que ces sécrétions d’IL-12p40 et d’IL-10 jouaient respectivement un rôle positif et négatif dans l’induction des réponses T CD8+ contre Lm. Ainsi, la génération des réponses T CD8+ contre Lm semble résulter, en début de vie, d’une balance entre la sécrétion de ces 2 cytokines aux propriétés antagonistes. Par ailleurs, nous avons démontré que ces cellules constituaient une cible privilégiée en vue d’améliorer les stratégies vaccinales en début de vie. En effet, l’administration à des nouveau-nés d’une construction anti-Clec9A/OVA, associée au poly(I:C), induit des réponses T CD8+ anti-Lm mémoires protectrices à l’âge adulte. Finalement, nous montrons que le TNF-α produit par les monocytes et les neutrophiles joue un rôle essentiel dans la génération des réponses T CD8+ en régulant notamment le statut et la fonction des DCs pre-CD8α Clec9A+ en début de vie. En effet, cette cytokine modifie, en faveur d’une production d’IL-12p40, la balance IL-12p40/IL-10 sécrétée par celles-ci. L’inhibition de la production d’IL-10 par le TNF-α pourrait s’expliquer au moins en partie par une inhibition de la β-caténine au sein des DCs pre-CD8α Clec9A+. En conclusion, nous avons caractérisé un précurseur des DCs CD8α+ biologiquement actif au sein de la rate du nouveau-né de 3 jours. Celui-ci représente une cible potentielle pour l’amélioration des stratégies vaccinales contre des bactéries intracellulaires ou des virus en début de vie, et ce pour autant que l’on puisse contrôler ses propriétés régulatrices.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished
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Montaudié, Henri. "CLEC12B un gène de la famille des lectines impliqué dans le processus de melanomagénèse en agissant comme un gène suppresseur de tumeurs : CLEC12B un gène suppresseur de tumeurs impliqué dans le mélanome." Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2019. http://www.theses.fr/2019AZUR6013.
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Malgré les progrès thérapeutiques importants accomplis ces dernières années, le mélanome garde un pronostic péjoratif au stade métastatique. Il est donc essentiel d’explorer les mécanismes moléculaires et cellulaires impliqués dans le processus de mélanomagénèse dans la perspective de découvrir de nouvelles cibles thérapeutiques.Une analyse transcriptomique comparative de la peau de patients atteints de vitiligo (et donc dénuée de mélanocytes) par rapport à de la peau non lésionnelle et la peau de sujets témoins, nous a permis de découvrir que le récepteur de la lectine C, CLEC12B (C-type lectin domain family 12-member B) était sélectivement et fortement exprimé par les mélanocytes. L'objectif de cette étude était d'étudier le rôle de CLEC12B in vitro et in vivo dans le mélanome. Nous avons d’abord montré que l’expression des transcrits de CLEC12B, par technique RT-PCR, était plus faible dans les lignées cellulaires de mélanome et dans les cellules de mélanome extraites de métastases de patients que dans les mélanocytes humains normaux. D’autre part, l'analyse protéique par immunohistochimie a montré une expression plus faible de CLEC12B, dans des échantillons de mélanome humain (mélanomes primaires et métastatiques de patients) par rapport aux nævi. La base de données TCGA, a révélé que les patients avec une expression élevée de CLEC12B avaient une survie médiane significativement supérieure à ceux avec une expression faible. Ces premiers résultats suggèrent un rôle potentiel de CLEC12B dans le processus de mélanomagénèse. Dans un second temps, en utilisant une construction de lentivirus, nous avons surexprimé (Ov-CLEC12B) et régulé négativement (Sh-CLEC12B) CLEC12B dans deux lignées cellulaires de mélanome humain (A375 BRAF muté et MeWo BRAF sauvage). Ainsi nous avons démontré que Ov-CLEC12B inhibait la prolifération et la formation de colonies, par l’activation de p53/p21/p27 et l’inhibition des STATs et notamment STAT3 qui est constitutivement activé dans le mélanome. Par ailleurs, par une expérience de co-immunoprécipitation et après avoir généré un mutant de CLEC12B sur son domaine ITIM, nous avons montré que CLEC12B par son domaine ITIM, recrute et active directement la tyrosine phosphatase SHP-2. Une fois activée par CLEC12B, SHP-2 inactive la voie STAT (diminution des formes phosphorylées de STAT1, 3 et 5) et augmente l’expression de p53/p21/p27 entrainant un ralentissement du cycle cellulaire en phase G0-G1. Des effets opposés sont observés après l’extinction de CLEC12B. Enfin, les propriétés tumorigèniques de CLEC12B ont été étudiées chez des souris nude avec des expériences de xénogreffe de tumeur (injection de la lignée A375 Ov et Sh-CLEC12B). En accord avec les résultats in vitro, la croissance tumorale dans le groupe Ov-CLEC12B était significativement réduite par rapport au groupe véhicule et était associée à une diminution de l'expression de pSTAT3 et à une augmentation de p53 dans les tumeurs. Le contraire a été observé dans les conditions Sh-CLEC12B.Au total, ce travail révèle que CLEC12B est un nouveau gène suppresseur du mélanome qui agit en régulant le cycle cellulaire et en réprimant l'activation de STATDespite significant progress in recent years, melanoma remains among the most aggressive and deadly human cancers. Thus, it still remains essential to explore the molecular and cellular mechanisms involved in the melanomagenesis process in order to discover new therapeutic options. A transcriptomic analysis from vitiligo patient skins allowed us to discover that the C-lectin receptor CLEC12B (C-type lectin domain family 12-member B) is selectively and strongly expressed by melanocytes. The objective of this study was to investigate the role of CLEC12B in melanoma. We first showed that the expression of CLEC12B is lower in melanoma cell lines, and in melanoma cells extracted from patient metastases, compared to the expression in normal human melanocytes. Immunohistochemical analysis further showed a lower expression of CLEC12B, in human melanoma samples (primary and metastatic melanomas from patients) compared to melanocytic nevi. Using the TCGA database, we found that patients with high CLEC12B expression have a significantly higher median survival than those with low expression. Taken together, these first results suggested a potential role of CLEC12B in melanomagenesis process. Subsequently, using a lentivirus construct, we overexpressed (Ov-CLEC12B) and downregulated (Sh-CLEC12B) CLEC12B in human melanoma cells lines, and we demonstrated that CLEC12B inhibits the proliferation and colony formation, through activation of p53/p21/p27 and the inhibition of STAT pathway. We demonstrated, using a co-immunoprecipitation assay, and after generating a mutant of CLEC12B ITIM domain, that CLEC12B function is mediated by its ITM domain, which directly recruits and activates the tyrosine phosphatase SHP-2. Once activated by CLEC12B, SHP-2 inactivates the STAT pathway, as observed with a decrease of STAT1, STAT3 and STAT5 phosphorylated forms and promotes p53/p21/p27 pathway activation with a slow down in G0-G1 phase of cell cycle. Opposite effects were observed after silencing CLEC12B. Finally, tumorigenic properties of CLEC12B were analyzed in nude mice with tumor xenograft experiments. In accordance with in vitro results, the tumor growth in Ov CLEC12B group was significantly decreased compared to vehicle group and was associated with a decreased expression of pSTAT3 and an increase of p53 within the tumors. The opposite was noted with Sh CLEC12B. This study reveals CLEC12B as a novel potent suppressor gene in melanoma by regulating cell cycle and repressing STAT activation
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Medina, Mendieta Clelia [Verfasser]. "Business-to-Consumer eCommerce Adoption in Nicaragua / Clelia Medina Mendieta." Berlin : Freie Universität Berlin, 2018. http://d-nb.info/1170814581/34.
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Khan, Kabir Ali. "Investigating the extracellular interactions of the tumour endothelial marker CLEC14A." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6909/.
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CLEC14A is an endothelial specific type I transmembrane glycoprotein, which is highly expressed on the vasculature of a wide range of different solid tumours. Identifying extracellular interactions of CLEC14A holds promise for new targets in anti-angiogenic strategies for cancer treatment. CLEC14A directly binds to the extracellular matrix protein multimerin-2 (MMRN2). Both proteins are upregulated with tumour progression and are implicated in endothelial cell function. The CLEC14A-MMRN2 interaction occurs when both proteins are expressed at endogenous levels in endothelial cells, and is dependent upon the C-type lectin domain of CLEC14A. Blocking the CLEC14A-MMRN2 interaction had anti-angiogenic effects and could inhibit the growth of mouse tumour models. Finally, the localisation and targeting of CLEC14A was investigated in vivo by use of humanised antibodies and antibody drug conjugates. Data presented in this thesis reinforce the pro-angiogenic functions of CLEC14A and the likelihood of it being a good target for cancer therapy.
