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1
Braga, Aécio Assunção. "Polimorfismos dos genes CD40, ICAM-1, VCAM, E-selectina, LIGHT, RAGE e CX3CR1 relacionados com inflamação e sua associação à obesidade." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-26052015-143307/.
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INTRODUÇÃO: A obesidade é um grave problema de saúde pública, sendo definida como o acúmulo excessivo de gordura, possivelmente decorrente do desequilíbrio, por um longo período, entre a quantidade de energia ingerida e o gasto energético. OBJETIVO: Investigar a contribuição dos polimorfismos dos genes CD40, ICAM-1, VCAM, E-selectina, LIGHT, RAGE e CX3CR1 na associação com a obesidade. CASUÍSTICA E MÉTODOS: O estudo foi realizado no Instituto Dante Pazzanese de Cardiologia (IDPC) e no Hospital Universitário da Universidade de São Paulo (HU/USP), com 199 indivíduos (40 com peso normal, 55 com sobrepeso e 104 obesos) brasileiros, sem vínculo genético, de etnias branca, parda, negra e amarela, de ambos os sexos (55 homens e 144 mulheres), com idade entre 30 e 68 anos. Foi realizado o estudo dos polimorfismos dos genes CD40 (rs1883832) C>T, CX3CR1 (rs3732379) C>T, CX3CR1 (rs3732378) G>A, E-selectina (rs5368) C>T, ICAM-1 (rs1799969) G>A, ICAM-1 (rs281432) C>G, LIGHT (rs344560) G>A, LIGHT (rs2291668) C>T, RAGE (rs2070600) G>A, RAGE (rs2236493) C>T e VCAM (rs3176878) C>T, por pirossequenciamento, a análise da expressão dos genes LIGHT, CX3CR1, RAGE e ICAM-1, pela PCR em tempo real, e as dosagens das formas solúveis de PAI-1, IL-6, TNF-α, resistina, adiponectina e leptina, utilizando o sistema LUMINEX. RESULTADOS: As frequências alélica e genotípica dos polimorfismos estudados CD40 (rs1883832) C>T, CX3CR1 (rs3732379) C>T, CX3CR1 (rs3732378) G>A, E-selectina (rs5368) C>T, ICAM-1 (rs1799969) G>A, ICAM-1 (rs281432) C>G, LIGHT (rs344560) G>A, LIGHT (rs2291668) C>T, RAGE (rs2070600) G>A, RAGE (rs2236493) C>T e VCAM (rs3176878) C>T não apresentaram associação significativa com a obesidade. Foi encontrada associação na análise da expressão do CX3CR1 com a obesidade e também foi encontrada associação do polimorfismo ICAM-1 (rs281432) G>C com a expressão do gene RAGE em indivíduos com peso normal. CONCLUSÕES: Não houve associação dos polimorfismos CD40 (rs1883832) C>T, CX3CR1 (rs3732379) C>T, CX3CR1 (rs3732378) G>A, E-selectina (rs5368) C>T, ICAM-1 (rs1799969) G>A, ICAM-1 (rs281432) C>G, LIGHT (rs344560) G>A, LIGHT (rs2291668) C>T, RAGE (rs2070600) G>A, RAGE (rs2236493) C>T e VCAM (rs3176878) C>T com a obesidade, mas houve associação da expressão do gene CX3CR1 com a obesidade. Houve, também, associação do polimorfismo ICAM-1 (rs281432) G>C com a expressão do gene RAGE em indivíduos de peso normal.<br>Background: Obesity is a serious health problem and it is defined as an excessive fat accumulation which is caused by an imbalance between the amount of energy intake and energy expenditure over a long period. Objective: The main objective of this study was to investigate the contribution of CD403 ICAM-1, VCAM, E-selectin, LIGHT, RAGE e CX3CR1 gene polymorphisms and its association with obesity. Material and Methods: The study was realized at Dante Pazzanese Institute of Cardiology and University Hospital of São Paulo University. There were included 199 individuals (40 normal weight, 55 overweight and 104 obese), all Brazilian, with no genetic link, from all ethnics in both genders (55 men and 144 women), aged between 30 and 68 years. The study of CD40 (rs1883832) C>T, CX3CR1 (rs3732379) C>T, CX3CR1 (rs3732378) G>A, E-selectin (rs5368) C>T, ICAM-1 (rs1799969) G>A , ICAM-1 (rs281432) C>G, LIGHT (rs344560) G>A, LIGHT (rs2291668) C>T, RAGE (rs2070600) G>A, RAGE (rs2236493) C>T and VCAM (rs3176878) C>T were conducted by pyrosequencing. The analysis of LIGHT, CX3CR1, RAGE and ICAM-1 gene expression were performed by real-time PCR and the measurements of PAI-1, IL- 6, TNF-a, resistin, leptin and adiponectin soluble forms using LUMINEX system. Results: The allele and genotype frequency of CD40 (rs1883832) C>T, CX3CR1 (rs3732379) C>T, CX3CR1 (rs3732378) G>A, E-selectin (rs5368) C>T, ICAM-1 (rs1799969) G>A , ICAM-1 (rs281432) C>G, LIGHT (rs344560) G>A, LIGHT (rs2291668) C>T, RAGE (rs2070600) G>A, RAGE (rs2236493) C>T and VCAM (rs3176878) C>T gene polymorphisms showed no significant association with obesity. There was found association in the analysis of CX3CR1 expression with obesity and it was found association of ICAM-1 gene polymorphism (rs281432) G>C with RAGE gene expression in the normal weight group. Conclusion: There was no association of CD40 (rs1883832) C>T, CX3CR1 (rs3732379) C>T, CX3CR1 (rs3732378) G>A, E-selectin (rs5368) C>T, ICAM-1 (rs1799969) G>A , ICAM-1 (rs281432) C>G, LIGHT (rs344560) G>A, LIGHT (rs2291668) C>T, RAGE (rs2070600) G>A, RAGE (rs2236493) C>T and VCAM (rs3176878) C>T gene polymorphisms with obesity. However, it was found association of CX3CR1 gene expression with obesity and an association of ICAM-1 (rs281432) G>C gene polymorphism with RAGE gene expression in normal weight individuals.
2
Lovejoy, Elizabeth A. "RAGE-based strategies for the control of gene expression." Thesis, University of Edinburgh, 1999. http://hdl.handle.net/1842/26699.
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The Cre/loxP site-specific recombinase system evolved within bacteriophage PI as a mechanism to maintain correct unit copy segregation of the prophage within host cells. This thesis reports the application of this system to regulate gene expression in murine cells. To regulate gene expression via RAGE (Recombination Activated Gene Expression) a novel floxed STOP cassette was designed, constructed and tested in murine embryonic fibroblasts (EF) and embryonic stem (ES) cells. When the floxed STOP cassette was used to regulate the expression of the Enhanced Green Fluorescent Protein (EGFP) marker gene a two-fold upregulation of EGFP transcription was observed after Cre mediated excisive recombination. However, no expression of the EGFP gene could be detected at the protein level and several reasons for this observation are discussed. The floxed STOP cassette was also utilised in RAGE-based strategies to achieve conditional expression of the tumour suppressor gene p53. A complex array of biological functions has been assigned to p53. For example, p53 is known to be involved in the regulation of apoptosis, multiple cell cycle checkpoints and the onset of replicative cellular senescence. The development of new approaches to achieve conditional p53 expression should be a valuable tool and permit further investigation into the pleiotropic nature of p53 function. Therefore, the floxed STOP cassette was used to regulate the expression of a p53 cDNA in p53 null primary EF cells <I>in vitro. </I>The upregulation of p53 expression after Cre administration was detected, but at a low frequency, by immunohistochemistry. The response of EF cells to the expression of p53 in terms of replicative cellular senescence was also characterised, including the first description of senescence-associated β-galactosidase expression in any murine cell. The floxed STOP technology was also used in an attempt to generate tools that will allow regulated expression of the endogenous murine p53 gene.
3
Carvalho, Vanessa Isabel Dias Ribeiro de. "C. albicans Cek1 and Ras1: cloning, expression and purification." Master's thesis, Universidade de Aveiro, 2012. http://hdl.handle.net/10773/9526.
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Mestrado em Biologia Aplicada - Biologia Molecular e Celular<br>Candida albicans é um fungo polimórfico e patogénico que reside de forma
comensal nas superfícies mucosas humanas. Este fungo apresenta um código
genético ambíguo, uma vez que, o codão universal leucina CUG é
predominantemente traduzido como serina (97%), mas também como leucina
(3%). A análise de proteínas de C. albicans que contêm resíduos CUG em
importantes posições funcionais, revela que a ambiguidade do codão modela a
função da proteína e poderá ter um papel determinante nas vias de sinalização
associadas a mudanças morfológicas e patogénicas.
Com o presente estudo pretende-se investigar o efeito da leucina e da serina
nas posições CUG (ambiguidade CUG) na estrutura e função de duas
proteínas chave nas vias de sinalização de C. albicans, a Ras1 (GTPase) e a
Cek1 (Cinase). Estas regulam a transcrição dos genes associados com
mudanças morfológicas, patológicas e, por outro lado, contêm resíduos CUG
numa posição estritamente conservada e com relevo funcional.
Neste contexto foi possível clonar com sucesso genes sintéticos para os
centros ativos da Ras1 e Cek1 (variantes de serina e de leucina para o codão
CUG) em vetores que apresentam diferentes caudas de solubilidade (MBP,
NusA, Trx, ZTag2 e Gb1). Foram desenvolvidos protocolos de alta expressão
bacteriana e de purificação para os domínios ativos Ras1 (ligado à Gb1) e
Cek1 (ligado à MBP). A análise dos resultados de purificação analítica e de
“Dynamic Light Scaterring” demonstraram que as proteínas recombinantes se
apresentam na forma monomérica.
Ensaios de cristalização estão a ser realizados esperando-se determinar as
estruturas tridimensionais das proteínas por cristalografia de raio-X. As
estruturas da Cek1 e Ras1 com leucina e serina nas posições CUG,
conjuntamente com uma análise meticulosa da sua estabilidade e função in
vitro, irão fornecer informações importantes sobre o papel estratégico da
ambiguidade natural do codão.<br>The polymorphic fungal pathogen Candida albicans has an ambiguous genetic
code, as the universal leucine CUG codon is predominantly translated as
serine (97%) but also as leucine (3%). Analysis of the rare C. albicans proteins
containing CUG-encoded residues in functionally relevant positions reveals that
codon ambiguity shapes protein function and might have a pivotal role in
signaling cascades associated with morphological changes and pathogenesis.
The present study investigates the effect of leucine or serine at CUG positions
(CUG ambiguity) in the structure and function of two key effectors of signaling
cascades in C. albicans, Ras1 (GTPase) and Cek1 (protein kinase), which
regulate the transcription of genes associated with morphological changes and
pathogenesis. These two proteins contain a CUG residue in a strictly
conserved and functionally relevant position.
Synthetic genes coding for the active domains of Ras1 and Cek1 (serine and
leucine variants for the CUG codon) were successfully cloned into expression
vectors carrying different solubility partners (MBP, NusA, Trx, ZTag2 and Gb1).
Furthermore, using an incomplete factorial approach, high level bacterial
expression and purification protocols for the active domains of Ras1 (in fusion
with Gb1) and Cek1 (in fusion with MBP) were developed. Analytical size
exclusion chromatography (SEC) and dynamic light scattering (DLS) results
indicate that both recombinant proteins are monomeric.
Crystallization trials must be done aiming for the determination of their threedimensional
structures by X-ray crystallography. The structures of Ras1 and
Cek1 with serine or leucine at CUG positions, together with a thorough analysis
of their stability and function in vitro, will provide valuable insights into a
possible strategic role of natural codon ambiguity.
4
Kim, Sun. "HAPLOINSUFFICIENCY OF RAI1 AND ITS EFFECT ON BDNF EXPRESSION." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/165.
