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Zhang, Lu. „IgG3 Complements IgM in the Complement-Mediated Regulation of Immune Responses“. Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-316618.
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An intact complement system is essential for the initiation of a normal antibody response. Antibodies can regulate their own production against the antigens that they are specific for. Both IgG3 and IgM are able to enhance the antibody response via complement. Here, we have compared the fate of OVA-TNP (ovalbumin-2,4,6-trinitrophenyl) administered intravenously to mice either alone or in complex with monoclonal IgG3 anti-TNP. IgG3-antigen complexes bind to marginal zone (MZ) B cells via complement receptors 1 and 2 (CR1/2) and are transported into splenic follicles. The majority (50% - 90%) of the antigens is deposited on follicular dendritic cells (FDC) and the antigen distribution pattern is strikingly similar to peripheral dendrites/processes of FDC already 2 h after immunization. The development of germinal centers (GC) induced by IgG3-antigen complexes is impaired in mice lacking CR1/2. Experiments on bone marrow chimeric mice show that CR1/2 expression on both MZ B cells and FDC is required for optimal IgG3-mediated enhancement of antibody responses. Complement factors C3 and C1q are essential for OVA-TNP delivery and deposition on splenic FDC. The production of IgG anti-OVA is abrogated in mice lacking CR1/2, C1q, and C3. Further, IgG3-antigen complexes dramatically upregulate the memory response against OVA-TNP by inducing OVA-specific memory cells. Besides small protein OVA, IgG3 can also upregulate humoral responses against large soluble keyhole limpet hemocyanin. To further study the role of MZ B-cells and CR1/2 in enhancement of antibody responses, a knock-in mouse strain, Cμ13, was used. IgM in this mouse strain is unable to activate complement due to a point mutation in the constant µ-heavy chain. Cμ13 mice have a higher proportion of MZ B cells, with higher CR1/2 expression, than wild-type mice. More IgG3-immune complexes are captured by MZ B cells and deposited on FDC in Cμ13 than in WT mice. In spite of this, IgG3 did not enhance the primary antibody response more efficiently in Cμ13 mice. The existence of endogenous IgM-mediated feedback regulation was suggested by the observation that GC development and antibody responses, after priming and boosting with suboptimal doses of SRBC, was lower in Cμ13 than in WT mice.
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Cabello, Olea Rocío del Pilar, Yakinoma Arturo Tomohiro Fukuhara, Matsuda Jhonny David Higa, Namisato Jenny Nagahama und Romero Maria Lisbet Reyes. „Elaboración de complemento proteico a base de pota y avena: Ika Complement“. Bachelor's thesis, Universidad Peruana de Ciencias Aplicadas (UPC), 2018. http://hdl.handle.net/10757/625458.
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El presente trabajo de investigación tiene como objetivo la implementación de un negocio innovador, que cubra las necesidades de alimentación del adulto mayor. Es así que de acuerdo al estudio realizado, identificamos que existe un alto índice de personas adultas que sufren de sobrepeso y tienen un nivel elevado de colesterol. Por lo tanto, decidimos crear un complemento alimenticio a base de pota y avena, siendo un producto peruano e innovador rico en proteínas y fibras, que ayude a mejorar la problemática mencionada, ya que según la tendencia por el consumo de productos naturales se encuentra en crecimiento.
Según el estudio de mercado desarrollado, hemos podido ver si existe algún otro producto que brinde los mismos beneficios que el nuestro, la aceptación que esta podría tener y cuáles serían los productos sustitutos que nos podrían afectar en la utilidad de nuestro negocio.
Hemos definido las estrategias de marketing, y nos vamos a dirigir al segmento B y C, en la zona de Lima Norte. Así mismo se ha podido determinar las necesidades financieras necesarias para poder llevar a cabo el proyecto, en la cual sea beneficioso tanto para la empresa como para los inversionistas.
Se debe mencionar que el objetivo principal de Ika Complement es diferenciarnos ante la competencia ya sea directa o indirecta, así como también satisfacer las necesidades de nuestro target, ofreciéndoles productos naturales y saludables.The objective of this research work is to set up an innovative business that covers the needs of the elderly. Thus, in the study conducted, we have identified that there is a high rate of adults who are overweight and have an elevated cholesterol levels. Therefore, we decided to create a dietary supplement based on squid and oats, being an innovative Peruvian product rich in proteins and fibers, which will help improve the aforementioned problems seeing as how there is an increase trend for the consumption of natural products. According to the market study carried out, we have tried to identify other products that offer the same benefits as ours, the acceptance that the product can have and substitute products that can affect our businesses’ revenue. We have defined our marketing strategies, and we will aim our business to the B and C segments located in the North Lima area. Likewise, it has been possible to determine the financial needs to be able to carry out a project, which will benefit both the company and the investors. It should be noted that the main objective of Ika Complement is to differentiate itself from direct or indirect competitors, as well as meet the needs of our objective, offering natural and healthy products.
Trabajo de investigación
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Franco, Jarava Clara. „Clinical and molecular characterization of Factor I and C5 complement deficiencies: from diagnosis to population studies“. Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/405650.
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El Sistema de Complemento es una parte de la respuesta inmune humoral que, entre otras funciones, se encarga de la defensa frente a patógenos y eliminación de inmunocomplejos. Está compuesto por más de treinta proteínas solubles y unidas a membrana, que se activan en forma de cascada proteolítica para poder ejercer su función. Los defectos congénitos en proteinas del sistema de complemento incrementan la susceptibilidad a infecciones por patógenos encapsulados y aumentan el riesgo de recurrencia de infecciones por bacterias del género Neisseria meningitidis. A pesar de considerarse enfermedades raras, la hipótesis del trabajo es que se están infradiagnosticando por la falta de conocimiento y de técnicas de laboratorio para el estudio de esta parte del sistema inmune. Además, consideramos que un diagnóstico temprano de este tipo de defectos permite adoptar medidas terapéuticas preventivas que mejoran la calidad de vida de los pacientes. En este trabajo de tesis se implementan 10 nuevas técnicas para el estudio del sistema de complemento en la rutina asistencial del Servicio de Inmunología del Hospital Universitario Vall d’Hebron. Este hecho ha permitido el diagnóstico y caracterización molecular de nueve casos de defectos de complemento (tres familias con defectos de C5 y tres familias con defectos de Factor I). Dos de los casos diagnosticados fueron en recién nacidos, hermanos de pacientes índice. Este hecho permitió la vacunación temprana y la indicación de profilaxis antibiótica para evitar futuras infecciones. Debido a la variabilidad geográfica descrita en la frecuencia de los defectos en moléculas de la vía terminal del complemento (C5-C9), estudiamos la presencia de alelos que presentaran la mutación p.A252T en 2710 muestras de poblaciones representativas de las diferentes regiones continentales. De acuerdo con nuestra hipótesis, observamos que existe una sobrerrepresentación de esta mutación en paises de África Sub-sahariana, coincidiendo en parte, con los paises englobados en el cinturón de la meningitis africano. Por contra, también identificamos dos muestras que eran portadoras del alelo mutado en regiones fuera de África (Israel y Pakistán). De cara a responder la pregunta de si es necesario estudiar el sistema de complemento en los casos de enfermedad meningocócica invasiva, en esta tesis recogemos un nuevo algoritmo en el que se suman a la presencia de recurrencias, el hecho de que haya consanguineidad, que la infección venga determinada por un serotipo poco frecuente o que el paciente sea originario de África o de Oriente Medio.The Complement System is a part of the humoral immune response that, among other functions, is responsible for the defense against pathogens and elimination of immune complexes. It is composed of more than thirty soluble and membrane-bound proteins, which are activated as a proteolytic cascade to be able to exert their function. Congenital defects in complement proteins increase susceptibility to infections by encapsulated pathogens and increase the risk of recurrence of infections by bacteria of the genus Neisseria meningitidis. Despite being considered rare diseases, the hypothesis of the work is that they are underdiagnosed by the lack of awareness and laboratory techniques for the study of this part of the immune system. In addition, we consider that an early diagnosis of this type of defects allows adopting preventive therapeutic measures that improve the quality of life of patients. In this work, 10 new techniques are implemented for the study of the complement system in the routine of the Immunology Department of the Hospital Universitario Vall d'Hebron. This fact allowed the diagnosis and molecular characterization of nine cases of complement defects (three families with defects of C5 and three families with defects of Factor I). Two of the diagnosed cases were in newborns, siblings of index patients. This fact allowed the early vaccination and the indication of antibiotic prophylaxis to avoid future infections. Due to the geographic variability described in the frequency of defects in molecules of the complement (C5-C9) terminal pathway, we studied the presence of alleles that presented the p.A252T mutation in 2710 samples from representative populations of the different continental regions. According to our hypothesis, we observe that there is an over-representation of this mutation in countries of Sub-Saharan Africa, coinciding in part with the countries included in the African meningitis belt. In contrast, we also identified two samples that were carriers of the mutated allele in regions outside of Africa (Israel and Pakistan). In order to answer the question of whether it is necessary to study the complement system in the cases of invasive meningococcal disease, in this thesis we present a new algorithm in which they are added to the presence of recurrences, the fact that there is consanguinity, that Infection is determined by a rare serotype or the patient is from Africa or the Middle East.
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Abraha, Arefaine. „The role of complement component C8 in complement mediated membrane damage“. Thesis, University of Cambridge, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292907.
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Oliveira, Thaís Rossini de 1989. „Estudo da participação dos reguladores de transcrição gênica VicRK e CovR na susceptibilidade de Streptococcus sanguinis à opsonização pelo sistema complemento“. [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/288674.
