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Motara, Yusuf Moosa. "Preimages for SHA-1." Thesis, Rhodes University, 2018. http://hdl.handle.net/10962/57885.
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This research explores the problem of finding a preimage — an input that, when passed through a particular function, will result in a pre-specified output — for the compression function of the SHA-1 cryptographic hash. This problem is much more difficult than the problem of finding a collision for a hash function, and preimage attacks for very few popular hash functions are known. The research begins by introducing the field and giving an overview of the existing work in the area. A thorough analysis of the compression function is made, resulting in alternative formulations for both parts of the function, and both statistical and theoretical tools to determine the difficulty of the SHA-1 preimage problem. Different representations (And- Inverter Graph, Binary Decision Diagram, Conjunctive Normal Form, Constraint Satisfaction form, and Disjunctive Normal Form) and associated tools to manipulate and/or analyse these representations are then applied and explored, and results are collected and interpreted. In conclusion, the SHA-1 preimage problem remains unsolved and insoluble for the foreseeable future. The primary issue is one of efficient representation; despite a promising theoretical difficulty, both the diffusion characteristics and the depth of the tree stand in the way of efficient search. Despite this, the research served to confirm and quantify the difficulty of the problem both theoretically, using Schaefer's Theorem, and practically, in the context of different representations.
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Hadmi, Azhar. "Protection des données visuelles : analyse des fonctions de hachage perceptuel." Thesis, Montpellier 2, 2012. http://www.theses.fr/2012MON20159/document.
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Avec une croissance considérable dans le domaine de la technologie multimédia et de la forte disponibilité des logiciels de traitement d'image, il est désormais facile de manipuler les images numériques. En même temps, il est devenu possible de réaliser des contrefaçons très élaborées, en laissant très peu de traces. Cela présente un grave problème, en particulier, si l'authenticité de l'image numérique est exigée. L'authentification des images devrait se baser sur leurs contenus visuels et non pas sur leurs contenus binaires. Par conséquent, pour authentifier une image, il faut tolérer quelques manipulations acceptables que pourrait subir une image telles que la compression JPEG et l'ajout de bruit Gaussien. En effet, ces manipulations préservent l'aspect visuel de l'image. En même temps un système de hachage perceptuel doit être suffisamment fragile pour détecter les manipulations malveillantes qui modifient l'interprétation du contenu sémantique de l'image comme l'ajout de nouveaux objets, la suppression ou la modification majeure d'objets existants.Dans cette thèse, nous nous intéressons aux fonctions de hachage perceptuel pour l'authentification et le contrôle d'intégrité des images numériques. Dans ce but, nous présentons tous les aspects relatifs aux fonctions de hachage perceptuel. Puis, nous exposons les contraintes qu'un système de hachage perceptuel doit satisfaire pour répondre aux exigences souhaitées au niveau de la robustesse des signatures perceptuelles. Enfin, nous présentons une méthode permettant d'améliorer la robustesse et la sécurité d'un système dehachage perceptuelThe widespread use of multimedia technology has made it relatively easy to manipulate and tamper visual data. In particular, digital image processing and image manipulation tools offer facilities to intentionally alter image content without leaving perceptual traces. This presents a serious problem, particularly if the authenticity of the digital image is required. The image authentication should be based on their visual content and not on their binary content. Therefore, to authenticate an image, some acceptable manipulations that could undergoes an image, such as JPEG compression and Gaussian noise addition, must tolerated. Indeed, these manipulations preserve the visual appearance of the image. At the same time a perceptual hashing system should be sufficiently sensitive to detect malicious manipulations that modify the interpretation of the semantic content of the imagesuch as adding new objects, deleting or major modification of existing objects.In this thesis, we focus on perceptual hash functions for authentication and integrityverification of digital images. For this purpose, we present all aspects of perceptual hashfunctions. Then, we discuss the constraints that perceptual hashing system must satisfy tomeet desired level of robustness of perceptual signatures. Finally, we present a method toimprove the robustness and security of a system of perceptual hashing
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Dufek, Ladislav. "Ovládání elektronických systémů přes webové rozhraní." Master's thesis, Vysoké učení technické v Brně. Fakulta elektrotechniky a komunikačních technologií, 2011. http://www.nusl.cz/ntk/nusl-219174.
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This master thesis goes into problematics of design of an electronic device control system and its realization. First of all its overall conception is specified and potential hardware platforms are analyzed afterwards. Based on this analysis the system’s final conception is drawn up, the device’s circuit layout is created and finally a functional prototype is manufactured. The later part of this thesis describes the software accessories and tools. The principles of a chosen operating system, management application and webbased interface are described along with the problems of authentization to solve. The proposed solutions for the authentization-specific tasks gave rise to the final implementation of the authentization methods and techniques.
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DE, PICCOLI ALESSANDRO. "OPTIMIZED REPRESENTATIONS IN CRYPTOGRAPHIC PRIMITIVES." Doctoral thesis, Università degli Studi di Milano, 2022. http://hdl.handle.net/2434/932549.
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Il lavoro di tesi si focalizza sull'ottimizzazione di primitive crittografiche sia dal punto di vista teorico che da quello pratico. Riguardo il punto di vista teorico sarà analizzato il problema dell'accelerazione degli algoritmi di moltiplicazione polinomiale, ampiamente impiegati in Crittografia Post-Quantum, come, ad esempio, NTRU e McEliece. Quest'ultimo, in particolare, utilizza campi di Galois e loro estensioni, i cui elementi possono essere rappresentati in forma polinomiale. Saranno dunque esposte nuove tecniche che permettono una riduzione del numero di porte logiche e verranno presentati i risultati sperimentali della loro applicazione all'implementazione del cifrario McEliece attualmente candidato come nuovo standard Post-Quantum al NIST. Dal punto di vista pratico, questo lavoro di tesi, si focalizza sull’ottimizzazione di attacchi alla prima pre-immagine dell'algoritmo di hash SHA-1 basati su SAT solvers. Nessuna delle rappresentazioni testate ha mostrato una particolare efficienza in termini di velocità di risoluzione. Al contrario, un'accurata scelta di valori ha permesso di raggiungere un nuovo stato dell'arte, rivelando al contempo la debolezza di alcune pre-immagini.This work focuses on optimization of cryptographic primitives both in theory and in applications. From a theoretical point of view, it addresses the problem of speeding up the polynomial multiplication used in Post-Quantum cryptosystems such as NTRU and McEliece. In particular, the latter extensively uses Galois fields whose elements can be represented in polynomial form. After presenting the reduction of the number of gates for polynomial multiplication through new techniques, in this work experimental results of such techniques applied to the current implementation of McEliece will be presented. From a practical point of view, this work focuses on the optimization of a SAT solver-based preimage attack against SHA-1 and on its strength. None of the tested representations of SHA-1 seems to be competitive in terms of resolution. On the contrary, an accurate choice of some pre-image bits allows one to reach a better state of art, revealing meanwhile the weakness of some pre-images.
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Beran, Martin. "Elektronická podatelna VUT 2." Master's thesis, Vysoké učení technické v Brně. Fakulta informačních technologií, 2007. http://www.nusl.cz/ntk/nusl-412777.
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This dissertation thesis attends to problems of electronic registry for VUT. It deals with the principal of electronic registry functioning, electronic signature and it compares offer of the commercial registries. It goes in for the proposal and implementation of the electronic registry for VUT. Since the using of the e- registry on all public service Office was legalized the people can avoid long queues and the employees are avoided from the stress before dead lines. By the communication through the electronic registry is very important the electronical signature. It is almost a full-valued and lawful alternative to the physical signature. For its safety and utility this system employes asymmetric codes and hash algorithm. Presently in many states, where the electronical signature is legalized it is used together with standard X 509 which defines the format of certificates, organization and action of certification authorities. The certification autority ensures safe connection of the person and general key for using of the electronical signature.
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Sweeney, Michael Cameron. "Synthetic combinatorial peptide libraries and their application in decoding biological interactions." Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1118952919.
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Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xv, 151 p.; also includes graphics. Includes bibliographical references (p. 134-151). Available online via OhioLINK's ETD Center
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Jin, Sha Verfasser], Erich [Gutachter] [Wanker, Jan [Gutachter] Bieschke, and Andreas [Gutachter] Herrmann. "Membrane interaction of amyloid–beta (1–42) peptide induces membrane remodeling and benefits the conversion of non–toxic Aβ species into cytotoxic aggregate / Sha Jin ; Gutachter: Erich Wanker, Jan Bieschke, Andreas Herrmann." Berlin : Lebenswissenschaftliche Fakultät, 2016. http://d-nb.info/1119212049/34.
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Bachtík, Martin. "Online validace záznamů DNSSEC." Master's thesis, Vysoké učení technické v Brně. Fakulta informačních technologií, 2011. http://www.nusl.cz/ntk/nusl-412834.
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Master's Thesis is studying an extension that secures the domain name system by introducing the verifiability of authenticity of data, known as DNSSEC. Productive output is proposal of application and its subsequent implementation that at each stage of browse the namespace to the selected domain name checks the appropriatenesses of this extension and in detail reports the trusted chain.
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Bone, Heather Karyn. "Interleukin-3 (IL-3) signal transduction in haemopoietic cells : the role of SHP-1, SHP-2, and SHC." Thesis, University of Bath, 1999. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300876.
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Hampel, Kornelia [Verfasser]. "Regulation der Enzymaktivität der Proteintyrosinphosphatase SHP-1 durch monophosphorylierte SH2-Domänen-Liganden / Kornelia Hampel." Jena : Friedrich-Schiller-Universität Jena, 2006. http://d-nb.info/1178253228/34.
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Krznaric, Anton. "License Management for EBITool." Thesis, Högskolan Kristianstad, Sektionen för hälsa och samhälle, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:hkr:diva-10175.
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This degree project deals with license management for EBITool. It´s about providing protection and monitoring for a Java Application via a license server, and the construction of it. An analysis that discusses the approach and other possible courses of action is also included. Additionally, it covers a discussion of a prototype implementation of the model solution from the analysis. The prototype is a Java EE application that deploys to JBoss AS7. It´s developed using the JBoss Developer Studio 5.0.0, an Eclipse IDE with JBoss Tools preinstalled. It exposes web services to Java Applications through SOAP via JAX-WS. Using Hibernate, the web service Enterprise Java Beans get access to a PostgreSQL 9.1 database via entity classes mapped to the database through the Java Persistence API.
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Martin, Alberto. "Activity regulation of murine SHP-1." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0017/NQ45722.pdf.
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França, Mônica Malheiros. "O papel do fator de transcrição POD-1 na regulação de SF-1 e LRH-1 em células tumorais da suprarrenal humana." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/42/42131/tde-03062014-162141/.
