Dissertations / Theses on the topic 'Homeostatis'
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Cooke, Jennifer. "The hypothalamic Regulation of Energy Homeostatis." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.503772.
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Dixon, Peter Hendy. "Molecular genetic studies of hypophosphataemic and hypoparathyroid disorders." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322579.
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Miller, C. "A study of the influences on mineral homeostatis in infants fed synthetic milk formulae." Thesis, Robert Gordon University, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.377550.
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Alessa, Lilian. "The effects of aluminum on cytoplasmic organization, the F-actin array and calcium homeostatis in Vaucharia longicaulis var.macounii." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0035/NQ27102.pdf.
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Dahdah, Albert. "Mast cell deficiency and calcium homeostatis : their imprints on cells of the immune systeme and implications in Sepsis." Paris 7, 2013. http://www.theses.fr/2013PA077213.
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Les cellules du sytème immunitaire ont un rôle important pour notre défense et l'élimination des agents pathogènes qui nous envahissent. De ce fait, il est nécessaire que les deux types de réponses (pro- et anti-inflammatoire) de ce système soient régulées, une réponse pro-inflammatoire insuffisante, ou trop forte, pourrait conduire à des lésions dans les tissus sièges de l'inflammation, et une réponse anti-inflammatoire excessive pourrait inhiber la réponse immune ouvrant la voie à une dissémination de bactéries, virus, et parasites. Heureusement, notre système immunitaire est bien équipé pour faire face à ces situations. Dans le cas du Sepsis, la réaction inflammatoire exagérée qui s'ensuit devient écrasante à l'hôte et conduit à une dérégulation du système, conduisant à une translocation des bactéries dans les organes, entraînant des lésions irréversibles, une perturbation de leur fonctionnement, et pouvant aller jusqu'à la mort. La dérégulation de ce système causé par le Calcium (Ca2+) en premier lieu et les Mastocytes étaient le centre de nos études. Dans une première étude chez la souris Trpm4-I-, nous montrons qu'un défaut de régulation de la réponse calcique chez le macrophage, est essentiel pour la survie des souris dans un modèle de Sepsis induit par CLP (Caecal Ligation and Puncture). Les macrophages déficitaires pour le canal TRPM4 (régulateur du Ca2+) présentent une surcharge calcique modifiant leurs fonctions de phogocytose. Ce qui se traduit par une augmentation du titre bactérien et une diminution de survie des souris. Dans une deuxième étude, nous proposons un nouveau modèle de souris déficientes en mastocyte, qui nous permet de décrypter le rôle de cette cellule dans les premières phases du Sepsis sévère, et son rôle anti-inflammatoire sur la phagocytose du macrophage. Un rôle qui se révèle délétère ; une ablation de ces cellules entraîne une meilleure survie, et un meilleur rétablissement des animaux. L'ensemble de nos études nous permet de préciser le rôle du Ca2+, ainsi que celui du Mastocyte dans le Sepsis, mais aussi d'établir de nouveaux mécanismes de régulation du système immunitaire dans les premiers stades du développement du SepsisImmune cells are important in host defense against invading pathogens, however, a balance is necessary between the beneficial and detrimental effects of this system. A strong pro-inflammatory response will help eliminate intrusions, but will also cause damage to neighboring tissues. On the orther hand, the role of an anti-inflammatory response, is to prevent such unnecessary scaring of organs, nevertheless, fairness of this immunoregulatory response is essential, because, otherwise, the inciting agents wont be eliminated, allowing microbial, viral, fungal, and parasitic infections to spread throughout the hosts system. Luckily, our immune system is well equipped to handle these situations, but in some cases, such as Sepsis, the exaggerated inflammatory reaction that ensues becomes overwhelming to the host and may result in organ damage ad mulfunction, leading to systemic shut down of the physiological system, and may cause death. The systemic deregulation of the immune system in Sepsis, and the shaping of the immune system by calcium or Mast cells in this disease was the focus of our studies. In a first study, we demonstrated, that calcium (Ca2+) homeostasis in Macrophages, and in Monocytes was essential for mice survival in a sepsis model induced by Ceacal Ligation and Puncture (CLP). In this model we showed, that an overflow of calcium could drastically impair survivability in mice defective in trpm4 channel, a channel responsible for limiting Ca2+ entry into Immune cells. The development of a new mice Mast Cell model in our laboratory, introduced a new tool for studying Mast Cells deficient models ; it allowed us to decrypt the role of mast cells in the development of sepsis. It appears, that in a model of severe peritonitis, Mast Cell presence is detrimental, because, its presence allowed a strong anti-inflammatory response, impairing phagocytes from achieving their role, and hence resulted in higher mortality rates when compared to mice lacking Mast Cells. The cumulated results generated by our team, allowed positioning the role of Ca2+, and Mast Cells in the pathogenesis of Sepsis. And provided new insights to regulation of immunity and the control of inflammation in early stages of Sepsis
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Valdez, Glenn R. "Restoration of homeostasis within the stress system : a novel therapeutic approach for alcohol dependence /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC IP addresses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3112199.
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Kisko, Mushtak. "Study of Physiological and molecular mechanisms underlying the co-regulation between phosphate and zinc homeostasis in plants." Thesis, Montpellier, SupAgro, 2018. http://www.theses.fr/2018NSAM0004/document.
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Chez les plantes, alors qu'il est clair que l'homéostasie des différents nutriments est fortement dépendante les uns des autres, ils sont généralement étudiés indépendamment les uns des autres. Étant donné la rareté des études antérieures évaluant la signification biologique de l'interaction de l'homéostasie des nutriments minéraux, on en sait très peu sur la base génétique et moléculaire de ces interactions. Au cours de ma thèse, nous avons progressé de manière significative vers une compréhension plus intégrative du problème et identifié les bases moléculaires et génétiques d'une interaction nutritive très importante et conservée: l'interaction du zinc et du phosphate, dans laquelle les gènes PHO1;H3 et Lyso PhosphatidylCholine (PC) AcylTransferase 1 (LPCAT1) jouent des rôles centraux. En combinant des approches de biologie systémique et de biologie fonctionnelle, nous avons identifié le module fonctionnel (quatre facteurs transcriptions) qui régule l'expression de PHO1; H3 en condition de carence en Zn. Suite à une étude de génétique d’association (GWAS) nous avons découvert un nouveau rôle du gène LPCAT1 dans l’accumulation du phosphate en conditions de carence en Zn, Ensuite, nous avons déterminé une voie moléculaire complète contrôlant l'expression de ce gène. Ce travail nous permis de révéler un lien fondamental entre le métabolisme des phospholipides et l'interaction homéostasie Pi-Zn, et de proposer un nouveau rôle pour Lyso-PC et PC dans le contrôle de l'interaction homéostasie macro- et micronutriments chez les plantes. Les résultats obtenus offrent une nouvelle perspective pour élabore des nouvelles stratégies pour améliorer l’accumulation de Pi dans les plantes via la modulation de la voie de signalisation de la carence en ZnIn plants, while it is clear the homeostasis of different nutrients is highly dependent on each other, they are usually studied independent of each other. Given the paucity of past studies assessing the biological significance of mineral nutrient homeostasis interaction, very little is known about the genetic and molecular basis of such interactions. During my thesis, we made significant progress in going towards a more integrative comprehension of the problem and identify the molecular and genetic bases for a highly important and conserved nutrients interaction: the interaction of zinc and phosphate. First, using the phosphate transporter PHO1;H3 as entry molecular point, and by combining system biology and functional genomics approaches we have identified the functional module (four transcription factors) that regulates the expression and activity of PHO1;H3 under Zn deficiency leading to control Pi accumulation in shoots. Second, following our discovery of Lyso PhosphatidylCholine (PC) AcylTransferase 1 (LPCAT1) using genome-wide association studies (GWAS), we determined complete molecular pathway controlling the expression of this gene. We further uncovered a fundamental link between phospholipid metabolism and Pi-Zn homeostasis interaction via LPCAT1, which lays the foundations to explore a new role for Lyso-PC and PC in control of macro- and micronutrients homeostasis interaction. Taken together, our discoveries offer a new perspective on how to improve Pi content in plants, as our findings suggests that modulating the Zn-deficiency signalling pathway might be a good and simple approach for that
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Sweeney, Yann Aodh. "Functional relevance of homeostatic intrinsic plasticity in neurons and networks." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/20982.
