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1
Rasid, Orhan. « NK cells and systemic inflammation : compartmentalization and memory responses ». Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB078.
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L'inflammation systémique est une réaction qui implique l’ensemble de l’organisme suite une agression sévère, potentiellement mortelle, illustrée par le syndrome de réponse inflammatoire systémique (SIRS). De nombreux acteurs cellulaires et moléculaires contribuent au développement de cette cascade inflammatoire parmi lesquels les cellules NK jouent un rôle clé. Malgré l'accumulation de preuves sur l’existence de propriétés spécifiques à chaque organe en réponse à l'inflammation systémique, en termes de cellules NK, on sait peu de choses sur la dynamique compartimentalisée de l’activation des cellules NK pendant un SIRS. En outre, le statut immunitaire des cellules NK après la résolution d’un SIRS est également mal connu. Dans le présent travail, nous avons étudié les réponses des cellules NK provenant de différents organes en utilisant un modèle d’endotoxinémie murine. Nous avons caractérisé la réponse des cellules NK au sein de la rate, du poumon, de la moelle osseuse, de la cavité péritonéale, et dans la circulation. Nous avons trouvé que, malgré une dynamique similaire de la réponse dans les différents organes, les réponses des cellules NK sont compartimentalisées avec des seuils différent et spécifiques. A l’aide de transferts adoptifs, nous avons constaté que la réactivité des cellules NK spécifiques d'organes peut refléter le compartiment d’origine lors des phases initiales de l'inflammation. Cependant, les cellules NK ont la capacité de s’adapter rapidement à leur nouvel environnement et d'ajuster leurs niveaux de réponse à ceux des cellules NK résidentes. Ainsi, cette étude fournit une preuve de concept qui confirme la compartimentalisation de la réponse des cellules NK lors de l'inflammation systémique. Dans une deuxième partie, nous avons analysé le statut des cellules NK à différents moments après une endotoxinémie. Les réponses des cellules NK au sein d’une préparation de cellules de la rate sont fortement supprimées en réponse à une restimulation in vitro, 14 jours après l'endotoxinémie. Cependant, nous avons montré que la réactivité intrinsèque des cellules NK est en fait augmentée après l'injection d’endotoxine, aboutissant à des cellules NK présentant des caractéristiques de cellules NK mémoires. Des expériences de transfert adoptif ont confirmé les propriétés de mémoire des cellules NK après endotoxinémie. Nos résultats accroissent la connaissance concernant le rôle des cellules NK dans un contexte d'inflammation systémique, révélant des réponses compartimentalisés et l’induction d’une mémoire suite à l’endotoxinémie. L'observation selon laquelle les cellules NK développent des propriétés de mémoire après une inflammation systémique dans le contexte d'un environnement suppressif est d’une grande nouveauté et ce phénomène est rapporté pour la première foisSystemic inflammation is whole-body reaction to a triggering insult that often results in life threatening illness like systemic inflammatory response syndrome (SIRS). Contributing to the development of this inflammatory cascade are numerous cellular and molecular players, among which, NK cells have been shown to play a key role. Despite accumulating evidence on the organ-specific properties of both systemic inflammation and NK cells, little is known about the compartmentalized dynamics of NK cell activation during SIRS. Furthermore, the status of NK cells after the resolution of SIRS is also poorly characterized. In the present work, we investigated NK responses in different organs using a mouse model of endotoxinemia and characterized the compartmentalized response of spleen, lung, bone marrow, peritoneal and circulating NK cells. We found that despite similar dynamics of response in different organs, NK cells responses, are compartmentalized with seemingly specific thresholds of maximum activation. Using a series of adoptive transfers, we found that while organ-specific NK cell responsiveness can affect the initial phases of inflammation, these cells have the capacity to quickly adapt to a new environment and adjust their response levels to that of resident NK cells. Thus, this study provides proof of concept data on the compartmentalization of the NK cell responses during systemic inflammation. In a second part, we assessed the status of NK cells at different times after endotoxemia. NK cells responses in the context of whole spleen preparations were severely suppressed in response to in vitro restimulation at 14 days after endotoxemia. However, intrinsic NK cell responsiveness was increased after endotoxemia, showing characteristics of NK cell memory. Adoptive transfer experiments confirmed memory properties of NK cells after endotoxemia. Overall, these results expand on the role of NK cells in the context of systemic inflammation revealing compartmentalized responses during and memory properties following endotoxemia. The observation that NK cells develop memory properties after systemic inflammation in the context of a suppressive environment is of the highest novelty and the first one to report such a phenomenon
2
Finan-Marchi, Amanda Rose. « THE SYSTEMIC STEM CELL RESPONSE TO CARDIAC PRESSURE OVERLOAD ». Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1333897602.
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Daba, Alina. « Insights on systemic and cellular iron homeostasis : hepcidin responses to oral and parenteral iron loading and an alternative mechanism for ferritin mRNA translation ». Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=107735.
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Iron is vital for all living organisms, but due to its ability to readily accept or donate electrons, it is also potentially toxic. Finely tuned mechanisms have evolved to control iron homeostasis at the systemic and cellular level. The peptide hormone hepcidin controls systemic iron homeostasis by binding to and degrading the iron exporter, ferroportin, leading to decreased iron efflux from duodenal enterocytes, macrophages and hepatocytes into the blood stream. Cellular iron homeostasis is regulated by the IRE / IRP system, which controls the levels of proteins involved in iron uptake, utilization, export and storage in a coordinated manner. Excess intracellular iron is stored and detoxified in ferritin. In this work, we study how an excess of iron is managed at the systemic and cellular level. In chapter II, we hypothesize that dietary and parenteral iron loading have differential effects on body iron status and hepcidin expression in mice. We perform time – course experiments and compare the effects of dietary and parenteral iron loading on circulating and tissue iron parameters. We show that dietary iron overload exceeds the capacity of hepcidin to lower body iron levels, and parenteral iron loading elicits a delayed hepcidin response. We provide evidence that circulating holo – transferrin and hepatocytic iron are the sole iron signals for hepcidin activation. In chapter III, we examine how an excess of iron is managed at the cellular level. We hypothesize that ferritin might benefit from an alternative, IRES - dependent mechanism of translation. We inhibit global or ferritin - specific cap – dependent translation initiation and challenge the cells with iron. We show that ferritin by – passes both the global and the specific inhibition of translation. We then test for the presence of an IRES in the 5'UTR of ferritin mRNA and further validate this sequence.Le fer est vital pour tous les organismes vivants, cependant étant donné son habilité à donner ou accepter des électrons facilement, il a aussi le potentiel d'être toxique. Des mécanismes très précis ont évolué pour contrôler l'homéostasie du fer aux niveaux systémique et cellulaire. L'hormone peptidique, hepcidine, contrôle l'homéostasie du fer au niveau systémique par la dégradation de la ferroportine, l'exportateur cellulaire du fer. En conséquence, l'efflux du fer des entérocytes, des macrophages et des hépatocytes vers la circulation diminue. Au niveau cellulaire, le système IRE / IRP contrôle, d'une manière coordonnée, les niveaux des protéines impliquées dans l'acquisition, l'utilisation, l'exportation et le stockage du fer. L'excès de fer est stocké dans la ferritine. Dans ce travail, nous examinons comment l'excès de fer est géré aux niveaux systémique et cellulaire. Dans le chapitre II, nous émettons l'hypothèse que les surcharges orale et parentérale en fer ont des effets différents sur l'homéostasie systémique du fer et sur l'expression de l'hepcidine chez les souris. Nous comparons les effets des surcharges orale et parentérale en fer aux niveaux circulatoire et tissulaire. Nous démontrons que la surcharge orale en fer excède la capacité hypoferrémique de l'hepcidine alors que la surcharge parentérale en fer induit une réponse retardée de l'hepcidine. Nous apportons aussi la preuve que la holo – transferrine circulatoire et le fer hépatocytaire sont les signaux uniques de l'activation ferrique de l'hepcidine. Dans le chapitre III, nous examinons comment l'excès de fer est géré au niveau cellulaire. Nous émettons l'hypothèse que la ferritine bénéficie d'un mécanisme alternatif de traduction, dépendant d'une séquence IRES. Nous inhibons l'initiation de la traduction dépendante de la coiffe 5' globalement, ou spécifiquement pour la ferritine, et traitons les cellules avec une source de fer. Nous démontrons que la ferritine surpasse le blocage global ou spécifique de la traduction dépendante de la coiffe 5'. Nous testons la présence d'une séquence IRES dans l'extrémité 5' de l'ARNm et par la suite nous la validons.
