Baseado na questão que surge a partir do fato de que numa mesma indústria, com condições similares de mercado, algumas empresas se apresentam como bem-sucedidas e outras não, este trabalho teve como objetivo somar algumas idéias a esta discussão que preocupa tanto acadêmicos quanto líderes do setor privado e público. Tendo como base a conhecida teoria da Visão da Firma Baseada em Recursos, este trabalho fixou como objetivo indagar sobre a função diferencial cumprida pelos recursos no desempenho competitivo internacional de empresas do Vale do Rio Negro argentino dedicadas à produção e exportação de vinhos finos. Para isso, foi revisada uma vasta literatura sobre o tema, percorrendo cronologicamente seus antecedentes a partir dos quais foi desenhado um modelo de aplicação para conduzir a operacionalização do estudo. Foram selecionadas cinco empresas da região com características bem diferentes entre si. Utilizando a análise de casos, foram realizadas entrevistas semi-estruturadas e aplicado um questionário para obter informações sobre a valorização dos recursos tangíveis e intangíveis por parte de cada uma das empresas. Sobre cada recurso selecionado da lista oferecida, foram solicitadas explicações acerca da importância e características de valor, raridade, inimitabilidade e insubstituibilidade. Os resultados obtidos e sua interpretação permitiram dividir as empresas selecionadas em dois tipos: alto e baixo desempenho competitivo internacional. Depois disso, foram comparados os recursos escolhidos em cada grupo. Pôde ser observado que as empresas de alto desempenho valorizaram mais aqueles recursos relacionados com aspectos comerciais e de mercado e as de baixo desempenho os recursos que intervêm em aspectos de tecnologia de produção e de acesso a capital e insumos. Ambos os grupos valorizaram a importância da localização geográfica e a dotação de Recursos Naturais, de fundamental importância para a produção e elaboração de vinhos. Por último, foram citadas as contribuições teóricas e práticas do trabalho, suas limitações, além de algumas questões que foram levantadas, as quais podem ser tratadas em estudos posteriores. / In response to the question as to why within the same industry and under similar market conditions some companies are successful and others are not, this paper seeks to provide some insight into the discussion of an issue that has long puzzled both academics and leaders of the private and public sector. Within the theoretical framework of the well-known resource-based view of the firm (VBR), this paper aims to probe the differential role that resources played in the international competitiveness shown by fine wine-producing and exporting firms in the Argentine Valley of Río Negro. To this end, we reviewed the vast literature on the subject in chronological order to design an application model for the operationalization of the study. Five quite distinct companies were selected from within the region. Using the case study analysis, we conducted semi-structured interviews and applied a questionnaire to collect data on the valuation of tangible and intangible resources by each of the companies under study. Each of the selected resources on the list provided was in turn broken down into the importance and characteristics of its value, rareness, inimitability, and non-substitutability. From the results and their interpretation it was possible to divide the selected companies into two groups in terms of their international competitiveness: high- and low-performing firms. Next, the resources chosen in each group were compared. It was found that the high-performing group attaches more value to business and market-related aspects while the low-performing group favors production technology, and capital and input access. Both groups accorded importance to geographical location and natural resource endowments, key factors in wine making and production. Finally, we cite the theoretical and practical contributions of the paper as well as its limitations. Some issues to be addressed in further studies are also presented.

