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1
Pierro, Annalisa. "Protein structural dynamics in bacteria via nitroxide-based SDSL-EPR spectroscopy : from method improvements to in-cell studies." Electronic Thesis or Diss., Aix-Marseille, 2021. http://theses.univ-amu.fr.lama.univ-amu.fr/211116_PIERRO_290xrxu60ryzjfl293g970fjmdnl_TH%20(1).pdf.
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L'étude des biomolécules dans leur environnement natif, la cellule, est l'un des principaux objectifs de la biologie structurale au cours de la dernière décennie. Ainsi, nous assistons à un remarquable développement des approches dites « in-cell », comme la CryoET, FRET (Förster Resonance Energy Tranfer), RMN. Parmi elles, la technique de marquage de spin couplée à la spectroscopie de Résonance Paramagnétique Electronique (SDSL-RPE) présente des caractéristiques intéressantes et avantageuses permettant de sonder la dynamique des protéines à l'intérieur des cellules. En particulier, l’utilisation des sondes de type nitroxyde combine sensibilité élevée et absence de contraintes de taille de la biomolécule d'intérêt avec la capacité d'étudier les transitions structurales et les interactions protéines-protéines à température physiologique. Cependant, même si de nombreux efforts ont été faits pour adapter cette technique à des études structurales dans les cellules, des progrès restent à faire.Dans cette thèse, nous traitons des principales limitations de l’utilisation des nitroxydes dans un contexte cellulaire. Nous nous sommes concentrés sur la stabilité des marqueurs nitroxydes dans des milieux reducteurs et dans la cellule, sur l’incorporation des protéines marquées dans les cellules et la viabilité de ces cellules en vue de mesures par RPE. Grâce aux résultats obtenus dans cette partie méthodologique, nous avons pu étudier la dynamique structurale de deux protéines chaperons (NarJ et UreG) dans des cellules bactériennes. Ces avancées ont permis de comparer les données obtenues in-cell à celles obtenues in vitro ou dans un environnement mimant le milieu cellulaire<br>The study of biomolecules in their native environment has been one of the main goals of structural biology in the last decade. As a result, we are assisting to a remarkable increase of new "in-cell" approaches, like Cryo-ET, FRET and NMR. Among these approaches, Site-Directed Spin Labeling (SDSL) coupled to Electron Paramagnetic Resonance (EPR) spectroscopy shows competitive and advantageous features to capture protein dynamics inside cells. In particular, nitroxide-based SDSL-EPR combines the advantages of high sensitivity and the lack of size constraints on the biomolecule of interest with the ability to capture protein structural transitions and interactions at physiological temperature. Despite the methodological advancements of the technique that have allowed the community to obtain increasingly relevant results, progresses still need to be done.In this work, the main limitation of nitroxide-based SDSL-EPR has been addressed. In the first time, we focused on the development of delivery methods to introduce the labeled protein in bacterial cells. Next, the stability of nitroxide labels in reducing environments and in-cell has been assessed, monitoring in parallel the viability of the cells during the EPR measurements. Thanks to the results achieved in this methodological part, we were able to study the structural dynamics of two flexible chaperone proteins directly in bacterial cells: NarJ from Escherichia coli and UreG from Sporosarcina pasteurii. Finally, to go further in understanding the impact of the cellular environment on the protein dynamics, the data obtained in cellular context were compared with those obtained in vitro or in a cell-mimicking environment
2
Noda, Yohei. "EPR studies on molecular orientation of all-organic paramagnetic liquid crystals in a surface-stabilized liquid crystal cell." 京都大学 (Kyoto University), 2007. http://hdl.handle.net/2433/136793.
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ROSSI, MARTINA. "Long Noncoding RNA “EPR” controls epithelial cell proliferation by coordinating CDKN1A transcription and mRNA decay in response to TGF-β". Doctoral thesis, Università degli studi di Genova, 2019. http://hdl.handle.net/11567/936734.
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Long noncoding RNAs (lncRNAs) are emerging as regulators of fundamental biological processes. Here we report on the functional characterization of an intergenic lncRNA (lincRNA) expressed in epithelial tissues which we termed EPR (Epithelial cell Program Regulator). EPR is rapidly downregulated by TGF-β and its sustained expression largely reshapes the transcriptome, favors the acquisition of epithelial traits, and reduces cell proliferation in cultured mammary gland cells as well as in an animal model of orthotopic transplantation. EPR generates a small peptide that localizes at epithelial cell junctions but the RNA molecule per se accounts for the vast majority of EPR-induced gene expression changes. Mechanistically, EPR interacts with chromatin and regulates Cdkn1a gene expression by affecting both its transcription and mRNA decay through its association with the transcription factor SMAD3 and the mRNA decay promoting factor KHSRP, respectively. We propose that EPR enables epithelial cells to control proliferation by modulating waves of gene expression in response to stimuli.
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Udyaningsih-Freisleben, Seruni Kusuma. "XAS and RR Structural Analysis of Hemoglobin and EPR Spectroscopic Labelling of Red Blood Cell Membranes Isolated from Thalassemia Patients in Jakarta, Indonesia." Thesis, The University of Sydney, 2003. https://hdl.handle.net/2123/27995.
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A study on thalassemia intermedia and major patients in Jakarta was initiated to obtain a comprehensive picture of metabolic dysregulation, iron overload, oxidative stress, and cell damage. Data were collected from a group of 10
transfusion-dependent patients in an age range of 11-25 years and another group of 5 frequently transfused (for at least 15 years) patients aged 17-30 years. A third group comprises 5 patients (aged 7 to 14 years) who had not yet obtained transfusions. The 10 controls were voluntary students without diagnosis or clinical signs of thalassemia up to 30 years of age. The study was approved by the Ethical Clearance Board of the Medical Faculty and all blood samples from controls and patients were obtained on fully informed consent. Levels of antioxidants (vitamins A, C, E and B-carotene) and reactive thiols are considerably decreased in transfused patients, whereas signs of iron overload and cell damage are increased (serum iron, ferritin, transferrin saturation, SGOT, SGPT, y-GT, bilirubin).
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Fernandez, Daniel. "Cell States and Cell Fate: Statistical and Computational Models in (Epi)Genomics." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:14226043.
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This dissertation develops and applies several statistical and computational methods to the analysis of Next Generation Sequencing (NGS) data in order to gain a better understanding of our biology. In the rest of the chapter we introduce key concepts in molecular biology, and recent technological developments that help us better understand this complex science, which, in turn, provide the foundation and motivation for the subsequent chapters.
In the second chapter we present the problem of estimating gene/isoform expression at the allelic level, and different models to solve this problem. First, we describe the observed data and the computational workflow to process the data. Next, we propose frequentist and bayesian models motivated by the central dogma of molecular biology and the data generating process (DGP) for RNA-Seq. We develop EM and Gibbs sampling approaches to estimate gene and transcript-specic expression from our proposed models. Finally, we present the performance of our models in simulations and we end with the analysis of experimental RNA-Seq data at the allelic level.
In the third chapter we present our paired factorial experimental design to study parentally biased gene/isoform expression in the mouse cerebellum, and dynamic changes of this pattern between young and adult stages of cerebellar development. We present a bayesian variable selection model to estimate the difference in expression between the paternal and maternal genes, while incorporating relevant factors and its interactions into the model. Next, we apply our model to our experimental data, and further on we validate our predictions using pyrosequencing follow-up experiments. We subsequently applied our model to the pyrosequencing data across multiple brain regions. Our method, combined with the validation experiments, allowed us to find novel imprinted genes, and investigate, for the first time, imprinting dynamics across brain regions and across development.
In the fourth chapter we move from the controlled-experiments in mouse isogenic lines to the highly variant world of human genetics in observational studies. In this chapter we introduce a Bayesian Regression Allelic Imbalance Model, BRAIM, that estimates the imbalance coming from two major sources: cis-regulation and imprinting. We model the cis-effect as an additive effect for the heterozygous group and we model the parent-of-origin detect with a latent variable that indicates to which parent a given allele belongs. Next, we show the performance of the model under simulation scenarios, and finally we apply the model to several experiments across multiple tissues and multiple individuals.
