Dissertations / Theses on the topic 'Medical regulation'
To see the other types of publications on this topic, follow the link: Medical regulation.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Medical regulation.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Meechan, Kenneth Alastair. "The regulation of British medical practice." Thesis, University of Glasgow, 2002. http://theses.gla.ac.uk/1587/.
Full textAbstract:
This thesis begins by considering that modern medicine as a profession has tremendous scope for both good and ill, and as an enterprise consumes a vast amount of the national wealth. Against this background, the thesis considers how and why medicine is regulated, and what the effects of this regulation are. The study aims to assess the regulation of the medical profession against the interests of the state, the profession, and the consumers of health care, to see whether the regulatory mechanisms adopted adequately safeguard the interests of all parties concerned with the practice of medicine. The methodology chapter spells out the analytical techniques which the bulk of the thesis utilises and delimits the scope of the research to cover only bodies having a legal genesis and which are universal in application. A series of "core evaluation criteria" are identified against which the four regulatory mechanisms are assessed. Chapters 3 to 6 contain the bulk of the actual research into the four main areas of regulatory endeavour which the study considers; each is analysed in turn in terms of the purpose, mechanism and effect of the regulatory machinery being considered and then assessed against the core evaluation criteria. Finally, the conclusions chapter draws together the different threads which the sector-specific analyses have identified as being points of concern, and the system as a whole is evaluated to see whether the interests of the relevant stakeholders are adequately safeguarded, to identify any regulatory gaps which exist in the present system, and to point out the direction which anyone seeking to improve the system should consider
2
Rofougaran, Reza. "DNA precursor biosynthesis-allosteric regulation and medical applications." Doctoral thesis, Umeå : Univ, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1678.
Full text
3
Stojan, Jure. "Regulation of complementary medical practitioners circa 1920-2000." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491060.
Full textAbstract:
$$aThis study describes the changing economic and social role of complementary medicine in twentieth-century Britain; and explains the intensity of its regulation. As a work of economic history, it is guided by three questions: (1) How did industry groups compete among themselves? (2) How did this competition influence the level of regulation which particular groups aspired to? (3) How did these preferences affect the regulatory outcomes?
4
Sandvick, Clinton Matthew. "Enforcing Medical Regulation in the United States 1875 to 1915." Thesis, Connect to title online (Scholars' Bank), 2008. http://hdl.handle.net/1794/7783.
Full text
5
Norlin, Nadine. "Disrupted epigenetic regulation causessyndromes of overgrowth- A systematic review." Thesis, Örebro universitet, Institutionen för medicinska vetenskaper, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-66817.
Full text
6
Li, Cathy Shije 1974. "Function and regulation of histone deacetylase 4." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=98750.
Full textAbstract:
Histone acetyltransferases and histone deacetylases (HDACs) maintain dynamic acetylation and deacetylation of histories and other proteins in vivo, and are actively involved in the control of gene transcription and other nuclear processes. One mechanism by which functions of these enzymes are regulated operates through differential intracellular compartmentalization. HDAC4, -5, -7 and -9, the four members of class IIa, shuttle between the nucleus and the cytoplasm in a manner dependent on specific phosphorylation stimulated by several known kinases, and these deacetylases possess intrinsic nuclear import and export signals for dynamic nucleocytoplasmic trafficking. The ability to change their intracellular localization implies that class IIa HDACs have some potential functions in different subcellular compartments. To gain additional insights into this, I first focused on studying the function and regulation of HDAC4. As a result, I identified protein kinase D3 as a novel kinase for HDAC4 and found that this kinase physically interacts with HDAC4 and stimulates its nuclear export. Then I tried to purify protein complexes of RFXANK and ANKRA2, two homologous ankyrin-repeat proteins that are known to associate with HDCA4, using the tandem affinity purification (TAP) strategy. The results that I have obtained reveal a novel mechanism for regulating the nuclear export of HDAC4 and suggest that its cytoplasmic localization may also be indicative of potential cytoplasmic functions rather than just for simple sequestration from its nuclear targets.
7
Kazemitabar, Maedeh Assadat. "A multifaceted approach to examining emotion regulation in medical settings." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=123282.
Full textAbstract:
The ability to detect and regulate emotions is an important aspect of emotional intelligence (Mayer, Salovey & Caruso, 2000) that can benefit individuals in their personal well-being and improve social interactions. This thesis examined emotional regulation (ER) in medical students as they participated in an international technology rich learning environment designed to help them learn how best to communicate undesired news to patients (Lajoie et al., 2011). Gross' (1998) process model of ER served as the theoretical model that guided the analysis of regulatory strategies, in a case study (Yin, 2011) of four medical students. An exploratory mixed methods approach was utilised to determine how multichannels of emotion representations (vocal characteristics, motor expressions, attention tendencies) indicate instances of (un)conscious ER. The design of the coding scheme was driven from emotion regulation and coping literature, and methodological techniques were extended from the field of affective computing. Pre-post observations were analyzed to identify patterns of change in using regulatory strategies. Analyses revealed four major findings as evidences of ER: (a) dissociation between emotion channels did occur; (b) changes in emotion expression occurred; (c) unexpected emotions sometimes occurred; and, (d) multiple emotion channels were used to demonstrate emotion regulatory responses. Results also showed that voice modulation (specifically a decrease in voice amplitude) was an important strategy used to extrinsically regulate the patients when giving bad news as it demonstrated an empathetic response by the physician. These findings can provide insights for educators in designing programs to enhance and evaluate ER strategies of students in order to regulate personal emotions as well as the emotional needs of others in stressful situations. This work also makes important contributions to the design of technology-rich environments to embed dynamic ER detection mechanisms that enable systems to gain a more holistic view of the participants, and to adapt instructions based on their affective needs.La capacité de détecter et de contrôler ses émotions est un aspect important de l'intelligence émotionnelle (Mayer, Salovey & Caruso, 2000) qui peut bénéficier le bien-être des individus et améliorer leurs interactions sociales. Cette thèse a examiné la régulation émotionnelle (RE) chez les étudiants en médecine lors de la participation à un environnement d'apprentissage international riche en technologie visant à les aider à apprendre la meilleure façon de communiquer de mauvaises nouvelles aux patients (Lajoie et al., 2011). Le modèle du processus de RE de Gross (1998) a servi en tant que modèle théorique afin d'analyser les stratégies réglementaires au moyen de l'étude de quatre cas (Yin, 2011). Une approche exploratoire utilisant des méthodes mixtes a été utilisée pour déterminer comment les représentations multidimensionnelles d'émotion se (les caractéristiques vocales, l'incarnation, les tendances d'attention) manifestent chez les cas (in)conscients de RE. Les observations avant et après ont été analysées pour identifier les tendances de changement dans l'utilisation de stratégies de RE. La conception d'un schéma de codage a été tirée de la littérature sur la RE et de l'adaptation, et les techniques méthodologiques ont été étendues du domaine de l'informatique affective. Les analyses ont révélé quatre résultats principaux: (a) la dissociation entre les canaux d'émotion est produite, (b) des changements dans l'émotion ont eu lieu; (c) des émotions inattendues ont eu parfois lieu; et (d) des canaux variées d'émotion ont été utilisés pour démontrer les réponses de RE. Les résultats ont également montré que la modulation de la voix (en particulier la diminution de l'amplitude vocale lors de la sympathie) était une stratégie importante utilisée pour réguler les patients de façon extrinsèque en donnant de mauvaises nouvelles. Ces résultats peuvent guider la conception de programmes visant à améliorer et évaluer les stratégies de RE chez les étudiants afin de réguler les émotions personnelles ainsi que les besoins émotionnels des patients dans les situations stressantes. Ce travail fait également d'importantes contributions à la conception d'environnements riches en technologie visant à intégrer des mécanismes dynamiques de détection de RE qui permettent aux systèmes d'avoir une vue plus globale aux besoins des participants et d'adapter les instructions en fonction de leurs besoins affectifs .
8
Higson, Gordon R. "The regulation of medical devices for public health and safety." Thesis, University of Aberdeen, 2000. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU123856.
Full textAbstract:
Medical products of all kinds have to comply with regulations to satisfy the demand for public health and safety. Medicinal products (drugs) were the first medical products to be regulated in most countries and regulations for medical devices - generally derived from drug regulations - followed. This thesis reviews the development of safety regulation for medical devices from its relatively recent introduction in the 1960s to the present day. The emphasis is on the situation in countries of the European Community but events in these countries are placed in a world-wide context. Landmark events in this process - notably the US Medical Device Amendments of 1976 and the EC Medical Device Directive of 1994 - are analysed and compared. An examination of current regulations in the three major markets for medical devices: Europe, Japan and USA, leads to the identification of quality systems, product standards, effectiveness/performance and post-market controls as key factors in modern regulatory approaches. The emergence of these key factors illustrates the movement towards an engineering, rather than a pharmaceutical, approach to regulation and their place in current and emerging regulations world-wide is discussed. Manufacturers have long pressed for uniformity in national regulations to reduce the time and cost involved in obtaining market approval and their case has been largely accepted by the regulatory authorities. Harmonization in Europe has been achieved as part of the Single Market programme. The last decade has seen remarkable progress towards the further harmonizing of national and regional regulations. The outstanding difficulties, notably controversy over the need for "effectiveness" determination and relative roles of clinical and laboratory testing, are discussed and solutions proposed. The prospects for achieving global harmonization are examined and a possible future global system is described.