Made available in DSpace on 2014-07-29T14:52:07Z (GMT). No. of bitstreams: 1 Tese Sara Lane Sousa Goncalves.pdf: 2446569 bytes, checksum: be2de6fce1dea2702fdaaeffdde00096 (MD5) Previous issue date: 2007-07-30 / The importance of maize and their quality is unquestionable, due to its diversification of use. The Green maize is considered a special type of corn, as sweet corn, popcorn, maize, waxy maize white corn, baby corn, etc., and as such, is not included in systematic surveys of agricultural crops of the Brazilian Institute of geography and statistics. In this sense porpose in this work, characterize some productive aspects of pamonharias of the metropolitan area of the city of Goiânia and identify, according to these aspects, characteristics phytotecnic and desirable technology for green maize producing pamonhas. Due to specificity of stewardship, green maize is ranked as one of the types of special maize, and to work with special types of maize, the producer must have a secure channel connection with buyers and market access. This conduit is performed largely by the distributors. The Green maize market for producing pamonhas requires rigorous qualitative assessments, which imposes a greater control of the quality of its products. According to these requirements, some commercial companies and producers are seeking to develop plant varieties, besides that they permit the achievement of high productivity of spikes, agronomic and technological characteristics have favorable, whereas microbiological aspects, physiological, throughout the product. The State of Goiás is nationally known for pamonhas and existing in their pamonharias cities. In Goiania, concentrates a large number of pamonharias, in which the goianiense is not limited to the traditional pamonha, offering its customers a wide variety of delicacies of corn. The pamonha, which in its formulation uses the mass obtained from green maize added to other products, is cooked in own corn straw and served for consumption, and fried, or baked after being baked. The State of Goiás is nationally known for pamonhas and existing in their pamonharias cities. In Goiania, concentrates a large number of pamonharias, in which the goianiense is not limited to the traditional pamonha, offering its customers a wide variety of delicacies of maize. However, the cultivation of green maize, whereas their by-products in particular pamonha, could provide the farmer profitability since the entire production chain is the most well studied quantitatively and qualitatively. Such studies may provide the producer with access to a differentiated market and expanding, offering consumers a healthy food the right price, approaching the farmer to the consumer. / The importance of maize and their quality is unquestionable, due to its diversification of use. The Green maize is considered a special type of corn, as sweet corn, popcorn, maize, waxy maize white corn, baby corn, etc., and as such, is not included in systematic surveys of agricultural crops of the Brazilian Institute of geography and statistics. In this sense porpose in this work, characterize some productive aspects of pamonharias of the metropolitan area of the city of Goiânia and identify, according to these aspects, characteristics phytotecnic and desirable technology for green maize producing pamonhas. Due to specificity of stewardship, green maize is ranked as one of the types of special maize, and to work with special types of maize, the producer must have a secure channel connection with buyers and market access. This conduit is performed largely by the distributors. The Green maize market for producing pamonhas requires rigorous qualitative assessments, which imposes a greater control of the quality of its products. According to these requirements, some commercial companies and producers are seeking to develop plant varieties, besides that they permit the achievement of high productivity of spikes, agronomic and technological characteristics have favorable, whereas microbiological aspects, physiological, throughout the product. The State of Goiás is nationally known for pamonhas and existing in their pamonharias cities. In Goiania, concentrates a large number of pamonharias, in which the goianiense is not limited to the traditional pamonha, offering its customers a wide variety of delicacies of corn. The pamonha, which in its formulation uses the mass obtained from green maize added to other products, is cooked in own corn straw and served for consumption, and fried, or baked after being baked. The State of Goiás is nationally known for pamonhas and existing in their pamonharias cities. In Goiania, concentrates a large number of pamonharias, in which the goianiense is not limited to the traditional pamonha, offering its customers a wide variety of delicacies of maize. However, the cultivation of green maize, whereas their by-products in particular pamonha, could provide the farmer profitability since the entire production chain is the most well studied quantitatively and qualitatively. Such studies may provide the producer with access to a differentiated market and expanding, offering consumers a healthy food the right price, approaching the farmer to the consumer.

