3 research outputs found
The use of experimental data in simulation model validation
The use of experimental data for the validation of deterministic dynamic simulation models based on sets of ordinary differential equations and algebraic equations is discussed. Comparisons of model and target system data are considered using graphical methods and quantitative measures in the time and frequency domains. System identification and parameter estimation methods are emphasized, especially in terms of identifiability analysis which can provide valuable information for experiment design. In general, experiments that are suitable for system identification are also appropriate for model validation. However, there is a dilemma since models are needed for this design process. The experiment design, data collection and analysis of model validation results is, inevitably, an iterative process and experiments designed for model validation can never be truly optimal. A model of the pulmonary gas exchange processes in humans is used to illustrate some issues of identifiability, experiment design and test input selection for model validation
Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease.
BACKGROUND & AIMS: Very early onset inflammatory bowel diseases (VEOIBD), including infant disorders, are a diverse group of diseases found in children less than 6 years of age. They have been associated with several gene variants. We aimed to identify genes that cause VEOIBD. METHODS: We performed whole-exome sequencing of DNA from 1 infants with severe enterocolitis and her parents. Candidate gene mutations were validated in 40 pediatric patients and functional studies were carried out using intestinal samples and human intestinal cell lines. RESULTS: We identified compound heterozygote mutations in the tetratricopeptide repeat domain 7 (TTC7A) gene in an infant from non-consanguineous parents with severe exfoliative apoptotic enterocolitis; we also detected the mutations in 2 unrelated families, each with 2 affected siblings. TTC7A interacts with EFR3 homolog B (EFR3B) to regulate phosphatidylinositol 4-kinase (PI4KA) at the plasma membrane. Functional studies demonstrated that TTC7A is expressed in human enterocytes. The mutations we identified in TTC7A result in either mislocalization or reduced expression of TTC7A. PI4KA was found to co-immunoprecipitate with TTC7A; the identified TTC7A mutations reduced this binding. Knockdown of TTC7A in human intestinal-like cell lines reduced their adhesion, increased apoptosis, and decreased production of phosphatidylinositol 4-phosphate. CONCLUSION: In a genetic analysis, we identified loss of function mutations in TTC7A in 5 infants with VEOIBD. Functional studies demonstrated that the mutations cause defects in enterocytes and T cells that lead to severe apoptotic enterocolitis. Defects in the PI4KA-TTC7A-EFR3B pathway are involved in the pathogenesis of VEOIBD