Team:Paris/Analysis/Construction2

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{{Paris/Menu}}
{{Paris/Menu}}
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{{Paris/Header|Model Construction}}
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{{Paris/Header|System Improvements Description}}
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== Description ==
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{{Paris/Section_contents_analysis}}
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<!--why use a chemostat-->
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* We chose to use a chemostat. We want to impose to our model the fact that the rate of production has to be proportional to the existing population and to the amount of available resources.
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<!--which model of chemostat we choose-->
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== Introduction ==
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* We assume a logistic model for the population kinetics in the chemostat (reference).
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<!--Autoinducer -->
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In this section, we investigate possible improvements of the [[Team:Paris/Network_analysis_and_design/Core_system/Model_construction|core system]]. Our objective is twofold : the system has to provide sustained oscillations and these oscillations should be synchronized amongst a population of cells. To this aim we explore designs inspired by quorum sensing and model in a chemostat cell growth and species diffusion outside cells. We consider two models relying on different designs principles.
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* To archieve synchronization we use QS. Explain the principle?
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== Kinetics ==
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{{Paris/Toggle|To join our quest for alternatives click here!|Team:Paris/DescriptionMoreModelConstruction2}}
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* The concentration variation of cells in the chemostat over time can be expressed in terms of a production (positive) term and degradation (negative) terms:
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<br>
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<center>[[Image:Final_chemostat.gif]],</center>
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<br>
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For the production term, we use a logistic equation to model cell growth, according to standard assumptions [Garcia-Ojalvor--ref]. The behaiviour obtained is the following one: at low population density, the concentration of cells in the chemostat (c) increase exponentialy with a growth rate α<sub>cell</sub> and at high population density, the population reaches a maximum concentration, c<sub>max</sub>.
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For the degradation term, it is considered that c decrease proportionaly to both a dilution phenomena cause by the renewal of the medium in the chemostat (D<sub>renewal</sub>) and cell death (d).
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== Modeling Alternatives ==
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*To model the quorum sensing dynamics, we consider the production of HSL as:
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The proposed systems are:
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{|align="center" cellpadding="0" cellspacing="20"
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|-style="background: #D4E2EF; text-align: center;"
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|'''HSL mediated coupled oscillators'''
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|'''HSL mediated simple oscillator'''
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|-style="background: #ffffff; text-align: center;"
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|[[Image:Bimo.png|400px]]
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|[[Image:Unimo.png|400px]]
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|}
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eqHSL 1,
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*In the first system, we use a modular design. Since the core system is a 'poor' oscillator we hope that by coupling it with a 'good' oscillator we could obtain sustained oscillations in the whole system. Thus, we consider that the core system is one of the modules of the system and that the other module is a two gene oscillator system presented in [[Team:Paris/Bibliography|[2]]] that accounts for quorum sensing. We call this alternative the 'HSL mediated coupled oscillators'.
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the transport of HSL is given by:
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*In the second system, namely the 'HSL mediated simple oscillator', we rewire the architecture of the core system to introduce delay via HSL export in the environment in a single circuit.
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<center> [[Image:HSLext_sum_2.jpg]],</center>
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Both the coupled and simple oscillators describe events that happen not only at the cellular level (as in the core system) but also at the population level due to interactions needed between a cell and its environment.
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where...
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In the following sections, we first describe the [[Team:Paris/Network_analysis_and_design/System_improvements/Description#Common_Description|common]] part among the two proposed models and then focus our attention to the  [[Team:Paris/Network_analysis_and_design/System_improvements/Description#Alternatives_Description| alternatives description]] where the characteristics that are specific to each of the modeling alternatives are presented.
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<!-- MORE DETAILS ABOUT THE CHEMOST
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* A chemostat is generally used to keep bacteria volume constant in the medium. The constant conditions provided by the chemostat help us to control bacteria growth rate.
