Natural history models for breast cancer describe the unobservable disease progression. These models can either be fitted using likelihood-based estimation to data on individual tumour characteristics, or calibrated to fit statistics at a population level. Likelihood-based inference using individual level data has the advantage of ensuring model parameter identifiability. However, the likelihood function can be computationally heavy to evaluate or even intractable. In this thesis likelihood-free estimation using Approximate Bayesian Computation (ABC) will be explored. The main objective is to investigate whether ABC can be used to fit models to data collected in the presence of mammography screening. As a background, a literature review of ABC is provided. As a first step an ABC-MCMC algorithm is constructed for two simple models both describing populations in absence of mammography screening, but assuming different functional forms of tumour growth. The algorithm is evaluated for these models in a simulation study using synthetic data, and compared with results obtained using likelihood-based inference. Later, it is investigated whether ABC can be used for the models in presence of screening. The findings of this thesis indicate that ABC is not directly applicable to these models. However, by including a sub-model for tumour onset and assuming that all individuals in the population have the same screening attendance it was possible to develop an ABC-MCMC algorithm that carefully takes individual level data into consideration in the estimation procedure. Finally, the algorithm was tested in a simple simulation study using synthetic data. Future research is still needed to evaluate the statistical properties of the algorithm (using extended simulation) and to test it on observational data where previous estimates are available for reference. / Natural history models för bröstcancer är statistiska modeller som beskriver det dolda sjukdomsförloppet. Dessa modeller brukar antingen anpassas till data på individnivå med likelihood-baserade metoder, eller kalibreras mot statistik för hela populationen. Fördelen med att använda data på individnivå är att identifierbarhet hos modellparametrarna kan garanteras. För dessa modeller händer det dock att det är beräkningsintensivt eller rent utav omöjligt att evaluera likelihood-funktionen. Huvudsyftet med denna uppsats är att utforska huruvida metoden Approximate Bayesian Computation (ABC), som används för skattning av statistiska modeller där likelihood-funktionen inte är tillgänglig, kan implementeras för en modell som beskriver bröstcancer hos individer som genomgår mammografiscreening. Som en del av bakgrunden presenteras en sammanfattning av modern ABC-forskning. Metoden består av två delar. I den första delen implementeras en ABC-MCMC algoritm för två enklare modeller. Båda dessa modeller beskriver tumörtillväxten hos individer som ej genomgår mammografiscreening, men modellerna antar olika typer av tumörtillväxt. Algoritmen testades i en simulationsstudie med syntetisk data genom att jämföra resultaten med motsvarande från likelihood-baserade metoder. I den andra delen av metoden undersöks huruvida ABC är kompatibelt med modeller för bröstcancer hos individer som genomgår screening. Genom att lägga till en modell för uppkomst av tumörer och göra det förenklande antagandet att alla individer i populationen genomgår screening vid samma ålder, kunde en ABC-MCMC algoritm utvecklas med hänsyn till data på individnivå. Algoritmen testades sedan i en simulationsstudie nyttjande syntetisk data. Framtida studier behövs för att undersöka algoritmens statistiska egenskaper (genom upprepad simulering av flera dataset) och för att testa den mot observationell data där tidigare parameterskattningar finns tillgängliga.

