A sepse é a Síndrome da Resposta Inflamatória Sistêmica decorrente de uma infecção por gram positivos/negativos, fungos ou vírus. É caracterizada por alta liberação de mediadores inflamatórios podendo levar à morte. As células B-1 são encontradas em cavidades peritoneal e pleural de camundongos e sua origem e função ainda não são completamente conhecidas. Apresentam marcadores de superfície de linhagem mielóide e linfóide e migram para focos inflamatórios comportando-se como macrófagos. Objetivo: investigar o papel da célula B-1 na resposta inflamatória após estímulo com lipopolissacáride (LPS) in vitro e in vivo. Métodos: TNF-, IL-6, IL-10 (ELISA) e nitrito (Griess) foram dosados em sobrenadante de cultura celular (106 cel./ml). As células em cultura receberam por 24h de estímulo com 10 g/mL de LPS de Escherichia coli (026:B6 Sigma®). Foram realizados os seguintes grupos cultura de célula B-1 (Balb/c), cultura de macrófagos de linhagem (RAW 264.7) coculturas (macrófagos de linhagem RAW 264.7 e células B-1 (Balb/c, C57BL/6 e C57BL/6 IL-10 -/-), e células peritoneais de camundongos Balb/c e Balb/Xid (imunodeficiente em célula B-1) A endotoxemia foi induzida com injeção de LPS 15 mg/kg (i.p.) em camundongos Balb/c e Balb/Xid. Foram quantificados, TNF-, IL-6, IL-10 e nitrito em soro, pulmão e intestino dos animais após 1,5, 4 e 6 horas após a injeção de LPS. Ensaios de inoculação de células B-1 (Balb/c) em camundongos Balb/Xid foram realizados, e curva de sobrevida foi analisada após indução de endotoxemia. Resultados: Após o estímulo com LPS, células B-1 produziram IL-10 e a presença destas células em cocultura com macrófago promoveu a diminuição na produção de TNF-, IL-6, Nitrito e aumento de IL-10. Contudo, célula B-1 (IL-10 -/-) em cocultura com macrófagos, não inibem a produção de mediadores pro inflamatórios. Análise com macrófagos peritoneais de camundongo Balb/Xid e Balb/c após estímulo com LPS em cultura mostrou reprodução do fenômeno encontrado com os experimentos com cultura de célula imortalizada, isto é, maior produção de TNF-, IL-6 e NO em Balb/Xid (B-1 deficiente). Os estudos in vivo mostraram 60% de mortalidade em camundongo Balb/Xid comparando com Balb/c (0%) após 16 horas de injeção de LPS. Nos animais Balb/Xid encontramos padrão pro inflamatório exacerbado com maiores concentrações de TNF-, IL-6 e menores concentrações de IL-10 no plasma e tecidos quando comparamos com Balb/c. Conclusões: Nossos dados mostraram que a presença de células B-1 promoveram diminuição de mediadores pro inflamatórios e aumento de IL-10 em coculturas com macrófagos e que a modulação da resposta inflamatória pode ser devida a secreção de IL-10 pela célula B-1. Este padrão de resposta pro inflamatória se repete in vivo e é a possível causadora da maior taxa de mortalidade em camundongos da linhagem Balb/Xid. / Sepsis syndrome is caused by inappropriate immune activation due to bacteria and bacterial components released during infection. This syndrome is the leading cause of death in intensive care units. Specialized B-lymphocytes located in the peritoneal and pleural cavities are known as B-1 cells. These cells produce IgM and IL-10, both of which are potent regulators of cell-mediated immunity. It has been suggested that B-1 cells modulate the systemic inflammatory response in sepsis. In this study, we conducted in vitro and in vivo experiments in order to investigate a putative role of B-1 cells in a murine model of LPS-induced sepsis. Macrophages and B-1 cells were studied in monocultures and in co-cultures. The B-1 cells produced the anti-inflammatory cytokine IL-10 in response to LPS. In the B-1 cell-macrophage co-cultures, production of proinflammatory mediators (TNF-, IL-6 and nitrite) was lower than in the macrophage monocultures, whereas that of IL-10 was higher in the co-cultures. Co-culture of B-1 IL-10/ cells and macrophages did not reduce the production of the proinflammatory mediators (TNF-, IL-6 and nitrite). After LPS injection, the mortality rate was higher among Balb/Xid mice, which are B-1 cell deficient, than among wild-type mice (65.0% vs. 0.0%). The Balb/Xid mice also presented a proinflammatory profile of TNF-, IL-6 and nitrite, as well as lower levels of IL-10. In the early phase of LPS stimulation, B-1 cells modulate the macrophage inflammatory response, and the main molecular pathway of that modulation is based on IL-10-mediated intracellular signaling.