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when in...:
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* We assume a logistic model to determine bacteria growth in the chemostat, in agreement with standar procedures (reference). This hypothesis implies that bacteria growth rate has to be proportional to the existing bacteria population size and to the amount of available resources in the medium.
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<center>[[Image:HSLext_final_2.jpg]], &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; where &nbsp;&nbsp;&nbsp;&nbsp;[[Image:cell_number_volume.jpg]];</center>
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-->
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<!-- MORE DETAILS ABOUT QS
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* As discussed [[Team:Paris/Network_analysis_and_design/System_improvements|previously]], we choose to use quorum sensing as a way to improve the oscillating behaviour of our [[Team:Paris/Network_analysis_and_design/Core_system|core system]] and, at the same time, as a way to archeive population synchronization. When a cultive of bacteria is synchronized, it means that every single cell express in average the same genes in unison. As a result, a maximum level of fluorescense is obtained.
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-->
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and the activation of ''envZ'' depends of the concentration of HSL according to:
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== Common Description ==
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{|align="center"
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|-style="background: #ffffff; text-align: left;"
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|Logistic growth in chemostat:
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|-style="background: #ffffff; text-align: center;"
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|[[Image:DescriptionCommonDynamicsPart1.png|center|600px]]
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|-style="background: #ffffff; text-align: left;"
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|Quorum sensing by HSL diffusion:
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|-style="background: #ffffff; text-align: center;"
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|[[Image:DescriptionCommonDynamicsPart2.png|center|600px]]
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|-style="background: #ffffff; text-align: left;"
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|As in [[Team:Paris/Network_analysis_and_design/Core_system|core system]] flhDC inhibited by EnvZ and fliA activated by FlhDC and FliA:
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|-style="background: #ffffff; text-align: center;"
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|[[Image:DescriptionCommonDynamicsPart3.png|center|600px]]
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|}
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{{Paris/Toggle|read more on common dynamics...|Team:Paris/DescriptionDetailsS4-S2Part1}}
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eqHSL 3.
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== Alternatives Description ==
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{|align="center" cellpadding="2" cellspacing="10"
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|-style="background: #D4E2EF; text-align: center;"
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|'''HSL mediated coupled oscillators'''
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|'''HSL mediated simple oscillator'''
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|-style="background: #ffffff; text-align: left;"
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|Core system coupled with an oscillator:
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|Modified core system that accounts for quorum sensing:
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|-style="background: #ffffff; text-align: center;"
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|[[Image:SumaryBiMo.png|450px]]
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|[[Image:SumaryUniMo.png|350px]]
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|}
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{{Paris/Toggle|read more on alternatives description...|Team:Paris/DescriptionDetailsS4-S2Part2}}
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<!-- equations in code:
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== Kinetic parameter values==
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d[c]/dt=alpha_cell*[c]*(c_max-[c])/c_max-(D_renewal+death)*[c]
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d[LasI]/dt=beta_FlhDC*theta_FlhDC^n_FlhDC/(theta_FlhDC^n_FlhDC+[TetR]^n_FlhDC)-gamma*[LasI]
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d[TetR]/dt=beta_TetR*[HSL]^n_TetR/(theta_TetR^n_TetR+[HSL]^n_TetR)-gamma*[TetR]
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d[HSL::ext]/dt=eta*v_cell*[c]*([HSL]-[HSL::ext])-(D_renewal+gamma_HSLext)*[HSL::ext]
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d[HSL]/dt=beta_HSL*[LasI]+eta*[HSL::ext]-(gamma+gamma_HSLint+eta)*[HSL]
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-->
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== Parameters Search==
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Remarkably, almost all parameter values are available from experimental measurements in [[Team:Paris/Bibliography|[1]]] and from the work of Garcia-Ojalvo in [[Team:Paris/Bibliography|[2]]]. Additionally minimizing the number of parameters is possible by rescaling as done for the core system. Relevant values for the sole two missing parameters are found by exploiting a modularity assumption as described in the  [[Team:Paris/Network_analysis_and_design/System_improvements/Analysis|next section]]. The following table summarize our findings:
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manly from literature but also from  [[Team:Paris/Network_analysis_and_design/System_improvements/Description/QS_Module|S0 analysis]].
 