A primeira etapa do Parque EcolÃgico do Cocà e as Ãreas relativas ao seu entorno localizados na porÃÃo sudeste de Fortaleza sÃo dotadas de caracterÃsticas naturais na paisagem, mesmo apÃs terem sofrido intensa urbanizaÃÃo a partir da segunda metade do sÃculo XX. A urbanizaÃÃo transformou um espaÃo caracterizado inicialmente por diversas restriÃÃes à ocupaÃÃo, devido aos obstÃculos naturais presentes, em um dos mais (des)valorizados na cidade. Essa Ãrea foi produzida ao longo desse perÃodo por diversos agentes modeladores do espaÃo, em especial o poder pÃblico no tocante à implementaÃÃo de uma infra-estrutura urbana bÃsica. As aÃÃes beneficiaram diversos segmentos da sociedade, em especial a elite e o segmento empresarial, o que contribuiu para a formaÃÃo de diferentes formas espaciais e diversas formas de agressÃo à natureza. O produto da relaÃÃo da sociedade com a natureza foi a produÃÃo de um espaÃo geogrÃfico singular e Ãnico nos limites territoriais da metrÃpole, uma vez que reÃne de forma compactada problemas de ordem socioeconÃmica e ambiental de grande monta. Tal caracterÃstica o torna ainda um espaÃo cheio de contrastes e contradiÃÃes, diante da variedade e complexidade das diversas formas de uso e ocupaÃÃo do solo, sejam elas para fins de moradia, comÃrcio, serviÃos e lazer. Ao analisar esse espaÃo à possÃvel verificar grupos minoritÃrios, representados por uma elite econÃmica e/ou polÃtica, com facilidade de acesso entre elas. Esse grupo tem nesse espaÃo, Ãvidos interesses de lucro em detrimento do restante da populaÃÃo do entorno. A sociedade, em meio a essa disputa de classes, à a que mais perde devido à reduÃÃo, quanto-qualitativa de seus recursos ambientais. / The first stage of the Ecological Park of the Cocà and located the relative areas to its roundness in the Southeastern portion of Fortaleza are endowed with natural characteristics in the landscape, exactly after to have suffered intense urbanization from the second half from century XX. The urbanization transformed a space characterized initially for diverse restrictions to the occupation, which had to the natural obstacles gifts, in one of more depreciated in the city. This area was produced to long of the this period for diverse agents modellers of the space, in special the public power in the moving one to the implementation of basic an urban infrastructure. The actions had benefited to diverse segments da society, in special the elite and the enterprise segment, the one that contributed for the formation of different space forms and diverse forms of aggression the nature. The product of these social relations on the way was capable to produce a singular and only geographic space in the territorial limits of the metropolis, a time that congregates of compact form problems of great economical-social and environmental order of sum. Such characteristic still becomes it a full space of contrasts and contradictions, ahead of the variety and complexity in moving to the diverse forms of use and occupation of the ground, is they stops ends of housing, commerce, services and leisure. When analyzing this space is possible to verify that minority, however with priority groups, represented for the economic elite and/or politics and with easiness of access between them, they have in this space, eager interests of profit in detriment of the remain of the population of roundness. The society, in way to this dispute of classes, is the one that more loses due to reduction, how much-qualitative of its environmental resources.

Produzida por macrófagos e células dendríticas, a IL-27 é uma citocina heterodimérica capaz de induzir células Tr1 produtoras de IL-10 e consequentemente regular linfócitos Th1, Th2 e Th17, dependendo da doença envolvida. Partindo-se do pressuposto de que a infecção causada por Trypanosoma cruzi normalmente induz miocardite refletida pela migração intensa de linfócitos Th1 para o tecido cardíaco, nós analisamos o papel regulador da IL-27 nesta condição inflamatória. Nós inicialmente verificamos que a IL-27 foi prontamente induzida in vitro em células infectadas com T. cruzi. Para gerar miocardite intensa coordenada por linfócitos Th1, nós polarizamos linfócitos T naïves para o padrão Th1 na ausência de moléculas relacionadas ao perfil Th17 (camundongos IL-17R-/-, IL-23-/- e IL-6-/-). Como esperado, a inflamação cardíaca intensa e o dano tecidual foram observados na ausência das moléculas do padrão Th17, o que contribuiu para a morte prematura dos animais IL-17R-/-, IL-23-/- e IL-6-/-, precisa e notoriamente pela indução da migração excessiva de linfócitos Th1 para o tecido cardíaco via CXCL-9 e CXCL-10. Para explorar os mecanismos pelos quais a IL-27 controla a miocardite induzida pelo T. cruzi, nós encontramos um recrutamento substancial de macrófagos produtores de IL-27 para o tecido cardíaco, o qual foi mediado pelas quimiocinas CCL3 e CCL4 na ausência de moléculas do padrão Th17. Para determinar quais os receptores necessários para a produção de IL-27, nós observamos que macrófagos derivados da medula óssea de camundongos deficientes de TLR4-/-, TLR9-/- e NLRP3-/- aboliram completamente a produção desta citocina após a infecção in vitro com T. cruzi, enquanto o receptor TLR2 foi dispensável. Nós também verificamos que macrófagos produtores de IL-27 suprimiram linfócitos Th1 através da indução de células Tr1 produtoras de IL-10 após a infecção com T. cruzi. Em seguida, nós avaliamos se a IL-27 foi correlacionada com a proteção cardíaca durante a doença de Chagas. Nós observamos níveis séricos elevados de IL-27 tanto em pacientes com a forma clínica indeterminada ou cardíaca leve, enquanto pacientes com cardiomiopatia moderada ou grave produziram níveis reduzidos de IL-27. Neste estudo, nós descrevemos