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1
Blanch, Graziela Torres [UNESP]. "Ajustes cardiovasculares e do equilibrio hidroeletrolítico induzidos por soluções hipertônicas em ratos com lesão do núcleo do trato solitário comissural." Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/106675.
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O sistema nervoso central (SNC) tem um papel fundamental na regulação de mecanismos que controlam a osmolaridade dos líquidos corporais. O núcleo do trato solitário (NTS) é o sítio primário das aferências cardiovasculares e de osmorreceptores periféricos e se projeta à áreas prosencefálicas envolvidas com a regulação cardiovascular e do equilíbrio hidroeletrolítico. Demonstramos anteriormente que animais com lesão da porção comissural do NTS (commNTS) tem maior ingestão de água, natriurese e resposta pressora frente a sobrecarga intragástrica (ig) de NaCl 2 M. Os mecanismos responsáveis por estas alterações ainda não foram determinados. Uma vez que o estímulo com NaCl 2 M ig (2 ml) ativa osmorreceptores centrais e periféricos, não sabemos até o momento os efeitos da lesão do commNTS sobre as respostas observadas após a estimulação específica de osmorreceptores periféricos, que pode ser feita com NaCl 0,6 M ig. (2 ml). Desta forma os nossos objetivos foram: a) estudar os mecanismos que medeiam o aumento da pressão arterial e da natriurese após a sobrecarga de NaCl 2 M em animais com lesão do commNTS; b) verificar as alterações na expressão da proteína c-Fos após NaCl 2 M ig em ratos com lesão fictícia (sham) ou lesão do commNTS; c) verificar as alterações na expressão gênica no PVN após NaCl 2 M ig, d) estudar os efeitos na pressão arterial, na ingestão de água e na excreção renal subseqüentes a administração de NaCl 0,6 M ig, bem como os mecanismos responsáveis pelas alterações, em ratos com lesão fictícia (sham) ou lesão do commNTS; e) verificar as alterações na expressão da proteína c-Fos após NaCl 0,6 M ig em ratos com lesão fictícia (sham) ou lesão do commNTS. Ratos Holtzman (280-320 g) foram utilizados. A lesão eletrolítica...
The central nervous system has an important role controlling the mechanisms involved in the regulation of body fluid osmolality. The nucleus of the solitary tract (NTS) is the primary site of cardiovascular and peripheral osmoreceptors afferents and projects to prosencephalic areas involved in hydroelectrolytic balance and cardiovascular regulation. We have demonstrated that commissural NTS (commNTS) lesioned rats had an increase in arterial pressure and a greater increase in water intake and natriuresis after 2 M NaCl intragastric (ig) load. The mechanisms involved in these responses are not known. Since 2 M NaCl ig (2 ml) activates central and peripheral osmoreceptors, it is not known the effects of the commNTS lesion on the responses induced only by the activation of the peripheral osmoreceptors, which can be done by 0.6 M NaCl (2 ml) ig. Thus, the aims of this study were: a) to study the mechanisms involved in the increase of the arterial pressure and natriuresis in commNTS lesioned rats after 2 M NaCl ig; b) to verify the changes in c-Fos expression after 2 M NaCl ig in sham and commNTS lesioned rats; c) to verify the changes in gene expression in PVN after 2 M NaCl ig in naïve rats; d) to study the effects on arterial pressure, water intake and renal excretion after 0.6 M NaCl, as well as, the mechanisms involved in these responses, in sham and in commNTS lesioned rats; e) to verify the changes in c-Fos expression after 0.6 M NaCl ig in sham and commNTS lesioned rats. Male Holtzman rats (280-320 g) were used. Electrolytic lesion of the commNTS and all experiments were be performed in chronic period of lesion (14 to 21 days. For the lesion, a partial craniotomy of the occipital bone was performed, and the dorsal surface of the brainstem was exposed. The electrolytic lesion was performed using... (Complete abstract click electronic access below)
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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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Blanch, Graziela Torres. "Ajustes cardiovasculares e do equilibrio hidroeletrolítico induzidos por soluções hipertônicas em ratos com lesão do núcleo do trato solitário comissural /." Araraquara : [s.n.], 2010. http://hdl.handle.net/11449/106675.
