Recent developments in the field of reduced-order modeling-and, in particular, active subspace construction-have made it possible to efficiently approximate complex models by constructing loworder response surfaces based upon a small subspace of the original high-dimensional parameter space. These methods rely upon the fact that the response tends to vary more prominently in a few dominant directions defined by linear combinations of the original inputs, allowing for a rotation of the coordinate axis and a consequent transformation of the parameters. In this paper, we discuss a gradient-free active subspace algorithm that is feasible for high-dimensional parameter spaces where finite-difference techniques are impractical. This analysis extends the gradient-free algorithm introduced in [A.
oxygenase-1 promotes migration and -epithelial Na ϩ channel expression in cytotrophoblasts and ischemic placentas. Am J Physiol Regul Integr Comp Physiol 306: R641-R646, 2014. First published February 19, 2014 doi:10.1152/ajpregu.00566.2013.-Preeclampsia is thought to arise from inadequate cytotrophoblast migration and invasion of the maternal spiral arteries, resulting in placental ischemia and hypertension. Evidence suggests that altered expression of epithelial Na ϩ channel (ENaC) proteins may be a contributing mechanism for impaired cytotrophoblast migration. ENaC activity is required for normal cytotrophoblast migration. Moreover, -ENaC, the most robustly expressed placental ENaC message, is reduced in placentas from preeclamptic women. We recently demonstrated that heme oxygenase-1 (HO-1) protects against hypertension in a rat model of placental ischemia; however, whether HO-1 regulation of -ENaC contributes to the beneficial effects of HO-1 is unknown. The purpose of this study was to determine whether -ENaC mediates cytotrophoblast migration and whether HO-1 enhances ENaC-mediated migration. We showed that placental ischemia, induced by reducing uterine perfusion suppressed, and HO-1 induction restored, -ENaC expression in ischemic placentas. Using an in vitro model, we found that HO-1 induction, using cobalt protoporphyrin, stimulates cytotrophoblast -ENaC expression by 1.5-and 1.8-fold (10 and 50 M). We then showed that silencing of -ENaC in cultured cytotrophoblasts (BeWo cells), by expression of dominant-negative constructs, reduced migration to 56 Ϯ 13% (P Ͻ 0.05) of control. Importantly, HO-1 induction enhanced migration (43 Ϯ 5% of control, P Ͻ 0.05), but the enhanced migratory response was entirely blocked by ENaC inhibition with amiloride (10 M). Taken together, our results suggest that -ENaC mediates cytotrophoblast migration and increasing -ENaC expression by HO-1 induction enhances migration. HO-1 regulation of cytotrophoblast -ENaC expression and migration may be a potential therapeutic target in preeclamptic patients. cytotrophoblast; preeclampsia; heme oxygenase-1; placenta; -ENaC PREECLAMPSIA IS A PREGNANCY-SPECIFIC condition characterized by hypertension, proteinuria, and maternal vascular dysfunction. It is the leading cause of maternal and perinatal mortality and morbidity. Currently, there are no effective preventive and treatment strategies except for the early delivery of the placenta and fetus. Because the symptoms of preeclampsia remit after delivery, the placenta has been implicated as the major contributor to the pathophysiology of the disorder. The prevailing hypothesis is that preeclampsia is initiated by abnormal cytotrophoblast migration and subsequent invasion of the maternal uterine spiral arteries, resulting in restricted blood flow to the developing uteroplacental unit and placental ischemia.
Sandia's Dakota software (available at http://dakota.sandia.gov) supports science and engineering transformation through advanced exploration of simulations. Specifically it manages and III analyzes ensembles of simulations to provide broader and deeper perspective for analysts and decision makers. This enables them to enhance understanding of risk, improve products, and assess simulation credibility. This manual offers Consortium for Advanced Simulation of Light Water Reactors (LWRs) (CASL) partners a guide to conducting Dakota-based VUQ studies for CASL problems. It motivates various classes of Dakota methods and includes examples of their use on representative application problems. On reading, a CASL analyst should understand why and how to apply Dakota to a simulation problem.
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