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Orientadores: Renata de Oliveira Mattos Graner, Flávia Sammartino Mariano RodriguesDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
Made available in DSpace on 2018-08-26T11:30:42Z (GMT). No. of bitstreams: 1 Oliveira_ThaisRossinide_M.pdf: 1438459 bytes, checksum: a127a667898930e41649ac3faebb8d1a (MD5) Previous issue date: 2014
Resumo: Streptococcus sanguinis é uma espécie pioneira comensal das superfícies dos dentes, que também está envolvida na endocardite infecciosa. Sua alta prevalência na cavidade oral indica capacidade de adaptar-se e sobreviver a diversos fatores de defesa presentes nesse nicho. Para se adaptar ao ambiente e a fatores do hospedeiro, as bactérias utilizam-se de sistemas reguladores de transcrição de dois componentes (SDC), que modulam a regulação de genes em respostas a diferentes estímulos. Neste estudo avaliou-se o papel do SDC VicRK e CovR, na susceptibilidade de S. sanguinis a opsonização pelo sistema complemento. Para isso, foram analisados os níveis de deposição de C3b / iC3b na presença de soro em um total de sete cepas clínicas de S. sanguinis, e as frequências de fagocitose por polimorfonucleares (PMNs) do sangue humano foram comparados entre as cepas S. sanguinis SK36 e mutantes knockout de vicK (SKvic) e covR (SKcov), genes estes que codificam componentes VicK e CovR, respectivamente. A cepa de S. mutans U159 foi utilizada como referência. Resumidamente, as cepas foram incubadas com soro humano a 2 ou 20% por 30 min (37 ° C, 10% de CO2), lavadas, e a presença de C3b associada à superfície foi detectado utilizando anticorpos anti-C3b humano (conjugado com FITC), sendo quantificadas por citometria de fluxo. Para avaliar as frequências de fagocitose por PMNs, as cepas foram incubadas com sangue humano durante tempos de 5, 15, 30 e 60 min (37 ° C, 10% de CO2), fixadas e coradas com Giemsa. PMNs com bactérias intracelulares, foram contados utilizando um microscópio de luz (1000 x) e os resultados expressos em relação a análise de um total de 200 PMNs. Resultados: As percentagens de deposição de C3b em SKvic, SKcov e SK36 foram de 11,3 (± 2,61), 40,2 (± 1,46) e 37,9% (± 3,97), respectivamente. Percentagem de superfície C3b foi significativamente menor em cepas de S. sanguinis em comparação a cepa de S.mutans (Kruskal Wallis, p <0,05), e em SKvic em comparação a cepa SK36 (Kruskal Wallis, p <0,05). As frequências médias de fagocitose por PMNs não foram afetadas, e foram 88, 99,3 e 99% em SKvic, SKcov e SK36, respectivamente. Conclusão: a inativação do VicK, mas não de CovR, reduz a deposição de C3b em S. sanguinis SK36. Cepas de S. sanguinis também são menos suscetíveis a deposição de C3b em comparação a S. mutans
Abstract: Streptococcus sanguinis is a commensal pioneer species of the tooth surfaces, which is also involved in infectious endocarditis. Its high prevalence in the oral cavity indicates ability to survive to several host defense factors present in the oral niches. To sense and respond to environmental and host factors, bacteria apply regulatory two-component systems (TCSs), which modulate gene transcription in response to different stimuli. This study evaluated the role of TCS VicRK and CovR in S. sanguinis susceptibility to opsonization by the complement system. To this aim, a total of seven S. sanguinis strains were analyzed, and levels of deposition of C3b/iC3b on the present of serum, and the frequencies of phagocytosis by polymorphonuclear (PMNs) in human blood were compared between parent S. sanguinis strain SK36 and knockout mutants of vicK (SKvic) and covR (SKcov) (genes encoding VicK and CovR components, respectively). S. mutans strain U159 was used as reference. Briefly, strains were incubated with 2 or 20% of human serum during 30 min (37°C, 10%CO2), washed, and the presence of surface-associated C3b was detected using anti-human C3b antibodies (FITC conjugated), which were quantified by flow cytometry. To assess the frequencies of phagocytosis by PMN, strains were incubated with human blood during 5, 15, 30 and 60 min (37°C, 10% CO2), fixed and stained with Giemsa. PMN with intracellular bacteria were counted using a light microscope (1000 x) and expressed in relation to a total of 200 PMN analyzed. Results: The percentages of C3b deposition on SKvic, SKcov and SK36 were 11.3 (± 2.61), 40.2 (± 1.46) and 37.9% (± 3.97), respectively. Percentage of surface C3b was significantly lower in S. sanguinis strains compared to S. mutans (Kruskal Wallis, p < 0.05), and in SKvic compared to SK36 (Kruskal Wallis, p < 0.05). The mean frequencies of phagocytosis by PMN was not affected, and were 88, 99.3 and 99% in SKvic, SKcov and SK36, respectively. Conclusion: the inactivation of the vicK, but not of covR, reduces the deposition of C3b in S. sanguinis SK36. S. sanguinis strains are also less susceptible to C3b deposition compared to S. mutans
Mestrado
Microbiologia e Imunologia
Mestra em Biologia Buco-Dental
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Miller, A. „Complement-carbohydrate interactions : studies of mannose binding lectin and complement factor H“. Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1338984/.
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The complement system is a fundamental component of innate immunity that orchestrates complex immunological and inflammatory processes. Complement comprises over 30 proteins that eliminates invading microorganisms while maintaining host cell integrity. Protein-carbohydrate interactions play critical roles in both the activation and regulation of complement. Mannose binding lectin (MBL) activates the lectin pathway of complement via the recognition of sugar arrays on pathogenic surfaces. X-ray scattering and AUC combined with constrained modelling were used to identify a bent structure for the MBL monomer in terms of crystal structures for its carbohydrate-recognition domain and its triple helical region. Near-planar solution structures were determined for the MBL dimer, trimer and tetramer. These solution structures clarified how MBL binds to pathogenic surfaces and provides a template for the binding and autoactivation of the MASP protease to initiate the lectin pathway of complement activation. Factor H (FH) with 20 short complement regulator (SCR) domains regulates the alternative pathway of complement by facilitating the breakdown of the central component C3b. FH binds to heparan sulphate (HS) and to heparin (a HS analogue) on host cell surfaces where it regulates C3b activity and protects these cells from complement attack. A Tyr402His polymorphism in SCR-7 is a major risk factor for the development of age-related macular degeneration (AMD), and is involved in heparin binding. Both the Tyr402 and His402 allotypes of the SCR-6/8 fragment of FH were cloned and expressed in an E. coli system. X-ray scattering, analytical ultracentrifugation and surface plasmon resonance were used to characterise the interactions of FH Tyr402 and His402 with heparin and HS. These polyanions induce the strong self-association of FH SCR-6/8, the extent of which was found to be dependent on the length of the polyanion and the presence of the His402 allotype. The formation of large FH-heparin aggregates may provide a molecular explanation for the link between the Tyr402His polymorphism and the initial formation of drusen deposits in AMD.
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Chamberlain-Banoub, Jayne L. „Role of complement and complement regulators in peripheral nerve and neuromuscular disorders“. Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/55602/.
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This thesis describes the evaluation of the role of Complement (C) and C regulators (CRegs) in experimental models of peripheral neuropathy and neuromuscular disease. Although a role for C in mediating peripheral neuropathy has previously been demonstrated in Guillain-Barre Syndrome (GBS) and its well characterised animal model Experimnetal Autoimmune Neuritis (EAN), evaluation of the role of individual components is lacking. C activation has also been widely implicated in the pathology seen in myasthenia gravis (MG) and its associated animal model Experimental Autoimmune Myasthenia Gravis (EAMG), although the precise effectors are uncertain. Evaluation of the extent of protection conferred by CRegs in the peripheral nervous system (PNS), and the ability of the myelin-producing Schwann cell to synthesize C components was a vital first step in determining the susceptibility of the system to C attack, and for providing a method of targeting key C-related molecules for further study in vivo. This work demonstrated that the PNS is well protected from membrane attack complex (MAC) attack, with high expression of the terminal pathway regulator, CD59. Crry was also highly expressed, while CD55 had a limited expression, suggesting a possible alternative role for this protein. CD46 was not expressed in the PNS. Testing the susceptibility of C and CReg deficient and knockout animals to induction of EAN and EAMG would enable further clarification of the role of individual C components to disease pathogenesis. For EAN, various antigens derived from myelin protein zero (PO) were generated to induce disease in rodents. Using this panel of antigens, specific, reproducible EAN was not achieved, and the possible reasons for this are discussed. C activation at the neuromuscular junction (NMJ) contributes to pathology in MG, although the precise role of the MAC is undear. EAMG was used to test the susceptibility of wikHype rats versus rats deficient in the terminal pathway component C6, to disease induction. Wildtype rats demonstrated severe weakness following induction of passively transferred EAMG, while C6 deficient rats were completely protected, demonstrated by protection against clinical disease, reduction in acetylcholine receptor (nAChR) loss, absence of inflammatory infiltrates and lack of C9 deposition. Reconstitution of human C6 to the C6 deficient rats resulted in increased disease. Soluble and fusion protein forms of CRegs, and a novel C5 inhibitor were also tested for their ability to abrogate disease in this model. Preliminary studies of EAMG induction in CReg knockout mice revealed that a lack of CD55 and CD59 markedly enhanced disease, although this remains to be confirmed. In conclusion, this work demonstrates: 1 The potential susceptibility of the PNS to C-mediated pathology 2 The difficulties in inducing EAN in rodents using published protocols 3 That MAC is the major drive to NMJ destruction in EAMG CRegs tested in EAMG hold promise for treatment of inflammatory disease, and analysis of the role of CRegs in EAMG in the mouse may shed new light on the precise effectors mediating disease pathogenesis.
