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1
Chaňo, Patrik. "Hobby CNC frézka." Master's thesis, Vysoké učení technické v Brně. Fakulta strojního inženýrství, 2020. http://www.nusl.cz/ntk/nusl-416606.
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This diploma thesis serves as a design and implementation of a hobby CNC milling machine, for the modeling community. The work is conceived as an overview of the most common machining technologies. The following is an introduction to the construction of CNC milling machines and an introduction to the basic components used. Furthermore, the actual design proposals and a description of the implementation of two of them are presented. When designing the machine, emphasis was placed on the lowest possible price and availability of individual components.
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Shimabukuro, Satoshi, Piero Diaz, and Leonardo Vinces. "Low cost semi-industrial 3GDL CNC vertical milling center design with non-ferrous metal machining capability." Institute of Electrical and Electronics Engineers Inc, 2020. http://hdl.handle.net/10757/656633.
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El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado.This work proposes the design of a low cost semi-industrial three degree of freedom CNC vertical milling center (VMC) with non-ferrous metal machining capabilities. The design seeks to mitigate the difficulties that acquiring a commercial industrial CNC can present, such as large dimensions, high cost and complications in its transportation within the plant. The proposed machine will be made up of 1 NEMA 23 stepper motor for each X, Y and Z axis, and will be controlled by open source firmware using an ATMEGA 2560 microcontroller. Likewise, the working area will be 320x180mm and will have a precision 100 microns with semi industrial capacities. This design is aimed at small and medium-sized companies that are looking for a low cost non-ferrous CNC milling machine that in turn has the quality, performance and precision of an industrial one.
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Stuchlý, Martin. "Návrh a realizace vrtačky na plošné spoje." Master's thesis, Vysoké učení technické v Brně. Fakulta strojního inženýrství, 2021. http://www.nusl.cz/ntk/nusl-449717.
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This thesis is focused on proposing a design and providing the realisation of a CNC drill used for printed circuits. The first section is concerned with researching the background of CNC drills, which is followed by the proposed design and realisation of a custom model. Fundamental calculations and individual constructional aspects were carried out based on the chosen parameters. Furthermore, the operating electronic functions and the description of a G-code generating program is the main content of the second section. Finally, the last part of this thesis includes economic evaluation and the CNC drill’s assessment in practice.
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Pospíšil, Jiří. "Hobby CNC frézka." Master's thesis, Vysoké učení technické v Brně. Fakulta strojního inženýrství, 2015. http://www.nusl.cz/ntk/nusl-232104.
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This diploma thesis serves as experimental proof of real world capabilities of computer designed hobby CNC milling machine with its parts printed on a 3D printer. First half is a brief introduction of CNC technologies to non-professional audience. Second part together with 3D model works as manual to build your own machine. Priority was to keep costs to minimum with decent accuracy still in mind.
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Blahút, Jozef. "Automatická expoziční jednotka pro výrobu DPS." Master's thesis, Vysoké učení technické v Brně. Fakulta strojního inženýrství, 2017. http://www.nusl.cz/ntk/nusl-318637.
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This diploma thesis deals with the issue of fast high-quality prototype production of printed circuit boards for the needs of the mechatronics lab. Within the scope of this thesis a prototype machine was proposed and created together with control software, which by the help of DLP projector and two stage axis allows to produce printed circuit board in relatively short period of time.
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Sears, Huei M. "Investigation of the Mass-Metallicity Relation of GRB Host Galaxies at z ~ 4.7." Ohio University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1597762492071921.
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McDonald, Caleb Benton. "Physicochemical Studies of the Grb2-Sos1 Interaction." Scholarly Repository, 2009. http://scholarlyrepository.miami.edu/oa_dissertations/260.
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Grb2, a modular protein comprised of a central SH2 domain flanked between a N-terminal SH3 (nSH3) domain and a C-terminal SH3 (cSH3) domain, is a component of cell signaling networks involved in the transmission of extracellular information in the form of growth factors and cytokines to downstream targets such as transcription factors within the nucleus. The Grb2-Sos1 interaction is mediated through the combinatorial binding of nSH3 and cSH3 domains of Grb2 to various sites - designated S1, S2, S3, and S4 - containing PXpsiPXR motifs within Sos1. Here, using a diverse array of biophysical techniques, including in particular isothermal titration calorimetry coupled with molecular modeling and semi-empirical analysis, I provide new insights into the Grb2-Sos1 interaction in thermodynamic and structural terms. My data show that Grb2 exists in monomer-dimer equilibrium in solution and that the dissociation of dimer into monomers is entropically-driven. The heat capacity change observed was much smaller than that expected from the rather large molecular surfaces becoming solvent-occluded upon dimerization, implying that monomers undergo conformational rearrangement upon dimerization. 3D structural models suggest strongly that such conformational rearrangement may arise from domain swapping. I further show that the nSH3 domain of Grb2 binds to the S1 site containing the proline-rich consensus motif PXpsiPXR with an affinity that is nearly three-fold greater than that observed for the binding of the cSH3 domain. It is also demonstrated that such differential binding of the nSH3 domain relative to the cSH3 domain is largely due to the requirement of a specific acidic residue, in the RT loop, to engage in the formation of a salt bridge with the arginine residue in the consensus motif PXpsiPXR. The data further reveal that, while binding of both SH3 domains to Sos1 is under enthalpic control, the nSH3 binding suffers from entropic penalty in contrast to entropic gain accompanying the binding of cSH3, implying that the two domains employ differential thermodynamic mechanisms for Sos1 recognition. Additionally, my data reveal that while the nSH3 domain of Grb2 binds with affinities in the physiological range to all four sites S1-S4, the cSH3 domain can only do so at the S1 site. Further scrutiny of these sites yields rationale for the recognition of various PXpsiPXR motifs by the SH3 domains in a discriminate manner. Unlike the PXpsiPXR motifs at S2, S3 and S4 sites, the PXpsiPXR motif at S1 site is flanked at its C-terminus with two additional arginine residues that are absolutely required for high-affinity binding of the cSH3 domain. In contrast, these two additional arginine residues augment the binding of the nSH3 domain to the S1 site but their role is not critical for the recognition of S2, S3 and S4 sites. Molecular modeling is employed to rationalize my new findings in structural terms. Taken together, this thesis provides novel insights into the physicochemical basis of a key protein-protein interaction pertinent to cellular signaling and cancer. My studies bear the potential for the development of novel therapies with less toxicity but more effectiveness for the treatment of disease.
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Albrecht, Sebastian. "Multivariate GRBF-Netzwerke und Systeme lokaler Experten." Diss., lmu, 2000. http://nbn-resolving.de/urn:nbn:de:bvb:19-1248.
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Su, Vi-Minh-Tri. "The role of Grb2 in HER2-mediates tumourigenesis." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110360.
