A aterosclerose é uma doença crônica onde duas características marcantes são observadas: retenção de lipídios e inflamação. Compreender as interações entre as células do sistema imunológico e as lipoproteínas envolvidas na aterogênese são desafios urgentes, uma vez que as doenças cardiovasculares são a principal causa de morte no mundo. Os macrófagos são cruciais para o desenvolvimento de placas ateroscleróticas e para a perpetuação da inflamação em tais lesões; estas células também estão diretamente envolvidas na ruptura de placa instável. Recentemente diferentes populações de macrófagos estão sendo identificadas nas lesões ateroscleróticas. Embora macrófagos M2 tenham sido identificados, a função destas células na aterosclerose ainda não está definida. Neste projeto, avaliamos se a adição de LDLox altera a função de macrófagos M2. Resultados: 1- Foi possível observar que os M2 se mantem viáveis após o estímulo com as lipoproteínas. 2- Quando avaliamos a expressão de moléculas co-estimulatórias, receptores Scavenger, lectinas e integrinas na superfície das células, observamos que a adição de LDLn ou LDLox em 2 concentrações diferentes (5 e 50ug/ml), por diferentes períodos de tempo não alterou a expressão de nenhum dos marcadores avaliados. A presença de LDL também não alterou outra função primordial dos M2, a capacidade de fagocitose. 3- Quando investigamos a presença de citocinas no sobrenadante das culturas estimuladas ou não com as lipoproteínas, identificamos um aumento na secreção de IL-8, uma citocina pró-inflamatória, na presença de LDLox, semelhante ao observado com a população de macrófagos M1. 4- Avaliamos se os macrófagos M2 estimulados ou não com LDL mantem sua capacidade de favorecer a angiogênese. Observamos que nas culturas estimuladas com o sobrenadante das culturas dos M2 mantidos na presença de LDLox houve uma inibição significativa da formação de túbulos pelas HUVECs. 5- Observamos que na presença do meio condicionado dos M2 estimulados com LDLox ocorreu uma intensa degradação dos filamentos de matriz extracelular produzida por MEFs. 6- Avaliamos a expressão gênica de componentes de matriz, membrana basal, moléculas de adesão, proteases e também inibidores de protease nestas células. Dos 96 genes avaliados, observamos que a adição de LDLox reduziu a expressão de 10 genes de maneira significativa, entre eles: beta-Actina (ACTB), Colágeno 6A2 (Col6A2), Integrina alfa 6 (ITGA6), Metaloproteinase 15 (MMP15), molécula de adesão celular endotelial plaquetária (PECAM) e Inibidor de metalopeptidase 2 (TIMP2). A adição de LDLox aumentou significativamente somente a expressão de trombospondina (TSP1). A adição de LDLn não alterou a expressão de nenhum gene de forma significativa. 7- A adição de LDLox induziu aumento da expressão da TSP1 e redução da expressão de colágeno 6, quando comparadas aos macrófagos M2 sem estímulo. Nossos resultados indicam que a adição de LDLox altera diversas funções dos macrófagos M2 in vitro. Em especial detectamos uma inibição significativa na angiogênese e também a secreção de mediadores que induzem a degradação da matriz extracelular. A adição de LDLox também inibiu a expressão de genes envolvidos com a estabilização da matriz extracelular. Nossos resultados sugerem que esta população de células pode contribuir para a perpetuação do processo inflamatório e degradação tecidual observados na lesão dos pacientes. Assim, acreditamos que este projeto contribuiu para o esclarecimento da participação dos M2 na patologia da aterosclerose / Atherosclerosis is a chronic disease where two key characteristics are observed: lipid retention and inflammation. Understanding the interactions between the cells of the immune system and the lipoproteins involved in atherogenesis are urgent challenges, since cardiovascular diseases are the leading cause of death in the world. Macrophages are crucial for the development of atherosclerotic plaques and for the inflammation in such lesions; These cells are also directly involved in unstable plaque rupture. Recently different populations of macrophages are being identified in atherosclerotic lesions. Although M2 macrophages has been identified, the function of these cells in atherosclerosis has not yet been defined. This project, we evaluated whether the addition of OxLDL alters the function of M2 macrophages. Results: 1- M2 macrophages remain viable after stimulation with the lipoproteins. 2- When evaluated the expression of co-stimulatory molecules, Scavenger receptors, lectins and integrins on the surface of the cells. We observed that the addition of LDLn or OxLDL at 2 different concentrations (5 and 50 ?g / ml) for different time periods did not alter the expression of any of the evaluated markers. 3- The presence of LDL also did not alter other primordial function of M2 cells, phagocytosis. 4- Was observed that cultures stimulated with conditioned medium of OxLDL-stimulated M2 there was a significant inhibition of tubule formation by HUVECs. 