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1
Barson, Helen. "Studies on the cellular function of the uPA/uPAR system." Thesis, University of Aberdeen, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419648.
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The uPA receptor, uPAR, is GPI-linked and therefore contains no transmembrane domains. Yet, uPA:uPAR binding can initiate cell signalling and may involve adaptor proteins, such as integrins. Various responses to uPA binding have been described, but the exact mechanisms remain undefined. To identify potential downstream changes caused by uPA binding, MCF7 cells were treated ± uPA or ATF (the uPAR-binding part of uPA) for various times. Gene expression was studied using custom cDNA microarrays, containing genes relating to a range of cellular processes. Changes in expression were normalised to 0 min and buffer-only controls, and genes with a fold change less than 2.5-fold were discounted. Gene expression changes that were observed in two or more treatments were shortlisted, from which thirteen were selected fro verification by real-time RT-PCR. These experiments were done on cDNA from a further cell treatment with uPA. The results did not reflect those of the microarrays; no changes in expression were observed. The microarray data were then analysed in a different, more stringent, way, but not target genes were identified. This study identified no clear candidate genes but gene expression after uPA:uPAR binding remains an important question. uPAR is present in lipid rafts and these may allow its association with signalling molecules. This study investigated whether potential uPAR adaptor proteins, αv or β1 integrins, moved into rafts when cells bound uPA. Mouse cells transfected with human uPAR were treated ±uPA, and lipid rafts were extracted from the cells. uPAR was readily detectable in lipid rafts under al conditions, but the integrins were not found to associate with lipid rafts even after uPA treatment.
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Arendholz, Tanja [Verfasser]. "Bedeutung des uPA/uPAR-Systems für die Proliferation glatter Gefäßmuskelzellen / Tanja Arendholz." Gießen : Universitätsbibliothek, 2012. http://d-nb.info/1064024483/34.
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Petzinger, Jutta [Verfasser]. "Urokinase-Rezeptor (uPAR) und Zellkontakte : Mechanismen uPAR-abhängiger Zelladhäsion, Zellmigration und Signaltransduktion / Jutta Petzinger." Gießen : Universitätsbibliothek, 2011. http://d-nb.info/1063177480/34.
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Randle, Diandra Dominique. "Snail mediates cell invasion through uPa-uPar and mark signaling in human prostate cancer cells." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2014. http://digitalcommons.auctr.edu/dissertations/1648.
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Epithelial-mesenchymal transition (EMT) is a process by which cancer cells acquire mesenchymal properties, such as induction of vimentin, while epithelial-associated genes like E-cadherin are lost. This enables the cells to be more metastatic. Factors that can induce EMT include growth factors like transforming growth factor -P (TGF-P) and epidermal growth factor (EGF), and transcription factors like Snail. Snail-induced EMT promotes migration and invasion and we hypothesized that this may be mediated by urokinase (uPA) and its receptor (uPAR) activities. LNCaP, 22Rvl and ARCaP human prostate cancer (CaP) cells stably transfected with constitutively active Snail displayed increased cell invasion as compared to the empty vector control (Neo). Superarray analysis revealed an up-regulation in uPA and uPAR RNA expression in Snailtransfected ARCaP cells as compared to Neo control. Next, the protein expression levels of Snail, uPA, and uPAR were measured by western blot analysis in various prostate cancer cell lines which showed that overexpression of Snail increased uPA and uPAR protein levels. The activity of uPA in conditioned media was measured using an ELISA assay which revealed that uPA activity was elevated in LNCaP, 22Rvl and ARCaP cells overexpressing Snail. Additionally, transient silencing of uPAR in ARCaP cells overexpressing Snail using siRNA resulted in abrogation of Snail-mediated invasion. Snail overexpression was associated with increased ERK activity and antagonism of this activity with MAPK inhibitor, UO126, inhibited cell invasion and decreased uPA activity. Therefore, Snail-mediated cell invasion in human prostate cancer cells may occur via the regulation of uPA/ uPAR and the MAPK signaling pathways.
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Sandoval, Rubenstein Cynthia Priscilla, and Rubenstein Cynthia Priscilla Sandoval. "Laminin Binding α6β1 Integrin Regulation in Aggressive Cancer Cells and Tissue." Diss., The University of Arizona, 2017. http://hdl.handle.net/10150/625446.
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Despite recent advances in early detection, in 2017 prostate cancer is estimated to claim over 26,000 lives in the United States alone. Prostate cancer related morbidity and mortality is a result of secondary skeletal metastasis. Therefore, better understanding of the underlying molecular mechanisms of prostate tumor cell migration and subsequent metastasis is vital for improved clinical outcomes. Interestingly, integrin α6, a laminin receptor, is highly expressed in a number of aggressive tumor types including prostate and is associated with increased metastasis and reduced patient survival. Preliminary studies by our group found that α6 integrin undergoes a post-translational modification mediated by the serine protease, uPA and its receptor, uPAR, leading to the cleavage of α6 integrin and production of the tumor specific structural variant integrin α6p. Cleavage of this laminin receptor and production of α6p variant gives rise to an aggressive phenotype, markedly increasing tumor cell migration and invasion. Thus, the work conducted here sought to identify the function and efficacy of these prominent proteins in various aspects of tumor cell migration as well as the factors regulating α6 integrin cleavage.
Interestingly, utilization of a co-culture system of prostate tumor cells and macrophages found that a direct and indirect interaction between the two cell populations influenced α6 integrin cleavage. Specifically, prostate tumor cell interactions with macrophages, a known immune cell population that is highly observed in a number of primary tumors, resulted in increased protein levels of uPAR on the surface of prostate tumor cells that led to a significant production of α6p and subsequently increased invasion. Additionally, key downstream effectors of integrin signaling, including FAK, ILK, and actin, were found to regulate production of the tumor specific variant integrin α6p. Depletion of FAK, ILK, or actin, resulted in a significant increase in uPAR protein expression and subsequent α6 integrin cleavage, a regulatory event previously not known of these integrin signaling effector molecules. In addition, silencing of another prominently expressed laminin receptor, integrin α3β1, led to a significant increase in the cohesive collective phenotype exhibited by aggressive prostate tumor cells that was found to be facilitated by α6 integrin cleavage. Depletion of integrin α3β1 resulted in increased surface uPAR expression and increased lateral association with α6 integrin, which resulted in a striking increase in α6p production, a novel finding showing the regulation of one laminin receptor is dependent on the expression of another. Furthermore, the expression of α6 integrin as well as uPAR, was found to be highly expressed in aggressive pancreatic tumor cells. This expression pattern was found to significantly increase in response to the development of drug resistance and increased invasive potential. This finding showed a never before seen efficacy of integrin and uPAR expression in dictating acquired drug resistance in pancreatic tumor cells and demonstrates their potential use as prognostic biomarkers for acquired chemotherapy resistance. Taken together, the work conducted here illustrates the utility in further understanding the role of integrins and their regulation in mediating tumor cell migration and subsequent metastasis in the progression of aggressive epithelial cancers.
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PIRAZZOLI, VALENTINA. "ROLE OF VITRONECTIN INTERACTION IN THE BIOLOGY OF THE UROKINASE RECEPTOR." Doctoral thesis, Università degli Studi di Milano, 2011. http://hdl.handle.net/2434/155510.
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Expression of uPAR has been extensively correlated with the malignant progression and metastasis of cancer; however, little evidence for a causal connection between increased uPAR expression and these processes has been documented to date. A complete functional alanine scan of human uPAR, pinpointed the extracellular matrix protein vitronectin (VN) as the critical uPAR-interactor required to induce cell adhesion, migration, and signaling in vitro, identifying this molecular interaction as a possible target for anti-cancer therapy (Madsen et al., 2007).
The same study helped to determine the binding epitope in uPAR responsible for its interaction to VN in an integrin-independent fashion. The composite epitope is fully conserved in mouse and included three amino acids (W32, R58, I63) in domain 1 (D1) and 2 amino acids (R92, Y93) in the linker region between D1 and D2.
We substituted these residues with alanine by site directed mutagenesis and analyzed the biological activity of resulting receptor variants in CHO Flp-In cells as compared to wild-type muPAR.
All the mutant receptors displayed a deficiency for the binding to VN, preserving the receptor binding to its natural ligand uPA. They also failed to induce muPAR-induced cell morphology changes. These changes include the formation of actin-rich lamellipodia, loss of stress fibers, reduced cell-cell contact as well as a complete failure to form colonies when seeded at low density. The mouse uPARW32A (muPARW32A) was chosen for further experiments since it did not show folding problems. Moreover the W32 position is not a part of the receptor chemotactic epitope and is not involved in the receptor cleavage.
Additional experiments using recombinant soluble muPAR confirmed the impaired VN-binding and a normal uPA-binding.
To determine if uPAR and/or VN are involved in tumor formation and progression, and more specifically, if the direct uPAR/VN-interaction is important in this process, we exploited a xenograft mouse model. For this purpose muPAR or muPARW32A or a muPAR variant lacking of the D1, required for both VN and uPA binding (muPARΔD1), were expressed in HEK293 Flp-In GFP positive cells and injected in the fourth mammary fat pad of immunodeficient mice.
In parallel the cells were tested for some in vitro assays. We demonstrated that HEK293 cells expressing muPAR are more proliferating and less apoptotic than the other cells. The interaction with VN is required to increased cell proliferation and to prevent from apoptosis. Moreover, muPAR-VN interaction induced cell spreading and migration.
muPAR expressing cells formed palpable tumors earlier than cells expressing the mutant receptors and the tumor growth was significantly faster. Despite the expression of the muPARW32A didn’t affect the timing of the primary tumor formation, it drastically slowed down the growth of the primary tumor mass.
Finally we conducted in vitro studies to determine the molecular mechanisms underlying the possible role of the uPAR/VN-interaction in vivo. From these tests emerged that VN may act as an adhesion “bridge” between different cells expressing uPAR and VN-integrins or cells expressing both uPAR, suggesting a possible role of the uPAR/VN-interaction not only in cell-ECM interactions but also in cell-cell adhesion events including the extravasation of metastatic cancer cells.
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MABILAT, PRAGNON CHRISTELLE. "Systeme upa/upar dans la migration cellulaire : localisation subcellulaire dans les cellules endotheliales et les eosinophiles." Paris 7, 1998. http://www.theses.fr/1998PA077253.