9
Fiandalo, Michael Vincent. "PROTEASOME REGULATION OF CASPASE-8: SIGNIFICANCE IN CANCER." UKnowledge, 2012. http://uknowledge.uky.edu/biochem_etds/3.
Full textAbstract:
Anti-tumor therapeutic strategies based on combinations of chemotherapeutic agents with a death inducing ligand such as TNF-α Related Apoptosis Inducing Ligand (TRAIL), are directed towards selective and effective cancer cell apoptosis and enhanced therapeutic response. We previously demonstrated that proteasome inhibition sensitizes TRAIL resistant prostate cancer cells to TRAIL-mediated apoptosis via stabilization of the active p18 subunit of initiator caspase-8. The present study investigated the functional link between caspase-8 and the proteasome, by analyzing the impact of caspase-8 ubiquitination and proteasomal degradation on the outcomes of the extrinsic apoptosis pathway in cancer cells. Caspase-8 ubiquitination status was assessed by polyubiquitin immunoprecipitation (IP) and fluorescent microscopy. Apoptosis induction in response to death receptor stimuli or proteasome inhibitor was evaluated using the Annexin V/Propidium iodide staining (PI). To determine the consequences of proteasome inhibition on caspase-8 stability, trafficking, and activity following death receptor activation, we used the TRAIL-resistant human prostate cancer LNCaP cells, and the caspase-8 deficient Neuroblastoma 7 (NB7) cells, as cellular models for reconstituting the non-cleavable mutant forms of caspase-8. Our findings demonstrate that the non-cleavable forms of caspase-8 are capable of inducing apoptosis comparably to wild-type caspase-8 upon treatment with proteasome inhibitor and GST-TRAIL. Furthermore, caspase-8 processing into its active subunits preceded caspase-8 polyubiquitination, implicating caspase-8 processing as a potential regulatory mechanism, rather than a requirement for caspase-8 activation in apoptosis induction. The mechanistic control of caspase-8 by ubiquitination in cancer cells may have significant significance in bypassing mechanisms of therapeutic resistance in human tumors and optimization of anti-cancer treatment strategies in human tumors and optimization of anti-cancer treatment strategies.
10
Aziz, Miriam. "The regulation of medical research involving human subjects : a comparative study." Thesis, University of Edinburgh, 1998. http://hdl.handle.net/1842/21357.
Full textAbstract:
This thesis is concerned with finding an appropriate legal response to medical research involving human subjects. The first section contains Chapter One which consists of an historical account of forms of unethical research and asks two questions; first, how could such things have been done in the name of research? Secondly, how could society allow them to take place? How were the safeguards overridden? What was the environment or climate within which unethical research was allowed to flourish? The history of the regulation of medical research testifies to the social climate within which research has been conducted. This includes the evolution of the doctor as scientist which led to the objectification of human beings as research subjects, the presence of ideologies in times of war, for instance, which took hold of national consciousness and conscience thereby shifting the goal posts of justification, and the development and maturing of medical careers. Chapters Two, Three and Four comprise section two and deal with the intellectualisation of questions of research at the abstract level of the medico/legal debate. In particular, Chapter Two outlines the terminology of medical research, the monopoly over which has been secured by scientists through scientific reasoning. Chapter Three considers legal reasoning in relation to the concept of informed consent and considers the implications of an approach based on medical negligence, in itself a retrospective 'after the fact' approach; it will be argued that medical research should be viewed prospectively within a framework which is more informed by public than private law. Chapter Four considers the role of moral reasoning in relation to its main protagonists, 'bioethicists', who retain a firm grip on the ethical implications of medical research. An alternative rationale will be suggested which is both universally applicable and normatively neutral. It will be further argued that moral reasoning should involve the public sphere and should not be confined to the private realms consisting of the educated intuitions of researchers and other members of the professional elite. The third section consists of Chapters Five and Six and are concerned with the applied level of the medical research debate as seen in research ethics committees in both the United Kingdom and Germany.
11
Liu, Qian. "Structural insights into apoptotic regulation by BCL-2 family." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=95022.
Full textAbstract:
Myeloid cell leukemia 1 (MCL-1), an anti-apoptotic BCL-2 member, is active in the preservation of mitochondrial integrity during apoptosis. By collective data from nuclear magnetic resonance (NMR) spectroscopy and titration calorimetry, we revealed the selectivity of MCL-1 in binding BH3 ligands of interest to mammalian biology, and proved that the core domain of MCL-1 (cMCL-1) is necessary and sufficient for BH3 ligand binding. We characterized the in vitro protein-protein interaction between cMCL-1 and activated BID, which occurs in a very slow manner in solution but is otherwise similar to the interaction between cMCL-1 and BID-BH3 peptide. We also present the solution structure of complex cMCL-1:BID-BH3, which may greatly facilitate drug discovery studies of human tumor malignancies. BAK, a multi-region pro-apoptotic protein, directly mediates the mitochondrial outer membrane permeablization (MOMP). We completed a structural investigation of BAK by X-ray crystallography. We report two structures of BAK's homo-dimers, one zinc-mediated (cBAK) and one disulphide-bond-linked (cBAK-o). Their dimerizing sites locate closely at D160 and H164 in cBAK and C166 in cBAK-o, which allow them to compose a unique regulatory element to switch BAK's activity as suggested in mitochondria activity-testing assays. BAK is tightly regulated through protein-protein interactions by MCL-1. We characterize the conformational changes in BAK and MCL-1 using detergents to mimic the membrane environment, and studied their interaction in vitro. The non-ionic detergent IGEPAL and the zwitterionic detergent CHAPS have different effects on these two proteins, but both initiate the heterodimerization. The complex of MCL-1 and BAK can be disrupted by either a BID-BH3 peptide, which acts through binding to MCL-1, or a mutation in BH3 region of BAK (L78A), demonstrating the essential role of BAK's BH3 in its regulation by MCL-1. This thesis concludes with a hybrid model for BAK activation:La protéine MCL-1 (Myeloid cell leukemia 1), qui appartient à la classe de protéines anti-apoptotiques BCL-2, joue un rôle dans le maintien de l'intégrité mitochondriale durant l'apoptose. Les résultats obtenus par résonance magnétique nucléaire (RMN) et par titrage calorimétrique, nous ont permis de mettre en évidence la sélectivité de la protéine MCL-1 pour les ligands mammifères d'interêt biologiques qui contiennent le motif BH3 et nous avons ainsi démontré que le domaine central du facteur MCL-1 (cMCL-1) est nécessaire et suffisant pour cette interaction. Nous avons caractérisé in vitro l'interaction entre le domaine cMCL-1 et le facteur activé BID; cette interaction se produit lentement en solution mais est similaire à celle observée entre le domaine cMCL-1 et le peptide BID-BH3. De plus nous avons résolu la structure du complexe cMCL-1:BID-BH3, qui est une cible potentielle qui pourrait être à la base d'un criblage d'une banque de petites molécules dans le cas de tumeurs humaines malignes. BAK, une protéine pro-apoptotic modulaire, permet la perméabilité de la membrane externe de la mitochondrie: ce mécanisme est dénommé MOMP pour the mitochondrial outer membrane permeablization. Nous avons accompli l'étude structurale de la protéine BAK par cristallographie et diffraction de rayons X. Nous présentons deux complexes de la protéine BAK: un homodimère lié par une molécule de zinc (cBAK) et une qui contient un pont disulfure (cBAK-o). Le site de dimérisation se situe proche des résidu D160 et H164 pour cBAK et C166 pour cBAK-o, ce qui leur confère un élément de régulation unique pour moduler l'activité de BAK comme suggéré dans des essais d'activité mitochondriale. La protéine BAK est finement régulée grâce à son interaction protéine-protéine avec MCL-1. Nous avons caractérisé les changements conformations des facteurs BAK et MCL-1 à l'aide de détergents pour modéliser un environnement m
12
Maranyane, Hapiloe 'Mabaruti. "Phosphoglucomutase 1 (PGM1) expression and regulation in cancer cells." Doctoral thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/16694.
Full textAbstract:
Includes bibliographical referencesCancer cells undergo metabolism that is significantly different to normal cells, with an increased dependence on glucose metabolism as a hallmark of most cancers. Changes in global gene expression patterns are the major driving forces behind cancer progression. These changes trigger events that result in the dysregulation of key enzymes associated with metabolic processes. Gene expression profiling studies done previously in our laboratory identified a group of genes involved in glucose metabolism to be differentially expressed in cervical cancer patient material. Of these, Phosphoglucomutase 1 (PGM1) was identified to have elevated expression in the cancer group. PGM1 is a phosphotransferase that catalyses the reversible conversion of the glycogen breakdown product, glucose-1-phosphate into glucose-6-phosphate, a substrate for glycolysis and the pentose phosphate pathway. This places PGM1 at a critical traffic point of glucose metabolism. In this study we investigated the expression, regulation and biological significance of PGM1 in cancer cells. Our results showed that PGM1 expression was elevated in cervical cancer tissue compared to normal. Its expression was also high in cervical, oesophageal and breast cancer cell lines. Elevated PGM1 expression associated with high promoter activity as well as with E2F and HIF1α activities in cancer cells. PGM1 expression at the level of mRNA, protein and promoter activation was significantly stimulated in hypoxia mimicking conditions. Our data showed that PGM1 expression in cancer cells was required mainly for glycogen accumulation with marginal changes on glycolysis and the pentose phosphate pathway. While PGM1 expression did not appear necessary for cancer cell proliferation in normoxia and nutrient sufficiency, our data shows that it is required for proliferation under conditions of glucose deprivation combined with hypoxia. Together these findings suggest that PGM1 expression is altered in cancer cells, that it is required for aberrant glycogen expression in cancer cells and that it has a role in cancer biology during severe stress conditions.