4
Hughes, Phillipa Jane. « Cellular responses to aluminium ». Thesis, University of Liverpool, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262389.
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Zhao, Ming-Hui. « Characterisation of autoimmune responses in systemic vasculitis ». Thesis, Anglia Ruskin University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.259510.
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Calay, Ediz Suha. « Cellular and Systemic Metabolic Adaptations to Energy Status ». Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11547.
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Roberts, Tara Laurine. « Cellular responses to immunostimulatory DNA / ». [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18175.pdf.
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Lidehäll, Anna Karin. « Cellular Immune Responses to Cytomegalovirus ». Doctoral thesis, Uppsala University, Department of Oncology, Radiology and Clinical Immunology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8578.
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Cytomegalovirus (CMV) is a widespread infection affecting 50-90% of the human population. A typical silent primary infection is followed by life-long persistence in the host under control by virus-specific CD8 (“killer”) and CD4 (“helper”) T cells. Although harmless in most people, CMV may cause disease and sequelae in patients with deficient cellular immunity, such as AIDS patients, recipients of organ transplants and children who have acquired the virus before birth. In this thesis we have characterized the cellular immunity to CMV in immunocompetent subjects, in patients receiving transplants and in infants.
In healthy individuals with latent CMV, the frequencies of CMV-specific CD8 T cells varied considerably between the donors. Within the same individual, the changes over time were usually small. In patients with primary, symptomatic CMV infection, the frequencies of CMV-specific CD8 T cells peaked within the first month after the appearance of symptoms. The frequencies then declined to levels similar to those in latently infected CMV carriers. The CD4 T-cell function followed the same pattern, but with lower peak values.
Immunosuppressed renal transplant patients with latent CMV had CMV-specific CD4 cell function similar to healthy controls. The frequencies of CMV-specific CD8 T cells were also comparable, but their function was impaired. When renal transplant recipients were investigated longitudinally, we found that their CMV-specific T cells decreased rapidly after transplantation. Whereas the frequencies and function of CD8 T cells rebounded within 3 months, CD4 T-cell recovery was impaired during the entire first year after transplantation.
Finally, the frequencies and function of CMV-specific T-cells were investigated in children with congenital and postnatal CMV. CMV-specific CD8 T cells could be detected in even the youngest children, suggesting that these cells can develop early in life. In contrast, CMV specific CD4 T cells were low or absent in the youngest children but increased slowly with age.
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Lidehäll, Anna Karin. « Cellular immune responses to cytomegalovirus / ». Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8578.
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Tomkins, C. E. « Cellular responses to genotoxic stress ». Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362104.
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Costa, Tatiana Lima de Vilhena Magalhães. « Cellular responses to genome mistranslation ». Doctoral thesis, Universidade de Aveiro, 2012. http://hdl.handle.net/10773/8075.
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Doutoramento em BioquímicaLow level protein synthesis errors can have profound effects on normal cell physiology and disease development, namely neurodegeneration, cancer and aging. The biology of errors introduced into proteins during mRNA translation, herein referred as mistranslation, is not yet fully understood. In order to shed new light into this biological phenomenon, we have engineered constitutive codon misreading in S. cerevisiae, using a mutant tRNA that misreads leucine CUG codons as serine, representing a 240 fold increase in mRNA translational error relative to typical physiological error (0.0001%). Our studies show that mistranslation induces autophagic activity, increases accumulation of insoluble proteins, production of reactive oxygen species, and morphological disruption of the mitochondrial network. Mistranslation also up-regulates the expression of the longevity gene PNC1, which is a regulator of Sir2p deacetylase activity. We show here that both PNC1 and SIR2 are involved in the regulation of autophagy induced by mistranslation, but not by starvation-induced autophagy. Mistranslation leads to P-body but not stress-granule assembly, down-regulates the expression of ribosomal protein genes and increases slightly the selective degradation of ribosomes (ribophagy). The study also indicates that yeast cells are much more resistant to mistranslation than expected and highlights the importance of autophagy in the cellular response to mistranslation. Morpho-functional alterations of the mitochondrial network are the most visible phenotype of mistranslation. Since most of the basic cellular processes are conserved between yeast and humans, this study reinforces the importance of yeast as a model system to study mistranslation and suggests that oxidative stress and accumulation of misfolded proteins arising from aberrant protein synthesis are important causes of the cellular degeneration observed in human diseases associated to mRNA mistranslation.