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Que ce soit dans des circonstances physiologiques ou pathologiques, la migration cellulaire est un phenomene ubiquitaire. Nous pouvons citer comme exemples, la migration des cellules endotheliales pendant la formation des vaisseaux sanguins (l'angiogenese) et la migration des globules blancs lors des reactions inflammatoires de l'organisme. Le systeme urokinase/recepteur de l'urokinase (upa/upar) joue un role majeur dans la migration cellulaire. L'objectif de ce travail etait 1) de caracteriser le systeme upa/upar dans deux types cellulaires differents ; 2) d'etudier l'effet du blocage de l'upar sur la migration cellulaire. Les resultats de cette these montrent que 1) la distribution subcellulaire du systeme upa/upar est tres differente entre les cellules endotheliales et les eosinophiles et qu'elle est tres finement controlee. Dans les cellules endotheliales, l'upar est associe a des structures membranaires particulieres, les caveoles, qui sont des invaginations specifiques de la membrane plasmique. Dans les eosinophiles, le systeme upa/upar, stocke dans des vesicules intracytoplasmiques, est retrouve au niveau de la membrane plasmique apres l'activation des cellules. Ainsi, la localisation du systeme upa/upar depend de l'etat d'activation et du potentiel migratoire de la cellule ; 2) la rupture de l'axe upa/upar, en bloquant l'upar avec une proteine chimerique, inhibe de maniere spectaculaire la migration des cellules endotheliales in vitro. Ainsi, le blocage de l'upar pourrait conduire a l'inhibition de l'angiogenese en inhibant la migration des cellules endotheliales. L'ensemble de ces resultats ouvre de larges perspectives de recherche sur le developpement d'agents bloquant l'upar, qui, en inhibant la migration des cellules endotheliales, peuvent etre utilises comme therapeutique anti-angiogenique pour le traitement du cancer.
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Moreau, Marie. "La ß-caténine et le NF-Kß coopèrent pour réguler le système uPA/uPAR dans des cellules tumorale." Paris 7, 2010. http://www.theses.fr/2010PA077113.
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La voie Wnt/ß-caténine est impliquée dans de nombreux événements comprenant l'adhésion, la migration, et la différenciation cellulaires. L'activateur du plasminogène de type urokinase (uPA) et son récepteur uPAR ont été décrits comme des gènes cibles de la voie Wnt/ß-caténine dans des cellules de cancer du colon. En utilisant deux lignées tumorales mammaires, MCF-7 et MDA-MB-231 et une lignée tumorale de colon, SW480, nous avons observé que l'inhibition de l'expression de la ß-caténine augmente l'expression d'uPA, d'uPAR et de l'inhibiteur de l'activateur du plasminogène PAI-1 ainsi que l'invasivité des cellules tumorales. La stabilisation de la ß-caténine par un traitement au chlorure de lithium (LiCl), inhibiteur de la glycogène synthase kinase-3beta (GSK-3ß) ou la co-transfection de vecteurs d'expression ß-caténine/Tcf-4 conduit à la diminution de l'expression des transcrits uPA, uPAR et PAI-1 dans les trois lignées. Le traitement des cellules transfectées par des siRNA ß-caténine avec un inhibiteur de la translocation nucléaire du nuclear factor-kappaB (NF-KB), le SN50, réduit significativement l'augmentation de l'expression des transcrits uPA, uPAR et PAI-1 et de l'invasivité cellulaire. De plus, nous avons observé une translocation nucléaire du NF-KB dans les cellules transfectées par un siRNA ß-caténine. Dans cette étude nous montrons un nouveau mécanisme de régulation du système uPA/uPAR par la ß-caténine, en coopération avec NF-KB, dans des cellules de cancer du sein et du colon. La ß-caténine peut exercer des effets inattendus dans les cellules tumorales et des stratégies thérapeutiques d'inhibition de son expression doivent être envisagées avec précautionThe Wnt/ß-catenin signaling influences many cellular processes including cell adhesion, growth and differentiation. Urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) have been reported as target genes of Wnt/ß-catenin signaling in colon cancer cells, since their expression is directly regulated through ß-catenin, binding to the T-cell factor binding element (TBE) motifs present in their promoters. Using three cancer cell models (MCF-7, MDA-MB-231 and SW480, breast and colon cancer cell lines, respectively) we demonstrated that silencing of ß-catenin increased uPA, uPAR and plasminogen activator inhibitor-1 (PAI-1) expression and the invasive potential of cancer cells. In addition, p-catenin stabilization and accumulation by lithium chloride (LiCl) treatment, an inhibitor of glycogen synthase kinase-3ß (GSK-3ß) or by ß-catenin/Tcf-4 expression vectors transfection led to a decrease in uPA, uPAR and PAI-1 mRNA expression in the studied cancer models. Moreover, the treatment of P-catenin siRNA transfected cells with a specific inhibitor of nuclear factor-kappaB (NF-KB) translocation, SN50, significantly reduced enhancement of uPA, uPAR and PAI-1 expression and cancer cell invasion. Furthermore, ß-catenin siRNA treated cells exhibited NF-KB nuclear translocation. In this study we present evidence of a novel cross-talk between ß-catenin and uPA/uPAR System through NF-KB cooperation in breast and colon cancer cells. Our results strengthen the emerging view that ß-catenin exerts different effects on tumor cells and that the therapeutic strategy of its inhibition could involve more complex mechanisms than originally anticipated
9
Kean, Thomas. "Development of a synthetic uPAR targeted gene delivery system." Thesis, Cardiff University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.635545.
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Planus, Emmanuelle. "Adherence et mecanotransduction via le complexe : recepteur de l'urokinase/urokinase/inhibiteur (upar/upa/pai-1) du systeme activateur du plasminogene." Paris 12, 1996. http://www.theses.fr/1996PA120085.
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Le systeme activateur du plasminogene (pas) via l'urokinase est un des principaux systemes proteolytiques des composants de la matrice extracellulaire. La voie de l'urokinase permet la formation d'un complexe compose d'un recepteur membranaire (upar), de l'urokinase (upa) et de l'inhibiteur de type 1 (pai-1). L'expression des composants de ce systeme est frequemment associee a la migration et a l'invasion cellulaire. Dans le but d'etudier l'implication du systeme pas dans ces phenomenes, nous avons voulu comprendre le role joue par le complexe tripartite upar/upa/pai-1 dans les mecanismes de l'adherence et de la mecanotransduction de signaux qui en decoule. Dans une premiere partie, nous avons montre que les cellules adheraient et s'etalent normalement sur une matrice uniquement constituee de pai 1. Dans une deuxieme partie, nous avons montre que ce processus etait dependant de la presence de l'upa a la surface cellulaire dans une derniere partie, nous avons montre qu'a travers le complexe upar/upa/pai-1 a la surface cellulaire, il etait possible de transmettre des forces mecaniques a l'interieur de la cellule. Nous en avons deduit que la formation du complexe tripartite upar/upa/pai-1 pouvait representer un des ponts moleculaires entre la cellule et le substrat, necessaires a l'adherence et a l'etalement des cellules. Enfin, nous avons discute des implications possibles du systeme pas comme 1) mediateur direct de l'adherence 2) mediateur eventuel de la deadherence par son activite proteolytique des composants de la matrice et 3) ainsi par ces deux actions son role dans la migration cellulaire.
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Smith, Harvey W. "Signalling from uPAR to the Activation of the Small GTPase Rac." Thesis, Institute of Cancer Research (University Of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.499157.
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Huber, Michaela Verfasser], Angelika [Akademischer Betreuer] [Gutachter] [Schnieke, Michaela M. [Gutachter] Aubele, and Jochen [Gutachter] Graw. "Das uPAR-System: Identifizierung neuer uPAR-Interaktionspartner und ihre Relevanz beim triple-negativen Brustkrebs / Michaela Huber ; Gutachter: Michaela M. Aubele, Jochen Graw, Angelika Schnieke ; Betreuer: Angelika Schnieke." München : Universitätsbibliothek der TU München, 2016. http://d-nb.info/1122482132/34.
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Xing, Hongmei Rosie. "Studies on the role of urokinase (uPA) and its cell surface receptor (uPAR) in the invasion and metastasis of hormone-dependent malignancies." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0017/NQ44631.pdf.
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Xing, Rosie Hongmei 1968. "Studies on the role of urokinase (uPA) and its cell surface receptor (uPAR) in the invasion and metastasis of hormone dependent malignancies." Thesis, McGill University, 1998. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=35651.
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Urokinase (uPA), a member of the serine protease family, and its cell surface receptor (uPAR) have been implicated in promoting the progression of various human malignancies including hormone dependent malignancies such as breast and prostate cancer. However, the underlying molecular mechanisms regulating uPA production in breast and prostate cancer progression are poorly understood.In the current studies, we have examined the role of uPAR in breast cancer progression by developing a homologous model of uPAR overexpression by a rat breast cancer cell line Mat B III. Overexpression of uPAR resulted in increased breast cancer growth, invasion and metastasis in vitro and in vivo. Development of this syngeneic breast cancer model allowed me to examine the ability of the anti-estrogen, tamoxifen (TAM) and a synthetic active site inhibitor of uPA, 4-iodo benzo[b]thiophene-2-carboxamidine (B-428), to prevent breast cancer progression. TAM and B-428 treatment alone or in combination effectively prevented breast tumor growth, invasion and metastasis in vitro and in vivo. Morever, TAM and B-428 treatments caused a decrease in uPAR gene expression and protein production. These results underscore the utility of anti-proteolytic agents (B-428) in addition to standard hormone therapy (TAM) in advanced breast cancer patients where the uPA/uPAR system plays a key role in tumor progression. Regulation of uPA production by androgens in prostate cancer was then examined in the androgen insensitive PC-3 cells transfected with the functional human androgen receptor cDNA (PC-3T). Androgens down regulate uPA gene expression and protein production in androgen sensitive PC-3T cells. Furthermore, restoration of androgen responsiveness in PC-3T cells caused a dramatic decrease in tumor growth, invasion and metastasis in vitro and in vivo. Due to the ability of sex steroids to inhibit uPA gene expression, I have also examined the correlation between hormone sensitivity and uPA expression in several hormone responsive (HR) and hormone insensitive (HI) breast and prostate cancer cell lines. uPA mRNA was expressed only in the highly invasive, HI breast (MDA-231) and prostate (PC-3) cell lines. Failure of uPA mRNA expression in the minimally invasive, HR breast (MCF-7) and prostate (LnCAP) cells was due to transcriptional suppression of uPA gene. Southern blot analysis usi
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Huber, Timo Adrian. "Design and synthesis of BACE1 inhibitors and uPAR-Selective ligands for radiotherapy /." München : Verl. Dr. Hut, 2009. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=018861815&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Kacsinta, Apollo Daniel. "Determining Biological Effectors of alpha6 Integrin Cleavage." Diss., The University of Arizona, 2010. http://hdl.handle.net/10150/193604.
