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1
El, Barbry Houssam. „Découverte du rôle crucial du résidu en position 2 des séquences MTS d’adressage mitochondrial“. Electronic Thesis or Diss., Sorbonne université, 2023. http://www.theses.fr/2023SORUS035.
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Les mitochondries sont des organites complexes impliquant un millier de protéines, la plupart codées dans le génome nucléaire. Leur biogenèse a nécessité au cours de l’évolution la mise en place de systèmes efficaces d’adressage et d’import protéique, et des défaillances de ces systèmes sont associées à des pathologies graves, neuropathies, troubles cardiovasculaires, myopathies, maladies neurodégénératives ainsi que cancers. De nombreuses protéines mitochondriales possèdent en N-terminal une séquence d’adressage appelée MTS (Mitochondrial Targeting sequence) qui forme une hélice alpha amphiphile essentielle pour leur import mitochondrial. La séquence des divers MTSs est néanmoins très variables et leur caractéristiques critiques ne sont pas encore bien comprises. Le point de départ de ma thèse est la découverte, chez les levures, d’une surreprésentation en position 2 des séquences MTSs de 4 acides aminés hydrophobes (F, L, I, W). Au cours de mes années de thèse, j’ai pu confirmer, par des expériences de mutagenèse dirigée, le rôle critique de la nature du résidu en position 2 des MTSs. En effet, grâce au développement d’un système novateur de criblage des défauts d’import basé sur le sauvetage fonctionnel de la toxicité d’une protéine mitochondriale, j’ai pu observer que seuls les résidus surreprésentés en position 2 des protéines mitochondriales permettaient un import efficace. Mon travail a ainsi démontré l'existence de fortes contraintes évolutives s’exerçant au niveau de la position 2 des MTSs dont la compréhension pourrait à terme être utile pour optimiser l’adressage mitochondrial de protéines thérapeutiques chez des patients atteints de maladies mitochondrialesMitochondria are complex organelles involving a thousand proteins, most of which are encoded in the nuclear genome. Their biogenesis has required the evolutionary development of efficient protein addressing and import systems, and failures of these systems are associated with serious pathologies, neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancers.Many mitochondrial proteins have an N-terminal addressing sequence called MTS (Mitochondrial Targeting Sequence) which forms an amphiphilic alpha helix essential for their mitochondrial import. However, the sequence of the various MTSs is highly variable and their critical characteristics are not yet well understood. The starting point of my thesis was the discovery in yeast of an overrepresentation of 4 hydrophobic amino acids (F, L, I, W) at position 2 of the MTSs sequences. During my thesis, I was able to confirm the critical role of the nature of the residue in position 2 of the MTSs through directed mutagenesis experiments. Indeed, thanks to the development of an innovative system for screening import defects based on the functional rescue of the toxicity of a mitochondrial protein, I was able to observe that only residues overrepresented at position 2 of mitochondrial proteins allowed efficient import. My work has thus demonstrated the existence of strong evolutionary constraints at position 2 of MTSs, the understanding of which could ultimately be useful for optimising the mitochondrial addressing of therapeutic proteins in patients suffering from mitochondrial diseases
2
Mayack, Shane Renee. „The role of Janus Kinase 3 in CD4+ T Cell Homeostasis and Function: A Dissertation“. eScholarship@UMMS, 2004. https://escholarship.umassmed.edu/gsbs_diss/94.
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This dissertation addresses the role for Janus Kinase 3 (Jak3) in CD4+ T cell homeostasis and function. Jak3 is a protein tyrosine kinase whose activity is essential for signals mediated by the γc dependent cytokines IL-2, -4, -7, -9, -15, and -21. Previous data have demonstrated that peripheral CD4+ T cells from Jak3-deficient mice have a memory phenotype and are functionally impaired in both proliferative and IL-2 responses in vitro. Interestingly, Jak3/γc activity has been previously shown to play a role in the prevention of T cell anergy.
These studies were initiated to more precisely define the role for Jak3/γc cytokines in the prevention of T cell anergy and the maintenance of functional CD4+ T cell responses. We began to address this question by assessing global gene expression changes between wild type and Jak3-/- CD4+ T cells. These data indicate that Jak3-/- CD4+ T cells have an increase in gene expression levels of inhibitory surface receptors as well as immunosuppressive cytokines.
Further analyses confirmed that Jak3-deficient T cells express high levels of PD-1, secrete a Trl-type cytokine profile following direct ex vivo activation, and suppress the proliferation of wild type T cells in vitro. These characteristics indicate that CD4+ Jak3-/- T cells share properties with regulatory T cell subsets that have an important role in peripheral tolerance and the prevention of autoimmunity.
We next addressed whether these regulatory characteristics were T cell intrinsic or rather the result of expanding in a Jak3-deficient microenvironment characterized by a number of immune abnormalities and a disrupted splenic architecture. Jak3-/- CD4+ T cells proliferate in vivoin a lymphopenic environment and selectively acquire regulatory T cell characteristics in the absence of any additional activation signals. While the precise mechanism by which Jak3-deficient T cells acquire these characteristics remains unclear, our data indicate that one important component is a T cell-intrinsic requirement for Jak3 signaling.
These findings indicate several interesting aspects of T cell biology. First, these studies, demonstrate that the homeostatic proliferation of CD4+ T cells is not dependent on signaling via γc-dependent cytokine receptors. And, second, that the weak activation signals normally associated with homeostatic expansion are sufficient to drive Jak3-/- T cells into a non-conventional differentiation program. Previous data indicate that, for wild type T cells, signaling through both the TCR as well as γc-dependent cytokine receptors promote the homeostatic proliferation of T cells in lymphopenic hosts. Since Jak3-/- T cells are unable to receive these cytokine signals, their proliferation is likely to be wholly dependent on TCR signaling. As a consequence of this TCR signaling, Jak3-/- T cells proliferate, but in addition, are induced to up regulate PD-1 and to selectively activate the IL-10 locus while shutting off the production of IL-2. Since this fate does not occur for wild type T cells in a comparable environment, it is likely that the unique differentiation pathway taken by Jak3-/- T cells reflects the effects of TCR signaling in the absence of γc-dependent cytokine signaling.
Interestingly, wild type T cells undergoing homeostatic expansion in lymphopenic hosts show many common patterns of gene expression to freshly-purified unmanipulated Jak3-/- T cells. For instance, micro array analysis of gene expression in wild type CD4+ T cells after lymphopenia induced homeostatic expansion show a similar pattern of upregulation in surface markers (PD-1 and LAG-3), and cytokine signaling molecules (IL-10 and IFN-γ cytokine, receptors, and inducible gene targets) to that of Jak3-/- CD4+ T cells immediately ex vivo. These data suggest that the process of homeostatic proliferation normally induces immune attenuation and peripheral tolerance mechanisms, but that full differentiation into a regulatory T cell phenotype is prevented by γc-dependent cytokine signals.
Taken together these data suggest that Jak3 plays an important role in tempering typical immune attenuation mechanisms employed to maintain T cell homeostasis and peripheral tolerance.
3
Bishop, Kenneth D. „Egr-2 and PD-1 Are Required for Induction and Maintenance of T Cell Anergy: A Dissertation“. eScholarship@UMMS, 2005. https://escholarship.umassmed.edu/gsbs_diss/354.