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Grb2, an adaptor protein, is ubiquitously expressed and is involved in mediating a multitude of cellular processes in various body tissues such as development and tumourigenesis. Grb2 binds to proteins via its Src-homology domains and by doing so brings them in proximity of each other. In breast tissue, Grb2 can recruit SOS and Gab1 to the plasma membrane by binding to a specific phosphorylated tyrosine residue of HER2, a member of the epidermal growth factor receptor family. HER2 is overexpressed and activated in 20-30% of human breast cancers and correlates with poor patient prognosis. In transgenic mouse models, activated Neu, a rat analog of HER2, has shown the ability to induce mammary tumours. Given that Grb2 is a link between HER2 and tumourigenic signaling pathways, the goal of the current study was to investigate how loss of Grb2 expression affects mammary gland development and mammary tumourigenesis using a conditional Grb2 mouse model. Differences in protein expression, ductal outgrowth, delay in tumour onset, metastasis to the lung were some of the measurements taken to evaluate the role of Grb2. Also, parallel in-vivo experiments were conducted by using shRNA construct targeted to Grb2 in mammary gland tumour-derived cell lines. As expected, it was uncovered that Grb2 is required for normal mammary gland development and mammary tumour initiation in a HER2-induced mammary tumour mouse model but its mechanism of action has yet to be elucidated.Growth factor receptor bound protein 2(Grb2) est une protéine adaptatrice, exprimée demanière ubiquitaire, qui joue un rôle important dans une multitude de processus cellulaires tels que le développement mammaire et la genèse de tumeurs mammaires. Grb2 regroupe diverses protéines grâce à ses domaines d'homologie Src afin de permettre leur interaction. Dans les tissues mammaires, Grb2 peut recruter SOS et Gab1 à la membrane plasmique en se liant à une tyrosine spécifique, phosphorylée et localisée sur HER2, un membre de la famille des récepteurs du facteur de croissance épidermique. HER2 est sur exprimé et activé dans 20-30% des cancers du sein et est lié à un mauvais pronostic chez le patient. Plusieurs études effectuées à partir de modèles de souris transgéniques, ont démontrées la capacité d'ErbB2, l'analogue d'HER2 chez la souris, à induire des tumeurs mammaires. L'objectif de ma recherche est d'étudier les conséquences de l'ablation fonctionnelle et spécifique de Grb2. Un modèle de souris avec un knock-out spécifique de Grb2 au niveau des glandes mammaires permet d'étudier le rôle distinctif de la protéine dans le cadre de la genèse des tumeurs mammaires. Les différences au niveau de l'expression protéique de Grb2, la longueur des canaux lactifères, le délai au niveau de l'apparition de tumeurs et les métastases aux poumons détectés chez l'animal représentent quelques-uns des paramètres évalués afin de déterminer l'importance de Grb2 dans le développement des tumeurs mammaires. Parallèlement, des expériences in vitro tel l'utilisation de constructions shRNA ciblant l'ARN messager de Grb2 introduits dans une lignée cellulaire dérivée d'une tumeur de la glande mammaire, permettent d'élaborer sur le rôle de la protéine d'intérêt dans le développement des tumeurs mammaires.
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Laskar, Tanmoy, Kate D. Alexander, Edo Berger, Wen-fai Fong, Raffaella Margutti, Isaac Shivvers, Peter K. G. Williams, et al. "A REVERSE SHOCK IN GRB 160509A." IOP PUBLISHING LTD, 2016. http://hdl.handle.net/10150/624020.
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We present the second multi-frequency radio detection of a reverse shock in a gamma-ray burst. By combining our extensive radio observations of the Fermi-Large Area Telescope gamma-ray burst 160509A at z - 1.17 up to 20 days after the burst with Swift X-ray observations and ground-based optical and near-infrared data, we show that the afterglow emission comprises distinct reverse shock and forward shock contributions: the reverse shock emission dominates in the radio band at. less than or similar to 10 days, while the forward shock emission dominates in the X-ray, optical, and near-infrared bands. Through multi-wavelength modeling, we determine a circumburst density of n(0) approximate to 10(-3) cm(-3), supporting our previous suggestion that a low- density circumburst environment is conducive to the production of long-lasting reverse shock radiation in the radio band. We infer the presence of a large excess X-ray absorption column, N-H approximate to 1.5. x 10(22) cm(-2), and a high rest-frame optical extinction, A(V) approximate to 3.4 mag. We identify a jet break in the X-ray light curve at t(jet) approximate to 6 days, and thus derive a jet opening angle of theta(jet) approximate to 4 degrees, yielding a beaming-corrected kinetic energy and radiated gamma-ray energy of E-K approximate to 4 x 10(50) erg and E-gamma approximate to 1.3 x 10(51) erg ( 1-10(4) keV, rest frame), respectively. Consistency arguments connecting the forward shocks and reverse shocks suggest a deceleration time of t(dec) approximate to 460 s approximate to T-90, a Lorentz factor of Gamma( t(dec)) approximate to 330, and a reverse-shock-to-forward-shock fractional magnetic energy density ratio of R-B equivalent to is an element of(B, RS)/is an element of(B, FS) approximate to 8. Our study highlights the power of rapid-response radio observations in the study of the properties and dynamics of gamma-ray burst ejecta.
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Valette, Jean-René. "La pensée du Graal : fiction littéraire et théologie : (XIIe - XIIIe siècle) /." Paris : Champion, 2008. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=016386743&line_number=0002&func_code=DB_RECORDS&service_type=MEDIA.
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Baccega, Marcus Vinicius de Abreu. "Logos do Sacramento, Retórica do Santo Gral. A sacramentalidade medieval do mundo e do homem na Demanda do Santo Gral de Heidelberg (século XIII)." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/8/8138/tde-13072012-162719/.
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O recorte temático desta tese são a Vita Apostolica e o Mistério Sacramental como sentido existencial e missão cristã para os homens do Ocidente Europeu na Idade Média Central (séculos XI-XIII) O documento a ser investigado é a versão alemã de Heidelberg do roman arturiano A Demanda do Santo Graal, cujo manuscrito germânico original foi compilado ao final do século XIII. O corpus corresponde ao códice 147 da Bibliotheca Palatina Germaniae de Heidelberg, não se tratando de mera versão dos originais bretões para o alemão medieval (Mittelhochdeutsch). A presente fonte constitui um corpus inaugural, um texto propriamente alemão, ainda que filiado ao Ciclo da Vulgata (Ciclo do Pseudo-Gautier Map), que correspondeu ao primeiro ciclo de prosificação das narrativas do Graal. Pretende-se perscrutar um elemento central do imaginário que caracterizou a experiência dos homens do Ocidente Europeu no apogeu da Idade Média Central. Tratase do sacramento, e a compreensão do sentido sacramental da existência humana no plano da imanência constitui relevante senha de compreensão e predicação de significado às experiências concretas destes homens. Isso se pode atingir por intermédio da apreensão do elemento axial de seu imaginário.The thematic cutting of this dissertation are the Vita Apostolica and the sacramental mystery as life meaning and Christian mission for the people of the European Western World during the Central Middle Ages (11th to 13th centuries). The document to be analysed is the German version of the Arthurian romance The Quest of the Holy Grail, whose original German manuscript was compiled by the end of 13th century. The corpus corresponds to the codex 147 pertaining to the Bibliotheca Palatina Germaniae in Heidelberg, and this is no sheer translation of the original Bretonnic version to Middle German (Mittelhochdeutsch). The present source constitutes an original corpus, a properly German text, although linked up to the Vulgate Cycle (Pseudo-Gautier Map Cycle), which corresponds to the first prosification cycle entailing the Grail narratives. This study aims at scruting a central element of the imaginary concerning the historical experience of people of Western European World at the peak the Central Middle Ages. It is the sacrament, and the comprehension of the sacramental meaning of human life in the sphere of immanence builds up a relevant key to understanding and endowing concrete experiences with meaning. This can be achieved by means of aprehending the shaft element concernig their imaginary.
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Lee, Kuisoon. "Characterisation of Grb7, Prel and GIGYF family genes in Zebrafish." Thesis, University of Bath, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500712.
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Growth factor receptor bound (Grb) protein 7 family and Proline-rich EVHl ligand (Prel) family proteins are adaptor proteins that share Pleckstrin homology (PH) and Ras-associating (RA) domain. Grb7 family members have been shown to play important roles in growth and signal transduction while members of the Prel family have been reported to function in cell adhesion and migration. Grb 10 interacting GYF domain (GIGYF) proteins were shown to interact with GrblO proline-rich moFif and have been implicated in familial Parkinson's Disease.
