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Levels of O2 flux were normalized to miR-negative controls. This study provides evidence that 1 elevated miR expression has the ability to alter EVT gene transcription in the first trimester of pregnancy, a time that is critical to normal placentation and fetal growth and 2 miR plays a critical role in EVT mitochondrial function in the first trimester of pregnancy suggesting that alterations in miR expression contribute to adverse obstetrical outcomes, especially PE.

In this study, we have shown that overexpression of miR in first trimester EVTs has the ability to repress or activate many genes across a wide range of biological functions with the most significant gene alterations being associated with mitochondrial function. Additionally, we show that increased miR in the EVT cells decreases mitochondrial respiratory function during the first trimester of pregnancy.

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Therefore, the results of this study support our hypothesis that altered miR expression results in EVT dysfunction that may contribute to the pathogenesis of PE. Many studies have shown that miR is elevated in the PE placenta suggesting a functional role for miR in placental pathogenesis Pineles et al. Interestingly, miR has been shown to be expressed predominately in the villous and EVT cells of the placenta with higher expression in the latter Lee et al.

Furthermore, miR is widely known to be induced by hypoxia Chan and Loscalzo, , as is seen in PE placentas Zhang et al. While this link between miR and hypoxia has been definitively established in many tissues, the regulation of miR by hypoxia in first trimester EVT cells has not been shown previously.

Notably, in a previous publication investigating the effects of miR on placental function, we showed that elevated miR significantly decreases first trimester EVT invasion Anton et al. In an effort to determine the functional pathways altered by miR, many studies have investigated the effects of this miRNA on downstream target genes in various disease states. In this study, we focused on identifying miR target genes in primary first trimester EVT cells, the cell type most predominantly associated with the pathogenesis of PE due to defective invasion.

Utilizing this novel approach, this study was able to identify specific target genes that were most significantly altered in the presence of elevated miR Only one other study has attempted to identify miR target genes in first trimester placental trophoblast cells using a transformed commercially available cell line, Swan 71 Straszewski-Chavez et al.

Using an Affymetrix Human GeneChip, this study identified differentially expressed genes in miR transfected Swan 71 cells Ahn et al. While the results of this study are useful when determining overall functional pathways that may be affected by miR, it remains unknown if these genes are direct targets of miR or are altered by an indirect response to miR Although a full list of differentially expressed genes was not provided, interestingly, the identification of genes altered by miR does seems to be different between the two studies, as only two of the genes discussed in the manuscript, were similarly identified NFIC and FCHSD2.

This would suggest that a transformed trophoblast cell line reacts differently to epigenetic modifications by miR The extent of the biological differences between first trimester primary EVT cells and the transformed Swan 71 cells is not completely known, however, several studies have found both similarities, including cytokine profile Straszewski-Chavez et al.

These results provide evidence that differences in gene expression due to epigenetic modifications between primary and transformed trophoblast cells is biologically plausible.

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Notably, the results of the custom TruSeq array identified genes with both increased 22 genes and decreased 27 genes expression after miR transfection suggesting that not all of the gene targets predicted by TargetScan are direct targets of miR In light of these results and in conjunction with previously published studies showing alterations in mitochondrial function in preeclamptic placentas Wang and Walsh, ; Muralimanoharan et al. Mitochondria act as the primary energy producers of the cell and are regulators of cellular metabolism. These organelles use oxygen to produce ATP through a series of steps in the electron transport chain as well as oxidative phosphorylation which occurs through the respiratory complexes I—V found in the inner mitochondrial membrane.

ISCU iron sulfur cluster assembly enzyme is a scaffold protein for the de novo synthesis of iron-sulfur clusters within the mitochondria that are critical for electron transport and oxidation-reduction reactions Tong and Rouault, Interestingly, similar to the results of this study, previous studies performed outside of the pregnancy field have shown that these three genes are directly regulated by miR Cellular respiration occurs through oxidative phosphorylation within the mitochondria where oxygen is transformed to ATP through a series of protein complexes known as the electron transport chain.

