Dagens tillgång till information från världen över har lett till att konsumenter kan bevittna och ifrågasätta konsekvenserna av företagens agerande på ett sätt som tidigare inte var möjligt. Det har i sin tur ökat konsumenternas press på företagen att ta ansvar och nyttja deras makt till positiv samhällspåverkan. I takt med denna ökad press från konsumenterna har allt fler företag börjat ge sig in i samhällsdebatter som de tidigare undvek och således växte ett nytt fenomen fram – varumärkesaktivism. Varumärkesaktivism innebär att varumärken tar publik ställning i kontroversiella frågor för att uppnå verklig förändring i något som oftast ligger utanför dess egna verksamhet.  Denna studie syftar till att beskriva millennials och centennials attityder till varumärkesaktivism i Sverige samt huruvida attityderna skiljer sig åt generationerna emellan. Genom att använda en väletablerad modell för attityder: ABC-modellen, har vi fått förståelse för hur de två generationernas attityder är uppbyggda och kan beskrivas. Tidigare forskning inom attityder har kompletterats med generationsteorin samt den något begränsade tidigare forskningen inom varumärkesaktivism, för att kunna utföra studien och därigenom besvara studiens frågeställning:  Vilka attityder har millennials och centennials gentemot varumärkesaktivism?  För att besvara frågeställningen genomfördes studien med en kvantitativ metod, där en enkät utformades och fördelades på sociala mediet Facebook. Via flertalet oberoende grupper nådde vi ut till sammanlagt 416 respondenter som valde att deltaga i vår enkätundersökning. I enkäten fick respondenterna ta ställning enligt en femgradig skala till olika påståenden som omfattar deras attitydkomponenter enligt ABC-modellen. Den insamlade empirin bearbetades därefter i statistikprogrammet SPSS och analyserades sedan med hjälp av den teoretiska referensramen. Resultatet mynnade ut i flertalet slutsatser. Först och främst visade det sig att båda generationernas attityder kunde beskrivas som övervägande positiva. Utöver det visade det sig även att både millennials och centennials attityder främst är uppbyggda av känslor, före beteendeintentioner och upplevd kunskap. Vidare fann vi dock inga signifikanta skillnader mellan generationernas sammanvägda attityd. Däremot upptäcktes en signifikant skillnad i en av attitydkomponenterna, vilket innebar att centennials uppvisade mer positiva känslor än millennials. Slutligen fann vi även att kvinnor och mäns attityder signifikant skiljer sig åt genom att kvinnor har en mer positiv attityd än män, samt att kvinnors attityder är mer uppbyggda av känslor och beteendeintentioner medan männens attityder mer utgörs av upplevd kunskap.

Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2010-2011 / La maladie de Stargardt est la dégénérescence maculaire la plus fréquente chez les enfants de 6 à 12 ans. La maladie se caractérise par une perte graduelle et irréversible de la vision centrale. La forme récessive du Stargardt (90% des cas) est causée par le gène ABCA4. Le but de notre étude était d'identifier la nature et la prévalence des mutations retrouvées dans ABC A4 chez la population canadienne-française souffrant de Stargardt. Parmi les 19 familles recrutées, 29 patients souffraient de Stargardt et se partageaient 39 haplotypes distincts. Sur les 20 variations détectées, 15 étaient de réelles mutations alors que les cinq autres étaient des polymorphismes sans conséquence sur la maladie. 45% des 58 chromosomes étudiés ont été associés à une mutation. Sept nouvelles mutations ont été confirmées, mais aucun effet fondateur n'a été observé. Ceci est dû au gène ABCA4 qui est extrêmement polymorphique et sujet aux réarrangements géniques.

