breed [pseudo pseudos] breed [epi-cell epi-cells] breed [epi-affector epi-affectors] ;; cental cluster of epi-cells to model focal injury with signal diffusion globals [mucous-layer epi-cell-layer systemic-layer step hour total-mucous total-tight-junctions total-bacteria total-exotoxin-lumen total-exotoxin-systemic total-pseudos total-epi-cells ] patches-own [mucous bacteria nutrient dynorphin interferon adenosine phosphate phosphate-lumen iron iron-lumen HQNO PQS-Fe PQS-Fe-rhamno PA1-lectin Mucinase RhlRI rhamnolipid quorum-signal exotoxin-lumen exotoxin-systemic tight-junction permeability p-inosine p-PQS ] turtles-own [life quorum i-interferon i-dynorphin i-adenosine i-HQNO i-PQS-Fe i-rhamnolipid i-PA1-lectin i-mucinase i-RhlR1 apoptosis innate-immune mvfr mvfr-reg mvfr-count inosine lecA lecA-reg lecA-count adenosine-deaminase luxbox i-RhlRI oprF phoB-Pi phoB phobox phobox-reg iPi phoR PstS i-PQS pqsABCDE TNA pre-exotoxin adhere make-exotoxin HIFa grow-colony cell-divide TJ-counter pre-TJ TJ-level stress-response sense-pseudo iron-sense pyoverdin ] to setup ca if random-runs = false [random-seed 1 ] set step 0 set hour 0 set phosphate-deplete false set enteral-phosphate false set mode "health" ask patches [set mucous 90 + random 10 ;; small variation in mucous thickness, determines carrying capacity of environment for bacteria set bacteria mucous ;; initial conditions bacteria fill carrying capacity, limited resources for pathogen population growth set total-bacteria bacteria + count pseudo set dynorphin 0 set interferon 0 set adenosine 0 set phosphate 100 set iron 20 set phosphate-lumen 0 set HQNO 0 set PQS-Fe 0 set PQS-Fe-rhamno 0 set rhamnolipid 0 set PA1-lectin 0 set mucinase 0 set RhlRI 0 set exotoxin-lumen 0 set exotoxin-systemic 0 set tight-junction 100 sprout 1 [set breed epi-cell set color blue set shape "square" set size 0.3 set life 100 set TJ-counter random 12 set pre-TJ 100 set TJ-level 100 ] if (pxcor > -4 and pxcor < 4 and pycor > -4 and pycor < 4) [sprout 1 [set breed epi-affector set color sky set shape "square" set size 0.3 set life 100 ] ] set-background ] create-pseudo initial-pseudo-population ;; starting population of pathogens can be regulated at interface [set color red set shape "pentagon" set size 0.7 setxy random-pxcor random-pycor set life 100 set grow-colony false ;; not in growth phase during initial colonization ] end to go tick if step = 12 [set hour hour + 1 set step 0 ] set step step + 1 ask pseudo [pseudo-function ] diffuse-solutes ask patches [set-background phosphate-metabolism iron-metabolism toxin-function flora-function set total-bacteria max list 0 bacteria + count pseudo ] ask epi-cell [if epi-effect = "focus" ;; central cluster of epithelial cells respond to host signal to produce focal injury signal [if (pxcor > -4 and pxcor < 4 and pycor > -4 and pycor < 4) [epi-cell-function ] ] if epi-effect = "all" [epi-cell-function ] ] do-plots if data = true [data-collect ] end to epi-cell-function if life = 0 [die ] if apoptosis = true [set life max list 0 (life - 1) ;; "red death" toxin induces epithelial apoptosis at 6hr post-injection in mice ] if PQS-Fe-rhamno > 10 ;; accumulation of toxin prior to induction of apoptosis [set PQS-Fe-rhamno max list 0 (PQS-Fe-rhamno - 10) set apoptosis true ] if mode = "inflammation" [if random 3 = 1 [set interferon interferon + 1 ] ] if stress-response = true [set dynorphin dynorphin + i-dynorphin set i-dynorphin 0 ifelse sense-pseudo = true [set i-dynorphin 3 ] [set i-dynorphin 1 ] ] if count pseudo-on patch-here > 0 [set sense-pseudo true ] if mode = "stress" or mode = "ischemia" [set stress-response true ] if i-adenosine >= 1 [set adenosine adenosine + 1 set i-adenosine i-adenosine - 1 ] set