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Orientador: Débora Simões de Almeida ColombariBanca: Colin Sumners
Banca: Cássia Marta de Toledo Bermagaschi
Banca: Vagner Roberto Antunes
Banca: Lucila Leico Kagohara Elias
Resumo: O sistema nervoso central (SNC) tem um papel fundamental na regulação de mecanismos que controlam a osmolaridade dos líquidos corporais. O núcleo do trato solitário (NTS) é o sítio primário das aferências cardiovasculares e de osmorreceptores periféricos e se projeta à áreas prosencefálicas envolvidas com a regulação cardiovascular e do equilíbrio hidroeletrolítico. Demonstramos anteriormente que animais com lesão da porção comissural do NTS (commNTS) tem maior ingestão de água, natriurese e resposta pressora frente a sobrecarga intragástrica (ig) de NaCl 2 M. Os mecanismos responsáveis por estas alterações ainda não foram determinados. Uma vez que o estímulo com NaCl 2 M ig (2 ml) ativa osmorreceptores centrais e periféricos, não sabemos até o momento os efeitos da lesão do commNTS sobre as respostas observadas após a estimulação específica de osmorreceptores periféricos, que pode ser feita com NaCl 0,6 M ig. (2 ml). Desta forma os nossos objetivos foram: a) estudar os mecanismos que medeiam o aumento da pressão arterial e da natriurese após a sobrecarga de NaCl 2 M em animais com lesão do commNTS; b) verificar as alterações na expressão da proteína c-Fos após NaCl 2 M ig em ratos com lesão fictícia (sham) ou lesão do commNTS; c) verificar as alterações na expressão gênica no PVN após NaCl 2 M ig, d) estudar os efeitos na pressão arterial, na ingestão de água e na excreção renal subseqüentes a administração de NaCl 0,6 M ig, bem como os mecanismos responsáveis pelas alterações, em ratos com lesão fictícia (sham) ou lesão do commNTS; e) verificar as alterações na expressão da proteína c-Fos após NaCl 0,6 M ig em ratos com lesão fictícia (sham) ou lesão do commNTS. Ratos Holtzman (280-320 g) foram utilizados. A lesão eletrolítica... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The central nervous system has an important role controlling the mechanisms involved in the regulation of body fluid osmolality. The nucleus of the solitary tract (NTS) is the primary site of cardiovascular and peripheral osmoreceptors afferents and projects to prosencephalic areas involved in hydroelectrolytic balance and cardiovascular regulation. We have demonstrated that commissural NTS (commNTS) lesioned rats had an increase in arterial pressure and a greater increase in water intake and natriuresis after 2 M NaCl intragastric (ig) load. The mechanisms involved in these responses are not known. Since 2 M NaCl ig (2 ml) activates central and peripheral osmoreceptors, it is not known the effects of the commNTS lesion on the responses induced only by the activation of the peripheral osmoreceptors, which can be done by 0.6 M NaCl (2 ml) ig. Thus, the aims of this study were: a) to study the mechanisms involved in the increase of the arterial pressure and natriuresis in commNTS lesioned rats after 2 M NaCl ig; b) to verify the changes in c-Fos expression after 2 M NaCl ig in sham and commNTS lesioned rats; c) to verify the changes in gene expression in PVN after 2 M NaCl ig in naïve rats; d) to study the effects on arterial pressure, water intake and renal excretion after 0.6 M NaCl, as well as, the mechanisms involved in these responses, in sham and in commNTS lesioned rats; e) to verify the changes in c-Fos expression after 0.6 M NaCl ig in sham and commNTS lesioned rats. Male Holtzman rats (280-320 g) were used. Electrolytic lesion of the commNTS and all experiments were be performed in chronic period of lesion (14 to 21 days. For the lesion, a partial craniotomy of the occipital bone was performed, and the dorsal surface of the brainstem was exposed. The electrolytic lesion was performed using... (Complete abstract click electronic access below)
Doutor
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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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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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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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Hoshi, Rosangela Akemi. "Análise da variabilidade da frequência cardíaca, variáveis cardiopulmonares e catecolaminas plasmáticas durante recuperação pós-exercício." Faculdade de Medicina de São José do Rio Preto, 2015. http://hdl.handle.net/tede/253.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
Introduction: Exercises promote changes in the Autonomic Nervous System, the mainly responsible for neurodegenerative functions. Due to its importance, several methods are used in evaluation such as Heart Rate Variability (HRV) analysis, considered an indirect technique to assess autonomic functions, but its use is still questioned. Objectives: To analyze the correlation between HRV indices and concentration of epinephrine and norepinephrine, and observe post-exercise recovery, by HRV linear and nonlinear indices and cardiopulmonary parameters. Methods: 28 participants, divided into two groups (N = 14) had their recovery after exercise evaluated. One group performed submaximal effort (55% V̇O2peak), for 5 minutes, and the other, supramaximal (110% of peak V̇O2) until exhaustion. During 90 minutes post-exercise, blood samples were collected, cardiopulmonary variables were registered and HRV was analyzed. Results: Between baseline and immediately postexercise, we detected that adrenaline and noradrenaline showed significant nonlinear correlation with RR intervals, heart rate, HRV linear indices and nonlinear parameters related to complexity and fractality. After exercise performed at 55% of peak V̇O2, recovery was observed between 30 and 60 minutes, whereas for exercise at 110%, 90 minutes were not enough for returning of variables to baseline levels. Conclusions: Plasma catecholamine concentrations after exercise presented correlation with HRV linear indices and nonlinear parameters related to complex and fractal characteristics of heartbeats, especially the Lyapunov exponent. The variables recovery occurred at different times, but the changes caused by supramaximal exercise were more expressive and lasting.