13
Alsharief, Fahda Fawaz. "Role of Translation Initiation in Regulation of Epithelial Junctions and Cell Motility." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/5018.
Full textAbstract:
The integrity and barrier properties of intestinal epithelium are determined by specialized adhesive structures known as intercellular junctions; composed of adherens junctions (AJs), tight junctions (TJs) and focal adhesions that mediate cell-cell and cell matrix interactions, respectively. These two types of epithelial cell adhesions regulate each other during disruption and restitution of the epithelial barrier. Inflammatory cytokines such as interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) are elevated during intestinal inflammation. The most notable effects of IFNγ and TNFα on intestinal epithelial homeostasis involve disruption of apical junctions and attenuation of cell migration. Although molecular mechanisms underlying these effects remain poorly understood, expressional downregulation of different adhesion proteins may play a major role in the cytokine-dependent disruption of the intestinal epithelial barriers. This thesis is based on the hypothesis that inhibition of the protein translation initiation machinery promotes the disruption of the intestinal epithelial barrier and attenuates epithelial restitution during mucosal inflammation. This study was focused on two eukaryotic translation initiation factors, eIF4G1 and eIF4G2, which play essential roles in the regulation of cap-dependent protein translation. Expression of both translation initiation factors was dramatically downregulated in model intestinal epithelial cell monolayers treated with IFNγ and TNFα in parallel to cytokine-induced disruption of the epithelial barrier. siRNA or shRNA-mediated downregulation of either eIF4G1, or eIF4G2 increased permeability of well-differentiated SK-CO15 intestinal epithelial cell monolayers and decreased expression of different adherens junction and tight junction proteins. Furthermore depletion of these translation initiating factors inhibits different modes of migration (wound healing and transfilter migration) of stem-cell like and well-differentiated intestinal epithelial cells. These findings suggest that eukaryotic translation initiation factors of the eIF4G family play unique roles in regulating integrity and restitution of the intestinal epithelial barrier. Downregulation of these translation initiating factors may mediate disruption of the intestinal epithelial barriers during mucosal inflammation.
14
Thunborg, Emelie, and Emma Österberg. "The Medical Device Regulation : What Impact Will the New Regulation Have on the Medical Device Industry and How Will Companies Use Standards to Meet the New Requirements." Thesis, KTH, Medicinteknik och hälsosystem, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-297862.
Full textAbstract:
The New Medical Device Regulations (MDR) will become affective on 26 May, 2021. The new regulation entails higher requirements for companies that develop medical devices, but also for all parties involved in the medical device industry. The strengthened requirements mean that it will be more difficult to meet all the criteria for placing medical devices on the market. This thesis has been carried out on behalf of the Swedish Institute for Standards (SIS) and examines companies' transition to MDR and how companies can get support from SIS, but also by other organizations and authorities. A qualitative literature study and document study has been carried out to ponder interview questions, which have then been answered by companies, authorities and organizations who are in one way or another affected by the transition to MDR. Part of the work was also to find out how the companies, depending on size, differ from each other to comply with the new regulation. The results showed that the transition to MDR differs significantly between all the interviewed parties, but that everyone agrees that standardization is important.Den nya förordningen om medicintekniska produkter (MDR) kommer att träda i kraft den 26 maj, 2021. Den nya förordningen innebär högre krav på företag som utvecklar medicintekniska produkter, men även på alla inblandade parter i den medicintekniska industrin. De stärkta kraven innebär att det kommer vara svårare att uppfylla alla kriterier för att kunna placera medicintekniska produkter på marknaden. Detta examensarbete har utförts på uppdrag av Svenska Institutet för Standarder (SIS) och undersöker företagens övergång till MDR och hur företag kan få stöd, bland annat av SIS, men också av andra organisationer och myndigheter. Det har genomförts en kvalitativ litteraturstudie och dokumentstudie för att formulera intervjufrågor som sedan har besvarats av företag, myndigheter och organisationer som på ett eller annat sätt blir påverkade vid övergången till MDR. En del av arbetet var även att ta reda på hur företagen, beroende på storlek, skiljer sig mellan varandra vad gälleratt uppfylla det nya regelverket. Resultatet visade att övergången till MDR skiljer sig markant mellan alla de intervjuade parterna, men att alla är eniga om att standardisering är viktigt.
15
Ren, Hui. "REGULATION OF HEPATIC GENE EXPRESSION DURING LIVER DEVELOPMENT AND DISEASE." UKnowledge, 2012. http://uknowledge.uky.edu/microbio_etds/6.
Full textAbstract:
My first project was to investigate the role of Hepatocyte Nuclear Factor 1 (HNF1) and Nuclear Factor I (NFI) on alpha-fetoprotein (AFP) promoter activity during liver development. AFP is highly expressed in the fetal liver, silenced at birth, and remains at very low levels in the adult liver. A GA substitution located at -119 of the human AFP promoter is associated with hereditary persistence of AFP (HPAFP) expression in the adult liver (Hum Molec Genet, 1993, 2:379). The -120 region harbors overlapping binding sites for HNF1 and NFI. While it has been shown that the GA substitution increases HNF1 binding, the role of NFI in AFP regulation has not been investigated. This overlapping HNF1/NFI site is conserved in other mammals, including mice. In this study, I used a combination of biochemical, tissue culture, and animal studies to explore further the role of this HNF1/NFI site in AFP regulation. Transient co-transfections in Hep3B hepatoma cells indicate that HNF1 activates while NFI represses the mouse AFP promoter. EMSAs indicate that HNF1 and NF1 compete for binding to this site. Transgenes regulated by the wild-type AFP promoter are expressed at low levels in the adult liver. Transgenes with a GGAA mutation (similar to the G-A human mutation) are more active in the adult liver. My data indicate that HNF1 and NFI compete for binding to the -120 region of the AFP promoter and this competition is involved in postnatal AFP repression.
My second project was to study the control of Elongation of very long chain fatty acids like 3 (Elovl3) in the liver by Zinc fingers and homeoboxes 2 (Zhx2). The Zhx2 gene was originally characterized in our lab based on its ability to control the developmental repression of several hepatic genes, including AFP (PNAS, 102:401). Zhx2 is a member of a small family of proteins found only in vertebrates that also includes Zhx1 and Zhx3. These proteins all contain two zinc fingers and four homeodomains, suggesting that they function as regulators of gene expression. My study shows that Zhx2 regulates Elovl3 expression in female liver. Mouse strain-specific differences in adult liver Elovl3 mRNA levels and transgenic mouse data indicate that Zhx2 activates Elovl3 expression in the female adult liver. I also demonstrate that Elovl3 is repressed in the regenerating liver and that the level of Elovl3 repression is controlled by alpha-fetoprotein regulator 2 (Afr2). In addition, I show that Elovl3 expression is reduced in liver tumors, fibrotic livers and fatty livers, raising the possibility that Elovl3 can serve as a marker for HCC and liver damage.
16
Chang, Cheng-Fu. "Structure-function and regulation studies of angiotensin-converting enzyme 2." Doctoral thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/3122.
Full text
17
Leaner, Virna Drucille. "Transcriptional regulation of the human alpha 2(I) procollagen gene." Doctoral thesis, University of Cape Town, 1997. http://hdl.handle.net/11427/26989.