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SF-1 e LRH-1 são fatores de transcrição que exercem um papel fundamental na produção de esteroides nas gônadas e na suprarrenal, além de estarem envolvidos no processo tumorigênico desses órgãos. Por outro lado, POD-1 apresenta menor expressão em carcinomas adrenocorticais, e parece regular Sf-1. Nesse trabalho foi analisado o papel de POD-1 na regulação de SF-1 e de LRH-1 em células de tumores adrenocorticais. A hiperexpressão de POD-1 resultou em redução da expressão SF-1/SF-1. Em contraste, houve um aumento da expressão gênica de LRH-1, devido à diminuição da expressão de SHP, um regulador negativo de LRH-1. Nas células transfectadas com siRNA-POD-1, os níveis de POD-1 foram reduzidos e de SF-1 aumentado, reforçando o mecanismo regulatório entre os fatores. No ChIP assay, POD-1 se ligou a sequência E-box do promotor de SF-1. Por outro lado, não foi caracterizado a ligação de POD-1 no promotor LRH-1, embora POD-1 tenha se ligado ao E-box do promotor SHP. A redução de SF-1 diminuiu a expressão de StAR, mas não modulou a proliferação das células tumorais. Em resumo, POD-1 pode ter um papel mais amplo como regulador da transcrição de fatores que controlam o processo tumorigênico, e é um candidato a gene supressor de tumor nas células adrenocorticais.SF-1 and LRH-1 have played a critical role in steroid production, adrenal and gonads. Moreover, there are evidences that they have acted in tumorigenesis process in these organs. POD-1 is downregulated in adrenocortical carcinoma (ACC) it seems to regulate Sf-1. In this work, it has been to analyse the role of POD-1 in SF-1 and LRH-1 regulation in adrenocortical tumor cells. The POD-1 overexpression has reduced SF-1/SF-1 expression. However, there was an increase of LRH-1 gene expression due to SHP expression decrease which is negative regulate of LRH-1. The POD-1 and SF-1 gene expression in transfected cells with siRNA-POD-1 has shown POD-1 decrease and SF-1 increase emphasizing a regulatory mechanism between POD-1 and SF-1. By ChIP assay it was shown that POD-1 binded in SF-1 promoter E-box sequence. It was not characterized that POD-1 binded in LRH-1 promoter, although POD-1 can bind in SHP promoter E-box sequence. The reduction of SF-1 expression by POD-1 has decreased the StAR expression, however, it was not enough to change tumor cell proliferation. In summary, POD-1 must have a wider role as regulator of fator transcription which controls tumorigenese process being a possible candidate as tumor supressor gene in adrenocortical cells.
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Magrin, Elisa. "Fosfo-tirosin-fosfatasi (PTPs): trasduttori positivi e negativi delle vie del segnale mediate da recettori di membrana." Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3422177.
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The tyrosine phosphorylation in eukaryotic proteins is a key event for transducing enviromental cues into cellular responses ranging from cell-to-cell communication to proliferation, differentiation, cell death and survival. This mechanism of signal transduction is mediated by the opposing and concerted action of Protein Tyrosin Kinases (PTKs), which add phosphoryl groups to target proteins, and Protein Tyrosin Phosphatases (PTPs), which remove them; both classes of enzymes can take part in activatory and inhibitory signalling processes. Tyrosin phosphorylation calls also into action the Src-homology 2 domain (SH2), which is contained in a myriad of proteins with varied functions and that directs protein-protein interaction by “sensing” the phosphorylated state of tyrosine residues, taking part in the modulation of signal transduction. This three-part system has recently been baptized as the “writer “ (PTK), “eraser” (PTP) and “reader” (SH2) tollkit, emphasizing how the combination and dynamic interplay of the elements can generate diverse and complex regulatory outputs.
The aim of this work was to determine how the tyrosine phosphorylation is involved in the cellular response to extracellular signals; we investigated the events which trigger an altered pathway in diseases, mainly the role of non-receptor PTPs in three different pathological conditions.
In Polycytemia Vera (PV) and Essential Thrombocythemia (ET), which are Philadelphia-negative myeloproliferative disorders (Ph-MPDs), our results demonstrate that in resting platelets the dephosphorylation of the Src-Tyr527 is due the SHP-2 constitutive activity, a non-receptor PTPs, leading to the Src preactivation. The anomalous activation of the kinase is implicated in the hypersensivity of Ph-MPDs and likely involved in the functional abnormalities of PV and ET platelets.
In Heparin-Induced-Thrombocytopenia (HIT), immunological reaction that lead to the activation of FcγRIIA in platelets, we have not identified any correlation between the polymorphisms of receptor and HIT, but our results demonstrate that the phosphorylation of FcγRIIA-ITAM motif is due the type of ligand and that influences the responses in the platelets. We stimulated normal platelets with either IV.3, functional blocking antibody against FcγRIIA, or complexes of IgG molecules, and we have not highlighted phosphorylation of the ITAM or aggregation, but we observed a mildly shape change. Interestingly, the pre-incubation of the platelets with PTP-1B, the largest PTPs in platelets, in association with IV.3 and IgG as agonists, leads to phosphorylation of the ITAM and to aggregation. This mechanism may be involved in the clearance of IgG-containing complexes from the circulation by platelets.
Finally, we demonstrate for the first time that the PDGF (platelet-derived growth factor)-induced proliferation in epatic stellate cells (HSCs), primary effector cells in liver fibrosis, is mediated by the PTPs SHP-2 and SHP-1: SHP-2 acts as positive regulator of PDGF-dependent signalling, whereas SHP-1 is a negative regulator and lead to the dephosphorylation of the PDGF-receptor. An altered activity and/or expression of these two PTPs causes an inhibited cell proliferation of HSCs, thus they may be a target for new antifibrotic therapies for patients with liver fibrosis.
The three pathological models analyzed in this work highlight the key role of PTPs in signalling pathways; they are not to be trivially dismissed as negative regulators because they can organize cellular responses to different stimulations. Furher studies on PTPs-induced signalling regulation may identify new pharmacological therapiesLa fosforilazione tirosinica di proteine degli organismi eucarioti è il meccanismo chiave di trasduzione del segnale indotto da stimoli ambientali a livello cellulare, e si esplica in eventi di proliferazione, differenziazione, morte cellulare e sopravvivenza. Questo processo è mediato dall’azione concertata di protein tirosin chinasi (PTKs), che trasferiscono un gruppo fosfato alle proteine bersaglio, e protein tirosin fosfatasi (PTPs), che lo rimuovono; entrambe le classi di questi enzimi possono prender parte ad eventi attivatori e inibitori del signalling. La fosforilazione in tirosina determina il coinvolgimento anche del dominio SH2 (Src-homology 2 domain), presente in numerose proteine con svariate funzioni, che coordina l’interazione proteina-proteina proprio grazie ai residui tirosinici fosforilati, prendendo quindi parte alla modulazione del segnale di trasduzione. Il sistema formato da PTKs, PTPs e dominio SH2 è noto come “writer” (PTK), “eraser” (PTP) e “reader”(SH2) tollkit, denominazione che vuole sottolineare come la relazione e la combinazione di questi tre elementi riesca a determinare una fine e complessa regolazione a livello di signalling. Questo lavoro di tesi intende esaminare il coinvolgimento della fosforilazione tirosinica nel mediare le risposte cellulari a diversi stimoli extracellulari e valutare quali sono i fattori responsabili della sua alterazione in determinate situazioni patologiche ed in particolare il ruolo delle PTPs non recettoriali in tre specifiche patologie. In Policitemia Vera (PV) e Trombocitemia Essenziale (ET), disordini mieloproliferativi Philadelphia-negative (Ph-MPDs), i nostri dati dimostrano che la mancata fosforilazione del sito inibitorio, Y527, della tirosin chinasi Src in piastrine non stimolate è dovuto alla costitutiva attivazione di SHP-2, una PTP non recettoriale, determinando una forma pre-attivata di Src. Questa forma di Src è implicata nella ipersensibilizzazione piastrinica ed è responsabile, almeno parzialmente, delle funzionalità anormali delle piastrine di PV e ET. Nella Trombocitopenia Indotta da Eparina (HIT), reazione autoimmune che porta all’attivazione del recettore FcγRIIA piastrinico, pur non avendo evidenziato una correlazione tra il polimorfismo del recettore e HIT, noi abbiamo indagato il diverso stato di fosforilazione della sequenza ITAM di FcγRIIA e conseguente risposta piastrinica in relazione al tipo di ligando. Stimolando infatti le piastrine di donatori con l’anticorpo monoclonale IV.3, noto per essere un inibitore di FcγRIIA, e con delle IgG complessate, non abbiamo evidenziato fosforilazione dell’ITAM del recettore nè aggregazione, anche se le piastrine vanno incontro ad un cambiamento di forma. In presenza però dell’inibitore di PTP1B, la fosfatasi più abbondante in questo tipo di cellule, gli stessi stimoli portano alla fosforilazione di ITAM e le piastrine vanno incontro ad aggregazione. Questo meccanismo potrebbe essere implicato nel ruolo svolto dalle piastrine nella clereance dei complessi contenenti IgG presenti in circolo. Infine noi abbiamo dimostrato per la prima volta che la risposta proliferativa dopo stimolazione di PDGF (platelet-derived growth factor) delle cellule stellate epatiche (HSCs), principali cellule coinvolte nella fibrosi epatica, è mediata dalle fosfatasi SHP-2 e SHP-1: SHP-2 partecipa come trasduttore positivo del segnale mediato da PDGF, mentre SHP-1 ha effetto negativo sul segnale mediato da PDGF catalizzando la defosforilazione del recettore di PDGF. L’alterazione della loro attività e/o espressione porta ad una inibizione della proliferazione cellulare di HSCs, perciò entrambe le fosfatasi si propongono come possibili bersagli di potenziali farmaci antifibrotici. In tutti i modelli patologici studiati, è chiaro che le PTPs rivestono un ruolo fondamentale nel signaling cellulare; la loro presenza non solo non ha significato esclusivamente negativo ma è necessaria per organizzare la risposta a diversi tipi di stimolo. Lo studio della regolazione del signaling indotto dalle PTPs potrebbe quindi aprire strade alternative per individuare nuove terapie farmacologiche
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Sha, Peng [Verfasser], Ulrich Akademischer Betreuer] Dilthey, and Hubertus [Akademischer Betreuer] [Murrenhoff. "Ableitung von Kennzahlen für die Prozessqualität und Prozesskenngrößen abhängige Regelung beim Laser-MSG-Hybridschweißverfahren / Peng Sha ; Ulrich Dilthey, Hubertus Murrenhoff." Aachen : Universitätsbibliothek der RWTH Aachen, 2017. http://nbn-resolving.de/urn:nbn:de:101:1-201805082047.
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Denhez, Benoit. "Inhibition des voies de signalisation de néphrine par SHP-1 dans la néphropathie diabétique." Mémoire, Université de Sherbrooke, 2015. http://hdl.handle.net/11143/6872.
