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Lascelles, Carol Veronica. "Regulation of human ketogenesis : role of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627391.
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White, Nicholas Edward. "The role of Relaxin-3 and 3-Iodothyronamine in the regulation of energy homeostasis." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.479156.
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Palacios, Arnold Raul. "Role of GSK-3 alpha beta in B cell proliferation during germinal center information." Thesis, Boston University, 2013. https://hdl.handle.net/2144/21229.
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Thesis (M.A.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Glycogen Synthase Kinase-3αß is an enzyme that is involved in cell cycle regulation by promoting the degradation of cyclin D1 and cycling D3 in cells. Special emphasis is placed in its regulatory role in B cells, as there it is evidence that suggests that this protein is inhibited during germinal center formation, where B cells undergo proliferation, somatic hypermutation and class switch recombination. By inducing DNA recombination via the Cre/lLxP recombination system and utilizing tamoxifen as a Cre activity inducer, B cells were culture in 40LB cells to form induced germinal center in vitro. Flow cytometry analysis suggests that in the absence of GSK-3 αß B cells proliferate extensively in germinal centers and being the process of class switch recombination. Although the results of this study are in accord with current theory, more experiments and research need to be made to validate the conclusions set forth in this study.
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Lindskog, Maria. "DARPP-32 in the striatum : multiple regulation and physiological role /." Stockholm : Karolinska Univ. Press, 2001. http://diss.kib.ki.se/2001/91-7349-011-3/.
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Cooke, Frank T. "The regulation of phosphoinositide 3-OH kinase and its role in 3-phosphorylated inositol lipid metabolism in U937 cells." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263009.
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Lindgren, Niklas. "Regulation and physiological role of tyrosine hydroxylase phosphorylation in the striatum /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-463-1/.
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Frantz, Aubrey Leigh. "THE ROLE OF INTESTINAL EPITHELIAL CELLS AND THE REGULATION OF THE POLYMERIC IMMUNOGLOBULIN RECEPTOR IN HOMEOSTASIS AND INFLAMMATION." UKnowledge, 2012. http://uknowledge.uky.edu/microbio_etds/3.
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The mammalian intestine harbors an estimated 100 trillion microorganisms, which normally maintain a mutually beneficial relationship with the host. The intestinal epithelium consists of a single layer of intestinal epithelial cells (IECs) that provides a physical barrier as well as innate immune defense, preventing this vast community of microbes from entering host tissues. Secretory immunoglobulin A (SIgA) acts as the first line of antigen-specific immunity at the interface between the gut microbiota and the intestinal epithelium. Polymeric IgA secreted by plasma cells in the intestinal lamina propria is transported across IECs by the polymeric immunoglobulin receptor (pIgR). Defects in epithelial barrier and immune functions can lead to infections with opportunistic and pathogenic microbes and contribute to the etiology of inflammatory bowel disease (IBD). Here we investigate the ability of IEC biomarkers to define the mechanism and severity of intestinal inflammation, as well as provide insight into the function of IEC in regulating intestinal homeostasis and inflammation. Importantly, down-regulation of pIgR expression was a common feature in human IBD and mouse models of experimental colitis. One molecule of pIgR is consumed for every molecule of SIgA transported, thus high expression of pIgR is required to maintain sufficient supply of SIgA. Accordingly, we investigate the mechanisms by which IECs regulate pIgR expression in response to colonic bacteria. Cross-talk between the microbiota and IECs is mediated by pattern recognition receptors, including Toll-like receptors (TLR), leading to expression of gene products that enhance epithelial barrier function and innate immunity. The cytoplasmic adaptor protein MyD88 transduces signals from TLRs that recognize bacterial products. We show that pIgR induction by colonic bacteria is dependent on TLR4-MyD88 activation of NF-κB signaling. We examined the role of epithelial-specific MyD88 signaling in antibacterial immunity and epithelial expression of key gene products that participate in innate immunity in the gut by generating mice with an IEC-targeted deletion of the Myd88 gene (MyD88ΔIEC). MyD88ΔIEC mice display immunological and antimicrobial defects resulting in increased susceptibility to experimental colitis. We conclude that cross-talk between bacteria and IECs via MyD88-dependent signaling is crucial for maintenance of gut homeostasis.
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Deshpande, Anagha. "Role of 3’UTR Elements in the Regulation of the Cyclin D1 Proto-oncogene." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-103346.
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Opel, Daniela. "Role of phosphoinositide-3-kinase (PI3K)/Akt signaling in apoptosis regulation of neuroectodermal tumors." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-63916.
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Seccareccia, Erica. "Studies on the regulation of the matrix metalloproteinase-3 and its role in metastasis." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=117079.
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Cancer metastasis is the major cause of death from malignant disease. The biological factors that dictate the secondary site(s) of a primary tumor remain largely unknown, yet their understanding would greatly facilitate the management of malignancy. Matrix metalloproteinases (MMPs) are responsible for the degradation of the extracellular matrix and regulate the tumor microenvironment. The expression of specific MMPs in primary tumors has been correlated with the extent and site of metastatic disease and may therefore potentially be predictive of the preferred site of metastasis. In this study, a subline of the Lewis lung carcinoma (M27 cells) was used to study the role of MMP-3 in lung metastasis as well as elucidate the signaling pathways that regulate its expression in a cellular context where expression of the insulin like growth factor-I receptor (IGF-IR) is altered. Previous work demonstrated that following ectopic expression of the IGF-IR in M27 cells (M27R cells) MMP-3 expression was downregulated and this coincided with a loss of lung metastasis. Here it is shown that the ectopic expression of the IGF-IR downregulates the expression of IκB kinase ε (IKKε). Reconstitution of IKKε expression (M27R/IKKε cells), partly restored MMP-3 expression in M27R cells and furthermore, it sensitized MMP-3 expression levels to induction by phorbol 12-myristate 13-acetate (PMA). This induction was, in turn, dependent on protein kinase C (PKC) α and the transcription factor p65. Finally, reconstituting MMP-3 expression in M27R cells enabled their metastasis to the lungs. Collectively, our results implicate IKKε as a regulator of MMP-3 expression and implicate MMP-3 in lung metastasis.Les métastases sont responsables de la majorité des décès causé par les cancers. Les facteurs biologiques qui déterminent le site des tumeurs secondaires ne sont pas bien compris, mais pourraient aider au traitement de cette maladie. Les métalloproteinases de la matrice (MMPs) sont responsables de la dégradation de la matrice extracellulaire et en plus, elles sont des régulateurs du microenvironnement. Une corrélation a déjà été montrée entre le profil des MMPs chez les tumeurs primaires et les sites où vont s'implanter les métastases. Dans cette étude, on a examiné le rôle de la MMP-3 dans la capacité à former des métastases d'une lignée cellulaire dérivée de carcinome des poumons de Lewis (M27). De plus, on a examiné les signaux de transduction responsables de la régulation de la MMP-3 dans un environnement où l'expression du récepteur au facteur de croissance à l'insuline (IGF-I) était altérée. Précédemment, on a demontré que l'expression de l'IGF-IR (M27R) régulait négativement l'expression de la MMP-3 et ceci a abrogé les métastases aux poumons. Ici, on démontre que l'expression d'IGF-IR régule négativement l'expression de la kinase IκB ε (IKKε). La surexpression d'IKKε dans les cellules M27R (M27R/IKKε), reconstitue partiellement l'expression de MMP-3 dans les cellules M27R. En addition, l'expression de MMP-3 dans ces cellules peuvent être stimulées suite à l'ajout de phorbol 12-myristate 13-acetate (PMA). Cette stimulation dépendait sur la kinase des protéines C (PKC) α et sur le facteur de transcription, p65. Finalement, la reconstitution de l'expression de la MMP-3, dans les cellules M27R, a permis à celles-ci de former des métastases dans les poumons. L'ensemble de nos résultats démontre qu'IKKε participe dans la régulation de l'expression de la MMP-3 et de plus que la MMP-3 serait impliquée dans la formation des métastases aux niveaux des poumons.