La résistance aux lactones macrocycliques (LM) constitue une préoccupation croissante dans le contrôle des nématodes parasitaires, notamment l'Haemonchus contortus chez les ruminants. Parmi les mécanismes étudiés dans la résistance aux LM chez les nématodes d’importance en santé animale, il y a les pompes ABC, principalement les glycoprotéines-p, connues pour leur rôle dans la détoxification des LM chez les strongles. Il n'existe toutefois aucune étude sur l'extrusion des lipides par les pompes ABC en tant que produits excrétoires/sécrétoires provenant d'H. contortus (Hc-PES). Nous émettons l’hypothèse que les pompes ABC chez H. contortus sont à la fois impliquées dans l’extrusion de LM (contribuant à la résistance aux antihelminthiques) et dans l’efflux de lipides secrétés par le parasite. Notre objectif était de caractériser le rôle des pompes ABC chez H. contortus dans le contexte de la résistance aux LM et de l'extrusion des lipides. L'efficacité de l'ivermectine, un membre de LM, a été évaluée dans 8 fermes étudiées par un test de réduction de la numération des œufs dans les selles (TRNOS). Les niveaux d'expression des pompes ABC ont été évalués dans des isolats de champ d’H. contortus avec des résultats TRNOS faibles (présumé souches résistantes). D’ailleurs, des vers adultes d’H. contortus ont été incubés avec trois inhibiteurs de pompes ABC, dont le Fumitremorgin C, le Kétoconazole et le Mk-571 à concentrations différentes. Les lipides ont été identifiés par CL/SM dans les milieux de culture récupérés à 2 h, à 4 h et à 8 h après l'incubation d’H. contortus dans les groupes contrôle et traités. L'expression des gènes Hco-pgp-2 et Hco-pgp-3 était augmentée chez les isolats de champ d’H. contortus. Nous avons identifié 1045 lipides appartenant à diverses catégories. L'extrusion des lipides en Hc-PES a changé en présence d'inhibiteurs de pompes ABC, en particulier pour les lipides composés de structures correspondant à celles pour le transport par les pompes ABC. Nous avons donc conclu que les pompes ABC chez H. contortus représentent un système de multi-extrusion et sont impliquées dans la sécrétion de lipides avec importance dans l’interaction avec l’hôte, mais aussi dans la résistance aux LM chez le nématode. / Macrocyclic lactones (MLs) resistance is a growing concern in controlling parasitic nematodes, particularly Haemonchus contortus in the ruminants’ industry. ABC transporters are known to participate in translocating various lipophilic molecules, including MLs and lipids. Some ABC transporters, mostly P-glycoproteins are known to be involved in MLs detoxification in parasitic nematodes; but there is no data about extrusion of lipids by ABC transporters as Excretory/Secretory Products in H. contortus (Hc-ESP). We hypothesize that ABC transporters in H. contortus have a dual role participating in the efflux of MLs, thus contributing to anthelmintic resistance, and in the extrusion of lipids out of the parasite. This study aimed to characterize the role of H. contortus ABC transporters in the context of ML resistance and the extrusion of lipids. Ivermectin (a member of MLs) efficacy was evaluated in 8 studied farms by the fecal egg count reduction test (FECRT). The expression levels of ABC transporters were evaluated in field isolates of H. contortus with low FECRT results (suspected of resistance). H. contortus adult worms were incubated with three ABC inhibitors, such as Fumitremorgin C, Ketoconazole and Mk-571 with different concentrations. Lipids were identified by LC/MS in culture media at 2h, 4h and 8h post incubation with H. contortus in control and treated groups. Hco-pgp-2 and Hco-pgp-3 were found upregulated in H. contortus field isolates. We identified 1045 lipid molecules belonging to different categories. Interestingly, the lipid profile in Hc-ESP was altered in the presence of ABC transporter inhibitors, which shows structural features compatible as substrates for nematode transporters’ activity. Therefore, ABC transporters in H. contortus participate in extrusion of lipids and also may help in detoxification of MLs, becoming a multipurpose pumping system involved in ML resistance and secretion of lipids at the interplay with the host and among nematodes.