um novo mecanismo regulador desempenhado por macrófagos produtores de IL-27 no controle da miocardite induzida por T. cruzi. Macrófagos produtores de IL-27 podem suprimir processos inflamatórios desencadeados por linfócitos Th1, os principais vilões na doença de Chagas. / IL-27 is a heterodimeric cytokine produced by macrophages and dendritic cells known to induce IL-10-producing Tr1 cells and to regulate Th1, Th2, and Th17 lymphocytes, depending on the underlying disease. Because the infection caused by Trypanosoma cruzi normally induces myocarditis mirrored by an outstanding migration of Th1 cells to the heart tissue, we analyzed the regulatory role of IL-27 in this inflammatory condition. We firstly verified that IL-27 was promptly induced by in vitro T. cruzi-infected spleen cells. To generate a robust myocarditis coordinated by Th1 lymphocytes, we polarized lymphocytes to a Th1 pattern by infecting mice in the absence of Th17-related molecules (IL-17R-/-, IL-23-/-, and IL-6-/- mice). As expected, an impressive cardiac inflammation and damage was observed in the absence of Th17-related molecules, leading IL-17R-/-, IL-23-/-, and IL-6-/- mice to the premature death, precisely and notably by inducing an exuberant Th1 migration to the heart tissue via CXCL9 and CXCL10 chemokines. To explore the mechanisms by which IL-27 controls T. cruzi-induced myocarditis, we found a striking recruitment of IL-27-producing macrophages to the heart tissue mediated by increased levels of CCL3 and CCL4 chemokines in the absence of Th17-associated molecules. To gain further insights into the receptors required to IL-27 production, we observed that bone marrow-derived macrophages from TLR4-/-, TLR9-/-, and NLRP3-/- mice completely abolished IL-27 production after in vitro T. cruzi infection, while TLR2 was dispensable. We also verified that IL-27-producing macrophages supressed Th1 lymphocytes by inducing IL-10-producing Tr1 cells after T. cruzi infection. We next assessed whether IL-27 was correlated to cardiac protection during Chagas Disease. We observed augmented serum levels of IL-27 in either patients with indeterminate (asymptomatic) form or mild cardiac form, whereas patients with moderate or severe cardiomyopathy were poor producers of IL-27. Here, we described a novel regulatory mechanism developed by IL-27-producing macrophages in the control of T. cruzi-induced myocarditis. IL-27-producing macrophages can suppress inflammatory processes caused by Th1 lymphocytes, the bona fide culprits of Chagas Disease.

Esta pesquisa aborda as políticas territoriais implementadas no Distrito Federal com foco na área de expansão urbana de Águas Claras, levando em consideração os diversos fatores que contribuíram e contribuem para a produção deste espaço como tal, sua dinâmica e suas transformações. A produção do espaço no Distrito Federal intermediada pelo Estado proporciona áreas de expansão urbana, que são definidas em diferentes períodos, direcionando o mercado imobiliário para uma área pré-estabelecida, até que esta área fique saturada, deslocando esse mercado para outra área determinada pelo Estado, dando continuidade nesse processo, proporcionando sempre novas áreas para a reprodução do capital. Águas Claras surge como exemplo dessas áreas de expansão urbana no DF, parte integrante deste processo, que são estabelecidas a partir de uma demanda de ordem política e econômica. É importante salientar a propriedade da terra, visto que, as terras onde se encontra Águas Claras anteriormente pertenciam ao Governo do Distrito Federal e foram vendidas aos promotores imobiliários com o discurso de construir um local para habitação da classe média entre duas áreas já urbanizadas. Com isso, ao longo desta pesquisa, percebe-se que Águas Claras se materializa como sendo mais um espaço de realização de reprodução do capital no DF, porém com características peculiares que tornam o enfoque desta pesquisa interessante e diferente das outras análises feitas no Distrito Federal. / This research boards the territorial politics implemented in the Distrito Federal with focus in the urbane expansion of Águas Claras, taking into account several factors that contributed and still contribute to the production of this space such as its dynamic and transformations.The production of the space in the Distrito Federal is intermediated by the State. This intermediation provides areas of urbane expansion, which are defined in different periods, taking the building market for an established area, until this area is saturated, moving this market for another area determined by the State, giving continuity in this process, always providing new areas for the reproduction of the capital. Águas Claras is an example of an area in urbane expansion in the DF. Águas Claras is integrant part of this process, which is established from a demand of political and economical order. It is important point out that the property of the lands where Águas Claras is situeated previously were belonging to the Government of the Distrito Federal and they were sold to the property promoters with the speech of building a place for dwelling of the middle class between two already built-up areas. With that, along this research, it is realized which Águas Claras it materializes like being one more space of realization of reproduction of the capital in the DF, however with special characteristics that make the approach of this research interesting and different from other analyses done in the Federal area.