Defects in the electron transport chain can produce ROS superoxide and hydrogen peroxide and free oxygen radicals oxidative stress which are well known to cause cellular damage and contribute to a large variety of human diseases including cardiovascular disease and cancer among many others. In PE, prolonged placental hypoxia due to defective trophoblast invasion in the first trimester has been associated with increased ROS production which is believed to contribute to the development of the maternal symptoms of this disease Kimura et al. Notably, a study done by Muralimanoharan et al.

The fact that both studies independently identified significant miRmediated changes in mitochondrial genes in placental trophoblasts provides strong evidence that miR contributes to trophoblast dysfunction throughout gestation. While the results of this prior study show that miR transfected third trimester villous cytotrophoblasts exhibit defects in mitochondrial respiration, it remained unknown if the development of PE was mechanistically associated with mitochondrial dysfunction as a cause or effect of late gestation placental injury.

The results of these two studies performed at two different gestational time points first trimester vs. This would suggest that defects in mitochondrial function initiated in the first trimester of pregnancy are sufficient to result in significant early or late gestation placental dysfunction and, consequently, PE. Overall this study provides evidence of a role for miR in regulating first trimester EVT function by directly targeting genes responsible for mitochondrial respiration.

Importantly, these results provide novel insight into the role of epigenetic modifications on placental function at a time in pregnancy that is most critical for normal placental development. Future studies investigating this mechanism would be warranted in order to determine if therapeutic options focused on miR or its downstream mitochondrial targets would prove useful in reducing the placental dysfunction associated with PE. LA wrote the manuscript and created the figures. LA, AB, and ME conceived and designed the experiments and contributed to the analysis and interpretation of all data.

EP and MF contributed to performing and analyzing the mitochondrial respiration experiments. All authors contributed to manuscript revision and approved the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. National Center for Biotechnology Information , U. Journal List Front Physiol v. Front Physiol. Published online Jun 6. Brown , 1 Marni J. Falk , 2 and Michal A. Elovitz 1.

Amy G. Marni J. Michal A. Author information Article notes Copyright and License information Disclaimer. This article was submitted to Reproduction, a section of the journal Frontiers in Physiology. Received Mar 11; Accepted May The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.

No use, distribution or reproduction is permitted which does not comply with these terms. Abstract Preeclampsia is associated with first trimester placental dysfunction. Cell Culture Primary EVT cells were isolated from first trimester villous tissue using a protocol that has been established and well documented by Graham et al. Open in a separate window. Table 1 Genes with significantly altered expression after extravillous trophoblast transfection with miR Table 2 Mitochondrial genes repressed by miR Responsible for transferring electrons from succinate to ubiquinone coenzyme Q.

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ISCU Iron-sulfur cluster assembly enzyme Involved in the assembly or repair of the iron sulfur clusters that are incorporated into enzymes involved in energy production, including mitochondrial respiratory complexes I, II, and III. Discussion This study provides evidence that 1 elevated miR expression has the ability to alter EVT gene transcription in the first trimester of pregnancy, a time that is critical to normal placentation and fetal growth and 2 miR plays a critical role in EVT mitochondrial function in the first trimester of pregnancy suggesting that alterations in miR expression contribute to adverse obstetrical outcomes, especially PE.

Data Availability The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher. Author Contributions LA wrote the manuscript and created the figures. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References Agani F. The role of mitochondria in the regulation of hypoxia-inducible factor 1 expression during hypoxia.

Identification of genes dysregulated by elevation of microRNA levels in human trophoblasts cell line, Swan Mitochondria and hypoxia-induced gene expression mediated by hypoxia-inducible factors. Lipopolysaccharide induces cytokine production and decreases extravillous trophoblast invasion through a mitogen-activated protein kinase-mediated pathway: possible mechanisms of first trimester placental dysfunction.

Human leucocyte antigen HLA expression of primary trophoblast cells and placental cell lines, determined using single antigen beads to characterize allotype specificities of anti-HLA antibodies. Immunology 26— Today, stroll the streets of Paris with a local gastronomic expert and explore authentic French food culture.

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