Diss. (sammanfattning) Stockholm : Karolinska institutet, 2001. / Härtill 6 uppsatser.

Thesis (Ph.D.)--Drexel University, 2008. / Includes abstract and vita. Includes bibliographical references (leaves 137-159).

Thesis (MS)--University of Montana, 2007. / Contents viewed on March 26, 2010. Title from author supplied metadata. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1982. / Typescript. Vita. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D. in Biochemistry)--Vanderbilt University, Dec. 2005. / Title from title screen. Includes bibliographical references.

Thesis (Ph.D.)--Victoria University (Melbourne, Vic.), 2009.

Thesis (Ph. D. in Biochemistry)--Vanderbilt University, May 2006. / Title from title screen. Includes bibliographical references.

RIBEIRO JÚNIOR, H. L. Expressão de genes relacionados às vias de reparo de danos em fita dupla no DNA em pacientes com Síndrome Mielodisplásica. 2016. 156 f. Tese (Doutorado em Ciências Médicas) - Faculdade Medicina, Universidade Federal do Ceará, Fortaleza, 2016. / Submitted by Erika Fernandes (erikaleitefernandes@gmail.com) on 2016-06-16T12:19:55Z No. of bitstreams: 1 2016_tese_hlrjunior.pdf: 3941169 bytes, checksum: da8ed2c501a8d8f79b2699dd21d36ce6 (MD5) / Approved for entry into archive by Erika Fernandes (erikaleitefernandes@gmail.com) on 2016-06-16T12:20:35Z (GMT) No. of bitstreams: 1 2016_tese_hlrjunior.pdf: 3941169 bytes, checksum: da8ed2c501a8d8f79b2699dd21d36ce6 (MD5) / Made available in DSpace on 2016-06-16T12:20:35Z (GMT). No. of bitstreams: 1 2016_tese_hlrjunior.pdf: 3941169 bytes, checksum: da8ed2c501a8d8f79b2699dd21d36ce6 (MD5) Previous issue date: 2016-06-09 / The myelodysplastic syndrome (MDS) is a group of clonal hematopoietic stem cell disorders characterized by cytopenia (s) peripheral (s), dysplasia of one or more myeloid cell lineages and increased risk of acute myeloid leukemia development. MDS is considered a disease of elderly people, since approximately 80% of patients are over 60 years of diagnosis. The causes of MDS are known only in 15% of cases. With respect to environmental factors such as MDS triggers may be included the use of prior chemotherapy, especially alkylating agents and purine analogs, radiation therapy and smoking. The pathogenesis of MDS involves DNA damage in hematopoietic stem cells affected probably by double-stranded damage (DSB) in the DNA and the case of joints by non-homologous ends (NHEJ) and homologous recombination main repair mechanisms necessary to ensure stability genomics of stem cells. This cohort study aimed to assess the level of expression of mRNA of the genes active in the repair mechanism of double-stranded DNA damage (BRCA1, BRCA2 and RAD51, operating in HR mechanism, the XRCC5, XRCC6 and LIG4 related mechanism for NHEJ and, finally, the ATM) linking the molecular findings with their polymorphic variants (rs4793191, rs9567623, rs1801320, rs3835, rs2267437, rs1805388 and rs228593, respectively) and with clinical and socio-demographic of patients of Myelodysplastic Syndromes. This genotyping analysis was based on qPCR methodology, including bone marrow samples from 83 patients with MDS and 10 bone marrow samples from healthy elderly volunteers. The MDS patients were diagnosed according to the criteria proposed by the World Health Organization and stratified according to the criteria established by prognósitoc Score Index International Prognostic revised. In this study we observed that: 1. the ATM, BRCA1, BRCA2 and RAD51 genes were significantly associated with cellularity variable bone marrow of patients with MDS; 2. the XRCC5 gene introduced is associated with the presence of ringed sideroblasts on the analysis of the bone marrow of patients with MDS; 3. The BRCA2, RAD51 and LIG4 genes correspond to potential markers of poor prognosis and progression in clonal cases of MDS de novo of high level, being associated with decreased survival and a high chance of progression to AML; 4. the XRCC6 gene is a negative prognostic factor for patients at low risk, it is evident that the decrease in expression of this gene is able to identify an unfavorable subgroup within the low-risk patients who have higher dependence transfusion and increased genomic instability and finally, 5 the results of analysis of influence of functional polymorphisms in MDS emphasize the importance of polymorphism rs228593, rs2267437 and rs1805388 in differentiating the expression levels of ATM, XRCC6 and LIG4 genes, respectively, compared to