TY - BOOK

T1 - Decision Making in Biological Systems

AU - Tian, Chengzhe

PY - 2017

Y1 - 2017

N2 - This thesis consists of five projects in three topics with a shared theme of understanding cellulardecision-making processes with mathematical modeling. In the first topic, we address thepossible interaction between bacterial Toxin-Antitoxin (TA) systems and stringent responsealarmone guanosine tetra- and pentaphosphate [(p)ppGpp] and examine how this interactioncontributes to bacterial persistence. We show that TA systems mediate a negative feedback toearly stringent response by reducing the available mRNA. We also show that the redundancyof TA systems can be realized if bacterial growth-dormancy transition is primarily mediatedby (p)ppGpp fluctuation.In the second topic, we discuss the transition paths between two stable steady states. Weconstruct a simple model of coupled bistable gene circuits and demonstrate the possibilityof bifurcation of transition path in biology. We then construct a theory to predict whether ageneral coupled bistable system exhibits bifurcated path or not and verify the theory throughnumerical simulation. We also show that a primary function of bifurcated paths is to facilitatetransition by lowering the associated action.In the third topic, we discuss the function of extrinsic noises in digital signaling usingmammalian NF-kB pathway. We show that when cells are stimulated by one ligand, digitalsignaling allows one to independently control the fraction of responding cells (population-levelresponse) and temporal profiles of NF-kB activity (individual-level response). We also showthat under co-stimulation of two ligands, cells respond to only one input rather than both.We term this behavior "non-integrative processing" and we propose a possible mechanism byintroducing an ultrasensitive negative feedback, allowing cells to block signaling pathwaysupon activation by one ligand.

AB - This thesis consists of five projects in three topics with a shared theme of understanding cellulardecision-making processes with mathematical modeling. In the first topic, we address thepossible interaction between bacterial Toxin-Antitoxin (TA) systems and stringent responsealarmone guanosine tetra- and pentaphosphate [(p)ppGpp] and examine how this interactioncontributes to bacterial persistence. We show that TA systems mediate a negative feedback toearly stringent response by reducing the available mRNA. We also show that the redundancyof TA systems can be realized if bacterial growth-dormancy transition is primarily mediatedby (p)ppGpp fluctuation.In the second topic, we discuss the transition paths between two stable steady states. Weconstruct a simple model of coupled bistable gene circuits and demonstrate the possibilityof bifurcation of transition path in biology. We then construct a theory to predict whether ageneral coupled bistable system exhibits bifurcated path or not and verify the theory throughnumerical simulation. We also show that a primary function of bifurcated paths is to facilitatetransition by lowering the associated action.In the third topic, we discuss the function of extrinsic noises in digital signaling usingmammalian NF-kB pathway. We show that when cells are stimulated by one ligand, digitalsignaling allows one to independently control the fraction of responding cells (population-levelresponse) and temporal profiles of NF-kB activity (individual-level response). We also showthat under co-stimulation of two ligands, cells respond to only one input rather than both.We term this behavior "non-integrative processing" and we propose a possible mechanism byintroducing an ultrasensitive negative feedback, allowing cells to block signaling pathwaysupon activation by one ligand.

UR - https://soeg.kb.dk/permalink/45KBDK_KGL/fbp0ps/alma99122540122005763

M3 - Ph.D. thesis

BT - Decision Making in Biological Systems

PB - The Niels Bohr Institute, Faculty of Science, University of Copenhagen

ER -