Molecular Systems Biology

Biphasic response as a mechanism against mutant takeover in tissue homeostasis circuits

Frequency doubling in the cyanobacterial circadian clock

Drug detoxification dynamics explain the postantibiotic effect

Protein abundance of AKT and ERK pathway components governs cell-type- specific regulation of proliferation

Design principles of nuclear receptor signaling: how complex networking improves signal transduction

Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range

D Biphasic control of stem-cell expansion, where stem-cell expansion is low both at high and low concentrations of y. The system has a stable fixed point at the concentration of y where pr = 0.5 and an unstable fixed point at some lower concentration of y.

SED-ML simulation
https://jjj.bio.vu.nl/models/experiments/karin2017_fig4d/simulate

C A mutated stem cell with a strong inactivation of the sensing of y has a
growth advantage (differentiates less), and therefore, it invades the stem- cell population. As a result, both the stem-cell pool and the number of terminally differentiated cells increase.

SED-ML simulation
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Mathematical simulation of a tamoxifen-induced conditional knock-in of a sixfold activating GCK mutant in beta cells. (C) The percentage of beta cells with mutated GCK increases to ~25% after 3 days, but then decreases and is eliminated after a few weeks. (D) Glucose levels initially decrease after the tamoxifen injection, but return to normal after a few weeks. Insets: Experimental results of Tornovsky-Babeay et al (2014).

SED-ML simulation
https://jjj.bio.vu.nl/models/experiments/karin2017_fig2/simulate
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C Trajectories of Z from different initial concentrations of cells (Z) (i) or y (ii) for the circuit of (B). The healthy concentration Z = ZST is reached regardless of initial
concentration of Z, as long as it is nonzero, and regardless of the initial concentration of y.

SED-ML simulation
https://jjj.bio.vu.nl/models/experiments/karin2017_fig1c/simulate

D An arrow marks the time when a mutant with a strong activation of the sensing of y arises (for the circuit depicted in B). This mutant has a selective advantage and
takes over the population.

SED-ML simulation
https://jjj.bio.vu.nl/models/experiments/karin2017_fig1d/simulate

G Trajectories of Z from different initial concentrations of Z (i) or y (ii) for the circuit depicted in (F). The healthy concentration Z = ZST is not reached for small values of
Z (Z << ZST) or large values of y (y >> yUST).

SED-ML simulation
https://jjj.bio.vu.nl/models/experiments/karin2017_fig1g/simulate

H The arrows mark the times when a mutant with a strong activation of the sensing of y arises (for the biphasic circuit depicted in F). This mutant has a selective
disadvantage and is thus eliminated.

SED-ML simulation
https://jjj.bio.vu.nl/models/experiments/karin2017_fig1h/simulate

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