5- We observed that in the presence of OxLDL-stimulated M2 cells conditioned médium an intense degradation of the matrix filaments occurred. 6- We evaluated the gene expression of matrix components, basement membrane, adhesion molecules, proteases and also protease inhibitors in these cells. Of the 96 evaluated genes, we observed that the addition of OxLDL significantly reduced the expression of 10 genes, among them: Actin-beta (ACTB), Collagen 6A2 (Col6A2), Integrin alfa 6 (ITGA6), Metaloproteinase 15 (MMP15), Platelet endothelial cell adhesion molecule (PECAM) and metallopeptidase 2 inhibitor (TIMP2). The addition of OxLDL significantly increased only the expression, thrombospondin-1 (TSP1). Addition of LDLn did not significantly alter the expression of any gene. 7- That OxLDL addition induced increased TSP1 expression and reduced collagen 6 expression, when compared to M2 macrophages without stimulation. Our results indicate that the addition of OxLDL alters several M2 macrophages functions in vitro. In particular we detected a significant inhibition in angiogenesis and also the secretion of mediators that induce the degradation of the extracellular matrix. The addition of OxLDL also inhibited the expression of genes involved in extracellular matrix stabilization. Our results suggest that this cell population may contribute to the perpetuation of the inflammatory process and tissue degradation observed in the lesion of the patients. Thus, we believe that this project contributed to better understand the participation of M2 in the pathology of atherosclerosis

O objetivo do presente trabalho foi à obtenção de aço rápido tipo AISI M2 pela técnica da conformação por “spray” e a avaliação deste, quanto ao seu desempenho quando aplicado como ferramenta de usinagem. O material obtido foi laminado a quente com razões de redução de 50 e 72%, resultando em placas a partir das quais foram confeccionadas pastilhas intercambiáveis para realização de testes de usinagem. O desempenho das pastilhas obtidas a partir do material conformado por “spray” e laminado a quente, foi confrontado com o de pastilhas confeccionadas a partir de material processado convencionalmente (lingotamento convencional), e com material processado pela técnica da metalurgia do pó (MP). As variações do material obtido por conformação por “spray”, assim como também os demais materiais, foram caracterizados química, física, mecânica e microestruturalmente. Adicionalmente, foram realizados testes de usinagem para avaliação de desempenho do material quando submetido a condições reais de trabalho. Os resultados da caracterização dos materiais evidenciaram o potencial da técnica de conformação por “spray”, em possibilitar a obtenção de materiais com boas características e propriedades. Para as condições de processamento, conformação mecânica e de tratamentos térmicos aplicados neste trabalho, às análises dos resultados dos testes de usinagem revelaram um comportamento muito próximo entre todos os materiais de ferramenta utilizados. Procedendo a uma análise mais refinada dos resultados dos testes de usinagem contínua, foi verificado um desempenho ligeiramente superior para o material obtido pela técnica da metalurgia do pó (MP), seguido pelo material obtido pela técnica da metalurgia convencional, o qual apresentou uma vantagem mínima em relação ao obtido pela técnica da conformação por “spray” e laminado com redução de 72%. Por fim, o desempenho inferior ficou por conta do material obtido pela técnica da conformação por “spray” e laminado com redução de 50%, o qual apresentou os maiores valores de desgaste. / The aim of the present work was the obtention of AISI M2 high-speed steel by spray forming technique and the material evaluation when used as machining tool. The obtained material was hot rolled at 50% and 72% reduction ratios, and from which it was manufactured inserts for machining tests. The performance of inserts made of the spray formed material was compared to inserts obtained from conventional and powder metallurgy (MP) processed materials. The spray formed material was chemical, physical, mechanical and microstructural characterised. For further characterisation, the materials were submitted to machining tests for performance evaluation under real work condition. The results of material characterisation highlight the potential of the spray forming technique, in the obtention of materials with good characteristics and properties. Under the current processing, hot rolling and heat treatments condition, the analysis of the results of the machining tests revealed a very similar behaviour among the tested materials. Proceeding a criterious analysis of the machining results tests, it was verified that the performance presented by the powder metallurgy material (MP) was slight superior, followed by conventional obtained material (MConv), which presented a insignificant advantage over the spray formed and hot rolled (72% reduction ratio) material. The worst result was encountered for the spray forming and hot rolled (50% reduction ratio) material that presented the highest wear values.

