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1
Tan, Sue Zanne. "Dynamic regulation of pathways by down-regulating competing enzymes." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/111402.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2017.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 106-116).
Microorganisms are promising hosts for the production of valuable chemicals, such as polymer and pharmaceutical precursors, fuel alternatives, flavors and fragrances. Achieving high yields of a product is often restricted by the interconnectivity of pathways in cells and finite nature of cellular resources. To overcome these limitations, dynamic pathway regulation has emerged as a strategy to balance flux between growth and production, such that titers and yields are maximized. Here, we demonstrate that dynamic pathway regulation by down-regulating competing enzymes can successfully improve yields of products. In Saccharomyces cerevisiae, we constructed a hexokinase valve where Hxk2 and GIk1 were deleted and the only remaining Hxk1 was placed under control of the tetracycline transactivating system (tTA) that enables repression of Hxk1 up to 10-fold in activity upon addition of doxycycline. Downregulation of this competing Hxk1 enzyme resulted in a 50-fold increase in gluconic acid and a 3-fold improvement in isobutanol yields from glucose. Extending this concept to other microorganisms, engineering downregulation of competing enzymes is dependent upon the ability to deplete a protein of interest in an inducible manner in the production host. In Pseudomonas spp., tools for specific protein depletion remain limited. Current methods involve promoter replacements and addition of degradation tags that require editing the genome, a process that can be laborious in Pseudomonas. Here, we developed a CRISPRi gene repression system by engineering the Streptococcus pasteurianus dCas9 and sgRNA. We demonstrate a robust and titratable gene depletion system, with up to 100-fold repression in [beta]-galactosidase activity in P. aeruginosa. We performed the first in vivo characterization of PAM site preferences of S. pasteurianus dCas9, revealing that targeting both NNGTGA and NNGCGA within the promoter can provide robust repression. Finally, the developed CRISPRi gene depletion system enabled the downregulation of competing muconate cycloisomerase in P. putida, leading to accumulation of muconic acid. In summary, we show that dynamic regulation of pathways by downregulating competing enzymes is an effective method to improve titers and yields of products. Controlling enzyme abundance at the transcriptional level proved successful with the existing tTA system in S. cerevisiae and with our developed CRISPRi system in Pseudomonas.
by Sue Zanne Tan.
Ph. D.
2
Matthews, Duncan Neville. "Characterising EC regulation : emulation, innovation, re-regulation." Thesis, London School of Economics and Political Science (University of London), 2008. http://etheses.lse.ac.uk/2577/.
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The thesis characterises European Community (EC) regulation in terms of three levels of ideas, namely that: (a) the EC regulatory process is best understood by particular styles or processes of regulation that the thesis terms emulation, innovation and re-regulation; (b) there are particular determinants or causes of regulation that are best understood as regulatory competition, consensus and co-operation; and (c) a hypothesis can be derived from the review of associated literature to the effect that diffusion of ideas and policy learning leading to consensus and co-operation are often of greater significance than regulatory competition in the EC regulatory process. To this end, taking as a frame of reference the characterisation of styles or processes of regulation as emulation, innovation and re-regulation, the thesis challenges the assumption, prevalent in much of the literature, that the main determinant or cause of EC regulation is regulatory competition among member states seeking to enhance their own competitive position in the European market and reduce the costs associated with legal adjustment. Using evidence from case study material relating to EC regulation of insurance services and drinking water quality the thesis tests the hypothesis that, although the literature has stressed regulatory competition as the main determinant or cause of EC regulation, in practice diffusion of ideas and policy learning are likely to occur, leading to co-operation between actors in a manner that ensures the emergence of a broad consensus on the preferred EC regulatory approach without recourse to regulatory competition at all. The thesis finds that regulatory competition is not, in fact, the only determinant or cause of EC regulation. Instead, diffusion of ideas and policy learning leading to consensus and co-operation are of crucial importance and should be accorded greater significance in the literature than has been the case in the past.
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Boyce, Toussant. "Dynamic financial regulation : automaticity and auto-regulation." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648541.
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Bonleu, Antoine. "Housing market regulation and labor market regulation." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM2009/document.
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Le premier chapitre montre l'interdépendance sur le marché locatif entre le formalisme procédural (FP) et les réseaux sociaux locaux. Tandis que le FP augmente le coût de résolution des conflits juridiques entre propriétaires et locataires, les réseaux sociaux présentent l'avantage de pouvoir régler un conflit sans la justice. Le FP permet de rendre plus intéressant aux yeux du propriétaire les individus appartenant à un réseau social. Le deuxième chapitre explique l'importance du soleil sur la demande de régulation du marché locatif. Les pays d'Europe du sud très ensoleillés sont attractifs de par leur douceur de vie. Cette immigration potentielle augmente la tension sur le marché locatif. Pour la réduire, les individus d'Europe du sud développent une complémentarité entre capital social local et régulation. Cette stratégie explique un équilibre méditerranéen où le capital social local et le FP sont élevés. A contrario, l'absence d'attractivité des pays faiblement ensoleillés explique un équilibre anglo-saxon et scandinave aux caractéristiques opposées. Le troisième chapitre explique le soutien pour la régulation du marché du travail par la présence de régulations sur le marché locatif. Lorsque ce dernier est très régulé, les propriétaires sélectionnent les locataires selon leur capacité à payer le loyer. Protéger les contrats à durée indéterminée oblige les entreprises à sélectionner les travailleurs et permet alors aux propriétaires de mieux estimer le risque individuel de licenciement. Nous construisons un modèle où les individus sans emploi demandent plus de régulations et de protections en dépit de l’augmentation du chômage et de la part des contrats temporairesThe first contribution studies the complementarities between the strength of social networks and the stringency of procedural formalism. While procedural formalism increases the cost of legal dispute resolution between landlords and tenants, social networks allow conflicts to be solved without recourse to justice. Procedural formalism is thus a way to provide a market advantage to local individuals embedded in dense local social networks at the expense of nonlocal agents without access to such networks.The second contribution deals with the importance of the sun on the demand for regulation in the rental market. Southern European countries with good climate amenities are attractive by their mildness of life. This potential immigration increases the pressure on the rental market. To reduce it, individuals in Southern Europe develop complementarities between social capital and local regulations. This strategy explains a Mediterranean equilibrium characterized by high levels of local social capital and procedural formalism. Conversely, the lack of attractiveness of countries with low climate amenities leads to an Anglo-Saxon and Scandinavian equilibrium with opposite features.The third contribution explains the support for labor market regulation by the presence of regulations on the rental market. When the rental market is very regulated, landlords screen applicants with regard to their ability to pay the rent. Protecting regular jobs offers a second-best technology to sort workers, thereby increasing the rental market size. We provide a model where non-employed workers demand protected jobs despite unemployment and the share of short-term jobs increase
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Hyder, Nishat. "Developing facilitative governance frameworks for emerging biotechnologies : exploring new approaches to cross-border regulation." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/developing-facilitative-governance-frameworks-for-emerging-biotechnologies-exploring-new-approaches-to-crossborder-regulation(525a9a76-d3bc-43a8-adb4-1cd8c91d8583).html.