Introdução: A realização de exercícios físicos promove alterações no sistema nervoso autônomo, principal responsável pelas funções neurovegetativas. Devido à sua importância, diversos métodos são utilizados para avaliação, como a análise da Variabilidade da Frequência Cardíaca (VFC), considerada uma técnica indireta de acesso ao funcionamento autonômico, porém seu emprego é ainda questionado. Objetivos: analisar a correlação entre índices de VFC e concentração de adrenalina e noradrenalina, e observar a recuperação pós-exercício, a partir dos índices lineares e não lineares de VFC e de parâmetros cardiopulmonares. Métodos: 28 participantes, divididos em dois grupos (N=14), foram submetidos à avaliação da recuperação após exercício. Um grupo realizou esforço submáximo (55% do V̇O2pico), por 5 minutos, e o outro, supramáximo ( 110% do V̇O2pico) até a exaustão. Durante 90 minutos pós-exercício foram realizadas coletas sanguíneas, registros das variáveis cardiopulmonares e análise da VFC. Resultados: No período entre o basal e imediatamente após o exercício, detectou-se que adrenalina e noradrenalina apresentaram correlações não lineares significantes com intervalos R-R, frequência cardíaca, índices lineares de VFC e parâmetros não lineares relacionados à complexidade e fractalidade. Após exercício realizado a 55% do V̇O2pico, a recuperação foi verificada entre 30 e 60 minutos, enquanto que para o esforço a 110%, 90 minutos não foram suficientes para o retorno das variáveis aos níveis basais. Conclusões: Concentrações de catecolaminas plasmáticas após exercícios apresentam correlação com índices lineares de VFC e parâmetros não lineares relacionados às características complexas e fractais dos batimentos cardíacos, sobretudo o expoente de Lyapunov. A recuperação das variáveis analisadas ocorreu em tempos diferentes, porém as alterações promovidas pelo exercício supramáximo foram muito mais expressivas e duradouras.
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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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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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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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Arosio, Daniele. "Imaging Chloride Homeostasis in Neurons." Doctoral thesis, Università degli studi di Trento, 2017. https://hdl.handle.net/11572/368512.
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Intracellular chloride and pH are fundamental regulators of neuronal excitability and they are often co-modulated during excitation-inhibition activity. The study of their homeostasis requires simultaneous measurements in vivo in multiple neurons. Combining random mutagenesis screening, protein engineering and two-photon-imaging this thesis work led to the discovery of new chloride-sensitive GFP mutants and to the establishment of ratiometric imaging procedures for the quantitative combined imaging of intraneuronal pH and chloride. These achievements have been demonstrated in vivo in the mouse cortex, in real-time monitoring the dynamic changes of ions concentrations during epileptic-like discharges, and in glioblastoma primary cells, measuring osmotic swelling responses to various drugs treatment.
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Arosio, Daniele. "Imaging Chloride Homeostasis in Neurons." Doctoral thesis, University of Trento, 2017. http://eprints-phd.biblio.unitn.it/1937/2/DECLARATORIA_ENG_signed.pdf.
Full textAbstract:
Intracellular chloride and pH are fundamental regulators of neuronal excitability and they are often co-modulated during excitation-inhibition activity. The study of their homeostasis requires simultaneous measurements in vivo in multiple neurons. Combining random mutagenesis screening, protein engineering and two-photon-imaging this thesis work led to the discovery of new chloride-sensitive GFP mutants and to the establishment of ratiometric imaging procedures for the quantitative combined imaging of intraneuronal pH and chloride. These achievements have been demonstrated in vivo in the mouse cortex, in real-time monitoring the dynamic changes of ions concentrations during epileptic-like discharges, and in glioblastoma primary cells, measuring osmotic swelling responses to various drugs treatment.
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Sá, Marina Granado e. "Efeitos do cobre na homeostase do caranguejo de mangue Ucides cordatus (Decapoda: Ucididae)." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/41/41135/tde-01052013-143047/.
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Recentemente, tem sido reconhecido que a água pode ser ao mesmo tempo uma fonte vital para os organismos e um veículo para eliminação de poluentes. Esse paradoxo pode ser considerado como parte da crise do presente ambiente que está inserida no conflito entre natureza e tecnologia, sendo acompanhado pelo emprego de biomarcadores, que consistem em indicadores bioquímicos e celulares da presença de contaminantes através da análise de fluidos corpóreos bem como células ou tecidos. O principal objetivo deste trabalho foi o de verificar quais os possíveis efeitos do cobre na homeostase do caranguejo de mangue Ucides cordatus expostos ao cobre na água (CuSO4) por diferentes períodos de tempo, através de teste agudo com exposição durante 24h e 96h e teste crônico com duração de 15 dias. Após a exposição dos animais à agua contaminada, estes foram crio-anestesiados pra dessensibilização e então foram retiradas alíquotas de hemolinfa e urina para determinação de concentrações de sódio, potássio, magnésio e cálcio, bem como as concentrações de glicose e lactato, além de brânquias e hepatopâncreas para a dosagem de enzimas como Na+/K+-ATPase, anidrase carbônica e a concentração da proteína metalotioneína, não esquecendo o músculo da quela que foi utilizado para determinação da concentração de glicogênio (assim como para o hepatopâncreas). Para complementar o amplo trabalho, foi determinado o transporte de cobre na membrana celular de brânquias e hepatopâncreas, através do qual foi possível verificar que a entrada do cobre pela membrana plasmática pode ocorrer através de diversas vias, podendo ser elas dependentes ou independentes de cálcio, porém é estritamente dependente da concentração de sódio no meio extra e intracelular, demonstrando interação entre transportadores para manutenção da homeostase. Além disso, o cobre se apresenta como um íon competidor com outros cátions como magnésio e potássio, além, claro, de alterar