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Rowlinson, Beatrix Antonia. "Using multiwavelength observations of short GRBs to constrain their progenitors." Thesis, University of Leicester, 2012. http://hdl.handle.net/2381/10197.
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Short gamma-ray bursts (SGRBs) are extremely bright flashes of gamma-rays, lasting less than 2 s, originating from beyond the Milky Way but their progenitors remain unknown. The most popular progenitor theory involves the merger of two compact objects, either two neutron stars (NSs) or a NS and a black hole (BH), which then collapse to form a BH. A small proportion of SGRBs may instead be giant flares from extragalactic soft gamma-ray repeaters (SGRs) in nearby galaxies. The aim of this Thesis is to place constraints on the progenitors of SGRBs using multiwavelength observational data. The extragalactic SGR giant flare theory is tested by considering the properties of three candidate SGRBs which may have occurred in nearby host galaxies. It is likely that only one of the three was an extragalactic SGR giant flare and, although they are all shown to be consistent with this progenitor, GRB 070201 is most convincing candidate. Afterglow predictions are made for future candidates. Following on from the giant flare candidates, more typical SGRBs are considered. GRB 080905A is the nearest confirmed SGRB, occurring offset from a spiral galaxy at z∼0.12 which is studied using spatially resolved spectroscopy. The properties of GRB 080905A are shown to be consistent with a compact binary merger. GRB 090515 was a SGRB with an extremely unusual bright X-ray plateau and extremely steep decay phase. However, the prompt and late time properties are consistent with typical SGRBs. The plateau is explained by an unstable magnetar, formed during the SGRB, which collapses to form a BH within a few hundred seconds. The magnetar is suggested to be formed via the merger of two NSs. Many Swift SGRBs are shown to have evidence of energy injection within their X-ray lightcurves and 44–76% are consistent with forming a magnetar.
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Wang, Yajun, and 王亚君. "Functional characterization of GRB7 and its variant, GRB7v, in ovariancancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45696731.
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Lin, C. C. "The role of Grb2 in FGFR2IIIc-mediated early signalling complexes." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1310259/.
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Receptor tyrosine kinases (RTKs) regulate cellular processes by undergoing autophosphorylation on their tyrosine residues upon ligand binding. Phosphotyrosine residues also provide binding sites for adaptor protein binding. Grb2 has been shown to play a role in RTK pathways by recruiting other signalling proteins. Previously we showed the direct binding of Grb2 SH3 domain to the last 15 residues of FGFR2 C-terminal tail. In the present study, it is demonstrated that the direct binding of full-length Grb2 to FGFR2 cytoplasmic domain is a 2:1 binding event. Importantly, the direct binding may induce an apparent FGFR2 conformational change and enhance the FGFR2 phosphorylation. It is also shown that the effect of Grb2 on FGFR2 phosphorylation is mediated by the Grb2 C-SH3 domain. In addition, both N-SH3 domain and SH2 domain of Grb2 may play a role in the enhancement of the C-SH3 domain-mediated FGFR2 phosphorylation by stabilising Grb2 polypeptide structure, thus increasing the binding affinity toward FGFR2. This study also shows Grb2 phosphorylation by FGFR2 mediated by the direct binding of Grb2 to the C-terminal of FGFR2. Three phosphorylation sites on Grb2 are identified; in vitro FGFR2 phosphorylation and ERK1/2 activation studies suggest that Grb2 phosphorylation may play a role in regulating FGFR2-mediated signalling pathway. Moreover, the interactions between Grb2 and SHP2, as well as FGFR2 and SHP2 have been characterised. It is also demonstrated that the binding of Grb2 to FGFR2 can prevent SHP2 binding to FGFR2, which is important in regulating FGFR2 activation. Finally, a model for the recruitment of FGFR2-Grb2-SHP2 signalling complex is proposed, in which Grb2 and SHP2 control FGFR2 early signalling complex formation. This study provides new insights into the role of Grb2 in the FGFR2-mediated signalling pathway.
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Bartelt, Rebekah Ruth. "Characterization of GRB2 and SOS1 binding downstream of TCR activation." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/3257.
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Despite their essential role in protection, T cells can be dangerous if unregulated. Dysfunctional T cell activity has been implicated in numerous diseases, including the failure of organ transplants, allergic reactions, multiple sclerosis, and coronary artery disease. Signal transduction pathways activated by the T cell receptor (TCR) are good targets for the development of therapies. However, we must first better understand the mechanisms of intracellular signaling that occur when a T cell is activated.
This thesis focuses on the scaffold protein LAT and its role in T cell activation. The localization of signaling proteins into LAT-nucleated complexes and subsequent aggregation of these complexes into microclusters is vital for the activation of intracellular signaling pathways, and the effector functions of T cells. Following TCR stimulation, LAT is phosphorylated and binds SH2 domain containing molecules, such as the adaptor protein Grb2. One LAT molecule is capable of binding up to three Grb2 molecules at one time. Grb2 also binds to the proline rich regions of several proteins, including SOS1. Recent studies indicate that at physiological ratios of Grb2 and SOS1, two Grb2 molecules bind to one SOS1 proline rich region, and this 2:1 stoichiometry is essential for LAT oligomerization and cluster formation.
The interaction of Grb2 and SOS1 is considered to be a model SH3 domain interaction, and has biased our understanding of these relationships for decades. Many studies have focused on the association between the Grb2 SH3 domains and the proline rich region of SOS1. This previous work identified four consensus-binding sites for Grb2 in the proline rich region of SOS1 using short 10-15 amino acid peptides, and indicated that this interaction has a low affinity. Interestingly, the interaction of full SOS1 with Grb2 appears to be at least 100-fold stronger than these peptide-based studies imply. While informative, the use of short peptides leaves the physiological relevance of the peptide-SH3 domain interaction ambiguous.
In this thesis, we specifically emphasize the LAT multi-protein complex and its role in the activation of T cells. First, we compare the differences in the phosphorylation states of various LAT-proximal molecules in two T cell lines and peripheral blood T cells. We then focus on the formation of this complex by investigating the essential interaction between Grb2 and SOS1. Using biochemical and biophysical techniques, we clearly demonstrate that although the previously identified consensus binding sites are important in the context of short peptides, they do not facilitate the interaction of full length Grb2 with the full proline rich region of SOS1. We also attempt to ascertain the role of LAT microclusters in T cell signaling.
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Knapek, Katie J. "The Role of Phospholipase D (PLD) and Grb2 in Chemotaxis." Wright State University / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=wright1230574811.
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Leduc, Dimitri. "Réponse des muscles respiratoires aux vibrations mécaniques du gril costal." Doctoral thesis, Universite Libre de Bruxelles, 2003. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211322.
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Nakauchi, Daisuke. "Gamma-Ray Bursts from First Stars and Ultra-Long Gamma-Ray Bursts." 京都大学 (Kyoto University), 2015. http://hdl.handle.net/2433/199100.
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Eid, Hala A. "Probing GRB environments through x-ray absorption." Connect to this title online, 2008. http://etd.lib.clemson.edu/documents/1239896812/.
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Gonzales, Jared, and Richard Vaillancourt. "The Development of a Novel Fluorescence Polarization Drug-Screening Assay for the Interaction Between GIT1 and GRB2." The University of Arizona, 2015. http://hdl.handle.net/10150/614109.
