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Cheng, Jade. "Regulation of cell division and cell death by GRASP65." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.544414.
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Otake, Andreia Hanada. ""Papel de dissialogangliosídios na proliferação e morte celular induzida de melanócitos e melanomas in vitro"." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-26052006-113740/.
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Dissialogangliosídios, como GD3 e derivados são marcadores da progressão de melanomas. Para avaliar as possíveis funções desta molécula, transfectamos células de melanócitos com o gene da enzima ST8Sia I, que converte GM3 em GD3. Mostramos que GD3 não interfere na capacidade proliferativa dessas células, porém a expressão de GD3 mostrou-se associada à sobrevivência celular. Melanomas adquirem autonomia quanto às vias dependentes do fator de crescimento de fibroblastos (FGF-1 e -2). A expressão de GD3 não interfere na resposta proliferativa a estes fatores, porém GD3 e outros glicoesfingolipídios de membrana modulam a resposta migratória induzida por FGF-2. A expressão de GD3 sensibiliza as células à morte celular induzida por diferentes quimioterápicos, como cisplatina e vimblastina; porém, torna as células resistentes ao tratamento com temozolamida. A sensibilização ao tratamento com vimblastina, mas não às outras drogas, depende da presença de GD3, como observado por ensaios de depleção metabólicaDisialoganglioside GD3 and its derivatives are melanoma progression markers. To evaluate the possible roles of these molecules along melanoma progression, we have transfected the GD3 synthase gene (ST8Sia I) in a melanocyte cell line. Accumulation of GD3 did not confer any proliferative advantage to melanocytes. However, GD3 expression was associated with cell survival. The autonomic growth of melanomas is in part related to a constitutive activation of fibroblast growth factor dependent pathways. GD3 expression did not alter the proliferative response to either FGF-1 or FGF-2. However, GD3 and other membrane glycospingolipids modulate the motogenic activity of FGF-2. GD3 expression sensitizes melanocytes to chemotherapeutic agent-induced cell death, as cisplatin and vimblastin. On the other hand, GD3 turned melanocytes more resistant to temozolomide. Chemosensitization to vimblastin, but not to the other drugs, was dependent on the presence of GD3 within the cells, as shown by metabolic depletion of glycosphingolipids
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Chalabi, Asma. "Processus d'analyse dynamique pour l'imagerie de cellules vivantes permettant la détection des réponses cellulaires aux anticancéreux, par traitement de l'image et du signal et apprentissage automatique profond." Electronic Thesis or Diss., Université Côte d'Azur, 2024. http://www.theses.fr/2024COAZ6004.
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La division et la mort cellulaires sont les principaux indicateurs permettant d'évaluer l'action des thérapies ciblées dans le cancer, et seules leurs mesures précises peuvent révéler l'efficacité réelles d'un traitement. La détection des événements de division et de mort cellulaires dans les essais sur cellules vivantes a le potentiel de produire des mesures robustes de la pharmacodynamique des anticancéreux et de permettre une compréhension plus complète des réponses de cellules tumorales aux combinaisons thérapeutiques. Connaître précisément le moment de la mort ou de la division cellulaire dans une expérience sur cellules vivantes permet d'étudier la contribution relative des différents effets des médicaments, tels que les effets cytotoxiques ou cytostatiques, sur une population de cellules. Cependant, les méthodes classiques nécessitent des colorants pour mesurer la viabilité cellulaire avec des comptages de populations à un temps final, où les taux de prolifération ne peuvent être estimés que lorsque les cellules viables et mortes sont marquées simultanément.L'imagerie de cellules vivantes est une technique prometteuse pour déterminer l'efficacité des médicaments, la principale limitation étant la précision et la profondeur des analyses pour extraire automatiquement des mesures de description de phénotypes de réponse cellulaire (mort et division cellulaires, qui partagent certaines caractéristiques morphologiques).Cette thèse propose une méthode intégrant de l'apprentissage automatique profond par réseau de neurones et du traitement de l'image et du signal afin d'effectuer des analyses de réponses cellulaires en utilisant l'imagerie dynamique de cellules uniques dans des expériences de profilage pharmacologique d'anticancéreux. Cette méthode procède par suivi automatique des cellules, extraction de caractéristiques cellulaires radiométriques et morphologiques, et analyse de l'évolution de ces caractéristiques au cours du temps pour chaque cellule afin de détecter des événements tels que la division et la mort cellulaire ainsi que d'enregistrer des dynamiques de signalisation cellulaire.Un cas d'étude comprenant l'analyse des dynamiques en cellules uniques de l'activité caspase-8 et de différentes caractéristiques cellulaires impactées par le traitement anticancéreux est présenté. L'objectif est de réaliser automatiquement et à grande échelle les analyses nécessaires pour faire évoluer la méthode de prédiction des phénotypes cellulaires (Fateseq) disponible dans le laboratoire, et de l'appliquer à diverses lignées cellulaires cancéreuses d'un panel de lignées cellulaires cancéreuses humaines afin d'améliorer les approches de profilage OMICS sur cellules vivantes et, à plus long terme, d'intensifier le criblage pharmacologique de nouveaux médicaments anticancéreuxCell division and cell death are the main indicators to evaluate cancer drug action, and only their accurate measures can reveal the actual potency and efficacy of a compound. The detection of cell division and cell death events in live-cell assays has the potential to produce robust metrics of drug pharmacodynamics and return a more comprehensive understanding of tumor cells responses to cancer therapeutic combinations. Knowing precisely when a cell death or a cell division occurs in a live-cell experiment allows to study the relative contribution of different drug effects -such as cytotoxic or cytostatic effects, on a cell population. Yet, classical methods require dyes to measure cell viability as an end-point assay with whole population counts, where the proliferation rates can only be estimated when both viable and dead cells are labeled simultaneously.Live-cell imaging is a promising cell-based assay to determine drug efficacies, with the main limitation being the accuracy and depth of the analyses to detect and predict automatically cellular response phenotypes (cell death and division, which share some morphological features).This thesis introduces a method integrating deep learning using neural networks, and image and signal processing to perform dynamic image analyses of single-cell events in time-lapse microscopy experiments of drug pharmacological profiling. This method works by automatically tracking the cells, extracting radiometric and morphologic cell features, and analyzing the temporal evolution of these features for each cell so as to detect cellular events such as division and cell death, as well as acquiring signaling pathway dynamics.A case of study comprising the analyses of caspase-8 single-cell dynamics and other cell responses to cancer drugs is presented. The aim is to achieve automatically, at a large scale the necessary analyses to augment the phenotype prediction method available in the lab (Fateseq) and to apply it to various cancer cell lines of a human cancer cell line panel to improve our live-cell OMICS profiling approaches, and, in a longer term, to scale up pharmacological screening of new cancer drugs
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Green, Katherine J. "The effect of acute exercise on T-lymphocyte function." Thesis, Queensland University of Technology, 2002. https://eprints.qut.edu.au/36777/1/36777_Digitised%20Thesis.pdf.
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An increased incidence of illness has been observed in athletic populations undergoing intensive training and competition. T-lymphocytes are central to cell-mediated adaptive immune responses and have been the subject of many studies investigating the relationship between T-lymphocyte function, exercise and athlete health. A decrease in T-lymphocyte function following acute intensive exercise has commonly been described, making them a possible factor contributing to increased susceptibility in athlete populations. However, there is much controversy regarding the interpretation of traditional methodology (mitogen-induced proliferation assays) used to assess Tlymphocyte function during and after exercise. Current lymphocyte proliferation assays do not determine individual T-lymphocyte function or independently establish the function of T-lymphocyte subsets. Therefore, the overall aim of this thesis was to develop and apply new techniques to the study of the effect of acute exercise on the function of T-lymphocytes. Specifically, this thesis aimed to determine the effect of acute intensive exercise on the function of individual T-lymphocytes and T-lymphocyte subsets. The major findings of this thesis are that acute intensive exercise does impair Tlymphocyte responses to mitogen. The cellular expansion of both CD4 and CD8 Tlymphocytes as measured by the application of the new CFSE technique is decreased by acute exercise. The exercise effect observed is not an initial effect on cell function, as exercise does not impair the ability of T-lymphocytes to respond to stimulus (activation) and undergo cell division (mitosis) in response to mitogen. Instead, acute exercise is associated with an increased level of apoptosis in mitogen-stimulated cultures and this results in a reduction of the overall expansion of the cell population in vitro. The mechanism by which exercise induces apoptosis was examined using carbohydrate supplementation and it was found that carbohydrate feeding can prevent exercise-induced apoptosis, and hence attenuates the decrease in T-lymphocyte function. However, the mechanism by which carbohydrate prevents apoptosis does not appear to be via moderation of T-lymphocyte numbers or blood cortisol concentrations, rather it may be due to improved glucose availability.