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Cancer metastasis is a multi–step process that initiates with a tumor cell obtaining the ability to migrate. A multitude of changes occur in such a cell including changes to cell adhesion molecules such as integrins. In cancer cells, integrins are known to be involved in migration, invasion and metastasis. Investigation by our group of the α6 integrin led to the discovery of a cleaved form of the integrin lacking the ligand binding domain, called α6p. While it is known that the integrin is cleaved by urokinase plasminogen activator (uPA) little is known about how this process is regulated. There is a need to better understand the players involved in regulation of α6 cleavage as inhibiting this event from occurring may contribute to prolonged or increased patient survival or ultimately a cure.The existence of the integrin–actin complex has been known for many years. In this study actin was identified as a potential regulator of α6 cleavage. Using a diverse set of tumor cell lines (DU145, PC3 and MDA–MB–231) and a number of actin modifing compounds (latrunculin A, jasplakinolide and siRNA) it is reported here that disassembling actin filaments leads to an increase in α6p production. Although the increase in cleavage product did not always correlate with an increase in uPA receptor, an increase in uPAR was observed when actin was complexed by small molecule inhibitors. Taken together the results demonstrate a potential role for actin filaments to protect α6 integrin from uPA–uPAR induced cleavage via a multi–protein complex.
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Patrizia, Marzorati. "Characterisation of Hematopoietic Stem/Progenitor cells and their mobilization in uPAR KO mice." Thesis, Open University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.524734.
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Sidenius, Nicolai. "Urokinase receptor cleavage and shedding : occurrence and consequences." Thesis, Open University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323274.
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Aßmann, Anke [Verfasser]. "Die Regulation von uPAR durch metabolische Faktoren in vivo und in vitro / Anke Aßmann." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2008. http://d-nb.info/1023098784/34.
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Bhaker, Sangita. "Novel insight into uPAR function in the bronchial epithelium in asthma using functional genomics." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/45133/.
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The urokinase plasminogen activator receptor (uPAR, PLAUR) is a cell surface receptor actively involved in the regulation of cell homeostasis. Expression is elevated in the bronchial epithelium in vivo and also in serum and sputum in asthma and elevated expression often indicates poor prognosis in a number of human diseases. The relative contribution of uPAR to asthma disease mechanisms is not fully understood and the functional roles of uPAR isoforms remains to be resolved. The key aims of this thesis were to i) investigate how the uPAR pathway may influence bronchial epithelial barrier properties; ii) investigate the gene expression patterns in the bronchial epithelium in asthma; iii) identify functions of different forms of uPAR in human bronchial epithelial cells (HBEC) and to iv) investigate the association between genetic polymorphisms spanning the PLAUR gene with clinical features and the presentation of asthma in moderate to severe asthma. Using two cell based approaches we identified an inverse relationship between soluble-cleaved uPAR expression and epithelial barrier properties. Importantly, we demonstrated that blocking uPAR-integrin interactions provides a potential therapeutic opportunity to improve epithelial barrier function. Using whole transcriptome analysis genes differentially expressed between cultured asthma and control subjects were identified which were related to cell growth, repair and immune regulation. Furthermore, uPAR expression was elevated in epithelial cells in asthma subjects compared to healthy controls, suggesting expression is inherently altered in the bronchial epithelium in asthma. Transcriptomics was used to provide novel insight into the specific and overlapping functions of uPAR isoforms and to determine the effects of elevated uPAR expression on HBEC function. Finally, the contribution of PLAUR genetic variants to clinical and immunological traits within asthma were investigated and found that PLAUR single nucleotide polymorphisms (SNPs) did not show an association with the traits measured in a severe asthma population. Overall this work has provided new insight into the function of uPAR as a regulator of the bronchial epithelium in asthma.
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de, Bock Charles Edo St George Clinical School UNSW. "Novel protein interactors of urokinase-type plasminogen activator receptor." Awarded by:University of New South Wales. St George Clinical School, 2005. http://handle.unsw.edu.au/1959.4/23009.
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The plasminogen activator (PA) system plays an important role in cell adhesion, migration and invasion, and may require the coordinated expression of various proteins. The human urokinase-type plasminogen activator (uPA) receptor (uPAR) is a central protein component of the PA system. By binding its ligand uPA, uPAR can direct proteolysis of the extracellular matrix. Also, it is now apparent that uPAR can initiate proteolytic independent signal transduction to influence angiogenesis, inflammation, wound repair and tumour progression. To determine whether any novel proteins interacted with uPAR, a yeast two-hybrid screening analysis was undertaken using alternate uPAR domain constructs as baits. These included full-length three domain uPAR (uPAR-DIDIIDIII), two domain uPAR (uPAR-DIIDIII), and each individual uPAR domain (uPAR-DI, uPAR-DII and uPAR-DIII). A number of proteins were identified as putative candidate interactors for the alternate constructs, with two of special interest for uPAR-DIDIIDIII. These were the heat shock protein Mrj, and the extracellular matrix protein fibulin-2. The protein Mrj was shown to bind uPAR both in vitro and in vivo using GST-pull down and co-immunoprecipitation assays respectively. The GST-pull down assay identified the interaction between Mrj and uPAR dependent on the C-terminal domain of Mrj and DI of uPAR. Using in vivo co-immunoprecipitation analysis, Mrj also bound to uPAR. Preliminary data suggest the association between uPAR and Mrj may play a role in the regulation of apoptosis. In regard to the uPAR interactor of fibulin-2, a calcium dependent binding interaction with uPAR was identified using the GST-pull down assay. However due to the large molecular weight and stringent conditions needed to solubilise fibulin-2, it was not possible to co-immunoprecipitate both uPAR and fibulin-2. Together, the identification of both Mrj and fibulin-2 amongst other candidate interactors of uPAR presented here provides further insight into the intricate relationship between uPAR and other proteins which may influence a range of biological functions.
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FALEIRO, Mariana Batista Rodrigues. "Expressão de mmp-2, mmp-9 e upar em próstatas caninas normais e c lesões proliferativas." Universidade Federal de Goiás, 2010. http://repositorio.bc.ufg.br/tede/handle/tde/941.
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Previous issue date: 2010-03-02Humans and dogs show dysplastic lesions in the prostate, such as prostatic intraepithelial neoplasms (PIN) and proliferative inflammatory atrophy (PIA), which are studied due to their malignance potential. The matrix metalloproteinases (MMP) are a family of proteolytic enzymes thought to play an important role in tumor invasion and metastasis in face of their ability to degrade the extracellular matrix (ECM) and basement membrane. The plasminogen activator (PA) system has been suggested to play a central role in cell adhesion, migration, wound healing, angiogenesis, inflammation, regulation of growth factors and tumor invasion. The receptor of plasminogen activator type activator (uPAR) is a component of the PA, with a range of expression in tumor cell and stromal cells. So, this study was aimed to evaluated the expression and correlation between MMP-2 (gelatinase A) and MMP-9 (gelatinase B) as well as the expression of uPAR in normal canine prostate tissue and also in tissue with proliferative disorders, including benign prostatic hyperplasia (HPB), PIA, PIN and carcinoma. And therefore establish relation among the role of these enzymes in the remodeling of the extracellular matrix (ECM) and in the process of tumor invasion and metastasis. For this, it was performed immunohistochemical staining in tissue microarray of 149 paraffin-embedded fragments of prostate tissue selected from 57 prostates of non-castrated adult dogs with or without prostatic diseases. A total of 298 cores were analyzed and it was made 363 diagnoses: 36 (9.9%) normal, 49 (13.5%) BPH, 132 (36.3%) PIA, 75 (20.7%) PIN and 71 (19.6%) carcinomas. It was observed differences in cytoplasmatic immunohistochemical staining by MMP-2 and MMP-9 antibodies in relation to the cell number and intensity of labeling of the acinar epithelial and stromal perilobular cells between normal tissue and in those with proliferative disorders. A correlation between MMP-2 and MMP-9 antibodies occurred just in canine prostates with PIA in relation to the number of labeled cells in acinar epithelium and perilobular stroma, as well as, the staining intensity in the perilobular stromal cells. In relation to uPAR, it was observed differences of immunohistochemical staining of uPAR antibodies in canine prostate. Likewise, there was over expression in dysplastic and neoplasic specimens, but not in normal and benign prostate tissue. A number of epithelial cells labeled for uPAR showed variation among the diagnoses, except between PIN and carcinoma. Less intensity of labeling was observed in acinar epithelial cells of normal prostates compared with PIA, PIN and carcinoma. However, in the normal cells and in those with PIA, there was a difference in the number of cells, as well as in the intensity of stromal labeling. The intensity of labeling of stromal perilobular cells was higher in the PIA. PIA-A (accentuated) and PIA-M (moderated) cells showed greater intensity staining stroma and stromal cells labeled for uPAR, respectively. Thus, this study concludes that there was variation in gelatinases and uPAR expression in canine prostate according to the lesion. Also, there was Less labeling in normal and BPH and higher in PIA, PIN and carcinoma prostate tissues. The correlation between MMP-2 and MMP-9 in canine prostates with PIA indicates that the inflammation likely influenced the activity of these enzymes with simultaneous increase in their expression. The uPAR high expression in inflammatory and neoplasic tissues suggests high ECM proteolytic activity in these situations
Nas espécies humana e canina lesões displásicas da próstata, como a neoplasia intra-epitelial prostática (PIN) e a atrofia inflamatória proliferativa (PIA), são estudadas quanto ao potencial de malignidade. As metaloproteinases (MMP) são enzimas proteolíticas envolvidas no processo de invasão tumoral e metástase, causando destruição de barreiras biológicas como a matriz extracelular (MEC) e a membrana basal (MB). O sistema ativador de plasminogênio (PA) compreende proteínas com ação na adesão celular, regulação da migração, cicatrização, angiogênese, inflamação, regulação de fatores de crescimento e invasão tumoral. O receptor de ativador de plasminogênio tipo uroquinase (uPAR) é um dos componentes do PA, com variação de expressão em células neoplásicas e estromais. Este trabalho teve por objetivo verificar a expressão e a correlação entre MMP-2 e MMP-9, assim como a expressão do uPAR no tecido prostático canino normal e com alterações proliferativas, incluindo a hiperplasia prostática benigna (HPB), a PIA, a PIN e o carcinoma, buscando avaliar o papel dessas proteínas no remodelamento da MEC e no processo de invasão tumoral e metástase. Para isso, foi realizada a imunoistoquímica em lâminas de microarranjo tecidual (TMA), com 149 cores selecionadas de 57 próstatas de cães adultos, não castrados, com ou sem histórico de afecções prostáticas. Foram analisados, para cada anticorpo, 298 cores, perfazendo 363 diagnósticos, sendo 36 (9,9%) normais, 49 (13,5%) HPB, 132 (36,3%) PIA, 75 (20,7%) PIN e 71 (19,6%) carcinomas. Foi possível observar diferença de imunomarcação citoplasmática de MMP-2 e MMP-9 em relação ao número de células e intensidade de imunomarcação nas células epiteliais acinares e estromais periacinares em relação aos diagnósticos. A correlação entre os anticorpos MMP-2 e MMP-9 ocorreu em próstatas caninas com PIA quanto ao número de células imunomarcadas no epitélio acinar e no estroma periacinar, bem como quanto à intensidade de imunomarcação nas células estromais periacinares. Quanto ao uPAR, houve diferença na imunomarcação em relação ao diagnóstico, com maior expressão nas displásicas e neoplásicas em relação ás normais e com HPB. O número de células epiteliais imunomarcadas para uPAR variou entre os diagnósticos, exceto entre PIN e carcinoma. Menor intensidade de imunomarcação epitelial foi constatada nas próstatas normais em relação às com PIA, PIN e carcinoma. Entre as normais e com PIA houve diferença no número de células e intensidade de imunomarcação estromal. A intensidade de imunomarcação estromal foi maior nas com PIA. As PIA-M (inflamação moderada) e PIA-A (inflamação acentuada) apresentaram maior intensidade de imunomarcação estromal e células estromais imunomarcadas para uPAR, respectivamente. Concluiu-se que há variação na expressão das gelatinases e do uPAR na próstata canina, de acordo com a lesão, com menor expressão nas normais e com HPB e maior naquelas com PIA, PIN e carcinoma. A correlação entre MMP-2 e MMP-9 em próstatas caninas com PIA indica que a inflamação influencia a atividade dessas enzimas, com aumento simultâneo na expressão de ambas no microambiente inflamatório. Ainda, o aumento na expressão do uPAR nos microambientes inflamatório e neoplásico sugere maior atividade proteolítica na MEC nesses casos
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Gorrasi, Anna. "Regolazione delle funzioni del recettore dell' urochinasi." Doctoral thesis, Universita degli studi di Salerno, 2015. http://hdl.handle.net/10556/1877.