In the fifth chapter we characterize the transcriptional regulation and gene expression of in-vitro Embryonic Stem Cells (ESCs), and two-related in-vivo cells; the Inner Cell Mass (ICM) tissue, and the embryonic tissue at day 6.5. Our objective is two fold. First we would like to understand the differences in gene expression between the ESCs and their in-vivo counterpart from where these cells were derived (ICM). Second, we want to characterize the active transcriptional regulatory regions using several histone modifications and to connect such regulatory activity with gene expression. In this chapter we used several statistical and computational methods to analyze and visualize the data, and it provides a good showcase of how combining several methods of analysis we can delve into interesting developmental biology.
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Hu, Zhengqing. "Investigating a cell replacement therapy in the inner ear /." Stockholm, 2004. http://diss.kib.ki.se/2005/91-7140-170-9/.
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Gregory, L. G. L. "Eph-ephrin signalling in cell sorting and directional migration." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1318081/.
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An important problem in developmental biology is to understand how precise patterns of cell types are maintained during development. Eph receptor tyrosine kinases and ephrins have key roles in stabilising these patterns of cell organisation and segregation during development and can restrict the movement of cells by promoting cell repulsion. Previous work by Alexei Poliakov in the Wilkinson lab has shown that Eph-ephrin signalling leads to directional persistence of migration, and modelling suggests that this can contribute to cell segregation. In order to test experimentally the contribution of directional persistence in cell segregation, I have used and developed in vitro assays to dissect the roles of EphB2-ephrinB1 signalling in cell segregation, boundary sharpening and directional persistence. In these assays, stable HEK293 cell lines expressing EphB2 or ephrinB1 are mixed in cell culture and this leads to segregation of the two cell populations. Plating these cells either side of a removable barrier and allowing migration of cells towards each other leads to the formation of a sharp boundary on interaction. Analysis of cell behaviour shows EphB2 cells to move more persistently after interaction with ephrinB1 cells. To analyse how EphB2-ephrinB1 interactions lead to directional persistence of migration, my studies have focussed on the role of components potentially involved in directional persistence that act downstream of EphB2-ephrinB1 signalling, including the planar cell polarity (PCP) pathway (Dishevelled and Daam1) and core polarity components such as the PAR proteins (PAR-3 and PAR-6B). The PCP and PAR components were all found to have roles in cell segregation, as siRNA-mediated knockdown of each of these components disrupted EphB2-ephrinB1 mediated cell segregation and boundary sharpening. However, cell behaviour studies showed that only Dishevelled and PAR-6B have roles in EphB2-ephrinB1 mediated directional persistence, whilst Daam1 knockdown has no effect on the migratory response of cells. PAR-3 knockdown affects the basal ability of cells to migrate, potentially due to its role in establishing front-rear polarity. Taken together, these findings can be explained by a model in which Dishevelled and PAR-6B have a role in EphB2-ephrinB1 mediated directional persistence required for cell segregation and boundary sharpening. I propose that Daam1 may function in the contact inhibition of locomotion between cells also required for segregation.
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Li, Lin. "Hair cell loss and repair processes in mammalian vestibular sensory epithelia." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266075.
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Omodho, Becky. "Early growth response gene (Egr) 2 and 3 control inflammatory responses of tolerant T cells." Thesis, Brunel University, 2016. http://bura.brunel.ac.uk/handle/2438/13516.
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This study investigated the role of tolerance induction in an inflammatory setting in regard to the early growth response genes Egr2 and Egr3. T cells robustly respond to pathogenic antigens during infection, but are tolerant to stimulation by self-antigens. The intrinsic mechanisms for self-tolerance in the periphery are still not clear. Egr2 and 3 are induced in tolerant T cells in response to antigen stimulation by NFAT-medicated tolerant signalling; however, their function in tolerant T cells is still unknown. The study demonstrated that Egr2 and 3, induced in tolerant T cells, are not directly involved in defective proliferation and IL-2 production, the hallmarks of T cell tolerance. However, they are essential for preventing inflammatory response of tolerant T cells. In the absence of Egr2 and 3, tolerant T cells show impaired proliferation and production of IL-2, but produce high levels of IFN-γ, a key inflammatory cytokine. This phenotype resembles CD4 T cells from autoimmune diseases such as lupus which show poor proliferative response, but hyper-inflammation. Our study demonstrated, for the first time, a distinctive mechanism to control inflammation from proliferative tolerance regulated by Egr2 and 3, which may be an important mechanism for the control of autoimmune diseases.
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Gallagher, Ewen. "The regulation of the egr-1 promoter in B cell lines." Thesis, University of Nottingham, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341970.
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Fu, Yu [Verfasser]. "Cell-type specific epi-genomic studies in Arabidopsis thaliana / Yu Fu." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2020. http://d-nb.info/1210700409/34.
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Sakamoto, Tatsunori. "Hair cell differentiation becomes tissue specific by E9.5 in mouse inner ear." Kyoto University, 2008. http://hdl.handle.net/2433/135785.
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Wang, Haoming. "Revealing the Role of Tmc2b in Hair Cell Subtypes Within the Inner Ear." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1619801272628693.
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Hackney, Jennifer Faye Dobens Leonard L. "Ecdysone Receptor (EcR) regulates cell migration and chorion gene amplification in the drosophila ovary." Diss., UMK access, 2008.
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Thesis (Ph. D.)--School of Biological Sciences. University of Missouri--Kansas City, 2008.<br>"A dissertation in molecular biology and biochemistry and cell biology and biophysics." Advisor: Leonard L. Dobens. Typescript. Vita. Title from "catalog record" of the print edition Description based on contents viewed Sept. 12, 2008. Includes bibliographical references (leaves 120-147). Online version of the print edition.
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Ebrahimi, Maryam. "Examining the expression of potential cell-cycle regulators in the developing mouse inner ear." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=123245.
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Sensory epithelia of the mammalian inner ear are composed of hair cells and supporting cells. These cells originate from common precursors, which exit the cell cycle during late embryogenesis. Thereafter, hair cells and supporting cells maintain a non-proliferative state. As a result, hair cell loss in mammals is irreversible. If inner ear organs are to be regenerated, supporting cells must reenter the cell cycle to produce new hair cells and supporting cells. Little is known about genes that maintain the post-mitotic state of inner ear supporting cells. Previous studies revealed the role of cell cycle inhibitors such as p27kip in regulating the post-mitotic fate of differentiated supporting cells (Lowenheim H, Furness DN et al. 1999) The purpose of our study was to identify other potential regulators of cell cycle in supporting cells and determine their expression at different ages. We used the Shared Harvard Inner-Ear Laboratory data base (SHIELD; shield.hms.harvard.edu) to select 15 candidate genes following these criteria: 1) an established role in cell cycle regulation in other cell types, 2) maintained postnatal expression in mouse utricular supporting cells, and 3) not previously studied in the mouse inner ear.We used RT-PCR and in situ hybridization to determine the expression of these candidate genes in inner ear sensory epithelia. Our RT-PCR results, from mouse utricles between postnatal days 7-8, (which contained hair cells, supporting cells, and non-sensory cells) confirmed the expression of all candidate genes. Our in situ hybridization results, which came from mice at embryonic days 13.5, E15.5 and 18.5, were mixed. In some cases expression was seen mainly in supporting cells, as expected based on the SHIELD data and in other cases in hair cells or non-sensory cells. Further studies are required to test whether these genes play a role in regulating cell cycle in the mouse developing inner ear.<br>Les épithéliums sensoriels de l'oreille interne des mammifères sont composés de cellules ciliées et des cellules de soutien. Ces cellules proviennent de précurseurs communs, qui sortent du cycle cellulaire vers la fin de l'embryogenèse. Ensuite, les cellules ciliées ainsi que les cellules de soutien ont maintenu un état non –prolifique. Conséquenment, la perte de cellules ciliées chez les mammifères est irréversible. Afin de régénéré les organes de l'oreille interne, les cellules de soutien se doivent réintégrer le cycle cellulaire afin de pouvoir produire de nouvelles cellules ciliées et des cellules de soutien .On en sait peu au sujet des gènes qui maintiennent l'état post- mitotique des cellules de soutien de l'oreille interne. Les études antérieures ont révélé le rôle des inhibiteurs du cycle cellulaire tel que p27kip dans la régulation du sort post- mitotique des cellules de soutien différenciées (Lowenheim H, Furness DN et al. 1999).Le but de notre étude était d'identifier d'autres régulateurs potentiels du cycle cellulaire dans les cellules de soutien et de déterminer leur expression à des âges différents. Nous avons utilisé la base de données Shared Harvard Inner-Ear Laboratory (SHIELD; shield.hms.harvard.edu) afin de sélectionner 12 gènes candidats suivant ces critères: 1) un rôle établi dans la régulation du cycle cellulaire chez les autres types de cellules, 2 ) maintenu l'expression postnatal des cellules de soutien utriculaire chez la souris, et 3) qui n'ont pas déjà étudié dans l'oreille interne de la souris.Nous avons utilisé la RT- PCR et l'hybridation in situ pour déterminer l'expression de ces gènes candidats dans l'épithéliums sensoriels de l'oreille interne. Nos résultats de RT-PCR, à partir de utricules de souris entre jour postnatal 7 et 8, ( qui contient des cellules ciliées, des cellules de soutien et des cellules non sensorielles ) ont confirmé l'expression de tous les gènes candidats. Nos résultats d'hybridation in situ, previennent de la souris entre les jours embryonnaires 13.5, E15.5 et 18.5, ont été mitigés. Dans certains cas, l'expression a été observée principalement dans les cellules de soutien, comme prévu sur la base de données SHIELD. Dans d'autres cas, l'expression a été observer dans les cellules ciliées ou des cellules non-sensorielles. D'autres études sont requises afin de déterminer si ces gènes jouent un rôle dans la régulation du cycle cellulaire pendant la développant de l'oreille interne chez la souris.