<center>
<center>
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! colspan="8" | &nbsp;
! colspan="8" | &nbsp;
|- style="background: #649CD7;" |
|- style="background: #649CD7;" |
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|style="background: #ffffff; text-align:center;" |'''Chemostat'''
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|style="background: #ffffff; text-align:center;" width=20% |'''Chemostat'''
|Parameter
|Parameter
|Meaning
|Meaning
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|Source  
|Source  
|- style="background: #dddddd;"|     
|- style="background: #dddddd;"|     
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| ! rowspan="5" style="background: #ffffff;" | figure / equations of Chemostat
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| ! rowspan="5" style="background: #ffffff;" |  
|style="background: #D4E2EF;" | α<sub>cell</sub>
|style="background: #D4E2EF;" | α<sub>cell</sub>
|style="background: #dddddd;"| Growth rate
|style="background: #dddddd;"| Growth rate
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| style="background: #dddddd;"|1
| style="background: #dddddd;"|1
|style="background: #dddddd;"|min<sup>-1</sup>
|style="background: #dddddd;"|min<sup>-1</sup>
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|style="background: #dddddd;"| [[Team:Paris/Modeling/BOB#Remarks|wet-lab]]  
+
|style="background: #dddddd;"| [[Team:Paris/Remarks|wet-lab]]  
|- style="background: #dddddd;"|     
|- style="background: #dddddd;"|     
| style="background: #D4E2EF;"| c<sub>max</sub>
| style="background: #D4E2EF;"| c<sub>max</sub>
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| style="background: #dddddd;"| 0.1
| style="background: #dddddd;"| 0.1
| style="background: #dddddd;"| µm<sup>3</sup>
| style="background: #dddddd;"| µm<sup>3</sup>
-
| style="background: #dddddd;"| [[Team:Paris/Modeling/BOB#Bibliography|[3]]]
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| style="background: #dddddd;"| [[Team:Paris/Bibliography|[3]]]
|- style="background: #dddddd;"|     
|- style="background: #dddddd;"|     
| style="background: #D4E2EF;"| D<sub>renewal</sub>
| style="background: #D4E2EF;"| D<sub>renewal</sub>
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| style="background: #dddddd;"| 0.1
| style="background: #dddddd;"| 0.1
| style="background: #dddddd;"| min<sup>-1</sup>
| style="background: #dddddd;"| min<sup>-1</sup>
-
| style="background: #dddddd;"| [[Team:Paris/Modeling/BOB#Remarks|wet-lab]] ([[Team:Paris/Modeling/BOB#Bibliography|[3]]])
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| style="background: #dddddd;"| [[Team:Paris/Remarks|wet-lab]] ([[Team:Paris/Bibliography|[3]]])
|- style="background: #dddddd;"|     
|- style="background: #dddddd;"|     
| style="background: #D4E2EF;"| d
| style="background: #D4E2EF;"| d
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| style="background: #dddddd;"| 0.5
| style="background: #dddddd;"| 0.5
| style="background: #dddddd;"| min<sup>-1</sup>
| style="background: #dddddd;"| min<sup>-1</sup>
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| style="background: #dddddd;"|[[Team:Paris/Modeling/BOB#Remarks|wet-lab]]
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| style="background: #dddddd;"|[[Team:Paris/Remarks|wet-lab]]
|- style="background: #ffffff;"
|- style="background: #ffffff;"
! colspan="8" | &nbsp;
! colspan="8" | &nbsp;
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|Source  
|Source  
|- style="background: #dddddd;"|     
|- style="background: #dddddd;"|     
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| ! rowspan="6" style="background: #ffffff;" | figure / equations of Quorum Sensing
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| ! rowspan="6" style="background: #ffffff;" |  
| style="background: #D4E2EF;" |γ<sub>HSL</sub>  
| style="background: #D4E2EF;" |γ<sub>HSL</sub>  
| style="background: #dddddd;"|Degradation rate
| style="background: #dddddd;"|Degradation rate
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| style="background: #dddddd;"|0.2690
| style="background: #dddddd;"|0.2690
| style="background: #dddddd;"|min<sup>-1</sup>
| style="background: #dddddd;"|min<sup>-1</sup>
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| style="background: #dddddd;"|[[Team:Paris/Modeling/BOB#Remarks|wet-lab]]  
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| style="background: #dddddd;"|[[Team:Paris/Remarks|see remarks]]  
|- style="background: #dddddd;"|  
|- style="background: #dddddd;"|  
| style="background: #D4E2EF;"|γ<sub>HSL<sub>ext</sub></sub> <br> <br>
| style="background: #D4E2EF;"|γ<sub>HSL<sub>ext</sub></sub> <br> <br>
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| style="background: #dddddd;"|0.5380
| style="background: #dddddd;"|0.5380
|style="background: #dddddd;"| min<sup>-1</sup>
|style="background: #dddddd;"| min<sup>-1</sup>
-
| style="background: #dddddd;"|[[Team:Paris/Modeling/BOB#Bibliography|[6]]]
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| style="background: #dddddd;"|[[Team:Paris/Bibliography|[2]]]
|- style="background: #dddddd;"|  
|- style="background: #dddddd;"|  
| style="background: #D4E2EF;" |β<sub>HSL</sub>  
| style="background: #D4E2EF;" |β<sub>HSL</sub>  
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| style="background: #dddddd;"|16
| style="background: #dddddd;"|16
| style="background: #dddddd;"|min<sup>-1</sup>
| style="background: #dddddd;"|min<sup>-1</sup>
-
| style="background: #dddddd;"|[[Team:Paris/Modeling/BOB#Bibliography|∅]]
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| style="background: #dddddd;"|[[Team:Paris/Bibliography|∅]]
|- style="background: #dddddd;"|  
|- style="background: #dddddd;"|  
| style="background: #D4E2EF;" |η
| style="background: #D4E2EF;" |η
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| style="background: #dddddd;"|505
| style="background: #dddddd;"|505
| style="background: #dddddd;"|min<sup>-1</sup>
| style="background: #dddddd;"|min<sup>-1</sup>
-
| style="background: #dddddd;"|[[Team:Paris/Modeling/BOB#Bibliography|[2]]]
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| style="background: #dddddd;"|[[Team:Paris/Bibliography|[2]]]
|- style="background: #dddddd;"|  
|- style="background: #dddddd;"|  
| style="background: #D4E2EF;" |n<sub>HSL</sub>
| style="background: #D4E2EF;" |n<sub>HSL</sub>
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| style="background: #dddddd;"|4
| style="background: #dddddd;"|4
| style="background: #dddddd;"|&nbsp;
| style="background: #dddddd;"|&nbsp;
-
| style="background: #dddddd;"|[[Team:Paris/Modeling/BOB#Bibliography|[3]]]
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| style="background: #dddddd;"|[[Team:Paris/Bibliography|[3]]]
|- style="background: #dddddd;"|  
|- style="background: #dddddd;"|  
| style="background: #D4E2EF;" |θ<sub>HSL</sub>
| style="background: #D4E2EF;" |θ<sub>HSL</sub>
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| style="background: #dddddd;"|&nbsp;
| style="background: #dddddd;"|&nbsp;
| style="background: #dddddd;"|0.5
| style="background: #dddddd;"|0.5
-
| style="background: #dddddd;"|[[Team:Paris/Modeling/BOB#Remarks|c.u]]
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| style="background: #dddddd;"|[[Team:Paris/Remarks|c.u.]]
-
| style="background: #dddddd;"|[[Team:Paris/Modeling/BOB#Bibliography|[3]]]
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| style="background: #dddddd;"|[[Team:Paris/Bibliography|[3]]]
|}</center>
|}</center>
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{{Paris/Navig|Team:Paris/Analysis}}