Full textAbstract:
The objective of this study was to investigate the cell- and species-specific regulation of the α2(1) pro collagen gene by analysing trans-acting factor interactions within the proximal promoter of the gene and to identify the genes coding for these trans-acting factors. α2(1) procollagen gene expression was examined in a number of diff erentiate<;l cell lines and shown to differ significantly between normal fibroblasts (WI-38, FG₀), transformed fibroblasts (CT-1, SVWI-38), HT1080 fibrosarcoma, HepG2 hepatocellular carcinoma, L77 lymphoblasts and breast cancer epithelial cells (MDA-MB-231, ZR-75-2). These differences were due to changes in transcription of the α2(1) procollagen gene as shown by Northern blot analysis and nuclear runon transcription experiments . Analysis of DNA-protein interactions with the proximal α2(1) procollagen promoter showed the presence of at least two DNA-protein complexes (complexes I and III) in collagen producing cell lines, while cells where collagen synthesis did not occur contained a third DNA-protein complex (complex II). α2(1) procollagen gene expression was therefore shown to be associated with the presence of complexes I and III while repression of the gene was associated with the presence of complexes I and II and the partial or complete absence of complex III. Complex I is a ubiquitous factor which binds the inverted CCAAT box located between -92 and -80 (G/CBE) with an apparent Kd of 2.9nM. Complexes II and III both bind an adjacent DNA sequence between -78 and -67 (the CME) with Kd values of 4.2 and 3.5nM respectively. While the CCAA T boxes in the human and mouse promoters are identical, a 3bp mismatch was detected in the CME. This mismatch abolished the formation of complex II and III on the mouse promoter, even though mouse cells contained complex II proteins. The difference in the CME binding site between rodent and human promoters implied species-specific regulation of the α2(1) procollagen gene. Transfection of human and mouse proximal α2(1) procollagen promoter/CAT constructs into human cells (CT-1) indicated that the human promoter had higher activity than the mouse promoter, whilst the two promoters had equivalent activities in rodent cells. These promoter activities may be accounted for by the differences in trans-acting factor binding to the two promoters. Complex I formation was competed out by the mouse CBF and NF-Y consensus oligonucleotides, while the mouse anti-CBF-B antibody resulted in a supershifted complex I. These results indicate that complex I is a member of the heterologous CCAAT-binding proteins and possibly related to or similar to the mouse CBF. The treatment of nuclear extracts with calf intestinal phosphatase resulted in a loss of complex I formation on the human and CBF binding to the mouse promoters. The Ser/Thr phosphatase, PP2A, specifically inhibited complexes II and ill formation. Nuclear extracts from CT-1 and U937 cell lines treated with the kinase inhibitor, staurosporin, was accompanied by a loss in DNA-protein interaction. This inhibition of DNA-binding activity was not observed using the tyrosine kinase inhibitor, genistein, and the PP2A phosphatase inhibitor, okadaic acid. Staurosporin also had a significant inhibitory effect on α2(1) procollagen promoter activity in CT-1 cells transfected with the human proximal α2(1) procollagen promoter and on steady state collagen mRNA levels. These results indicate that phosphorylation is required for the binding of trans-acting factors to the proximal α2(1) procollagen promoter and in transcriptional regulation of this gene. In support of the suggestion that phosphorylation events play a role in transcriptional regulation of the α2(1) procollagen gene, CT-1 cells treated with the protein kinase C activator, PMA, showed a significant reduction in α2(1) procollagen mRNA levels. A lambda gt11 expression library was screened to obtain cDNA's encoding proteins that bind the CME in the human α2(1) proximal promoter. A cDNA clone of 958 bp with a predicted open reading frame of 116 amino acids (12.5kD) was obtained. No significant DNA or polypeptide sequence homologies existed in the databank, indicating the possibility of a novel trans-acting factor. Binding of this fusion protein was specific for the CME as observed in South Western blotting and gel shift assays using competitor DNA sequences. Northern blot analysis detected a mRNA transcript of approximately 4kb predominantly in cells where α2(1) procollagen expression is repressed.
18
Hull, Lynn. "Enzymatic Regulation of Opioid Antinociception and Tolerance." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1875.
Full textAbstract:
ENZYMATIC REGULATION OF OPIOID ANTINOCICEPTION AND TOLERANCE By Lynn C. Hull, Ph.D. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. Virginia Commonwealth University, 2009 Director: William L. Dewey, Ph.D. Department of Pharmacology and Toxicology The involvement of kinases in opioid actions has long been established. The acute actions of opioids, through the Gi/Go G-proteins, cause the inhibition of adenylyl cyclase and therefore a decrease in protein kinase A (PKA) activation. Additionally, acute opioid administration may cause the G-protein to activate the phospholipase C (PLC)-mediated cascade leading to the activation of protein kinase C (PKC). The phosphorylation of the MOR which can lead to both desensitization by uncoupling of the G-protein coupled receptors (GPCRs) from the G-proteins and to internalization by recruitment of β-arrestins has long been identified as a key process in tolerance. Phosphorylation by PKA and PKC leads primarily to uncoupling of the receptor from the G-proteins. Phosphorylation of the receptor by G-protein coupled receptor kinase (GRK) leads to the recruitment of β-arrestins and internalization of the receptor. Many in vitro studies have come to the conclusion that GRK induced internalization plays a more central role in the tolerance to high efficacy opioids and a lesser role in low- and moderate-efficacy opioid tolerance. In fact it has been hypothesized that morphine, a moderate-efficacy opioid, causes no internalization at all, while the desensitization of the receptor via phosphorylation by PKA and PKC plays a more central role in low- and moderate-efficacy opioid tolerance. We sought to test these in vitro findings in an in vivo model of opioid tolerance. Animals were made tolerant to one of a number of opioids of varying efficacy (low-efficacy meperidine, moderate-efficacy morphine and fentanyl, and high-efficacy [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO)) over an 8 hour period and then were administered one of the kinases’ inhibitors. Tolerance reversal was determined by challenging these mice with the same opioids to which they were tolerant. Calcium is known to play an important role in the acute antinociceptive actions of opioids as well as in opioid tolerance. Therefore it is important to determine how opioids are affecting the regulation of intracellular calcium. Our laboratory has previously shown that Calcium Induced Calcium Release (CICR), the ryanodine receptor and intracellular microsomal Ca2+ pools all play a role in opioids’ actions. It is also well known that mammalian ADP-ribosyl cyclase, CD38’s, product cADPR acts on the ryanodine receptor to cause Ca2+ release into the intracellular space. We chemically and genetically altered CD38 and then tested the acute effect of morphine as well as what effect these treatments had on morphine tolerance to determine what role if any, that CD38 may play in the acute actions of morphine antinociception as well as in morphine tolerance. Together, studies focusing on the role of an ADP-ribosyl cyclase, CD38, and 3 separate kinases, PKA, PKC and GRK, in opioids’ actions were performed in order to better understand the roles of these enzymes’ pathways in the actions of opioid-induced antinociception and subsequent development of tolerance. It is hoped that the results herein add useful knowledge to the general understanding of this drug class, and will one day be of use in the development of future analgesics and in the clinical treatment of pain and reduction in tolerance.
19
Dyer, Sarah Elizabeth. "Applying bioethics : local research ethics committees and their regulation of medical research." Thesis, King's College London (University of London), 2006. https://kclpure.kcl.ac.uk/portal/en/theses/applying-bioethics--local-research-ethics-committees-and-their-regulation-of-medical-research(c0840da4-23fb-49a1-a712-eb2a0d5a08ac).html.
Full text
20
Pliuskys, Laurynas. "Epigenetic regulation of the myeloid cell lineage." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:f4ee6659-ce0b-4730-ae5b-95c141f82e10.
Full textAbstract:
The myeloid cell lineage is a fundamental element of the immune system and it can give rise to a diverse set of terminally differentiated cells, such as macrophages or osteoclasts among many others. Mutations or misregulation of gene expression may lead to severe clinical conditions, such as arthritis, osteoporosis or cancers. Epigenetics, the regulation of gene expression and chromatin remodelling, is implicated in cell differentiation, function and disease, and hence it is a promising new area to explore in order to explain underlying cellular mechanisms. Firstly, human macrophage subtypes were studied. Chemokine (C-C motif) ligand (CCL) 1 and mannose receptor were validated to be granulocyte macrophage (GM) colony stimulating factor (CSF) induced macrophage markers, while CCL2 was specifically expressed in macrophage CSF (MCSF) macrophage population. By utilising publicly available high-throughput sequencing data, new biomarkers dehydrogenase/reductase (SDR family) member 2 and CCL26 were discovered to be MCSF-macrophage specific while guanylate binding protein 5 and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A were highly up-regulated in GMCSF cells. Secondly, a range of gene knock-down techniques for the myeloid cell lineage were optimised and established. Lentiviral short-hairpin RNA (shRNA) delivery methods were shown to induce an undesirable pro-inflammatory response in macrophages. Furthermore, the frequently utilised cytomegalovirus promoter for gene expression was shown to be completely silenced in macrophage populations. Locked nucleic acids were selected as a suitable alternative to shRNA knock-down and by employing this new tool it was shown that a histone demethylase lysine (K)-specific demethylase (KDM) 6B is fundamental for macrophage differentiation. Finally, a small molecule GSK-J4, a potent inhibitor of histone demethylases KDM6A, KDM6B and KDM5B specific for H3K27me3 and H3K4me3, respectively, was used to dissect epigenetic signalling in osteoclasts and multiple myeloma. In osteoclasts it was shown to act mainly by inhibiting transcriptional changes required for osteoclastogenesis when MCSF-macrophages are stimulated with Receptor Activator Of Nuclear Factor Kappa-B Ligand (RANKL), as indicated by the differential increase in H3K27me3 marks, leading to inhibition of c-Jun and potentially abolition of transcription factor AP-1, required for the transcriptional initiation of nuclear factor of activated T-cells 1 (NFATc1). In multiple myeloma cells, GSK-J4 causes a dramatic increase in expression, further supported by the build-up of global H3K4me3 marks, which results in the upregulation of the unfolded protein response pathway. In both cell systems, there is an early upregulation of metallothionein genes, which in multiple myeloma was shown to increase potentially due to rapid influx of zinc ions within the first 30 minutes, and as such may cause induction of apoptosis in multiple myeloma and may inhibit differentiation of osteoclasts.
21
Chadha, Gibran. "Role of Anillin in Regulation of Epithelial Junctions." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3363.