atividades enzimáticas como da Na+/K+-ATPase e anidrase carbônica. No entanto é válido notar que, principalmente para as brânquias anteriores, que são predominante respiratórias, houve aumento da síntese de metalotioneína, proteína esta induzida na presença de altas concentrações de cobre, que dentre outras funções, é principal componente da hemocianina, pigmento respiratório dos crustáceosRecently, it has been recognized that water can be both a vital source for the organisms and a vehicle for disposal of pollutants. This paradox may be considered as part of the environment crisis that is inserted between nature and technology conflict, accompanied by the use of biomarkers that consists of cellular and biochemical indicators of contamination by analysis of body fluids as well as cells or tissues. The main objective of this study was to determine what the possible effects of copper homeostasis mangrove crab Ucides cordatus exposed to copper in water (CuSO4) for different periods of time, by testing acute exposure for 24h and 96h and chronic test, lasting 15 days. After exposure of the animals to contaminated water, they were cryo-anesthetized for desensitization and then aliquots of haemolymph and urine were collect to determine hemolymph and urine concentration of sodium, potassium, magnesium and calcium, and the concentrations of glucose and lactate as well as gills and hepatopancreas for measure enzymes such as Na+/K+-ATPase, carbonic anhydrase and metallothionein protein concentration, not forgetting the muscle which was used for the determination of glycogen concentration (as for the hepatopancreas). To complement the extensive study, it was determined copper transport in gills and hepatopancreas epithelial cells, whereby it was verified that the input of copper by plasma membrane can occur through various routes, which can be dependent or independent of calcium, but it is strictly dependent on the sodim concentration in intracellular and extracellular medium, showing interaction between transport proteins for maintaining homeostasis. Furthermore, copper is presented as a competitive with other cations such as magnesium and potassium, in addition of course to alter enzymatic activity as Na+/K+-ATPase and carbonic anhydrase. However it is worth noting that, especially prior to the anterior gill cells, which are predominant respiratory, that there was increased synthesis of metallothionein, which is a protein induced in the presence of high concentrations of copper, which among other functions, is the main component of hemocyanin, the respiratory pigment crustaceans
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Dandaro, Priscila Aparecida Faitanini [UNESP]. "Ultradiluições de Natrum muriaticum no desempenho agronômico do tomateiro-cereja submetidos a estresse salino." Universidade Estadual Paulista (UNESP), 2017. http://hdl.handle.net/11449/151909.
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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
A utilização de preparados homeopáticos tem se tornado crescente na agricultura em especial nas plantas. Vários segmentos como a germinação, a produção de mudas, o controle de pragas e doenças de planta, o aumento de princípios ativos, desintoxicação de plantas por meios contaminantes e no metabolismo tem sido abordados através dos conceitos de Homeopatia. Os procedimentos que permitem reverter o quadro de estresse salino são pouco conhecidos, os custos são elevados e os recursos não são renováveis, tornando-se necessárias a adoção de novas tecnologias. O objetivo deste trabalho foi avaliar o efeito de preparados homeopáticos no desempenho agronômico e parâmetros fisiológicos em tomateiro-cereja submetido a estresse salino. O delineamento estatístico utilizado foi inteiramente casualizado, com oito tratamentos e cinco repetições. Foram avaliadas diferentes dinamizações de Natrum muriaticum (3CH; 5CH; 7CH; 9CH; 11CH; 13CH), e as testemunhas (água destilada e etanol 70%). As características avaliadas foram: altura (cm), diâmetro do colo (mm), número de folhas, número de flores por cacho, número de frutos, número de frutos por cachos, fluorescência da clorofila A, condutância estomática, teor relativo de água, potencial hídrico, determinação da área foliar, determinação de fitomassa fresca de frutos (gramas), teor de sólidos solúveis (°Brix) e teor de prolina do tomateiro-cereja. A aplicação da Ultradiluição de Natrum muriaticum promoveu incremento em todas as variáveis avaliadas referentes ao desempenho agronômico do tomateiro. Natrum muriaticum 11CH e 13CH atuam positivamente no desenvolvimento vegetativo e reprodutivo de tomate-cereja submetidos à estresse salino.
The use of homeopathic preparations has become increasing in agriculture, especially in plants. Several segments such as germination, production of seedlings, pest control and plant diseases, increased raw material assets, detoxification of plants by contaminating means and at metabolism had been reached by the concepts of Homeopathy. The procedures that allow the reversal of the salinity stresses are little known, the costs are high and the resources are not renewable, becoming necessary the adoption of new technologies. The objective of this work was to evaluate the effect of homeopathic preparations on agronomic performance and physiological parameters on cherry tomatoes submitted to saline stress. The statistical design was completely randomized, with eight treatments and five replicates. Different dynamizations of Natrum muriaticum (3CH; 5CH; 7CH; 9CH; 11CH; 13CH) and the controls (distilled water and 70% ethanol) were evaluated. The evaluated characteristics were: height (cm), lap diameter (mm), number of leaves, number of flowers per cluster, number of fruits, number of fruits per bunches, chlorophyll A fluorescence, stomatal conductance, relative water content, hydric potential, leaf area determination, fresh fruit phytomass determination (grams), soluble solids content (° Brix), and proline content of tomato-cherry. The application of the ultradilution of Natrum muriaticum promoted the increase in all evaluated variables related to the agronomic performance of the tomato. Natrum muriaticum 11CH and 13CH acts positively on vegetative and reproductive development of cherry tomatoes submitted to saline stress.
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PRESTIGIO, COSIMO. "A REST/NRSF-dependent transcriptional remodeling governs GABAergic synaptic upscaling induced by chronic hyperactivity." Doctoral thesis, Università degli studi di Genova, 2020. http://hdl.handle.net/11567/996544.