ABC-Transporter sind ein wichtiger Aspekt bei der Entwicklung von Resistenzen gegen Chemotherapeutika. Ziel dieser Studie war es, die Resistenzentwicklung in HNSCC-Zelllinien im Zusammenhang mit verschiedenen Cisplatinkozentrationen und Inkubationszeiten zu analysieren, sowie die Expression von ABC-Transportern via semi-quantitativer RT-PCR in diesen Zellen zu untersuchen. Die Zellen zeigten dabei keine relevante Resistenzentwick-lung im Sinne eines Anstiegs der IC50. Bei drei der Zelllinien konnte jedoch eine hohe intrin-sische Cisplatinresistenz beobachtet werden. Diese resistenten Zelllinien wiesen nach Inku-bation mit Cisplatin deutlich höhere Expressionswerte für TAP1, TAP2, ABCG2 sowie die ABCC-Transporterfamilie auf. Dabei zeigte sich, dass die Expression der ABCC-Familie mit zunehmender Inkubationsdauer abnahm. TAP1 in PCI-9 und PCI-68 war auch noch nach vierwöchiger Inkubation stark überexprimiert. Die initiale IC50 dieser Zelllinien lag dabei deutlich über der Plasmakonzentration von Pati-enten mit Hochdosis-Chemotherapie. Die Expression der Transporter aus der ABCC-Familie ließ die Vermutung zu, dass diese Transporter initial zur Resistenz gegen Cisplatin beitrugen, allerdings mit zunehmender Inkubationsdauer an Bedeutung verloren. Diese Annahme wurde dadurch gestützt, dass die HNSCC-Zelllinien nach einem inkubationsfreien Intervall von vier Wochen im Anschluss an die Inkubation mit Cisplatin deutliche Überexpressionen der ABCC-Transporterfamilie zeigten. Auch für Transporter (ABCG2 und TAP-Transporter), die keine Effluxfunktion für Cisplatin besitzen, konnte ein Zusammenhang der Expression mit der Resistenz der HNSCC-Zellen beobachtet werden. Der Beitrag dieser Transporter zur Resistenz von Tumorzellen könnte über deren Funktionen im Metabolismus von Tumorzel-len, deren Fähigkeiten Tumorstammzellen zu bilden und dem Efflux endogener Zellstress verursachender Substrate erklärt werden. Allerdings werden diese Transporter erst seit kur-zem mit Resistenzen gegen Cisplatin in Verbindung gebracht. Aufbauend auf diese Studie wäre eine Verifizierung der Kausalität des Resistenzmechanismus durch knock-down und Inhibition der von uns untersuchten Transporter sinnvoll. / ABC transporters are an important aspect in the development of resistance to chemotherapeutic agents. The aim of this study was to analyse the development of resistance in HNSCC cell lines in connection with different cisplatin concentrations and incubation times, as well as to investigate the expression of ABC transporters in these cells via semi-quantitative RT-PCR. The cells did not show any relevant development of resistance in the sense of an increase in the IC50. However, a high intrinsic cisplatin resistance was observed in three of the cell lines. These resistant cell lines showed significantly higher expression values for TAP1, TAP2, ABCG2 and the ABCC transporter family after incubation with cisplatin. It was shown that the expression of the ABCC family decreased with increasing incubation time. In PCI-9 and PCI-68 TAP1 was still strongly overexpressed after four weeks of incubation. The initial IC50 of these cell lines was significantly higher than the plasma concentration of patients with high-dose chemotherapy. The expression of transporters from the ABCC family led to the assumption that these transporters initially contributed to resistance to cisplatin, but lost importance with increasing incubation time. This assumption was supported by the fact that the HNSCC cell lines showed clear overexpression of the ABCC transporter family after an incubation-free interval of four weeks following incubation with cisplatin. For transporters (ABCG2 and TAP transporters) that do not have an efflux function for cisplatin, a correlation of expression with the resistance of HNSCC cells was also observed. The contribution of these transporters to the resistance of tumour cells could be explained by their functions in the metabolism of tumour cells, their ability to form tumour stem cells and the efflux of endogenous cell stress-causing substrates. However, these transporters have only recently been linked to resistance to cisplatin. Building on this study, it would be useful to verify the causality of the resistance mechanism by knocking down and inhibiting the transporters we studied.

No description available.