Full textAbstract:
Adherens junctions (AJs) and tight junctions (TJs) are characteristic features of differentiated epithelial cells and are critical for regulation of epithelial barriers and cell polarity. Integrity and remodeling of epithelial junctions depend on their interactions with underlying actomyosin cytoskeleton. Anillin is a multifunctional scaffold able to interact with different cytoskeletal proteins including F-actin and Myosin II. This project aimed to investigate roles of anillin in regulating epithelial AJs and TJs. Using A549 human lung epithelial and DU145 human prostate epithelial cells, we demonstrated the anillin depletion-induced loss of AJs and TJs. This was accompanied by disorganization of perijunctional actomyosin belt and disruption of the adducin-based membrane skeleton that links actin filaments to the plasma membrane and epithelial junctions. Depletion of anillin decreased protein levels of γ-adducin and downregulation of γ-adducin mimicked effects anillin knockdown on AJ and TJ integrity. These findings suggest a novel role for anillin in the assembly of epithelial junctions.
22
Simon, Christopher R. "Exploring the performance and self-regulation of medical students through an intervention aimed at regulating the way they feel." Thesis, University of Ottawa (Canada), 2008. http://hdl.handle.net/10393/27729.
Full textAbstract:
Research has shown that how individuals feel affects their performance (Doell et al., 2006; Durand-Bush et al., 2005). Since felt experiences in the context of medicine have been shown to be of importance (Novack et al., 1997; Sotile & Sotile, 2002), and self-regulation skills have been found to help foster learning (Zimmerman, 1990), the purpose of this study was to examine the self-regulation of the felt experiences of four medical students through an intervention guided by the Resonance Performance Model (RPM) (Newburg et al., 2002), and determine how it affected self-defined standards of performance. Results of this multiple case study (Stake, 2006) showed that each student was able to identify and experience, the way they wanted to feel within their performance environment, and reach an optimal level of performance during the intervention process by attuning to and regulating the way they felt. Implications for future research on performance as a self-defined process, and the provision of opportunities for self-regulated learning in medical education are discussed.
23
Mayat, Nureen. "A Tet-repressible regulation system in mycobacteria for application to vaccine design." Master's thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/2714.
Full text
24
Costin, Blair. "ETHANOL REGULATION OF GLUCOCORTICOID RESPONSIVE GENES." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/462.
Full textAbstract:
Glucocorticoid hormones modulate acute and chronic behavioral and molecular responses to drugs of abuse including psychostimulants and opioids. Acute ethanol activates the hypothalamic pituitary adrenal (HPA) axis causing the release of adrenal glucocorticoid hormones, but following chronic ethanol the HPA axis is dysregulated in both humans and rodents. Thus, there is growing evidence that glucocorticoids might also modulate behavioral and molecular responses to ethanol. Previous microarray studies in the Miles’ laboratory have shown that the well-known glucocorticoid responsive gene, Serum and Glucocorticoid-regulated Kinase 1, Sgk1, is prominently up regulated by acute ethanol (2 g/kg) in the prefrontal cortex (PFC) of DBA/2J mice. Functionally, Sgk1 is an important focal point of intracellular signaling cross-talk through which the cell surface receptors, nuclear receptors, and cellular stress pathways converge to control many cellular processes including receptor or ion channel trafficking, cell proliferation and/or apoptotic responses. In the aforementioned microarray studies, Sgk1 was accompanied by a highly correlated group of genes, many of which are also known to respond to glucocorticoids. This suggests that stress-related signaling events might play an important role in ethanol regulation of the Sgk1 gene network. Prior work by others showed that Sgk1 plays an important role modulating synaptic plasticity occurring in memory. Based on these findings, it is hypothesized that glucocorticoids and glucocorticoid responsive genes are responsible for modulating acute and chronic cellular and behavioral responses to ethanol including locomotor activation and ethanol sensitization. In particular, because Sgk1 is regulated by ethanol, has a well-established role in learning and memory and is responsive to glucocorticoid signaling we hypothesize that Sgk1 is involved in modulating acute and chronic cellular and behavioral responses to ethanol including ethanol sensitization. Our results indicate that the induction of glucocorticoid responsive genes may play a role in regulating acute behavioral and cellular responses to ethanol. Adrenalectomized (ADX) and mifepristone (RU-486) both impaired acute ethanol (2 g/kg) induced locomotor activation in DBA/2J mice without affecting basal locomotor activity. ADX mice showed microarray gene expression changes in the PFC that significantly overlapped with acute ethanol-responsive gene sets derived by our prior microarray studies. Additionally, acute ethanol regulates Sgk1 transcription via glucocorticoid receptor binding to the Sgk1 promoter. Furthermore, increases in Sgk1 may occur to compensate for decreases in SGK1 protein and phosphorylation of SGK1 and its well-known target N-myc downstream-regulated gene 1 (NDRG1) is significantly increased 15 minutes following ethanol administration. Finally, Sgk1 intensifies and prolongs the expression phase of sensitization in D2 mice. Our studies suggest that ethanol’s activation of adrenal glucocorticoid release and subsequent glucocorticoid receptor activation may partially modulate ethanol’s acute locomotor activation in male D2 mice. Furthermore, adrenal glucocorticoid basal tone regulates PFC gene expression. A significant set of acute ethanol-responsive genes are regulated by adrenal glucocorticoid basal tone suggesting that glucocorticoid regulated PFC gene expression may be an important factor modulating acute behavioral responses to ethanol. Sgk1 is acutely regulated following ethanol administration by the glucocorticoid receptor binding to the Sgk1 promoter. Altogether, these results suggest a critical role for the hypothalamic pituitary adrenal axis and Sgk1 in regulating the acute and chronic cellular and behavioral responses to ethanol.
25
Sachs, Patrick. "REGULATION OF TELOMERASE EXPRESSION IN STEM CELL REPROGRAMMING." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/40.
Full textAbstract:
A great need exists for an abundant, easily accessible source of patient-specific cells that will function for use in regenerative medicine. One promising source is the adult stem cell derived from adipose tissue (ASCs). Isolated from waste lipoaspiration, these cells could serve as a readily available source for the regeneration of damaged tissues. To further define the biology of ASCs, we have isolated multiple cell strains from different adipose tissue sources, indicating wide-spread distribution in the body. We find that a widely used set of cell surface markers fail to distinguish ASCs from normal fibroblasts. However, our ASC isolations are multipotent while fibroblasts show no differentiation potential. In further contrast to fibroblasts, these cells also show expression of genes associated with pluripotent cells, Oct-4, SOX2, and NANOG. Together, our data suggest that while the cell surface profile of ASCs do not distinguish them from normal fibroblasts and their lack of telomerase shows their limited proliferation capacity, the expression of genes closely linked to pluripotency and their differentiation capacity clearly define ASCs as multipotent stem cells. iPS cells are another promising cell type for tissue regeneration, due to their expression of hTERT and their capacity to differentiate into all three germ layers. Interestingly, telomerase is activated during the induction process, accomplished by the exogenous expression of four genes in normal, non-hTERT-expressing fibroblasts. To elucidate the mechanisms behind this activation, we examined the overexpression of these four factors in BJ fibroblasts and ASCs, which resulted in undetectable hTERT expression. We then demonstrated a lack of an acetylated histone H3K9 with the opposing di-methylation, indicative of a closed chromatin state at the hTERT promoter. Subsequent treatment of cells with TSA alone showed an upregulation of hTERT mRNA without telomerase activity. However, telomerase activity was found when ASCs, but not BJs were treated with TSA and all four factors, indicating differential regulation of hTERT in cells of similar mesenchymal origins. Our data suggest that while hTERT’s expression is universally dependent on the presence of a relaxed chromatin state and sufficient transactivating factors, other cell to cell differences can prevent its expression.
26
Clouse, Michele Lee. "Administering and administrating medicine : regulation of the medical marketplace in Philip II's Spain /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2004. http://uclibs.org/PID/11984.
Full text
27
Stern, Ariel Dora. "Essays in the Economics of Health Care and the Regulation of Medical Technology." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11678.
Full textAbstract:
The first chapter of this dissertation explores how the regulatory approval process affects innovation incentives in medical technologies. While prior studies of medical innovation under regulation have found an early mover regulatory advantage for drugs, I find the opposite to be true for medical devices. Using detailed data on over three decades of high-risk medical device approval times in the United States, I show pioneer entrants spend approximately 34 percent (7.2 months) longer in the approval process than the first follow-on innovator. Back-of-the-envelope calculations suggest that the opportunity cost of capital of a delay of this length is upwards of 7 percent of the total cost of bringing a new device to market. I consider how different types of regulatory uncertainty affect approval times and find that a product's technological novelty is largely unrelated to time spent under review. In contrast, uncertainty about application content and format appears to play a large role: when objective guidelines for evaluation are published, approval times quicken for subsequent entrants. Finally, I consider how the regulatory process affects firms’ market entry strategies and find that financially constrained firms are less likely to enter new device markets as pioneers.
28
Dzobo, Kevin. "Matrix-mediated regulation of type 1 collagen synthesis and degradation in cultured fibroblasts." Doctoral thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/3125.
Full textAbstract:
Includes abstract.Includes bibliographical references (leaves 122-157).