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REST/NRFS (RE1-silencing transcription factor) has been initially identified as a negative transcription factor. Its target genes encode postsynaptic receptors, ion channels and transporters, neuropeptides and synaptic proteins. Evidences show that in mature neurons, REST can be upregulated by neuronal hyperactivity and works as a master epigenetic modulator, acting mostly as transcriptional repressor and, occasionally, as a transcriptional activator (Perera et al., 2015; Kallunki et al., 1998). We have previously demonstrated that REST is critical for the downscaling of intrinsic excitability in excitatory neurons subjected to prolonged elevation of electrical activity (Pozzi et al., 2013) and that it participates to the synaptic homeostasis of glutamatergic synapses by reducing their strength at the presynaptic level (Pecoraro-Bisogni et al., 2017). The aim of our work is to verify if REST plays a role in the synaptic homeostasis of GABAergic transmission evoked by hyperexcitability. Here we show that neuronal hyperactivity, obtained by treating for two days primary hippocampal neurons with 4-aminopyridine (4AP), induces a REST-dependent potentiation of the strength and number of somatic GABAergic synapses onto excitatory neurons, while the effect was lacking when the postsynaptic target cell was another inhibitory neuron. Our data suggest that the postsynaptic target specificity depends on a REST-dependent induction of a downstream transcription factor, NPAS4, known for its role in the development of inhibitory synapses, thanks to its capability of activating BDNF release from excitatory neurons upon hyperactivity (Lin et al. 2008). BDNF is synthetized only by excitatory neurons (Hofer et al., 1990). Thus, the retrograde action of BDNF, released from the soma of excitatory neurons onto the somatic GABAergic presynaptic contacts, could explain the observed postsynaptic target specificity of REST-action.
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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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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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Howarth, Frank Christopher. "Magnesium homeostasis in the mammalian heart." Thesis, University of Central Lancashire, 1994. http://clok.uclan.ac.uk/20059/.
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The magnesium ion (Mg2 ) is involved in a variety of physiological and biochemical processes including the activation of over 300 enzymes and the control of transmembrane movement of cations. In most mammalian cells intracellular Mg2+ is kept well below electrochemical equilibrium. In cardiac muscle cells recent studies suggest that the intracellular and extracellular concentrations of Mg2+ are around I and 0.5 mIs4, respectively. The equilibrium potential for Mg2 is approximately - 10 mV. In resting muscle the membrane potential is far more negative than this and M g2+ extrusion must take place aganist an electrochemical gradient. Factors which may be important in preserving intracellular Mg2+ include; changes in membrane potential which occur during the action potential, intracellular buffering, intracellular compartmental redistribution, the permeability characteristics of the plasma membrane and transport stystems in the plasma membrane. The aims of the study are to investigate the effects of extracellular Mg2+ on contractility and coronary flow and the effects of hormonal and extracellular cationic control of Mg2+ homeostasis in the rat heart. Subsequently, the effects of dietary magnesium on the magnesium, calcium, sodium and potassium content of the heart (and other tissues) in young rats is also investigated. Perfusion of the isolated heart with elevated extracellular Mg2+ (1.2 - 7.2 mM) caused a profound reduction in the force of contraction and an associated increase in the coronary flow rate. The selective 13-adrenoceptor agonist isoprenaline (10 M), evoked a large Mg2+ efflux and an associated increase in the force and rate of contraction in the isolated perfused heart. Quantitativley, similar increases in Mg2+ efflux were seen during stimulation of the isolated heart with the adenylate cyclase activator, forskolin (10 M). Stimulation of superfused electrically paced ventricle segments with either isoprenaline, noradrenaline or adrenaline (10-6 M) also evoked a large net Mg2+ efflux. The isoprenaline-evoked Mg2+ efflux was significantly reduced during treatment of the heart with either the 0- antagonist, propranolol (I o-5 M), or the Ca2 -channel blocker, verapamil (1 o-5 M) Stimulation of mag-ftira-2 AM loaded cardiac myocytes in suspension with isoprenaline did not result in any change in intracellular M g2+. Elevations of extracellular Na+ concentration (as NaCl or sodium isethionate), elevated chloride (as choline chloride) and sucrose (at concentrations osmotically equivalent to elevated Na+) all evoked large Mg2+ eftiuxes in the isolated perfused heart. The elevated Na (as NaCl) -evoked Mg 2 efflux was partially, though not significantly, inhibited by the Na channel blocker, amiloride (10 M) and propranolol (lOs M). During stimulation of the heart with elevated Na+ there was no increase in lactate dehydrogenase activity indicating that the release of Mg2+ was not due to cell damage. Treatment of the heart with verapamil (I o-6 M), which dramatically reduced the force of contraction, had little effect on the Mg2+ efflux evoked by elevated Na+ (as sodium sulphate). Acute perfusion of the isolated heart with nominally Mg2+ free physiological solution over 15 min caused a significant reduction in the magnesium content of the heart, thereafter, magnesium was well conserved. Magnesium deficient diets fed to young rats over a period of approximately one month caused reduction in food consumption, retardation of growth, reductions in some organ weights and various cationic disturbances in the heart and other tissues. In the heart there were no significant changes to sodium or potassium but there was a significant increase in calcium and reduction in magnesium. Collectively, these results suggest that magnesium is well conserved in the heart and that the catecholamines and changes in extracellular osmolarity may be important physiological regulators of magnesium homeostasis in the heart.
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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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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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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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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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Andrew, S. C. "Potassium homeostasis during intracellular Chlamydia development." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1430699/.