Erros no processo da síntese proteica podem ter profundos efeitos na fisiologia celular e no desenvolvimento de doenças, nomeadamente doenças neurodegenerativas, cancro e envelhecimento. A introdução de erros durante a síntese de proteínas e, em particular durante o processo da tradução, é designado por “mistranslation” que é um processo pouco estudado e mal compreendido. Neste projecto, construímos leveduras que, sistemática e constitutivamente, treslêem o codão de leucina CUG como serina, o que corresponde a um aumento de erro de 240 vezes relativamente à taxa de erro basal da síntese proteica (0.001%). Os resultados obtidos demonstram que os erros de tradução induzem a actividade autofágica, acumulação de proteínas insolúveis, produção de espécies reactivas de oxigénio, disrupção funcional e morfológica das mitocôndrias, não ocorrendo, no entanto, destruição selectiva destas. A expressão do gene PNC1, associado ao aumento da longevidade e regulador da actividade da deacetilase Sir2p, é fortemente aumentada em resposta aos erros da tradução. Os genes PNC1 e SIR2 estão envolvidos no controlo da autofagia induzida pelos erros de tradução mas não em situações de stress nutricional. O aumento dos erros de tradução leva à formação de P-bodies, mas não induz a formação de grânulos de stress e reduz a expressão de genes que codificam proteínas ribosomais em vez de se verificar destruição selectiva de ribosomas - ribofagia. Este estudo mostra que as células de levedura são muito mais resistentes aos erros na tradução do que o esperado. Os resultados mostram um papel fundamental da autofagia na resposta celular aos erros de tradução e indicam que estes têm um forte impacto em alterações morfo-funcionais das mitocondrias, sendo este um dos fenótipos mais marcantes nestas células. Considerando que a maior parte dos mecanismos celulares são conservados entre leveduras e células humanas, este estudo mostra que a levedura é um excelente modelo para estudar a resposta celular aos erros de tradução e sugere que o stress oxidativo, a acumulação de espécies reactivas de oxigénio e a acumulação de proteínas insolúveis podem ser a causa da degeneração celular observada em múltiplas doenças humanas associadas a defeitos na síntese proteica.
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Davies, Stuart M. « Cellular responses to potential biomaterials ». Thesis, Aston University, 1991. http://publications.aston.ac.uk/9696/.
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The aim of this study was to systematically investigate the factors considered to be responsible for anchorage-dependent cell behaviour to determine which, if any, of these factors exerts greater influence. An efficient means of doing so is the in vitro fibroblast cell culture model. The interaction of fibroblasts with novel substrata gives information about how a biological system reacts to a foreign material. The may ultimately lead to the development of improved biomaterials. This interdisciplinary study combines the elements of surface characterisation and biological testing to determine the nature of the biomaterial/host interface. Polarity and surface charge were found to have an important influence on fibroblast adhesion to hydrogel polymers, by virtue of their water-structuring effects. The same factors were found to affect cell adhesion on undegraded PHB-HV copolymers and their blends with polysaccharides. On degraded PHB-HV copolymers, the degradation process itself played the greatest role in influencing cell response. Increasing surface charge and mechanical instability in these polymers inhibited cell adhesion. Based on the observations of hydrogels and PHB-copolymers a novel material, gel-spun PHB was designed for use as a wound scaffold. In vitro tests using human and mammalian fibroblasts accentuated the importance of polarity and surface charge in determining cellular response. The overall view of cellular behaviour on a broad spectrum of materials highlighted the effects that polarity and surface charge have on water-structuring, and how this affects interfacial conversion. In degradable systems, mechanical stability also plays an inportant role in determining anchorage-dependent cell behaviour.
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Riahi, Reza. « Engineered Molecular Probes for Systematic Studies of Cellular Response in Collective Cell Migration ». Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/312515.
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The investigation of complex biological processes, such as wound healing, cell migration, cancer cell invasion, and gene regulatory networks can be benefited tremendously by novel biosensing techniques with high stability and spatiotemporal resolution. In particular, molecular probes with qualities including high stability, sensitivity, and specificity are highly sought-after for long-term monitoring of gene expression in individual cells. Among different single-cell analysis techniques oligonucleotide optical probes is a promising detection method to monitor the dynamics of cellular responses. Herein, the design and optimization of double-stranded LNA probes are first investigated. With alternating DNA/LNA monomers for optimizing the stability and specificity, we show that the probe is highly stable in living cells and is capable of detecting changes in gene expression induced by external stimuli. Using dsLNA probes we then demonstrate the novel approaches to monitor the spatiotemporal gene expression response during cell injury. Our results also suggest a potential autoregulatory role of Nrf2 in injury induced EMT. We also show that the signaling level of dsLNA probe can serve as a molecular signature for the leader cells near the wound which allows us to track the behaviors of leader cells during collective cell migration. Finally multimodal GNR-LNA approach is proposed to map spatiotemporal gene expression profile and reveal dynamic characteristics of heat shock response in photothermal operations.
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Isobe, Ken-ichi, Sachiko Ito, Masataka Haneda, Yoshiyuki Ishida, 健一 磯部 et 佳幸 石田. « Cellular and systemic defense system against age-promoting stimuli ». Nagoya University School of Medicine, 2006. http://hdl.handle.net/2237/6128.
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Hansson, Anna. « Cellular responses to respiratory chain dysfunction / ». Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-493-7/.
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Pinheiro, Susana Frazão Ferreira Fernandes. « Cellular immune responses in HIV infection ». Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400437.
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Trainor, Colman Joseph. « Cellular responses to modulated radiation fields ». Thesis, Queen's University Belfast, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603426.
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The primary aim of radiotherapy is to deliver sufficient doses in order to eradicate a tumour whilst sparing damage to normal tissue. Advanced radiotherapy techniques such as Intensity modulated radiation therapy (IMRT) have been developed that aspire to improve the conformity of beam delivery in order to improve tumour control and reduce normal tissue complications. It is of vital importance to determine the response to modulated fields within the directly targeted and out-of-field regions and to gain greater understanding of the mechanisms driving the response, This work investigates the cell survival and DNA damage responses following modulated radiation field delivery. It has shown that significant decreases in cell survival occur within regions outside the radiation field following the delivery of modulated radiation. It has demonstrated for the first time the spatial and temporal characteristics of DNA damage and repair across a modulated radiation fie ld. Initial and residual DNA damage was shown to increase within out-of-field regions following modulated radiation field delivery. The bystander effects were observed to occur independently of several parameters such as dose-rate, hypoxia and dose fractionation. It can be concluded that intercellular communication between populations ill- and out-of-field is pivotal for the induction of out-of-field cellular responses that may need to be considered further as potential effectors of clinical outcome.
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Matthews, Timothy. « Cellular responses in rotator cuff tears ». Thesis, Queen Mary, University of London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498371.
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Pele, Laetitia. « Cellular responses to calcium phosphate microparticles ». Thesis, King's College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414584.
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Ballweg, Richard A. III. « Computational Analysis of Heterogeneous Cellular Responses ». University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin159216973756476.
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Mageean, Craig. « Cellular responses to oncogenic Ras signalling ». Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/2003301/.
