IMECE2008-67360 GASTROESOPHAGEAL REFLUX 2D AND 3D STEADY STATE CFD SIMULATIONS

ABSTRACT Gastro-Esophageal Reflux Disease (GERD) is a condition which affects up to 20% of the adult US population on a weekly basis. It is a condition where acid is allowed to flow from the stomach and into the esophagus where it causes damage to the local tissue. In chronic cases the condition can lead to cancer. Dysfunction of the Esophagogastric Junction is indicated as a primary cause. The recently developed Functional Lumen Imaging Probe (FLIP) is designed for assessment of the EGJ. It measures the cross sectional area at eight locations through the junction. This data has been used to construct a series of computational fluid dynamic simulations. These simulations showed a jet of fluid which squirts into the esophagus under the gastric pressure. This jet corresponds with previously gathered anecdotal evidence. The centerline velocities of this jet were measured and this suggested that the jet could travel up to 20 times the minimum diameter of the EGJ into the esophagus before decelerating to 25% of its original velocity. This means that if an EGJ was curved then this jet could impinge on the walls causing a localized area of increased damage to the mucosa compared to the surrounding tissue

The Non-Catalytic Carboxyl-Terminal Domain of ARFGAP1 Regulates Actin Cytoskeleton Reorganization by Antagonizing the Activation of Rac1

The regulation of the actin cytoskeleton and membrane trafficking is coordinated in mammalian cells. One of the regulators of membrane traffic, the small GTP-binding protein ARF1, also activates phosphatidylinositol kinases that in turn affect actin polymerization. ARFGAP1 is a GTPase activating protein (GAP) for ARF1 that is found on Golgi membranes. We present evidence that ARFGAP1 not only serves as a GAP for ARF1, but also can affect the actin cytoskeleton.As cells attach to a culture dish foci of actin appear prior to the cells flattening and spreading. We have observed that overexpression of a truncated ARFGAP1 that lacks catalytic activity for ARF, called GAP273, caused these foci to persist for much longer periods than non-transfected cells. This phenomenon was dependent on the level of GAP273 expression. Furthermore, cell spreading after re-plating or cell migration into a previously scraped area was inhibited in cells transfected with GAP273. Live cell imaging of such cells revealed that actin-rich membrane blebs formed that seldom made protrusions of actin spikes or membrane ruffles, suggesting that GAP273 interfered with the regulation of actin dynamics during cell spreading. The over-expression of constitutively active alleles of ARF6 and Rac1 suppressed the effect of GAP273 on actin. In addition, the activation of Rac1 by serum, but not that of RhoA or ARF6, was inhibited in cells over-expressing GAP273, suggesting that Rac1 is a likely downstream effector of ARFGAP1. The carboxyl terminal 65 residues of ARFGAP1 were sufficient to produce the effects on actin and cell spreading in transfected cells and co-localized with cortical actin foci.ARFGAP1 functions as an inhibitor upstream of Rac1 in regulating actin cytoskeleton. In addition to its GAP catalytic domain and Golgi binding domain, it also has an actin regulation domain in the carboxyl-terminal portion of the protein