1,720,961 research outputs found
Metabolism And Adverse Effects of Arsenic In Genetically Diverse Mouse Strains
Full text linkThrough drinking water and food, millions of people worldwide are exposed to arsenic (As), which is a naturally occurring diabetogenic metalloid 13. Inorganic arsenic (iAs) exposure may disrupt glucose homeostasis leading to type 2 diabetes (T2D), including: (i) insulin resistance due to inhibition of insulin signaling, (ii) inhibition of insulin secretion, and (iii) aberrant micro RNA expression and activity 1, 2, 13. Arsenic methyltransferase (AS3MT) is the key enzyme in iAs detoxification pathway that determines disease outcome 3. Polymorphisms in AS3MT is the single most important genetic factor affecting iAs metabolism and susceptibility to adverse effects of iAs exposure, including diabetes. This study aims to examine the relationship between As3mt polymorphism and the adverse outcomes of iAs exposure in two Collaborative Cross (CC) mouse strains, CC021/Unc (CC021) and CC027/TauUnc (CC027), with different genetic backgrounds. Metabolic phenotype and susceptibility to adverse effects of iAs exposure are hypothesized to differ in CC021 and CC027 due to the differences in their hepatic As3mt expression and iAs metabolism (in liver). The metabolic/diabetic phenotype and iAs metabolism were assessed in both strains after 12 weeks of exposure to 100 ppb or 50 ppm iAs (sodium arsenite) in drinking water. The differences we observed between phenotypes of CC021 and CC027 mice were determined mainly by the genetic backgrounds of these strains and only to smaller extent by iAs exposure. Differences due to iAs exposure were found in weight gain, glycemia and insulin response to i.p. glucose injection, as well as in total As level in urine and in the percentage of total As represented by iAs. In future studies, we aim to identify other genes that underlie the susceptibility to iAs-associated T2D and establish a better mouse model in which As3mt expression and iAs metabolism resemble those in humans.Bachelor of Science in Public Healt
Inhibition of insulin secretion in β-cells exposed to arsenic, cadmium and manganese is associated with altered microRNA expression
Full text linkDiabetes Mellitus (DM) is a global public health epidemic characterized by the inability of the body to properly regulate blood glucose and can manifest in different forms. A variety of risk factors, such as obesity, family history and a high-caloric diet, increase the risk of developing Type II DM. Recently, environmental exposures, including inorganic arsenic (iAs), cadmium (Cd) and manganese (Mn) have been associated with diabetes and altered glucose homeostasis. Previous research from our lab has shown that while iAs, Cd and Mn impair glucose stimulated insulin secretion (GSIS) in rat insulinoma (beta) cells, they may be operating through different mechanisms which remain unknown. MicroRNAs, which are short, non-coding RNA molecules that regulate gene expression post-transcriptionally, have recently emerged as a candidate link between metal exposure and the development of diabetes. The goal of the present study was to evaluate iAs, Cd or Mn exposure on insulin response in rat insulinoma cells and their association with dysregulated miRNA expression. As anticipated, 24-hour exposure to a non-cytotoxic concentration of iAs (1 μM) inhibited GSIS by nearly 50%, while non-cytotoxic concentrations of Cd (5 μM) and Mn (25 μM) inhibited GSIS by more than 50%. These same metal exposures did not have the same effect on the three probed microRNAs (miR-29b, miR-146a, miR-217), which suggests each metal may be operating in a unique way. Small RNA sequencing revealed that these exposures resulted in a unique miRNA profile, with all of the exposures sharing a set of miRNAs found to be highly enriched in pancreatic islets and specifically β-cells. By combining sequencing data with in vitro techniques, we have begun to investigate the relationship between heavy metal exposure, miRNAs, and impaired insulin secretion.Bachelor of Science in Public Healt
The Role of In Vivo Exposure to Inorganic Arsenic and Folate Intake on Gene Expression in Humanized C57BL/6 Sperm Cells