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Class of 2015 AbstractObjectives: To develop an assay to permit the identification of compounds that can inhibit the interaction between GIT1 and the amino-terminal SH3 domain (SH3-N) of GRB2. Methods: The GIT1 protein was expressed in Sf9 insect cells and purified using Talon resin beads. The SH3-N domain of GRB2 was expressed in the E. coli strain, BL21(DE3)pLysS, and purified using glutathione resin beads. The SH3-N domain was fluorescently tagged on cysteine 32 using Cyanine 3 maleimide. The fluorescence of the assay was measured by using a plate reader with excitation wavelength of 555 nm and emission wavelength of 570 nm. Results: The GIT1 protein was expressed in Sf9 cells and purified using the Talon beads. The SH3-N domain of GRB2 was expressed in BL21 cells and purified from the glutathione resin beads. The SH3-N domain was cleaved from GST by using thrombin, which was engineered into the GST fusion protein and were fluorescently labeled using Cyanine 3 maleimide. Conclusions: The fluorescence polarization assay that will detect the interaction between GIT1 and the SH3-N domain of GRB2 is still under development, but it has progressed towards completion since both components of the assay are in hand.
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West, Maria. "Frihet, närhet och livsviktiga gräl : Ett gott föräldraskap enligt Gunnel Linde." Thesis, Mittuniversitetet, Institutionen för humaniora, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:miun:diva-13959.
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Giuri, Chiara. "The time resolved Ep-L correlation in GRBs: characterization and implications." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2017. http://amslaurea.unibo.it/14082/.
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Our understanding of the GRB phenomenon is still affected by several open issues including the prompt emission physics, the problem related to the trigger of the GRB activity, the classification of different classes of GRBs and the degree of collimation of their emission. All of these issues have strong implications for a full comprehension of the nature of GRBs progenitors. In addition, their huge luminosity and their redshift distribution up to the early Universe make GRBs very promising as cosmological tools. The most investigated way for using them to measure cosmological parameters and the properties and evolution of dark energy is the correlation between the radiated energy and the photon energy at which the spectrum peaks Ep. This work aims at a further investigation of the time-resolved Ep - L correlation, based on large data sets from the BATSE/CGRO and Fermi/GBM experiments, and its application to cosmology. This is an innovative approach leading to a significant improvement in the estimates of cosmological parameters w/r to previous time integrated analysis. Indeed, in time-resolved analysis we can use the correlation between flux and Ep existing in individual GRBs allowing a cosmology independent and unbiased calibration of the slope and of the extra-statistical scatter of the correlation. The results of my thesis also provide important inputs for discriminating among different emission models of the prompt emission of GRBs and the comparison between the dispersion of the time-resolved correlation and that obtained through the averaged spectra provides an estimate of the dispersion of jet opening angles, with strong implications regarding the nature of GRB progenitors. Finally, my research activity includes also the fit of time-resolved spectra of some GRBs with both empirical models and a physical Comptonization model recently delevoped and simulations of the expected contribution by spectral measurements of GRBs through the Chinese satellite HXMT.
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Lewitzky, Marc. "Signalling through small SH2/SH3 adaptor proteins of the Grb2 family." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421030.
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Murray, Helen. "Role of Grb2 in growth and differentiation of embryonic stem cells." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5894.
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Embryonic stem (ES) cells are derived from the inner cell mass of the blastocyst stage embryo. They exhibit unlimited proliferation in culture and have the ability to differentiate into all three germ layers of the developing organism, a property defined as pluripotency. Previously it was reported that growth factor-bound protein 2 (Grb2) is required for differentiation of the epiblast, the embryonic tissue that harbours the pluripotent founder cells of the foetus. GRB2 is an adapter protein involved in the activation of the mitogen-activated protein kinase (MAPK) pathway in response to extracellular signals. It has also been implicated in the activation of the phosphoinositol-3-kinase (PI3K) pathway in response to fibroblast growth factor (FGF) signaling. The work presented in this thesis examines the role of Grb2 in ES cells and describes previously unreported contributions of this adaptor protein in regulating ES cell growth and differentiation. It has been previously been shown by others that Grb2 deficient (Grb2-/-) cells grow relatively normally in ES growth medium containing serum. However, in serum free conditions (N2B27 medium) in this project, proliferation of Grb2-/- cells is reduced compared with wild type and “restored” Grb2-/- cells stably expressing a Grb2 cDNA mini gene. Under serum free conditions, Grb2-/- cells grow in tight, refractive colonies. Nanog expression was uniformly upregulated, in contrast to the heterogeneous pattern reported in serum-based medium. Colony expansion on the substratum appears to be compromised, although there is no apparent defect in the initial attachment of Grb2-/- cells. Cell cycle analysis indicates that the slower growth of Grb2-/- cells in serum free medium could be due to lengthening of the G1 phase of the ES cell cycle. In an attempt to identify the signalling deficiency responsible for the growth defect of Grb2-/- cells, MAPK activation was restored by two methods, PMA a ligand that bypasses the requirement for Grb2, and Raf-ER, a conditionally regulated component of the MAPK pathway that acts downstream of Grb2 in the MAPK pathway. Although both approaches increased MAPK signalling they were unable to rescue the growth defect. This suggests that MAPK is not required or alone is not sufficient. Inhibition of Glycogen synthase kinase 3 β (GSK3 β ) is known to augment growth of ES cells under MAPK inhibition. Surprisingly, GSK3 β inhibition did not enhance Grb2-/- cell growth. Under GSK3 β inhibition, Grb2-/- ES cells fail to thrive. It is hypothesised that under these conditions cells undergo hyper-self-renewal at the cost of growth. Grb2-/- ES cells are reported to exhibit limited differentiation potential. To examine the potency of Grb2-/- cells, these cells were subjected to embryoid body (EB) and monolayer differentiation. Analysis of EBs showed a loss of Gata4, Gata6 and endoderm marker gene expression. However, markers of ectoderm (Sox1, Pax6, MAP2), the late epiblast/nascent mesoderm (Brachyury) and markers associated with gastrulation (Twist and Snail) were expressed. Outgrowths of morphologically and immunohistochemically identifiable neuronal cells confirmed differentiation of ectodermal cell types, indicating Grb2 is not required for neuronal differentiation. However, beating cardiomyocytes could not be identified in Grb2-/- EBs, though readily found in restored Grb2-/- cells expressing the Grb2 cDNA. This suggests that there is an essential role for Grb2 in the mesoderm/cardiomyocyte differentiation pathway. This may be due to a defect in GATA factor expression since these factors are essential for cardiogenesis. In serum-free monolayer differentiation, Grb2-/- cells formed neuronal cells. Additional inhibition of the MAPK pathway using a small chemical inhibitor failed to prevent this differentiation. However, biochemical analysis of the cells indicates that this occurs when ERK activation is very low, indicating differentiation was not MAPK-independent. Grb2 mediates FGF-MAPK induced exit from the naïve ground state. These data suggest a Grb2-independent pathway can also facilitate this transition. Grb2 is dispensable for differentiation in to some lineages. However as differentiation of Grb2-/- ES cells is restricted, this indicates Grb2 is required for true pluripotency.
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Moncoq, Karine. "Structure-fonction des différents domaines des adaptateurs moléculaires Grb14 et Grb7." Paris 7, 2003. http://www.theses.fr/2003PA077174.
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Casey, James David. "Search for high energy GRB neutrinos in IceCube." Diss., Georgia Institute of Technology, 2015. http://hdl.handle.net/1853/53839.