Neste trabalho foi medida a tenacidade à fratura de quatro ligas fundidas com composição química base do aço AISI M2 – uma de composição química convencional (liga I), e as demais modificadas por adições de nitrogênio (liga II), cério (liga III) e antimônio (liga IV) – submetidas a tratamentos térmicos visando a decomposição do carboneto M2C, a esferoidização e engrossamento dos carbonetos produto M6C e MC, em altas temperaturas e por diversos tempos. A metodologia empregada nesta avaliação da tenacidade à fratura foi a dos corpos de prova curtos com entalhe chevron segundo ASTM E 1304-97, de forma a superar a necessidade do pré-trincamento por fadiga, procedimento de difícil controle e custoso em materiais como os aços rápidos temperados e revenidos. Verificou-se que a metodologia utilizada para obtenção e ensaio de corpos de prova chevron foi de fácil execução (comparada à metodologia convencional) permitindo grande número de experimentos. Para verificar a consistência dos resultados, em algumas condições, também se utilizou a metodologia convencional segundo a ASTM E 399-90, cujo pré-trincamento foi feito utilizando os procedimentos propostos por Harris e Dunegan. Os resultados obtidos para os aços fundidos foram correlacionados com os obtidos para outros aços rápidos convencionais (VM2, M2 Thyssen) e um aço rápido sinterizado (SINTER 23). A microestrutura foi caracterizada utilizando-se técnicas de ataques metalográficos diferenciais, metalografia quantitativa manual e computadorizada e microscopia eletrônica de varredura. A avaliação microestrutural indica que não ocorreu precipitação eutética do carboneto M6C, em nenhuma das ligas fundidas. O carboneto M2C apresenta morfologia tanto irregular (plaquetas – tipo 1) quanto regular-complexa (lamelas – tipo 2). As ligas I, III e IV, apresentaram a predominância da morfologia tipo 1 enquanto que a liga II modificada pelo nitrogênio, apresentou apenas a morfologia tipo 2. O carboneto MC apresentou-se com morfologia regular-complexa. Medidas do espaçamento interdendrítico indicam que não houve influência significativa dos elementos modificadores sobre este parâmetro. Ensaios de resistência à flexão, indicam pouca influência dos elementos modificadores, mas forte influência dos tratamentos térmicos sobre o limite de resistência à ruptura transversal do aço fundido. Em todas as ligas, a resistência à flexão cresceu com o tempo de tratamento a 1200°C, bem como com a temperatura de decomposição em tratamentos por 2 horas. Análise das fraturas por microscopia eletrônica de varredura indicou que o crescimento das trincas se deu na região interdendrítica. O aço convencional apresentou resistência à ruptura transversal muito superior à dos aços fundidos. Os ensaios de tenacidade à fratura apresentaram resultados compatíveis com a literatura para os aços AISI M2 convencional e SINTER 23. Os resultados obtidos para o aço fundido, indicam queda nos valores de tenacidade à fratura nos materiais tratados a 1050°C com o avanço do tempo de tratamento; pouca variação dos valores com o tempo nas amostras tratadas a 1150°C; e aumento significativo da tenacidade à fratura com o tempo de tratamento a 1200°C. Os valores de tenacidade obtidos para os aços rápidos fundidos foram mais elevados que os obtidos para os materiais trabalhados e para o material sinterizado. / Fracture Toughness of four cast alloys with chemical composition based on the High-Speed Steel AISI M2 were measured. One of the alloys (alloy I) had the conventional AISI M2 composition, while the other three were modified by the addition of N (alloy II), Ce (alloy III) and Sb (alloy IV). The cast alloys were heat-treated in order to promote the decomposition of the M2C carbide as well as spheroidize and coarsen the product M6C e MC carbides. The method chosen for measuring fracture toughness was based on the use of short rod and bar chevron notched samples, according to ASTM E1304 – 97, in order to evade the need for fatigue pre-cracking, notoriously difficult for High Speed Steels quenched and tempered. The chevron-notch method proved straightforward and allowed for successful testing a great number of specimens. Conventional compact sample fracture toughness, according to ASTM E 399-90, with pre-cracking obtained using Harris-Dunegan drop-weight procedure, was used to validate the results. The results for cast alloys were compared with conventionally produced High Speed Steels (VM2, M2 Thyssen) and with a powder metallurgy High Speed Steel (SINTER 23). Microstructural characterization