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Maintaining the intrinsic excitability of neurons is crucial for stable brain activity. This can be achieved by the homeostatic regulation of membrane ion channel conductances, although it is not well understood how these processes influence broader aspects of neuron and network function. One of the many mechanisms which contribute towards this task is the modulation of potassium channel conductances by activity-dependent nitric oxide signalling. Here, we first investigate this mechanism in a conductance-based neuron model. By fitting the model to experimental data we find that nitric oxide signalling improves synaptic transmission fidelity at high firing rates, but that there is an increase in the metabolic cost of action potentials associated with this improvement. Although the improvement in function had been observed previously in experiment, the metabolic constraint was unknown. This additional constraint provides a plausible explanation for the selective activation of nitric oxide signalling only at high firing rates. In addition to mediating homeostatic control of intrinsic excitability, nitric oxide can diffuse freely across cell membranes, providing a unique mechanism for neurons to communicate within a network, independent of synaptic connectivity. We next conduct a theoretical investigation of the distinguishing roles of diffusive homeostasis mediated by nitric oxide in comparison with canonical non-diffusive homeostasis in cortical networks. We find that both forms of homeostasis robustly maintain stable activity. However, the resulting networks differ, with diffusive homeostasis maintaining substantial heterogeneity in activity levels of individual neurons, a feature disrupted in networks with non-diffusive homeostasis. This results in networks capable of representing input heterogeneity, and linearly responding over a broader range of inputs than those undergoing non-diffusive homeostasis. We further show that diffusive homeostasis interferes less than non-diffusive homeostasis in the synaptic weight dynamics of networks undergoing Hebbian plasticity. Overall, these results suggest a novel homeostatic mechanism for maintaining stable network activity while simultaneously minimising metabolic cost and conserving network functionality.
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Taylor, Michael Jay. "The Role of Homeostatic Imbalance in the Reported Immunomodulation of T-2 Toxin." DigitalCommons@USU, 1988. https://digitalcommons.usu.edu/etd/3836.
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T-2 toxin (T-2), produced by the genus Fusarium, is a cytotoxic trichothecene mycotoxin, a feed contaminant, and has been shown to be immunomodulatory. It is suspected that T-2-associated immunomodulation is mediated partly through the hypothalamic-pituitary-adrenal axis. The presence of endotoxin, a bacterial product capable of activating the hypothalamic-pituitary-adrenal axis as well as the levels of several hormones, also associated with activation of the hypothalamic-pituitary-adrenal axis, were determined in both vehicle- and toxin-treated animals. Endotoxemia was evident twenty-four hours after a single oral exposure to T-2. Blood levels of adrenocorticotropic hormone and corticosterone, parameters of the stress response, also increased twenty-four hours after T-2 exposure. Hypothalamic norepinephrine and serum corticosterone levels increased in a dose-related manner after two weeks of T-2 exposure. An increased corticosteroid level was associated with thymic involution leading potentially to decreased T-dependent antibody response, a known effect of T-2. The effects of exposure to T-2 on the development of both T-dependent and T-independent antibody response were determined in nonoperated, sham-operated and adrenalectomized mice. T-2 decreased the antibody response to a T-dependent antigen and increased a T-independent response. The effects of T-2 were partially nullified by adrenalectomy. These results provide a further confirmation of the postulate that the hypothalamic-pituitary-adrenal axis plays an important role in T-2 toxin-immunomodulation. In vitro studies were undertaken to investigate the direct effects of T-2 on various populations of lymphatic cells. Exposure to T-2 after twenty-four hours caused an increase in the uptake of 3H-thymidine by mouse splenic cells. Pokeweed mitogen stimulation also increased in this system; the response to lipopolysaccharide increased to a lesser extent. However, T-cell responses to phytohaemagglutinin and concanavalin A (Con A) decreased. Thymic cells were also sensitive to T-2. The possibility of pharmacological activity of T-2 with thymocytes was investigated. Both specific and nonspecific cell associations were observed. The association of T-2 with thymocytes was altered in the presence of dexamethasone, a synthetic corticosteroid. T-2 was shown to have both indirect as well as direct activities on the immune system. Endocrine dysfunction resulting from chronic stress and possible pharmacologic activity of T-2 provide the impetus for further investigations.
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Val, Casals Maria 1993. "Circadian regulation of macrophages in homeostasis and disease." Doctoral thesis, Universitat Pompeu Fabra, 2020. http://hdl.handle.net/10803/669532.
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Els ritmes circadians són oscil·lacions diàries en paràmetres fisiològics necessaris per a què els organismes adaptin la seva activitat als cicles de llum i foscor. A nivell molecular, la maquinària circadiana consisteix en bucles oscil·latoris de traducció-transcripció dirigides per l’activitat de les proteïnes BMAL1 i CLOCK de manera autònoma a cada cèl·lula. La maquinària circadiana regula l’activitat de diversos tipus de cèl·lules immunitàries, inclosos els macròfags. Concretament, BMAL1 pot controlar la magnitud diària de les respostes inflamatòries dels macròfags.
En el present treball, es caracteritza la regulació circadiana dels macròfags en contextos encara no explorats. Hem analitzat l’expressió i els patrons oscil·ladors dels components del rellotge en poblacions de macròfags i també hem valorat el paper potencial dels rellotges en les funcions dels macròfags. Presentem resultats identificant aspectes de la funció del rellotge en macròfags que poden ajudar a comprendre la influència dels ritmes circadians en la modulació de respostes immunitàries innates.Circadian rhythms are daily oscillations in physiological parameters required for organisms to adapt their activity to cycles of light and darkness. At the molecular level, the circadian machinery consists of cell-autonomous transcription-translation oscillation loops led by the activity of BMAL1 and CLOCK proteins. The circadian machinery regulates the activity of diverse immune cell types, including macrophages. Specifically, BMAL1 can control the daily magnitude of macrophage inflammatory responses. In the present work we characterize the circadian regulation of macrophages in yet unexplored contexts. We have analyzed the expression and oscillatory patterns of clock components in macrophage populations, and also assessed the potential role of clocks in macrophage functions. We present results identifying aspects of clock function in macrophages that can help understand the influence of circadian rhythms in the modulation of innate immune responses.
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Garrido, Damien. "Etude de l’homéostasie lipidique chez Drosophila melanogaster." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS030.
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Le métabolisme des acides gras (AG) est crucial dans le maintien de l’homéostasie. Son implication dans des processus tels que la signalisation, le stockage énergétique, l’isolation thermique, la régulation du comportement ne révèle qu’une fraction de la complexité et de la variabilité des rôles dans lesquels il peut être associé. En outre, ce métabolisme est dérégulé dans de nombreuses pathologies, diabète, obésité, cancers,... C’est pourquoi les enzymes de ce métabolisme constituent des cibles attractives pour développer de nouveaux traitements. Cependant les conséquences de ces dérégulations sur l’organisme sain sont encore mal connues, surtout à l’échelle de chaque organe.L’objectif de ma thèse était d’évaluer comment le métabolisme des AGs participe à la régulation de l’homéostasie au sein d’un organisme entier. Pour cela, j’ai utilisé les possibilités génétiques du modèle drosophile dont le métabolisme est comparable à celui des mammifères. J’ai ainsi montré que la synthèse d’AGs contribue à neutraliser les effets toxiques du sucre alimentaire. Ce processus se fait en coopération avec la voie de la détoxification du méthylglyoxal qui permet de prévenir la formation de composés issus de la glycation non enzymatique. J’ai aussi contribué à montrer que les précurseurs des hydrocarbures et phéromones ont une origine flexible, qui dépend du maintien de l’homéostasie et qui peut perturber les interactions entre individus. Je suis actuellement en train d’étudier la sensibilité à l’inhibition de la synthèse d’AG de différents modèles de croissance dérégulée. Enfin, dans un travail préliminaire, j’ai montré que le métabolisme des AGs est essentiel dans le tube digestif, possiblement en perturbant l’homéostasie hydrique de la larve.L’ensemble de ces résultats aidera à mieux cerner l’importance du métabolisme des AGs dans le maintien de l’homéostasie d’un organisme sain et dans des processus dérégulésFatty acid (FA) metabolism is crucial in maintaining homeostasis, but also in a numerous of processes including signaling, energy storage, protection to temperature loss, regulation of behavior... In addition, FA metabolism is deregulated in several pathologies including diabetes, obesity, and cancers... Therefore, the enzymes that catalyze the reactions of the FA metabolic pathways constitute attractive targets to develop novel therapies. However the consequences of these deregulations in healthy organism are still poorly known, in particular at the level of each organ.The aim of my PhD was to estimate how FA metabolism participates in the regulation of homeostasis within a whole body organism. To address these issues, I used the genetic possibilities of the Drosophila model, whose metabolism is similar to that of mammals.I showed that FA synthesis contributes to neutralize the toxic effects of dietary sugar. This process operates in cooperation with the methylglyoxal detoxification pathway, which prevents the formation of compounds resulting from the non-enzymatic glycation. I also contributed to a project showing that the precursors of hydrocarbons and pheromones have a flexible origin, which depends on lipid homeostasis and may affect sexual recognition between individuals. Currently, I’m studying the consequences of FA synthesis inhibition in various deregulated growth models. Finally, in a preliminary work, I showed that the FA metabolism is essential in the digestive tract, possibly by disrupting water homeostasis in larvae. Taken together, these results will help to characterize the importance of FA metabolism in healthy organism as well as in deregulated processes
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Gomes, Patricia Rodrigues Lourenço. "Efeito da exposição à dexametasona sobre a expressão de miRNA no pâncreas endócrino e a homeostasia glicêmica de ratas prenhes." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/42/42137/tde-02062015-095423/.