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The prevalence of diabetes is approaching epidemic proportions worldwide. There is currently no cure for type 1 diabetes, and successful treatment requires constant monitoring of blood sugars and use of exogenous insulin to prevent hyperglycemia. Diabetes will be curable when pancreatic β-islet cells can be transplanted into diabetes patients without requiring long-term immunosuppression. This will require learning more about the induction of functional tolerance, a state that maintains the competence of the immune system to most antigens but protects graft-specific antigens from immune rejection, permitting transplantation. One known mechanism of peripheral tolerance is T cell anergy, a phenotype of hypo-reponsiveness in CD4+ T cells. The focus of this thesis is a description of factors shown to be specific to the induction and maintenance of T cell anergy, whose loss reverses the anergic phenotype, restoring the ability of the cells to proliferate in response to antigen. The first of these is Egr-2, a zinc-finger transcription factor, whose presence is required for the induction of anergy induced in T cell clones by TCR stimulation in the absence of costimulation. Egr-2 is shown to be important to anergy induction but not anergy maintenance. In contrast, a negative costimulation receptor, PD-1, is shown to be necessary for the maintenance of anergy. It is possible that learning more about the genetic factors that orchestrate T cell anergy will prove useful in the development of tolerance-based protocols for organ and tissue transplantation without the use of long-term immunosuppression.
4
Genet, Roger. „La l-tryptophane 2',3'-oxydase de chromobacterium violaceum : purification, caracterisation et clonage du gene. l'introduction d'une double liaison en position c alpha-c beta des residus tryptophanyles, au sein des peptides et des proteines“. Paris 11, 1992. http://www.theses.fr/1992PA112391.
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Chromobacterium violaceum possede la capacite de metaboliser le carboxybenzoyl-l-tryptophane en un compose insature, possedant une double liaison entre ses carbones alpha et beta (davis et al. , bba (1975) 385:133-144). A partir de cette souche, nous avons purifie une nouvelle enzyme, nommee l-tryptophane 2,3-oxydase (trpox) ou l-tryptophane: oxygene 2,3-oxydoreductase (e. C. 1. 3. 3. X), qui catalyse specifiquement la formation d'une double liaison en position c alpha-c beta du l-tryptophane. Les caracteristiques structurales de l'enzyme ont ete etablies, et une etude des proprietes fonctionnelles nous a permis de preciser les interactions stabilisatrices du substrat au site actif. La trpox n'agit pas seulement sur le l-tryptophane et ses derives, mais catalyse egalement la deshydrogenation des residus tryptophanyles au sein des peptides et des proteines. Sa stabilite en conditions reductrices et denaturantes, et sa thermostabilite, font de cette enzyme un outil particulierement performant pour la synthese de dehydropeptides et de dehydroproteines. Une etude genetique des conditions d'expression de l'activite enzymatique chez c. Violaceum, nous a permis de mettre en evidence une correlation avec la biosynthese d'un pigment, la violaceine, et la presence d'un plasmide de 27 megadaltons, prg100, isole au laboratoire. L'un des genes specifiant la trpox a ete localise sur prg100. Nous disposons aujourd'hui d'un faisceau d'arguments en faveur d'une participation de cette enzyme au processus de biosynthese du pigment de c. Violaceum
5
Vincent, Karla Kristine. „Transactivation of Beta 2 Adrenergic Receptor by Bradykinin type 2 Receptor via heterodimerization“. Diss., Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/37117.
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Although a long standing convention maintained that G Protein Coupled Receptors (GPCRs) exist in the plasma membrane solely as monomers, substantial work over the last two decades has demonstrated that these ubiquitous receptors can and in many cases, preferentially, exist as homodimers, heterodimers, or higher order oligomers. Often, two GPCRs of the same class heterodimerize; it is less common for two GPCRs of different signaling pathways to interact. The work presented here studied the physical and functional interaction of two GPCRs from discrete classes, the Beta 2 Adrenergic Receptor (β2AR), a Gαs-coupled receptor, and Bradykinin type 2 Receptor (Bk2R), a Gαq coupled receptor. These data show that Bk2R and β2AR are physically coupled when heterologously expressed in Xenopus oocytes, and in pheochromocytoma (PC12) cells and in freshly isolated murine ventricular myocytes, two systems that endogenously express these receptors. This physical coupling led to functional consequences in heterologous and endogenous expression systems, as Bk2R was able to transactivate β2AR signaling via its direct interaction with the receptor. Furthermore, coexpression of Bk2R shifted the dose response curve of β2AR for its selective agonist rightward in Xenopus oocyte electrophysiology experiments, suggesting the presence of Bk2R negatively affected β2AR native pharmacology. Up to thirty minutes of either bradykinin (BK) or isoproterenol exposure did not change the relative amount of Bk2R/β2AR heterodimer in PC12 cells, a rat adrenal medulla tumor cell line that endogenously expresses these receptors. Despite the obvious signaling consequences, the Bk2R/β2AR heterodimer accounted for only 10% of the total β2AR protein detected and 20% of the total Bk2R protein detected. When other Bk2R-specific ligands were also tested to examine the extent of β2AR transactivation, our data showed that both Lys-des-Arg-Bradykinin, a Bk2R partial agonist and NPC 567, a Bk2R antagonist, transactivated β2AR to the same extent as BK. Taken together, our data provide a novel mode of receptor regulation and signaling via Bk2R/β2AR heterodimerization. Because a large percentage of therapeutics target GPCRs, a greater understanding of how a GPCR heterodimer functions could be beneficial for targeting new drugs and refining existing drugs. Understanding the Bk2R/β2AR heterodimer provides a new perspective on the myriad of fucntional consequences that occur when a GPCR is activated.
6
Reed, Eric Christopher. „Improvement of MPEG-2 compression by position-dependent encoding“. Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/38823.
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Ozkaya, Tugba. „Hezbollah And Its Position Towards Israel“. Master's thesis, METU, 2009. http://etd.lib.metu.edu.tr/upload/2/12611119/index.pdf.
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This thesis analyses how Hezbollah has perceived Israel since its establishment. In
this study it is argued that Israel is the main enemy of and source of hatred for
Hezbollah. The references of this overall statement are the ideology and political,
social and military history of Hezbollah. The armed struggle of Hezbollah against
Israel started with the 1982 Israeli invasion of Lebanon evolved into both a
political participation with the continued armed militia in the period between 1982
to today. During this period, in addition to its armed conflict with Israel,
Hezbollah came on the stage with social services for Lebanese society and
political propaganda in Lebanese elections. The intersection point of these three
identities is the endless encouragement of Hezbollah for a determined resistance
against Israel. While on the one hand Hezbollah defines Israel to be the most
dangerous threat for the world, in addition to being a prominent enemy for the
Arab and Muslim communityon the other hand Israel regards Hezbollah to be the highest impact menace. Consequently, the thesis is finalized with outputs and predictions taking all historical and ideological aspects into concern.
8
FREVILLE-HERENTHALS, STEPHANIE. „Synthese enantioselective d'alcaloides monosubstitues en position 2 et disubstitues en positions 2 et 6“. Paris 6, 1996. http://www.theses.fr/1996PA066557.