patients with clinical variables MDS representing novel targets for the study of the pathogenesis of this disease. We demonstrate that the DSBs repair related genes are also related to the pathogenesis of MDS. These results support the importance of the expression levels of ATM, BRCA1, BRCA2, RAD51, XRCC5, XRCC6 and LIG4 genes, as well as the frequency of the respective polymorphisms (rs228593, rs4793191, rs9567623, rs1801320, rs3835, rs2267437 and rs1805388) in the maintenance genomic stability of hematopoietic stem cells promoting a better understanding of the etiology, diagnosis and prognostic stratification and the process of clinical development of Myelodysplastic Syndromes. / Síndrome Mielodisplásica (SMD) é um grupo de doenças clonais das células progenitoras hematopoiéticas, caracterizadas por citopenia(s) periférica(s), displasia de uma ou mais linhagens celulares mielóides e aumento do risco de desenvolvimento de leucemia mielóide aguda. A SMD é considerada uma doença de pessoas idosas, pois aproximadamente 80% dos pacientes possuem mais de 60 anos ao diagnóstico. As causas da SMD são conhecidas em apenas 15% dos casos. Em relação aos fatores ambientais como desencadeadores da SMD, podem ser incluídos o uso de quimioterapia prévia, especialmente de agentes alquilantes e análogos da purina, radioterapia e tabagismo. A patogênese da SMD envolve danos no DNA nas células tronco hematopoéticas acometido provavelmente pelos danos de fita dupla (DSB) no DNA tendo o processo de junções por extremidades não-homólogas (JENH) e recombinação homóloga como principais mecanismos de reparo necessários para garantir a estabilidade genômica das células-tronco. Este estudo de coorte propôs avaliar o nível de expressão do mRNA dos genes atuantes no mecanismo de reparo em danos de fita dupla no DNA (BRCA1, BRCA2 e RAD51, atuantes no mecanismo de Recombinação Homóloga; o XRCC5, XRCC6 e LIG4 relacionados ao mecanismo de Junções por Extremidades não-Homólogas e, por fim, o ATM) associando os achados moleculares com suas variantes polimórficas (rs4793191, rs9567623, rs1801320, rs3835, rs2267437, rs1805388 e rs228593, respectivamente) e com variáveis clínicas e sócio-demográficas de pacientes portadores de Síndrome Mielodisplásica. Esta análise de genotipagem baseou-se na metodologia de qPCR, entre amostras de medula óssea de 83 pacientes com SMD e 10 amostras de medula óssea de idosos voluntários sadios. Os pacientes com SMD foram diagnosticados de acordo com os critérios propostos pela Organização Mundial de Saúde e estratificados de acordo com os critérios prognósitoc estabelecidos pelo Índice de Score Prognóstico Internacional revisado. Com este estudo foi possível identificar que: 1. os genes ATM, BRCA1, BRCA2 e RAD51 foram associados significativamente com a variável de celularidade da medula óssea dos pacientes com SMD; 2. o gene XRCC5 apresentou-se associado com a presença de sideroblastos em anel quanto à análise da medula óssea dos pacientes com SMD; 3. os genes BRCA2, RAD51 e LIG4 correspondem a possíveis marcadores de pior prognóstico e de progressão clonal em casos de SMD de novo de alto grau, estando associados a uma diminuição da sobrevida e a uma elevada chance de evolução para LMA; 4. o gene XRCC6 é um fator de prognóstico desfavorável para os pacientes de baixo risco, sendo evidente que a diminuição da expressão deste gene é capaz de identificar um subgrupo desfavorável dentro dos pacientes de baixo risco que apresentariam maior dependência transfusional e maior instabilidade genômica e, por fim, 5. os resultados das análises de influência dos polimorfismos funcionais na SMD realçam a importância dos polimorfismos rs228593, rs2267437 e rs1805388 na diferenciação dos níveis de expressão dos genes ATM, XRCC6 e LIG4, respectivamente, frente às variáveis clínicas de pacientes com SMD, representando novos alvos para o estudo da patogênese desta doença. Demonstramos que os genes relacionados à reparação das DSBs são também relacionados a patogênese da SMD. Estes resultados suportam a importância dos níveis de expressão dos genes ATM, BRCA1, BRCA2, RAD51, XRCC5, XRCC6 e LIG4, como também da frequência dos seus respectivos polimorfismos (rs228593, rs4793191, rs9567623, rs1801320, rs3835, rs2267437 e rs1805388) na manutenção da estabilidade genômica das células tronco hematopoiéticas promovendo um melhor entendimento da etiologia, estratificação diagnóstica e prognóstica e do processo de evolução clínica da Síndrome Mielodisplásica.