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Horan, Lucas H. "Testing the role of ribosomal intersubunit movement in translocation & discovery of the Clec2 hammerhead ribozyme /." Diss., Digital Dissertations Database. Restricted to UC campuses, 2009. http://uclibs.org/PID/11984.
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Yoshikawa, Fábio Seiti Yamada. "A participação dos receptores da imunidade inata na resposta contra Trichophyton rubrum." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-04052016-104324/.
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Dermatofitoses são infecções fúngicas de natureza crônica cujo principal agente etiológico é Trichophyton rubrum. Apesar de sua alta ocorrência mundial, pouco se sabe sobre os mecanismos imunológicos envolvidos nestas infecções. Neste trabalho investigamos a participação de duas classes de receptores de imunidade inata (NLRs e CLRs) na resposta a T.rubrum e avaliamos o perfil proteômico de macrófagos quando estimulados com o fungo. Observamos que T.rubrum foi capaz de induzir a produção de IL-1β dependente do inflamassomo NLRP3 e destacamos o papel da sinalização de IL-1 na modulação da resposta de IL-17. Determinamos os CLRs dectina-1 e dectina-2 como receptores essenciais na produção de citocinas inflamatórias e para o controle da infecção experimental. Curiosamente, a IL-17 e os linfócitos T e B foram dispensáveis para a eliminação do fungo. Também identificamos a proteína CLEC1A como uma novo receptor para fungos, envolvido no reconhecimento de glicolipídeos de T.rubrum. Por fim, a análise proteômica de macrofagos revelou a vimentina e a plastina-2 como duas proteínas potencialmente envolvidas na relação patógeno-hospedeiro.Dermatophytosis are chronic fungal infections whose main causative agent is Trichophyton rubrum. Despite its high incidence worldwide, the immunological mechanisms underlying these infections remain largely unknown. Here we investigated the involvement of two classes of innate immune receptors (NLRs and CLRs) in the reponse to T.rubrum and performed a proteomic profiling of macrophages upon T.rubrum stimulation. We observed that T.rubrum was able to drive NLRP3 inflammasome-derived IL-1β production and highlighted IL-1 signaling as an important component in the shaping of the IL-17 response. We defined the CLRs dectin-1 and dectin-2 as key receptors for the induction of inflammatory cytokines and for the infection control in the in vivo settings. Curiously, IL-17 cytokines and T and B lymphocytes were dispensable for fungal clearance. In addition, we uncovered CLEC1A as a new receptor in fungal sensing, involved in the recognition of T.rubrum glycolipids. Finally, the proteomic analysis revealed Vimentin and Plastin-2 as two proteins potentially involved in the host-pathogen interaction.
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Bulzacca, Sofia, and Virginia Spoglianti. "Scavo archeologico di Villa Clelia a Imola. Musealizzazione di un luogo sacralizzato." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2018. http://amslaurea.unibo.it/15615/.
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Il progetto di musealizzazione dell'area archeologica di Villa Clelia nasce dalla volontà di valorizzare il luogo dell'antica cattedrale di S. Cassiano, dedicata al santo patrono della città di Imola e sorta sulle sue spoglie. L'area si trova in una zona periferica e residenziale della città che si presenta come un vuoto urbano. Partendo da un accurato lavoro di rilievo e analisi storica del sito, il progetto propone una visita dello scavo archeologico lungo un percorso che scende alla quota dei reperti e risale attraverso tre livelli individuati. Un confronto tipologico con il sistema basilicale ravennate e milanese ha permesso di ipotizzare una ricostruzione planivolumetrica dell'antica cattedrale, di cui è stato evocato il fronte.
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Cruz, Cesar A. "Letting Go of Clecha, While Holding Corazón; Developing a New Approach to Empowering Youth in Gangs the Homeboy Industries Way." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:27013337.
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This capstone seeks to assess and support Homeboy Industries (HBI), a leader in wrap-around services for formerly gang-involved and incarcerated men and women, in their co-creation of a youth services committee and a comprehensive system of care for young people. In doing so, my strategic project consists of conducting stakeholder interviews, focus groups, and synthesizing those findings to present to the organization. The second part of the strategic project involves building and working with a team of individuals from various departments, including case management, mental health, education, job services within two separate agencies, Homeboy Industries and Learning Works Charter School Network, to create a youth services committee that can carry the work forward. In service of evaluating the progress of the strategic project, I will utilize the 4I Framework of Organizational Learning, developed by management professor, Mary Crossan, and her associates from the Ivey School of Business. The 4I Framework contains “four related (sub)processes-intuiting, interpreting, integrating, and institutionalizing-that occur over three levels: individual, group, and organization” (Crossan et al., 1999, p. 524). Ultimately, the goal is to help an already successful leader in wrap-around support services for adults, Homeboy Industries, create an “organized system of care for young people” (Torres, 2015). This goal can be achieved by maximizing its strengths, coupling them with best practices in youth development, and in creating a team that can place the needs of young people in its core mission. Creating an organized system of care, Homeboy Industries-style, can have national implications as the new secretary of education, John King, has made it a point to visit with the leaders of Homeboy Industries (August 2015, Appendix A) in search of models for empowering the youth in a non-traditional way. If clecha, or knowledge that is passed down in prison is the old way of empowering young people, as it often goes in one ear and out the other, then this capstone seeks to capture the experience of Homeboy Industries and Learning Works, the profound work of founder Father Greg Boyle and many amazing practitioners on site at HBI, and combine it with the wisdom of young people, to offer a new approach to empower youth in gangs, the ever-evolving, Homeboy Industries Way. See, the idea of clecha or street wisdom has been passed down for generations as the way that older homies “lace” (give) younger homies advice. In the research on best practices to reach gang involved youth, this clecha notion dates back to the curbside counselor of the 1930s from the seminal work of psychologist Clifford Shaw, but often times, that form of advice has not worked. This has created what Reed Larson, a pioneer in positive youth development, calls the Intentionality Paradox. According to Larson, the paradox lies in that adults want to be intentional with their advice-giving to young people because “it is easier to think about molding clay than about helping the clay mold itself.” (Larson, 2006, p. 682) Larson along with many other experts in the field of youth development are telling us, what young people have been saying for a long time, “stop telling me what to do.” They don’t care to know how much we know (about life or the struggle), they need to know (and feel) how much we actually care. Many adults care so much that they struggle to balance letting youth learn on their own, and sharing their own experiences or clecha. While we are trying to figure it out in the field of youth development and education, too many young people are dying. Every 26 seconds a young person drops out of school in the U.S. (American Graduate, 2016). Over 1 million youth per year are system-involved in “courts with juvenile jurisdiction handling delinquency cases.” (Hockenberry, 2015, p. 6) Thousands of those youth are ending up caged in juvenile halls and prison, and many are dying in our cities nationwide. We must search for new ways to engage and walk with youth in gangs. This is part of that search.
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Maia, William Pedrosa. "Projeto, implementação e desempenho dos algoritmos criptográficos AES, PRESENT e CLEFIA em FPGA." Universidade Federal de Sergipe, 2017. https://ri.ufs.br/handle/riufs/5029.