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Este estudo investigou se o tratamento com glicocorticoide durante a gestação altera o metabolismo energético, hormonal e molecular materno, a função das ilhotas pancreáticas e mudanças correlativas sobre miRNAs. Foram utilizadas 80 ratas dividas em dois grupos de 40 animais, sendo um grupo destinado para envelhecimento até um ano após o desmame da prole, e o seguinte grupo destinado para experimentação no 20º dia de gestação, ambos dispostos em: CTL - controle, CTL-Dex - controle tratadas com dexametasona por 6 dias, P - prenhes e P-Dex - prenhes tratadas com dexametasona do 14º-19º dia de gestação. A expressão de miRNA das ilhotas foram analisadas em larga escala. Os genes alvos foram rastreados em banco de dados e confirmados. Por fim, investigou-se o mecanismo de modulação da homeostasia glicêmica. Inúmeras modificações resultaram da terapia com DEXA na gestação concluindo que a associação do tratamento ao período gravídico modula positivamente membros da família miRNA-29 ocasionando um desequilíbrio na homeostasia glicêmica por meio de falha na maquinaria exocitótica em longo prazo, desencadeado pela modulação negativa de progesterona e seu receptor promovendo prejuízo no processo de remodelação da ilhota pancreática na fase final da gestação.This study investigated whether treatment with glucocorticoids during pregnancy alters the energetic, hormonal and molecular maternal metabolism, function of pancreatic islets and correlative changes of miRNAs. Were used 80 rats divided into two groups of 40 animals, one group designed to aging up one year after weaning, and the next group destined to experimentation at 20th day of gestation, both arranged: CTL - control, CTL-Dex - control treated with dexamethasone for 6 days, P - pregnant rats and P-Dex - pregnant rats treated with dexamethasone from 14th to 19th day of pregnancy. Pancreatic islets were collected for large-scale analysis of miRNA expression. The target genes were screened and confirmed by qPCR. Finally it was investigated the mechanism of modulation of glucose homeostasis through qPCR and Western Blot. We can be observed numerous changes resulting from therapy with DEXA in pregnancy concluded that the association of treatment to the pregnancy period modulates members of the miRNA-29 family causing an imbalance in glucose homeostasis through long-term failure in exocytotic machinery, triggered by the downregulation of the progesterone and its receptor promoting injury in the pancreatic islet remodeling process in late pregnancy.
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Williams, Hywel Thomas Parker. "Homeostatic adaptive networks." Thesis, University of Leeds, 2006. http://etheses.whiterose.ac.uk/1344/.
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Homeostasis is constancy in the face of perturbation. The concept was originally developed to describe the fixed internal environment of an organism and this descriptive view of homeostasis has been prevalent in literature. However, homeostasis cal also be seen as the dynamic process of self-regulation and as such it is an organising principle by which systems adapt their behaviour over time. In this thesis we adopt this casual view of homeostasis and develop a theory of homeostatic adaptive systems. We study homeostatic adaptive networks by looking at specific examples of homeo-static systems: the Homeostat, homeostatic plasticity in neural networks, and homeostatic regulation of the environment by the biota. Investigation of these cases studies forms the basis for the development of a generalised theory of homeostatic adaptive systems. The Homeostat was an electromechanical device designed by W.A. Ross Ashby to demonstrate the principle of ultra stability, where the stability of a system requires homeostasis of essential variables. Ashby put forward a theory of mammalian learning as a process of homeostatic adaptation that was based on the idea of the ultra stable system. Here we develop a simulated Homeostat and explore its properties as a homeostatic adaptive system, looking at its ultra stable nature and its ability to adapt to external perturbations. The second case study, neural homeostasis, has recently been a topic much interest in the neurosciences, with new data being presented concerning the existence and functioning of a variety of mechanisms by which neural activity is regulated. Homeostatic plastic mechanisms prevent long term quiescence or hyper-excitation in biological neurons and this suggests that such mechanisms may be used to solve the problem of node saturation in artificial neuron networks. Here we develop homeostatic plastic mechanisms for use in continuous-time recurrent neural networks; a kind of network often used in evolutionary robotics, and studies the effect of these mechanisms on network behaviour. Node saturation effects can make these networks difficult to evolve as robot controllers and we also look at the effect of homeostatic plasticity on evolvabilty. The third case study is the evolution of homeostatic regulation of the physical environment by the biota. The Gaia theory state that life regulates the entire biosphere to conditions suitable for life, but the general concept of biological regulation of the environment is applicable on a variety of scales. However, there are major theoretical issues concerning the compatibility of environmental regulation with environmental theory. Here we develop a modified version of the Daisyworld model and use it to determine the compatibility of global regulation with individual selection. We show that regulation in Daisyworld depends on several key assumptions and fails if these assumptions are removed. We develop the Flask model, in which environmental regulation by microbial communities evolves as a result of multi-level selection, in order to show how regulation can occur when the core assumptions of Daisyword are relaxed. At the end of the thesis we try to draw some general conclusions concerning homeostatic adaptive systems. We consider the adaptive and homeostatic properties of each of the case study systems, and then generalise from these to give some principles of homeostatic adaptation. Our analysis shows that the perturbations to a system can be classified in terms of their effects on homeostasis, and that the ability of a system to adapt to a perturbation and maintain homeostasis depends on the variety of responses it can produce. We argue that the parameter change caused by a loss of homeostasis depends on the variety of responses it can produce. We argue that parameter change caused by a loss of homeostasis causes 'organisation death' in a homeostatic adaptive system, where the system does not survive in its current form. This suggests a view of learning and evolution of organisms as second order homeostatic adaptive process.
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Sousa, Jucilene Pereira de. "Peixe-zebra (Danio rerio) Transgênico para o gene bmal1a: efeitos no relógio molecular do músculo esquelético." Universidade Federal da Paraíba, 2016. http://tede.biblioteca.ufpb.br:8080/handle/tede/8838.
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Most organisms have circadian rhythms with a periodicity of 24-hour that are generated by an endogenous mechanism, the molecular clock, which has the ability to synchronize biological functions with environmental signals. This mechanism has fundamental importance in the homeostasis of the tissues that are under its influence. Among the genes of the molecular clock machinery, the clock and bmal are positive regulators of clock mechanism and they present sigmoid expression profile in the skeletal muscle in zebrafish (Danio rerio). CLOCK and BMAL participate on the activation of the myogenic regulatory factors (MRFs - myoD, myog, myf5 and myf6), which are important in the development and differentiation of muscle cells. Despite this knowledge, the physiological importance of circadian rhythm in skeletal muscle of fish is not known. Therefore, the objective of the present study was to produce a zebrafish transgenic lineage that expresses bmal1a constitutively in the skeletal muscle to investigate the role of the molecular clock in the muscle. The transfer rate of the transgene to offspring, effect of transgenesis in the survival and fish growth, and expression of the bmal1a, clock1a and MRFs were investigated. The founding transgenic population (F0) was obtained after microinjection, and positive larvae were observed as specimens which presented green fluorescent heart. F1 was obtained from natural crossings between F0 and NT fish. Likewise, F2 was obtained from F1. F2 transgenic and NT were used in this study. The transgenic lineage was successfully generated with 50% transmission from the transgene to the offspring following a Mendelian model. The analysis of gene expression was made by qPCR. The survival (41,4±0% F2 and 44,3±6% NT) and growth (3.7±0.1 cm F2 and 3.8±0.2 cm NT) of F2 were not statistically different from NT fish. Among the genes, clock1a and myog presented statistically significant differences between the lineages with circadian profile in NT fish, suggesting that myog may be a clock controlled genes. The other genes (bmal1a, myf5, myf6, and myoD) presented constitutive expression. In general, it can be verified that the constitutive expression of bmal1a did not present change in the expression of the molecular clock, not affecting the homeostasis of the skeletal muscle, survival and growth.