Introdução: A evolução dos marcadores sorológicos da hepatite B em pacientes com hepatite B crônica coinfectados com o vírus da imunodeficiência humana (HIV) tem sido pouco documentada. Objetivos: O objetivo deste estudo foi descrever a evolução dos marcadores sorológicos AgHBe e AgHBs, com ênfase na avaliação da frequência de perda definitiva ou transitória desses marcadores, neste grupo de pacientes. Buscamos, também, comparar as variáveis clínicas e demográficas desses pacientes segundo a evolução desses marcadores sorológicos. Pacientes e métodos: A população de estudo foi composta por pacientes atendidos em um ambulatório de referência para atendimento a pacientes infectados pelo HIV em São Paulo, Brasil. Todos os pacientes selecionados eram portadores de HIV e de hepatite B crônica. Foram incluídos nesse estudo pacientes AgHBs positivos, com confirmação da presença desse marcador em, no mínimo, duas sorologias consecutivas, com intervalo mínimo de seis meses entre elas. Variáveis clínicas foram coletadas: idade, sexo, fator de exposição ao HIV/VHB, contagem de células T CD4+, carga viral do HIV, níveis de alaninoaminotransferase (ALT), uso de terapia antirretroviral, incluindo lamivudina, tenofovir ou outras drogas com ação anti-VHB. Resultados: Entre 2.242 pacientes HIV positivos encontrados, foram identificados 105 (4,68%) pacientes com hepatite B crônica. O tempo de seguimento variou de 06 meses a 20,5 anos e o número de coletas variou de 2 a 18 por paciente no período. A maioria dos pacientes era do sexo masculino (97%) e 43,9% (46/105) tinha história de uma ou mais infecções oportunistas. Todos os pacientes tiveram terapia antirretroviral iniciada durante o seguimento. Entre os pacientes com hepatite B crônica, 58% (61/105) eram AgHBe positivos na primeira avaliação. Entre eles, 15% (16/105) apresentaram clareamento de AgHBs e 50% (8/16) dos que clarearam AgHBs apresentaram posterior reativação desse marcador durante a evolução clínica. Dentre os pacientes AgHBe positivos na primeira sorologia, 57% (35/61) apresentaram clareamento desse marcador, sendo que 28,5% (10/35) dos que clarearam AgHBe voltaram a apresentar este marcador durante a evolução clínica. Conclusão: Observamos uma significativa taxa de clareamento e posterior reativação dos marcadores AgHBs e AgHBe no grupo de pacientes avaliados. Estes resultados sugerem que o monitoramento frequente desses marcadores sorológicos deveria ser recomendado / Introduction: Evolution of hepatitis B serological markers among HIV co-infected patients has rarely been documented. Objectives: The aim of this study was to describe the evolution of HBsAg and HBeAg serological markers, with emphasis on the frequency of transient or permanent loss of these markers, among this group of patients. It was also our objective to compare patients\' demographic and clinical variables according to the evolution of these serological markers. Patients and methods: The enrolled patients were selected from those registered at a HIV-Outpatient Clinic in Sao Paulo, Brazil. All included patients were diagnosed with HIV infection and chronic hepatitis B. HBsAg patients who underwent at least two repeated HBV serological testing during clinical follow up , with tests taken at least six months apart, were included in the analysis. Clinical information was collected: age, sex, patient history regarding HIV/HBV transmission, CD4 T+ cell count, HIV viral load, alanine amino transferase (ALT) level, and use of antiretroviral drugs including lamivudine, tenofovir or other anti-HBV drugs. Results: Among 2,242 HIV-positive patients 105 (4.68%) patients were identified with chronic hepatitis B. Follow-up time for these patients varied from 06 months to 20.5 years and the number of serological testing for each patient varied from 2 to 18 along this period. Most patients were male (97%) and 43.9% (46/105) had a history of one or more opportunistic infections. All patients had initiated antiretroviral medication during follow-up. Among patients with chronic hepatitis B, 58% (61/105) were HBeAg reagent at the first assessment. Also, fifteen percent of them (16/105) underwent HBsAg clearance and 50% (8/16) of those who initially lost HBsAg underwent HBsAg reactivation during clinical follow up. Among HBeAg positive patients in the first serology, 57% (35/61) lost this marker during clinical follow up, whereas 28.5% (10/35) of those who initially cleared this serological marker underwent HBeAg reactivation. Conclusion: A significant rate of changes of HBsAg and HBeAg was observed, during clinical follow up among this group of patients. These results suggest that periodic monitoring of HBV serological markers should be recommended