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Addison, M. E. "Investigating the roles of cell identity regulation and Eph/ephrin signalling in early hindbrain segmentation." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1559130/.
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During development of the vertebrate hindbrain, the neuroepithelium becomes subdivided into seven morphological units, known as rhombomeres. It is necessary that rhombomeres have sharp, well-defined boundaries, which are established from initially rough gene expression domains during early hindbrain segmentation. The mechanisms involved in early hindbrain segmentation that create sharp segment borders are not well understood. There is evidence to suggest that both regulation of cell identity and Eph/ephrin-mediated cell sorting are required for establishing sharp interfaces between rhombomeres. This thesis investigates the extent to which identity regulation contributes to hindbrain border sharpening in zebrafish. I created a new zebrafish reporter line by CRISPR/Cas9-mediated reporter integration at the egr2b locus, which enables cell identity and cell intermingling to be visualised in live embryos during border sharpening. This new reporter line indicates a contribution of cell identity regulation to border sharpening. I also demonstrate that the contribution of cell identity switching to border refinement is greater in cases where cell intermingling is increased by perturbed Eph/ephrin signalling. To help study the role of Eph/ephrin signalling in border sharpening, I have also created a novel EphrinB3b mutant. The thesis also investigates the mechanisms of identity regulation by community effects and discusses their contribution to border refinement by identity respecification; community effects are suspected to help overcome noise in early gene induction through spatial averaging and thus help establish regions of homogeneous gene expression. The ability of candidate genes to non cell-autonomously regulate the identity of neighbouring cells in the hindbrain is investigated. Of particular focus is the potential involvement of retinoic acid (a morphogen involved in specification of anteroposterior identity) and segmentally-expressed Cyp26 enzymes involved in its metabolism. Analysis of mosaic embryos is used to compare the ability of isolated cells and clustered groups of cells to maintain a different identity to their surroundings. Results presented here are consistent with segmental regulation of retinoic acid signalling contributing to border sharpening.
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Kabashima, Kenji. "The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut." Kyoto University, 2003. http://hdl.handle.net/2433/148729.
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Papworth, Karin. "Prognostic factors in renal cell carcinoma : evaluation of erythropoietin and its receptor, carbonic anhydrase IX, parathyroid hormone-related protein and osteopontin." Doctoral thesis, Umeå universitet, Onkologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-40047.
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A prognostic factor is a marker or a feature that can be used to estimate the risk of recurrence of disease, metastatic spread and clinical outcome. Despite intensive search for more sophisticated markers in renal cell carcinoma (RCC), few have added prognostic information to earlier described factors like stage of disease, nuclear grade, tumour type, and in metastatic disease; performance status, anaemia, hypercalcaemia and increased erythrocyte sedimentation. In the dominating tumour type, clear cell renal RCC (cRCC), hypoxia is common, leading to an up-regulation of hypoxia inducible factor (HIF). The majority of cRCC have a mutation in the von Hippel Lindau gene (VHL-gene), which regulates HIF and in turn leads to up-regulation of a number of target genes for potential growth factors. The aim of the study was to evaluate the possible prognostic information of a few factors associated to pVHL/HIF, anemia and/or hypercalcaemia in RCC; erythropoietin (EPO) and it´s receptor (EPO-R), carbonic anhydrase IX (CA IX), parathyroid hormone-related protein (PTHrP) and osteopontin (OPN). Patients diagnosed with RCC between 1982-2007 were included in the studies. The tumour tissue expressions of EPO, EPO-R and PTHrP were assessed using immunohistochemistry. Serum/plasma levels of EPO, CA IX, PTHrP and OPN were also analyzed using immunometric methods. Our study demonstrated that the expression of EPO and EPO-R were related, and the expressions differed significantly between RCC types. The serum EPO levels did not associate to the tumour expression of EPO or EPO-R, indicating that circulating EPO derives from other sources than tumour cells. Erythropietin receptor expression was more frequent in advanced stages of disease, but neither EPO, nor EPO-R, were independent prognostic factors for survival. Serum CA IX levels were higher in cRCC compared to papillary RCC (pRCC). In cRCC, the CA IX serum levels correlated positively to TNM stage, but serum CA IX did not add independent prognostic information. Parathyroid hormone-related protein is a cause of hypercalcaemia in malignancy, and we observed that circulating PTHrP related to hypercalcaemia in RCC. The tumour expression of PTHrP associated positively to serum PTHrP, but not to serum calcium. We found an association between PTHrP and OPN in plasma, and both plasma PTHrP and OPN were positively associated to TNM stage. Neither serum/plasma PTHrP nor tumour expression of PTHrP were independent prognostic factors for survival. The serum OPN levels were higher in pRCC but no impact on survival was observed in this RCC type. In contrast, plasma/serum OPN was an independent prognostic factor for disease-specific survival in cRCC. Our results support a role for these factors in RCC. The expressions vary between tumour types, which can be explained by different gene aberrations. Some of the factors have a close relation to para-malignant symptoms like hypercalcaemia. Most of the factors correlate positively to TNM-stage, reflecting a relation to advanced disease. Although expression of EPO, EPO-R, PTHrP and CA IX did not add independent prognostic information, the results might contribute to greater understanding of important mechanisms and associations in RCC. Osteopontin is a strong independent prognostic factor in cRCC, and should be further evaluated as a tool in the clinic when treating RCC patients.
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Taylor, Ruth Rebecca. "An in vitro study of hair cell regeneration in the inner ear of the newt, Notopthalmus viridescens." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406187.
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Kadner, Diana. "Mechanism of cell adhesion at the midbrain-hindbrain neural plate in the teleost Danio rerio." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2009. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-23142.
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The correct development of multicellular organisms is tightly regulated by intrinsic and extrinsic factors at specific time points. Disturbance on any level of these multiple processes may result in drastic phenotypes or eventually death of the organism.
The midbrain-hindbrain boundary (also termed isthmic organizer) is a region of high interest as well in early as also in later development. The isthmic region carries organizer identity by the expression and subsequent release of FGF8. False patterning events of this region in early developmental stages would therefore display dramatic results over time. As it has been shown that the midbrain-hindbrain boundary (mhb) in the zebrafish is a compartment (or lineage restriction) boundary I tried to understand the underlying molecular mechanism for its correct establishment.
In this work I focused both on embryological, molecular and genetic means to characterize involved molecules and mechanisms. In the first part of the thesis I followed in vivo cell transplantation assays, having started with an unbiased one. Cells of either side the mhb were challenged with this boundary by bringing them into direct cell contact with their ectopic counterpart. In a biased approach, cells overexpressing mRNA of specific candidate genes were transplanted and their clonal distribution in host embryos was analyzed.