A maioria dos organismos apresentam ritmos circadianos em torno de um período de 24 horas que são gerados por um mecanismo endógeno, o relógio molecular, que tem a capacidade de sincronizar-se com sinais ambientais. Este mecanismo tem fundamental importância na homeostase dos tecidos que estão sob sua influência. Dentre os genes que compõem a maquinaria do relógio molecular os genes clock e bmal são os reguladores positivos do mecanismo desse relógio e apresentam expressão com perfil sigmoide em tecido como o músculo do peixe-zebra (Danio rerio), participando da ativação de alguns fatores regulatórios miogênicos (MRFs – myoD, myog, myf5 e myf6), os quais possuem importância para o desenvolvimento e diferenciação do músculo. Apesar deste conhecimento, não se sabe a importância fisiológica do ritmo de expressão circadiana no músculo esquelético de peixes. Neste sentido, o objetivo desse estudo foi investigar a taxa de transferência do transgene para a prole; se a transgenia para o gene bmal1a no músculo esquelético interferiu na sobrevivência e crescimento dos peixes; e avaliar se a expressão dos genes bmal1a, clock1a e MRFs apresentaram diferenças na linhagem transgênica comparada à linhagem não-transgênica (NT). Os fundadores (F0) foram obtidos após a microinjeção do plasmídeo e as larvas positivas foram observadas com coração verde fluorescente. A F1 foi obtida a partir de cruzamentos entre peixes F0 e NT. Da mesma forma, F2 foi obtida a partir da F1, os quais foram utilizados no presente estudo. A análise da expressão gênica das linhagens aos 11 meses de idade foi realizada utilizando a técnica qPCR. A linhagem transgênica foi gerada com sucesso, transmitindo o transgene para a prole seguindo a herança mendeliana. A sobrevivência e crescimento da prole F2 não apresentaram diferenças entre as linhagens, sendo 41,4±0% para a linhagem transgênica e 44,3±6% NT até 30 dpf e 3.7±0.1 cm transgênicos e 3.8±0.2 cm para NT aos 11 meses de idade, respectivamente. Dentre os genes, o clock1a e o myog apresentaram diferenças estatisticamente significativas entre as linhagens com perfil circadiano em peixes NT, sugerindo que myog seja um gene controlado pelo relógio. Os demais genes apresentaram expressão constitutiva. De um modo geral, pode-se verificar que a expressão constitutiva do bmal1a não apresentou alteração na expressão do relógio molecular, desta forma, não afetou a homeostasia do organismo, a sobrevivência das larvas, bem como não afetou o crescimento.
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Davies, Luke C. "Control of macrophage homeostasis." Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/112185/.
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Tissue resident macrophages are extremely heterogeneous, which reflects their unique microenvironments and tissue specific functions. They are a constituent of all tissues, and are involved in homeostatic processes and inflammatory disease. Recent studies have shown that select tissue resident macrophage populations, such as Langerhans cells of the skin and microglia of the brain, are able to self-renew independently from the bone marrow. This is contrary to the prevailing model macrophage origins, the ‘mononuclear phagocyte system’, which dictates that all macrophages are derived from bone marrow monocytes. The work carried out in this thesis investigated the self-renewing potential of peritoneal tissue resident macrophages, and its control. Several novel discoveries were made: i) peritoneal resident macrophages proliferate at low levels to maintain their numbers during homeostasis, at higher levels during neonatal growth, and undergo a burst in proliferation during acute inflammation to restore their depleted population; ii) renewal of peritoneal resident macrophages during an acute inflammatory episode was found to be independent from the bone marrow, and dependent upon macrophage colony stimulating factor, but importantly, not interleukin-4; iii) Monocyte-derived macrophages could also proliferate within an inflammatory lesion. Collectively, these observations challenge the dogma of the mononuclear phagocyte system: they demonstrate that in vascular tissues, tissue resident macrophages could self-renewal independently of monocytes, and that monocyte-derived cells are not terminally-differentiated. Additional work leading up to these studies implicated Gata6 as a peritoneal macrophage-specific transcription factor. In this thesis, Gata6 was found to be necessary for peritoneal macrophage phenotype, normal proliferation, euploidy, and normal responses to inflammation. In summary, these studies demonstrate not only are macrophages capable of self-renewal, but this is dependent upon discrete transcriptional control. Understanding the molecular controls of tissue macrophage heterogeneity and renewal could provide novel avenues for the therapeutic manipulation of their activities.
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Wassif, Christopher A. "Dysregulation of cholesterol homeostasis." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:da3374f0-9285-4490-b2e7-af493556d925.
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Cholesterol plays a critical role in the health and normal function of every mammalian cell. Cholesterol has multiple cellular functions including maintenance of cell membrane stability and fluidity, steroid hormone and bile acid synthesis, and membrane receptor signaling. As with any critical metabolite, cholesterol is highly regulated. I will detail my research focusing on the two prevalent disorders of cholesterol homeostasis. The first is a disorder of cholesterol biosynthesis, Smith-Lemli-Opitz syndrome (SLOS), and the second a disorder of cholesterol trafficking, Niemann-Pick disease, type C1 (NPC). I have identified a unique cellular phenotypic overlap between these two previously unrelated disorders. Specifically, increasing concentrations of the precursor sterol present in SLOS, 7-dehydrocholesterol, leads to the induction of an NPC-like cellular phenotype. Aspects of the NPC cellular phenotype that can be induced in SLOS fibroblasts include lysosomal storage of unesterified cholesterol, sphingosine, and glycosphingolipids. Also, similar to what is observed in NPC, dysregulation of acidic calcium stores is present in SLOS. Further research indicates that this cellular phenotype extends into both the mouse models of SLOS and the patients. The dysregulation of cholesterol trafficking in SLOS cells likely decreases cellular cholesterol bioavailabilty and thus potentially limits the therapeutic efficacy of dietary cholesterol supplementation in SLOS patients. I also show that treatment of SLOS cells with miglustat, an established therapy for NPC, ameliorates the NPC-like cellular phenotype and thus may have therapeutic benefit in SLOS. The incidence of both SLOS and NPC has been the subject of debate. Thus, using data generated from massively parallel sequencing of the human exome, I demonstrate that the previously predicted incidence of SLOS of 1:40,000 births is likely correct, but call into question the predicted NPC rate of 1:120,000 . In fact, NPC maybe closer to a rate of 1:40,000. The role of oxysterols in the teratogenicity of SLOS and the underlying secondary storage of lipids in the phenotypic presentation of SLOS has been investigated.
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Lai, Wai Ling. "The homeostatic means : philosophical naturalization of content based on the notion of homeostatic maintenance." Thesis, University of Sussex, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.402017.
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Smith, Kirsty Louise. "Metabolic hormones and energy homeostasis." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411789.
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Allstaff, Alison Jane. "Novel factors in bone homeostasis." Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=128211.
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Microarray analysis of gene expression in osteoblasts from patients with osteoporosis (OP) and osteoarthritis (OA) showed that 115 genes were robustly differentially expressed (P<0.05). Functional annotation clustering revealed cell adhesion to be the gene ontology classification most likely to be associated with this gene list. In addition scrutiny of the list revealed several genes with strong biological support for the involvement in bone homeostasis (FOSL1, BMPR2 and TGFBR1). Real -time PCR validated the trends seen in the microarray analysis, but failed to reach statistical significance for any of the genes examined. This analysis supports the value and potential of larger scale comparison of gene expression in OA and OP osteoblasts as a method for identifying novel factors involved in bone homeostasis. The cannabinoid system has recently been identified as involved in the regulation of bone homeostasis. In vitro investigation revealed that although cannnabinoid receptor agonists N-arachidonoylethanolamine (AEA), 2-arachidonoylglycerol (2-AG) and JWH015 had no effect on metabolic activity, cell number, or alkaline phosphatase activity of calvarial mouse osteoblasts there were changes in gene expression. RankL expression was reduced relative to Opg expression by both JWH015 and AEA. Preliminary results indicate that JWH015 was also capable of increasing PPARγ expression which could alter the balance of osteoblastic and adipocytic differentiation of mesenchymal stem cells (MSC). This could have implications for use of these drugs in vivo. Using the 3T3-F442A cell line to develop a model of MSC differentiation highlighted difficulties associated with using cell models. Necessary additional factors required to induce differentiation of a cell line compared to a primary cell make interpretation of results more complicated. This model also highlighted that alkaline phosphatase and osteocalcin (markers usually used to identify osteogenic differentiation) were expressed during adipocytic differentiation. Future use of such markers in MSC models should be closely scrutinized.
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Thompson, Shirley Patricia. "Calcium homeostasis in the elderly." Thesis, University of Nottingham, 1989. http://eprints.nottingham.ac.uk/14012/.
