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Thesis (Ph. D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Vita. Bibliography: 199-250.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / This study addresses the distribution of trace metals in sediment cores from the dam Marcela in order to evaluate the occurrence of impacts associated with human and industrial activity. The dam is located in the city Itabaiana in the state of Sergipe, it was built in the period 1953 - 1957 barring Fuzil stream. It has an area of 1.4 km2 with storage capacity of 2,700,000 m3. Two sediment cores were collected in November of 2008 with approximately 45cm in two distinct points. The samples were sectioned in 5 cm each and they were analyzed by to determine the following chemical elements: Co, Cr, Cu, Ni, Pb, Zn, Mn, Al, Fe, Corg and Ntotal. The average value of Corg/Ntotal in the range 4,97- 7,64 and 6,39-7,69, for cores I and II respectively, indicative autochthonous and allochthonous origin of the organic matter. The multivariate statistical analysis (Principal component analysis) applied to the set of results showed that the two cores in relation to concentrations of metals are different, with evidence of enrichment for Cr, Cu, Mn and Zn in the surface layers. The contamination factor calculed showed contamination moderate level for metals Cr, Cu, Mn and Zn. The risk assessment code (RAC), which consider the percentage of metal extracted in the label fraction (F1) of BCR procedure, showed that chromium does not present risk to the environment, copper, nickel and lead were low to medium risk, and zinc had of very high to High risk to the aquatic environment. Small variations in environmental conditions, such as pH or salinity, could therefore increase availability of the elements to the aquatic system. The metals concentrations were always at the lower limit the TEC and PEC, defined by consensual sediment quality guidelines (SQGs), in this case, it is not possible to predict what adverse effects the metal can cause in this environment. / Neste trabalho foi determinada a distribuição de metais traço em testemunhos de sedimento do Açude Marcela com o objetivo de avaliar a ocorrência de impactos associados à atividade humana e industrial, desenvolvidas naquela região. O Açude Marcela localiza-se na cidade de Itabaiana Sergipe, foi construído no período 1953 à 1957 pelo barramento do riacho Fuzil e tem uma área de 1,4km2 , com capacidade de armazenamento de 2.700.000 m3. Foram coletados em novembro de 2008 dois testemunhos de sedimentos com aproximadamente 45cm de profundidade em dois pontos distintos do açude. Os testemunhos foram secionados a cada 5cm para determinação dos seguintes elementos químicos: Co, Cr, Cu, Ni, Pb, Zn, Mn, Al, Fe, Corg e Ntotal. A relação Corg/Ntotal variou de 4,97-7,64 e 6,39-7,69 para os testemunhos I e II, respectivamente, indicando origem autóctone e alóctone para a matéria orgânica presente no sedimento. A análise estatística multivariada (análise de componentes principais-ACP), aplicada ao conjunto dos resultados, mostrou que os dois testemunhos, em relação às concentrações dos metais, são estatisticamente diferentes, com evidências de enriquecimento por Cr, Cu, Mn e Zn, nas camadas mais superficiais. O fator de contaminação calculado mostrou um nível de contaminação moderado para os metais Cr, Cu, Mn e Zn. O Fator de Risco (RAC), que compreende a percentagem do metal extraída na fração lábil (F1) do procedimento (BCR) empregado, indicou que o cromo não apresentou risco ao ambiente. Cobre, níquel e chumbo apresentaram risco baixo a médio, e zinco apresentou risco alto a altíssimo para o ambiente aquático. Sendo assim, pequenas variações nas condições ambientais podem remobilizar esses elementos do sedimento para a coluna d água. As concentrações dos metais nos testemunhos estiveram entre TEC e o PEC, definidos pelos valores guias de qualidade de sedimento consensual (VGQS), indicando que, nas condições atuais, o sedimento pode exercer efeito adverso aos organismos do açude em questão.

Thesis (Ph. D.)--Uniformed Services University of the Health Sciences, 2005. / Typescript (photocopy).

<p>Neutrophils are the first cells recruited to an immune stimulus stemming from infection or sterile injuries via a mixture of chemoattractant cues. In addition to eliminating pathogens, neutrophils coordinate the overall inflammation by activating and producing inflammatory signals in the tissue while modulating the activation of other immune cells which in some cases leads to adverse tissue damage. Over amplified or chronic neutrophil recruitment directly leads to autoimmune diseases including rheumatic arthritis, diabetes, neurodegenerative diseases, and cancer. Dampening neutrophil recruitment is a strategy to intervene in neutrophil-orchestrated chronic inflammation. Despite intensive research over the past several decades, clinical studies targeting neutrophil migration have been largely unsuccessful, possibly due to the prominent redundancy of adhesion receptors and chemokines. Additional challenges lie in the balance of dampening detrimental inflammation while preserving immunity. Neutrophils are terminally differentiated cells that are hard to study in cell culture. Mouse models are often used to study hematopoiesis, migration, and chemotaxis of neutrophils but is very labor intensive. To discover novel therapeutic targets that modulate neutrophil migration, we performed a neutrophil-specific microRNA (miRNA) overexpression screen in zebrafish and identified eight miRNAs as potent suppressors of neutrophil migration. We have generated transgenic zebrafish lines that overexpresses these candidate miRNAs where we recapitulated the mitigation in neutrophil motility and chemotaxis to tissue injury or infection. Among those we further characterized two miRNAs which have not been reported to regulate neutrophil migration, namely miR-722 and miR-199.</p> <p> </p> <p>MiR-722 downregulates the transcript level of <i>rac2</i> through binding to the <i>rac2</i> 3'UTR. Furthermore, miR-722-overexpressing larvae display improved outcomes in both sterile and bacterial systemic models, which correlates with a robust upregulation of the anti-inflammatory cytokines in the whole larvae and isolated neutrophils. miR-722 protects zebrafish from lethal lipopolysaccharide challenge. In addition, overexpression of mir-722 reduced chemotaxis of human neutrophil like cells, indicating that miR-722 is a potential agent to reduce inflammation in humans. </p> <p>MiR-199<i>,</i> decreases neutrophil chemotaxis in zebrafish and human neutrophil-like cells. Intriguingly, in terminally differentiated neutrophils, miR-199 alters the cell cycle-related pathways and directly suppresses cyclin-dependent kinase 2 (<i>cdk2</i>), whose known activity is restricted to cell cycle progression and cell differentiation. Inhibiting Cdk2, but not DNA replication, disrupts cell polarity and chemotaxis of zebrafish neutrophils without inducing cell death. Human neutrophil-like cells deficient in CDK2 fail to polarize and display altered signaling downstream of the formyl peptide receptor. Chemotaxis of primary human neutrophils is also reduced upon CDK2 inhibition. Furthermore, miR-199 overexpression or CDK2 inhibition significantly improves the outcome of lethal systemic inflammation challenges in zebrafish. </p> <p> </p> <p>In summary, our results reveal previously unknown functions of these miRNAs, and provide potential avenues to modulate neutrophil migration as well as lead to discoveries of novel factors which can regulate this process. We have also discovered a non-classical role of CDK2 in regulating neutrophil migration which provides directions for alleviating systemic inflammation and a better understanding of neutrophil biology. </p>