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This thesis considers the applicability of 'new governance' techniques within the field of emerging biotechnologies. Through three contrasting case studies I construct an argument in favour of new governance, contending that the qualities of this regulatory trend (flexibility, reflexivity, nuance, open discourse, and participation - 'regulatory desirables' ) have much to offer the regulation of emerging biotechnologies. The first case study examines the existing European and international regulatory frameworks for genetically modified organisms (GMOs). This case study explores the role of (bio)ethics within the regulatory process through each progressive stage: design, operation, and assessment. The regime's failure to provide adequate space for ethical reflection, and the limited role of ethics throughout the regulatory process prompts a proposal for an alternative approach that recognizes the multiple contexts in which regulation operates, and is able to accommodate the socio-ethical nuances of the GMO products being assessed. This case study analyses a traditionally structured regulatory framework. It exemplifies a number of qualities that I consider undesirable in the context of regulating biotechnologies: inflexibility, lack of reflexivity, lack of nuance within the regime, absence of ethical discussion, absence of participation from all interested/affected parties. In the second and third case studies I show how these 'regulatory undesirables' can be addressed through new governance techniques. The second case study focuses on the international regulation of stem cell research; I propose developing a polycentric, principles-based regulation (PBR) regime. The third case study centres on the international governance of the gene synthesis industry; here I recommend adopting a risk-based regulation (RBR) approach. In both these fields, voluntary, interdisciplinary, international organisations have collaborated to produce guidelines, codes, protocols, standards, and statements addressing matters of practice. I argue that these 'soft law' documents form the ideal starting point for the development of more sophisticated regulatory regimes in both fields. Furthermore, I argue that the informal organisations producing these documents are, in certain instances, best placed to step into the role of 'regulator' due to their in-depth, inside knowledge of the field, and network. Thus, I collapse the regulator-regulatee distinction held in traditional, 'command and control' style systems, as these organisations typically include those who would traditionally be seen as the 'regulatee'. Each case study considers the nuances of context vis-à-vis the regulatory approach advocated. I conclude by engaging in a comparative analysis of these three case studies, drawing out the qualities, characteristics and considerations that I regard as essential to the construction of responsible, facilitative governance frameworks across the field of emerging biotechnologies. I conclude that new governance is best suited to achieving these (aforementioned) 'regulatory desirables'.
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Tong, González Francisco. "Administrative Simplification and "Positive Regulation" in the Environmental and Mining Regulations." Derecho & Sociedad, 2015. http://repositorio.pucp.edu.pe/index/handle/123456789/119160.
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In this article, the author studies the objectives and principles established during the 90’s,with respect to administrative simplification in contrast with the current governmental objectives for the optimization of the economy and reduction of unnecessary procedures,basically related to mining and environmental proceedings. Finally, the author proposes theneed for a structural change in Peruvian Mining and Environmental Regulations under the framework of what he calls a «positive regulation».En el presente artículo el autor reflexiona acerca de los objetivos y principios trazados en la década del noventa, en lo que respecta específicamente a la simplificación administrativa comparándolos con los objetivos actuales de dinamización de la economía y reducción de trámites innecesarios; principalmente, los referidos a procedimientos mineros y ambientales. Finalmente, el autor plantea la necesidad de un cambio estructural en la regulación ambiental y minera bajo la forma de lo que denomina una «regulación positiva».
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Ross, John D. "Regulating Hypermedia: Self-regulation learning strategies in a hypermedia environment." Diss., Virginia Tech, 1999. http://hdl.handle.net/10919/26921.
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Students of all abilities and ranges of achievement have become familiar with a variety of hypermedia-based settings which offer information on virtually any content area. The concept of self-regulation implies that learners can initiate processes to facilitate learning regardless of their perceived learning ability or environment, two learning characteristics once thought to be immutable forces. The purpose of the study was to design and implement hypermedia components that provide various levels of user support based upon known self-regulatory learning strategies. The components were applied within an existing web-based learning environment which combined class lecture and presentation with web-based components. Student input provided impetus for the revision of existing components and suggestions for new components designed to promote regulatory behavior within the web-based environment. Through participant observation, student desires for hypermedia components which promote self-regulatory behaviors are described and compared with the actual usage patterns of these components. Significant differences were found in measures of students perceived level of self-efficacy for performance and learning, metacognitive self-regulation, and test anxiety. In addition, one of the added components was rated as "highly effective" by the participants and the second-most-used component of the web site. Discussion incorporates student input to provide support for incorporating components which promote self-regulatory learning strategies in a hypermedia instructional environment and offers generalizations for educators and instructional designers based on these findings.Ph. D.
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Averis, Roslyn Ann. "Regulation revisited : Australia's new economy and regulation theory /." Title page, abstract and table of contents only, 2001. http://web4.library.adelaide.edu.au/theses/09AR/09ara952.pdf.
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李詠欣 and Wing-yan Lee. "Regulation of genes involved in cellular osmotic regulation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1999. http://hub.hku.hk/bib/B31223011.
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Lee, Wing-yan. "Regulation of genes involved in cellular osmotic regulation /." Hong Kong : University of Hong Kong, 1999. http://sunzi.lib.hku.hk/hkuto/record.jsp?B21301165.
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Marrs, Kevin L. "The cystic fibrosis transmembrane conductance regulator regulation by HSP-90 /." View the abstract Download the full-text PDF version, 2007. http://etd.utmem.edu/ABSTRACTS/2007-031-Marrs-index.html.
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Thesis (Ph.D.)--University of Tennessee Health Science Center, 2007.Title from title page screen (viewed on July, 18, 2008). Research advisor: Anjaparavanda Naren, Ph.D. Document formatted into pages (xv, 72 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 66-72).
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Madera, Laurence. "Mechanisms of immune response regulation by innate defense regulator peptides." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/43066.
