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Ursachen und Folgen vermehrter Expression des nukleären Rezeptors Constitutiver-Androstan-Rezeptor (NR1I3) durch Agonisten des nukleären Rezeptors Peroxisomenproliferator-aktivierter-Rezeptor-alpha (NR1C1) / Cause and Effect of enhanced expression of the nuclear receptor constitutive androstane receptor (NR1I3) induced by agonists of the nuclear receptor peroxisome proliferator activated receptor alpha (NR1C1)Wieneke, Nadine January 2008 (has links)
Der Fettsäurestoffwechsel unterliegt vielfältigen Kontrollmechanismen. So wird der Fettsäureabbau über die Induktion und Aktivität spezifischer Enzyme reguliert. Ein zentraler Regulator ist dabei der nukleäre Rezeptor Peroxisomenproliferator-aktivierter-Rezeptor-α (PPARα). PPARα wird durch freie Fettsäuren in der Zelle aktiviert und fördert über die Induktion von Zielgenen den Fettsäuretransport und -abbau sowie die Gluconeogenese und Ketogenese. Der Anstieg an freien Fettsäuren beim Fasten, aber auch im Diabetes aktiviert PPARα. Unabhängig davon wurde in beiden Stoffwechsellagen auch eine erhöhte Expression des nukleären Rezeptors Constitutiver-Androstan-Rezeptor (CAR) und einiger CAR-Zielgene, vorrangig Enzyme des Fremdstoffmetabolismus wie Cytochrom P450 2B (CYP2B), festgestellt. Bei der Adaption an eine Fastensituation scheinen PPARα- und CAR-Signalwege über einen bisher unbekannten Mechanismus miteinander verschaltet zu sein.
In der vorliegenden Arbeit sollte der der Verschaltung zugrunde liegende Mechanismus anhand eines Modelsystems, der PPARα-Agonisten-vermittelten Verstärkung der Phenobarbital (PB)-abhängigen Induktion des CAR-Zielgens CYP2B, in vitro untersucht werden. Zudem sollte die physiologische Relevanz einer durch PPARα-Agonisten vermittelten Modulierung der CYP2B-Aktivität in einer Ganztierstudie in vivo belegt werden.
Die verwendeten synthetischen PPARα-Agonisten steigerten in primären Hepatozyten der Ratte signifikant die Phenobarbital (PB)-abhängige mRNA- und Protein-Expression sowie die Aktivität von CYP2B. Ohne vorherige PB-Behandlung induzierten PPARα-Agonisten CYP2B nicht. In Gegenwart von PB war die Steigerung der CYP2B-Aktivität durch PPARα-Agonisten dosisabhängig. In einem Luciferase-Reportergenassay wurde gezeigt, dass die Induktion durch PB unter der Kontrolle des CYP2B1-Promotors von einem distalen PBREM (PB-responsive-enhancer-module), an welches CAR binden kann, abhängig war. PPARα-Agonisten steigerten diese PB- und PBREM-abhängige Reportergentranskription und induzierten die CAR-mRNA und CAR-Proteinexpression. Sie aktivierten die Transkription eines Reportergens unter der Kontrolle eines Promotorfragments von bis zu 4,4 kb oberhalb des mutmaßlichen CAR-Transkriptionsstarts. Mit Hilfe von Deletionskonstrukten konnte ein potentielles Peroxisomenproliferator-aktivierter-Rezeptor-responsives Element (PPRE) im CAR-Promotorbereich von -942 bp bis -930 bp identifiziert werden, welches essentiell für die Initiation der Transkription durch PPARα-Agonisten ist. In band shift Experimenten akkumulierte verstärkt Kernprotein mit diesem PPRE. Ein Überschuss an unmarkiertem Wildtyp-CAR-Reportergenvektor, nicht aber an CAR-Reportergenvektor mit PPRE-Deletion, konnte mit dem markierten PPRE um die Bindung von Kernprotein konkurrieren. Nach Chromatin-Immunpräzipitation mit einem PPARα-Antikörper wiederum wurde das betreffende PPRE amplifiziert.