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Smith-Magenis Syndrome (SMS) [OMIM, #182290] is a congenital anomaly and mental retardation (MCA/MR) syndrome associated with deletion of chromosome17p11.2 [1]. The clinical phenotype has been well described and includes minor craniofacial anomalies, self-injurious behaviors as well as sleep disturbances, speech delays, and obesity [1,2,3]. The incidence of SMS is estimated to be ~ 1:15,000 - 25,000 births [2,6]. Among SMS patients, ~90% are comprised of 17p11.2 deletions, while ~10% have RAI1 mutations [8]. All 17p11.2 deletions associated with SMS include RAI1 deletion [10]. RAI1 is thought to function as a transcriptional factor although its cellular role is still unclear. First, in order to better understand the role of RAI1 as a transcriptional factor and its relation to SMS, we confirmed that RAI1 regulates BDNF within an intronic region. This sequence was further narrowed down by utilizing the luciferase reporter assay. This test confirmed what was previously found using ChIP-chip assay and microarray analysis of Rai1+/- mice hypothalami. Next, in order to evaluate the role of Bdnf, an ampakine drug was administered to the Rai1+/- mouse model. A mouse model is a powerful tool for studying a specific gene. Rai1+/- mice exhibit the SMS phenotypes of obesity, craniofacial abnormalities, reduced pain sensitivities, seizures and others. Many physical, neurological, and behavioral tests were performed on the mice to see if any of the phenotypes can be rescued. Interestingly, twice-daily injections of ampakine CX1837 restored the pain sensitivities in Rai1+/- mice. The hot plate data suggest that BDNF potentially has a role in regulating the SMS phenotype of decreased pain sensitivity. In order to evaluate other genes that are altered as a result of the CX1837 ampakine drug, the whole brain's global gene expression was evaluated via microarray analysis. Two potential pain-related genes were identified to be upregulated due to drug administration, which could account for the pain phenotypes observed. One of the genes upregulated in treated mice was Osm, which is interesting because Osm is responsible for pain sensitivity. Further analysis is needed to confirm that an ampakine drug can potentially be used to treat SMS patients.
5
Chen, Suzi Su-Hsin, and suzi chen@med monash edu au. "Cyclooxygenase Expression in Human Diabetes." RMIT University. Medical Sciences, 2007. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20080206.121439.
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Cyclooxygenase (COX) is the rate limiting enzyme that catalyses the production of prostanoids, which are crucial to vascular homeostasis. Evidence suggests that endothelial dysfunction and inflammation play a role in vascular complications in aging and diabetes. Previous animal studies by our laboratory at RMIT University reported enhanced COX expression with aging in rat aortas, platelets and monocytes. Potentially, alteration in COX expression may result in an imbalanced prostanoid production favoring the synthesis of vasoconstrictors and hence increase the risk of cardiovascular events in the aging population. The regulation of altered COX expression in aging, however, is not clear. It has been suggested that histone hyperacetylation may be an important mechanism that regulates COX levels during the aging process as increased histone acetylation has been shown to occur with aging. Thus, we hypothesized that COX expression is modulated by histone hyperacetylati on. This was investigated by measuring COX expression in histone hyperacetylated cultured endothelial cells. In the case of diabetes, studies have reported that the development of diabetes and its complications is associated with persistent inflammatory activity, evident with increased inflammatory markers in the circulation. COX-mediated pathways may be involved in this inflammatory process in diabetes. Furthermore, the formation of advanced glycation end products (AGEs) is accelerated in diabetes. AGEs can bind to receptors for AGEs (RAGE), which has also been suggested to play a role in inflammation in diabetes. We hypothesized that COX- and RAGE-mediated pathways contribute to increased inflammation in diabetes and potentiate the development of diabetic vascular complications. This was investigated by measuring changes in COX-mediated pathways in both rat and human diabetic models. The current thesis reports: 1) in cultured endothelial cells, histone hyperacetylation was associated with increased COX expression; 2) an overall increase in inflammation was observed in diabetes involving COX- and RAGE-mediated pathways. This was supported by increased platelet COX-1 and monocyte COX-2 levels in Zucker rats, increased monocyte COX-2 in human Type 1 diabetes and elevated plasma TXB2 and PGE2 levels in both human Type 1 and Type 2 diabetic subjects. Up-regulation of RAGE expression was further found in platelets and monocytes in both human diabetes types. When treated with NSAIDs, plasma prostanoid levels, COX and RAGE expression were reduced significantly in both platelets and monocytes in human diabetic subjects. 3) It is unclear how COX and RAGE expression was regulated, but histone modifications may be one of the mechanisms. Data from cultured cells indicated that increased COX expression was associated with increased histone acetylation levels induced by TSA. Concurrent increases in histone acetylation and COX-2 levels were also observed in human Type 1 diabetes, but similar findings were not observed in human Type 2 diabetes. In addition, we failed to find an age-dependent increase in monocyte histone H4 acetylation in human Type 2 diabetes despite an age-dependent increase in monocyte COX-2 expression. Thus, whether histone hyperacetylation modulates COX expression and in what conditions require further investigation.
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Sikora, Kristin [Verfasser]. "RAGE-abhängige S100A8- und S100A9-Expression in humanen THP-1 Zellen / Kristin Sikora." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2009. http://d-nb.info/1023749920/34.
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Gonçalves, Carolina de Souza. "Expressão de proteínas RAP1 recombinantes e produção de anticorpos anti- RAP1: potencial uso como biomarcador no diagnóstico de tumores." s.n, 2014. https://www.arca.fiocruz.br/handle/icict/9945.
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Previous issue date: 2014<br>Fundação Oswaldo Cruz. Centro de Pesquisa René Rachou. Belo Horizonte, MG, Brasil<br>Alterações imunofenotípicas qualitativas e quantitativas na expressão da proteína RAP1, uma pequena GTPase da superfamília RAS, estão presentes em diversos tipos de cânceres, tais como carcinomas de células escamosas de orofaringe, câncer papilar da tireóide, câncer de mama, carcinoma de células renais, leucemia, melanoma, neoplasias intraepiteliais e câncer cervical. Entretanto, para a utilização de RAP1 como biomarcador para auxiliar no diagnóstico imuno-histoquímico de tumores, especialmente do câncer cervical, são necessários anticorpos anti-RAP1 a baixo custo, uma vez que, atualmente, os anticorpos disponíveis no Brasil são importados e de custo elevado, tornando inviável sua utilização no diagnóstico de rotina. Assim, este trabalho tem como objetivos a expressão de proteínas RAP1 recombinantes (rRAP1) em sistema bacteriano, e a produção de anticorpos monoclonais e policlonais anti-rRAP1, visando a sua aplicação no diagnóstico de diversos tumores por imuno-histoquímica. Dois genes RAP1 sintéticos codificantes para as proteínas rRAP1A e rRAP1AB foram desenhados, sintetizados e subclonados no plasmídeo de expressão bacteriano pQE9 e sua expressões obtidas na linhagem hospedeira E.coli M15. Após indução com IPTG, as proteínas rRAP1 foram purificadas por cromatografia líquida em coluna de afinidade de quelato de níquel, obtendo-se o rendimento, por litro de cultura bacteriana, de 185,6 mg/L de rRAP1A e 103,9 mg/L de rRAP1AB. As proteínas rRAP1 purificadas foram inoculadas em animais para a produção de anticorpos monoclonais e policlonais anti-rRAP1A e antirRAP1AB. Ensaios imuno-histoquímicos foram realizados em tecidos de pacientes com neoplasia cervical para a avaliação da reatividade dos anticorpos anti-rRAP1 com a proteína RAP1 humana. Uma intensa imunorreatividade foi verificada com o anticorpo anti-rRAP1A (policlonal produzido em coelhos) considerado, até o momento, o melhor candidato para uso na detecção da expressão de RAP1 em ensaios imuno-histoquímicos, o que pode auxiliar no diagnóstico de várias neoplasias, especialmente, do câncer do colo uterino.<br>Qualitative and quantitative immunophenotypical changes in the expression of RAP1 protein, a small GTPase of the RAS superfamily, have been detected in many types of cancers such as oropharyngeal squamous cell carcinomas, papillary thyroid cancer, breast cancer, renal cell carcinoma, leukemia, melanoma, intraepithelial neoplasia and cervical cancer. However, to use RAP1 as a putative biomarker for immunohistochemical assays to support tumor diagnosis, especially cervical cancer, anti-RAP1 antibodies at low cost are essential, since here in Brazil the anti-RAP antibodies available are imported and expensive making them impractical to use in routine diagnostics. This work aims to express recombinant proteins RAP1 (rRAP1) in bacterial system for the production of monoclonal and polyclonal anti-rRAP1 to be used for diagnosis of various tumors by immunohistochemistry. Two synthetic RAP1 genes coding for rRAP1A and rRAP1AB proteins were designed, synthesized, and subcloned into the pQE9 vector for recombinant protein production in E. coli (strain M15). After IPTG induction, both rRAP1 proteins were purified by nickel chelate affinity chromatography yielding, per liter of bacterial culture, 185,6 mg/L of rRAP1A and 103,9 mg/L of rRAP1AB protein. The purified rRAP1 proteins were used to generate polyclonal and monoclonal antibodies against rRAP1A and against rRAP1AB. Immunohistochemistry experiments were performed on tissues samples from patients with cervical neoplasia to evaluate the reactivity of the anti-rRAP1 antibodies to the human RAP1. An intense immunoreactivity was observed for a rabbit polyclonal anti-rRAP1A antibody, considered so far, the best candidate to be used for RAP1 immunohistochemical testing to support tumor diagnosis, especially cervical cancer.
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Di, Candia Leonarda. "The expression and function of RAGE and HMGB1 in airway structural cells in asthma." Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/32339.
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Asthma is characterised by airway hyperresponsiveness, airflow obstruction, chronic inflammation and airway remodelling, with an increase in airway smooth muscle (ASM) mass and contractility. ASM also releases mediators that support inflammation and remodelling. High-mobility group box 1 (HMGB1) is a nuclear protein that is released by damaged/stressed cells and activated immune cells. HMGB1 signals through pattern recognition receptors (PRRs) including the receptor for advanced glycosylation end products (RAGE) to promote inflammation and tissue repair. HMGB1 binding and function are governed by its redox state. Evidence suggests HMGB1 elevation in asthma; however, the redox state of airway HMGB1 is unknown. Moreover, the expression and role of RAGE in regulating airway mesenchymal cells are unknown. We aimed to investigate HMGB1 and RAGE expression in bronchial tissue; the redox form of sputum HMGB1; the expression and role of HMGB1 and RAGE in airway structural cells. HMGB1 was 3.5-fold higher in sputa of moderate-to-severe asthmatics (n=34), and the reduced form was shown to be increased in this group (n=16) for the first time. Reduced HMGB1 was chemotactic for peripheral blood leukocytes, and sputum HMGB1 correlated with sputum total cell counts. HMGB1, but not RAGE, expression was ~3-fold higher ex vivo in ASM of severe asthmatics (n=16). ASM and human bronchial epithelial cells (HBECs) expressed both HMGB1 and cell-surface RAGE in vitro. HMGB1 expression was upregulated in ASM cells stimulated with inflammatory cytokines. HMGB1 stimulation caused increased reactive oxygen species production in ASM cells from non-asthmatics, but not in asthmatics; ASM contraction and inhibition of ASM cell migration and HBEC wound healing. These results suggest that HMGB1 promotes inflammatory cell recruitment, impairs epithelial and ASM repair, and promotes ASM contraction in asthma. Further work is required to determine whether antagonising HMGB1 or its receptors would be a viable therapeutic approach for the treatment of asthma.
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Lalk, Michael [Verfasser]. "Tumorregionen-abhängige Expression der Aminosäure-Sensoren MAP4K3, RagC und VPS34 in Glioblastomen / Michael Lalk." Magdeburg : Universitätsbibliothek, 2018. http://d-nb.info/1174626593/34.
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Rösch, Daniela. "Regulation der Expression der Rezeptoren für advanced glycation end products (RAGE) auf humanen Monozyten." [S.l. : s.n.], 2006.
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Gillis, L. Jane. "Expression and recombinase activity of RAG 1 and two splice variants of RAG 2 in mature human primary tonsilar B lymphocytes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0004/MQ46022.pdf.
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Ferhani, Nassima. "Expression pulmonaire et rôle fonctionnel d'HMGB1 et de son recepteur, RAGE, dans la bronchopneumopathie chronique obstructive." Paris 7, 2010. http://www.theses.fr/2010PA077265.