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La these presentee porte sur l'elaboration de nouvelles syntheses enantioselectives d'alcaloides piperidiniques monosubstitues en position 2 et disubstitues en positions 2 et 6. Le travail a pour point de depart un substrat bicyclique oxazolopiperidonique, lui-meme issu de la condensation du phenylglycinol et d'un -cetoacide dont une nouvelle methode de preparation a ete developpee. Ce bicycle possede en et de l'atome d'azote des reactivites potentielles: fonction carbonyle du lactame et fonction iminium aminal masquee. Une ouverture stereoelectronique en (cycle oxazolidinique) conduit aux lactames n-proteges. Trois voies sont alors envisagees: la premiere donne acces aux 2-alkylpiperidines apres une reaction d'extrusion d'oxygene et une elimination de la partie chirale. La deuxieme conduit aux lactames chiraux par debenzylation. Ces derniers sont des synthons-cles permettant l'acces direct aux 2-alkylpiperidines apres une reaction d'extrusion d'oxygene et aux 2,6-dialkylpiperidines trans ou cis par une suite de reactions stereoselectives effectuee en de la fonction carbonyle. Une inversion de configuration du carbone portant la fonction hydroxyle de l'un de ces derives conduit au (-)-pinidinol. C'est la premiere synthese enantioselective de ce compose. La derniere voie conduit aux oxazolopiperidines par action d'organomagnesiens sur la fonction carbonyle du lactame. L'ouverture ulterieure du cycle oxazolopiperidinique et la debenzylation conduisent stereoselectivement aux 2,6-dialkylpiperidines trans. La plupart des composes obtenus sont des produits naturels et presentent un interet biologique
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Roy, Guylaine. „Characterization of PABP-interacting proteins 1 and 2“. Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84317.
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The 3' poly(A) tail of eukaryotic mRNAs and the poly(A) binding protein (PABP) play key roles in the regulation of translation. Recently, our group identified two human PABP-interacting proteins (Paip), Paip1 and Paip2, which stimulate and repress translation, respectively. Paip2 also inhibits the binding of PABP to the poly(A) tail and competes with Paip1 for binding to PABP. My research project was divided into two parts to allow me to gain a greater understanding of the roles of these two PABP-interacting proteins. First, in order to study the mechanism of interaction of Paip1 and PABP, their binding sites were mapped by Far Western and GST pull-downs experiments. The Paip1-PABP interaction involves two distinct binding regions in each protein. The PABP interacting motif-1 (PAM1) of Paip1 is rich in acidic amino acids and is located in the C-terminus (a.a. 440--479). PAM1 interacts with the RNA recognition motifs (RRMs) 1 and 2 of PABP. PAM2 consists of a 15 amino acid stretch residing in the N-terminus of Paip1 (a.a. 123--137) and interacts with the C-terminal domain of PABP. In addition, the stoichiometry and the kinetic and thermodynamic constants for the Paip1-PABP interaction were determined using a Surface Plasmon Resonance (SPR)-biosensor. Paip1 interacts with PABP with an apparent KD of 1.9 nM and with a 1:1 stoichiometry. In the second part of my thesis research, the Drosophila Paip2 (dPaip2) was isolated and characterized in order to ascertain a biological role for Paip2. dPaip2 was found to be the bona fide homologue of human Paip2 since it interacts with the Drosophila PABP (dPABP) via two independent binding sites, interferes with the ability of dPABP to bind to poly(A), and represses translation. Ectopic overexpression of dPaip2 in wings resulted in a size reduction phenotype, which was due to a decrease in the cell number but not to a difference in cell size. Clones of cells overexpressing dPaip2 in wing discs also contai
10
Kimura, Atsuko. „Isolation and identification of imidazoline-2 binding proteins“. Thesis, University of Bristol, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399960.
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Khalil, Ahmed. „Synthèse et étude d'analogues nucléosidiques fluorés en position 2' ou 3'“. Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20070/document.
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Dans le premier chapitre de cette thèse, nous nous sommes intéressés aux virus de l'immunodéficience humaine et des hépatites B et C ainsi qu'aux thérapies utilisées dans le traitement de ces affections. Nous avons introduit l'importance des nucléosides fluorés, et nous avons donné quelques exemples de nucléosides fluorés utilisés en chimiothérapie antivirale et antitumorale. Dans le second chapitre, nous avons présenté une synthèse rapide de 2',3'-didésoxy-3'-fluoro-beta-D-thréo-nucléosides portant les bases pyrimidiques naturelles et substituées en position N3 par un groupement nitro ou amino. Les composés obtenus ont été évaluées contre divers virus à ADN et ARN (y compris le VIH) dans des expériences de culture cellulaire. Dans le troisième chapitre, nous nous somme intéressés à la synthèse de différents 2',3'-didésoxy-2'-fluoro-3'-(N-hydroxyimino), (N-methoxyimino) and (hydroxyl-amino) nucléosides en série pyrimidine. Les composés obtenus ont été évaluées contre divers virus à ADN et ARN dans des expériences de culture cellulaireIn the first chapter, we presented the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), as well as the therapies used to treat these diseases. In a second part, we discussed about the importance of the incorporation of fluorine atom into nucleoside analogues, and in a third part of this chapter, we presented the recent literature sources of the synthesis and biological activity of fluorinated nucleosides. In the second chapter, we designed and synthesized a series of 2',3'-dideoxy-3'-fluoro-threo-pyrimidine nucleosides by direct and rapid methodology and evaluated them for their inhibitory effects on a number of RNA and DNA viruses in cell culture experiments. None of these nucleoside derivatives showed any antiretroviral activity nor cytotoxicity. In the third chapter of this manuscript, we synthesized a new series of 2',3'-dideoxy-2'-fluoro-3'-(N-hydroxyimino),(N-methoxyimino) and (hydroxylamino)pyrim idine nucleosides and also evaluated for their inhibitory effects on a number of RNA and DNA viruses, without finding any activity or cytotoxicity
12
Molano, Alberto. „Peptide binding, TCR recognition and intrathymic positive selection : by an MHC H-2Kb class I molecule devoid of the central anchor ("c") pocket /“. Access full-text from WCMC, 1998. http://proquest.umi.com/pqdweb?did=733066101&sid=11&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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13
Patel, Prakash. „Investigations of Streptomyces coelicolor A3(2) siderophore binding proteins“. Thesis, University of Warwick, 2009. http://wrap.warwick.ac.uk/2786/.
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Siderophores are small, high-affinity ferric iron chelators released by many microorganisms and some plants to solubilize iron. They are of great interest due to their clinical use to treat iron overload in humans, and also in relation to the development of novel antibiotics that target the biosynthetic and uptake pathways for iron in pathogens. Pathogens such as Bacillus anthracis excrete more than one type of siderophore. This is linked to increased pathogenicity. The Gram-positive soil bacterium Streptomyces coelicolor A3(2) excretes three siderophores: desferrioxamine B, desferrioxamine E and coelichelin. These displace iron from insoluble ferric hydroxides, and the resulting ferric complexes are transported into the cell via siderophore-binding proteins (lipoprotein receptors) associated with ATP-binding cassette (ABC) transporters. Previous studies showed that some of the genes in the biosynthetic clusters of the desferrioxamines (des) and coelichelin (cch) were required for efficient uptake of ferrioxamine E and ferri-coelichelin respectively and a third ABC transporter gene cluster (cdt), not associated with siderophore biosynthesis genes, was implicated in the import of ferrioxamine B. In this study, the lipoprotein receptors encoded within the des, cch and cdt clusters - DesE, CchF and CdtB – were recombinantly overproduced in E. coli and purified by immobilized metal affinity chromatography. Also, ferri-coelichelin was purified from cultures of S. coelicolor. The binding of the ferric complexes of the three cognate siderophores, as well as the xenosiderophores ferrichrome and ferrialbomycin, to the lipoprotein receptors was monitored by intrinsic fluorescence quenching. Dissociation constants of receptor-siderophore complexes were found to be in the nanomolar range, and a revised model of cognate siderophore transport in S. coelicolor was proposed. In collaboration with researchers at St. Andrews University, an X-ray crystal structure was solved for apo-DesE and DesE bound to ferrioxamine B, which demonstrated the similarity of DesE to other bacterial siderophore-binding proteins and the negligible conformational change on substrate binding. Ferrioxamine B also exhibited an unusual configuration not observed before in X-ray crystals of this ferri-siderophore. Also, a forcefield was constructed to model the structure and distortions ferric-tris-hydroxamate complexes, which could be used in the future to investigate the molecular basis of the tight and specific binding of ferri-siderophores to siderophore-binding proteins.