A Região Amazônica é considerada área de alta endemicidade para hepatite B. No Estado do Acre e na capital Rio Branco caracteriza-se um quadro em que jovens e adultos jovens, em pleno período reprodutivo e produtivo para o trabalho e para o estudo, constituem população gravemente acometida pela doença. Assim, procurouse neste estudo a compreensão do modo de vida de pessoas portadoras do HBV, de ambos os sexos, entre 15 e 30 anos, para contribuir no enfrentamento da complexidade desse quadro, através de ações de saúde mais condizentes com as necessidades desses sujeitos. Os métodos qualitativos se mostraram mais apropriados, pois possibilitam a compreensão dos acontecimentos e da forma como os sujeitos vivenciam as experiências. Reconheceu-se no cotidiano, históricooriginal- significativo, uma oportunidade de se descobrir novos caminhos de entendimento para a realidade. Buscou-se os participantes a partir do Serviço de Assistência Especializada, valendo-se de instrumentos de pesquisa exclusivos, utilizados para obtenção de informações socioeconômicas e para nortear as entrevistas com os sujeitos. Foram realizadas doze entrevistas, duas das quais com familiares. Os depoimentos prestados, juntamente com as anotações de campo e os apontamentos da observação participante, além das informações colhidas pelos questionários iniciais, constituíram os registros analisados. A análise do material possibilitou as seguintes categorias: descoberta da doença, contemplando as situações que precipitaram o diagnóstico nos casos assintomáticos e sintomáticos, além das principais informações acerca da enfermidade; doença no cotidiano, abrangendo as percepções quanto aos efeitos adversos do tratamento, as restrições procedentes da doença e/ou do tratamento farmacológico e os cuidados profiláticos; modo de vida, apresentando as estratégias de enfrentamento à doença, modalidades através das quais os sujeitos confrontam-se com as implicações da hepatite B, quais sejam, a religiosidade, o apoio espiritual e familiar, e o planejamento para o futuro, além das relações afetivas no cotidiano, e por último, a categoria preconceito e estigma, realidade ainda presente no contexto de doenças infecciosas. Assinalam-se assim, as compreensões do modo de vida, a partir do cotidiano, de pessoas que vivem com o vírus B, para colaborar no maior entendimento de suas necessidades de saúde, podendo subsidiar estratégias de assistência mais equânimes, vislumbrando a atenção integral desses sujeitos / The Amazon region is considered an area of high endemicity for hep B. In the State of Acre, and in the city of Rio Branco, the reality of teens and young adults, on the heights of their reproductive and work/study productive period, constituting a population severely affected by the disease, is characteristic. Therefore, it\'s been aimed in this study, the comprehension of the way of life of the HBV affected people, both sexes, between 15 and 30 years, to contribute on the understanding of the complexity of this situation., through health actions more appropriate to the needs of these individuals. The qualitative methods were shown more suitable, because they allow the understanding of the events and the way those individuals lived their experiences. It\'s been recognized on the routine, \"historical-original-meaningful\", an opportunity of discovering new paths of understanding for reality. The participants were found on the Specialized Assistance Service, by the use of exclusive research tools, handled for obtaining socioeconomic informations and guiding the interviews with the individuals. Eleven interviews were made, two of them with relatives. The testimonies given, along with the field notes and the pointers of the participant observation, as well as the information gathered by the initial questionnaires, constituted the analyzed records. The material analysis permitted the following categories: disease discovery, covering the situations that hastened the diagnosis on the asymptomatic and symptomatic cases, as well as the main information about the disorder; everyday disease, covering the perceptions around the adverse effects of the treatment, the restrictions derived of the disease and/or farmacologic treatment and the prophylactic care; way of life, presenting the strategies of coping the disease, arrangements which the individuals confront with the implications of Hep B, whichever they are, religiosity, familiar and spiritual support, and planning for the future, as well as the affective relations on routine, and at last, the discrimination and stigma, reality still present on the context of infectious diseases. So, the comprehension of the way of life of people who live with the B virus, based on the routine, is pointed out to colaborate on the greater understanding of their health needs, enabling the allowance of fairer assistance strategies, glimpsing the full attention of these individuals