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The initial aims of this investigation were to develop a reliable assay system for measuring serum 1,Z5-dihydroxyvitamin D [1,Z5(OH)ZD] concentrations and to establish a normal range in young healthy adults. Compared with young healthy individuals, the elderly population are indeed vitamin D deficient. Vitamin D deficiency was also demonstrated in a group of elderly osteomalacic patients. Slight improvements in osteomalacia was achieved by one month of treatment with vitamin D3' or alphacalcidiol with or without calcium supplements. The improvements were small and occured slowly. A significant increase in the strength of bone seems unlikely to occur in the short term. On the present evidence the combination of alphacalcidiol and calcium supplements seems no better than vitamin D3 or alphacalcidiol alone although it may require closer monitoring to avoid hypercalcaemia. In a group of elderly patients with osteoporosis and femoral neck fracture (FNF), serum osteocalcin concentrations rose significantly in the first week after fracture fixation. The change in osteocalcin correlated well (p < 0.001) with the change in serum 1,Z5(OH)ZD concentration. Histomorphometric measurements of the extent of osteoid correlated better with osteocalcin than alkaline phosphatase. Serum concentrations of 1,Z5(OH)ZD were also reduced in elderly patients with FNF irrespective of the presence of osteomalacia and therefore cannot be used as a screening test for osteomalacia in this patient group. Reduction of 1,Z5(OH)ZD was not due to a reduction in vitamin D binding protein. It is suggested that the low rate of bone turnover in these elderly patients reduces the requirement of vitamin D. Of the ten elderly patients who had underwent laryngo pharyngeal surgery all developed hypocalcaemia. This immediate post-operative decrease, due to a rapid reduction in circulating PTH concentrations, lead to an overall increase in urinary calcium excretion. Serum concentration of 1,25(OH)2D also fell postoperatively thus potentiating the hypocalcaemic state in these patients. Thus, it is important to give parenteral feeding supplemented with calcium and vitamin D, preferably alphacalcidiol. If delayed then profound as well as prolonged hypocalcaemia can occur. The human osteosarcoma cell 20S metabolised 25(OH)D3 in a substrate concentration and time dependent manner to produce products which were secreted into the extracellular medium. These products eluted from HPLC with a retention time coincident with 24,25(OH)2D3 and exhibited an UV absorption spectrum characteristic of a vitamin D sterol. Mass spectroscopy analysis indicated at least two products were synthesised by the cells. One was identical to 24,25(OH)2D3; the other appeared to be an unsaturated trihydroxylated derivative of vitamin D3.
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Kershaw, Christopher John. "Copper homeostasis in Escherichia coli." Thesis, University of Birmingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419690.
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Ali, Simon Alistair. "Zinc homeostasis in the elderly." Thesis, University of Liverpool, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343990.
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Chaharmahali, Pegah M. "Calcium homeostasis in Pichia pastoris." Scholarly Commons, 2014. https://scholarlycommons.pacific.edu/uop_etds/179.
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Pichia pastoris is a methylotrophic yeast that has been used widely in biological and industrial researches. P. pastoris is able to produce from milligram to gram quantities of protein. In this study, we examined the effects of calcium and magnesium on growth, heterologous protein expression, and calcium homeostasis in P. pastoris . The divalent cations calcium and magnesium are responsible for diverse roles in in the function of the cells in eukaryotes. Although it is known that calcium is responsible for many biological functions in eukaryotes, there is a limited understanding of the calcium homeostasis in P. pastoris . In this study, we found that addition of calcium and magnesium to yeast extract peptone dextrose (YPD) does not increase the cell growth of wild type P. pastoris . However, the original concentrations of calcium and magnesium in YPD were critical to cells, as removing calcium and magnesium using EGTA and EDTA, respectively, decreased the cell growth of wild type P. pastoris . Changes to cytoplasmic calcium concentration in P. pastoris was studied using the fluorescent calcium sensitive dye, indo-1 (10 μM) and fluorescent spectrophotometer. The intracellular calcium concentration increased with addition of calcium chloride, magnesium chloride, and phosphate buffered saline (PBS). PBS (standard 1x) induced a significantly higher increase in intracellular calcium concentration compared to inductions with calcium chloride (1.2 mM). Our results showed that the addition of calcium and magnesium into the growth medium did not increase the expression of alcohol oxidase-1 driven β-galactosidase expression. However, calcium and magnesium may still play crucial roles in protein expression as EDTA and EGTA caused an increase in β-galactosidase expression as indicated by higher β-galactosidase activity. Our findings suggest that EDTA and EGTA may also increase the expression of other heterologous proteins in P. pastoris .
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Doupé, David Patrick. "Quantitative analysis of epithelial homeostasis." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611770.
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White, Rachel. "Calcium homeostasis in articular chondrocytes." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611988.
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Domínguez, Hüttinger Elisa. "Mathematical modelling of epithelium homeostasis." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/47969.
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The body and organs of all animals are covered by epithelial tissues, such as the epidermis and the airway epithelium. Epithelial tissues play a key role in protecting the body from environmental aggressors. Failure to maintain a competent epithelium can lead to the onset of many diseases, including Atopic dermatitis (AD) and infection by Streptococcus pneumoniae. Treatment of AD is currently restricted to the relief of symptoms, mainly because the underlying mechanisms remain elusive. Antibiotic resistance threatens the effectiveness of the prevalent treatments for infection. Devising new and effective therapeutic strategies that halt the progression of these diseases requires an understanding of the different disease mechanisms that can cause loss of epithelial homeostasis in different patients. Intricate regulatory networks of several biochemical and cellular interactions maintain epithelium homeostasis in healthy individuals, but can also propagate different disturbances, resulting in a wide spectrum of possible disease phenotypes. In this thesis, we propose mathematical models of these regulatory networks to analyse the mechanisms that lead to the onset and progression of AD and pneumococcal infection from a systems-level perspective. Our mathematical model of AD reproduced, for the first time, the different stages of the disease that have been observed in the clinic. Moreover, we proposed different pathogenic mechanisms, triggered by different genetic and environmental risk factors that are known to predispose to AD. By assessing the effects of common treatments for AD, we suggested effective treatment strategies that can prevent the aggravation of the disease, in a patient-specific way. Our data-driven mathematical model of pneumococcal infection identified four qualitatively different mechanisms by which co-infection can drive the pathogenic process. They can be counteracted by distinctive treatment strategies that only partially involve antibiotics. Our work provides a theoretical framework for the integration and analysis of clinical and experimental data describing epithelial homeostasis.
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Topal, Salih. "Chromatin Dynamics Regulate Transcriptional Homeostasis." eScholarship@UMMS, 2019. https://escholarship.umassmed.edu/gsbs_diss/1062.
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Eukaryotic promoters are inherently bidirectional and allow RNA Polymerase II to transcribe both coding and noncoding RNAs. Dynamic disassembly and reassembly is a prominent feature of nucleosomes around eukaryotic promoters. While H3K56 acetylation (H3K56Ac) enhances turnover events of these promoter-proximal nucleosomes, the chromatin remodeler INO80C ensures their proper positioning. In my dissertation, I explore how chromatin dynamics regulate transcriptional homeostasis. In the first part, I investigate the role of H3K56Ac on the nascent transcriptome throughout the eukaryotic cell cycle. I find that H3K56Ac is a global, positive regulator for coding and noncoding transcription by promoting both initiation and elongation/termination. On the contrary, I find that H3K56Ac represses promiscuous transcription following replication fork passage by ensuring efficient nucleosome assembly during S-phase. In addition, I show that there is a stepwise increase in transcription in the S-G2 transition, and this response to gene dosage imbalance does not require H3K56Ac. This study clearly shows that a single histone modification, H3K56Ac can exert both positive and negative effects on transcription at different cell cycle stages. In the second part, I investigate the role of the chromatin remodeler INO80C on the nascent transcription around replication origins. I show that INO80C, together with the transcription factor Mot1, prevents cryptic transcription around yeast replication origins, and the loss of these proteins lead to an increase in DNA double strand breaks. I hypothesize that recruitment of INO80C ensures proper positioning of nucleosomes around origins and the exclusion of RNA Pol II to prevent cryptic initiation. Together these findings indicate that H3K56Ac regulates transcription globally by enhancing nucleosome turnover, and it prevents cryptic transcription and reinforces transcriptional fidelity by promoting efficient nucleosome assembly in the S-phase. In addition, INO80C maintains genome stability by preventing cryptic transcription around the origins.
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Kenny, Glen. "Thermal homeostasis following dynamic exercise." Thesis, University of Ottawa (Canada), 1994. http://hdl.handle.net/10393/6486.
