<p>Bakgrund: Dagens industriföretag har ägnat mycket tid och tankeverksamhet åt att förbättra produktiviteten men i regel betydligt mindre till att beräkna enskilda produkters kostnader. Allt högre krav ställs på en kundanpassad produktion med differentierade produkter. Produkternas heterogenitet innebär även heterogen resursförbrukning och det gör det svårt att veta vilka kostnader en produkt verkligen orsakar. Inom ABC är det kostnadsdrivarens uppgift att koppla samman resursförbrukningen med produkterna. Valet av kostnadsdrivare kan ge stora effekter på produktens kostnad och visa att produkter som tidigare betraktas som lönsamma säljs med förlust.</p><p>Syfte: Syftet är att beskriva och analysera problematiken kring val av kostnadsdrivare.</p><p>Genomförande: En fallstudie har genomförts kring val av kostnadsdrivare vid Swedish Tissue.</p><p>Resultat: Det finns inga optimala kostnadsdrivare utan en komplex avvägning med kalkylens syfte i bakhuvudet krävs. Riktlinjen bör inte vara perfekt kausalitet utan minimering av totalkostnaden. Denna består av mätkostnad för kostnadsdrivaren och felkostnad orsakad av beslut baserade på kalkyler med brister i beroende på valet av kostnadsdrivare. Hänsyn måste även tas till beteendeeffekter som kostnadsdrivare medför, vilka kan vara avgörande. En avvägning måste göras mellan variablerna mätkostnad, felkostnad och beteendeeffekter men det är kontexten; företagets struktur, informationssystem och strategi, som avgör komplexiteten. I uppsatsen utvecklas en modell för att analysera totalkostnaden vid valet av kostnadsdrivare där de tre variablerna står i fokus.</p><p>Vid ledig kapacitet måste företag ha klart för sig hur de ska hantera kostnaden för denna innan valet av kostnadsdrivare sker, då valet kan påverka kalkylens lämplighet som styrningsverktyg. En analysmodell utvecklas med syftet att fungera som stöd vid beslutsfattande om hur ledig kapacitet skall hanteras.</p><p>Diskussionen kring problematiken vid ledig kapacitet bör kunna generaliseras till alla företag med ledig kapacitet allra helst företag i process- och tillverkningsindustrin. Problematiken som diskuteras med hjälp analysmodell II bör vara giltig, om än av olika vikt, för alla företag som använder sig av kostnadsdrivare men kanske även för alla som överhuvudtaget använder sig av kostnadsfördelning oavsett kalkylmetod.</p> / <p>Background: Today’s industrial concerns have devoted considerable time and attention to improve productivity, but usually significantly less to calculate individual product costs. The demand for customised production with differentiated products is continuously increasing. The product heterogeneity also leads to heterogenic resource consumption, which makes it hard to determine what costs a product causes. In ABC the cost driver’s function is to link the resource consumption with the products. The choice of cost drivers can have large effects on the product’s costs and reveal that products previously regarded profitable are sold with a loss.</p><p>Purpose: The purpose is to describe and analyse the difficulties regarding choice of cost drivers.</p><p>Completion: A case study concerning the choice of cost drivers has been carried out at Swedish Tissue.</p><p>Result: There are no optimal cost drivers. A complex assessment of the pros and cons has to be performed with the costing systems purpose taken into account. Perfect causality should not serve a guideline bur rather to minimize total cost. It includes the cost driver’s cost of measurement and cost of errors caused by decisions based on product costing systems allocating costs poorly caused by the choice of cost driver. Behavioural effects resulting from the choice must also be considered as they can be decisive. An assessment of these three variables has to be conducted, but it is the context, the company structure, the information system and the strategy that determines the complexity. A model for analysing total cost when choosing cost drivers has been developed, in which the three variables are in focus.</p><p>In case of free capacity companies must know how to handle its cost prior to choosing cost drivers. The choice can affect the appropriateness of the product costing system as a tool for management control. A model has been developed with the purpose to assist in decision making situation regarding handling of free capacity.</p><p>The discussion concerning free capacity difficulties should be possible to generalise to all companies with free capacity, but primarily to companies within the processing and manufacturing industries. The difficulties discussed by means of analysis model II should be valid, however of different importance, to all companies using cost drivers, but probably also for companies in general that practice cost allocation regardless of cost system</p>

