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1
McIlroy, Graham William. "Toll-7 and Toll-6 : central nervous system functions as Drosophila neurotrophin receptors." Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3098/.
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The Drosophila Toll receptor is crucial for dorsoventral patterning in embryos, and for innate immunity. Toll also functions during central nervous system development, promoting neuronal survival and targeting. There are nine Toll paralogues in Drosophila, and it is unknown whether any of these also function in the CNS. Toll’s ligand, Spz, has an NGF domain. NGF is a vertebrate neurotrophin - a growth factor that regulates the development and function of the nervous system. Drosophila Neurotrophin 1 (DNT1), identified by homology to the vertebrate neurotrophin BDNF, and DNT2 are paralogues of spz. The three DNTs – DNT1, DNT2 and spz – are structural and functional homologues of vertebrate neurotrophins, and they promote neuronal survival, targeting and synaptogenesis in Drosophila. However, the receptors for DNT1 and DNT2 are unknown. Here, using a combination of in situ hybridisations and reporters that drive GFP expression, I investigate the expression of Toll paralogues in the Drosophila nervous system. By generating null mutant flies and gain-of-function transgenic flies, I examine genetic interactions between Tolls and DNTs. I also investigate the rolls of these receptors in adult locomotion, axon targeting and cell survival. Finally, in cell culture, I test whether DNTs can signal through Tolls to activate NFκB.
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Ng, Wing-suen Sammuel. "Electronic road pricing in Singapore : lessons for Hong Kong /." Hong Kong : University of Hong Kong, 1999. http://sunzi.lib.hku.hk/hkuto/record.jsp?B21213185.
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Jinek, Daniel. "Český elektronický mýtný systém z pohledu implementace evropské elektronické mýtné služby." Master's thesis, Vysoká škola ekonomická v Praze, 2017. http://www.nusl.cz/ntk/nusl-359244.
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The thesis deals with electronic fee collection systems and their interoperability within European Electronic Toll Service. It closely looks on future of Czech EFC system with scope on dealing with obligations of European Electronic Toll Service legislation. In the first part the basic terms of EFC systems are described and basic technologies to be used within EFC systems are explained. The second part then deals with European Electronic Toll Service matters, its legislation and present stage of implementation. In the third part, there are specific technological applications on national EFC systems of chosen European Union countries described. The last part closely describes Czech EFC system, its history, present and its possible future outcomes.
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Novák, Jaroslav. "Mýtný systém a jeho vliv na silniční dopravu v České republice." Master's thesis, Vysoké učení technické v Brně. Ústav soudního inženýrství, 2012. http://www.nusl.cz/ntk/nusl-232659.
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This thesis deals with the toll systems which have been in operation in the Czech Republic since 2007. The first part defines the basic concepts of transportation and describes the development, goals and the direction of transport policy of the European Union, and the Czech Republic. It also describes the different ways of collecting tolls on roads and the possibility of charging for entrance into cities. The second part analyses the current state of the toll system, not only in our country, but also in neighboring countries. Practical knowledge is supplemented by the hand counting of trucks, avoiding toll communication and a questionnaire survey among carriers. The third part is focused on proposals for solving current situations. The aims are: bring trucks back to the toll roads, reduce the noise levels on highways at night, improve the quality of roads in the Czech Republic, increase user comfort levels of toll systems and increase the number of "green" trucks on the roads
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Chaudhary, Rajesh H. "A Model for the Benefits of Electronic Toll Collection System." [Tampa, Fla.] : University of South Florida, 2003. http://purl.fcla.edu/fcla/etd/SFE0000208.
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Němeček, Robert. "Analýza efektivnosti mýtného systému v ČR." Master's thesis, Vysoká škola ekonomická v Praze, 2008. http://www.nusl.cz/ntk/nusl-12085.
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Ng, Wing-suen Sammuel, and 伍永璇. "Electronic road pricing in Singapore: lessonsfor Hong Kong." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1999. http://hub.hku.hk/bib/B31952288.
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Chang, Yuet-mei Marky. "Policy formulation process : a case study of the Electronic Road Pricing Scheme of Hong Kong in the 1980s /." Hong Kong : University of Hong Kong, 1997. http://sunzi.lib.hku.hk/hkuto/record.jsp?B18595637.
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Chang, Serena Soyoung Yunmee. "Toll-Like Receptors: Target of Hepatitis C Virus: A Dissertation." eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/386.
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Hepatitis C Virus (HCV) is the primary cause of liver transplantation due to its chronic nature in up to eighty percent of infected cases. Around 3 percent of the world’s population is infected with HCV. Treatment for HCV is a combined Ribavirin and interferon-α (IFN-α) therapy effective in only fifty to eighty percent of patients depending on HCV genotype. The growing health concern with this disease is the lack of a cure despite liver transplantation. HCV targets hepatocytes, liver cells, but is not cytolytic. HCV has been shown to induce end stage liver disease through sustained inflammation from the host’s immune system in the liver. One of the key dilemmas in HCV research and the search for fully effective treatments or vaccines is the lack of animal models. HCV infectivity and disease is limited to primates, most specifically to humans, which cannot be fully replicated in any other living being. The mechanisms for HCV evasion or activation of the immune system are complex, many and discoveries within this field are crucial to overcoming this destructive hepatic infection.
Toll-like receptors (TLR) are cellular activators of the innate immune system that have been a target of HCV. Activated TLRs trigger both the inflammatory and anti-viral pathways to produce inflammatory cytokines and interferons. HCV proteins have been reported to activate a number of TLRs in a variety of cell types. In order to identify possible targets of HCV within the TLR family, we first characterized TLR presence and function in both human hepatic carcinoma cell lines and purified primary human hepatocytes. RNA from TLRs 1-10 was observed to varying degrees in both the hepatoma cell lines and the primary hepatocytes. We show the extracellular and/or intracellular presence of TLR2, TLR1, TLR3 and TLR7 proteins in hepatoma cell lines. TLR3 and TLR7 are located within the endosome and recognize viral RNA products. We recently reported that TLR2-mediated innate immune signaling pathways are activated by HCV core and NS3 proteins. TLR2 activation requires homo- or heterodimerization with either TLR1 or TLR6. We show NF-κB activation in hepatoma cells by TLR2/1, TLR2/6 ligand and HCV protein stimulation. In primary hepatocytes, HCV proteins induced both IL-8 and IL-6 production. We also show that primary hepatocytes initiate a Type 1 IFN response in addition to IL-8 and IL-6 production upon stimulation with a TLR7/8 ligand. Human hepatoma and primary hepatocytes are responsive to TLR2, TLR1, TLR6, TLR7/8 ligands and HCV proteins. Activation of these TLRs may contribute to the inflammatory mediated destruction caused by HCV or could be targets of HCV contributing to its immune evasion.
We found previously that hepatoma cells and primary hepatocytes are responsive to TLR2 ligands and HCV proteins. We also reported that TLR2 is activated by HCV proteins. Here we aimed to determine whether TLR2 coreceptors participated in cellular activation by HCV core or NS3 proteins. By designing siRNAs targeted to TLR2, TLR1 and TLR6, we showed that knockdown of each of these receptors impairs pro- and anti-inflammatory cytokine activation by TLR-specific ligands as well as by HCV core and NS3 proteins in Human Embryonic Kidney cells (HEK/TLR2) and in primary human macrophages. We found that HCV core and NS3 proteins induced TNF-α and IL-10 production in human monocyte-derived macrophages, which was impaired by TLR2, TLR1 and TLR6 knockdown. Contrary to human data, results from TLR2, TLR1 or TLR6 knockout mice indicated that the absence of TLR2 and its coreceptor TLR6, but not TLR1, prevented the HCV core and NS3 protein-induced peritoneal macrophage activation. TLR2 may utilize both TLR1 and TLR6 coreceptors for HCV core- and NS3-mediated activation of macrophages and innate immunity in humans. These results imply that multiple pattern recognition receptors could participate in cellular activation by HCV proteins contributing to inflammatory disease.
Two critical factors in chronic HCV infection are inflammatory disease and immune evasion. We have demonstrated that TLR2 and its co-receptors play a role in inflammatory-mediated induction via HCV NS3 and core administration. It has recently been shown that HCV targets the TLR3 pathway to aid in immune evasion. TLR3 is only one of four viral recognition receptors located within the endosome and it is plausible that HCV may target others. We hypothesized that HCV infection may interfere with the expression and function of TLR7, a sensor of single stranded RNA. Investigating any effect on TLR7 by HCV may reveal a new mechanism for HCV immune evasion. Low levels of both TLR7 mRNA and protein were measured in HCV replicating cells compared to control cells while reducing HCV infection with either IFNα or restrictive culture conditions restored the decreased TLR7 expression. Downstream of the TLR7 pathway, an increased baseline IRF7 nuclear translocation was observed in HCV replicating cells compared to controls. Stimulation with a TLR7 ligand, R837, resulted in significant IRF7 nuclear translocation in control cells. In contrast, HCV replicating cells showed impaired IRF7 activation. Use of RNA polymerase inhibitors on hepatoma cells, control and HCV replicating, revealed a shorter TLR7 half life in HCV replicating cells compared to control cells which was not seen in TLR5 mRNA. These data suggest that reduced TLR7 expression, due to RNA instability, directly correlates with HCV replication and results in impaired TLR7-induced IRF7-mediated cell activation.