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Pat, Sze Wa. "Cell metabolism in cell death and cell growth." HKBU Institutional Repository, 2007. http://repository.hkbu.edu.hk/etd_ra/775.
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Dix, Christina Lyn. "Adhesion-dependent cell division." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10044469/.
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Animal cells undergo a dramatic series of cell shape changes as they pass through mitosis and divide which depend both on remodelling of the contrac- tile actomyosin cortex and on the release of cell-substrate adhesions. Here, I use the adherent, non-transformed, human RPE1 cell line as a model system in which to explore the dynamics of these shape changes, and the function of mitotic adhesion remodelling. Although these cells are highly motile, and therefore polarised in interphase, many pause migration and elongate to be- come bipolar prior to mitosis. Interestingly, and in contrast to most reported cell types, these cells do not round fully, and many leave long adhesive tails con- nected to the underlying substrate. These are typically bipolar, persist through- out mitosis, and guide cell respreading following mitotic exit. Further analysis shows that while many proteins are lost from focal adhesion complexes during mitotic rounding, integrin-rich contacts remain in place along these tails as well as defining the tips of retraction fibres. These adhesions are functionally impor- tant in RPE1 cells, since these cells fail to divide when removed from the sub- strate prior to entry into mitosis. The restoration of cell-substrate adhesions at anaphase are sufficient to rescue division in control cells. However, adhesions must persist into mitotic exit for division in cells compromised in their ability to construct an actomyosin ring. Division in these cells depends on respreading, since Ect2 RNAi cells fail to divide on small adhesive islands, but successfully divide on larger patterns with the cytoplasmic bridge connecting daughter cells narrowing as they migrate away from one another. Together these results re- veal the importance of coupling adhesion remodeling to mitotic progression.
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Ellison, David William. "Cell proliferation, cell death, and differentiation in gliomas." Thesis, University of Southampton, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295912.
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Crisby, Milita. "Cell death in atherosclerosis /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-3191-7/.
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Gorak-Stolinska, Patricia. "Activation induced cell death in human T cell subsets." Thesis, King's College London (University of London), 2002. http://kclpure.kcl.ac.uk/portal/en/theses/activation-induced-cell-death-in-human-t-cell-subsets(eb708e24-eccb-42fc-8930-d62ddf6794c1).html.
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RUNYAN, CHRISTOPHER MICHAEL. "The Role of Cell Death in Germ Cell Migration." University of Cincinnati / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1210732680.
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Skoog, Karl. "Cell division in Escherichia coli." Doctoral thesis, Stockholms universitet, Institutionen för biokemi och biofysik, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-62908.
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The Gram-negative bacterium Escherichia coli is a model system to describe the biochemistry and cell biology of cell division in bacteria. This process can be divided into three major steps. The first step involves the replication of the DNA, followed by an elongation step in which the cells become twice as long. In the last step the elongated cell constricts in the middle and the two daughter cells are separated. The cell division process in E. coli has been extensively studied for at least 50 years and a lot is known, however many details are still vague. New proteins involved in the process continue to be identified and the number of these proteins as well as the interactions among them are not yet fully known. It is therefore not completely understood how the contraction proceeds to form two daughter cells. In this thesis, I have carried out experiments that contribute to our understanding of cell division in E. coli. Using fluorescence microscopy I show that the contraction of the inner membrane in dividing E. coli proceeds in a linear fashion and that the periplasm closes after the cytoplasm. I have also analyzed the oligomeric state of two proteins involved in the cell division and I show that the early cell division protein ZipA can dimerize. This could explain how this protein can bundle FtsZ protofilaments, as it could bridge two protofilaments. Penicillin-binding protein 5 (PBP5) has been found to localize to the septum and it has been suggested to be connected to cell division. I have found that PBP5 forms a homo-oligomeric complex, most likely a dimer. The dimer can be modeled in a back-to-back conformation with the catalytic domains being flexible. This allows PBP5 to reach for pentapeptides of the peptidoglycan at different distances from the membrane. An understanding of the mechanisms used by the cell division proteins and their protein: protein interactions can be a first step towards determining new antibiotic targets.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 4: Manuscript.
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Uppington, Kay Marie. "Cell death in prion disease." Thesis, University of Bath, 2008. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.488879.
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Prion diseases are a group of fatal neurodegenerative diseases, including CJD and scrapie, which are thought to be caused by a protein termed a prion (PrP). As manganese has previously been suggested to be involved in prion disease we have investigated manganese binding to PrP and its role in the toxicity of the protein. We have shown that manganese bound PrP (MnPrP) has several of the characteristics of the disease form of PrP, including protease resistance and toxicity that is dependent on cellular PrP expression. Further investigation into the mechanism of toxicity revealed that MnPrP is significantly more toxic to neuronal cells than nonmanganese bound PrP and that toxicity requires the presence of known metal binding residues within the protein. We have demonstrated that treatment of neuronal cells with MnPrP causes caspase 3 activation and apoptosis, as demonstrated by DNA laddering, and we hypothesise that caspase 3 is activated by a p38 pathway. Treatment of neurones with MnPrP also caused a significant increase in cellular ROS production, although this did not appear to be a major cause of cell death as antioxidants were unable to save cells from cell death. We also investigated mechanisms by which cells can survive scrapie infection and MnPrP toxicity. We have shown that cells infected with scrapie have increased ERK activation which was important for their survival. Cells that survived MnPrP treatment were also found to have increased ERK activation. This suggests that ERK may have a protective role in prion diseases and may be a potential therapeutic target.
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Wongchaowart, Michael B. "Optimization of cell adhesion environments for a liver cell bioreactor." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/34156.
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Thesis (M. Eng.)--Massachusetts Institute of Technology, Biological Engineering Division, February 2006.Includes bibliographical references (p. 40-44).
The MilliF bioreactor offers great potential for the formation of i vivo-like liver tissue outside the body, making it a valuable tool for applications such as drug toxicity models and biosensors. Cell adhesion is an important factor in the maintenance of differentiated hepatocyte functions. Hepatocyte adhesion environments were examined in two settings: spheroid culture prior to seeding in the bioreactor and 2D surface culture methods that could be applied to the bioreactor scaffold. Spheroids were formed either by culturing in spinning suspension or on a static, non-adherent surface. In spheroid culture, the addition of extracellular matrix (ECM) signaling through the use of soluble Matrigel or adhesion protein-coated microspheres did not improve hepatocyte viability or function as assessed by liver-specific gene expression. These results suggest the importance of cell-cell rather than cell-surface interactions in maintaining hepatocytes. Optimal culturing of spheroids in spinning suspension without the ECM addition was found to be 3 days without media changes. 2D surfaces were treated with an adhesion peptide-conjugated comb polymer, preventing nonspecific cell adhesion and allowing attachment through the [alpha]₅[beta]₁ integrin.
(cont.) Varying the proportion of adhesion peptide presented to cells was found to regulate hepatocyte morphology and function; a surface with decreased hepatocyte spreading and liver-specific gene expression closer to in vivo was characterized. Immunoblotting for activated focal adhesion kinase (FAK) revealed that FAK signaling was not induced by attachment to the comb polymer surfaces. Immunostaining for other liver cell types demonstrated that the surface allowed hepatic stellate cell and Kupffer cell adhesion.
by Michael B. Wongchaowart.
M.Eng.
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Rabodzey, Aleksandr. "Flow-induced mechanotransduction in cell-cell junctions of endothelial cells." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/41586.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2006.Includes bibliographical references (leaves 86-92).