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The growing threat of antibiotic-resistant bacteria necessitates the development of new anti-infective therapeutics. Innate defense regulator (IDR) peptides are a novel class of immunomodulatory agents shown to combat bacterial pathogens in murine models of infection via the augmentation of host immune functions, including the stimulation of chemokine production and enhancement of leukocyte recruitment, while suppressing bacterial-induced inflammation. Although IDR-peptides present the potential for future broad-range anti-infective agents, our limited understanding of how they modulate host immunity remains an obstacle in their development as clinical therapeutics. I hypothesized that IDR-peptides impact host immunity by modulating the immune responses of monocytes, a cell population necessary for IDR-mediated protection against infection. In this study, IDR-1002 was found to be a multi-faceted regulator of monocyte migration. IDR-1002 induced the production of monocyte-specific chemokines MCP-1 and MCP-3, as well as neutrophil-specific chemokines, IL-8 and GRO-α in human peripheral blood mononuclear cells (PBMCs), correlating with the activation of the mitogen-activated protein kinases (MAPK), p38 and extracellular-regulated kinase (ERK)-1/2, in monocytes. IDR-1002 was also found to enhance human monocyte migration towards chemokines through the enhancement of β1-integrin-mediated adhesion to fibronectin via regulation of the phosphatidylinositol-3-kinase (PI3K)-Akt signalling pathway. In addition, IDR-1002 increased monocyte responsiveness to the chemokines MIP-1α and RANTES via modulation of CCR5 expression. These results demonstrate an overall promotion of monocyte motility by IDR-1002. In contrast to the immune-strengthening effects of IDR-1002, the production of pro-inflammatory cytokines in human PBMCs stimulated with bacterial lipopolysaccharide (LPS) was suppressed by the peptide, and correlated with a suppression of LPS-induced NFκB and p38 MAPK signalling and activation of PI3K-Akt signalling in monocytes. These results demonstrate that IDR-peptides are potent modulators of human monocyte function via their extensive regulation of monocyte signalling networks, potentially accounting for their multifunctional effects on host immunity in murine models of bacterial infection.
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Tsao, Hui-Lan. "Telecommunication regulation." Thesis, University of Canterbury. Department of Economics, 2002. http://hdl.handle.net/10092/4662.
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Telecommunications has gained in importance in the world economy. Regulation of
this industry therefore has become a crucial policy issue of the governments around
the world. In the thesis, I examine regulation of telecommunications services in OECD
countries. Special attention is given to the New Zealand regulatory regimes before and
after the second regulatory reform. As the first regulatory reform in telecommunications
in New Zealand occurred over a decade ago, regulatory measures had to be adjusted
to suit the current environment. This was the main reason for the establishment of
a government-mandated inquiry. Measures were sought and evaluated to reduce or
eliminate problems that were associated with the old regime, especially the not-very productive
commercial negotiations and the not-very-efficient process and the institution
that operators relied on for solving their disputes. I use Coase Theorem to examine why
commercial negotiations did not work as effectively as the government envisaged. With
the adjustments of regulatory institutions and their functions, the government wishes to
counter the time-consuming dispute resolution process that works against new entrants,
and to increase the incentive to negotiate. The second regulatory reform shifted the
regulatory burden from the courts to the industry and the Commerce Commission.
Comparisons of the two regimes are made to analyse the differences of the two regimes
to achieve better understanding of the social and economic goals of the New Zealand
government. The two regimes are evaluated to provide information on the potential
problems that might emerge in the future. Topics such as the difficulties a regulator
faces in imposing appropriate regulatory measures, the direct relationships of regulation
and competition and the indirect relationships of regulation and telecommunications performance are analysed in depth.
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Thomas, David John. "Transcription regulation : models for combinatorial regulation and functional specificity." Thesis, University of Sussex, 2014. http://sro.sussex.ac.uk/id/eprint/48754/.
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Gene regulation id controlled by transcription factor proteins that bind to specific DNA sequences, known as transcription factor binding sites (TFBSs). Combinations of transcription factors working, co-operatively in cis-regulatory modules (CRMs), play a role in regulating gene expression. Current computational methods for TFBS prediction cannot distinguish between functional and non-functional sites, and predict very large numbers of false positives. The thesis focuses on the development of a novel computational model, based on artificial neural networks (ANNs), for the identification of functional TFBSs, and the CRMs within which they operate in the human genome. Datasets of 12,239 experimentally verified true positive (TP) TFBSs and 130,199 false positive (FP) TFBSs were extracted using a combination of position weight matrices from the JASPAR database and experimentally verified sites from the Encyclopedia of DNA elements (ENCODE). A number of machine learning alsgorithms were tested using a range of genetic information including gene expression, necleosome positioning, DNA methylation states and DNA entropy. The best model, that gave a mean area under the curve under a receiver operator characteristic curve of 0.800, was based on a feedforward ANN using backpropagation. This model was then used to predict functional TFBSs in a number of gene sets from the human genome. The predictions, combined with experimentally proven TFBSs from ENCODE, were used to investigate combinatorial patterns of TFBSs operating in CRMs. CRM patterns have been analysed in disease-associated genes located in linkage disequilibrium blocks containing SNPs obtained from Genome Wide Association Studies (GWAS). The potential for the model to make functional TFBS predictions to aid in the annotation of orphan genes of unknown function is discussed. In addition this thesis presents computational work on a number of smaller published studies.
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Chu, May. "The internationalisation of regulation : food safety regulation in China." Thesis, London School of Economics and Political Science (University of London), 2014. http://etheses.lse.ac.uk/961/.
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The aim of the thesis is to examine the implications of the internationalisation of regulation in China as a developing country. To achieve this, variations in different Chinese food regulatory regimes are compared, ranging from those for domestic consumption to export. In particular, the three control components of a regulatory regime, namely standard-setting, information-gathering and behaviour-modification are analysed. This study finds a pattern of changes in the Chinese food regulatory regimes. At the initial stage, Chinese national food standards were less stringent than international standards, and the gap between established national standards and local enforcement was significantly high. In recent years, it is observed that Chinese national food standards have witnessed an upward movement to converge with international food standards. In the meantime, regulatory enforcement in the localities has undergone continual adjustment to strengthen enforcement force towards areas under public concern. This thesis aims to explain this trend of changes in terms of the internationalisation of regulation. It argues that while coercive international pressure is mainly exerted on the Chinese exported food regulatory regime, the domestic food regulatory regime in China has also been increasingly influenced by global forces over the past decade, in terms of policy transfer from developed countries and policy learning from the transnational professional networks. Regarding domestic food standard-setting, normative influence from the international community has induced a generally higher level of Chinese national food standards. With respect to regulatory enforcement, while enforcement work has been constrained by the incapacity of regulators and the inextricably linked interests in the localities, these domestic factors are becoming less influential under the context of internationalisation of regulation. In particular, food safety crises prompt the Chinese government to push forward regulatory changes in spite of strong resistance in the localities. This has been attributed to the aim of the Chinese government to safeguard the reputation of products ‘Made in China’ under the context of internationalisation of regulation, and build up an international image that China is a committed and responsible trading partner and world leader.
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L'Huillier, Dominic. "Economic regulation of Queensland ports : market power and price regulation /." St. Lucia, Qld, 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18085.pdf.