During the last decade, Activity-Based Costing (ABC) has been recognized as a means to obtain more accurate and relevant information of product cost. Consultants have tried using the ABC concept as leverage for new projects, representatives from companies have attended seminars, and articles have been written on the theoretical foundations, the empirical justification, and on the implementation process. However, little progress seems to have been made despite of these activities. The question, whether ABC is the solution to the “Relevance Lost” or not, still remains to be answered. The research is based on a case study of an Ericsson company that has introduced Activity-Based Costing model for product costing. The purpose is to provide a critical evaluation and analysis of the existing model and to discuss how to “regain the relevance” of product costing through ABC. The study is conducted by interviewing relevant persons who are responsible for costing model and production process at Ericsson Mobile Communications AB in Linköping (ECS). Relevant documents during the implementation of ABC model have also been examined. Despite of a logical ABC model within ECS, the accuracy of cost information has not been improved. Many factors have been forgotten. Keeping costing model update, relating managers’ responsibility to activities performed and taking the cost of unused capacity into account are several examples. The study shows that ABCis not and will not be, however, the solution to the aging traditional product costing unless one uses it properly.

Biliary excretion is an important elimination route for many drugs and metabolites. For such compounds, it is important to know the extent of excretion and drug exposure in the bile, e.g., for the risk assessment of drug interactions, liver toxicity and the effects of genetic variants. In this thesis, duodenal aspiration of bile was performed in healthy volunteers and complemented with experiments in an in vivo model in pigs to increase the understanding of the intestinal and hepatobiliary disposition of two direct thrombin inhibitors. The compounds investigated, ximelagatran and AZD0837, are both prodrugs that require bioactivation to exert their pharmacological effect. Upon co-administration with erythromycin and ketoconazole, respectively, altered plasma exposure to ximelagatran and AZD0837 and their respective metabolites has been observed. The main objective of this thesis was to characterize the biliary excretion of the compounds, and investigate whether this elimination route explains the observed drug-drug interactions. High plasma-to-bile AUC ratios were observed, in particular for ximelagatran, its active metabolite melagatran, and AR-H067637, the active metabolite of AZD0837. These high ratios indicate the involvement of active transporters in the biliary excretion of the compounds, which is important since transporters constitute possible sites for drug interactions. The effects of erythromycin and ketoconazole on the plasma exposure of the prodrugs and metabolites were confirmed in both the pig and the clinical studies. The changes seen in plasma for ximelagatran and its metabolites were partly explained by reduced biliary clearance. Inhibited CYP3A4 metabolism likely caused the elevated plasma levels of AZD0837, whereas reduced biliary clearance was seen for AR-H067637 suggesting an effect on its excretion into bile. In summary, the studies led to mechanistic insights in the hepatobiliary disposition of ximelagatran and AZD0837, and demonstrate the value of combined clinical and animal studies for the investigation of the biliary drug excretion.