Bei in vivo Experimenten an männlichen Ratten resultierte die Behandlung mit PPARα-Agonisten in einer signifikanten Induktion der CAR-mRNA-Expression und signifikant erhöhter PB-abhängiger CYP2B-Aktivität. Die physiologisch Relevanz wurde durch weiterführenden Experimente unterstrichen, in denen gezeigt wurde, dass die Fasten-abhängige Induktion von CAR in PPARα-defizienten Mäusen unterdrückt war.
Diese Experimente legen nahe, dass durch PPARα-Agonisten aktiviertes PPARα an das PPRE im CAR-Promotorbereich von -942 bp bis -930 bp bindet und dadurch die CAR-Transkription induziert. Somit kann CAR als PPARα-Zielgen betrachtet werden, was die Schlussfolgerung zulässt, dass die PPARα- und CAR-Signalwege über die direkte Bindung von PPARα an den CAR-Promotor unmittelbar miteinander verknüpft sind. Allerdings ist davon unabhängig eine Aktivierung von CAR, etwa durch PB, für die vermehrte Induktion von CAR-Zielgenen notwendig .
Die physiologische Relevanz der PPARα-abhängige CAR-Expression zeigt sich in den Ganztierexperimenten, bei denen die Wirksamkeit der PPARα-Agonisten bestätigt werden konnte. CAR-abhängig induzierte Enzyme sind nicht nur in großem Umfang am Fremdstoffmetabolismus beteiligt, sondern auch am Abbau von Schilddrüsenhormonen und Glucocorticoiden. Sie können damit direkt Einfluss auf den Kohlenhydrat- und Energiestoffwechsel sowie die Regulation der Nahrungsaufnahme nehmen. Über eine PPARα-abhängige Induktion von CAR im Rahmen der Fastenadaption könnten die CAR-Zielgene UDP-Glucuronyltransferase 1A1 und Sulfotransferase N beispielsweise verstärkt Schilddrüsenhormone abbauen und in der Folge den Grundumsatz senken. Der in dieser Arbeit erstmals beschriebene Mechanismus ist dafür von zentraler Bedeutung. / Fatty acid metabolism is tightly regulated. Thus the activity and expression level of specific enzymes involved in fatty acid turnover are controlling fatty acid catabolism. The nuclear receptor peroxisome proliferator activated receptor α (PPARα) acts as the key regulator of these pathways. PPARα is activated by intracellular free fatty acids and promotes the fatty acid transport and break down, as well as gluconeogenesis and ketogenesis, via induction of target genes. An increase in free fatty acids as seen in fasting and diabetes activates PPARα. Under these conditions, an elevated expression of another nuclear receptor, the constitutive androstane receptor (CAR) and its target genes, mainly enzymes catalysing biotransformation such as cytochrome P450 2B (CYP2B1), was also observed. It is therefore likely that as yet unidentified modes of interaction between PPARα and CAR signalling exist.
The object of the present work was to discover these underlying mechanisms utilising an in vitro model, the PPARα-agonist induced increase of the phenobarbital (PB)-dependent induction of the CAR target gene CYP2B1. Furthermore, an in vivo study would serve to demonstrate the physiological relevance of a PPARα-agonist induced modulation of the CYP2B activity.
The synthetic PPARα agonists under investigation significantly enhanced the PB-dependent mRNA and protein expression as well as activity of CYP2B in primary rat hepatocytes. Without prior treatment with PB, PPARα agonists did not induce CYP2B activity. In the presence of PB, PPARα agonists increased the CYP2B activity dose-dependently. Luciferase reporter gene assays showed that the PB-dependent induction of the CY2B1 promoter relied on a distal PBREM (PB-responsive enhancer module), a well-known CAR binding site. PPARα agonists enhanced this PB- and PBREM-dependent reporter gene transcription and induced the upregulation of CAR mRNA and CAR protein expression. The PPARα agonists also activated the transcription of a reporter gene controlled by up to 4.4 kb upstream of the putative CAR-transcription start site. A potential peroxisome proliferator activated receptor responsive element (PPRE), essential for the initiation of transcription by PPARα agonists, could be identified between -942 bp to -930 bp upstream of the transcription start site using CAR promoter deletion constructs. In subsequent band shift experiments, enhanced nuclear protein accumulation with this specific promoter region was observed. In contrast to unlabelled wild-type CAR reporter gene vector, an excess of unlabelled CAR reporter gene vector with PPRE deletion did not compete with the binding of nuclear protein. Furthermore, this PPRE could be amplified with specific primers after chromatin immunoprecipitation with a PPARα antibody.