i-adenosine max list 0 i-adenosine + HIFa ifelse mode = "ischemia-limited" or mode = "ischemia" ;; representation of HIFa from publication, represent transient ischemia [set HIFa random 3 set life max list 0 life - 0.1 ] [set HIFa 0 set life max list 100 life + 0.1 ] if mode = "health" [set HIFa 0 ] ifelse adenosine >= 1 [set TJ-level 100 ] [set TJ-level 100 - ((100 * PA1-lectin) / (5 + PA1-lectin)) ] TJ-function end to pseudo-function if i-PA1-lectin > 0 ;; PA1 lectin causes adhesion to epi cell layer [set adhere true] ifelse adhere = true [move-to patch-here] [rt random 45 lt random 45 fd 1 ] iron-scavenge reproduce if quorum = true ;; Pseudomonas needs to sense quorum before virulence expression [mvfr-function lecA-function opioid-response immune-reponse ischemia-response phosphate-response ] if quorum-signal > quorum-threshold ;; threshold for quorum sensing at interface control [set quorum true ] set quorum-signal min list 10 quorum-signal + random 5 ;; constituitive release of generic quorum signal end to diffuse-solutes diffuse dynorphin 0.95 diffuse interferon 0.9 diffuse adenosine 0.9 diffuse PA1-lectin 0.3 diffuse p-inosine 0.9 diffuse phosphate 1.0 diffuse HQNO 0.9 diffuse p-PQS 0.9 diffuse PQS-Fe 0.9 diffuse PQS-Fe-rhamno 0.3 diffuse quorum-signal 0.9 ask patches [set PA1-lectin PA1-lectin * 0.95 set interferon interferon * 0.95 set p-inosine p-inosine * 0.95 set dynorphin dynorphin * 0.95 set adenosine adenosine * 0.90 if interferon < 0.5 [set interferon 0] if adenosine < 0.5 [set adenosine 0] if p-inosine < 0.5 [set p-inosine 0] if dynorphin < 0.5 [set dynorphin 0] if PA1-lectin < 0.5 [set PA1-lectin 0] ] end to toxin-function set PQS-Fe-rhamno PQS-Fe-rhamno + PQS-Fe set PQS-Fe 0 if tight-junction <= 50 [set exotoxin-systemic exotoxin-systemic + (0.01 * exotoxin-lumen) set exotoxin-lumen exotoxin-lumen * 0.99 ] end to opioid-response if mvfr-reg = true ;; delay expression of mvfr [set mvfr-count mvfr-count + 1 ] if dynorphin >= 1 [set mvfr-reg true ] set i-dynorphin min list 10 (dynorphin / 5) ;; sets magnitude of response based on maximum dynorphin concentration end to immune-reponse set luxbox RhlRI set RhlRI oprF set oprF max list oprF interferon ;; sets magnitude of response based on maximum interferon concentration end to ischemia-response set inosine min list 20 (adenosine-deaminase * 2) ;; inosine 2x potent as adenosine set adenosine-deaminase i-adenosine set i-adenosine max list i-adenosine adenosine ;; sets magnitude of response based on maximum adenosine concentration end to phosphate-response if phobox-reg = true [set mvfr-count mvfr-count + 1 ] set phobox phoB-Pi set phoB-Pi phoB set phoB phoR set phoR max list 0 PstS if phosphate < 90 ;; hypophosphatemia sets magnitude of virulence response via PstS [set PstS min list 10 (90 - phosphate) set phobox-reg true ] end to lecA-function if lecA-reg = true [set lecA-count lecA-count + 1 ] if luxbox + inosine + i-PQS > 0 [set lecA-reg true ] if lecA-count > 40 [set PA1-lectin PA1-lectin + min list 10 random i-PA1-lectin set i-PA1-lectin max list 0 lecA set lecA min list 30 (inosine + luxbox + i-PQS) set i-PQS max list 0 i-PQS - 1 ] end to mvfr-function set PQS-Fe PQS-Fe + i-PQS-Fe set HQNO HQNO + i-HQNO set i-PQS-Fe max list 0 min list pyoverdin i-PQS set i-PQS max list 0 pqsABCDE set i-HQNO max list 0 pqsABCDE set pqsABCDE max list 0 TNA set TNA max list 0 mvfr ifelse mvfr-count > 80 [set mvfr min list 20 i-dynorphin + phobox ] [set mvfr 0 ] end to phosphate-metabolism set phosphate min list 100 phosphate + (phosphate-lumen * 0.25) ;; mucosal phosphate can be repleted by luminal phosphate repletion set phosphate-lumen phosphate-lumen * 0.75 if phosphate-deplete = true [set phosphate phosphate * (990 + random 10) / 1000 ] if enteral-phosphate = true [set phosphate-lumen min list 20 phosphate-lumen + random 3 ] end to iron-scavenge ifelse iron-sense = true [set pyoverdin min list 10 (pyoverdin + 1) ] [set pyoverdin max list 0 (pyoverdin - 1) ] ifelse iron <= 10 [set iron-sense true ] [set iron-sense false ] end to iron-metabolism set iron min list 20 iron + (iron-lumen * 0.25) ;; mucosal phosphate can be repleted by luminal phosphate repletion set iron-lumen iron-lumen * 0.75 if iron-deplete = true [set iron iron * (990 + random 10) / 1000 ] if enteral-iron = true [set iron-lumen min list 10 iron-lumen + random 3 ] end to reproduce if mucous - bacteria - count pseudo-on patch-here > 20 [set grow-colony true ] if cell-divide > 20 [set cell-divide 0 set grow-colony false hatch 1 [set heading random 360 ;; new agents spread out at random fd 1 set adhere true set grow-colony false ] ] if grow-colony = true [set cell-divide cell-divide + 1 ] end to TJ-function if TJ-counter = 18 ;; halflife for occludin ~ 1.5 hours [set TJ-counter 0 set tight-junction pre-TJ set pre-TJ TJ-level ] set TJ-counter TJ-counter + 1 end to flora-function set bacteria min list mucous bacteria * (1.02 - min list 0.01 (HQNO / 1000)) ;; normal population growth rate affected by HQNO toxin set bacteria max list 0 bacteria - random 3 ;; constant clearance rate keeps bacteria population stable with normal growth rate end to set-background if background = "mucous" [set pcolor scale-color yellow mucous 0 200 ] if background = "permeability" [set pcolor scale-color 129 tight-junction 0 200 ] if background = "quorum" [set pcolor scale-color orange quorum-signal 0 100 ] if background = "bacteria" [set pcolor scale-color brown bacteria 0 300 ] if background = "phosphate" [set pcolor scale-color green phosphate 0 250 ] if background = "epi-cells" [set pcolor white] if background = "interferon" [set pcolor scale-color gray interferon 10 0 ] if background = "adenosine" [set pcolor scale-color gray adenosine 10 0 ] if background = "inosine" [set pcolor scale-color gray p-inosine 10 0 ] if background = "dynorphin" [set pcolor scale-color gray dynorphin 50 0 ] end to do-plots set-current-plot "Barrier permeability" set-current-plot-pen "PA1-lectin" plot (sum [PA1-lectin] of patches) / 100 set-current-plot-pen "tight-junction" plot sum [tight-junction] of patches / count patches set-current-plot "Iron" set-current-plot-pen "iron" plot sum [iron] of patches / count patches set-current-plot-pen "iron-sense" plot count pseudo with [iron-sense = true] / count pseudo set-current-plot-pen "pyoverdin" plot sum [pyoverdin] of pseudo / count pseudo set-current-plot "Gut bacteria" set-current-plot-pen "Pseudos" plot count pseudo set-current-plot-pen "Flora" plot sum [bacteria] of patches / count patches set-current-plot "Phosphate response" set-current-plot-pen "Phosphate" plot sum [phosphate] of patches / count patches set-current-plot-pen "PstS" plot sum [PstS] of pseudo / count pseudo set-current-plot-pen "phoR" plot sum [phoR] of pseudo / count pseudo set-current-plot-pen "phoB" plot sum [phoB] of pseudo / count pseudo set-current-plot-pen "phoB-Pi" plot sum [phoB-Pi] of pseudo / count pseudo set-current-plot "Mucous phosphate" set-current-plot-pen "mucous-phosphate" plot sum [phosphate] of patches / count patches set-current-plot-pen "lumen-phosphate" plot sum [phosphate-lumen] of patches / count patches end to make-movie ;; prompt user for movie location user-message "First, save your new movie file (choose a name ending with .mov)" let path user-new-file if not is-string? path [ stop ] ;; stop if user canceled ;; run the model setup movie-start path movie-grab-view while [ticks < 251 ] [ go movie-grab-view if ticks = 125 [set background "bacteria" ] if ticks = 175 [set background "permeability" ] if ticks = 225 [set background "epi-cells" ] ] ;; export the movie movie-close user-message (word "Exported movie to " path) end to data-collect if step = 1 [print hour print sum [bacteria] of patches / count patches print count pseudo if hour = 36 and step = 2 [print " "] ] end @#$#@#$#@ GRAPHICS-WINDOW 166 55 605 515 16 16 13.0 1 10 1 1 1 0 1 1 1 -16 16 -16 16 0 0 1 ticks CC-WINDOW 5 569 1232 664 Command Center 0 BUTTON 231 10 294 43 go go\n T 1 T OBSERVER NIL NIL NIL NIL BUTTON 166 10 229 43 setup setup NIL 1 T OBSERVER NIL NIL NIL NIL SWITCH 3 10 129 43 random-runs random-runs 0 1 -1000 MONITOR 302 10 364 55 step step 17 1 11 MONITOR 367 10 429 55 hour hour 17 1 11 CHOOSER 3 47 141 92 background background "mucous" "bacteria" "permeability" "quorum" "phosphate" "interferon" "adenosine" "inosine" "dynorphin" "epi-cells" 1 PLOT 818 10 1022 131 Barrier permeability NIL NIL 0.0 300.0 0.0 10.0 true false PENS "PA1-lectin" 1.0 0 -2674135 true "tight-junction" 1.0 0 -13345367 true PLOT 1023 10 1223 131 Mucous phosphate NIL NIL 0.0 300.0 0.0 10.0 true false PENS "mucous-phosphate" 1.0 0 -13345367 true "lumen-phosphate" 1.0 0 -10899396 true MONITOR 610 300 667 345 PstS sum [PstS] of pseudo 17 1 11 MONITOR 669 300 726 345 phoB sum [phoB] of pseudo 17 1 11 MONITOR 728 300 785 345 phoR sum [phoR] of pseudo 17 1 11 MONITOR 787 300 844 345 phoB-Pi sum [phoB-Pi] of pseudo 17 1 11 MONITOR 925 362 982 407 mvfr sum [mvfr] of pseudo 17 1 11 MONITOR 846 300 903 345 i-mucin sum [i-mucinase] of pseudo 17 1 11 MONITOR 11 506 70 551 pseudos count pseudo 17 1 11 BUTTON 436 10 506 43 NIL make-movie NIL 1 T OBSERVER NIL NIL NIL NIL MONITOR 511 10 596 55 movie-status movie-status 17 1 11 SWITCH 12 470 115 503 data data 0 1 -1000 MONITOR 73 508 130 553 epi-cells count epi-cell 17 1 11 MONITOR 611 363 668 408 IFN sum [interferon] of patches 17 1 11 MONITOR 671 363 728 408 oprF sum [oprF] of pseudo 17 1 11 MONITOR 731 363 788 408 RhlRl sum [i-RhlRI] of pseudo 17 1 11 MONITOR 790 363 847 408 luxbox sum [luxbox] of pseudo\n 17 1 11 MONITOR 925 427 982 472 lecA sum [lecA] of pseudo 17 1 11 MONITOR 984 427 1041 472 i-PA1 sum [i-PA1-lectin] of pseudo 17 1 11 MONITOR 1043 428 1100 473 PA1 sum [PA1-lectin] of patches 17 1 11 MONITOR 849 510 906 555 dynorph sum [dynorphin] of patches 17 1 11 MONITOR 909 510 967 555 i-dynorph sum [i-dynorphin] of pseudo 17 1 11 MONITOR 983 362 1040 407 TNA sum [TNA] of pseudo 17 1 11 MONITOR 1041 362 1098 407 pqsABC sum [pqsABCDE] of pseudo 17 1 11 MONITOR 1100 362 1157 407 i-PQS sum [i-PQS] of pseudo 17 1 11 MONITOR 1158 362 1215 407 i-HQNO sum [i-HQNO] of pseudo 17 1 11 TEXTBOX 612 288 762 306 Phosphate Response 11 0.0 1 TEXTBOX 612 348 762 366 Interferon Response 11 0.0 1 TEXTBOX 850 495 1000 513 Opioid Response 11 0.0 1 TEXTBOX 613 411 763 429 Adenosine Response 11 0.0 1 TEXTBOX 926 347 1076 365 MvfR pathway 11 15.0 1 MONITOR 611 427 668 472 adenosine sum [adenosine] of patches 17 1 11 MONITOR 670 427 734 472 i-adenosine sum [i-adenosine] of pseudo 17 1 11 MONITOR 736 427 796 472 deaminase sum [adenosine-deaminase] of pseudo 17 1 11 MONITOR 798 427 856 472 i-inosine sum [inosine] of pseudo 17 1 11 MONITOR 858 427 915 472 inosine sum [p-inosine] of patches 17 1 11 TEXTBOX 926 411 1076 429 lecA pathway 11 15.0 1 SLIDER 12 263 164 296 initial-pseudo-population initial-pseudo-population 0 100 100 1 1 NIL HORIZONTAL CHOOSER 12 299 163 344 Mode Mode "health" "stress" "ischemia-limited" "ischemia" "inflammation" 0 CHOOSER 12 349 162 394 epi-effect epi-effect "focus" "all" 1 PLOT 607 10 817 131 Gut Bacteria NIL NIL 0.0 300.0 0.0 200.0 true false PENS "Pseudos" 1.0 0 -2674135 true "Flora" 1.0 