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The three human Ras proto-oncogenes encode for four highly homologous protein isoforms, H-, K(A)-, K(B)- and N-Ras, that function as molecular switches and timers to transduce signals from activated cell surface receptors to modulate signalling pathways responsible for cell proliferation, growth, survival and apoptosis. Oncogenic mutations of Ras occur in ~16% of all human cancer cases and most often affect codons 12, 13 and 61, each resulting in constitutive activation of the protein. Currently, it is uncertain how many Ras molecules are present per cell and which isoform is most abundant, essential information for the emerging field of systems biology, which utilises mathematical modelling to understand the behaviour of complex signalling pathways in a holistic approach. In the first part of this thesis, a selected reaction monitoring (SRM)-based Ras quantification technique is established for the measurement of each major isoform, along with the generation of isotope-labelled Ras protein standards that support quantification using the protein standard absolute quantification (PSAQ) strategy. Combining targeted SRM-based proteomics with the PSAQ strategy enabled the most accurate measurement of cellular Ras isoform abundance to date, as detailed in the second part of this thesis. The target cell lines in the present thesis were a panel of isogenic SW48 colorectal cells, which express a variety of heterozygous Ras mutations following the exchange of a wild-type allele for a mutant Ras sequence through targeted homologous recombination. Over 250,000 Ras molecules per wild-type SW48 cell were quantified, with K(B)-Ras the major Ras isoform. ~114 Ras molecules are predicted to be bound per μm2 of plasma membrane, with the cellular molarity of Ras at 253 mM. Intriguingly, the presence of certain K-Ras mutations induced significant changes in cellular Ras abundance, which may be attributable to the specific transforming potential of each mutant protein. The presented data also suggests that, in addition to their structural and biochemical variations, Ras mutant proteins may exert their different biological effects through differential protein expression. Many cancer types demonstrate a preference for a single Ras isoform to be mutated and present a codon-specific mutation signature. In colorectal cancer, K-Ras is the most frequently mutated isoform, with over 75% of mutations accounted for by G12D, G12V and G13D in colon tumours with a K-Ras mutation. Clinical data suggests that patients harbouring codon 12 or 13 K-Ras mutations have different overall survival rates and responsiveness to treatment. Isogenic SW48 cells harbouring the aforementioned K-Ras mutations were subject to mass spectrometry-based proteome and phosphoproteome quantitative analysis, to investigate the effects of different amino acid substitution (G12D vs. G12V) or codon mutation (G12D vs. G13D) on oncogenic Ras signalling. The presented data in the third part of this thesis provide the first quantitative proteomic and phosphoproteomic profile of signatures associated with specific K-Ras mutant proteins expressed at endogenous levels. Each K-Ras mutation induced a distinct signalling output, with the most variability observed between codon 12 mutants and G13D. This indicates that the position of a Ras point mutation may have more impact on signalling than an amino acid substitution. Several proteins relevant to colorectal carcinogenesis were found to specifically up-regulated by codon 12 or 13 mutations, with one notable example being the recently described colon cancer stem cell marker double cortin-like kinase 1, which was sensitive only to codon 12 K-Ras mutations. Together, the data presented in this thesis provides a novel insight into the behaviour of a range of Ras mutations in a colorectal cancer setting.
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Newnham, Donald Mackenzie. « Airways and systemic responses to β₂-agonists in man ». Thesis, University of Aberdeen, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295588.
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The primary aim of this thesis was to evaluate the two following hypotheses: (i) the β-adrenoceptor selectivity of fenoterol and salbutamol is comparable, but fenoterol is more potent for β2-adrenoceptors, and (ii) subsensitivity of β2-adrenoceptors develops following chronic-dosing with the long-acting β2-agonist, eformoterol. Subsequent data demonstrated no significant differences in relative cardiac β1/β2-activity between inhaled fenoterol and salbutamol. However, fenoterol was significantly more potent for hypokalaemic and finger tremor responses but not bronchodilator or chronotropic effects. Furthermore, in two chronic dosing studies, significant subsensitivity of β2-adrenoceptors in-vivo and in-vitro, was demonstrated in asthmatic patients after chronic-dosing with eformoterol. Three secondary hypotheses, generated from the results of the preliminary studies, were also evaluated, and data showed that (i) the hypokalaemic response to inhaled terbutaline was additive to that of frusemide, but was not attenuated by the addition of triamterene, (ii) enhanced in-vivo β2-responsiveness to salbutamol was demonstrated in female subjects compared with male controls, and this may be explained by ovarian hormone regulation of β2-adrenoceptor function, and (iii) when inhaled after ipratropium bromide, no significant improvement occurred in the bronchodilator response to high dose terbutaline, over and above a low dose, in patients with COPD suggesting that prior attenuation of vagal tone permits optimal achievable bronchodilatation to be attained by low-dose β2-agonist alone.
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Lewis, Phillip Andrew. « A systemic approach to the design of cellular manufacturing systems ». Thesis, Aston University, 1994. http://publications.aston.ac.uk/10740/.
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Cellular manufacturing is widely acknowledged as one of the key approaches to achieving world-class performance in batch manufacturing operations. The design of cellular manufacturing systems (CMS) is therefore crucial in determining a company's competitiveness. This thesis postulated that, in order to be effective the design of CMS should not only be systematic but also systemic. A systemic design uses the concepts of the body of work known as the 'systems approach' to ensure that a truly effective CMS is defined. The thesis examined the systems approach and created a systemic framework against which existing approaches to the design of CMS were evaluated. The most promising of these, Manufacturing Systems Engineering (MSE), was further investigated using a series of cross-sectional case-studies. Although, in practice, MSE proved to be less than systemic, it appeared to produce significant benefits. This seemed to suggest that CMS design did not need to be systemic to be effective. However, further longitudinal case-studies showed that the benefits claimed were at an operational level not at a business level and also that the performance of the whole system had not been evaluated. The deficiencies identified in the existing approaches to designing CMS were then addressed by the development of a novel CMS design methodology that fully utilised systems concepts. A key aspect of the methodology was the use of the Whole Business Simulator (WBS), a modelling and simulation tool that enabled the evaluation of CMS at operational and business levels. The most contentious aspects of the methodology were tested on a significant and complex case-study. The results of the exercise indicated that the systemic methodology was feasible.
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Dolling, Jo-Anna. « Cellular responses to ionizing radiation and cisplatin ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ28336.pdf.
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Engstrand, Mats. « Cellular Immune Responses to Allografts and Cytomegalovirus ». Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3441.
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Young, Lauren Jill. « Cellular immune responses of marsupials : family Macropodidae / ». View thesis, 2002. http://library.uws.edu.au/adt-NUWS/public/adt-NUWS20030724.151428/index.html.
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Thesis (Ph.D.) -- University of Western Sydney, 2002."A thesis submitted to the University of Western Sydney in fulfilment of the requirements for the degree of Doctor of Philosophy" Bibliography : leaves 400-437.
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Chen, Hsuan-Fu. « Cellular responses to jasmonate in Arabidopsis roots ». Thesis, University of East Anglia, 2011. https://ueaeprints.uea.ac.uk/38236/.