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Rados-Blanusa, Tijana. "Climatic and physiological regulation regulation of premature cherry fruit abscission." Thesis, Lancaster University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420175.
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Evans, Daniel R. "SELF-REGULATION IN OLDER ADULTS: THE PRIORITIZATION OF EMOTION REGULATION." UKnowledge, 2014. http://uknowledge.uky.edu/psychology_etds/43.
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Despite having fewer cognitive resources, older adults regulate their emotions as well as, if not better than, younger adults. This study aimed to (1) test the limits of older adults’ emotion regulation capacity and (2) gain a better understanding of how older adults use their more limited resources to regulate their emotions. Participants included 48 healthy older adults aged 65-85 from the community and 50 healthy younger adults aged 18-25 from the student population. They were randomly assigned to one of four experimental groups involving an initial activity that was high or low in self-regulatory demand followed by a test task of emotion regulation or attention regulation. As expected, older adults performed equally as well as younger adults on the emotion regulation test task, though worse on the attention regulation test task. Using resting heart rate variability (HRV) as a physiological measure of self-regulatory capacity, older adults appeared to allocate more resources toward the emotion regulation task compared to the attention regulation task, and relative to younger adults. The results suggest that older adults maintain their emotion regulation capacity in part by allocating more resources toward emotion regulation goals.
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Annosi, Maria Carmela. "Regulation and Self-Regulation of Team Learning and Innovation Activities." Doctoral thesis, Stockholm, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-193568.
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Self-regulated learning and innovation activities within teams are those processes with which team members collectively activate and sustain cognition, affects and behaviors which are systematically oriented towards the achievement of their team’s goals. Although research on self-managing teams exists, there remains considerable confusion on many issues including what self-regulation is and how regulation of self-regulated learning and innovation activities is carried out. A primary contribution of this dissertation is to introduce a theoretical framework for analysing and applying regulative actions in organizational environment. The aim of this dissertation is to advance the understanding on how regulation of self- managing team learning and innovation activities can happen starting from an analysis of the self-regulative learning processes of individuals within teams and of their own determinants. This dissertation has three objectives: 1) to present internal team mechanisms involved in the self-regulation of teams’ learning activities, their interactive dynamics and their corresponding major organisational determinants; 2) to rely on this novel understanding to detect relevant regulative actions which are able to indirectly influence teams’ self-regulatory learning and innovative behaviour; 3) to offer empirical evidence of how specific regulative actions affect team learning and innovation performance. We discover that there are four major constructs associated with the regulation of teams’ learning and innovation activities: feedback loops and goals equally combining learning and performance items, networks of influence made up of managers and stakeholders interacting with teams through systematic routines, training programmes for team members, dialectical perspective on learning and innovation to force in the managerial layers.QC 20161005
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Sinclaire-Harding, Lysandra. "Profiling emotion regulation : exploring patterns of regulation in classroom behaviour." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/271634.
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Emotion Regulation describes the ability to influence the experience and expression of affect. Adaptive emotion regulation contributes to healthy development, social competence and academic success (Kochanska, Murray & Harlan, 2000). This study investigated the behavioural strategies for emotion regulation, emotion expression, regulatory styles and classroom behaviour in middle childhood. One hundred and twenty-eight children were recruited from five UK public and private primary schools. From within their school setting, participant sensitivity to emotion-eliciting events was recorded using ambulatory skin conductance technology whilst age-group paired children performed two LEGO construction tasks. Observed behaviours were video-recorded and coded to establish frequencies of distinct regulatory behaviours. These were compared to self-reports of emotion regulation strategies and teacher-reports of classroom behaviour. Iterative partitioning cluster analysis methods were used to identify four regulatory profiles: 1) the ‘Adaptive’ cluster: employed high levels of positive problem solving and reappraisal strategies and frequently expressed both positive and negative emotions; 2) the ‘Maladaptive’ cluster: used more negative regulation (avoidant or obstructive strategies), expressed more negative emotion and had more social and behavioural problems in class; 3) the ‘Reactive’ cluster showed high levels of electrodermal activity, expressed little emotion and were reported as inattentive/hyperactive in class; and 4) the ‘Distracted’ cluster demonstrated high levels of behavioural and cognitive distraction. These results indicate four meaningful profiles that could support the identification of vulnerable individuals for positive school-based intervention and support.
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Szellas, Tanjef. "Regulation des CFTR." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=964740117.
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Aviram, Amitai. "Regulation by networks." Diss., John M. Olin Program in Law and Economics working paper series Social Science Research Network Electronic Paper Collection, 2003. http://ssrn.com/abstract%5Fid=387960.
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Ionescu, Irina Gabriela. "Aircraft noise regulation." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82660.
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Aircraft noise is one of the most controversial environmental concerns in the aviation industry, partly due to the difficulty in harmonizing countries' regulation regarding this issue. The purpose of this thesis is to analyze the ways in which aircraft noise is regulated at the national and international levels, and to compare the legislative responses to aircraft noise issues in Europe and North America. Each of the four main chapters of the thesis takes into consideration a different aspect of the problem. The first chapter describes the objective and subjective ways of measuring aircraft noise. This process is necessary in order to allow the legislation to meet its purpose, namely, to protect the environment, the sources of the aircraft noise, and the effects of the aircraft noise on people. The second chapter describes the evolution of aircraft noise issues at the national levels in the US and throughout the EU, respectively, as well as at the international level, such as at the ICAO. The third chapter analyses the EU Regulation 925/1999, which created tension between the EU and the US due to its alleged discriminatory nature. This thesis examines the arguments of both sides. Finally, the fourth chapter analyses the noise certification standards developed by ICAO, namely the "balanced approach".
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RAMOS, PAULO DANIEL SALLES. "DYNAMIC MONOPOLY REGULATION." PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIRO, 2011. http://www.maxwell.vrac.puc-rio.br/Busca_etds.php?strSecao=resultado&nrSeq=18422@1.
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COORDENAÇÃO DE APERFEIÇOAMENTO DO PESSOAL DE ENSINO SUPERIORPROGRAMA DE SUPORTE À PÓS-GRADUAÇÃO DE INSTS. DE ENSINO
O artigo estuda o problema de um regulador social que deseja induzir um monopolista natural a implementar um projeto de forma socialmente eficiente. O projeto tem longa duração e os custos do projeto variam de período a período de acordo com um processo estocástico. Adicionalmente, estuda-se a decisão de investimento do monopolista em tecnologia para se reduzir os custos deste projeto e como esta decisão está ligada ao contrato de produção oferecido pelo regulador. Mostra-se a forma que o contrato ótimo de regulação assume sob estas condições e como as distorções envolvidas no contrato são tão maiores quanto maiores forem as informações que a firma possui acerca de seus custos futuros. Mostra-se também que as distorções são tão maiores quanto maior for o investimento da firma em tecnologia e que por sua vez esse investimento caminha oposto aos custos sociais líquidos da tributação.