Orientador: Tomomasa Yano / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-23T11:52:53Z (GMT). No. of bitstreams: 1 Bernedo-Navarro_RobertAlvin_D.pdf: 2646572 bytes, checksum: 02b50bc28d5be6cddb78abfe621a047c (MD5) Previous issue date: 2013 / Resumo: Escherichia coli produtora de toxina de Shiga (STEC) é um grupo de importantes patógenos para humanos. Essas bactérias são relacionadas a várias doenças, como por exemplo, Síndrome Urêmica Hemolítica e produzem potentes toxinas denominadas toxinas de Shiga. Essas toxinas, tanto Stx1 quanto Stx2, compartilham um receptor celular comum, a globotriaosilceramida (Gb3) e exibem a mesma atividade biológica intracelular. O desenvolvimento de novos agentes neutralizantes dos danos induzidos por Stx pode representar uma estratégia promissora para o tratamento das doenças causadas por STEC em humanos. No presente estudo, nós desenvolvemos peptídeos sintéticos que exibem atividade neutralizante contra a citotoxicidade induzida por Stx tanto in vitro quanto in vivo e, além disso, que se ligam eficientemente ao receptor Gb3. O peptídeo P12-26 compete eficientemente com Stx2 para a ligação ao Gb3 in vitro. Além disso, os peptídeos PC7-12, P12-26 e PC7-30 inibiram a citotoxicidade de Stx1 e Stx2 em células Vero. Nós observamos que o peptídeo PC7-30 em forma de loop e o peptídeo P12-26 que é linear produziram as maiores porcentagens de inibição de Stx1 e Stx2 em células Vero, respectivamente. No entanto, o peptídeo P12-26 não inibiu a letalidade em camundongos, enquanto que o peptídeo PC7-30 inibiu a letalidade causada pela toxina Stx1. Nossos resultados indicam que os peptídeos P12-26 e PC7-30 são candidatos promissores para o desenvolvimento de agentes terapêuticos contra as doenças em seres humanos causadas por STEC / Abstract: Shiga toxin-producing Escherichia coli strains are important pathogens for humans. These bacteria are linked with severe diseases such as hemolytic uremic syndrome and produce potent known as Shiga toxins. These toxins, Stx1 and Stx2, share a common cellular receptor called globotriaosylceramide (Gb3) and exhibit the same intracellular biological activity. The development of new neutralizing agents for Stx-induced damage may represent a promising strategy for the treatment of diseases caused by STEC infections. In this study, we developed synthetic peptides that exhibit neutralizing activity against Stxinduced cytotoxicity both in vitro and in vivo and that bind efficiently to the Gb3 receptor. The peptide P12-26 competed efficiently with Stx2 for binding to Gb3 in vitro. Moreover, the peptides PC7-12, P12-26 and PC7-30 inhibited the cytotoxicity of Stx1 and Stx2 in Vero cells. We observed that the loop-constrained peptide PC7-30 and linear peptide P12-26 produced higher percentages of inhibition of Stx1 and Stx2 in Vero cells, respectively. However, the peptide P12-26 did not inhibit lethality in mice, whereas the loopconstrained peptide PC7-30 inhibited the lethality caused by Stx1. Our results indicate that the peptides P12-26 and PC7-30 are promising candidates for the development of therapeutic agents against diseases caused by STEC in humans / Doutorado / Bioquimica / Doutor em Biologia Funcional e Molecular

L’hyperaldostéronisme primaire [HAP] résulte d’une hypersécrétion d’aldostérone d’origine surrénale. La compréhension de la pathogénie de cette maladie, dont la prévalence est estimée à 10% de la population hypertendue, est essentielle pour le développement de nouveaux outils diagnostiques et thérapeutiques. Dans ce contexte, ce travail de doctorat avait pour but d’identifier de nouvelles orientations thérapeutiques en testant un inhibiteur de l’aldostérone synthase et de rechercher de nouveaux marqueurs diagnostiques par l’étude du profil d’expression des microARN [miRs]. Dans une étude de phase II, 14 patients présentant un HAP ont reçu un inhibiteur de l’aldostérone synthase : le LCI699 pendant 4 semaines. Nous avons ainsi pu montrer que le LCI699 permet de diminuer les concentrations d’aldostérone de 70 à 80% et de normaliser la kaliémie chez tous les patients. En revanche, il n’a qu’un effet modéré sur la pression artérielle et sur l’élévation des concentrations de rénine, et n’est que partiellement sélectif pour l’aldostérone synthase. De plus son efficacité est moindre que celle de l’éplérénone, antagoniste minéralocorticoide administré aux mêmes patients au décours du LCI699. Nous avons ensuite étudié l’expression de 754 miRs dans des adénomes produisant de l’aldostérone [APA] et dans des surrénales contrôles. L’hypothèse était qu’une dérégulation de leur expression pouvait être impliquée dans la tumorigénèse et la surproduction d’aldostérone. L’objectif secondaire était d’identifier des miRs utilisables en tant que biomarqueurs. Cette analyse par carte microfluidique a révélé que 27 miRs sont significativement sous exprimés dans les APA et un seul miR est surexprimé. L’expression différentielle de deux de ces miRs : miR 137 et miR 