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Higher plants respond to biotic and abiotic stress through activation of the JA pathway, which suppresses growth and activates defence. This project describes the expression and subcellualr localisation of two of the JA signalling proteins, and the mechanism of MeJA-mediated root growth inhibition. By using immunolocalisation and reporter gene expression, localisation of COIl was shown at the subcellular and tissue level. Although COIl was constitutively expressed in the root and shoot, increased expression of COIl in MeJA-treated roots suggested that the COIl gene and the COIl protein was also regulated by the JA pathway. Co-localisation of COIl and JAZ3 protein in the nucleus confirmed that the previously reported interaction between COIl and JAZ3 took place in the nucleus. To investigate the morphological basis of root growth inhibition by MeJA, time-lapse and still imaging by confocal microscopy was used to compare root growth parameters in untreated and MeJA-treated roots. MeJA inhibited root growth by reducing the number of dividing cells and rapidly-elongating cells, and causing earlier maturation of the elongating cells, so that they ceased elongating before reaching normal mature cell length. However, the rate of individual cell elongation was unaltered. The physiological basis of MeJA-mediated growth inhibition was investigated by examining the orientation of microtubules, acid efflux from the root elongation zone, and the effect of low water potential on root elongation. MeJA-treated roots had reduced acid efflux and water uptake in the elongating cells, while microtubule orientation was not required for the inhibitory effect. The crosstalk between JA, auxin, GA and ABA was studied by measuring the change of morphological growth parameters in mutants under different hormone treatment. The impaired MeJA-mediated growth inhibition in auxl indicated that MeJA reduced root growth by altering auxin transportation. However, MeJA-mediated growth inhibition was DELLA- and ABA- independent. In summary, MeJA reduced cell division by decreasing mitosis, and inhibited cell elongation by reducing acid efflux, which prevented water uptake, possibly by regulating the auxin transportation, in the Arabidopsis root.
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Smith, James George William. « Cellular responses to dental extracellular matrix molecules ». Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3432/.
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Dental pulp contains mesenchymal stem cells (MSCs) similar to those present within bone marrow. Several factors are postulated to contribute to the signalling involved in regulating these cells. This project aimed to investigate the role of pulp and dentine extracellular matrix (pECM/dECM) in the regulation of pulp cell behaviour during health and disease. pECM/dECM molecules were extracted using 10% EDTA, pH7.2 followed by 0.5M-NaCl, pH11.7 and 0.1M tartaric acid, pH2.0, respectively containing protease inhibitors. Proteomic analysis demonstrated the complexity of the ECM extractions. pECM-coated cultureware reduced pulp cell proliferation rates and increased stem cell marker expression compared with controls. Pulp cells exhibited multipotential capacity, with pECM-coated culture surfaces enhancing differentiation activity. pECM and dECM promoted pulp cell migration through an active rho dependent pathway and the chemotactic effects of these ECM molecules were enhanced following acidic/proteolytic degradation. Recruited cells exhibited increased stem cell marker expression. dECM and pECM possessed demonstrable bacteriostatic activity against three anaerobic bacteria associated with dental disease. Dental pulp cells were shown to be viable and capable of secreting mineral when encapsulated within a pECM/alginate scaffold and exposed to dECM molecules. Dental ECMs play important roles in regulating cellular and tissue responses during health and disease.
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Yarema, Kevin J. (Kevin Jon). « Cellular responses to platinum-based anticancer drugs ». Thesis, Massachusetts Institute of Technology, 1994. http://hdl.handle.net/1721.1/33495.
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Davis, Andrew E. M. « The Impact of Systemic Infection Upon Acute CNS Inflammatory Responses ». Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491366.
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Systemic infection often accompanies or precedes acute brain injury, but it is unclear how systemic responses contribute to clinical outcome. Herein, acute CNS injury in the rat has been modelled using the microinjection of interleukin-l beta (IL-I~) into the brain, or by controlled compression injury to the spinal cord. The impact of systemic bacterial or viral infection upon the pathogenesis of the inflammatory response in these models was studied. Pre-conditioning with intravenous lipopolysaccharide (LPS), mimicking early immune responses to bacterial infection, dose-dependently reduced both the leukocytosis, and the number of leukocytes recruited to the brain parenchyma in response to IL-I ~ challenge. This effect was not mimicked by systemic challenge with IL-I~, suggesting LPS-specific mechanisms were operating. In addition, LPS challenge in a dorsal air pouch did not mirror the actions of LPS administered intravenously, suggesting focal immune responses were not sufficient to stimulate protective signalling pathways. Interestingly, a post-challenge with LPS similarly inhibited the leukocytosis, and leukocyte recruitment to the IL-I ~-challenged brain and compression-injured spinal cord, an effect that was found to be partially mediated by the action of endogenous glucocorticoids. In marked contrast, the protection afforded by LPS was not conserved in a viral infection model. Systemic administration of a luciferase-expressing adenovirus (AdLuc) significantly increased the leukocytosis and numbers of leukocytes recruited to the IL-I ~-challenged brain. This was particularly evident in the contralateral hemisphere, which in our injury model is largely devoid of leukocyte recruitment. Furthermore, viral challenge increased the recruitment of leukocytes to the liver, a factor of potential significance to multi organ dysfunction, which is often concomitant with CNS injury. It can be concluded from this thesis that systemic infection can have dramatic effects upon leukocyte recruitment to sites of injury and disease in the CNS, and that the outcome is specific to the nature of the pathogen.
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Bulmer, J. Todd. « Cellular responses to the anti-cancer drug, cisplatin / ». *McMaster only, 2001.
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Barkefors, Irmeli. « Directing Angiogenesis : Cellular Responses to Gradients in vitro ». Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-145525.
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Blood vessels are essential for the delivery of nutrients and oxygen to tissues, as well as for the removal of waste products. Patients with tumors, wounds or diabetes all have active angiogenesis, formation and remodeling of blood vessels, a process that is initiated and manipulated by gradients of secreted signaling proteins. This thesis describes the development of new microfluidic in vitro assays where directed migration of single endothelial cells and three dimensional vascular structures can be monitored in real time. Combining these assays with live imaging microscopy we have studied the behavior of endothelial cells in gradients of proangiogenic factors as well as directed sprouting in embryonic kidneys and stem cell cultures. With the 2D assay we have quantified endothelial cell chemotaxis towards FGF2, VEGFA165 and VEGFA121 and we also demonstrate that constant levels of VEGFA165, but not of FGF2, are able to reduce chemokinesis of endothelial cells. In the 3D migration chamber we have studied directed endothelial cell sprouting in mouse embryonic kidneys and embryoid bodies in response to VEGFA gradients. In both models directed angiogenesis is detected towards increasing levels of growth factor. Using the microarray technique on differentiating embryonic stem cells we have been able to identify the gene exoc3l2 as potentially involved in angiogenesis and endothelial cell migration and we present evidence that ExoC3l2 is associated with the exocyst complex; an important regulator of cell polarity. We have also shown that siRNA mediated gene silencing of exoc3l2 results in impaired VEGFR2 phosphorylation as well as loss of directionality in response to a VEGFA gradient.(Faculty of Medicine)
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Singh, Rekha. « Cellular immune responses in HSV and CMV infections ». Thesis, University of Ottawa (Canada), 2003. http://hdl.handle.net/10393/29036.