was performed using selective etching of polished surfaces, manual and automated quantitative metallography and SEM. Microstructural evaluation of as-cast alloys showed that there was no eutectic precipitation of M6C carbides. The M2C carbides show an irregular eutectic morphology (Type 1- plates) as well as a regular-complex eutectic morphology. Measurements of interdendritic spacing did not detect any effect of the modification. The bending test rupture strengths did not vary with the addition of modifying elements, but increased with the time and temperature of decomposition, spheroidization and coarsening of carbides. Rupture strengths increased with the heat-treatment time at 1200°C as well as with increasing temperatures for 2 h heat-treatments. SEM examination of the fracture surfaces showed that crack preferential growth path was interdendritical. Conventional High Speed Steels tested in bending presented better results for the rupture strength than cast steels. Fracture toughness results for M2 conventional steels and for the SINTER 23 steel were similar to the results from the literature. Fracture toughness results obtained for cast steels diminished with increasing decomposition time at 1050°C, did not change much with increasing decomposition time at 1150°C, increased markedly withy increasing decomposition times at 1200°C. The fracture toughness results for the as-cast steels were higher than the results obtained for the wrought steels and for the powder metallurgy steel.

Le Virus Respiratoire Syncytial (VRS) est le principal agent responsable d’infections respiratoires sévères chez les nourrissons et les veaux. Le génome du VRS est constitué d’un ARN simple brin de polarité négative qui est répliqué et transcrit par le complexe ARN-polymérase viral (RdRp). Ce complexe est composé de la nucléoprotéine N, de la polymérase L, de la phosphoprotéine P et du facteur anti-terminateur de transcription M2-1. Le but de ce travail était de mieux caractériser la structure et le fonctionnement de deux protéines du complexe RdRp: P et M2-1.M2-1 est un tétramère constitué de 4 domaines : un « doigt de zinc », un domaine d’oligomérisation hélicoïdal, une région flexible, un domaine globulaire interagissant avec l'ARN et P, et une région C-terminale désordonnée. À partir de la structure cristalline de M2-1 pleine longueur, j'ai identifié des résidus critiques sur le doigt de zinc et la région flexible pour l'activité d'anti-terminaison de transcription de M2-1.Par la suite j'ai identifié une région de P critique pour l’interaction P - M2-1 et montre qu’elle est nécessaire au recrutement de M2-1 dans des corps d’inclusion cytoplasmiques. Je montre également que la déphosphorylation de M2-1, nécessaire à la transcription virale, est modulée par un complexe formé entre P et la phosphatase cellulaire PP1.Enfin, la cyclopamine, composé chimique naturel, inhibe la réplication du VRS. Je démontre qu'une seule mutation R151K sur M2-1 est suffisante pour conférer une résistance virale à la cyclopamine. Ces données ouvrent de nouvelles perspectives pour le développement de futures thérapies contre le VRS. / Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract illness in infants and calves. The RSV genome consists of a single strand, negative-sense RNA, which is replicated and transcribed by the viral RNA-dependent RNA polymerase complex (RdRp). This complex is composed of the nucleoprotein N, the large protein L, the phosphoprotein P and the transcription anti-terminator M2-1. The aim of this work was to better characterize the structure and function of P and M2-1.M2-1 is a tetramer with 4 domains: a zinc-finger, a helical oligomerization domain, a flexible region, a RNA and P binding core domain and a C-terminal disordered region. Based on the crystal structure of the full-length M2-1 protein, I identified residues in the zinc-finger and the flexible loop critical for M2-1 antitermination activity.Then I identified a region of P critical for P – M2-1 interaction and show that it is required for the recruitment of M2-1 to cytoplasmic inclusion bodies. I also show that M2-1 dephosphorylation, which is critical for viral transcription, is modulated by a complex formed by P and the cellular phosphatase protein-1 (PP1).Finally cyclopamine, a natural chemical compound, inhibits the RSV replication. I show that a single R151K mutation in M2-1 is sufficient to confer virus resistance to cyclopamine. These data open a new avenue for the development of future therapies against RSV infection.