In conclusion, two new methods of cccDNA quantitation were developed and validated. The two assays are complementary to each other and may be used in patients with extreme HBV DNA levels. These cccDNA assays should be further validated in larger studies and may become important tests for diagnostic, prognostic and treatment monitoring purposes. / Over 350 million people worldwide suffer from chronic hepatitis B virus (HBV) infection, which leads to many cases of cirrhosis and hepatocellular carcinoma. HBV covalently closed circular DNA (cccDNA) is a critical intracellular replicative intermediate and cannot be eliminated during antiviral therapy. Current methods for cccDNA detection are limited by false positive detection due to the interference by HBV relaxed circular DNA (rcDNA). The tests also have limited sensitivity to detect cccDNA at low concentrations. Hence, we aimed to develop a highly sensitive and highly specific assay for cccDNA detection with wide linear range. / The modified Bowden's assay had the highest intrahepatic cccDNA detection rate (60 positive results out of 61 cases). The detection rate of the modified Bowden's assay is significantly higher than that of the Bowden's assay. On the other hand, the cccDNA detection rate in serum samples was low at 20--27% by all 3 assays. In 5 samples in which cccDNA was undetectable by the Bowden's assay but detectable by the other two assays, a point mutation in the HBV genome was found in the forward primer binding site of the Bowden's assay. This partly explained the false negative results. / The quantification result of cccDNA by the bisulfite conversion assay was significantly lower than that by the Bowden's assay assay (P=0.001) and the modified Bowden's assay (P=0.003). When the total HBV DNA was higher than 107 copies/ml, the serum cccDNA level detected by the bisulfite conversion assay was significantly lower than that detected by the Bowden's assay (P=0.008) and the modified Bowden's assay (P=0.046). When the total HBV DNA is less than 107 copies/ml, there were no significant differences. This suggests that the bisulfite conversion assay was less affected by rcDNA even in samples containing a high viral load. / With this background, two new cccDNA assays were developed and optimized. Bowden's assay was used as a standard to evaluate the performance of new assays. The first new assay (modified Bowden's assay) involved the use of new primers and probes that targeted more conserved regions in the HBV genome. The second assay adopted the bisulfite conversion method, which introduced gene sequence changes into the HBV genome and thereby enhance the specificity of the assay. Capillary sequencing was performed to find mutations in primers and probe range of different assays. / Yu, Ling. / Advisers: Vincent Wai-Sun Wang; Joseph Jao-Yiu Sung. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 105-111). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Orientador: Artênio José Isper Garbin / Banca: Renato Moreira Arcieri / Banca: Paula Caetano Araújo / Resumo: A hepatite B e a AIDS são doenças virais de grandes destaques na saúde pública, devido seus elevados índices epidemiológicos, de morbidade e mortalidade. O estigma criado às doenças virais, principalmente pelo vírus da hepatite B (VHB) e vírus da imunodeficiência humana (HIV), repercute de forma negativa e impactante à vida da pessoa infectada, gerando atitudes discriminatórias e preconceituosas, principalmente no acesso aos serviços de saúde. Entre as duas doenças, a hepatite B é a única que tem a imunoprevenção, a qual é realizada através da vacinação. A imunização contra VHB é a principal forma de prevenção da doença, além de ser uma medida de autocuidado que deve ser preconizado no exercício da odontologia. O objetivo deste estudo foi avaliar o conhecimento e a existência da discriminação, através das atitudes dos graduandos em odontologia, frente à representação da Hepatite B e HIV/AIDS; e verificar a imunização dos graduandos, contra o vírus da hepatite B utilizando o teste imunocromatográfico, para o rastreamento de anticorpos anti-HBs. No primeiro capítulo, o universo amostral do estudo foi composto de todos os alunos de graduação regularmente matriculados (n=525). Foi