Treatment of rats with a PPARα agonist resulted in a significant induction of CAR mRNA expression and significantly increased PB-dependent CYP2B activity. A physiological relevance of this newly-discovered mechanism is confirmed by the observation that PPARα-deficient mice, unlike wild-type mice, do not respond to fasting with an increase of CAR mRNA expression.
The results of these experiments suggest that activated PPARα binds to the PPRE of the CAR promoter to initiate transcription of the CAR gene. CAR therefore could be regarded as a PPARα target gene, which implicates that PPARα- and CAR-signalling are directly linked through binding of PPARα to the CAR promoter. For subsequent enhanced induction of CAR target genes, activation of CAR, for instance using PB, is required.
In vivo studies with PPARα agonists in rats support the relevance of the PPARα-dependent CAR expression. CAR target genes code for enzymes that metabolise not only a wide range of xenobiotics, but also thyroid hormones and glucocorticoids. CAR target genes could therefore directly interfere with carbohydrate and energy metabolism, as well as with food intake. PPARα-dependent induction of CAR upon fasting could lead to an increased expression of the CAR target genes UDP-glucuronyl transferase 1A1 and sulfotransferase N, resulting in an enhanced degradation of thyroid hormones, and decreased resting energy expenditure. The findings of this present study are of primary importance since it is the first time that this mechanism has been described.
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Reconciling the Car and the City: A Vision of Productive Urban MobilityPavlov, Ventzislav January 2011 (has links)
The relationship between cars and cities is changing. The auto-centric development predominant in America in the 20th century is beginning to subside and disappear. It is being replaced by efforts to make cities more sustainable, enjoyable, and accessible by their citizens without the need to always own a personal vehicle. Given the issues inherent in building more infrastructure to support the ever-growing demand for automobiles, continuing to rely on fossil fuels to power them, or living in neglected spaces designed for machines, an alternative solution is needed. While entirely giving up the car today is socially, politically, economically, and physically impossible, new ways of dealing with it are becoming viable. These developments are currently in their nascent stages, but they hold immense potential to transform the way urban mobility operates in the near future.
This thesis explores architecture's response to this emerging reality and proposes that it is time for the car and the city to foster a productive relationship. In the past, architects and urban planners have designed and re-designed the built environment to accommodate the needs of the automobile. Today, there is a need for an architecture which integrates mobility and the means of powering it with vibrant and social urban space. Through the design of a networked mobility hub for Long Island City in Queens, New York, this thesis will re-imagine the relationship between cars and architecture, creating a new paradigm for dealing with the automobile in the city.
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Automatische vektorbezogene Generierung von Straßennetzabbildern auf Basis von Floating Car DataKörner, Matthias, Krimmling, Jürgen, Oertel, Robert 24 July 2012 (has links) (PDF)
Straßen-Knoten-Netze als modelliertes Abbild der Straßeninfrastruktur bilden die Grundlage für eine Vielzahl von Diensten und Anwendungen. Die Verortung von Fahrzeugen, aber auch die Verkehrsumlegung, basieren darauf. Die Ermittlung optimaler Routen und die Visualisierung der Verkehrslage werden ermöglicht. Die resultierenden Anforderungen an das Netzabbild sind vielfältig und deren Bewältigung mit nicht unerheblichem Aufwand verbunden. Kernpunkte sind Genauigkeit, Aktualität und Flächendeckung. Ferner werden geringe Kosten bei dessen Erstellung angestrebt. Als Ergänzung zu manueller Digitalisierung und der Erfassung durch Messfahrzeuge mit hochpräziser Ortung stellt die Nutzbarmachung von Mehrwerten aus Floating Car Systemen einen viel versprechenden Ansatz dar. Vorgestellt wird ein Verfahren, welches mittels eines vektorbasierten Ansatzes Straßen-Knoten-Netze aus Floating Car Daten ermittelt. / Node-edge-networks representing road infrastructure are base for various applications and services. Georeferencing of vehicles as well as traffic assignment are based on. Routing and traffic conditions visualisation become possible. Requirements concerning precision, topicality and area coverage of road network image are caused by. Low costs are aspired as well. Utilisation of additional benefits from floating car systems is a promising approach, supplementing common technologies like manual digitalisation or capturing road trajectories by special equipped probe vehicle. A vector based method aggregating positions information of floating car to process road infrastructure images will be presented.