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Yannoutsos, Nikos. „Complement regulation and xenotransplantation“. Thesis, Open University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309817.
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Williamson, Lorna McLeod. „Complement-mediated neutrophil activation“. Thesis, University of Edinburgh, 1987. http://hdl.handle.net/1842/19420.
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Pasch, Marcel Christian. „Regulation of expression of complement components, complement regulatory proteins, and chemokines in keratinocytes“. [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2000. http://dare.uva.nl/document/56902.
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Lewis, Ruth D. „The role of complement and complement regulatory proteins in the progression of atherosclerosis“. Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/54224/.
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Whilst evidence from human studies suggests that complement activation is pro-atherogenic, studies using animals models of the disease, including the low density receptor deficient (ldlr
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Vernon, Katherine Anne. „The role of local complement factor H production in complement-mediated renal disease“. Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/28078.
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The aim of my research was to define the roles of local and hepatic-derived factor H, in particular the contribution of extra-hepatic factor H to plasma C3 regulation and spontaneous renal disease associated with factor H deficiency. Factor H is the major soluble regulator of the alternative pathway of complement activation, synthesised predominantly by the liver. To investigate the role of extra-hepatic factor H, I generated mice with hepatocyte-specific factor H deficiency (hepatocyte-Cfh-/-) by intercrossing conditional factor H-deficient animals with mice expressing Cre recombinase under the control of the murine albumin promoter. Plasma factor H levels in hepatocyte-Cfh-/- mice were 19% of wild-type levels and were associated with a secondary reduction in plasma C3 levels. Higher plasma C3 levels than in Cfh-/- animals demonstrated that extra-hepatic factor H contributes to plasma C3 regulation, confirmed by tubulointerstitial C3 staining in hepatocyte-Cfh-/- mice. Extra-hepatic factor H prevented the GBM C3 deposition typical of complete factor H deficiency and was associated with spontaneous mesangial C3 deposition. To test the hypothesis that underlying dysregulation of the alternative pathway predisposes to exaggerated renal injury in the presence of additional complement activation, I assessed the response of hepatocyte-Cfh-/- mice to accelerated serum nephrotoxic nephritis. Injection of nephrotoxic serum led to the rapid onset of haemolytic uraemic syndrome. Subtotal deficiency of factor H in hepatocyte-Cfh-/- mice therefore provides a novel model of either C3 glomerulopathy or atypical haemolytic uraemic syndrome depending on the environmental milieu. This mouse model will enable the pathophysiological mechanisms involved to be further defined and new therapeutics investigated. I also examined the association between abnormalities in factor H-related protein 5 and C3 glomerulopathy. Minimal expression of normal factor H-related protein 5 within the kidney could not prevent CFHR5 nephropathy. Serum factor H-related protein 5 levels may be a marker of renal complement deposition.
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Chen, Jin. „Role of Complement Regulatory Protein Properdin in Hemolytic Anemias Caused by Complement Dysregulation“. University of Toledo Health Science Campus / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=mco1576192779405742.
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Sobrinho, Natália Umetsu. „Caracterização molecular dos componentes C1q, C4 e C2 do sistema complemento em pacientes pediátricos com lúpus eritematoso sistêmico“. Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5141/tde-05112013-163219/.
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Objetivo: Realizar a caracterização molecular dos genes C1q, C4 e C2 em pacientes com lúpus eritematoso sistêmico juvenil (LESJ). Métodos: Quatro pacientes com LESJ e deficiências de C1q,C4 e/ou C2 foram selecionados. O paciente P1 apresentava níveis séricos indetectáveis de C1q e níveis normais de C3 e C4; paciente P2 níveis baixos de C2 e C4 no soro; P3 apresentava níveis baixos de C2 e normais de C3 e C4 e P4 constantes níveis baixos de C4 e níveis normais de C1q, C2 e C3 no soro. Foram sequenciados os genes C1q e C2. Células mononucleares dos pacientes P1, P3 e P4 e de três indivíduos saudáveis foram cultivadas, estimuladas com interferon gama e incubadas por 36 horas e PCR quantitativo (qRTPCR) foi realizado para verificar a expressão de mRNA. Resultados: A caracterização molecular do gene C1q (P1) mostrou trocas heterozigotas na cadeia A (c.276 A>G Gly) e na cadeia C (c.126 C>T Pro). Foram observadas também duas trocas de base em homozigose na região 5\'UTR (c. -159 T>G) e na região 3\'UTR (c*78 A>G) da cadeia B. O qRT-PCR mostrou que a expressão de mRNA de C1qA no paciente P1 sem estimulo estava 1,3 vezes mais baixo e com estímulo de interferon gama estava 1,6 vezes mais expresso se comparado aos indivíduos saudáveis. A expressão de mRNA de C1qB sem estímulo foi 2,2 vezes mais baixo e com estímulo foi 1,5 vezes mais expresso quando comparados aos controles. Para C1qC os indivíduos controles não expressaram mRNA porém o paciente P1 apresentou pequena expressão com e sem estímulo. O sequenciamento do gene C2 dos pacientes P2 e P3 apresentou 100% de similaridade com a sequência de referência com exceção da deleção de 28pb no exon 6 (deficiência heterozigota de C2 do tipo I). A expressão de mRNA de C2 do paciente P3 foi sem estímulo 23 vezes mais baixo e com interferon 4,2 vezes menos expresso quando comparado aos controles. P4 apresentou 2 copias de C4A e 3 copias de C4B e no qRT-PCR o gene C4B estava 14 vezes menos expresso sem estímulo e com estímulo estava semelhante aos controles. Conclusões: As trocas de base em homozigose nas regiões 5\'UTR (região promotora) e 3\'UTR (região de estabilização do mRNA) na cadeia B do gene C1q podem ter modificado a região de transcrição do mRNA pois sua expressão sem estimulo foi baixa. Outras investigações são necessárias para relacionar as variações do gene C1q encontradas com os níveis séricos indetectáveis de C1q. A deficiência de C2 do tipo I heterozigota pode levar a redução na expressão de mRNA e pode estar presente em pacientes lúpicos com níveis séricos detectáveis de C2. Por fim, a baixa expressão de mRNA de C4B mostrou que as dosagens séricas e a avaliação do número de copias podem não ser suficientes para estabelecer a deficiência de C4Objective: To perform the molecular characterization of C1q, C4 and C2 genes in patients with Juvenile Systemic Lupus Erythematosus (JSLE). Methods: Four patients with JSLE and C1q, C4 and/or C2 deficiencies were chosen. Patient P1 had undetectable C1q serum level and normal levels of C3 and C4; Patient P2 had decreased levels of C2 and C4 serum while P3 had decreased C2 with normal C3 and C4 levels. Lastly P4 had repeated decreased C4 and normal C1q, C2 and C3 serum levels. C1q and C2 genes were sequenced. Peripheral mononuclear cells from patients P1, P3 and P4 and from three healthy individuals were both cultivated and stimulated with interferon gamma and a quantitative PCR (qRT-PCR) was also performed to verify mRNA expression. Results: C1q molecular characterization for P1 revealed heterozygous silent mutations in A chain (c.276 A>G Gly) and in C chain (c.126 C>T Pro). Additionally, in B chain two homozygous single-base exchanges were detected in the 5´UTR (c. -159 T>G) and 3\'UTR region (c*78 A>G). The qRTPCR revealed that C1qA gene mRNA expression without stimulation was decreased 1.3 times and with interferon gamma was 1.6 times more expressed compared with controls samples. C1qB gene expression without stimulation was 2.2 times decreased and when stimulated was 1.5 times more expressed. Controls did not expressed C1qC gene and patient P1 had low expression both with and without stimulation. P2 had 2 copies of C4A and 1 copy of C4B. C2 gene sequencing (P2 and P3) showed 100% match with referenced sequence, with exception to 28bp deletion at the exon 6 (heterozygous C2 deficiency type I). C2 mRNA expression from P3 without stimulation was 23 times decreased and with interferon was 4.2 times decreased compared with controls. P4 had 2 copies of C4A and 3 copies of C4B. The qRT-PCR were performed only in C4B gene showed without stimulation a 14 times decreased expression and with interferon stimulation the expression were similar to controls. Conclusions: The two homozygous single-base exchanges in 5\'UTR and 3\'UTR that correspond to the promoter region and stabilization mRNA region in B chain of C1q gene, may have modified mRNA transcription as its expression was decreased without stimulation. Further analysis is necessary to relate C1q gene variations and undetectable serum C1q. In addition, heterozygous C2 deficiency type I may lead to reduced mRNA expression and may be present in JSLE patients with detectable C2 levels. Finally, the decreased C4B gene expression showed that serum dosage and gene copy number may not be sufficient to assess C4 deficiency
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Ulbrich, Axel Gustavo. „Estudo de um caso de deficiência do componente C3 do sistema complemento humano“. Universidade de São Paulo, 2000. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-30032001-124158/.