criado um inquérito semiestruturado e autoaplicável, exclusivamente para este estudo, que versava sobre HIV/AIDS e Hepatite B. No segundo capítulo, foram convidados a participar da pesquisa, todos os alunos que desenvolviam atividades clínicas (n=263). Como instrumento de pesquisa, foi utilizado ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: To assess the knowledge, and the existence of discrimination by the attitudes of academic dentistry when facing HIV / AIDS and hepatitis B. Method ology: This is an exploratory cross - sectional study conducted in a public college of dentistry. The sample consisted of 462 (88%) academics who agreed to participate. In data collection, we used a semi - structured questionnaire, created exclusively for this study, addressing the theme HIV / AIDS and hepatitis B. In the data analysis, we used the chi - square test of proportions, in order to verify the associations between the study variabilities and the academic level. The significance level was 5% (0.050). Re sults: It was found that although 85.5% and 88.7% of the students affirm that they knew or have had some information about AIDS and hepatitis B, only 58.9% and 55.8% respectively, had some knowledge on etiological agents. The statistical differences found in relation to the knowledge of the disease and the success of the etiological agent of AIDS, was evident as in undergraduate students it's been noticed a relevant raise on statistical data but the knowledge of the etiology of hepatitis B was significant at the beginnin g of the course. On the attitudes of students in dental treatment of patients infected with HIV and HBV, 85.3% and 91.8% respectively they said that would accept performing it, however, a considerable part of the students believed that there are difference s in clinical procedures to be followed, with statistical values significant for those who attend the first year of graduation. When asked to participants if they would accept to be treated by a dental surgeon with AIDS or hepatitis B, only 31.4% and 38.7% would consent to do the treatment. Conclusion: We conclude that there are gaps in knowledge of students in relation to AIDS and Hepatitis B. The attitudes of students, compared ... (Complete abstract electronic access below) / Mestre

An angular analysis of the rare decay B0 → K∗ (K+ π− )µ+ µ− is presented. The study is based on a data sample from pp collisions at centre-of-mass energy of 8 TeV recorded by the ATLAS detector at the Large Hadron Collider which corresponds to an integrated luminosity of 20.3 fb−1 . An extended unbinned maximum-likelihood fit of the decay angular distribution is used to measure the CP-averaged angular observables FL, S3, S4, S5, S7 and S8 and the cor- responding form-factor independent observables P1, P4, P5, P6 and P8. The measurements are performed in the region 0.04 GeV2 < q2 < 6 GeV2 , where q is the dimuon invariant mass. The results are in agreement with the Standard Model predictions and com- patible with measurements published by other experiments. The most signifi- cant deviations are observed for parameters P4, P5 at the level of 2.7 standard deviations and for P8 which is 1.9 standard deviations away from one of the predictions. The P5 deviation in bin 4 GeV2 < q2 < 6 GeV2 is consistent with the one reported by the LHCb collaboration. The second part of this work shortly summarises the operation of the ATLAS Semiconductor Tracker, testing of the prototype module for the Inner Tracker strip upgrade, and the monitoring of non-collision background which was devel- oped as a part of this thesis.

Ng Wah. / Thesis submitted in: August 2006. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 101-113). / Abstracts in English and Chinese. / ABSTRACT --- p.II / 摘要 --- p.IV / ACKNOWLEDGEMENT --- p.VI / TABLE OF CONTENTS --- p.VII / LIST OF TABLES --- p.X / LIST OF FIGURES --- p.XI / ABBREVIATIONS --- p.XII / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Introduction --- p.2 / Chapter 1.2 --- Etiological Factors of Hepatocellualr Carcinoma (HCC) --- p.4 / Chapter 1.2.1 --- Dietary Aflatoxins --- p.4 / Chapter 1.2.2 --- Liver Cirrhosis --- p.5 / Chapter 1.2.3 --- Alcohol Abuse --- p.6 / Chapter 1.2.4 --- Viral Hepatitis Infection --- p.6 / Chapter 1.3 --- Literature Review on the Investigations of HBV Integrants in HCC --- p.16 / Chapter 1.3.1 --- Affected Host Junctions --- p.17 / Chapter 1.3.2 --- Viral Junctions --- p.18 / Chapter 1.4 --- Restriction Site Polymerase Chain Reaction (RS-PCR) --- p.19 / Chapter 1.5 --- Aims of Thesis --- p.21 / Chapter Chapter 2 --- Materials and Methods --- p.22 / Chapter 2.1 --- Materials --- p.23 / Chapter 2.1.1 --- Chemicals --- p.23 / Chapter 2.1.2 --- Buffers --- p.24 / Chapter 2.1.3 --- Cell Cultures --- p.24 / Chapter 2.1.4 --- Nucleic Acids --- p.24 / Chapter 2.1.5 --- Enzymes --- p.25 / Chapter 2.1.6 --- Equipment --- p.25 / Chapter 2.1.7 --- Software and Web Resources --- p.26 / Chapter 2.2 --- Methods --- p.27 / Chapter 2.2.1 --- DNA Extraction --- p.27 / Chapter 2.2.2 --- RS-PCR --- p.31 / Chapter 2.2.3 --- Sequencing --- p.37 / Chapter 2.2.4 --- Spectral Karyotyping (SKY) --- p.38 / Chapter 2.2.5 --- Fluorescence In situ hybridization --- p.39 / Chapter Chapter 3 --- Investigation of HBV Integration Sites in HCC Cell lines --- p.45 / Chapter 3.1 --- Introduction --- p.46 / Chapter 3.2 --- Materials and Methods --- p.47 / Chapter 3.2.1 --- Cell Lines --- p.47 / Chapter 3.2.2 --- RS-PCR --- p.47 / Chapter 3.2.3 --- Spectral Karyotyping --- p.48 / Chapter 3.2.4 --- Tyramide Signal Amplification for HBV in FISH Analysis --- p.48 / Chapter 3.3 --- Results --- p.51 / Chapter 3.3.1 --- Identification of HBV Integration Sites in Cell Lines --- p.51 / Chapter 3.3.2 --- Evaluation of RSO Primer Efficiency --- p.52 / Chapter 3.3.3 --- SKY and FISH Analysis --- p.53 / Chapter 3.4 --- Discussion --- p.64 / Chapter 3.4.1 --- HBV Insertions in HCC Cell Lines --- p.64 / Chapter 3.4.2 --- Efficacy of RSO Primers --- p.65 / Chapter 3.4.3 --- Investigation of HBV Integration on Chromosomal Rearrangement --- p.65 / Chapter Chapter 4 --- Investigation of Hepatitis B Virus Integration Sites in Primary HCC --- p.67 / Chapter 4.1 --- Introduction --- p.68 / Chapter 4.2 --- Materials and Methods --- p.69 / Chapter 4.2.1 --- Patients --- p.69 / Chapter 4.2.2 --- RS-PCR --- p.70 / Chapter 4.3 --- Results --- p.72 / Chapter 4.3.1 --- HBV Integration Sites in Primary HCC Tumors and Adjacent Non- malignant Liver --- p.72 / Chapter 4.4 --- Discussion --- p.88 / Chapter 4.4.1 --- HBV integration Sites in Primary HCC Tumors and Adjacent Non- malignant Liver --- p.88 / Chapter 4.4.2 --- Summary on HBV Integrants Identified --- p.91 / Chapter Chapter 5 --- Proposed Future Studies --- p.98 / Chapter 5.1 --- Correlation of Structural Aberrations with HBV Integrations --- p.99 / Chapter 5.2 --- Transcriptional Expression Study on the Genes Interrupted by or Located near the Virus Host Junctions --- p.100 / Chapter Chapter 6 --- References --- p.101

For the past twenty years, drawing on the Industrial Network Approach, Industrial Marketing and Purchasing Group researchers have been trying to get a better understanding of organisational networks related issues. Researchers frequently highlight that whatever the researched phenomena, it is important to consider actors’ subjective views of the world. The concept of Network Pictures as introduced in the IMP (Industrial Marketing and Purchasing) body of literature by Ford et al. (2002b), refers to those subjective views and despite its recognised importance no in-depth research had been conducted so far on the concept which has thus remained blurred. Ford et al. (2002b) brought in this concept to emphasise that the network is in fact a varying thing depending on what people see. The question is whether this can be translated into a research device, so that researchers may see in a structured and analytical way what an actor’s picture is. This is what this research project is about. The concept’s theoretical foundations are uncovered by reviewing some principles from Sense-Making Theory. This review results most importantly in the identification of a close association between actors’ views of the world and the outcome of those actors’ sense making processes or frameworks. The relevance of actors’ views to obtain a clearer understanding of organisational networks is highlighted when the relation that is believed to exist between those views and action in organisational networks is addressed. With the aim of developing Network Pictures as research tool a two-stage method is put forward and carried out. The method consisted of operationalising the construct of Network Pictures and then testing it in two different network contexts to see if it was usable and useful for carrying out research in organisational networks. The results point to the usability and usefulness of the developed device: not only does it allow for capturing what is believed to be individuals’ views of the world in a rich and comprehensive way, as it also shows diversity between individuals in different contexts. Also and interestingly, some of the identified ‘practitioner theories’ were found to be not coherent with some IMP theoretical cornerstones.

