Acinar Cell Apoptosis in Serpini2-Deficient Mice Models Pancreatic Insufficiency

Pancreatic insufficiency (PI) when left untreated results in a state of malnutrition due to an inability to absorb nutrients. Frequently, PI is diagnosed as part of a larger clinical presentation in cystic fibrosis or Shwachman–Diamond syndrome. In this study, a mouse model for isolated exocrine PI was identified in a mouse line generated by a transgene insertion. The trait is inherited in an autosomal recessive pattern, and homozygous animals are growth retarded, have abnormal immunity, and have reduced life span. Mice with the disease locus, named pequeño (pq), exhibit progressive apoptosis of pancreatic acinar cells with severe exocrine acinar cell loss by 8 wk of age, while the islets and ductal tissue persist. The mutation in pq/pq mice results from a random transgene insertion. Molecular characterization of the transgene insertion site by fluorescent in situ hybridization and genomic deletion mapping identified an approximately 210-kb deletion on Chromosome 3, deleting two genes. One of these genes, Serpini2, encodes a protein that is a member of the serpin family of protease inhibitors. Reintroduction of only the Serpini2 gene by bacterial artificial chromosome transgenic complementation corrected the acinar cell defect as well as body weight and immune phenotypes, showing that deletion of Serpini2 causes the pequeño phenotype. Dietary supplementation of pancreatic enzymes also corrected body size, body weight, and immunodeficiency, and increased the life span of Serpini2-deficient mice, despite continued acinar cell loss. To our knowledge, this study describes the first characterized genetic animal model for isolated PI. Genetic complementation of the transgene insertion mutant demonstrates that Serpini2 deficiency directly results in the acinar cell apoptosis, malabsorption, and malnutrition observed in pq/pq mice. The rescue of growth retardation, immunodeficiency, and mortality by either Serpini2 bacterial artificial chromosome transgenic expression or by pancreatic enzyme supplementation demonstrates that these phenotypes are secondary to malnutrition in pq/pq mice

Optimal vorticity accuracy in an efficient velocity-vorticity method for the 2D Navier-Stokes equations

We study a velocity-vorticity scheme for the 2D incompressible Navier-Stokes equations, which is based on a formulation that couples the rotation form of the momentum equation with the vorticity equation, and a temporal discretization that stably decouples the system at each time step and allows for simultaneous solving of the vorticity equation and velocity-pressure system (thus if special care is taken in its implementation, the method can have no extra cost compared to common velocity-pressure schemes). This scheme was recently shown to be unconditionally long-time H-1 stable for both velocity and vorticity, which is a property not shared by any common velocity-pressure method. Herein, we analyze the scheme's convergence, and prove that it yields unconditional optimal accuracy for both velocity and vorticity, thus making it advantageous over common velocity-pressure schemes if the vorticity variable is of interest. Numerical experiments are given that illustrate the theory and demonstrate the scheme's usefulness on some benchmark problems

<i>pequeño</i> Malnutrition Is Rescued by BAC Transgenic Expressing <i>Serpini2</i> Gene or Pancreatic Enzyme Diet Supplementation

<div><p>(A–C) Treatment of <i>pq/pq</i> mice (blue) pharmacologically with daily pancreatic enzyme diet supplement (purple) or genetically with BAC 150E1 transgene (green), rescues (A) size, (B) weight, and (C) animal viability in comparison to wild-type mice (black). For (B) weight measurements are averaged from <i>n =</i> 6 males from each genotype.</p><p>(D–G) Hematoxylin and eosin staining of pancreas sections from 8-wk-old mice. Wild-type mice (D) have normal pancreatic acinar cells present and normal pancreatic morphology while in (E) <i>pq/pq</i> mice there is a loss of acinar cells. In the BAC+; <i>pq/pq</i> mice (F), pancreas acinar cells are present. The acinar cell loss in <i>pq/pq</i> mice treated with enzyme supplementation (G) is the same as untreated <i>pq/pq</i> mice (A–C), although diet supplementation is effective in combating the effects of malnutrition. Bar represents 25 μm.</p></div