# the following are the equations of kinase pathways #pathway of ApNT --> Raf pRaf'=((K_fRaf*ApNT+K_fRafb)*Raf-K_bRaf*pRaf) Raf=Raf_total-pRaf p K_fRaf=0.0373 p K_fRafb=0.000133 p K_bRaf=0.000378 p Raf_total=0.5 #pathway of Raf --> MAPKK MAPKK'=-K_fMAPKK*pRaf*(MAPKK/(MAPKK+K_1mkk))+(K_bMAPKKb+K_bMAPKK*act_dp38*heav(ppMAPKK-0.25))*(pMAPKK/(pMAPKK+K_2mkk)) ppMAPKK'=K_fMAPKK*pRaf*(pMAPKK/(pMAPKK+K_1mkk))-(K_bMAPKKb+K_bMAPKK*act_dp38*heav(ppMAPKK-0.25))*(ppMAPKK/(ppMAPKK+K_2mkk)) pMAPKK=MAPKK_tt-MAPKK-ppMAPKK p K_fMAPKK=0.41 p K_bMAPKKb=0.04 p K_bMAPKK=0.04 p K_1mkk=0.20 p K_2mkk=0.19 p MAPKK_tt=0.5 # pathway of p38 MAPK --> MAPKK act_dp38'=(k_EP38MEK*(dpp38-0.15)*heav(dpp38-0.15)-k_dEPMEK*act_dp38) k_EP38MEK=0.33 k_dEPMEK=0.0013 #pathway of MAPKK --> MAPK MAPK'=(-K_fMAPK*(ppMAPKK+ppMEKtgf)*(MAPK/(MAPK+K_1mk))+K_bMAPK*(pMAPK/(pMAPK+K_2mk))) ppMAPK'=(K_fMAPK*(ppMAPKK+ppMEKtgf)*(pMAPK/(pMAPK+K_1mk))-K_bMAPK*(ppMAPK/(ppMAPK+K_2mk))) pMAPK=MAPK_tt-ppMAPK-MAPK p K_fMAPK=0.41 p K_1mk=0.19 p K_2mk=0.21 P K_bMAPK=0.12 p MAPK_tt=0.5 #pathway of TGF --> MAPK MEKtgf'=-K_fMAPKK*TGF*(MEKtgf/(MEKtgf+K_1mkk))+(K_bMAPKKb+K_bMAPKK*act_dp38)*(pMEKtgf/(pMEKtgf+K_2mkk)) ppMEKtgf'=K_fMAPKK*TGF*(pMEKtgf/(pMEKtgf+K_1mkk))-(K_bMAPKKb+K_bMAPKK*act_dp38)*(ppMEKtgf/(ppMEKtgf+K_2mkk)) pMEKtgf=MAPKK_tt/6-MEKtgf-ppMEKtgf TGF'=(k_TBLTGF*TBL^2/(TBL^2+(0.0078)^2)-k_dTGF*TGF) p k_TBLTGF=0.0087 p k_dTGF=0.0058 #pathway of 5-HT--> p38 MAPK pRafP'=((k_fRafp38*5HT+k_bfRfp38)*RafP-k_bRafp38*pRafP) RafP=RafP_to-pRafP p k_fRafp38=0.0009 p k_bfRfp38=0.036 p k_bRafp38=0.1 p RafP_to=0.5 MEK6'=(-K_fMAPKK*pRafP*(MEK6/(MEK6+K_1mkk))+K_bMAPKK*(pMEK6/(pMEK6+K_2mkk))) ppMEK6'=(K_fMAPKK*pRafP*(pMEK6/(pMEK6+K_1mkk))-K_bMAPKK*(ppMEK6/(ppMEK6+K_2mkk))) pMEK6=MEK6_tt-MEK6-ppMEK6 p38'=(-(K_fp38)*(p38/(p38+K_1mk))+K_b38*(pp38/(pp38+K_2mk))) dpp38'=((K_fp38)*(pp38/(pp38+K_1mk))-K_b38*(dpp38/(dpp38+K_2mk))) pp38=p38_total-dpp38-p38 K_fp38=(k_fp38MEK*ppMEK6+k_fp38RSK*pRSK)/(1+act5HT) act5HT'=(k_E5HT*5HT/(5HT+50)-k_dE5HT*act5HT) p k_fp38MEK=0.25 p k_fp38RSK=0.99 p MEK6_tt=0.5 p p38_total=0.5 p K_b38=0.12 p k_E5HT=0.8 p k_dE5HT=1 #pathway of PKA and ERK--> RSK pRSK'=((0.262*(PKAC-0.35)*heav(PKAC-0.35)+0.82*ppMAPK)*RSK-0.31*(pRSK/(pRSK+0.2))) RSK=RSK_total-pRSK RSK_total=0.5 #pathway of 5-HT--> PKA cAMP'=lamda*(5HT/(5HT+K_5HT)+ApNT/(ApNT+12))-K_bcamp*cAMP+cAMPbas PKAR'=V_syn+K_fpka*PKARC*cAMP^2-K_bpka*PKAR*PKAC-K_dpka*PKAR PKARC'=-K_fpka*PKARC*cAMP^2+K_bpka*PKAR*PKAC-K_dpka*PKARC