A hierarchy of models for simulating experimental results from a 3D heterogeneous porous medium

In this work we examine the dispersion of conservative tracers (bromide and fluorescein) in an experimentally-constructed three-dimensional dual-porosity porous medium. The medium is highly heterogeneous ($\sigma_Y^2=5.7$), and consists of spherical, low-hydraulic-conductivity inclusions embedded in a high-hydraulic-conductivity matrix. The bi-modal medium was saturated with tracers, and then flushed with tracer-free fluid while the effluent breakthrough curves were measured. The focus for this work is to examine a hierarchy of four models (in the absence of adjustable parameters) with decreasing complexity to assess their ability to accurately represent the measured breakthrough curves. The most information-rich model was (1) a direct numerical simulation of the system in which the geometry, boundary and initial conditions, and medium properties were fully independently characterized experimentally with high fidelity. The reduced models included; (2) a simplified numerical model identical to the fully-resolved direct numerical simulation (DNS) model, but using a domain that was one-tenth the size; (3) an upscaled mobile-immobile model that allowed for a time-dependent mass-transfer coefficient; and, (4) an upscaled mobile-immobile model that assumed a space-time constant mass-transfer coefficient. The results illustrated that all four models provided accurate representations of the experimental breakthrough curves as measured by global RMS error. The primary component of error induced in the upscaled models appeared to arise from the neglect of convection within the inclusions. Interestingly, these results suggested that the conventional convection-dispersion equation, when applied in a way that resolves the heterogeneities, yields models with high fidelity without requiring the imposition of a more complex non-Fickian model.Comment: 27 pages, 9 Figure

Acute Mechanical Stress in Primary Porcine RPE Cells Induces Angiogenic Factor Expression and In Vitro Angiogenesis

Background Choroidal neovascularization (CNV) is a major cause of blindness in patients with age-related macular degeneration. CNV is characterized by new blood vessel growth and subretinal fluid accumulation, which results in mechanical pressure on retinal pigment epithelial (RPE) cells. The overexpression of RPE-derived angiogenic factors plays an important role in inducing CNV. In this work, we investigated the effect of mechanical stress on the expression of angiogenic factors in porcine RPE cells and determined the impact of conditioned medium on in-vitro angiogenesis. Results The goal of this study was to determine whether low levels of acute mechanical stress during early CNV can induce the expression of angiogenic factors in RPE cells and accelerate angiogenesis. Using a novel device, acute mechanical stress was applied to primary porcine RPE cells and the resulting changes in the expression of major angiogenic factors, VEGF, ANG2, HIF-1α, IL6, IL8 and TNF-α, were examined using immunocytochemistry, qRT-PCR, and ELISA. An in vitro tube formation assay was used to determine the effect of secreted angiogenic proteins due to mechanical stress on endothelial tube formation by human umbilical vein endothelial cells (HUVECs). Our results showed an increase in the expression of VEGF, ANG2, IL-6 and IL-8 in response to mechanical stress, resulting in increased in vitro angiogenesis. Abnormal epithelial-mesenchymal transition (EMT) in RPE cells is also associated with CNV and further retinal degeneration. Our qRT-PCR results verified an increase in the expression of EMT genes, CDH2, VIM and FN1, in RPE cells. Conclusions In conclusion, we showed that acute mechanical stress induces the expression of major angiogenic and EMT factors and promotes in vitro angiogenesis, suggesting that mechanical stress plays a role in promoting aberrant angiogenesis in AMD

Optimizing Management of Patients With Barrett's Esophagus and Low-Grade or No Dysplasia Based on Comparative Modeling