In the second part of the thesis I started interfering with specific candidate genes by transiently knocking down their protein translation. The adhesion molecules of the Eph/ephrin class had been shown to restrict cell mixing and thereby creating compartment boundaries in other tissues, such as the hindbrain, in the zebrafish and other organisms. Additionally, we generated several stable genetic mutant lines in cooperation with the Tilling facility at the Max-Planck-Institute. The only acquired potential null mutant ephrinB2bhu2971 was analyzed and characterized further. I observed that a knock down or knock out of only one of the ephrinB2 ligands does not seem to be sufficient for a loss of compartment boundary formation. The combinatory approach of blocking translation of EphrinB2a in ephrinB2bhu2971 mutants gave very complex and interesting phenotypes, which need to be investigated further.
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Presley, Tennille D. "Electron paramagnetic resonance (EPR) oximetry as a quantitative tool to measure cellular respiration in pathophysiological conditions." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1187014988.
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Goodyear, Richard John. "Distribution and development of hair-cell surface and extracellular matrix components in the chick inner ear." Thesis, University of Sussex, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.359083.
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Quint, Elizabeth. "An investigation of hair-cell degeneration and regeneration in the guinea-pig inner ear in vivo and in vitro." Thesis, Keele University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337090.
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Davies, Alexander Lloyd. "Role of the frizzled signalling pathway in control of hair cell production and polarity in the developing inner ear." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399278.
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Pamarthi, Pavan Kumar [Verfasser]. "Role of prostanoid receptor EP1 in the progression of non-small cell lung cancer (NSCLC) / Pavan Kumar Pamarthi." Gießen : Universitätsbibliothek, 2013. http://d-nb.info/106518395X/34.
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Cortina, Duran Carme. "Role of EphB receptors in intestinal epithelial cell positioning and colorectal cancer progression." Doctoral thesis, Universitat Pompeu Fabra, 2009. http://hdl.handle.net/10803/35692.
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In the intestinal epithelium, Wnt signaling drives the expression of the genes encoding
tyrosine kinase receptors EphB2 and EphB3 and represses the expression of their
membrane-tethered ligands, ephrin-Bs. Eph-ephrin interactions result in cellular
repulsion and are involved in boundary formation. The project of this thesis is to
understand the mechanism by which EphB−ephrin-B signals restrict cell positioning of
cell types (cell sorting) in the normal intestinal epithelium and suppress colorectal
cancer (CRC) progression beyond the earliest stages.
We have demonstrated that at the onset of CRC EphB receptors impair the expansion
of tumor cells through a mechanism dependent on E-cadherin–mediated adhesion. We
show that EphB-mediated compartmentalization restricts the spreading of EphB+ tumor
cells into ephrin-B1+ territories in vitro and in vivo. Our results indicate that CRC cells
must silence EphB expression to avoid repulsive interactions imposed by normal
ephrin-B1+ intestinal cells at the onset of tumorigenesis.
We have discovered that cell sorting is the outcome of two integrated mechanisms: cell
contraction/repulsion and differential cell adhesion. The latter is the driving force to
induce EphB/ephrin-B−mediated cell compartmentalization. We have developed in vitro
models to analyze the mechanisms that induce E-cadherin remodeling upon EphB
activation. We found RhoA, p120-catenin and the metalloproteinase ADAM10 as
downstream effectors of EphB signaling involved in the control of cell sorting in CRC
cells.<br>A l'epiteli intestinal, la ruta de senyalització Wnt indueix l'expressió dels gens que
codifiquen per als receptors tirosina kinasa EphB2 i EphB3 i reprimeixen la dels seus
lligands transmembrana, efrines de tipus B. Les interaccions Eph-efrina causen
repulsió cel·lular i estan implicades en la formació de fronteres entre compartiments.
La finalitat d'aquesta tesi és entendre el mecanisme pel qual la senyalització per
EphB−efrina-B restringeix el posicionament dels diferents tipus cel·lulars a l'epiteli
intestinal normal i suprimeix la progressió del càncer colorectal (CRC) en els primer
estadis.
Hem demostrat que, a l’inici del CRC, els receptors EphB restringeixen l'expansió de
les cèl·lules tumorals a través d'un mecanisme depenent d'adhesió intercel·lular a
través d’E-cadherina. En aquest treball es mostra in vitro i in vivo que la
compartimentalització mitjançada per la senyalització dels receptors EphB restringeix
l’invasió de les cèl·lules tumorals EphB+ als territoris efrina-B+. Aquests resultats
indiquen que les cèl·lules de CRC han de silenciar l’expressió d'EphB per evitar les
interaccions repulsives imposades per les cèl·lules intestinals normals efrina-B+
circumdants al començament del procés de tumorigènesi.
Hem pogut discernir que el reordenament cel·lular per senyals EphB−efrina-B és el
resultat de dos mecanismes integrats: la contracció/repulsió intercel·lular i l’adhesió
diferencial entre diferents poblacions cel·lulars. Aquesta última és la força principal que
condueix a la compartimentalització cel·lular mitjançada per EphB−efrina-B. Hem
desenvolupat models in vitro per analitzar els mecanismes que provoquen el
remodelament de la E-cadherina sota la senyalització per EphB. Presentem RhoA,
p120-catenina i ADAM10 com a efectors de la senyalització de la ruta EphB implicats
en el control de la compartimentalització cel·lular en el CRC.
27
Lin, Chia-Hui. "The Effects of Growth Hormone in the Inner Ear of Zebrafish (Danio rerio) during Hair Cell Regeneration." TopSCHOLAR®, 2010. http://digitalcommons.wku.edu/theses/191.
Texto completoResumen
Although deafness is a universal problem, effective treatments have remained elusive. In order to develop potential treatments, an overall understanding of the cellular process of auditory hair cell regeneration, which occurs in fish but not mammals, must be established. A previous microarray analysis and qRT-PCR validation of noise-exposed zebrafish showed that growth hormone (GH) was significantly upregulated during the process of auditory hair cell regeneration. Thus, GH may play an important role during hair cell regeneration. However, cellular effects of exogenous GH in the zebrafish auditory hair cell regeneration have not been examined after noise exposure. To understand the effect of GH in hair cell regeneration, adult zebrafish were exposed to a 150 Hz pure tone at a source level of 179 dB re 1 μPa RMS for 36 hours. Afterward the fish were immediately injected intraperitoneally with carp recombinant GH (20 μg/gram of body mass) or buffer (0.1 M, pH 7.4 phosphate buffer) and then placed in a recovery tank. The effect of GH on apoptosis in fish inner ear end organs were examined using TUNEL-labeling. Cell proliferation was measured by BrdU incorporation assay. Hair cell regeneration was determined by phalloidin-labeling to allow visualization of hair cell stereociliary bundles. After GH injection, the numbers of TUNEL-labeled cells showed a significant decrease in all three inner ear end organs (saccule, lagena, utricle), suggesting GH may suppress hair cell death induced by acoustic trauma. Higher levels of cell proliferation were also observed in the ears of GH-injected fish, indicating that GH is capable of activating cell mitosis in the zebrafish auditory system. Following sound exposure, the GH-injected group exhibited greater numbers of saccular hair cell bundles compared to the buffer-injected group. These results indicate that GH promotes hair cell regeneration following acoustic damage. Future studies are needed to examine the potential therapeutic benefits of GH in the mammalian ear.
28
Serra, Pagès Mariona. "Selective EP2 agonism attenuates hdm-induced murine airway pathology and mast cell activity, and triggers intracellular inhibitory signaling in mast cells." Doctoral thesis, Universitat Autònoma de Barcelona, 2012. http://hdl.handle.net/10803/84009.