Bakgrund: Dagens industriföretag har ägnat mycket tid och tankeverksamhet åt att förbättra produktiviteten men i regel betydligt mindre till att beräkna enskilda produkters kostnader. Allt högre krav ställs på en kundanpassad produktion med differentierade produkter. Produkternas heterogenitet innebär även heterogen resursförbrukning och det gör det svårt att veta vilka kostnader en produkt verkligen orsakar. Inom ABC är det kostnadsdrivarens uppgift att koppla samman resursförbrukningen med produkterna. Valet av kostnadsdrivare kan ge stora effekter på produktens kostnad och visa att produkter som tidigare betraktas som lönsamma säljs med förlust. Syfte: Syftet är att beskriva och analysera problematiken kring val av kostnadsdrivare. Genomförande: En fallstudie har genomförts kring val av kostnadsdrivare vid Swedish Tissue. Resultat: Det finns inga optimala kostnadsdrivare utan en komplex avvägning med kalkylens syfte i bakhuvudet krävs. Riktlinjen bör inte vara perfekt kausalitet utan minimering av totalkostnaden. Denna består av mätkostnad för kostnadsdrivaren och felkostnad orsakad av beslut baserade på kalkyler med brister i beroende på valet av kostnadsdrivare. Hänsyn måste även tas till beteendeeffekter som kostnadsdrivare medför, vilka kan vara avgörande. En avvägning måste göras mellan variablerna mätkostnad, felkostnad och beteendeeffekter men det är kontexten; företagets struktur, informationssystem och strategi, som avgör komplexiteten. I uppsatsen utvecklas en modell för att analysera totalkostnaden vid valet av kostnadsdrivare där de tre variablerna står i fokus. Vid ledig kapacitet måste företag ha klart för sig hur de ska hantera kostnaden för denna innan valet av kostnadsdrivare sker, då valet kan påverka kalkylens lämplighet som styrningsverktyg. En analysmodell utvecklas med syftet att fungera som stöd vid beslutsfattande om hur ledig kapacitet skall hanteras. Diskussionen kring problematiken vid ledig kapacitet bör kunna generaliseras till alla företag med ledig kapacitet allra helst företag i process- och tillverkningsindustrin. Problematiken som diskuteras med hjälp analysmodell II bör vara giltig, om än av olika vikt, för alla företag som använder sig av kostnadsdrivare men kanske även för alla som överhuvudtaget använder sig av kostnadsfördelning oavsett kalkylmetod. / Background: Today’s industrial concerns have devoted considerable time and attention to improve productivity, but usually significantly less to calculate individual product costs. The demand for customised production with differentiated products is continuously increasing. The product heterogeneity also leads to heterogenic resource consumption, which makes it hard to determine what costs a product causes. In ABC the cost driver’s function is to link the resource consumption with the products. The choice of cost drivers can have large effects on the product’s costs and reveal that products previously regarded profitable are sold with a loss. Purpose: The purpose is to describe and analyse the difficulties regarding choice of cost drivers. Completion: A case study concerning the choice of cost drivers has been carried out at Swedish Tissue. Result: There are no optimal cost drivers. A complex assessment of the pros and cons has to be performed with the costing systems purpose taken into account. Perfect causality should not serve a guideline bur rather to minimize total cost. It includes the cost driver’s cost of measurement and cost of errors caused by decisions based on product costing systems allocating costs poorly caused by the choice of cost driver. Behavioural effects resulting from the choice must also be considered as they can be decisive. An assessment of these three variables has to be conducted, but it is the context, the company structure, the information system and the strategy that determines the complexity. A model for analysing total cost when choosing cost drivers has been developed, in which the three variables are in focus. In case of free capacity companies must know how to handle its cost prior to choosing cost drivers. The choice can affect the appropriateness of the product costing system as a tool for management control. A model has been developed with the purpose to assist in decision making situation regarding handling of free capacity. The discussion concerning free capacity difficulties should be possible to generalise to all companies with free capacity, but primarily to companies within the processing and manufacturing industries. The difficulties discussed by means of analysis model II should be valid, however of different importance, to all companies using cost drivers, but probably also for companies in general that practice cost allocation regardless of cost system

Malaria is a life threatening parasite disease caused and transmitted by infected female anopheles mosquito. However, the parasite, Plasmodium falciparum, has become resistant to most anti malarial drugs, such as chloroquine, which contributes to fever and anaemia because of its ability to digest the haemoglobin in the red blood cells. The aims of this project were to establish whether “Bac to Bac” Baculoviral Expression System is suitable for expression of pfmdr 1 gene and for purification of the pgh 1 protein. The pfmdr 1 gene encodes an ABC transporter protein, pgh 1, fixed in the cell membrane of the Plasmodium falciparuum gut, which assist in elimination of drug compounds. Furthermore, “Bac to Bac” Baculoviral Expression System uses vectors with histidine tags to clone the pfmdr 1 gene and subsequently transform these into DH10Bac cells to produce the recombinant bacmid DNA. Since pfmdr 1 gene is an AT-rich sequence, PCR was optimized, by lowering the annealing and extension temperature to 47Co and 66Co respectively. The results show that “Bac to Bac” Baculoviral Expression System can be used to express the pfmdr 1 gene, though further experiments has to be performed.