Cette thèse est consacrée à l’étude de l’interaction cryosphère-climat depuis le milieu du Pliocène jusqu’au quaternaire pendant l’installation pérenne de la calotte groenlandaise. Nous étudions d’abord les causes du développement et de la disparition de l’importante mais courte glaciation qui a eu lieu pendant le stade isotopique marin M2 (MIS M23.264-¬3.312 Ma). Ensuite, dans le cadre du programme international sur la modélisation du Pliocène (PLIOMIP2), nous étudions le climat de la période chaude du Plaisancien moyen(MPWP, 3.3-3.0Ma). Enfin, la troisième période étudiée est la transition Plio-Pléistocène transition (PPT, 3.0-2.5Ma), que nous avons étudiée grâce à un couplage asynchrone entre un modèle de climat et un modèle de calotte. A travers ces différentes périodes, nous avons amélioré la connaissance des relations entrepCO2, tectonique et climat pendant la transition d’un monde chaud et riche en CO2 vers le monde bien plus froid et à faible pCO2 des glaciations quaternaires. Ce résultat montre l’importance de mieux comprendre les relations entre dynamique océanique, pCO2 et climat. / This thesis is devoted tounderstanding the interaction betweencryosphere and climate from the mid Plioceneto the early Quaternary during the onset ofNorthern Hemisphere Glaciation (NHG).Firstly, we investigate the causes for thedevelopment and decay of the large but shortliving glaciation that occurred during MarineIsotope Stage 2 (M2, 3.264-¬3.312 Ma);Secondly, in the framework of the internationalPliocene Model Intercomparison Project(PLIOMIP2), we study the climate of Mid-Piacenzian Warm Period (MPWP, 3.3-3.0Ma).Thirdly, we explore the Plio-PleistoceneTransition (PPT, 3.0-2.5Ma) with anappropriate asynchronously coupled climatecryosphere model. Through these differentperiods, we provide a better understanding ofthe relationship between pCO2, tectonics andclimat during the transition from a warm andhigh-CO2 world to the cold and low-CO2Quaternary glaciations. This work also pointsout the necessity to further study the linkbetween ocean dynamics, carbon cycle andclimate.

Basische Benzilsäureester stellen mit ihrer ausgeprägten anticholinergen Wirksamkeit potenzielle Arzneistoffe zur Behandlung der Harninkontinenz, der Ulkuserkrankung und des Morbus Parkinson dar. Von besonderem Interesse sind Benzilsäurevertreter, die neben anticholinergen auch dopaminerge Effekte aufweisen. Wegen ihrer dualistischen Wirkung könnten sie eine neue Klasse von Antiparkinsonica begründen. Aufgrund der vielfältigen Funktionen von Muscarinrezeptoren treten bei wenig selektiv wirksamen Arzneistoffen atropinartige Nebenwirkungen auf. Mit der Entwicklung von Verbindungen, die eine erhöhte muscarinerge Subtypenselektivität besitzen, lassen sich Nebenwirkungen reduzieren. Ziel der Arbeit war eine Wirkungsoptimierung chiraler N-Methyl-4-piperidyl benzilate durch Variation von stereochemischen Parametern und Einführen elektronisch verschiedenartiger Substituenten in die aromatischen Ringe. In Radioligand-Bindungsstudien an M1- bis M3-Rezeptoren wurden die Auswirkungen der sterischen und strukturellen Variationen untersucht. Die Ergebnisse der Bindungsstudien zeigen, dass sich Affinität und Subtypenselektivität durch die absolute Konfiguration des stereogenen Zentrums und die Art der Kernsubstitution modifizieren lassen. Mit Hilfe von Molecular Modelling ist es gelungen, auf Basis der experimentellen Bindungsdaten ein aussagekräftiges Rezeptormodell für N-Methyl-4-piperidyl benzilate zu entwickeln. Sowohl die Affinitätsunterschiede enantiomerer Benzilate als auch die Unterschiede der Rezeptorsubtypenselektivität werden durch das Rezeptormodell umfassend erklärt. / Basic substituted benzilic esters with distinctive anticholinergic effects are potential drugs for the