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Chlamydia trachomatis is an obligate intracellular bacterium, which is the leading cause of acquired blindness and the most prevalent bacterial sexually transmitted infection worldwide. Chlamydiae exist in two distinct forms. The infectious spore-like elementary bodies (EBs) that invade host cells differentiate into non-infectious reticulate bodies (RBs) that replicate intracellularly within a modified membrane-bound vacuole called the inclusion. Under stress, Chlamydiae can enter a persistent state, in which aberrant bodies (ABs) with reduced metabolic activity are formed. Surprisingly little is known about the mechanisms employed by the bacteria to maintain and manipulate their environment within host cells. This thesis investigates the role of inorganic ions in sustaining the inclusion throughout the Chlamydia infection cycle. Potassium starvation of intracellular RBs either after specific ionophore treatment or inhibition of inward rectifying cellular potassium channels induced the formation of ABs, which no longer differentiated into infectious EBs. These data demonstrate an essential role for potassium during C.trachomatis replication. Analysis of live RBs, using a potassium sensitive fluorescent probe, illustrated that potassium is actively scavenged from the host cell. Furthermore, when bacteria undergo RB-EB differentiation accumulated potassium is released prior to inclusion lysis. Experimentally reducing potassium ion concentration at this stage caused cells to expel bacteria in bursts. This event is distinct from previously described extrusion mechanisms, where either the inclusion is released intact or the host cell is lysed. These data show that RBs actively accumulate potassium during replication, with starvation leading to persistence. Loss of potassium ions during re-differentiation into EBs suggests that potassium efflux has a role in triggering inclusion lysis or bacteria exit from the host cell.
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Nordquist, Emily M. "Exploring Heart Valve Homeostasis and Repair." The Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu1617621956339594.
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Carvalho, Menarim Bruno. "Macrophage-mediated regulation of joint homeostasis." Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/95316.
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Osteoarthritis (OA) is the leading cause of musculoskeletal disability in people and horses, and is characterized by progressive joint degeneration. There is a critical need for a better understanding of disease processes leading to OA in order to develop more efficient therapies. A shared feature among different arthritic conditions is chronic synovitis. Macrophages are the main drivers of synovitis and can display pro-inflammatory (M1) or pro-resolving responses (M2). Macrophages promote joint health through phagocytic and secretory activities; however, when these functions are overwhelmed, macrophages upregulate inflammation, recruiting more cells to counteract damage. Once cell recruitment is efficiently accomplished, macrophages coordinate tissue repair and further resolution of inflammation. Bone marrow mononuclear cells (BMNC) are a source of macrophages used to treat inflammation and produce essential molecules for cartilage metabolism; however, little information exists regarding their use in joints. The studies presented in this dissertation focus on understanding the dual role of macrophages in driving and resolving synovitis and how to harness their therapeutic potential.
In the first study, patterns of macrophage phenotypes (M1:M2) in healthy and osteoarthritic equine synovium were compared and correlated with gross pathology, histology, and synovial fluid cytokines. M1 and M2 markers were co-expressed in normal and osteoarthritic joints, varying in intensity of expression according to degree of inflammation. Concentrations of synovial fluid IL-10, a macrophage-produced cytokine that is vital for chondrocyte recovery from injury, was lower in OA joints. The combined findings of this study suggest homeostatic mechanisms from synovial macrophages in OA may be overwhelmed, preventing inflammation resolution.
In the second study we investigated the response of BMNC to normal (SF) and inflamed synovial fluid (ISF). BMNC cultured in autologous SF or ISF developed into macrophage cultures that were more confluent in ISF (~100%) than SF (~25%), and exhibited phenotypes that were ultimately similar to cells native to normal joints. BMNC cultured in SF or ISF were neither M1 nor M2, but exhibited aspects of both phenotypes and a regulatory response, characterized by increasing counts of IL-10+ macrophages, decreasing concentrations of IL-1β, and progressively increasing concentrations of IL-10 and IGF-1, all more marked in ISF. These findings suggest that homeostatic mechanisms were preserved over time, and potentially favored by macrophage proliferation. Our data suggest that BMNC therapy could potentiate the macrophage- and IL-10-associated mechanisms of joint homeostasis lost in OA.
Finally, using an equine model of synovitis, the last study investigated the response of normal and inflamed joints to autologous BMNC injection. Inflamed joints treated with BMNC showed gross and analytical improvements in synovial fluid and synovial membrane, with increasing numbers of regulatory macrophages and synovial fluid concentrations of IL-10, not observed in saline-treated controls. Autologous BMNC are readily available, downregulate synovitis through macrophage-associated effects, and can benefit thousands of patients with OA.