Stromal cells and the extracellular matrix (ECM) components provide the microenvironment that is pivotal for cell growth, motility, attachment and differentiation. Fibroblasts are some of the cells responsible for the synthesis of most of the extracellular matrix proteins. Type I collagen is the most abundant extracellular matrix protein in the human body and is found in tissues requiring high tensile strength. In this study we investigated the effect of a pre-formed fibroblast-derived extracellular matrix on the expression of type I collagen and associated matrix metalloproteinases in fibroblasts.
29
Felthousen, Jessica G. "Assembly and regulation of the DREAM complex." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4148.
Full textAbstract:
The DREAM complex assembles during G0/G1 when RB-like protein p130 recruits E2F4, DP1, and a core complex of five MuvB proteins to repress genes involved in cell cycle progression. In S-phase, the MuvB core dissociates from p130 and binds to BMYB transcription factor. Binding of the MuvB core to p130 requires phosphorylation of its subunit LIN52 at S28 residue by DYRK1A protein kinase. However, little is known about how the MuvB core interacts with p130 to form the DREAM complex, and how these interactions are manipulated throughout the cell cycle. In collaboration with Dr. Seth Rubin, we characterized the structural basis for DREAM assembly, and found that the LxSxExL sequence in LIN52 directly interacts with the LxCxE binding cleft within the pocket domain of p130. Furthermore, immunoprecipitation and proliferation assays revealed that mutating the LIN52 LxSxExL sequence to mimic the canonical LxCxE motif found in viral oncoproteins reduces cellular proliferation and stabilizes the DREAM complex in the presence of viral proteins. We addressed how the DREAM complex is disassembled upon cell cycle entry and found that CDK phosphorylation of p130 inactivates the DREAM complex by displacing p130 from the MuvB core. Under certain conditions, we found that BMYB and p130 simultaneously bind the MuvB core, while overexpression of BMYB disrupts DREAM assembly. Together, our study provides insight into the structural mechanisms of DREAM assembly and function, which can help identify novel approaches to halt tumor cell proliferation or dormancy.
30
Heur, J. Martin. "Lysosomal Regulation of Gene Expression." University of Cincinnati / OhioLINK, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1026512116.
Full text
31
Germundsson, Frida, and Nicole Kvist. "MDR 2017/745 - New EU Regulation for Medical Devices: A Process Description for EHR Manufacturers on How to Fulfill the Regulation." Thesis, KTH, Medicinteknik och hälsosystem, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-279137.
Full textAbstract:
On the 26th of May 2021 the new regulation for medical devices, MDR 2017/745, will come into force. The underlying incentives to go from the medical device directive (MDD 93/42/EEC) to MDR are a series of adverse events involving medical devices. The main goal of MDR is to strengthen and improve the already existing legislation and thus will entail large changes for manufactures, one of them being manufacturers of Electronic Health Record (EHR) systems. For medical software, such as EHR systems, the new regulation will imply an upgrade in risk classification. This upgrade will bring additional requirements for EHR manufacturers. Furthermore, the released guidelines have been insufficient regarding the specific requirements for medical device software and thus EHR manufacturers are in need of tools and guidance to fulfill MDR. This thesis examines the new regulation for medical devices and thus identifies main requirements for EHR manufacturers. A qualitative approach was conducted comprising a literature study as well as a document study of the medical device regulation along with interviews with experts within the field of medtech regulatory affairs and quality assurance. The information gathered was analyzed to create a process description on how EHR manufacturers are to fulfill MDR. The process description is a general outline and presents the main steps on the route to be compliant with MDR in a recommended order of execution. The main steps are: divide the system into modules, qualify the modules, classify the modules, implement a quality management system, compile a technical documentation, compile the declaration of conformity, undergo a conformity assessment and finally, obtain the CE-mark. To each of the main steps additional documentation provides further information and clarification. The process description functions as a useful tool for EHR manufacturers towards regulatory fulfillment. Even though the process description is created for EHR manufacturers, it can be useful for other medical device software manufacturers. The process description provides an overview of the path to a CE mark and functions as a guidance. It can be used in educational purposes as well as to serve as a checklist for the experienced manufacturer to make sure everything is covered. However, it is not sufficient to rely solely on the process description in order to be in full compliance with MDR. Moreover, there is still a need for further clarifications from the European Commission regarding specific requirements on medical device software.
32
Papaspyropoulos, Angelos. "RASSF1A regulation of transcription factors in tumourigenesis and stem cell fate determination." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:b4d9f50d-3a2a-4655-ab38-8bc0d45d36b8.
Full textAbstract:
RASSF1A silencing is the most widely reported epigenetic event in sporadic human malignancies and is increasingly observed to be associated with poorer prognosis and outcome in lung, breast and bladder cancers amongst others. By performing a genetic screen in mice using Sleeping Beauty (SB) transposon-mediated insertional mutagenesis, we identified candidate genes associated with tumourigenesis in the absence of Rassf1a. A top hit in our screen was the terminal differentiation transcription factor Runx2. In this study, we describe how together loss of RASSF1A and RUNX2 exacerbate oncogenic YAP1-TEAD complexes and how RUNX2, p73 and TEAD effectively compete for YAP1 association. Interestingly, YAP1-TEAD complexes, as well as RUNX factors have been known to be important regulators of embryonic development by affecting cell fate. We show that RASSF1A is a novel regulator of stem cell pluripotency by introducing a cross link between the Hippo and Wnt signalling pathways, via TEAD and β-catenin. More specifically, we demonstrate that RASSF1A is a barrier to somatic cell reprogramming by activating differentiation circuits, but its loss results in upregulation of the core stem cell marker network (NANOG, OCT4 and SOX2) in embryonic stem cells and the pre-implantation mouse embryo. In addition, we find that deregulation of the Hippo pathway in the absence of RASSF1A also leads to increased prevalence of stem cell characteristics in cancer and higher proportion of 'cancer stem cells'. This effect is mediated through both YAP and its paralog TAZ. Finally, we show that a second isoform of RASSF1, RASSF1C, the expression of which is maintained in cancers, contributes to cancer stem cell generation through a similar mechanism. This work concentrates on establishing the biology of RASSF1A in normal tissue and answering whether the broad prognostic value in tumours from biologically distinct tissues is due to a fundamental control of stem cell pluripotency.
33
Ling, I.-Fang. "REGULATION OF LOW DENSITY LIPOPROTEIN RECEPTOR SPLICING EFFICIENCY." UKnowledge, 2009. http://uknowledge.uky.edu/gradschool_diss/794.
Full textAbstract:
Low density lipoprotein receptor (LDLR) is an apolipoprotein E (apoE) receptor and may play a role in Alzheimer’s disease (AD) development. A single nucleotide polymorphism (SNP), rs688, that has been identified to modulate the splicing efficiency of LDLR exon 12 and is associated with higher cholesterol and AD in some case-control populations. The exon 12 deleted mRNA is predicted to produce a soluble form of LDLR that fails to mediate apoE uptake. To gain additional insights, in this study, I seek to understand the regulation of LDLR splicing efficiency. To identify functional cis-elements within LDLR exon 12, I mutated several conserved putative exonic splicing enhancers (ESEs) to neutralize their affinity to serine/arginine-rich (SR) proteins. Transfection of wild type (WT) or mutant LDLR minigenes in HepG2 cells was performed, and splicing efficiency evaluated by quantitative RT-PCR. The results showed that two functional ESEs within exon 12, near rs688, are critical to LDLR splicing. To identify splicing factors that modulate exon 12 splicing, I co-transfected an LDLR minigene and vectors encoding different SR proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs). After quantifying the splicing efficiency, I found that SRp20 and SRp38 increased exon 11- skipping. Moreover, ectopic expression of SRp38-2 and hnRNP G increased exon 11&12-skipping. Interestingly, the actions of hnRNP G did not require its RNA recognition motif (RRM). To further investigate the role of theses splicing factors on LDLR splicing, I quantified the expression level of these splicing factors as well as LDLR splicing efficiency in human brain and liver. I found that SRp38 mRNA expression is associated with LDLR splicing efficiency. In conclusion, this study discovered that rs688 is located close to the two functional ESEs within LDLR exon 12, and revealed a role of SRp38 in LDLR splicing efficiency.
34
Wilkins, James. "Functional analysis of polymorphisms associated with osteoarthritis susceptibility that affect cis-regulation." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:cfbed303-bdfd-4bb4-bd8f-a3dcd63167bc.