Endothelial cells show an unexpected behavior shortly after the onset of laminar flow: their crawling speed decreases ~40% within the first 30 min, but only in a confluent monolayer of endothelial cells, not in subconfluent cultures, where cell-cell interactions are limited. This led us to study early shear effects on cell-cell adherens junctions. We found a 30±6% increase in the number of VE-cadherin molecules in the junctions. The strength of interactions of endothelial cells with surfaces coated with recombinant VE-cadherin protein also increased after laminar flow. These observations suggest that endothelial cell junction proteins respond to flow onset. The process of clustering may induce diffusion of monomers to the junction area, resulting in an overall increase in VE-cadherins in the junctions. To directly confirm the role of adherens junctions in the decrease in cell crawling speed, we used siRNA-knockdown technique to produce cells lacking VE-cadherin. These cells showed no decline in crawling speed under flow. Our interpretation is consistent with previous data on junction disassembly 8 hr after flow onset. The speed of endothelial cell crawling returns to the original level by that time, and junctional disassembly may explain that phenomenon. In order to understand better the change in VE-cadherin distribution under flow and during junction formation and remodelling, we developed a mathematical model of VE-cadherin redistribution in endothelial cells. This model allowed us to develop a quantitative framework for analysis of VE-cadherin redistribution and estimate the amount of protein in the junctions and on the apical surface. In addition to that, the model explains rapid junction disassembly in the leukocyte transmigration and junction formation in subconfluent cells.
(cont.) These studies show that intercellular adhesion molecules are important in the force transmission and shear stress response. Their role, however, is not limited to flow mechanotransduction. Intercellular force transmission has an important application - organ development and, specifically, angiogenesis. We studied the role of VE-cadherin in vessel development in HUVECs and showed that VE-cadherin-null cells do not form vessels in the in vitro assay. This observation confirms the important role of intercellular force transmission in response to external force caused by flow or exerted by other cells.
by Aleksandr Rabodzey.
Ph.D.
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Jahnke, Ulrike. "Cell cycle de-regulation and cell death in leukaemia chemotherapy." Thesis, Queen Mary, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439424.
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Watson, Andrea. "Heat shock proteins in leukaemia cell differentiation and cell death." Thesis, Aston University, 1990. http://publications.aston.ac.uk/12533/.
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When HL60 cells were induced to differentiate to granulocyte-like cells with the agents N-methylformamide and tunicamycin an concentrations marginally below those which were cytotoxic, there was a decrease in the synthesis of the glucose- regulated proteins which preceded the expression of markers of a differentiated phenotype. There was a transient increase in the amount of hsp70 after 36 hours in NMF treated cells but in differentiated cells negligible amounts were detected. Inducers which were known to modulate hsp70 such as azetadine carboxylic acid did not induce differentiation suggesting early changes in the endoplasmic reticulum may be involved in the commitment to terminal differentiation of HL60 cells. These changes in group synthesis were not observed when K562 human chronic myelogenous leukemia cells were induced to differentiate to erythroid-like cells but there was a comparable increase in amounts of hsp70. When cells were treated with concentrations of drugs which brought about a loss in cell viability there was an early increase in the amount of hsp70 protein in the absence of any increase in synthesis. HL60 cells were treated with NMF (225mM), Adriamycin (1 jiM), or CB3717 (5iM) and there was an increase in the amounts of hsp70, in the absence of any new synthesis, which preceded any loss of membrane integrity and any significant changes in cell cycle but was concomitant with a later loss in viability of > 50% and a loss in proliferative potential. The amounts of hsp70 in the cell after treatment with any of the drugs was comprable to that obtained after a heat shock. Following a heat shock hsp70 was translocated from the cytoplasm to the nucleus, but treatment with toxic concentrations of drug caused hsp70 to remain localised in the cytoplasm. Changes in hsp70 turn-over was observed after a heat shock compared to NMF-treated cells. Morphological studies suggested that cells that had been treated with NMF and CB3717 were undergoing necrosis whereas the Adriamycin cells showed characteristics that were indicative of apoptosis. The data supports the hypothesis that an increase in amounts of hsp70 is an early marker of cell death.
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Sciacovelli, Marco. "Cell death regulation by mitochondrial chaperones in tumor cell models." Doctoral thesis, Università degli studi di Padova, 2011. http://hdl.handle.net/11577/3421645.
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Cancer cells are endowed with the capability to evade normal apoptotic signaling, as they display a constitutive hyperactivation of kinase signaling pathways. Integration of survival and death stimuli occurs on mitochondria, where many of these signals converge in the regulation of a channel termed permeability transition pore (PTP). PTP opening commits cells to death, and it is regulated by a variety of factors, among which molecular chaperones play a pivotal role. Here I have studied how mitochondrial chaperones interact with signal transduction pathways, modulate the PTP and more in general mitochondrial bioenergetics, and how these regulatory networks control tumor cell viability. In a first part of my work, I have explored a functional connection between the Ras/ERK signaling axis, whose constitutive activation characterizes most tumors and prompts their growth and survival, and cyclophilin D (CyP-D), a mitochondrial chaperone that regulates the PTP. A fraction of active ERK was found to be located in mitochondria in RWPE-2 cells, obtained by v-Ki-Ras transformation of the epithelial prostate RWPE-1 cell line; in metastatic prostate cancer DU145 cells; and in osteosarcoma SAOS-2 cells. All these tumor cells displayed marked resistance to death caused by apoptotic stimuli like arachidonic acid and the BH3 mimetic EM20-25, which cause cell death through the mitochondrial PTP. PTP inhibition and the ensuing resistance to cell death induced by arachidonic acid or EM20-25 could be ablated by inhibiting ERK with the drug PD98059 or with a selective ERK activation inhibitor peptide. ERK inhibition enhanced GSK-3-dependent phosphorylation of CyP-D), whereas GSK-3 inhibition protected from PTP opening. Neither active ERK in mitochondria nor pore desensitization were observed in non-transformed RWPE-1 cells. Thus, in tumor cells mitochondrial ERK activation desensitizes the PTP through a signaling axis that involves GSK-3 and CyP-D. In a second part of my thesis work, I have investigated the activity of a second mitochondrial chaperone, TRAP1/HSP75, overexpressed in tumor cells and proposed to be involved in regulation of the pore. I have determined that TRAP1 interacts with CyP-D and characterized its survival function against a wide spectrum of death stimuli inducing oxidative stress, including diamide, exposure to TNFα, and glucose deprivation. Moreover, I have found that knocking-down TRAP1 expression level through RNA interference in SAOS-2 osteosarcoma cells facilitates PTP opening, thus lowering the threshold for committing cells to death. TRAP1 modulates cell metabolism and possibly the response to oxidative stress by reducing mitochondrial respiration and the activity of respiratory chain complex I, with which TRAP1 directly interacts, both in cells and in tumor samples. Notably, down-modulation of TRAP1 ablates the tumorigenic potential of SAOS-2 cells both in vitro and in-vivo. Altogether, these data indicate that mitochondrial chaperones such as CyP-D and TRAP1 play an important role in tumor progression and constitute a possible target for anti-neoplastic intervention.Le cellule tumorali sono caratterizzate dalla capacità di evadere il normale signale apoptotico, così come mostrano una iper-attivazione costitutiva delle vie di signale kinasico. L’integrazione degli stimoli di sopravvivenza e morte si concentra nei mitocondri, dove molti di questi segnali convergono nella regolazione di un canale chiamato poro della transizione di permeabilità (PTP). L’apertura del PTP porta le cellule alla morte ed è regolata da una varietà di fattori e fra questi gli chaperoni giocano un ruolo fondamentale. Nel mio lavoro di tesi ho studiato come gli chaperoni mitochondriali si integrano nelle vie di trasduzione del segnale , modulando il PTP e più in generale la bioenergetica mitocondriale e come questi network regolatori controllano la vitalità cellualre. Nella prima parte del mio lavoro ho studiato una possibile connessione fra la via del segnale Ras/ERK, la cui attivazione costitutiva caratterizza molti tumori favorendo la loro crescita e sopravvivenza, e la ciclofilina D (CyP-D), uno chaperone mitocondriale che regola il PTP. Una frazione di ERK attivo è stato trovato nei mitocondri delle cellule RWPE-2, ottenute tramite trasformazione con v-ki-Ras a partire da cellule dell’epitelio prostatico RWPE-1; in cellule metastatiche di tumore prostatico DU145; e in cellule di osteosarcoma SAOS-2. Tutte queste cellule tumorali mostrano una marcata resistenza alla morte indotta da stimoli pro-apoptotici come l’acido arachidonico e il BH3 mimetico EM20-25, i quali inducono la morte cellulare attraverso il PTP mitocondriale. L’inibizione del PTP e la conseguente resistenza alla morte cellulare indotta da acido arachidonico o EM-20-25 può essere abolita dall’inibizione di ERK con il farmaco PD98059 o con un peptide selettivo inibitorio di ERK. L’inibizione di ERK aumenta la fosforilazione GSK-3 dipendente della CyP-D, mentre l’inibizione di GSK3 protegge dall’apertura del poro. Ne ERK attivo nei mitocondri, ne desensibilizzazione del poro è stata osservata in cellule non trasformate RWPE-1. In conclusione, nelle cellule tumorali l’attivazione dell’ERK mitocondriale desensibilizza il PTP attraverso un asse di segnale che coinvolge GSK3 e Cyp-D. Nella seconda parte del mio lavoro di tesi, ho studiato l’attività di un secondo chaperone mitocondriale, TRAP1/HSP75, fortemente espresso nelle cellule tumorali e che è stato proposto essere coinvolto nella regolazione del poro. Ho dimostrato che TRAP1 interagisce con la CyP-D ed ho caratterizzato la sua funzione di pro-sopravvivenza nei confronti di un vasto spettro di stimoli di morte, incluso lo stress ossidativo, la diamide, il TNFα, e la deplezione di glucosio. Inoltre ho trovato che il knocking-down dei livelli di espressione di TRAP1 attraverso la tecnica dell’RNA interference in cellule di osteosarcoma SAOS-2 facilita l’apertura del PTP, abbassando la soglia per portare le cellule alla morte. TRAP1 modula inoltre il metabolismo cellulare probabilmente la risposta allo stress ossidativo e l’attività della del complesso I della catena respiratoria, con il quale TRAP1 interagisce direttamente sia in cellule che campioni tumorali. La down- regolazione di TRAP1 abolisce il potere tumori genico delle cellule SAOS-2 sia in vitro che in vivo. Tutti insieme questi dati indicano che gli chaperoni mitocondriali come CyP-D e TRAP! Giocano un ruolo importante nella progressione tumorale e costituiscono un possibile target di nuove terapie antineoplastiche.