375 a pu être confirmée dans une cohorte de validation de 36 APA: Des résultats préliminaires in vitro indiquent que le miR 375 pourrait induire une diminution de la synthèse d’aldostérone. Enfin, l’analyse de l’expression de ces miRs dans le plasma a permis de mettre en évidence une sous-expression du miR 375 chez les patients atteints d’HAP en comparaison à des sujets sains. En conclusion, le blocage de la biosynthèse de l’aldostérone représente une nouvelle option thérapeutiques, cependant il est nécessaire de développer une seconde génération de molécules : plus puissantes et plus sélectives. Les analyses effectuées sur les APA ouvrent de nouvelles perspectives pour l’identification de nouveaux biomarqueurs tels que les miRs circulants / Primary aldosteronism [PA] results from the hypersecretion of aldosterone by the adrenals. Understanding the pathogenesis of the disease is essential for identifying new diagnostic and therapeutic tools. In this context the purpose of my PHD was to investigate the effects of an aldosterone synthase inhibitor and second to investigate new diagnostic options by the extensive study of microRNA [miRNA]. In a phase II clinical study, 14 patients with PA were administered an aldosterone synthase inhibitor: LCI699. Four weeks of treatment lead to a 70 to 80% decrease in aldosterone concentration, associated with the cure of hypokalemia. However, there was only a mild effect on blood pressure and volemia (reflected by renin concentration). In addition, these results demonstrated an incomplete selectivity of LCI699 for aldosterone synthase in vivo, and showed that LCI699 is less potent than the blocker of the mineralocorticoid receptor: eplerenone . We also characterized the miRNA profile of Aldosterone producing adenomas [APA]. The hypothesis was that a dysregulation of the expression of miRNA could induce tumorigenesis and increase the production of aldosterone. The secondary aim of the study was to identify miRNA that could be measured in plasma as biomarkers. miRNA profiling of 754 miRNA using quantitative PCR Low Density array, revealed 28 miRNA whose expression was significantly different in APA. The differential expression of two miRNA: miRNA 137 and miRNA 375 was confirmed in a validation cohort of 36 APA. Preliminary in vitro studies showed that up-regulation of intracellular levels of miR 375 may reduce aldosterone secretion in H295R cells. Lastly, circulating plasma levels of miR 375 are differentially expressed between patients with PA and healthy volunteers. In conclusion, the blocking of the aldosterone pathway in hypertensive patients is a novel therapeutic option but second-generation drugs more potent and more selective of aldosterone synthase are required. Profiling miRNA in APA offers new prospect for the development of biomarkers, such as measuring circulating miRNA in plasma

Unilateral cortisol producing adenoma (CPA) is the most common cause of ACTH-independent Cushing’s syndrome and is surgically curable. On the other hand, adrenocortical carcinomas (ACCs) are rare and aggressive tumours. Although the overall survival of the patients with ACC is very poor, the outcome can be heterogeneous and vary significantly between the patients. This thesis comprises studies showing genetic and genomic events occurring in CPAs and ACCs, their functional impact and clinical correlations. The Wnt/β-catenin and cAMP/PKA signalling pathways are crucial in adrenal homeostasis and frequent mutations in members of these pathways (CTNNB1, GNAS, and PRKACA) are found in CPAs. Mutational analysis revealed that ~60% of the CPAs harboured mutations in either of these genes. Transcriptome signature exhibited increased expression of genes involved in steroidogenesis in PRKACA/GNAS mutated (Cluster1) tumours in comparison to CTNNB1 mutated /wildtype (Cluster2) tumours. In addition we have also observed that gain of chromosome arm 9q was the most frequent arm level copy number variation (CNV) occurring in CPAs and were exclusively present in Cluster2 tumours. We also discovered novel PRKACA mutations occurring in ACCs, causing activation of cAMP/signalling pathway.    Comprehensive analysis of Wnt/β-catenin signalling pathway in ACCs revealed novel interstitial deletions occurring in CTNNB1 leading to deletion of the N-terminus of β-catenin. This is a novel and yet another frequent event leading to activated Wnt/β-catenin signalling and downstream targets in ACCs. Both, mutations occurring in CTNNB1 and nuclear expression of its protein were associated with poor overall survival. Through multiregional sampling approach we discovered intra-tumour heterogeneity in ACC tumours. Although all the multiregions within a tumour showed presence of shared basal CNVs, they encompassed private CNVs, different ploidy levels and private mutations in known driver genes. We found intra-tumour heterogeneity in CTNNB1, PRKACA, TERT promoter and TP53 mutations as well as ZNRF3 and CDKN2A/2B homozygous deletions.