Texto completoResumen
L'asma al lèrgica és una malaltia respiratòria crònica amb una alta prevalença en
els països desenvolupats. Els tractaments actuals no aturen el procés al lèrgic
subjacent ni aconsegueixen el control dels símptomes de la malaltia. El tractament
més eficaç és l'ús de corticoesteroids, que es basen en modificacions químiques de
potents hormones endògenes antiinflamatòries. L'estudi de vies antiinflamatòries
endògenes és una estratègia experimental eficaç per descobrir noves dianes
terapèutiques potencials contra l'asma. Una d'aquestes vies endògenes és la de la
ciclooxigenasa (COX). Prostaglandina (PG) PGE2, un producte de la COX, s'ha
suggerit que exerceixen un efecte protector en els pulmons. En particular, els
estudis experimentals en pacients amb asma van revelar que la PGE2 inhalada
redueix la hiperreactivitat bronquial i la inflamació. Aquest efecte de protecció de la
PGE2 també s'ha demostrat, directament i indirectament, en ratolins sensibilitzats
amb OVA o HDM. Els mecanismes subjacents als efectes beneficiosos de la PGE2 en
l'asma no es coneixen. Una de les característiques més constants de la PGE2 és la
seva capacitat de modular l’activitat dels mastòcits in vitro. Els nostres darrers
estudis in vivo van mostrar que la PGE2 també inhibeix l’activitat dels mastòcits en
ratolins sensibilitzats a HDM i que aquest efecte modulador sobre els mastòcits és
paral lel a la sobreexpressió del receptor EP2. D’aquests resultats sorgeix la
hipòtesi que la PGE2 podria interactuar amb els receptors EP2 dels mastòcits de la
superfície bronquials i així exercir una acció protectora enfront la patologia
impulsada pels al lèrgens en contactar amb les vies respiratòries. El coneixement
precís d’aquests mecanismes sens dubte ajudarà a descobrir potencials molècules
diana contra l'asma.
L'objectiu general d'aquesta tesi és establir preclínicament la rellevança del
receptor EP2 mastocitari en l’efecte beneficiós de la PGE2 en l'asma al lèrgica, i
descobrir els mecanismes moleculars que resulten d’aquesta activació selectiva del
receptor. Per aconseguir aquest objectiu hem dut a terme diversos abordatges in
vitro i in vivo.
En primer lloc, determinar el patró d’expressió dels receptors EP de la PGE2 en
diferents poblacions de mastòcits humans i murins, i es va avaluar a partir de
llavors (a) si aquestes diferències en l’expressió relativa dels receptors de EP 1-4
influïa en la capacitat de PGE2 per modular la degranulació dels mastòcits i la
mobilització del calci i (b) si els mastòcits humans es van comportar de manera
similar als murins en diferents escenaris d'expressió dels receptors EP. Els resultats
van apuntar a EP2 com el principal contribuent a l’efecte inhibitori de la PGE2 sobre
els mastòcits murins i humans. Quan EP2 es va suggerir com a el receptor primari
de protecció, vam abordar la importància de l’activació selectiva d’EP2 (a) en la protecció de la patologia de les vies respiratòries induïda per HDM en ratolins, i (b)
la correlació d’aquesta patologia amb la capacitat de l’agonista selectiu EP2 en
prevenir l’activitat de mastòcits in vivo. Hem demostrat que un agonista selectiu
d’EP2 impedia el desenvolupament de l’AHR i la inflamació, i que aquest efecte
estava relacionat amb la capacitat d'aquesta acció de l’agonista selectiu per atenuar
l’activitat dels mastòcits de les vies respiratòries. A continuació, es van estudiar
possibles mecanismes inhibitoris de senyalització implicats en aquest efecte de
bloqueig intervingut per EP2. Hem observat que l’agonisme d’EP2 inhibeix in vivo i
in vitro, l'activitat dels mastòcits. Hem descrit que la interacció amb PGE2-EP2
inhibeix la degranulació mastocitària a través de la supressió de la mobilització de
calci intervinguda per la inhibició de la via Src-Fyn, i cAMP/PKA.
Les nostres observacions ressalten que l’eix "la PGE2" - "l’EP2 mastocitari" - "les
vies respiratòries" és una via endògena que condueix a una protecció natural contra
la patologia de les vies respiratòries induïda pels aeroal lergens i ajuda a dilucidar
els mecanismes precisos que descobreixen molècules diana objectiu de possibles
nous tractaments antiasmàtics.<br>Allergic asthma is a chronic respiratory disease with a high prevalence in developed
countries. Current treatments do not halt the underlying allergic process and do not
always control the symthomps of the disease. The most effective treatment is the
use of glucocorticoids, which are based on chemical modifications of potent natural
endogenous anti-inflammatory hormones. Studying endogenous anti-inflammatory
pathways to explore new therapeutic targets is an efficient experimental strategy to
uncover potential novel targets against asthma. One of such endogeneous
pathways are cyclooxygenase (COX)-mediated. Prostaglandin (PG) PGE2, a COX
product, has been suggested to exert a protective effect in the lungs. Notably,
experimental studies with asthma patients revealed that inhaled PGE2 reduces
airway hyperresponsiveness and inflammation. This protective PGE2 effect has also
been demonstrated, directly and indirectly, in mice sensitized to OVA or HDM. The
mechanisms underlying the beneficial effect of PGE2 in asthma are not understood.
One of the most consistent features of PGE2 is its ability to modulate mast cell
activity in vitro. Our recent in vivo studies showed that PGE2 also prevents mast cell
activity in HDM sensitized mice and that this mast cell modulatory effect was
paralleled by EP2 receptor overexpression. These results brought up the hypothesis
that PGE2 might interact with EP2 receptor on the bronchial mast cells surface to
exert a protective action against allergen-driven airway pathology. The precise
understanding of such mechanisms will certainly help uncover potential anti-asthma
target molecules along the way.
The general objective of this thesis was to establish preclinically the relevance of
the mast cell EP2 receptor to PGE2 beneficial effect in allergic asthma, and to
uncover molecular mechanisms resulting from this receptor selective activation. To
achieve this objective we have undertaken several in vitro and in vivo approaches.
We first determined the PGE2 EP receptors expression pattern on different human
and murine mast cell population, and thereafter assessed (a) whether such
differences in the relative expression of EP receptors 1 to 4 influenced the ability of
PGE2 to modulate mast cells degranulation and calcium mobilization, and (b)
whether human mast cells behaved similarly to murine mast cells under different
EP receptors expression scenarios. The results pointed at EP2 as the main
contributor to mediate the inhibitory effect of PGE2 on both murine and human
mast cells. Once EP2 had been suggested to be the primary protective receptor, we
addressed the relevance of selective EP2 activation to (a) protection against HDMinduced
airway pathology in mice, and (b) correlation of such pathology to the
ability of selective EP2 agonism to prevent mast cells activity in vivo. We showed
that a selective EP2 agonist prevented AHR and inflammation from developing, and that such effect was linked to the ability of such selective agonistic action to
attenuate airway mast cell activity. We then studied potential inhibitory signaling
mechanisms involved in such EP2-mediated blocking effect. We observed that EP2
agonism inhibited in vivo and in vitro, mast cell activity. We described that the
PGE2-EP2 interaction on mast cells inhibiting mast cell degranulation through the
supression of calcium influxes mediated by an inhibition of the Src-Fyn pathway,
and cAMP/PKA.
Our observations highlight that the “PGE2”-“mast cells EP2”-“airway” axis is an
endogeneous pathway leading to natural protection against aeroallergens-induced
airway pathology, and helps elucidate the precise mechanisms that will uncover
clue molecules to be targeted by potential novel antiasthma treatments.
29
Lewis, Stephanie Rochelle. "Experimental infection with Sarcocystis neurona alters the immune response: the effect on CD4+, CD8+, B-cell, monocyte and granulocyte populations in horses." Thesis, Virginia Tech, 2009. http://hdl.handle.net/10919/33919.