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Do They Really Car(e) : The greening of the brand: the case of Volvo Cars in Sweden 1972 to 2014Näsman, Mattias January 2015 (has links)
Denna magisteruppsats i ekonomisk historia har som syfte att utforska varför den svenska bilparken är mer bränslekrävande än genomsnittet i Europa, samt att identifiera de historiska processer som påverkat formandet av den svenska bilparken. Tidigare miljöinriktad forskning inom ekonomisk historia har fokuserat på strukturomvandling och institutionell förändring inom industri- och hushållssektorn. Denna studie utforskar den privata transportsektorn genom att studera Volvo som varit tongivande i att forma sammansättning av den svenska bilparken. Genom att studera två av Sveriges största biltidningar – Teknikens värld och Volvos egen konsumenttidning, Ratten – samt årsberättelser och hållbarhetsrapporter från Volvo, har historien om varumärket Volvo och Volvos relation till miljön utforskats. Volvo antog ’kvalitet’ och ’säkerhet’ som kärnvärden vid starten 1927. ’Omsorg om miljön’ lades till som ett tredje kärnvärde 1972 vilket antas vara av relevans för hur Volvo byggt sin identitet. Hur Volvo tolkat ’omsorg om miljön’ i relation till sitt varumärke och hur det integrerats i företagets produktionsprocesser är utgångspunkter för uppsatsens undersökande del som sträcker sig från 1972 till 2014. Resultatet visar på att begreppet ’miljö’ har omtolkats av Volvo och följt den samhälleliga diskursen ganska väl. Från att handla om den lokala ’arbetsmiljön’ och det som kopplas därtill, till att handla om regionala utsläpp av partiklar för att till sist innefatta ett globalt perspektiv. Resultatet visar också att Volvo på grund av höga kostnader för arbetare och en stor efterfrågan från den amerikanska marknaden drivits till att producera stora och dyra bilar som drar mycket bränsle. På grund av att Volvo inte kunnat konkurrera med höga försäljningsvolymer har man istället satsat på säkra och hållbara bilar som kunnat bringa högre vinstmarginaler. Efter krisen på 1990-talet och ett byte av ledarskap från Pehr G. Gyllenhammar till Sören Gyll, visar resultatet att ’omsorg om miljön’ fick en mer framskjuten roll i Volvos varumärkesbyggnad. Samtidigt beslutades att Volvo skulle ta ytterligare steg mot att tillverka bilar i premiumsegmentet vilket var svårt att kombinera med miljöhänsyn vad gäller bränsleförbrukning. Slutsatserna som dragits från denna uppsats är att Volvo efter andra världskriget lyckades skaffa sig en ’pionjärsfördel’ – pioneering advantage – genom en stark introduktion av PV 444/544-modellerna på 1940- och 1950-talet och att man sedan kunnat använda denna fördel för att omtolka svenskars preferenser att välja bränslekrävande bilar. Detta innebär att företag, om de vill, har möjlighet att styra konsumenter mot att välja bättre miljöanpassade produkter. I uppsatsen argumenteras för att avsättningsmarknader spelar stor roll för möjligheten för företag att ställa om produktionen till att leverera ’grönare’ produkter.
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Reconciling the Car and the City: A Vision of Productive Urban MobilityPavlov, Ventzislav January 2011 (has links)
The relationship between cars and cities is changing. The auto-centric development predominant in America in the 20th century is beginning to subside and disappear. It is being replaced by efforts to make cities more sustainable, enjoyable, and accessible by their citizens without the need to always own a personal vehicle. Given the issues inherent in building more infrastructure to support the ever-growing demand for automobiles, continuing to rely on fossil fuels to power them, or living in neglected spaces designed for machines, an alternative solution is needed. While entirely giving up the car today is socially, politically, economically, and physically impossible, new ways of dealing with it are becoming viable. These developments are currently in their nascent stages, but they hold immense potential to transform the way urban mobility operates in the near future.