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La BPCO est une maladie pulmonaire caractérisée par une inflammation et un remodelage tissulaires. HMGBl, une protéine nucléaire libérée durant l'inflammation et la réparation, interagit principalement avec son récepteur, RAGE, constitutivement exprimé dans le poumon. Nous avons montré des taux élevés d'HMGBl dans le lavage bronchoalvéolaire (LBA), la muqueuse et l'épithélium bronchiques, ainsi que dans les macrophages alvéolaires de patients avec BPCO, comparativement à des sujets fumeurs et non-fumeurs. HMGBl dans le LBA corrèle significativement avec le degré de l'obstruction bronchique et de l'emphysème et avec le taux de nombreux médiateurs pro-inflammatoires qui participent à la pathogenèse de la BPCO. Dans tous ces types cellulaires, HMGBl est présente à la fois dans le noyau et le cytoplasme, suggérant que sa sécrétion extracellulaire pourrait expliquer l'augmentation de ses taux dans le LBA. L'expression de RAGE est également majorée dans l'épithélium et le muscle lisse de patients avec BPCO et elle coïncide avec celle d'HMGBl, suggérant l'existence d'interactions autocrines et paracrines entre ces deux protéines. Nous avons également mis en évidence la présence de complexes HMGBl/IL-lp, dans le LBA et les macrophages alvéolaires des patients BPCO. Ces complexes sont fonctionnels car ils potentialisent la synthèse de TNF-a. Enfin, dans des expériences préliminaires, nous avons montré que HMGB1 ralentit la régénération épithéliale in vitro, contribuant ainsi au remodelage tissulaire. En conclusion, les données présentées dans cette thèse suggèrent que le blocage de la voie HMGBl/RAGE représente une cible thérapeutique prometteuse dans le traitement de la BPCO<br>COPD is characterized by airway inflammation and remodeling. HMGBl, a nuclear protein that is released during inflammation and repair, interacts with pro-inflammatory cytokines and with its receptor, RAGE, which is highly expressed in the lung. In the present study, we have shown higher levels of HMGB 1 in bronchoalveolar lavage (BAL) from smokers with COPD, as compared to smokers and never smokers, and similar differences wer observed in epithelial cells and alveolar macrophages. BAL HMGBl correlated positively with the levels of pro-inflammatory mediators in BAI including IL-1D, and with the degree of airflow obstruction and emphysema. HMGBl-IL-1D D complexes were found in BAL supernatant and alveolar macrophages from smokers and COPD patients, as well as in the human macrophage cell line, THP-1, where they enhanced the synthesis of TNF-C RAGE was overexpressed in the airway epithelium and smooth muscle of COPD patients and it co-localized with HMGBl. Finally, in preliminary experiments we demonstrated that HMGBl delays epithelium repair in an in vitro model of mechanical wound injury using human bronchial epithelial cells growth in a air-liquid interface conditions. We conclude that elevated HMGBl expression in COPD airways may sustain inflammation through i interaction with IL-1D and RAGE and may contribute to airway remodeling by interfering with the normal epithelial repair process. Therefore strategies aimed at inhibiting the expression of HMGBl and RAGE or at blocking their interaction in target cells would be of therapeutic value f( attenuating lung remodelling and the accompanying respiratory functional deterioration in COPD
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Alexander, Kristen Lena. "Differential Receptors for Advanced Glycation End-Products (RAGE) Expression in Preeclampsia, Intrauterine Growth Restriction and Gestational Diabetes." BYU ScholarsArchive, 2015. https://scholarsarchive.byu.edu/etd/5463.
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Preeclampsia (PE), intrauterine growth restriction (IUGR) and gestational diabetes (GDM) increase the risk of maternal and fetal morbidity and mortality. The roles of Advanced Glycation End-products (AGEs) are already well documented concerning inflammation, hypoxia and oxidative stress. AGEs bind to its receptor, Receptor for Advanced Glycation End-products (RAGE), and activate an inflammatory pathway. This pathway alters the efficacy of invasive trophoblast cells and in the placenta and can result in placental dysfunction. We hypothesized that the placental dysfunction found in PE, IUGR, and GDM resulted from an over activation of the RAGE-mediated inflammatory pathway. Using human placental samples, we found that RAGE protein expression via western blotting was increased in PE and decreased in IUGR while GDM remained similar to that of control placentas. We then wanted to determine the efficacy of RAGE activation to alter the invasive nature of invasive cytotrophoblasts cells. We found that the addition of AGEs to SW71 cells decreases invasion through the activation of JNK and ERK cellular signaling pathways. Altogether these findings suggest that RAGE activation in trophoblast cells seems result in insufficient placental pathogenesis causing PE, however the IUGR and GDM samples we obtained did not seem to have resulted from RAGE activation. We also found that RAGE activation can alter the ability of invasive trophoblasts to invade, thus limiting the ability of the placental cells to remodel the maternal spiral arteries. We believe that further research into specific triggers of IUGR (smoking-induced) and un-treated diabetes could result in RAGE stimulated placental insufficiency.
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Silva, Marcela Claudino da. "Análise da expressão de citocinas e dos receptores RAGE no periodonto de ratos diabéticos." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/25/25149/tde-02062011-150539/.
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As doenças periodontais (DPs) são alterações inflamatórias crônicas que acometem os tecidos de sustentação do órgão dental. A presença do diabetes é refletida em maior severidade e prevalência das DPs tanto em humanos quanto em modelos experimentais. Contudo, os mecanismos biológicos envolvidos no aumento da prevalência e da severidade permanecem pouco conhecidos. Desta forma, o objetivo deste estudo foi avaliar o número de células marcadas por imunohistoquímica para TNF- , IL-1 , IL-6, RANKL, MMP-2, MMP-9 e para os receptores RAGE na doença periodontal experimental decorrente da indução do diabetes em ratos. Inicialmente, os ratos (n=25) foram submetidos à indução do diabetes através de administração endovenosa de aloxana (42mg/kg) e, juntamente com o grupo controle (n=25), acompanhados por 1, 3, 6, 9 e 12 meses. Em seguida, as hemimandíbulas foram coletadas e submetidas aos procedimentos de imunohistoquímica. Os resultados revelam que a presença do diabetes resulta em alterações significativas no número de células imunomarcadas para diferentes mediadores do processo inflamatório. Nos animais diabéticos, foi observado aumento estatisticamente significativo (p<0,05 ANOVA) no número de células imunomarcadas para TNF- (6 e12 meses), IL-1 (12 meses), IL-6 (9 e 12 meses), RANKL (9 meses) e para os receptores RAGE (6, 9 e 12 meses). Não foram observadas diferenças em relação ao número de células imunomarcadas para MMP-2 e MMP-9 entre os grupos controle e experimental, apesar da tendência a aumento no número de células MMP-9+ nos ratos após 12 meses da indução do diabetes (p>0,05 ANOVA). Assim, a desregulação na expressão de citocinas inflamatórias e fatores osteoclastogênicos parece ser um dos mecanismos biológicos envolvidos no aumento da prevalência e da severidade das doenças periodontais em decorrência do diabetes.<br>Periodontal diseases (PD) are chronic inflammatory diseases leading the destruction of connective tissue and alveolar bone supporting the teeth. The establishment of diabetes increases PD prevalence and severity in humans and experimental model. However, biological mechanisms regarding to increase of prevalence and severity remains poorly known. The aim of this study was to evaluate the number of immuno-staining cells to TNF- IL-1 , IL-6, MMP-2, MMP-9, RANKL and RAGE receptors in experimental periodontal disease in diabetic rats. Diabetes was induced in Wistar rats (n=25) by endovenous administration of 42 mg/kg of alloxan, and together with control animals (n=25), were analyzed at 1, 3, 6, 9 and 12 months after diabetes induction. The animals were sacrificed and the jaws were removed and submitted to immunohistochemistry procedures. Our data demonstrated that diabetes induction and progression resulted in significant alterations in number of immuno-staining cells to different mediators of inflammatory process. In diabetic rats, we observed an increased number of immuno-staining cells to TNF- (6 and 12 months), IL-1 (12 months), IL-6 (9 e 12 months), RANKL (9 months) and RAGE receptors (6, 9 and 12 months) (p<0,05 ANOVA). Regarding to MMP-2+ and MMP-9+ cells, we did not found differences between control and experimental groups. However, we found a trend of towards in MMP-9+ cells in diabetic rats after 12 months of diabetes induction (p>0,05 ANOVA). Then, our data demonstrated that diabetes establishment and progression resulted in an increase of immuno-staining cells to TNF- , IL-1 IL-6, RANKL and RAGE receptors. Taken together, desregulation of inflammatory cytokines and osteoclastogenic factor expression seems to be one of biological mechanisms involved in the increase of periodontal disease prevalence and severity associated with diabetes.
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Hausherr, Carolin Kim. "Konditionale Expression von HER-2, H-Ras oder BXB-Raf1 in einem Maustumormodell molekuare [molekulare] Mechanismen der Tumorremission /." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=975920693.
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Chavez, Matias Elizabeth Murayama. "Expression of Osteoarthritis Biomarkers in Temporomandibular Joints of Mice with and Without Receptor for Advanced Glycation End Products (RAGE)." BYU ScholarsArchive, 2014. https://scholarsarchive.byu.edu/etd/5242.
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This thesis will be organized into three chapters discussing the mechanism underlying the onset and progression of osteoarthritis (OA) in the temporomandibular joint (TMJ). Understanding the mechanism of OA development in the TMJ helps in understanding how OA progresses and how to treat this disease. The goal of this investigation is to examine the process of cartilage degeneration and OA biomarker expression in the TMJ to understand their role in TMJ OA onset and development.Chapter one covers mechanisms that are altered in TMJ OA during disease progression. Using animal models with different stressors such as mechanical disturbances, direct injury, and changes in the extracellular matrix composition revealed the role of the different mechanisms that are up-regulated and down regulated during cartilage destruction. Chapter two will cover a paper I wrote that introduces a novel non-invasive technique applied to mice, which induces an early onset of OA in the TMJ. I developed this technique with the aim to provide a new mouse model where the onset and progression of OA more closely mimic the natural TMJ OA progression in humans. The histopathological analysis of the cartilage demonstrates that onset of OA starts at 2 weeks after treatment induction and is aggravated by week eight. This data demonstrated the effectiveness of our technique in inducing OA in the TMJ. Chapter three will cover a second paper I wrote on the association of RAGE with the progression of OA in the TMJ of mice by using mice with and without RAGE expression. RAGE has been show to contribute to the progression of OA by releasing several pro-inflammatory and catalytic cytokines. Additionally, RAGE has been shown to modulate the expression of specific OA biomarkers, including HtrA-1, Mmp-13, and Tgf-β1 in knee cartilage. The objective of this study was to study the effect of knocking out RAGE on the expression of Mmp-1 3, HtrA-1, and Tgf-β1 in the TMJ. After histophatological and quantitative analysis of biomarkers expression, the results demonstrated for the first time that absence of RAGE expression in the TMJ provides a protective effect against development of TMJ OA in mice.
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Ejdesjö, Andreas. "Teratogenic Predisposition in Diabetic Rat Pregnancy." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-178175.
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Pre-gestational diabetes increases the risk of congenital malformation in the offspring and both morbidity and mortality in the diabetic mother and her offspring. During pregnancy, high glucose levels act as a teratogen through several cellular and biochemical pathways and increased production of reactive oxygen species (ROS) has a central role in diabetic embryopathy. The aim of this work was to investigate the importance of genetic predisposition for congenital malformations and to study the genes involved in the teratogenic process of diabetic pregnancy. The crossbreeding of two rat strains, with both low and high incidence of diabetes-induced malformations, indicated that strain-specific maternal factors, such as disturbed serum levels of amino acids, triglycerides, and β-hydroxybutyrate, were associated with malformation. In addition, disturbed fetal expression of genes involved in ROS defense and development (Shh, Bmp4, Ret and Gdnf) in mandible and heart, and decreased activity of Gapdh and Aldose Reductase were associated with the teratogenic process, and the trans-generational heredity of the mother determined the type of malformations induced by maternal diabetes. In rat embryos, a diabetic environment in utero changed the expression of genes involved in ROS defense (Nrf2, Gpx1 and Cat), development of mandible and heart (Msx2, Shh, Bmp4, Ret and Gdnf), and neural tube closure and apoptosis (Pax3 and p53). The changes were divergent with tissue-specific alterations of gene expression in developing mandible, heart anlage, and whole embryo. Disruption of the Receptor for Advanced Glycation End products (RAGE) had a protective effect against diabetic embryopathy in mice, and the blockage of RAGE diminished ROS production in the offspring: this supported oxidative stress being a necessary etiological component in diabetic embryopathy. Maternal metabolic state and genetic susceptibility influence fetal outcome in experimental diabetic pregnancy. Disturbed protection against oxidative stress and tissue-specific derangements in the expression of developmental genes play pivotal roles in the teratogenic mechanism, and enhanced levels of Advanced Glycation End products (AGE) and RAGE-induced oxidative stress are involved in diabetic dysmorphogenesis.
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Sawafta, Ashraf. "Design of vector for the expression of shRNA in transgenic animals." Phd thesis, Université Pierre et Marie Curie - Paris VI, 2008. http://tel.archives-ouvertes.fr/tel-00812776.