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The development of dedicated cryptography systems for applications requiring low cost and consumption has been the current focus of research. This work addresses the design and performance analysis of cryptographic algorithms AES-128 (NIST standard), PRESENT-80 and CLEFIA-128 (ISO/IEC standard for Lightweight Cryptography), im-plemented in FPGA (Basys 3 Artix-7 - 28 nm technology) using VHDL. Performance metrics were analyzed and compared: occupied area in the FPGA, throughput (Mbps), efficiency (Mbps/slice), energy efficiency (Ws/bit) and current consumption. The metrics were obtained through the synthesis and implementation tool in FPGA, Vivado Design Suites (Xilinx), and by means of a current measurement prototype, which uses the Ada-fruit INA219 sensor board (Sensor from Texas Instruments) and microcontroller Arduino Uno (Atmega328 - Atmel). We also analyzed the graphical representation of current con-sumption through the mathematical model based on the Welch periodogram, applied on the current consumption variables during the data encryption process. The results show current curves that facilitate the identification and comparison of the algorithms. The data of area consumption, processing speed and efficiency in the FPGA obtained satisfactory performance in comparison with other implementations existing in the literature, besides providing relevant information to choose an algorithm of encryption.O desenvolvimento de sistemas dedicados de criptografia, para aplicações que exigem baixo custo e consumo tem sido enfoque atual de pesquisas. Este trabalho aborda o projeto e análise de desempenho dos algoritmos de criptografia AES-128 (padrão NIST), PRESENT-80 e CLEFIA-128 (padrão ISO/IEC para Criptografia Leve), implementados em FPGA (Basys 3 Artix-7 – tecnologia de 28 nm), utilizando VHDL. Foram analisadas e comparadas as métricas de desempenho: área ocupada no FPGA, velocidade de proces-samento (Mbps), eficiência (Mbps/slice), eficiência energética (Ws/bit) e consumo de corrente. As métricas foram obtidas através da ferramenta de síntese e implementação em FPGA, Vivado Design Suites (Xilinx), e por meio de um protótipo de medição de corrente, que utiliza a placa sensor Adafruit INA219 (sensor da Texas Instruments) e microcontro-lador Arduino Uno (Atmega328 - Atmel). Foram analisadas também a representação grá-fica do consumo de corrente através do modelo matemático baseado no periodograma de Welch, aplicado sobre as variáveis de consumo de corrente durante o processo de encrip-tação de dados. Os resultados mostram curvas de corrente que facilitam a identificação e comparação dos algoritmos. Os dados de consumo de área, velocidade processamento e eficiência no FPGA obtiveram desempenho satisfatório, em comparação com outras im-plementações existentes na literatura, além de fornecer informação relevante para escolha de um algoritmo de criptografia.
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Neulen, Marie-Luise. "Das Hühner CLEC-2 Homolog." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-151348.
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Castiñeiras, Vilariño Mercedes María Verfasser], Jürgen [Akademischer Betreuer] Ruland, Ulrike [Akademischer Betreuer] [Protzer-Knolle, and Philipp J. [Akademischer Betreuer] Jost. "Generation and analysis of a Clec12a-deficient mouse model / Mercedes María Castiñeiras Vilariño. Gutachter: Ulrike Protzer ; Philipp J Jost. Betreuer: Jürgen Ruland." München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1064523048/34.
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Pirolla, Renan Augusto Siqueira. "Aplicação de fosfolipase A2 de veneno de serpentes em biocatalise." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/250602.
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Orientador: Jose Augusto Rosario RodriguesDissertação ( mestrado) - Universidade Estadual de Campinas, Instituto de Quimica
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Resumo: O projeto explora o potencial catalítico de fosfolipases A2, isoladas de venenos de serpentes brasileiras para efetuar resolução enzimática de substratos com relevância científica, visto que nenhum trabalho anterior foi feito analisando-se sua enantiosseletividade. Foram feitos estudos sobre a resolução do Binol, do a-tetralol, do 1-feniletanol, do para-nitro-1-feniletanol, do ácido 3-(2-bromo-hexanoiloxi)-4-nitrobenzóico e ácido 3-(2-metil-hexanoiloxi)-4-nitrobenzóico.Devido a dificuldade de obtenção e purificação das fosfolipases, a enzima foi imobilizada utilizando a formação de um agregado com ligações cruzadas (Cross-Linked Enzyme Aggregate . CLEA). Os agregados foram produzidos com quatro tipos de precipitantes (solução 55 % de sulfato de amônio, polietilenoglicol 600 Da, dimetoxietano e acetona) e dois adicionantes (TRITON-X100 e polietilenodiimina). Com os testes, observou-se que o CLEA formado com sulfato de amônio, sem adicionante apresentou os melhores resultados, sendo utilizado nas reações de biocatálise. A resolução dos substratos foi feita com a esterificação dos álcoois, formando-se ésteres (acetatos, propanoatos e hexanoatos), e posterior hidrólise com a enzima não-imobilizada e CLEA da fosfolipase A2, para comparação. Alíquotas das reações foram e analisadas por GC/FID com fase estacionária quiral para estudo dos excessos enantioméricos. As reações foram feitas a temperatura ambiente e a 45 °C. Os resultados indicam atividade enzimática sendo possível obter o tetralol com 16% de e.e. utilizando-se o CLEA e o p-nitro-1-feniletanol com 19% de ee usando-se a PLA2 livre. Os outros álcoois foram obtidos com baixos ee. O ácido 3-(2-bromo-hexanoiloxi)-4-nitrobenzóico não pode ser analisado por sofrer hidrólise química completa no meio reacional, e com a hidrólise do ácido 3-(2-metil-hexanoiloxi)-4-nitrobenzóico foi possível a obtenção do ácido 2-metil-hexanóico com 9 % utilizando-se CLEA e 7 % com a enzima livre. A baixa enantiosseletividade foi interpretada como decorrente da fraca interação dos substratos com o sítio ativo da enzima
Abstract: This project explores the catalytic potential of fosfolipases A2, isolated from poisons of brazilian serpents to effect enzymatic substrate resolution with scientific relevance, since no previous work was made analyzing its enantioselectivity. Studies on the resolution of several compounds had been made, including Binol, a-tetralol, 1-phenylethanol, para-nitro-1- phenylethanol, 3-(2-bromohexanoiloxy)-4-nitrobenzoic acid and 3-(2-methylhexanoiloxy)-4-nitrobenzoic acid.Due to difficulty of attainment and purification of the phospholipase, the enzyme was immobilized using the formation of an aggregate with cross-links (Cross-Linked Enzyme Aggregate ¿ CLEA). These aggregates had been produced with four types of precipitation agents (ammonium sulphate solution 55%, polietileneglycol 600 Da, dimethoxyethane and acetone) and two additives (TRITON-X100 and poliethylenediimine). With the tests, it was observed that the CLEA formed with ammonium sulphate, without additives presented the best results, being used in the reactions of biocatalysis.The resolution of substrates was made with the alcohol¿s esterification, forming different (acetates, propanoates and hexanoates) followed by hydrolysis with the free enzyme and CLEA, for comparison. Aliquots of the reactions had been made and analyzed with GC/FID with quiral stationary phase for study of the enantiomerics excesses. The reactions had been made at ambient temperature and 45 °C.The results indicate enzymatic activity and was possible to get tetralol with 16% of ee using CLEA and p-nitro-1-phenylethanol with 19% of ee. The other alcohols had been gotten with low ee. The 3- (2-bromohexanoiloxy) - 4-nitrobenzoic acid cannot be analyzed by suffering complete chemical hydrolysis during the reaction, and with hydrolysis of acid the 3- (2-metilhexanoiloxi) - 4-nitrobenzoic the attainment of the acid 2-metilhexanoic with 9% was possible using CLEA and 7% with the free enzyme. The low enantioselectivity was explained due to the weak interaction of substrates with the active site of enzyme
Mestrado
Quimica Organica
Mestre em Química
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Prati, Davide. "L'invisibile agli occhi. Proposte per la valorizzazione dell'area archeologica di Villa Clelia ad Imola (BO)." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2021. http://amslaurea.unibo.it/23076/.
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Progetto di valorizzazione e conservazione dell’area archeologica di Villa Clelia, Imola (BO).
Il sito, che allo stato di fatto presenta dei manufatti che versano allo stato di rudere, gode di un importante riconoscimento nell’immaginario locale, in quanto presunto luogo di sepoltura delle antiche spoglie del santo martire Cassiano, patrono della città. Attorno ad esso si sarebbe presumibilmente eretta la “Basilica Beati Cassiani”, edificio per eccellenza dell’omonimo episcopio, citato dalle fonti storiche con il toponimo “Castrum Sancti Cassiani”.
L’area presenta numerose criticità dovute alla sua conformazione: su tutte, la scarsa leggibilità nei confronti del tessuto urbano, a discapito della portata del valore storico e culturale dei beni presenti in situ. Obiettivo principale, nonché scopo di questa tesi, è quello di ridare identità ad un luogo attraverso un progetto di valorizzazione e conservazione attiva del palinsesto archeologico, affrontando tematiche legate al restauro, con altre a carattere urbanistico.
Un’unità introduttiva, a supporto di un ‘testo’ che il visitatore dovrà comprendere successivamente, sarà la chiave di volta per la custodia della memoria del luogo.
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Probst, Lilli Teresa [Verfasser], and Thomas [Gutachter] Hünig. "Immune cell function in the Clec16a Knock-down Mouse / Lilli Teresa Probst. Gutachter: Thomas Hünig." Würzburg : Universität Würzburg, 2015. http://d-nb.info/1111784191/34.