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Shahbazian, David. "Eukaryotic initiation factor 4B (eIF4B) : regulation by signaling pathways and its role in translation." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115902.
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Due to the high energetic expenditure for the cell, the protein biosynthesis in eukaryotes is an extensively controlled process predominantly regulated at the ribosomal biogenesis and translation initiation steps. The ribosomal biogenesis defines the global translational aptitude of the cell. It is a mainly nucleolar process which is regulated at multiple steps (e.g. transcription, rRNA processing and modification, ribosomal protein translation etc). However, the most extensively regulated and the rate limiting step of translation is the initiation. Multiple eukaryotic translation initiation factors (eIFs) function to facilitate this priming step of translation. The initial recognition of the mRNA molecule happens through the 5' cap structure found in all mRNAs of nuclear origin. This event is mediated through the recruitment of heterotrimeric complex eIF4F consisting of cap-binding protein eIF4E, scaffolding protein eIF4G and the RNA helicase eIF4A unwinding secondary structures found in 5'UTR of mRNA and thus thought to facilitate the scanning process. The helicase activity of elF4F complex or of eIF4A alone is further potentiated by eIF4B in vitro. The latter protein is at the focus of present thesis.Signal transduction regulates multiple cellular processes including mitogenesis, differentiation, apoptosis, chemotaxis etc. Signaling pathways also regulate ribosomal biogenesis to coordinate mitogenic cues, nutrient and energy availability with the translational capacity of the cells. Mounting evidence links PI3K-Akt-mTOR and Ras-MAPK cascades to the translational control. In this thesis, I show that PI3K/mTOR and MAP kinase cascades converge to phosphorylate eIF4B on Ser422. This phosphorylation results in an increased interaction with eIF3, an essential factor bridging between eIF4F and the small ribosomal subunit. Physiological significance of eIF4B phosphorylation on Ser422 has been demonstrated by the stimulatory effect of eIF4B Ser422Asp phosphomimetic mutant on cap-dependent translation. Taken together, this represents a new paradigm of translational control mechanism regulated by signaling crosstalk. The function of eIF4B in vitro is well characterized but its in vivoeffects are disputed in literature. To address this I established HeLa cell line stably expressing shRNA targeting eIF4B. eIF4B silencing inhibits proliferation rates and anchorage-independent growth. Expression of luciferase reporter gene containing 5' terminal oligopyrimidine tract (TOP) is selectively repressed in eIF4B-silenced cells and can be rescued by exogenous eIF4B regardless of Ser422 phosphorylation status. Moreover, the de novo synthesis rates of endogenous ribosomal proteins in serum starved cultures recapitulate the luciferase reporter assay data. Utilizing polysomal analysis, I was able to show more significant inhibition of translation initiation in serum starved eIF4B-silenced cells. Our attempt to discover novel eIF4B-interacting proteins by Mass Spectrometry approach led to the identification of nucleolar RNA helicase DDX21. Confocal microscopy has shown partial co-localization of tagged eIF4B and DDX21 in nucleolar periphery. Pulse chase experiments metabolically labeling rRNA show an attenuated 28S rRNA production and concomitant accumulation of 36S intermediates in eIF4B-silenced cells. Since ribosomal biogenesis is highly coordinated process and requires strict stoichiometry maintenance of ribosomal components the observed inhibition of rRNA processing could be consequential to the decreased ribosomal protein expression. However, given the fact that eIF4B is associated with the nucleolar pre-ribosomal particle complexes its direct effect on rRNA processing cannot be ruled out. Regulation of ribosomal biogenesis by translation initiation factor may represent an important control mechanism allowing cells to co-ordinate these two processes.
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Dai, Yanzhenzi. "The role and regulation of insulin-like peptide 3 (INSL3) in the female reproductive system." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/48136/.
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The peptide hormone Insulin-like peptide 3 (INSL3) shows important roles in the reproductive system. In the male, the testicular Leydig cell peptide INSL3 is involved in fetal testis descent and sperm maturation during the adulthood. In females of reproductive age INSL3 is mainly produced by the ovarian follicular theca interna cells. The current project aims to explore the detailed actions of INSL3 in the female reproductive system. Firstly, the secretion pattern of the INSL3 peptide in the serum of young women and women attending an infertility clinic was assessed. The serum levels of INSL3 peptide appeared to increase during the follicular phase, decrease during the luteal phase, and drop to a nadir at menses. The secretion pattern corresponded to the growth of antral follicles within a follicular wave. Pathological conditions leading to an alteration of the antral follicle count, such as polycystic ovarian syndrome and low ovarian reserve, were accompanied by an increase or decrease in the serum INSL3 level, respectively. The bovine system was adopted and validated as a model for the human in regard to the follicular production of INSL3, as the secretion pattern for INSL3 in bovine serum through estrous cycles was similar to that in women. Primary bovine theca interna cells were then used to study the regulation of the INSL3 gene and its secreted peptide products. At both peptide and mRNA levels INSL3 production could be up-regulated by progesterone receptor signalling. Together with the analysis of the transcriptional activity of the bovine INSL3 gene promoter, it could be shown that estradiol (E2) – estrogen receptor alpha (ERα) signalling stimulated and E2-ERß signalling decreased INSL3 production. Dihydrotestosterone (DHT) acting through the androgen receptor (AR) and androstenedione (A4) probably acting through ERα and/or ERß both contribute to regulation of INSL3 production. Moreover, luteinising hormone (LH) from the anterior pituitary also influenced the INSL3 production, with the downstream pathway from low level LH stimulation probably involving synergy between cAMP-PKA and ER signalling. The potential target of INSL3 was also identified in the female bovine reproductive system; full-length transcripts for the INSL3 receptor, RXFP2, were detectable in ovarian theca interna cells, in oocytes, as well as in the myometrium. Meanwhile, full-length transcripts for the closely related receptor, RXFP1, were detected in theca interna cells, endometrium and in myometrium, although the gene encoding the ligand for this receptor, relaxin, has been deleted during ruminant evolution. When transfecting DNA expression plasmids encoding the individual RXFP2 and RXFP1 receptors into HEK293T cells, the expressed bovine RXFP2 could be activated by bovine and human INSL3 (EC50 = 0.7 & 0.6nM) and porcine and human relaxin (EC50 = 10.5 & 27.3nM). The expressed bovine RXFP1 could be activated by porcine and human relaxin (EC50 = 10.8 & 48.7nM) and human relaxin 3 (EC50 = 97.9nM). Functional analysis showed that bovine myometrial cells were able to respond to both exogenous relaxin and INSL3, whereas theca interna cells could respond to INSL3 only. Together, however, these experiments support the view that endogenous RXFP2 and RXFP1 are both fully functional in the bovine even though the primary ligand for the latter is missing. The results showed that for the female INSL3 is mainly produced by the theca interna cells of antral follicles, and is thus a potential biomarker of ovarian functionality. The expression of INSL3 can be regulated by sex steroid hormones in an auto/paracrine manner, as well as by LH in an endocrine manner. In conclusion, the INSL3-RXFP2 system acts in follicles and probably also the uterus to enable and orchestrate female reproductive physiology.