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Les petits ARN interférents (siRNA) sont encore rarement utilisés chez les vertébrés transgéniques pour inhiber l'expression de gènes. En effet, les vecteurs contenant un promoteur de type ARN polymérase III comme ceux des gènes U6 et H1 qui permettent une expression élevée des gènes codant pour des ARNi dans des cellules sont souvent silencieux in vivo. Dans cette thèse, divers vecteurs exprimant des petits ARN double brins (shRNA) ont été testés dans des cellules en culture et chez des souris transgéniques pour inhiber l'ARN m du gène précoce IE du virus de la pseudo rage porcine responsable de la maladie d'Aujeszky. La quantité et la séquence des si RNA produits ont été étudiées par qPCR. Dans des cellules CHO transfectées pour une expression transitoire, les vecteurs contenant les gènes U6-shRNA ont été de loin les plus efficaces pour inhiber le gène IE en raison du niveau élevé de siRNA produit. Par ailleurs, deux constructions contenant le promoteur de type ARN polymérase II, le promoteur du gène eF1-α etune séquence de shRNA bordée par 5T ou introduite dans un gène de microARN (miRNA) le miR30 ont permis d'obtenir une inhibition significative mais limitée de l'ARNm du gène IE. Ceci parait être du au niveau relativement faible de siRNA produit. Le siRNA produit par le gène du miRNA s'est avéré aussi efficace que ceux obtenus à partir des constructions U6-shRNA bien que ces derniers soient un peu plus longs. Ces diverses constructions ont été utilisées pour obtenir des souris transgéniques. Des souris contenant la séquence du shRNA n'ont pu être obtenues qu'à partir de la construction miRNA. Ceci peut être du au fait que les siRNA produits par les autres constructions ont exercé un effet inhibiteur sur des cibles aspécifiques (off-targeting) qui ne s'est pas produit avec le siRNA provenant de la construction miRNA car il contient quelques nucléotides en moins. Les souris transgéniques contenant la construction miRNA ont été soumises à une infection par le virus de la pseudo rage porcine. Bien que les souris exprimaient le gène shRNA qu'à un faible niveau. Quelques souris transgéniques ont résisté à l'infection. La seconde partie de la thèse a consisté à sélectionner d'autres séquences de shRNA capables d'inhiber l'expression du gène IE sans exercer des effets aspécifiques. Deux séquences de shRNA ont permis une telle inhibition. L'une est dirigée contre la région 5'UTR du gène IE et l'autre contre la région 3'UTR. Ces données suggèrent que (1) l'efficacité d'un shRNA n'est pas déterminée par sa séquence d'une manière totalement prévisible (2) l'efficacité d'un siRNA est d'autant plus élevé que sa séquence cible dans l'ARNm est en structure double brin (3) un effet inhibiteur intense et optimum peut être obtenu avec des concentrations faibles d'un siRNA (4) les effets secondaires et en particulier le off-targeting peuvent avoir lieu à faible concentration du siRNA mais ils ont d'autant plus de chance de se produire que la concentration du si RNA est plus élevée (5) un siRNA destiné à être utilisé chez des animaux transgéniques devrait être choisi pour sa capacité à inhiber efficacement un gène à faible concentration pour réduire ses effets secondaires.
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Maxwell, Morgan. "Rage and social media: The effect of social media on perceptions of racism, stress appraisal, and anger expression among young African American adults." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4311.
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Recently, social media has become a sociopolitical hotbed for discussions of racism. However, no extant studies have questioned if social media use increases how often African Americans vicariously and/or personally experience discrimination in America. The current study sought to answer this question. By examining the relationships between social media use, general stress, race-related stress, and anger expression, and the mediating role of perceived racism, this study explored if frequent social media use influences young African American adults’: a) perceptions of racism, b) experiences with general and race-related stress, and/or c) expressions of anger. The current study conducted an online survey of 199 young African American adults between the ages of 18-29 using Amazon Mechanical Turk (M-Turk). Results showed Facebook interactive use significantly predicted anticipatory bodily alarm response and anger expression, but not anticipatory race-related stress. Facebook and Twitter use predicted anticipatory race-related stress, anticipatory bodily alarm response, and anger expression. Neither Facebook interactive use or Facebook and Twitter use predicted general stress. However, serial multiple mediation analyses revealed perceived racism and everyday discrimination fully mediated the relationship between Facebook interactive use and anger expression, such that the more young African Americans perceive racism and everyday discrimination via social media the more anger they experience. Findings also revealed perceived racism and everyday discrimination indirectly affected relations between Facebook interactive use and anticipatory bodily alarm response, anticipatory race-related stress, and general stress. Health implications and directions for future research are discussed.
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Tahiri-Alaoui, Abdessamad. "Modifications cellulaires et moléculaires après infection des racines de Nicotiana par le champignon pathogène Chalara elegans (Nag Rag & Ken. ) : mécanismes de défense et comparaison avec une infection symbiotique." Dijon, 1992. http://www.theses.fr/1992DIJOS035.
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Ce travail a permis de mettre en évidence des mécanismes de défense actifs développés par des Nicotiana vis-à-vis de l'agent de la pourriture noire des racines C. Elegans. Nous avons identifié et localisé cytochimiquement chez C. Elegans des polysaccharides pariétaux pouvant être à l'origine des phénomènes de reconnaissance cellulaire et d'incompatibilité. L'étude ultrastructurale du processus d'infection des racines de l'hôte modérément résistant par C. Elegans a révélé que des modifications pariétales différentielles, selon les couches cellulaires infectées, peuvent conférer à la paroi un certain degré de résistance à l'invasion fongique. Chez l'hôte sensible, aucune modification pariétale n'est observée. Nous avons pour la première fois mis en évidence les différents groupes de protéines PR-b dans les racines de N. Tabacum cv Xanthi nc infectées par C. Elegans, et localisé dans les tissus infectés et particulièrement au niveau des structures pariétales de défense de l'hôte, les protéines PR-b1 dont la fonction reste inconnue; ceci nous a amené à suggérer l'implication de ces protéines dans les mécanismes de défense contre l'invasion fongique. L'étude de l'expression du gène de la PR-b1* en fonction de la résistance de l'hôte et de la virulence du champignon, a révélé que le niveau d'accumulation des transcrits de la PR-b1* est lie au taux d'infection plutot qu'a la resistance de la plante ou a la virulence du pathogene. Chez l'hybride amphidiploide, l'expression constitutive de la pr-b1* n'est pas affectée par le taux d'infection. Nous avons démontré que lors d'une association endomycorhizienne entre les racines de N. Tabacum cv Xanthi nc et G. Mosseae, les gènes PR-b1 ne s'expriment que très faiblement, et que leurs produits de traduction sont limités à l'interface des deux symbiotes dans les cellules vivantes du parenchyme cortical. La faible activation de ces gènes est par contre corrélée avec l'induction d'autres gènes pouvant être impliqués dans l'établissement et le fonctionnement de la mycorhize.
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Figueiredo, Anna Carolina Cançado. "Caracterização imunocitoquímica da expressão da proteína RAP1 em blocos de células escamosas provenientes de citologia cervical em meio líquido." s.n, 2015. https://www.arca.fiocruz.br/handle/icict/10915.
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Previous issue date: 2015<br>Fundação Oswaldo Cruz. Centro de Pesquisa René Rachou<br>O diagnóstico precoce acurado do câncer cervical, relevante problema de saúde
pública no mundo e no Brasil, pela citologia oncótica (Teste de Papanicolaou), é muito prejudicado pela subjetividade e variabilidade dos resultados falsos negativos
e falsos positivos do método, particularmente diante de células escamosas atípicas (ASC). Recentes inovações técnicas, como citologia em meio líquido e
imunocitoquímica com biomarcadores de proliferação celular, aumentaram a
expectativa de melhorias no rastreamento do câncer cervical. No entanto, a
aplicabilidade destas inovações nos estágios mais iniciais de atipia e displasias
epiteliais permanecem incertas. Assim, considerando resultado prévio do nosso
grupo de pesquisa, que identificou a proteína RAP1 como biomarcador diagnóstico
da displasia cervical, este trabalho tem como objetivo caracterizar a expressão da
proteína RAP1, comparativamente à expressão dos biomarcadores p16 e Ki-67, por
imunocitoquímica, em blocos de células escamosas cervicais para possível
aplicabilidade na triagem do câncer do colo do útero. Para tal, 34 amostras, 27
pacientes com diagnóstico de alterações celulares benignas (ACB) e 7 pacientes
com diagnóstico de ASC foram coletadas na unidade Jenny Faria do Hospital das
Clínicas da UFMG. Os resultados indicaram que 85% das amostras de blocos celulares foram satisfatórias para análise morfológica e a técnica reproduziu os principais parâmetros citopatológicos da citologia convencional. Em relação a sua utilização para diagnóstico, o bloco de células apresentou sensibilidade de 38,46%,
especificidade de 90,47% e uma variabilidade interobervador com taxa de concordância de aproximadamente 30% para os grupos ACB e ASC. A expressão da proteína RAP1 foi positiva na maioria das amostras do grupo “ACB” (15/27 ou 55,56%) e resultado negativo na maioria das amostras do grupo “ASC” (4/7 ou 57,14%) com sensibilidade de 16,66%, especificidade de 75, %. As reações
imunocitoquímicas das proteínas p16 e Ki-67 demonstraram, em ambos os grupos,
apresentaram predomínio absoluto ou totalidade de resultados negativos. O DNA de
HPV foi detectado em 9 (33,33%) das 27 amostras do grupo ACB e em 4 (57,14%)
das 7 amostras do grupo ASC. O HPV-16 foi detectado nas 4 amostras do grupo ASC. Nas amostras do grupo ACB foram detectados os HPV-16, em 5 amostras, HPV-58, em 2 amostras, HPV-45, em 1 amostra e HPV-66 em 1 amostra.
Observamos inexistência de relação entre a presença do HPV e a expressão
imunocitoquímica de RAP1 em ambos os grupos. Em conclusão, os blocos de células podem complementar o teste de Papanicolaou na triagem do câncer do colo uterino e a expressão da proteína RAP1 está aumentada em células cervicais em ambiente inflamatório, associado ou não à presença de HPV<br>The accurate early diagnosis of cervical cancer, relevant public health problem
worldwide and in Brazil by cytology (Pap test), is hampered by its subjectivity and
variability of false positive and false negative results, particularly on atypical
squamous cell (ASC). Recent technical innovations, such as based liquid cytology
and immunocytochemistry for with cell proliferation biomarkers, increased the
expectation cervical cancer screening. However, the applicability of these innovations in early stages of epithelial dysplasia and atypia remains uncertain. Considering previous findings of our research group, which identified the RAP1 protein as a biomarker diagnosis of cervical dysplasia, this study aims to characterize the expression of RAP1 (compared to the expression of p16 and Ki-67 biomarkers) by
immunocytochemistry in cell blocks of cervical squamous cells, for possible
applicability in screening for cervical cancer. For this purpose, 27 patients with
benign cellular changes (ACB) and 7 patients with ASC diagnosis were collected in
Hospital das Clínicas from UFMG. The results indicated that 85% of the samples of
cell blocks were satisfactory for morphological analysis and also that the cytological technique reproduces the main parameters of the conventional cytology. Regarding its use for diagnosis, the cell block had a sensitivity of 38.46%, specificity of 90.47% and an interobserver variability with concordance rate of approximately 30% for the ACB and ASC groups. The RAP1 expression was positive in most of the samples of the group "ACB" (15/27 or 55.56%) and most negative in the sample group "ASC" (4/7 or 57.14%) with a sensitivity of 16.66% and specificity of 75%. The immunocytochemical reactions for p16 and Ki-67 showed predominance of negative
or all negative staining in both groups. HPV DNA was detected in 9 (33.33%) of the 27 samples of the ACB group and in 4 (57.14%) of 7 ASC group samples. HPV-16 was detected in 4 samples ASC group. Samples from the group ACB HPV-16 were detected in 5 samples, HPV-58 in 2 samples, HPV-45, HPV-1 sample, and 66 in one sample. We observed no relationship between the presence of HPV and
immunostaining of RAP1 in both groups. In conclusion, cell blocks can be a ancillary
tool to the Pap test for cervical cancer in screening and the expression of the RAP1
protein is increased in cervical cells in an inflammatory environment, with or without
the presence of HPV.
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Labrie, Joseph E. III. "Expression of rag2 and V(D)J Recombinase Activity are Reduced in Aged Mice as a Result of Changes in the Bone Marrow Microenvironment: a Dissertation." eScholarship@UMMS, 2004. https://escholarship.umassmed.edu/gsbs_diss/236.