In conclusion, Hepatitis C Virus manipulates specific Toll-like receptors’ expression and their signaling pathways to induce cytokine production. HCV utilizes surface receptors TLR2 and its co-receptors which once activated could contribute to inflammatory disease by production of inflammatory cytokines and possibly immune evasion. HCV down-regulates TLR7, a viral recognition receptor, by decreasing mRNA stability which could facilitate evasion of host immune surveillance.
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Offord, Victoria Anne. "Toll-like receptors : from sequence to structure." Thesis, Royal Veterinary College (University of London), 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.669195.
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Jarl, Adam. "Classification of busses and lorries in an automatic road toll system." Thesis, Linköping University, Department of Electrical Engineering, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-1696.
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An automatic road toll system enables the passing vehicles to change lanes and no stop is needed for payment. Because of different weight of personal cars, busses, lorries (trucks) and other vehicles, they affect the road in different ways. It is of interest to categorize the vehicles into different classes depending of their weight so that the right fee can be set. An automatic road toll system developed by Combitech Traffic Systems AB (now Kapsch TrafficCom AB), Joenkoping, Sweden, classifies the vehicles with help of a so called height image. This is a three dimensional image produced by two photographs of a vehicle. The photographs displays the same view but are mounted with a little spacing. This spacing makes it possible to create a height image. The existing classification uses only length, width and height to divide vehicles into classes. Vehicles of the same dimensions would then belong to the same class independent of their weight. An important example is busses and lorries (trucks) which often have the same dimensions, but trucks often have greater weight and should therefore require a larger fee. This work describes methods for separating busses from lorries with the help of height images. The methods search for variations in the width and height, and other features specific for busses and lorries respectively.
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Kwok, Shi-chung Colin. "The role of electronic road pricing in tackling traffic congestion in Hong Kong." Hong Kong : University of Hong Kong, 1999. http://sunzi.lib.hku.hk/hkuto/record.jsp?B21128832.
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Kačala, Tomáš. "Interoperabilita slovenského mýtného systému se sousedními státy." Master's thesis, Vysoká škola ekonomická v Praze, 2012. http://www.nusl.cz/ntk/nusl-142227.
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Abstract: The purpose of this thesis is to provide a complex overview of selection of toll system fees for the usage of charged sections of highways and first class roads in countries Poland, Slovakia, Hungary and Czech Republic in present time. Familiarization with various types of toll systems used in Europe, with legislative preconditions for pricing of road infrastructure in European Union and with basic principles of freight and road transport. A part of thesis is a description of companies' functioning which intermediate payments for the usage of charged road communications. Followed by a proposal of common toll system for countries of Visegrad Four, its technical aspect, price calculation and legislative requirements for its introduction into practice. At the end of thesis there are recommendations and possibilities of this system implementation into commom european toll system.
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Rodgers, Charner Lynn. "High occupancy toll lanes ignoring the potential for a environmental justice violation." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/39615.
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In the US transportation system, environmental justice (EJ) issues are regulated by a variety of laws to ensure that all have fair treatment with respect to implementation of policies. If State Departments of Transportation adhere to all regulations properly but unconsciously, then an underlying negative impact on a community may still exist as a result of a newly implemented project. Since the implementation of High Occupancy Toll (HOT) lanes are fairly new, and since there have been numerous concerns from the public about their discriminatory nature, a decision support system is needed to identify potential EJ violations and issues when implementing a new or converted HOT lane. No prior model exists.
The goal of this research is to assist state's Department of Transportation (DOT) in the early stages of the development of an HOT lane by developing a Potential Environmental Justice Violation Model that will help state agencies predict potential EJ violations before additional resources are invested into a project. By developing a model, this study identifies and classifies characteristic drivers of potential EJ violations related to communities' economic, social, or health and safety status. The Potential Environmental Justice Violation Model (PEJVM) allows state DOTs employees to define and evaluate the distribution of impacts in the relevant categories. The model provides a method for transforming complex qualitative and quantitative data about a project into a user-friendly format where the results can then be visualized using a spider radar diagram to determine the level of impact of each identified variable.
The PEJVM was validated using two previous anonymous HOT case studies and demonstrated using the Interstate 85 Case Study in Atlanta, Georgia. This model offers a uniform method of identifying potential environmental justice violations when implementing a HOT lane. The model will also help inform state agencies of potential violations early in the planning stages of HOT lane projects so that the agency can solve any potential EJ issues before additional resources are invested.
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Raštica, Marek. "Vliv měnového kurzu CZK na výši příjmů z mýtného systému na komunikacích v ČR." Master's thesis, Vysoká škola ekonomická v Praze, 2016. http://www.nusl.cz/ntk/nusl-262313.
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This thesis examines the impact of the real exchange rate on the amount of revenues from a system of tolled and time tolled roads in the Czech Republic in the years 1999-2014. This effect is investigated on monthly data using regression analysis on two systems of tolled roads separately, system of tolled roads and system of time-tolled roads. Based on available dataset was shown a statistically significant negative effect of the real exchange rate on toll revenues in the system of tolled roads. In the case of time-tolled roads system was demonstrated negative effect of real exchange rate on time-toll revenues, but this effect is questionable, since the influence has been demonstrated only in a model with limited explanatory power.
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Chang, Yuet-mei Marky, and 張月薇. "Policy formulation process: a case study of the Electronic Road Pricing Scheme of Hong Kong in the 1980s." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1997. http://hub.hku.hk/bib/B31965143.
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Šindelářová, Jana. "Inovační aspekty elektronickeho výběru mýtného v ČR." Master's thesis, Vysoká škola ekonomická v Praze, 2008. http://www.nusl.cz/ntk/nusl-10475.
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This thesis deals with the innovation of information system (IS) as a decision problem. The main objective of this thesis is the construction and the application of a method to select an optimal innovation variant of IS in an organisation of any scale. The designed method is based on the conception of the innovation of IS in the methodology "Multidimensional Management and Development of Information System (MMDIS)". The proposed selection method (Method of Innovation Modules based on MMDIS - MIM) is intended to serve mainly for decision-making on a strategic level. The IS structure is mapped in accordance with the MMDIS methodology. Innovation aspects are derived from two approaches: innovation aspects based on the MMDIS principles ("module of principles" - e.g. integration, flexibility, standardisation, measurability) and innovation aspects based on the IS dimensions defined in MMDIS methodology ("module of dimensions" - e.g. software, hardware, processes and functions, finances). The proposal method enforces a systematic approach to evaluation of the innovation variants, ensuring that the innovation aspects (the principles and the dimensions) are aligned with key requirements. As an example, this method is applied to an existing electronic toll system operated in the Czech Republic. Basic innovation variants of the electronic toll system are described - the microwave, the satellite and the hybrid toll system. Case studies from the Czech Republic, Austria and Germany are used for support the proposed innovation variants, as well as evaluation of variants. The principles and the dimensions form a framework for description and evaluation of the telematics, of the electronic toll and of the innovation variants of the electronic toll. The variants are compared within the framework of refined principles and dimensions, the optimal variant is proposed. The used evaluation parameters are a result of an analysis of published studies and specific toll system technical designs. The Method of Innovation Modules was constructed on the basis of MMDIS methodology and demonstrated by application in an example scenario (electronic toll). The key result of the proposed method is the comprehensive structured map of available system innovation opportunities.
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Imbert, Paul. "Multi-targeting of the innate immune system by Toll/interleukin-1 receptor domain-containing bacterial effectors and the consequences in bacterial immune-evasion." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1226.