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Owen, Gillian Audrey. „Stress induced ribosomal proteins of Streptomyces coelicolor A3(2)“. Thesis, University of Sussex, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421519.
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Gauthier, Florian. „Synthèse et propriétés d’ARNs modifiés en position 2’ via des ponts disulfures“. Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTS120/document.
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Les ARNs sont impliqués dans de nombreux processus biologiques et peuvent adopter des structures secondaires différentes. Par leurs propriétés, ils constituent des outils biologiques puissants pour des applications diverses, tels les ARNs interférents (siARN) qui permettent l’extinction de l’expression des gènes par exemple. L’introduction de modifications sur des ARNs s’est avérée essentielle pour améliorer leurs propriétés et faciliter l’étude de leurs rôles biologiques et leurs applications thérapeutiques.Ce manuscrit rapporte la synthèse et les propriétés d’ARNs modifiés en position 2’ du ribose par des groupements contenant des ponts disulfures, sensibles à un environnement réducteur.Dans la première partie, la synthèse de prodrogues de siARNs partiellement modifiés par des groupements benzyldithiométhyles est décrite. Leurs stabilités thermiques et enzymatiques, ainsi que leur démasquage en milieu réducteur, sont montrés. Les résultats prometteurs d’activité inhibitrice et de pénétration cellulaire, sur une lignée cellulaire du sarcome d’Ewing, permettent d'envisager une application potentielle de ces siARNs modifiés comme outils thérapeutiques.La deuxième partie décrit une approche de co-délivrance par des siARNs couplés avec une drogue anticancéreuse, la doxorubicine, via un lien auto-immolable contenant des ponts disulfures. Les propriétés physico-chimiques des conjugués sont déterminées, et la libération du siARN et de la drogue en milieu réducteur est mise en évidence.La troisième partie présente une autre méthode de conjugaison en solution entre la position 2’ d’un ARN et des petites molécules (sucres, coumarine, biotine, acide désoxycholique, glutathion) via un pont disulfure. La synthèse des ARNs conjugués et leur devenir en milieu réducteur sont décrits.Dans la dernière partie, l’impact d’un lien avec un pont disulfure intrabrin entre les positions 2’ de deux nucléotides adjacents est étudié dans un duplex ou la partie boucle d’hairpins. L’influence du pont disulfure sur l’équilibre des conformations duplex et hairpin d’un ARN d’intérêt biologique est évaluée, en absence et en présence d’agents réducteurs. Une application en fluorescence d’une hairpin contrainte en tant que « molecular beacon » montre des utilisations potentielles de ce lien dans des outils pour étudier la conformation de structures secondaires d’ARNs ou dans des sondes pour détecter les agents réducteursRNAs are involved in numerous biological processes and can adopt different secondary structures. Thanks to their properties, they are powerful biological tools for diverse applications, such as small interfering RNA (siRNA) for gene silencing. Modified RNAs have proven to be essential to improve their properties, and to facilitate the study of their biological and therapeutic functions.This manuscript reports the synthesis and properties of 2’-O-modified RNAs bearing disulfide-containing groups, sensitive to reductive environment.The first part describes the synthesis of siRNAs prodrugs bearing lipophilic benzyldithiomethyl groups. The thermal stability, the serum stability and the response to glutathione treatment of modified siRNAs are thoroughly investigated. The gene silencing and the gymnotic delivery of several siRNAs are assessed, and demonstrates promising results on Ewing’s sarcoma cell line.A second part concerns the co-delivery of siRNAs and a hydrophobic anti-cancer drug (doxorubicin) using a self-immolative spacer bearing disulfide bonds. The chemico-physical properties of these conjugates are determined and the recovery of native siRNA and doxorubicin in response to reductive treatment is highlighted.A third part presents the conjugation of RNAs to small molecules (sugars, coumarin, biotin, deoxycholic acid, glutathione) using disulfide linkages. The synthesis of the RNA conjugates and their release in reducing conditions are also demonstrated.The last part reports the synthesis and the impact of an intrastrand dimethylene disulfide bridge between 2’-O-positions of two adjacent nucleotides in an RNA duplex and in the loop of RNA hairpins. Then, the influence of this linkage on the folding of a biologically relevant RNA structure is reported. Finally, an application of a constrained hairpin as a fluorescent molecular beacon highlights its potential use in tools for understanding RNA folding and in probes for the detection of reducing reagents
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Nashed, Salomé. „Étude fonctionnelle et évolutive du résidu situé en position 2 des protéines“. Electronic Thesis or Diss., Sorbonne université, 2023. http://www.theses.fr/2023SORUS219.