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Résumé : La néphropathie diabétique (ND) est la principale cause d’insuffisance rénale de stade terminal en Amérique du Nord. Les podocytes, cellules épithéliales hautement spécialisées du glomérule, supportent et maintiennent les mécanismes de filtration glomérulaire. Des biopsies de reins de patients diabétiques ont montré que le nombre de podocytes est significativement réduit chez les patients avec un diabète récent. Néphrine est une protéine transmembranaire qui a été démontrée comme ayant un rôle majeur dans le maintien de l’intégrité de ces cellules. Une diminution de l’expression de néphrine est observée chez les personnes atteintes de la ND. Des études ont démontré que la phosphorylation en tyrosine de néphrine était impliquée dans la régulation de l’inhibition des voies de l’apoptose et le remodelage du cytosquelette d’actine. Notre laboratoire a publié que l’expression de la tyrosine phosphatase SHP-1 était augmentée dans les podocytes exposés à des concentrations élevées de glucose (HG). Les résidus tyrosines de néphrine sont contenus dans des séquences pouvant être reconnues par SHP-1. Notre hypothèse est que SHP-1 interagit avec néphrine, et que l’augmentation de l’expression de SHP-1 en condition d’hyperglycémie et de diabète viendrait déréguler les voies de signalisation de néphrine, contribuant aux dommages des podocytes dans la maladie. Des coimmunoprécipitations dans des podocytes montrent une interaction entre SHP-1 et néphrine, qui est augmentée en condition HG. Cette augmentation en HG était associée à une baisse des niveaux de phosphorylation de néphrine. La surexpression de la forme inactive de SHP-1 dans les podocyte rétablie les niveaux de phosphorylation de néphrine en condition HG. Dans un modèle de surexpression avec des cellules HEK, la surexpression de SHP-1 diminue les niveaux de phosphorylation des tyrosines 1176/1193 et 1217, qui sont associées au remodelage de l’actine. Des coimmunoprécipitations avec des mutants de néphrine montrent que les tyrosines 1114 et 1138 sont essentielles pour l’interaction de SHP-1 avec néphrine. Dans un modèle murin de diabète de type 1, une diminution de l’expression et de la phosphorylation de néphrine sont observée comparativement aux souris de type sauvage. Ces diminutions sont associées avec une augmentation de l’expression de SHP-1. En conclusion, l’augmentation de l’expression de SHP-1 en condition d’hyperglycémie réduit les niveaux de phosphorylation en tyrosine de néphrine et vient potentiellement inhiber ses voies de signalisation dans le diabète, contribuant à la dysfonction podocytaire et à la néphropathie diabétique.Abstract : Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in North America. Podocytes are highly specialized epithelial cells involved in the glomerular filtration process. Morphometric observation from kidney biopsies of diabetic patients showed a significant reduction in the number of podocytes in patients with short duration of diabetes before the apparition of microalbuminuria. Nephrin, a transmembrane protein found in the slit diaphragm, has been found to play a key role in the integrity of the podocytes. Clinical observations indicated that nephrin expression was reduced in kidney biopsy of diabetes patients. Recent studies have shown that phosphorylation of tyrosine residues of nephrin participate in intracellular pathways regulating actin dynamics and podocyte survival. Our laboratory has recently published that the expression of the tyrosine phosphatase SHP-1 is elevated in podocytes exposed to high glucose concentrations (HG). Nephrin contains sequences that are known to be potential target for SHP-1. Our hypothesis is that SHP-1 can interact with nephrin, and the increase of SHP-1 expression in diabetic nephropathy deregulates nephrin-mediated pathways, contributing to podocyte’s damage in the disease. Coimmunoprecipitation experiments show an interaction between SHP-1 and nephrin which is increased in podocytes exposed to HG. Overexpression of the inactive form of SHP-1 in podocytes exposed to HG restores nephrin phosphorylation. In HEK cells, overexpression of SHP-1 reduces nephrin phosphorylation specifically on tyrosine 1176/1193 and 1217, which regulates actin dynamics. Coimmunoprecipitation experiments with nephrin mutants show that tyrosine 1114 and 1138 are essentials to the interaction between SHP-1 and nephrin. In a type 1 diabetic murine model, a reduction of the expression and phosphorylation levels of nephrin are observed. Both reductions are associated with an increase in SHP-1 expression. In conclusion, diabetes triggered SHP-1 expression in podocytes which reduces nephrin tyrosine phosphorylation and potentially inhibits nephrin signaling in diabetes, contributing to podocytes dysfunction in diabetic nephropathy.
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Ng, Chun-laam, and 吳圳嵐. "Wnt inhibitory factor 1 (Wif-1) coordinates Shh and Wnt signaling activities in urorectal development." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48329629.
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In vertebrates, the urogenital sinus and the hindgut are connected at a hollow region called cloaca. A midline mesenchymal structure known as urorectal septum (urs) descends from the ventral body wall to separate the urogenital sinus from the hindgut before the formation of an anal opening. Subsequent cloaca membrane regression at the ventral midline of the genital tubercle (GT) is crucial for the formation of an anal opening. These two events are important during cloaca septation in urorectal development.
Mice with defective Shh or Wnt signaling displayed similar urorectal defects such as GT agenesis, un-partitioned cloaca (persistent cloaca) and proximal urethral opening that are attributable to increased cell apoptosis. Furthermore, Shh and Wnt signal transduction coordinate with each other and regulate cell survival of the developing urorectum. However, the molecular mechanisms by which these two signaling pathways coordinate in urorectal development remain unclear.
We previously identified Wnt inhibitory factor1 (Wif1) from Affymetrix array analysis for genes/pathways that is implicated in urorectal development. Wif1 is a secreted protein that binds directly to Wnt ligands preventing Wnts from binding to receptors. This leads to -catenin degradation and thereby inhibits their activities. It is known that Wif1 binds to Wnt3a and Wnt5a with high affinity and deletion of Wnt3a, Wnt5a and -catenin in mice caused GT agenesis, persistent cloaca and proximal hypospadias. Using ETU-induced anorectal malformations model, I found out that Wif1 is ectopically expressed in the un-tubularized and un-septated urorectum. Wif1 is mainly expressed at the fusing endoderm that associates with programmed cell death during cloaca septation. Exogenous addition of Wif1 protein in urorectum culture also caused cloaca membrane disintegration, and proximal urethral opening that may be due to aberrant apoptosis.
Shh and Wif1 are differentially expressed at the cloaca endoderm. In normal mice, Shh is highly expressed at the cloaca endoderm except those Wif1-expressing endodermal cells. Blockage of Shh pathway by cyclopamine in urorectum culture induced ectopic expression of Wif1, concomitant with genital tubercle hypoplasia and un-septated cloaca. More importantly, deletion of Shh in mice hastened Wif1 expression at the cloaca membrane endoderm and elicited increased cell death in the
Wif1 expressing endoderm. Wif1-/- embryos display urorectal defects including delayed genital outgrowth and proximal hypospadias. Therefore, disruption of spatiotemporal expression of Wif1 could lead to defective Wnt signaling and contributes to abnormal urorectal development in Shh-/- mutant.
Current study revealed that Wif1 is involved in urorectal development and is implicated in urorectal defects. It may function as a pro-apoptotic factor to regulate endodermal cell death which is essential for the septation process. Its specific expression is restricted at the midline cloaca endoderm by Shh signaling to inhibit local Wnt--catenin activities during cloaca septation. I proposed novel hypothetical models to explain (1) the significance of the tempo-spatial expression of Wif1; (2) the significance of cell death; and (3) the molecular mechanism that Shh signaling regulates Wnt signaling activities through Wif1 in urorectal development.published_or_final_version
Surgery
Doctoral
Doctor of Philosophy
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Martino, Giovanni. "SHP-1-dependent, caspase-8-mediated, acidification precedes mitochondrial dysfunction." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0032/MQ64404.pdf.
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Ralph, Benjamin. "SHP-1/PTP-1B Macrophage interactome upon «Leishmania mexicana» infection." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110597.
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Leishmaniasis is a disease endemic to 88 countries that affects 12 million people worldwide. The causative agents are species of the genus Leishmania, with the clinical manifestation of this disease depending on the species. Once in the host, the parasite lives inside various cell types including macrophages, and must modulate the host cell functions to survive. Host macrophages are capable of detecting various foreign molecules and mounting cellular responses. Macrophages engulf their target pathogen and, through the maturation of the phagolysosome, will destroy it. To prevent aberrant activation of the cell, macrophages use protein tyrosine phosphatases (PTPs) to return activation signals (i.e. phosphorylation) in signalling pathways to their resting state. Leishmania employs multiple strategies to alter the host signalling and functions. One such mechanism is the ability of the parasite to activate host PTPs by proteolytic cleavage. In this study, we isolated the plasma membrane and the cytoplasm of macrophages to identify the localization of and alteration in host PTPs, PTP-1B and SHP-1 during infection with Leishmania mexicana. We observed that during an infection, cleaved SHP-1 is no longer found at the plasma membrane. Prior to an infection, we also noted that the proportion of PTP-1B and SHP-1 located in the plasma membrane is minute compared to the amount found in the cytoplasm. The second part of the study was to compare the interactomes of PTP-1B and SHP-1 in resting cells and during an infection. We noticed distinct groups of proteins interacted with these PTPs, including proteins involved in translation and RNA manipulation, cell metabolism, and subcellular localization. We also observed large variations in the level of interaction with the interactants and the PTPs. This study demonstrates Leishmania refined ability to control the host cell to prevent its destruction.La leishmaniose est une maladie endémique dans 88 pays et qui affecte 12 millions de personnes à travers le monde. Les agents étiologiques de la maladie sont des espèces du genre Leishmania, toutefois la manifestation de cette maladie varie selon les espèces. Le parasite, une fois à l'intérieur de l'hôte, vit de façon intracellulaire dans différents types de cellules, dont les macrophages. Pour survivre à l'intérieur de son hôte, Leishmania doit moduler les fonctions cellulaires de ce dernier.Les macrophages sont des cellules capables de détecter différentes substances étrangères et, par le fait même, d'engager des réponses cellulaires contre ces substances. Les macrophages vont généralement engloutir les pathogènes et les détruiront grâce à la maturation du phagolysosome. Afin de prévenir l'activation aberrante de la cellule, les macrophages utilisent les protéines tyrosine phosphatase (PTP) pour envoyer des signaux activateurs (phosphorylation) aux voies de signalisation au repos. Pour ce faire, Leishmania utilise de multiples stratégies lui permettant d'altérer la signalisation et les fonctions de l'hôte. Un de ces mécanisme est sa capacité d'activer les PTP de son hôte par clivage protéolytique.Dans cette étude, nous avons isolé la membrane plasmique et le cytoplasme des macrophages dans le but d'identifier la localisation, de même que l'altération des PTP, plus précisément PTP-1B et SHP-1, et ce lors de l'infection par Leishmania mexicana. Nous avons observé que lors d'une infection, la forme clivée de SHP-1 ne se retrouve plus à la membrane plasmique. Avant l'infection, nous avons aussi noté que la proportion de PTP-1B et SHP-1 située dans la membrane plasmique est négligeable par rapport à celle trouvée dans le cytoplasme. La deuxième partie de l'étude était d'identifier l'interactome de PTP-1B et SHP-1 dans les cellules non infectées et de le comparer à l'interactome dans le contexte d'une infection. Nous avons remarqué que les protéines qui intéragissent avec ces PTP proviennent de groupes distincts. Ces groupes étant notamment impliqués dans de nombreuses fonctions cellulaires telles; la traduction et la manipulation d'ARN, le métabolisme cellulaire, de même que la localisation subcellulaire. Nous avons également observé de grandes variations dans le niveau d'interaction entre ces différents groupes de protéines et les PTP. Cette étude démontre donc l'habileté très sophistiquée qu'à le parasite Leishmania de contrôler la cellule hôte afin d'en empêcher la destruction.
