BackgroundMUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. The inflammatory bowel disease ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, but the aetiology remains obscure. In this study we used random mutagenesis to produce two murine models of inflammatory bowel disease, characterised the basis and nature of the inflammation in these mice, and compared the pathology with human ulcerative colitis.Methods and FindingsBy murine N-ethyl-N-nitrosourea mutagenesis we identified two distinct noncomplementing missense mutations in Muc2 causing an ulcerative colitis-like phenotype. 100% of mice of both strains developed mild spontaneous distal intestinal inflammation by 6 wk (histological colitis scores versus wild-type mice, p < 0.01) and chronic diarrhoea. Monitoring over 300 mice of each strain demonstrated that 25% and 40% of each strain, respectively, developed severe clinical signs of colitis by age 1 y. Mutant mice showed aberrant Muc2 biosynthesis, less stored mucin in goblet cells, a diminished mucus barrier, and increased susceptibility to colitis induced by a luminal toxin. Enhanced local production of IL-1β, TNF-α, and IFN-γ was seen in the distal colon, and intestinal permeability increased 2-fold. The number of leukocytes within mesenteric lymph nodes increased 5-fold and leukocytes cultured in vitro produced more Th1 and Th2 cytokines (IFN-γ, TNF-α, and IL-13). This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis, and wound repair. Expression of mutated Muc2 oligomerisation domains in vitro demonstrated that aberrant Muc2 oligomerisation underlies the ER stress. In human ulcerative colitis we demonstrate similar accumulation of nonglycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in noninflamed intestinal tissue. Although our study demonstrates that mucin misfolding and ER stress initiate colitis in mice, it does not ascertain the genetic or environmental drivers of ER stress in human colitis.ConclusionsCharacterisation of the mouse models we created and comparison with human disease suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of human colitis and that clinical studies combining genetics, ER stress-related pathology and relevant environmental epidemiology are warranted.

This paper is concerned with the design of gain-scheduled controllers for Linear Parameter-Varying systems. Two alternative LMI characterizations are investigated. Both characterizations are amenable t o a finite number of LMI conditions either via a gridding of the parameter range or via grid-free techniques which rely on multi-convexity concepts. Practicality and implementation issues are discussed and examples are provided.

A haptic interface is a kinesthetic link between a human operator and a virtual environment. This paper addresses fundamental stability and performance issues associated with haptic interaction. It generalizes and extends the concept of a virtual coupling network, an artificial link between the haptic display and a virtual world, to include both the impedance and admittance models of haptic interaction. A benchmark example exposes an important duality between these two cases. Linear circuit theory is used to develop necessary and sufficient conditions for the stability of a haptic simulation, assuming the human operator and virtual environment are passive. These equations lead to an explicit design procedure for virtual coupling networks which give maximum performance while guaranteeing stability. By decoupling the haptic display control problem from the design of virtual environments, the use of a virtual coupling network frees the developer of haptic-enabled virtual reality models from issues of mechanical stability.

This paper is concerned with the design of gain-scheduled controllers for uncertain Linear Parameter-Varying systems. Two alternative design techniques for constructing such controllers are discussed. Both techniques are amenable to Linear Matrix Inequality problems via a gridding of the parameter space and a selection of basis functions. These problems are then readily solvable using available tools in convex semi-de nite programming. When used together, these techniques provide complementary advantages of reduced computational burden and ease of controller implementation. The problem of synthesis for robust performance is then addressed by a new scaling approach for gain-scheduled control. The validity of the theoretical results are demonstrated through a two-link exible manipulator design example. This is a challenging problem that requires scheduling of the controller in the manipulator geometry and robustness in face of uncertainty in the high frequency range.