Latest revision as of 03:18, 30 October 2008

System Improvements Description


Contents

Introduction

In this section, we investigate possible improvements of the core system. Our objective is twofold : the system has to provide sustained oscillations and these oscillations should be synchronized amongst a population of cells. To this aim we explore designs inspired by quorum sensing and model in a chemostat cell growth and species diffusion outside cells. We consider two models relying on different designs principles.

↓ To join our quest for alternatives click here! ↑


Same environment
Chemostat.png
Using a chemostat
Same starting point, different synchronization mechanisms
HSL mediated simple oscillator (learn more...)
HSL mediated coupled oscillators (learn more...)

Modeling Alternatives

The proposed systems are:

HSL mediated coupled oscillators HSL mediated simple oscillator
Bimo.png Unimo.png
  • In the first system, we use a modular design. Since the core system is a 'poor' oscillator we hope that by coupling it with a 'good' oscillator we could obtain sustained oscillations in the whole system. Thus, we consider that the core system is one of the modules of the system and that the other module is a two gene oscillator system presented in [2] that accounts for quorum sensing. We call this alternative the 'HSL mediated coupled oscillators'.
  • In the second system, namely the 'HSL mediated simple oscillator', we rewire the architecture of the core system to introduce delay via HSL export in the environment in a single circuit.