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Uma criança brasileira (LAS) vítima de infecções recidivantes e vasculite, cujos pais são consangüíneos em segundo grau apresentou 0,15 µg/mL de C3 plasmático e atividades hemolíticas nulas pelas vias clássica e alternativa, já outras proteínas do complemento e Igs estavam normais (exceto IgG4, que foi indetectável). Diferentemente de sua mãe os fibroblastos da criança não foram capazes de sintetizar as cadeias a e b de C3, como observado por SDS-PAGE. O probando possui dois alelos C3S, assim como seu irmão mais novo e saudável, enquanto a mãe é FS. A migração de leucócitos, em resposta ao soro do probando ativado com LPS foi menor que a obtida com soro normal e estatisticamente semelhante àquela gerada por SHN inativado a 56oC (SHNi). A ingestão e a morte de C. albicans, opsonizadas por soro do probando, por fagócitos normais foram semelhantes às dos fungos opsonizados por SHNi. Nós concluimos que, em conseqüência da incapacidade de sintetizar C3, o probando não é capaz de exercer as funções imunológicas dependentes do complemento, resultando em uma maior susceptibilidade a infecções.A brasilian child (LAS) victim of recurrent infections whose parents have second degree consanguinity presented 0.15 µg/mL of serum C3 and no hemolytic activities either after activation of the classical or alternative pathways. His mother presented C3 alpha and beta chains of normal sizes, while LAS's fibroblasts did not secrete any C3 as observed by SDS-PAGE. The proband possesses two C3S alleles, like his younger and healthy brother whereas his mother is FS. Leukocyte migration across nitrocellulose membrane in response to the proband's LPS-activated serum was less intense than that obtained in response to normal serum. Phagocytosis and killing of C. albicans opsonized with the proband's serum was comparable to fungi opsonized with inactivated serum, incdicating that chemotactic and opsonic activities of the proband's serum are greatly diminished. We colclude that as a consequence of C3 deficiency the proband's complement system is uncapable of performing it's normal effector functions resulting in greater susceptibility to infections.
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Tso, Cynthia K. W. „A reassessment of the interaction between complement C3d and complement receptor CD21 SCR1-2“. Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:29114281-a320-459d-88a6-9b5fad7c3f7f.
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Biophysical characterisation of protein – ligand interactions can provide vital information to dissect complex biochemical binding mechanisms. C3d has been shown to interact with a number of different protein ligands, namely CD21 SCR1-2, S. aureus Efb-C, S. aureus Ehp, S. aureus Sbi and complement regulatory protein factor H. Although much is known about the relationship of C3d and CD21 in the induction of humoral immunity, the structural aspects of this interaction remained controversial until very recently. The aim of this thesis was to gain a detailed understanding of the C3d/CD21 SCR1-2 interaction using different biophysical methods and to identify potential low molecular weight inhibitors of the interaction. A crystal structure of the C3d/CD21 complex solved by Szakonyi et al. in 2001 indicated the C3d binding site on CD21 was in the SCR2 domain. It did not agree with mutagenesis studies and recent NMR titration experiments show that only residues from the SCR1 domain of CD21 appear to mediate binding under physiologically relevant ionic strength. In the current work, NMR was employed to monitor ligand binding to C3d and to provide residue specific information that reflects a physiologically relevant binding mode to complement the crystallographic model solved by van den Elsen and Isenman in 2011. Microcalorimetric analysis on the site-directed mutagenesis studies also supported a model of hydrophobically- and electrostatically-driven protein-protein interaction for C3d and CD21 SCR1-2. Complement C3d forms a non-specific thioester linkage with antigen, which then binds to CD21 SCR1-2 and coligates with membrane immunoglobulin of the B cell receptor. While the interactions triggers B cell activation and hence the production of antibody under normal circumstances, it has been demonstrated that the interactions also lead to undue B cell activation and auto-antibody production. There is a well established collagen-induced arthritis (CIA) mouse model to support the significance of C3d and CD21 in disease susceptibility. To this end, a high-throughput SPR-based screening platform was set up to screen a fragment library against C3d, so as to identify low molecular weight compounds that could serve as a starting point for drug development programme. Unfortunately, the work did not yield C3d-binding inhibitors and future work could include screening large fragment libraries that are designed to target protein-protein interfaces.
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Westacott, Laura. „Neuroimmune regulation of adult hippocampal neurogenesis by Complement Component 3 and Complement C3a Receptor“. Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/100061/.
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New neurons are added to the dentate gyrus of the hippocampus throughout adult life, through the process known as adult hippocampal neurogenesis (AHN). This important form of structural plasticity supports learning and memory in mammalian species. AHN is tightly regulated by a myriad of factors, including the immune system. Previous evidence suggests that signalling via Complement Component 3 (C3) and Complement C3a Receptor (C3aR) may regulate AHN under physiological conditions, although the mechanism of this putative regulation is unclear. In addition, C3a/C3aR signalling may regulate neuronal morphology. Using C3-/- and C3aR-/- mice, I used a combined in vitro and in vivo approach to investigate the role of C3/C3aR signalling in AHN. In Chapter 2, I demonstrate that C3a/C3aR signalling is able to directly influence hippocampal precursor cells in primary cultures. Furthermore, in the adult mouse brain, there is an increase in the number of immature neurons in the absence of C3 and C3aR, suggesting that C3a/C3aR signalling exerts an anti-neurogenic effect in the healthy brain. In Chapter 3 I report that the dendritic arborisation of newborn neurons is altered in the absence of C3aR, but not C3, suggesting involvement of an alternative ligand. Therefore, C3aR signalling via an as yet-unidentified ligand is important for maintaining the normal neuronal morphology of adult born neurons. Both the net levels of AHN and immature neuronal morphology have important functional consequences for cognitive and affective processes involving the hippocampus, which I investigate in Chapter 4. I report superior performance of C3-/- and C3aR-/- mice in a hippocampus-dependent spatial discrimination task, consistent with their elevated levels of AHN. Furthermore, C3a/C3aR deficiency was associated with abnormal anxiety phenotypes. In conclusion,these results demonstrate a novel mechanism for neuroimmune regulation of AHN, which is of functional consequence to learning, memory and affective behaviour.
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Zdinak, Paul M. „A Little Complement Goes a Long Way: Neisseria gonorrhoeae and Membrane-Bound Complement Inhibitors“. Ohio University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1596567376927017.
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Wrona, Janick. „The Old Japanese complement system“. Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399466.
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Miguel, Maria Enriqueta Real San. „Complement activation at biomaterial surfaces“. Thesis, University of Sheffield, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.544021.
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Leath, Kirstin J. „Structural Studies of Complement Regulators“. Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526076.
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Walport, M. J. „The biology of complement receptors“. Thesis, University of Cambridge, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383309.
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Tarnoff, David. „Episode 3.02 – Tens Complement Arithmetic“. Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/computer-organization-design-oer/18.
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In 1645, Blaise Pascal presented his Pascaline to the public. Using only addition and the method of tens complement, the device could add, subtract, multiply, and divide. We discuss tens complement as an introduction to signed representations in binary.
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Słodowicz, Szymon. „Control in Polish complement clauses“. München Sagner, 2006. http://d-nb.info/992349672/04.
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Fredrikson, Gunilla Nordin. „Analysis of complement deficiency states with focus on molecular characterization of C-4 and properdin deficiency /“. Lund : Dept. of Medical Microbiology, Section of Clinical Immunology, Lund University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/39752489.html.
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Lee, Hyun Clinical School St Vincent's Hospital Faculty of Medicine UNSW. „The role of C5a receptors (C5aR and C5L2) in immune responses : targeting C5aR for human therapeutic application“. Awarded by:University of New South Wales. Clinical School - St Vincent's Hospital, 2008. http://handle.unsw.edu.au/1959.4/40995.
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The complement system is one of the most ancient immune defense mechanisms, providing rapid protection against invading micro-organisms. It is essential for the complement cascade to be under tight regulation in order to prevent excessive production of complement proteins. C5a is the most potent anaphylotoxin produced by the complement system, it binds C5a receptor (C5aR, CD88) and C5L2 (GPR77). C5a binding to C5aR induces leukocyte chemotaxis and release of inflammatory mediators. Over-production of C5a is known to be involved in many inflammatory and pathological conditions such as RA, I1R injury and sepsis, making it an attractive therapeutic target. Human and mouse C5aR share low homology and blocking C5a/C5aR signaling with small molecules has been challenging. We generated human C5aR knockout/knockin (hC5aR KI) mice in which the mouse C5aR coding region was replaced with that of human C5aR to utilize them for the development of human therapeutics targeting C5aR. hC5aR KI mice showed normal development, and leukocytes from hC5aR KI mice responded well to mouse C5a. We used two approaches to generate monoclonal antibodies (mAbs) against hC5aR. We used a mouse cell line transfected with hC5aR or neutrophils from hC5aR KI mice to immunize wild-type mice and generated high-affinity antagonistic mAbs which are specific to human C5aR. Anti-hC5aR mAb 7F3 blocked C5a-induced signaling completely without agonistic activity in vitro. In the animal model of K/BxN inflammatory arthritis, 7F3 both prevented and reversed inflammation. Currently, the function of the second C5a receptor, C5L2, remains controversial. There are contradicting reports from C5L2 KO mice that were generated by independent groups. We assessed the function of human C5L2 using an antagonistic mAb that specifically blocks C5L2 function and not C5aR. In vitro analysis using the C5L2-blocking mAb showed that C5a does not signal via C5L2 to affect chemotaxis or phagocytosis by neutrophils, indicating that C5L2 is not a signaling receptor for C5a, at least in these cellular functions.