Combined, the results of these studies support the role of macrophage-driven synovial homeostasis and identified a therapeutic way to recover homeostatic mechanisms of synovial macrophages lost during chronic inflammation. Our findings also uncover new research directions and methods for future studies targeting modulation of joint inflammation.Doctor of Philosophy
Osteoarthritis (OA) is a common cause of joint deterioration in people and horses. Current treatments provide limited recovery of joint function, creating an urgent need for more efficient therapies; however, development of new treatments requires better understanding of the mechanism causing OA. A shared characteristic among many arthritic conditions is long-standing inflammation. Cells called macrophages are the main drivers of joint inflammation and can exert pro- and anti-inflammatory effects. Macrophages promote joint health by clearing aggressor agents and secreting molecules required for optimal joint function. However, when these housekeeping functions are overwhelmed by damage, macrophages drive inflammation recruiting more cells to cope with increased demands for repair. If this process is efficiently accomplished, macrophages then resolve inflammation, recovering joint health. Macrophages in the bone marrow (BMNC - bone marrow mononuclear cells) are used to treat inflammation in several tissues and are known to produce molecules essential for joint health. Although little information exists regarding their use in joints, studies treating different organs suggest it can provide high rewards. The studies presented in this dissertation focused on understanding the dual function of macrophages in driving and controlling joint inflammation, and harnessed their therapeutic potential. In the first study, macrophages were investigated in normal and OA-affected joints, and curiously exhibited a hybrid pro- and anti-inflammatory identity in both groups. The indicators of this mixed identity were more markedly expressed in arthritic joints showing gross inflammation. Low levels of a macrophage-derived anti-inflammatory protein called IL-10 were detected in OA joints. The results of this study suggest that anti-inflammatory mechanisms from macrophages may be overwhelmed in OA-affected joints, preventing inflammation to be resolved, and that recovering this anti-inflammatory function may aid in the treatment of OA. In the second study we investigated how the incubation of BMNC in fluid from normal and inflamed joints affects the response of macrophages. Similar to what we observed in the first study, BMNC incubated in both normal and inflamed joint fluid induced macrophages to develop a hybrid identity that was ultimately similar to native cells from normal joints. Macrophages proliferated more when incubated in fluid from inflamed joints. Macrophages in both groups produced anti-inflammatory effects with high levels of IL-10 that were highest in ISF cultures. These observations suggest that higher proliferation of macrophages in inflamed joint fluid helped preserve anti-inflammatory mechanisms. Therefore, our study suggests that joint injection with BMNC could maximize macrophage- and IL-10-associated mechanisms required to resolve joint inflammation. The third and final study investigated the response of normal and inflamed joints to BMNC injection using a model of joint inflammation in horses. Inflamed joints treated with BMNC showed visual and laboratorial markers of improvement, with increasing numbers of macrophages and concentrations of IL-10 in the joint fluid, which remained lower in joints treated with placebo. BMNC provide means to recover macrophage-associated effects required to control joint inflammation and can benefit thousands of patients with OA. Together, the results of these studies show that macrophages are biased promoters of joint health, leading to inflammation when their anti-inflammatory mechanisms are overwhelmed. Replenishing inflamed joints with healthy macrophages maximizes their anti-inflammatory effects, favoring the recovery of a healthy articular environment.
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Raynor, Jana L. "Regulatory T Cell Homeostasis in Aging." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416570329.
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Tichi, Mary A. "Phototropic redox homeostasis in Rhodobacter Capsulatus /." The Ohio State University, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=osu1488205318510068.
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Hoyes, Thomas W. "Risk homeostasis theory in simulated environments." Thesis, Aston University, 1992. http://publications.aston.ac.uk/10858/.
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This thesis has two aims. First, it sets out to develop an alternative methodology for the investigation of risk homeostasis theory (RHT). It is argued that the current methodologies of the pseudo-experimental design and post hoc analysis of road-traffic accident data both have their limitations, and that the newer 'game' type simulation exercises are also, but for different reasons, incapable of testing RHT predictions. The alternative methodology described here is based on the simulation of physical risk with intrinsic reward rather than a 'points pay-off'. The second aim of the thesis is to examine a number of predictions made by RHT through the use of this alternative methodology. Since the pseudo-experimental design and post hoc analysis of road-traffic data are both ill-suited to the investigation of that part of RHT which deals with the role of utility in determining risk-taking behaviour in response to a change in environmental risk, and since the concept of utility is critical to RHT, the methodology reported here is applied to the specific investigation of utility. Attention too is given to the question of which behavioural pathways carry the homeostasis effect, and whether those pathways are 'local' to the nature of the change in environmental risk. It is suggested that investigating RHT through this new methodology holds a number of advantages and should be developed further in an attempt to answer the RHT question. It is suggested too that the methodology allows RHT to be seen in a psychological context, rather than the statistical context that has so far characterised its investigation. The experimental findings reported here are in support of hypotheses derived from RHT and would therefore seem to argue for the importance of the individual and collective target level of risk, as opposed to the level of environmental risk, as the major determinant of accident loss.
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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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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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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.
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Cadart, Clotilde. "Cell size homeostasis in animal cells." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS103/document.