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Wu, Shu Fang. "Effectiveness of self-management for persons with type 2 diabetes following the implementation of a self-efficacy enhancing intervention program in Taiwan." Thesis, Queensland University of Technology, 2007. https://eprints.qut.edu.au/16385/1/Shu-Fang_Wu_Thesis.pdf.
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Objective
The aim of this study firstly, was to translate and test the validity and reliability of two diabetes-specific self-efficacy instruments (the Diabetes Management Self-Efficacy Scale; DMSES and the Perceived Therapeutic Efficacy Scale; PTES) in a Taiwanese population. The main aim of this study was then to develop an intervention based on self-efficacy theory that was appropriate for the Taiwanese population and to examine the effects of a self-efficacy enhancing intervention program (SEEIP).
Background
In Taiwan, the prevalence, mortality rate and healthcare cost of diabetes has dramatically increased. People with diabetes have low participation rates in performing self-care activities, with some two-thirds of diabetic patients not controlling their disease appropriately. Moreover, few studies in Taiwan have conducted randomised controlled trials or had improvement in patient self-care or self-management as their primary goal and no instruments that measure self-efficacy related to the management of diabetes (especially for outcome expectations) have yet been found and appropriately used to measure the effectiveness of self-management. Therefore, there is a particular need for research on self-efficacy enhancing intervention programs for people with type 2 diabetes.
Design
A convenience sample survey (n=230) was used in order to test the validity and reliability of C-DMSES and C-PTES in a Taiwanese population. Moreover, a randomised controlled trial (RCT) (n=145; the intervention group (72); the control group (73)) design was conducted in the main study with pre (baseline) and post-testing (undertaken at 3 months and 6 months following baseline collection).
Intervention
Both the control group and intervention group received the standard diabetic educational program in the outpatient clinic. The intervention group participants received the standard diabetic educational program and the following additional interventions: (1) viewed a 10-minute DVD (2) received a "Diabetes Self-Care" booklet (3) participated in four efficacy- enhancing counselling intervention sessions, and (4) participated in telephone follow-up. The self-efficacy model was adapted from Shortridge-Baggett & van der Bijl (1996). Diabetes self-management principles were used in program development and evaluation.
Main outcome measures
Instruments used in data collection included 1) Self-efficacy towards management of type 2 diabetes (as measured by the Chinese version of the Diabetes Management Self-Efficacy Scale; C-DMSES and the Chinese version of the Perceived Therapeutic Efficacy Scale; C-PTES); 2) self management behavior (as measured by the Summary of Diabetes Self-Care Activities; SDSCA); 3) health-related quality of life for diabetes (as measured by the Short Form-12; SF-12); 4) psychosocial well-being (as measured by the Medical Outcomes Study (MOS), Social Support Survey (SSS) tool and the Center for Epidemiology Studies Short Depression Scale; CES-D) and 5) health care utilisation (as measured by health care utilisation self report instrument).
Data analysis
Data were double-entered for verification using SPSS® statistical software. Study I: Descriptive statistics, regression analysis, Pearson's correlation, Cronbach's alpha-coefficients, factor analysis and Bland-Altman plots with 95% limits of agreement (LOA) were performed to evaluate validity and reliability of C-DMSES and C-PTES.
Study II: Descriptive analysis was used to examine demographic variables and outcome variables. T-tests were used to analyse differences on continuous data between mean scores for the intervention and control groups. Categorical data were analysed using Chi-square statistics to test the significance of different proportions. To assess the group differences of dependent variable changes, repeated measures ANOVA/ ANCOVA were used.
Results
Study I: Convergent validity showed that C-DMSES correlated well with the validated measure of the General Self-Efficacy Scale (GSE) in measuring self-efficacy. Criterion-related validity showed that the C-DMSES was a significant predictor of the Summary of Diabetes Self-Care Activities (SDSCA) scores. Factor analysis supported the C-DMSES being composed of four subscales with good internal consistency (Cronbach's alpha=.77 to .93) and stability (ICC=.82).
Similarly, significant criterion-related validity was demonstrated between the C-PTES and SDSCA scores. Convergent validity was confirmed as the C-PTES converged well with the GSE Scale in measuring self-efficacy. Construct validity of the C-PTES was confirmed through factor analysis and a single subscale formed. Internal consistency with a Cronbach's alpha was .95 and the test-retest reliability (ICC) was .77 and a Bland-Altman plot showed 97% of the subjects were within 2 standard deviations of the mean.
Study II: The 3- and 6-month benefits of the intervention over usual care were increases in self-efficacy, outcome expectation, self-care activities, and social support.
However, the results of the health-related quality of life and depression scores indicated that the change over time was not different in the two groups. A smaller proportion of the participants significantly in the intervention group, had been hospitalised and visited the emergency room than participants who were in the control group at the 6-month period. However, health-related quality of life and depression were not significantly increased in the intervention group at the 3- and 6-month compared to the control group.
Conclusion
Results of Study I support the psychometric properties of C-DMSES and C-PTES in providing a measure for self-efficacy specific to persons with type 2 diabetes in Taiwan. The main study revealed that the SEEIP for type 2 diabetes based on self-efficacy theory was culturally acceptable to Taiwanese people with diabetes and that the SEEIP was effective in the self-management of people with type 2 diabetes.
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Liang, Shu-Yuan. "Opioid-taking self-efficacy in Taiwanese Outpatients with cancer pain." Thesis, Queensland University of Technology, 2007. https://eprints.qut.edu.au/16516/1/Shu-Yuan_Liang_Thesis.pdf.
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Despite the fact that as many as 80-90% of patients with cancer pain can be effectively treated using pharmacological therapies and other advanced approaches, 31% to 85% of cancer patients in Taiwan still experience varying levels of pain. Pain is one of the symptoms that patients fear most; it overwhelms all aspects of patients' lives and creates a sense of uncertainly and hopelessness. Pain control is, therefore, a high priority in the treatment of cancer patients. Pharmacological therapy is the cornerstone of cancer pain management. With the current trend toward outpatient care, many patients are being required to assume greater responsibility for self-management of prescribed analgesics at home to deal with the variable and complex nature of cancer pain and side effects of opioids. Patients however, have misconceptions regarding analgesics and a series of difficulties when attempting to put a pain management regimen into practice.
This research addressed the hypothesis that self-efficacy beliefs might play an important role in analgesic adherence and pain experience in Taiwanese outpatients with cancer. The purpose of this study was to develop a scale to measure the self-efficacy expectations relating to opioid-taking in Taiwanese outpatients with cancer. Another purpose was to explore how opioid-taking self-efficacy and beliefs about opioid analgesics contribute to patients' analgesic adherence and pain experience in Taiwanese outpatients with cancer.
In the first stage semi-structured interviews were conducted to collect data from a purposeful sample (n=10) of oncology outpatients from two teaching hospitals in the Taipei area of Taiwan. The purpose of this phase was to identify behaviours and situational impediments associated with analgesic taking. Findings from this phase were used to develop a scale to measure opioid-taking self-efficacy. In the second stage a pilot test with a convenience sample (n=30) was conducted to test the validity and reliability of the new scale and to identify the feasibility of using the scale in a cross-sectional survey. In the third stage a cross-sectional survey was undertaken (n=92) to describe pain experiences, analgesic adherence, beliefs about opioid analgesics, and opioid-taking self-efficacy in Taiwanese outpatients with cancer and to explore how opioid-taking self-efficacy and beliefs about opioid analgesics contributed to analgesic adherence and pain experience.
Results of this study highlight an important issue - under-treatment of cancer pain in this group of Taiwanese outpatients. As well, low adherence rates to opioid analgesics in cancer outpatients arose as an important issue in this study. A range of misconceptions about using opioids for pain was also common amongst the sample. Despite these misconceptions, patients reported being moderately confident in their ability to perform self-management behaviours related to their prescribed opioid-taking. Results of this research supported the notion that patients' self-efficacy in relation to taking their prescribed opioid regimen was a significant independent predictor of patients' adherence behaviour and pain relief, but not of pain severity. Beliefs about opioid analgesics were also an independent predictor of patients' adherence, but not of pain relief or pain severity. In addition, findings from this study provided support for the validity and reliability of the opioid-taking self-efficacy scale.
Results suggested there is a need for systematic assessment of beliefs affecting patients' opioid adherence behaviours for cancer pain control, including perceived personal self-efficacy and beliefs about opioid analgesics. Educational programs that focus on overcoming patients' misconceptions (beliefs) about taking opioid analgesics may be particularly beneficial. In addition, this study advocates that conducting self-efficacy-enhancing interventions may improve medication adherence for patients and therefore pain relief. More research is needed to demonstrate the construct validity of the self-efficacy scale and to evaluate self-efficacy enhancing interventions in cancer pain management.
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Liu, Shi-Qiang. "Modelling and solving train scheduling problems under capacity constraints." Thesis, Queensland University of Technology, 2008. https://eprints.qut.edu.au/37181/1/Shi-Qiang_Liu_Thesis.pdf.