treatment of urinary incontinence, duodenal and gastric ulcers and Parkinson disease. Derivatives of benzilic esters, exhibiting a combination of anticholinergic and dopaminergic effects, are of special interest because, as a consequence of their dualistic effect, they are in a position to form a new class of Antiparkinson drugs. As muscarinic receptor subtypes possess a large variety of functional properties, drugs which show less selectivity on muscarinic receptors exhibit atropine-like side effects. A reduction of these side effects may be achieved by the development of more selective anticholinergic compounds. The objective was to optimise the effect of N-Methyl-4-piperidyl benzilates through a variation of sterical parameters and the introduction of electronically differentiated substituents within the aromatic rings. The effect of sterical and structural variations was investigated in radioligand binding studies on muscarinic receptors (M1 – M3). The results of these binding studies reveal that a modification of affinity and selectivity can be achieved by varying the absolute configuration of the stereogenic center and the properties of the substitution of the aromatic system. The development of a relevant model of the receptor ligand complex for N-Methyl-4-piperidyl benzilates was achieved by molecular modelling on the basis of experimental binding studies. Both the diverse affinity of enantiomeric benzilic esters and the subtype selectivity on muscarinic receptors are comprehensively explained by this model.

Global paleogeography exerts a first order control on both the deep and surficial components of the Earth system. Temporal and spatial constraints on the Mozambique Belt of Eastern Africa are needed to understand its crustal evolution and its role in assembly of Gondwana. This thesis provides detailed data on the timing, sources and nature of tectono-thermal events responsible for magmatism in the Mozambique Belt in southern Malawi. An integrated approach of petrography, geochemistry, radiogenic isotopes, and single zircon geochronology has been used to determine spatial and temporal constraints and to better constrain models of the assembly of East and West Gondwana, which occurred along the Mozambique Belt. In particular the thesis attempts to address key unresolved questions about the number and timing of accretionary pulses within the orogen. LA-ICP-MS single zircon U-Pb results show tectono-thermal events in four periods: Mesoproterozoic from 1128 ± 30 Ma to 1033 ± 20 Ma; Neoproterozoic (956 ± 12 Ma – 594 ± 65 Ma); Cambrian (530 ± 3 Ma – 515 ± 12 Ma); and Cretaceous (118 ± 2 Ma). Metamorphism is dated from a charnockitic gneiss that yielded a lower intercept age of 515 ± 18 Ma. The granitoids are intermediate to acidic with relative enrichment in LILEs and depletion in HFSEs with moderately negative anomalies in Th, Nb, P, Zr and Ti. REE spider plots show enrichment in LREEs and depleted HREEs with negative Eu anomalies. The meta-granites are largely metaluminous with a few peraluminous, I-type granites belonging to the calc-alkaline series. Radiogenic isotope data reveals slight differences with older, Mesoproterozoic rocks showing positive ɛNd and ɛHf values signifying derivation from depleted mantle material, whilst the younger rocks display negative epsilon values suggestive of crustal material recycling and mixing for their source and origins. Granitoids of southern Malawi display characteristics consistent with derivation in a continental Andean type arc with some aspects of the chemistry resembling tonalite-trondhjemite-granite (TTG) suites mapped in the Mozambique Belt in Kenya, Tanzania, Mozambique, and Antarctica although the data are not sufficiently compelling to assign the Malawi rocks to classic TTGs.

