Efficient control of sea lice is a major challenge for the sustainable production of farmed Atlantic salmon (Salmo salar (Linnaeus, 1758)). These marine ectoparasites feed on mucus, skin and blood of their hosts, thereby reducing the salmon’s growth rate and overall health. In the northern hemisphere, the most prevalent species is Lepeophtheirus salmonis (Krøyer, 1837). In 2006, global costs of sea lice infections are estimated to have exceeded €300 million, with the majority spent on a limited number of chemical delousing agents. Emamectin benzoate (EMB; SLICE®), an avermectin, has been widely used since its introduction in 2000, due to its convenient administration as an in-feed medication and its high efficacy against all parasitic stages of L. salmonis. However, over-reliance on a single or limited range of medicines favours the emergence of drug resistance and, as a result, the efficacy of this compound in treating L. salmonis has decreased in recent years, as reported from e.g. Chile, Norway, Scotland and Canada. Declining efficacy underlines the need for an improved understanding of the molecular mechanisms underlying EMB drug resistance in L. salmonis. Elucidation of these mechanisms would allow for improved monitoring tools, earlier detection of developing resistance, extended usability of current delousing agents and development of new parasiticides. The work described in this thesis sets out to examine the molecular mechanisms underlying EMB resistance in L. salmonis. In earlier studies, research in nematodes and arthropods has linked drug efflux transporters belonging to the family of ATP-binding cassette (ABC) transporters to ivermectin (IVM) resistance, a parasiticide with high chemical similarity to EMB. ABC transporters such as permeability glycoprotein (P-gp), transport a wide range of substrates, including drugs, and have been suggested to provide a potential molecular mechanism through which EMB resistance might be mediated in sea lice. As an example of such mechanisms, increased expression of P-gp is one of the causative factors for drug resistance in human cancer cells and avermectin resistance in nematode parasites such as Caenorhabditis elegans or Haemonchus contortus. Initial research involved screening for novel salmon lice P-gps that might contribute to EMB resistance. A novel P-gp, SL-PGY1, was discovered using a combined bioinformatic and molecular biological approach. The expression was compared in two well-characterised L. salmonis strains differing in their susceptibility to EMB (S = susceptible, R = resistant). Prior to EMB exposure, mRNA levels did not differ from each other, while, after 24 h exposure, a 2.9-fold increase in SL-PGY1 mRNA expression was observed in the R strain. SL-PGY1 appears not to be a major factor contributing to reduced EMB susceptibility, although it could play a role, as expression levels increased upon exposure to EMB. A further four additional drug transporters (ABC C subfamily) were also discovered showing high homology to multidrug-resistance proteins (MRP). The relative expression levels of each MRP was compared in the strains S and R, before and after exposure to EMB. No significant changes were found in their expression patterns. If ABC drug transporters mediate the efflux of EMB and thereby reduce the intracellular concentrations of the drug in exposed animals, the inhibition of those ABC drug transporters was expected to lead to higher intracellular levels of EMB. This could result in an enhanced toxic effect when EMB is co-administered with an inhibitor. Two known inhibitors of human P-gps and MRPs, cyclosporin A (CSA) and verapamil (VER), were co-administered with EMB. CSA increased the toxic effect of EMB in both tested strains, implying that the targets of CSA are expressed at comparable levels and that they may be part of the mechanism conferring EMB resistance. VER increased the toxic effect of EMB in the R strain, but had no significant effects on the S strain. This implies that the expression of factors inhibited by VER differs between the two L. salmonis strains. It is hypothesised that a number of ABC transporters with distinct, yet overlapping patterns of inhibitor specificity are affected by those inhibitors. The search for drug-resistance conferring genes was complemented with a systematic, genome-wide survey of ABC transporters in L. salmonis to find additional members of this important gene family. Next-generation high-throughput RNA sequencing (RNA-seq) was employed to assemble a reference transcriptome from pooled total RNA of salmon lice at different development stages. The transcriptome was assembled against the L. salmonis genome and annotated. Thirty-nine putative ABC transporters were found. Of further interest were transcripts of the subfamily B, C and G, as they contain