Introduction: Service companies and its offerings on the market are becoming increasingly standardized, which makes it difficult for service providers to distinguish themselves from the amount. In many cases this leads to a price squeeze. Many service companies do not understand the importance of building a relationship with their customer, and how to maintain long-term partnerships to increase customer value. Purpose: The purpose of the study is to investigate what aspects service-producing companies should take into account in order to achieve a high customer value and thus become more attractive in the market. Methods: In order to respond to the purpose of the study, a case study was conducted, where the approach consisted of both qualitative and quantitative data collection to test the existing theoretical reference frames and to generalize the study. The quantitative data collection consisted of a survey sent to the company's customer base, which consisted of different industries and sizes of companies, where the answers were then weighted in a model. The survey was also sent to the case company to find possible differences between their own opinion and the customers. The qualitative consisted of three deep interviews with leading actors in different industries to gain a deeper understanding. Results: The quantitative survey showed that quality is the most valued aspect with a supplier, followed by the price. The remaining questions showed that the customers and the case company shared a relatively even view of previous collaborations. The qualitative survey showed that all three respondents appreciated the same aspects of a service company; competence, customer focus and availability. They also agreed that the reputation of the relationship and service providers is valued very high. The relationship has been shown to be linked to several aspects such as flexibility, risk minimization and the quality of the work process. Customers have a greater tendency to choose service companies that are committed to trying to integrate long-term cooperation, which makes the customers feel priority and choose to place greater responsibility on the service company. Conclusion: Companies should not focus on trying to find added value to their customers, the focus should be on creating and developing a deep and committed relationship with their customers. The advantages of this are illustrated by further development of the model presented in the theoretical reference framework, in which important aspects to be considered are described. / Introduktion: Tjänsteföretag och dess erbjudanden på marknaden håller på att standardiseras alltmer vilket leder till att det blir svårt för tjänsteföretag att särskilja sig från mängden. Detta leder i många fall till en prispressning. Många tjänsteföretag förstår inte vikten av relationsbyggandet och hur de ska upprätthålla långsiktiga samarbeten för att även öka kundvärdet. Syftet: Syftet med studien är att undersöka vilka aspekter tjänsteproducerande företag ska beakta för att uppnå ett högt kundvärde och därmed bli mer attraktiva på marknaden. Metod: För att kunna svara på studiens syfte utgicks det ifrån en fallstudie, där angreppssättet bestod av både kvalitativ och kvantitativ datainsamling för att testa den befintliga teoretiska referensramen och kunna generalisera arbetet. Kvantitativa datainsamlingen bestod av en enkätundersökning som skickades ut till fallföretagets kundbas som bestod av olika branscher och storlekar på företag, där svaren sedan viktades i en modell. Enkäten skickades även ut till fallföretaget för att hitta eventuella differenser mellan deras egen uppfattning och kundernas. Den kvalitativa bestod av tre djupintervjuer med ledande aktörer inom olika branscher för att få en djupare förståelse. Resultat: Den kvantitativa undersökningen visade att kvalitet är det som värderas mest hos en leverantör, följt av priset. De resterande frågorna visade att kunderna och fallföretaget delade en relativt jämn uppfattning om tidigare samarbeten. Den kvalitativa undersökningen visade att alla tre respondenter värderade samma aspekter hos ett tjänsteföretag; kompetens, kundfokusering och tillgänglighet. De var även eniga om att relationen och tjänsteleverantörers rykte värderas väldigt högt. Relationen har visat sig vara kopplad till flera aspekter såsom flexibilitet, riskminimering och kvaliteten av arbetsprocessen. Kunder har en större tendens att välja tjänsteföretag som lagt vikt vid att försöka integrera ett långsiktigt samarbete, vilket gör att kunderna känner sig prioriterade och väljer att lägga större ansvar på tjänsteföretaget. Slutsats: Företag ska inte lägga sitt fokus på att försöka finna mervärden till sina kunder, utan fokusen ska ligga på att skapa och utveckla en djup och engagerad relation med sin kund. Fördelarna med detta illustreras med hjälp av en vidareutveckling av den modell som tas fram i den teoretiska referensramen, där viktiga aspekter som bör beaktas beskrivs.