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The herpes simplex virus (HSV) and cytomegalovirus (CMV) are the prominent members of the Herpesviridae family collectively responsible for the majority of herpes-related morbidity and mortality in humans. These viruses are therefore the subjects of this study that was undertaken to improve our understanding of the nature of immune response and the mechanism of viral modulation leading to suppression of viral replication or evasion of the host immune response in vivo.
The present study has examined the T helper responses to HSV-2 and murine CMV (MCMV) and provides new insights into the nature and the modulation of the T helper responses by these viruses in vivo.
B7-1/B7-2 costimulation of T cells by antigen-presenting cells is essential for T cell activation by antigen. HSV-2 infection affects the expression of both B7-1 and B7-2 on monocytes, the key antigen presenting cells in vivo, potentially in two ways with opposing outcomes. It abrogates or diminishes the IFN-gamma-upregulation of B7-1 (in 8 out of 9 patients) and B7-2 (in 6 out of 9 patients) on monocytes. However, the infection also augments the expression of B7-1 and B7-2 on monocytes through an IFN-gamma-independent mechanism (in 9 out of 9 patients). Although the clinical significance of these opposing effects is presently unclear, these may be related to the immunological mechanism or strategy leading to recurrent disease in immunocompetent hosts.
Like HSV-2, infections with MCMV in mice also led to a predominant Thl type immune response characterized by high levels of IFN-gamma and low IL-4 production. Studies with specific MCMV mutants, containing Tn3 transposon in the open reading frame of M25, M27, M43, or m09 gene, led to the identification of M43 gene that specifically suppresses IL-4 response. The Tn3 disruption of M43, but not M25, M27 or m09, gene of MCMV led to a strong IL-4 response (p = 0.0002) despite the presence of a dominant IFN-gamma response. These results provide insight into the possible role of a herpesvirus gene that can profoundly modulate the nature of T helper response in vivo. The presence of a homologous genetic element in other herpesvirus genomes may explain the dominant Th1 immune response triggered by HSV-2 and possibly other herpesviruses. The obvious importance of this finding, beyond herpesvirus immunopathogenesis, lies in the ability of M43 and homologous genes to globally modulate the nature of cytokine response in vivo and suppress Th2 cytokine-mediated diseases. (Abstract shortened by UMI.)
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Hassanzadeh, Golnoush. « Characterizing Cellular Responses During Oncolytic Maraba Virus Infection ». Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/35871.
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The rising demand for powerful oncolytic virotherapy agents has led to the identification of Maraba virus, one of the most potent oncolytic viruses from Rhabdoviridae family which displays high selectivity for killing malignant cells and low cytotoxicity in normal cells. Although the virus is readied to be used for clinical trials, the interactions between the virus and the host cells is still unclear. Using a newly developed interferon-sensitive mutant Maraba virus (MG1), we have identified two key regulators of global translation (4E-BP1 and eIF2α) responsible for the inhibition of protein synthesis in the infected cells. Despite the translational arrest upon viral stress, we showed an up-regulation of anti-apoptotic Bcl-xL protein that provides a survival benefit for the host cell, yet facilitates effective viral propagation. Given the fact that eIF5B canonically regulates 60S ribosome subunit end joining, and is able to replace the role of eIF2 in delivering initiator tRNA to the 40S ribosome subunit upon the phosphorylation of eIF2α, we have tested whether eIF5B mediates the translation of target mRNAs during MG1 infection. Our results show that the inhibition of eIF5B significantly down-regulates the level of Bcl-xL steady-state mRNA, thus indirectly attenuates viral propagation.
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Henderson, Livia. « Cellular stress responses in equine tendon fibroblast monolayers ». Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/6725/.
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The superficial digital flexor tendon (SDFT) is one of the most frequently injured tendons in Thoroughbred racehorses. Exercise associated factors including hyperthermia are thought to lead to cellular dysfunction and cell death of the resident tendon fibroblasts, the cells responsible for the repair of the tendon lesions. The main aim of this thesis was to investigate the sensitivity of SDFT fibroblasts to hyperthermia and to compare this with the deep digital flexor tendon (DDFT), a non-injury prone tendon. Understanding the physiological mechanisms of the heat shock response in these cells e.g. the use of protein markers will allow preventative strategies to be devised to protect these cells from damage. I determined whether thermotolerance associated with the induction of heat shock proteins (a survival mechanism that allows cells to withstand a subsequent lethal shock) could be induced with both heat and cold shock in these cells. Firstly, the basal DNA damage levels were quantified in both SDFT and DDFT fibroblasts as the cell culture environment is known to damage cells. My research showed both SDFT and DDFT fibroblasts were susceptible to replication induced DNA damage in vitro. The SDFT in particular had high levels of DNA damage when cultured on a fibronectin matrix in ambient oxygen. SDFT and DDFT fibroblasts were shown to be susceptible to a lethal heat shock (52oC). When a preconditioned sub-lethal heat shock was given to both tendons, induction of thermotolerance occurred and these cells survived a lethal heat shock. Thermotolerance was induced in preconditioned cold shocked SDFT fibroblasts but not in DDFT fibroblasts. Finally, a useful protein marker, DAXX (that is involved in cellular stress pathways as a transcriptional repressor and in apoptosis) was shown to disperse into the nucleoplasm during a mild heat shock in SDFT fibroblasts. One of the limitations of this thesis is that sample size was small and as a result, larger numbers of animals will be required for future experiments to determine whether my results are of biological significance.
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Isa, Adiba. « Cellular immune responses against human parvovirus B19 infection / ». Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-662-X/.
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Lööv, Camilla. « Cellular and Molecular Responses to Traumatic Brain Injury ». Doctoral thesis, Uppsala universitet, Neurokirurgi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-215154.
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Traumatic brain injury (TBI) is a relatively unknown disease considering the tens of millions of people affected around the world each year. Many TBI patients die from their injuries and survivors often suffer from life-long disabilities. The primary injury initiates a variety of cellular and molecular processes that are both beneficial and detrimental for the brain, but that are not fully understood. The focus of this thesis has been to study the role of astrocytes in clearance of dead cells after TBI and to identify injury specific proteins that may function as biomarkers, by using cell cultures, animal models and in cerebrospinal fluid (CSF) from TBI patients. The result demonstrates a new function in that astrocytes, the most numerous cell type in the brain, engulf dead cells after injury both in cell cultures and in adult mice and thereby save neurons from contact-induced apoptosis. Astrocytes are effective phagocytes, but degrade the ingested dead cells very slowly. Moreover, astrocytes express the lysosome-alkalizing proteins Rab27a and Nox2 as well as major histocompatibility complex class II, the receptors on which antigens are being presented. By lowering the pH of the lysosomes with acidic nanoparticles, the degradation increases, but the astrocytes still remained less effective than macrophages. Taken together, the data indicates that the low acidification in astrocytes can preserve antigens and that astrocytes may be able to activate T cells. The expression and secretion of injury-specific proteins was studied in a cell culture model of TBI by separate mass spectrometry analysis of cells and medium. Interestingly, close to 30 % of the injury-specific proteins in medium are linked to actin, for example ezrin of the ezrin/radixin/moesin (ERM) protein family. Ezrin, but none of the other ERM proteins or actin, is actively secreted after injury. Extracellular ezrin also increases in CSF in response to experimental TBI in rats and is present in CSF from TBI patients, indicating that ezrin is a potential biomarker for TBI.