This dissertation presents an investigation of the impact of Multidrug Resistance-associated Protein 2/ATP-binding cassette superfamily C member 2 (Mrp2/Abcc2) and 3 (Mrp3/Abcc3) on the pharmacokinetics (PKs) of methotrexate (MTX) using gene knockout murine models. MTX is a substrate for numerous human ATP-binding cassette (ABC) efflux transporters, yet the impact of these transporters on the pharmacokinetics of MTX over a large dose range has not been examined. To investigate the effects of two transporters, Abcc2 (Mrp2) and Abcc3 (Mrp3), involved in MTX hepatobiliary disposition in vivo, MTX plasma, urine and feces concentrations were analyzed after 10, 50, and 200 mg/kg intravenous (IV) doses to groups of wild type (WT), Abcc2-/- and Abcc3-/- mice. The absence of Abcc2 caused a decrease in total clearance of MTX relative to WT mice at all dose levels yet was accompanied by compensatory increases in renal excretion and metabolism to 7-hydroxymethotrexate (7OH-MTX). In Abcc3-/- mice total clearance was elevated at the two lower dose levels that was attributed to stimulation of biliary excretion and confirmed by elevated fecal excretion; however at the high 200 mg/kg dose clearance was severely retarded and could be attributed to hepatotoxicity as conversion to 7OH-MTX was diminished. We also sought to characterize the effects of Abcc2 and Abcc3, on the PKs of MTX after oral dosing. Plasma, urine, and fecal concentrations of MTX were measured after 10, 50, and 200 mg/kg oral doses to cohorts of WT, Abcc2-/- and Abcc3-/- mice mouse strains. The absence of Abcc2 caused an approximate 2-fold increase in system exposure and a slight increase in oral bioavailability of MTX relative to WT mice at all dose levels. These elevations were accompanied by compensatory increases in conversion to 7OH-MTX, and based on AUC7OH-MTX/AUCMTX (area under the curve ratio of metabolite and parent drug) that ranged from 3% to 9% in WT mice increased to a range of 16% to 26% in Abcc2-/- mice. Renal excretion of unchanged MTX was unaltered in the Abcc2-/- strain; fraction urinary excretion (fr) ranged from about 4% to 11% in WT mice, whereas in Abcc2-/- mice fr ranged from about 7% to 23%. Abcc3-/- mice exhibited more than a 2-fold decrease in Cmax and significant reductions in AUCMTX when compared to WT mice at all dose levels. There were no compensatory increases in either metabolism or in renal and biliary excretion, which suggests future studies for investigating a potential unknown mechanism. Regardless of the mouse strain, increases in the MTX dose were not accompanied by proportional increases in AUCMTX. The PKs of MTX in different mouse strains was successfully modeled by a nonlinear semi-mechanistic 3-compartmental conditional model incorporating key efflux transporters. The model employed population-based analysis and conditional transport terms to well capture the nonlinear properties of MTX systemic disposition for a wide dose range of 10 - 200 mg/kg in WT and knockout strains. The model correlates the mechanistic nature of the nonlinear phenomenon with the key efflux transporters effects on MTX PKs and provides insight for preclinical therapeutic study design. Overall, the information obtained in this investigation underscores the significance of efflux transporters, Abcc2 and Abcc3, for they significantly influence the pharmacokinetics of MTX and their impact can be reflected by a nonlinear semi-mechanistic 3-compartmental conditional model. The studies also provide implication in the preclinical therapeutic study design and insights on the source of inter-patient variability as well as on the combination drug regimens to maximize drug activity yet without toxicity. / Pharmaceutical Sciences

Mosquitoes affect human health worldwide as a result of their ability to vector multiple diseases. Mosquitocide resistance is a serious public health challenge that warrants the development of improved chemical control strategies for mosquitoes. Previous studies demonstrate the mosquito blood-brain barrier (BBB) to interfere with the target-site delivery and action of anticholinesterase chemistries. The ATP-binding cassette (ABC) transporters are efflux proteins that assist in maintaining the BBB interface and serve as a first line of defense to mosquitocide exposures. To date, there are three subfamilies (ABC -B, -C, -G) of ABC transporters; however, knowledge of these chemistries interacting with mosquito ABC