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Le résidu situé en position 2 des protéines, suivant leur méthionine initiatrice, est un signal clé pour le recrutement co-traductionnel de diverses enzymes de modification qui impactent précocement leur destinée cellulaire (adressage, repliement, temps de demi-vie). Bien que l’importance de ce résidu soit établie pour quelques protéines, son rôle à l’échelle globale du protéome et la nature des pressions sélectives auxquelles il pourrait être soumis demeurent à ce jour inexplorés. Durant ma thèse, j’ai pour la première fois utilisé des méthodologies d’analyse globale pour réaliser une étude fonctionnelle et évolutive du résidu situé en position 2 des protéines. J’ai mis au profit de cette étude deux approches complémentaires, développées in silico chez la levure modèle Saccharomyces cerevisiae. La première approche utilisée consiste en l’étude d’enzymes de modification dont le recrutement dépend du résidu en position 2 de leurs cibles. Je me suis en particulier intéressée aux N-acétyltransférases. Celles-ci possèdent la même activité enzymatique de N-acétylation, mais ciblent des sous-ensembles distincts de protéines et leurs délétions sont associées à des phénotypes différents, ce qui pose la question du rôle spécifique de chacune dans la physiologie cellulaire. Grâce à l’analyse de données expérimentales relatives à ces enzymes, j’ai caractérisé leur sélectivité globale in vivo et j’ai formellement démontré qu’elles ont effectivement des rôles physiologiques différentiels. La seconde approche utilisée est l’étude de la distribution des acides aminés en position 2 dans le protéome et dans les groupes fonctionnels de protéines définis par la Gene Ontology. Alors que les outils actuels utilisés pour réaliser des analyses de Gene Ontology ne tiennent pas compte de la structure hiérarchique de cette ressource, j’ai développé un algorithme permettant de synthétiser et de visualiser les résultats obtenus par une telle analyse pour en faciliter l’interprétation. Cette approche a permis l’identification de groupes fonctionnels de protéines présentant en position 2 une utilisation d’acides aminés distincte de celle observée dans le protéome à cette position. Ces deux méthodes d’analyse globale ont convergé vers un même résultat, à savoir que les précurseurs mitochondriaux possédant une séquence N-terminale d’adressage (MTS pour mitochondrial targeting sequence) présentent en position 2 une sur-représentation de larges résidus hydrophobes, critique pour leur import à la mitochondrie et permettant leur reconnaissance par la N-acétyltransférase NatC. Le biais d’acides aminés en position 2 des MTS est très conservé dans la lignée des Saccharomycotina et a partiellement évolué chez l’Homme et la plante Arabidopsis thaliana. J’ai de plus mis en évidence l’existence de plusieurs catégories de MTS en fonction de la nature du résidu qu’ils portent en position 2, ce qui peut indiquer une co-évolution de la position 2 des MTS et de leur composition globale et pose la question des propriétés optimales de ces séquences. Enfin, j’ai montré que les peptides signaux de la levure et la séquence N-terminale d’adressage au chloroplaste d’Arabidopsis thaliana présentent également des biais d’acides aminés en position 2, suggérant que le résidu à cette position pourrait jouer un rôle clé dans la reconnaissance de ces séquences par les systèmes d’adressage et d’import associésThe residue located at position 2 of proteins, following their initiator methionine, is a key signal for the co-translational recruitment of various modification enzymes that early impact their cellular fate (addressing, folding, half-life). Although the importance of this residue is established for a few proteins, its role at the global scale of the proteome and the nature of the selective pressures it may be subject to remain unexplored to this day. During my thesis, I used for the first time global analysis methodologies to conduct a functional and evolutionary study of the residue located at position 2 of proteins. I used two complementary in silico approaches developed in the model yeast Saccharomyces cerevisiae. The first approach I used is the study of modification enzymes whose recruitment depends on the residue at position 2 of their targets. I focused in particular on N-acetyltransferases. These enzymes have the same enzymatic activity of N-acetylation but target distinct subsets of proteins, and their deletions are associated with different phenotypes, raising the question of the specific role of each enzyme in cellular physiology. Through the analysis of experimental data related to these enzymes, I characterized their global selectivity in vivo and formally demonstrated that they indeed have differential physiological roles. The second approach I used is the study of the distribution of amino acids at position 2 in the proteome and in functional groups of proteins defined by the Gene Ontology. While current tools used to perform Gene Ontology analyses do not take into account the hierarchical structure of this resource, I developed an algorithm to synthesize and visualize the results obtained by such analyses to facilitate their interpretation. This approach allowed the identification of groups of proteins that present a distinct amino acid usage at position 2 compared to that observed in the proteome at this position. These two global analysis methods converged toward the same result, namely that mitochondrial precursors possessing an N-terminal addressing sequence (MTS for mitochondrial targeting sequence) exhibit at position 2 an overrepresentation of large hydrophobic residues, critical for their import into mitochondria and enabling their recognition by the NatC acetyltransferase. The amino acid bias at position 2 of MTS is highly conserved in the Saccharomycotina lineage and has partially evolved in humans and the plant Arabidopsis thaliana. I also highlighted the existence of several categories of MTS depending on the nature of the residue they carry at position 2, which may indicate co-evolution of position 2 of MTS and their overall composition and raises the question of optimal properties of these sequences. Finally, I showed that yeast signal peptides and the chloroplast N-terminal addressing sequence in Arabidopsis thaliana also exhibit amino acid biases at position 2, suggesting that the residue at this position could play a key role in the recognition of these sequences by associated addressing and import systems
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Kilic, Ergin. „Novel Position Measurement And Estimation Methods For Cnc Machine Systems“. Master's thesis, METU, 2007. http://etd.lib.metu.edu.tr/upload/2/12608762/index.pdf.
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Precision control of translational motion is vital for many CNC machine tools as the motion of the machinery affects the dimensional tolerance of the manufactured goods. However, the direct measurement along with the accurate motion control of machine usually requires relatively expensive sensors i.e. potentiometers, linear scales, laser interferometers. Hence, this study attempts to develop reference models utilizing low-cost sensors (i.e. rotary encoders) for accurate position estimation. First, an indirect measurement performance is investigated on a Timing Belt driven carriage by a DC Motor with a backlash included Gearbox head. An advanced interpolated technique is proposed to compensate the position errors while using indirect measurement to reduce the total cost. Then, a similar study was realized with a ball screw driven system. Next, a cable drum driven measurement technique is proposed to the machines which have long travel distance like plasma cutters. A test setup is proposed and manufactured to investigate the capstan drive systems. Finally, characteristics of Optical Mouse Sensors are investigated from different point of views and a test setup is proposed and manufactured to evaluate their performances in long terms. Beside all of these parts, motion control algorithms and motion control integrated circuits are designed and manufactured to realize experimental studies in a detailed manner.
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Schacht, Teresa [Verfasser]. „Neuronal calcium-binding protein 2 (NECAB2): Charakterisierung eines striatalen Ca 2+ -bindenden Proteins / Teresa Schacht“. Mainz : Universitätsbibliothek Mainz, 2017. http://d-nb.info/1141937689/34.
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Alt, Johanna_Clarissa [Verfasser]. „Spinocerebelläre Ataxie Typ 2 : Untersuchung des zellulären Wirkmechanismus des krankheitsassoziierten Proteins Ataxin-2 / Johanna_Clarissa Alt“. Hamburg : Staats- und Universitätsbibliothek Hamburg, 2011. http://d-nb.info/1010758128/34.
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Li, Xiaoman. „Study on memapsin 2 cleavage properties and its interacting proteins“. Oklahoma City : [s.n.], 2010.
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21
Papadopoulos, Maria. „The prion protein interacts with Bcl-2 and Bax proteins“. Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0026/MQ50849.pdf.
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22
Valks, Donna Mary. „Regulation of Bcl-2 family proteins in cardiac myocyte apoptosis“. Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405884.
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Fricker, M. „Bcl-2 family proteins and cell death in cortical neurons“. Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599226.
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This thesis explores the function and regulation of a subset of Bcl-2 proteins, the pro-apoptotic BH3-only proteins (BOPs), in cortical neuron apoptosis. Sodium arsenite (NA) is used as a model toxin in murine cortical murine cultures. Three BOPs were upregulated, Puma, Noxa and Bim. Primary cortical neuron cultures derived from mice lacking Puma, Noxa or Bim expressions were used to demonstrate that Puma, but not Bim or Noxa, was required for execution of NA-induced apoptosis. Adenovirus-mediated expression of exogenous Puma in cortical neurons was sufficient to induce cytochrome c release form mitochondria and apoptosis in a Bax-dependent manner, implicating Puma as an important upstream activator of Bax in cortical neurons. Furthermore, Puma knockout afforded cortical neurons substantial protection against many apoptotic insults, establishing Puma as an important apoptotic mediator of a variety of disease-relevant apoptotic signalling pathways. Whilst some insults induced Puma expression and apoptosis in a p53-dependent manner, others, including NA and ER stress, were predominantly p53-independent. NA treatment resulted in an accumulation of TA-p73α and a p53-independent increase in a number of p53/p63/p73 target genes, indicating that p73 may be involved in Puma induction. Expression of the inhibitory ΔNp73α and –β isoforms largely prevented NA-mediated induction of Puma and other p53/p63/p73 target genes, as well as protecting neurons from NA-induced apoptosis. In addition, luciferase assays using Puma promoter fragments demonstrated that the promoter region encompassing the p53 response elements was required for arsenite-mediated activation of the Puma motor. Finally, a novel post-translational modification of Puma was investigated using cell lines. Puma-α is phosphorylated at several sites in cycling cells, the major site being serine 10. Initial experiments have failed to identify a functional consequence of Puma phosphorylation, although the identification if casein-kinase I as a candidate Puma kinase merits further investigation.