MAIA, A. R. S. Expressão de genes relacionados às vias de reparo de danos em fita simples (ERCC8, ERCC6, ERCC5, XPA e XPC) no DNA em pacientes com síndrome mielodisplásica. 2016. 148 f. Tese (Doutorado em Ciências Médicas) - Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2016. / Submitted by Erika Fernandes (erikaleitefernandes@gmail.com) on 2017-01-20T13:58:14Z No. of bitstreams: 1 2016_tese_arsmaia.pdf: 3701253 bytes, checksum: c3322842914233c54fcab7682a83f144 (MD5) / Approved for entry into archive by Erika Fernandes (erikaleitefernandes@gmail.com) on 2017-01-20T13:58:22Z (GMT) No. of bitstreams: 1 2016_tese_arsmaia.pdf: 3701253 bytes, checksum: c3322842914233c54fcab7682a83f144 (MD5) / Made available in DSpace on 2017-01-20T13:58:22Z (GMT). No. of bitstreams: 1 2016_tese_arsmaia.pdf: 3701253 bytes, checksum: c3322842914233c54fcab7682a83f144 (MD5) Previous issue date: 2016-12-22 / Myelodysplastic Syndrome (MDS) is a group of clonal diseases of hematopoietic progenitor cells, characterized by peripheral cytopenia (s), dysplasia of one or more myeloid cell lines and increased risk of developing acute myeloid leukemia. SMD is considered a disease of the elderly, as approximately 80% of patients over 60 years are diagnosed with the disease. The causes of MDS are known in only 15% of cases. Regarding environmental factors as triggers of MDS, the use of prior chemotherapy, especially of alkylating agents and purine analogs and radiotherapy may be included. The pathogenesis of SMD involves DNA damage in hematopoietic stem cells, also resulting from single stranded DNA damage (SSB) in the DNA having three mechanisms: base excision repair (BER), base pair mismatch repair (MMR), and repair By nucleotide excision (NER), as repair processes necessary to ensure the genomic stability of stem cells. This cohort study aimed to evaluate the mRNA expression level of the single-stranded DNA repair mechanism, ERCC8 (CSA), ERCC6 (CSB) acting on the transcription-linked nucleotide excision repair mechanism (TC (XPG) and XPA acting at the confluence of the GG-NER and TC-NER subunits, associating the molecular findings with clinical variables (NER), XPC acting on the nucleotide excision repair mechanism linked to the global genome (GG-NER), ERCC5 And socio- demographic characteristics of patients with Myelodysplastic Syndrome. This analysis was based on the qPCR methodology, between bone marrow samples from 74 patients with MDS and 10 bone marrow samples from healthy elderly volunteers. Patients with MDS were diagnosed according to the criteria proposed by the World Health Organization and stratified according to the prognostic criteria established by the revised International Prognostic Score Index. With this study, it was possible to identify that: 1. patients diagnosed with hypocellular MDS presented increased levels of XPA and XPC gene expression and reduced ERCC8 (CSA) gene expression level; 2. Increased levels of ERCC8 (CSA), ERCC5 (XPG) and XPA gene were identified in poorer prognostic variables for MDS; 3. increased expression of the ERCC6 (CSB), ERCC5 (XPG) and XPA genes in cytopenic profiles representative of a more aggressive disease picture was observed; 4. MDS patients with increased ERCC8 (CSA) gene expression levels exhibited longer survival, and when increased expression levels of the ERCC5 (XPG), XPA and XPC genes exhibited lower survival; 5. In the analysis of correlations, the expression of the XPA gene showed a correlation of 26.8% with the expression of the ERCC5 gene (XPG), as well as, the expression of the XPA gene showed a 70.5% correlation with the expression of the XPC gene and, finally, XPC gene expression was found to have a 36.7% correlation with ERCC5 (XPG) gene expression. / A Síndrome Mielodisplásica (SMD) é um grupo de doenças clonais das células progenitoras hematopoiéticas, caracterizadas por citopenia(s) periférica(s), displasia de uma ou mais linhagens celulares mielóides e aumento do risco de desenvolvimento de leucemia mielóide aguda. A SMD é considerada uma doença de pessoas idosas, pois aproximadamente 80% dos pacientes acima de 60 anos são diagnosticados com a doença. As causas da SMD são conhecidas em apenas 15% dos casos. Em relação aos fatores ambientais como desencadeadores da SMD, podem ser incluídos o uso de quimioterapia prévia, especialmente de agentes alquilantes e análogos da purina e radioterapia. A patogênese da SMD envolve danos no DNA nas células tronco hematopoéticas, oriundas também pelos danos de fita simples (SSB) no DNA tendo três mecanismos: reparo por excisão de bases (BER), reparo de erros de emparelhamento de bases (MMR) e reparo por excisão de nucleotídeo (NER), como processos de reparo necessários para garantir a estabilidade genômica das células-tronco. Este estudo de coorte propôs avaliar o nível de expressão do mRNA dos genes atuantes no mecanismo de reparo em danos de fita simples no DNA, ERCC8 (CSA), ERCC6(CSB) atuantes no mecanismo de reparo de excisão de nucleotídeos ligado a transcrição (TC-NER), XPC atuante no mecanismo de reparo por excisão de nucleotpideos ligado ao genoma global (GG-NER), ERCC5(XPG) e XPA atuantes na confluência das subvias GG-NER e TC-NER, associando os achados moleculares com variáveis clínicas e sócio-demográficas de pacientes portadores de Síndrome Mielodisplásica. Esta análise baseou-se na metodologia de qPCR, entre amostras de medula óssea de 74 pacientes com SMD e 10 amostras de medula óssea de idosos voluntários sadios. Os pacientes com SMD foram diagnosticados de acordo com os critérios propostos pela Organização Mundial de Saúde e estratificados de acordo com os critérios prognósticos estabelecidos pelo Índice de Escore Prognóstico Internacional revisado. Com este estudo foi possível identificar que: 1. pacientes diagnosticados com SMD hipocelular apresentaram aumento nos níveis de expressão dos genes XPA e XPC e reduzido nível de expressão do gene ERCC8(CSA); 2. identificou-se que níveis de expressão aumentados do gene ERCC8(CSA), ERCC5(XPG) e XPA em variáveis de pior prognóstico para SMD; 3. foi observado um aumento de expressão dos genes ERCC6(CSB), ERCC5(XPG) e XPA em perfis de citopenias representativas de um quadro de doença mais agressiva; 4. pacientes com SMD apresentando níveis de expressão aumentados do gene ERCC8(CSA) exibiram maior sobrevida e quando apresentando níveis de expressão aumentados dos genes ERCC5(XPG), XPA e XPC exibiram menor sobrevida; 5. nas análises de correlações verificou-se que a expressão do gene XPA apresentou correlação de 26,8% com a expressão do gene ERCC5(XPG), bem como, a expressão do gene XPA exibiu correlação 70,5% com a expressão do gene XPC e, por fim, foi verificado que a expressão do gene XPC exibiu correlação de 36,7% com a expressão do gene ERCC5(XPG).