drug-transporting ABC proteins. For the ABC B subfamily, one full (SL-PGY1) and three half transporter transcripts were found. Only full transporters are known to transport drugs and SL-PGY1 is apparently not a major factor contributing to EMB resistance. Fourteen ABCC sequences were found – 11 MRPs and 3 homologues to sulfonylurea receptors. Of interest are MRPs, as they contribute to drug detoxification in humans and invertebrates. Four MRPs had been identified previously and their expression ratios did not differ between S and R strain parasites. Seven sequences belonging to ABCG subfamily were found. However, none of the L. salmonis ABCG transcripts identified showed sufficient homology to known drug transporters in other species. With the currently limited understanding of the mechanisms conferring EMB resistance, monitoring the susceptibility of L. salmonis subpopulations is essential. Dose-response bioassays are currently widely used. Tests with pre-adult II or adult parasites requires relatively large numbers of parasites (~150) to conduct this type of bioassay, which may not always be available. Addressing this issue, we tested the feasibility of a single-dose bioassay (requiring fewer test animals than dose-response bioassays) to discriminate between L. salmonis strains with differing EMB susceptibility. This alternative approach uses time-course toxicity analysis, where the toxic effect of EMB is monitored over time. After clearly defining the effect criteria, we found that it is possible to discriminate between those L. salmonis strains. However, while requiring fewer test animals, time course toxicity analysis is more labour-intensive, but the alternative design can be suitable under certain circumstances. The work reported here has provided new knowledge concerning the mechanisms of EMB resistance in sea lice. Several novel putative drug transporters have been identified, an important first step toward unravelling the complex interactions of genes involved in EMB resistance in this commercially important parasite.

ABCG2 est un transporteur de la famille ABC impliqué dans le phénotype de résistance aux drogues développé par certaines cellules, par exemple les cellules cancéreuses. Ce transporteur a aussi un rôle physiologique de détoxication de composés endogènes, notamment les porphyrines, molécules indispensables mais qui présentent une toxicité potentielle. Cette toxicité nécessite une prise en charge particulière, évitant à ces composés d’être libres en solution. Dans ce contexte, nous avons fait l’hypothèse qu’ABCG2 pourrait participer à cette détoxication en limitant l’accumulation des porphyrines dans les cellules en les présentant à un partenaire extracellulaire. Nous montrons qu’ABCG2 transporte de l’hème ainsi que certains de ses dérivés et précurseurs et que ces porphyrines, contrairement aux autres substrats d’ABCG2, se fixent sur un domaine extracellulaire spécifique d’ABCG2, ECL3, composé d’environ 70 acides aminés. L’affinité d’ECL3 pour les porphyrines est de 0,5 à 3,5 μM, suffisamment affine pour permettre leur fixation après transport.Nous montrons aussi que l’albumine sérique humaine, impliquée dans la détoxication de l’hème, récupère les porphyrines fixées sur ECL3 par une interaction directe avec ABCG2. L’ensemble de ce travail a donc permis d’une part de mieux comprendre le rôle d’ABCG2 dans la régulation de l’homéostasie des porphyrines, notamment l’hème, et d’autre part, de façon originale, d’identifier le mécanisme moléculaire par lequel cette détoxication s’effectue. / ABCG2 belongs to the ABC-transporter family, involved in drug resistance developed by cells, notably cancer cells. This transporter has also a physiological role of endobiotic detoxification, in particular porphyrins that are essential but potentially toxic molecules. This toxicity implies a specific handle, to avoid them to remain free in solution. In that context, we hypothesized that ABCG2 participate to this detoxification, limiting the intracellular porphyrin accumulation by presenting them to an extracellular partner. We show that ABCG2 transports heme and some of its derivatives and precursors. Interestingly, these porphyrins, unlike other ABCG2 (non-porphyric) substrates, can bind to an extracellular domain, specific of ABCG2, ECL3, 70 residues-long. ECL3 displays affinities for porphyrins in the range of 0.5 to 3.5 μM, high enough to allow their binding after transport. We also show that human serum albumin, implicated in heme detoxification, releases porphyrins bound to ECL3 by a direct interaction with ABCG2. This work established a better comprehension of ABCG2 role in porphyrin and in particular heme homeostasis regulation. In addition, our results contribute to elucidate part of the molecular mechanism by which such regulation is carried out.