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Recent published work showed post-exercise (PostEx) esophageal temperature (Tes) recovered rapidly to a persistent plateau that was significantly elevated (0.5$\sp\circ$C or more) above pre-exercise (PreEx) values. Non-acral skin temperatures, except over exercised muscle, returned rapidly to PreEx levels. Rectal temperatures (Tre) fell gradually during recovery reaching a plateau late in recovery (45 min) equal in magnitude of difference from Tes to PreEx values. Surface temperatures over the quadriceps remained high, indicating that heat was trapped in muscle. A similarity between the exercise Tes at which skin surface dilation occurred (Tdil) and the PostEx Tes was identified. These observations contradict the widely accepted "load-error" prinicple of thermoregulation which predicts that displacement of core temperature (Tco) from a hypothalamic set point (SPhy) will induce defense reflexes until the displacement is reversed. These data lead to the hypothesis that there was some residual influence related to exercise that retained the modulation of thermal reflex thresholds during recovery. Testing of the hypothesis was conducted with experiments to establish if: (1) the PostEx Tes was related to PreEx temperature; (2) exogenous thermal loading would produce the same post treatment elevation; (3) PostEx Tes elevation followed by exogenous thermal loading would result in an increase in the Tes elevation and (4) a 5 min exercise generating Tes below Tdil would result in a PostEx elevation of Tes. It was demonstrated that repeated running-recovery cycles produced patterns of rise and then fall of Tes to an elevated PostEx plateau that was equal to Tdil. This was similar to previous results except that the second exercise was begun at an elevated Tes and produced further elevation of Tdil with a comparable effect on PostEx Tes. Similarly, the third exercise further increased Tes following which it recovered to an even higher plateau equal in magnitude to Tdil. We observed that exogenous heat loading, by immersion of subjects in a bath of water at 44$\sp\circ$C to produce a rate of increase and peak elevation of Tes equal to exercise, did not result in a post-treatment elevation in Tes. Similarly, the PostEx Tes elevated plateau, equal to Tdil, remained unchanged following water immersion at 44$\sp\circ$C despite a larger total heat gain during the immersion. These observations eliminate whole body heat content changes as the primary cause of the Tes elevation and support the hypothesis that the homeothermic defense mechanisms become inoperative during recovery at a temperature above resting values as defined by Tdil. The physiological importance of Tdil in defining upper limits of resting temperature cannot be determined at this point. However, the physiological relationship of Tdil with PostEx Tes suggests that neuro-muscular activity significantly influences thermolytic controls which persist in recovery. That Tdil may represent the upper limit of a range of "normal temperatures" is supported by data from a 5 min exercise performed to a Tes elevation below Tdil. Within minutes of exercise termination Tes achieved a stable elevated PostEx Tes (0.3$\sp\circ$C or greater) which was maintained with no change over 65 min of recovery. The data suggest the possibility of: (1) a metabolically induced change in SPhy thermosensitivity, (2) a decreased sensitivity to an increase LE, or (3) a range of temperature regulation defined by an upper threshold control for thermolytic temperature defense reflexes.
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Hensley, Mart Patrick. "Zinc Homeostasis in E. coli." Miami University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=miami1333655875.
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Yelhekar, Tushar. "Chloride Homeostasis in Central Neurons." Doctoral thesis, Umeå universitet, Institutionen för integrativ medicinsk biologi (IMB), 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-127655.
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The overall aim of the present thesis is to clarify the control of intracellular chloride homeostasis in central neurons, because of the critical role of chloride ions (Cl–) for neuronal function. Normal function of the central nervous system (CNS) depends on a delicate balance between neuronal excitation and inhibition. Inhibition is, in the adult brain, most often mediated by the neurotransmitter γ-aminobutyric acid (GABA). GABA may, however, in some cases cause excitation. GABA acts by activating GABA type A receptors (GABAARs), which are ion channels largely permeable to Cl–. The effect of GABAAR-mediated neuronal signaling - inhibitory or excitatory - is therefore mainly determined by the Cl– gradient across the membrane. This gradient varies with neuronal activity and may be altered in pathological conditions. Thus, understanding Cl– regulation is important to comprehend neuronal function. This thesis is an attempt to clarify several unknown aspects of neuronal Cl– regulation. For such clarification, a sufficiently sensitive method for measuring the intracellular Cl– concentration, [Cl–]i, is necessary. In the first study of this thesis, we examined two electrophysiological methods commonly used to estimate [Cl–]i. Both methods, here called the interpolation and the voltage-ramp method, depend on an estimate of the Cl– equilibrium potential from the current-voltage relation of GABA- or glycine-evoked Cl– currents. Both methods also provide an estimate of the membrane Cl– conductance, gCl. With a combination of computational and electrophysiological techniques, we showed that the most common (interpolation) method failed to detect changes in [Cl–]i and gCl during prolonged GABA application, whereas the voltage-ramp method accurately detected such changes. Our analysis also provided an explanation as to why the two methods differ. In a second study, we clarified the role of the extracellular matrix (ECM) for the distribution of Cl– across the cell membrane of neurons from rat brain. It was recently proposed that immobile charges located within the ECM, rather than as previously thought cation-chloride transporter proteins, determine the low [Cl–]i which is critical to GABAAR-mediated inhibition. By using electrophysiological techniques to measure [Cl–]i, we showed that digestion of the ECM decreases the expression and function of the neuron-specific K+ Cl– cotransporter 2 (KCC2), which normally extrudes Cl- from the neuron, thus causing an increase in resting [Cl–]i. As a result of ECM degradation, the action of GABA may be transformed from inhibitory to excitatory. In a third study, we developed a method for quantifying the largely unknown resting Cl– (leak) conductance, gCl, and examined the role of gCl for the neuronal Cl– homeostasis. In isolated preoptic neurons from rat, resting gCl was about 6 % of total resting conductance, to a major part due to spontaneously open GABAARs and played an important role for recovery after a high Cl– load. We also showed that spontaneous, impulse-independent GABA release can significantly enhance recovery when the GABA responses are potentiated by the neurosteroid allopregnanolone. In a final commentary, we formulated the mathematical relation between Cl– conductance, KCC2-mediated Cl– extrusion capacity and steady-state [Cl–]i. In summary, the present thesis (i) clarifies how well common electrophysiological methods describe [Cl–]i and gCl, (ii) provides a novel method for quantifying gCl in cell membranes and (iii) clarifies the roles of the ECM, ion channels and ion transporters in the control of [Cl–]i homeostasis and GABAAR-mediated signaling in central neurons.
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Neary, Nicola Marguerite. "Gut hormones and energy homeostasis." Thesis, Imperial College London, 2007. http://hdl.handle.net/10044/1/7152.
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Easton, James Allen. "Identification and Characterization of Zn(II)-responsive Genes and Proteins in E. coli." Oxford, Ohio : Miami University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1189685688.
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Oswald, Corina. "Mitochondrial copper homeostasis in mammalian cells." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2010. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-61580.
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Assembly of cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, requires a concerted activity of a number of chaperones and factors for the correct insertion of subunits, accessory proteins, cofactors and prosthetic groups. Most of the fundamental biological knowledge concerning mitochondrial copper homeostasis and insertion of copper into COX derives from investigations in the yeast Saccharomyces cerevisiae. In this organism, Cox17 was the first identified factor involved in this pathway. It is a low molecular weight protein containing highly conserved twin Cx9C motifs and is localized in the cytoplasm as well as in the mitochondrial intermembrane space. It was shown that copper-binding is essential for its function.
So far, the role of Cox17 in the mammalian mitochondrial copper metabolism has not been well elucidated. Homozygous disruption of the mouse COX17 gene leads to COX deficiency followed by embryonic death, which implies an indispensable role for Cox17 in cell survival.
In this thesis, the role of COX17 in the biogenesis of the respiratory chain in HeLa cells was explored by use of siRNA. The knockdown of COX17 results in a reduced steady-state concentration of the copper-bearing subunits of COX and affects growth of HeLa cells accompagnied by an accumulation of ROS and apoptotic cells. Furthermore, in accordance with its predicted function as a copper chaperone and its role in formation of the binuclear copper center of COX, COX17 siRNA knockdown affects COX-activity and -assembly. It is now well accepted that the multienzyme complexes of the respiratory chain are organized in vivo as supramolecular functional structures, so called supercomplexes. While the abundance of COX dimers seems to be unaffected, blue native gel electrophoresis reveals the disappearance of COX-containing supercomplexes as an early response. Accumulation of a novel ~150 kDa complex containing Cox1, but not Cox2 could be observed. This observation may indicate that the absence of Cox17 interferes with copper delivery to Cox2, but not to Cox1. Data presented here suggest that supercomplex formation is not simply due to assembly of completely assembled complexes. Instead an interdependent assembly scenario for the formation of supercomplexes is proposed that requires the coordinated synthesis and association of individual complexes.
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Roth-Alpermann, Claudia. "Homeostatic regulation of long-term potentiation." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-38403.