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2013-2015Il recettore per l'attivatore di tipo urochinasico del plasminogeno (uPAR), è un recettore ad áncora GPI presente sulla superficie della cellula; esso è coinvolto nei processi di migrazione cellulare e di invasione tissutale. L'uPAR lega anche la vitronectina (VN) e si associa alle integrine; è iper-espresso nei tumori ed è considerato un fattore prognostico negativo in vari tipi di cancro. Queste considerazioni ci hanno spinti a chiarire i meccanismi che regolano le attività e le interazioni dell'uPAR, al fine di esplorare nuove strategie in grado di inibire le sue funzioni nel cancro. Questo progetto ha lo scopo di esaminare le possibili interazoni dell'uPAR con nuove molecole di superficie, in particolare con i recettori chemiotattici per il peptide formilato di origine batterica fMLF (fMLF-R). Abbiamo dimostrato che l'uPAR co-localizza e co-immunoprecipita con FPR1, il recettore ad alta affinità per fMLF, sulla superficie di cellule HEK-293, trasfettate con uPAR. Abbiamo, inoltre, osservato la co-localizzazione uPAR/Integrine β1 e FPR1/Integrine β1. La stimolazione con siero o con il peptide WKYMVm (W Pep), ligando di FPR1, incrementa fortemente tutte le co-localizzazioni osservate nelle cellule uPAR-293, inclusa la co-localizzazione FPR1/Integrine β1. La co-localizzazione FPR1/Integrine β1 non è stata osservata nè in assenza, nè in presenza di stimoli in cellule HEK-293 trasfettate col vettore vuoto (V-293), uPAR-negative. Abbiamo, poi, analizzato il ruolo delle interazioni dell'uPAR nella migrazione cellulare. Sia le cellule uPAR-293 che le cellule HEK-293 trasfettate col vettore vuoto (V-293) di controllo, migrano efficacemente verso siero o verso EGF purificato. I trattamenti effettuati su tali cellule per bloccare le interazioni dell'uPAR con fMLF-R o integrine, o per inibire mediatori di segnale specifici, riducono la migrazione cellulare, senza sortire alcun effetto sulle cellule controllo uPAR-negative V-293. Tali cellule possono, quindi, migrare utilizzando meccanismi sia uPAR-dipendenti che uPAR-indipendenti. La degradazione dell'áncora GPI dell'uPAR o la disgregazione dei lipid raft, inibisce la migrazione uPAR-dipendente delle cellule uPAR-293, ripristinando i meccanismi di migrazione uPAR-indipendenti, indicando un ruolo cruciale dell'áncora GPI nella migrazione uPAR-dipendente. Risultati analoghi sono stati ottenuti in cellule PC3, in cui l'uPAR è espresso costitutivamente. In tali cellule è osservata solo la migrazione uPAR-dipendente. Parallelamente, poichè uPAR e il suo ligando non proteolitico (VN) sono iper-espressi nel cancro, abbiamo selezionato e caratterizzato due composti organici in grado di bloccare tale legame. Tali composti inibiscono selettivamente l'adesione di cellule uPAR-293 alla VN e la loro migrazione su VN. Poichè questi due composti bersagliano i residui aminoacidici R91 e S88, residui chiave anche nel legame dell'uPAR con fMLF-Rs, abbiamo esaminato e dimostrato anche la loro capacità di bloccare l'associazione di uPAR a fMLF-Rs.[a cura dell'autore]
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Malengo, Gabriele. "Dynamics and oligomerization of urokinase plasminogen activator receptor (uPAR): a GIP-anchored receptor studied by fluorescence micro-spectoscopy." Thesis, Open University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489898.
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This work is addressed to the search for functional links between GPI-protein monomeroligomer exchange and membrane dynamics and confinement. To this end, uPAR was chosen as a GPI-receptor involved in the regulation of cell adhesion, migration and proliferation. The work is focused on tracking the molecular dynamics and the homotypic interactions of uPAR, using fully fiinctional fluorescent protein-tagged chimeras expressed in HEK293 cells.
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FERRARIS, G. M. SARRA. "NON-INTEGRIN CELL ADHESION TRIGGERS LIGAND-INDEPENDENT INTEGRIN SIGNALING." Doctoral thesis, Università degli Studi di Milano, 2011. http://hdl.handle.net/2434/157459.
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Integrins are the major family of cell surface adhesion receptors responsible for the regulation of the physical contact and biochemical communication between the cell and the surrounding extracellular matrix (ECM). Binding of the extracellular domains of integrins to components in the ECM triggers a series of molecular events commonly referred to as “outside-in” signaling, leading to context-dependent changes in cell morphology, migration and proliferation. In this prevailing paradigm of cell adhesion induced signaling the primary functions of the integrin is to provide the physical transmembrane bridge connecting the intracellular signaling machinery and cytoskeleton to the extracellular environment.
We now present evidence that most, if not all, cell adhesion receptors trigger integrin-dependent outside-in signaling independently of direct contacts between the integrins and their ligands in the ECM. The urokinase-type plasminogen activator receptor (uPAR/CD87) is a non-integrin vitronectin (VN) cell adhesion receptor linked to the outer membrane leaflet by a GPI-anchor. Through an extensive structure-function analysis of uPAR, VN, β1 and β3 we document that cell adhesion induced by the uPAR/VN-interaction triggers integrin-mediated, but ligand independent, cell spreading and signaling. This signaling is fully active on VN lacking functional integrin binding sites and by integrin mutants deficient in ligand binding, but is crucially dependent on an “active” conformation of the integrin as well as its binding to intracellular adaptor proteins including talin and kindlin. This novel paradigm of ligand-independent integrin signaling is not restricted to uPAR as it poses no identifiable constraints to the adhesion receptor with respect to ternary-structure, ligand type or means of membrane anchorage. In full accordance with a general validity of this paradigm, we show that cell adhesion physically mediated by a signaling-incompetent β3 integrin is effectively translated into cell spreading and signaling by the β1 integrin.
Our results show that integrins are active in transducing adhesion-induced signaling in the absence of their cognate ligands, suggesting that the bi-directional signaling capability of these receptors may have evolved primarily to allow for tightly regulated inside-out signaling.
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Sloan, Stakleff Kimberly Denise. "CHARACTERIZATION OF UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR (UPAR) AND INTEGRIN SUBUNITS IN BREAST CARCINOMA CELL LINES WITH DIVERSE INVASIVE CAPACITIES." Kent State University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=kent1195663733.
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Piccolella, M. "Caratterizzazione del sistema attivatore del plasminogeno nella progressione metastatica del cancro prostatico umano." Doctoral thesis, Università degli Studi di Milano, 2007. http://hdl.handle.net/2434/166305.
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GnRH analogues are used for the treatment of prostate cancer (PCa) because their ability to suppress the activity of the pituitary-testicular axis, with consequent blockade of testosterone production. However, after an initial responsiveness to hormonal deprivation, PCa progresses and then metastatises. It is known that the system of the plasminogen activator (uPA, uPA inhibitors PAI-1/2 and uPA receptor, uPAR) has been involved in the local degradation of the extracellular matrix and PCa progression and metastases. Studies performed in our laboratory have demonstrated the presence of GnRH receptors, suggesting a direct effect of GnRH analogues in inhibiting the proliferation of human PCa cell lines. The aim of this study was to test the effect of an agonist (Leuprolide) and an antagonist (Cetrorelix) of GnRH on uPA/uPAR and PAI-1 expression and activity, on the migratory and invasion capabilities in the two androgen-independent cell lines, DU145 and PC3 cells. The results obtained in DU145 and PC3 cells show that both Leuprolide and Cetrorelix: 1) significantly decrease the enzymatic activity of uPA; 2) induce a marked decrease of uPA and a significant increase of PAI-1 protein levels; 3) increase the presence of soluble uPAR in the cell media; 4) decrease the migratory and invasion capabilities. In conclusions, GnRH analogues might interfere with the mechanisms of metastatic progression of human androgen-independent PCa by inhibiting the activity of the plasminogen activator system.
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Fuchs, Frieder [Verfasser], Julia [Akademischer Betreuer] Kitz, Philipp [Gutachter] Ströbel, Peter [Gutachter] Burfeind, and Margarete [Gutachter] Schön. "uPAR und c-MYC beim duktalen Adenokarzinom des Pankreas / Frieder Fuchs ; Gutachter: Philipp Ströbel, Peter Burfeind, Margarete Schön ; Betreuer: Julia Kitz." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2018. http://d-nb.info/116586908X/34.
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Li, Santi Anna. "Regolazione post-trascrizionale dell’espressione del recettore dell’urochinasi." Doctoral thesis, Universita degli studi di Salerno, 2016. http://hdl.handle.net/10556/2468.