Texto completoResumen
Previous studies have demonstrated differences in CD4+, CD8+ and B-cell populations between EPM affected and normal horses. The overall goal of our project was to further define the immune deficiencies associated with S. neurona infection. We hypothesized that PMA/I stimulated suppression in EPM horses is due to decreased proliferation of monocytes, CD4+ and CD8+ cells. Our objectives were 1) to determine whether S. neurona infection causes an increase in apoptosis of a particular immune subset, and 2) to determine whether S. neurona causes a decrease in the number of cellular divisions (proliferation) of a particular immune cell subset. <p>
For this study, nine S. neurona antibody negative, immunocompetent horses were obtained. Baseline neurologic examinations, SnSAG1 (S. neurona Surface Antigen 1) ELISAs on cerebrospinal fluid (CSF) and serum, and baseline immune function assays were performed. Horses were randomly divided into groups. Five horses were challenged for ten days via intravenous injection of autologous lymphocytes infected with S. neurona. Neurologic parameters of all horses were assessed for 70 days following infection. Immune function was based on proliferation responses to mitogens, as assessed through thymidine incorporation. Enumeration of cellular subsets, degree of apoptosis and number of cellular divisions were assessed through flow cytometry. SnSAG1 ELISA of serum and CSF samples performed post-infection confirmed infection and disease. All infected horses displayed moderate neurologic signs on clinical examination. Some significant differences in cellular activities were noted. Additionally, this is the first time the method using S. neurona infected lymphocytes has been reproduced successfully by different investigators.<br>Master of Science
30
Rubbini, Davide 1985. "Retinoic acid signaling mediates hair cell regeneration by repressing p27kip and sox2 in supporting cells." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/380543.
Texto completoResumen
Hair cell damage, caused by various insults, results in hearing loss in humans, one of the major health problems nowadays. In mammals damaged hair cells cannot regenerate, whereas lower vertebrates have retained the ability to replace them by inducing cell proliferation of supporting cells and/or their transdifferentiation. Retinoic Acid (RA) has been implicated in several organs regeneration but its role in hair cell regeneration is unknown. A combination of gene expression profiling, functional assays and cell-lineage tracing experiments allows us to highlight the importance of the RA pathway in hair cell regeneration in zebrafish. Regeneration is impaired upon blockade of the RA pathway in both the inner ear and lateral line systems together with a reduction of supporting cell proliferation. Moreover, the expression of RA pathway components is induced during hair cell regeneration, confirming the activation of the pathway. Finally, we demonstrate that RA is critical for downregulating p27kip and sox2 in supporting cells, allowing them to re-enter the cell cycle. This pivotal role of RA could be relevant in the development of future therapeutic strategies
31
Dieckmann, Mark Eric. "A survey of elementary plasma instabilities and ECH wave noise properties relevant to plasma sounding by means of particle in cell simulations." Thesis, University of Warwick, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327557.
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Hammad, Mira. "Reconstruction of auricular cartilage using natural-derived scaffolds with an in vivo application in rabbit model Effects of hypoxia on chondrogenic differentiation of progenitor cells from different origins Cell sheets as tools for ear cartilage reconstruction in vivo Cartilage tissue engineering using apple cellulosic scaffolds Cell-secreted matrices as cell supports: Novel approaches for cell culture applications." Thesis, Normandie, 2021. http://www.theses.fr/2021NORMC404.
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La reconstruction des défauts du cartilage auriculaire nécessite une restauration appropriée par des sources cellulaires adéquates ainsi que la fourniture de supports appropriés pour les tissus. Ce travail visait à étudier différents échafaudages et biomatériaux pour l'ingénierie in vitro du cartilage auriculaire ainsi que la réparation in vivo du cartilage auriculaire chez des modèles de lapin. Nous avons d'abord montré que les périchondrocytes auriculaires sont les meilleurs candidats pour la régénération du cartilage auriculaire et que l'hypoxie n'est pas nécessaire à leur différenciation chondrogénique. Ces cellules ont formé avec succès des feuillets de cellules cartilagineuses que nous avons utilisés pour régénérer le tissu cartilagineux in vitro et pour combler et reconstruire les défauts du cartilage in vivo dans des modèles allogèniques de lapins. Nous avons ensuite testé des tissus dérivés de la cellulose en décellularisant un tissu de pomme. Une fois recolonisés avec des cellules, ces échafaudages ont surpassé les hydrogels d'alginate en augmentant la croissance et en régulant l'expression cartilagineuse dans différentes cellules de mammifères. Dans la dernière partie de la thèse, nous avons examiné des matrices sécrétées par les cellules et les avons utilisées comme revêtement pour différentes applications de culture cellulaire. Il est intéressant de noter que ces supports, une fois lyophilisés, ont favorisé la culture de cellules allo- et xénogéniques, augmenté la prolifération et stimulé la chondrogenèse. Nous avons également mis en évidence la préservation du phénotype lors de l’amplification des chondrocytes par passages successifs. Notre étude fournit de nouveaux outils et approches pour de multiples applications de culture cellulaire<br>Successful reconstruction of auricular cartilage defects requires the appropriate restoration of the cartilaginous deformities by potential cell sources as well as providing suitable tissue supports. This work aimed to investigate different scaffolds and biomaterials for in vitro auricular cartilage engineering as well as in vivo auricular cartilage repair in rabbit models. We first showed that auricular perichondrocytes are the best candidates for auricular cartilage regeneration and hypoxia is not necessary for their chondrogenic differentiation. These cells successfully formed cartilaginous cell sheets which were used to regenerate cartilage tissue in vitro and to fill and reconstruct cartilage defects in vivo in allogenic rabbit models. Furthermore, we tested cellulose-derived tissue by decellularizing apple tissue and its use as a scaffold. Repopulated with cells, these scaffolds surpassed alginate hydrogels by enhancing colonization and upregulating the cartilaginous expression in different mammalian cells. In the final part of the thesis, we examined cell-secreted matrices and used them as a coating for different cell culture applications. Interestingly, these coatings promoted both allo- and xenogeneic cell culture, increased proliferation, and boosted chondrogenesis. We also highlighted phenotype preservation during chondrocytes expansion on these cell-secreted matrices. Our study provides novel tools and approaches for multiple cell culture applications
33
Ferguson, Shawn. "Non-steriodal anti-inflammatory drug-mediated regulation of COX-2 and EP3 receptor expression in the M-1 murine cortical collecting duct cell line." Thesis, University of Ottawa (Canada), 1999. http://hdl.handle.net/10393/8909.
Texto completoResumen
The cortical collecting duct (CCD) is a major site of intrarenal prostaglandin E2 (PGE2) synthesis. By indirect immunofluorescence using isoform specific antibodies, we have localized COX-1 and -2 immunoreactivity to all cell types of the murine M-1 CCD cell line. By, immunohistochemistry, both COX-1 and COX-2 were localized to the intercalated cells of the collecting duct on paraffin embedded mouse kidney sections. When COX enzyme activity was measured in the M-1 cells, both indomethacin (COX-1 and -2 inhibitor) and the specific COX-2 inhibitor NS-398 effectively blocked PGE2 synthesis. These results demonstrate that COX-2 is a major contributor to the pool of PGE2 synthesized by the CCD. PGE2 exerts predominantly diuretic and natriuretic effects upon the CCD. Our results which document the expression of COX-2 in the CCD provide a mechanism through which the newly developed class of COX-2 specific inhibitors could exert side effects with respect to the regulation of fluid and electrolyte homeostasis. (Abstract shortened by UMI.)
34
Shani, Saeideh. "The implication of cell-derived microvesicles in retinal pigment epithelium degeneration." Thèse, 2018. http://hdl.handle.net/1866/22150.
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Ashby, Edwina Kingsley. "EphA4 and ephrin-A interactions in avian neural crest cell segmentation." Thesis, 2005. http://hdl.handle.net/2440/61969.
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This thesis has involved the analysis of Eph/ephrin-A gene expression with respect to NC (neural crest) cell segmentation, identified EphA4 as a putative regulator of cell-cell communication during NC cell migration and more specifically, established that this protein plays a critical negative regulatory role in EMT.<br>Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biological Sciences, 2005
36
Newton, Sandra Claire. "Effects of a classroom-based direct instruction reading intervention for young children with sickle cell disease." 2004. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=81089&T=F.
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Watson, H., A. J. Cockbain, Jade A. Spencer, et al. "Measurement of red blood cell eicosapentaenoic acid (EPA) levels in a randomised trial of EPA in patients with colorectal cancer liver metastases." 2016. http://hdl.handle.net/10454/10200.