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Le domaine TIR (Toll/interleukin (IL)-1 receptor) est une composante essentielle du système immunitaire inné, celui-ci est présent dans les récepteurs TLR (Toll-like receptor) et les protéines adaptatrices associées comme MyD88 et TIRAP. La détection de pathogènes déclenche l'interaction entre les domaines TIR permettant ainsi l'initiation et la propagation de la signalisation par les TLRs. Aussi, de nombreux pathogènes produisent des effecteurs contenant un domaine TIR tels que BtpA et BtpB chez Brucella abortus, TirS chez Staphylococcus aureus ou TcpC chez l'uropathogènique Escherichia coli. Tous ces effecteurs bloquent la signalisation des TLRs et sont capables de perturber les voies de signalisation de l'immunité innée pendant l'infection. Cependant les mécanismes moléculaires impliqués restent la plupart du temps non caractérisés et dans certains cas controversés. Dans le but de mieux comprendre le fonctionnement de ce type d'effecteurs bactériens, j'ai caractérisé chez Pseudomonas aeruginosa PA7 un nouvel effecteur contenant un domaine TIR que nous avons renommé PumA pour Pseudomonas UBAP1 Modulator A. En parallele, j'ai aussi participé à des projets de caractérisation de deux autres effecteurs avec un TIR domain : BtpB et TirS. Ainsi, PumA est un facteur essentiel pour la virulence de P. aeruginosa PA7 et son domaine TIR est essentiel pour interaction avec deux protéines adaptatrice, TIRAP et MyD88. Durant l'infection de cellules épithéliales pulmonaires par P. aeruginosa PA7, PumA est responsable du contrôle de la translocation du facteur de transcription NF-κB dans le noyau. De plus, la production de PumA dans une souche de P. aeruginosa non-TIR confère à cette bactérie de nouvelles propriétés d'immuno-modulation. PumA cible aussi UBAP1, une protéine du complexe de tri endosomal requis pour le transport, ESCRT-I (endosomal sorting complex require for transport I) qui a été récemment montré pour moduler l'activation de récepteur de cytokine. Nos résultats montrent que UBAP1 peut s'associer avec TIRAP et MyD88, provoquant le mouvement de MyD88 à la membrane cytoplasmique, suggérant une nouvelle voie cellulaire commune entre UBAP1 et les TLRs, et révélant UBAP1 comme nouvelle cible pour des effecteurs bactériens dans le cadre du contrôle des réponses immunitaires de l'hôteIn higher eukaryotes, the innate immune system provides the first line of defense against invading pathogens. The Toll/interleukin-1 receptor (TIR) domain is an essential component of the innate immune system. This domain is present in Toll-like receptors (TLRs) and associated adaptor proteins such as MyD88 and TIRAP. Pathogen detection requires interaction between the TIR domains, which initiates and triggers propagation of TLR signaling. However, many pathogens produce a TIR domain-containing protein such as BtpA and BtpB in Brucella abortus, TirS in Staphylococcus aureus or TcpC in the uropathogenic strain Escherichia coli. These effectors block TLR signaling and are able to disrupt innate immune response during infection. However, the molecular mechanisms involved remain mostly uncharacterized and in some cases controversial. The objective of this thesis was to study bacterial effectors containing a TIR domain particularly at the molecular level. For this, we focused on Pseudomonas aeruginosa PA7, an atypical multi-drug resistant strain that contains an effector with a TIR domain that we named PumA, for Pseudomonas UBAP1 Modulator A. In addition, during these four years of thesis work I also participated in the characterization of two other effectors with a TIR domain: BtpB in B. abortus and TirS in S. aureus.We found that PumA is essential for virulence of P. aeruginosa PA7 and its TIR domain is the key element for interaction with two adaptor proteins MyD88 and TIRAP. During infection of lung epithelial cells by P. aeruginosa PA7, PumA is responsible for controlling the translocation of NF-?B into the nucleus indicative of activation of this transcription factor. In addition, production of PumA by a TIR-deficient strain of P. aeruginosa confers to this bacterium a new immuno-modulation property. Furthermore, PumA targets ubiquitin-associated protein 1 (UBAP1), a protein of the endosomal sorting complex required for transport I (ESCRT-I) which has recently been shown to modulate cytokine receptor activation. Our results also show that UBAP1 can associated with TIRAP and MyD88, causing movement of MyD88 to the cytoplasmic membrane and suggesting a new cellular pathway between UBAP1 and TLRs. In summary, our data reveal UBAP1 as a novel target for bacterial effectors implicated in control of host immune responses
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Beneš, Vojtěch. "Mýtný systém v České republice." Master's thesis, Vysoká škola ekonomická v Praze, 2010. http://www.nusl.cz/ntk/nusl-134941.
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The goal of the thesis is to give reader a detailed description of the Czech electronic toll system with emphasis to the potential future system development and infrastructure toll extension. The National Transportation Policy, legislative framework concerning the infrastructure tolling, and particular European toll systems are described in the first part of the thesis. Within the other part of the thesis, the reader is given a simplified cost-profit model of future toll extension efficiency to evaluate the optimal outcome of the toll extension.
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Yan, Nan, and 燕楠. "The feasibility study of implementation of ERP system in tackling traffic congestion in Hong Kong." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/195122.
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Though billions of dollars has been spent on traffic infrastructure in Hong Kong for the past decades, it is still an unsolved traffic problem. Especially in peak hours, vehicles have to pay for the traffic congestion in the way of waiting time and air pollution. The public is interested in congestion pricing as it is effective in allocating resource. Also the revenues raised in road pricing can be used to invest in transport infrastructures which will benefit the whole society, especially in Hong Kong where more than 90% trips are taken by public transit.
The existing policy is that growth in the private vehicle fleet should not exceed 3% per year. Currently, the increase rate of private vehicles is much higher than 3%. This generates the need to do the feasibility of ERP system in tackling congestion in Hong Kong. The ERP system is not a new term for the public as the Hong Kong Government has done two studies about road pricing in 1983 and 1998. However, the studies did not promote the implementation of ERP system in Hong Kong for various reasons. At the same time, the ERP system has been tested successful in many areas, such as Singapore and London. Lessons learnt from the two cases will guide the implantation of ERP system in Hong Kong.
The study is conducted to evaluate the proposed implementation of the ERP system and attempts to recommend on future practices in order to achieve a more efficient, equitable and flexible means of managing the road space particularly in congested areas during busy hours. Questionnaire surveys will be conducted to get data for analysis of effect of ERP system. Combined with analysis of supply of transport infrastructure in next five years, the research finding is that the ERP system is not proper to be adopt to solve traffic congestion in Hong Kong.published_or_final_version
Urban Planning and Design
Master
Master of Science in Urban Planning
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Kwok, Shi-chung Colin, and 郭仕聰. "The role of electronic road pricing in tackling traffic congestion in Hong Kong." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1999. http://hub.hku.hk/bib/B31952069.
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Klaas, Reinhard. "Charakterisierung der biologischen Aktivität von Hühner Interleukin-6 und erste Untersuchungen zum Toll-like Rezeptor-System des Huhnes." Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-10259.
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Rosenberger, Karen [Verfasser]. "The impact of Toll-like receptor activation on neuroinflammation and neurodegeneration in the central nervous system / Karen Rosenberger." Berlin : Freie Universität Berlin, 2015. http://d-nb.info/1078505322/34.
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Wlasiuk, Battagliotti Gabriela. "THE MOLECULAR EVOLUTION OF INNATE IMMUNITY GENES." Diss., The University of Arizona, 2009. http://hdl.handle.net/10150/195184.
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It is not clear whether genes of the innate immune system of vertebrates are subject to the same selective pressures as genes of the adaptive immune system, despite the fact that innate immunity genes lie directly at the interface between host and pathogens. The lack of consensus about the incidence, type, and strength of selection acting on vertebrate innate immunity genes motivated this study. The goal of this work was to elucidate the general principles of innate immune receptor evolution within and between species. A phylogenetic analysis of the Toll-like receptor 5 (TLR5) in primates showed an excess of nonsynonymous substitutions at certain codons, a pattern that is consistent with recurrent positive selection. The putative sites under selection often displayed radical substitutions, independent parallel changes, and were located in functionally important regions of the protein. In contrast with this interspecific pattern, population genetic analysis of this gene in humans and chimpanzees did not provide conclusive evidence of recent selection. The frequency and distribution of a TLR5 null mutation in human populations further suggested that TLR5 function might be partially redundant in the human immune system (Appendix A). Comparable analyses of the remaining nine human TLRs produced similar results and further pointed to a biologically meaningful difference in the pattern of molecular evolution between TLRs specialized in the recognition of viral nucleic acids and the other TLRs (Appendix B). The general picture that emerges from these studies challenges the conventional idea that pattern recognition receptors are subject to an extreme degree of functional constraint dictated by the recognition of molecules that are essential for microbial fitness. Instead, TLRs display patterns of substitution between species that reflect an old history of positive selection in primates. A common theme, however, is that only a restricted proportion of sites is under positive selection, indicating an equally important role for purifying selection as a conservative force in the evolution of this gene family. A comparative analysis of evolutionary rates at fifteen loci involved in innate, intrinsic and adaptive immunity, and mating systems revealed that more promiscuous species are on average under stronger selection at defense genes (Appendix C). Although the effect is weak, this suggests that sexual promiscuity plays some role in the evolution of immune loci by affecting the risk of contracting infectious diseases.
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Ponter, Lloyd Anthony. "An assessment of e-tolling as a method of financing Gauteng roads." Thesis, Rhodes University, 2015. http://hdl.handle.net/10962/d1017185.
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E-tolling was recently implemented on roads in Gauteng, South Africa. This gave rise to a great deal of protest by road users and a court battle between the South African National Roads Agency (SANRAL) and the Opposition to Urban Tolling Alliance, a body representing road users. The e-tolling system was criticised at various levels and on numerous grounds, some financial and others appearing to be emotional. This thesis attempted to analyse the various grounds for objection against the system, the main goal of the research being to analyse e-tolling in Gauteng to ascertain whether or not the introduction of e-tolling was justified or whether an alternative method of taxation to pay for the upgrading of Gauteng roads would have been more cost-effective. Secondary data in the form of documents from multiple sources was used in the analysis, including an Economic Impact Assessment that was one of the key inputs into the decision to introduce e-tolling. It was found that there are multiple problems plaguing the e-toll system and e-tolling is not the most cost-effective taxation method of paying for Gauteng roads. Using a fuel levy or general tax revenue available to the National Treasury were both found to be more cost-effective methods as they would have achieved the same result (repairing and upgrading specific Gauteng roads), at a cost of R20,0913 billion less than e-tolling. It was suggested that the best taxation method/s to pay for the roads would have been using a fuel levy and general tax revenue as the primary funding methods, with vehicle licensing fees and long distance toll roads as secondary methods to aid the primary methods.