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Mühlbauer, Kristina. "Berücksichtigung der ausländischen Eingriffsnormen im Art. 9 Rom I-VO." Doctoral thesis, Humboldt-Universität zu Berlin, 2021. http://dx.doi.org/10.18452/22884.
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Die Arbeit setzt sich mit dem neuen europäischen Anknüpfungskonzept für ausländisches Eingriffsrecht in der Rom I-VO auseinander. Im Fokus der Untersuchung steht die politisch motivierte und restriktiv ausgefallene Regelung des Art. 9 Abs. 3 Rom I-VO. Zudem widmet sich ein Teil der Untersuchung allgemein der hinter dem Eingriffsrecht – insbesondere dem Konzept des ausländischen Eingriffsrechts im IPR – stehenden Dogmatik, die aus einer dogmatisch-historischen Perspektive beleuchtet wird.
Schwerpunktmäßig gilt es der Frage nachzugehen, welche Überlegungen hinter der neuen Kollisionsnorm stehen und ob die Sonderanknüpfung des Art. 9 Abs. 3 Rom I-VO einen dogmatisch geeigneten, mit der Zielsetzung der Rom I-VO vereinbaren rechtlichen Rahmen für die einheitliche kollisionsrechtliche Berufung der berücksichtigungswürdigen ausländischen Eingriffsnormen in den Mitgliedstaaten schafft.The thesis examines the European concept of the newly defined connecting factor for foreign overriding mandatory rules in the Rome I Regulation. The central attention of the study is the analysis of the politically motivated and restrictive regulation of Art. 9 (3) of the Rome I Regulation. In addition, the first part of the study is dedicated to the examination of the general approach behind the application of foreign overriding mandatory rules in private international law from a dogmatic-historical perspective. The main focus of the thesis, however, is on the research of the considerations behind the new conflict of laws rule. The author specifically questions whether the new connecting factor defined in the Art. 9 (3) Rome I Regulation provides a worthy and sufficient legal framework for the application of foreign overriding mandatory rules.
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Ye, Liang. "The Role of Sorting Nexin 10 (Snx10) in Control of Osteoclast Function and Regulation of Bone Homeostasis." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:14226085.
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Sorting Nexin 10 (Snx10) is expressed in osteoclasts and is required for osteoclastic bone resorption in vitro. To study the role of Snx10 in osteoclastic bone resorption and bone homeostasis in vivo, we investigated the expression of Snx10 and created mouse models in which Snx10 was deficient in osteoclasts or globally. Osteoclast-specific Snx10-deficient mice exhibited severe osteopetrosis with abnormal bone micro-architectural parameters in vivo, consistent with the failure of osteoclasts to normally resorb bone. Osteoclast-derived Snx10 deficiency didn’t completely inhibit osteoclast formation, however, the capacity to resorb bone was significantly reduced. Intracellular vesicular transport, ruffled border formation and extracellular acidification were found to be severely impaired due to osteoclast-derived Snx10 deficiency. We also discovered that Snx10 was highly expressed in gastric zymogenic cells, with mutations leading to gastric dysfunction and low calcium solubilization. Global Snx10-deficiency in mice results in a combined phenotype: osteopetrosis (due to osteoclast defect) and rickets (due to gastric dysfunction and low calcium availability, resulting in impaired bone mineralization and hypocalcemia). Osteopetrorickets, the paradoxical association of insufficient mineralization in the context of a positive total body calcium balance, was thought to occur due to failure of the osteoclasts to maintain normal calcium homeostasis. However, osteoclast-specific Snx10 deficiency had no effect on calcium balance, and therefore led to severe osteopetrosis without rickets. Moreover, supplementation with calcium gluconate prevented the rachitic phenotype and rescued the early death in global Snx10-deficient mice, suggesting that this may be a life-saving component of the clinical approach to Snx10-dependent human ARO with hypocalcaemia and/or no improvement after HSCT. We concluded that tissue-specific effects of Snx10 mutation need to be considered in clinical approaches to this disease entity. Reliance solely on hematopoietic stem cell transplantation can leave hypocalcemia uncorrected with sometimes-fatal consequences.
To our knowledge, this is the first study to explore the role of Snx10 using the genetically modified mouse model. This study not only uncovered the cellular mechanism by which Snx10 regulates osteoclastic bone resorption but also established an essential role for Snx10 in bone homeostasis and underscore the importance of Snx10-dependent gastric function in calcium homeostasis.
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Paling, Nicholas Robert Dixon. "The role of the tyrosine phosphatase SHP-1 in the regulation of interleukin-3 signal transduction." Thesis, University of Bath, 2002. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.760792.
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Wright, Lyndsey Claire. "Analysis of the physiological role of histone deacetylase 3 (HDAC3) and its regulation by inositol phosphates." Thesis, University of Leicester, 2017. http://hdl.handle.net/2381/40315.
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Histone deacetylase 3 (HDAC3) acts as the catalytic core of the SMRT/NCoR co-repressor complex which regulates chromatin structure and gene expression. It was recently shown that HDAC3 binds, and is regulated in vitro, by the binding of inositol phosphates (IP). We used transcriptional reporter assays to interrogate whether HDAC3-mediated repression in vivo is dependent of IP. Manipulation of intracellular IP levels through chemical inhibition of enzymes involved in IP metabolism or RNAi-mediated protein knockdown were inconclusive. However, mutation of key IP binding residues in both SMRT and HDAC3 directly impacts the repressive ability of the co-repressor complex, presumably through an impaired ability to bind IP and failure to fully activate the enzyme. Germline deletion of HDAC3 in the mouse results in early embryonic lethality (around e9.5) suggesting it plays an essential role in embryogenesis. To further investigate the role of HDAC3 in embryonic development, I have generated a conditional knockout embryonic stem cell line in which HDAC3 can be specifically inactivated. Loss of the protein occurs within 3 days suggesting a half-life of approximately 24 hours and correlates with concomitant decrease in co-repressor complex components, indicating HDAC3 contributes to co-repressor integrity. Unlike deletion of HDAC1 and -2, loss of HDAC3 does not cause a significant reduction in total deacetylase activity with only minor changes in the acetylation levels of histones. However, the proliferative capacity of knockout cells is inhibited with a delay in cell doubling time. Upon differentiation, we find that embryoid bodies (EBs) lacking HDAC3 are significantly smaller and morphologically different compared to controls. Microarray analysis over a 7-day time course of EB differentiation reveals that endodermal cell markers are over-expressed at both early and late stages of development, suggesting that HDAC3 plays an important role in regulating gene expression during embryonic development.
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Buys, Christa. "The role of the ESX-3 gene cluster and iron on mycobacterial viability / C. Buys." Thesis, North-West University, 2013. http://hdl.handle.net/10394/9498.