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The IceCube Neutrino Observatory has reported the observation of 35 neutrino events above 30 TeV with evidence for an astrophysical neutrino flux using data collected from May 2010 to May 2013. These events provide the first high-energy astrophysical neutrino flux ever observed. The sources of these events are currently unknown. IceCube has looked for correlations between these events and a list of TeV photon sources including a catalog of 36 galactic sources and 42 extragalactic sources, correlations with the galactic plane and center, and spatial and temporal clustering. These searches have shown no significant correlations. The isotropic distribution of the event directions gives indications that the events could be extragalactic in nature and therefore may originate in the same processes that generate ultra-high-energy cosmic rays (UHECRs). The sources of these UHECRs are still unknown; however, gamma-ray bursts (GRBs) have been proposed as one possible source class. By determining the source of these high-energy neutrinos, it may be possible to determine the sources of UHECRs as well. This study is a search for directional and temporal correlation between 856 GRBs and the astrophysical neutrino flux observed by IceCube. Nearly 10,000 expanding time windows centered on the earliest reported time of the burst were examined. The time windows start at ±10 s and extend to ±15 days. We find no evidence of correlations for these time windows and set an upper limit on the fraction of the astrophysical flux that can be attributed to the observed GRBs as a function of the time window. GRBs can contribute at most 12% of the astrophysical neutrino flux if the neutrino-GRB correlation time is less than ≈20 hours, and no more than 38% of the astrophysical neutrino flux can be attributed to the known GRBs at time scales up to 15 days. We conclude that GRBs observable by satellites are not solely responsible for IceCube’s astrophysical neutrino flux, even if very long correlation time scales are assumed.
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Greco, Giuseppe <1977>. "Multiwavelength study of GRB emissions and TORTORA project." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2009. http://amsdottorato.unibo.it/1863/.
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Traymore, Bonnie. "Dangerously sensual: the sexual revolution, feminisim, and grrl power in postwar America." Thesis, University of Hawaii at Manoa, 2003. http://hdl.handle.net/10125/6914.
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This dissertation, "Dangerously Sensual: The Sexual Revolution, Feminism, and Grrl Power in Postwar America," analyzes the impact of the sexual revolution and feminism on women in postwar America. I argue that the cumulative impact of these two forces produced a "dangerously sensual" brand of female empowerment. I trace through an interrogation of American media and culture the evolution of a highly sexualized femininity from its postwar origins in the mid-1950s to the present. This assertive, sexualized female identity developed both as a response to the cultural and social backlash against feminism and women's liberation in the 1970s and 1980s and as a consequence of the increasing sexualization of America's cultural landscape. Women's issues have been inexorably linked to wider concerns in American society involving foreign policy and domestic affairs. The sexualization of American femininity began during the cold war when the consumer culture promoted consumption as patriotism and bolstered women's consumer power through a "sexual sell." The sexual revolution and the subsequent recognition of sex as a lucrative market furthered this trend. By the early 1960s, both married and single women struggled to embody new sexualized notions of femininity as the feminist movement gained momentum. The women's movement took a radical turn in the late 1960s and early 1970s, and radical feminists rooted their concerns about sexism in a wider critique of American society and foreign policy, particularly regarding the Vietnam War and racism. Liberationists also resis'ted the objectification and sexualization of women and some advocated lesbianism. This feminist extremism, however understandable, hastened a backlash against feminism and shifted some women's rights moderates into the anti-feminist camp. Part of the wider assault by the New Right on the Left and on an American society transformed by the liberalism of the 1960s and 1970s, this conservative critique of feminism contributed to women's dangerously sensual compromise: accepting the sexualization of femininity for the benefits of liberation and empowerment. The legacy of this compromise has become visible in the current "Grrl Power" movement, where many younger American women find flaunting their sexuality a perfectly valid expression of their liberation.vii, 302 leaves
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Bo, Chengyuan. "Role of growth factor receptor-bound protein7 (Grb7) in mammary tumour progression." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=107757.
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Gene amplification and elevated expression of ErbB2 receptor tyrosine kinase has been implicated in the development and progression of human breast cancer, and correlates to poor clinical outcomes. Transgenic mouse models provide a good tool to study ErbB2 mediated mammary tumourigenesis. In both human ErbB2 positive mammary tumour and ErbB2 knock-in mouse model derived mammary tumours, Grb7 is found to be co-amplified and co-expressed with ErbB2. Here we demonstrated ectopic expression of Grb7 in MDCK cells correlates to the loss of epithelial cell polarity, and this was also found true in primary mammary epithelial cells derived from transgenic mice overexpressing Grb7. Elevated expression of Grb7 in mouse mammary gland during developing stage can lead to incomplete mammary ductal outgrowth accompanied by mammary ducts with multiple epithelial layers and myoepithelial missing. NDL transgenic overexpressing Grb7 had longer tumour latency, and it was found that NDL tumours selectively down-regulated the induced-expression of Grb7.L'amplification génique et l'expression élevés de récepteur tyrosine kinase ErbB2 a été impliqués dans le développement et la progression du cancer du sein humain, et corrèle avec de mauvais résultats cliniques. Les modèles de souris transgéniques constituent un bon outil pour étudier la formation de tumeurs médiées par ErbB2 dans la glande mammaire. Dans le cancer mammairehumaines positif pour ErbB2 et le modèle de cancer mammaire de souris ErbB2 knock-in, Grb7 est co-amplifié et co-exprimé avec ErbB2. Ici, nous avons démontré que l'expression ectopique de Grb7 dans les cellules MDCK corrèle avec la perte de polarité des cellules épithéliales, et qui est aussi consistent dans les cellules épithéliales mammaires primaires dérivés de souris transgéniques surexprimant Grb7. Expression élevée de Grb7 dans la glande mammaire de souris pendant la phase de développement peut causer l‟incomplets excroissance canalaires mammaires accompagnés par des conduits mammaires avec de multiples couches épithéliales et myoépithéliales manquants. NDL transgéniques surexprimant Grb7 avait une plus longue délais avant formation de tumeur, et il a été constaté que les tumeurs NDL, de façon sélective, perde la capacité d`induirel`expression de Grb7.
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Priewisch, Beate. "Photoschaltbare Aminosäuren Synthese, photochrome Eigenschaften und Einbau in peptidische Grb2-SH2 Antagonisten /." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=981782051.
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Maignan, Sébastien. "Structure cristallographique de l'adaptateur Grb2 et étude des intéractions avec ses partenaires." Paris 11, 1996. http://www.theses.fr/1996PA112249.
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La transduction du signal de l'exterieur de la cellule vers son noyau met en jeu des processus complexes dont certains commencent a etre elucides. L'etude de ces mecanismes presente de nombreux interets dont celui de la comprehension de la cancerogenese. La proteine grb2 joue un role de relais dans la transduction d'un grand nombre de signaux extracellulaires, en se liant directement ou indirectement sur les recepteurs transmembranaires. Grb2 est exclusivement composee d'un domaine sh2 encadre par deux domaines sh3. Ces domaines se rencontrent dans un tres grand nombre de proteines de la transduction du signal car ils permettent la reconnaissance specifique proteine-proteine. En effet, le domaine sh2 se fixe sur des peptides contenant une tyrosine phosphorylee et sa specificite est regulee par l'acide amine en position +2 ou +3 de la phosphotyrosine. Le domaine sh3 quant a lui, reconnait specifiquement des peptides riches en proline dans la conformation d'helice polyproline de type ii. Le travail presente dans ce memoire concerne la resolution de la structure de grb2 par cristallographie des rayons x a une resolution de 3,1a. La structure a ete resolue par la methode siras grace a un derive acetate de mercure et au rayonnement synchrotron du lure. Grb2 presente plusieurs points interessant. D'une part le domaine sh2 ne fait aucun contacts avec les deux domaines sh3, d'autre part les domaines sh3 sont en contact mais leur interface semble faible. Ceci suggere une certaine flexibilite de grb2, c'est a dire que les differents domaines pourraient bouger les uns par rapport aux autres. L'unite asymetrique contient deux molecules de grb2 imbriquees dont tous les sites de liaisons aux peptides sont accessibles. Grb2 fonctionnerait donc peut-etre sous forme de dimere dans la cellule. Finalement pour etudier l'interaction de grb2 avec ses partenaires, une etude biochimique a ete realise pour purifier et cristalliser un complexe entre grb2 et un fragment de sos, et des donnees de diffraction sur un complexe grb2-peptide phosphoryle sont a l'etude
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Ye, Yunbin. "The effect of a Grb2-SH3 inhibitor on Bcr-Abl expressed K562 cell." Paris 5, 2008. http://www.theses.fr/2008PA05S008.