transporter(s) is limited. Here, I report that tacrine and bis(7)-tacrine are relative non-toxic anticholinesterases at solubility limits; however, the addition of verapamil enhances toxicity of both tacrine and bis(7)-tacrine to mosquitoes. Verapamil significantly increases the mortality of mosquitoes exposed to tacrine and bis(7)-tacrine compared to the tacrine- and bis(7)- tacrine-only treatments. Tacrine and bis(7)-tacrine reduce acetylcholinesterase activity in mosquito head preparations compared to the untreated mosquitoes; however, the addition of verapamil significantly increases the anticholinesterase activity of tacrine and bis(7)-tacrine compared to the tacrine-and bis(7)-tacrine-only treatments. Tacrine and bis(7)-tacrine increase ATPase activity in Aedes aegypti at lower concentrations compared to that of verapamil (Fig. 3). The differential increase in ATPase activity suggests that tacrine and bis(7)-tacrine are more suitable substrates for ABC transporter(s) compared to verapamil and, thus, provides putative evidence that ABC transporter(s) is a pharmacological obstacle to the delivery of these anticholinesterases to their intended target site. / Master of Science in Life Sciences

No / Metal ion acquisition and homeostasis are essential for bacterial survival, growth and physiology. A family of metal ion, ABC-type import systems have been identified in Gram-positive bacteria, in which the solute-binding proteins are predicted to be membrane-anchored lipoproteins. The prediction that the MtsA protein of Streptococcus agalactiae A909 is a lipoprotein was confirmed. The expression of MtsA was co-ordinately regulated by the presence of both manganese and ferrous ions suggesting that MtsA may be involved in the uptake of both these ions. MtsA was shown to be expressed at levels of ferrous ions known to be present in amniotic fluid, a growth medium for S. agalactiae during neonatal infection.

No / Streptococcus agalactiae is a significant pathogen causing invasive disease in neonates and thus an understanding of the molecular basis of the pathogenicity of this organism is of importance. N-terminal lipidation is a major mechanism by which bacteria can tether proteins to membranes. Lipidation is directed by the presence of a cysteine-containing 'lipobox' within specific signal peptides and this feature has greatly facilitated the bioinformatic identification of putative lipoproteins. We have designed previously a taxon-specific pattern (G+LPP) for the identification of Gram-positive bacterial lipoproteins, based on the signal peptides of experimentally verified lipoproteins (Sutcliffe I.C. and Harrington D.J. Microbiology 148: 2065-2077). Patterns searches with this pattern and other bioinformatic methods have been used to identify putative lipoproteins in the recently published genomes of S. agalactiae strains 2603/V and NEM316. A core of 39 common putative lipoproteins was identified, along with 5 putative lipoproteins unique to strain 2603/V and 2 putative lipoproteins unique to strain NEM316. Thus putative lipoproteins represent ca. 2% of the S. agalactiae proteome. As in other Gram-positive bacteria, the largest functional category of S. agalactiae lipoproteins is that predicted to comprise of substrate binding proteins of ABC transport systems. Other roles include lipoproteins that appear to participate in adhesion (including the previously characterised Lmb protein), protein export and folding, enzymes and several species-specific proteins of unknown function. These data suggest lipoproteins may have significant roles that influence the virulence of this important pathogen.

Les parasites protozoaires du genre Leishmania sont responsables de différentes pathologies et représentent une cause importante de morbidité et de mortalité au niveau mondial. En absence de vaccins, le contrôle de la leishmaniose repose sur l’administration d’agents chimiothérapeutiques. Les médicaments disponibles sont peu nombreux et la plupart d’entre eux sont associés à des facteurs limitants, comme une toxicité relative à leur administration ou un coût trop élevé pour être utilisés de routine au niveau des zones endémiques les plus pauvres. Les composés à base d’antimoine pentavalent sont utilisés en thérapie depuis plusieurs décennies et demeurent encore aujourd’hui un traitement de première ligne contre les différentes formes de leishmanioses. Cependant, l’augmentation du nombre d’infections réfractaires au