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According to the World Health Organization (WHO), M. tuberculosis, the causative agent of TB, accounts for approximately 1.7 million deaths annually. Further contributing causes to the worldwide TB incidence, is the widespread unavailability and ineffectiveness of TB vaccines, time consuming diagnostic methods and unsuccessful treatment approaches. Research for better characterising mycobacteria in general, or other Mycobacterium species, may help us to better understand M. tuberculosis and TB disease mechanisms, which will in turn lower the future TB disease prevalence, as this may lead to the development of better treatments, diagnostics and vaccines. Mycobacteria use various secretion pathways, including the ESX- or type VII secretion (T7S) system, to ensure transport across the complex cell wall. The genome of M. tuberculosis has five copies of a gene cluster known as the ESX gene cluster region, which is associated with virulence and viability of mycobacteria. The ESX-3 gene cluster is thought to be essential for growth of M. tuberculosis and proposed to be involved in iron / zinc homeostasis. Mycobacteria synthesise siderophores, which are proposed to be involved in the uptake of iron over their cell wall. M. tuberculosis are known to produce two types of siderophores, namely: carboxymycobactins and mycobactins. Loots and colleagues, however illustrated, that ESX-3 knockouts, show signs of iron overload, despite the absence of the mycobactins induced by knocking out the ESX-3 gene cluster. It was hypothesised, that this overload occurs due to an increase in exochelin synthesis, another iron uptake protein not associated with ESX-3, overcompensating for the perceived iron depletion in the knockout organism. A Metabolomics research approach was subsequently used in this study, to generate new information in order to better characterise the role of iron on the metabolism of these organisms, and additionally confirm the role of ESX-3 in iron uptake.
In this study, we firstly determined the most optimal extraction conditions for this metabolomics investigation. Two extraction methods were subsequently investigated and compared, considering their repeatability and their respective capacities to extract those compounds which best differentiate the M. smegmatis ESX-3 knockouts and wild-type parent strains. Considering the results generated, the total metabolome method was chosen for further analyses, for the following reasons: 1) it is simpler, 2) faster, 3) showed better repeatability, 4) extracts those compounds best differentiating the compared groups and 5) has been previously described for metabolomics analyses characterising ESX-3 gene functionality, hence potentially allowing us to compare results to that previously generated and published data.
Subsequently, we used the chosen extraction method, followed by GCxGC-TOFMS analysis of the separately cultured M. smegmatis wild-type sample extracts, cultured in normal, low and high iron conditions, to determine the influence of varying iron concentrations on the metabolome of this organism, by metabolomics comparisons of these groups. Following this, an identical research approach was used to compare the metabolome of a M. smegmatis ESX-3 knock-out strain, to that of a M. smegmatis wild type parent strain, both cultured in normal / standardised iron concentrations. Considering the results generated when comparing the metabolome of a M. smegmatis ESX-3 knock-out strain to that of a M. smegmatis wild type parent strain, the altered metabolome of the M. smegmatis ESX-3 knockouts correlated well to that of the M. smegmatis wild type cultured in elevated iron growth conditions. This suggests ESX-3 is involved in iron uptake, and that knocking out the ESX-3 gene cluster of M. smegmatis does in fact result in a metabolome profile suggesting iron overload, as was proposed by Loots et al (2012), most probably due the exochelins overcompensating for the absence of mycobactins, in M. smegmatis ESX-3 knockouts.MSc (Biochemistry) North-West University, Potchefstroom Campus 2013.
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Myer, David. "Role of the Mammalian Polo-Like Kinase 3(Plk3) in Cell Cycle Regulation and DNA Damage Checkpoints." University of Cincinnati / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1141395911.
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Moore, Carlene Drucilla. "The role of centaurin alpha-1 in the regulation of neuronal differentiation." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2008d/moore.pdf.
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Astarita, Jillian Leigh. "The role of the podoplanin-CLEC-2 pathway in stromal cell regulation of dendritic cell motility and lymph node architecture." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13065022.
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In addition to leukocytes, secondary lymphoid organs are populated by non-hematopoietic stromal cells. This diverse group of cells supports lymphocyte migration and homing, facilitates antigen delivery, and promotes T cell survival. However, there is relatively little known about the specific molecules governing the roles that these cells play in regulating dendritic cell (DC) motility and lymph node architecture. Here, we examine the interaction between two molecules, CLEC-2 and podoplanin (PDPN), that are critical for DC migration and maintaining structural integrity of lymph nodes. Together, these studies identify novel functions of lymph node stromal cells and a unique function for PDPN in the immune system.
In response detecting an potentially harmful antigen, DCs in peripheral tissues mature and travel to downstream lymph nodes by following chemokine gradients secreted by lymphatic endothelial cells (LECs) and fibroblastic reticular cells (FRCs) present in the lymph node paracortex. We discovered that, in addition to chemokines, DC migration requires CLEC-2 on DCs, as engagement of CLEC-2 with PDPN, which is expressed by LECs and FRCs, incites DC motility and is required for DC entry into the lymphatics, efficient arrival in the lymph node, and migration along the FRC network within the lymph node.
Next, we examined the effect of this interaction with respect to the stromal cell. Through a combination approaches, we discovered that PDPN is a master regulator of contractility in FRCs. The fact that FRCs are contractile cells was previously reported, but our study is the first to identify a function for this contractility: upon blockade of PDPN-mediated contractility, lymph nodes became enlarged, the FRC network became more sparse, and there were increased numbers of lymphocytes in the lymph node. Importantly, during an immune response, these changes resulted in more proliferation of antigen-specific T cells and impaired contraction of the lymph node upon resolution of inflammation. Finally, we found that CLEC-2 binding PDPN recapitulated the effect of PDPN deletion. Thus, during an immune response, CLEC-2+ DCs would use PDPN to efficiently migrate to the lymph node and simultaneously cause FRCs to relax and prepare the lymph node for expansion.
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Cattie, Douglas J. (Douglas John). "Identifying a role for nonessential elF3 subunits eif-3.K and eif-3.L in the regulation of endoplasmic reticulum homeostasis and longevity in Caenorhabditis elegans." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/108885.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, February 2017.Cataloged from PDF version of thesis. "October 5, 2016."
Includes bibliographical references.
The eukaryotic initiation factor 3 (elF3) is a protein complex composed of 13 subunits in mammals, and is an essential scaffold of the molecular interactions required for the formation of the 43S preinitiation complex (PIC). While these 13 subunits are broadly conserved within the eukaryotic phylogeny, both biochemical and evolutionary evidence suggests that translation initiation can proceed with a vastly reduced number of elF3 subunits, with as few as six subunits in the yeast species Saccharomyces cerevisiae. In this study, I report that homologs of eIF3 subunits elF3k and elF3I are nonessential in Caenorhabditis elegans, and that in their absence there is no defect in bulk protein translation. Surprisingly, mutants lacking these subunits exhibit both enhanced endoplasmic reticulum homeostasis and increased longevity, which implicates a potential regulatory role for these subunits in the maintenance of organismal physiology.
by Douglas J. Cattie.
Ph. D.
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Ho, Lien Ha. "Labile zinc and its role in regulation of pro-caspase-3 and NF-kB activation in mast cells." Title page, contents and summary only, 2003. http://web4.library.adelaide.edu.au/theses/09PH/09phh6783.pdf.
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"June 2003" Bibliography: leaves 197-260. The aim of this thesis was to further investigate the relationship between Zinquin-detectable intracellular pools of labile Zn and caspase activation since caspases have now been shown to be important effector enzymes in apoptosis. This was largely studied in mast cells and some findings confirmed in neuronal cells, a cell type with quite different function and cell physiology. As a summation of the findings reported in this thesis, a general model is proposed describing possible interactions between Zn, pro-caspases and NF-kB.