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Correia, Alexandre Pires. „Avaliação de mutações no gene do inibidor de C1 esterase em pacientes com angioedema hereditário“. Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5133/tde-24022010-173619/.
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A ativação dos sistemas complemento e de contato resulta na formação de peptídeos vasoativos tais como a bradicinina e anafilatoxinas. O inibidor de C1-esterase (C1-INH) é o principal regulador desses dois sistemas e a deficiência desta proteína resulta no Angioedema Hereditário (AEH). Trata-se de uma doença rara, de herança autossômica dominante, caracterizada pela deficiência de C1-INH, a qual ocorre devido a mutações no seu gene estrutural, levando a episódios graves de edema em tecido subcutâneo, gastrointestinal e respiratório, potencialmente fatais. Existem dois fenótipos variantes: AEH do tipo I, com reduzidos níveis antigênicos de C1-INH no plasma e AEH tipo II com níveis reduzidos ou normais de C1-INH e atividade disfuncional. Várias mutações já foram descritas no gene de inibidor de C1 esterase (SERPING1), porém, não há estudos que avaliem a relevância desta doença e as mutações gênicas em nosso meio. O objetivo do presente estudo foi avaliar as alterações moleculares em pacientes com AEH, correlacionando-as com as manifestações clínico-laboratoriais. Amostras de plasma, soro e DNA de quinze pacientes de uma mesma família foram coletadas. O ensaio hemolítico CH50 para avaliação da integridade da via clássica do sistema complemento e avaliação quantitativa de C4 e C1-INH por nefelometria foram os ensaios realizados para confirmação do diagnóstico da doença. A atividade funcional da proteína foi avaliada através de ensaio colorimétrico e a relação existente entre possíveis mutações na proteína e o fenótipo da doença foi avaliada por meio de reação de polimerase em cadeia (PCR) e seqüenciamento do DNA genômico. A atividade hemolítica de complemento total e a dosagem de C3 foram normais nos pacientes e controles analisados, os níveis da atividade antigênica de C1-INH e C4 mostraram-se diminuídos na maioria dos avaliados (13/15). A avaliação funcional detectou baixa atividade (<50%) do valor normal (70% - 130%) em todos os pacientes analisados. A distribuição das mutações entre os 8 éxons relativos ao gene de C1- INH concentraram-se nos éxons 4 (g.4706-88A>G) , 7 (g.14145+20A>G) e 8 (Val480Met). Duas dessas mutações nunca foram descritas ainda, o que contribui para a compreensão da função das serpinas e também ajuda a definir mais completamente o papel biológico do inibidor de C1Activation of complement and contact systems results in the formation of vasoactive peptides such as bradykinin and anafilatoxinas. The C1 esterase inhibitor (C1-INH) is the main regulator of these two systems and the deficiency of this protein results in hereditary angioedema (HAE). It is a rare disease of autosomal dominant inheritance, characterized by deficiency of C1-INH, which is due to mutations in its structural gene, leading with severe episodes of edema in subcutaneous tissue, gastrointestinal and respiratory tract, potentially fatal. There are two phenotypic variants: HAE type I, with reduced plasma antigen levels and HAE type II with normal or low levels of C1-INH and dysfunctional activity. Several mutations have been described in the gene of the C1 esterase inhibitor (SERPING1), however, no studies to assess the relevance of this disease and the gene mutations in our population. The purpose of this study was to evaluate the molecular changes in patients with HAE, correlating it with clinical and laboratory manifestations. Samples of plasma, serum and DNA from fifteen patients from the same family were collected. CH50 hemolytic assay for assessing the integrity of the classical pathway of the complement system and quantitative evaluation of C1-INH and C4 by nephelometry tests were performed to confirm the diagnosis of disease. The functional activity of the protein was assessed by colorimetric assay and the possible relationship between mutations in the protein and the phenotype of the disease was assessed by polymerase chain reaction (PCR) and sequencing of genomic DNA. Hemolytic activity of complement and the total dosage of C3 were normal in patients and controls. Levels of antigenic activity of C1-INH and C4 were shown to be less valued in most (13/15). Functional evaluation found low activity (<50%) of normal (70% - 130%) in all patients examined. The distribution of mutations among the 8 exons of the gene for C1-INH concentrate in the exons 4 (g.4706-88A> G) and 7 (g.14145 +20 A> G) and 8 (Val480Met). Two of these mutations have not been described yet, which contributes to understanding the function of serpins and also helps to define more fully the biological role of the C1 inhibitor
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Arias, Cabrales Carlos E. „Estudio del daño renal inducido por la activación del sistema del complemento durante el fenómeno de isquemia reperfusión“. Doctoral thesis, Universitat Autònoma de Barcelona, 2021. http://hdl.handle.net/10803/673110.
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Els avenços realitzats en els últims anys en les tècniques d'extracció i preservació dels òrgans trasplantats, així com en la medicació immunosupressora i l'avaluació de risc immunològic, han permès millorar la supervivència de l'empelt renal i del receptor a curt termini. Aquesta millora no es veu tan clarament reflectida a mitjà i llarg termini. Probablement, una de les causes d'això últim és la funció retardada de l'empelt, una forma de dany renal agut, que es presenta en un 20-50% dels receptors de donant cadàver i que empitjora el pronòstic dels ronyons trasplantats que la pateixen .
En aquesta línia, la principal causa de funció retardada de l'empelt és el dany induït per la isquèmia-reperfusió, procés en part inherent a la tècnica del trasplantament renal, que es pot veure agreujat per múltiples factors com poden ser la situació del donant previ a la extracció de l'òrgan, la mateixa intervenció quirúrgica o per característiques del receptor. L'activació de el sistema del complement és un dels principals mecanismes involucrats en la fisiopatologia d'aquest fenomen.
L'objectiu de la present tesi és aprofundir en el coneixement de el dany induït per l'activació del sistema del complement en el fenomen d'isquèmia-reperfusió, en l'àmbit del trasplantament renal.
Per això, hem dissenyat tres estudis que abasten diferents aspectes clínics i etiopatogènics del dany pel complement en la isquèmia-reperfusió. Inicialment, vam analitzar l'impacte de la funció retardada de l'empelt, en una àmplia cohort de pacients trasplantats renals. Detectem pitjor supervivència de l'empelt i pitjor funció renal a l'any del trasplantament, en aquells pacients que van presentar funció retardada de l'empelt. D'altra banda, analitzem, la dinàmica de les concentracions solubles de el complex d'atac de membrana, producte de l'activació de la via final de el sistema del complement; també, examinem el patró histològic dels dipòsits del complex d'atac de membrana, C3d i el factor H. Aquesta anàlisi va ser realitzat en pacients trasplantats renals, amb i sense funció retardada de l'empelt, seguits de manera prospectiva. Vam trobar un augment rellevant tant dels nivells plasmàtics, com dels dipòsits histològics del complex d'atac de membrana, C3d i factor H, en aquells casos amb funció retardada de l'empelt. A més, vam detectar que una major concentració de nivells plasmàtics de complex d'atac de membrana es relaciona amb pitjor funció renal a 1 i 2 anys després de l'trasplantament.
També vam desenvolupar un model d'hipòxia-reoxigenació, utilitzant cèl·lules tubulars proximals humanes (HK-2). Aquest model va revelar activació local de diferents components de sistema del complement, inclòs el complex d'atac de membrana, i els receptors de C5a (C5aR1 i C5L2), un altre producte final de el sistema del complement, poc estudiat en aquest àmbit. Finalment, avaluem l'expressió histològica de C5aR1 i C5L2, en biòpsies de pacients trasplantats renals amb funció retardada de l'empelt i un grup control. Aquesta anàlisi ens va mostrar, major expressió de C5aR1 a la membrana de les cèl·lules tubulars i de C5L2 en endoteli capil·lar peritubular en les biòpsies de pacients amb funció retardada de l'empelt, comparat amb els controls.Los avances realizados en los últimos años en las técnicas de extracción y preservación de los órganos trasplantados, así como en la medicación inmunosupresora y la evaluación del riesgo inmunológico, han permitido mejorar la supervivencia del injerto renal y del receptor a corto plazo. Esta mejoría no se ve tan claramente reflejada a medio y largo plazo. Probablemente, una de las causas de esto último es la función retrasada del injerto, una forma de daño renal agudo, que se presenta en un 20-50% de los receptores de donante fallecido y que empeora el pronóstico de los riñones trasplantados que la sufren. En esta línea, la principal causa de función retrasada del injerto es el daño inducido por la isquemia-reperfusión, proceso en parte inherente a la técnica del trasplante renal, que puede verse agravado por múltiples factores como pueden ser la situación del donante previo a la extracción del órgano, la propia intervención quirúrgica o por características del receptor. La activación del sistema del complemento es uno de los principales mecanismos involucrados en la fisiopatología de este fenómeno. El objetivo de la presente tesis es profundizar en el conocimiento del daño inducido por la activación del sistema del complemento en el fenómeno de isquemia-reperfusión, en el ámbito del trasplante renal. Para ello, hemos diseñado tres estudios que abarcan diferentes aspectos clínicos y etiopatogénicos del daño por el complemento en la isquemia-reperfusión. Inicialmente, analizamos el impacto de la función retrasada del injerto, en una amplia cohorte de pacientes trasplantados renales. Detectamos peor supervivencia del injerto y peor función renal al año del trasplante, en aquellos pacientes que presentaron función retrasada del injerto. Por otro lado, analizamos, la dinámica de las concentraciones solubles del complejo de ataque de membrana, producto de la activación de la vía final del sistema del complemento; también, examinamos el patrón histológico de los depósitos del complejo de ataque de membrana, C3d y el factor H. Este análisis fue realizado en pacientes trasplantados renales, con y sin función retrasada del injerto, seguidos de forma prospectiva. Encontramos un aumento relevante tanto de los niveles plasmáticos, como de los depósitos histológicos del complejo de ataque de membrana, C3d y factor H, en aquellos casos con función retrasada del injerto. Además, detectamos que una mayor concentración de niveles plasmáticos de complejo de ataque de membrana se relaciona con peor función renal a 1 y 2 años después del trasplante. También desarrollamos un modelo de hipoxia-reoxigenación, utilizando células tubulares proximales humanas (HK-2). Este modelo reveló activación local de diferentes componentes del sistema del complemento, incluido el complejo de ataque de membrana, y los receptores de C5a (C5aR1 y C5L2), otro producto final del sistema del complemento, poco estudiado en este ámbito. Finalmente, evaluamos la expresión histológica de C5aR1 y C5L2, en biopsias de pacientes trasplantados renales con función retrasada del injerto y un grupo control. Este análisis nos mostró, mayor expresión de C5aR1 en la membrana de las células tubulares y de C5L2 en endotelio de capilar peritubular en las biopsias de pacientes con función retrasada del injerto, comparado con los controles.