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Brown, Matthew. "The expression of Toll-like receptors-2 and-4 by human crypt intestinal epithelial cells, intestinal myofibroblasts and putative intestinal stem cells in inflammatory bowel disease." Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/13437/.
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Host-microbial interactions are of major importance in the pathogenesis of inflammatory bowel disease (IBD). Toll-like receptors (TLR) are pattern recognition receptors which recognise conserved molecular patterns derived from micro-organisms. Crypt intestinal epithelial cells (IEC) were isolated form mucosal specimens of healthy controls and patients with IBD (ulcerative colitis, UC, and Crohn's disease). A population of IEC enriched for intestinal stem cells (ISC) were identified using Hoechst dye exclusion and by their adherence to cultured primary intestinal myofibroblast cell monolayers. Compared to healthy control colon, TLR2 and TLR4 mRNA and surface protein were significantly up-regulated in crypt IEC isolated from the inflamed mucosa of UC and Crohn's colitis. Compared to healthy control ileum, TLR4 mRNA was significantly up-regulated in crypt epithelial cells isolated from the inflamed mucosa of Crohn‟s ileitis. TLR2 and TLR4 mRNA expression from histologically normal and inflamed colonic mucosa in UC did not significantly differ, and expression of TLR4 transcripts was significantly greater in crypt IEC isolated from histologically normal proximal colonic mucosal samples compared to healthy controls. Myofibroblast-adherent crypt cells expressed TLR2 and TLR4 protein to a greater level than the underlying myofibroblasts. Hoechst-effluxing putative intestinal stem cells expressed both TLR2 and TLR4 transcripts and protein, and TLR3 and TLR5 transcripts. In conclusion, crypt intestinal epithelial cells up-regulated TLR2 and TLR4 expression in UC and Crohn's colitis and up-regulated TLR4 expression in Crohn's ileitis. TLR2 and TLR4 was expressed constitutively in crypt IEC from histologically normal mucosa, suggesting differential TLR expression may in part be a primary event in UC. This provides further insights into the pathogenesis of IBD. Putative intestinal stem cells expressed TLR2, TLR3, TLR4 and TLR5, suggesting that direct microbial sensing by ISC may be important in maintaining intestinal homeostasis and in regulating ISC function.
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Ji, Jie. "Targeting the innate immune system to develop novel prophylactic strategies: lessons from amphioxus (B. lanceolatum) and zebrafish (D. rerio)." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/525852.
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La vacunació és una de les estratègies més efectives de control de les malalties infeccioses. Tot i així hi ha una clara falta de vacunes eficients o d’eines profilàctiques efectives per moltes especies de peixos d’interès comercial. Es necessiten més estudis de recerca bàsica i aplicada per millora la prevenciIBsTNFα) i els liposomes miniaturitzats NLc. Els IBsTNFα són altament estables, no toxics, i són un tipus de biomaterial proteic amb un baix cost de producció. Mitjançant intubació oral de peixos zebra adults i l’ús combinat de citometria, histologia i microscòpia confocal hem demostrat que els IBsTNFα poden atravessar l’epiteli de la mucosa intestinal, passar per la lamina propria i arribar a la capa muscular subjacent. A més l’expressió de gens relacionats amb la resposta innata està significativament regulada a l’alça en intestins de peix zebra. Finalment hem demostrat que els IBsTNFα poden protegir al peix zebra d’una infecció per Mycobacterium marinum. D’altra banda el sistema de nanoliposomes encapsulant LPS i Poly(I:C) o NLc, desenvolupats previament al laboratory, també protegeix al peix zebra contra una infecció letal de M. marinum. També hem explorat la viabilitat d’utilitzar M. marinum i A. hydrophila per desenvolupar un model d’infecció en larves de peix zebra. El model d’infecció de M. marinum no és viable ja que no podem induir mortalitats per inmersió; però el model amb A. hydrophila ha demostrat ser adequat ja que la mortalitat de les larves és depenent de la dosi infective d’A. hydrophila. Els NLc i els IBsTNFαadministrats per inmersió els localitzem a la faringe i l’intestí de les larves de peix zebra a dia 3 i 5 post fertilització. L’expressió de gens de resposta immune es veu regulada a l’alça després del tractament amb NLc. Encanvi no observem una expression a l’alça de gens inmunes després del tractament amb IBsTNFα i això correlaciona amb el fet que els IBsTNFα no protegeixen d’una infecció letal per A. hydrophila.Immunization through vaccination is one of the most effective strategies to control infectious diseases. However, effective vaccines and alternative prophylactic tools for many fish diseases are still lacking. More studies on basic and applied immunology are required to improve the prevention and control of diseases in aquaculture. In this context, the thesis presents both basic and applied research. The Toll-like receptors (TLRs) are important for raising innate immune defense and their ligands are used as vaccine adjuvants to improve the immune responses. We studied the TLR system in the amphioxus B. lanceolatum. We identified 28 new putative TLR genes which consist in both non-vertebrate- and vertebrate-like TLRs. We cloned one of these genes, Bl_TLRj. The phylogenetic analysis together with functional analysis showed that it clusters with TLR11 family and particularly with subfamily 13. Moreover, Bl_TLRj responded against viral stimuli and showed high sequence identity with fish TLR13 and TLR22. Second, we developed two different infection models in zebrafish and we tested two potential nanoparticle adjuvants, IBsTNFα and NLc. The IBsTNFα are a highly stable, non-toxic, and low-cost protein-based biomaterial formed with nano-structured trout tumor necrosis factor alpha cytokine. Via oral intubation of adult zebrafish, combining flow cytometry, histology, and confocal microscopy, we show that IBsTNFα are able to cross the intestinal mucosal epithelial barriers, pass through the lamina propria, and reach the muscle layer. The expression of innate immune-related genes was significantly up-regulated in zebrafish intestine. Finally, IBsTNFα could protect zebrafish against a Mycobacterium marinum lethal infection when i.p. injected. The second particle tested, NLc, was previously developed in our lab and is composed by nanoliposomes encapsulating LPS and Poly I:C. The NLc was tested in our M. marinum bacterial infection model and it could protect zebrafish against a lethal infection when i.p. injected. Next, we explored the infective possibilities of two fish pathogens, M. marinum and Aeromonas hydrophila, in zebrafish larvae by immersion. The mortality of zebrafish larvae immersed with M. marinum showed no significant differences but zebrafish larvae infected with A. hydrophila by immersion showed significant differences compared to controls in a dose-dependent manner. NLc and IBsTNFα localized in the pharynx and intestine of zebrafish larvae at 3 and 5 dpf, respectively. The expression of immune-related genes such as IL-1β and IRF1α was significantly up-regulated after 48 h treatment with NLc in 2 dpf larvae. The 5 dpf larvae immersion in IBsTNFα could not significantly alter immune-related gene expression and IBsTNFα could not protect zebrafish larvae against A. hydrophila lethal infection.
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Gharaibeh, Mohammad Hamdi [Verfasser]. "Involvement of Toll-like Receptor 2 in Recognition of Orientia tsutsugamushi by the Innate Immune System / Mohammad Hamdi Gharaibeh." Berlin : Freie Universität Berlin, 2013. http://d-nb.info/1038694922/34.
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Anthoney, Niki Cathryn. "Functional analysis of the toll receptor protein family and their downstream signaling pathways in the central nervous system of Drosophila." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7343/.
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Cell number plasticity drives organismal growth, and is coupled in the CNS to the emergence of neural circuits, ensuring appropriate function. In mammals, neurotrophins promote cell survival via Trk and p75\(^{NTR}\) receptors or induce cell death via p75\(^{NTR}\) and Sortilin. In \(Drosophila\), DNTs bind Toll receptors promoting cell survival, but whether they regulate cell death within the CNS remains unknown. I show Toll receptors have distinct and overlapping spatial and temporal expression and functions. Driving RNAi knockdown and overexpression of each Toll, I show that different Toll receptors are required in glia for adult locomotion; in neurons for the regulation of VNC size; and to induce cell survival or death in distinct contexts. I focused on the signalling mechanisms downstream of Toll-6. My data show DNT-Toll-6 signalling switches between promoting cell survival or death via NFkB, ERK, or JNK signalling. These outcomes depend on the cleavage state of the DNT, time and available downstream adaptors. Toll-6 induces cell survival via MyD88 and cell death via dSarm, and these alternative outcomes depend on Weckle. Altogether, my data contribute to showing that the Toll receptors, DNTs and downstream signalling adaptors constitute a novel mechanism of cell number plasticity within the CNS.
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Lim, Mei Ann. "Functional analysis of Drosophila neurotrophin and toll receptor families in the development and repair of the larval central nervous system." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6104/.