The fairs are representations of the oldest forms of commercialization of products, conforming a place with particularities and spatialities, replete of colors, sounds, smells, movements and sociocultural links. The geography of the fairs in the Northeast region is permeated by peculiarities, being possible to find in its territory products of diverse origins. Their periocity is associated with their organization from each place it usually happens on alternate days in the surrounding space. The residents of more distant communities move to commercialize the fruit of their production as well as buy products they need for they survival. In this work we took as spacial indention the city of Lagarto/SE which is located in the south-central region of the state, in order to understand the social, cultural and economic dynamics of the fairs held at Lagarto/SE. In this city we observed that the fair happens on Sundays, Mondays, Thursdays and Saturdays and it is rooted in population identity who demand agricultural products, traditional food, meat, clothing, footwear, live animals and industrialized products, in addition to assets of miscellaneous consumption. The used methodology is of qualitative feature and it is based on review of literature and research in loco - which we perform semi-structured interview with marketers and consumers, using the field diary as an auxiliar tool for the researcher to perform later the analysis to obtain information for the organization of the dissertation. The configuration of the market space of the fair is inserted in the market of the informal sector, and its relations are based, mainly, on the use of the liquid money, indispensable for the social and economic reproduction of the inserted family groups. In addition to commercial space, the fairs are a place of encounter, exchange, a territory marked by a mixture of colors, sounds, smells, tastes, signs and meanings, and the diversity of actions, functions and activities. It is common to see in the network of actors in question the relations of power, especially from the municipal inspectors and guards who exert it in the sense of delimiting the microterritories of the marketers, and sometimes they get involved in conflicts solved in the place. However, in contrast to this characteristic, we have demonstrated the constitution and strengthening of relations of sociability and proximity between the groups of marketers, as well as between marketers and consumers, relations permeated by trust, so that in the act of " make the fair ", bonds of friendship are becoming established. The day of the fair is not only an eminently economic meeting, but a differentiated day in which experiences, knowledge and actions are shared and social networks are strengthened. / As feiras são representações das formas mais antigas de comercialização de produtos, conformando um local com particularidades e espacialidades, repleto de cores, sons, cheiros, movimentos e vínculos socioculturais. A geograficidade das feiras na região Nordeste está permeada de peculiaridades, sendo possível encontrar em seu território produtos de diversas origens. Sua periodicidade associa-se à organização de cada localidade, geralmente acontecendo em dias alternados nos espaços circunvizinhos. Os moradores de comunidades mais distantes se deslocam para comercializar o fruto de sua produção, bem como adquirir produtos de que necessitam para a sua sobrevivência. Neste trabalho tomamos como recorte espacial o município de Lagarto/SE, localizado na microrregião Centro-sul do estado, com o objetivo de compreender a dinâmica social, cultural e econômica das feiras realizadas na cidade de Lagarto/SE. Nesse município observamos que a feira acontece aos domingos, segunda-feira, quinta-feira e sábado e encontra-se enraizada na identidade da população que demanda produtos agrícolas, alimentos tradicionais, carnes, vestimentas, calçados, animais vivos e produtos industrializados, além de bens de consumo diversos. A metodologia utilizada é de caráter qualitativo e baseia-se em revisão da literatura e pesquisas in loco – com as quais realizamos entrevistas semiestruturadas com os feirantes e consumidores, utilizando o diário de campo como ferramenta de auxílio ao pesquisador para posteriormente realizar as análises das informações obtidas para a organização da dissertação. A configuração do espaço de comercialização da feira está inserida no mercado do setor informal, e suas relações estão fundamentadas, principalmente, no uso do dinheiro líquido, indispensável para a reprodução social e econômica dos grupos familiares ali inseridos. Para além de espaço comercial, as feiras conformam um lugar do encontro, da troca, um território marcado pela mistura de cores, sons, cheiros, sabores, saberes, signos e significados, e da diversidade de ações, funções e atividades. É comum constatarmos na rede de atores em questão as relações de poder, sobretudo a partir dos fiscais e guardas municipais que o exercem no sentido de delimitar os microterritórios dos feirantes, e, por vezes, envolvem-se em conflitos resolvidos no local. Porém, em contraposição a essa característica, evidenciamos a constituição e o fortalecimento das relações de sociabilidade e de proximidade entre os grupos de feirantes, bem como entre os feirantes e os consumidores, relações essas permeadas pela confiança, de modo que, no ato de “fazer a feira”, vão se conformando vínculos de amizade. O dia da feira constitui não somente um encontro eminentemente econômico, mas, um dia diferenciado no qual são partilhadas experiências, saberes e fazeres e fortalecidas as redes de sociabilidades. / São Cristóvão, SE