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Many large coal mining operations in Australia rely heavily on the rail network to transport coal from mines to coal terminals at ports for shipment. Over the last few years, due to the fast growing demand, the coal rail network is becoming one of the worst industrial bottlenecks in Australia. As a result, this provides great incentives for pursuing better optimisation and control strategies for the operation of the whole rail transportation system under network and terminal capacity constraints. This PhD research aims to achieve a significant efficiency improvement in a coal rail network on the basis of the development of standard modelling approaches and generic solution techniques. Generally, the train scheduling problem can be modelled as a Blocking Parallel- Machine Job-Shop Scheduling (BPMJSS) problem. In a BPMJSS model for train scheduling, trains and sections respectively are synonymous with jobs and machines and an operation is regarded as the movement/traversal of a train across a section. To begin, an improved shifting bottleneck procedure algorithm combined with metaheuristics has been developed to efficiently solve the Parallel-Machine Job- Shop Scheduling (PMJSS) problems without the blocking conditions. Due to the lack of buffer space, the real-life train scheduling should consider blocking or hold-while-wait constraints, which means that a track section cannot release and must hold a train until the next section on the routing becomes available. As a consequence, the problem has been considered as BPMJSS with the blocking conditions. To develop efficient solution techniques for BPMJSS, extensive studies on the nonclassical scheduling problems regarding the various buffer conditions (i.e. blocking, no-wait, limited-buffer, unlimited-buffer and combined-buffer) have been done. In this procedure, an alternative graph as an extension of the classical disjunctive graph is developed and specially designed for the non-classical scheduling problems such as the blocking flow-shop scheduling (BFSS), no-wait flow-shop scheduling (NWFSS), and blocking job-shop scheduling (BJSS) problems. By exploring the blocking characteristics based on the alternative graph, a new algorithm called the topological-sequence algorithm is developed for solving the non-classical scheduling problems. To indicate the preeminence of the proposed algorithm, we compare it with two known algorithms (i.e. Recursive Procedure and Directed Graph) in the literature. Moreover, we define a new type of non-classical scheduling problem, called combined-buffer flow-shop scheduling (CBFSS), which covers four extreme cases: the classical FSS (FSS) with infinite buffer, the blocking FSS (BFSS) with no buffer, the no-wait FSS (NWFSS) and the limited-buffer FSS (LBFSS). After exploring the structural properties of CBFSS, we propose an innovative constructive algorithm named the LK algorithm to construct the feasible CBFSS schedule. Detailed numerical illustrations for the various cases are presented and analysed. By adjusting only the attributes in the data input, the proposed LK algorithm is generic and enables the construction of the feasible schedules for many types of non-classical scheduling problems with different buffer constraints. Inspired by the shifting bottleneck procedure algorithm for PMJSS and characteristic analysis based on the alternative graph for non-classical scheduling problems, a new constructive algorithm called the Feasibility Satisfaction Procedure (FSP) is proposed to obtain the feasible BPMJSS solution. A real-world train scheduling case is used for illustrating and comparing the PMJSS and BPMJSS models. Some real-life applications including considering the train length, upgrading the track sections, accelerating a tardy train and changing the bottleneck sections are discussed. Furthermore, the BPMJSS model is generalised to be a No-Wait Blocking Parallel- Machine Job-Shop Scheduling (NWBPMJSS) problem for scheduling the trains with priorities, in which prioritised trains such as express passenger trains are considered simultaneously with non-prioritised trains such as freight trains. In this case, no-wait conditions, which are more restrictive constraints than blocking constraints, arise when considering the prioritised trains that should traverse continuously without any interruption or any unplanned pauses because of the high cost of waiting during travel. In comparison, non-prioritised trains are allowed to enter the next section immediately if possible or to remain in a section until the next section on the routing becomes available. Based on the FSP algorithm, a more generic algorithm called the SE algorithm is developed to solve a class of train scheduling problems in terms of different conditions in train scheduling environments. To construct the feasible train schedule, the proposed SE algorithm consists of many individual modules including the feasibility-satisfaction procedure, time-determination procedure, tune-up procedure and conflict-resolve procedure algorithms. To find a good train schedule, a two-stage hybrid heuristic algorithm called the SE-BIH algorithm is developed by combining the constructive heuristic (i.e. the SE algorithm) and the local-search heuristic (i.e. the Best-Insertion- Heuristic algorithm). To optimise the train schedule, a three-stage algorithm called the SE-BIH-TS algorithm is developed by combining the tabu search (TS) metaheuristic with the SE-BIH algorithm. Finally, a case study is performed for a complex real-world coal rail network under network and terminal capacity constraints. The computational results validate that the proposed methodology would be very promising because it can be applied as a fundamental tool for modelling and solving many real-world scheduling problems.
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Wong, Shi Yee. "Improving property practitioners' involvement in information flow of sustainability features of residential property." Thesis, Queensland University of Technology, 2017. https://eprints.qut.edu.au/112508/1/Shi%20Yee_Wong_Thesis.pdf.
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This research explores the type and quantity of sustainability-related information that is distributed to potential home buyers and examines the role of practitioners. This thesis makes a significant contribution to the roles of property practitioners in assisting home buyers to make informed-decision during property purchase selection phase. A framework has been created to involve property practitioners in the information gathering and distribution process that helps to provide a more complete information flow from the design and construction stage to the purchasing stage of the property.
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Wang, Peng. "Screening Combinatorial Peptide Library for Optimal Enzyme Substrates and High Affinity Protein Ligands." The Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1039797438.
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Lizotte, Farah. "Mémoire hyperglycémique dans la néphropathie diabétique : implication potentielle de SHP-1." Mémoire, Université de Sherbrooke, 2015. http://hdl.handle.net/11143/6980.
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Résumé : La néphropathie diabétique (ND) est une complication microvasculaire du diabète évoluant ultimement en insuffisance rénale et l’hyperglycémie est connue comme étant l’un des facteurs de risques. De larges études cliniques, tel que le DCCT et l’UKPDS, ont montré que si le contrôle intensif de la glycémie se faisait de façon précoce, il serait possible de retarder le développement de la ND. Cependant, les résultats de l'EDIC montrent que si ce contrôle intensif se faisait plus tardivement, suite à une période d’hyperglycémie, il n’empêcherait plus sa progression. Les podocytes ont un rôle critique dans le maintien des fonctions rénales et leur apoptose corrèle de façon très spécifique avec la progression de la ND. Récemment, nous avons rapporté que SHP-1, une protéine tyrosine phosphatase, était augmentée en concentrations élevées de glucose (HG), menant à une inhibition des voies de signalisation de l'insuline. Notre hypothèse est que l’augmentation de l’expression de SHP-1 causée par l’hyperglycémie persiste même après réduction des niveaux de glucose, phénomène de mémoire hyperglycémique, causant une résistance à l'insuline, la mort des podocytes et une absence de réversibilité liée à la progression de ND. Les résultats in vivo montrent que la fonction et la pathologie rénale continuent de progresser et ce en dépit de la normalisation des niveaux de glucose avec implants d’insuline de 5 à 7 mois d’âge La progression de la pathologie corrèle avec le maintien de l’augmentation de l’expression de SHP-1, contribuant au maintien de l’inhibition des voies de l’insuline. En culture, des podocytes murins exposés en HG pendant 96 h et ensuite exposés en condition normale de glucose(NG) pour les dernières 24 h montrent une persistance de l’inhibition des voies de signalisation de l’insuline qui corrèle avec l’augmentation persistante de l’expression et l’activité phosphatase de SHP-1. L’activité des caspases 3/7 dans les podocytes est plus élevée lorsque ceux-ci sont exposés en HG qu’en NG. Le retour en NG pour les dernières 24 h n’a aucun effet bénéfique à réduire l’activité des caspases 3/7. Finalement, l’analyse épigénétique a été suggérée comme étant une explication du phénomène de mémoire hyperglycémique. La monométhylation de la lysine 4 de l’histone 3 (H3K4me1), un marqueur d’activation génique, est augmentée sur le promoteur de SHP-1 en HG et demeure élevée malgré le retour en NG pendant les dernières 24 h. En conclusion, l’hyperglycémie engendre une augmentation persistante de SHP-1 due possiblement à des modifications épigénétiques, causant le maintien de l’inhibition les voies de signalisation de l’insuline même après un retour à des niveaux normaux de glucose, contribuant à la progression de la ND.Abstract : Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Renal podocytes apoptosis induced by hyperglycemia is an early event of DN. Clinical studies have shown that intensive blood glucose control reduced the development of DN but is not sufficient, if started late, to prevent its progression, introducing the concept of “hyperglycemic memory”. We have recently published that the tyrosine phosphatase SHP-1 is elevated in renal cortex of type 1 diabetic mice (Akita), contributing to insulin unresponsiveness and DN. We hypothesized that SHP-1 expression remains elevated regardless of systemic blood glucose normalization, and is responsible for hyperglycemic memory in podocytes leading to DN progression. In vivo contribution of SHP-1 in hyperglycemic memory was evaluated using Akita mice treated with insulin implants after 4 months of diabetes. Both urinary albuminuria and glomerular filtration rate were significantly increased in diabetic mice compared to non-diabetic mice and remained elevated despite normalization of blood glucose levels. Renal dysfunction was associated with a persistent increase of SHP-1 expression in renal cortex and inhibition of insulin action that were not normalized following insulin implants. Mouse podocytes were cultured in normal (5.6mM; NG), high glucose concentrations (25mM; HG) for 120 h or HG (96 h) followed by NG for an additional 24 h (HG+NG). We observed that Akt and ERK phosphorylation induced by insulin was inhibited in HG and were not restored despite returning glucose level to 5.6 mM after the HG period. This inhibition was associated with persistent increase of SHP-1 expression and phosphatase activity, leading to insulin signaling pathway inhibition. Moreover, caspase 3/7 activity in podocytes exposed to HG was higher than in podocytes cultured in NG and returning glucose concentrations to normal range for the last 24 h after the 96 h HG exposure had no effect on reducing caspase 3/7 activity. Epigenetic changes were studied to explain the hyperglycemic memory effect. On SHP-1 promoter, H3K4me1 levels, an activation mark, tended to be more elevated in podocytes exposed to HG and were maintained despite returning to NG levels after the HG conditions. In conclusion, hyperglycemia induces persistent and epigenetic changes of SHP-1 causing insulin unresponsiveness in the podocytes contributing to DN progression.
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Lin, Zhiyuan. "On preparing co-workers for a preaching ministry : a study of II Timothy 2:1-26 = Cong Timotai hou shu er zhang 1-26 jie tan tao jiang dao shi feng tong gong de zai pei /." Theological Research Exchange Network (TREN), 2008. http://www.tren.com/search.cfm?p078-0054.
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Wavreille, Anne-Sophie Marie. "SRC homology 2 domain proteins binding specificity from combinatorial chemistry to cell-permeable inhibitors /." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1164738844.
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Minoo, Parham. "Regulation of prolactincytokine receptor signaling by the cytoplasmic protein tyrosine phosphatases, SHP-1 and SHP-2 : by Parham Minoo." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111829.
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Prolactin (PRL) is a polypeptide hormone that regulates diverse biological processes such as those involved in mammary gland and reproductive organ development. These biological functions are mediated by interaction of PRL with its membrane-bound receptor, a member of the class I cytokine receptor superfamily. Ligand binding to the PRL receptor (PRLR) induces dimerization of the receptor and activation of Janus kinase-2 (Jak2). These events lead to PRLR tyrosine phosphorylation creating binding sites for cellular signaling molecules containing SH2 domains such as the signal transducer and activator of transcription 5 (Stat5). Jak2/Stat5 pathway has emerged as the main signaling pathway mediating many physiological effects of PRL such as the terminal differentiation of mammary epithelial cells and milk protein production.Work in this thesis was performed to understand the molecular mechanisms of PRL actions in target tissues by investigating the role of cytoplasmic protein tyrosine phosphatases containing SH2 domain, SHP-1 and SHP-2, in regulation of PRLR intracellular signaling events. These phosphatases participate in signaling as enzymes and/or adapter proteins. Both SHP-1 and SHP-2 contain specific tyrosine residues at their C-terminal parts that undergo phosphorylation in response to PRLR stimulation. The focus of this doctoral work was to investigate the adapter function of these proteins, which is mediated by their C-terminal tyrosine residues. These studies revealed that these tyrosine residues can function to recruit legitimate substrate(s) for the catalytic domain of SHP-2 including a highly phosphorylated p29 protein. Subsequent studies showed that p29 is growth factor receptor-binding protein-2 (Grb2), suggesting that Grb2 is phosphorylated in response to PRL and the level of phosphorylation is regulated by SHP-2. Grb2 phosphorylation by PRLR was further shown to be a new mechanism by which PRLR inhibits EGFR-induced signaling.