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Tam, Chun-yee, and 譚雋怡. "Dissecting the physiological role of the novel lupus-associated C-type lectin-like protein CLEC16A." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206749.
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The CLEC16A locus has been identified as a susceptibility gene for multiple autoimmune diseases, including multiple sclerosis, type-I diabetes and systemic lupus erythematosus (SLE), in genome-wide association studies. CLEC16A encodes a novel C-type lectin-like protein, by virtue of a predicted C-type lectinlike domain (CTLD), with unclear function. Studies on the disease-associated SNPs have suggested that CLEC16A polymorphisms affect the expression of neighboring genes, while the effect on its own expression is unclear. Several functional studies have interrogated the physiological role(s) of CLEC16A in disparate directions. The Drosophila ortholog of CLEC16A, Ema, has been reported to regulate endosomal protein trafficking and the autophagic process, while CLEC16A has been found to participate in LPS-induced inflammatory cytokine response in rat astrocytes. Since there is not a consenting role ascribed to CLEC16A, this study was undertaken to investigate the functional involvement(s) of CLEC16A in mammalian cells and the expression of CLEC16A in lupus patients, with the attempt to comprehend the association between CLEC16A and SLE.
By overexpressing in non-immune epithelial cells, CLEC16A was revealed to be an intracellular protein of ~130 kDa in size. CLEC16A displayed a punctated expression pattern, which did not co-localize with endosomes, lysosomes, autophagosomes or endoplasmic reticulum in steady state. When treated with rapamycin or serum-starved, CLEC16A-overexpressing cells exhibited a reduced autophagic response, suggesting that CLEC16A may have an inhibitory role in autophagy. Besides the predicted CTLD, motif prediction has also implicated an immunomodulatory role for CLEC16A. Due to the observed inhibition on autophagy, coupled with recent findings linking autophagy and inflammasome activation, the involvement of CLEC16A in NLRP3 inflammasome was investigated. By knocking down CLEC16A in the human macrophage-like THP-1 cells, CLEC16A was found to potentially regulate NLRP3 inflammasome activation via inhibiting the LPS-induced pro-IL-1aasynthesis. Finally, the expressions of the long and short isoforms, CLEC16A_V1 and CLEC16A_V2 of CLEC16A in PBMCs were compared between healthy controls and SLE patients. A higher CLEC16A_V1 expression was observed in SLE patients, whereas the reverse was found for CLEC16A_V2. The expressions of the isoforms, however, were not correlated with the disease severity and clinical manifestations.
The finding that CLEC16A may inhibit autophagy is in contrast with the reported function of Ema in supporting autophagy, and such discrepancy could be because of the different cell systems used. The finding that CLEC16A may downregulate NLRP3 inflammasome activation has not been previously reported, and the mechanism(s) of such regulation warrant(s) future studies. The molecular basis of how CLEC16A regulates autophagy and inflammasome waits to be delineated. Such knowledge, together with information of where endogenous CLEC16A is expressed, shall incite better understanding of the contribution of CLEC16A to SLE development.published_or_final_version
Medicine
Doctoral
Doctor of Philosophy
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Mesquita, Regina Clelia da Costa. "Separação de uma mistura de compostos digitalicos em escala semi-preparativa atraves de cromatografia liquida por deslocamento." [s.n.], 1994. http://repositorio.unicamp.br/jspui/handle/REPOSIP/249755.
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Orientador : Carol H. CollinsDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica
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Mestrado
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Manne, Bhanu Kanth. "CLEC-2 SIGNAL TRANSDUCTION IN PLATELET ACTIVATION." Diss., Temple University Libraries, 2015. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/340495.
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PhysiologyPh.D.
Platelets are involved in many processes ranging from fighting microbial infections and triggering inflammation to promoting tumor angiogenesis and metastasis. Nevertheless, the primary physiological function of platelets is to act as essential mediators in maintaining homeostasis of the circulatory system by forming hemostatic thrombi that prevent blood loss and maintain vascular integrity. CLEC-2 is a C-type lectin-like receptor that is highly expressed in platelets and lesser extent, in other cell types such as activated dendritic cells and B cells. Rhodocytin was the first ligand used to identify CLEC-2 receptor and it’s signaling on platelets. In the first chapter we identified a new agonist for CLEC-2 receptor. Fucoidan, a sulfated polysaccharide from fucus vesiculosus, decreases bleeding time and clotting time in hemophilia, possibly through inhibition of tissue factor pathway inhibitor. However, its effect on platelets and the receptor by which fucoidan induces cellular processes has not been elucidated. In this study, we demonstrate that fucoidan induces platelet activation in a concentration-dependent manner. Fucoidan-induced platelet activation was completely abolished by the pan-Src family kinase (SFK) inhibitor, PP2, or when Syk is inhibited. PP2 abolished phosphorylation of Syk and Phospholipase Cγ−2. Fucoidan-induced platelet activation had a lag phase, which is reminiscent of platelet activation by collagen and CLEC-2 receptor agonists. Platelet activation by fucoidan was only slightly inhibited in FcRγ chain null mice, indicating that fucoidan was not acting primarily through GPVI receptor. On the other hand, fucoidan-induced platelet activation was inhibited in platelet-specific CLEC-2 knock-out murine platelets revealing CLEC-2 as a physiological target of fucoidan. Thus, our data show fucoidan as a novel CLEC-2 receptor agonist that activates platelets through a SFK-dependent signaling pathway. Furthermore, the efficacy of fucoidan in hemophilia raises the possibility that decreased bleeding times could be achieved through activation of platelets. Lipid rafts are distinct areas of the plasma membrane implicated in the regulation of signaling in a variety of cells including platelets. A previous study C-type lectin like receptor 2 (CLEC-2) has been reported to activate platelets through a lipid raft-dependent manner. Secreted ADP potentiates CLEC-2-mediated platelet aggregation. We have investigated whether the decrease in CLEC-2-mediated platelet aggregation, previously reported in platelets with disrupted rafts, is a result of the loss of agonist potentiation by ADP. We disrupted platelet lipid rafts with methyl-β-cyclodextrin (MβCD) and measured signaling events downstream of CLEC-2 activation. Lipid raft disruption decreases platelet aggregation induced by CLEC-2 agonists. The inhibition of platelet aggregation by the disruption of lipid rafts was rescued by the exogenous addition of epinephrine but not 2-methylthioadenosine diphosphate (2MeSADP), which suggests that lipid raft disruption effects P2Y12-mediated Gi activation but not Gz. Phosphorylation of Syk (Y525/526) and PLCγ2 (Y759), were not affected by raft disruption in CLEC-2 agonist-stimulated platelets. Furthermore, tyrosine phosphorylation of the CLEC-2 hemi-ITAM was not effected when MβCD disrupts lipid rafts. Lipid rafts do not directly contribute to CLEC-2 receptor activation in platelets. The effects of disruption of lipid rafts in in vitro assays can be attributed to inhibition of ADP feedback that potentiates CLEC-2 signaling. Tyrosine kinase pathways are known to play an important role in the activation of platelets. In particular, the GPVI and CLEC-2 receptors are known to activate Syk upon tyrosine phosphorylation of an Immune Tyrosine Activation Motif (ITAM) and hemi-ITAM, respectively. However, unlike GPVI, the CLEC-2 receptor contains only one tyrosine motif in the intracellular domain. The mechanisms by which this receptor activates Syk are not completely understood. In chapter 3, we identified a novel signaling mechanism in CLEC-2-mediated Syk activation. CLEC-2-mediated, but not GPVI-mediated, platelet activation and Syk phosphorylation were abolished by inhibition of PI3-Kinase, which demonstrates that PI3-Kinase regulates Syk downstream of CLEC-2. Ibrutinib, a Tec family kinase inhibitor, also completely abolished CLEC-2-mediated aggregation and Syk phosphorylation in human and murine platelets. Furthermore, embryos lacking both Btk and Tec exhibited cutaneous edema associated with blood-filled vessels in a typical lymphatic pattern similar to CLEC-2 or Syk-deficient embryos. Thus our data show, for the first time, that PI3-Kinase and Tec family kinases play a crucial role in the regulation of platelet activation and Syk phosphorylation downstream of CLEC-2 receptor.