Background & Aims: Endoscopic treatment is recommended for patients with Barrett's esophagus (BE) with high-grade dysplasia, yet clinical management recommendations are inconsistent for patients with BE without dysplasia (NDBE) or with low-grade dysplasia (LGD). We used a comparative modeling analysis to identify optimal management strategies for these patients. Methods: We used 3 independent population-based models to simulate cohorts of 60-year-old individuals with BE in the United States. We followed up each cohort until death without surveillance and treatment (natural disease progression), compared with 78 different strategies of management for patients with NDBE or LGD. We determined the optimal strategy using cost-effectiveness analyses, at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY). Results: In the 3 models, the average cumulative incidence of esophageal adenocarcinoma was 111 cases, with costs totaling$5.7 million per 1000 men with BE. Surveillance and treatment of men with BE prevented 23% to 75% of cases of esophageal adenocarcinoma, but increased costs to $6.2 to$17.3 million per 1000 men with BE. The optimal strategy was surveillance every 3 years for men with NDBE and treatment of LGD after confirmation by repeat endoscopy (incremental cost-effectiveness ratio, $53,044/QALY). The average results for women were consistent with the results for men for LGD management, but the optimal surveillance interval for women with NDBE was 5 years (incremental cost-effectiveness ratio,$36,045/QALY). Conclusions: Based on analyses from 3 population-based models, the optimal management strategy for patient with BE and LGD is endoscopic eradication, but only after LGD is confirmed by a repeat endoscopy. The optimal strategy for patients with NDBE is endoscopic surveillance, using a 3-year interval for men and a 5-year interval for women

A Hierarchy of Models for Simulating Experimental Results from a 3D Heterogeneous Porous Medium: Data Sets

This repository contains the data associated with the paper "A Hierarchy of Models for Simulating Experimental Results from a 3D Heterogeneous Porous Medium" to be published in Advances in Water Resources and currently available as a preprint on arXiv (https://arxiv.org/abs/1802.01978). These data include the information required to reproduce the results reported in the publication. In particular, the data set includes (1) the breakthrough curves for concentration at the effluent of the experimental flow cell, (2) the files required to fully specify the geometry of the flow cell and the 203 low-conductivity inclusions, (3) mesh files in open-source format providing the mesh used in the computations associated with the paper, and (4) the input files needed to run the numerical simulations in the software COMSOL should users have access to that proprietary set of solvers

A Hierarchy of Models for Simulating Experimental Results 6 from a 3D Heterogeneous Porous Medium

In this work we examine the dispersion of conservative tracers (bromide and fluorescein) in an experimentally constructed three-dimensional dual-porosity porous medium, and in the absence of adjustable parameters. The medium is highly heterogeneous (σ2 Y = 5.7), and consists of spherical, low-hydraulic-conductivity inclusions embedded in a high-hydraulic-conductivity matrix. The bi-modal medium was saturated with tracers, and then flushed with tracer-free fluid while the effluent breakthrough curves were measured. The focus for this work is to examine a hierarchy of decreasingly complex models to assess their ability to accurately represent the measured breakthrough curves. The most information-rich model was a direct numerical simulation of the system in which the geometry, boundary and initial conditions, and medium properties were fully independently characterized experimentally with high fidelity. The reduced models included (1) a simplified numerical model identical to the fully-resolved DNS model, but using a domain that was one-tenth the size; (2) an upscaled mobile-immobile model that allowed for a time-dependent mass-transfer coefficient; and, (3) an upscaled mobile-immobile model that assumed a space-time constant mass-transfer coefficient. The results illustrated that all four models provided accurate representations of the experimental breakthrough curves as measured by global RMS error. The primary component of error induced in the upscaled models appeared to arise from the neglect of convection within the inclusions. We discuss the necessity to assign value (via a utility function or other similar method) to assign value to outcomes if one is to further select from among model options

Mechanical control of neural plate folding by apical domain alteration

Abstract Vertebrate neural tube closure is associated with complex changes in cell shape and behavior, however, the relative contribution of these processes to tissue folding is not well understood. At the onset of Xenopus neural tube folding, we observed alternation of apically constricted and apically expanded cells. This apical domain heterogeneity was accompanied by biased cell orientation along the anteroposterior axis, especially at neural plate hinges, and required planar cell polarity signaling. Vertex models suggested that dispersed isotropically constricting cells can cause the elongation of adjacent cells. Consistently, in ectoderm, cell-autonomous apical constriction was accompanied by neighbor expansion. Thus, a subset of isotropically constricting cells may initiate neural plate bending, whereas a ‘tug-of-war’ contest between the force-generating and responding cells reduces its shrinking along the body axis. This mechanism is an alternative to anisotropic shrinking of cell junctions that are perpendicular to the body axis. We propose that apical domain changes reflect planar polarity-dependent mechanical forces operating during neural folding