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Edwards, H. C. „Ca'2'+-sensitive proteins of the human placental microvillar cytoskeleton“. Thesis, University of Leeds, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304146.
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Korbmacher, François. „Towards functional assignment of Plasmodium membrane transport proteins: an experimental genetics study on four diverse proteins“. Doctoral thesis, Humboldt-Universität zu Berlin, 2021. http://dx.doi.org/10.18452/23029.
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Etliche Membran Transport Proteine (MTP) sind essentiell in den Plasmodium Blutstadien, und geraten zunehmend in den Fokus der Wirkstoffentwicklung. Die physiologischen Rollen der Transporter sind jedoch oft ungeklärt. In dieser Arbeit wurden mittels experimenteller Genetik funktionelle Charakteristika der MTPs untersucht. Am Maus Parasiten Plasmodium berghei und der Plasmodium falciparum Blutstadien-Kultur wurden vier MTPs ausgewählt: ein konservierter Folat Transporter (FT2), sowie eine P. falciparum-spezifisches P-Typ ATPase und zwei essentielle MTPs (CRT und ATP4). Diese Auswahl verkörpert ein breites Spektrum an MTP Kandidaten und reflektieren zudem das Potenzial und die Grenzen funktioneller Analysen von Plasmodium MTPs mittels reverser Genetik. Für den Folat Transporter 2 (FT2) wurde eine Kombination von transgenen Strategien auf P. berghei angewandt. Durch ein endogenes tag von FT2 wurde die Lokalisierung im Apicoplast, sowie dessen Expression über fast den kompletten Zyklus hinweg gezeigt. Nach der Deletion von FT2, wiesen die Parasiten einen Defekt während der Sporulation auf. Demzufolge bilden sich nur nicht infektiöse Sporozoiten, was letztendlich zur Unterbrechung des Lebenszyklus der Parasiten führt. Eine Aminophospholipid P-Typ ATPase, wurde mittels CRISPR/Cas9 in P. falciparum genetisch deletiert und die Mutante analysiert. Im Gegensatz zu den meisten vitalen P-Typ ATPasen erweist sich das Gen in den asexuellen Blutstadien als entbehrlich. Des Weiteren bilden die MTPs ATP4 und CRT einen einflussreichen Faktor bei Malaria-Therapien. Eine umfassende Analyse von räumlichen und zeitlichen Expressionsmustern von transgenen Parasiten mit mCherry-getaggten Proteinen zeigt ein Expression der beiden MTPs über die Blutstadien hinaus, was auf zusätzliche Funktionen in den jeweiligen Stadien verweist. Diese Studie trägt, basierend auf Lokalisation, Expression und funktioneller Deletion, zur funktionellen Entschlüsselung der vier untersuchten MTPs bei.Many membrane transport proteins (MTP) are essential for Plasmodium infection and gain importance as candidate drug targets in malaria therapy, whereas the physiological functions often remain enigmatic. In this thesis, we applied experimental genetics to determine key characteristics of four Plasmodium MTPs. We employed the murine malaria model parasite Plasmodium berghei and in vitro blood cultures of Plasmodium falciparum. We selected one conserved MTP called FT2, which was previously shown to transport folate, a P-type ATPase that is specific for P. falciparum as well as two essential MTPs, CRT and ATP4. These targets exemplify the range of druggable candidates and illustrate the potential and limitations of reverse genetics to decipher their physiological roles. A combination of transgenic and knockout strategies was applied to the P. berghei folate transporter 2 (FT2). We show that endogenously tagged FT2 localises to the apicoplast membranes, and is broadly expressed throughout the parasite’s life cycle. Analysis of FT2-deficient parasites revealed a severe sporulation defect in the vector; the vast majority of ft2– oocysts form large intracellular vesicles which displace the cytoplasm. Very few sporozoites are generated and these are non-infectious to the mammalian host, resulting in a complete arrest of Plasmodium transmission. A candidate aminophospholipid P-type ATPase, was assessed by a CRISPR/Cas9-mediated gene disruption. Compared to many vital P-type ATPases this gene is dispensable for asexual blood replication. Two MTPs, ATP4 and CRT are prime targets for antimalarial therapies. A comprehensive spatio-temporal expression analysis of transgenic parasites expressing mCherry-tagged proteins revealed expression beyond blood infection, indicative of functions in additional parasite stages. The findings of this study contribute towards a better understanding of the roles of the four MTPs based on localisation, expression and functional deletion.
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Yang, Chih-Chin. „Identification and characterization of proteins that interact with myocyte enhancer factor 2, E12, and smooth muscle LIM proteins“. Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0023/NQ49928.pdf.
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Dekki, Wenna Nancy. „Serum proteins in type 1 diabetes /“. Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-057-2/.
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Asmar, Jasmin. „Struktur-Funktionsanalyse des Immediate-early-Proteins-2 (IE2) des humanen Zytomegalievirus“. [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=974146021.
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Ahmed, Najma Nusarat. „Proteins which interact with and regulate the chloride channel, ClC-2“. Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ58848.pdf.
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Johns, Emma Clare. „Modified myofibrillar proteins : effects on cardiac relaxation following diazo-2 photolysis“. Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388957.
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Ewings, Katherine Elizabeth. „Regulation of Bcl-2 family proteins by cell survival signalling pathways“. Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614144.
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McCutcheon, Sandra. „Isolation of microtubule-associated proteins from the tobacco BY-2 cytoskeleton“. Thesis, University of East Anglia, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327432.
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Armstrong, G. D. „Active site chemistry of hemerythrin and other Osub(2)-binding proteins“. Thesis, University of Newcastle Upon Tyne, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373075.
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Idowu, Seraphina Maria. „Characterisation of two retinal proteins peripherin/RDS and retinaldehyde dehydrogenase 2“. Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392125.
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Scott, Mark Andrew Ph D. Massachusetts Institute of Technology. „Ultra-rapid 2-D and 3-D laser microprinting of proteins“. Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/79248.
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Thesis (Ph. D. in Electrical and Medical Engineering)--Harvard-MIT Program in Health Sciences and Technology, 2013.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 124-135).