Temple University--Theses
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Gerold, Kay [Verfasser], and Stephan [Akademischer Betreuer] Kissler. "CTLA4 and CLEC16A in Type 1 Diabetes - Looking behind the association / Kay Gerold. Betreuer: Stephan Kissler." Würzburg : Universitätsbibliothek der Universität Würzburg, 2013. http://d-nb.info/1029975086/34.
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Lobry, J. R. "RE-EVALUATION DU MODELE DE CROISSANCE DE MONOD.EFFET DES ANTIBIOTIQUES SUR L'ENERGIE DE MAINTENANCE." Phd thesis, Université Claude Bernard - Lyon I, 1991. http://tel.archives-ouvertes.fr/tel-00410686.
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Le contexte expérimental et les hypothèses biologiques sous-jacentes du modèle de croissance Monod sont présentées. L'importance de ce modèle, ses principaux champs d'application, la variabilité de la valeur de ses paramètres, ainsi que la dynamique de la croissance de son impact sont exposés. Ce modèle était supposé se justifier de façon analogue au modèle de Michaelis et Menten, mais cette approche soulève plusieurs difficultés.Nous montrons comment le modèle de Monod peut être obtenu à partir du modèle de croissance logistique, avec pour corollaire la prédiction inattendue d'une augmentation apparente de la valeur du paramètre <> avec le paramètre <>. Une ré-examination des résultats publiés montre que cette tendance est observée. Il est cependant difficile de savoir si ces résultats sont réellement probants.
Pour tester l'hypothèse de l'augmentation de la valeur du paramètre <> avec le paramètre <>, nous avons estimés ces deux paramètres pour Escherichia coli K12 CIP 54117 cultivé dans deux milieux de culture pour modifier la valeur du paramètre <>. Les résultats expérimentaux ne semblent pas être en contradiction avec la prédiction faite. Le paramètre <> ne devrait plus être considéré comme une constante physiologique, et le rapport de Healey <> lui être préféré pour caractériser l'affinité des micro-organismes pour un substrat limitant.
L'énergie de maintenance d'une population de micro-organismes peut être déterminée avec une relation développée par Monod. Les conditions de son utilisation pour caractériser l'effet des antibiotiques sur la croissance sont précisées. Une augmentation exponentielle de l'énergie de maintenance avec la concentration en antibiotique est fréquemment observée.
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Carpisassi, Daniela. "La strategia discorsiva dell'ironia nella narrativa "muliebre" agli inizi del XX secolo : Clelia Pellicano (Jane Grey) e Gabrielle Willy (Collette)." Paris 3, 2008. http://www.theses.fr/2008PA030169.
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Ce travail présente la réflexion sur la comparaison de la stratégie de l'ironie dans les oeuvres des deux auteures du début du XX siècle l'italienne Clelia Romano Pellicano et la française Colette. Nous avons comparé le cycle des Claudine de cette dernière avec les recueils de nouvelles Coppie et Novelle calabresi signées par Pellicano, retraçant aussi une biographie de cette femme écrivain méconnue. Pour cette étude, une notion sexuée d'ironie et d'humour au féminin a été créée, reconstituant le cadre des théories existantes que l'on a mis en relation aux études sur les dimensions interdiscursives et relationnelles propres à l'ironie littéraire. Notre discours a aussi été contextualisé par une reconstruction des aspects dominants de l'esprit de la Belle Époque. Nous avons identifié les termes du débat sur la surabondance et la qualité de la littérature féminine, qui était (dis)qualifiée de « muliebre » ; débat dans lequel Colette figurait comme élément principal de comparaison par rapport aux auteures italiennes. L'ironie de Pellicano et Colette s'est révélée être la stratégie discursive qui amorce un conflit (amoureux) avec l'Autre. Par l'ironie elles ont dénoncé les contradictions de leur temps et évoqué des sujets sensibles ou considérés scabreux (dans la relation entre les deux sexes, par exemple). Elles se sont aussi rapportées au canon littéraire réaliste de façon désacralisée ; aspect que nous avons étudié en analysant la relation de l'ironie au naturalisme-vérisme. Les auteures ont, en outre, instauré une relation de complicité avec leurs lecteurs notamment grâce à l'ironie et à l'auto-ironie dont elles font preuve quant à leur propre statut d'écrivainesWe have compared how irony was used by two women writers at the beginning of the 20th century: the French Colette and the Italian Clelia Romano Pellicano. We have examined the navels of Claudine's series by Colette, and the two collections of short-stories Coppie and Novelle calabresi by Pellicano. The missing biography of the Italian writer has also been reconstructed. For this analysis we have revised the notion of feminine irony (and humor) and of women's comedy, reconstrueting the panorama of the existing theories and reconsidering some studies about the interdiscursive and relational dimensions proper of literary irony. We have historically contextualised our analysis identifying the characteristics of Belle Epoque's esprit and the relationship between caricatures and literary charge. We have picked out the ternis of the debate of this period about the excess and the quality of that female literature disqualified by the adjective « muliebre ». In this debate Colette has appeared as term of comparison for the works of the Italian women witers. Pellicano and Colette's irony emerges as a discursive strategy through which it is possible to inaugurate a "caring" conflict with the Other, in order to uncover the contradictions of their time and to deal with delicated subjets or themes considered awkward (i. E. The authorities' corruption or the relationship between sexes). Both women writers were related to the literary realistic model of their time by an irreverent way. We have studied it also reflecting upon the relationship between irony and Naturalism. Through irony and even self-irony about their status as women writers, they have created a relation with their readers
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Lee, Timothy Shan Wei. "The effect of crystal form on the catalytic and mechanical stability of cross linked enzyme crystals (CLECs)." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312347.
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Clark, Alexandra Elsie. "Characterisation of the C-type lectin-like receptor 1 (CLEC-1)." Thesis, University of Aberdeen, 2013. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=210080.
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Lombard, Stephanie Eileen. "Role of platelet CLEC-2 and podoplanin in inflammation and vascular integrity." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7398/.
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Introduction: The platelet receptor CLEC‐2 is believed to play a key role in many of the newly emerging roles of platelets, such as development and inflammation. The aim of this thesis was to look further into the interaction of CLEC‐2 and podoplanin and to investigate the role these proteins play in inflammation. Methods: In‐vitro flow experiments using recombinant podoplanin and whole blood were used to investigate the interaction of CLEC‐2 and podoplanin under shear stress. The role of CLEC‐2 in inflammation was investigated using a range of mouse models such as LPS induced peritonitis model, DSS induced colitis and a mouse model of atherosclerosis. Results: Mouse podoplanin induces platelet aggregation under arterial rates of shear through the receptor CLEC‐2. The aggregation is likely due to the high affinity interaction between mouse CLEC‐2 and podoplanin. The results of role of CLEC‐2 in inflammation revealed a lack of CLEC‐2 from inception causes a more acute inflammatory reaction to LPS. CLEC‐2 (removed post development) also plays a protective role in an acute model of ulcerative colitis. Mice lacking CLEC‐2 do not upregulate podoplanin on lymphatic endothelial cells and epithelial cells in the colon to the same degree as their wildtype counterparts following induction of colitis. CLEC‐2 is also protective against atherosclerosis however there was a greater upregulation of podoplanin in the plaques of atheroprone platelet CLEC‐2 deficient mice. The results of this thesis highlight the complicated role of CLEC‐2 in inflammatory disorders. There is also a clear difference in the affinity of mouse and human forms of CLEC‐2 and podoplanin which has important consequences for the interpretation of mouse models examining the role of these proteins in human diseases.
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Schober, Kilian [Verfasser], Martin [Gutachter] Fassnacht, and Stephan [Gutachter] Kissler. "Der Einfluss von CLEC16A auf Autophagie - ein neuer Mechanismus in der Pathogenese von Typ-1-Diabetes / Kilian Schober ; Gutachter: Martin Fassnacht, Stephan Kissler." Würzburg : Universität Würzburg, 2016. http://d-nb.info/1115145282/34.
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Souto, Maior Mourão Sá D. "Characterisation of the C-type lectin receptor CLEC-2 : expression, ligands and functions." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1302407/.