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Cragg, Mark Steven. "Monoclonal antibody induced growth arrest and cell death in B-cell lymphoma cell lines." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242713.
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Haddad, F. "Analysis of cell division fidelity of human repair defective cell lines." Thesis, Swansea University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.637194.
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In this study the fidelity of cell cycle division in terms of fidelity of chromosome segregation was analysed in cell lines from Xeroderma pigmentosum groups A & D, and Trichothiodystrophy cell lines with comparison with a normal human fibroblast cell line. The XP and TTD cell lines, are both defective in nucleotide excision repair with susceptibility to skin cancer in the case of XPs but not the TTDs. The study was conducted using a micronucleus assay of cytokinesis-blocked binucleated cells combined with the kinetochore labelling technique and FISH for centromeric regions of two specific chromosomes (16 & 18). Analysis was performed in two different protocols, one assessing chromosome loss and the other one measuring chromosome non-disjunction after exposure of the cells to doses of colcemid and vinblastine. In the first protocol the ability of cell lines for regaining the division fidelity after several cell cycles was also determined. Data showed that XP and TTD cell lines were more sensitive to chemical-induced chromosome non-disjunction compared to a normal human cell line. Chemicals induced chromosome-loss in all normal and NER defective cell lines. However, in the case of XPD cell lines, the frequencies remained stable while frequency was reduced for normal and XPA cell lines. The results indicated that XP and TTD cell lines were defective in NER as well as in mechanisms monitoring the fidelity of cell cycle division. The possible relationship of p53-mediated checkpoint/apoptosis and defective transcription in XPD mutated cell lines was discussed.
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Jorge, Ana Maria. "Insights into cell wall synthesis and cell division in Staphylococcus aureus." Doctoral thesis, Universidade Nova de Lisboa. Instituto de Tecnologia Química e Biológica, 2012. http://hdl.handle.net/10362/8592.
Full textAbstract:
Dissertation presented to obtain the Ph.D degree in BiologyStaphylococcus aureus is a gram-positive bacterial pathogen that besides persistently colonizing healthy individuals, is responsible for a large number of hospital-associated bacterial infections. The extraordinary capacity of S. aureus to acquire resistance to antibiotics led to the emergence of highly resistant strains, mainly methicillin-resistant S. aureus (MRSA) strains, that are a major cause of soft skin and tissue infections and bacteremia. In one third of European countries, including Portugal, more than 25% of S. aureus infections are caused by MRSA strains. The capacity of MRSA strains to resist β-lactam antibiotics (such as penicillin) is mainly due to the acquisition of an extra-species penicillin-binding protein (PBP), PBP2A. PBPs are bacterial enzymes involved in the synthesis of the cell wall polymer peptidoglycan. Besides PBP2A, which is present only in MRSA strains, S. aureus has 4 native PBPs (PBP1-4), which catalyze the polymerization (transglycosylation) and the cross-linking (transpeptidation) of glycan chains, forming a strong yet flexible structure that protects the cell from the high internal osmotic pressure. Peptidoglycan is unique to the bacterial kingdom and its biosynthesis is the target of a vast number of clinically important antibiotics such as β-lactams and glycopeptides. β-lactam antibiotics target the transpeptidase domain of PBPs, halting peptidoglycan synthesis and eventually leading to cell lysis. However, in MRSA strains the existence of PBP2A, which has a low affinity for β-lactams, enables cell wall synthesis to continue even in the presence of these antibiotics. Under these conditions, the transpeptidase domain of PBP2A functionally cooperates with the transglycosylase domain of the unique bifunctional PBP, PBP2, to ensure continued cell wall synthesis and cell survival.(...)
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Nestor-Bergmann, Alexander. "Relating cell shape, mechanical stress and cell division in epithelial tissues." Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/relating-cell-shape-mechanical-stress-and-cell-division-in-epithelial-tissues(ebf1bce8-ca35-4f5a-8be9-f2e19c96e20d).html.
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The development and maintenance of tissues and organs depend on the careful regulation and coordinated motion of large numbers of cells. There is substantial evidence that many complex tissue functions, such as cell division, collective cell migration and gene expression, are directly regulated by mechanical forces. However, relatively little is known about how mechanical stress is distributed within a tissue and how this may guide biochemical signalling. Working in the framework of a popular vertex-based model, we derive expressions for stress tensors at the cell and tissue level to build analytic relationships between cell shape and mechanical stress. The discrete vertex model is upscaled, providing exact expressions for the bulk and shear moduli of disordered cellular networks, which bridges the gap to traditional continuum-level descriptions of tissues. Combining this theoretical work with new experimental techniques for whole-tissue stretching of Xenopus laevis tissue, we separate the roles of mechanical stress and cell shape in orienting and cueing epithelial mitosis. We find that the orientation of division is best predicted by the shape of tricellular junctions, while there appears to be a more direct role for mechanical stress as a mitotic cue.
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Spanoudis, Catherine M. "Cell Division Regulation in Staphylococcus aureus." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/7090.
Full textAbstract:
Cell division is a fundamental biological process that occurs in all kingdoms of life. Our understanding of cell division in bacteria stems from studies in the rod-shaped model organisms: Gram-negative Escherichia coli and Gram-positive Bacillus subtilis. The molecular underpinnings of cell division regulation in non-rod-shaped bacteria remain to be studied in detail. Rod-shaped bacteria possess many positive and negative regulatory proteins that are essential to the proper placement of the division septa and ultimately the production of two identical daughter cells, many of which are absent in cocci. Given that essential cell division proteins are attractive antibacterial drug targets, it is imperative for us to identify key cell division factors especially in pathogens, to help counter the emergence of multi-drug resistance. In Staphylococcus aureus, a spherical Gram-positive opportunistic pathogen that causes a range of diseases from minor skin infections to life-threatening sepsis, we have identified the role of an essential protein, GpsB, in the regulation of cell division. We discovered that GpsB preferentially localizes to cell division sites and that overproduction of GpsB results in cell enlargement typical of FtsZ inhibition, while depletion of GpsB results in cell lysis and nucleoid-less minicell formation. The identification of GpsB’s interaction partners will allow us to understand the molecular mechanism by which GpsB regulates cell division.