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Drosophila neurotrophins (DNTs) - Spätzle (Spz), DNT1 and DNT2 - and 3 members of the Toll protein family - Toll, Toll-6 and Toll-7, of which Toll is Spz’s receptor - have been shown to promote neuronal survival and motoneuron targeting in embryos. Yet, it remains to be understood (1) whether the DNTs influence cell number and central nervous system (CNS) development after embryonic stages to result in the behaving larva, and in turn (2) whether these events influence larval CNS repair after injury. Here, the functions of DNTs and Tolls in the formation and repair of the larval CNS were investigated, focusing mostly on Spz. \(GAL4\) reporters, \(Mi\){\(MIC\)} protein traps and antibodies to the DNTs and Tolls were used to describe larval CNS distributions. Interestingly, Spz was restricted to the mechanosensory domain in the ventral nerve cord (VNC). New alleles for \(spz\) were generated and a loss of function allele was shown to affect glial numbers in the larval abdominal VNC. The loss of function allele also weakly antagonised wound closure, but further work needs to be undertaken to conclude whether or not the role of Spz in larval CNS repair is prominent.
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Lauener, Roger Pascal. "Pattern recognition receptors of the innate immune system : CD14, Toll-like receptors 2 and 4, and their role in inflammatory diseases /." [S.l.], 2003. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253377.
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Grano, Fernanda Grecco. "Investigação do perfil de expressão gênica de receptores tipo toll e citocinas inflamatórias no encéfalo e no baço de cães com leishmaniose visceral /." Araçatuba, 2017. http://hdl.handle.net/11449/151332.
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Orientador: Gisele Fabrino MachadoBanca: Valéria Marçal Felix de Lima
Banca: Flávia Lombardi Lopes
Banca: Paulo Ricardo Dell'Amerina Rocha
Banca: Monica Regina Vendrame Amarante
Resumo: A leishmaniose visceral (LV) é uma doença parasitária que apresenta distribuição mundial e que pode afetar homens e animais, sendo que o cão é considerado o principal hospedeiro da doença. Cães infectados pelo parasito Leishmania podem apresentar-se assintomáticos ou com desordens generalizadas, incluindo alterações neurológicas. Existem alguns relatos do acometimento do encéfalo durante a infecção, mas a neuropatogenia da doença não foi completamente elucidada. Há evidências do comprometimento das barreiras encefálicas e da presença do DNA do parasito no encéfalo. Os receptores tipo Toll (TLRs) são sensores do sistema imune inato capazes de detectar padrões moleculares associados aos patógenos (PAMPs), desencadeando uma resposta inflamatórias com produção de diversos mediadores inflamatórios, incluindo citocinas. Desta forma, o objetivo deste estudo foi avaliar o perfil de expressão gênica dos Tolls 1-10, assim como a produção de citocinas pró-inflamatórias TNF-α, IFN-γ, IL-1β e IL-6 no encéfalo e no baço de cães com leishmaniose visceral. No baço houve aumento de expressão gênica de TLR-5 e TLR-9, enquanto no encéfalo houve aumento de TLR-4 em uma pequena população de cães infectados. Em relação às citocinas, todas as citocinas foram detectadas nos dois tecidos avaliados, com excessão de IL-6. Nos cães infectados, TNF-α e IL-1β estavam presentes em maiores concentrações no encéfalo e no baço, respectivamente. Este estudo fornece suporte para explicar o envolvimento de TLRs ... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract:Visceral leishmaniasis (VL) is a parasitic disease that presents world distribution, affecting humans and animals. Dogs are considered the main hosts of the disease. Infected dogs with the Leishmania parasite can be asymptomatic or present generalized disorders, including neurological alterations. There are some reports of brain commitment during infection. Nevertheless, neuropathogenesis of VL is not completely elucidated. There are evidences of brain barriers breakdown and of the presence of Leishmania DNA in the brain. Toll-like receptors (TLRs) are innate immune sensors capable of detecting pathogen-associated molecular patterns (PAMPs), trigger an inflammatory response with production of several inflammatory mediators, including cytokines. Therefore, the aim of this study was to evaluate gene expression profile of TLRs1-10, along with the production of proinflammatory cytokines in both brain and spleen in dogs with VL. In spleen there was an upregulation of TLR-5 and TLR-9 while in the brain there was up-regulation of TLR- 4 in a few number of infected animals. Regarding cytokines, all cytokines were detected in both tissues, except IL-6. In the infected dogs, TNF-α and IL-1β were present at higher concentrations in the brain and spleen, respectively. This study provides support to explain the involvement of TLRs in VL and our data confirm the brain as an affected organ in this disease
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Gonçalves, Mariana Torrente. "Ação do imunomodulador P-MAPA sobre o sistema complemento e receptores do tipo Toll em modelo de inflamação induzida por lipopolissacarídeo." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-12082014-155111/.
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O agregado proteico P-MAPA apresentou potencial imunomodulatório em diversos estudos, mas a sua ação sobre o sistema complemento e receptores do tipo Toll (TLRs) não é, ainda, conhecida. Neste estudo o P-MAPA promoveu ativação das vias clássica e alternativa do sistema complemento e produção de C3a e C5a. Utilizando um modelo ex vivo de sangue total humano, o composto promoveu aumento da expressão de CD11b e CD14, diminuição da expressão de C5aR, TLR2 e TLR4, em leucócitos de sangue periférico e também quando combinado com LPS, porém não promoveu alterações na expressão de C3aR. O P-MAPA induziu redução de IFN-g no plasma, aumento da produção de TNF-α, IL-8, IL-12 e peróxinitrito, mas não induziu produção de superóxido, IL-6, IL-1β, TGF-β ou IL-10. Por meio de testes in vivo, foi possível determinar a dose letal do P-MAPA. Em conjunto, os dados obtidos mostram que o P-MAPA apresenta ação pró-inflamatória em modelo ex vivo de sangue total humano e que o tratamento combinado com LPS leva a uma amplificação dos seus efeitos.P-MAPA, a protein aggregate has been described as a promising immunomodulator, however, its role on the complement system and Toll-like receptors (TLRs) is unknown. In the study, P-MAPA has promoted activation of the complement\'s classical and alternative pathways and the production of C3a and C5a. Using an ex vivo model of human whole blood, the compound promoted increase of CD11b and CD14 expression, decrease of C5aR, TLR2 and TLR4, in peripheral blood leucocytes and when combined with LPS, but did not change C3aR expression. P-MAPA promoted reduction of IFN-g in plasma, increased production of TNF-α, IL-8, IL-12 and peroxynitrite, but did not induce the production of superoxide, IL-6, IL-1β, TGF-β or IL-10. Through in vivo tests, we were able to determine a lethal dose for P-MAPA. Altogether, our data indicate that P-MAPA has proinflammatory action in ex vivo model of human whole blood and that the treatment combined with LPS leads to amplification of its effects.
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Vicente-Suarez, Ildefonso. "Immunomodulatory role of flagellin in antigen-presenting cells." [Tampa, Fla] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0002201.
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Opitz, Bastian. "Pathogenerkennung durch das Immunsystem." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2001. http://dx.doi.org/10.18452/14762.