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Both humans and mice display an age-related decline in immunity. Reduced generation of mature B cells may be a contributing factor due to reduced entry of mature B cells with novel B cell receptors and specificity for pathogens into the mature B cell pool. In aged mice the numbers of B cell precursors within the bone marrow are diminished; there is a severe reduction in numbers of pre-B cells and an increase in numbers of re-circulated mature B cells. Other defects in developing B cells include reduced expression of rag1 and rag2 when measured in total bone marrow precursor populations. In the pro-B cell stage of development rag expression is essential to the process of V(D)J recombination and the generation of pre-B cells. It was not known prior to this work if rag levels were lower in pro-B cells. In Chapter 2 I show that rag2 expression is reduced in pro-B cells of aged mice. The reduction in rag2 expression is correlated with a loss of V(D)J recombinase activity in pro-B cells and reduced numbers of pre-B cells. This suggests that in aged mice the reduction in rag2 expression is sufficient to result in reduced V(D)J recombinase activity and reduced generation of pre-B cells, thus contributing to fewer pre-B cells in aged mice. Furthermore, I have shown that the loss of rag2expression and recombinase activity in pro-B cells are the result of age-associated defects in the bone marrow-microenvironment as opposed to cell-intrinsic defects in developing precursors.
In Chapter 3 of this thesis I examine genetic influences on age-related defects in murine B cell development and correlations between bone marrow B cell subsets and peripheral T cell subsets. It was known that longevity and age-related defects in T cell subsets are influenced by genetic differences between strains of inbred mice. The impact of genetic polymorphisms on age-related defects in B cell development had not been previously assessed. Nor was it known if these defects were correlated with age-related changes in peripheral T cell subsets. Here I present evidence that B cell subsets in the bone marrow are influenced by genetic polymorphisms between mice strains. Genetic polymorphisms on Chromosomes 15 and 19 were found to influence the frequency of re-circulated and pre-B cells in the bone marrow of aged mice. Frequencies of bone marrow B cell subsets were compared with peripheral T cell subsets. Interestingly, an association between the frequency of pre-B cells was not observed with either re-circulated B cells in the bone marrow nor peripheral T cell subsets. However the frequency of pre-B cells was inversely correlated with the frequency of B220intIgM+cells, a subset that was found to correlate with more advanced age-related T cell defects. In addition, frequencies of re-circulated B cells in the bone marrow were found to be associated with less advanced age-related defects in peripheral T cell subsets.
These observations indicate that defects in B cell development, including reduced rag2 expression and V(D)J recombinase activity, are the result of changes in the aged murine bone marrow microenvironment. In addition, a genetic polymorphism located on Chromosome 19 influences the frequency of pre-B cells in aged mice. Furthermore the frequencies of B cell precursors in aged mice are not correlated with peripheral T cell subsets, but are correlated with frequencies of B220intIgM+ cells in the bone marrow. These observations advance our understanding of age-related defects in murine B cell development and may lead to identification of genes that influence B cell development in aged mice and humans as well as to help devise therapeutics aimed at restoring humoral immunity in aged individuals.
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Fantino, Emmanuelle. "Expression transcriptionnelle du gène SRP1 de Saccharomyces cerevisiae : caractérisation d'une séquence intragénique cis-activatrice et implication du facteur général de transcription TUF/RAP1/GRF1." Aix-Marseille 2, 1991. http://www.theses.fr/1991AIX22006.
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Ce memoire decrit un exemple original de regulation de l'expression genique au niveau transcriptionnel, dans la levure saccharomyces cerevisiae. Le gene srp1 est efficacement transcrit et cette transcription est regulee en fonction du substrat et/ou de la phase de croissance. L'utilisation de la technique de retardement de migration a permis de mettre en evidence in vitro une interaction proteine-adn specifique impliquant une region de 33 pb situee en aval du promoteur, dans la region codante du gene srp1, et un facteur proteique specifique et abondant. Le role essentiel de la sequence cible de l'interaction proteine-adn dans l'expression transcriptionnelle du gene srp1 a ete demontre in vivo par l'etude d'une souche de levure mutante portant une deletion de la region intragenique de 33 pb au locus srp1 chromosomique obtenue par transformation integrative. Alors que dans cette souche l'expression transcriptionnelle des genes situes en aval du gene srp1 n'est pas effectuee, l'abondance des arnm srp1 est fortement diminuee. La stabilite des armm srp1 n'est pas modifiee: la deletion de la region de 33 pb dans la region codante du gene srp1 est sans effet lorsque l'expression de ce gene est placee sous le controle d'un promoteur de levure different. Le facteur proteique reconnaissant specifiquement l'element activateur intragenique a ete identifie au facteur tuf/rap1/grf1. En effet, l'element de 33 pb presente des similitudes de sequence avec le site consensus de fixation de ce facteur. La determination precise de la sequence d'adn impliquee dans l'interaction, des experiences de competition pour la fixation in vitro de la proteine ainsi que la masse moleculaire de la proteine purifiee ont confirme que ce facteur est identique au facteur general de transcription tuf/rap1/grf1
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Kanellopoulou, Chrysi. "Analysis of locus accessibility for V(D)J recombination and its potential in generating a mouse model for monitoring RAG protein expression in peripheral B cells." [S.l. : s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=965433579.
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Gravel, William-Édouard. "Expression de la dystrophine humaine dans le Tibialis anterior de souris Rag/mdx suite à une greffe de cellules myogéniques dérivées d'hiPSCs dystrophiques et corrigées génétiquement." Master's thesis, Université Laval, 2016. http://hdl.handle.net/20.500.11794/26698.
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Les cellules souches embryonnaires humaines (hESCs) et les cellules souches pluripotentes induites humaines (hiPSCs) ont démontré leur capacité d'auto-renouvellement et peuvent potentiellement se différencier en tous les types de lignées cellulaires. Elles représentent donc une source illimitée de cellules pour le développement de thérapies curatives pour les maladies dégénératives, telles que la dystrophie musculaire de Duchenne (DMD). Cette maladie héréditaire est le résultat de diverses mutations dans le gène de la dystrophine. Ces mutations engendrent un changement dans le cadre de lecture du gène de la dystrophine, abolissant ainsi son expression. Elle se caractérise cliniquement par une progression rapide de la dégénérescence musculaire qui débute tôt dans la vie. Les hiPSCs dystrophiques ont été corrigées par notre collaborateur, le Dr. Hotta, en insérant une paire de bases dans l’exon 45 avec les Transcription Activator-Like Effector Nucleases (TALENs) pour rétablir le cadre de lecture du gène. Notre laboratoire a mis au point une procédure en deux étapes pour différencier des hiPSCs en cellules myogéniques. Nous avons d'abord utilisé un milieu de culture myogénique préparé spécialement dans le laboratoire (appelé MB1) pour promouvoir la différenciation des hiPSCs en cellules de type mésenchymateuses. Nous les avons ensuite transduites avec un lentivirus exprimant MyoD, un facteur de transcription myogénique sous le contrôle du promoteur synthétique CAG, afin d'induire leur différenciation en myoblastes. Ces myoblastes modifiés ont été greffés dans le muscle Tibialis anterior d’une souris Rag/mdx, un animal immunodéficient et dystrophique, et ont par la suite fusionné avec les fibres musculaires existantes. La présence de la protéine dystrophine humaine a été confirmée par immunohistofluorescence dans les muscles greffés avec les cellules corrigées génétiquement ainsi que dans le contrôle positif réalisé avec des myoblastes provenant d'un donneur sain. La thérapie cellulaire homotypique à partir de cellules corrigées génétiquement présente de grands avantages pour les patients souffrant de DMD, car elle permet l’expression d’un gène capable de produire une dystrophine fonctionnelle dans les fibres musculaires, de diminuer les risques de rejet de la greffe et d’accroitre la capacité de régénération du muscle et la force musculaire.<br>Human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) have shown self-renewal capacity and can potentially differentiate into all types of cell lineages. They represent an unlimited source of cells for the therapy of degenerative diseases, such as Duchenne Muscular Dystrophy (DMD), a disease characterized by a rapid degeneration of muscles that starts early in life. Dystrophic hiPSCs have been corrected by our collaborator, Dr. Hotta, by inserting of a single base pair in the exon 45 with Transcription Activator-Like Effector Nucleases (TALENs) to restore the reading frame of the gene. Our laboratory has developed a two-step procedure to differentiate hiPSCs into myogenic cells. We first used a myogenic culture medium especially developped in the laboratory (called MB-1) to promote the differentiation of hiPSCs into mesenchymal-like precursor cells. We next transduced them with a lentivirus expressing the myogenic transcription factor MyoD under the control of the composite CAG promoter, in order to induce their differentiation into myoblasts. Transduced cells have been grafted in the Tibialis anterior muscle of Rag/mdx mice where they fused with existing muscle fibers. The presence of the human dystrophin protein has been confirmed by immunohistofluorescence in muscles grafted with the genetically corrected cells and in a control graft with myoblasts of a healthy donor. Cell therapy shows great promises for DMD patients since it allows the expression of a normal gene capable of producing a functional dystrophin in muscle fibers and increase the regenerative capacity of the muscle and the muscle strength.
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Degani, G. "MOLECULAR CHARACTERIZATION OF MEMBRANE-BOUND GLYCOPROTEINS INVOLVED IN HUMAN DISEASES AND POTENTIAL TARGETS FOR NEW THERAPIES." Doctoral thesis, Università degli Studi di Milano, 2015. http://hdl.handle.net/2434/274187.
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The present thesis is focused on the molecular characterization of two eukaryotic membrane glycoproteins that are promising candidates for new therapeutic approaches to human diseases.
The first glycoprotein is the human Receptor for the Advanced Glycation End products (hRAGE), a member of the immunoglobulin superfamily. RAGE is a type I transmembrane glycoprotein that is beneficial in normal physiological conditions but it is also a key player in the etiology and progression of several chronic pathologies such as neurodegenerative disorders (Alzheimer), atherosclerosis, cancer and complications of metabolic diseases such as diabetes, by exacerbating the inflammatory response. A variety of ligands sharing an acidic charge, as the advanced glycation End products (AGEs), S100 proteins, HMGB1, Aβ-amyloids, bind to the extracellular V or VC1 domains of RAGE. These domains are N-glycosylated and stabilized by disulphide bonds. To overcome the tendency to aggregate of the V and VC1 domains expressed in bacteria, in this work V and VC1 domains were expressed as secreted proteins in the methylotrophic yeast Pichia pastoris. While VC1 was secreted into the culture medium and was functional, the V domain was retained intracellularly, providing the first in vivo indication that V requires C1 to fold into a structurally stable domain. The glycosylation pattern of VC1 reflects the glycosylation of RAGE isolated from mammalian sources. A simple procedure for the purification to homogeneity of VC1 from the medium was generated and the folded state of the purified protein was assessed by thermal shift assays. The protein showed a remarkable improved thermal stability compared to VC1 expressed in bacteria. The stability and full solubility of glycosylated VC1 may be beneficial for in vitro studies aimed at the identification of new ligands or inhibitors of RAGE.
The second object of this thesis was the Phr family of Candida albicans, a dimorphic fungal pathogen responsible of life-threatening invasive infections. These glycoproteins are anchored to the plasma membrane through a GPI. Phr proteins belong to family GH72 of cell wall glucan remodelling enzymes that are unique to fungi and essential for morphogenesis, cell wall integrity and virulence. For these reasons, these enzymes are targets for inhibitors of the cell wall formation to be used in therapy, similarly to what penicillins have been for bacteria. The catalytic properties of Phr proteins were studied using a new fluorescent assay. Phr1p and Phr2p are specific for β-1,3-glucan, the pH optimum was 5.8 for Phr1p and 3 for Phr2p and the temperature optimum was 30°C. Pga4p was inactive suggesting that it turned out into a structural cell wall protein. Finally, we studied the transcriptome of cells lacking β-1,3-glucan remodelling (phr1Δ cells) after induction of growth as hypha, the invasive form of this pathogen. About 310 genes were modulated and genetic analysis showed that chitin synthesis by the Chs3p isoform is essential for viability of phr1Δ cells.
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Rosa, Júnior Nevton Teixeira da. "Determinação da correlação entre as proteínas do complexo shelterin, disquerina, citocinas inflamatórias e comprimento dos telômeros em indivíduos portadores de obesidade." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2017. http://hdl.handle.net/10183/157951.