In addition, our results indicate that the inhibitory effect of SHP-1 on cytokine-induced Jak/Stat pathway could occur independently of its catalytic activity. Based on our data, SHP-1 C-terminal tyrosine residues contribute to the inhibitory effect of SHP-1 by recruiting inhibitory complex Grb2/SOCS-1 and targeting SOCS-1 to Jak2. Together these findings highlight new mechanisms of PRL/cytokine receptor signaling by the protein tyrosine phosphatases SHP-1 and SHP-2.
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Somani, Ally-Khan B. "The role of SHP-1 tyrosine phosphatase in modulating lymphocyte signaling cascades." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ59036.pdf.
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Viant, Charlotte. "Régulation du développement et de la fonction des cellules innées lymphoïdes NKp46+." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4018/document.
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Il existe différents groupes de cellules lymphoïdes innées (ILC) qui ont été caractérisées en fonction des facteurs de transcriptions indispensables à leur différenciation et des cytokines qu’elles sécrètent. Les ILC1, dont font partie les cellules Natural Killer (NK), expriment T-bet et produisent de l’IFN-γ. Les ILC2 sont caractérisées par GATA-3 et sécrètent de l’IL-5 et de l’IL-13. Quant aux ILC3, elles ont été identifiées par leur sécrétion d’IL-17 et d’IL-22 ainsi que par l’expression de RORγt.Mon travail de thèse m’a amené à étudier différents aspects de la biologie des cellules NK et ILC3 : leur tolérance, leur homéostasie et leur plasticité.Les cellules NK jouent un rôle dans l’élimination de cellules cancéreuses et des cellules infectées par des bactéries et des virus. J’ai mis en évidence le rôle de la phosphatase SHP-1 (Src homology region 2 domain-containing phosphatase-1) dans les mécanismes de tolérance et d’activation des cellules NK. J’ai également montré que la protéine anti-apoptotique Bcl2 (B-cell lymphoma 2) est importante pour l’homéostasie des cellules NK. Seules les cellules en cycle cellulaire peuvent compenser l’absence de Bcl2, notamment du fait de l’augmentation de l’expression d’une autre protéine anti-apoptotique, Mcl1 (Myeloid Cell Leukemia 1). Les ILC3 sont des cellules principalement localisées dans l’intestin et qui peuvent être classées en différents groupes en fonction des marqueurs qu’elles expriment. J’ai montré qu’il existe une plasticité entre les différentes populations d’ILC3, et que cette plasticité est régulée par des facteurs environnementaux tel que le TGF-β et le ligand de Notch, DL1There are three groups of innate lymphoid cells (ILC), defined notably by the transcriptions factors essential to their differentiation and their cytokines secretion. ILC1, including natural killer (NK) cells, express T-bet and secrete IFN-γ. ILC2 are characterized by GATA3 expression and the production of IL-5 and IL-13. ILC3 secrete IL-17 and IL-22 and express RORγt.My PhD work dealt with different aspects of NK cells and ILC3: their tolerance, homeostasis and plasticity.NK cell are involved in killing tumor cells and bacteria- or virus-infected cells. I found that the phosphatase SHP-1 (Src homology region 2 domain-containing phosphatase-1) has a role in NK cell tolerance and activation.I also showed that the anti-apoptotic Bcl2 protein (B-cell lymphoma 2) is important for NK cell homeostasis. Only cycling NK cells could compensate the Bcl2 deficiency, due to the increase expression of another anti-apoptotic protein, Mcl1 (Myeloid Cell Leukemia 1).ILC3 are mainly located in the gut and are classified in different groups, depending on the markers that they expressed. I showed that there is plasticity between ILC3 populations and that this plasticity is regulated by environmental factors, including TGF-β and the Notch ligand, DL1
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Hussainkhel, Angela. "Understanding the functional of SAM and SH3 domain containing adaptor protein 1, SASH1." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42920.
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TLR4 is the most extensively studied of TLR pathways in innate immune signaling that provides the first line of defense against invading pathogens. SASH1, a large protein composed of SAM and SH3 domain, is a novel positive regulator of the pathway in endothelial cells. SASH1 acts as a scaffold protein in the TLR4 pathway by independently binding TRAF6/TAK1/ IKKβ/IKKα and regulating TRAF6 and TAK1 ubiquitination leading to LPS-induced activation of NF-κB resulting in production of pro-inflammatory cytokines. To investigate SASH1 in vivo function, SASH1 gene-trap mice were generated. These mice have a β-galactosidase reportor construct inserted into intron 14-15 resulting in a truncation of the SH3 domain, and thereby loss of the two SAM domains and TRAF6 binding motif. However, SASH1 gene-trap mice do not provide any viable homozygous adults . X-gal staining of the heterozygous SASH1 adult tissues demonstrated SASH1 transcripts to be predominantly expressed in microvascular endothelium. This thesis is the continuation of the above findings to further characterize the role of SASH1 in vitro and in vivo. Work presented here confirms the role of SASH1 as a positive regulator of the TLR4 pathway by promoting activation of NF-κB. SASH1 does not interact with the E2 ligases and IKKγ. These results further elucidate a model for SASH1 in the TLR4 pathway where the E2 ligases and IKKγ are incorporated into a complex through interaction with proteins that are assembled by SASH1 to promote the downstream signaling. SASH1 homozygous gene-trap mice die in the perinatal period and preliminary analysis shows the lung as the potential organ being affected by SASH1 disruption. Homozygous gene-trap lungs appear deflated, sink in PBS and have smaller airways compared to wild-type control. However, morphometric analysis of the lung is still required to conclusively define a lung defect. In addition, I generated SASH1-floxed embryonic stem cells to be used for generating mice with a conditionally targeted allele of SASH1 in endothelial cells to study the role of SASH1 in the endothelial response to LPS in TLR4 signaling in vivo, hence contributing to the field of innate immune signaling.
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Thompson, Alice Nicola. "The role of Shp-1 in murine ES cell self-renewal and differentiation." Thesis, University of Bath, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501514.
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Bergeron, Sébastien. "La régulation du métabolisme du glucose par la protéine tyrosine phosphatase SHP-1." Thesis, Université Laval, 2007. http://www.theses.ulaval.ca/2007/24862/24862.pdf.
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Lorsque l’insuline se lie à son récepteur, elle induit une cascade de réactions indispensables à l’utilisation du glucose. La résistance à l’insuline et le diabète de type 2 qui affectent une fraction croissante de la population résultent d’un défaut de signalisation de l’insuline. La voie de signalisation PI3K qu’emprunte l’insuline pour promouvoir l’utilisation du glucose est d’abord décrite en introduction de cette thèse. Aussi, il existe plusieurs mécanismes de désensibilisation qui sont essentiels pour limiter l’ampleur du signal à la réponse métabolique requise. Cependant, ces mécanismes sont altérables et de faibles dérèglements peuvent devenir responsables d’une propagation défaillante du signal insulinique.
Les souris viable motheaten (mev), déficientes en activité SHP-1, nous ont permis au premier chapitre de démontrer que SHP-1 constitue un de ces mécanismes de désensibilisation. Ces souris montrent une plus grande tolérance au glucose et une meilleure sensibilité à l’insuline que les souris non-déficientes en SHP-1, ainsi qu’une meilleure signalisation de l’insuline dans le foie et le muscle squelettique. De plus, nous avons pu démontrer que SHP-1 contrôle aussi la clairance hépatique de l’insuline, importante pour réguler la concentration et la sensibilité systémique de l’insuline. Cette première étude a donc permis d’établir un nouveau rôle pour SHP-1 dans la régulation de l’action de l’insuline.
Par la suite, il devenait primordial de décrire les mécanismes impliqués dans la sensibilisation à l’insuline par la déficience en SHP-1 dans le muscle et le foie. À l’aide d’adénovirus codant pour un mutant catalytiquement inerte de SHP-1 (DNSHP-1), nous rapportons au deuxième chapitre, par l’expression de DNSHP-1 dans les hépatocytes Fao, que la diminution de la production hépatique de glucose observée chez les souris mev résulte d’une augmentation de la glycogénèse plutôt que d’une diminution de la gluconéogenèse. Enfin, au dernier chapitre, DNSHP-1 exprimé dans les myocytes L6 favorise la signalisation via Akt, et accroît l’expression de GLUT4, le principal transporteur de glucose sensible à l’insuline.
Ensemble, nos résultats suggèrent clairement que SHP-1 est un nouveau modulateur de l’action de l’insuline dans le foie et le muscle squelettique. SHP-1 pourrait donc représenter une nouvelle cible thérapeutique pour traiter le diabète de type 2.After binding to its receptor, insulin induces a reaction cascade that is essential for glucose utilization. Insulin resistance and type 2 diabetes are affecting an increasing portion of the population and result from insulin signaling impairment. Insulin signaling pathways promoting glucose utilization are reviewed in the introduction of the thesis, as well the desensitization mechanisms which are crucial to limit insulin signal duration and intensity. Viable motheaten (mev) mice, harboring a spontaneous mutation leading to SHP-1 activity deficiency, allowed us to demonstrate in chapter I that SHP-1 constitutes one of these desensitization mechanisms. Indeed, mev mice showed an increased glucose tolerance and insulin sensitivity as compared to wild type littermates, resulting from increased insulin signaling in liver and skeletal muscle. Moreover, we show that SHP-1 controls hepatic insulin clearance, which is important to control systemic insulin concentration and sensitivity. This first study thus establishes a novel role for SHP-1 in the regulation of insulin action and glucose homeostasis. Thereafter, it became primordial to describe cell autonomous mechanisms by which SHP-1 enhances insulin sensitivity in liver and muscle. In the second chapter, expression of DNSHP-1 using adenoviral gene transfer into Fao rat hepatoma cells indicates that decreased hepatic glucose production observed in mev mice is likely the result of enhanced glycogenesis rather than reduced gluconeogenesis. Finally, I show in the last chapter that DNSHP-1 expression in myocytes increased insulin signaling to Akt, and increased GLUT4 expression, the main insulin responsive glucose transporter. Together, our results clearly establish that SHP-1 is a new modulator of insulin action in liver and skeletal muscle. SHP-1 may represent a novel therapeutic target to combat type 2 diabetes.
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Bengtsson, Johnny. "Forensisk hårddiskkloning och undersökning av hårddiskskrivskydd." Thesis, Linköping University, Department of Science and Technology, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-2378.
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Detta examensarbete reder ut arbetsprinciperna för olika typer av hårddiskskrivskydd; hårdvaruskrivskydd, mjukvaruskrivskydd, hybridskrivskydd och bygelskrivskydd. Slutsatsen av utredningen är att endast hårdvaruskrivskydd Detta examensarbete reder ut arbetsprinciperna för olika typer av hårddiskskrivskydd; hårdvaruskrivskydd, mjukvaruskrivskydd, hybridskrivskydd och bygelskrivskydd. Slutsatsen av utredningen är att endast hårdvaruskrivskydd bedöms ha tillräckligt pålitliga skyddsprinciper, vilket motiveras av dess oberoende från både hårdvara och operativsystem.