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2014 - 2015The urokinase type plasminogen activator (uPAR) is a three domain GPI-anchored cell surface receptor. uPAR expression is strongly up-regulated and represents a negative prognostic factor in various tumors, including hematologic malignancies. uPAR expression is post-transcriptionally regulated by RNA binding proteins (RBPs). RBPs bind specific sequences in the 3’untranslated region (3’UTR) of uPAR-mRNA, stabilizing or destabilizing the transcript. The 3’UTR of transcripts from a large number of genes includes target sequences also for small translational repressors RNAs (miRNAs). miRNAs play key roles in many cellular pathways; their aberrant expression is a common feature of various malignancies. We selected three miRNAs miR-146a, miR-335 and miR-622 that could bind the 3’UTR of uPAR-mRNA; these three miRNAs, as reported in literature, are expressed in CD34+ HSC or in acute myeloid leukemia (AML) cells and can act as oncosuppressors by inhibiting oncogene expression. We found that selected miRNAs regulate uPAR expression by directly targeting its 3’UTR in AML cell lines. Indeed, uPAR expression is reduced by their overexpression and increased by their specific inhibitors. Overexpression of selected miRNAs impaired cell migration, invasion and proliferation of AML cell lines. Interestingly, we found an inverse relationship between uPAR expression and miR- 146a and miR-335 levels in AML blasts. This suggests their possible role in regulating uPAR expression also in vivo. We also investigated the capability of uPAR-3’UTR to act as competing endogenous RNA (ceRNA). We showed that uPAR-3’UTR overexpression up-regulates uPAR expression and expression of other targets of selected miRNAs; these results suggest that uPAR-3’UTR may recruit selected miRNAs, allowing translation of their targets, thus acting as ceRNA. [edited by Author]
XIV n.s.
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Kendziora, Elena Stephanie [Verfasser], Viktor [Akademischer Betreuer] Magdolen, Wilko [Gutachter] Weichert, and Viktor [Gutachter] Magdolen. "Analysis of Urokinase-type Plasminogen Activator (uPA), Plasminogen Activator Inhibitor Type-1 (PAI-1), and Urokinase Plasminogen Activator Receptor (uPAR) Protein Expression by Immunohistochemistry in Triple-Negative Breast Cancer (TNBC) / Elena Stephanie Kendziora ; Gutachter: Wilko Weichert, Viktor Magdolen ; Betreuer: Viktor Magdolen." München : Universitätsbibliothek der TU München, 2020. http://d-nb.info/1208325000/34.
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Lee, Adrian P. S. "Therapy and venous thromboembolism in glioblastoma: a clinical and molecular study." Thesis, The University of Sydney, 2019. https://hdl.handle.net/2123/22600.
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Glioblastomas are high grade brain tumours with a median survival of approximately 1 year. Amplification of the oncogene EGFR is a common aberration. This thesis assessed the hypothesis that EGFR is an effective target for glioblastoma treatment. A Cochrane review was undertaken that systematically analysed 9 clinical trials in glioblastoma patients that included EGFR targeting therapies. It concluded that the addition of EGFR therapies to standard of care provided no overall survival benefits. Venous thromboembolisms (VTEs) are highly prevalent amongst glioblastomas. Prophylaxis is not recommended, and thus early identification of at-risk patients and initiation of treatment may be beneficial. EGFR enhances activation of the coagulation cascade by upregulating pro-coagulant factors like Tissue Factor (TF). This thesis examined the hypothesis that EGFR-driven glioblastomas have more VTE events and this leads to poorer survival. A retrospective study of 330 glioblastoma patients diagnosed between 2009 and 2014 found no association between VTE incidence and tumour EGFR status or survival. However, a positive correlation was identified between VTE and tumor uPAR expression (p=0.032). An unexpected finding was a positive correlation between overall survival and tumor TF expression (p=0.028). In further work, gene expression profiling of glioblastomas from an independent cohort of 26 patients, 50% of whom developed VTE, identified collagen as an alternative initiator of thrombus formation and confirmed the importance of extracellular matrix in facilitating these malignant activities. Findings from this thesis do not support anti-EGFR therapies in glioblastoma. This thesis identified the potential of uPAR as a predictive biomarker for VTE. It provides support for further investigation of biomarkers that may contribute to a VTE risk assessment for glioblastomas, permitting early identification and intervention of at-risk patients to change their disease outcome.
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Grismayer, Bettina Verfasser], Horst [Akademischer Betreuer] [Kessler, Steffen [Akademischer Betreuer] Glaser, and Viktor [Akademischer Betreuer] Magdolen. "Characterization of breast cancer cell lines overexpressing the urokinase receptor splice variant uPAR-del4/5 or the GTP binding protein rab31 / Bettina Grismayer. Gutachter: Steffen Glaser ; Viktor Magdolen. Betreuer: Horst Kessler." München : Universitätsbibliothek der TU München, 2012. http://d-nb.info/1022885650/34.
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Farthmann, Anna Juliane [Verfasser], Viktor [Akademischer Betreuer] Magdolen, and Falko [Akademischer Betreuer] Fend. "Quantifizierung und Charakterisierung der mRNA Expression des Urokinase Rezeptors uPAR (CD87) in Zelllinien und Tumorproben von Brustkrebs Patientinnen mittels quantitativer real-time RT-PCR / Anna Juliane Farthmann. Gutachter: Viktor Magdolen ; Falko Fend. Betreuer: Viktor Magdolen." München : Universitätsbibliothek der TU München, 2006. http://d-nb.info/1058140078/34.
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Peng, Luo-Gen [Verfasser]. "Urokinase-type plasminogen activator receptor contributes to chemosensitivity and epithelial-to-mesenchymal transition in PDAC : uPAR and p38 regulate autophagy dependent gemcitabine resistance in AsPC1: autophagy inhibitors and gemcitabine as a potential combined therapy for a subgroup of pancreastic cancers / Luogen Peng." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2020. http://d-nb.info/1221802313/34.
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Peng, Luogen [Verfasser]. "Urokinase-type plasminogen activator receptor contributes to chemosensitivity and epithelial-to-mesenchymal transition in PDAC : uPAR and p38 regulate autophagy dependent gemcitabine resistance in AsPC1: autophagy inhibitors and gemcitabine as a potential combined therapy for a subgroup of pancreastic cancers / Luogen Peng." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2020. http://d-nb.info/1221802313/34.
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Alsén, Maria, and Nils Järgenstedt. "Kommunikation med hjälp av mock-uper." Thesis, Blekinge Tekniska Högskola, Institutionen för programvaruteknik och datavetenskap, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:bth-4919.
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In several cases, systems that have been developed have been very time consuming and cost a lot of money, but they still do not fulfil the users requirements and requests. To make new systems better, you have to find a way to communicate that allows the developers to understand the needs of the user. The aim for our thesis is to highlight the importance of communication in system development. To investigate this we have choosen to do a study of the real-estate system. The work methods that have been used include mock-ups and informal conversations with the user, who is employed by the Church of Sweden in Ronneby. The purpose of this thesis is, among other things, to provide the Church of Sweden in Ronneby with a report, which can be of help for further development of the system. The system was developed by a work group at Blekinge Institute of Technology. Our question of issue is: Would the Church of Sweden in Ronneby obtain a more useful system if the developers applied the guidelines and experience that exists within the area of HCI? Further more we have looked in to if the communication has improved with the use of mock-ups to increase the interaction? Human-computer interaction as a term was adopted in the mid-1980s as a means of describing this new field of study. The focus of interest described the new way of looking at the interaction between computers and people. In this field it is important to involve the user in the developing process from the beginning to the end. Together with the user, we have made some propositions based on previous documentation from the project. Mock-ups are a prototype of paper that shows the user what the system will look like. This method was applied together with the user, to find a more logical structure for the system. After gathering the result of the case study, we can honestly say that communication do increase because of mock-ups. Good communication is not something that you can learn from books; you have to adjust to the situation. It is important when you develop a system to work with a model that allows you to go back and change things in previous phases that are incorrect, and also to include the user in the whole process.
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SaÌnchez, Luis Gustavo Alvarez. "Suspended sediment dynamics in the uper gulf of California." Thesis, Bangor University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401909.
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Papaioannou, Alexandra. "Fine-tuning UPR signals and subsequent cellular outputs." Thesis, Rennes 1, 2019. http://www.theses.fr/2019REN1B013.
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La présente thèse explore le monde de la biologie du stress du RE (réticulum endoplasmique). Une vue globale du RE et du stress du RE est d'abord fournie en commençant par les mécanismes de base impliqués pour aller vers de possibles applications cliniques. L'accent est ensuite mis sur le rôle crucial de l'UPR dans la cancérogénèse, qui est activée en réponse au stress du RE dans la micro-environnement de la tumeur. Après avoir passé en revue ces aspects, nous mettons en évidence des éléments manquants dans notre compréhension de la façon dont les signaux UPR sont affinés et conduisent soit à la restauration de l'homéostasie du RE et des cellules soit à la mort cellulaire. Parmi les branches de l'UPR, les signaux ATF6 et IRE1 deviennent notre sujet d'investigation en raison de leur convergence dans la régulation du facteur XBP1 favorisant la survie. D'une part, nous découvrons les mécanismes provenant du lumen du RE qui régulent l'activation de l'ATF6 en réponse au stress du RE et affectant la signalisation adaptative cellulaire de l'ATF6 en aval. D'autre part, nous observons l'existence d'un réseau autorégulateur de l'activité RNase de l’IRE1 consistant en un système tyrosine kinase-phosphatase ciblant la RtcB et impactant l'épissage de l'ARNm de XBP1. Ainsi, grâce à nos études, nous avons découvert un circuit de signalisation intégré capable d’ajuster avec précision les sorties cellulaires de l’activation conjointe ATF6 et IRE1 en réponse au stress du REThe present thesis explores the world of ER (endoplasmic reticulum) stress biology. A global view of ER and ER stress is first provided with a transition from the basic mechanisms involved to possible clinical applications. The focus is then placed to the crucial role of the UPR in carcinogenesis that is activated in response to ER stress in the micro-environment of the tumor. After reviewing these aspects, we point to missing parts in our comprehension of how UPR signals are fine-tuned and lead to either restoration of ER and cell homeostasis or cell death. Among the UPR branches, ATF6 and IRE1 signaling become our focus of investigation because of their convergence in the regulation of the pro-survival factor XBP1s. On the one hand, we unravel mechanisms originating from the ER lumen that regulate the ATF6 activation in response to ER stress and affect its downstream cell adaptive signaling. On the other hand, we witness the existence of an auto-regulatory network of IRE1 RNase activity consisted of a tyrosine kinase-phosphatase system that targets RtcB and impacts on XBP1 mRNA splicing. Hence, through our studies we uncover an integrated signaling circuit that can fine-tune the cellular outputs of the joint ATF6 and IRE1 activation in response to ER stress
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Guo, Jinbai. "Control of cell division by nutrients, and ER stress signaling in Saccharomyces cerevisiae." Texas A&M University, 2003. http://hdl.handle.net/1969.1/5912.
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Cell cycle progression of Saccharomyces cerevisiae cells was monitored in
continuous cultures limited for glucose or nitrogen. The G1 cell cycle phase, before
initiation of DNA replication, did not exclusively expand when growth rate decreased.
Especially during nitrogen limitation, non-G1 phases expanded almost as much as G1. In
addition, cell size remained constant as a function of growth rate. These results contrast
with current views that growth requirements are met before initiation of DNA replication,
and suggest that distinct nutrient limitations differentially impinge on cell cycle
progression. Therefore, multiple mechanisms are hypothesized to regulate the
coordination of cell growth and cell division.