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Berthoud, Tamara Katherine. « Human cellular immune responses to candidate malaria vaccines ». Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.445763.
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Habib, M. « In vitro cellular responses to phosphorylcholine-based polymers ». Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599819.
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In this study the biocompatibility of PC polymers modified with various amounts of cationic charge was investigated. Three PC polymers, PC20, PC5 and PC0, containing 20%, 5% and 0% cationic charge were used. The response of primary human endothelial, osteoblast (HOB) and mononuclear cells to PC-coated surfaces was investigated using a range of in vitro techniques. All three cell types adhered to PC surfaces in both serum-supplemented and serum-free media. However increased cell adhesion was observed in the presence of serum. Similarly cell adhesion increased with the presence of cationic charge in the polymer. The cationic charge also induced specific morphologies in each cell type. Endothelial cells were noted to require serum for their maximal spreading on PC-coated surface. The adhesion of endothelial cells was also found to increase with pre-coating of PC surfaces with fibronectin. HOB cell did not show an inflammatory response to PC surface, while mononuclear and endothelial cells did. However no differences were noted in the inflammatory response of endothelial cells to PC polymers in the presence and absence of lipopolysaccharide. HOB cells’ proliferation was greater on PC20 compared to PC5 and tissue culture plastic. Enzymatic activity of alkaline phosphatase as well as its messenger RNA levels was higher on PC24 than PC5 and tissue culture plastic. HOB cells also formed nodules on PC20 but not on PC5, suggesting that 20%o cationic charge may be optimal for HOB cell differentiation. These findings have extended an understanding of bioeompalibility of PC polymers and ultimately could expand their clinical applications.
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Cooney, Rory Patrick. « Cellular responses of Mycobacterium tuberculosis to antimycobacterial agents ». Thesis, University of Newcastle Upon Tyne, 2000. http://hdl.handle.net/10443/1662.
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The effects of clinically important antimycobacterial drugs on Mycobacterium tuberculosis at the single cell level using cytochemical indicators of cellular activity were studied. Procedures based on rhodamine 123 (R 123) uptake as an indicator of cytoplasmic membrane energisation, propidium iodide (PI) exclusion and iodonitrophenyltetrazolium chloride (INT) reduction were established. Some cells in every preparation were found to resist labelling by all of the procedures applied. This proportion was highest in broth culture (up to 70%) and lowest in cell suspensions prepared from agar spread plates. R123 uptake in growing cells was reversibly sensitive to carbonylcyanide m-chlorophenylhydrazone (CCCP), an uncoupler of oxidative phosphorylation. Several tuberculocidal treatments (70°C/30 min, 70% ethanol and 4% formaldehyde) lead to development of uncoupler insensitive R 123 labelling of dead cells, demonstrating the requirement for a physiologically validated procedure where labelling was unambiguously attributed to membrane energisation. All antimycobacterial drug treatments (isoniazid, rifampicin, ethambutol, streptomycin and capreomycin) produced an excess of between 1 and 4 orders of magnitude of uncoupler sensitive R 123 labelling cells over culturable units. Thus, large populations of active but nonculturable (ABNC) cells were produced by antimycobacterial drugs commonly used in the treatment of tuberculosis. Non-labelling and ABNC cell populations were further investigated using a GFP reporter strain and by exposure to the lytic mycobacteriophage D29. In addition to demonstrating many of the potential pitfalls that may be encountered when the results of cellular activity/integrity assays are equated with viability/nonviability, these studies illustrate the heterogeneous nature of M tuberculosis cultures and the extent to which bulk analysis may give a misleading picture of cellular composition and physiology. Although the significance of the non-labelling and ABNC cells observed remains to be established, we speculate that these populations may have implications for the chemotherapy of tuberculosis.
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Al-Jarrah, Hatim A. « Cellular immune responses in hepatitis C virus infection ». Thesis, University of Nottingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250590.
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Tsolou, Avgi. « Cellular responses to uncapped telomeres in eukaryotic cells ». Thesis, University of Newcastle Upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442349.
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Karlsson, Mattias. « Modulation of cellular innate immune responses by lactobacilli ». Doctoral thesis, Örebro universitet, Institutionen för naturvetenskap och teknik, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-22138.
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Lactobacillus is a genus of lactic acid bacteria frequently used as healthpromoting probiotics. Using probiotics to treat or prevent infections is a novel experimental approach with vast impact on future therapy. Lactobacillus rhamnosus GR-1 is a probiotic investigated for its ability to reduce urogenital disease including urinary tract infections caused by pathogenic Escherichia coli. L. rhamnosus GR-1 has been shown to modulate immunity, thought to influence its probiotic effect. In this thesis, the aim was to study immunomodulation by L. rhamnosus GR-1 and other lactobacilli, with emphasis on elicited immune responses such as nuclear factor-kappaB (NF-κB) activation and cytokine release from human urothelial cells. Viable, heat-killed, and isolated released products from L. rhamnosus GR-1 augmented NF-κB activation in E. coli-challenged urothelial cells. Blocking of lipopolysaccharide binding to toll-like receptor 4 completely quelled this augmentation. Size-fractionation, urothelial cell challenge, and two-dimensional gel electrophoresis of L. rhamnosus GR-1 released products presented several candidate proteins with NF-κB modulatory actions including chaperonin GroEL, elongation factur Tu, and a protein from the NLP/P60 protein family. While tumor necrosis factor was correspondingly augmented by L. rhamnosus GR-1, the release of two other cytokines, interleukin (IL)-6 and CXCL8, was reduced. Similar effects were observed in macrophage-like cells stimulated with L. rhamnosus GR-1. Many immunomodulatory effects of lactobacilli are believed to be species and strain dependent. Therefore, twelve Lactobacillus strains were used to screen for their effects on CXCL8 release from urothelial cells. A majority of these strains were able to influence CXCL8 release from the cells. Phylogenetic analysis revealed close evolutionary linkage between lactobacilli with similar actions on CXCL8. Increased knowledge on probiotic bacterial products and the mechanism(s) of action could lead to improved future treatments for infections.
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Hay, Jennifer R. « Vascular and cellular responses to traumatic brain injury ». Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/30819/.