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Dans la LMC, Grb2 se lie à Bcr-Abl et active la voie de Ras qui induit la transformation de cellules souches hématopoïétiques. Le peptidimer-c a été conçu pour bloquer l'interaction entre Grb2 et ses ligands. Dans les cellules K562 exprimant Bcr-Abl, le peptidimer-c peut pénétrer dans les cellules et d'interagir avec les domaines SH3 de Grb2. Il inhibe la prolifération des cellules dans une manière dose-dépendante. Le traitement combiné du peptidimer-c avec l'imatinib ou d'autres médicaments a un effet synergique ou additif sur l'inhibition du clonage de cellules. Le peptidimer-c induit la nécrose et l'apoptose. Il induit l'arrêt en phase S, par régulation négative de la cycline A et de la cdk2. Par ailleur, le peptidimer-c provoque le changement de l'expression de certaines gènes impliques dans l'apoptose, l'angiogenèse, le cycle cellulaire dans les cellules K562In CML, Grb2 binds to Bcr-Abl and activates the Ras signal pathway which induces the transformation of haemotopoietic stem cell. Peptidimer-c had been designed to block the interaction between the Grb2 and its ligands. In Bcr-Abl positive K562 cells, the peptidimer-c can enter the cells and interact with Grb2 SH3 domains. It inhibits K562 cell proliferation in a dose-dependent manner. The combined treatment of peptidimer-c with Gleevec and other anti-CML drugs had synergetic or additive effects on the inhibition of K562 colony formation. Peptidimer-c significantly increases K562 cell hypodiploid percentage. It results in K562 cell necrosis, induces the cell apoptosis by activating the caspase-3. It induces S phase arrest, concomitantly with down-regulation of cyclin A and phospho-cdk2. Gene chip assay demonstrated that peptidimer-c causes the change of gene expression of K562 cells which are those for apoptosis, angiogenesis, cell cycle, and some other functions
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Cassart, Marie. "Etude radiologique des effets de l'emphysème sur le gril costal et le diaphragme." Doctoral thesis, Universite Libre de Bruxelles, 2001. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211534.
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Alexander, K. D., T. Laskar, E. Berger, C. Guidorzi, S. Dichiara, W. Fong, A. Gomboc, et al. "A Reverse Shock and Unusual Radio Properties in GRB 160625B." IOP PUBLISHING LTD, 2017. http://hdl.handle.net/10150/626042.
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We present multi-wavelength observations and modeling of the exceptionally bright long gamma-ray burst GRB 160625B. The optical and X-ray data are well fit by synchrotron emission from a collimated blastwave with an opening angle of theta(j) approximate to 3 degrees.6 and kinetic energy of E-K approximate to 2 x 10(51) erg, propagating into a low-density (n approximate to 5 x 10(-5) cm(-3)) medium with a uniform profile. The forward shock is sub-dominant in the radio band; instead, the radio emission is dominated by two additional components. The first component is consistent with emission from a reverse shock, indicating an initial Lorentz factor of Gamma(0) greater than or similar to 100 and an ejecta magnetization of R-B approximate to 1-100. The second component exhibits peculiar spectral and temporal evolution and is most likely the result of scattering of the radio emission by the turbulent Milky Way interstellar medium (ISM). Such scattering is expected in any sufficiently compact extragalactic source and has been seen in GRBs before, but the large amplitude and long duration of the variability seen here are qualitatively more similar to extreme scattering events previously observed in quasars, rather than normal interstellar scintillation effects. High-cadence, broadband radio observations of future GRBs are needed to fully characterize such effects, which can sensitively probe the properties of the ISM and must be taken into account before variability intrinsic to the GRB can be interpreted correctly.
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Ma, Qingbo Verfasser], and Harald [Akademischer Betreuer] [Weinfurter. "First star signatures on high-z GRBs and DLAs / Qingbo Ma ; Betreuer: Harald Weinfurter." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1139977725/34.
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Nioche, Pierre. "Etudes structurales et biochimiques de Grb2, une protéine adaptatrice de la transduction du signal." Paris 6, 2000. http://www.theses.fr/2000PA066352.
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Depuis une quinzaine d'annees, de tres nombreux travaux, issus de laboratoires pharmaceutiques ou publiques, ont cherche a elucider les voies de signalisation qui controlent la division et la differenciation cellulaires. Le schema qui est apparu est celui d'une chaine d'interaction proteine-proteine qui conduit le signal extracellulaire de la membrane plasmique jusqu'au noyau. Certaines de ces proteines de signalisation sont appelees onco-proteines en raison de leur capacite a transformer des cellules normales en cellules tumorales. La recherche d'inhibiteurs ayant la capacite de bloquer specifiquement les voies de transduction du signal deregulees est une strategie prometteuse dans la conception de nouveaux medicaments anti-cancereux. La proteines grb2 est un adaptateur qui fait le lien entre un recepteur et un facteur d'echange. Il a ete montre que l'inhibition de cette proteine pouvait ralentir fortement ou stopper la croissance de cellules tumorales transformees notamment par l'egfr. Les travaux presentes ici concernent une etude de la proteine grb2 entreprise selon trois axes : 1) une etude physicochimique de grb2 afin de caracteriser l'equilibre entre les formes monomerique et dimerique observees en solution. 2) une etude cristallographique du domaine sh2 de grb2, i) sous sa forme native, ii) en complexe avec le peptide pspyvnvqn issu de la proteine shc, iii) en complexe avec un peptidomimetique maz-py-(me)py-nnh 2 dans le but de caracteriser les interactions atomiques pouvant permettre la synthese de nouveaux inhibiteurs plus efficaces. 3) des etudes a la fois biochimique et de biologie cellulaire visant a caracteriser de nouvelles fonctions de grb2 dans la polymerisation de l'actine et le controle de la phase g2/m. Ces trois parties distinctes font apparaitre les principaux resultats suivants : 1) le dimere de grb2 observe en solution est different de celui visualise dans l'unite asymetrique de la structure cristallographique. Le premier ne fixe plus les peptides phosphotyrosyles, de sequence consensus pyxn, alors que la structure du second presente un site accessible pour chacune des molecules du dimere. 2) la comparaison des trois structures cristallographiques montrent que i) la structure du domaine sh2 est globalement conservee, ii) les interactions du residu py(0) sur le site principal et du residu asparagine (+2) sur le site secondaire sont identiques dans les deux complexes, iii) le tryptophane 121 forme le troisieme point d'ancrage du peptide en coiffant l'asparagine par des contacts de van der waals, w121 ayant une orientation opposee dans la structure native, iv) (me)py(+1) interagit par de nombreuses liaisons hydrogenes avec des residus de la boucle bg entrainant un mouvement de 2a de sa chaine principale. Toutes ces interactions sont responsables de la forte affinite de cet inhibiteur pour le domaine sh2 de grb2 (kd = 3nm). 3) la recherche de nouvelles fonctions a permis d'etablir que i) grb2 activait la polymerisation de l'actine par son interaction avec n-wasp, principalement par son domaine sh3 c-terminal, ii) l'injection de grb2 dans des oocytes de xenopes active la transition g2/m. Ceci ouvre la possibilite que la proteine grb2 ait des fonctions biologiques autres que celle d'adaptateur.