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Franca-Koh, Jonathan. "An investigation of the role of the Frat oncogene in Wnt signalling and glycogen synthase kinase-3 regulation." Thesis, Institute of Cancer Research (University Of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409938.
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Hamad, Ahmed El-Sayed Mansour Abd El-Mohsen. "Guanosine 3': 5'-cyclic monophosphate regulation in cultured human airway smooth muscle cells and its role in proliferation." Thesis, University of Nottingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298959.
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Diab, Thoria. "Role of the 3' untranslated region in the post-transcriptionnal regulation of KLF6 gene expression in hepatocellular carcinoma." Toulouse 3, 2013. http://www.theses.fr/2013TOU30202.
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Krüppel-like factor 6 (KLF6) a été identifié comme gène suppresseur de tumeur impliqué dans le contrôle de la croissance, de la différentiation cellulaire et dans la mort par apoptose. L'expression de KLF6 est altérée au cours de la carcinogenèse hépatique, et cette protéine joue un rôle prépondérant dans le contrôle de la prolifération des cellules tumorales hépatiques. Nous avons étudié le rôle de la région 3'UTR de l'ARNm de KLF6 dans la régulation de son expression. Nous avons établi que la demi-vie de l'ARNm de KLF6 est fortement diminuée dans les lignées cellules dérivées du foie. La région 3'UTR inhibe fortement l'expression et l'activité de gènes rapporteurs en corrélation avec la région entre les nucléotides 1835 et 2615Krüppel-like factor 6 (KLF6) is a tumor suppressor gene that is involved in the regulation of cell cycle, cellular proliferation, differentiation and cell death by apoptosis. KLF6 expression is altered in liver carcinogenesis. However, little is known on the mechanisms governing KLF6 expression in HCC. In the current study, we asked whether 3’UTR may be responsible for down regulation of KLF6 mRNA in HCC. Our results demonstrated that KLF6 mRNA half-life was greatly decreased in cells derived from HCC. Moreover, 3'UTR strongly inhibited the activity and expression of the reporter gene. In addition, we found that most of KLF6 3’UTR destabilisation activity resides between nucleotides 1835 and 2615
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Caberlotto, Laura. "Distribution and regulation of neuropeptide Y and its receptors in the human and rat brain : role in affective disorders /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-3310-3.
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Breland, Benjamin Tyson. "The Role of 3-Dimensional State Goal Orientation in the Process of Goal Establishment and Task Performance." Diss., Virginia Tech, 2004. http://hdl.handle.net/10919/27691.
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The present research expanded upon the work of Breland and Donovan (in press) and examined the role of three-dimensional state goal orientation in an integrative model of goal setting and task performance. In addition, mental focus (Lee, Sheldon, & Turban, 2003) was also incorporated into the model. Results indicated that each of the three-dimensions of state goal orientation uniquely affected oneâ s level of self-efficacy. More specifically, state learning goal orientation and state performance-approach goal orientation both enhanced an individualâ s level of self-efficacy, while state performance-avoidance goal orientation reduced their level of self-efficacy. In turn state goal orientation indirectly impacted mental focus, goals, and performance through its influence on self-efficacy. Implications of these findings as well as suggestions for future research on the personality construct of state goal orientation are discussed.Ph. D.
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Pierce, Stephanie Lynn. "The role and regulation of small conductance CA2+ activated K+ channel subtype 3 in myometrial contraction and placental development." Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/1059.
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SK3 channels contribute to membrane repolarization and hyperpolarization that leads to both relaxation of smooth muscle and vascular branching. These two distinct properties are intensified in the SK3T/T mice possibly influencing pregnancy by dampening uterine contractions and causing dysfunctional placental development. SK3T/T mice have delayed or hindered parturition, suggesting a role for SK3 channels in labor contractions (Chapter 2 & 3). Based on these findings, we hypothesized that SK3 channel expression must be reduced late in normal pregnancy to enable the uterus to produce the forceful contractions required for parturition. The mechanism(s) downregulating this channel in the uterus during pregnancy is unknown. The SK3 gene promoter region contains two Specificity Protein (Sp) binding sites; Sp1, a transcription factor that enhances transcription of genes in response to estrogen, and Sp3, a factor that competes for the same binding motif as Sp1 to reduce gene expression (Chapter 4). SK3 channels may also be involved in the vascular remodeling that occurs during pregnancy. The SK3 channel is present in vascular endothelial cells and overexpression of this channel leads to abnormal vessel branching and an increase in vessel diameter. During pregnancy, the vascular system must adapt to accommodate dramatic increases in blood volume necessary to sustain the developing fetus. Overexpression of SK3 channels could produce abnormalities in the placental vascular network, similar to the abnormal vessel branching and vasodilatation found in the mesenteric circulation, thus leading to poor fetal outcome (Chapter 5). The aim of this research was to determine the function of the SK3 channel in pregnancy by focusing on its role in myometrial contractility in addition to identifying its role in remodeling the maternal vasculature and its impact on placental blood flow and fetal demise.
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Brown, Louise E. "Role of human Desmoglein 3 in the regulation of cell morphology and motility via AP-1 and PKC dependent Ezrin activation." Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/26964.
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Desmoglein 3 (Dsg3) belongs to the desmoglein subfamily and functions as an adhesion molecule in desmosomes. Two pools of Dsg3 have been identified, detergent soluble and insoluble proteins. Recent studies show that DSG3 is upregulated in squamous cell carcinoma (SCC). However, its biological function in cancer remains poorly understood. The aim of this study was to investigate the extra-junctional functions of Dsg3, in particular its roles in signalling that regulates cell morphology and locomotion in cancer cells. This study adopted a unique cancer cell model with Dsg3 gain-of-function and has discovered two novel regulatory signal pathways that may play a crucial role in the control of cell invasion and metastasis in Dsg3 associated cancers. Firstly, Dsg3 regulates the phosphorylation of Ezrin at Thr567 in a PKCdependent manner that is crucial for its activation and regulation of actin based membrane projections and accelerated cell locomotion in SCC. Secondly, Dsg3 modulates the transcriptional activity of cJun:AP1 that is responsible for regulating a cohort of genes to confer an invasive phenotype. It is likely that these two pathways are closely linked in that the Dsg3-mediated activation of cJun:AP1 elicits PKCdependent Ezrin activation that in turn enable it to form a complex with Dsg3 at the plasma membrane to promote membrane projection and cell locomotion. Several lines of evidence support these conclusions: Dsg3 forms a complex with Ezrin at the plasma membrane and induces phosphorylation of Ezrin resulting in augmented membrane protrusions and cell migration. Dsg3 silencing inhibits junction formation concomitant with collapse of membrane protrusion. Furthermore, Dsg3 regulates the activity of cJun:AP1. Collectively, these findings provide new insight regarding Dsg3 in cancer, suggesting it acts as a key regulator of cell invasion and metastasis in SCC. Therefore, targeting Dsg3 could be a potential new strategy in the control of cancer progression and metastasis.
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Klement, Göran. "Role of potassium channels in regulating neuronal activity /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-315-3/.
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Linebarger, Carla R. Lyerly. "Characterization of the arabidopsis G-box binding Factor 3 and its role in the regulation of the alcohol dehydrogenase gene." [Gainesville, Fla.] : University of Florida, 2001. http://etd.fcla.edu/etd/uf/2001/ank7118/dissertation2.PDF.