This thesis explores architecture's response to this emerging reality and proposes that it is time for the car and the city to foster a productive relationship. In the past, architects and urban planners have designed and re-designed the built environment to accommodate the needs of the automobile. Today, there is a need for an architecture which integrates mobility and the means of powering it with vibrant and social urban space. Through the design of a networked mobility hub for Long Island City in Queens, New York, this thesis will re-imagine the relationship between cars and architecture, creating a new paradigm for dealing with the automobile in the city.
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Automobile Travel Reduction In Urban Areas And City Centers, Case Study: AnkaraAkar, Gulsah 01 June 2004 (has links) (PDF)
This thesis analyzes the car ownership and use issues worldwide and in Ankara. There has been an extremely rapid increase in car traffic in major cities, leading to car dependence and its adverse affects, all over the world. This thesis takes its starting point the driving forces behind car ownership and use, and the increasing problems caused by the car traffic in urban centers. Then, car travel reduction measures and their consequences are reviewed by examples.
The urban transportation in Ankara is analyzed, both in terms of recent policies and the data obtained, in order to find out if the car ownership and use would generate similar problems in Ankara. The applicability of car travel reduction options in Ankara and the conflicts in the recent urban transportation policies are discussed. This research does not recommend simple solutions, but concludes that a broad spectrum of measures must be applied in order to reduce the problems.
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Diagnostika automobilu / Car diagnosticsHRDINA, Jan January 2014 (has links)
This thesis focuses on maintenance and car diagnostics in the field of car mechanic and autotronic. I focused on the history of these branches and on the history of car maintenance. I further focused on the technological procedures in car maintenance and on the modern educational means. My aim was to introduce the possibilities of modern diagnostic technology and individual diagnostic machines at work. In the practical part I focused on specific car defects, their diagnostics and subsequent removal.
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Cars : The future is flexibleSchmitz, Lennart January 2018 (has links)
Cars have been around for over a century and have grown to become an essential part of society with an increasing number of different models being sold and developed each year. Car manufacturers steadily expand the offered product portfolio and invent new market niches constantly. Often, this is not done to meet the customers’ expectations but rather to match and rival a competitor’s model lineup. The increase in model variety results in a significant increase in the complexity of production and manufacturing, more difficult and demanding work surrounding employees, and massive negative impacts on the environment. Not only are cars unsustainable in the way they are used, but also in the way they are produced. For a more sustainable future of and with cars to be possible, this practice of product portfolio expansion needs to be critically analyzed. It is, in my eyes, additionally necessary to evaluate the essence of the car industry, the car itself, and to re-think what defines a car. This paper critically analyzes the car industry and the production and development of cars, and it proposes an alternative to standard car design based on the idea and ability of speculative and critical design to highlight issues of today. The proposed concept is a speculative design alternative to car design, aiming to put sustainability and the customers back into the focus of car development, and discover what is possible, rather than probable, in the future of cars. The proposed concept aims at changing the understanding of cars and turns the car from being fixed and immutable into alterable and changeable objects, depending on the use-case and user. By analyzing manufacturing procedures and future trends, and interviewing experts from various disciplines, insights are used to evaluate the proposed alternative.
