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A two-dimensional model of the colonic crypt accounting for the role of the basement membrane and pericryptal fibroblast sheath.

ABSTRACT: The role of the basement membrane is vital in maintaining the integrity and structure of an epithelial layer, acting as both a mechanical support and forming the physical interface between epithelial cells and the surrounding connective tissue. The function of this membrane is explored here in the context of the epithelial monolayer that lines the colonic crypt, test-tube shaped invaginations that punctuate the lining of the intestine and coordinate a regular turnover of cells to replenish the epithelial layer every few days. To investigate the consequence of genetic mutations that perturb the system dynamics and can lead to colorectal cancer, it must be possible to track the emerging tissue level changes that arise in the crypt. To that end, a theoretical crypt model with a realistic, deformable geometry is required. A new discrete crypt model is presented, which focuses on the interaction between cell- and tissue-level behaviour, while incorporating key subcellular components. The model contains a novel description of the role of the surrounding tissue and musculature, based upon experimental observations of the tissue structure of the crypt, which are also reported. A two-dimensional (2D) cross-sectional geometry is considered, and the shape of the crypt is allowed to evolve and deform. Simulation results reveal how the shape of the crypt may contribute mechanically to the asymmetric division events typically associated with the stem cells at the base. The model predicts that epithelial cell migration may arise due to feedback between cell loss at the crypt collar and density-dependent cell division, an hypothesis which can be investigated in a wet lab. This work forms the basis for investigation of the deformation of the crypt structure that can occur due to proliferation of cells exhibiting mutant phenotypes, experiments that would not be possible in vivo or in vitro.

SUBMITTER: Dunn SJ

PROVIDER: S-EPMC3359972 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This paper presents a new two-dimensional Multiple-Choice Model accounting for Omissions (MCMO). Based on Thissen and Steinberg multiple-choice models, the MCMO defines omitted responses as the result of the respondent not knowing the correct answer and deciding to omit rather than to guess given a latent propensity to omit. Firstly, using a Monte Carlo simulation, the accuracy of the parameters estimated from data with different sample sizes (500, 1,000, and 2,000 subjects), test lengths (20, 40, and 80 items) and percentages of omissions (5, 10, and 15%) were investigated. Later, the appropriateness of the MCMO to the Trends in International Mathematics and Science Study (TIMSS) Advanced 2015 mathematics and physics multiple-choice items was analyzed and compared with the Holman and Glas' Between-item Multi-dimensional IRT model (B-MIRT) and with the three-parameter logistic (3PL) model with omissions treated as incorrect responses. The results of the simulation study showed a good recovery of scale and position parameters. Pseudo-guessing parameters (d) were less accurate, but this inaccuracy did not seem to have an important effect on the estimation of abilities. The precision of the propensity to omit strongly depended on the ability values (the higher the ability, the worse the estimate of the propensity to omit). In the empirical study, the empirical reliability for ability estimates was high in both physics and mathematics. As in the simulation study, the estimates of the propensity to omit were less reliable and their precision varied with ability. Regarding the absolute item fit, the MCMO fitted the data better than the other models. Also, the MCMO offered significant increments in convergent validity between scores from multiple-choice and constructed-response items, with an increase of around 0.02 to 0.04 in R 2 in comparison with the two other methods. Finally, the high correlation between the country means of the propensity to omit in mathematics and physics suggests that (1) the propensity to omit is somehow affected by the country of residence of the examinees, and (2) the propensity to omit is independent of the test contents.

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A two-dimensional model of the colonic crypt accounting for the role of the basement membrane and pericryptal fibroblast sheath.

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