Genetic interactions were identified between the dose-dependent cell-cycle
regulator 2 (DCR2) phosphatase and genes involving in secretion/unfolded protein
response pathway, including IRE1, through a genome-wide dominant negative genetic
approach. Accumulation of unfolded proteins in the endoplasmic reticulum triggers the
unfolded protein response (UPR). How the UPR is downregulated is not well
understood. Inositol requirement 1 (IRE1) is an endoplasmic reticulum transmembrane UPR sensor in Saccharomyces cerevisiae. When the UPR is triggered, Ire1p is
autophosphorylated, on Ser 840 and Ser 841, inducing the cytosolic endonuclease
activity of Ire1p, thereby initiating the splicing and translational de-repression of HAC1
mRNA. Homologous to Atf/Creb1 (Hac1p) activates UPR transcription. We found that
that Dcr2p phosphatase functionally and physically interacts with Ire1p. Overexpression
of DCR2, but not of a catalytically inactive DCR2 allele, significantly delays HAC1
splicing and sensitizes cells to the UPR. Furthermore, Dcr2p physically interacts in vivo
with Ire1p-S840E, S841E, which mimics phosphorylated Ire1p, and Dcr2p dephosphorylates
Ire1p in vitro. Our results are consistent with de-phosphorylation of
Ire1p being a mechanism for antagonizing UPR signaling.
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Menezes, Simone Alves Prado. "Qualidade do ambiente construído : o caso da UPA Samambaia." reponame:Repositório Institucional da UnB, 2012. http://repositorio.unb.br/handle/10482/12595.
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Dissertação (mestrado)—Universidade de Brasília, Faculdade de Arquitetura e Urbanismo Programa de Pesquisa e Pós-Graduação em Arquitetura e Urbanismo, 2012.Submitted by Albânia Cézar de Melo (albania@bce.unb.br) on 2013-02-01T14:40:45Z No. of bitstreams: 1 2012_SimoneAlvesPradoMenezes.pdf: 3100705 bytes, checksum: 94e83e61d1caf4cbb102a6bde8ac0cde (MD5)
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Este trabalho trata do tema “Qualidade do Ambiente Construído”, por meio da descrição detalhada da política de atenção proposta para as Unidades de Pronto Atendimento (UPA), e a estrutura física que esta sendo oferecida para este atendimento a partir de um sistema construtivo pré-fabricado. Consideradas como estabelecimentos de saúde de complexidade intermediária entre as Unidades Básicas e os Hospitais Gerais, as UPAs possuem o foco na atenção integral às urgências. Baseado na atual política do Sistema Único de Saúde (SUS) que propõe a universalidade, equidade, resolutividade, controle social, planejamento/avaliação das ações de saúde, acolhimento e respeito aos aspectos culturais, sob o olhar dos princípios da sustentabilidade, avaliando a qualidade do espaço construído o estudo propõe a avaliação da unidade pré-fabricada em aço galvanizado de Samambaia/DF. A pesquisa foi desenvolvida através da aplicação de um instrumento de avaliação da qualidade dos ambientes hospitalares, o Achieving Excellent Design Evaluation Toolkit - AEDET. Desenvolvido na Inglaterra e adaptado para o Brasil por Guelli (2006), este instrumento promove a discussão sobre a avaliação da estrutura física de atenção a saúde para a verificação da qualidade dos ambientes construídos com recurso público no país. Deste modo a pesquisa apresentada promove a discussão sobre a elaboração de projetos de edifícios de saúde cada vez mais saudáveis, indicando para a Unidade de Pronto Atendimento de Samambaia/DF, alternativas de planejamento nos aspectos que promovem a qualidade e a melhoria do conforto para o alcance da excelência em sua estrutura. ______________________________________________________________________________ ABSTRACT
oposed policy attention for Emergency Care Units (UPA) and the physical structure that is being offered for this service from a prefabricated building system. Healthcare facilities of intermediate complexity between the Basic and General Hospitals, the PSUs have the focus on comprehensive care for emergencies. Based on the current policy of the Unified Health System (SUS) proposes that the universality, equity, resolution, social control, planning / evaluation of health, care and respect for cultural, under the gaze of the principles of sustainability, assessing the quality of built space study proposes an evaluation unit prefabricated galvanized steel Samambaia / DF. The study is done by applying an instrument for assessing the quality of hospital environments, developed in England to Achieving Excellent Design Evaluation Toolkit - AEDET. Guelli (2006) translated and adapted the instrument AEDET available for use in Brazil. Through this tool, the discussion on the evaluation of the physical structure of health care gains a strong ally for checking the quality of the built environment with public resource in the country. Promoting discussions on the economic viability of public resources and the application of social and environmental initiatives in the architecture of health buildings, building environments increasingly harmonious among people, building and the environment. Thus the research presented promotes discussion on the drafting of health buildings increasingly healthy. Indicating to the Emergency Care Units prefab, quality alternatives to improve the comfort and excellence in its structure.
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Zimmermann, Alexander. "Prognostische Wertigkeit der tumorassoziierten Proteasen (uPA, uPA-R, Kathepsin D) und ihrer Inhibitoren (PAI-1, PAI-2) beim R0-resezierten Kolon- und Rektumkarzinom." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=964905221.
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Fattouh, Nour. "Caractérisation du mode de vie intracellulaire des endosymbiotes Wolbachia." Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT079.
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Les bactéries intracellulaires Wolbachia ont développé une vaste gamme d’interactions symbiotiques, du parasitisme reproductif au mutualisme chez les arthropodes terrestres et les nématodes filaires, devenant ainsi les endosymbiotes les plus répandus sur terre. Bien qu’elles se développent lentement dans les cultures cellulaires d’insectes pour lesquelles les marqueurs sont limités et qu’elles ne sont génétiquement pas manipulables, il existe un intéret croissant de déchiffrer leur mode de vie intracellulaire pour 2 raisons. Premièrement, Wolbachia intervient dans le développement et la transmission des arbovirus et deuxièmement, les filarioses lymphatiques sont traitables grâce à la susceptibilité des Wolbachia qui infectent les nématodes filaires aux antibiotiques. Au début de ce projet, j’ai infecté 2 lignées cellulaires de Drosophila melanogaster qui sont transcriptomiquement divergentes par une même souche de Wolbachia pouvant naturellement infecter Drosophila melanogaster. J’ai utilisé ces 2 lignées cellulaires qui sont différentiellement permissive à l’infection pour explorer l’interaction de Wolbachia avec le réticulum endoplasmique. Les observations par microscopie à fluorescence en temps réel et par microscopie électronique prouvent que cet organite est une source de membranes pour Wolbachia et possiblement, une source de nutriments. Pourtant, les analyses d’expression génique et les approches d’immunofluorescence démontrent que Wolbachia n’induit ni un stress au niveau du réticulum endoplasmique ni une protéolyse via la voie de signalisation ERAD suggérant dès lors, que Wolbachia subvertissent d’autres mécanismes pour assurer leur besoin en acides aminés. Au cours de ce projet, j’ai commencé à mettre en place une technique pour transformer Wolbachia par biolistique. La validation de cette technique de transformation a ouvert la voie vers l’optimisation de la procédure de sélection des transformants pour enfin pouvoir génétiquement manipuler WolbachiaThe intracellular bacteria Wolbachia have developed a wide range of symbiotic interactions, from being opportunistic reproductive parasites to mutualists with terrestrial arthropods and filarial nematode species, making them the most common endosymbionts on earth. The discovery that they interfere with arboviruses development and transmission by mosquito vectors and that filarial diseases can be cured by targeting Wolbachia, have created a strong interest in deciphering the mechanisms underlying their intracellular lifestyle. However, being obligate intracellular endosymbionts, Wolbachia remain genetically intractable. They grow slowly in insect cell cultures, for which markers are limited. Despite these obstacles, and to limit cell line-specific phenotypes, I chose to infect 2 Drosophila melanogaster cell lines presenting different sets of expressed genes, with a unique Wolbachia strain, naturally hosted by Drosophila melanogaster. Using these 2 cell lines that are differently permissive to the infection, I explored the interaction of Wolbachia with the endoplasmic reticulum (ER). Through fluorescence time-lapse confocal and electron microscopy observations, I provide strong evidence that this organelle is the source of membrane for Wolbachia, and possibly a source of nutrients. However, gene expression analyses and immunofluorescence approaches demonstrate that Wolbachia do not induce ER stress nor an increased ERAD- induced proteolysis, suggesting; unlike previously reported, that Wolbachia salvage amino acids by other subversion mechanisms. Additionally, I pioneered biolistic bombardement of Wolbachia-infected cells and the validation of this transformation technique has paved the way towards optimization of transformant selection steps and ultimately to the genetic engineering of Wolbachia
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Kuribayashi, Juliana Sayuri. "A desregulação da via UPR associada à imunodeficiência comum variável." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-05102007-153124/.
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A imunodeficiência comum variável (CVID) é caracterizada por hipogamaglobulinemia e infecções recidivantes. Neste estudo verificamos o papel da via Unfolded Protein Response (UPR) na patogênese da doença. Uma paciente com CVID apresentou expressão aumentada do RNAm XBP-1 unspliced e co-localização de IgM e BiP no retículo endoplasmático (RE). Verificamos a ausência de mutações nos produtos obtidos por RT-PCR de XBP-1 e nos domínios quinase/endonuclease da IRE-1a. Análises por Q-PCR dos RNAm XBP-1 spliced, IRE-1a e BiP após tratamento com LPS ou brefeldina A mostrou que, ao contrário dos controles saudáveis que respondem a estes estressores com ondas de transcrição destes três genes, esta paciente apresenta baixos níveis de transcrição, não atingindo o mesmo nível de resposta apresentado pelos indivíduos saudáveis. Nossos achados associam o splicing diminuído do RNAm XBP-1 ao acúmulo de IgM no RE e baixas taxas de transcrição de chaperonas, fornecendo um mecanismo para explicar a hipogamaglobulinemia observada em uma paciente com CVID.Common Variable Immunodeficiency (CVID) is characterized by hypogammaglobulinemia and recurrent infections. Herein we addressed the role of Unfolded Protein Response (UPR) in the pathogenesis of the disease. Augmented unspliced XBP-1 mRNA concurrent with co-localization of IgM and BiP was found in one CVID patient. Sequencing of RT-PCR amplicons did not reveal any mutation on XBP-1 neither on the kinase/endonuclease domains of IRE-1a. Q-PCR analysis of spliced XBP-1, IRE-1a and BiP after LPS or Brefeldin A treatment showed that, unlike healthy controls that respond to these ER stressors by presenting waves of transcription of these three genes, the cells presented lower rates of transcription, not reaching the same level of response of healthy subjects. Our findings associate diminished splicing of XBP-1 mRNA with accumulation of IgM within the ER and lower rates of chaperone transcription, therefore providing a mechanism to explain the observed hypogammaglobulinemia.