Many pathogenic bacteria use their iron acquisition mechanisms to live inside hosts. Streptococcus pyogenes is a pathogenic bacterium that uses streptococcal iron acquisition ABC transporter to obtain heme. SiaA (HtsA, spy1795), a lipoprotein located on the cell surface, serves as a heme binding protein. To understand the iron-uptake mechanism, histidine 229, one of the two proposed axial ligands in SiaA, was mutated to alanine. SiaA H229A was expressed in E. coli, lysed by French Press, and purified by fast protein liquid chromatography (FPLC). SDS-PAGE indicated that pure protein was isolated. Nickel affinity FPLC gave purer H229A when 0.5 M imidazole was added to the binding buffer. Overall, histidine 229 is likely to be an axial ligand in wild type SiaA, as shown by the fact the mutant readily lost heme as evidenced by UV-vis spectra.

Cytoplasmic membrane proteins CvaB and CvaA and the outer membrane protein TolC form the bacteriocin colicin V (ColV) secretion system in Escherichia coli. CvaB functions as an ATP-binding cassette transporter with nucleotide-binding motifs in the C-terminal domain (CTD). To study the role of CvaB-CTD in the ColV secretion, a truncated construct of this domain was made and over-expressed. Different forms of CvaB-CTD were obtained during purification, and were identified as monomer, dimer, and oligomer on gel filtration. Nucleotide binding was shown critical for the CvaB-CTD dimerization: oligomers could be converted into dimers by nucleotide bindings; the removal of nucleotide from dimers resulted in transient monomers followed by CTD oligomerization and aggregation; no dimer form could be cross-linked from the nucleotide-binding deficient mutant D654H. The spatial proximity of the Walker A site and ABC signature motif in CTD dimer was identified through disulfide cross-linking of mixed CvaB-CTD with mutants A530C and L630C, while mutations did not dimerize individually. Those results indicated that the CvaB-CTD formed a nucleotide-dependent head-to-tail dimer. Molecular basis of differential nucleotide bindings was also studied through bioinformatics prediction and biochemical verification. Through sequence alignment and homology modeling with bound ATP or GTP, it was found that the Ser503 and Gln504 on aromatic stacking region (Y501DSQ-loop) of CvaB-CTD provided two additional hydrogen-bonds to GTP, but not to ATP. Site-directed mutations of the S503A and/or Q504L were designed based on the model. While site-directed mutagenesis studies of Walker A&B sites or the ABC signature motif affected little on the GTP-binding preference, the double mutation (S503A/Q504L) on the Y501DSQ-loop increased both ATP-binding and ATPase activity at low temperatures. The double mutant showed slight decrease of GTP-binding and about 10-fold increase of the ATP/GTP-binding ratio. Similar temperature sensitivity in nucleotide-binding and activity assays were identified in the double mutant at the same time. Mutations on the Y501DSQ-loop did not affect the ColV secretion level in vivo. Together, the Y501DSQ-loop is structurally involved in the differential binding of GTP over ATP.

En este estudio, analizamos la obra piadosa de Huon le Roi de Cambrai, autor francés del S.XIII. Para ello, realizamos la traducción al castellano de Li Abc par ekivoche et li significations des letres, La Descrissions des relegions, Li Ave Maria en roumans, Li Regrès Nostre Dame y de Li Vie et li martyres mon signeur saint Quentin, el análisis estructural de estas, estudio del lenguaje simbólico empleado y de los recursos retóricos utilizados. En el análisis estructural, prestamos especial atención a la forma de composición de los alfabetos como género literario, al uso de proverbios y a las vidas de santos. / In this doctoral thesis, we analyse Huon le Roi de Cambrai's pious work, French author of the XIIIth century. In order to get it, we have gone into the translation into Spanish of Li Abc par ekivoche et li significations des letres, La Descrissions des relegions, Li Ave Maria en roumans, Li Regrès Nostre Dame and of Li Vie et li martyres mon signeur saint Quentin, the structural analysis of them, the study of symbolic language employed as well as their rhetorical resources.We pay an special attention, in the structural analysis, to the way of composing of the alphabets as a literary genre, the use of proverbs and the lives of saints. / Dans cette thèse de doctorat, on analyse l'oeuvre pieuse de Huon Le Roi de Cambrai, auteur français du XIIIe siècle. Tout d'abord, on réalise la traduction à l'espagnol de Li Abc par ekivoche et li significations des letres, La Descrissions des relegions, Li Ave Maria en roumans, Li Regrès Nostre Dame y de Li Vie et li martyres mon signeur saint Quentin, l'étude des formes de composition des αuvres, du langage symbolique y employé et des ressources rhétoriques y utilisées.En ce qui concerne l'analyse de la composition, on fait spécialement attention à la structure des alphabets comme genre littéraire, à l'utilisation de proverbes et aux vies de saints.