Vidare undersöks hårdvaruskrivskyddet Image MASSter(TM) Drive Lock från Intelligent Computer Solutions (ICS). Några egentliga slutsatser gick inte dra av kretskonstruktionen, bortsett från att den är uppbyggd kring en FPGA (Xilinx Spartan-II, XC2S15) med tillhörande PROM (XC17S15APC).
En egenutvecklad idé till autenticieringsmetod för hårddiskkloner föreslås som ett tillägg till arbetet. Principen bygger på att komplettera hårddiskklonen med unik information om hårddisk såväl kloningsomständigheter, vilka sammanflätas genom XOR-operation av komponenternas hashsummor.Autenticieringsmetoden kan vid sjösättning möjligen öka rättsäkerheten för både utredarna och den som står misstänkt vid en brottsutredning.
Arbetet är till stora delar utfört vid och på uppdrag av Statens kriminaltekniska laboratorium (SKL) i Linköping.
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Richter, Raik. "Ein Beitrag zur Modellierung und Realisierung der direkten digitalen Frequenzsynthese." Doctoral thesis, [S.l. : s.n.], 1999. http://deposit.ddb.de/cgi-bin/dokserv?idn=963112023.
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Richter, Raik. "Ein Beitrag zur Modellierung und Realisierung der direkten digitalen Frequenzsynthese." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2000. http://nbn-resolving.de/urn:nbn:de:swb:14-994337562500-99246.
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In der Dissertationsschrift wird ein neuartiges Konzept der Realisierung der Direkten Digitalen Frequenzsynthese (DDS) vorgestellt. Ausgehend von der analysierten Literatur werden das Wirkprinzip eines Standard-DDS-Synthesizer analysiert und Möglichkeiten zur Aufwandsreduktion untersucht. Ein neuartiger Ansatz zur Realisierung einer vollständig digitalen DDS ergibt sich in der Anwendung der Pulse-Output-DDS. Bei der Pulse-Output-DDS wird neben dem D/A-Wandler auch die Sinus-ROM-Tabelle aus dem prinzipiellen Aufbau der Standard-DDS entfernt. Ausgehend von einer derart modifizierten DDS-Struktur wird ein geeignetes DDS-Modell entwickelt, mit welchem alle auftretenden Synthesefehler systematisch erfaßt und bewertet werden können. Die gewonnenen Erkenntnisse über die prinzipbedingten Synthesefehler bilden die Grundlage für Erweiterungen der Pulse-Output-DDS mit deren Hilfe eine qualitative Verbesserung des synthetisierten Signals erreicht wird. Dabei steht vor allem die Anwendung von Verfahren der digitalen Signalverarbeitung im Vordergrund, die zu einer Verringerung bzw. Kompensation oder zu einer spektralen Veränderung des auftretenden DDS-Fehlersignals geeignet sind. Es werden die erreichbaren Verbesserungen, aber auch die theoretischen und praktischen Grenzen von folgenden Verfahren aufgezeigt: absolute Verringerung des DDS-Fehlersignals Dithering des DDS-Fehlersignals Rauschformung (Noise-Shaping) des Fehlersignalspektrums Insbesondere bei der Rauschformung werden unterschiedliche Ansätze untersucht und bewertet mit dem Ziel, ein optimales Verfahren für den Rauschformungsprozeß bei der Verwendung in einer Pulse-Output-DDS zu finden. Durch die echtzeitfähige Implementation eines erweiterten DDS-Systems in einem Standard-CMOS-Prozeß werden die gefundenen theoretischen Lösungen verifiziert.
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Joliat, Melissa J. "Autoimmunity, Immune Deficiency and Cancer: Multiple Roles of the Protein Tyrosine Phosphate SHP-1." Fogler Library, University of Maine, 2001. http://www.library.umaine.edu/theses/pdf/JoliatMJ2001.pdf.
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Dolton, Garry. "Role of SHP-1 in in vivo CD8+ T cell responses to antigenic stimulation." Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/55794/.
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The immune system has immense clinical potential for combating pathogens and tumourigenesis. More specifically, CD8+ T cells have the ability to eradicate infected and malignant cells. In light of this, the factors that may influence the speed at which antigen is detected, the magnitude of the response and the efficiency of pathogen/tumour clearance require ongoing investigation. The src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) is a negative regulator of T cell signalling pathways. Prior to this study, in vitro data had demonstrated that SHP-1 deficient CD8+ T cells possess a hyper-responsive phenotype when stimulated with cognate peptide. Therefore, the remit of this study was to establish whether this in vitro observation has an in vivo relevance. In order to explore the role of SHP-1 in an in vivo setting, CD8+ T cells from the spontaneous mouse mutant, motheaten, which lacks SHP-1 expression were utilised. Specifically, CD8+ T cells were purified from motheaten (SHP-1 deficient) and control (SHP-1 sufficient) mice and adoptively transferred to recipient mice where they could be studied. This study demonstrates that following adoptive transfer, naive SHP-1 deficient CD8+ T cells exhibit an enhanced in vivo expansion upon antigenic stimulation, which notably results in the killing of more peptide labelled target cells. Furthermore, SHP-1 deficient CD8+T cells also exhibit an enhanced memory response upon antigenic challenge. These findings suggest that modulation of SHP-1 expression may improve the efficacy of tumour immunotherapy strategies, which use antigen specific CD8+ T cells to eradicate malignant cells in tumour-bearing patients. In further support of potentially targetting SHP-1 expression in CD8+ T cells used in immunotherapy strategies, it has been importantly shown in this study that mice receiving SHP-1 deficient CD8+ T cells exhibit an enhanced protection against pulmonary tumour formation when compared to mice receiving SHP-1 sufficient CD8+ T cells.
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Sharma, Kamal. "Human somatostatin receptor mediated antiproliferative signaling, SHP-1-dependent subtype selective cytotoxic and cytostatic actions." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0027/NQ50258.pdf.
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Sharma, Kamal 1971. "Human somatostatin receptor mediated antiproliferative signaling : SHP-1 dependent subtype selective cytotoxic and cytostatic actions." Thesis, McGill University, 1998. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=35484.
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The ability of cells to undergo cell death is inherent. As such, some cells tend to exist for a shorter period of time than others. This cognate response of cells to master their own demise is known as programmed cell death or apoptosis. Changes in the rate of apoptosis within a cellular system can give rise to hyperproliferation like in cancer or to degeneration like in Alzheimer's disease. The G-protein coupled receptor agpnist somatostatin (SST) and its analogs inhibit tumor cell growth by exerting direct antiproliferative effects through five SST receptor (SSTRs) subtypes. Its actions have been reported to result in either apoptosis (AtT-20 pituitary and MCF-7 breast cancer cells) or growth arrest (GH3 pituitary cells) but the underlying mechanisms have not been elucidated. Given the role played by numerous tumor suppressor proteins, like wt p53, Rb and protein tyrosine phosphatases (PTP), in the regulation of tumor cell growth, it is possible that SST could be recruiting these proteins to effectuate growth inhibition. Thus, I set out to investigate the involvement of PTPs and the status of prominent cell cycle regulatory proteins, like wt p53, Rb, p21WAF1/Cip1, bax and bcl-2, in the signal transduction cascade of antiproliferative signals by SST using MCF-7 cells. Moreover, I investigated the regulation of wt p53, p21 WAF1/Cip1, Rb and bax in rotation to cell cycle progression leading to apoptosis or growth arrest in a subtype selective manner, in CHO-K1 cells stably expressing hSSTRs1-5. Conclusions. (i) SST-induced MCF-7 cell apoptosis is associated with induction of wt p53 and bax. (ii) Apoptosis requires intracellular acidification and activation of an acidic ondonuclease. (iii) Overexpression of the ER-targeted bcl-2 protects MCF-7 calls from SST-induced acidification and apoptosis. (iv) Apoptosis is unique to hSSTR3 and involves the induction of wt p53 and bax. (v) hSSTR1,2,4 and 5 signal a G1 growth arrest with the induction of Rb and p21 WAF1/Cip1. (
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Drapeau, Nicolas. "L’expression de SHP-1 induite par l’hyperglycémie inhibe les actions de l’insuline dans les podocytes." Mémoire, Université de Sherbrooke, 2014. http://savoirs.usherbrooke.ca/handle/11143/129.
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Résumé : Les podocytes, cellules épithéliales rénales, sont nécessaires au maintien de la structure et de la fonction de filtration des glomérules rénaux. La dédifférenciation et l’apoptose des podocytes sont des évènements précoces de la néphropathie diabétique. Des études ont rapporté que l’insuline est nécessaire à la survie des podocytes puisque la délétion du récepteur à l’insuline dans les podocytes de souris entraîne une pathologie glomérulaire semblable à la néphropathie. D’autres études ont montré que la protéine tyrosine phosphatase Src homology-2 domain-containing phosphatase-1 (SHP-1) inhibe les voies de signalisation de l’insuline au niveau du foie et du muscle en déphosphorylant la sous-unité bêta du récepteur à l’insuline (IRβ) et la kinase Phosphatidylinositide 3-kinase (PI3K). Il a récemment été démontré que l’expression de SHP-1 est élevée dans les cortex rénaux de souris diabétiques. Nous avons donc émis l’hypothèse que l’expression de SHP-1 induite par l’hyperglycémie altère les actions de l’insuline dans les podocytes. Nous avons premièrement utilisé un modèle in vivo de souris diabétiques de type 1 (Ins2+/C96Y; Akita). Comparées aux souris contrôles (Ins2+/+), les souris Akita présentaient une apoptose élevée des podocytes ainsi qu’une perte des pédicelles. La phosphorylation de la protéine kinase B (Akt) et de Extracellular signal-regulated kinase 1/2 (ERK1/2), suite à une injection systémique d’insuline, était également significativement diminuée dans les cortex rénaux des souris Akita. Cette diminution correspondant à une résistance à l’insuline corrélait avec une augmentation de deux fois de l’expression de SHP-1 dans les glomérules. Nous avons ensuite utilisé une lignée immortalisée de podocytes murins en culture et avons observé que l’exposition à des concentrations élevées de glucose (HG; 25 mM) pendant 96 h, entraînait l’augmentation de l’expression de marqueurs apoptotiques et de l’activité enzymatique de caspase-3/7 en comparaison aux concentrations normales de glucose (NG; 5,6 mM). L’exposition en HG a augmenté l’expression de l’ARNm et protéique de SHP-1, en plus de réduire la signalisation de l’insuline dans les podocytes. La surexpression de la forme dominante-négative de SHP-1 dans les podocytes a permis de renverser les effets de HG et de restaurer les actions de l’insuline. Finalement, l’augmentation de l’expression de SHP-1, tant in vivo qu’in vitro, a été directement corrélée à son association avec IRβ et à la diminution de la phosphorylation de IRβ, Akt et ERK1/2 suite à une stimulation à l’insuline. En conclusion, nous avons montré que l’expression élevée de SHP-1 dans les glomérules cause une résistance à l’insuline et la mort des podocytes contribuant ainsi à la néphropathie diabétique. // Abstract : Podocytes are epithelial renal cells required to preserve glomerular structure and filtration. Their dedifferentiation and apoptosis are early events of diabetic nephropathy progression. Previous studies have shown that insulin action is critical for podocyte survival since deletion of its receptor lead to a glomerular pathology similar to nephropathy. It has also been demonstrated that Src homology-2 domain-containing phosphatase-1 (SHP-1), a protein tyrosine phosphatase, inhibits insulin signaling pathway in liver and muscle by dephosphorylating tyrosine residues on insulin receptor beta-subunit (IRβ) and the Phosphatidylinositide 3-kinase (PI3K). A recent study concluded that SHP-1 is elevated in kidney cortex of type 1 diabetic mice. We hypothesized that hyperglycemia-induced SHP-1 expression may affect insulin actions in podocytes. To confirm this hypothesis, we used type 1 diabetic Akita mice (Ins2+/C96Y). Compared to control littermate mice (Ins2+/+), Akita mice developed elevated podocyte foot process effacement and podocyte apoptosis. In contrast to control mice, insulin-stimulated protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was remarkably reduced in renal podocytes of Akita mice. This phosphorylation diminution associated to a renal insulin resistance was correlated with a two-fold increase of SHP-1 expression in the glomeruli. We then used cultured murine podocytes cell line to confirm our in vivo results. Podocytes exposed to high glucose concentration (HG; 25 mM) for 96 h exhibited high levels of apoptotic markers and caspase-3/7 enzymatic activity as compared to normal glucose concentration (NG; 5,6 mM). HG exposure raised mRNA and protein levels of SHP-1 and reduced the insulin-signaling pathway in podocytes. Overexpression of dominant-negative SHP-1 in podocytes prevented HG effects and restored insulin actions. Finally, elevated SHP-1 expression induced by high glucose levels was directly correlated to an increased association with insulin receptor-β subunit (IRβ) in vitro and in vivo. This association is therefore leading to the reduction of both IRβ phosphorylation and insulin-stimulated Akt and ERK phosphorylation. In conclusion, our results showed that high levels of SHP-1 in glomeruli cause insulin resistance and podocyte loss, thereby contributing to diabetic nephropathy.