Thesis is focused on management of business informatics. The aim of this thesis is to develop Reference management model for managing business informatics and to integrate this reference model into ITGPM Reference management model for managing business informatics. Within an analytical part is reviewed current situation in the field of managing economics of business informatics as well as managing economics out of business informatics. Attention is paid to costs in busi-ness informatics, their classification, categorisation and their management. Very important part is analysis of methods for cost management thought various types of calculations and especially thought ABC methods. The principles of these methods are applied in the design of the Reference model. Further are solved questions of business informatics effect, their categorisations, classification, definition of their attributes and also their management. Development of this field is an important part of this thesis. The main part of the thesis contains the Business informatics management Reference model design. This design contains identification of the most important metrics of measuring business informatics, dimen-sions used for analysis of proposed metrics and relationships between metrics and dimensions. An impor-tant part is also a presentation level design and definition of condition that should be fulfilled, if the pres-entation level should be beneficial to final users. The main part also contains designed method for imple-mentation of the Reference model into a company. Application parts are devoted to preparation of a pilot application based on the Reference model design developed in the main part of the thesis. Designed Reference model for managing business informatics is adapted according to the needs, requests and characteristics of the company in which this pilot application is implemented. In these parts are also verified designs, processes and methods designed in the first and second part of this thesis, so there are verified possibilities of adaption of the designed model to the requests of the target company, adaption of the pilot application to the target environment including data level, ELT procedures and presentation level. In application part of the thesis is verified correctness of the designed implantation methodology into the company.

OCP est une grande entreprise marocaine spécialisée dans l’extraction de minerai de phosphate, cette entreprise a élargi ses activités vers la production de fertilisants phosphatés selon un processus de transformation chimique. Dans le cadre de notre recherche, nous nous intéressons au pilotage économique d’une chaine logistique hybride (la plateforme chimique Jorf). Cette chaine logistique est constituée d’un ensemble articulé de chaine logistique discrète et chaine logistique continue organisant les processus de transformation du fournisseur jusqu’au client final. Les chaînes logistiques hybrides combinent des processus discrets et continus. Dans un premier temps, nous nous sommes focalisé sur la représentation du fonctionnement physique. Donc, un modèle de simulation qui permet de reproduire ce fonctionnement a été réalisé à partir de la cartographie de processus que nous avons fait. La technique de Modélisation / Simulation mobilisable dans le cadre de la modélisation de ce type de chaîne logistique est la Simulation à Événements Discrets (SED) qui permet de reproduire le fonctionnement opérationnel de la CLH.En travaillant à la commande, ceci implique un contrôle de gestion spécifique avec une définition d’un référentiel dynamique qui va dépendre du modèle de simulation. Ce référentiel est utilisable par le système interactif d’aide à la décision (SIAD) du contrôle de gestion afin d’améliorer la prise de décision. Donc, il faut, ensuite, mesurer l’impact économique, évaluer les alternatives décisionnelles et analyser les écarts. Pour ce faire, il faut s’appuyer sur une comptabilité de gestion fondée sur une seconde modélisation / simulation afin de proposer un modèle de coût. Cette seconde simulation, repose sur une représentation plus fine des processus dans une perspective de reporting financier périodique et doit permettre de mieux apprécier les inducteurs de coûts. Dans ce contexte, nous avons choisi la méthode de valorisation Activity Based Costing (ABC). En outre, dans la cartographie des processus, chaque étape de production impliquant un changement de processus et contribuant à son discrétisation représente un événement déclencheur mettant en évidence un inducteur de coût. Nous avons ainsi traité chaque processus au niveau de la Business Unit (BU) "acide" et au niveau de la BU "engrais" afin de déterminer les inducteurs utilisés pour répartir les dépenses. Notre modèle ABC sert donc à mesurer la création de valeur pour chacun des BUs de la CLH et il est capable de prendre en compte toutes les sorties et entrées de chaque entité de traitement.Par la suite, notre but est d’explorer l’intégration de la notion de coût dans le modèle de simulation. La limite de la simulation à événements discrets se manifeste dans le niveau d'informations fourni sur les coûts. Pour évaluer les coûts de production, et l'influence de la diversité de scénario de production, les coûts variables doivent être inclus. Ceci peut être fourni par la combinaison de la simulation à