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Die angeborene Immunität ist in der Lage, Pathogene schon beim erstmaligen Eindringen zu erkennen und zu bekämpfen. Haupteffektoren der schnellen, angeborenen Immunantwort sind Makrophagen und polymorphkernige neutrophile Granulozyten. Diese erkennen und phagozytieren Pathogene und koordinieren die weitere Immunantwort durch die Freisetzung von inflammatorischen Mediatoren und Zytokinen. Die Erkennung mikrobieller Bestandteile, wie Lipopolysaccharid (LPS) Gram-negativer Bakterien bzw. Peptidoglykan (PG) und Lipoteichonsäuren (LTA) Gram-positiver Bakterien, führt zur Aktivierung von unterschiedlichen Proteinkinasen, des Transkriptionsfaktors NF-(B und zur Freisetzung von Zytokinen. Mitglieder der Toll-Proteinfamilie, sogenannte Toll-like-Rezeptoren (TLR), wurden kürzlich als Rezeptoren auf Immunzellen identifiziert, die für die Erkennung solcher mikrobieller Bestandteile verantwortlich sind. Während TLR-4 der LPS-Erkennung dient, und TLR-2 und -6 verschiedene Liganden von Gram-positiven Bakterien binden, blieb die Frage der Erkennung von LTA und verwandten Glykolipiden strittig. Sowohl TLR-2 als auch TLR-4 wurden für diese Rolle diskutiert. Zielsetzung dieser Arbeit war, die Rolle von TLRs in der LTA- und Glykolipid-Erkennung zu untersuchten. Glykolipide von zwei eng verwandten Treponemen-Spezies, T. maltophilum (TM) und T. brennaborense (TB), sowie neuartig aufgereinigte Lipoteichonsäuren von Staphylococcus aureus (SA) und Bacillus subtilis (BS) wurden eingesetzt, um die nukleäre Translokation von NF-(B in verschiedenen Zellsystemen zu induzieren. Diese Zellstimulationsexperimente wurden mit verschiedenen TLR-2-negativen Zellinien sowie mit Peritonealexsudatzellen TLR-4-defizienter C3H/HeJ-Mäuse durchgeführt. Weitere Informationen lieferten TLR-2-Überexpressions-Experimente sowie Zellstimulationen unter Verwendung von anti-TLR-4-Antikörpern. Die Aktivierung von NF-(B wurde anhand von Gelshifts nachgewiesen. Mit der Überexpression von dominant-negativen Mutanten verschiedener Moleküle der Signalkaskade, mit Kinase-Hemmstoffen und mit Western Blots wurden die intrazellulären Signaltransduktionswege untersucht. Für Glykolipide von T. maltophilum und beide verwendeten Lipoteichonsäuren ließ sich eine klare TLR-2-Abhängigkeit in der Aktivierung von NF-(B und der Induktion von proinflammatorischen Zytokinen zeigen. Die Glykolipide von T. brennaborense hingegen waren überraschender Weise gleichzeitig auch TLR-4-Liganden. Beide untersuchten Glykolipide sowie beide LTAs aktivierten einen Signalweg unter Einbeziehung des Adaptermoleküls MyD88 und der NF-(B-induzierenden Kinase (NIK). Des weiteren konnte der Einfluß der MAP-Kinasen p42/44 und p38 auf die Treponema-Glykolipid- und LPS-induzierte TNF-(-Ausschüttung dargestellt werden. Zusammenfassend zeigen diese Ergebnisse, daß TLR-2 der Hauptrezeptor von Lipoteichonsäuren ist, und TLR-2 und -4 beide Rezeptoren der Treponema-Glykolipide sein können. Diese Ergebnisse sollten dazu beitragen, die molekularen Grundlagen der Reaktionen des Immunsystems auf Gram-positive Bakterien und Treponemen zu verstehen.The innate immune response to microbial pathogens is able to protect the host after a first pathogen contact. This immediate immune response is largely mediated by macrophages and neutrophils. They recognize and phagocytose pathogens, and coordinate host responses by secreting inflammatory mediators, such as cytokines. The recognition of lipopolysaccharide (LPS) of Gram-negative bacteria, or peptidoglycan (PG) and lipoteichoic acids (LTAs) of Gram-positive bacteria leads to the induction of protein-kinases, the transcription factor NF-(B, and subsequently the release of proinflammatory cytokines. Recently, members of the Toll-protein-family, the so-called Toll-like receptors (TLRs) have been found to be involved in immune cell activation by microbial products. While TLR-4 has been identified as the transmembrane signal transducer for LPS, and TLR-2 and -6 for different ligands originating from Gram-positive bacteria, the molecular basis of recognition of lipoteichoic acids and related glycolipids has not been completely understood: Both, TLR-4 and -2 have been postulated as receptors. In order to determine the role of TLRs in immune cell activation by Treponema glycolipids and LTAs experiments involving TLR-2-negative cell lines, macrophages from TLR-4-deficient C3H/HeJ-mice, cells overexpression TLR-2, and inhibitory TLR-4 antibodies were performed. The induction of NF-(B was assessed by electrophoretic mobility shift assays. Glycolipids of two related Treponema species, T. maltophilum (TM) and T. brennaborense (TB), and LTAs from Staphylococcus aureus (SA) and Bacillus subtilis (BS) were investigated for induction of nuclear translocation of NF-(B in different cell systems. Glycolipids from T. maltophilum and both LTAs studied revealed TLR-2-dependency in induction of NF-(B and proinflammatory cytokines. Surprisingly, glycolipids from T. brennaborense were found to be TLR-4-ligands. Furthermore an involvement of the signaling molecules MyD88 and NIK in cell stimulation by LTAs and glycolipids was revealed by dominant-negative overexpression experiments. The induction of TNF-( by Treponema glycolipids furthermore was dependent on activation of MAP kinases p42/44 and p38, as indicated by specific kinase inhibitors. Tyrosinephosporylation of the p42/44 kinase induced by Treponema glycolipids were detected by western blots. In summary, the results presented here indicate that TLR-2 is the main receptor for LTAs. Both TLR-2 and -4 serve as receptors for Treponema glycolipids. These results may potentially contribute to explain immune responses to Gram-positive bacteria and treponemes.
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Smerk, Cari L. "P1 Bacteriophage and Tol System Mutants." Bowling Green State University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1182462962.
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Orsatti, Cláudio Lera [UNESP]. "Avaliação do polimorfismo genético da lecitina ligante de manose (MBL2) e da expressão gênica dos receptores Toll-Like (TLR) como bio-marcadores do risco cardiovascular em mulheres na pós-menopausa." Universidade Estadual Paulista (UNESP), 2014. http://hdl.handle.net/11449/123279.
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FAPESP: 2009/14884-9
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Orsatti, Cláudio Lera. "Avaliação do polimorfismo genético da lecitina ligante de manose (MBL2) e da expressão gênica dos receptores Toll-Like (TLR) como bio-marcadores do risco cardiovascular em mulheres na pós-menopausa /." Botucatu, 2014. http://hdl.handle.net/11449/123279.
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Orientador: Eliana Aguiar Petri NahasCoorientador: Steven Witkins
Banca: Maria Terezinha Serrão Peraçoli
Banca: Cesar E. Fernandes
Banca: Aarão Mendes Pinto
Banca: Renata D. Jouiliano
Resumo: Não disponível
Abstract: Not available
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Bitter, Sondhja. "Influence of specific farming activities of pregnant mothers on gene-expression of CD14 and toll-like receptors of the newborn : indicators for prenatal priming of the immune system /." Basel, 2007. http://www.public-health-edu.ch/new/Abstracts/BS_07.04.08.pdf.
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Julià, Manresa Marc. "Receptores del sistema inmunitario innato (Toll-like receptors y receptores de la Fc-gamma) y adaptativo (CD5 y CD6) como factores de susceptibilidad, modificadores de la enfermedad y respuesta al tratamiento biológico en psoriasis." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668023.
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La psoriasis es una enfermedad inflamatoria crónica inmunomediada principalmente cutánea caracterizada por la presencia de placas eritematodescamativas en zonas de extensión y cuero cabelludo. En su fisiopatogenia se implican múltiples componentes tanto al sistema inmunitario innato como adaptativo. En esta Tesis Doctoral, se presentan 4 trabajos originales en los que se analiza el impacto de distintos polimorfismos genéticos de receptores del sistema inmunitario innato (receptores toll-like y de la Fc-gamma) y de sistema inmunitario adaptativo (CD5 y CD6) como factores modificadores del fenotipo, de susceptibilidad a la enfermedad y de respuesta al tratamiento de la psoriasis. Además, se aportan las primeras evidencias experimentales in vivo e in vitro de la implicación del receptor linfocítico CD6 en la fisiopatogenia de la enfermedad.Psoriasis is a chronic immuno-mediated inflammatory cutaneous disease characterized by the presence of erythematous and desquamative plaques tipically appearing in extension areas and the scalp. In its pathophysiology, multiple components of both the innate and adaptive immune system have been implicated. In this Doctoral Thesis, 4 original studies are presented analyzing different genetic polymorphisms of receptors belonging to both the innate (toll-like and Fc-gamma receptors) and adaptive immune system (CD5 and CD6) as potential factors that modify the phenotype, the susceptibility and the response to treatment in psoriasis. In addition, the first in vivo and in vitro experimental evidences of the involvement of CD6 lymphocyte receptor in psoriasis are provided.
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Eckert, Jana Kristin. "Funktionelle Analyse von Mutanten des LPS-bindenden Proteins (LBP)." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/15955.