Full textAbstract:
Osteoarthritis (OA) is a common, multifactorial disease that is characterized by focal degeneration of the smooth articular cartilage in any of the synovial joints. Although the underlying molecular mechanisms for OA are still not fully understood, epidemiological studies have evidenced a significant genetic component to OA susceptibility. Genome-wide linkage scans and large-scale association studies have had success in unraveling the genetic architecture underlying OA with the identification of a number of susceptibility genes. In this work, functional analyses are reported of OA associated polymorphisms within two susceptibility genes: BMP5 and GDF5, both members of the TGF-β superfamily of secreted proteins. The extent of differential allelic expression (DAE) of BMP5 in human mesenchymal tissues was first examined with significant differences in BMP5 allelic output observed (allelic ratios exceeding 4:1 in the tissues of some donors). Significant variability in allelic expression within the different tissues of donors was also observed, suggesting that polymorphism in cis-regulation of BMP5 expression is common and that there is a considerable effect of tissue specific elements on BMP5 expression. DAE was then used as a phenotype to map tissue-specific cis-regulatory polymorphisms with the identification of a single nucleotide polymorphism (SNP) located downstream of BMP5 that was significantly associated with DAE as well as OA, suggesting that variability in cis-regulation of BMP5 is important in OA susceptibility. Moreover, the functional effect of a previously identified OA associated microsatellite within intron 1 of BMP5 was investigated using luciferase reporter assays and electrophoretic mobility shift assays (EMSAs) with significant differences observed both in the ability of various microsatellite alleles to modulate BMP5 promoter activity and to bind GATA-3 nuclear proteins, further suggesting a role for variability in BMP5 expression in OA susceptibility that may in part be due to altered GATA-3 binding. Finally, functional characterization of a previously reported OA associated SNP in the 5′ UTR of GDF5 is presented in which EMSAs show differential binding of nuclear factors between the two SNP alleles, strengthening the possible functional contribution of this SNP to OA susceptibility. Overall, this work demonstrates that polymorphism in cis-regulation is likely to play a role in OA susceptibility.
35
Siddaway, Robert T. "Role and regulation of MITF in melanocytes and melanoma." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:9a6d568f-ab2c-4821-aecc-51adf5190118.
Full textAbstract:
One key to understanding how cells integrate and how they respond to diverse stimuli in order to direct a transcriptional response is knowing how a transcription factor may be directed to an appropriate subset of its target genes. One mechanism with which this may be achieved is by modulation of the transcription factor’s post-translational modification status. The microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage, and it is also a lineage addiction gene in melanoma. Low or high levels of MITF expression induce a reversible cell cycle arrest. Invasive behaviour is characteristic of low MITF expression; differentiation a product of high MITF activity; and moderate levels of MITF expression promote proliferation. A major, unaddressed problem is how DNA binding by MITF may be differentially directed such that it regulates either a proliferation-associated or a differentiation-associated gene expression programme appropriate to the cellular microenvironment. This thesis explores the function and regulation of the signalling pathways controlling novel post-translational modifications of MITF. One such modification, in the DNA binding domain of MITF, defines a key switch that controls MITF’s DNA binding affinity and specificity. Moreover, a novel set of MITF target genes are revealed that extend its control beyond pigmentation and cell cycle regulation to implicate MITF as an overall regulator of cell behaviour in the melanocyte lineage.
36
Faurholm, Bjarne. "Gene structure, transcripts and transcriptional regulation of primate type II gonadotropin-releasing hormone receptors." Doctoral thesis, University of Cape Town, 2004. http://hdl.handle.net/11427/3127.
Full text
37
Tshuikina, Wiklander Marina. "Epigenetic Regulation of Gene Transcription in Hematopoietic Tumors." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9206.
Full text
38
Gutbrod, Tina. "Emotion regulation in very preterm infants : the influence of infant, maternal and medical factors." Thesis, University of Hertfordshire, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247327.
Full text
39
Rose, Beverley Ann. "The regulation of type I collagen gene expression in stromal fibroblast by breast tumour cells." Doctoral thesis, University of Cape Town, 2011. http://hdl.handle.net/11427/10861.
Full textAbstract:
Includes abstract.Includes bibliographical references (leaves 110-135).
Recent studies have revealed that interactions between tumour cells and the surrounding stroma play an important role in facilitating tumour growth and invasion. Stromal fibroblasts produce most of the extracellular matrix (ECM) components found in the stroma, including type I collagen. Previous in vivo studies in our laboratory have shown that type I collagen mRNA levels are decreased in stage II and III breast tumour tissue compared to adjacent normal tissue.
40
Scrace, Simon Francis. "Novel regulation of SRC family kinase signalling by RASSF1 isoforms." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:bce16eb9-9f93-47de-bfa6-15c7e0bc19a3.
Full textAbstract:
RASSF1A is a tumour suppressor, the silencing of which occurs through promoter methylation in a variety of human cancers. Loss of RASSF1A is associated with decreased sensitivity to DNA damaging agents and worse prognosis in breast, colon and lung cancers amongst others. RASSF1A functions in a number of cellular processes, promoting apoptosis in response to DNA damage or death receptor signalling, or cell cycle arrest at both G1/S and pro-metaphase checkpoints. As a scaffold protein, RASSF1A imparts these functions through direct interaction with target proteins. We have identified a novel interaction between RASSF1A and the SRC activator, OSSA. Further studies identify a role for RASSF1 in SRC signalling. We find that a second isoform of RASSF1, RASSF1C, the expression of which is maintained in cancers, is able to activate SRC. We also identify a novel tumour suppressor role for RASSF1A inhibiting SRC activation through binding of RASSF1C. SRC activation by RASSF1C expression promotes internalisation of adherens junctions leading to subsequent loss of tight junctions and cell polarity markers from sites of cell-cell contact. -catenin is also found to be re-localised throughout the cells from where it is hypothesised to be able to upregulate pro-proliferative genes. In addition, we find that RASSF1C expression promotes cell motility in both scratch wound and transwell assays. Finally, we show that RASSF1C expression enhances tumour cell aggressiveness using a mammosphere growth assay. We conclude that RASSF1C is an oncogene that can promote EMT through the activation of SRC family kinases. This function is inhibited by the tumour suppressor RASSF1A. This work highlights why RASSF1A is lost through epigenetic mechanisms and not mutation and why loss of RASSF1A is associated with more aggressive, metastatic cancers.
41
Rego, José. "Temporal Distancing and Emotion Regulation : An ERP Study." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-16062.
Full textAbstract:
Reappraisal is a cognitive emotion regulation strategy that induces a reduction in the arousal response elicited by both unpleasant and pleasant stimuli.One form of reappraisal is that of temporal distancing. Temporal distancing is the cognitive tool that allows the individual to perceive the stimuli in a broader temporal perspective.Reappraisal’s impact on the arousal response can be measured by assessing the amplitude of the event-related potential (ERP) component the late positive potential(LPP), a centro-parietal slow-wave ERP beginning around 350 ms post-stimulus and sustaining for up to several seconds. The aim of this study was to test various temporal-related perspectives in order to see their effect on the LPP. The analysis of the data suggests that a decrease in the amplitude of the LPP in response to emotionally unpleasant facial stimuli corresponds to adopting a temporal distancing strategy, regardless of the exact temporal distance chosen.
42
Virtanen, Marie. "On keratin mutations in epidermolytic hyperkeratosis and the regulation of keratin expression by retinoids." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5058-X/.
Full text
43
Andel, Stephanie A. "The Impact of Traumatic Event Exposure in the Emergency Medical Services: A Weekly Diary Study." Scholar Commons, 2017. https://scholarcommons.usf.edu/etd/7391.
Full textAbstract:
Emergency Medical Service (EMS) professionals are consistently exposed to a variety of traumatic events on the job, such as cases that involve the death or injury of a patient, being physically threatened, or encountering a mass casualty incident. Not surprisingly, research has found that such traumatic exposure has major implications, as it has been related to a plethora of negative strain outcomes such as posttraumatic stress (PTS) symptoms and burnout. However, at this point, research has not empirically examined the mechanisms by which these traumatic events lead to strain. Therefore, this study aims to further investigate these mechanisms by incorporating the role that emotion regulation (i.e., expressive suppression) plays in this process. Further, this study investigates various moderators in this process, including one individual difference factor (i.e., implicit theories about emotion expression) and two contextual factors (i.e., social support and organizational constraints).
To test the links in the aforementioned process, a weekly diary study was conducted online with 200 current EMS professionals. Specifically, participants completed a baseline survey (Time 0) that measured trait-level variables and demographics. Then, participants completed 10 weekly diary studies that included measures of exposure to traumatic events, negative affective reactions, expressive suppression, and strain outcomes. Multilevel structural equation modeling was used to test the study hypotheses.
Results of this study show that within person, traumatic event exposure was related to strain. Further, although traumatic event exposure was not consistently related to expressive suppression, the positive link between expressive suppression and strain was consistent. Additionally, organizational constraints were found to serve as a moderator in the relationship between expressive suppression and strain, such that higher organizational constraints exacerbate this relationship. Overall, these results provide a better understanding of the process that links traumatic event exposure to strain in the EMS profession. This research has implications for organizations, as it examines various factors that may be addressed in order to ensure that EMS professionals are better equipped to deal with these unfortunate exposures. Ultimately, the results of this study will hopefully prove helpful in devising interventions to enhance the wellbeing of EMS professionals in the wake of exposure to traumatic events.
44
Nguyen, Peter. "CANNABINOID RECEPTORS IN THE 3D RECONSTRUCTED MOUSE BRAIN: FUNCTION AND REGULATION." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/2274.