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A distribuição de automóveis novos em mudança? : estudo a partir de survey e pesquisa qualitativa em concessionárias. / The distribution of new automobiles is changing? : study carried out from a survey and qualitative research in dealers franchise.Márcia Mazzeo Grande 06 December 2004 (has links)
Esse trabalho teve por objetivo analisar as mudanças que estão ocorrendo nos canais de distribuição de carros novos no Brasil, especificamente no que concerne à constituição de novos formatos de negócio no varejo de automóveis novos e à relação com as montadoras. O sistema de distribuição de carros novos baseado em redes de revendedores exclusivos e independentes de cada marca/montadora que integra em um só lugar as funções de vendas de carros novos, vendas de carros usados, distribuição de pecas de reposição, assistência técnica e reparo e financiamento entrou na pauta da indústria automotiva na última década, devido ao aumento da concorrência e à ineficiência do sistema em atender as expectativas dos consumidores em termos de qualidade de serviços e preços. No Brasil, várias discussões sobre uma reestruturação das redes de distribuição e do formato de negócio da revenda estão em andamento desde o início dos anos 2000. Este estudo, realizado através de entrevistas e de um survey em concessionárias, levantou que as concessionárias estão terceirizando parte dos seus serviços de assistência técnica e reparo e obtendo ganhos em termos de rapidez, qualidade dos serviços e redução de custos, bem como adotando algumas novas práticas de gestão e tecnologias da informação. Apurou-se também que montadoras estão aumentando o controle sobre a produção de serviços das concessionárias através de exigências de padronização de lojas e processos de atendimento. / The objective of this work is to analyze the changes that are occurring in the distribution channels of new cars in Brazil, more specifically concerning the constitution of new retailing business format and its relation with the car manufactures. The distribution system based on exclusive and independent franchise dealership of each brand/manufacturer that integrates in the same place the functions of new cars sales, used cars sales, spare parts supply, services and financing, has being taken into consideration in the automobile industry since the last decade. This was due to the increase in competition and the inefficiency of the system to match the expectations of the consumer in terms of quality of services and prices. In Brazil several discussions about distribution network restructuring and retailing business form are being carried out since the beginning of 2000. This study, made through interviews and survey in car retailers, has found out that the dealers are outsourcing part of their support and repair services and with that procedure gaining in quality of services, time and cost reduction as well as adopting new managing practices and new technological information. Also it has been found out that the car manufactures are increasing the control on services production of the dealers through the requirement of standardization of the shops and sales and services processes.
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Economic analysis of travelling:studies on travel behaviour in FinlandPekkarinen, S. (Saara) 09 December 2005 (has links)
Abstract
A great deal of research in transportation economics has been motivated by the need to solve traffic congestion problems and to diminish negative environmental effects of road transport. The question, whether the economic measures are efficient, motivates this dissertation on the value of travel time, the rules of optimal pricing and the demands for public transportation and private car use.
Three concepts of the marginal value of travel time (MVT) are specified in this thesis. The first concept involves only the direct disutility of the travel time to work in addition to the utility of market goods and leisure. The second concept also includes the disutility from the time spent at work. The third concept furthermore takes into account the effect of the length of working hours, travel time, cost and income. The length of travel time, gender, family structure and flexibility of working hours have different effects on empirical MVTs, but travel costs and income affect them in a similar fashion.
The pricing decisions of the firms providing bus services are analysed with and without public subsidies. The consumption externality, i.e. the quantity demanded by other users, affects the individual bus demand. The results indicate that under uniform pricing, a socially optimal subsidy equals the increase in consumer's surplus minus the fare revenue lost from current users due to lower fare. Under nonlinear pricing, the optimal pricing can be achieved when the regulator sets the subsidy so that it is inversely proportional to the network elasticity. The welfare loss due to increasing tax burden and the opportunity cost of providing cash fare service is also taken into account in the optimal pricing rule.
A model of bus demand with asymmetric information on the characteristics of bus users is developed. The model allows for habit formation and network effects. The latter effect is due to the positive influence of the aggregate demand for Regional Bus Cards (RBC) on an individual's own demand. The empirical results indicate that in RBC services positive network effects are present and the elasticity of network size is less than one, which implies that the regional bus card is an impure public good. The own price elasticity of RBC in the short run is within the range of -0.3 and -1.1. The demand for RBC cards is more elastic than demand for RBC trips or passenger kilometres. The estimated price elasticity of urban bus demand is in line with that of RBC. A reasonably high cross-price elasticity of RBC trips and the ticket of 40 trips but a lower reverse elasticity were found.
A weakly separable demand for car mileage from car ownership and labour supply was rejected as was the exogeneity of car ownership in the mileage model. Therefore, the price elasticity of car mileage with respect to fuel price was estimated from the two equation model of car mileage with endogenous car ownership. The estimated parameters of the Tobit model are consistent but slightly higher than those estimated from the least squares. The fuel price elasticity varies from -0.2 to -0.9 with exogenous and endogenous car ownership, respectively.
The findings of this study can be applied in the analysis and implementation of different pricing and subsidy schemes for public transportation, as well as in the evaluation of the effectiveness of economic instruments for managing the growth of private car use.
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