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Myeloid cells express a plethora of C-type lectin receptors (CLR) that can regulate inflammatory responses. Dectin-1 belongs to a sub-family of CLRs that possesses an extracellular C-type lectin domain (CTLD) and a single YxxL intracellular motif (hemITAM) that allows signalling via Syk kinase and induction of downstream functions. Based on consensus sequences for the CTLD and hemITAM, we identified CLEC-2 as a dectin-1-like receptor. CLEC-2 was previously characterised as a Syk-coupled platelet receptor able to induce platelet aggregation when targeted by the snake venom rhodocytin and by cells expressing the endogenous protein podoplanin. I generated monoclonal antibodies against mouse CLEC-2 and found that CLEC-2 is also expressed on lymphoid and myeloid cells, including dendritic cells (DC). Notably, treatment with LPS increases CLEC-2 expression by myeloid cells and synergises with CLEC-2 signaling to induce increased secretion of IL-10 but not IL-12. This increased IL-10 production is also observed in the serum of mice administered with anti-CLEC-2 mAb and LPS, and is dependent on the presence of macrophages and DCs. Furthermore, I generated a CLEC-2 conditional KO mouse line that will provide a tool to study CLEC-2 function in myeloid cells in vivo. Collectively, these data indicate that CLEC-2 expression is not restricted to platelets and that it plays a role on the vascular development and modulation of TLR responses.
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Alshehri, Osama Mohammed D. "The role of GPVI and CLEC-2 in platelet activation by miscellaneous ligands." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6880/.
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Platelets are an essential factor in wound repair and blood clotting, where exposed sub-endothelial extracellular matrix (ECM) proteins induce activation during vascular injury. However, platelets can also be activated by a diverse range of stimuli that share little-to-no resemblance in structure to each other, or to recognized ligands of platelet receptors. These stimuli include diesel exhaust particles (DEP), various peptides including 4N1-1 and Champs, lipoproteins such as PAM3-CSK4, and large polysaccharides for example, fucoidan, and dextran. In this thesis, I demonstrate that this seemingly miscellaneous group of stimuli cause aggregation of human and mouse platelets through Src and Syk tyrosine kinases in association with stimulus-specific tyrosine phosphorylation of the GPVI/FcRγ-chain complex and/or CLEC-2. A critical role for GPVI and/or CLEC-2 in mediating aggregation is shown using platelets from receptor-deficient mouse platelets. Additionally, in double deficient mouse platelets these stimuli activate Src tyrosine kinases independent of GPVI and CLEC-2. DEP, fucoidan and dextran were shown to activate transfected GPVI or CLEC-2 in a cell line model. However, 4N1-1, Champs and PAM3-CSK4 did not activate transfected GPVI or CLEC-2 in a cell line model, nor could they bind to recombinant forms of either receptor. In addition, I demonstrate the unexpected observation that fibrin also activates GPVI revealing a new stage of haemostasis in which the generation of fibrin from fibrinogen reinforces platelet activation.
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Pavelková, Olga. "Význam a výsledky jednání ministerských konferencí WTO." Master's thesis, Vysoká škola ekonomická v Praze, 2007. http://www.nusl.cz/ntk/nusl-1111.
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Cílem práce je demonstrovat výsledky jednání vrcholného orgánu WTO, zhodnotit dopady na světovou ekonomiku a tím podpořit smysluplnost WTO. Nejdříve jsou popsány historické souvislosti vzniku WTO, tedy vývoj GATT. Dále se práce věnuje WTO, jejímu fungování, cílům, organizační struktuře, principům a struktuře dohod. Poslední část je zaměřena na vývoj jednání v rámci ministerských konferencí.
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Lopez, Sarah. "De nouveaux biocatalyseurs hétérogènes pour des réactions d'oxydation : des cristaux de métalloenzymes artificielles." Thesis, Université Grenoble Alpes (ComUE), 2018. http://www.theses.fr/2018GREAV022/document.
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Depuis la révolution industrielle, la chimie ne cesse de prospérer en développant des procédés de plus en plus performants souvent aux dépens de l’environnement. Dans le cadre du développement d’une chimie durable, des procédés catalytiques dans le domaine de la chimie d’oxydation sont mis en place en utilisant des métaux physiologiques et des oxydants doux. En combinant les avantages de la catalyse homogène et de la biocatalyse, de nouveaux catalyseurs bio-inspirés ont émergé, les métalloenzymes artificielles. Elles sont constituées d’un complexe inorganique, choisi en fonction de la réaction visée, qui est ancré au sein d’une protéine, qui apporte la sélectivité de la réaction. Au cours des travaux de cette thèse, de nouvelles métalloenzymes artificielles ont été créées par ancrage de divers complexes de Fe ou de Ru au sein de la protéine NikA. Dans un premier temps, l’hybride NikA/Ru-bpza a été synthétisé pour réaliser l’hydroxychloration d’alcènes en présence d’un iode hypervalent. Bien que d’excellentes propriétés catalytiques aient été obtenues, l’amélioration de la stabilité de ce type de catalyseurs, en particulier pour des réactions d’oxydation, reste un challenge important à relever pour leur utilisation au niveau industriel. Une des solutions originale est basée sur le développement de la catalyse hétérogène, en utilisant de cristaux de métalloenzymes artificielles grâce à la technologie CLEC (Cross-Linked Enzyme Crystals). Cette technologie permet, d’une part, d’améliorer la stabilité et la recyclabilité des catalyseurs, et d’autre part, d’élargir les conditions réactionnelles utilisées (solvants, pH, températures). Trois réactivités ont été développées à base de CLEC NikA/FeL : (i) la sulfoxydation de thioéthers, (ii) l’hydroxychloration d’alcènes en présence d’Oxone® et de chlore et (iii) la coupure oxydante d’alcènes par activation d’O2. Ces résultats ont permis d’explorer de nouvelles réactivités en chimie cascade soit en combinant les CLEC mis au point, soit en combinant différents catalyseurs homogènesSince the industrial revolution, chemistry has continually thriven by developing new efficient processes at the expense of the environment. As an example, oxidation reactions are performed under harsh conditions with the use of toxic oxidants. With the emergence of green chemistry, catalytic processes using physiological metals and soft oxidants are privileged. Combining the advantages of biocatalysis and homogeneous catalysis, the design of novel bioinspired catalysts, consisting on the synthesis of artificial enzymes has recently emerged. These hybrids are composed of an inorganic complex, driving the reactivity of the enzyme, inserted into a protein, which drives the reaction selectivity. The thesis described new developments in original artificial metalloenzymes, based on the use of the NikA protein and Fe or Ru catalysts. First, a new hybrid has been developed by anchoring the Ru-bpza complex to NikA to catalyze alkene hydroxychloration with hypervalent iodine. Although excellent catalytic efficiencies were obtained, the stability improvement remains a major challenge for the industrial use of these catalytic processes, especially when oxidation chemistry is concerned. One possible strategy is based on the development of heterogeneous catalysis, by using a crystal/solution version of the artificial metalloenzymes thank to the cross-linked enzyme crystals (CLEC) technology. On the one hand, this technology allows to increase the stability and the recyclability of the catalysts. On the other hand, catalysis can be performed under a various reactions conditions (organic solvent, temperature, pH). Three reactivities have been developed with NikA/FeL-CLEC catalysts: (i) thioether sulfoxidation with NaOCl, (ii) alkene hydroxychloration with Oxone® and chloride source and (iii) oxidative cleavage of alkenes by O2 activation. To go further, new reactivities in cascade reactions have been explored combining either NikA-based CLEC developed, or different homogenous catalysts
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Börner, Kevin [Verfasser], Thomas [Gutachter] Hünig, Thomas [Gutachter] Herrmann, Wolfgang [Gutachter] Kastenmüller, Nicolas [Gutachter] Schlegel, Stephan [Gutachter] Kissler, and Hans-Peter [Gutachter] Tony. "How CLEC16A modifies the function of thymic epithelial cells / Kevin Börner ; Gutachter: Thomas Hünig, Thomas Herrmann, Wolfgang Kastenmüller, Nicolas Schlegel, Stephan Kissler, Hans-Peter Tony." Würzburg : Universität Würzburg, 2020. http://d-nb.info/1206540362/34.
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Caldeira, Cleusa. ""Sou negra? sim, e sou bela!" : uma aproximação do Cântico dos Cânticos 1.5-6 a partir da hermenêutica negra feminista / Cleusa Caldeira ; orientador, Vicente Artuso." reponame:Biblioteca Digital de Teses e Dissertações da PUC_PR, 2011. http://www.biblioteca.pucpr.br/tede/tde_busca/arquivo.php?codArquivo=2767.