Full textAbstract:
CB1 receptors (CB1R) mediate the psychoactive and therapeutic effects of cannabinoids including ∆9-tetrahydrocannabinol (THC), the main psychoactive constituent in marijuana. However, therapeutic use is limited by side effects and tolerance and dependence with chronic administration. Tolerance to cannabinoid-mediated effects is associated with CB1R adaptations, including desensitization (receptor-G-protein uncoupling) and downregulation (receptor degradation). The objectives of this thesis are to investigate the regional-specificity in CB1R function and regulation. Previous studies have investigated CB1Rs in a subset of regions involved in cannabinoid effects, but an inclusive regional comparison of the relative efficacies of different classes of cannabinoids to activate G-proteins has not been conducted. A novel unbiased whole-brain analysis was developed based on Statistical Parametric Mapping (SPM) for 3D-reconstructed mouse brain images derived from agonist-stimulated [35S]GTPgS autoradiography, which has not been described before. SPM demonstrated regional differences in the relative efficacies of cannabinoid agonists methanandamide (M-AEA), CP55,940 (CP), and WIN55,212-2 (WIN) in mouse brains. To assess potential contribution of novel sites, CB1R knockout (KO) mice were used. SPM analysis revealed that WIN, but not CP or M-AEA, stimulated [35S]GTPgS binding in regions that partially overlapped with the expression of CB1Rs. We then examined the role of the regulatory protein Beta-arrestin-2 (βarr2) in CB1R adaptations to chronic THC treatment. Deletion of βarr2 reduced CB1R desensitization/downregulation in the cerebellum, caudal periaqueductal gray (PAG), and spinal cord. However in hippocampus, amygdala and rostral PAG, similar desensitization was present in both genotypes. Interestingly, enhanced desensitization was found in the hypothalamus and cortex in βarr2 KO animals. Intra-regional differences in the magnitude of desensitization were noted in the caudal hippocampus, where βarr2 KO animals exhibited greater desensitization compared to WT. Regional differences in βarr2-mediated CB1R adaptation were associated with differential effects on tolerance, where THC-mediated antinociception, but not catalepsy or hypothermia, was attenuated in βarr2 KO mice. Overall, studies using SPM revealed intra- and inter-regional specificity in the function and regulation of CB1Rs and underscores an advantage of using a whole-brain unbiased approach. Understanding the regulation of CB1R signaling within different anatomical contexts represents an important fundamental prerequisite in the therapeutic exploitation of the cannabinoid system.
45
Zhao, Zhe. "Transcription regulation of Nrp1 during endothelial cell differentiation." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:a76152dd-72f0-450c-aad2-d0db732f2e6d.
Full textAbstract:
Various diseases, including cancer, stroke and heart attack, are associated with disruption of the vascular system. However, lack of a profound understanding of the transcription regulation during vascular development hinders the formation of effective molecular intervention strategies targeting angiogenesis. Here we describe an enhancer of Neuropilin1 (Nrp1) from the second intron of the gene that directs arterial and coronary endothelial cell-specific expression. Mice transgenic for either human or mouse sequences of the Nrp1in2 enhancers drove expression of the LacZ reporter gene specifically in the endothelial cells within the arterial compartment from early in development, while no expression was detected in veins. In addition, the hNrp1in2 enhancer directed expression to the endothelial cells in the developing coronary vasculature, with the initial expansion from around the sinus venosus at E11.5, and eventually contributed to the capillary, venous and arterial compartments of the coronary vessels but not the endocardium. This expression pattern is consistent with that reported in the Apelin-nlacZ line (Red-Horse et al., 2010), making the Nrp1 enhancer the first identified mammalian regulating enhancer of the coronary endothelial cell. Phylogenetic footprinting, and a tissue culture reporter assay suggested that this enhancer contains a 184bp minimal core region hNrp1in2peakA2 that recapitulates the expression profile of the full length enhancer. hNrp1in2peakA2 has conserved and in vitro validated recognition sites for Gata, Ets, and Fox. The validated Fox and Ets sites form a functional FOX:ETS motif, and the FOX:ETS motif is responsible for synergistic activation ofthe enhancer by FoxC2 and Etv2 in reporter assays. Mutation introduction to the functional Ets sites or compound ablation of the Gata and Fox site in hNrp1in2peakA2 result in total loss of vascular expression, in terms of both arterial and coronary expression. The Fox, Ets and Gata recognition sites may be sufficient to achieve arterial- and coronary- specific expression of the hNrp1in2peakA2.
46
Maxwell, Rachel Sarah. "The sufficiency of legal and professional regulation for the medical profession with respect to torture." Thesis, University of Dundee, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.494030.
Full text
47
Van, der Watt Pauline Janet. "Expression and regulation of the nuclear transport proteins, Crm1 and Kpnß1, in cervical cancer and transformed cells." Doctoral thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/3152.
Full text
48
Bracher, Jacqueline Claire. "Expression and regulation of N-Myc Downstream- Regulated gene 1 in squamous cell carcinoma of the oesphagus." Doctoral thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/3120.
Full textAbstract:
Squamous cell carcinoma of the oesophagus is a formidable disease which poses a significant health risk in developing countries where the incidence is frequently high and access to health care facilities is often limited. The identification of genes involved in oesophageal tumourigenesis may provide new targets for therapy and improved diagnostics techniques, thereby improving the prognosis of this pernicious disease. In this study, real-time RT-PCR and immunohistochemistry described the overexpression of N-Myc Downstream-Regulated Gene 1 (NDRG1) in oesophageal squamous cell carcinoma (OSCC) tissue compared to normal tissue in a cohort of South African cancer patients. Despite more than ten years of research into the role of NDRG1 in cancer, the precise function of this protein remains enigmatic. Reports have been contentious, suggesting both tumour suppressor and tumour promoter functions for NDRG1, implicating it in tumourigenic processes such as metastasis and angiogenesis. Our immunohistochemical analysis if NDRG1 expression in OSCC tissue and matched normal epithelium (n=83) showed that NDRG1 expression is elevated by 2.6-fold in cancer tissue compared to normal tissue. Moreover, the expression and localisation of NDRG1 appeared to track with epithelial cell maturation where basal cells of normal oesophageal epithelium displayed plasma membrane-associated NDRG1 while maturing cells were mostly positive for NDRG1 in the cytoplasm and nucleus. Likewise, NDRG1 displayed interesting patterns of localisation in tumour tissue of the xiii oesophagus. Dysplastic tissue and poorly differentiated tumour tissue stained positively for NDRG1 in the plasma membrane, while moderately and well differentiated tumours displayed mixed staining for NDRG1 in the plasma membrane, cytoplasm and nucleus. Analysis of NDRG1 expression in cell lines cultured under anchorage-independent conditions revealed that NDRG1 expression is strongly induced when cells are prevented from adhering to the surface of culture dishes. Induced NDRG1 expression correlated inversely with mRNA expression of invasion genes, MMP-2 and MMP-9, as well as the mRNA expression of angiogenic factors Ang- 1, PDGF-B and VEGF-C but, in contrast, showed positive correlation with the angiogenesis cytokine, VEGF-A. Knock-down of NDRG1 expression with siRNA had no effect on anchorage-independent cell proliferation or apoptosis but did inhibit VEGF-A expression. Moreover, VEGF-A promoter activity, induced by culturing cells under anchorage-independent conditions was shown to be NDRG1-dependent. In order to identify factors that may drive NDRG1 transcription in cultured OSCC cell lines we cloned and partly characterised the NDRG1 promoter. Through the generation of promoter deletion constructs, site-directed mutagenesis and Chromatin Immunoprecipitation (ChIP) assays, we showed that both EGR-1 and cJun/AP-1 are capable of driving transcription of NDRG1 in response to 12-o-tetradecanoylphorbol- 13-acetate (TPA) through activation of PKC/MEK/ERK1/2 and JNK MAPK pathways. Taken together, we describe the regulation of NDRG1 expression by EGR-1 and AP-1 and we show that NDRG1 is overexpressed in squamous cell carcinoma of the oesophagus compared to normal oesophageal tissue. We associate NDRG1 with an xiv oncogenic function in OSCC through its potential role in angiogenesis via modulation of VEGF-A expression.
49
Zhao, Xiaomin. "Regulation of Human Papillomavirus Type 16 mRNA Splicing and Polyadenylation." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5919.
Full text
50
Hilbun, Allison Leich. "Strategies of Balancing: Regulation of Posture as a Complex Phenomenon." Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etd/3014.
Full textAbstract:
The complexity of the interface between the muscular system and the nervous system is still elusive. We investigated how the neuromuscular system functions and how it is influenced by various perturbations. Postural stability was selected as the model system, because this system provides complex output, which could indicate underlying mechanisms and feedback loops of the neuromuscular system. We hypothesized that aging, physical pain, and mental and physical perturbations affect balancing strategy, and based on these observations, we constructed a model that simulates many aspects of the neuromuscular system. Our results show that aging changes the control strategy of balancing from more chaotic to more repetitive. The chaotic elements ensure quick reactions and strong capacity to compensate for the perturbations; this adeptly reactive state changes into a less reactive, slower, probably less mechanically costly balancing strategy. Mental tasks during balancing also decreased the chaotic elements in balancing strategy, especially if the subject experienced chronic pain. Additional motoric tasks, such as tying knots while balancing, were correlated with age but unaffected by chronic pain. Our model competently predicted the experimental findings, and we proceeded to use the model with an external data set from Physionet to predict the balancing strategy of Parkinson’s patients. Our neurological model, comprised of RLC circuits, provides a mechanistic explanation for the neuromuscular system adaptations.