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Thesis (Ph. D.)--University of Florida, 2001.Title from first page of PDF file. Document formatted into pages; contains vii, 135 p.; also contains graphics. Vita. Includes bibliographical references (p. 125-134).
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Jatho-Gröger, Jasmin [Verfasser]. "Deciphering the role of the deubiquitinating enzyme Ataxin-3 in transcriptional regulation and the cellular response to stress / Jasmin Jatho-Gröger." Bonn : Universitäts- und Landesbibliothek Bonn, 2018. http://d-nb.info/1202848389/34.
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Clements, Craig. "The novel role of epidermal growth factor (EGF) in the regulation of ion channels in the calu-3 submucosal cell line." Thesis, University of East Anglia, 2012. https://ueaeprints.uea.ac.uk/52152/.
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Cystic fibrosis transmembrane conductance regulator (CFTR) is a cell membrane bound chloride ion channel regulated by cyclic AMP-dependent phosphorylation and levels of intracellular ATP. Mutations in this channel, such as the common deletion of phenylalanine at residue 508 (CFTRΔF508), leads to a decrease in chloride transport seen in the disease condition cystic fibrosis (CF). The mutant CFTR is not processed in the normal way and consequently not delivered to the cell membrane. Currently, the effect of growth factors such as epidermal growth factor (EGF) on ion transport in the airway has not been previously researched and is consequently unknown. Therefore the aim of this thesis is to determine (i) if EGF has an effect on ion transport in the submucosal cell line Calu-3, (ii) what the mechanisms are behind this, and (iii) if the effect of EGF was due to induction of gelatinase activity or a transactivation process. Functional investigations looking at ion transport were carried out by using short circuit current. This technique was complemented by traditional molecular biology techniques such as RT-PCR, Western blotting, flow cytometry and gelatin zymography. The level of EGF, a potent inducer of gelatinases, is known to be elevated in the lungs during tissue repair in CF. Calu-3 cells preincubated with EGF on the basolateral membrane increased initial current at one hour via a EGFR-PI3K-PKC-δ-KCNN4/KCNQ1 signalling pathway. Similarly, preincubation with EGF also decreased forskolin induced short circuit current compared to untreated monolayers at 1 to 3 hours, with a recovery at 24 hours. The decreases were found to be dependent on the activation of KCNQ1 since chromanol 293B, a specific inhibitor for KCNQ1, restored the short circuit current back to untreated levels. Stimulation of the β2 adrenergic receptors with salbutamol were not reduced using metalloproteinase inhibitor, GM-6001 and EGFR inhibitor, AG1478. This suggested that stimulation of β2 adrenergic receptors does not lead to transactivation of EGFR via activation of sheddases and the release of EGF ligand. β3 adrenergic receptors are present in Calu-3, but produce negligible currents when stimulated. It was concluded that EGF induced potassium channel activation led to a change in chloride driving force. This activation of potassium channels has previously been linked to wound repair in the airway during disease. The implications of this study suggest that manipulation of the EGF signalling pathway and / or potassium channel activity in the lungs may be beneficial in disease conditions such as CF for increasing chloride transport.
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Bouvet, Philippe. "Regulation de la stabilite des arns chez escherichia coli et dans les embryons de xenope=role des regions 5 et 3 non traduites." Rennes 1, 1992. http://www.theses.fr/1992REN10126.
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Chez e. Coli, la demi-vie moyenne des arns est de 2-3 min. Cependant, quelques arns sont tres stables; par exemple l'arn qui code pour ompa a une demi-vie de 17 min. Lorsque les cellules ont un temps de generation court. Cette stabilite est due a la presence d'une structure en epingle a l'extremite 5 de l'arn. Une simple structure en epingle a cheveux est capable de stabiliser un arn instable comme bla lorsqu'elle est placee a son extremite 5. En utilisant l'arn1 de pbr322 dont la degradation est initiee par l'endoribonuclease e, comme systeme d'etude, nous avons pu demontrer que l'activite de la rnasee peut controler par l'extremite 5 de l'arn. Ce resultat peut expliquer comment l'extremite 5 d'un arn controle la degradation des arns chez e. Coli, en depit de l'absence d'exonuclease 5-3. Le developpement precoce du xenope est caracterise par une accumulation d'arn maternel au cours de l'ovogenese. Les familles d'arns eg et c11 sont desadenylees et adenylees respectivement apres la fecondation. Les arns de ces deux familles sont stables jusque la transition mid-blastuleenne (mbt). Apres, ils sont degrades avec des cinetiques differentes. Seul le blocage de la traduction d'un autre arn maternel est necessaire pour provoquer la degradation des arns maternels eg. De plus, ce fragment de 497 nt n'est pas capable de provoquer une desadenylation lorsqu'il est place en 3 de l'arn cat. Alors que, un fragment de 410 nt, qui est en aval du fragment de 497 nt est capable de conferer le comportement d'adenylation de l'arn maternel. La desadenylation et la degradation sont donc deux mecanismes qui necessitent des informations en cis differentes
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Persson, Madelen. "The role of transcriptional repression in Shh signalling and patterning of the ventral neural tube /." Stockholm : Karolinska institutet, 2004. http://diss.kib.ki.se/2004/91-7349-834-3/.
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Rahal, Pamela. "Role of GSK3β - MLK3 - p38γ MAPK Signalling in Satellite Cell Proliferation Regulation." Thesis, Lyon, École normale supérieure, 2015. http://www.theses.fr/2015ENSL1000.
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MLK3 est une ser/thr MAP3K qui active la voie de signalisation des MAPKs dans différents types cellulaires. GSK3β interagit et active MLK3 en la phosphorylant sur le residue ser 792. Cependant, le rôle de MLK3 ainsi que l’interaction entre MLK3 et GSK3β n’ont pas été précédemment étudiés dans le muscle squelettique. La croissance post-natale du muscle et la régénération musculaire chez l’adulte sont dépendantes de l’accrétion de myonoyaux, un processus médié par les cellules satellites qui prolifèrent, se différencient puis fusionnent aux fibres préexistantes. Durant ma thèse, j’ai démontré que GSK3β agit en amont de MLK3 pour induire la prolifération des cellules satellites, et cela par l’activation de la voie de signalisation MLK3-p38γ MAPK. In vivo, les muscles de souris déficientes injectés par la CTX montrent une diminution du nombre de cellules satellites prolifératrices Pax7+/ki67+, ainsi qu’une accélération du processus de régénération. En conclusion, mes résultats évoquent un nouveau rôle de MLK3 dans le muscle squelettique pouvant servir pour vaincre les dystrophies musculaireMLK3 is a Ser/Thr MAP3K, which activates MAPKs signalling pathways in different cell types. The Ser/Thr kinase GSK3-β directly phosphorylate Ser 792 residue and activate MLK3. Since neither the role of MLK3, nor GSK3-β -MLK3 interaction have been previously investigated in muscle, the aim of my thesis was to elucidate their contribution in the regulation of muscle mass and physiology.Skeletal muscle post-natal growth and adult regeneration relies on satellite cell-mediated myonuclear accretion, during which, activated satellite cells, proliferate, differentiate and fuse with preexisting myotubes.I have demonstrated that in skeletal muscle, GSK3-β acts upstream of MLK3 to induce satellite cells proliferation through the induction of MLK3-p38γ MAPK signalling. Similarly, in vivo CTX-induced TA damage in MLK3 KO mice resulted in decreased number of proliferating Pax7+/ki67+ satellite cells, with a rapid muscle regeneration ability.These data suggest provide a yet unknown role of MLK3 in skeletal muscle tissue that could help in curing age-related muscle dystrophies
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Poser, Steven Walter. "Coincident signaling of cAMP with phosphatidylinositol 3' kinase and mitogen activated protein kinase signal transduction cascades : a role in regulating gene exression during development and synaptic plasticity /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/10633.