Le virus de l'hépatite B (VHB) reste un problème de santé majeur dans le monde malgré la disponibilité du vaccin. Le VHB n’est pas éradiqué par les thérapies actuelles et 240 millions de personnes infectées chroniquement restent à risque de développer une cirrhose du foie et un carcinome hépatocellulaire (CHC).Le VHB est un petit virus hépatotrope doté d'un génome à ADN double brin partiel (ADNrc). Après infection l'ADNrc est converti en ADN épisomal (ADNccc) qui est ensuite organisé en minichromosome viral, qui est le modèle pour la transcription et qui initie la réplication. La protéine de l'hépatite B x (HBx) est recrutée sur l'ADNccc pour initier et maintenir la transcription de l'ADN ccc. HBx cible aussi directement des gènes cellulaires impliqué dans le développement du CHC.Nous avons utilisé une approche ChIP-Seq pour identifier toutes les cibles génomiques de HBx dans les cellules qui répliquent le VHB. Les cibles HBx sont à la fois des gènes codant les protéines et des ARNnc (75 miARN et 34 lncRNA). Nous avons montré que HBx réprimait un sous-ensemble de miARNs qui réguleraient négativement la réplication virale (ex : miR-24) et des miARNs impliqués dans le développement du CHC (ex : miR-21). Parmi les lncARNs ciblés pour HBx, nous avons étudié DLEU2, qui est fortement surexprimé dans l’infection par le VHB et le CHC. Nous avons en outre montré que DLEU2 lie à la fois HBx et l’histone méthyltransférase Ezh2, la sous-unité catalytique du complexe répressif PRC2. L'interaction avec DLEU2 et HBx relie les fonctions Ezh2/PRC2 conduisant à l'activation constitutive d'un sous-ensemble de gènes cibles d'Ezh2 qui sont normalement conservés dans un état réprimé. Nous avons également montré que l’interaction de HBx avec DLEU2 se produisait sur le minichromosome de l’ADNccc où elle stimulait la transcription/réplication du virus. Enfin, nous avons caractérisé par ATAC-Seq les changements d'accessibilité de la chromatine imposés par HBV dans les hépatocytes humains primaires / Hepatitis B virus (HBV) remains a major health problem worldwide despite the availability of the vaccine. No cure is available for the 240 million peoples chronically infected with HBV that are at risk to develop liver cirrhosis and hepatocellular carcinoma (HCC). Viral suppression, achieved by long term treatment with nucleotides analogues (NUCs), impacts on liver fibrosis and prevents liver decompensation but HCC risk is not reduced in the first 5 years of treatment. HBV is a small hepatotropic virus with a partially double strand DNA (rcDNA) genome. After hepatocyte infection the rcDNA is converted into the cccDNA episome that is then organized into a viral minichromosome that is the template for all viral transcripts and initiates replication. The hepatitis B x protein (HBx) is recruited on the cccDNA and is required to launch and maintain cccDNA transcription. HBx has also been shown to directly target cellular genes and this has been related to HCC development.We used a ChIP-Seq approach to determine the full repertoire of HBx genomic targets in HBV replicating cells. HBx targets include both protein coding genes and ncRNA (75 miRNAs and 34 lncRNAs). We showed that HBx represses a subset of miRNAs that would negatively regulate viral replication (i.e. miR-24) and miRNAs involved in HCC development (i.e. miR-21). Among the HBx targeted lncRNAs we focused DLEU2, which is strongly upregulated in HBV infection and HCC. We further showed that DLEU2 binds both HBx the Ezh2 histone methyltransferase, the catalytic subunit of the repressive PRC2 complex. The interaction with DLEU2 and HBx re-wires Ezh2/PRC2 functions leading to the constitutive activation of a subset of Ezh2 target genes that are normally kept in a repressed state. We also showed that HBx interaction with DLEU2 occurs on the cccDNA minichromosome where it boosts HBV transcription/replication. Finally, we characterized by ATAC-Seq HBV imposed changes of chromatin accessibility in primary human hepatocytes