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Damasceno, Andreia Goreti Marques. "Mapping UPR elements in male reproductive system: a bioinformatics approach." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22006.
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Mestrado em Biomedicina MolecularA Unfolded Protein Response (UPR) é um mecanismo de defesa crucial que protege as células contra o enrolamento incorreto de proteínas, através da ativação de três sensores principais: ATF6, PERK e IRE1. Cada sensor guia a célula em diferentes mecanismos de transdução de sinal culminando na produção de fatores de transcrição que, por sua vez, regulam genes que aumentam a capacidade da célula corrigir a conformação de proteínas mal enoveladas, impedindo, em último caso, a sua agregação. Nos últimos anos a UPR tem sido associada a várias patologias. Na infertilidade masculina, poucos estudos se têm focado na influência dos componentes da UPR, sendo importante numa primeira abordagem, a identificação destes componentes no sistema reprodutor masculino. Através de pesquisa de bases de dados e com abordagens bioinformáticas, com o objetivo de identificar potenciais candidatos associados a fenótipos de infertilidade, foi realizada uma recolha de proteínas UPR no testículo, espermatozoide e plasma seminal. De forma a determinar possíveis alvos envolvidos na infertilidade masculina, as interações proteínaproteína foram analisadas, destacando-se 6 proteínas com elevado grau de interação: HSP90AA1, HSPA5, SEC61A1, VCP, PERK e ATF4. Considerando ainda a sua importância funcional, as proteínas efetoras da via PERK, a GADD34 e a eIF2 foram destacadas para estudos de deteção experimentais. Neste sentido, foi confirmada pela primeira vez a presença das proteínas PERK e GADD34 em espermatozoides humanos. Estes resultados constituem o primeiro passo fundamental para avançar para estudos mais aprofundados relativamente à expressão e níveis de atividade destes candidatos, procurando perceber a contribuição dos mesmos na via de sinalização UPR e a sua eventual desregulação na infertilidade masculina.
The unfolded protein response (UPR) is an essential cell defense response against defects in protein folding and it is mainly triggered by the activation of ATF6, PERK and IRE1. Each sensor leads to different signal transduction mechanisms through the production of transcription factors that, in turn, regulate genes that increase the cell's ability to correct conformation of poorly folded proteins, ultimately hindering their aggregation. The past years shed light on the role of the UPR in several diseases. Regarding male infertility, few studies have focused on the implications of UPR components, hence the need to a prior approach concerning the presence of these components on the male reproductive system. Through a database search and using bioinformatics approaches, with the aim of identifying potential candidates associated with infertility phenotypes, a collection of UPR proteins in the testis, spermatozoa and seminal plasma was performed. To determine potential targets to scrutinize possible involvement in male infertility, a protein-protein interaction network analysis was performed, depicting 6 key proteins highly interconnected: HSP90AA1, HSPA5, SEC61A1, VCP, PERK and ATF4. Considering their functional value, the effector proteins of the PERK pathway, GADD34 and eIF2 were highlighted for experimental studies. Thus, the presence of the PERK and GADD34 were confirmed for the first time in human spermatozoa. These results constitute the first fundamental step towards further studies on the expression and activity levels of these candidates and understand their contribution to the UPR signaling pathway and their possible deregulation in male infertility
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Gonçalves, Amanda Hellen. "Estudo experimental do controle de movimento de uma plataforma Stewart do tipo 6-UPUR /." Bauru, 2019. http://hdl.handle.net/11449/183123.
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Orientador: Marcos SilveiraCoorientador: Mauricio Becerra Vargas
Banca: Douglas Domingues Bueno
Banca: Fabricio Cesar Lobato de Almeida
Resumo: Robôs paralelos ou robôs de cadeia cinemática fechada vêm ganhando destaque no cenário industrial e acadêmico, principalmente diante da necessidade de robôs com altas acelerações e velocidades, alta relação capacidade de carga/peso e alta rigidez e precisão, motivo pelo qual são usados em simuladores de voo e robôs pick-and-place. Muitos trabalhos foram publicados tratando sobre o controle de posição de robôs paralelos, porém muitos mantiveram-se restritos ao estudo teórico, sem considerar algumas limitações na aplicação prática. Neste contexto, esta dissertação apresenta o projeto e a implementação prática de um controlador PD (Proporcional-Derivativo) independente para cada junta de um robô paralelo de seis graus de liberdade do tipo 6-UPUR (universal-prismáticauniversal- rotational) acionado por atuadores lineares eletromecânicos. Inicialmente foi realizada a calibração e o acondicionamento do sinal dos sensores de realimentação, do driver e dos atuadores eletromecânicos. Posteriormente, modelos matemáticos do comportamento dinâmico dos atuadores lineares foram identificados e, finalmente, considerando critérios de desempenho específicos para simuladores de voo, foram projetados os controladores para cada atuador. O desempenho de cada controlador foi avaliado por meio de sinais de entrada em degrau, rampa e parábola em coordenadas cartesianas e, por meio da cinemática inversa, foram calculadas as entradas desejadas para cada atuador. O desempenho do robô na frequência foi ... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Parallel robots or closed kinematic chain robots has gained more attention from both in industry and in academic research, especially in view of the need for robot whith high velocities and accelerations, high payload-weight ratio, high stiffness and accuracy. That is why they are used in flight simulators and robots pick-and-place. Many studies have been published addressing the problem of motion control of parallel robots, but many are limited to the theoretical study, without considering some limitations in practical application. In this context, this dissertation presents the design and practical imple- mentation of independent-joint PD (Proportional-Derivative) controller for a 6-UPRU (universal-prismatic-universal-rotational) degree-of-freedom parallel manipulator driven by electromechanical linear actuators. First, the feedback sensors, drive and electrome- chanical actuators are calibrated, and their signals are processed. Later, mathematical models of the dynamical behaviour of the linear actuators are identified. Then, conside- ring specific performance criteria for flight simulators, the controller for each actuator is designed. The performance of each controller was evaluated for step, ramp and parabolic inputs in cartesian coordinates, then the cartesian trajectory is converted to desired actu- ator trajectory by using inverse kinematics. The perfomance of the robot was evaluated in frequency domain using sinousoidal inputs in cartesian coordinates, describing fu... (Complete abstract click electronic access below)
Mestre
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Vidal, Iglesias Berta. "The fibrinolitys system in muscle regeneration and dystrophy." Doctoral thesis, Universitat Pompeu Fabra, 2008. http://hdl.handle.net/10803/7143.
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Duchenne muscular dystrophy (DMD) is a fatal degenerative disorder of locomotor and respiratory muscles, in which myofibers are progressively replaced by non-muscular fibrotic tissue. Here, we show that fibrin/ogen accumulates in dystrophic muscles of DMD patients and of the mdx mouse model of DMD. Genetic loss or pharmacological depletion of fibrin/ogen in mdx mice attenuated muscular dystrophy progression and improved locomotor capacity. More importantly, fibrin/ogen depletion reduced fibrosis in mdx mouse diaphragm. Our data indicate that fibrin/ogen, through induction of IL-1 Ò, drives the synthesis of TGF Ò by mdx macrophages, which in turn, induces collagen production in mdx fibroblasts. Fibrin/ogen-produced TGF Ò further amplifies collagen accumulation through recruitment and activation of pro-fibrotic alternatively activated macrophages. Fibrin/ogen also stimulated collagen synthesis directly in mdx fibroblasts, via Ñv Ò3 integrin engagement. In addition, when analyzing a group of 39 DMD patients, fibrin/ogen accumulation in locomotor muscles was found associated with fibrosis and disease severity. These data unveil a novel role of fibrin/ogen in muscular dystrophy and, importantly, in the replacement of muscle by fibrotic tissue.
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Roriz, Semiramis de Moura. "Upas e hospitais metropolitanos: a terceirização do serviço público de saúde no estado de Pernambuco." Universidade Católica de Pernambuco, 2017. http://tede2.unicap.br:8080/handle/tede/944.
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Based on changes created by administrated reform and creation of public qualification of social organization as a partnership between public administration and private institution, several qualified institutions emerged and began to execute public services. The purpose of this research is to analyze Health social organizations from the State of Pernambuco, focused on those which execute public services at Unidades de Pronto Atendimento and Hospitais Metropolitanos verifying if a partnership between public admiration and private institutions exist or if there is an outsourcing service from public administration. To do so, a deep analyze of Federal legislation as well State Legislation which qualify non-profit private institutions as social organizations were made as well a bibliographic review to find out if the link between qualified health institutions and the state of Pernambuco is classified as partnership or outsourcing. As for a conclusion, after an analyze of all arguments, it was verified that, as it was proposed by the state of Pernambuco, the health social organizations were not executing a public service as a partnership with the state of Pernambuco, instead such organizations were executing a service as an outsourcing organization.
Tendo em vista as alterações provocadas pela reforma administrativa e a criação da qualificação pública da organização social como forma de parceria entre a Administração Pública e a iniciativa privada, surgiram diversas entidades qualificadas que passaram a executar serviços públicos. O objetivo da presente pesquisa é realizar uma análise das Organizações Sociais de Saúde do Estado de Pernambuco, em especial as que atuam na prestação de serviços públicos de saúde nas Unidades de Pronto Atendimento e Hospitais Metropolitanos e verificar se há parceria entre o ente público e o ente privado ou terceirização. Para tanto, foi realizada uma análise da legislação federal e estadual que regulamenta a qualificação das instituições privadas sem fins lucrativos como organizações sociais, bem como realizou-se um levantamento bibliográfico a fim de verificar se o vínculo que une as entidades qualificadas na área de saúde e o Estado de Pernambuco corresponde a parceria ou a terceirização. Como conclusão, após a análise de todos os argumentos propostos, verificou-se que, na forma como foi proposta pelo Estado de Pernambuco, as organizações sociais de saúde não estavam prestando serviço público de saúde de forma complementar em parceria com o Estado de Pernambuco, mas terceirização ilícita
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Pedroso, Marcel de Moraes. "Inteligência decisória e análise de políticas públicas : o caso das Unidades de Pronto Atendimento (UPAs)." reponame:Repositório Institucional da UnB, 2011. http://repositorio.unb.br/handle/10482/9663.
