1. Information
    majorVersion:3 minorVersion:0 projectID:local projectVersionID:undef fileName:/home/ikeda/eclipse/workspace/macrophage/csml/ok/csml/1757110.csml convertedTime:2009.07.01.11:05

  2. Original Literature
  3. Model OverView
  4. Model Abstracts
  5. Model Detail
  6. Download
Original Literature Model OverView
Publication
Title Genetic regulation of macrophage priming/activation: the Lsh gene story.
Authors Blackwell JM, Roach TI, Atkinson SE, Ajioka JW, Barton CH, Shaw MA.
Affiliation Department of Medical Parasitology, London School of Hygiene and TropicalMedicine, U.K.
Abstract This paper describes functional and genetic studies on the macrophage resistancegene Lsh/Ity/Bcg first described almost two decades ago. Working in vitro withresident peritoneal, liver (Kupffer cells) and bone marrow derived macrophagesfrom congenic B10 (LshS) and B10.L-LshR mice it has been possible to demonstratethat the final effector mechanism for the gene in regulating antileishmanialactivity involves production of reactive nitrogen rather than reactive oxygenintermediates. This in turn is dependent upon priming/activation of macrophagesfor enhanced TNF-alpha release which acts back on the macrophage in an autocrinemanner to increase nitric oxide production. The precise point at which Lsh actsto control macrophage priming/activation has not been identified, but studies ofearly response gene expression show differences in KC mRNA levels at 2 h afterLPS stimulation, and in c-fos mRNA as early as 20 min after stimulation with PMAplus ionophore, in peritoneal macrophages from congenic LshS and LshR mice. Dataavailable suggest that both negative and positive signals may be involved inmacrophage priming/activation, with LshS macrophages down-regulating theircapacity for continued response to the autocrine loop. Work in progress willexamine the role of TPA and cAMP response element-binding proteins in regulatinggene expression in Lsh congenic mice. A major new initiative has also commencedto clone the Lsh gene by reverse genetics using yeast artificial chromosomes towalk towards Lsh from the closet proximal and distal markers on mouse chromosome1.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID 1757110
Model Abstract

Entity

G010214:c-fos G010232:c-jun G010239:c-myc G010329:TNF-alpha MO000000049:c-Jun MO000000214:IL-1 MO000000279:c-Fos MO000000289:TNF-alpha MO000016665:IFNgamma MO000016882:LPS MO000019394:TLR4 MO000055986:c-Jun:c-Fos(AP-1) MO000088573:aconitate hydratase e1: e10: e11:KC e12:IFNgamma R e13:IFNgamma:R e14:PMA e15:ionophore e16:TNF-alpha:receptor e17:TNF-alpha receptor e18:Phorbol ester TPA e19:cAMP e2: e20:PGE2(exogenous) e21:Theophylline e22:AMP e23:L.donovani e24:PGE2 e25:Il-1 e26:LPG e27:TNFAR e28:Dibutyryl cAMP e29:NO e3: e30:L-arginine e31:NO synthase e32:nitrite e33:L-citrulline e34:nitrate e35:Labile Iron atoms e36:L-NMMA e37:neutralizing anti TNF-alpha antibody e38:L.major e4: e5:LPS:TLR4 e50: e51: e52: e53: e54: e55: e56: e57: e58: e59: e6:JE e60: e61: e62: e7: e8: e9:

Process

p1 p10 p11 p12 p13 p14 p15 p16 p17 p18 p19 p2 p20 p21 p22 p23 p24 p26 p28 p29 p3 p30 p31 p32 p4 p5 p6 p7 p8 p9
Model Detail
467.0, 695.0
33.0, 33.0

c-fos

--

G010214

cso30:c:mRNA

cso30:i:CC_Nucleoplasm

--

true true true true

csml-variable:Double

m93203

10

false

infinite

0

unit false false false
TRANSFACG010214

--

Go back
595.0, 787.0
33.0, 33.0

c-jun

--

G010232

cso30:c:mRNA

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m93221

10

false

infinite

0

unit false false false
TRANSFACG010232

--

Go back
487.0, 779.0
33.0, 33.0

c-myc

--

G010239

cso30:c:mRNA

cso30:i:CC_CellComponent

--

p3

--

true true true true

csml-variable:Double

m93227

10

false

infinite

0

unit false false false
TRANSFACG010239

--

Go back
651.0, 715.0
34.0, 34.0

TNF-alpha

--

G010329

cso30:c:mRNA

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m93309

10

false

infinite

0

unit false false false
TRANSFACG010329

--

Go back
540.0, 992.0
31.0, 31.0

c-Jun

--

MO000000049

cso30:c:Protein

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m46

10

false

infinite

0

unit false false false
InterProIPR002112
TRANSPATHMO000000049

--

Go back
1069.0, 369.0
30.0, 30.0

IL-1

--

MO000000214

cso30:c:Protein

cso30:i:CC_CellComponent

--

p18

--

true true true true

csml-variable:Double

m185

10

false

infinite

0

unit false false false
TRANSPATHMO000000214

--

Go back
416.0, 988.0
32.0, 32.0

c-Fos

--

MO000000279

cso30:c:Protein

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m221

10

false

infinite

0

unit false false false
InterProIPR002114
TRANSPATHMO000000279

--

Go back
1056.0, 692.0
31.0, 31.0

TNF-alpha

--

MO000000289

cso30:c:Protein

cso30:i:CC_CellComponent

--

true true true true

csml-variable:Double

m230

10

false

infinite

0

unit false false false
InterProIPR003636
TRANSPATHMO000000289

--

Go back
67.0, 287.0
33.5, 33.5

IFNgamma

--

MO000016665

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p6

true true true true

csml-variable:Double

m1639

10

false

infinite

0

unit false false false
InterProIPR002069
TRANSPATHMO000016665

--

Go back
58.0, 526.0
35.0, 35.0

LPS

--

MO000016882

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p1

true true true true

csml-variable:Double

m155666

10

false

infinite

0

unit false false false
TRANSPATHMO000016882

--

Go back
156.0, 548.0
32.0, 32.0

TLR4

--

MO000019394

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p1

true true true true

csml-variable:Double

m3961

10

false

infinite

0

unit false false false
InterProIPR000157
TRANSPATHMO000019394

--

Go back
584.0, 1116.0
34.0, 34.0

c-Jun:c-Fos(AP-1)

