We present a framework enabling dissection of the effects of motif structure (feedback or feedforward), nature of the controller (mRNA or protein), and regulation mode (transcriptional, post-transcriptional or translational) on the response to a step change in the input. We have used a common model framework for gene expression where both motif structures have an activating input and repressing regulator, with the same set of parameters to enable comparison of the responses. We studied the global sensitivity of the system properties such as steady-state gain, overshoot, peak time, and peak duration, to parameters. We find that, in all motifs, overshoot correlated negatively whereas peak duration varied concavely, with peak time. Differences in other system properties were found to be mainly dependent on the the nature of the regulator, than the motif structure. Protein mediated motifs showed a higher degree of adaptation; feedforward motifs exhibited perfect adaptation. RNA mediated motifs had a mild regulatory effect; they also exhibited lower peaking tendency and mean overshoot. Protein mediated feedforward motifs showed higher overshoot and lower peak time compared to corresponding feedback motifs.
Chinese hamster ovary (CHO) cells express several amino acid (AA) transporters including uniporters and exchangers. Each transporter transports multiple AAs, making prediction of the effect of changed medium composition or transporter levels on individual AA transport rate challenging. A general kinetic model and a simplified analytical expression for the uptake rate is presented. A CHO cell-specific AA transport model, to our knowledge the first such network model for any cell type, is constructed. The model is validated by its prediction of reported uptake flux and amino acid inter-dependencies from experiments that were not used in model construction or parameter estimation. The model defines theoretical conditions for synergistic/repressive effect on the uptake rates of other AAs upon external addition of one AA. This model will help formulate testable hypotheses of the effect of process changes on AA initial uptake, and serve as the AA transport component of kinetic models for cellular metabolism.
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