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Iqbal, Syed Amir. "Asymmetric Cell Division in Mammalian Cells." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.503635.
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Kirby, Melissa Jane. "Regulation of sugar beet cell division." Thesis, De Montfort University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391029.
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Harrington, Elizabeth Anne. "Analysis of the molecular regulation of cell proliferation and cell death." Thesis, Imperial College London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283286.
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Weston, Claire Rosemary. "The effects of δMEKK3:ER* on cell death and cell survival." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621377.
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Wong, Mei Mei. "Effects of Cell Death and Phagocytosis on Mesenchymal Stem Cell Function." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511852.
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Abulayha, Abdulmunem M. "Mechanisms of CD20 mediated cell death in B lymphoma cell lines." Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403306.
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Courtois-Moreau, Charleen Laetitia. "Programmed Cell Death in Xylem Development." Doctoral thesis, Umeå universitet, Umeå Plant Science Centre, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1831.
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Concerns about climate changes and scarcity of fossil fuels are rising. Hence wood is becoming an attractive source of renewable energy and raw material and these new dimensions have prompted increasing interest in wood formation in trees, in both the scientific community and wider public. In this thesis, the focus is on a key process in wood development: programmed cell death (PCD) in the development of xylem elements. Since secondary cell wall formation is dependent, inter alia, upon the life time of xylem elements, the qualitative features of wood will be affected by PCD in xylem, about which there is little information. This thesis focuses on the anatomical, morphological and transcriptional features of PCD during xylem development in both the stem of hybrid aspen, Populus tremula (L.) x tremuloides (Michx.) and the hypocotyl of the herbaceous model system Arabidopsis thaliana (L. Heynh.). In Populus, the progressive removal of organelles from the cytoplasm before the time of death (vacuolar bursts) and the slowness of the cell death process, illustrated by DNA fragmentation assays (such as TUNEL and Comet assays), have been ascertained in the xylem fibres by microscopic analyses. Furthermore, candidate genes for the regulation of fibre cell death were identified either from a Populus EST library obtained from woody tissues undergoing fibre cell death or from microarray experiments in Populus stem, and further assessed in an in silico comparative transcriptomic analysis of Arabidopsis thaliana. These candidate genes were either putative novel regulators of fibre cell death or members of previously described families of cell death-related genes, such as autophagy-related genes. The induction of the latter and the previous microscopic observations suggest the importance of autophagy in the degradation of the cytoplasmic contents specifically in the xylem fibres. Vacuolar bursts in the vessels were the only previously described triggers of PCD in the xylem, which induce the very rapid degradation of the nuclei and surrounding cytoplasmic contents, therefore unravelling a unique previously unrecorded type of PCD in the xylem fibres, principally involving autophagy. Arabidopsis is an attractive alternative model plant for exploring some aspects of wood formation, such as the characterisation of negative regulators of PCD. Therefore, the anatomy of Arabidopsis hypocotyls was also investigated and the ACAULIS5 (ACL5) gene, encoding an enzyme involved in polyamine biosynthesis, was identified as a key regulator of xylem specification, specifically in the vessel elements, though its negative effect on the cell death process. Taken together, PCD in xylem development seems to be a highly specific process, involving unique cell death morphology and molecular machinery. In addition, the technical challenges posed by the complexity of the woody tissues examined highlighted the need for specific methods for assessing PCD and related phenomena in wood.Oron för klimatförändringar och brist på fossila bränslen har ökat påtagligt under de senaste åren. De enorma möjligheter som skogsråvaran erbjuder som alternativ källa för förnyelsebar energi och råmaterial har väckt ett stort intresse också för den biologiska processen bakom vedbildning i träd. Denna avhandling fokuserar på en viktig process i vedbildning: programmerad celldöd (PCD) i xylemet. Xylemcellernas livstid påverkar bildningen av sekundära cellväggar, vilket i sin tur påverkar vedens kvalitativa egenskaperna, så som veddensitet. Trots dess betydelse för viktiga egenskaper hos vedråvaran existerar fortfarande väldigt lite information om xylem PCD på cellulär eller molekylär nivå. I den här avhandlingen belyses de anatomiska, morfologiska och genetiska aspekterna av PCD i xylemutveckling i både stam av hybridasp, Populus tremula (L.) x tremuloides (Michx.) och hypokotyl av det örtartade modellsystemet Arabidopsis thaliana (L. Heynh.). Xylemet i både Populus och Arabidopsis består av två olika celltyper; de vattentransporterade kärlen och de stödjande fibrerna. Det är känt att celldöd i kärlen pågår mycket snabbt efter att den centrala vakuolen brister och de hydrolytiska enzymer släpps in i cytoplasman. I den här avhandlingen ligger fokus på fibrerna i Populus xylemet. Med hjälp av mikroskopianalyser av cellmorfologin (elektronmikroskopi) och DNA-fragmentering i cellkärnan (TUNEL- och Comet-analyser) kunde vi konstatera att till skillnad från kärlen så uppvisar fibrerna en långsam och progressiv nedbrytning av organellerna och cellkärnans DNA före vakuolbristning. Dessutom har kandidatgener för reglering av fibercelldöd identifierats antingen från ett Populus EST bibliotek från vedartade vävnader som genomgår fibercelldöd eller från mikroarray experiment i Populus stam. Dessa kandidatgener är antingen potentiella nya regulatorer av fibercelldöd eller medlemmar av tidigare beskrivna familjer av celldödsrelaterade gener. Bland de sistnämnda finns autofagi-relaterade gener, vilket stöder funktionen av autofagi i samband med autolys av cellinnehållet i xylemfibrerna. Dessa studier pekar därför på en typ av PCD som har inte tidigare beskrivits för xylemet. Arabidopsis är ett alternativt växtmodellsystem för studier av vissa aspekter av vedbildningen, såsom karakteriseringen av negativa regulatorer av PCD. Därför har också hypokotylanatomin analyserats, och ACAULIS5 (ACL5) genen, som kodar för ett enzym i biosyntesen av polyaminer, har visats vara en viktig regulator av xylemspecifikation genom dess negativa effekt på kärlens celldöd. Sammantaget visar denna avhandling att PCD i xylemutvecklingen verkar involvera unika morfologiska och molekylära mekanismer. Vi visar dessutom att komplexiteten hos de vedartade vävnaderna leder till ett behov av bättre anpassade verktyg för att djupare kunna bedöma PCD och liknande fenomen i veden.
Även med namnet Moreau-Courtois, Charleen L. samt Moreau, Charleen.
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Klassen, Shaun Scott. "Nitric oxide-induced cardiomyocyte cell death." Thesis, University of British Columbia, 2006. http://hdl.handle.net/2429/31539.
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Nitric oxide (NO), a regulator of diverse cardiovascular functions, modifies cardiac cell
viability through mechanisms that remain uncertain. Several pathways were studied to
understand these effects. The possibility that the protein p53 is involved in the cardiomyocyte
response to the NO donor s-nitrosoglutathione (GSNO) or the peroxynitrite donor 3-
morpholinosydnonimine (SIN-1) was explored. These donors induced a concentration-dependent
increase of cell death in cultured embryonic chick cardiomyocytes. Expression of p53
protein was increased in response to GSNO, specifically in the nucleus. GSNO also caused
DNA damage, but pifithrin, an inhibitor of p53 transactivation activity, did not alter the extent of
this damage or cell death. Therefore, the role of increased nuclear p53 in response to NO and
NO-induced DNA damage may not be specifically operative in NO-induced cell death. The
action of GSNO also appears independent of mitochondrial pathways in cell death, as there was
no association of p53 with the mitochondria. Neither GSNO- or SIN-1-induced cell death was
altered by cyclosporin A, suggesting that permeability transition pore opening is not operative in
these modes of induction of death. In contrast to SIN-1, GSNO did not reduce mitochondrial
transmembrane potential, implying separate mechanisms of cell death. Immunocytochemistry
demonstrated increased amounts of nitrotyrosine in response to GSNO or SIN-1, confirmed by
Western blot following SIN-1. FeTPPS, an isomerase that converts peroxynitrite into the less
toxic nitrate, produced a significant reduction of SIN-1-induced cell death and cellular protein
nitration. FeTPPS did not reduce cell death from GSNO alone, but did from the combination of
GSNO and hydrogen peroxide, a condition which promotes the generation of peroxynitrite. In
summary, NO-induced cardiomyocyte cell death is due in part to the disruption of normal
cellular functions by nitration of key proteins. Peroxynitrite decomposition reduces protein
nitration and cell death, while p53 appears functions independent of the mitochondria or gene
transactivation and may act in other pathways, such as cell repair.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
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Martinez, Bermudez Ana Katherine. "Isoprostanes in brain endothelial cell death." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0025/MQ50832.pdf.