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Dissertação (mestrado) - Pontifícia Universidade Católica do Paraná, Curitiba, 2011Bibliografia: p. 130-149
O objetivo desta pesquisa é apresentar um exercício de Hermenêutica Negra Feminista que visa a interpretar Cântico dos Cânticos 1.5-6. Neste exercício hermenêutico, que privilegia a experiência da mulher negra marcada pelo sexismo, racismo e classismo, pr
The objective of this research is to present an exercise in Black Feminist Hermeneutics that aims to interpret the Song of Songs, Chapter 1, Verses 5-6. It is intended in this exercise, that highly considers the Black woman experience marked by sexism, ra
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Tomlinson, Neil David. "Regulation of C-type lectin-like receptors dectin-1 and CLEC-2 by tetraspanins." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/826/.
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Tetraspanins are a superfamily of glycoproteins that function as ‘organisers’ of membranes by clustering with each other to form tetraspanin-enriched microdomains, into which certain other receptors and signalling proteins are recruited and regulated. Tetraspanin microdomains have been implicated in a range of biological processes including cell signalling, adhesion, intracellular trafficking, cell-cell fusion and viral entry. The tetraspanin CD37 was recently shown to negatively regulate the C-type lectin-like receptor dectin-1, which is essential for innate immune responses to fungal pathogens. The aim of this thesis was to firstly develop a cell line model system to investigate the mechanism by which tetraspanins inhibit dectin-1, and to secondly extend this work to the dectin-1-related CLEC-2, which is essential for platelet thrombus formation and stability. Using a nuclear factor of activated T-cells (NFAT) transcriptional reporter assay in the Jurkat T-cell line, transient over-expression of CD37 was found to powerfully inhibit dectin-1 signalling following stimulation with its ligand, β-glucan. Over-expression of other tetraspanins also inhibited dectin-1 signalling, but did not globally inhibit receptor signalling because the platelet collagen receptor, GPVI, was unaffected. Similar to dectin-1, CLEC-2 signalling in response to its ligand, the snake venom toxin rhodocytin, was also abrogated following tetraspanin over-expression. However, stable tetraspanin over-expression only partially reduced signalling. Moreover, knockdown of the major Jurkat cell tetraspanin, CD81, and deletion of the major platelet tetraspanin, CD9, did not affect dectin-1 and CLEC-2 signalling, respectively. In summary, the importance of transient tetraspanin over-expression for dectin-1 and CLEC-2 inhibition, and the fact that any tetraspanin can inhibit, suggests that tetraspanin microdomains are disrupted by the presence of one over-expressed tetraspanin. This leads to a failure of dectin-1 and CLEC-2 signalling by a mechanism that is not clear, but suggests that tetraspanin microdomains are important for signalling by these C-type lectin-like receptors.
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Hughes, Craig Edward. "Comparison of CLEC-2 and GPVI signaling in platelets : the role of adaptor proteins." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1204/.
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GPVI activates platelets through an ITAM pathway by activation of Src and Syk kinases leading to activation of PLC\(_y\)2. CLEC-2 has been shown to activate platelets using an ITAM-like sequence in its cytoplasmic tail that is also dependent on Src and Syk kinases, but shows a partial rather than an absolute dependence on adapter SLP-76 for activation of PLC\(_y\)2. The aim of this thesis is to understand some of the key differences in these signalling pathways. GPVI is in complex with FcRwhich contains the ITAM sequence (Yxx(L/I)x\(_{6-12}\)Yxx(L/I)). These two tyrosines provide a docking site for the tandem-SH2 domains of Syk. In this thesis I show that CLEC-2 signalling through Syk is mediated by phosphorylation of the CLEC-2 YxxL sequence, receptor dimerisation and cross-linking by the Syk SH2 domains. I also show that the differential requirement for SLP-76 is not mediated by Gads. Both signalling pathways also show partial dependency for LAT. I also show that a novel protein, G6f, is not able to substitute for LAT in this signalling pathway and also exclude the LAT-family proteins PAG, LIME, LAX and NTAL as potential LAT replacements in platelet activation by GPVI. These results extend our understanding of platelet activation by CLEC-2.
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Donà, Clelia [Verfasser], Ulrich [Akademischer Betreuer] Fischer, and Timothy [Akademischer Betreuer] Ferdelman. "Mobilization of sulfur by green sulfur bacteria : physiological and molecular studies on Chlorobaculum parvum DSM 263 / Clelia Donà. Gutachter: Ulrich Fischer ; Timothy Ferdelman. Betreuer: Ulrich Fischer." Bremen : Staats- und Universitätsbibliothek Bremen, 2011. http://d-nb.info/1071992880/34.
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Neulen, Marie-Luise [Verfasser], and Thomas [Akademischer Betreuer] Göbel. "Das Hühner CLEC-2 Homolog : ein Trombozytenrezeptor mit aktivierender Funktion / Marie-Luise Neulen. Betreuer: Thomas Göbel." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1029662223/34.
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Lowe, Kate. "The roles of podoplanin and clec-2 in the development and maintenance of the cerebral vasculature." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/5791/.
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The C-type lectin-like receptor, CLEC-2, is constitutively expressed on platelets, with reported expression on a number of leukocyte subsets in adult mice. Constitutive or platelet-specific deletion of CLEC-2 in mice induces cerebral haemorrhaging by midgestation. In this thesis, I investigated the basis of this defect, hypothesising that it is mediated by the loss of CLEC-2 activation by its endogenous ligand, podoplanin, expressed on the developing neural tube. Podoplaninfl/fl mice were crossed to mice expressing PGK-Cre to induce deletion of podoplanin at the two-cell stage. Developing blood vessels were visualized by 3-dimensional microscopy and found to be aberrantly patterned in CLEC-2- and podoplanin-deficient mice, culminating in widespread cerebral haemorrhaging by mid-gestation. Haemorrhages were also observed following Nestin-Cre driven deletion of podoplanin on neural progenitors and following deletion of the platelet integrin, αIIbβ3. Together these studies support that neuro-epithelial-derived podoplanin interacts with platelet-CLEC-2 to guide the maturation and integrity of the cerebral vasculature and to prevent haemorrhage by stimulating platelet aggregation. Using tamoxifen-inducible deletion of CLEC-2 in adult mice, the expression profile of CLEC-2 was investigated and shown to be restricted to platelets and circulating B-lymphocytes and CD11bhigh Gr1high myeloid cells. Furthermore, loss of CLEC-2 in adult mice was shown to be dispensable for maintaining blood-brain barrier permeability.
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Bittelbrunn, Cleima Coltri. "A importância da opinião multidisciplinar na formação conceitual do projeto de produto : um estudo de caso de cadeira de arremesso para paraatletas / Cleima Coltri Bittelbrunn ; orientador, Osíris Canciglieri Júnior." reponame:Biblioteca Digital de Teses e Dissertações da PUC_PR, 2007. http://www.biblioteca.pucpr.br/tede/tde_busca/arquivo.php?codArquivo=1126.
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Dissertação (mestrado) - Pontifícia Universidade Católica do Paraná, Curitiba, 2007Bibliografia: f. 186-194
Atualmente a globalização exige que o processo de desenvolvimento de produtos seja composto de distintas fases e estas estejam bem orquestradas para que o produto chegue ao seu destino em um menor tempo, com a qualidade requerida, e principalmente, a um c
The globalization, requires, nowadays, that the product development process be composed of very well orchestrate distinct phases in order that the product rises into the market with high quality, in a short time as possible and mainly with a adequate cost
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Chauhan, Abhishek. "Contribution of the platelet receptor CLEC-2 and its ligand podoplanin to the pathogenesis of liver disease." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8234/.
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Increasing lines of evidence place platelets as having a central role in liver disease. Platelets are recruited to the liver and, depending upon stage and type of liver injury play varying roles ranging from driving liver fibrosis to aiding regeneration. However the molecular basis and consequences of platelet activation in the liver are less clear. The work presented in this thesis demonstrates for the first time that platelet activation via CLEC-2 is important in the pathogenesis of liver disease. In chronic human diseases (CLD) such as Primary Biliary Cirrhosis, and Alcoholic Liver disease I have demonstrated that the ligand for CLEC-2, podoplanin is upregulated on portal venules and increases proportionately to disease activity. I also note podoplanin staining on macrophage populations in CLD. Furthermore I show that this enhanced podoplanin expression may be a useful predictor of portal venous thrombosis, and correlates with MELD score for some categories of disease. In acute liver injury, CLEC-2-depended platelet activation has a profound effect on disease development. Here podoplanin expression occurs upon Kupffer cells in both humans and mice. Using carbon tetrachloride and paracetamol to induce acute liver injury in mice, I show that macrophage-expressed podoplanin activates platelets via CLEC-2. This interaction worsens liver injury, I next show that by blocking this interaction (using either CLEC-2 or podoplanin-deficient mice, or by using a function- blocking podoplanin antibody) liver recovery from toxic liver injury was remarkably enhanced. This was dependent upon enhanced hepatic neutrophil recruitment in a TNF dependent fashion.