Submitted by Angela Maria de Oliveira (amolivei@uepg.br) on 2018-12-19T13:31:11Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Alceu de Oliveira Toledo Junior.pdf: 3822777 bytes, checksum: 8621dbda843628c32379a4d6c54e0ac2 (MD5) / Made available in DSpace on 2018-12-19T13:31:11Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Alceu de Oliveira Toledo Junior.pdf: 3822777 bytes, checksum: 8621dbda843628c32379a4d6c54e0ac2 (MD5) Previous issue date: 2018-12-17 / Este estudo tem como objetivo avaliar comparativamente perfis de marcadores bioquímicos que melhor caracterizem e/ou associem-se às dislipidemias, na modalidade diagnóstica por ampliar a estratificação do risco cardiovascular ou no seu monitoramento para melhor condução. Para isso avaliamos o perfil lipídico composto por colesterol total, triglicérides, colesterol da lipoproteína de alta densidade e da lipoproteína de baixa densidade; esta com a fórmula de Martin, e ainda o colesterol em conteúdo que não faz parte das lipoproteínas de alta densidade, correlacionando-os com os marcadores: lipoproteína a, apoproteína B e colesterol da lipoproteína de baixa densidade; com uso do método homogêneo. Foram selecionados 1012 pacientes, segmentados por faixas etárias, sexo e condição de uso ou não de inibidores de produção hepática do colesterol. Para ampliar o poder dessa análise agrupada os exames realizados foram separados em subgrupos, considerando-se valores obtidos e metodologias utilizadas; correlacionando-se os resultados. A pesquisa foi realizada com variáveis qualitativas e quantitativas, procedendo-se ao uso de testes estatísticos não paramétricos para sua compreensão, distribuição e análise agrupada. Nossos resultados mostraram evidências que o risco cardiovascular não se associa apenas ao colesterol da lipoproteína de baixa densidade obtido pela fórmula de Martin, mas a outras variáveis, sob associação às seguintes análises comparativas: que o uso da apoproteína B amplia o diagnóstico de inclusão das dislipidemias em 43% usando valores referenciais sexo-independentes e com uma nova faixa de monitoramento em 84 mg/dL. Que o colesterol da lipoproteína de baixa densidade obtido pelo método homogêneo apresenta discordância analítica em +3,5% e tendo estratificação diagnóstica 48% superior. E que a lipoproteína a apresenta-se superior a 30 mg/dL em 26% dos pacientes, porém com prevalência e segmentação específicas nas mulheres entre 51 a 60 anos, sendo necessária sua análise numa aparente discordância, superior a 10 mg/dL, quando da comparação de resultados entre a fórmula de Martin e o método homogêneo. / This study aims to comparatively evaluate the profiles of biochemical markers that best characterize and / or associate with dyslipidemias, in the diagnostic modality by increasing the stratification of cardiovascular risk or its monitoring for better conduction. For this, we evaluated the lipid profile composed of total cholesterol, triglycerides, high density lipoprotein cholesterol and low density lipoprotein; and the cholesterol in non-high density lipoprotein content, correlating them with the markers: lipoprotein A, apoprotein B and low density lipoprotein cholesterol; using the homogeneous method. A total of 1012 patients were selected, segmented by age, sex and condition of use or inhibition of hepatic cholesterol production. In order to increase the power of this group analysis the exams were separated into subgroups, considering the obtained values and methodologies used; correlating the results. The research was carried out with qualitative and quantitative variables, using nonparametric statistical tests for their comprehension, distribution and grouped analysis. Our results showed evidence that cardiovascular risk is not only associated with the low density lipoprotein cholesterol obtained by Martin's formula, but other variables, in association with the following comparative analyzes: that the use of apoprotein B expands the diagnosis of inclusion of dyslipidemias in 43 % using genderindependent baseline values and with a new monitoring range of 84 mg/dL. That the low density lipoprotein cholesterol obtained by the homogeneous method presents an analytical disagreement at + 3.5% and having a 48% higher diagnostic stratification. In addition, lipoprotein a levels were higher than 30 mg/dL in 26% of the patients, but with a specific prevalence and segmentation in women between the ages of 51 and 60 years, with an apparent disagreement of more than 10 mg/dL when of the comparison of results between the Martin formula and the homogeneous method.