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Tese (doutorado)—Universidade de Brasília, Programa de Pós-Graduação em Administração, 2011.Submitted by Albânia Cézar de Melo (albania@bce.unb.br) on 2011-12-01T14:57:56Z No. of bitstreams: 1 2011_MarcelMoraesPedroso.pdf: 15130057 bytes, checksum: 6739fad8371c01ccd44ea7a6d6d57712 (MD5)
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Esta tese proporciona uma contribuição ao campo de análise de processos decisórios em políticas públicas, mais especificamente sobre a tomada de decisão para implantação das Unidades de Pronto Atendimento (UPAs), financiadas pelo governo federal em parceria com estados e municípios brasileiros. Esta tese visa estabelecer bases teórico/metodológicas para construção de processos decisórios estruturados por um conjunto de regras para decidir que incorporem as preferências dos decisores, promovam a capacidade de adaptação e aprendizagem por meio de artefatos sociais e tecnológicos com uso intensivo de informações geográficas. Com esse intuito, revisa diferentes abordagens do paradigma da racionalidade limitada em três modelos de análise de políticas públicas: múltiplos fluxos, equilíbrio pontuado e coalizões de defesa; sumariza e diferencia os usos da informação geográfica nesses modelos, bem como, discute a metodologia de análise multicritério de decisão espacial-construtivista (SMCDA-C). O desenho metodológico da pesquisa combina a análise de dados qualitativos e quantitativos, operacionalizados por três componentes de pesquisa: (i) componente estrutura narrativa (qualitativo); (ii) componente estudo de caso (qualitativo e quantitativo) e; (iii) componente análise contrafactual (quantitativo). O componente estudo de caso é composto por três unidades de análise: Modelo Atual, Modelo Racional e Modelo Construtivista. Dentre as principais contribuições deste trabalho, destacam-se: (i) resgate dos eventos principais do processo de construção do programa UPAs e sua ascensão à agenda da segunda fase do PAC; (ii) construção de estudo de caso que resultou na descrição dos arranjos espaciais e no mapeamento das decisões geradas pela aplicação dos modelos de tomada de decisão Atual, Racional e Construtivista nas dez Unidades da Federação pesquisadas; (iii) definição e cálculo dos Índices de Inteligência Decisória (IIDs) das UFs relativos a cada um desses modelos; (iv) comparação entre as decisões sobre a localização UPAs resultantes dos três processos decisórios analisados e a realização de testes de associação entre os IIDs e os arranjos espaciais decorrentes da aplicação dos modelos contrafactuais. ______________________________________________________________________________ ABSTRACT
This thesis offers a contribution towards the field of the decision-making processes in public policy analysis, more specifically in relation to the decision to locate Emergency Service Units (Unidades de Pronto Atendimento – UPAs), financed by the federal government in partnership with Brazilian states and municipalities. This thesis aims to analyze the theoretical/methodological basis for this decision-making processes and propose a set of rules embodying the preferences of decision makers, and promote capacity for adaptation and learning through the use of social and technological artifacts as well with intensive use of geographical information. With this objective in mind, a revision was made of the different approaches of the paradigm of bounded rationality in three public policy models of analysis: multiple streams theory, punctuated equilibrium theory and advocacy coalition framework; to summarize and to differentiate the use of geographical information in these models, as well as to discuss the spatial multicriteria decision analysis-constructivist (SMCDA-C). The methodological design of the research combines an analysis of qualitative and quantitative data that was possible to put into operation by means of three components: (i) the narrative structure component (qualitative); (ii) the case study component (qualitative and quantitative) and; (iii) the contrafactual analysis component (quantitative). The case study component is composed of three units of analysis: the Actual, the Rational and the Constructivist Models. Some of the main contributions of this work should be highlighted: (i) registering the principal events related to the construction process of the UPA programme and its ascension to the second phase of the agenda for the Accelerated Growth Programme - PAC; (ii) constructing a case study that resulted in a description of the spatial arrangements and mapping the decisions generated through the application of the Actual, Rational and Constructivist decision-making models in the ten Units of the Federation that were researched; (iii) Decision Intelligence Indexes (DII) definitions and calculations made for the Federal States in relation to each one of these models; (iv) comparisons made between decisions in relation to the location of the UPAs resulting from the three decision-making processes analyzed, and the carrying out of association tests between the DIIs and the spatial arrangements that resulted from the application of contrafactual models.
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Gerakis, Yannis. "Stress réticulaire et maladie d'Alzheimer : contribution du facteur de transcription XBP-1s." Thesis, Université Côte d'Azur (ComUE), 2016. http://www.theses.fr/2016AZUR4097/document.
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La maladie d'Alzheimer est une pathologie neurodégénérative progressive liée à l'âge qui détériore premièrement les fonctions liées aux mémoires de travail et épisodiques, avant de s'étendre à l'ensemble des procédures mémorielles dans les stades plus avancés. L'ensemble des traitements existant à ce jour sont palliatifs. Au niveau histologique, la maladie d'Alzheimer est caractérisée par l'accumulation extra- et intracellulaire de différentes protéines agrégées (appelées amyloïde) dans les tissus cérébraux, entrainant des dysfonctions importantes du circuit neuronal. De fait, la majorité des approches thérapeutiques en développement consistent à tenter de réduire ou supprimer ces agrégats protéiques. Cependant, la maladie d'Alzheimer étant étroitement corrélée au vieillissement, certaines de ses caractéristiques biologiques sont parfois confondues avec celles du vieillissement non pathologique. L'une de ces caractéristiques est la diminution des différents mécanismes liés à l'homéostasie protéique (protéostasie). L'hypothèse réalisée au cours de mes travaux est que le rétablissement de ces mécanismes diminués par l'âge constituerait une approche thérapeutique crédible, complémentaire aux approches actuelles, à la pathologie complexe qu'est la maladie d'Alzheimer. C'est en suivant cette optique que je me suis intéressé au rôle et à la régulation de l'un des systèmes majeusr du contrôle de la protéostasie : l'UPR (unfolded protein response), et en particulier au facteur de transcription XBP-1s, considéré comme l'une des pièces maîtresses de ce réseau de signalisation cellulaireAlzheimer's disease is a neurodegenerative pathology strongly correlated to aging. Its symptoms are characterized by an impaired short term memory process in the early stages of the disease and later on by a loss of all type of memory process. There is actually no cure for this pathology. At the histo-pathological levels, the disease show an accumulation of aggregated proteins in the brain (called amyloid protein) in the intra or extra cellular space, which act as a disruptor of the normal neuronal function and activity. Thus, most of the therapeutic approach to treat the disease aim at removing those proteins aggregates from the brain. However, some of the Alzheimer's disease characteristics could be melded with normal aging : One such case is the global decrease of the proteostasis mechanism in the cell which normally happen in normal brain. The assumption made during this work is that the recovery of these mechanisms impaired by age would constitute a credible therapeutic approach, complementary to the other existing approaches to the complex disease that is Alzheimer's disease. Following this hypothesis I was interested in the role and regulation of one of the major system controlling proteostasis: the UPR (unfolded protein response), and particulary to the XBP-1s transcription factor , considered one of the master regulator of this cellular network
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Silva, Fabio Nauer da. "Filogenia molecular e diversidade do gênero Hypnea (Gigartinales, Rhodophyta) na costa brasileira." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/41/41132/tde-25032014-180135/.
Full textAbstract:
O presente trabalho utiliza marcadores moleculares para auxiliar na caracterização e filogenia das espécies de macroalgas vermelhas do gênero Hypnea na costa do Brasil. O gênero Hypnea Lamouroux (1813) apresenta cerca de 67 espécies descritas e possui distribuição geográfica em águas quentes ao redor do mundo. Além disso, o gênero possui grande importância econômica e ecológica, como fonte de alimento e produção industrial de carragenana. Porém, a identificação das espécies de Hypnea com base exclusivamente em dados morfológicos é dificultada em virtude da plasticidade fenotípica presente no grupo, de sua morfologia relativamente simples e da ampla distribuição geográfica de suas espécies. Em vista disso, utilizamos a técnica de \"DNA barcoding\" que permite a análise de um grande número de amostras. Neste trabalho foram utilizados dois \"DNA barcodes\" (a região 5\' do gene mitocondrial cox1 e o \"universal plastid amplicon\" UPA), e para as análises filogenéticas foi utilizado o gene plastidial rbcL. Além disso, estudos morfológicos foram feitos a fim de delimitar o real valor dos caracteres morfo-anatômicos citados na literatura para a separação de espécies do gênero Hypnea. Ao todo, foram obtidas 230 amostras brasileiras de Hypnea, provenientes de 11 estados brasileiros, e 10 amostras de outros países. Um total de 367 sequências de marcadores moleculares foi obtido neste trabalho. Confirmamos a ocorrência de nove espécies para o gênero: H. cervicornis, \"H. flexicaulis\", \"H. musciformis\", H. spinella, \"H. stellulifera\", Hypnea sp. 1, Hypnea sp. 2, Hypnea sp. 3 e Hypnea sp. 4. As amostras coletadas e previamente identificadas em campo como H. cornuta revelaram-se, pelos estudos da biologia molecular, serem \"H. stellulifera\". As espécies H. musciformis, H. nigrescens, H. valentiae foram consideradas variações morfológicas de uma mesma espécie, denominada de \"H. musciformis\". A identificação das espécies com base apenas em características morfológicas mostrou-se insatisfatória, devido principalmente a plasticidade fenotípica presente no grupo, além da existência de espécies com morfologias convergentes. A técnica de \"DNA barcode\", principalmente com relação ao marcador cox1, mostrou-se essencial na identificação e delimitação das espécies, revelando cenários que passariam despercebidos com o uso apenas da morfologiaThis study uses molecular markers to aid in the characterization and phylogeny of species of the genus Hypnea, a red macroalgae, on the coast of Brazil. The genus Hypnea Lamouroux (1813) presents about 67 described species and has geographical distribution in warm waters around the world. Furthermore, the genus has great economic and ecological importance as a source of food and industrial production of carrageenan. However, the identification of the species of Hypnea based solely on morphological data is difficult due to phenotypic plasticity present in this group, its relatively simple morphology and broad geographical distribution of its species. In view of this, we use the technique of \"DNA barcoding\" that allows the analysis of a large number of samples. In this work we used two \"DNA barcodes\" (the 5 \'region of the mitochondrial gene cox1 and universal plastid amplicon UPA), and for phylogenetic analysis the plastid gene rbcL was used. In addition, morphological studies were made in order to delimit the actual value of morpho-anatomical caracters cited in the literature for the separation of species of Hypnea. Altogether, 230 Hypnea samples were obtained from 11 Brazilian states, and 10 samples from other countries. A total of 367 sequences of molecular markers were obtained in this study. We confirm the occurrence of nine species of the genus: H. cervicornis, \"H. flexicaulis\", \"H. musciformis\", \"H. spinella, \"H. stellulifera\", Hypnea sp. 1, Hypnea sp. 2, Hypnea sp. 3 and Hypnea sp. 4. Samples collected in the field and previously identified as H. cornuta based on molecular data, proved to be \"H. stellulifera\". The species H. musciformis, H. nigrescens and H. valentiae were considered morphological variations of the same species, named \"H. musciformis\". The identification of species based on morphological characteristics proved unsatisfactory, mainly due to phenotypic plasticity in this group and the existence of species with convergent morphologies. The technique of \"DNA barcode\", especially with respect to cox1 marker, was essential for the identification and definition of species, revealing scenarios that would go unnoticed by using only morphology