The advances made during the last years in the extraction and preservation of the organs for transplantation, immunosuppressive medication, and the evaluation of immunological risk have improved patient and renal allograft survival. However, these improvements have had a limited effect on long-term survival. One of the reasons that negatively influence this long-term survival is the appearance of delayed graft function, a form of acute kidney damage, which occurs in 20-50% of deceased donor recipients and worsens the graft outcomes. The leading cause of delayed graft function is the damage induced by ischemia-reperfusion, a process inherent to the kidney transplantation process. The ischemia-reperfusion injury could be aggravating by different variables such as the donor's situation before organ retrieval or recipient characteristics. In the pathophysiology of this phenomenon, the activation of the complement system is highly relevant. This thesis's objective has been to expand our understanding of the damage induced by the activation of the complement system during ischemia-reperfusion injury in kidney transplantation. To this end, we designed three studies that evaluated different clinical and etiopathogenic aspects of the ischemia-reperfusion phenomenon. We initially assessed the impact of delayed graft function in a large cohort of kidney transplant patients. The development of delayed graft function was associated with worse graft survival and worse kidney function in the first year after transplantation. On the other hand, we analyze the dynamics of plasma levels of the membrane attack complex's soluble form, the final product from complement system activation in kidney transplant patients with and without delayed graft function. Additionally, we examined the histological pattern of the deposits of the membrane attack complex, C3d, and factor H in kidney biopsies from patients who were experiencing delayed graft function and controls with normal biopsies. We detected a relevant increase in plasma levels and histological deposits of the membrane attack complex, C3d, and factor H, in those patients with delayed graft function. A high concentration of membrane attack complex levels was related to worse kidney function at one and two years after transplantation. Finally, we developed a model of hypoxia-reoxygenation with human proximal tubular cells (HK-2). We demonstrated local activation of the complement system's different components, including the membrane attack complex, and the C5a receptors (C5aR1 and C5L2), another product of the complement system, scarcely studied in this area. Besides, we observed a higher expression of C5aR1 in the tubular cell membrane and C5L2 in the peritubular capillary endothelium, in biopsies of patients with delayed graft function, compared to controls.
Universitat Autònoma de Barcelona. Programa de Doctorat en Medicina
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Ståhl, Martin. „Numerical modeling to complement wood tests“. Thesis, Uppsala universitet, Tillämpad mekanik, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-207269.
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Pressure tests on wood have been conducted to determine its properties. The resultswere not as expected, and it is therefore difficult to obtain the parameters of thewood. This project examines how a specific defect in the wood sample affects theresult.The pressure test is simulated with numerical modeling. In the numerical model thecube’s top side is non-parallel with the bottom side, it is in other words somewhattilted.The results from the model agreed with the findings from some pressure tests. Withthose we can easily calculate the wood's properties. For other pressure tests, otherfactors might need to be examined before we can draw any conclusions.Tryckprover på trä har utförts för att ta reda dess egenskaper. Resultaten blev intevad som förväntades, och det blir därför svårt att få fram träets egenskaper. Dettaprojekt undersöker hur en viss defekt i träprovet påverkar resultatet.Tryckprovet simuleras med numerisk modellering. I modellen är kubens toppsida inteparallell med bottensidan, den är med andra ord något sned.Resultatet från modellen stämde med resultat från vissa tryckprover. Då kan man fåfram träets egenskaper. För andra tryckprover kan andra faktorer behöva undersökasinnan man kan dra några slutsatser.
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Gibb, Alison L. „Studies on human complement component C4“. Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.358680.
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Presanis, Julia. „The lectin pathway of complement activation“. Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413519.
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Senior, Jonathan Mark. „Complement and endotoxins in equine colic“. Thesis, University of Liverpool, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501730.
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Colic (abdominal pain) is a relatively common disease of horses ranging from mild, transient episodes to a life-threatening syndrome that requires surgical intervention. Equine intestinal abnormalities that involve local stasis are often accompanied by marked proliferation of Gram negative enteric bacteria and breakdown of the mucosal barrier resulting in the transmural and transvascular migration of bacteria and their endotoxins into the circulation (endotoxaemia). Even if the original cause of colic is corrected or resolved, the presence of endotoxaemia can isult in significant morbidity and mortality in horses. This project aimed to characterise specific equine complement component, complement 1 esterase-inhibitor (Cl-inh) because it is considered a key inhibitor of the connplement, coagulation and contact activation pathways.
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Krarup, Anders. „The lectin pathway of complement activation“. Thesis, University of Oxford, 2007. http://ora.ox.ac.uk/objects/uuid:46255854-bfba-4d57-9185-3e6ed970a2db.
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The complement system is an important immune system mechanism involved in both the recognition and elimination of invading pathogens. It is activated by three different pathways: The classical pathway, which relies on binding of C1, and results in the cleavage of C4 and C2 through activation of C1r and C1s; the alternative pathway that relies on the spontaneous hydrolysis of C3 and the lectin pathway. The lectin pathway is activated by binding of Mannan-binding lectin (MBL) or the ficolins (L-ficolin, H-ficolin and M-ficolin) to microbial binding motifs, and the subsequent activation of the MBL-associated serine proteases (MASP) 1/ 2/ 3. Of these MASP2 has been identified as the enzyme responsible for the activation of complement by C4 and C2 cleavage. The work presented here will focus on four different aspects of the lectin pathway: specificity and stoichiometry of the L-ficolin protein complex, expression of H-ficolin, substrate characterization for MASP1 and investigation of the prothrombin activation potential of MASP2. L-ficolin binding specificity was investigated using glycan array technology, and it was found that L-ficolin, instead of recognizing single monosaccharides like MBL, instead binds to extended oligosaccharide structures. The binding to these was dependent not only on the presence of acetyl groups, but also on their orientation in space. It was also found that L-ficolin in serum is found as a multimeric protein complex composed of 18 polypeptide chains and associated with one MASP dimer. The expression of H-ficolin resulted in the generation of a stable mammalian cell line producing oligomerized and biologically functional H-ficolin. MASP1 substrate specificity was investigated by two different procedures. Firstly fractionated plasma was subjected to MASP1 treatment in an attempt to identify a plasma protein substrate. This did not yield any substrate candidates, since only cleavage of the protease inhibitor α-2-macroglobulin could be detected. Additionally the thrombin-like activity of MASP1 was investigated through cleavage experiments done with factor XIII and fibrinogen. These experiments showed that the factor XIII cleavage site for MASP1 and thrombin is identical. This was also found for the fibrinogen β-chain but not for the α-chain showing that MASP1 interaction with fibrinogen is distinct from that of thrombin. An earlier observation that MASP2 was capable of activating prothrombin and generating thrombin was further characterized. Here it was shown that the activation of prothrombin by MASP2 is identical to that by factor Xa, which is the enzyme undertaking this role in the coagulation system, and that the activation can result in deposition of fibrin on the surface upon which MASP2 is bound. The prothrombin activation potential of MASP2 was also utilized to develop a new MASP2 activity assay, which was shown to be capable of measuring MASP2 activity, when MASP2 is bound, via MBL (or L-ficolin) to appropriate surfaces.
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Wright, Mathew William. „Retinal photoreceptor complement of paleognathous birds“. Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313609.
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Farris, Lindsey. „Normal p-Complement Theorems“. Youngstown State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ysu1525865906237554.
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Erdoğan, Sultan Eylem Alizade Refail. „Absolutely Supplement And Absolutely Complement Modules/“. [s.l.]: [s.n.], 2004. http://library.iyte.edu.tr/tezler/master/matematik/T000339.pdf.
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Hakulinen, Juha. „Complement-mediated killing of cancer cells“. Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/hakulinen/.
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Pierre, Andrew F. „The effect of complement inhibition with soluble complement receptor 1 (sCR1) on pig allo-transplant lung function“. Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ29290.pdf.
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Piccoli, Amanda Kirchner. „Expressão de proteínas reguladoras do complemento CD55/CD59/CD35/CD46 em pacientes com artrite reumatóide“. reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2011. http://hdl.handle.net/10183/28210.