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Maianski, Nikolai. "Neutrophil cell death: mechanisms and regulation." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2004. http://dare.uva.nl/document/88280.
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Martinez, Bermudez Ana Katherine. "Isoprostanes in brain endothelial cell death." Thesis, McGill University, 1998. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=21605.
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Oxygen free radicals have been implicated in several diseases including ischemic stroke, and myocardial infarction. They can trigger chain reactions like peroxidation of membrane phospholipids, leading to osmotic imbalance and cell death. Isoprostanes are stable products of lipid peroxidation that have a constrictor effect on the vasculature and bronchii. As isoprostanes are abundantly generated in tissues under oxidant stress, we have hypothesized that they could be related to endothelial dysfunction observed during ischemia/reperfasion by affecting endothelial cell survival. The effects of 8-iso-PGE2 and 8-iso-PGF2alpha, two abundantly produced isoprostanes, were studied on porcine endothelial cultures and isolated brain microvessels. Cell survival was evaluated by MTT reduction, double staining with DNA-binding fluorochromes and in situ DNA fragmentation labeling,8-Iso-PGF2alpha (1--10 nM) induced 20--25% cell death in endothelial cultures after 24 h coincident with similar increase in the number of cells that become permeable to PI. On the contrary, 8-iso-PGE 2 did not affect endothelial cell survival. Approximately 9% of the cells suffered apoptosis. This percentage remained unchanged regardless the treatment. Several observations indicate a role for thromboxane A2 to mediate 8-iso-PGF2alpha-induced death: (1) the levels of thromboxane A2 increased dramatically in endothelial cultures after 8-iso-PGF2alpha-treatment; (2) inhibitors of thromboxane synthase, CGS12970 and U6355A and Ibuprofen, a non-selective inhibitor of cyclooxygenases, reverted the effect of the isoprostane; (3) analogs of thromboxane A2 U46619 and IBOP, reproduce the effect of 8-iso-PGF 2alpha after 24 h. 8-Iso-PGF2alpha also decreased endothelial viability on isolated brain microvessels. These results suggest, that 8-iso-PGF2alpha, might be a direct contributor to ischemia/reperfusion injury.
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Spanos, Sophia. "Cell death during preimplantation embryo development." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398228.
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Świdziński, Jodi A. "Programmed cell death in Arabidopsis thaliana." Thesis, University of Oxford, 2003. http://ora.ox.ac.uk/objects/uuid:6e2580fc-8873-4722-89f7-b206d4be2a5f.
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Programmed Cell Death (PCD) describes an orderly cellular breakdown that occurs in both plants and animals throughout development and in response to biotic and abiotic stresses. The molecular machinery that functions in the induction and execution of animal PCD has been characterised in great detail. Conversely, few genes and proteins involved in plant PCD have been identified. While certain features of animal PCD may be conserved, the induction and execution of plant PCD is also likely to involve novel proteins and mechanisms. The aim of the work presented in this thesis was to investigate experimental approaches for studying plant PCD and to gain an understanding of the molecular mechanisms involved. To this end, an Arabidopsis thaliana cell suspension system was developed in which PCD could be induced by both a heat treatment (55°C, 10 min) and senescence (13 to 14 days-old). This system allowed for the molecular responses related to programmed cell death to be distinguished from those that were a specific response to the inducing stimulus. The Arabidopsis cell suspension system was utilised for an analysis of transcriptomic and proteomic changes that occur following the induction of PCD. A custom cDNA microarray analysis of ~100 putative cell death-related genes was used to measure the abundance of transcripts of these genes during PCD, and this work was extended to a whole-genome transcriptomic analysis of PCD. A number of candidate genes that may play a role in plant PCD were identified. These included those encoding antioxidant enzymes, cytosolic heat shock proteins, the mitochondrial adenine nucleotide translocase, ion transporters, a two-component response regulator (ARR4), several pathogenesis-related proteins, phospholipases and proteases, extracellular glycoproteins and enzymes (including a subtilisin-like protease, chitinases, and glucanases), and transcriptional regulators such as a homeobox leucine zipper and NAC-domain proteins. The induction and execution of plant PCD is also likely to involve mechanisms that are not transcriptionally regulated. A proteomic analysis of changes in the total cellular protein profile during heat- and senescence-induced PCD was therefore used to identify 12 proteins that are modulated in both systems and may play a PCD-specific role. These included the mitochondrial voltage-dependent anion channel (Athsr2), catalase, mitochondrial superoxide dismutase, an extracellular glycoprotein, and aconitase. Selected genes and proteins identified in the transcriptomic and proteomic analyses were further investigated in an attempt to define their role in plant PCD. Since PCD is difficult to quantitatively analyse at the whole-plant level, initially a strategy of transient expression of genes of interest in Arabidopsis protoplasts was adopted. However, it proved to be technically difficult to accurately quantify the number of dead cells in this system. As an alternative, Arabidopsis T-DNA insertional mutants within genes of interest were investigated for PCD-related phenotypes. Mutants in Senescence-Related Gene 3, the mitochondrial voltage-dependent anion channel (Athsr2), and cytosolic Heat shock protein 70-3 were isolated. The mutant lines were not visibly affected in their development, formation of xylem, onset and progression of senescence, or responses to abiotic and biotic stresses. This indicated that these genes are either not involved in the PCD pathway or that their functional role can be fulfilled by other gene products.
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Cox, Orla T. "Vascular cell death in diabetic retinopathy." Thesis, Queen's University Belfast, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343079.
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Sharma, Pundrique Radheyshyam. "Programmed cell death during heart development." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272255.
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Fitzgerald, Julia. "Monoamine oxidase in neuronal cell death." Thesis, Nottingham Trent University, 2008. http://irep.ntu.ac.uk/id/eprint/51/.
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Monoamine oxidase (MAO) is an oxidative enzyme that deaminates a variety of amine substrates, including the neurotransmitter dopamine. The enzymatic reaction requires molecular oxygen and produces hydrogen peroxide as a by-product. MAO is localised in the outer mitochondrial membrane and exists as two isoforms, MAO-A and MAO-B, which are differentially expressed in the body and differ in their substrate and inhibitor specificities. Previous studies have suggested that MAO-generated reactive oxygen species (ROS) contribute to oxidative stress in the cell and can directly inhibit electron transport, cause damage to mitochondrial DNA and enhance cell death signalling. In this study the role of MAO in cell death was investigated in dopaminergic neuroblastoma (SH-SY5Y) cells, in three diverse models of mitochondrially-mediated apoptosis. The relevance of MAO in cell death signalling was confirmed with the use of two unrelated MAO inhibitors and the creation of stable SH-SY5Y cell lines that either over express MAO-A or have reduced levels of MAO-A. The study is the first to over express MAO-A using recombinant technology and to use miRNA to stably knock-down MAO-A expression in human neuronal cells. Results confirm that MAO-A is involved in modulating cell death but the mechanism and extent of the involvement depends on the apoptotic inducer. In classical apoptosis induced by staurosporine (STS), cells undergo rapid morphological and biochemical changes indicative of mitochondrially-mediated apoptosis, which is partly dependent on ROS production by MAO-A and induction of mitogen-activated protein kinase (MAPK) signalling cascades. MAO-A protein and catalytic activity are increased in this model, however the mechanism by which this occurs is unknown and is not a result of increased gene transcription. In death induced by growth factor withdrawal, the MAO-A gene is up regulated via p38 and JNK MAPK pathways, which occurs downstream of caspase activation. In both the STS and growth factor withdrawal models, MAO inhibition reduced apoptosis. Most significantly reduced levels of MAO-A expression in 'knock down' cells protected against cell death induced by the complex I inhibitor rotenone, suggesting that MAO has an important role in mitochondrial function. Over expression of MAO-A resulted in stress and apoptosis, followed by a period of cellular senescence and eventually death by necrosis. These data compliment the effects of chronic exposure to oxidative stress in ageing and neurodegeneration. For the first time this work has shown that the MAO-A isoform is an important regulator of STS-induced apoptosis, that MAO-A gene expression is regulated by JNK signalling, and that MAO-A is significantly involved in mitochondrial dysfunction induced by complex I inhibition. These data raise important questions regarding predisposition to the development of neurodegenerative diseases such as Parkinson's disease and to approaches used for their treatment.