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Fresno, Gladis Rosa, and Glady Teresa Montoya. "Atención despersonalizada que se efectúa a los pacientes internados en el Hospital Gral. Alverar." Bachelor's thesis, Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Escuela de Enfermería, 2004. http://bdigital.uncu.edu.ar/8793.
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La atención despersonalizada es aquella atención que no cubre las necesidades básicas del paciente ni reduce la incomodidad, no hay comunicación entre el personal y los usuarios para resolver los problemas de salud, donde el paciente pasa a ser un número más dentro del centro sanitario. Por el contrario la atención personalizada tiene como propósito preservar la dignidad o la humanidad individual del paciente, la armonía interna y el potencial de curación. El objetivo de los distintos modelos de atención de enfermería es incrementar la calidad de vida, a través de una relación interpersonal de ayuda al individuo, familia y la comunidad en general. Este trabajo de investigación tiene como objetivo determinar cuáles son los factores que influyen en la atención despersonalizada, que se efectúa a los pacientes en servicios de internación del Hospital de General Alvear, Mendoza en el año 2002.Fil: Fresno, Gladis Rosa. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Escuela de Enfermería..
Fil: Montoya, Glady Teresa. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Escuela de Enfermería..
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Landry, Mélissa. "L'implication de la dualité fonctionnelle de la protéine p66Shc en aval des récepteurs tyrosine kinase dans la progression du cancer." Mémoire, Université de Sherbrooke, 2012. http://hdl.handle.net/11143/6327.
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Le gène ShcA code pour trois isoformes de protéines adaptatrices (p46, p52 et p66Shc), possédant entre eux une forte homologie structurelle. Les études antérieures ont attribué un rôle essentiel à l'isoforme p52Shc dans l'activation de la voie mitogénique des MAPK, ainsi que dans la transformation cellulaire en aval des récepteurs de type tyrosine kinase (RTK). L'activation des MAPK fait intervenir une liaison directe de p52Shc aux RTK suivant leur activation, ce qui permet la phosphorylation sur tyrosines de Shc et ainsi, le recrutement de la protéine adaptatrice Grb2. Pendant longtemps, ces fonctions ont été attribuées aux trois isoformes des protéines Shc. Cependant, il est maintenant évident que Pisciforme p66Shc joue des rôles distincts de p52Shc. En effet, l'expression de p66Shc n'induit pas la transformation cellulaire et inhibe l'activité des MAPK en aval des RTK. D'ailleurs, p66Shc induit l'apoptose en réponse aux stress oxydatifs, par le biais de la phosphorylation d'une sérine située dans son domaine unique en N-terminal. Bien que ces caractéristiques proposent un pouvoir anti-tumorigénique à p66Shc, son rôle dans la progression du cancer demeure controversé. Mes travaux de recherche démontrent que p66Shc est constitutivement associé au récepteur dii facteur de croissance des hépatocytes, le RTK Met, et diminue fortement l'interaction entre le récepteur Met actif et Grb2. Nos études in cellulo et in vivo dans un modèle de cellules épithéliales intestinales transformées par Tpr-Met (Tpr-Met-IEC-6), une forme oncogénique du récepteur Met, révèlent que l'expression de p66Shc induit l'apoptose à l'atteinte de la confluence et diminue la croissance tumorale, dépendamment de sa phosphorylation sur sérine. En revanche, p66Shc augmente la capacité de ces cellules à survivre sans ancrage à la matrice extracellulaire et favorise la formation de métastases. En conclusion, nous démontrons qu'une protéine Shc s'associe à un RTK indépendamment de son activation. Il s'agit de la première évidence que les modes d'interaction de p66Shc avec les RTK different de ceux caractérisés pour p52Shc. De plus, nos études permettent d'illustrer la dualité fonctionnelle de p66Shc, où son expression diminue la capacité tumorigénique des cellules en adhésion, mais augmente leur potentiel métastatique lorsqu'elles sont en suspension, dénotant le rôle controversé de p66Shc dans le cancer. Cette nouvelle compréhension des rôles distincts associés à p66Shc selon le contexte de la cellule cancéreuse permet de cibler différentes étapes du développement du cancer.
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Aippersbach, Elke Daniela. "Targeted disruption of the Grb4 and Nck loci and generation of homozygous null nck mice." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0004/MQ40788.pdf.
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Radtke, Daniel [Verfasser], and Lars [Akademischer Betreuer] Nitschke. "Das Adapterprotein Grb2 in B- und T-Lymphozyten der Maus / Daniel Radtke. Gutachter: Lars Nitschke." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2015. http://d-nb.info/1075837308/34.
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Adamopoulos, Ioannis. "Roles of SRC homology 3 domains (SH3) of GRB2 in downstream pathways elicited by HGFMET." Thesis, University College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426061.
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Courme, Caroline. "Conception de novo et synthèse de ligands non peptidiques potentiels du domaine SH2 de Grb2." Paris 5, 2008. http://www.theses.fr/2008PA05P605.
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Grb2 est une protéine adaptatrice qui intervient dans plusieurs voies de signalisation mitogéniques. Elle est constituée de deux domaines SH3 et d’un domaine SH2, ce dernier reconnaissant les phosphotyrosines situées dans la partie intracellulaire des récepteurs à tyrosine kinase activés. Ces voies contrôlent divers processus comme la prolifération et la survie cellulaire et sont impliquées dans les cancers du sein (Ras/MAPK) et du rein (HGF/cMet). Depuis plus d’une décennie, plusieurs groupes de recherche se sont intéressés à l’inhibition de Grb2, qui ouvrirait de nouvelles perspectives en oncologie. La co-cristallisation de Grb2 avec un de ses ligands endogènes, Bcr-Abl, a permis de définir les pharmacophores essentiels à la reconnaissance par la protéine. De nombreux inhibiteurs peptidiques ou peptidomimétiques ont été développés mais très peu d’inhibiteurs non-peptidiques ont été décrits jusqu’à présent. C’est dans ce contexte que s’est inséré notre programme de recherche, en partant des structures de deux ligands de référence : un peptide développé par l’équipe de C. Garbay et un thiazole non-peptidique développé par Novartis, à trois et deux pharmacophores, respectivement. Nous décrivons dans cette thèse la conception de novo et la synthèse multi-étapes de ligands nonpeptidiques potentiels de Grb2-SH2. Des composés originaux basés sur les sous-structures dites privilégiées 2-anilinopyrimidine et triazine ont été conçus à partir de la structure cristallographique de Grb2-SH2 avec le peptide de Garbay et coll. De plus, une stratégie de synthèse d’analogues du ligand de Novartis a été développée en exploitant la structure triazine via la chimie ‘click’Grb2 is an adaptor protein involved in several mitogenic signaling pathways. It consists of two SH3 domains and one SH2 domain, the latter recognizing phosphotyrosines located in the intracellular part of activated tyrosine kinase receptors. These pathways control various processes such as cell proliferation and survival and are involved in the development of breast cancer (Ras/MAPK) and kidney cancer (HGF/cMet). For over a decade, several research groups have been interested in Grb2 inhibition, which could open new perspectives in oncology. The co-crystallization of Grb2 with one of its endogenous ligands, Bcr-Abl, permitted the identification of key pharmacophores for protein recognition. Many peptidic or peptidomimetic inhibitors have been developed but very few non-peptidic inhibitors have been described until today. In this context, we have based our research program on the structure of two reference ligands: a peptide developed by the team of C. Garbay and a non-peptidic thiazole developed by Novartis, with three and two pharmacophores, respectively. We have described in this PhD the de novo design and multi-step synthesis of potential Grb2-SH2 non-peptidic inhibitors. Novel compounds based on 2-anilinopyrimidine and triazine ‘privileged’ scaffolds have been designed using the X-ray structure of Grb2-SH2 co-crystallized with the peptide developed by the team of Garbay. Furthermore, a synthesis strategy has been developed to prepare analogs of Novartis’ ligand, using the triazine scaffold via ‘click’ chemistry
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Bilal, Mahmood. "The role of the GRB2 family of adaptor proteins in T cell receptor-mediated signaling." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1548.