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There is growing evidence that suggests Traumatic brain injury (TBI) may initiate long-term neurodegenerative processes. Exposure to a single moderate or severe TBI, or to repetitive TBI, reveals a complex of pathologies including abnormalities of tau, amyloid-β and TDP-43; neuronal loss; neuroinflammation; and white matter degradation. The mechanisms driving these late post-TBI neurodegenerative pathologies remain elusive. Firstly, a potential association between blood-brain barrier (BBB) disruption and TBI was investigated. Results showed that increased and widespread BBB disruption was observed in material from patients dying in the acute phase following a single, moderate to severe TBI and persisted in a high proportion of patients surviving years following injury. Furthermore, there was preferential distribution to the deep layers of the cortex and to the crests of the gyri rather than the depths of the sulci. This post-TBI BBB disruption was investigated further within a paediatric TBI cohort. BBB disruption was noted in both paediatric and adult TBI in a similar pattern and distribution, however, interestingly, in sharp contrast to adult TBI cases, BBB disruption in paediatric cases appears preferentially distributed to capillary sized vessels. This vulnerability of the small vessels was rarely observed in adult material. In addition to the post-TBI vascular change observed, the cellular response was investigated, which interestingly, demonstrated regional differences. Specifically, in the grey matter, reactive astrogliosis was observed subpially, around cortical vessels, at the grey and white matter boundaries and subependymally. This astrogliosis was evident in a proportion of acute and continued into the late phase following TBI. In contrast, microglial activation was observed as a delayed response and localised to the white matter tracts. In addition, this delayed microglial response expressed an M2-like phenotype. Furthermore, there was an increased population of inactivated perivascular microglia beyond the perivascular space in the grey matter regions, observed in the acute phase and persisted in a proportion of patients surviving years following injury. Collectively these findings are interesting and indicate TBI induces both a vascular and cellular responses which may contribute to the long-term post-TBI neurodegenerative processes.
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Saborano, Raquel Teixeira. « Metabolomic study of cellular responses to silk nanoparticles ». Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/15306.
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Mestrado em Bioquímica - Bioquímica ClínicaThe use of metabolomics to reveal response markers of efficacy or toxicity, as well as to provide biochemical insight into mechanisms of action has gained increasing interest in the research community. In this work, the effects of silk nanoparticles on the metabolism of macrophages, which are an important cell type in regard to NP uptake, was addressed through Nuclear Magnetic Resonance (NMR) spectroscopy metabolomics. Firstly, 1D and 2D NMR spectroscopy was applied to determine the metabolic composition of murine macrophages (RAW 264.7 cell line), through the analysis of both aqueous and lipid extracts. Almost forty metabolites were identified, establishing a database of metabolites of murine macrophages. Afterwards, murine macrophages were exposed to two concentrations of silk nanoparticles (10 and 500 μg/mL), selected based on cytotoxicity data collected previously to this work, and the impact on their metabolic composition was assessed. Multivariate analysis was applied to the 1D 1H NMR spectra in order to search the compositional changes in macrophages during silk nanoparticles’ (SNPs) exposure. It was found that the low concentration SNPs induced few changes in the cells metabolome compared to the high concentration SNPs, which resulted in biochemical changes related to energy metabolism and TCA cycle, disturbance of amino acids metabolism and cell membrane modification. Some variations were common to all exposure periods, such as the increase in branched chain amino acids, lactate and tyrosine and the decrease in glutamine, taurine, myo-inositol and ATP/ADP, whereas other variations seemed to be more time-specific. The time-dependent fluctuations were also visible in lipids, where cholesterol, cholesterol esters and sphingomyelin were found to be relatively higher in SNP-exposed samples, while unsaturated fatty acids, plasmalogen and phosphatidylcholine were higher in controls. These results have shown that the use of NMR metabolomics to evaluate a nanomedicine performance may be a powerful tool to improve our understanding of cell-nanomaterial interactions and of the mechanisms underlying observed toxicities.
A aplicação da metabolómica com o intuito de revelar biomarcadores de eficácia ou toxicidade, assim como de fornecer uma compreensão bioquímica de mecanismos de ação, tem ganho maior interesse na comunidade científica. Neste trabalho os efeitos das nanopartículas de seda no metabolismo de macrófagos, que são um tipo celular importante no que diz respeito à incorporação de nanopartículas, foram investigados por metabolómica de espectroscopia de Ressonância Magnética Nuclear (RMN). Inicialmente, espectroscopia de RMN 1D e 2D foi aplicada para determinar a composição metabólica de macrófagos de rato (linha celular RAW 264.7), através da análise de extratos aquosos e lipídicos. Cerca de quarenta metabolitos foram identificados, estabelecendo uma base de dados dos metabolitos de macrófagos de rato. De seguida, esses macrófagos foram expostos a duas concentrações de nanopartículas de seda (10 e 500 μg/mL), selecionadas com base nos dados citotoxicológicos recolhidos previamente a este trabalho, e o seu impacto no metabolismo foi averiguado usando a mesma metodologia. Análise multivariada foi aplicada aos espectros de 1H RMN 1D de forma a investigar as alterações na composição dos macrófagos durante a exposição às nanopartículas de seda (SNPs). A concentração baixa de SNPs induziu poucas alterações no metaboloma celular comparativamente à concentração alta de SNPs, que resultou em alterações bioquímicas no metabolismo energético e ciclo do ácido cítrico, distúrbios no metabolismo de aminoácidos e modificações na membrana celular. Algumas variações foram comuns a todos os períodos de exposição, tais como o aumento dos aminoácidos de cadeia ramificada, lactato e tirosina, e a diminuição de glutamina, taurina, myo-inositol e ATP/ADP, enquanto que outras se revelaram ser mais específicas em relação ao tempo de exposição. As flutuações dependentes do tempo foram também visíveis nos lípidos, onde o colesterol, ésteres de colesterol e esfingomielina se encontraram mais elevados nas amostras expostas à concentração elevada de SNPs, enquanto que os ácidos gordos insaturados, plasmalogénio e fosfatidilcolina estavam mais elevados nos controlos. Estes resultados demonstraram que a aplicação de metabolómica de RMN para avaliar o desempenho de nanofármacos pode ser uma ferramenta importante para melhorar a nossa compreensão das interações célula-nanomaterial e os mecanismos subjacentes à toxicidade observada.
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Wiater, Ezra M. « Modulation of cellular responses to activins and BMPs / ». Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3112876.
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Mathieson, Peter William. « Role of T lymphocytes in autoimmune responses ». Thesis, University of Cambridge, 1992. https://www.repository.cam.ac.uk/handle/1810/251527.
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Soroa-Koury, Sandra. « Consumers' responses to mobile advertising a normative social behavior perspective / ». To access this resource online via ProQuest Dissertations and Theses @ UTEP, 2008. http://0-proquest.umi.com.lib.utep.edu/login?COPT=REJTPTU0YmImSU5UPTAmVkVSPTI=&clientId=2515.
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Davies, Marie Louise. « Autoantigen specific T cell responses in relation to systemic lupus erythematosus ». Thesis, University of Birmingham, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394161.
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Steel, Margaret. « The regulation of systemic immune responses by the dietary antigen ovalbumin ». Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360280.
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