Bakgrund: För att företag ska lyckas uppnå en önskad servicenivå krävs ettsäkerhetslager. Vid för litet säkerhetslager riskerar företag att inte kunna levereramedan man vid för stora lager riskerar att binda ohållbart mycket kapital. För atteffektivisera och underlätta styrningen kan man dela in artiklar i olika klasser.Dessa klasser kan styras efter olika principer. Vid säkerhetslager dimensioneringkan målkonflikter mellan den säljande och operativa delen av verksamhetenuppstå. Detta då man arbetar efter olika mål, för att minska dessa kan S&OPimplementeras. Forskningsfrågor: 1. Vilken säkerhetslager dimensionering metod lämpar sig tillsammans meden ABC/XYZ-analys för Invacare REA? 2. Hur kan S&OP användas för att minska målkonflikter mellan den säljandeoch distribuerande delen av organisationen, genom en integrerad samsynpå säkerhetslager dimensionering? Syfte: Syftet med detta arbete är att fram till ett teoretiskt ramverk för hurInvacare REA skulle kunna arbeta med säkerhetslager dimensionering. Arbetetsyftar även till att ge en gemensam samsyn på servicenivåer av de olikaartikelklasserna genom att integrera säkerhetslager dimensionering i S&OPprocessen. Metod: Detta är en fallstudie genomförd på Invacare REA. För att möjliggöraresultatet av denna studie har både kvalitativ och kvantitativ metod använts.Primärdata för denna studie har inhämtats genom åtta semi- och ostruktureradeintervjuer. Sekundärdata består av sammanställd litteratur men också avinsamlade affärsdata från det studerade fallföretaget.  Resultat: Implementering av serv 2 med artikelklassificering bidrar till eneffektiv säkerhetslager dimensionering. Detta genom att minska och omfördelakapitalbindningen. Genom att inkludera säkerhetslager dimensioneringen iS&OP-processen kan målkonflikter kopplade till säkerhetslagret minska.  Studiens bidrag: Praktiskt bidrag i en metod som fallföretaget kan använda somsäkerhetslager dimensioneringsmetod samt lösning för de målkonflikter sompresenteras. Det teoretiska bidraget ligger i hur man kan klassificera artiklar iS&OP-processen samt hur säkerhetslager dimensioneringen kan inkluderas iprocessen.  Vidare forskning: Undersöka beställningspunkt och prognosframtagning samthur dessa kan inkluderas i S&OP-processen.

Целью работы является усовершенствование алгоритма планирования материальных запасов на предприятиях атомно промышленности. Основным его отличием от существующего алгоритма является включения дополнительных этапов в виде построения и оценки контрольных карт Шухарта. Усовершенствованный алгоритм позволяет более точно определить размер материального запаса и осуществлять непрерывный контроль над его состоянием, что повышает эффективность управления материальными запасами. / The aim of the work is to improve the algorithm of inventory planning at nuclear industry enterprises. Its main difference from the existing algorithm is the inclusion of additional stages in the form of construction and evaluation of Schuhart control maps. The improved algorithm allows you to more accurately determine the size of the inventory and continuously monitor its condition, which increases the efficiency of inventory management.

A quantitative, descriptive and comparative study was conducted to determine the attitudes of young people aged 15-25 years towards the “ABC” strategy in the prevention of HIV/AIDS in Francistown, Botswana. Differences between two age groups and gender were determined. Structured questionnaire was used and 241 young people participated in the study. Data were analysed with SPSS version 13.0, guided by the Health Belief Model. The findings revealed that young people did not perceive the seriousness and severity of the HIV/AIDS when it came to the practice of “ABC” strategy. Young people’s cue to action was very high but their confidence to adopt and practice the “ABC” strategy were low. They had adequate knowledge of the benefits of abstinence and condoms but they perceived barriers towards the use of condom. The differences between the two age groups, 15-19 and 20-25 years and between the males and females were not statistically significant. / Public Health / M.A. (Public Health)

BACKGROUND:Microalgae hold promise for yielding a biofuel feedstock that is sustainable, carbon-neutral, distributed, and only minimally disruptive for the production of food and feed by traditional agriculture. Amongst oleaginous eukaryotic algae, the B race of Botryococcus braunii is unique in that it produces large amounts of liquid hydrocarbons of terpenoid origin. These are comparable to fossil crude oil, and are sequestered outside the cells in a communal extracellular polymeric matrix material. Biosynthetic engineering of terpenoid bio-crude production requires identification of genes and reconstruction of metabolic pathways responsible for production of both hydrocarbons and other metabolites of the alga that compete for photosynthetic carbon and energy.RESULTS:A de novo assembly of 1,334,609 next-generation pyrosequencing reads form the Showa strain of the B race of B. braunii yielded a transcriptomic database of 46,422 contigs with an average length of 756 bp. Contigs were annotated with pathway, ontology, and protein domain identifiers. Manual curation allowed the reconstruction of pathways that produce terpenoid liquid hydrocarbons from primary metabolites, and pathways that divert photosynthetic carbon into tetraterpenoid carotenoids, diterpenoids, and the prenyl chains of meroterpenoid quinones and chlorophyll. Inventories of machine-assembled contigs are also presented for reconstructed pathways for the biosynthesis of competing storage compounds including triacylglycerol and starch. Regeneration of S-adenosylmethionine, and the extracellular localization of the hydrocarbon oils by active transport and possibly autophagy are also investigated.CONCLUSIONS:The construction of an annotated transcriptomic database, publicly available in a web-based data depository and annotation tool, provides a foundation for metabolic pathway and network reconstruction, and facilitates further omics studies in the absence of a genome sequence for the Showa strain of B. braunii, race B. Further, the transcriptome database empowers future biosynthetic engineering approaches for strain improvement and the transfer of desirable traits to heterologous hosts.