PKAC'=V_syn+K_fpka*PKARC*cAMP^2-K_bpka*PKAR*PKAC-K_dpka*PKAC p V_syn=0 p K_dpka=0 p cAMPbas=0.7 p lamda=3.64 p K_5HT=85 p K_bcamp=1 p K_fpka=20 p K_bpka=12 #pathway of PKA--> ApNT ApNT'=(k_fNT*(PKAC-0.35)/((PKAC-0.35)+1)*heav(PKAC-0.35)-k_bNT*ApNT) p k_fNT=0.3 p k_bNT=0.05 #initial values of kinases init pRaf=0.13 init MAPKK=0.095 init ppMAPKK=0.26 init MAPK=0.19 init PPMAPK=0.145 init pRafP=0.13 init MEK6=0.095 init ppMEK6=0.26 init p38=0.19 init dpp38=0.145 init act_dp38=0 init PKAC=0.35 init cAMP=0.7 init PKAR=0.35 init PKARC=0.15 init pRSK=0.042 # the following are the equations of CREB1, CREB2, and CEBP #phosphorylated CREB1 protein pCREB1'=(k_RSKCREB*(pRSK-0.042)*heav(pRSK-0.042)+k_PKACREB*(PKAC-0.35)*heav(PKAC-0.35))*CREB1-K_dephC1*pCREB1 CREB1=0.05-pCREB1 p k_RSKCREB=1.25 p k_PKACREB=0.3 p K_dephC1=0.05 #phosphorylated CREB2 protein pCREB2e'=(K_phosC2*ppMAPK*CREB2-K_dephC2*pCREB2e) pCREB2p'=(K_phosC2*dpp38*CREB2-K_dephC2*pCREB2p) CREB2=0.05-pCREB2e-pCREB2p p K_phosC2=3.5 p K_dephC2=0.5 #synthesis OF TGF protein TBL'=(pCREB1^2/0.003^2)/(1+pCREB1^2/0.003^2+CREB2^2/0.003^2+pCREB2p^2/0.0003^2)-TBL #initial values of pCREB1, pCREB2, CEBP init pCREB1=0 init pCREB2e=0.0164 init pCREB2p=0.0168 # training protocols, 5 PULSES OF 5-HT 5HT'=(50*(on0*heav(t-t2)*heav(t2+5-t)+on1*heav(t-t2-inter1)*heav(inter1+5+t2-t)+on2*heav(t-t2-inter1-inter2)*heav(inter1+inter2+5+t2-t)+on3*heav(t-t2-inter1-inter2-inter3)*heav(inter1+inter2+inter3+5+t2-t)+on4*heav(t-t2-inter1-inter2-inter3-inter4)*heav(inter1+inter2+inter3+inter4+5+t2-t))*turnon-5HT) #ISI 1 inter1=5*(1+a1) #ISI 2 inter2=5*(1+a2) #ISI 3 inter3=5*(1+a3) #ISI 4 inter4=5*(1+a4) # On and off of 1st pulse p on0=1 # On and off of 2nd pulse p on1=1 # On and off of 3rd pulse p on2=0 # On and off of 4th pulse p on3=0 # On and off of 5th pulse p on4=0 p turnoff=0 p turnon=1 #pre-run for 2 days p t2=2880 p step=8333 a4=(step-10*flr(step/10)) a3=flr((step-100*flr(step/100))/10) a2=flr((step-1000*flr(step/1000))/100) a1=flr(step/1000) aux 1=(t-t2) aux 4=5HT aux 7=a1 aux 8=a2 aux 9=a3 aux 10=a4 aux 14=ApNT aux 18=ppMAPK/0.14*100 aux 19=dpp38/0.145*100 AUX 20=pRSK/0.041*100 aux 22=PKAC/0.35*100 aux 24=TGF aux 25=TBL aux 26=pCREB1 aux 28=pCREB2p @ total=3200, xlo=0, xhi=5000, ylo=0, yhi=10, bounds=10e30, MAXSTOR=1300000,xp=vs, yp=mk,nout=200, dt=0.01, @ delay=6000 @ output=test1.txt #@ RANGE=1, RANGEOVER=step2, RANGESTEP=10, RANGELOW=0, RANGEHIGH=10, RANGERESET=yes, RANGEOLDIC=yes, output=test7