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CD4+ T cells are critical in the fight against parasitic, bacterial, and viral infections, but are also involved in many autoimmune and pathological disorders. Ligation of the T Cell Receptor (TCR) is the primary signal required for T cell activation proliferation, differentiation and cytokine release. Upon TCR activation, several kinases and adaptor proteins are assembled at the TCR/linker for activation of T cells (LAT) signaling complexes, a process indispensable for optimal signal transduction. One important group of proteins recruited to the TCR/LAT complexes is the GRB2 family of adaptors.
Due to their role in mediating signaling complexes, the GRB2 family of adaptors are critical for development, proliferation, and survival of diverse cell types. These proteins have been linked to the initiation and progression of numerous pathological conditions including diabetes, asthma/allergy, and solid and hematopoietic malignancies. Therefore, it is essential to characterize and understand the complete functions of these proteins for the generation of safe and efficient targeting treatments for diseases mediated by these proteins. In T cells, GRB2 and its homologs, GADS and GRAP, are crucial for the propagation of signaling pathways through the TCR and adaptor protein LAT. These proteins recruit distinct sets of proline-rich ligands to LAT thereby inducing multiple signaling pathways such as MAP kinase activation, calcium influx and cellular adhesion. However, the role of GRB2 family members in controlling TCR and LAT mediated signaling in mature human T cells is not completely understood. Moreover, the relative role of GRB2 family members in the extent and timing of the recruitment of SH3 domain ligands to the LAT complex is unknown. Our hypothesis is that these proteins recruit distinct sets of ligands to the LAT complex that can drive differential downstream signaling events.
As presented in CHAPTER III, we developed microRNA and shRNA targeting viral vectors to effectively inhibit the expression of GRB2 and GADS in human CD4+ T cells to examine the role of these adaptors in mature human T cells. We also established optimized protocols for high efficacy retro or lentiviral transduction of human T cell lines, activated and "hard-to-transduce" non-activated primary human CD4+ T cells. In CHAPTER IV, we demonstrate the requirement for GRB2 in TCR-induced IL-2 and IFN-γ release. The defects in cytokine release in the absence of GRB2 were attributed to diminished formation of LAT signaling microclusters, which resulted in reduced MAP kinase activation, calcium flux and PLC-γ1 recruitment to LAT signaling clusters. Overall, the data presented in this chapter demonstrate that the ability of GRB2 to facilitate protein clustering is as important in regulating TCR-mediated functions as its capacity to recruit effector proteins. This highlights that GRB2 regulates signaling downstream of adaptors and receptors by both recruiting effector proteins and regulating the formation of signaling complexes. In CHAPTER V, we describe the role for GADS in mediating TCR-induced IL-2 and IFN-γ production. GADS was critical for the recruitment of SLP-76 and PLC-γ1 to the LAT complex and subsequent calcium influx. We also show, in contrast to the current paradigm, that recruitment of GADS/SLP-76 complexes to LAT is not required for TCR-mediated adhesion and cytoskeletal arrangement.
Overall, our studies reveal novel mechanisms for the role of GRB2 family members in TCR-mediated signaling. They also provide insight into the mechanisms that regulate growth factor, cytokine and insulin receptors. Importantly, studies presented in this thesis will help us understand the mechanisms of T cell activation and highlight potential new therapies for T cell-mediated diseases, including leukemia, lymphomas, autoimmune disorders and cardiovascular disease.
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Olivo, Martino. "Neutrino emission from high-energy component gamma-ray bursts." Licentiate thesis, Uppsala universitet, Högenergifysik, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-132961.
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Gamma-ray bursts (GRBs) are brief and sudden explosions radiating most of their energy in the soft γ-ray band ( 100 keV). In the context of multimessenger astroparticle physics recent observations of GRBs provide an excellent benchmark for testing theoretical models of high energy emission mechanisms. Acceleration of hadrons in the engine is expected to produce high energy neutrinos and gamma-rays simultaneously via π±/π0 decays, thus reinforcing the motivation for coincident searches in km3 neutrino telescopes. The Waxman-Bachall spectra and the corresponding expected neutrino rates in IceCube are derived here for GRB090510 amd GRB090902B recently detected by the Fermi Large Area Telescope. The implications of the significant detection of deviations from the Band function fit in photon spectra and a model that explains these extra-components in terms of π0-decay photons are presented here and the relevance to neutrino astronomy is shown.
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Dallaire, Marc. "Étude sur la susceptibilité de différentes souches commerciales de poulet de gril au syndrome de l'ascites." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq25546.pdf.
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Leroux, Vincent Maigret Bernard. "Modélisation d'inhibiteurs du domaine SH2 de la protéine Grb2 par dynamique moléculaire, docking et criblage virtuel." [S.l.] : [s.n.], 2006. http://www.scd.uhp-nancy.fr/docnum/SCD_T_2006_0220_LEROUX.pdf.
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Malhotra, Shikha. "B-cell-antigen receptor endocytosis uses a distinct signaling pathway, involving LAB, Vav, dynamin and Grb2." Oklahoma City : [s.n.], 2009.
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Leroux, Vincent. "Modélisation d’inhibiteurs du domaine SH2 de la protéine Grb2 par dynamique moléculaire, docking et criblage virtuel." Nancy 1, 2006. http://docnum.univ-lorraine.fr/public/SCD_T_2006_0220_LEROUX.pdf.
Full textAbstract:
Ce manuscrit constitue une étude théorique de l’inhibition de l’activité du domaine SH2 de la protéine Grb2 par la liaison de ligands. La première partie décrit le contexte de ce travail, qui se situe plus généralement à travers le ciblage de Grb2 SH2 parmi les multiples approches de lutte contre le cancer, de l’étude du vivant à l’échelle moléculaire (domaine interdisciplinaire par excellence), et, plus précisément, de la recherche pharmaceutique. La seconde partie s’emploiera à détailler les connaissances disponibles sur la cible au moment de débuter ce travail, en incluant les avancées qui sont apparues en parallèle à ce travail. On trouvera dans la troisième partie un résumé des principaux résultats obtenus au cours de cette thèse. Ceux-ci se classent selon trois approches méthodologiques distinctes : celle de la dynamique moléculaire, du docking et enfin du screening virtuel. On pourra constater que de nouvelles connaissances sur la nature physico-chimique de la liaison de certains ligands sur Grb2 SH2 sont mises en évidence dans le premier cas, tandis que les deux autres approches ont surtout donné naissance à des avancées méthodologiques.