為提升營運財務績效，在營運管理上，不少企業會採行節約成本與裁減員工等迅速明快的措施來提升生產力。但其作法不僅往往會造成許多不愉快，且即使在短時間內的成本控制頗見成效，但不久又會故態復萌，生產力停滯不前，甚至下降，直到下一波的成本削減措施推出為止。因此針對其關鍵作業流程進行持續性改善，才可謂真正達到減少營運成本卻又不降低品質之方法。又在規模越大的公司中，通常成本交叉補貼的情況會越嚴重，越是有必要實施作業制成本管理制度來增加作業及資源分配的透明度。為達此目標，推行作業制成本管理制度（Activity-based costing Management）以獲得必要之作業相關資訊極為重要，而作業制管理遂成為提升競爭力及達到持續性改善之有效制度。 筆者會以個案公司為例，採實地實證之研究方式，探討作業制管理制度實施後，個案公司在作業時間、成本、品質面之持續性改善效果。根據研究假說與實證模型，以t統計量檢定或複迴歸分析（Multiple Regression）的方式，進行橫斷面之資料分析，探討作業制成本管理制度資訊釋放前後期，對於公司在策略面及營運面之各種效益變化。 / In order to improve the operational performance quickly, many enterprise cut down staff to economize cost without modifying the process. This method is just a temporary solution to a problem. It may cause a lot of unhappiness and would not do any help to increase productivity. Continuing improving critical process works for long-term cost down. And In most of the large-scale companies, the problem of cost cross-subsidization is usually more serious. So it is necessary to implment the the cost allocation management system to make cost transparency. In order to reach this goal, it’s extremely important to imply Activity-based costing Management. And it is the effective system that helps to improve business competition. The author will take a bank to do case study and the evidence research to compose this thesis. And this research discusses the effect on time,cost and quality after implementing Acitivty-based costing. Besides that, the author also discuss the benefit on strategy and operation before and after the acitivity-based-costing information is released.The author take t-test and the Multiple Regression to examine the study hypothesis and evidence research model.

Première cause de décès par cancer chez la femme, le cancer du sein développe souvent une résistance à la chimiothérapie pouvant impliquer des transporteurs ABC (ATP Binding Cassette). Ils transportent les médicaments hors de la cellule et diminuent leur efficacité thérapeutique. Nous nous sommes intéressés à la protéine ABCC11 ou MRP8 (Multidrug Resistance Protein 8), exprimée dans le sein et responsable de l'efflux de certains anticancéreux (5FdUMP et méthotrexate). Nous avons démontré que l'expression d'ABCC11 était dépendante des voies de signalisation impliquant ER (Récepteur aux œstrogènes) ou PR (Récepteurs à la Progestérone). De plus, le tamoxifène (antagoniste d'ER) et la dexaméthasone (activateur de PR), utilisés en association avec la chimiothérapie, induisent l'expression d'ABCC11 et influenceraient négativement la réponse aux traitements anticancéreux à base de substrats d'ABCC11. L'expression d'ABCC11 a été positivement corrélée à celles d'ER et PR dans des cancers du sein. En parallèle, nous avons généré 2 modèles in silico en conformation ouverte vers l'intracellulaire ou vers l'extracellulaire et identifier des acides aminés potentiellement critiques dans l'architecture de la protéine ainsi que dans la liaison avec certains substrats (5FdUMP et GMPc). Nous avons également généré les outils moléculaires permettant l'étude de l'impact de 13 SNP (Single Nucleotide Polymorphism) non synonymes d'ABCC11. En raison d'une instabilité des lignées cellulaires, l'étude n'a pu être menée à son terme. Notre travail a ainsi contribué à une meilleure caractérisation d'ABCC11 et souligne sa potentielle valeur pronostic et prédictive dans le traitement du cancer du sein.