The paper studies the problem of a social regulator that wants to induce a natural monopolist to implement a project in a socially efficient way. The project has a long duration and project costs vary from period to period according to a stochastic process. Additionally, we study the investment decision of the monopolist in technology to reduce the cost of this project and how this decision is linked to the production contract offered by the regulator. We show the optimal contract that arises under these conditions and how the distortions involved in the contract are greater the higher the information that the firm has about its future costs. We also show that the distortions are greater the higher the firm’s investment in technology and in turn that investment goes to the opposite net social cost of taxation.
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Hirte, Georg, and Hyok-Joo Rhee. "Regulation versus Taxation." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-210925.
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We examine the working mechanisms and efficiencies of zoning (regulation of floor area ratios and land-use types) and fiscal instruments (tolls, property taxes, and income transfer), and extend the instrument choice theory to include the congestion of road and nonroad infrastructure. We show that in the spatial model with heterogeneous households the standard first-best instruments do not work because they trigger distortion of spatial allocations. In addition, because of the household heterogeneity and real estate market distortions, zoning could be less efficient than, as efficient as, or more efficient than pricing instruments. However, when the zoning enacted deviates from the optimum, zoning not only becomes inferior to congestion charges but is also likely to reduce welfare. In addition, we provide a global platform that extends the instrument choice theory of pollution control to include various types of externalities and a wide range of discrete policy deviations for any reasons beyond cost–benefit uncertainties.
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Zhang, Fan. "Regulation of G1 /." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/zhang/.
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Toh, Yew Kwang. "Docking-dependent regulation of checkpoint kinase chk1 by the growth regulator p21WAF1." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4215.
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Checkpoint kinase 1 (Chk1) is a key player in the DNA damage response signalling pathway and the mode of Chk1 activation whereby it undergoes ATRdependent phosphorylation at Ser317 and Ser345 is well characterised. It has been suggested that phosphorylation at the ATR sites relieves the auto-inhibitory action conferred by the C-terminal negative regulatory domain on the catalytic core of Chk1. In this study, we show that Chk1 activity can also be stimulated by docking to an N-terminal region of the growth regulator p21waf1 and this docking domain is necessary for efficient Chk1-dependent phosphorylation of p21 at Ser146. In addition, Chk1 and p21 are shown to form a transient interaction by immunoprecipitation. Interestingly, although the isolated p21 docking domain can activate Chk1 in trans, a mutant where the C-terminal 70 amino acids are truncated is refractory to stimulation whereas mutation of the ATR phosphoacceptor sites does not affect docking dependent activation. Furthermore, when the amino acid sequence of the p21 docking domain was aligned with the sequence of Chk1, homology to the F region on the kinase domain was identified. Mutation of two conserved tryptophan residues within the homology region appears to release the C-terminus from intramolecular interactions rendering it susceptible to cleavage and refractory to allosteric stimulation. Furthermore, small peptides based on this region of Chk1, like the p21 docking domain, are able to activate Chk1 in trans and disrupt interaction between the N-terminal and Cterminal domains. Interestingly, peptide microarray showed that Chk1 stimulated by activating peptide is able to phosphorylate novel peptide substrates which are not observed with unstimulated Chk1. The data suggest that the last C-terminal 70 amino acids of Chk1 play an important role in auto-inhibition through interaction with the F region of the core catalytic domain. Binding to p21 is able to activate Chk1 by inhibiting the auto-inhibitory interaction independent of phosphorylation at the Ser317 and Ser345 sites. Furthermore, activating peptide is able to modulate Chk1 specificity towards other substrates.
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Sangha, Dalvinder Singh. "The role of the regulator, auditor and banker : the limits of regulation." Thesis, University of Wolverhampton, 2002. http://hdl.handle.net/2436/96285.
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Crutzen, Helene Sabine Giovanna. "Cis-regulation of MyoD : a systems analysis of a fate master regulator." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/17977/.
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Myogenesis is highly regulated and its activation in the embryo is controlled by a series of complex transcriptional regulatory networks that ultimately result in the expression of myogenic regulatory factors (MRFs). The MRFS, particularly MyoD and Myf5, are responsible, in concert with a vast range of cofactors, for directing the expression of genes responsible for muscle formation and activity. Several candidate proteins have emerged as being responsible for MRF expression, as well as numerous downstream effectors involved in muscle formation in vivo. Several cis-regulatory elements have been identified for MyoD, but only a handful of factors have been identified that bind these elements. In addition, knockout experiments of these regions do not result in a complete loss of MyoD expression, suggesting a certain level of redundancy and the existence of other yet unidentified cis-regulatory modules. In this study, novel potential regulatory regions within the MyoD upstream genomic locus were identified by comparative genomics. These regions, named ReMos 9, 10 and 11, were conserved in mammals, chick and fish. Reporter assays in C2C12 cells using these regions cloned upstream of the MyoD promoter revealed that they positively enhanced the promoter activity. A synergy was uncovered between ReMo 9 and 10, which have a strong positive effect on promoter activity, but none individually; ReMo 11 seemed to disrupt this synergy. In addition, ReMos 9+10 and the CER enhancer were shown, by double fluorescent RNA in situ hybridisations, to be transcribed and possess cryptic promoter activity. This suggested that these elements acted as alternative promoters and encoded RNAs that regulated MyoD gene expression. Furthermore, the use of a newly engineered database generated predictions of DNA-binding factors interacting with the cis-regulatory regions, as well as protein interaction networks involved in MyoD regulation. These predictions were refined and constrained with biological input data derived by microarrays of single-cells transiently expressing relevant constructs. A list of candidate muscle-specific binding factors was then tested in vitro by siRNA knockdown experiments, and showed that MyoD disrupts the positive synergistic effect of ReMos 9 and 10 on the PRR. In conclusion, this study identified a number of regions that seem to be involved in MyoD regulation, and candidate factors binding to the MyoD cis-regulatory regions. Further in vivo validation will identify their function in MyoD spatio-temporal gene expression.
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Senesac, Erin. "Cognitive depletion in emotion regulation: age differences depend on regulation strategy." Thesis, Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/34837.