When viewed under the microscope, biological tissues reveal an exquisite microarchitecture. These complex patterns arise during development, as cells interact with a multitude of chemical and mechanical cues in the surrounding extracellular matrix. Tissue engineers have sought for decades to repair or replace damaged tissue, often relying on porous scaffolds as an artificial extracellular matrix to support cell development. However, these grafts are unable to recapitulate the complexity of the in vivo environment, limiting our ability to regenerate functional tissue. Biomedical engineers have developed several methods for printing two- and three-dimensional patterns of proteins for studying and directing cell development. Of these methods, laser microprinting of proteins has shown the most promise for printing sub-cellular resolution gradients of cues, but the photochemistry remains too slow to enable large-scale applications for screening and therapeutics In this work, we demonstrate a novel high-speed photochemistry based on multi-photon photobleaching of fluorescein, and we build the fastest 2-D and 3-D laser microprinter for proteins to date. First, we show that multiphoton photobleaching of a deoxygenated solution of biotin-4-fluorescein onto a PEG monolayer with acrylate end-group can enable print speeds of almost 20 million pixels per second at 600 nanometer resolution. We discovered that the mechanism of fluorescein photobleaching evolves from a 2-photon to 3- and 4-photon regime at higher laser intensities, unlocking faster printing kinetics. Using this 2-D printing system, we develop a novel triangle-ratchet method for directing the polarization of single hippocampal neurons. This ability to determine which neurite becomes an axon, and which neuritis become dendrites is an essential step for developing defined in vitro neural networks. Next, we modify our multiphoton photobleaching system to print in three dimensions. For the first time, we demonstrate 3-D printing of full length proteins in collagen, fibrin and gelatin methacrylate scaffolds, as well as printing in agarose and agarose methacrylate scaffolds. We also present a novel method for 3-D printing collagen scaffolds at unprecedented speeds, up to 14 layers per second, generating complex shapes in seconds with sub-micron resolution. Finally, we demonstrate that 3-D printing of scaffold architecture and protein cues inside the scaffold can be combined, for the first time enabling structures with complex sub-micron architectures and chemical cues for directing development. We believe that the ultra-rapid printing technology presented in this thesis will be a key enabler in the development of complex, artificially engineered tissues and organs.
by Mark Andrew Scott.
Ph.D.in Electrical and Medical Engineering
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Popgeorgiev, Nikolay. „Involvements of Bcl-2 family of proteins during early zebrafish development“. Thesis, Lyon 1, 2011. http://www.theses.fr/2011LYO10172.
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Asmar, Jasmin. „Struktur-Funktionsanalyse des Immediate-Early Proteins 2 (IE2) des humanen Zytomegalievirus“. Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2005. http://dx.doi.org/10.18452/15197.
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Das Immediate-Early Protein 2 (IE2) des humanen Zytomegalievirus ist ein essentieller Regulationsfaktor des lytischen Infektionszyklus. Es aktiviert verschiedene early Promotoren, autoreprimiert seine eigene Expression und besitzt darüber hinaus auch zellzyklusregulatorische Aktivitäten. Um einzelne Funktionen des IE2 Proteins gezielt analysieren zu können, ist eine genaue Kenntnis seiner regulatorischen Domänen unabdingbar. Im Rahmen dieser Arbeit wurde daher eine Struktur-Funktionsanalyse des IE2 Proteins durchgeführt mit dem Ziel, seine funktionellen Domänen genauer zu charakterisieren. Hierfür wurden verschiedene IE2-Mutanten hergestellt und ihre Aktivität im Hinblick auf Transaktivierung, Autorepression und DNA-Bindung sowie Zellzylusarrestinduktion bestimmt. Die Untersuchungen ergaben, dass innerhalb einer Core-Region im C-Terminus des Proteins (AS 450-544) die regulatorischen Domänen der untersuchten Funktionen überlappen und hier schon kleinere Mutationen zu einem Funktionsverlust führen. Im Gegensatz dazu ist der Bereich N-terminal des Core deutlich weniger sensitiv gegenüber Mutationen. Hier konnten Sequenzen identifiziert werden, die spezifisch für einzelne Funktionen wie die Transaktivierung oder die Zellzyklusarrestinduktion erforderlich sind. Darüber hinaus hat sich gezeigt, dass eine im bisherigen Verständnis essentielle putative Zinkfingerdomäne außerhalb des Core liegt und für die Funktionalität des Proteins, vor allem für seine DNA-Bindung, nicht benötigt wird. Somit ist der Bereich, in dem die regulatorischen Domänen der untersuchten Funktionen überlappen, deutlich kleiner, als bisher angenommen. Vor diesem Hintergrund lässt sich eine Strategie für die Erstellung von diskriminierenden Virusmutanten ableiten, bei der Einzelfunktionen von IE2 im Viruskontext eliminiert und somit im Sinne ihrer physiologischen Relevanz analysierbar werden.The Immediate Early Protein 2 (IE2) of human cytomegalovirus is an essential regulatory factor of the viral replicative cycle. It fulfills several functions including transactivation, negative autoregulation and cell cycle regulation. In order to analyse the physiological significance of each of the IE2 functions a precise knowledge of the regulatory protein domains is needed. Therefore, a structure-function analysis of the IE2 protein was performed in this work. Different sets of IE2 mutants were tested in parallel with regard to transactivation, DNA-binding, autoregulation and cell cycle regulation. We found the IE2 protein to contain an unexpectedly clear-cut core domain (amino acids (aa) 450-544) that is defined by its absolute sensitivity to any kind of mutation. In contrast, the region adjacent to the core (aa 290-449) generally displays greater tolerance towards mutations. Although specific sequences correlate with distinct IE2 activities none of the mutations analysed completely abolished any particular function. The core is separated from the adjacent region by the putative zinc finger (428-452) which was found to be entirely dispensable for any function tested. Our work supports the view that the 100 amino acids of the core domain hold the key to most functions of IE2. A systematic, high-density mutational analysis of this region may identify informative mutants which discriminate between various IE2 functions. Such mutants could then be tested in a viral background.
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Funabashi, Teruki. „Roles of kinesin-2 motor proteins involved in intraciliary protein trafficking“. Kyoto University, 2018. http://hdl.handle.net/2433/232321.
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Koumanov, Assen. „Theoretical prediction of ionisation properties of proteins /“. Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-535-2.
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Jeannot, Frédéric. „Synthèse et étude d'analogues nucléosidiques incorporant le groupement trifluorométhyle en position 2' et 3'“. Montpellier 2, 2002. http://www.theses.fr/2002MON20117.
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Cha, Jae H. „Application of the photodiode in design and implementation of a 2-D position detector“. Master's thesis, This resource online, 1994. http://scholar.lib.vt.edu/theses/available/etd-03172010-020148/.
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elMasry, Nadia Farida. „Folding studies on mutants of Chymotrypsin Inhibitor 2“. Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309338.
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Daniell, Sarah Jane. „Site-directed mutagenesis of the rat Dâ†2(Long) dopamine receptor“. Thesis, University of Kent, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241618.
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Bucurgat, Mahmut. „Study Of One Dimensional Position Dependent Effective Mass Problem In Some Quantum Mechanical Systems“. Phd thesis, METU, 2008. http://etd.lib.metu.edu.tr/upload/2/12609405/index.pdf.
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The one dimensional position dependent effective mass problem is studied by solving the Schrödinger equation for some well known potentials, such as the deformed Hulthen, the Mie, the Kratzer, the pseudoharmonic, and the Morse potentials. Nikiforov-Uvarov method is used in the calculations to get energy eigenvalues and the corresponding wave functions exactly. By introducing a free parameter in the transformation of the wave function, the position dependent effective mass problem is reduced to the solution of the Schrö
dinger equation for the constant mass case. At the same time, the deformed Hulthen potential is solved for the position dependent effective mass case by applying the method directly. The Morse potential is also solved for a mass distribution function, such that the solution can be reduced to the constant mass case.
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Cagatay, Kartal. „Modeling, Identification And Real Time Position Control Of A Two-axis Gimballed Mirror System“. Master's thesis, METU, 2010. http://etd.lib.metu.edu.tr/upload/2/12611668/index.pdf.