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Kerrigan, Ann. "The functional characterisation of murine CLEC-2 and analysis of the expression of its ligand, podoplanin, on macrophages." Doctoral thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/3169.
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Saxby, Donald William. "Sampling problems and hydraulic factors related to the dispersion of scheelite in drainage sediments, Clea property, Yukon Territory." Thesis, University of British Columbia, 1985. http://hdl.handle.net/2429/24913.
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Multifractional analysis for scheelite (G=5.9-6.1), magnetite (G=5.2), heavies (G>3.3), mediums (3.3Earth, Ocean and Atmospheric Sciences, Department of
Graduate
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Astarita, Jillian Leigh. "The role of the podoplanin-CLEC-2 pathway in stromal cell regulation of dendritic cell motility and lymph node architecture." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13065022.
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In addition to leukocytes, secondary lymphoid organs are populated by non-hematopoietic stromal cells. This diverse group of cells supports lymphocyte migration and homing, facilitates antigen delivery, and promotes T cell survival. However, there is relatively little known about the specific molecules governing the roles that these cells play in regulating dendritic cell (DC) motility and lymph node architecture. Here, we examine the interaction between two molecules, CLEC-2 and podoplanin (PDPN), that are critical for DC migration and maintaining structural integrity of lymph nodes. Together, these studies identify novel functions of lymph node stromal cells and a unique function for PDPN in the immune system.
In response detecting an potentially harmful antigen, DCs in peripheral tissues mature and travel to downstream lymph nodes by following chemokine gradients secreted by lymphatic endothelial cells (LECs) and fibroblastic reticular cells (FRCs) present in the lymph node paracortex. We discovered that, in addition to chemokines, DC migration requires CLEC-2 on DCs, as engagement of CLEC-2 with PDPN, which is expressed by LECs and FRCs, incites DC motility and is required for DC entry into the lymphatics, efficient arrival in the lymph node, and migration along the FRC network within the lymph node.
Next, we examined the effect of this interaction with respect to the stromal cell. Through a combination approaches, we discovered that PDPN is a master regulator of contractility in FRCs. The fact that FRCs are contractile cells was previously reported, but our study is the first to identify a function for this contractility: upon blockade of PDPN-mediated contractility, lymph nodes became enlarged, the FRC network became more sparse, and there were increased numbers of lymphocytes in the lymph node. Importantly, during an immune response, these changes resulted in more proliferation of antigen-specific T cells and impaired contraction of the lymph node upon resolution of inflammation. Finally, we found that CLEC-2 binding PDPN recapitulated the effect of PDPN deletion. Thus, during an immune response, CLEC-2+ DCs would use PDPN to efficiently migrate to the lymph node and simultaneously cause FRCs to relax and prepare the lymph node for expansion.
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Lopez, Robles Maria Dolores. "Étude de CLEC-1, un récepteur lectin-like de type C dans la fonction des cellules dendritiques et la tolérance immune." Thesis, Nantes, 2017. http://www.theses.fr/2017NANT1025.
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Les cellules dendritiques (DCs) sont essentielles pourconnecter l'immunité innée et adaptative et orienter lesréponses des lymphocytes T. Les récepteurs Lectin de type-Cprésents dans les DCs sont activés par des ligands exogènes etendogènes, ce qui dicte la réponse aux agents pathogènes parla modulation de la réponse T immunitaire. Nous avons déjàdécrit chez le rat, l'expression de CLEC-1 dans les DCs etnous avons démontré in vitro son rôle inhibiteur dansl'activation de la réponse T helper (Th17) ). Dans cette étude,nous avons examiné l'expression et la fonction de CLEC-1dans les DCs humaines et nous avons montré son expression àla surface cellulaire de la sous-population de DCs CD16- dansle sang et sur les DCs dérivées des monocytes (moDCs).L'expression de CLEC-1 sur les moDCs est diminuée par desstimuli inflammatoires et renforcée par le TGF-β. De plus,nous avons démontré que CLEC-1 est un récepteurfonctionnel sur les moDCs humains et que, bien qu'il nemodule pas la voie classique d’activation du facteur detranscription NFкB lié à la protéine kinase Syk, il réprime laréponse ultérieure Th17. De façon très importante, en utilisantdes rats déficients pour CLEC-1, nous avons montré que laperturbation de la signalisation de CLEC-1 conduit à unesurexpression de la sous-unité Il-12p40 dans les DCs, et à uneexacerbation des réponses CD4+ Th1 et Th17 in vitro et invivo. Collectivement, nos résultats établissent le rôleinhibiteur de CLEC-1 dans les DCs, capable d'amortir leuractivation et la réponse ultérieure Th17. CLEC-1 peutreprésenter une cible thérapeutique utile pour moduler lesréponses immunitaires T dans un contexte cliniqueDendritic cells (DCs) represent essential antigen-presentingcells that are critical for linking innate and adaptive immunity,and influencing T-cell responses. Among pattern recognitionreceptors, DCs express C-type lectin receptors triggered byboth exogenous and endogenous ligands, therefore dictatingpathogen response, and also shaping T-cell immunity. Wepreviously described in rat, the expression of the orphan Ctypelectin-like receptor-1 (CLEC-1) by DCs anddemonstrated in vitro its inhibitory role in downstream Thelper 17 (Th17) activation. In this study,we examined theexpression and functionality of CLEC-1 in human DCs, andshow a cell-surface expression on the CD16+ subpopulation ofblood DCs and on monocytederived DCs (moDCs). CLEC-1expression on moDCs is downregulated by inflammatorystimuli and enhanced by TGF- β. Moreover, we demonstratethat CLEC-1 is a functional receptor on human moDCs andthat although not modulating the spleen tyrosine kinase (Syk)dependent canonical nuclear factor-kB (NFкB) pathway,represses subsequent Th17 responses. Importantly, usingCLEC-1–deficient rats, we showed that disruption of CLEC-1signaling led to an enhanced Il-12p40 subunit expression inDCs, and to an exacerbation of downstream in vitro and invivo CD4+ Th1 and Th17 responses. Collectively, our resultsestablish a role for CLEC-1 as an inhibitory receptor in DCsable to dampen activation and downstream effector Thresponses. As a cell-surface receptor, CLEC-1 may representa useful therapeutic target for modulating T-cell immuneresponses in a clinical setting
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Aytar, Burcu Selin. "Preparation Of Cross-linked Tyrosinase Aggregates." Master's thesis, METU, 2006. http://etd.lib.metu.edu.tr/upload/2/12607318/index.pdf.
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ABSTRACT
PREPARATION OF CROSS-LINKED TYROSINASE AGGREGATES
Aytar, Burcu Selin
M.S., Department of Chemical Engineering
Supervisor: Prof. Dr. Ufuk Bakir
June 2006, 82 pages
The aim of this study was to prepare cross-linked enzyme aggregate (CLEA) from crude mushroom (Agaricus bisporus) extract. However, the optimization of CLEA production was performed by using pure tyrosinase. Important parameters were determined as protein, ammonium sulfate and glutaraldehyde concentrations, CLEA particle size, and cross-linking temperature and period. On the other hand, the order of ammonium sulfate and glutaraldehyde addition did not affect the yield of CLEA. Optimum CLEA preparation conditions were 60 % ammonium sulfate saturation, 2 % (v/v) glutaraldehyde, and 3 hour cross-linking reaction at room temperature. Particle size of the CLEAs should be reduced by mechanical stirring to eliminate mass transfer limitations. Under these circumstances, 100 % recovery was obtained from both pure and crude tyrosinases. Optimum temperature and the activation energy for catechol oxidation were determined as 34 oC and 16.9 kcal/mol for CLEAs, whereas, 32 oC and 12.5 kcal/mol for the free enzyme. Furthermore, the thermostability of CLEAs was significantly higher than the free enzyme. CLEAs, prepared from crude mushroom extract, retained 72 % of its maximum activity in eight months storage at 4 oC. Moreover, changing the storage temperature from 4 oC to room temperature did not decrease CLEAs stabilities.