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LBP vermittelt im Wirtsorganismus die direkte Immunantwort auf bakterielle Liganden wie das Lipopolysaccharid (LPS) von Gram-negativen oder Lipopeptide von Gram-positiven Bakterien. In dieser Arbeit wurde die Funktionsweise von LBP weiter aufgeklärt. Im ersten Teil der Arbeit wurde eine natürlich vorkommende Mutation des LBP (c998t), die an Position 333 zu einem Austausch der Aminosäure Prolin zu Leucin führt, hinsichtlich ihrer Auswirkungen auf Struktur und Funktionalität des Proteins untersucht. Westernblot-Analysen des rekombinant hergestellten Proteins und humaner Seren von Mutationsträgern weisen auf einen Zerfall des mutierten Proteins hin. Es kommt zu einer Beeinträchtigung der Bindung bakterieller Liganden und einer deutlichen Reduktion der LBP-vermittelten Zytokinausschüttung von Immunzellen. Der hier untersuchte Polymorphismus hat eine Allelfrequenz von 0,072 in einer gesunden europäischen Population. Genotypanalysen von Patientengruppen zeigten, dass es durch die Mutation zu einer deutlich erhöhten Mortalität bei Patienten mit septischen Komplikationen und einer durch Gram-negative Erreger verursachten Pneumonie kommt. Unsere Ergebnisse zur eingeschränkten Funktion des LBP-c998t bieten eine erste Erklärung dafür, wie diese Mutation vermutlich die Fähigkeit, Krankheiten zu bewältigen, beeinträchtigt. Innerhalb dieser Arbeit ging es um die Analyse der Bindung von bakteriellen Liganden an LBP. Dabei wurde eine potentiell gemeinsame Bindungsstelle für Liganden untersucht, die von Gram-positiven und Gram-negativen Bakterien stammen und später von den Toll-like Rezeptoren (TLRs) 2 und -4 erkannt werden. Dazu wurden Bindungsversuche zwischen Lipopeptiden und LPS mit einer zweiten LBP-Variante (LBP-E94/95) durchgeführt. Beim LPS führt dies zu einem Bindungsverlust. Auch für die Lipopeptide war durch die Mutationen die Interaktion mit LBP beeinträchtigt, was die These einer gemeinsamen Bindungsstelle von TLR2- und TLR4-Liganden an das Protein weiter unterstützt.LBP enhances the innate immune reaction against bacterial ligands like LPS from gram negative or lipopeptides from gram positive bacteria in the host. Here we investigated the function of LBP using two recombinant mutants of the protein. The first part of this work examines a natural occurring mutation of LBP (c998t) leading to an amino acid exchange of proline to leucine at position 333 with regard to the impact on structure and function of the protein. Western blot analyses of the recombinant protein and sera obtained from individuals differing in the LBP genotype indicate the disaggregation of the mutated protein. Thereby binding of bacterial ligands to LBP is diminished and the LBP mediated cytokine secretion of immune cells is reduced. The gene polymorphism leading to the occurrence of the mutation is present with an allelic frequence of 0.072. A recent study has shown that this LBP-SNP led to a higher mortality in patients with septic complications and gram negative pneumonia. The results presented here, showing the negative impact on the function of LBP due to the mutation, may therefore be a first explanation on how this mutation affects the ability of people to deal with disease. Within this work binding of ligands to LBP was also explored. It was investigated whether ligands which are later recognized by Toll-like receptors (TLRs) 2 and – 4 share a common binding site on LBP. Assays with immobilized lipopeptides and LPS were performed with a second mutated LBP (LBP-E94/95). LPS binding to LBP is diminished completely. Here we showed that binding of lipopeptide to LBP is affected likewise, furthermore supporting the hypothesis of a common binding site for TLR2- and TLR4- ligands.
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Gutzeit, Cindy. "Interference of Varicella-Zoster Virus (VZV) with the CD1 antigen presenting system on immature dendritic cells." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/16059.
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Das human pathogene Varicella-Zoster Virus (VZV) gehört zur Familie der Herpesviren und ist weltweit verbreitet. Die Primärinfektion verursacht Varicellen, welche durch einen bläschenartigen Hautausschlag charakterisiert ist. Im Anschluss daran etabliert VZV eine lebenslange Latenz und verursacht nach Reaktivierung Herpes Zoster. Seit 2004 ist der Lebendimpfstoff aus attenuierten Virionen des VZV-Stammes V-Oka in Deutschland empfohlen. Im Gegensatz zur Infektion mit zirkulierenden virulenten VZV Stämmen tritt nach Verimpfung des Vakzin-Stammes V-Oka kein Exanthem auf. Die Haut ist der Hauptreplikationsort von VZV und immunologische Unterschiede zwischen virulentem VZV und dem Vakzin-Stamm treten hier am deutlichsten auf. In der vorliegenden Arbeit konnte eine neue Immunevasionsstrategie virulenter VZV Stämme aufgedeckt werden, welche erklären könnte, wie virulente VZV Stämme frühe antivirale Immunantworten umgehen. In Hautläsionen von Herpes Zoster Patienten konnte eine massive Infiltration von myeloiden inflammatorischen Dendritischen Zellen beobachtet werden. In vitro Studien mit Monozyten abgeleiteten Dendritischen Zellen (DC), welche inflammatorische DC repräsentieren, zeigten, eine signifikant erhöhte Expression von CD1c Molekülen nach Infektion mit dem Vakzin-Stamm, sowie virulentem VZV. Funktionelle Untersuchungen mit intraepithelialen CD1c-restringierten gamma delta T Zellen zeigten, dass DC nach Infektion mit dem Vakzin-Stamm phänotypisch und funktionell reiften und somit die T Zellen zur IFN-gamma Sekretion stimulierten. Im Gegensatz dazu wurde die funktionelle Reifung von DC, die mit virulentem VZV infiziert waren, geblockt. Folglich wurde kein bioaktives IL-12 sezerniert, welches als entscheidendes Cytokin zum Aufbau einer antiviralen T-Helfer 1 Immunantwort beiträgt. Darüber hinaus konnte gezeigt werden, dass virulentes VZV die Signalkaskade des Toll-like Rezeptors 2 (TLR2) in DC inhibiert und somit die IL-12 Produktion verhindert.Varicella-zoster virus (VZV) which belongs to the family of herpesviruses is restricted to humans and distributed worldwide. Primary infection of VZV causes chickenpox characterized by a disseminated rash. Thereafter, VZV establishes a lifelong latency and can be reactivated to cause herpes zoster. Since 2004 the attenuated strain V-Oka of VZV was licensed for Germany to immunize children against VZV infection. In contrast to infection by circulating virulent VZV strains, vaccination with V-Oka remains asymptomatic. The skin is the major replication site of VZV and immunological differences between virulent VZV and the vaccine should become most apparent within this immune organ. In summary, this study discovered a new immune evasion strategy of virulent VZV strains which might explain how virulent VZV strains overcome innate antiviral responses. A strong infiltration of myeloid-derived inflammatory DCs has been detected in skin lesions of herpes zoster patients. In vitro studies with monocyte-derived dendritic cells (DCs), reflecting inflammatory DCs, showed that they were efficiently infected by both, the vaccine and a virulent VZV strain. Intriguingly, a significant upregulation of CD1c molecules on VZV-infected DCs was observed. Functional investigations using intraepithelial CD1c-restricted gamma delta T cells revealed that DCs infected with the vaccine virus were fully instructed to mature, thereby promoting IFN-gamma secretion of gamma-delta T cells. In striking contrast, DCs infected with virulent VZV strains were efficiently blocked to mature functionally. In detail, they did not secrete bioactive IL-12 which is an instrumental cytokine for generation of antiviral T helper 1 responses. Moreover, virulent VZV blocked Toll-like receptor 2 (TLR2) signaling in DCs thereby preventing production of bioactive IL-12 which in turn inhibited IFN-gamma secretion by gamma-delta T cells.
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Abrahão, Mariana Vieira. "Papel do Sistema Renina-Angiotensina (SRA) na hipertrofia cardíaca induzida por lesão renal isquêmica." reponame:Repositório Institucional da UFABC, 2015.
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Orientadora: Profa. Dra.Marcela Sorelli Carneiro RamosTese (doutorado) - Universidade Federal do ABC, Programa de Pós-Graduação em Biossistemas, 2015.
Recentemente, dados na literatura demonstram a estreita interacao patofisiologica existente entre os rins e o coracao. Conhecida como sindrome cardio-renal, essa patologia e capaz de promover hipertrofia e falencia cardiaca a partir de um quadro de lesao renal. Sabe-se que a lesao renal isquemica (LRI) promove a liberacao de diferentes citocinas inflamatorias que tem o coracao como tecido alvo e sao capazes de promover a instalacao do quadro hipertrofico, agindo, por exemplo, por meio de receptores semelhantes ao Toll (toll-like receptors - TLR). Alem de mediadores inflamatorios, trabalhos presentes na literatura ja comprovaram a direta relacao entre alteracoes no sistema renina-angiotensina (SRA) e nos niveis de Angiotensina II (Ang II) com o aumento da massa cardiaca. O presente estudo objetivou investigar o papel do SRA com a hipertrofia cardiaca (HC) induzida por um modelo experimental de LRI em camundongos tratados ou nao com bloqueadores do SRA, Losartan (Los) e Enalapril (Ena). O quadro de LRI foi induzido cirurgicamente atraves da oclusao do pediculo renal esquerdo por 60 minutos seguido de reperfusao. Apos 12, 15 ou 20 dias os tecidos foram removidos para a realizacao de analises macromorfometricas, moleculares e funcionais. Os principais resultados indicam que a cirurgia de isquemia renal e reperfusao foi capaz de gerar um quadro de falencia renal e induzir HC de maneira independente de aumento na pressao arterial. Ainda, no periodo analisado, observou-se aumento nos niveis sericos de TNF-¿¿ e Ang II, elevados niveis de expressao genica ou proteica de AT1, ECA-2, TLR-2, TLR-4 e NFk¿À, sugerindo relacao desses componentes com a HC. Os tratamentos com Los e Ena reverteram completamente a HC observada e aboliram o aumento na expressao cardiaca de TLRs, AT1R e ECA-2 e modularam diferencialmente os niveis sericos de Ang II e citocinas inflamatorias. Juntos, os dados sugerem um papel crucial do SRA na regulacao do quadro patologico neste modelo, atuando juntamente com o sistema imune inato na regulacao da patogenese da HC atraves da modulacao de seus principais componentes.