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Ramos, Paulina Joanna. "Fibronectin Enhances Carfilzomib Mediated Cell Death." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/579327.
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Cell Adhesion Mediated Drug Resistance (CAM-DR) is a factor in Multiple Myeloma (MM) drug resistance. Despite advances in treatment, multiple myeloma remains incurable and often results in drug resistance. It is known that cell adhesion to fibronectin via integrin β1 confers survival in myeloma cells. We show here that adherence of the NCI-H929 and MM.1S myeloma cells to fibronectin, promotes cell death when treated with proteasome inhibitor Carfilzomib (Kyprolis). These data are in contrast to other cytotoxic drugs, such as melphalan or doxorubicin, and different myeloma cell lines in which the CAM-DR survival phenotype is expressed. We found a significant amount of death in myeloma cells adhered to fibronectin when exposed to carfilzomib. In addition, we demonstrate that pan-caspase inhibitor, Q-VD-OPH, inhibits cell death in myeloma cells in suspension. Carfilzomib cytotoxicity is caspase dependent in suspension. We propose that the increased cytotoxicity in cells adhered to fibronectin may be caspase independent, perhaps due to failed autophagy. These data support the hypothesis that β1 mediated adhesion to fibronectin induces an autophagic response in MM cells contributing to CAM-DR phenotype. We propose that further induction of autophagy by proteasome inhibitors exceeds the adaptive threshold survival response and initiates caspase independent cell death.
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Orchard, Craig Brailsford. "Relationship between programmed cell death and the cell cycle in the tobacco BY-2 cell line." Thesis, Cardiff University, 2004. http://orca.cf.ac.uk/55931/.
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Ethylene is an established plant growth regulator linked with programmed cell death (PCD). To investigate the relationship between the cell cycle and PCD, ethylene was used to see if it induced mortality in a cell cycle specific manner. Tobacco BY-2 cultures synchronized with aphidicolin were treated with ethylene. Cell cycle progression and mortality, measured at hourly intervals, showed distinct peaks of mortality at the G2/M boundary and S-phase. In conjunction with this, DNA fragmentation increased at G2/M. Furthermore, ethylene caused a significant reduction in cell size of the cycling population. Simultaneous addition of silver nitrate with ethylene ameliorated ethylene-induced G2/M mortality, although a toxic effect of silver alone was evident. Due to the toxicity of silver, 1-MCP, an alternative chemical for blocking ethylene receptors was used. 1-MCP neither affected the BY-2 cell cycle nor mortality levels. In addition, 1-MCP ameliorated ethylene-induced G2/M mortality. To balance the chemical approaches to blocking ethylene receptors, tobacco BY-2 cells were transformed with Atetrl that encodes a dominant insensitive form of the Arabidopsis ETR1 ethylene receptor. Atetrl expression caused a massive perturbation to the tobacco BY-2 cell cycle, especially in S-phase, and resulted in high levels of mortality throughout the cell cycle. Ethylene treatment caused a doubling of G2 duration but did not affect temporal distribution of mortality. However, ethylene treatment generated a peak of mortality in S-phase. These results suggest that ethylene induces PCD at G2/M through the known ethylene signaling pathway. Furthermore, it confirms that 1-MCP and Atetrl result in ethylene insensitivity. To examine the G2/M transition, Spcdc25, a positive regulator of G2/M in fission yeast was transformed into the tobacco BY-2 cell line. This resulted in premature entry into mitosis, a shortened cell cycle, and reduced cell size. This was similar to Spcdc25 over-expression in fission yeast and suggests the presence of a CDC25-like phosphatase in plants.
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Ganz, Michal. "Investigation of growth factors and cytokines that suppress adult stem cell asymmetric cell kinetics." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/33874.
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Thesis (S.M.)--Massachusetts Institute of Technology, Biological Engineering Division, 2005.Includes bibliographical references (leaves 40-43).
Adult stem cells are potentially useful in many biomedical applications that can save lives and increase the quality of a patient's life, such as tissue engineering, cell replacement, and gene therapy. However, these applications are limited because of the difficulty in isolating and expanding pure populations of adult stem cells (ASCs). A major barrier to ASC expansion in vitro is their property of asymmetric cell kinetics. Our lab has developed a method, Suppression of Asymmetric Cell Kinetics (SACK), to expand ASCs in vitro by shifting their cell kinetics program from asymmetric to symmetric. We have found that guanine nucleotide precursors can be used to convert the kinetics of adult stem cells from asymmetric to symmetric, which promotes their exponential expansion. Previously, we have used the SACK method to derive hepatic and cholangiocyte stem cell strains from adult rat livers in vitro. These cell strains provide an assay to evaluate whether growth factors and cytokines previously implicated in proliferation of progenitor cells act by converting the kinetics of the stem cells in the population from asymmetric to symmetric, and thus identify new SACK agents. We are evaluating three agents, Wnt, IGF- 1, and Sonic hedgehog (Shh).
(cont.) Wnt has been found to cause self-renewal and proliferation of hematopoietic stem cells (HSCs) in vitro. IGF- 1 also plays a role in hematopoietic progenitor self-renewal in vivo as well as in tissue maturation. Shh has been implicated in the proliferation of primitive neural cells as well as in cellular proliferation during invertebrate development. Thus far, we have found that Wnt peptide shifts the cell kinetics from asymmetric to symmetric and may reduce the generation time, whereas IGF-1 appears only to affect generation time. Studies involving Shh are currently underway. We are also currently investigating whether Wnt acts additively or synergistically with guanine nucleotide precursors to shift cell kinetic symmetry. Discovering new SACK agents will allow us to obtain purer populations of ASCs that can be used to study properties unique to stem cells. Furthermore, the observation that Wnt shifts the kinetics of adult rat hepatic stem cells from asymmetric to symmetric implicates the involvement of similar cell kinetics symmetry mechanisms in the proliferation effect of Wnt on murine and human HSCs.
by Michal Ganz.
S.M.
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Edwards, Joanna Marie. "Cell survival and cell death: Role of potassium channels in Alzheimer's disease." Thesis, University of Leeds, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487723.
Full textAbstract:
Amyloid beta protein (AP) is found in elevated levels in the brains of individuals with Alzheimer's disease, the increased levels of AP are thought to be a causative factor in the pronounced cortical atrophy that is observed post-mortem. Application of exogenous Apuo at physiological and pathological concentrations did not induce cell death in SH-SY5Y cells, differentiated SH-SY5Y cells nor in primary ortical neurone cultures when viability was measured using the Live/Dead cytotoxicity assay. Therefore, rather than a cytotoxic role of Ap this data suggests a more neuroprotective role.
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Hoopes, Justin Darrel. "Mechanisms of Induced Cell Death in Bluetongue Virus Challenged Human Cell Lines." DigitalCommons@USU, 2009. https://digitalcommons.usu.edu/etd/252.
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Bluetongue virus (BTV) is a pathogenic member of the Reoviridae family. BTV does not cause disease in humans, but is capable of selectively infecting and killing certain transformed human cell lines. Understanding BTV's oncotrophism may lead to new therapeutics for treating cancer. This study focused on the underlying mechanisms of BTV-induced cell death in carcinoma cell lines. It was our hypothesis that BTV infects human carcinoma transformed cells, produces mRNA and protein, induces a strong inflammatory response, induces mitogen activated protein kinase (MAPK)-based pro-apoptotic signaling, inhibits PKB-based signaling, and eventually kills the cell by inducing apoptosis.
