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Browsing by Author "Wang, J."
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Item A SNP in Steroid Receptor Coactivator-1 Disrupts a GSK3β Phosphorylation Site and Is Associated with Altered Tamoxifen Response in Bone(Oxford University Press, 2012-02) Hartmaier, R.J.; Richter, A.S.; Gillihan, R.M.; Sallit, J.Z.; McGuire, S.E.; Wang, J.; Lee, A.V.; Osborne, C.K.; O'Malley, B.W.; Brown, P.H.; Xu, J.; Skaar, Todd C.; Philips, S.; Rae, J.M.; Azzouz, F.; Li, L.; Hayden, J.; Henry, N.L.; Nguyen, A.T.; Stearns, V.; Hayes, D.F.; Flockhart, D.A.; Oesterreich, S.The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3)β phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3β increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3β-mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3β phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.Item Unraveling the effects of hydrological connectivity and landscape characteristics on reservoir water quality(Elsevier, 2022-10) Wang, J.; Yin, W.; Wang, L. X.; Li, N. X.; Hao, R.; Xu, J. F.; Ziao, H. B.; Zhong, Z. M.; Zhang, Y. P.; Shi , Z. H.; Earth and Environmental Sciences, School of ScienceDam construction and reservoir operation altered the landscape and hydrological process of reservoir bays, affecting reservoir water quality. However, many landscape and hydrological connectivity metrics are highly correlated and may introduce redundancies and misleading results when use conventional multivariate regression techniques. Knowledge concerning the pure effects of landscape and hydrological connectivity metrics are crucial for understanding nonpoint pollution processes and guiding water quality protection strategies in reservoirs. Based on water quality monitoring data for six years (2015–2020) from 66 reservoir bays of the Danjiangkou Reservoir in China during both flood discharge periods (FDPs) and water storage periods (WSPs), machine learning approaches (boosted regression trees and random forest) were conducted to decipher the effects of hydrological connectivity and landscape characteristics on water quality. The results showed that landscape composition, landscape configuration, and topography had the combined importance of 46.69%, 31.48%, and 10.14% on the overall water quality changes during the FDPs, respectively. However, landscape configuration was the largest importance factor controlling overall water quality for the WSPs with the combined importance of 38.57%. For the FDPs, the top two importance variables of overall water quality variation were the proportions of shrub and agricultural land in the reservoir bay. For the WSPs, the top two importance variables were flow length and index of connectivity. For specific water quality parameters, the highest importance factor controlling the variation in total nitrogen, total phosphorus, ammonia nitrogen, nitrate and chlorophyll a were landscape configuration, while the landscape composition had the highest importance on the variation in permanganate index, suggesting landscape characteristics affected water quality with specific responses to distinct water quality parameters. These findings emphasize the distinct roles of landscape and hydrological characteristics on water quality and provide important information for the efficient formulation of water quality protection strategies in reservoirs.