Full text linkArsenic is a naturally occurring element found in water sources, foods, soil, and air. However, arsenic is considered a human carcinogen, specifically in its inorganic form(s), due to its strong links to several illnesses. Inorganic arsenic (iAs) is mainly metabolized in the liver to methylated metabolites. Arsenic methylation is dependent on SAM presence in the body. AS3MT is a hepatic enzyme that is responsible for catalyzing the methyl group transfer from SAM to iAs to produce MA and subsequently DMA. This study aims to explore the role that folate plays in the arsenic methylation process, specifically in sperm cells. The overall goal is to understand whether altering folate intake impacts arsenic metabolism as well as determining which genes are upregulated and downregulated based on exposure group. I hypothesized that altering folate intake will impact arsenic metabolism as well as gene expression in the humanized (Hu) mice. Our results show that folate intake does affect gene expression in humanized sperm cells, with similar effects between the folate adequate and folate supplemented groups in certain annotated pathways.Bachelor of Science in Public Healt
The Role of Dietary Folate Intake in Metabolism of Arsenic in Wild-Type C57BL/6N Mice and C57BL/6N Mice Carrying the Human AS3MT Gene
Full text linkChronic exposure to inorganic arsenic (iAs) is a public health concern and is associated with type 2 diabetes. iAs metabolism consists of methylation reactions catalyzed by arsenic methyltransferase (AS3MT) in most mammals. In humans, folate intake has been shown to affect iAs metabolism efficiency. Mouse models are commonly used to study iAs exposure, but mice are more efficient at metabolizing iAs than humans. This study examined a new mouse model carrying human AS3MT to better represent human iAs metabolism. We also assessed the role of folate in iAs metabolism and development of diabetic phenotypes in humanized and wild-type mice fed a folate deficient, adequate, or supplemented diet. We found that the humanized mice are a suitable model for human iAs metabolism but do not exhibit the same effects of folate intake on iAs metabolism seen in humans. Folate intake did not alter iAs metabolism efficiency in mice of either genotype.Master of Scienc
Peroxide dependent effects in human airway epithelial cells exposed to oxidant air pollutants
Full text linkAir pollution is a global public health problem. The induction of oxidative stress, or the cellular response to avoid cytotoxicity due to an increase in reactive oxygen species or decrease in antioxidants, is frequently cited as a mechanism of toxicity for air pollutants. In addition to the role of oxidative stress in disease, there is growing evidence that oxidative processes including the generation of reactive oxygen species is essential for normal cellular function. This dissertation provides evidence that the reactive oxygen species, hydrogen peroxide, is a key mediator in air pollutant-induced adverse cellular responses. First, it is demonstrated that the divalent metal, zinc, induces hydrogen peroxide-dependent adaptive gene expression in human airway epithelial cells. This builds upon previous work to establish that zinc-induced pro-oxidant effects and electrophilic activity are both critical in its mechanism of toxicity. We next show that the organic component, 1,2-naphthoquinone, increases protein sulfenylation of regulatory proteins via hydrogen peroxide. This is the first report that protein sulfenylation is effected by an environmentally relevant exposure, establishing a potential new mechanism of toxicity as well as a new biomarker for future studies. Finally, two approaches to utilize readouts of oxidative stress in a translational manner are discussed. Specifically, the biological basis of a genetic risk factor of a susceptible population to air pollution is explored using a primary human airway epithelial cell culture. We report that there is an intimate relationship between hydrogen peroxide and glutathione in the air pollutant-induced outcomes, and that the genetic risk factor, GSTM1-null, enhances the effect of 1,2-NQ to induce the novel readout protein sulfenylation. Furthermore, we were able to use a live cell imaging analysis of oxidative stress to rank the toxicity of fibers of importance to respiratory toxicity and show that asbestos fibers obtained from the Libby Montana Superfund Site have similar toxicity to that of crocidolite asbestos fibers. Together the data suggests a vital and important role of hydrogen peroxide in air pollutant-induced adverse responses and provides the basis to use redox-based readouts as biomarkers to improve public health.Doctor of Philosoph
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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