0 -13345367 true SWITCH 3 98 156 131 Phosphate-deplete Phosphate-deplete 1 1 -1000 SWITCH 3 134 156 167 Enteral-phosphate Enteral-phosphate 1 1 -1000 SLIDER 12 397 162 430 smooth-colonies smooth-colonies 0 10 0 1 1 NIL HORIZONTAL SLIDER 12 434 162 467 quorum-threshold quorum-threshold 0 50 3 1 1 NIL HORIZONTAL MONITOR 1017 510 1092 555 quorum/patch sum [quorum-signal] of patches / count patches 1 1 11 MONITOR 1094 510 1176 555 pseudo quorum count pseudo with [quorum = true] 17 1 11 BUTTON 166 518 269 551 test ischemia go\nif hour = 1 and step = 1\n[set mode \"ischemia\"]\nif hour = 1 and step >= 6\n[set mode \"health\"]\n T 1 T OBSERVER NIL NIL NIL NIL BUTTON 273 519 356 552 test phos go\nset phosphate-deplete true\nif hour >= 3\n[set phosphate-deplete false] T 1 T OBSERVER NIL NIL NIL NIL PLOT 607 131 817 252 Phosphate Response NIL NIL 0.0 10.0 0.0 10.0 true false PENS "phosphate" 1.0 0 -10899396 true "PstS" 1.0 0 -13345367 true "phoB" 1.0 0 -8630108 true "phoR" 1.0 0 -5825686 true "phoB-Pi" 1.0 0 -955883 true BUTTON 361 518 476 551 test inflammation go\nset mode \"inflammation\" T 1 T OBSERVER NIL NIL NIL NIL SWITCH 4 171 129 204 Iron-deplete Iron-deplete 1 1 -1000 SWITCH 5 207 129 240 Enteral-iron Enteral-iron 1 1 -1000 PLOT 835 146 1035 296 Iron NIL NIL 0.0 10.0 0.0 10.0 true false PENS "iron" 1.0 0 -16777216 true "iron-sense" 1.0 0 -13345367 true "pyoverdin" 1.0 0 -955883 true @#$#@#$#@ WHAT IS IT? ----------- This section could give a general understanding of what the model is trying to show or explain. HOW IT WORKS ------------ This section could explain what rules the agents use to create the overall behavior of the model. HOW TO USE IT ------------- This section could explain how to use the model, including a description of each of the items in the interface tab. THINGS TO NOTICE ---------------- This section could give some ideas of things for the user to notice while running the model. THINGS TO TRY ------------- This section could give some ideas of things for the user to try to do (move sliders, switches, etc.) with the model. EXTENDING THE MODEL ------------------- This section could give some ideas of things to add or change in the procedures tab to make the model more complicated, detailed, accurate, etc. NETLOGO FEATURES ---------------- This section could point out any especially interesting or unusual features of NetLogo that the model makes use of, particularly in the Procedures tab. It might also point out places where workarounds were needed because of missing features. RELATED MODELS -------------- This section could give the names of models in the NetLogo Models Library or elsewhere which are of related interest. CREDITS AND REFERENCES ---------------------- This section could contain a reference to the model's URL on the web if it has one, as well as any other necessary credits or references. @#$#@#$#@ default true 0 Polygon -7500403 true true 150 5 40 250 150 205 260 250 airplane true 0 Polygon -7500403 true true 150 0 135 15 120 60 120 105 15 165 15 195 120 180 135 240 105 270 120 285 150 270 180 285 210 270 165 240 180 180 285 195 285 165 180 105 180 60 165 15 arrow true 0 Polygon -7500403 true true 150 0 0 150 105 150 105 293 195 293 195 150 300 150 box false 0 Polygon -7500403 true true 150 285 285 225 285 75 150 135 Polygon -7500403 true true 150 135 15 75 150 15 285 75 Polygon -7500403 true true 15 75 15 225 150 285 150 135 Line -16777216 false 150 285 150 135 Line -16777216 false 150 135 15 75 Line -16777216 false 150 135 285 75 bug true 0 Circle -7500403 true true 96 182 108 Circle -7500403 true true 110 127 80 Circle -7500403 true true 110 75 80 Line -7500403 true 150 100 80 30 Line 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