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Kamali-Zare, Padideh. "Modeling Biophysical Mechanisms underlying Cellular Homeostasis." Doctoral thesis, KTH, Cellens fysik, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-11880.
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Cellular homeostasis is the effort of all living cells to maintain their intracellular content when facing physiological change(s) in the extracellular environment. To date, cellular homeostasis is known to be regulated mainly by time-consuming active mechanisms and via multiple signaling pathways within the cells. The aim of this thesis is to show that time-efficient passive (physical) mechanisms also, under the control and regulation of bio-physical factors such as cell morphology and distribution and co-localization of transport proteins in the cell membrane, can regulate cellular homeostasis. This thesis has been developed in an interface between physics and biology and focuses on critical cases in which cells face physiologically unstable environments at their steady state and therefore may need a constituent effort to maintain their homeostasis. The main hypothesis here is that the cell geometry is oriented in such a way that cellular homeostasis is preserved in a given environment. For exploring these cases, comparative spatial models have been developed that combine transporting function of membrane proteins with simple versus complex geometries of cells. Models confirm the hypothesis and show that cell morphology, size of extracellular space and intercellular distances are important for a dynamic regulation of water and ion homeostasis at steady state. The main clue is the existence of diffusion limited space (DLS) in the bulk extracellular space (ECS). DLS can, despite being ECS, maintain its ionic content and water balance due a controlled function of transport proteins in the membrane facing part of DLS. This can significantly regulate cellular water and ion homeostasis and play an important role in cell physiology. In paper I, the role of DLS is explored in the kidney whereas paper II addresses the brain. The response of cells to change in osmolarity is of critical importance for water homeostasis. Cells primarily respond to osmotic challenge by transport of water via their membranes. As water moves into or out of cells, the volumes of intra- and extracellular compartments consequently change. Water transport across the cell membrane is enhanced by a family of water channel proteins (aquaporins) which play important roles in regulation of both cell and the extracellular space dimensions. Paper III explores a role for aquaporins in renal K+ transport. Experimentally this role is suggested to be different from bulk water transport. In a geometrical model of a kidney principal cell with several DLS in the basolateral membrane, a biophysical role for DLS-aquaporins is suggested that also provides physiological relevance for this study. The biophysical function of water channels is then extensively explored in paper IV where the main focus has been the dynamics of the brain extracellular space following water transport. Both modeling and experimental data in this paper confirmed the importance of aquaporin-4 expressed in astrocytes for potassium kinetics in the brain extracellular space. Finally, geometrically controlled transport mechanisms are studied on a molecular level, using silicon particles as a simplified model system for cell studies (paper V and VI). In paper V the role of electrostatic forces (around the nano-pores and in between the loaded material and the silicon surface) is studied with regard to transport processes. In paper VI the roles of pore size and molecular weight of loaded material are studied. All together this thesis presents various modeling approaches that employ biophysical aspects of transport mechanisms combined with cell geometry to explain cell homeostasis and address cell physiology-based questions.QC20100727
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Schapiro, Florencia Beatriz. "pH homeostasis of the Golgi complex." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq58920.pdf.
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Hawke, Zoe Belinda. "Ventromedial hypothalamic neurones in energy homeostasis." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.495608.
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The processes that control energy homeostasis are extremely complex and involve /nteractions between peripheral organs, the hypothalamus and the brainstem, as well as inputs from sensory and reward centres of the brain. Researchers have come a long way in recent years in elucidating the networks that control energy balance, but recent transgenic models have shown that over-emphasis may have been put on the arcuate nucleus Research is now shifting to extra-arcuate sites'including the ventromedial nucleus (VMN) which, unlike characterised in terms of its cellular phenotypes.
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Sekar, Revathi. "Role of secretin in lipid homeostasis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/198810.
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Secretin, the first hormone commencing the field of endocrinology, has been studied for its pleiotropic role in the body inclusive of its neuroactive and body water homeostatic and gastrointestinal functions. Yet, the metabolic effect of secretin remains elusive and is being proposed recently for a revisit. Recent discovery from our lab showed an anorectic response for secretin, while its role in lipid homeostasis remains largely unexplored. Exerting functions such as exocrine pancreatic secretion and gastric motility inhibition, intestinal fatty acid induced release of secretin was recently shown to be mediated by CD36. Fasting related increase in plasma secretin concentration has been proposed to be involved in lipolysis but evidences regarding lipolytic actions of secretin remain contradictory. Recent report has suggested that secretin stimulates both lipolysis and lipogenesis in adipose cells. Thus, we hypothesize that secretin modulates lipid homeostasis, which was examined under two opposite, energy deficient and energy excess, conditions.
Under energy deficient/starved state, secretin level in circulation and secretin receptor level in epididymal adipose tissue were found to be upregulated. Using secretin receptor knockout (SCTR-/-) and secretin knockout (SCT-/-) mice as controls, it was found that secretin stimulated a dose- and time-dependent lipolysis in vitro and acute lipolysis in vivo. H-89, a protein kinase A (PKA) inhibitor, attenuated the lipolytic effects of secretin in vitro, while secretin induced an increase in cAMP dependent PKA activity in vivo. Using western blot analysis, secretin was found to phosphorylate hormone sensitive lipase (HSL) at serine residue 660. Additionally, immunofluorescent studies revealed that secretin stimulated translocation of HSL from cytosol to surface of lipid droplet subsequently leading to lipolysis.
Under excess energy condition, when SCTR-/- mice and its littermates SCTR+/+ mice were subjected to high fat diet (HFD) feeding for 3 months, it was found that SCTR-/- mice gained lesser weight. Nuclear magnetic resonance imaging revealed that SCTR-/- mice exhibited lower body fat content. Additionally, HFD-associated hyperleptinaemia was alleviated in SCTR-/- mice along with metabolic syndrome as they performed better in insulin and glucose tolerance tests. Continuous monitoring by indirect calorimetry revealed similar food intake, energy expenditure and locomotor activity between SCTR-/- and SCTR+/+ mice. Interestingly, intestinal fatty acid absorption, measured by a noninvasive method, was impaired in HFD-fed SCTR-/- mice. While postprandial triglyceride release was reduced in SCTR-/- mice, it also had a significant reduction in transcript and protein levels of CD36 and its downstream mediator MTTP. Secretin, when incubated with isolated enterocytes, upregulated the expression of CD36.
In summary, during starvation, secretin stimulates lipolysis through a HSL and PKA mediated pathway. When fed a HFD, SCTR-/- mice is resistant to diet induced obesity due to impaired intestinal lipid absorption. A novel short positive feedback pathway between CD36 and secretin, functioning to maximize lipid absorption, is also being proposed. Thus for the first time, two independent role of secretin in lipolysis and in intestinal lipid absorption were discovered along with their mechanistic insights. This study paves way for developing new therapeutic strategies against metabolic disorders associated with lipid metabolism.published_or_final_version
Biological Sciences
Doctoral
Doctor of Philosophy
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Rizvi, Abbas. "Systems Level Studies of Nutrient Homeostasis." Thesis, Harvard University, 2011. http://dissertations.umi.com/gsas.harvard:10022.
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In conditions of phosphate deprivation, the budding yeast, Saccharomyces cerevisiae activates the phosphate starvation response pathway (PHO pathway). Induction of the PHO pathway causes the transcription of genes involved with phosphate metabolism. Phosphate transport genes are activated during starvation, giving rise to the presence of Pho84, the high affinity transporter. In high phosphate conditions low affinity transporters reside at the plasma membrane. Here we show that Spl2, a suppressor of phospholipase-C, is involved in the down-regulation of the low affinity transport system. This phenomenon gives rise to complex population dynamics and bistability. Furthermore, we demonstrate how the phenotype of strains lacking Pho84 can be explained in context of unconstrained positive feedback through Spl2. We then turn our attention towards comparative studies of the PHO pathway, comparing the transcriptional response of S. cerevisiae to C. glabrata. Using expression microarrays and deep sequencing, we find that the transcriptional circuit in C. glabrata has been altered such that transcriptional cooperativity is lost, nucleosome positioning is altered, and transcriptional competition between the transcription factor Pho4 and centromere binding factor, Cbf1, is relatively conserved.
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Bains, I. K. "Mathematical modelling of T cell homeostasis." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/20159/.