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This work focuses on modeling, parameter estimation, and real-time position control of a two axis Gimbaled Mirror System (GMS) which is designed and manufactured to move an IR spot generated by an Infra Red Scene Generator System (IRSGS) in two orthogonal axes (elevation and azimuth) within the IR scene which is also generated by the IRSGS.
Mathematical models of the GMS, the control system, and the disturbance torque originated from the movements of Flight Motion Simulator (FMS), on which the IRSGS will be mounted, are constructed using MATLAB®/Simulink®
and MATLAB/Simulink/SimMechanics®
. Parameter estimations of the GMS and control system elements are achieved using MATLAB/Simulink Parameter Estimation Tool®
. The controller tuning is performed using the developed mathematical models in MATLAB/Simulink environment. Optimized digital PID controllers are implemented in the real-time control system. Performances of the controllers for both GMS axes are evaluated by both real system tests and simulation runs
and the results of these runs are compared. Controller performances under the effect of disturbances are analyzed by using the mathematical models developed in the MATLAB/ Simulink environment.
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Dampanaboina, Lavanya. „FUNCTIONAL CHARACTERIZATION OF WD REPEAT PROTEINS, AtCstF50 AND AtFY IN CLEAVAGE AND POLYADENYLATION“. UKnowledge, 2011. http://uknowledge.uky.edu/pss_etds/2.
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Polyadenylation is an essential post-transcriptional modification resulting in a mature mRNA in eukaryotes. Three cis-elements the Far Upstream Element (FUE), Near Upstream Element (NUE), and Cleavage Site (CS) - guide the process of cleavage and polyadenylation with the help of multi-subunit protein complexes cleavage and polyadenylation specificity factor (CPSF), cleavage stimulation factor (CstF) along with cleavage factors and poly(A) polymerase. Protein-protein interactions play an important role in the cleavage and polyadenylation process. WD repeat proteins play an important role in protein-protein interactions and have diverse functions in plant system. In the present study WD repeat proteins AtCstF50 and AtFY were studied for their role in polyadenylation process.
Mammalian CstF50 is a WD repeat protein that is one of the subunit of CstF that aids in the cleavage step by associating with CPSF and cleavage factors. AtCstF50 was functionally characterized using T-DNA knock-out lines and by identifying the proteins that interacts with it in the process. Results shows that AtCstF50 is essential and was identified as part of CPSF complex, which is different from its mammalian counter part. CPSF was known to interact with Fip (factor interacting with PAP), Poly(A) polymerase and Poly(A) binding protein and AtCstF50 also interacts with these complexes.
AtFY is a 3’ end processing factor which contains WD repeats is one of the subunits of the CPSF complex in Arabidopsis polyadenylation machinery. The AtFY interacts with FCA and promotes the alternative polyadenylation and also plays a role in polyadenylation site choice of FCA mRNA. We characterized the FY expression and localization of FY in the cell by fusing with RFP reporter. Results show that FY accumulates in the nucleus while FY with deleted calmodulin binding domain localizes both to the nucleus and outside the nucleus. The individual N-terminal and C-terminal domains also localized in the nucleus suggesting that they are multiple nuclear localization signals in FY and calmodulin might play a direct or indirect role in FY localization. Using a tethering assay we proved that AtFY is able to recruit the 3’ end processing complex in the proximal polyadenylation site choice of the reporter mRNA.
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Dzikaitė, Vijolė. „Studies of proteins in heme and iron metabolism /“. Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-762-2/.
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Cartlidge, Rachael Charlotte. „The Epstein-Barr virus BCL-2 homologues : interactions with cellular BCL-2 proteins and their role in apoptosis“. Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/5898/.
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Epstein-Barr virus (EBV) encodes two viral BCL-2 homologues, BHRF1 and BALF1. BHRF1 is expressed in a subset of EBV-positive Burkitt’s lymphoma (BL) tumours; as BHRF1 is highly anti-apoptotic, expression could result in treatment-resistant BL. Little is known about BALF1, including whether BALF1 is pro- or anti-apoptotic. Interactions between BHRF1 and cellular BCL-2 homologues have not been fully characterised, but previous studies have focused on BIM as a key binding partner. We stably expressed wild-type or mutant vBCL-2s in EBV-negative BL lines to investigate interactions between BHRF1 and cellular BCL-2 homologues. The ability to bind BIM, whilst well documented, had no impact on BHRF1-mediated protection. Our data suggests that BHRF1’s protective ability may be mediated through binding to BID and BAK. This work also identified two amino acids, located in the binding groove of BHRF1, which are highly important for protein function. We detected BALF1 expression, at potentially functionally relevant levels, in a wide variety of EBV-associated tumour lines. BALF1 mRNA was detectable in lines with highly varied patterns of viral gene expression, indicating that expression is not restricted to one part of the viral life-cycle. In BL, BALF1 was found to be anti-apoptotic, and co-operated with, rather than antagonized, BHRF1.
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Behzad, Hayedeh. „Diverse roles of the Bcl-2 family proteins in hemopoietic cell regulation“. Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/30719.
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In this thesis, the roles of Bcl-2 family proteins in hemopoietic cell regulation were
investigated. We first examined the effects of phosphatidylinositol 3-kinase (PI3K) dependent
survival signalling pathways in cytokine dependent hemopoietic cells. Following cytokine
withdrawal or PI3K inhibition, there was a loss of FOXO3A phosphorylation, resulting in
increased expression of FasL and Fas at the cell surface. However, the Fas mediated signalling
did not appear to be involved in apoptosis of cytokine dependent hemopoietic cells. These
results support the belief that mitochondrial mediated signals through regulation of Bcl-2 family
proteins may play the major role in hemopoietic cell apoptosis.
Amongst the pro-survival Bcl-2 family members, Bcl-2 and Bcl-xL are assumed to have
a redundant function. To explore the differential ability of Bcl-2 and Bcl-xL in protecting cells
against apoptosis, we over-expressed these proteins in cytokine dependent hemopoietic cell line
FDCP-1. Based on our results, Bcl-2 appears to be a more potent pro-survival protein than Bcl-xL
against apoptosis induced by cytokine withdrawal.
In addition to their localization at the mitochondria, Bcl-2 family members also localize
at ER. To examine the physiological relevance of the membrane targeting of Bcl-xL, we used
Rat-1 fibroblast cell lines over-expressing Bcl-xL mutants that were targeted to ER,
mitochondrial outer membrane, or wild type Bcl-xL and showed that the ER targeted Bcl-xL
was as effective or even more effective than the mitochondrial targeted or wild type Bcl-xL
against certain cytotoxic stimuli.
A number of studies have shown involvement of Bcl-2 family proteins in processes other
than apoptosis. We explored a role of Mcl-1 in cell cycle regulation, DNA damage checkpoint
response, and cellular differentiation and found an interaction between Mcl-1 and the cell cycle regulatory protein Cdk-1 in nuclear compartment. In addition, Mcl-1 was found to associate
with the DNA damage checkpoint regulator, Chk-1, and the hallmark of DNA damage
checkpoint response, phospho-histone H2AX. Mcl-1 level also increased in HL-60 cells upon
induction of cellular differentiation by PMA. However, over-expression of Mcl-1 in these cells
did not appear to enhance cellular differentiation. We, therefore, concluded that Mcl-1 might not
play a prominent role in cellular differentiation.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
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Snaith, Michael. „Applications and expression of proteins encoded by the yeast 2#mu# plasmid“. Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337410.
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