événements discrets avec la méthode ABC. Donc, nous avons proposé une approche qui sera mise en œuvre dans le contexte de la CLH de l’OCP. Cette approche va prendre en compte le couplage entre ABC et SED avec toutes les règles de traduction pour pouvoir, à partir du système de contrôle de gestion existant qui est associé à des centres de coûts par entité fonctionnelle, passer à des BUs orientées processus industriels. Elle va également nous permettre de structurer les indicateurs de performance du flux physique et financier sous la forme d’un tableau de bord / OCP SA is Morocco’s largest company. It is widely considered as owning some 60% of phosphate world reserves and is engaged in a process of Supply Chain control. Initially specialized in phosphate ore extraction, OCP SA has expanded, few years ago, its activities to include production of phosphate fertilizers using chemical processing. Under our research project, we focus on economic management of OCP’s Hybrid Supply chain (HSC). A HSC comprises multiple interrelated discrete and continuous processes together forming an integrated process from the supplier down to the end customer. In such a system, the production rationale includes both batch and flow models. Each discrete or continuous process seeks to capture part of the value created by the organizational collaboration performed either in internal supply chains made up of business unit or in external ones made up of legally independent entities.At first, we focused on the representation of physical functioning. So a simulation model that allows us to reproduce this functioning has been done from the process mapping we have done. The modeling / Simulation technique mobilized in the modeling framework of this type of supply chain is the Discrete Event Simulation (DES) which allows reproducing the operational functioning of the HSCBy working on the command, this implies a specific management control with a definition of a dynamic repository that will depend on the simulation model. This repository can be used by the interactive decision support system of management control in order to improve decision-making. Therefore, we must measure the economic impact, evaluate the decision-making alternatives and analyze the gaps. To do this, it is necessary to rely on a management accounting based on a second modeling / simulation in order to propose a cost model. This second simulation relies on a finer representation of the processes in a perspective of periodic financial reporting and must allow better appreciate the cost drivers. In this context, we have chosen the Activity Based Costing (ABC) method. In addition, in process mapping, each production step involving a process change and contributing to its discretization represents a triggering event highlighting a cost driver. We have thus processed each process at the level of the "acid" BU and at the level of the "fertilizer" BU to determine the inductors used to allocate the expenses. Our ABC model is therefore used to measure the value creation for each BUs of the HSC and it is able to take into account all the outputs and inputs of each processing entity.Later, our aim is to explore the integration of the notion of cost in the simulation model. The limit of the discrete event simulation is manifested in the level of information provided on costs. To assess production costs, and the influence of the diversity of production scenario, variable costs must be included. This can be provided by the combination of the discrete event simulation with the ABC method. So we have proposed an approach that will be implemented in the context of the OCP HSC. This approach will take into account the coupling between ABC and SED with all the translation rules to can, from the existing management control system that is associated with a functional unit cost centers, go to the BUs oriented industrial processes. It will also enable us to structure the physical and financial flow performance indicators in the form of a scorecard

Made available in DSpace on 2016-04-25T18:40:31Z (GMT). No. of bitstreams: 1 Kazuyochi Tsurumaki.pdf: 521696 bytes, checksum: 912d104397ea951da960d0b3ce725646 (MD5) Previous issue date: 2008-06-02 / The study has as main objective explore the characteristics of the activities of services and understand how they should be handled by systems cost, as the scenario of the world economy in recent decades has led the service sector to a level higher than the sectors of industry and Agriculture. In other words, services are the activities that most grew in most developed and developing countries highlighting itself as an activity generator of wealth. Thus, it is necessary to the understanding of the major systems of cost and identifying the differences between the product service and product manufacturing. Through analysis of the system of funding of Ecosorb SA Tecnologia em Proteção Ambiental, object of case study, it was possible, using interviews, verification of documents and analysis of reports, understand premises, attributes and operation of the system costing adopted by the company. The economic development and globalization have created a competitive environment and therefore the market has become more disputed. In this environment, companies that have a need to control their costs have a competitive advantage and survival / O