Rational strain design with minimal phenotype perturbation.

Devising genetic interventions for desired cellular phenotypes remains challenging regarding time and resources. Kinetic models can accelerate this task by simulating metabolic responses to genetic perturbations. However, exhaustive design evaluations with kinetic models are computationally impractical, especially when targeting multiple enzymes. Here, we introduce a framework for efficiently scouting the design space while respecting cellular physiological requirements. The framework employs mixed-integer linear programming and nonlinear simulations with large-scale nonlinear kinetic models to devise genetic interventions while accounting for the network effects of these perturbations. Importantly, it ensures the engineered strain's robustness by maintaining its phenotype close to that of the reference strain. The framework, applied to improve the anthranilate production in E. coli, devises designs for experimental implementation, including eight previously experimentally validated targets. We expect this framework to play a crucial role in future design-build-test-learn cycles, significantly expediting the strain design compared to exhaustive design enumeration.

An inverse method for mechanical characterization of heterogeneous diseased arteries using intravascular imaging.

The increasing prevalence of finite element (FE) simulations in the study of atherosclerosis has spawned numerous inverse FE methods for the mechanical characterization of diseased tissue in vivo. Current approaches are however limited to either homogenized or simplified material representations. This paper presents a novel method to account for tissue heterogeneity and material nonlinearity in the recovery of constitutive behavior using imaging data acquired at differing intravascular pressures by incorporating interfaces between various intra-plaque tissue types into the objective function definition. Method verification was performed in silico by recovering assigned material parameters from a pair of vessel geometries: one derived from coronary optical coherence tomography (OCT); one generated from in silico-based simulation. In repeated tests, the method consistently recovered 4 linear elastic (0.1 ± 0.1% error) and 8 nonlinear hyperelastic (3.3 ± 3.0% error) material parameters. Method robustness was also highlighted in noise sensitivity analysis, where linear elastic parameters were recovered with average errors of 1.3 ± 1.6% and 8.3 ± 10.5%, at 5% and 20% noise, respectively. Reproducibility was substantiated through the recovery of 9 material parameters in two more models, with mean errors of 3.0 ± 4.7%. The results highlight the potential of this new approach, enabling high-fidelity material parameter recovery for use in complex cardiovascular computational studies.