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Rapone, Roberta. "Essential cytoplasmic role(s) of the histone lysine methyltransferase Setdb1 in post-transcriptional regulation of gene expression." Thesis, Université de Paris (2019-....), 2019. https://theses.md.univ-paris-diderot.fr/RAPONE_Roberta_va.pdf.
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Setdb1 est une «histone» lysine méthyltransférase (KMT) appartenant à la famille SUV39, l’une des principales machineries épigénétiques de répression des gènes. Setdb1 établit notamment la mono-, la di- et la tri- méthylation sur la lysine 9 de l'histone H3 (H3K9).Setdb1 est essentiel pour la survie, la pluripotence et l'auto-renouvellement des cellules souches embryonnaires de souris (mESCs); son knock-out est mortel au stade de la péri-implantation à 3,5 dpc chez la souris. Setdb1 est également nécessaire pour la différenciation de nombreux types de cellules progénitrices : spermatogenèse, neurogenèse, différenciation des chondrocytes et différenciation des muscles squelettiques. De plus, Setdb1 a été associé à plusieurs maladies: il est amplifié dans le mélanome et le cancer du poumon et il est dérégulé dans les cancers du foie, de la prostate, colorectal et du sein, dans la maladie de Huntington et la schizophrénie. Remarquablement, au-delà des histones, Setdb1 méthyle nombreux substrats non-histones, y compris UBF, p53, Akt, Tat et Ing2.Bien que Setdb1 ait toujours été associé à son rôle nucléaire, il s'avère que Setdb1 est la seule KMT de la famille SUV39 à avoir également une localisation cytoplasmique, dans plusieurs types de cellules, y compris les mESCs, les fibroblastes embryonnaires de souris (MEFs) et les cellules HeLa. Cependant, la fonction de Setdb1 dans le cytoplasme reste totalement inconnue. Pour étudier le rôle cytoplasmique de Setdb1, nous avons utilisé des cellules souches embryonnaires de souris (mESCs), dans lesquelles Setdb1 est essentiel. Nos résultats montrent que Setdb1 cytoplasmique est crucial pour la survie des mESCs: en effet, le nombre de cellules apoptotiques augmente après la perte de Setdb1 cytoplasmique. Nous avons constaté que le Setdb1 cytoplasmique affecte la synthèse de protéines dans les mESCs. Nous montrons en outre que le Setdb1 cytoplasmique interagit avec la protéine Trim71 spécifique de mESC (également appelée Lin41) et avec le facteur de traduction d'initiation eIF3c dans les mESC. Enfin, nous avons démontré que Setdb1 et Trim71 co-régulent ensemble la stabilité et la traduction des mARNs. Nos données actuelles mettent au jour la fonction cytoplasmique essentielle d'une lysine méthyltransférase appelée Setdb1, au début considérée comme étant spécifique uniquement des histones et apportent de nouvelles informations sur la régulation post-transcriptionnelle de l'expression génique médiée par un régulateur épigénétique fondamentalSetdb1 is a “histone” lysine methyltransferase (KMT) belonging to the SUV39 family that methylates lysine 9 of histone H3 (H3K9), one of the major epigenetic machineries mainly involved in gene repression. Notably, Setdb1 establishes mono-, di- and tri-methylation of H3K9. Setdb1, or Eset in mice, is essential for the survival, the pluripotency and the self-renewal of mouse embryonic stem cells (mESCs); Eset knockout is lethal at the peri-implantation stage at 3.5 dpc in mice. Setdb1 is also required for the differentiation of many progenitor cell types: spermatogenesis, neurogenesis, chondrocyte differentiation and skeletal muscle differentiation. Moreover, Setdb1 has been associated with several diseases: it is amplified in melanoma and lung cancer and it is dysregulated in liver, prostate, colorectal and breast cancers, Huntington disease and schizophrenia.Remarkably, beyond histones, Setdb1 methylates many non-histone substrates, such as UBF, p53, AKT, Tat and ING2 proteins. Although Setdb1 has been always associated with its nuclear role, it turns out that Setdb1 is the only H3K9 KMT to have also a cytoplasmic localization, in several cell types, including mESCs, mouse embryonic fibroblasts (MEFs) and HeLa cells. However, the function of Setdb1 in the cytoplasm remains totally unknown. To investigate Setdb1 cytoplasmic role, we have used mouse embryonic stem cells (mESCs), in which Setdb1 is essential. Our results show that cytoplasmic Setdb1 is crucial for the survival of mESCs: indeed, the number of apoptotic cells increases after the loss of cytoplasmic Setdb1. We found that cytoplasmic Setdb1 affects newly protein synthesis in mESCs. We further show that cytoplasmic Setdb1 interacts with mESCs-specific protein Trim71 (also called Lin41) and with the initiation translation factor eIF3c in mESCs. Finally, we reported that Setdb1 and Trim71 together co-regulate mRNA stability and translation. Our current data unravel the essential cytoplasmic function of Setdb1, for long time considered exclusively an “histone” lysine methyltransferase, and provide new insights into the post-transcriptional regulation of gene expression mediated by a fundamental epigenetic regulator
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Witschel, Christian. "Krise, Rezession, Stagnation ? : der Westen des römischen Reiches im 3. Jahrhundert n. Chr. /." Frankfurt am Main : M. Clauss, 1999. http://catalogue.bnf.fr/ark:/12148/cb40926152d.
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Pohl, Hartel. "Die römische Politik und die Piraterie im östlichen Mittelmeer vom 3. bis zum 1. Jh. v. Chr. /." Berlin : W. de Gruyter, 1993. http://catalogue.bnf.fr/ark:/12148/cb35610709b.
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Kühnen, Angela. "Die Imitatio Alexandri in der römischen Politik : 1. Jh. v. Chr. - 3. Jh. n. Chr. /." Münster : Rhema, 2008. http://catalogue.bnf.fr/ark:/12148/cb41293881k.
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Schäfer, Christoph. "Spitzenmanagement in Republik und Kaiserzeit : die Prokuratoren von Privatpersonen im Imperium Romanum vom 2. Jh. v.Chr. bis zum 3. Jh. n.Chr. /." St. Katharinen : Scripta Mercaturae, 1998. http://catalogue.bnf.fr/ark:/12148/cb37050170t.
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Krieckhaus, Andreas. "Senatorische Familien und ihre "patriae" : (1./2. Jahrhundert n. Chr.) /." Hamburg : Kovač, 2006. http://www.verlagdrkovac.de/3-8300-1836-3.htm.
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Walker, Thomas. "The role of BCL-3 feedback loops in regulating NF-κB signalling." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-bcl3-feedback-loops-in-regulating-nfkappab-signalling(ed8214ca-e5f5-4edd-9754-59692ffbda9d).html.