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.

Chondroitin sulfate proteoglycans (CSPGs) are one major class of axon growth inhibitors that are upregulated and accumulated around the lesion site after spinal cord injury (SCI), and result in regenerative failure. To overcome CSPG-mediated inhibition, digestion of CSPGs with chondroitinase ABC (chABC) has been explored and it has shown promising results. chABC digests glycosaminoglycan chains on CSPGs and can thereby enhance axonal regeneration and promote functional recovery when delivered at the site of injury. However, chABC has a crucial limitation; it is thermally unstable and loses its enzymatic activity rapidly at 37 ºC. Therefore, it necessitates the use of repeated injections or local infusions with a pump for days to weeks to provide fresh chABC to retain its enzymatic activity. Maintaining these infusion systems is invasive and clinically problematic. In this dissertation, three studies are reported that demonstrate our strategy to overcome current limitations of using chABC and develop a delivery system for facilitating chABC treatment after SCI: First, we enhanced the thermostability of chABC by adding trehalose, a protein stabilizer, and developed a system for its sustained local delivery in vivo. Enzymatic activity was assayed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and dimethylmethylene blue (DMMB), and conformational change of the enzyme was measured via circular dichroism (CD) with and without trehalose. When stabilized with trehalose, chABC remained enzymatically active at 37 ºC for up to 4 weeks in vitro. We developed a lipid microtube-agarose hydrogel delivery system for a sustained release and showed that chABC released from the delivery system is still functionally active and slowly released over 2 weeks in vitro. Second, the hydrogel-microtube system was used to locally deliver chABC over two weeks at the lesion site following a dorsal over hemisection injury at T10. The scaffold consisting of hydrogel and chABC loaded lipid microtubes was implanted at the top of the lesion site immediately following injury. To determine effectiveness of topical delivery of thermostabilized chABC, animal groups treated with single injection or gel scaffold implantation of chABC and penicillinase (P'ase) were included as controls. Two weeks after surgery, the functionality of released chABC and the cellular responses were examined by immunohistological analysis with 3B3, CS-56, GFAP and Wisteria floribunda agglutinin (WFA). The results demonstrated that thermostabilized chABC was successfully delivered slowly and locally without the need for an indwelling catheter by using the hydrogel-microtube delivery system in vivo. The results demonstrated that released chABC from the gel scaffold effectively digested CSPGs, and therefore, there were significant differences in CSPG digestion at the lesion site between groups treated with chABC loaded microtube-hydrogel scaffolds and controls. Third, a long term in vivo study (45 days) was conducted to examine axonal sprouting/regeneration and functional recovery with both a single treatment each of microtube loaded chABC or Neurotrophin-3 (NT-3), and a combination of them by using the hydrogel-microtube delivery system. Over the long term study period, the treated animals showed significant improvement in locomotor function and more sprouting of cholera toxin B subunit (CTB)-positive ascending dorsal column fibers and 5-HT serotonergic fibers around the lesion site. We demonstrated that this significant improvement of chABC thermostability facilitates the development of a minimally invasive method for sustained, local delivery of chABC that is potentially a useful and effective approach for treating SCI. In addition to that, we demonstrated that combinatorial therapy with chABC and neurotrophic factors could provide a synergistic effect on axonal regrowth and functional recovery after SCI.