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Nos indivíduos com obesidade, o excesso de tecido adiposo, exerce um papel fundamental induzindo um estado inflamatório crônico e sistêmico. A obesidade mimetiza processos celulares semelhantes aos do envelhecimento tais como a deterioração de tecidos e órgãos e diminuição na capacidade de reparo dos danos induzidos ao DNA. Nesse contexto, as citocinas pró-inflamatórias induzem atritos ao DNA que impactam, principalmente nas regiões mais susceptíveis dos cromossomos, os telômeros. Os telômeros, presentes nas extremidades dos cromossomos, estão associados a um complexo proteico denominado complexo shelterin. O complexo shelterin é formado por 6 proteínas (TRF1, TRF2, TIN2, POT1, TPP1 e RAP1), que junto com proteínas acessórias como a disquerina (DKC1), participam da regulação do comprimento dos telômeros e protegem os cromossomos dede atividades indesejadas de erosão enzimática, recombinação não-homóloga e fusão das terminações cromossômicas. Nos últimos anos, foram estabelecidas relações positivas entre condições patológicas clinicamente diferentes, como as moduladas por inflamação, e o comprimento dos telômeros. Recentemente, nosso grupo demonstrou telômeros encurtados em indivíduos portadores de obesidade mórbida. Assim o objetivo do presente trabalho foi explorar fatores adicionais associados ao metabolismo telomérico, como a expressão gênica das proteínas do complexo shelterin e citocinas pró-inflamatórias, as quais podem contribuir para o encurtamento acelerado de telômeros. Utilizamos amostras de células mononucleares de sangue periférico (PBMC) de indivíduos adultos saudáveis (n = 27) e indivíduos adultos portadores de obesidade (n = 39). Quantificamos a expressão gênica por transcrição reversa e PCR quantitativa (RT-qPCR) de todos os genes do complexo shelterin, DKC1, IL-1β e TNF-α. Nossos resultados demonstram um perfil de expressão gênica alterado quando comparada a expressão gênica das proteínas analisadas nos dois grupos estudados, controles e portadores de obesidade. Os indivíduos portadores de obesidade mostraram um perfil significativamente elevado dos genes TRF1, POT1, RAP1 e DKC1 (P < 0,05). Não observamos correlação de expressão gênica entre os diferentes genes e o comprimento dos telômeros nos grupos estudados, mas sim com a DKC1 na obesidade. Entretanto, quando analisamos as associações entre os genes de complexo shelterin observamos mudanças significativas nas associações intra-grupo dependentes da condição de obesidade. Nossos resultados salientam a complexa e intrincada rede de fatores associados e desregulados durante o processo fisiopatológico da obesidade. Estudos adicionais serão necessários acrescentando novos fatores para tentar dissecar a regulação coordenada do comprimento dos telômeros na homeostase e no processo patológico da obesidade.<br>In individuals with obesity, the excess of adipose tissue plays a key role in inducing a chronic and systemic inflammatory state. Like aging, obesity mimics cellular processes such as deterioration of tissues and organs and decreased ability to repair age-dependent DNA damages. In this context, the proinflammatory cytokines induce DNA damage that impact, especially in the most susceptible regions of the chromosomes, the telomeres. The telomeres, present at the ends of the chromosomes, are associated with a protein complex called the shelterin complex. The shelterin complex consists of 6 proteins (TRF1, TRF2, TIN2, POT1, TPP1 and RAP1), which together with accessory proteins such as dyskerin (DKC1), participate in telomere’s length regulation and protect chromosomes from undesired erosion, enzymatic activities, non-homologous recombination and fusion of chromosomal terminations. In recent years, positive relationships have been established between clinically different pathological conditions, such as those modulated by inflammation, and telomeres’ length. Recently, our group demonstrated shortened telomeres in individuals with morbid obesity. Thus, the aim of the present study was to explore additional factors associated with telomeres’ metabolism, such as gene expression of the shelterin complex components and proinflammatory cytokines, which may contribute to the accelerated shortening of the telomeres. We used peripheral blood mononuclear cells (PBMC) samples from healthy adults (n = 27) and adults with obesity (n = 39). We quantified gene expression by reverse transcription and quantitative PCR (RT-qPCR) of all shelterin complex genes, DKC1, IL-1β and TNF-α. Our results demonstrate an altered gene expression profile when compared to the gene expression of the proteins analyzed in the two studied groups, controls and individuals with obesity. Individuals with obesity showed a significantly elevated profile of TRF1, POT1, RAP1 and DKC1 (P < 0.05) genes. We did not observe correlation of gene expression between the different shelterin genes and the length of telomeres in the studied groups, but with DKC1 in obesity. However, when we analyzed the associations between the shelterin complex genes we observed significant changes in the intra-group associations dependent on the obesity condition. Our results highlight the complex and intricate network of associated and deregulated factors during the pathophysiological process of obesity. Further studies are needed together with the inclusion of additional factors to try to dissect the coordinated regulation of telomeres’ length in homeostasis and in the pathological process of obesity.
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Muth, Ingrid Elisabeth Verfasser], and Mathias [Akademischer Betreuer] [Bähr. "Die Expression von High Mobility Group Box 1 (HMGB1) und dessen Receptor for Advanced Glycation Endproducts (RAGE) als Pathomechanismus der sporadischen Einschlusskörpermyositis / Ingrid Elisabeth Muth. Gutachter: Mathias Bähr. Betreuer: Mathias Bähr." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2009. http://d-nb.info/1043027270/34.
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Waern, Johan [Verfasser], and Michael [Akademischer Betreuer] Ott. "Effects of ectopic murine CD47 expression on human hepatocyte engraftment in Rag, gamma c uPA mice / Johan Martin Waern. Klinik für Gastroenterologie, Hepatologie und Endokrinologie der Medizinische Hochschule Hannover. Betreuer: Michael Ott." Hannover : Bibliothek der Medizinischen Hochschule Hannover, 2012. http://d-nb.info/1025784057/34.
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Medeiros, Marcell Costa de [UNESP]. "Modulação da proliferação, morte celular e expressão gênica de mediadores inflamatórios pela ativação de RAGE e TLR4 em células da resposta imune inata e adaptativa: papel das vias de sinalização p38 MAPK e NF-kB." Universidade Estadual Paulista (UNESP), 2012. http://hdl.handle.net/11449/96192.
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medeiros_mc_me_arafo.pdf: 437623 bytes, checksum: c85b61f51fbdc5822633362a48f3573b (MD5)<br>Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)<br>O diabetes está associado à maior susceptibilidade à infecções e sepsis, demonstrando uma influência desta condição sobre a resposta imune. A doença periodontal é um tipo de infecção crônica, modulada pela resposta imune que apresenta maior prevalência e severidade em pacientes diabéticos. Nosso objetivo foi avaliar um possível sinergismo entre os receptores RAGE e TLR4 na modulação da proliferação celular, atividade metabólica, apoptose e expressão de citocinas inflamatórias em células da resposta imune inata e adaptativa. Como objetivo secundário, avaliamos o papel das vias de sinalização p38 MAPK e NF-kB na expressão dos genes inflamatórios por estas células após estimulação de RAGE e TLR4. Linhagens de células humanas de linfócitos T (JM) e monócitos (U937) foram estimulados com LPS e AGE-BSA tanto de forma independente como associados. A estimulação foi realizada também na presença e na ausência de inibidores bioquímicos para p38 MAPK (SB203580) e NF-kB (Bay 11-7082). A proliferação celular foi determinada por ensaio de exclusão azul de trypan, a apoptose pela via intrínseca e atividade metabólica foi avaliada por um ensaio bioquímico da função 18 mitocondrial, a expressão de citocinas foi estudada por RT-PCR e RT-qPCR e a ativação das vias de sinalização de interesse pelos estímulos utilizados foi investigada através de Western blotting. LPS e AGE-BSA não influenciaram a proliferação e sobrevivência celular de monócitos e linfócitos T após 24, 48 e 72 h. LPS, isoladamente ou associado a AGE, induziu a expressão de IL-6 e TNF-α em monócitos e células T, respectivamente. A ativação de p38 MAPK...<br>Diabetes is associated to increased susceptibility to infections and sepsis, indicating that this condition modulates the immune response. Periodontal disease is one type of chronic infection, which is modulated by the immune response and presents with increased prevalence and severity in diabetic patients. Our objective was to evaluate a possible synergism between RAGE and TLR4 signaling on the modulation of cell proliferation, metabolic activity, apoptosis and gene expression of inflammatory cytokines by cells of the innate and adaptive immune response. As a secondary objective, we assessed the role of p38 MAPK and NF-kB signaling pathways on the expression of the inflammatory genes by these cells after stimulation of RAGE and TLR4. Human cell lines of T lymphocytes (JM) and monocytes (U937) were stimulated with LPS and AGE-BSA both independently and associated. Stimulation was also performed in the presence and absence of biochemical inhibitors for p38 MAPK (SB203580) and NF-kB (Bay 11-7082). Cell proliferation was determined by trypan blue dye exclusion assay, apoptosis by the intrinsic pathway and metabolic activity were assessed by a biochemical assay of 21 the mitochondrial function, cytokine gene expression was studied by RT-PCR and RT-qPCR and the activation of the selected signaling pathways after RAGE and TLR4 activation was investigated by Western blotting. LPS and AGE-BSA did not influence cell proliferation and survival 24, 48 and 72 h after stimulation. LPS, alone or associated with AGE-BSA, induced expression of IL-6 and TNF- mRNA by monocytes and T cells, respectively. Activation of p38 MAPK, but not of NF-kB, was required for LPS and LPS/AGE-induced induction of IL-6 and TNF. RAGE mRNA expression was detected in both cell types. CCL3 mRNA expression levels were higher in monocytes upon... (Complete abstract click electronic access below)
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Medeiros, Marcell Costa de. "Modulação da proliferação, morte celular e expressão gênica de mediadores inflamatórios pela ativação de RAGE e TLR4 em células da resposta imune inata e adaptativa : papel das vias de sinalização p38 MAPK e NF-kB /." Araraquara : [s.n.], 2012. http://hdl.handle.net/11449/96192.
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Orientador: Carlos Rossa Junior<br>Banca: José Eduardo Cezar Sampaio<br>Banca: Adriana Campos Passanezi Sant'Ana<br>Resumo: O diabetes está associado à maior susceptibilidade à infecções e sepsis, demonstrando uma influência desta condição sobre a resposta imune. A doença periodontal é um tipo de infecção crônica, modulada pela resposta imune que apresenta maior prevalência e severidade em pacientes diabéticos. Nosso objetivo foi avaliar um possível sinergismo entre os receptores RAGE e TLR4 na modulação da proliferação celular, atividade metabólica, apoptose e expressão de citocinas inflamatórias em células da resposta imune inata e adaptativa. Como objetivo secundário, avaliamos o papel das vias de sinalização p38 MAPK e NF-kB na expressão dos genes inflamatórios por estas células após estimulação de RAGE e TLR4. Linhagens de células humanas de linfócitos T (JM) e monócitos (U937) foram estimulados com LPS e AGE-BSA tanto de forma independente como associados. A estimulação foi realizada também na presença e na ausência de inibidores bioquímicos para p38 MAPK (SB203580) e NF-kB (Bay 11-7082). A proliferação celular foi determinada por ensaio de exclusão azul de trypan, a apoptose pela via intrínseca e atividade metabólica foi avaliada por um ensaio bioquímico da função 18 mitocondrial, a expressão de citocinas foi estudada por RT-PCR e RT-qPCR e a ativação das vias de sinalização de interesse pelos estímulos utilizados foi investigada através de Western blotting. LPS e AGE-BSA não influenciaram a proliferação e sobrevivência celular de monócitos e linfócitos T após 24, 48 e 72 h. LPS, isoladamente ou associado a AGE, induziu a expressão de IL-6 e TNF-α em monócitos e células T, respectivamente. A ativação de p38 MAPK... (Resumo completo, clicar acesso eletrônico abaixo)<br>Abstract: Diabetes is associated to increased susceptibility to infections and sepsis, indicating that this condition modulates the immune response. Periodontal disease is one type of chronic infection, which is modulated by the immune response and presents with increased prevalence and severity in diabetic patients. Our objective was to evaluate a possible synergism between RAGE and TLR4 signaling on the modulation of cell proliferation, metabolic activity, apoptosis and gene expression of inflammatory cytokines by cells of the innate and adaptive immune response. As a secondary objective, we assessed the role of p38 MAPK and NF-kB signaling pathways on the expression of the inflammatory genes by these cells after stimulation of RAGE and TLR4. Human cell lines of T lymphocytes (JM) and monocytes (U937) were stimulated with LPS and AGE-BSA both independently and associated. Stimulation was also performed in the presence and absence of biochemical inhibitors for p38 MAPK (SB203580) and NF-kB (Bay 11-7082). Cell proliferation was determined by trypan blue dye exclusion assay, apoptosis by the intrinsic pathway and metabolic activity were assessed by a biochemical assay of 21 the mitochondrial function, cytokine gene expression was studied by RT-PCR and RT-qPCR and the activation of the selected signaling pathways after RAGE and TLR4 activation was investigated by Western blotting. LPS and AGE-BSA did not influence cell proliferation and survival 24, 48 and 72 h after stimulation. LPS, alone or associated with AGE-BSA, induced expression of IL-6 and TNF- mRNA by monocytes and T cells, respectively. Activation of p38 MAPK, but not of NF-kB, was required for LPS and LPS/AGE-induced induction of IL-6 and TNF. RAGE mRNA expression was detected in both cell types. CCL3 mRNA expression levels were higher in monocytes upon... (Complete abstract click electronic access below)<br>Mestre
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Karol, Sven. "Well-Formed and Scalable Invasive Software Composition." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-170162.