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T cell homeostasis describes the process through which the immune system regulates cell survival, proliferation, differentiation and death to maintain T cell numbers and diversity in a range of different conditions. The aim of this thesis is to better understand how this process leads to the development of the naive CD4+ T cell compartment during childhood. Mathematical modelling is used in combination with experimental observations to estimate naive T cell kinetics over the lifetime of an individual. The analysis described here shows that post-thymic proliferation contributes more than double the number of cells entering the pool each day from the thymus. This ratio is preserved from birth to age 20 years; as the thymus involutes, the average time between naive T-cell divisions in the periphery lengthens with age and the naive population is maintained by improved naive cell survival. Thymic output is quantified from birth to age 60 years by combining models to interpret naive T cell TRECs and Ki67 expression data. Three distinct phases of thymic T cell output are identified: (i) increasing production from birth to age 1 year; (ii) steep decline to age 8 years; (iii) slow decline from age 8 years onwards. Finally, the role of inter-cellular variation in T cell residency times is explored. It is able to explain the persistence of PTK7+ naive CD4+ T cells in thymectomised individuals. Importantly, the model predicts the accumulation of veteran PTK7+ T cells in older individuals and suggests that the residual population in thymectomised individuals will also consist predominantly of veteran PTK7+ T cells. The model has implications for the use of PTK7 as a marker of recent thymic emigration and also naturally explains improved T cell survival in older individuals.
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Franklin, Paul Anthony. "Zinc and manganese homeostasis in brain." Thesis, University of Sunderland, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283763.
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Bird, Amanda Jane. "Zinc homeostasis in Synechococcus PCC 7942." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245707.
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Cham, Chee Wee. "Glucose homeostasis in rat liver transplantation." Thesis, University of Newcastle Upon Tyne, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309095.
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Wharton, Stephen J. "Metal ion homeostasis in Staphylococcus aureus." Thesis, University of Sheffield, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392723.
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Ste, Marie Linda. "Role of norepinephrine in glucose homeostasis /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/9258.
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Wang, Zaiqi. "Lens calcium homeostasis and selenite cataract." Diss., This resource online, 1992. http://scholar.lib.vt.edu/theses/available/etd-05042006-164509/.
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Eldridge, Suzanne. "Agrin contributes to articular cartilage homeostasis." Thesis, Queen Mary, University of London, 2016. http://qmro.qmul.ac.uk/xmlui/handle/123456789/12812.
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Osteoarthritis is a leading cause of disability for which there is no cure. We have discovered that the multidomain signalling protein Agrin, most commonly known for its requirement at the neuromuscular junction, strongly promotes chondrocyte differentiation and cartilage formation in vivo. Agrin is expressed in normal cartilage but absent in osteoarthritis. In vitro, Agrin knockdown resulted in the downregulation of the cartilage transcription factor SOX9 and other cartilage-specific extracellular matrix molecules. Conversely, the addition of exogenous Agrin supported cartilage differentiation in vitro and ectopic cartilage formation in vivo. In contrast to other biological contexts where Agrin signalling requires the interaction with either LRP4 or α-dystroglycan, chondrocytes require the presence of both receptors. Our results identify Agrin as a novel potent anabolic growth factor with strong therapeutic potential in cartilage regeneration.
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Tripodi, Marco. "Structural homeostasis during dendritic arbor development." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611147.
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Deraze, Jérôme. "Epigenetic control of ribosome biogenesis homeostasis." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066342/document.
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La traduction est une activité cellulaire essentielle, réalisée par les ribosomes. Ces particules sont synthétisées dans le nucléole, ce qui nécessite l'expression coordonnée de 4 ARN ribosomaux, 80 protéines ribosomales, et plus de 200 facteurs d'assemblage. Leur biogenèse est complexe et sollicite plus de la moitié de l'énergie des cellules en prolifération. La quantité de ribosomes varie selon les conditions environnementales et métaboliques et de ce fait, leur synthèse est modulée en réponse à de nombreux stimuli. Plusieurs mécanismes coordonnent la biogenèse des ribosomes avec l'homéostasie cellulaire. L'un d'eux est la capacité des protéines ribosomiques à réguler l'expression des gènes à plusieurs niveaux. Ces fonctions effectuées hors du ribosome sont dites extraribosomales. Notre équipe a mis en évidence l'une de ces fonctions de la protéine ribosomale uL11 chez la Drosophile. Quand sa lysine 3 est triméthylée (uL11K3me3), elle interagit avec Corto, un facteur de transcription de la famille des Enhancers de Trithorax et Polycomb. L'étude de leur fixation à la chromatine montre que ces protéines se répartissent différemment à l'échelle du génome, et que uL11K3me3 est présente au niveau de gènes actifs enrichis en composants du ribosome. Nous avons généré les premiers allèles génétiques du gène uL11 chez la Drosophile, et décrivons la stratégie de crible moléculaire employée pour leur isolation. Finalement, nous avons étudié les allèles de uL11 dont la lysine 3 est mutée. Leurs phénotypes ressemblent à ceux des mutants Minute, suggérant que le domaine N-terminal de uL11 possède une fonction essentielle, mais peut-être indépendante d'une interaction avec CortoTranslation is an essential metabolic activity carried by ribosomes. These complexes are synthetized in the nucleolus, and require the coordinated expression of 4 ribosomal RNA, 80 ribosomal proteins, and more than 200 assembly factors. Indeed, their biogenesis is complex and expensive, consuming more than half of the energy in proliferating cells. As the cellular need for ribosomes varies with environmental or metabolic conditions, their synthesis is tightly regulated in response to a number of cues. Many mechanisms ensure that the intensity of ribosome biogenesis is coupled to cell homeostasis. Such is the ability of ribosomal proteins to regulate gene expression at many levels, from translation specificity to activation or repression of transcription. Many such functions are carried off the ribosome, and are thus termed extraribosomal. Our team discovered a new extraribosomal function of ribosomal protein uL11 in Drosophila. Indeed, when trimethylated on lysine 3 (uL11K3me3), it associates with Corto, a transcription factor of the Enhancers of Trithorax and Polycomb family. By studying their genome-wide binding profile on chromatin, we show that these proteins are distributed along different patterns, and that uL11K3me3 specifically binds a subset of active genes enriched in ribosome biogenesis components. Additionally, we generated the first genetic alleles for Drosophila uL11 and describe the molecular screening method that we employed. Last, we studied the uL11 alleles that delete or replace lysine 3. We describe that their Minute-like phenotypes suggest an essential role for the N-terminal domain of uL11, though it may be independent of its association with Corto
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BonDurant, Lucas Donald. "Regulation of glucose homeostasis by FGF21." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6060.
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Fibroblast Growth Factor 21 (FGF21) is an endocrine hormone derived from the liver that exerts pleiotropic effects on the body to maintain overall metabolic homeostasis. During the past decade, there has been an enormous effort to understand the physiological roles of FGF21 in regulating metabolism and to identify the mechanism for its potent pharmacological effects to reverse diabetes and obesity. Through both human and rodent studies, it is now evident that FGF21 is dynamically regulated by nutrient sensing and consequently functions as a critical regulator of nutrient homeostasis. In addition, recent studies with new genetic and molecular tools have provided critical insight into the actions of this exciting endocrine factor. Dissection of these FGF21-regulated pathways has tremendous potential for new targeted therapies to treat metabolic disease. The goals of this thesis are 1) to identify FGF21’s physiological role as a carbohydrate-regulated signal of macronutrient-specific satiety and 2) to determine the mechanism and tissues responsible for mediating the pharmacological effects of FGF21.
To address the first goal, we used different FGF21 genetic knockout mouse models to determine if loss of FGF21 would affect macronutrient preference. We found that loss of FGF21 led to an increase in simple sugar intake whereas this had no effect on other macronutrients such as lipid or protein. To further characterize the relationship between carbohydrates and FGF21, in vitro and in vivo techniques revealed that FGF21 transcription in the liver increased in response to carbohydrate intake and this was dependent on the presence of a transcription factor activated by carbohydrates, ChREBP. We next addressed whether or not increased FGF21 levels would affect preference for simple sugars. We found that in response to increased circulating levels of FGF21, either through genetic overexpression or pharmacological administration, FGF21 would lead to a significant decrease in caloric and non-caloric sweeteners. Finally, we were able to determine that FGF21 was signaling to the hypothalamus to mediate this suppression of simple sugar intake through region specific knockout of the co-receptor beta-klotho.
To address the pharmacological actions of FGF21, we generated an adipose-specific KLB KO mouse using mice that express Cre-recombinase under the adiponectin promoter. These mice lack the co-receptor for FGF21 in adipose tissue and are a more reliable adipose knockout model than previous studies that have used aP2-Cre mice. We were able to determine that the acute glucose lowering effects of FGF21 are mediated through direct signaling to adipose tissue and that FGF21 enhances insulin sensitivity by increasing glucose uptake in brown adipose tissue. However, FGF21 mediates its chronic effects, including lowering body weight and triglycerides, by signaling to some other non-adipose tissue. Overall our work has shown that FGF21 can significantly regulate glucose metabolism through multiple mechanisms.