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Yes<br>We investigated red blood cell (RBC) PUFA profiles, and the predictive value of RBC EPA content for tumour EPA exposure and clinical outcomes, in the EMT study, a randomised trial of EPA in patients awaiting colorectal cancer (CRC) liver metastasis surgery (A.J. Cockbain et al., 2014). There was a significant increase in RBC EPA in the EPA group (n=43; median intervention 30 days; mean absolute 1.26 [±0.14]% increase; P<0.001), but not in the placebo arm (n=45). EPA incorporation varied widely in EPA users and was not explained by treatment duration or compliance. There was little evidence of ‘contamination’ in the placebo group. The EPA level predicted tumour EPA content (r=0.36; P=0.03). Participants with post-treatment EPA ≥1.22% (n=49) had improved OS compared with EPA <1.22% (n=29; HR 0.42[95%CI 0.16–0.95]). RBC EPA content should be evaluated as a biomarker of tumour exposure and clinical outcomes in future EPA trials in CRC patients.
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Krupke, Oliver A. "Cell signaling guides morphogenesis: roles for Eph-Ephrin signaling in sea urchin morphogenesis." Thesis, 2015. http://hdl.handle.net/1828/6443.
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The role that signaling molecules play during morphogenesis and their interactions is a field of intense study and the sea urchin represents a facile system to study these aspects of development in the early embryo. In many instances, the S. purpuratus genome contains relatively simple receptor-ligand signaling systems compared to vertebrate counterparts and this provides interesting opportunities to study their diversity of function during the morphogenetic events that shape the embryo. The Eph-Ephrin signaling components are an excellent example of this and they are represented by dozens of members in the vertebrate system with developmental functions that include axon guidance, cell migration and tissue segregation. In contrast, the sea urchin genome contains a single Eph receptor and a single Ephrin ligand and by interacting with different effectors of signal transduction, this simple, bipartite system can fulfill a variety of functional roles during morphogenesis. Studying the function of Eph-Ephrin signaling in the sea urchin embryo, I have revealed two distinct morphogenetic movements in which Eph-Ephrin signaling is necessary; apical constriction of ciliary band cells and pigment cell migration. In both examples, a functionally relevant Ephrin gradient establishes spatial information in the developing tissues, producing a reaction from cells expressing the Eph receptor. In the case of pigment cells, the distribution of migrating cells is affected and in the case of ciliary band cells, apical constriction occurs. The different outcomes of Eph-Ephrin signaling in these two tissues exemplifies signaling components communicating spatial information and initiating morphogenetic programs with outcomes dependent on cellular context. Furthermore, I have identified downstream components of Eph-Ephrin signaling that have necessary functions in both models, illustrating how different cellular programs can be induced by the same signaling
iii
iv components. My research contributes to understanding fundamental aspects of how
complex 3 dimensional tissues arise from the genes and regulatory elements encoded in metazoan genomes.<br>Graduate
39
Martinez, Calixto Luis Edmundo. "In situ expression of cytokeratins and Ber-EP4 antigen in ameloblastomas and basal cell carcinomas." 2006. http://proquest.umi.com/pqdweb?did=1075713341&sid=9&Fmt=2&clientId=39334&RQT=309&VName=PQD.
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Thesis (M.S.)--State University of New York at Buffalo, 2006.<br>Title from PDF title page (viewed on July. 19, 2006) Available through UMI ProQuest Digital Dissertations. Thesis adviser: Aguirre, Alfredo. Includes bibliographical references.
40
Pai, Chien-Hua, and 白倩華. "Erythropoietin (EPO) Attenuated Nitric Oxide Cytotoxicity in a Human Neuronal Progenitor NT2 Cell Line." Thesis, 2000. http://ndltd.ncl.edu.tw/handle/73861155463822622457.
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碩士<br>國立陽明大學<br>醫學生物技術研究所<br>88<br>Erythropoietin (EPO), a 34-kD glycoprotein produced in the mammalian kidney and liver, was originally thought to act only on erythroid progenitor cells by stimulating their survival, proliferation, and differentiation. There is now evidence that EPO and EPO receptor mRNA are present in certain nonhematopoietic tissues such as the developing human CNS, and a human committed neuronal precursor cell line (NT2) derived from teratocarcinoma. However, the physiological role of EPO at these sites remains to be elucidated. In this study, we assessed the protective effect of EPO on nitric oxide-induced as opposed to ceramide- or H2O2-induced cytotoxicity in NT2 cells. Cell viability was monitored by vital dye (trypan blue) exclusion or by measuring mitochondrial dehydrogenase activity, using the commercial cell proliferation WST-I reagent. We found that sodium nitroprusside (SNP; a nitric oxide donor) at 10-11~10-3 M decreased NT2 cell viability after either 15 minutes or 24 hr incubation. Pretreatment of cells with recombinant human EPO at 0.31~2.5 IU/mL for 24 hr attenuated SNP- induced reduction in cell viability in a dose-related manner. The protective effect of EPO was evident at 0.5 hr after EPO exposure, the shortest time examined. EPO repressed the activity of an apoptosis-promoting enzyme, caspase 3 (CPP32), and enhanced the expression of an anti-apoptosis protein bcl-2, as assessed by Western blotting. By contrast, EPO had no protective effect on either ceramide (10-5~10-4 M)- or H2O2(100 mM)- induced reduction of cell viability. Furthermore, EPO did not alter proliferation of NT2 cells, as evidenced by proliferating cell nuclear antigen (PCNA) expression and [3H]thymidine incorporation. In conclusion, we have demonstrated that EPO appears to specifically protect NT2 cells from nitric oxide-induced cell death by down-regulating pro-apoptotic mechanisms such as the activation of CPP32, and by up-regulating anti-apoptotic signals such as bcl-2 expression.
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Koo, Diana Hung-Hung. "The role of discoidin domain receptor 1 in maintaining E-cadherin-mediated cell-cell contacts in the mammary gland." 2007. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=452872&T=F.
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Elghouche, Alhasan Najib. "Modulation of the Notch Signaling Pathway in 3D Stem-Cell Derived Culture of Inner Ear Organoids." 2016. http://hdl.handle.net/1805/10907.
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Indiana University-Purdue University Indianapolis (IUPUI)<br>Hearing loss and vestibular dysfunction are inner ear disease states that arise from
an array of diverse etiologies that interfere with mechanosensory hair cell function,
including: congenital syndromes, noise-induced trauma, ototoxic drugs, and aging. The
investigation of normal inner ear development and the pathological aberrations that cause
inner ear disease has been previously advanced through formation of an easily generated,
scalable, accurate in vitro model system that readily facilitates experimental applications.
This model utilizes a 3D floating cell culture protocol which guides differentiation of
stem cell aggregates into inner ear organoids, which are vesicles containing a sensory
epithelium with functioning mechanosensory hair cells. Inner ear organoid formation
enables studying the effects of modulating the signaling pathways that guide developing
inner ear structure and function. The Notch signaling pathway heavily influences the
formation of the inner ear through two major mechanisms: lateral induction of sensory
progenitor cells and lateral inhibition to determine which of those progenitors
differentiate into mechanosensory hair cells. The effects of inhibiting Notch signaling
within the inner ear organoid system were explored through application of the ɣ-secretase
inhibitor MDL28170 (MDL) at a concentration of 25μM on day 8 of organoid culture.
Aggregates were harvested on day 32, fixed, sectioned, and stained according to a
standard immunohistochemistry protocol. Sections were stained for the mechanosensory
hair cell markers Myosin7a (Myo7a) and Sox2. MDL-treated aggregates demonstrated statistically significant reductions in the total number of vesicles and the number of
vesicles containing hair cells compared to control aggregates. In contrast to control
aggregates which demonstrated two distinct organoid variants (protruding and
embedded), MDL-treated aggregates only formed the embedded variant. Differences in
the expression pattern of Sox2, which is also a marker of stemness and neural progenitor
cells were also noted between the two conditions. MDL-treated aggregates demonstrated
regions of ‘ectopic’ Sox2 expression whereas Sox2 expression in control aggregates was
consistently expressed within Myo7a+ regions.
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Kuo, Kuang-Tai, and 郭光泰. "The Roles of PGE2 Receptor EP2 and Epithelial-Mesenchymal Transition in Tumor Invasion in Esophageal Squamous Cell Carcinoma." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/43206953913702866705.