traitement, associée à la présence de foyers épidémiques de résistance, amenuisent le potentiel thérapeutique de ces molécules. Les mécanismes impliqués dans la résistance sont partiellement élucidés et ont révélé l’importance de la famille des protéines ATP-binding cassette (ABC) dans la résistance. De plus, l’étude de mutants résistants sélectionnés en laboratoire indique la présence de mécanismes de résistance supplémentaires, pour lesquels les gènes impliqués n’ont pas encore été identifiés. Les objectifs de cette thèse étaient i) de définir la famille des protéines ABC chez Leishmania et d’en effectuer l’analyse phylogénique, pour ensuite ii) étudier l’implication de la sous-famille ABCC dans la résistance à l’antimoine chez ce parasite, et finalement iii) de profiter de la disponibilité de la séquence du génome de Leishmania pour évaluer le profil d’expression génique associé au phénotype de résistance à l’antimoine à l’échelle génomique. L’analyse phylogénique a d’abord permis de démontrer la diversité de la famille des protéines ABC chez Leishmania, qui semble avoir évoluée par des événements de duplication génique suite à la divergence évolutive du parasite. Ensuite, des études de localisation protéique, associées à des expériences de surexpression génique, ont permis de déterminer la localisation intracellulaire de l’ensemble des protéines appartenant à la sous-famille ABCC chez Leishmania et de démontrer l’implication de deux d’entre elles dans la résistance à l’antimoine chez ce parasite. Enfin, une étude transcriptomique a confirmé l’importance du gène MRPA dans la résistance à l’antimoine et a permis d’identifier les mécanismes de recombinaison homologue impliqués dans son amplification chez une souche de L. infantum hautement résistante. Finalement, l’analyse transcriptomique a également révélé la présence de chromosomes aneuploïdes chez différents mutants résistants à l’antimoine, alors que la sélection d’une souche révertante partielle a permis d’observer une bonne corrélation entre les niveaux de résistance et le nombre de copies des chromosomes aneuploïdes. / The parasite Leishmania is responsible for considerable morbidity and mortality around the world. No effective vaccine is yet available against this parasite and treatment thus relies on chemotherapy. Few drugs are available and most of them are associated with limitations such as toxicity and high cost. Pentavalent antimonials have been used for decades in the treatment of leishmaniasis and remain the mainstay against all forms of Leishmania infections in most endemic regions. However, the efficacy of these compounds is compromised by the selection of resistant parasites that are now described on a frequent basis in several endemic regions. The mechanisms involved in antimony resistance are partly understood and have pinpointed the role of ATP-binding cassette (ABC) proteins. Moreover, drug resistance studies with different in vitro-selected mutants have suggested the presence of unidentified mechanisms involved in antimony resistance. The objectives of this thesis were i) to define the complete ABC protein family in Leishmania and to analaze their evolution by phylogenetic analyses, ii) to assess the role of the entire ABCC subfamily in antimony resistance, and iii) to take advantage of the availability of the Leishmania genome sequence to study the gene expression profile associated with an antimony resistance phenotype at the genomic level. Phylogenetic analyses revealed the magnitude of the ABC gene family in Leishmania, which seemed to have undergone gene duplication events following the divergence of the Leishmania lineage. Moreover, subcellular localization experiments indicated that the entire ABCC protein subfamily is located to intracellular compartments in Leishmania, and gene overexpression experiments revealed the involvement of two of these proteins in antimony resistance. Finally, a whole-genome transcriptomic study confirmed the involvement of MRPA in antimony resistance and revealed the recombination events associated with its amplification in the highly resistant L. infantum Sb2000.1 mutant. More importantly, the transcriptomic study revealed the presence of aneuploid chromosomes in at least two different antimony-resistant mutants and selection of a partial revertant strain allowed the observation of a good correlation between the antimony resistance levels and the copy number of the aneuploid chromosomes.