trabalho tem como principal objetivo explorar as características das atividades de serviços e entender como elas devem ser tratadas pelos sistemas de custeio, visto que o cenário da economia mundial nas últimas décadas tem levado o setor de serviços a um patamar superior aos setores da indústria e agricultura. Ou seja, os serviços são as atividades que mais cresceram na maioria dos países desenvolvidos e em desenvolvimento destacando-se como uma atividade geradora de riqueza. Para tanto, faz-se necessário o entendimento dos principais sistemas de custeio e a identificação das diferenças entre o produto serviço e o produto manufatura. Por meio da análise do sistema de custeio da Ecosorb SA Tecnologia em Proteção Ambiental, objeto de estudo de caso, foi possível utilizando-se de entrevistas, verificação de documentos e análise de relatórios, entender premissas, atributos e funcionamento do sistema de custeio adotado pela empresa. O desenvolvimento econômico e a globalização criaram um ambiente competitivo e consequentemente o mercado passou a ser mais disputado. Neste ambiente, as empresas que tiverem um controle preciso dos seus custos têm uma vantagem competitiva e de sobrevivência

Glycosaminoglycans are heterogeneous polysaccharides that mediate important biological functions. There has been considerable interest in deciphering the precise GAG sequences that are responsible for protein interactions. In fact, several GAG oligosaccharides have been discovered to date as targeting proteins with higher level of specificity. Yet, it has been difficult to develop GAG oligosaccharides as drugs. One of the key reasons for this state of art is that GAG synthesis is extremely challenging and is highly structure-specific. Thus, much of the biology and pharmacology of GAG remains unknown and unexploited to date. An alternative approach is to prepare GAG oligosaccharides using enzymatic depolymerization of polymeric GAGs. GAG lyases, including heparinases and chondritinases represent powerful tools that can theoretically generate multiple oligosaccharides in parallel. However, it is difficult to implement such procedures with high consistency. Moreover, GAG lyases can digest GAGs down to disaccharides. A priori, non-polymeric GAGs, or alternatively GAG oligosaccharides containing 4 to 10 residues, would be expected to function better as therapeutic agents because they would be more homogeneous and less non-specific than their polymeric precursors. Thus, we reasoned that immobilization of these enzymes may engineer altered biopolymer processing, which may afford longer oligosaccharides in higher proportions and greater consistency. Heparinase-I and chondroitinase ABC were immobilized on CNBr-activated Sepharose and compared with the free form of the enzyme. Immobilized GAG lyases retained high efficiency of depolymerization over a wide range of pH, temperature and reusability. Most importantly, the immobilized enzyme was found to produce larger proportions of oligosaccharides longer than di- and tetra-saccharides as compared to lyases in the free form. A two dimensional separation involves size exclusion chromatography followed by reversed phase ion-pairing ultra performance liquid chromatography coupled to electrospray ionization mass spectrometry was employed to separate and characterize oligosaccharide structures. We have identified 40 heparin oligosaccharides, including regular and rare structures ranging from dp4 to dp10 and 39 chondroitin sulfate oligosaccharides in high homogeneity and significant yields. Overall, this technology is likely to offer a simple and cost effective route to preparation of larger amounts of sequences that can be expected to bind and modulate protein function.

<p>Transport into and across the cells of the human body is a prerequisite for the pharmacological action of drugs. Passive membrane permeability and active transport mechanisms are major determinants of the intestinal absorption of drugs, as well as of the distribution to target tissues and the subsequent metabolism and excretion from the body. In this thesis, the role of ATP-binding cassette (ABC) transporters and passive permeability on drug absorption and disposition was investigated. Particular emphasis was placed on defining the molecular properties important for these transport mechanisms. </p><p>The influence of different transport pathways on predictions of intestinal drug absorption was investigated using experimental models of different complexity. Experimental models that include the paracellular pathway gave improved predictions of intestinal drug absorption, especially for incompletely absorbed drugs. Further, the inhibition of the ABC transporters breast cancer resistance protein (BCRP/ABCG2) and multidrug-resistance associated protein 2 (MRP2/ABCC2) was experimentally investigated using structurally diverse datasets that were representative of orally administered drugs. A large number of previously unknown inhibitors were identified among registered drugs, but their clinical relevance for drug-drug interactions and drug-induced toxicity remains to be determined. The majority of the inhibitors affected all three major ABC transporters BCRP, MRP2 and P-glycoprotein (P gp/ABCB1), and these multi-specific inhibitors were found to be enriched in highly lipophilic weak bases. </p><p>To summarize, the present work has led to an increased knowledge of the molecular features of importance for ABC transporter inhibition and passive membrane permeability. Previously unknown ABC transporter inhibitors were identified and predictive computational models were developed for the different drug transport mechanisms. These could be valuable tools to assist in the prioritization of experimental efforts in early drug discovery.</p>