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A Artrite Reumatóide (AR) é uma doença autoimune associada a poliartropatia inflamatória que acomete principalmente as articulações periféricas. Cerca de 1% da população mundial é afetada, sendo duas a três vezes mais prevalente em mulheres. Apresenta uma patogênese complexa e multifatorial. A sinóvia das articulações afetadas é infiltrada por linfócitos T e B, macrófagos e granulócitos. A sinóvia reumatóide adquire características proliferativas, formando o pannus, e invade a cartilagem articular e o osso, levando à destruição da arquitetura normal da articulação e perda de função. Em vários modelos de doenças autoimunes, a ausência ou diminuição da expressão de proteínas reguladoras do complemento tem sido observada, associada com o agravamento dos sintomas clínicos, sendo que, muitos destes casos, a superativação do sistema complemento pode ser a causa da exacerbação da doença. O presente artigo tem por objetivo revisar os principais aspectos relacionados à regulação do sistema complemento na artrite reumatóide, a fim de propiciar uma melhor compreensão do potencial papel desse sistema na fisiopatologia da doença.Rheumatoid arthritis (RA) is an autoimmune disease associated with polyarticular inflammatory synovitis that affects mainly the peripheral joints. About 1% of the world population is affected, and it is two to three times more prevalent in women. RA has a complex and multifactorial pathogenesis. The rheumatoid synovium acquires proliferative characteristics, forming the pannus, and invades cartilage and bone, leading to the destruction of normal architecture and loss of function. In several models of autoimmune diseases, the absence or decreased expression of complement regulatory proteins has been observed, associated with worsening of the clinical symptoms, and many of these cases the over-activation of the complement system is the cause of disease exacerbation. This article aims to review the main aspects related to regulation of the complement system in rheumatoid arthritis in order to provide a better understanding of the potential role of this system in the pathophysiology of the disease.
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Silva, Ludmila Bezerra da. „Interação da proteína de superfície LcpA de Leptospira com Fator H, principal regulador solúvel da via alternativa do sistema complemento humano“. Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/10/10134/tde-26112013-143254/.
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A leptospirose é uma zoonose de distribuição mundial, com maior incidência nas regiões tropicais. As bactérias que causam a doença pertencem ao gênero Leptospira, família Leptospiracea e ordem Spirochaetales. A leptospirose é mantida na natureza pela colonização persistente dos túbulos renais proximais dos animais portadores. Uma estratégia adotada por estas espiroquetas para sobreviver à ação do sistema imune inato do hospedeiro é a capacidade que possuem de interagir com os reguladores do sistema complemento Fator H (FH) e proteína de ligação a C4b (C4BP). O sistema complemento é um componente vital da imunidade inata, uma vez que desempenha um papel crucial na defesa do hospedeiro, particularmente contra bactérias Gram-negativas. Dados recentes gerados por nosso grupo mostraram que C4BP interage com a proteína de superfície LcpA de Leptospira. Com cerca de 20 kDa, essa proteína é capaz de se ligar a C4BP purificado ou solúvel no soro de maneira dose-dependente. Uma vez ligado à proteína, C4BP permanece funcional agindo como cofator de Fator I na clivagem de C4b. O presente estudo teve como principal objetivo avaliar a interação da proteína LcpA com FH humano, principal regulador solúvel da via alternativa do sistema complemento. A proteína LcpA e suas porções N-Terminal, Intermediária e CTerminal recombinantes foram purificadas por cromatografia de afinidade a metal a partir da fração insolúvel. A interação dessas proteínas com FH foi avaliada por dois métodos distintos: ELISA e Western blot com overlay. Os resultados indicaram que a porção C-Terminal da proteína LcpA é responsável pela interação com FH. Curiosamente, C4BP também se liga a esse domínio da proteína. Uma vez que esses dois reguladores solúveis do sistema complemento interagem com o mesmo segmento da LcpA, realizaram-se, a seguir, ensaios de competição com o objetivo de avaliar se ambos compartilhariam os mesmos sítios de interação. Os dados mostraram que FH e C4BP devem se ligar a sequências distintas desta proteína. Com o objetivo de se avaliar a funcionalidade de FH ligado à LcpA, realizou-se um ensaio para investigar sua atividade de co-fator de Fator I na clivagem de C3b. Produtos de degradação de 46 kDa e 43 kDa da cadeia α' de C3b foram detectados, indicando que FH permanece funcional. Em se tratando de uma proteína com funções relacionadas ao processo de evasão ao sistema imune inato, decidiu-se realizar ensaios de desafio em modelo de hamster com a finalidade de se avaliar seu potencial imunoprotetor. Os três ensaios realizados indicaram que a proteína não é capaz de conferir proteção. Os ensaios de ELISA visando à avaliação dos títulos de anticorpos mostraram que LcpA não é imunogênica, fato que explica os resultados dos ensaios de desafio observados. Portanto, embora interaja com moléculas do hospedeiro e pareça contribuir para o processo de evasão ao sistema imune inato, essa proteína de membrana não se mostrou promissora como candidato vacinal contra leptospirose.Leptospirosis is a zoonosis of global distribution, with higher incidence in tropical areas. The bacteria that cause the disease belong to the genus Leptospira, family Leptospiracea and order Spirochaetales. Leptospirosis is maintained in nature by persistent colonization of proximal renal tubules of carrier animals. One strategy adopted by these spirochetes to escape from host´s innate immune system is the ability to interact with the complement regulators Factor H (FH) and C4b Binding Protein (C4BP). The complement system is a vital component of the innate immune system, being crucial for host´s defense, particularly against Gram-negative bacteria. According to our recent published data, C4BP interacts with the leptospiral surface protein LcpA. This 20 kDa outer membrane protein binds both purified and serum C4BP in a dose-dependent manner. Once bound, C4BP remains functional acting as a cofactor for Factor I in the cleavage of C4b. In the present study we evaluated the interaction of LcpA with human FH, the main soluble regulator of the alternative pathway of complement. The intact protein as well as its N-terminal, intermediate and C-terminal portions were purified by metal-affinity chromatography from the insoluble pellet. The interaction of these proteins with FH was evaluated by two distinct methods: ELISA and Western blot overlay. Our results indicate that the C-terminal domain of LcpA mediates interaction with FH, and also with C4BP. Since both complement regulators interact with the same fragment of LcpA, we next performed competition assays to assess if they would share binding sites. According to our data, FH and C4BP have distinct binding sites on LcpA. Cofactor activity of FH bound to immobilized LcpA was confirmed by detecting the C3b α' chain cleavage fragments of 46 and 43 kDa upon incubation with Factor I, thus indicating that it remains functionally active. Given the LcpA´s role in host´s innate immune evasion, we also evaluated its vaccine potential in a hamster model. Data from three challenge assays indicated that the protein can not afford protection. Low ELISA antibody titers of hamsters immunized with LcpA were observed, which strongly suggests that this protein is not immunogenic. In conclusion, LcpA interacts with host´s molecules and seems to contribute to the bacterial immune evasion. Nevertheless, this outer membrane protein is not a promising vaccine candidate against leptospirosis.
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Anjolette, Fernando Antonio Pino. „Isolamento e caracterização bioquímica do componente presente no veneno de Rhinella schneideri com atividade sobre o sistema complemento“. Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/60/60134/tde-30062011-162359/.