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Recent work has suggested that emotion regulation of inner emotional experience requires fewer cognitive resources for older adults than for young adults (Scheibe&Blanchard-Fields, 2009). The present study investigated whether cognitive costs are reduced for various types of emotion regulation strategies or only for certain types. The suppression of emotional expression, for example, is a particularly costly strategy for young adults, but little information exists regarding its cognitive costs for older adults. Furthermore, suppression of emotional expression is not a strategy that older adults are likely to use or that they become more effective at using. By contrast, the regulation of inner emotional experience has been shown to be more effective in older adults and presents less of a cognitive cost. The present study examined the cognitive costs of regulation of inner emotional experience (to conceptually replicate previous findings) and the cognitive costs of suppression of the outer expression of emotion. The results suggest that regulating and suppressing emotions do not require the same degree of resources for older and young adults. Whereas older adults may require more resources to suppress expression of emotions than to regulate emotions, young adults appear to require more resources to regulate emotions than to suppress the expression of emotions.
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Dodd, Jessica Amen Alexandra Fineman Stephanie. "Mechanisms of self-regulation associations between cognitive control and emotion regulation /." Diss., Connect to the thesis, 2008. http://hdl.handle.net/10066/1427.
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Guimbellot, Jennifer S. "Role of hypoxia in epithelial gene regulation." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2009r/guimbellot.pdf.
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Ansari, Saira. "Calcium control of smooth muscle myofilament activity : an integrated dual regulations [i.e regulation system]." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405559.
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Quirin, Markus. "Self-System and Regulation of Negative Affect [Selbstsystem und Regulation negativen Affekts]." Doctoral thesis, [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=979018439.
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Doelker, Andreas. "Self-regulation and co-regulation : prospects and boundaries in an online environment." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/27918.
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Industry self-regulation and governmental regulation compete for the best model of Internet regulation. This thesis challenges the argument that they have to be antagonistic schemes and evaluates the possibility of cooperation in the form of co-regulation or ‘regulated self-regulation’. It uses a comparative method to analyze the preference for the regulatory models in Europe, the United States and Canada, which draws upon the role of governments in a historical context and the impact of fundamental rights in the respective constitutional frameworks. Before considering the peculiarities of Internet regulation, the thesis identifies and analyzes the advantages and difficulties of both self-regulation and co-regulation. Whereas self-regulation lacks democratic legitimacy, has little incentive to detect violations and to maintain high standards, governments have the ability to compensate for some of these problems. In the Internet context, this analysis reveals the need to deal with regulatory effects of code, transborder conduct, and ways to sanction non-compliance. However, governments with traditional command-and-control legislature have not adapted to these specifics. A system that would suit the Internet environment is composed of certification and accreditation of codes of conduct, and support of self-regulatory institutions. The thesis proposes ten criteria for efficient co-regulation that attend to fundamental values and favor an open, transparent collaboration. It further evaluates the substitution of governmental influence by external self-regulatory bodies, and the integration of Internet users to create a democratic link between regulators and regulated. The ten criteria are applied to some exemplary regimes to demonstrate practical application and ways to improve existing regulation. This shows the potential of models in which the public sector defines the goals and the private sector offers the solutions.
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Smith, G. "Corporate governance : In search of balance between state regulation and self regulation." Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.517519.
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Wong, Lai-ching Elyssa, and 黃麗菁. "Government re-regulation and de-Regulation of the Hong Kong bus industry." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1995. http://hub.hku.hk/bib/B31954510.
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Wong, Lai-ching Elyssa. "Government re-regulation and de-Regulation of the Hong Kong bus industry." [Hong Kong : University of Hong Kong], 1995. http://sunzi.lib.hku.hk/hkuto/record.jsp?B15967347.
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Kulacz, Wojciech. "Regulation of Inverted Formin-1 (INF1) by Microtubule-Affinity Regulating Kinase 2 (MARK2)." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/22801.
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The actin and microtubule cytoskeleton plays a critical role in the establishment of cell polarity. Cell processes like mitosis and migration rely on the reorganization of the cytoskeleton to properly function. One driver of cell polarity is the formin, Inverted Formin-1 (INF1). INF1 is able to induce F-actin formation, activate the Serum Response Factor (SRF) pathway, stabilize microtubules, associate with microtubules, and disperse the Golgi body. Regulation of INF1 is unique, since it does not possess conserved formin regulatory domains. However, INF1 does possess many potential phosphorylation sites. In this study, we demonstrate that INF1’s ability to induce F-actin stress fibers and activate SRF is inhibited by Microtubule-Affinity Regulating Kinase 2 (MARK2). Inhibition of INF1’s actin polymerization activity by MARK2 likely occurs near INF1’s C-terminus. However, MARK2 was unable to inhibit INF1’s ability to stabilize microtubules, associate with microtubules, and disperse the Golgi. Furthermore, we show that INF1 overexpression is associated with primary cilium absence and in some cases, the presence of long cilia, suggesting that INF1 plays a role in primary cilium formation.
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Rowntree, Rebecca Kate. "Regulation of expression of the human cystic fibrosis transmembrane conductance regulator (CFTR) gene." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393265.
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Lovewell, Thomas. "A study into the regulation and function of the Autoimmune Regulator (AIRE) Gene." Thesis, University of Sheffield, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500224.
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England, Alice. "The regulation of the cystic fibrosis transmembrane conductance regulator in human respiratory epithelia." Thesis, University of Sheffield, 2013. http://etheses.whiterose.ac.uk/3788/.
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Cystic fibrosis transmembrane conductance regulator (CFTR) is activated by cAMP-dependent phosphorylation, and functions as an ATP-dependent chloride channel involved predominantly in the movement of chloride ions to maintain cellular ionic homeostasis. Mutations in this channel cause cystic fibrosis, the most common lethal autosomal recessive disease in caucasians. The regulation of CFTR forms a large body of research; this thesis investigated the role of three potential components of the regulatory machinery – nucleoside diphosphate kinase B (NDPK-B), tyrosine phosphorylation and G proteins. This thesis aimed to: 1. Describe the functional relationship between NDPK-B and CFTR. 2. Describe the effect of altered tyrosine phosphorylation in 16HBE14o- cells on CFTR function. 3. Identify the tyrosine phosphatases involved in CFTR regulation. 4. Explain how alterations in tyrosine phosphorylation change CFTR function. 5. Describe the effect of G protein stimulation on CFTR channels which have already been activated by an increase in cellular cAMP. The whole cell patch clamp technique was used to examine ion channel function in two cell types - human bronchial epithelial cells (16HBE14o-) and baby hamster kidney cells (BHK-21). Due to alterations in the function of cultured cells, it was not possible to describe the functional relationship between the histidine kinase NDPK-B and CFTR. Further work is required in this area to elucidate the role of this protein in CFTR regulation. The use of general tyrosine phosphatase inhibitors resulted in a significant decrease in the CFTRinh-172-sensitive conductance in 16HBE14o- cells, and specific inhibitors ruled out the involvement of PTP1B and Shp1/2 phosphatases. Further work is required to explain how tyrosine phosphatase inhibition alters CFTR function. Finally, G protein stimulation in 16HBE14o- after increasing intracellular cAMP had no significant effect on channel function. This suggested that the cAMP-dependent activation of the channel is the predominant mechanism for stimulating channel function.