Both the coupled and simple oscillators describe events that happen not only at the cellular level (as in the core system) but also at the population level due to interactions needed between a cell and its environment.

In the following sections, we first describe the common part among the two proposed models and then focus our attention to the alternatives description where the characteristics that are specific to each of the modeling alternatives are presented.

Common Description

Logistic growth in chemostat:
DescriptionCommonDynamicsPart1.png
Quorum sensing by HSL diffusion:
DescriptionCommonDynamicsPart2.png
As in core system flhDC inhibited by EnvZ and fliA activated by FlhDC and FliA:
DescriptionCommonDynamicsPart3.png
↓ read more on common dynamics... ↑


Common Dynamics: Chemostat
The variation of cells' concentration in the chemostat over time can be expressed in terms of a production (positive) term and degradation (negative) terms:
Final chemostat.png
    For the production term, we use a logistic equation to model cell growth, according to standard assumptions. The behaviour obtained is the following one: at low population density, the concentration of cells in the chemostat (c) increase exponentially with a growth rate αcell and at high population density, the population reaches a maximum concentration, cmax.
    For the degradation term, we consider that c decrease proportionally to both a dilution phenomena cause by the renewal of the medium in the chemostat (Drenewal) and cell death (d).
Common Dynamics: Quorum Sensing
In order to model the quorum sensing dynamics, we consider that:
     1) Inside a cell, the HSL concentration increases proportionally to the concentration of LasI and decreases according to both a degradation term (proportional to the internal HSL concentration) and a transport term (proportional to the difference between the internal and external concentration of HSL). Thus, the equation for the internal HSL concentration is:
Final HSL.png
     2) Outside the cells, HSL is accumulated with the same transport term that we use in the previous equation. The degradation of HSL in the external medium and the dilution controlled via the chemostat accounts for HSL external decrease. So the external HSL concentration is given by:
HSLext.png
that is equivalent to:
HSLext2.png
where    Hsl average.png    and     Cell number volume.png
Common Network Dynamics: FlhDC and Flia
FlhDC and Flia are regulated in the same way in both systems. FlhDC is produced under the influence of EnvZ via an inhibition. Flia is regulated for its self and FlhDC.
FlhDC-FliaEq.png

Alternatives Description

HSL mediated coupled oscillators HSL mediated simple oscillator
Core system coupled with an oscillator: Modified core system that accounts for quorum sensing:
SumaryBiMo.png SumaryUniMo.png
↓ read more on alternatives description... ↑


HSL mediated coupled oscillators HSL mediated simple oscillator
     a) The expression of lasI is under the control of the same promotor that used for FlhDC.      a) The expression of lasI is regulated by FlhDC and Flia (as in the core system)
LasIEqInBIMOdularSys.png LasIEqInUNIModularSys.png
     b) The expression of envZ depends on both the activation from FlhDC and Flia (as in the core system) and the concentration of HSL present in the cell.      b) The expression of envZ depends only on the concentration of HSL present in the cell.
EnvZInBIMOdularSys.png EnvZInUNIModularSys.png

Kinetic parameter values

Remarkably, almost all parameter values are available from experimental measurements in [1] and from the work of Garcia-Ojalvo in [2]. Additionally minimizing the number of parameters is possible by rescaling as done for the core system. Relevant values for the sole two missing parameters are found by exploiting a modularity assumption as described in the next section. The following table summarize our findings:


Parameters
 
Chemostat Parameter Meaning Original Value Normalized Value Unit Source
αcell Growth rate 0.0198 1 min-1 wet-lab
cmax Carrying capacity for cell growth 0.1 0.1 µm3 [3]
Drenewal Dilution rate 0.00198 0.1 min-1 wet-lab ([3])
d Death rate 0.0099 0.5 min-1 wet-lab
 
Quorum Sensing Parameter Meaning Original Value Normalized Value Unit Source
γHSL Degradation rate 0.0053 0.2690 min-1 see remarks
γHSLext

Degradation rate 0.0106 0.5380 min-1 [2]
βHSL Production rate 0.3168 16 min-1
η Diffusion rate 10 505 min-1 [2]
nHSL Hill coefficient   4   [3]
θHSL Hill characteristic concentration for the second operator   0.5 c.u. [3]