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Importantes estudos voltados para a análise das secreções de anfíbios fundamentam-se na grande quantidade de componentes biologicamente ativos presentes nas mesmas, tais como aminas biogênicas, esteróides, aminopolissacarídeos, glicosídeos, inibidores de proteases e diversos outros compostos, responsáveis pela complexa sintomatologia observada no envenenamento. O gênero Bufo apresenta diversas moléculas em suas excreções que podem ser divididas em categorias como aminas biogênicas, bufadienolídeos (bufogeninas), esteróides (bufotoxinas), alcalóides, peptídeos e proteínas. Marongio (2006) verificou que o veneno do sapo Bufo paracnemis, hoje classificado como Rhinella schneideri, apresenta componente ativo sobre a via clássica do sistema complemento (SC), necessitando de melhores estudos e caracterização. Os objetivos deste trabalho foram, portanto, o isolamento e caracterização química do componente do veneno de Rhinella schneideri responsável pelos efeitos observados sobre o sistema complemento. Para a purificação, o veneno foi inicialmente submetido a uma cromatografia catiônica (CM-Celulose-52), obtendo-se 7 frações denominadas C1, C2, C3, C4, C5, C6 e C7. A fração C1 foi cromatografada em resina aniônica (DEAE-SepharoseTM), resultando em 4 subfrações denominadas D1, D2, D3, e D4. A subfração D3 apresentou atividade sobre o sistema complemento e foi submetida a uma Gel Filtração (SephacrylTMS-200), fornecendo 5 subfrações denominadas S1, S2, S3, S4, e S5. As subfrações S2 e S5 induziram redução da atividade hemolítica das vias clássica/lectinas. Ambas apresentaram resultados positivos nos ensaios de migração de neutrófilos e imunoeletroforese bidimensional. No ensaio de capacidade geradora de SC5b-9, a subfração S2 apresentou maior significância frente as demais subfrações utilizadas. Visando esclarecer o mecanismo de ação das subfrações ativas sobre o sistema complemento, testes de determinação da atividade proteolítica ou inibitória de proteases (tripsina, quimotripsina e elastase) foram realizados. No entanto, nas concentrações utilizadas, as amostras não mostraram atividade proteolítica ou inibitória de protease. Os compostos isolados foram também submetidos ao sequenciamento amino-terminal inicial. Foi possível a identificação dos primeiros 15 aminoácidos da banda protéica majoritária do gel de poliacrilamida e 10 e 5 aminoácidos das subfrações S2 e S5, respectivamente. No entanto, os resultados de sequenciamento N-terminal apresentaram baixa confiabilidade, devido à baixa quantidade de material utilizada. Neste trabalho foram isolados e caracterizados dois compostos capazes de induzir a ativação do sistema complemento. Esta ação foi evidenciada, após exposição do soro humano normal às subfrações, por induzirem à formação do complexo SC5b-9 e aumentarem a migração de neutrófilos, provavelmente por induzirem a formação de fatores quimiotáticos. Este estudo permitiu avaliar melhor alguns componentes presentes na complexa mistura que é o veneno de Rhinella schneideri, que, no futuro, poderão se tornar ferramentas farmacológicas importantes para o estudo de diversas patologias relacionadas ao sistema complemento.Important studies focused on amphibians secretions analysis are based on large amount of biologically active components present in them, such as biogenic amines, steroids, polysaccharide amine, glycosides, protease inhibitors and several other compounds, responsible for complex symptomatology observed in the envenomation by Bufo paracnemis. The genus Bufo presents several molecules in their excretions that can be divided into categories such as biogenic amines, bufadienolides (Bufogenin), steroids (Bufotoxins), alkaloids, peptides and proteins. Marongio (2006) found in one of his studies the toad poison of Bufo paracnemis, now classified as Rhinella schneideri, has an active component of the classical pathway of the complement system (SC), which needs further studies and characterization. The purification process of this study was accomplished through cation chromatography (CM-Cellulose-52), and seven fractions were obtained, called C1, C2, C3, C4, C5, C6 e C7. The fraction C1 was chromatographed on anion-exchange resin (DEAE- SepharoseTM) resulting in 4 subfractions referred to as D1, D2, D3, and D4. The subfraction D3 showed activity on complement system and was subjected to gel filtration (SephacrylTMS-200) giving 5 subfractions termed S1, S2, S3, S4, and S5. The subfractions S2 and S5 induced reduction of the hemolytic activity of the classical/lectin pathway. Both showed positive results in the assays of migration of neutrophils and bidimensional immunoelectrophoresis. In the assay of generating capacity of SC5b-9, the subfraction S2 presented greater significance when compared to the other used subfractions. Aiming to clarify the action mechanism of the active subfractions on the complement system, tests of determination of the proteolytic or inhibitory activity of proteases (trypsin, chymotrypsin and elastase) had been done. However, in the used concentrations, the samples had not shown proteolytic or inhibitory activity of protease. The isolated compounds also had been submitted to the initial amino-terminal sequence. The identification of the first 15 aminoacids of the major proteinic band of the polyacrylamide gel and 10 and 5 aminoacids of the subfractions S2 and S5 was possible, respectively. However, the sequence of N-terminal results had presented low trustworthiness, due to the low amount of used material. In this work, were isolated and characterized two capable compounds to induce the activation of the complement system. This action was evidenced, after exposition of the normal human serum to the subfractions, for inducing to the formation of the SC5b-9 complex and will increase the migration of neutrophils, probably because they can induce the formation of chemotactic factors. This study allowed a better evaluation of some components present in the complex mixture which is the poison of Rhinella schneideri, that, in the future, important pharmacological tools for the study of diverse pathologies related the complement system.
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Aude, Catherine. „Etude de la structure et du mécanisme d'activation de C1s-C1r-C1r-C1s, sous-unité catalytique de C1, premier composant de la voie classique du complément“. Grenoble 1, 1988. http://www.theses.fr/1988GRE10143.
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Belic, Bojan. „Complement verb variation in present-day Serbian“. Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1125075094.
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Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xv, 231 p.; also includes graphics. Includes bibliographical references (p. 226-231). Available online via OhioLINK's ETD Center.
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Conway, Morris Andrew. „Complement-mediated neutrophil dysfunction in critical illness“. Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/27824.
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Critical illness, constituting an acute illness or injury resulting in organ dysfunction and failure, is associated with a profound, systemic activation of the immune system and inflammation-mediated organ damage. However, critically ill patients suffer a high rate of nosocomial infection with secondary sepsis being a common cause of death. This high prevalence of secondary infections argues for the influence of an immune suppression that may, at first glance, appear paradoxical in light of the pro-inflammatory nature of critical illness. Although immune cell hypo-function has been noted in clinical and experimental critical illness, the mediators of these effects remain poorly defined. In this thesis, neutrophil function was examined in the context of clinically suspected ventilator-associated pneumonia, a common and lethal intensive care acquired infection (ICU-AI), This demonstrated impaired bactericidal functions (phagocytosis and reactive oxygen species production) in neutrophils from both the peripheral and pulmonary compartments; however there was ample evidence of coexistent neutrophil activation (both cell surface markers and soluble mediators) and inflammation. An investigation of possible mediators of neutrophil dysfunction revealed a major role for C5a, the pro-inflammatory anaphylotoxin derived from complement C5. Recombinant C5a applied to healthy donor neutrophils was able to drive the defect in phagocytosis by phospho-inositol 3 kinase delta-mediated inhibition of RhoA and subsequent down regulation of actin polymerisation. The defects in RhoA and actin function were reversible with granulocyte-macrophage colony stimulating factor (GM-CSF) applied ex vivo, restoring phagocytic function to normal. Similar defects in RhoA and actin, and effective treatment with GMCSF, were found in neutrophils from critically ill patients. In a second cohort of critically ill adults recruited prior to developing any ICU-AI, C5a-mediated neutrophil dysfunction was an independent predictor of acquiring nosocomial infection, being associated with a 5.4 fold increased risk (95% Confidence interval 1.4-21.0). The same cohort of patients also displayed two other features of immune suppression, namely monocyte deactivation and elevated proportions of regulatory T-cells that were also associated with increased risk of infection (relative risk of infection 3 (95%CI1.3-6.9) and 2.4 (95%CI1.3-4.2) respectively). These measures acted additively with C5a-mediated dysfunction, those with no immune impairment having a zero rate of nosocomial infection with cumulative increases in impairments being associated with a progressive increase in risk of infection (p=0.0004 by Chi squared for trend). In conclusion, critical illness is characterised by a complex inflammatory state with features of simultaneous hyper- and hypoactivation. This remarkable duality is illustrated by the ability of a proinflammatory molecule, C5a, to drive neutrophil dysfunction, with this dysfunction being associated with a serious adverse event-nosocomial infection.
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Timár, Krisztina Klára. „Human keratinocytes production of complement and chemokines /“. [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2006. http://dare.uva.nl/document/20321.
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Vaishnaw, Akshay Krishnakant. „Molecular genetics of the complement protein C4“. Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336579.
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Malhotra, V. „Cellular receptors for the third complement component“. Thesis, University of Oxford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.355763.
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Soames, Candida J. „Factor H : a major complement regulatory protein“. Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307011.
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Bramley, J. C. „Complement regulation in microorganisms : Herpesvirus saimiri CD59“. Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596865.
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Herpesvirus saimiri (HVS) is a T-lymphotropic γ-herpesvirus of New World Monkeys. The entire genome of HVS has been mapped and shown to contain several open reading frames (ORFs) with striking homology to mammalian cellular proteins, suggesting that host genes have been captured during the course of evolution. Such a gene is ORF 15 that has 64% homology to human CD59 and 69% homology to CD59 from squirrel monkey, the natural host for HVS. CD59 is a membrane glycoprotein which inhibits cell lysis induced by the membrane attack complex of complement, an important component of the innate immune response. Therefore, its acquisition could provide the virus with a potent method for evasion of host immune defences. The aim of the study was to discover whether ORF 15 does indeed encode a functional protein. The sequence was expressed in insect cells using the baculovirus expression system. HVS CD59 expressing cells were found to be protected against lysis by human complement in comparison with cells infected with a control virus, demonstrating the presence of functionally active HVS CD59 on the cell surface. However, no cross-reactivity with antibodies to Hu CD59 was observed, despite the high degree of sequence homology. Therefore, a number of alternative approaches were explored to facilitate purification of the protein. The most successful of these proved to be creation of an epitope tagged molecule by inserting the FLAG octapeptide N-terminal to the main coding region. This has permitted the recognition of an 18 kDa molecule by an anti-FLAG monoclonal antibody in a Western blot under reducing conditions, opening the way for purification and characterisation of this novel protein.
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Mackinnon, Charlotte M. „Molecular cloning of human complement component Cls“. Thesis, University of Aberdeen, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327928.
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Cls cDNA clones, which together contained the entire coding region of the protein, were isolated from two human-liver cDNA libraries. The initial Cls clones were identified using a synthetic oligonucleotide probe which corresponded to a region of low degeneracy near the C-terminus of the Cls catalytic chain. Fragments of the Cls cDNA were used to screen a cosmid library in an attempt to isolate the Cls gene, but this proved unsuccessful and no positive clones were isolated. The complete primary sequence of Cls revealed that the homology between the Cls and Clr catalytic chains also extends throughout their non-catalytic chains. Like Clr, Cls can be divided into six structurally independent domains of which the sixth represents the catalytic B chain. Domains I and III in the A chain of Cls are internally homologous, as are domains IV and V. The latter domains are homologous to the internally repeating 60-residue sequences found in Factor B, C2 and other proteins. Domain II of Cls is similar to the 40-residue repeat sequences found in epidermal growth factor precursor and many of the vitamin K-dependent proteins. The assignment of these domains to the different regions of Cls tertiary structure has still to be achieved, but studies in this area should be facilitated now that the complete primary sequence for the Cls zymogen is available.