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NF-κB signalling induces transcriptional upregulation of a wide array of genes in response to inflammatory signalling caused by, for example, TNFα cytokine. In addition to inducing the expression of factors which mediate an intracellular response, such stimuli also cause the expression of further signalling factors, including TNFα itself, to propagate and refine an initial stimulus. However, while such positive feedback signalling can be seen to be beneficial in amplifying potentially small initial stimuli, excessive production can cause hyper-inflammatory responses; an occurrence linked to several autoimmune diseases. Therefore, correct regulation – in regards to both too little and too much TNFα signal production – is essential for a balanced immune response. In this thesis I have focussed on the effects of the IκB protein family member BCL-3 on TNFΑ transcription: demonstrating NF-κB dependent induction of both TNFΑ and BCL3 genes and a subsequent negative role for BCL-3 in regulating TNFΑ transcription in the human fibrosarcoma HT1080 cell line – forming an Incoherent Feed Forward Loop (I-FFL) motif. Notably, I have shown a differential rate of induction of TNFΑ (rapid) and BCL3 (delayed) transcript levels; demonstrating that while the TNFΑ gene has a pre-stimulus RNA polymerase II bound and poised for a rapid response, the BCL3 promoter requires histone modification and chromatin remodelling for binding of NF-κB and RNA polymerase II. Extensive characterisation of the temporal sequence of events constituting BCL3 promoter remodelling, mRNA plus protein levels and NF-κB nuclear localisation through live cell microscopy allowed the construction of a mathematical model which has been tested to ensure it can accurately recreate biological behaviour. This model has been utilised to show that the delayed production of inhibitory BCL-3 produces distinct TNFΑ transcript dynamics: (i.) initially allowing a high magnitude response but coupled to later strong repression of TNFΑ expression and (ii.) producing a non-monotonic response to pulsed stimuli. This behaviour cannot be quantitatively recreated with models in which BCL3 transcription is induced simultaneously with TNFΑ and proposed physiological benefits are outlined. Based on this work, time delays in I-FFLs are proposed as a novel mechanism to produce varied output dynamics. Future research tools have also been developed in this work - including generation of an expression vector to visualise BCL-3 protein in live cells (utilising a BAC recombinant engineering approach) - plus further research questions and predictions regarding TNFα signalling have been raised by additional modelling work.
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Denans, Diana. "Les exemptions de l'article 81, paragraphe 3 du traité de Rome." Nice, 2001. http://www.theses.fr/2001NICE0012.
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Les exemptions de l'article 81, paragraphe 3 constituent un sujet digne du plus grand intérêt. Ces dernières n'ont pas suscité une grande attention depuis l'adoption du règlement nʿ17/62. De grands auteurs ont apprécié les différentes formes d'accords susceptibles de bénéficier d'exemptions. Cependant, la matière dans son ensemble ne suscitait pas l'attention qui lui est aujourd'hui portée. Les exemptions n'étaient jusqu'alors qu'une section minime du droit de la concurrence présentant moins d'attrait que l'interdiction des ententes (articles 81, paragraphe 1). Cependant, le droit des exemptions fait l'objet d'une réforme substantielle concernant sa mise en œuvre. En effet, les restrictions verticales et les accords horizontaux disposent désormais d'une nouvelle législation laissant apparaître une plus grande intervention des autorités nationales. La compétence exclusive de la Commission a été partiellement remise en cause. Cette modification est très importante puisqu'elle revient sur un principe largement affirmé par la Commission pendant de longues années. Le plus intéressant reste à venir. Une proposition de modification des textes concernant l'application des articles 81 et 82 est sur le point d'être adoptée. Il est prévu notamment que les juridictions nationales puissent désormais prononcer des exemptions. L'objectif final est de mettre en place un système d'exception légale en lieu et place du contrôle a priori.
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Milton, Alasdair Hugh. "The regulation of E2F by 14-3-3 proteins." Thesis, University of Glasgow, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439225.
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Jaffery, Hussain. "The role of NF-κB regulator Bcl-3 in the skeleton." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/9146/.
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Bone and joint erosion and fragility fractures are associated with osteoarthritis and osteoporosis, and represent a major unmet clinical problem. In health, the balance between chondrocytes, osteoblasts and osteoclasts is a dynamic process under tight regulation. In disease, regulation is uncontrolled resulting in overt skeletal dysfunction and bone loss. NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) is a master regulator of cellular function and is an essential element in the development and homeostasis of the skeletal system. As such it is a critical controller of chondrocyte, osteoblast and osteoclast differentiation and function. Bcl-3 (B-cell lymphoma 3-encoded protein) is an atypical IκB protein and via its selective interaction with p50 and p52 homodimers of NF-κB is a regulator of cellular function. As a regulator of NF-κB, the role of Bcl-3 was hypothesised to be critical in affecting skeletal health. With the aim of defining the role of Bcl-3 in the skeleton, mice deficient in Bcl-3 (Bcl-3-/-) were compared to wild-type (Wt) mice. Ex vivo phenotypic analysis of Bcl-3-/- mice and in vitro cellular differentiation assays of Bcl-3-/- chondrocytes, osteoblasts and osteoclasts were performed. In neonatal Bcl-3-/- mice, multiple phenotypes were discovered, including dwarfism and increased mineral density. Morphometric analysis of developing and adult mice showed that 20-week Bcl-3-/- mice had a profoundly divergent phenotype from Wt. Male 20-week Bcl-3-/- mice had increased bone density in the trabecular and cortical regions and increased biomechanical strength, compared to Wt, implicating increased bone formation. Female 20-week Bcl-3-/- mice did not differ from Wt in the trabecular region; however, they possessed decreased bone area in cortical bone. Bone turnover rates of 20-week Bcl-3-/- males were lower than in Wt, implicating an accelerated rate of bone resorption, following peak bone density. While no differences in chondrocyte differentiation were found, Bcl-3-/- osteoblasts were found to have accelerated osteogenesis. Complementarily, simulated overexpression with Bcl-3 mimetic peptide restricted osteoblast differentiation. An expression repertoire of marker genes and miRNAs reflected increased RUNX2 (Runt-related transcription factor 2) activity in early-differentiating Bcl-3-/- osteoblasts. Compared to Wt, Bcl-3-/- osteoblasts had an altered whole-transcriptomic profile in early osteogenesis, with multiple NF-κB-driven osteogenic gene clusters identified. Osteoblasts increased expression of RANKL (RANK ligand) and decreased OPG (osteoprotegerin) expression, involved in signalling cross-talk with osteoclasts. Bcl-3-/- osteoclasts had increased intrinsic osteoclastogenesis and resorption, while treatment with Bcl-3 peptide restricted osteoclast differentiation and function. The ex vivo phenotypic results were complementary to in vitro assays, showing increased bone turnover. The lack of Bcl-3 in both, osteoblasts and osteoclasts, increased their differentiation and activities. Thus, Bcl-3 functions as an inhibitor of NF-κB-driven early osteogenesis and osteoclastogenesis. These findings help identify Bcl-3 as a novel target for the treatment of diseases involving skeletal pathology.
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Stambolic, Vuk. "Regulation of glycogen synthase kinase-3." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0003/NQ27730.pdf.
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Stambolic, Vuk. "Regulation of glycogen synthase kinase-3." Ottawa : National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.nlc-bnc.ca/obj/s4/f2/dsk2/tape16/PQDD%5F0003/NQ27730.pdf.
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Easom, R. A. "The regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme a reductase." Thesis, University of Glasgow, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.380463.
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