Recently published data demonstrate the close pathophysiological interaction between the kidneys and the heart. Known as cardio-renal syndrome, this pathology is capable of promoting hypertrophy and heart failure starting from renal injury. It is known that ischemic renal injury (IRI) promotes the release of various inflammatory cytokines that have the heart as a target tissue and are capable of promoting hypertrophy acting through the Toll-like receptors (TLR). In addition to inflammatory mediators, literature has extensively demonstrated the direct correlation between changes in the renin-angiotensin system (RAS) and the levels of angiotensin II (Ang II) within the increase in cardiac mass. This study aimed to investigate the role of the RAS with cardiac hypertrophy (CH) induced by an experimental model of IRI in mice treated or not with RAS blockers, Losartan (Los) and Enalapril (Ena). The IRI was surgically induced by occlusion of the left renal pedicle for 60 minutes followed by reperfusion. After 12, 15 or 20 days, tissues were removed and morphological, molecular, and functional analysis were performed. The leading results indicate that renal ischemia and reperfusion surgery was capable of generating renal failure which subsequently induced HC in a blood-pressure independent manner. Also, over this period, there was an increase in serum levels of TNF-á and Ang II, high levels of gene or protein expression of AT1, ACE-2, TLR-2, TLR-4 and NFkâ, suggesting a cross-talk within these components and CH development. Treatment with Los or Ena has completely reversed the CH and abolished the increase observed in cardiac expression of TLRs, NFkâ, ACE-2 and AT1R, and also differentially modulated Ang II and inflammatory cytokines serum levels. Together, the data suggest a critical role for RAS in the regulation of the pathological condition in this model, acting together with the innate immune system in the pathogenesis of CH through modulation of its main components.
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Legat, Amandine. "Contribution à l'étude du monde d'action de deux adjuvants synthétiques ciblant TLR4, diC14-amidine et CRX-527." Doctoral thesis, Universite Libre de Bruxelles, 2010. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210171.
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Une compréhension fine et détaillée ciblant les mécanismes d’action de nouvelles molécules adjuvantes sur notre système immunitaire vise de manière directe à l’élaboration de nouveaux vaccins plus ciblés et plus efficaces, mais aussi à élargir nos connaissances quant à l’induction d’une réponse immune protectrice.Au cours de cette thèse nous avons voulu comprendre les modes d’action de deux molécules lipidiques distinctes.
La première est le lipide cationique diC14-amidine dont il avait été démontré une action sur les cellules dendritiques en culture par une voie qui restait à élucider. Ce lipide cationique s'organise sous forme de liposomes en milieu aqueux et peut s'associer à de nombreux antigènes. La seconde est un analogue synthétique de l'adjuvant monophosphoryl lipide A (MPL), un dérivé du LPS, nommé CRX-527. À l'instar de sa molécule parente, le CRX-527 active le récepteur TLR4 et est considéré comme un adjuvant potentiel de vaccin ou comme immunostimulant isolé.
Au cours de notre travail, nous avons démontré que la diC14-amidine active les cellules cibles via le récepteur TLR4. En effet, l'absence de ce récepteur abolit les réponses induites par le lipide cationique diC14-amidine et la transfection du gène codant pour TLR4 rend répondeuses des cellules qui n'exprimaient pas ce récepteur. De plus, la diC14-amidine active et mature des cellules dendritiques, aussi bien de provenance murine qu'humaine, suggérant qu'elle puisse être utilisée en tant qu’adjuvant. Il avait d’ailleurs été précédemment décrit que l'injection d'un complexe diC14-amidine / allergène chez la souris induisait une réponse immune suffisante pour conférer une protection contre cet allergène. Dans ce contexte, nous avons caractérisé au niveau cellulaire la réponse induite suite à l'injection du complexe diC14-amidine / ovalbumine chez la souris. Cette réponse se manifeste par une production d'IFNγ lors d'une re-stimulation ex vivo par l'antigène OVA.
En ce qui concerne la molécule CRX-527, nous nous sommes particulièrement focalisés sur le rôle du co-récepteur du TLR4, le CD14, dans les réponses innées induites par le CRX-527. Nous avons établi que, de manière inattendue et contrairement à la plupart des ligands TLR4, le CRX-527 induit la production de nombreuses cytokines et chimiokines en complète absence de CD14, même à faible dose. De plus, l'ajout de CD14 sous sa forme soluble ne modifie pas le niveau des réponses associées à la voie de signalisation MyD88 / NF-κB. Cependant, il semblerait que la stimulation de cellules par du CRX-527 en présence de CD14 soluble recombinant, favorise plutôt la voie TRIF / IRF3, comme le suggère l'augmentation du taux de production d'IFNβ et d'activation d'IRF3. La molécule CD14 (membranaire et/ou soluble) ne serait donc pas qu'un simple transporteur de ligands, comme il l'a été décrit par le passé, mais bien une protéine impliquée dans la modulation des réponses induites lors de l'activation du TLR4. Le CD14 jouerait donc un rôle, aussi bien au niveau de la discrimination des ligands, que celle des voies de signalisation activées.
Doctorat en Sciences agronomiques et ingénierie biologique
info:eu-repo/semantics/nonPublished
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Lazar, Ashley T. "Group A Colicin Specific Residues in Domain III of the Escherichia coli TolA Protein." Bowling Green State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1404315005.
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Hänninen, Kaj. "Introducing a Memory Efficient Execution Model in a Tool-Suite for Real-Time Systems /." Västerås : Department of Computer Science and Electronics, Mälardalen University, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-152.
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Asplund, Fredrik. "Tool Integration and Safety : A Foundation for Analysing the Impact of Tool Integrationon Non-functional Properties." Licentiate thesis, KTH, Mekatronik, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-102876.
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The increasing complexity of embedded systems development is becoming difficult to handle with development environments based on disjoint engineering tools. Support for interactions between various engineering tools, especially through automated means, has therefore received an increased amount of attention during the last few years. The subsequent increase in the amount of tool integration is leading to an increased impact of tool integration on non-functional properties of development efforts, development environments and end products. At the same time there is a lack of methods and tools for analysing the relationship between these properties and tool integration. To establish a foundation for analysing this generic relationship, the specific relationship between tool integration and the safety of end products is analysed in this thesis. A survey was conducted to analyze the State of the Art of tool integration as related to safety. This survey specifically identified the lack of an efficient handling of tool integration by modern safety standards as an important concern. In relation to this survey, three theories were identified as of specific importance. These are the school of thought known as Systems Thinking, the Systems-Theoretic Accident Model and Processes (STAMP) causality model and the System-Theoretic Process Analysis (STPA) hazard analysis technique. Building on these theories, this thesis provides original contributions intended to (1) describe concepts and models related to tool integration and safety (the first and second contribution), (2) link tool integration to safety in a way that reduces complexity during analysis (the third contribution) and (3) propose how to interpret and make use of the implications of the presented theories and the first three contributions (the fourth and fifth contribution). • The first contribution is a new conceptual model of a development effort that emphasizes tool integration. • The second contribution is a new reference model for tool integration in highly heterogeneous environments. • The third contribution consists of nine safety-related tool chain properties, i.e. properties of tool chains that could mitigate at least part of the risks introduced by tool integration. • The fourth contribution is a proposition on how to identify safety implications due to a high level of automation of tool integration. • The fifth contribution is a proposition for a new software tool qualification process.
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Fjellby, Per Kristian J. "Protocols for toll road systems." Thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for telematikk, 2013. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-23054.
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A problem in a tolling system like AutoPASS is the number of unidentified passages due to unreadable license plates. As a consequence money is lost for the toll road companies. A scheme is proposed that uses anonymous statistics to aid in the process of allocating resources for manual controls. Due to legal requirements for anonymity of data produced at toll plazas, a model that simulates the traffic frequencies on Norwegian roads is developed and implemented in Java. Using the toll plazas that make upMiljøpakken in Trondheim as a starting point, a simulation generatingthree months worth of traffic amounting to almost 460 MiB of data is performed. The simulated data were checked for its reliability and similarity with real data. Calculations based on an optimistic estimate on the number of AutoPASS subscriptions with rebated fares have shown that nearly 370 000 NOK are lost due to unidentified vehicles over the three months simulated. The outlined solution shows that toll plazaswith a higher number of unregistered passages can be identified and this information can be used in subsequent planning activities for the purpose of executing manual controls to reduce the losses.
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Kuthy-Saenger, Juan Arturo. "Comparison study of the savings between a single and a double step toll systems." Morgantown, W. Va. : [West Virginia University Libraries], 2001. http://etd.wvu.edu/templates/showETD.cfm?recnum=1899.
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Thesis (M.S.)--West Virginia University, 2001.Title from document title page. Document formatted into pages; contains x, 48 p. : ill. Vita. Includes abstract. Includes bibliographical references (p. 41-42).
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Pravlovský, Petr. "Informační systém pro nákladový index v kamionové dopravě." Master's thesis, Vysoká škola ekonomická v Praze, 2012. http://www.nusl.cz/ntk/nusl-165255.
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The topic of the thesis is costs in truck transport. There is analyzed theme Progress of costs in time, using indexes. The theoretical part is focused on the methodology for calculating the cost index published by the Czech Association of Road Carriers Česmad Bohemia and compared with several foreign indexes. The practical part has two objectives. The first focuses on the design of a new methodology that will be more accurate and reflect the true situation. The second objective of this methodology is to design basic informatics support, for both users, indexes users and persons, who are responsible for publishing these statistics. The summary points to the possibilities of alteration of the current designed index methodology and the potential for cooperation of Česmad Bohemia and Czech Statistical Office.