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Software components provide essential means to structure and organize software effectively. However, frequently, required component abstractions are not available in a programming language or system, or are not adequately combinable with each other. Invasive software composition (ISC) is a general approach to software composition that unifies component-like abstractions such as templates, aspects and macros. ISC is based on fragment composition, and composes programs and other software artifacts at the level of syntax trees. Therefore, a unifying fragment component model is related to the context-free grammar of a language to identify extension and variation points in syntax trees as well as valid component types. By doing so, fragment components can be composed by transformations at respective extension and variation points so that always valid composition results regarding the underlying context-free grammar are yielded. However, given a language’s context-free grammar, the composition result may still be incorrect.
Context-sensitive constraints such as type constraints may be violated so that the program cannot be compiled and/or interpreted correctly. While a compiler can detect such errors after composition, it is difficult to relate them back to the original transformation step in the composition system, especially in the case of complex compositions with several hundreds of such steps. To tackle this problem, this thesis proposes well-formed ISC—an extension to ISC that uses reference attribute grammars (RAGs) to specify fragment component models and fragment contracts to guard compositions with context-sensitive constraints. Additionally, well-formed ISC provides composition strategies as a means to configure composition algorithms and handle interferences between composition steps.
Developing ISC systems for complex languages such as programming languages is a complex undertaking. Composition-system developers need to supply or develop adequate language and parser specifications that can be processed by an ISC composition engine. Moreover, the specifications may need to be extended with rules for the intended composition abstractions.
Current approaches to ISC require complete grammars to be able to compose fragments in the respective languages. Hence, the specifications need to be developed exhaustively before any component model can be supplied. To tackle this problem, this thesis introduces scalable ISC—a variant of ISC that uses island component models as a means to define component models for partially specified languages while still the whole language is supported. Additionally, a scalable workflow for agile composition-system development is proposed which supports a development of ISC systems in small increments using modular extensions.
All theoretical concepts introduced in this thesis are implemented in the Skeletons and Application Templates framework SkAT. It supports “classic”, well-formed and scalable ISC by leveraging RAGs as its main specification and implementation language. Moreover, several composition systems based on SkAT are discussed, e.g., a well-formed composition system for Java and a C preprocessor-like macro language. In turn, those composition systems are used as composers in several example applications such as a library of parallel algorithmic skeletons.
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Nilavar, Namrata M. "Investigation of RAG1 in lymphoid and brain cells: Understanding mechanism and regulation." Thesis, 2020. https://etd.iisc.ac.in/handle/2005/5132.
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In summary, we show that RAG1 expression is regulated through a novel miRNA (miR-
29c) mediated mechanism and establish that as an additional mode of RAG1 regulation.
Studies described in the thesis reveal that among the 3 clinically approved HIV integrase
inhibitors (Elvitegravir, Dolutegravir, and Raltegravir) investigated, Elvitegravir can cause
harmful effects on long term treatment. In nonlymphoid organ, brain, we observe that RAG1,
but not RAG2 is expressed in an age dependent manner. Importantly, RAG1 expression was
primarily limited to astrocytes and its expression in neuron appears to be minimal. Further,
various lines of evidence indicate that RAG1 expression in the astrocytes may play a critical
role in cell proliferation. Besides, absence of RAG1 expression may lead to elevated levels of
DNA breaks culminating in cellular senescence as seen in RAG1 knockout mice. Thus, RAG1
could play a potential role in the maintenance of cell homeostasis in mouse brain
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Wang, Ya-Jean, and 王雅貞. "Cloning recombination activating gene 1 and 2 ( rag1 and rag2 ) and analyzing of the genes expression in adaptive immunity ontogenesis of Orange-Spotted Grouper (Epinephelus coioides)." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/38350825233940536103.
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碩士<br>國立成功大學<br>生物學系碩博士班<br>97<br>Orange-spotted grouper (Epinephelus coioides) is a fish species with a high economic importance in the aquaculture industry in Taiwan. The high mortalities observed throughout early development such as viral nervous necrosis (VNN) causes the highest mortalities up to 100% always occur among 1-month-old larvae with total body lengths of 2.0 cm. Teleost is the oldest species has the adaptive immune system. However, there is a risk of inducing immunological tolerance if fish that are immunised at a very early age before they are immunocompetent. Thus, it is important to establish the earliest time that grouper can be vaccinated or give immunopotentiating agent. Recombination activating genes, rag1 and rag2, encode components of the recombinase involved in V(D)J recombination. During B lymphocyte development, the variable region of Ig gene is assembled by the recombination of multiple V, D, J segments, which can generate a vast array of immunoglobulin M (IgM) to against numerous antigen. IgM produced by B lymphocytes is also an important gene that can be used in the study of the ontogenesis of the immune system, as it is the first formed antibody of the primary humoral component of the acquired immune system in fish species. These genes are expressed together in this study in order to understand the expression profile of them. The genes, rag1 and rag2, of E. coioides were cloned and sequenced the open reading frames. The full-length cDNA of rag1 and rag2 were 3653 and 1875 base pairs (bp) long respectively. The lengths of rag1 and rag2 open reading frame were 3216 and 1602 bp encoding 1071 and 533 amino acids with the molecular weight of putative protein were about 117 and 58 kDa. Subsequently, the rag1, rag2 and IgM mRNA expression level in ontogeny of fish and different organs was evaluated by reverse transcriptase PCR (RT-PCR). The result showed the expression level of rag1, rag2 and IgM mRNA raised after 13, 13 and 22 dpf of fries respectively. This data was suggested that orange-spotted grouper at this stage might possess mature immunity and is able to produce immunoglobulin. The expression of rag1 was observed in thymus, head kidney and trunk kidney. The expression of rag2 was observed in thymus and head kidney. The expression of IgM was observed in thymus, head kidney, trunk kidney, spleen, intestines and pancreas. This data forms the basis for a proposal that the thymus and head kidney of teleost species play an essential developmental role in lymphopoiesis and thus can be regarded as a primary lymphoid organ.
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Manyoni, Julian R. "Prophets of rage : expressions of Black nationalism in hip hop." Thesis, 2000. http://hdl.handle.net/2429/10663.
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This paper deals with the development of Black nationalist politics in hip hop,
focusing primarily on the years up to 1994. This investigation examines two primary
strains of nationalist hip hop which emerged in the late 1980s: Afrocentric hip hop
nationalism and pro-Black hip hop nationalism. Afrocentric nationalism is based
primarily on the notion of Africa as the root of all Black diasporic culture and the idea
that a return (either physically or intellectually) to Africa and it's glorious past is the
key to develop the Black nation and confront white racism and oppression. Pro-Black
hip hop nationalism is expressed by rappers who look to the recent past in order to find
their inspiration. They draw their inspiration from the leaders and ideologies of the
civil rights struggles of the 1950s, 1960s and 1970s, in particular the 1960s when the
movement developed a more militant stance. The paper seeks to examine critically
these two forms of hip hop nationalism with special focus on how they envision and
represent the Black nation through their art. What becomes apparent is that the main
themes in the visual and lyrical imagery tend to be somewhat consistent in both these
two forms. In Afrocentric hip hop, the central theme and preoccupation is with
location. The literal and symbolic return to the African motherland is what the Black
nationalist agenda must be predicated upon, while in pro-Black hip hop the concept of
time (and Nation Time) is central. The paper then examines the way in which the
above forms of hip hop nationalism use their respective themes, both in terms of
effectiveness and coherence, ending in a sharp critique of the almost universally sexist
nature of the discourse of nation. Finally, the thesis touches briefly on the next
generation (1996-2000) of nation conscious hip hop artists in relation to the artists
examined in the main body of the paper and looks at their socio-political ideologies
and aims in relation to their predecessors.
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FORMICHI, CATERINA. "CEBPb expression pattern regulates RAP1 protein levels in adipose tissue of obese patients and distinguishes subjects with metabolic impairment." Doctoral thesis, 2020. http://hdl.handle.net/11573/1362185.
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The prevalence of obesity and its associated mortality/morbidity has dramatically increased in the last decades, however, factors involved in the development of metabolic complications of obesity are still to be fully elucidated. It has been shown in mouse that a deletion of the telomeric protein RAP1 could have a pathogenic role in obesity and metabolic syndrome (MS). The aim of the present work was to evaluate RAP1 expression in human adipose tissues. RAP1 expression was evaluated in visceral (VAT) and subcutaneous (ScAT) adipose tissue of 49 obese patients and 14 metabolically healthy normal-weight subjects, demonstrating a significantly reduced RAP1 expression in VAT from obese subjects with MS compared to metabolically healthy obese and controls. No differences were found in RAP1 expression in ScAT. To explore the cause of the reduced RAP1 expression in VAT of obese patients, predicted transcription factors were investigated, using predictive algorithms, and the adipogenic transcription factor CEBPb was selected, given that previous studies demonstrated the inhibition of target genes’ transcription following an increased ratio between the inhibiting isoform (LIP, liver-enriched transcriptional inhibitory protein) and the activating isoform (LAP, liver-enriched transcriptional activating protein) of CEBPb. A higher LIP/LAP ratio was found in VAT from obese patients compared to controls. Moreover, obese patients with higher LIP/LAP ratio showed an unfavorable metabolic profile compared to obese patients with lower LIP/LAP ratio. ChIP analysis confirmed that CEBPb can bind RAP1 promoter. The role of RAP1 in metabolism seems to be independent from its telomeric role. In the present work, a significantly shorter telomere length has been found in VAT from obese patients with MS compared to controls, while no difference was found between obese patients with and without MS, suggesting that metabolic changes between obese patients with and without metabolic impairment, associated with RAP1 reduced expression, are not due to abnormal telomere length. In conclusion, present data highlight a role of the altered expression pattern of CEBPb in RAP1 reduced expression in VAT, a mechanism potentially involved in the development of obesity and its metabolic comorbidities.
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Rösch, Daniela [Verfasser]. "Regulation der Expression der Rezeptoren für advanced glycation end products (RAGE) auf humanen Monozyten / vorgelegt von Daniela Rösch." 2005. http://d-nb.info/99540819X/34.
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Wan-Hsuan, Tung, and 董宛璇. "The Role of Rac1/MLK3/JNK/AP-1 in CTGF-Induced Type I Collagen Expression in Lung Fibroblasts." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/53899417254003645945.
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碩士<br>臺北醫學大學<br>醫學科學研究所<br>98<br>Several evidences suggest that connective tissue growth factor (CTGF) overproduction underlies the development of lung fibrosis. Development of lung fibrosis is characterized by excessive deposition of collagens in the lung interstitium. Mixed linage kinase 3 (MLK3) can be regulated by Rac and then activate downstream molecule JNK, which in turns activates transcription factor activator protein-1(AP-1). In this study, we found that CTGF could induce collagen expression, and overexpression of wild-type MLK3 also enhanced collagen expression. Overexpressed dominant negative of MLK3 (MLK3 DN) and K252a (a MLK3 inhibtor) concentration-dependently inhibited CTGF-induced collagen expression. CTGF also induced phosphorylation of MLK3 at Thr277/Ser281. Pretreatment of SP600125 (a JNK inhibtor) or transfection with JNK1/2 DN decreased CTGF-induced collagen expression in WI38 fibroblasts. CTGF also induced JNK phosphorylation in time-dependent manner. We also found that curcumin (an AP-1 inhibtor) reduced CTGF-induced collagen expression in a concentration-dependent manner. CTGF induced increase in c-Jun phosphorylation and AP-1-luciferase activity and also increased binding of AP-1 to collagen promoter region. In addition, CTGF induced increases in Rac1 activity, and RacN17 DN inhibit CTGF-induced collagen expression, MLK3 phosphorylation and JNK phosphorylation. CTGF-mediated AP-1 activation was inhibited by RacN17 DN、MLK3 DN and JNK1/2 DN. Taken together, these results suggest that the Rac1/MLK3-dependent JNK/AP-1 signaling pathway plays an important roles in CTGF-induced collagen expression in WI38 fibroblasts.