Three carcinoma cell lines (A498, HEP-G2, and A549) were independently infected with BTV. In each cell line we determined: (1) cell viability over the course of infection; (2) BTV induced cytokine expression profile and magnitude of expression; (3) BTV viral RNA expression profile and magnitude of expression; (4) BTV viral protein expression profile and magnitude of expression; (5) changes in BTV induced cell death and cytokine expression in cells with protein kinase B (PKB), p38-MAPK, extracellular receptor kinase (ERK-1/2), stress-activated protein kinase (SAPK-JNK), Src kinase, platelet-derived growth factor receptor (PDGFR) kinase, epidermal growth factor receptor (EDGFR) kinase, or Janus kinase (JAK) activity inhibited; (6) intracellular changes in PKB, p38-MAPK, ERK-1/2, and SAPK-JNK phosphorylation as a result of BTV infection; and (7) BTV-induced changes in tyrosine phosphorylation.
We determined that BTV infects and kills all three cell lines in a cell line dependent manner. Relative cell death between cell lines was proportional to cytokine expression, but inversely proportional to viral protein expression. Only tyrosine kinase inhibitors influenced BTV-induced cell death and cytokine expression. Both A498 and A549 cells constitutively expressed phosphorylated PKB and p38 MAPK, of which both were de-phosphorylated during BTV infection. Tyrosine phosphorylation remained active, with elevated tyrosine phosphorylation exclusively in infected cells.
We conclude that BTV-induced cell death and cytokine expression are a function of the cell's response to infection and are directly related through intracellular signaling. These pathways are only partially poly I:C inducible, but include PKB and tyrosine kinase signaling.
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Berry, David (David A. ). "Glycosaminoglycan regulation of cell function." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/34153.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2005.Includes bibliographical references (p. 252-285).
Glycosaminoglycans (GAGs) are complex polysaccharides that exist both on the cell surface and free within the extracellular matrix. The intrinsic sequence variety stemming from the large number of building blocks that compose this biopolymer leads to substantial information density as well as to the ability to regulate a wide variety of important biological processes. With the recent and progressive emergence of biochemical and analytical tools to probe GAG structure and function, efforts can be taken to understand the role of GAGs in cell biology and in disease in the various physiological locations where GAGs can exist. As a first step to probe the functions of GAGs, the heparin/heparan sulfate-GAG (HSGAG)-fibroblast growth factor (FGF) system was examined. Understanding the role of HSGAGs in inducing FGF2 dimerization led to the development of a novel engineered protein that was found to be effective at promoting functional recovery in stroke. Subsequently, methods to isolate HSGAGs from the cell surface were optimized and the ability of HSGAGs to support FGF signaling was investigated. Cell surface HSGAGs can define the responsiveness of a given cell to FGF1 and FGF2 through multiple receptor isoforms. Stromal cell derived HSGAGs were also identified as critical regulators of tumor cell growth and metastasis, effecting not only FGF2., but also 1-integrin signaling.
(cont.) Other GAGs, including dermatan sulfates, were characterized as modulators of FGFs and vascular endothelial growth factors. Finally, FGFs and HSGAGs were found to have important roles in maintaining epithelial monolayer integrity, with syndecan-l serving as a critical factor in inflammatory bowel disease. In addition to understanding HSGAGs in their normal physiological settings, techniques to internalize them were developed. Poly(3-amino ester)s were found to condense heparin and enable its endocytosis into cells. Internalized heparin is preferentially taken up by cancer cells, which often have a faster endocytic rate than non-transformed cells, and promotes apoptotic cell death. Internalized heparin can also be used as a tool to probe cell function. In Burkitt's lymphoma, poly(3-amino ester)-heparin conjugates served to identify cell surface HSGAGs as an important modulator of cell growth that can be harnessed to inhibit growth. Finally, studies that sought to broaden the scope of GAG biology were undertaken. Cell surface HSGA(:is were identified as mediators of vascular permeability. Furthermore a novel technique to immobilize GAGs was employed. The interactions between GAG and substrate were via hydrogen bonding. Immobilization of GAGs alters their properties, such that they can affect cells in ways distinct from GAGs free in the ECM.
(cont.) Furthermore, immobilized GAGs can regulate cancer cell adhesion, growth and progression, and may offer a new way to regulate the activity of cancer cells. In addition to directly providing new potential therapeutics and drug targets, these studies represent a foundation to enable additional studies of GAG function. Future work harnessing the techniques presented may open new avenues of research and facilitate the development of novel GAG-based therapeutics.
by David Berry.
Ph.D.
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Rosenthal, Adam D. (Adam David) 1978. "Cell patterning technology for controlling the stem cell microenvironment." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/39007.
Full textAbstract:
Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007.Includes bibliographical references (leaves 93-101).
Embryonic stem cells serve as powerful models for the study of development and disease and hold enormous potential for future therapeutics. Yet, over two decades after mouse embryonic stem cells (mESCs) were first isolated, there is still little known about the role of cell-cell signaling in self-renewal. Since traditional cell-culture techniques do not provide significant control of the stem cell microenvironment, the goal of this thesis was to develop a cell patterning technology that allows us to precisely control stem cell signaling and monitor cell proliferation over time. In the first aim of this thesis, we describe the development of our first cell patterning technology using dielectrophoresis (DEP). DEP uses nonuniform electric fields to trap cells on or between electrodes. We first used beads as model particles to validate the strength of our DEP square trap, and then demonstrated efficient cell patterning with multiple cell types. In the second aim of this thesis, we describe the development of a novel cell patterning technology that we created, called the Bio Flip Chip (BFC).
(cont.) The BFC is a microfabricated polymer chip, containing thousands of microwells, that enables cell patterning with single-cell resolution anywhere on a substrate and onto any substrate. In the last aim of this thesis, we used our BFC technology to control the stem cell microenvironment, allowing us to incrementally and independently modulate cell-cell contact. We present the first quantitative evidence that cell-cell contact depresses mESC colony formation and show that E-cadherin signaling is responsible for this negative regulatory pathway.
by Adam Rosenthal.
Ph.D.
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Dyche, G. H. "IAA production during cell division and xylogenesis." Thesis, University of Cambridge, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384461.
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Patient, Michaela Eileen. "Rcd, a ColE1-encoded cell division inhibitor." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309210.
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Hung, Yuen-mang Venus, and 洪婉萌. "Meaningful learning of cell division and genetics." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/209665.
Full textAbstract:
Meaningful learning is where the learner actively integrates new knowledge to his or her existing knowledge base. It involves the use of cognitive strategies and self-regulation. What motivates a learner to do so is found to be related to variables like the motivational beliefs, personal goal orientation and affect as well as the perception towards the teacher and his or her classroom context. The study surveyed a group of S6 biology students to examine the correlations between some of the different variables noted above. Students learning of cell division and inheritance is investigated to find out how pedagogy involving hybrid dynamic visualization (integration of dynamic animations to a static diagram) may promote meaningful learning. Two teachers, a subject teacher and a tutor, taught the same topics to the same group. The perception towards these two teachers and their classroom contexts were compared to see how much their perceptions were correlated to the student’s motivational beliefs, personal goal orientation, self-regulated learning behaviour and affect. The findings of the study support previous research that students relate their motivational beliefs and goal orientations to the cognitive strategy used. Besides, female students relate their personal goal orientations, self-regulated learning behavior and emotions to teachers of either gender more than male counterparts. The tutor and her classroom context have been perceived as more mastery goal oriented which aligns with the motivational beliefs and personal goal orientation of the students, whereas the subject teacher is perceived as one with a mixture of both mastery and performance goals and this has no statistical correlation with students’ motivational beliefs, achievement goal orientation or self-regulated learning strategies. The pedagogy seemed to more successfully help students master the concepts of cell division and inheritance and apply them to solve genetics problems compared with traditional teaching. Individual interviews, however, shows that the relevant skills of reasoning are yet to be improved. To conclude, a classroom with a mastery goal orientation through carefully designed pedagogy may promote meaningful learning.published_or_final_version
Education
Master
Master of Education
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Fowler, M. R. "Gene expression during sugar beet cell division." Thesis, De Montfort University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264308.
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Trambaiolo, Daniel Marco. "Crystallographic studies of bacterial cell division proteins." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611977.
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