Bridge substructures are generally constructed using cast-in-place concrete and designed to undergo inelastic deformation in earthquake events. Although this construction approach has proven to be economical and provides adequate seismic performance through the formation of ductile plastic hinges, there are downsides relating to construction speed and quality, and post-earthquake repairability. This thesis explores two categories of Accelerated Bridge Construction (ABC) connection types, which use precast concrete instead of cast-in-place concrete to offer advantages including increased construction speed and quality. High Damage (HD) ABC connection types emulate the seismic behaviour of cast-in-place construction through the formation of ductile plastic hinges. Controlled Damage (CD) ABC connection types use unbonded post-tensioned precast connections to offer additional advantages including reduced residual drifts, limited and controlled damage and simple repair options. Novel buckling-restrained, fused mild steel energy dissipators suitable for use in CD connections are also developed and tested. These designs utilise 'dry' fabrication to simplify the fabrication process and minimise cost. Half-scale experimental testing is carried out to demonstrate both the assembly processes and behaviour under reversed cyclic uniaxial and biaxial loading representing an earthquake event. Following benchmark testing, repair strategies are applied to the CD connection types and the columns are tested again, representing a subsequent earthquake event. Good results are obtained from all cases with relatively straightforward construction and repair processes. With further developments and testing, the connection types proposed can provide competitive alternatives to conventional bridge pier design with regard to seismic performance and life cycle costs, with the additional benefits associated with precast construction.

Cancer continues to be a leading cause death in the United States despite improved treatments. Cancerous lesions form after acquiring oncogenic driver mutations or losing tumor suppressor function in normal cells. Traditional therapies have included use of genotoxic substances that take advantage of the increased growth rate and loss of tumor suppressor function to cause cell death. One such drug is the anthracycline antibiotic doxorubicin (DOX). DOX interchelates into DNA and disrupts transcriptional machinery while also poisoning topoisomerase II. This results in single and double stranded DNA breaks, which if severe enough leads to either necrotic or apoptotic cell death. DOX has been very effective at treating several different cancers and is still widely used today however its clinical use is limited due to cumulative dose dependent cardiotoxicity. Therefore, combination therapy targeting survival pathways is utilized to minimize the cumulative dose of DOX without ameliorating its anti-tumor effects. We investigated the potential anti-cancer effects of combining the dual PI3K/mTOR inhibitor, BEZ235 (BEZ), with DOX in pancreatic, breast and other cancer cells lines as well as its associated effects on the heart. Our results showed that co-treatment of BEZ with DOX increased apoptosis in a manner that was dependent on inhibition of the AKT survival pathway. Moreover, BEZ co-treatment with DOX had additive effects towards cell viability while it significantly enhanced necrotic cell death compared to either drug alone. Furthermore, we observed that physiological concentrations of BEZ inhibited ABCB1 efflux resulting in increased intracellular accumulation of DOX, which led to increased DNA damage. In addition, BEZ in combination with gemcitabine (Gem) reduced cell proliferation but did not enhance necrosis or apoptosis. Treatment with BEZ and DOX in mice bearing tumor xenographs reduced tumor growth as compared to BEZ, DOX or Gem. Moreover, BEZ reduced DOX toxicity in rat myoblast cells and did not potentiate the effects of DOX in tumor-bearing mice. We propose that combining BEZ with DOX could be a novel therapeutic approach for the treatment of patients with cancer in the hope of improving the prognosis of this deadly disease.