<p>The relationship between alcohol consumption and alcohol-related violence has been firmly established in a wide array of studies concerning various forms of violence including intimate partner violence, domestic violence as well as sexual assault. One factor which has been highlighted as having a moderating effect on the relationship between alcohol consumption and alcohol-related aggression is the specific aggression-related alcohol expectancies concerning the effects of alcohol consumption on aggressive behaviour. In light of the prevalence of alcohol-related violence in South African communities it becomes important to examine the specific factors that moderate the relationship between alcohol consumption and alcohol-related aggression and violence. The aim of this study was to examine aggressionrelated alcohol expectancies as a moderating factor in the relationship between alcohol consumption and alcohol-related aggression and to examine the possible influence of exposure to community alcohol-related aggression in the formulation of aggression-related alcohol expectancies. The main objectives of this were to examine aggression-related alcohol expectancies as well as exposure to community alcohol-related aggression as domains for intervention to prevent alcohol-related violence.</p>

Transport into and across the cells of the human body is a prerequisite for the pharmacological action of drugs. Passive membrane permeability and active transport mechanisms are major determinants of the intestinal absorption of drugs, as well as of the distribution to target tissues and the subsequent metabolism and excretion from the body. In this thesis, the role of ATP-binding cassette (ABC) transporters and passive permeability on drug absorption and disposition was investigated. Particular emphasis was placed on defining the molecular properties important for these transport mechanisms. The influence of different transport pathways on predictions of intestinal drug absorption was investigated using experimental models of different complexity. Experimental models that include the paracellular pathway gave improved predictions of intestinal drug absorption, especially for incompletely absorbed drugs. Further, the inhibition of the ABC transporters breast cancer resistance protein (BCRP/ABCG2) and multidrug-resistance associated protein 2 (MRP2/ABCC2) was experimentally investigated using structurally diverse datasets that were representative of orally administered drugs. A large number of previously unknown inhibitors were identified among registered drugs, but their clinical relevance for drug-drug interactions and drug-induced toxicity remains to be determined. The majority of the inhibitors affected all three major ABC transporters BCRP, MRP2 and P-glycoprotein (P gp/ABCB1), and these multi-specific inhibitors were found to be enriched in highly lipophilic weak bases. To summarize, the present work has led to an increased knowledge of the molecular features of importance for ABC transporter inhibition and passive membrane permeability. Previously unknown ABC transporter inhibitors were identified and predictive computational models were developed for the different drug transport mechanisms. These could be valuable tools to assist in the prioritization of experimental efforts in early drug discovery.

Skolan befinner sig i en förändringsprocess där lärares auktoritet inte längre är självklar, istället söker lärare efter nya sätt att hålla ordning och skapa arbetsro. Hanteringen av konflikter har visat sig viktig i en tid då konflikter tillåts komma upp för diskussion och upplevs som en allt större del av lärares vardag. Syftet med denna undersökning är att se på hur lärare hanterar konflikter mellan elever på lågstadiet och mellanstadiet. Dessutom är syftet att undersöka vilka faktorer hos lärarna som påverkar hur de hanterar konflikter. Frågeställningen handlar om hur lärare hanterar konflikter och hur de förstår vad som ligger bakom konflikterna. Vidare undersöks ifall djupare förståelse för bakgrunden till konflikterna leder till mer omfattande konflikthantering. Slutligen undersöks andra faktorer som påverkar hur lärarna hanterar konflikter. Metoden utgörs av kvalitativa intervjuer med sju klasslärare på låg- och mellanstadiet. Lärarna uppmanas att berätta om elevkonflikter som upplevts som svåra. Dessutom ställs frågor om det pyskosociala klimatet i lärarens klass, denna information används för att analysera lärares attityder inom olika områden. Analysen, som har både kvalitativa och kvantitativa inslag, ger en översikt som beskriver relationen mellan konflikthanteringen och konflikterna i jämförelse med en idealmodell. Utifrån lärarnas uttalande undersöks lärarnas kunskap och förmågor, vilket därefter jämförs med konflikthanteringen. Resultaten indikerar att flera faktorer gällande lärares kunskap, förmågor och attityder har inverkan på hur de hanterar konflikter.