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Beebe, Kirk. "Substrate recognition through modular domains : protein tyrosine phosphatase SHP-1 and tail-specific protease (TSP) /." The Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu1488203158827833.
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Amin, Shahreen. "Regulation of the tyrosine phosphatase SHP-1 expression by C-jun-N-terminal kinase and RFX-1 and AP-4 transcription factors in insulin-like growth factor-1 (IGF-1) stimulated breast adenocarcinoma MCF-7 cells." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/26837.
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This thesis is devoted to reveal the negative regulators in IGF-1 (Insulin like growth factor 1) stimulated growth of a human breast adenocarcinoma cell line. It is a well established fact that increased circulating levels of IGF-1 correlate with increased risk of breast cancer. IGF-1 activation of its receptor, IGF-1R, is implicated in the progression of breast cancer, where IGF-1 stimulation leads to proliferative and anti-apoptotic responses by stimulating MAPK Erk and PI3K, respectively. In this study, IGF-1 stimulated MCF-7 cells proliferated more in the absence of MAPK JNK, implicating the involvement of MAPK JNK in the negative regulation of IGF-1 stimulated cell growth.
In this research study, we show for the first time that IGF-1 stimulation of breast cancer cells induces SHP-1-expression by activating JNK, which in turn, activates RFX-1 and AP-4 transcription factors to allow them to bind to the high-expression region of the SHP-1 P-1 promoter in breast adenocarcinoma MCF-7 cells. (Abstract shortened by UMI.)
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Papademetriou, Suzanne Andrea. "Role of the SHP-1 tyrosine phosphatase in the regulation of oocyte growth and follicle development." Thesis, University of Ottawa (Canada), 2002. http://hdl.handle.net/10393/6300.
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The tyrosine kinase Kit is expressed in oocytes and is involved in primordial germ cell (PGC) proliferation and oocyte growth. Our goal was to determine the involvement of the SHP-1 phosphatase in regulating PGC proliferation and oocyte growth by examining SHP-1 deficient motheaten mice. Ovaries from wild-type and motheaten mice were observed at 10--13 days of age and after transplantation under the kidney capsule of SCID mice. Ovaries were analyzed by histological and western analyses. SHP-1 was expressed in all ovarian cell types throughout follicle development. At 10--13 days, motheaten animals had smaller ovaries, increased numbers of PGCs and decreased granulosa cell proliferation compared to controls. After transplantation, both groups had formed large antral follicles in similar proportions. Interestingly, motheaten oocytes achieved larger sizes than controls. These results suggest that SHP-1 may interact with Kit to regulate PGC proliferation and oocyte growth, however, the loss of SHP-1 does not impair granulosa cell proliferation and follicle development.
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Xu, Yan 1958. "Human protein tyrosine phosphatase SHP-1 : gene regulation and role in apoptosis in MCF-7 cells." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=38441.
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SHP-1, a SH2 domain-containing protein-tyrosine phosphatase, plays a critical role in regulation of cell signal transduction. SHP-1 is expressed not only in cells of hematopoietic lineages, but also in many non-hematopoietic cells under the control of a tissue-specific promoter, P1. In the first part of this thesis, the activity of the P1 promoter was analyzed in a region spanning 3.5 kb upstream of the major transcription start site in non-hematopoietic MCF-7 cells. An upstream Sp1 element (-126 to -118) positively regulated this TATA-box-lacking promoter. Two inverted CCAAT-elements (-332 to -328 and -66 to -62) played the important, but opposite roles, and transcription factor NF-Y predominantly bound to the two CCAAT-elements to control SHP-1 gene expression. Furthermore, incubation of MCF7 cells with 100 ng/ml trichostatin A (TSA), an inhibitor of histone deacetylase, significantly increased the activity of the P1 promoter. Mutation in the proximal CCAAT-element, however, eliminated the activating effect of trichostatin A on the promoter. In the second part of this thesis, the mechanism by which SHP-1 modulated TSA-induced MCF-7 cell apoptosis was elucidated. Analysis of cell survival signaling pathways revealed that overexpression of SHP-1 inactivated Akt ( eg. diminished phosphorylation resulted from modulation of PI3K expression) and increased caspase-9 and caspase-7 activities. Interestingly, a parallel decrease was observed in the phosphorylation of the pro-apoptosic Bcl-2 family member Bad at Ser112 as well as in the stress-activated MAP kinase JNK, both of which have been implicated in Akt- as well as ERK1/2-mediated functions. It was not surprising, therefore, to detect a diminished level of phosphorylated ERK1/2 in SHP-1-overexpressiog cells and that this effect was exacerbated by TSA treatment. Taken together, the data presented in this thesis suggest that SHP-1 expression is regulated by Sp1 and NF-Y factors, and SHP-1 sensitizes MCF-7 cells to TS
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Shah, Nilay [Verfasser], and Dirk [Akademischer Betreuer] Eick. "Functional analysis of Tyrosine-1 of mammalian RNA polymerase II CTD / Nilay Shah ; Betreuer: Dirk Eick." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1170061184/34.
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Paling, Nicholas Robert Dixon. "The role of the tyrosine phosphatase SHP-1 in the regulation of interleukin-3 signal transduction." Thesis, University of Bath, 2002. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.760792.
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Shi, Meng [Verfasser]. "Phenomenology of U(1)Lμ-Lτ Gauge Extension of the Standard Model at LHC / Meng Shi." Bonn : Universitäts- und Landesbibliothek Bonn, 2021. http://d-nb.info/1238687482/34.
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Leblanc, Caroline. "Le rôle de la tyrosine phosphatase Shp-1 dans le maintien de l’homéostasie de l’épithélium intestinal." Mémoire, Université de Sherbrooke, 2015. http://hdl.handle.net/11143/10601.
Full textAbstract:
Shp-1 (Src homology 2 domain-containing phosphatase 1) est une tyrosine phosphatase
retrouvée principalement chez les cellules hématopoïétiques, mais également chez les
cellules épithéliales. Bien que Shp-1 soit reconnue comme étant un régulateur négatif de
plusieurs voies de signalisation intracellulaire chez les cellules hématopoïétiques, son rôle
dans les cellules épithéliales a été jusqu’ici très peu étudié. Afin de mieux comprendre son
rôle dans les cellules épithéliales intestinales, nous avons généré un modèle murin de
délétion conditionnelle de Shp-1 spécifiquement dans l’épithélium intestinal (Shp-1CEI-KO).
De manière intéressante, dès l’âge de 6 semaines, les souris expérimentales présentent une
intestinalomégalie associée à une légère augmentation de la prolifération cryptale. La taille
des cellules épithéliales est également augmentée, suggérant de l’hypertrophie cellulaire
chez les souris invalidées pour Shp-1. Parallèlement, la voie de signalisation
PI3K/Akt/mTor est activée dans l’épithélium des souris mutantes. Nous avons également
noté une production accrue de cellules caliciformes et de leurs précurseures, les cellules
intermédiaires, en absence de Shp-1. Par contre, la maturation des cellules de Paneth
semble grandement compromise vu la baisse importante d’expression du lysozyme et des
RegIIIβ et RegIIIγ, de même que la faible densité de leurs granules de sécrétion. La
comparaison du phénotype intestinal des souris Shp-1CEI-KO avec celui des souris PtenCEI-KO
suggère que l’hyperactivation de la voie PI3K/Akt/mTor est responsable en partie des
altérations phénotypiques observées chez la souris invalidée pour Shp-1. En conclusion, nos
résultats montrent que la tyrosine phosphatase Shp-1 est un régulateur important de
l’homéostasie de l’épithélium intestinal en contrôlant notamment la croissance cellulaire et
la différenciation des cellules de la lignée sécrétrice.
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Konarski, Yulia. "SHP-1/ Src Complex is a Master Regulator of the IL-12/IL-23 pro- and IL-10/IL-27 Anti-inflammatory Axis in TLR4-activated Signaling Pathways in Human Monocytes and Macrophages." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/25999.
Full textAbstract:
Although the etiology surrounding many autoimmune diseases remains unknown, the underlying characteristic of many of these diseases is a disruption in the balance of pro- and anti- inflammatory cytokines It is well established that the dysregulation of the IL-12 family of cytokines, an increase in IL-12/IL-23 and a decrease in IL-27 production has been implicated in these conditions. We used ELISA, RT-PCR, Immunofluorescence and Western immunoblotting in conjunction with pharmalogical inhibitors and siRNA to demonstrate the role of SHP-1/Src in the regulation of IL-12, IL-23, IL-27 and IL-10 in LPS-stimulated human THP-1 cells, monocytes and MDMs. My results show for the first time that Src kinase activity relies on SHP-1 activity, and together this complex functions in TLR4-mediated MyD88 and TRIF pathways. Furthermore Src exhibits a dual role as a positive regulator for anti-inflammatory IL-10/IL-27 and as a negative regulator of pro-inflammatory IL-12/IL-23 downstream of TLR4. Moreover, the involvement of PI3K and JNK MAPK, dependent on SHP-1/Src complex, in the regulation of IL-12 family and IL-10 downstream of TLR4 was shown.