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博士<br>國立陽明大學<br>臨床醫學研究所<br>100<br>Esophageal cancer is ranking the sixth most lethal cause for male cancer patients in Taiwan and is responsible for nearly 1,500 deaths per year. Currently, its 5-year survival is still less than 20%. Recently, it has been well known that cyclooxygenase-2 (COX-2) plays an important role in tumor progression of several cancers and PGE2 is linked to carcinogenesis more closely than other prostaglandins. PGE2 elaborates its biological activities via PGE2 receptors, namely EPs, which are composed of four isoforms (EP1 to EP4). Regarding esophageal cancer, previous cell line studies have shown that the expression of EP2 was stronger than other EPs in esophageal cancer.
In the first part of this thesis, EP2 expression was evaluated by immunohistochemical staining in the surgical specimens in 226 patients of esophageal squamous cell carcinoma (ESCC) undergoing en bloc resection and the relationship between EP2 expression and clinicopathologic parameters was analyzed. The results showed that EP2 overexpression was found in 43.4% (98/226) of patients. Meanwhile, EP2 overexpression correlated positively with the T status (p=0.016) and was associated with a worse overall survival (p=0.047). EP2 overexpression also predicted a worse prognosis in 84 patients with earlier stages (T1-3N0M0, stage I and IIA) (p=0.027) and even became an independent factor under multivariate analysis among them (p=0.048).
Because EP2 overexpression was found to correlate positively with the depth of tumor invasion (T status) in ESCC, the topics regarding tumor invasion therefore became our interest of investigation. Recently, Snail is acknowledged as a key regulator of epithelial-mesenchymal transition (EMT). Regarding the studies investigating Snail, it has been reported that NBS1 overexpression induces EMT through up-regulation of Snail in head and neck squamous cell carcinoma (HNSCC). Because head and neck cancer and esophageal cancer are both composed of squamous cell carcinoma in majority, our question is whether the relationship between NBS1 and Snail in HNSCC also exists in ESCC.
In the second part of this thesis, NBS1 and Snail expression was evaluated in the surgical specimens in 153 patients of ESCC undergoing en bloc resection by immunohistochemical staining and the relationship between NBS1, Snail expression and clinicopathologic parameters was analyzed. NBS1 overexpression was found to associate with better overall survival (p=0.002). On the other hand, Snail overexpression was associated with worse overall survival (p=0.036). Interestingly, NBS1 overexpression correlated inversely with Snail overexpression marginally (correlation coefficient: -0.14, p=0.084). From the abovementioned results, we found that both EP2 and Snail were associated with worse prognosis in ESCC. Because EP2 is an upstream receptor and Snail is a transcription factor, it is interesting to know whether there exists some relationship between EP2 and Snail.
In the third part of this thesis, the expression of EP2 was evaluated in 4 ESCC cell lines including CE48T (or 48T), CE81T (or 81T), CE146T (or 146T) and CETE2 (or TE2). It was found that at both mRNA and protein level, the 48T and 146T cell lines exhibited stronger expression of EP2 than 81T and TE2. Subsequently, it was shown that treating with PGE2 or the selective EP2 agonist Butaprost caused significant increase of migration and invasion in 48T and 146T but not in 81T and TE2. Using 48T and viral transfection with Lentivirus, the protein expression of EP2 was successfully knocked down to 50% and 30% of original level in clone 48T-sh-EP2(144147)-0.5 and 48T-sh-EP2(144147)-1, respectively. Further studies revealed that irrespective of the treatment of Butaprost, migration and invasion of 48T-sh-EP2(144147)-1 decreased significantly. To elucidate whether Butaprost influences cell proliferation of ESCC cells, the SRB (Sulforhodamine B) test was also conducted on cell lines and it was found that cell proliferation was not significantly changed by the treatment of Butaprost.
In the fourth part of this thesis, using real-time quantitative polymerase chain reaction (Q-PCR), matrix metalloproteinase (MMP) array, reverse transcription PCR (RT-PCR) and Western blot analysis, it was found that Snail and Slug increased, whereas E-cadherin decreased, after treatment of Butaprost. The changes of MMPs were not remarkable. Finally, different inhibitors including SQ22536 (inhibitor of adenylyl cyclase), H89 (inhibitor of PKA) and LY294002 (inhibitor of PI3K) were applied in combination with Butaprost to treat 48T cells and it was found that SQ22536 and LY294002 both inhibited migration and invasion of 48T cells after treating by Butaprost but H89 increased migration and invasion. Based on the results, it was speculated that apart from the cAMPàPKAàCREB pathway, the PI3K/Aktàβ-catenin pathway also plays an important role in the process of EP2àEMT.
To sum up, our current study showed that the PGE2 receptor EP2 does play an important role in tumor invasion in ESCC cells. EP2 may mediate Snail, Slug and subsequent EMT through different signaling pathways to increase invasiveness of ESCC cells.
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Kauzman, Adel. "Cyclin D1 alterations in giant cell tumor of bone and central giant cell granuloma of the jaw." 2004. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=80965&T=F.
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Li, Elaine Y. H. "Immunological reaction in cell transplantation into the infarcted myocardium." 2004. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=95206&T=F.
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Austin, James W. "Molecular mechanisms of Fas mediated cell death in oligodendrocytes." 2006. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=450581&T=F.
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Yau, Daphne. "Insulin resistance precipitates beta-cell dysfunction and beta-cell expansion in a non-obese model of type 2 diabetes." 2005. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=370474&T=F.
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Ashtiani, Kaihan Abidi. "A two-dimensional particle-in-cell (PIC) model of an axisymmetric electron-cyclotron-resonance (ECR) plasma-processing system." 1995. http://catalog.hathitrust.org/api/volumes/oclc/32864984.html.
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Lu, Carole Chih-Chen. "Cranial Neural Crest Cell Migration in the Avian Embryo and the Roles of Eph-A4 and Ephrin-A5." Thesis, 2007. https://thesis.library.caltech.edu/4073/1/carole_lu.pdf.
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<p>The neural crest is a transient population of cells that migrate away from the dorsal neural tube in the vertebrate embryo. As the developing hindbrain constricts into rhombomeres, cranial neural crest cells migrate in three discrete streams adjacent to even-numbered rhombomeres, rhombomere 2 (r2), r4, and r6.</p>
<p>To test the role of intrinsic versus extrinsic cues in influencing an individual cell’s trajectory, we implanted physical barriers in the chick mesoderm, distal to emerging neural crest cells (NCCs). We analyzed spatio-temporal dynamics as NCCs encountered and responded to the barriers by using time-lapse confocal microscopy and cell tracking analysis. The majority of NCCs were able to overcome physical barriers. Even though the lead cells become temporarily blocked by a barrier, follower cells find a novel pathway around a barrier and become de novo leaders of a new stream. Quantitative analyses of cell trajectories find cells that encounter an r3 barrier migrate significantly faster but less directly than cells that encounter an r4 barrier, which migrate normally. NCCs can also migrate into normally repulsive territory as they reroute. These results suggest that cranial neural crest cell trajectories are not intrinsically determined. NCCs can respond to minor alterations in the environment to retarget a peripheral destination. Both intrinsic and extrinsic cues are important in patterning.</p>
<p>We then tested the role of Eph/ephrin signaling on cranial neural crest migration by ectopically expressing full-length ephrin-A5 ligand; a truncated, constitutively active EphA4 receptor; and a truncated, kinase-dead EphA4 receptor within migratory neural crest cells. Ectopic expression of ephrin-A5 specifically causes the r6 subpopulation of neural crest cells to have truncated migration but does not affect directionality, suggesting that the r6 neural crest cells properly follow guidance cues. Our results support a role for ephrin-A5 in regulating the extent of migration.</p>
<p>Ectopic expression of constitutively active, truncated EphA4 causes NCCs to migrate aberrantly around the otic vesicle. Pathfinding errors are accompanied by changes in migratory behavior, with the NCCs migrating faster but with less directionality. Expression of a truncated, kinase-dead version of EphA4 also leads to pathfinding errors. Our results suggest Eph activity is involved in guidance and extent of migration.</p>
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Saibil, Samuel David. "Protein kinase B signaling in T cell survival and tolerance." 2009. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=968417&T=F.
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