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Wang, Chun-Chieh, and 王俊傑. "Cloning of rag-1 and Ig gene from cobia, Rachycentron canadum, and their expression during ontogenesis." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/k75y3u.
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碩士<br>國立成功大學<br>生物科技研究所碩博士班<br>90<br>Immunoglobulin produced by B lymphocytes is a major protein involved in the humoral immune response. The variable region of Ig gene is assembled during B lymphocyte development by the recombination of multiple V, D, J segments. This V(D)J rearrangement process generates a vast array of antigen receptors and is strictly mediated by RAG recombinase, encoded by recombination activation gene-1 and -2. Because rag-1 gene, especially in the enzyme-activating core region, is highly conserved among species from teleost to mammals and is critical to the differentiation of pre-B cells, its expression within an associated primary lymphoid organ can serve as an ideal developmental marker to determine the location of immune organs. Besides, in order to study the maturity level of immune system with respect to time during cobia ontogeny, the expression patterns of rag-1 and Ig gene at different cobia growth stages (from embryo to fry stages) were examined.
In addition to the use of β-actin gene as an internal control, partial rag-1 and Ig genes form cobia, Rachycentron canadum, each with an amplified size 637bp and 225bp respectively, were successfully clones. When compared with other previously reported rag-1 or Ig sequences of different fish species, the predicted rag-1 and Ig amino acid sequences of cobia displayed a minimum of 87% and 33% similarity. Tissue-specific expression of rag-1 was examined both by northern blotting and RT-PCR assay. The highest level of rag-1 expression was observed in the thymus, and a weaker expression was observed in spleen and kidney. This result indicated that thymus might be the most important immune organ compared to spleen and kidney.The expression patterns of rag-1 and Ig genes were both detected on the 7th day after hatching by RT-PCR assay. This suggested that cobia at this stage might possess mature immunity and is able to produce immunoglobulin.
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Hagel, Marion [Verfasser]. "Hemmende Wirkung von Östrogenen auf die Rac1-Expression und die Freisetzung von Sauerstoffradikalen in humanen Monozyten / vorgelegt von Marion Hagel." 2008. http://d-nb.info/996205101/34.
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Hausherr, Carolin Kim [Verfasser]. "Konditionale Expression von HER-2, H-Ras oder BXB-Raf1 in einem Maustumormodell : molekuare [molekulare] Mechanismen der Tumorremission / Carolin Kim Hausherr." 2005. http://d-nb.info/975920693/34.
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Faber, Claudius. "Die Expression der Rekombination Aktivierenden Gene (RAG) in Gedächtnis B Zellen von Kindern mit ANA-positiver Juveniler Idiopathischer Arthritis." Doctoral thesis, 2006. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-23099.
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In dieser Arbeit wurden Gedächtnis-B-Zellen von Kindern mit ANA-positiver Juveniler Idiopathischer Arthritis auf die Expression der Rekombination Aktivierenden Gene untersucht<br>We examined memory-B-cells from children with ANA-positive Juvenile Idiopathic Arthritis for the expression of Recombination Activating Genes
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Muth, Ingrid Elisabeth. "Die Expression von High Mobility Group Box 1 (HMGB1) und dessen Receptor for Advanced Glycation Endproducts (RAGE) als Pathomechanismus der sporadischen Einschlusskörpermyositis." Doctoral thesis, 2009. http://hdl.handle.net/11858/00-1735-0000-0006-AF6D-C.
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Nitti, Maria. "Interfering with Rac1 activity in FRT thyroid epithelial cells impairs the expression of the polarized phenotype and of the E-cadherin function." Tesi di dottorato, 2013. http://www.fedoa.unina.it/9450/1/nitti_maria_25.pdf.
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The acquisition of cell polarity, which includes the establishment of the tight junction barrier, polarized assembly of the cytoskeleton and appropriate organization of membrane traffic, requires external cues, that in epithelial cells are represented by the interaction of cells with their neighbors and with the extracellular matrix. The Rho family of small GTPases, regulate many biological processes including cell cycle progression, apoptosis, migration and intercellular adhesion.
We focused on the analysis of the role of Rac1 protein in the acquisition and maintenance of the polarized phenotype in the FRT rat thyroid epithelial cell line. In this work a novel experimental approach, i.e. the use of an inducible dominant-negative form of the Rac1 protein, ER-Rac1N17, was used to demonstrate the involvement of this small GTPase in the epithelial polarization process and to unravel its mechanism of action.
Oriented cell migration, transepithelial resistance acquisition, and formation of polarized cysts in suspension cultures were investigated. All these parameters are related to the polarized phenotype and were found to be affected after inhibition of Rac1 activity. To unravel the molecular mechanism by which Rac1 affected cell polarity, we investigated the establishment of E-cadherin-dependent cell-cell contacts, which is another key event in the process of epithelial polarization, by calcium switch assays. We determined the dynamics of subcellular localization of Rac1 and of E-cadherin molecules to understand if, and how, the two proteins were intimately related functionally. We conclude that Rac1 inhibition affects cell polarity by impairing E-cadherin recycling to the plasma membrane.
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Félix, Daniela Ribeiro Bettencourt. "As GTPases RAC1 e RAC1b na modulação da expressão do simportador de sódio e iodo em tecido tiroideu normal." Master's thesis, 2017. http://hdl.handle.net/10362/26982.
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O simportador de sódio e iodo (NIS) é altamente expresso no tecido da tiróide. Uma vez que a expressão de NIS resulta na acumulação de iodeto, a sua expressão em células tumorais permite o uso de iodo radioativo (131I) no diagnóstico e no tratamento da doença. No entanto, os níveis de expressão de NIS e a absorção de iodo no carcinoma de tiróide são reduzidos quando comparados ao tecido normal.
Estudos recentes mostraram que, embora desencadeadas por diferentes vias de sinalização, a estimulação da expressão de NIS envolve a indução da atividade da cinase mitogénica p38 pela GTPase RAC1. O nosso grupo também descreveu recentemente a sobre-expressão de RAC1b (uma variante hiperativa do RAC1) numa série de carcinomas papilares da tiróide, associada à mutação BRAF V600E. Notavelmente, a presença da mutação BRAF V600E tem sido igualmente correlacionada a uma diminuição da expressão do NIS.
O objetivo do presente estudo foi investigar o papel das GTPases RAC1/1b na modulação da expressão do NIS e ainda desenvolver um sistema repórter para estudar e identificar reguladores pós-traducionais deste simportador.
Utilizando como modelo experimental uma linha celular de tiróide normal, os resultados obtidos suportam um papel da sinalização RAC1/1b na regulação da expressão do NIS. RAC1b demonstrou ter um papel na inibição dos níveis de expressão do simportador, enquanto RAC1 demonstrou poder ter um papel na estimulação dos mesmos, ao reduzir a expressão do NIS após a sua inibição e ao induzir a ativação da cinase mitogénica p38.
Este estudo suporta um efeito da sinalização RAC1/1b na regulação da expressão de NIS. A identificação de novos moduladores dos níveis funcionais deste simportador será de extrema relevância para o desenvolvimento de estratégias terapêuticas co-adjuvantes ao 131I que permitam um aumento da eficiência na captação de iodo por parte das células tumorais.<br>The sodium iodide symporter (NIS) is highly expressed in thyroid tissue. Since the expression of NIS results in the accumulation of iodide, its expression in tumor cells allows the use of radioactive iodine (131I) as a diagnostic and therapeutic tool.
Recent studies showed that, although triggered by different intracellular signaling pathways, stimulation of NIS expression involves the induction of the p38 mitogenic kinase activity by the GTPase RAC1. Our group has recently described the overexpression of the RAC1b protein (a hyperactive variant of RAC1) in a number of papillary thyroid carcinomas with unfavorable outcome, carrying the activating mutation V600E in the mitogenic kinase BRAF. Notably, the presence of BRAF V600E mutation has been associated with downregulation of NIS.
The aim of the present study was to investigate the role of RAC1/1b GTPases in modulating the expression of the symporter and also to develop a reporter system to study and identify post-translational regulators of this symporter.
Using a normal thyroid cell line, the results obtained support a role for RAC1/1b signaling in the regulation of NIS expression. RAC1b was shown to play a role in inhibiting the expression levels of the symporter, whereas RAC1 seems to exert the opposite effect, since inhibition of endogenous RAC1 decreases the expression of NIS and it overexpression induces the activation of mitogenic p38 kinase.
This study supports a role for RAC1/1b signaling in the regulation of NIS expression. The identification of new modulators of the functional levels of this symporter will be extremely relevant for the development of therapeutic strategies that allow an increase in the efficiency in 131I uptake by tumor cells.<br>Financiado por Bolsa Prof. E. Limbert Sociedade Portuguesa de Endocrinologia Diabetes e Metabolismo / Sanofi-Genzyme em Patologia da Tiróide
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Faber, Claudius [Verfasser]. "Die Expression der Rekombination-aktivierenden Gene (RAG) in Gedächtnis-B-Zellen von Kindern mit ANA-positiver juveniler idiopathischer Arthritis / vorgelegt von Claudius Faber." 2007. http://d-nb.info/984710825/34.
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Weidmann, Rolf Günter [Verfasser]. "Endothel und Regulation der Inflammation : Überexpression inaktiver Mutanten der kleinen GTP-bindenden Proteine RhoA/Rac1/Cdc42 inhibiert die LPS-induzierte Expression von Interleukin-8/CXCL8 in humanen mikrovaskulären Endothelzellen / von Rolf Günter Weidmann." 2005. http://d-nb.info/978803736/34.
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Kanellopoulou, Chrysi [Verfasser]. "Analysis of locus accessibility for V(D)J recombination and its potential in generating a mouse model for monitoring RAG protein expression in peripheral B cells / vorgelegt von Chrysi Kanellopoulou." 2001. http://d-nb.info/965433579/34.
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Karol, Sven. "Well-Formed and Scalable Invasive Software Composition." Doctoral thesis, 2014. https://tud.qucosa.de/id/qucosa%3A28724.
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Software components provide essential means to structure and organize software effectively. However, frequently, required component abstractions are not available in a programming language or system, or are not adequately combinable with each other. Invasive software composition (ISC) is a general approach to software composition that unifies component-like abstractions such as templates, aspects and macros. ISC is based on fragment composition, and composes programs and other software artifacts at the level of syntax trees. Therefore, a unifying fragment component model is related to the context-free grammar of a language to identify extension and variation points in syntax trees as well as valid component types. By doing so, fragment components can be composed by transformations at respective extension and variation points so that always valid composition results regarding the underlying context-free grammar are yielded. However, given a language’s context-free grammar, the composition result may still be incorrect.
Context-sensitive constraints such as type constraints may be violated so that the program cannot be compiled and/or interpreted correctly. While a compiler can detect such errors after composition, it is difficult to relate them back to the original transformation step in the composition system, especially in the case of complex compositions with several hundreds of such steps. To tackle this problem, this thesis proposes well-formed ISC—an extension to ISC that uses reference attribute grammars (RAGs) to specify fragment component models and fragment contracts to guard compositions with context-sensitive constraints. Additionally, well-formed ISC provides composition strategies as a means to configure composition algorithms and handle interferences between composition steps.
Developing ISC systems for complex languages such as programming languages is a complex undertaking. Composition-system developers need to supply or develop adequate language and parser specifications that can be processed by an ISC composition engine. Moreover, the specifications may need to be extended with rules for the intended composition abstractions.
Current approaches to ISC require complete grammars to be able to compose fragments in the respective languages. Hence, the specifications need to be developed exhaustively before any component model can be supplied. To tackle this problem, this thesis introduces scalable ISC—a variant of ISC that uses island component models as a means to define component models for partially specified languages while still the whole language is supported. Additionally, a scalable workflow for agile composition-system development is proposed which supports a development of ISC systems in small increments using modular extensions.
All theoretical concepts introduced in this thesis are implemented in the Skeletons and Application Templates framework SkAT. It supports “classic”, well-formed and scalable ISC by leveraging RAGs as its main specification and implementation language. Moreover, several composition systems based on SkAT are discussed, e.g., a well-formed composition system for Java and a C preprocessor-like macro language. In turn, those composition systems are used as composers in several example applications such as a library of parallel algorithmic skeletons.