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Le mécanisme d’homéostasie de taille chez les cellules animales est très peu compris actuellement. Cette question est pourtant d’un intérêt majeur car le maintien de l’homéostasie de taille dans une population de cellules prolifératives doit se faire par une coordination entre la croissance et la division. Chez la levure S. pombe, il a ainsi été montré que la taille est une information cruciale pour déclencher l’entrée en mitose (Fantes, 1977). Chez plusieurs bactéries et les cellules filles de la levure S. cerevisiae au contraire, de récentes études ont au contraire montré que l’homéostasie de taille était le résultat d’une addition constante de volume, indépendamment de la taille initiale des cellules (Campos et al., 2014; Soifer et al., 2016; Taheri-Araghi et al., 2015). Ce mécanisme est appelé « adder » et génère une régression des tailles à la moyenne, génération après génération. Ces résultats ont été possibles grâce au développement de techniques permettant la mesure dynamique du volume à l’échelle de la cellule unique et sur plusieurs générations. Une telle mesure est cependant très difficile chez les cellules de mammifère dont le volume fluctue constamment et qui cyclent sur des temps plus longs (environ 20 heures). Pour cette raison, la plupart des approches proposées sont indirectes (Kafri et al., 2013; Sung et al., 2013; Tzur et al., 2009) ou reposent sur une mesure de la masse plutôt que du volume (Mir et al. 2014; Son et al., 2012). Ensemble, ces études ont montré que les cellules de mammifère croissaient de manière exponentielle. Elles ont aussi remis en cause le modèle traditionnel qui proposait que l’homéostasie de taille reposait sur l’adaptation de la durée du cycle et mis en avant un rôle de la régulation de la vitesse de croissance. Cependant, aucun modèle n’a réellement été proposé ou démontré. La nature et l’existence même d’un mécanisme maintenant l’homéostasie de taille des cellules de mammifère est en fait discutée (Lloyd, 2013).Pour caractériser l’homéostasie de taille des cellules de mammifères, nous avons développé une technique permettant pour la première fois la mesure du volume de ces cellules sur des cycles complets (Cadart et al., 2017; Zlotek-Zlotkiewicz et al. 2015). Nous montrons que plusieurs types cellulaires (HT29, MDCK et HeLa) se comportent d’une manière similaire à celle d’un « adder ». Pour tester davantage cette observation, nous induisons artificiellement des divisions asymétriques en confinant les cellules dans des micro-canaux. Nous observons que les asymétries de tailles sont réduites mais pas complètement corrigées au cours du cycle suivant, à la manière d’un « adder ». Pour comprendre comment la croissance et la progression dans le cycle sont coordonnées et génère cet « adder », nous combinons notre méthode de mesure de volume avec un suivi de la progression dans les différentes phases du cycle. Nous montrons que la durée de la phase G1 est inversement corrélée au volume initial des cellules. Cependant, cette corrélation semble contrainte par une durée minimale de G1 mise en évidence lors de l’étude de cellules artificiellement poussées à atteindre de grandes tailles. Néanmoins, même dans cette condition où la modulation de la durée du cycle est perdue, l’observation du « adder » est maintenue. Ceci suggère un rôle complémentaire de la régulation de la vitesse de croissance des cellules. Nous proposons donc une méthode pour estimer théoriquement la contribution relative de l’adaptation de la vitesse de croissance et de la durée du cycle dans le contrôle de la taille. Nous utilisons cette méthode pour proposer un cadre général où comparer le processus homéostatique des bactéries et de nos cellules. En conclusion, notre travail apporte pour la première fois la démonstration que les cellules de mammifères maintiennent l’homéostasie grâce à un mécanisme similaire au « adder ». Ce mécanisme semble impliquer à la fois une modulation de la durée du cycle et du taux de croissanceThe way proliferating mammalian cells maintain a constant size through generations is still unknown. This question is however central because size homeostasis is thought to occur through the coordination of growth and cell cycle progression. In the yeast S. pombe for example, the trigger for cell division is the reach of a target size (Fantes, 1977). This mechanism is referred to as ‘sizer’. The homeostatic behavior of bacteria and daughter cells of the yeast S. cerevisiae on the contrary was recently characterized as an ‘adder’ where all cells grow by the same absolute amount of volume at each cell cycle. This leads to a passive regression towards the mean generation after generation (Campos et al., 2014; Soifer et al., 2016; Taheri-Araghi et al., 2015). These findings were made possible by the development of new technologies enabling direct and dynamic measurement of volume over full cell cycle trajectories. Such measurement is extremely challenging in mammalian cells whose shape constantly fluctuate over time and cycle over 20 hours long periods. Studies therefore privileged indirect approaches (Kafri et al., 2013; Sung et al., 2013; Tzur et al., 2009) or indirect measurement of cell mass rather than cell volume (Mir et al. 2014; Son et al., 2012). These studies showed that cells overall grew exponentially and challenged the classical view that cell cycle duration was adapted to size and instead proposed a role for growth rate regulation. To date however, no clear model was reached. In fact, the nature and even the existence of the size homeostasis behavior of mammalian cells is still debated (Lloyd, 2013).In order to characterize the homeostatic process of mammalian cells, we developed a technique that enable measuring, for the first time, single cell volume over full cell cycle trajectories (Cadart et al., 2017; Zlotek-Zlotkiewicz et al. 2015). We found that several cell types, HT29, HeLa and MDCK cells behaved in an adder-like manner. To further test the existence of homeostasis, we artificially induced asymmetrical divisions through confinement in micro-channels. We observed that asymmetries of sizes were reduced within the following cell cycle through an ‘adder’-like behavior. To then understand how growth and cell cycle progression were coordinated in way that generates the ‘adder’, we combined our volume measurement method with cell cycle tracking. We showed that G1 phase duration is negatively correlated with initial size. This adaptation is however limited by a minimum duration of G1, unraveled by the study of artificially-induced very large cells. Nevertheless, the adder behavior is maintained even in the absence of time modulation, thus suggesting a complementary growth regulatory mechanism. Finally, we propose a method to estimate theoretically the relative contribution of growth and timing modulation in the overall size control and use this framework to compare our results with that of bacteria. Overall, our work provides the first evidence that proliferating mammalian cells behave in an adder-like manner and suggests that both growth and cell cycle duration are involved in size control