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Azzini, Matilde. "Sustainable Financial Disclosure Regulation." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2021.
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L’obiettivo dell’elaborato è quello di analizzare e descrivere l’implementazione di un progetto di adeguamento alla Normativa 2019/2088/UE.
Attraverso l’analisi del legame esistente tra sostenibilità e finanza svolta mediante un progetto di consulenza presso Accenture S.p.A per un gruppo bancario italiano sono stati approfonditi gli interventi necessari da implementare in ambito di disclosure finanziaria.
In particolare, attraverso la pubblicazione della normativa 2019/2088 o “”Sustainable Finance Disclosure Regulation”, l’Unione Europea ha predisposto delle norme armonizzate sulla trasparenza per gli intermediari finanziari in merito all’integrazione dei rischi di sostenibilità e la considerazione degli effetti negativi per la sostenibilità nei loro processi e nella comunicazione delle informazioni connesse alla sostenibilità relative ai prodotti finanziari.
Il contenuto della normativa mira a limitare la diffusione di fenomeni di greenwashing e a promuovere lo sviluppo e la diffusione di investimenti sostenibili, che integrino gli aspetti ESG a quelli finanziari.
Nell’elaborato viene presentato un quadro teorico-normativo introduttivo, utilizzato poi successivamente come strumento di implementazione nel progetto di adeguamento richiesto dal cliente. Attraverso l’analisi dello stato AS-IS dell’intermediario finanziario, sono state sviluppate dal team di progetto le successive fasi da sviluppare. Grazie all’analisi della documentazione del cliente e lo studio dei requisiti normativi richiesti dal regolamento sono state analizzate le aree di applicabilità al cliente e il perimetro d’azione del progetto, portando all’identificazione dei gap presenti e alla successiva pianificazione degli interventi necessari.
Al termine dell’elaborato vengono illustrati i risultati del progetto attraverso l’analisi degli interventi implementati, accompagnati dalle considerazioni finali sviluppate in relazione alla tematica trattata e all’esperienza svolta.
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Martínez, Corral Rosa 1991. "Modelling spatiotemporal cell regulation." Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/664968.
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In this Thesis we have studied how dynamics and space modulate cellular behaviour, by means of mathematical modelling of particular biological examples. At the single cell level, we show how pulsatile input signals can be decoded by downstream targets with an appropriate circuit architecture and response timescales. Regarding pulse generation, we show that stochastic pulses of protein activity can arise from a perturbation amplified by negative feedback. Beyond a single cell, we propose that oscillations in bacterial communities emerge from glutamate limitation in the biofilm centre that is transmitted by potassium signalling throughout the community, and can be conceptualised in terms of a subcritical Hopf bifurcation. Moreover, pairs of biofilms synchronise their dynamics resulting into a nutrient timesharing strategy. Finally, we propose that the contact area of cell-cell interactions modifies cell fate outcomes in the context of Drosophila midgut homeostasis.En aquesta Tesi hem estudiat com la dinàmica i l’espai modulen el comportament cel·lular, mitjançant models matemàtics de diversos exemples biològics. A nivell de cèl·lules individuals, mostrem que senyals polsàtils poden ser interpretats per les corresponents dianes intracel·lulars gràcies a circuits amb arquitectures i escales temporals de resposta adequades. Pel que fa a la generació de polsos, mostrem que polsos estocàstics poden produir-se a partir de l’amplificació d’una pertorbació mitjançant interaccions de retroalimentació negativa. Més enllà de cèl·lules individuals, proposem que oscil·lacions en comunitats bacterianes emergeixen de la limitació de glutamat al centre del biofilm, transmesa per senyalització per potassi a través de la comunitat, i que poden ser conceptualitzades en termes d’una bifurcació de Hopf subcrítica. A més a més, parelles de biofilms sincronitzen la seva dinàmica, donant lloc a un fenomen de compartició de recursos en el temps. Finalment, proposem que l’àrea de contacte entre cèl·lules modifica el destí cel·lular en el context de l’homeòstasi intestinal de Drosophila.
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Kollmeyer, Jessica Elaine. "Regulation of Galactosylceramide Biosynthesis." Thesis, Georgia Institute of Technology, 2006. http://hdl.handle.net/1853/11630.
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An important branchpoint of mammalian sphingolipid metabolism occurs at the step where ceramides are glycosylated to glucosylceramide (GlcCer) versus galactosylceramide (GalCer), which are precursors of all mammalian glycosphingolipids. Relatively few studies have focused on this branchpoint because these monohexosylceramides are somewhat difficult to resolve chromatographically and because molecular biology tools have only recently become available to follow expression of these genes. The goal of this thesis is to better understand the mechanisms of cell regulation determining galactosylceramide synthesis.
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Mellberg, Sofie. "Molecular Regulation of Angiogenesis." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9418.
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Angiogenesis, de novo formation of blood vessels from the pre-existing vasculature, is crucial in embryo development, and in processes in the adult such as wound healing and ovulation. Angiogenesis is also involved in pathological conditions such as cancer and chronic inflammatory diseases, which are propagated by dysregulated, excess angiogenesis. On the other hand, lack of functional vessels and poor blood flow is a major problem in myocardial and peripheral ischemia. A detailed understanding of the molecular mechanisms underlying angiogenesis is of vital importance for the development of drugs to regulate angiogenesis. The aim of this thesis has been to identify genes involved in regulation of angiogenesis. We have investigated gene expression over time in endothelial cells (ECs), using different in vitro models. We show that the proteoglycan endocan is upregulated in ECs invading a fibrin matrix in response to vascular endothelial growth factor (VEGF)-A. There was increased expression of endocan in renal tumour cells and tumour vessels compared to normal renal tissues, indicating that endocan might have a role in tumour growth and tumour angiogenesis. We also show that vascular endothelial protein tyrosine phosphatase (VE-PTP) is induced in ECs during differentiation into vessel structures in a three dimensional collagen matrix. Silencing of VE-PTP disrupts vessel formation and increases the activity of VEGF receptor-2 (VEGFR-2) and downstream signalling, leading to increased EC proliferation. This presents a possible mechanism for the failure of vessel formation, as EC morphogenesis requires growth arrest of the cells. We also show that VE-PTP and VEGFR-2 are closely associated in resting ECs. VEGF-A stimulation leads to rapid loss of association, coinciding with increased phosphorylation of VEGFR-2. The function of VE-PTP in vivo was investigated using the zebrafish model. We demonstrate specific expression of a zebrafish VE-PTP orthologue (zVE-PTP) in the developing vasculature. Silencing of zVE-PTP leads to defective vessel sprouting and branching, indicating a critical role for zVE-PTP in development of the zebrafish vasculature. In conclusion, this thesis presents gene regulation during endothelial cell morphogenesis and details the expression pattern of endocan and the function of VE-PTP in regulation of VEGFR-2-driven angiogenesis.