Generally, service industries require a rapid innovation of service portfolios to gain and maintain a competitive advantage. In this context, service elimination is a tool of portfolio renewal, where customer retention is a strategic priority for companies. This is especially so because service elimination usually causes higher churn rates than an average churn in telecommunications. Thus, customer retention is seen as a major aspect in enhancing service elimination success. The purpose of this paper is to investigate the factors that increase customer churn in the case of service elimination. We use one of the three Hungarian telecommunication Operator's databases containing usage data three months before and after Service elimination in the course of a major service package reform. Contract-related information and demographics of 10 065 customers are used to differentiate between high and low churn factors, taking care of a possible sample selection problem. The results show that in the course of service elimination there is a significant positive relationship between price decrease, tenure, interaction intensity on the one, and customer retention on the other side. Besides these, demographics (age and residence) also play an important role in explaining churn rates during service elimination. Furthermore, we find that a higher monthly fee after elimination increases the customer´s usage intensity. This research aims to contribute both to service elimination, as well as to customer retention literature, by hierarchical modeling of retention and usage during service elimination with practical implications for decision-makers in rapidly innovating telecommunication markets. / Series: Department of Economics Working Paper Series

High mass loss rates in evolved stars make them the major contributors to recycling processed material back into the interstellar medium. This mass loss creates large circumstellar shells, rich in molecular material. This dissertation presents millimeter and submillimeter studies of the end stages of low mass and high mass stars in order to probe their molecular content in more detail. In low mass stars, the molecular material is carried on into the planetary nebula (PN) stage. Observations of CS, HCO⁺, and CO in planetary nebulae (PNe) of various post-asymptotic giant branch ages have shown that molecular abundances in these objects do not significantly vary with age, as previously thought. More detailed observations of the slightly oxygen-rich PN NGC 6537 resulted in the detection of CN, HCN, HNC, CCH, CS, SO, H₂CO, HCO⁺ and N₂H⁺, as well as numerous ¹³C isotopologues. Observations of the middle-aged PN M2-48 showed the presence of CN, HCN, HNC, CS, SO, SO₂, SiO, HCO⁺, N₂H⁺, and several ¹³C isotopologues. These observations represent the first detections of CS, SO, SO₂, and SiO in any planetary nebula. The implications of these observations are discussed. A 1 mm spectral survey of the supergiant star NML Cygni has been carried out with the Arizona Radio Observatory Submillimeter Telescope resulting in the observation of 102 emission features arising from 17 different molecules and 4 unidentified features. The line profiles observed in this circumstellar shell are asymmetric and vary between different molecules, akin to what has been seen in another supergiant, VY Canis Majoris. The non-LTE radiative transfer code ESCAPADE has been used to model molecular abundances in the various asymmetric outflows of VY Canis Majoris, showing just how chemically and kinematically complex these supergiant circumstellar envelopes really are.

During our lifetime, our bones constantly go through remodelling to maintain the skeletal system. This is done by osteoblasts that deposit new bone tissue, osteoclasts that remove the bone matrix and mechanosensing osteocytes. In case of bone implants, increased resorption by osteoclasts due to inflammation (inflammatory osteolysis) leads to aseptic implant loosening. This study focuses on how to detect these inflammatory resorbing cells at an early stage and prevent their activity with appropriate medication. To achieve this, we differentiated classical monocytes into macrophage-like cells, osteoclasts(OCs) and foreign body giant cells (FBGC) and their secretome was studied to identify specific biomarkers. Previously, tartrate resistant acid phosphatase (TRAP) was studied as an important biomarker for OCs and macrophages. An ELISA to separate and quantitate the two TRAP isoforms was used to distinguish the resorbing OCs from inflammatory FBGCs on the basis of the isoform ratio. This assay gave high levels of 5b isoform for osteoclastic stimulation and high 5a levels for the inflammatory stimulation. Also, different aminothiazole inhibitors were tested which were shown to be efficient drugs in inhibiting inflammatory osteolysis by reducing osteoclast formation and resorption in sub-micromolar concentration. Further to apply this study to patient samples, an immunoassay panel can be developed which will help detect TRAP and multiple biomarkers like CTX specific to aseptic loosening simultaneously. This will help in early, efficient and accurate diagnosis of inflammatory osteolytic bone loss and provide us with an accurate diagnosis and sufficient time for appropriate treatment.