Course: Degree project in Logistics, the Business Administration and Economics Programme, 4FE19E, VT16 Authors: Marcus Lundgren and Tobias Nilsson Supervisor: Peter Berling Examiner: Helena Forslund Title: Product Costing in Small Craft Companies – A Case Study at Gemla Fabrikers AB Background: Today a competitive price is no guarantee to keep a company profitable. Cost control has become more central and especially cost control considering work put in to the product and tradeoffs connected to the product in question has become central to secure the company’s competitiveness. A useful tool to secure the competitiveness is product costing when making profit analysis, setting price levels as well as other decision making. The challenge is to find a product costing method which fits right and distribute the direct and indirect costs in a fair manner. Purpose: The purpose of this study is by constructing a flowchart over the production process adapt a model for product costing that supports pricing and decision making of the product assortment at Gemla Fabrikers AB, and theoretically raise the discussion of the adapted models suitability in a context of small time manufacturers that is characterized by an artisan production. Method: The study is conducted as a case study at Gemla Fabrikers AB and uses a research strategy containing both qualitative and quantitative approaches. Collected data is mainly obtained via unstructured interviews, direct observations and time studies. A process mapping was made as a start to serve as a foundation for other parts of the study. A product costing method was later adapted to fit the parameters and way of working in a company with high levels of craftsmanship. Conclusions: After mapping the process of the company it was clear that the production was characterized by a time-consuming manufacturing process with a large number of activities. This resulted in an adapted product costing method, which origins from the activity based costing model, in order to distribute the costs in a more correct way based v on the actual time consumption. The adapted model is designed with a distinct activity based distribution on product level where every activity cost is established at a given volume of production, resulting in guidance and basis for cost control and when setting prices. Based on the company in the case study the conclusion was made that this way of working with product costing can be used in other companies with similar production and high level of craftsmanship, merging support activities together and focus on the value adding activities. The cost allocation is made using cause and effect based on the actual time put into the activities where a smaller number of time related cost drivers are used. The model is therefore to consider suitable for increased cost control as well as serving as a foundation for product pricing and decision making. / Kurs: Examensarbete i logistik för Civilekonomprogrammet, 4FE19E, VT16 Författare: Marcus Lundgren och Tobias Nilsson Handledare: Peter Berling Examinator: Helena Forslund Titel: Produktkalkylering i mindre hantverksföretag – En fallstudie på Gemla Fabrikers AB Bakgrund: Ett konkurrenskraftigt pris är i dagsläget inte tillräckligt då även en noggrann kostnadskontroll som tar hänsyn till arbetskraftsinsatsen och produktrelaterade avvägningar krävs för att säkerställa konkurrensförmågan. Ett användbart verktyg för detta är upprättandet av produktkalkyler som grund för lönsamhetsanalyser, prissättningsstrategi och beslutsunderlag. Svårigheten ligger dock i att finna rätt kalkyleringsmetod gällande detaljeringsnivån som fördelar en verksamhets direkta och indirekta kostnader på ett rättvisande sätt. Syfte: Syftet med studien är att genom en kartläggning av tillverkningsprocessen anpassa en produktkalkyl för prissättning och beslutsfattande av produktsortimentet på Gemla Fabrikers AB, samt teoretiskt lyfta diskussionen om anpassad modells lämplighet i en kontext för mindre tillverkande företag som karaktäriseras av en hantverksmässig produktion. Metod: Studien utförs enligt en fallstudie på Gemla Fabrikers AB med en flerfaldig forskningsstrategi av kvalitativ art med kvantitativa inslag. Datainsamlingen bygger främst på ostrukturerade intervjuer, direkta observationer och tidsstudier. En processkartläggning genomfördes till en början för att utgöra ett underlag för resterande delar. Vidare anpassades en produktkalkyl utifrån företaget och tillverkningens karaktär vilket slutligen utgjorde ett underlag för modellens lämplighet i en hantverksmässig tillverkningskontext. Slutsatser: Efter genomförd kartläggning av tillverkningsprocessen på fallföretaget framgick det att tillverkningen karaktäriseras av en tidskrävande process med ett stort antal ingående aktiviteter. Detta resulterade i att anpassad produktkalkyl utformades enligt en ABC-modell då slutsatsen blev att fördelningen av kostnaderna skulle göras iii mer rättvisande om dessa fördelades till respektive aktivitet baserat på det faktiska tidsutnyttjandet. Anpassad modell utformades genom en tydlig aktivitetsfördelning utifrån produktnivå där varje aktivitets kostnad fastställs vid en given produktionsvolym vilket möjliggör underlag för en ökad kostnadskontroll, prissättningsstrategi och beslutsunderlag. Baserat på studerat fallföretag drogs slutsatsen att anpassad modell görs lämplig för andra företag i en liknande hantverksmässig kontext utifrån att i högre grad göra sammanslagningar av aktiviteter med ett större fokus på de värdeadderande aktiviteterna. Kostnadsfördelningen sker via ett orsak-verkan samband utifrån det faktiska tidsutnyttjandet där ett mindre antal tidsrelaterade kostnadsdrivare används. Modellen blir då lämplig för ökad kostnadskontroll samt underlag för prissättning och beslutsfattande.