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Wardęga, Piotr. "Regulation of PDGFRβ signaling ." Doctoral thesis, Uppsala universitet, Ludwiginstitutet för cancerforskning, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-123045.
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Platelet-derived growth factor (PDGF) isoforms, which bind to closely related a- and b-tyrosine kinase receptors, induce migration, proliferation, survival and differentiation of mesenchymal cells. They signal by the active receptor attracting Src homology 2 (SH2) domain containing proteins, which subsequently initiate a set of signaling pathways. The aim of this thesis was to elucidate regulatory mechanisms involved in PDGFRb signaling. In the first two projects we investigated the roles in downregulation of PDGFRb of two related adaptor proteins, i.e. ALG-2 interacting protein X (Alix) and His-domain containing protein tyrosine phosphatase (HD-PTP) functions of. We found that Alix and HD-PTP influence ubiquitination of PDGFRb following PDGF stimulation, by affecting the E3 ligase c-Cbl. Alix enhances complex formation between c-Cbl and PDGFRb, increases c-Cbl phosphorylation and decreases its stability. Interestingly, while both HD-PTP and Alix participate in degradation of PDGFRb, only Alix affects receptor internalization. Moreover, we demonstrated that absence of HD-PTP promotes cell proliferation. In conclusion, we suggest that both Alix and HD-PTP are important adaptor proteins in regulation of PDGFRb downregulation, although the observed differences between their actions suggest that Alix and HD-PTP exert their functions via different mechanisms. The third study explored the importance of tyrosine residue 857 in the activation loop of PDGFRb. We report that, in vitro the tyrosine residue 857 to phenylalanine (Y857F) mutant receptor kinase activity is diminished while in vivo it does not affect the phosphorylation of PDGFRb. The phosphorylation pattern of PDGFRb revealed that most sites in the Y857F mutant receptor were phosphorylated similarly as in the wild-type receptor. However, tyrosine residue 771 was found to be hyperphosphorylated in the Y857F mutant receptor. This may be due to defective phosphorylation and activation of SHP-2, since it has been shown to dephosphorylate the receptor at Y771. In addition, activation of the Erk1/2 and Akt pathways was defective downstream of the Y857F mutant receptor. Interestingly, the Y857F mutant receptor was able to mediate cell migration, but not proliferation. The last study investigated a role of the tyrosine kinase Fer in PDGF signaling. We showed that Fer interacted with and was activated by PDGFRb in a ligand-dependent manner. In cells depleted of Fer, receptor phosphorylation was decreased and phosphorylation of Stat3 was abolished, whereas Stat5, Erk1/2 and Akt were activated normally. Colony formation in soft agar was abolished in cells depleted of Fer, but no effect was seen on cell proliferation and migration. Since Stat3 has been shown to be involved in transformation, we speculate that phosphorylation of Stat3 in Fer-depleted cells, affects the ability of cells to form colonies.
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Turner, Martin John Charles. "Regulation of cytokine production." Thesis, Imperial College London, 1990. http://hdl.handle.net/10044/1/46588.
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Hillier, Stephen Gilbert. "Regulation of ovarian function." Thesis, University of Edinburgh, 1992. http://hdl.handle.net/1842/26607.
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(i) Basic Experimental studies Publications 1-35 deal mainly with the use of cultured rat and marmoset monkey granulosa cells to study endocrine and paracrine mechanisms underlying gonadotrophin action on the ovaries. Primary cell cultures were used to define the roles of FSH and LH in controlling granulosa cell function and to assess the intrafollicular functions of sex steroids and putative nonsteroidal regulatory factors, such as inhibin. A particular contribution was the demonstration that androgens produced by thecal cells exert specific (receptor-mediated) modulation of granulosa cell differentiation - notably expression of aromatase, the enzyme uniquely responsible for oestrogen synthesis. Synthesis of inhibin and expression of messenger RNA species encoding inhibin and activin subunits in granulosa cells were also shown to be under gonadotrophic control and modulated by sex steroids, leading to the suggestion that the androgen/oestrogen and inhibin/activin axes of the ovarian paracrine system are functionally interlinked. (ii) Basic Clinical Studies Publications 36-56 are concerned with in vitro research on 'normal' ovarian tissues obtained from women undergoing elective surgical procedures. Techniques and experience acquired from experimental work on animal ovarian tissues were used to study the regulation of steroid hormone synthesis in human follicular and luteal cells. This work demonstrated that granulosa cells are primary cellular sites of oestradiol biosynthesis in the human ovary. It also confirmed the potential that theca-derived androgens have to modulate FSH-induced granulosa cell function, including aromatase activity and inhibin production. Conversely, androgen production by thecal cells was shown to be promoted by inhibin. Based on these findings it is postulated that an intrafollicular positive feedback loop exists mediated by theca-derived androgen and granulosa-derived inhibin, which may underpin preovulatory follicular 'selection' and oestrogen synthesis in the human menstrual cycle.
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Livingstone, Karen. "Emotion regulation in psychosis." Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/29225.
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The relatively new field of emotion regulation may provide insight into emotional dysfunction in psychosis and therefore the aim of this thesis is to better understand emotional experience and regulation in psychosis in comparison with other mental health problems and healthy volunteers. This study used a between-groups design and was based on an opportunity sample of patients attending clinical psychology departments. Three groups of participants were recruited for this study comprising of 21 individuals who had experienced psychosis, 21 individuals with an anxiety/mood disorder and 21 healthy volunteers. The participants completed 2 measures of emotion regulation: the Emotion Regulation Questionnaire (ERQ) and the Emotion Regulation Questionnaire-2 (ERQ-2); a measure of emotional experience: the Basic Emotions Scale and a measure of coping strategies: the Brief COPE. The clinical groups were found to utilise similar emotion regulation strategies and in comparison to healthy volunteers they used significantly more dysfunctional and less functional strategies. The clinical groups were found to experience similar levels of emotions and in comparison to healthy volunteers they experienced greater levels of negatively valenced emotions and lower levels of happiness. The clinical groups were also found to use greater amounts of maladaptive coping strategies and lesser amounts of problem-focussed coping strategies than the healthy volunteers. Overall it appears that emotional experience and regulation in psychosis may be more similar to neuroses than originally was believed to be the case. This would suggest therefore that theories of psychosis should take into consideration emotional dysfunction. Difficulties with emotion regulation should be considered as potential contributory factors in the development, maintenance and course of psychosis.