Secondary metabolism occurs after the main growth phase in Streptomyces. A 'transition phase' occurs to remodel global patterns of gene expression at the onset of physiological and developmental differentiation. Many different signals influence this transition phase, integrating, for example, information on nutritional status, growth rate, and stress responses. Several pleiotropic transcription factors that regulate the transition phase have been identified, but aspects of epigenetic control of gene expression are not well understood. This study focused on the characterisation of a novel gene sco2075 in S. coelicolor encoding a protein that combines a histone-like domain with a conserved DksA-like domain, the latter considered a ppGpp cofactor. The protein is important for integrating responses to both oxidative and osmotic stresses. The sco2075- mutant strain is sensitive to oxidative stress at least in part due to reduced induction of the alternative sigma factor sigmaR. SCO2075, similarly to E. coli DksA, may play a possible role in the liberation of core RNA polymerase to bind alternative sigma factors such as sigmaR. In addition DSCO2075 has an altered topological profile of a reporter plasmid under osmotic stress, showing little alteration in negative supercoiling when compared to the significant increase in wildtype. DSCO2075 also has a reduction in aerial hyphae and a possible reduction in actinorhodin production when grown with osmolyte. The histone-like domain of SCO2075 binds DNA non-specifically. SCO2075 expression appears to coincide with diffused FtsZ expression prior to Z-ring formation when SCO2075 appears to become nucleoid associated. Analysis of pre-spore compartment lengths showed SCO2075 is one of several nucleoid associated proteins involved in nucleoid compaction during aerial hyphal erection and sporulation. Absence of sco2075, however, does not affect the production of unigenomic spore chains. Finally, over-expression of SCO2075 suppresses defects in secondary metabolism of a relA mutant affected in ppGpp synthesis. SCO2075 could potentially be a new type of regulator, likely acting as a node to integrate stress and physiological cues by modulating DNA topology/compaction and RNA polymerase activity.