--

MO000055986

cso30:c:Protein

cso30:i:CC_CellComponent

--

p12

--

true true true true

csml-variable:Double

m31310

10

false

infinite

0

unit false false false
TRANSPATHMO000055986

--

Go back
665.0, 261.0
30.0, 30.0

aconitate hydratase

--

MO000088573

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p28

true true true true

csml-variable:Double

m62266

10

false

infinite

0

unit false false false
TRANSPATHMO000088573

--

Go back
139.75, 77.99690800911759
856.2594311764528, 1243.2886940682085

--

e1

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane

--

--

--

true true true true

csml-variable:Double

m1

0

false

infinite

0

unit false true false

--

Go back
142.70269031272042, 165.30942636206527
811.27490780959, 1141.2356773020367

--

e10

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cytosol

--

--

--

true true true true

csml-variable:Double

m10

0

false

infinite

0

unit false true false

--

Go back
447.0, 651.0
50.50173010380623, 26.93425605536332

KC

--

e11

cso30:c:mRNA

cso30:i:CC_Nucleoplasm

--

p5

--

true true true true

csml-variable:Double

m11

0

false

infinite

0

unit false false false

--

Go back
157.5, 265.0
29.312829525483306, 45.09666080843584

IFNgamma R

--

e12

cso30:c:Protein

cso30:i:CC_Cytosol

--

--

p6

true true true true

csml-variable:Double

m12

0

false

infinite

0

unit false false false

--

Go back
157.5, 371.0
29.538697654023238, 57.17167287875466

IFNgamma:R

--

e13

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

--

true true true true

csml-variable:Double

m13

0

false

infinite

0

unit false false false

--

Go back
1061.0, 543.0
46.450798990748524, 26.322119428090833

PMA

--

e14

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

--

--

p7

true true true true

csml-variable:Double

m14

0

false

infinite

0

unit false false false

--

Go back
1073.0, 651.0
45.542472666105965, 25.807401177460047

ionophore

--

e15

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

--

--

p7

true true true true

csml-variable:Double

m15

0

false

infinite

0

unit false false false

--

Go back
950.5, 818.0
26.94913396185047, 52.15961411971058

TNF-alpha:receptor

--

e16

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

--

true true true true

csml-variable:Double

m16

0

false

infinite

0

unit false false false

--

Go back
948.5, 900.0
31.300527240773288, 48.15465729349736

TNF-alpha receptor

--

e17

cso30:c:Protein

cso30:i:CC_PlasmaMembrane_ExternalSideOfPlasmaMembrane_

--

true true true true

csml-variable:Double

m17

0

false

infinite

0

unit false false false

--

Go back
1049.0, 1017.0
53.313708999158955, 30.211101766190072

Phorbol ester TPA

--

e18

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

--

--

p14

true true true true

csml-variable:Double

m18

0

false

infinite

0

unit false false false

--

Go back
868.5, 985.0
30.18740290919362, 30.69905380595961

cAMP

--

e19

cso30:c:SmallMolecule

cso30:i:CC_Cytosol

--

--

p16 p26 p30 p31

true true true true

csml-variable:Double

m19

0

false

infinite

0

unit false false false

--

Go back
139.75, 77.99690800911759
856.2594311764528, 1243.2886940682085

--

e2

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_ExternalSideOfPlasmaMembrane_

--

--

--

true true true true

csml-variable:Double

m2

0

false

infinite

0

unit false true false

--

Go back
1059.0, 434.0
52.60723296888141, 29.8107653490328

PGE2(exogenous)

--

e20

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

--

--

p26 p30 p31

true true true true

csml-variable:Double

m20

0

false

infinite

0

unit false false false

--

Go back
1062.0, 1079.0
48.16652649285115, 27.29436501261564

Theophylline

--

e21

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

--

--

p16

true true true true

csml-variable:Double

m21

0

false

infinite

0

unit false false false

--

Go back
792.0, 1182.5
47.75431861804223, 26.26487523992322

AMP

--

e22

cso30:c:SmallMolecule

cso30:i:CC_Cytosol

--

p16

--

true true true true

csml-variable:Double

m22

0

false

infinite

0

unit false false false

--

Go back
1034.5, 91.0
34.01268699110017, 49.77466388941488

L.donovani

--

e23

cso30:c:Cell

cso30:i:CC_Extracellular

--

--

p19 p18 p31

true true true true

csml-variable:Double

m23

0

false

infinite

0

unit false false false

--

Go back
718.0, 177.0
52.60723296888141, 29.8107653490328

PGE2

--

e24

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

--

p19

--

true true true true

csml-variable:Double

m24

0

false

infinite

0

unit false false false

--

Go back
656.0, 611.0
47.647058823529406, 25.411764705882355

Il-1

--

e25

cso30:c:mRNA

cso30:i:CC_Nucleoplasm

--

--

p18

true true true true

csml-variable:Double

m25

0

false

infinite

0

unit false false false

--

Go back
1048.0, 251.0
47.333894028595466, 26.82253994953743

LPG

--

e26

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

--

--

p20 p21 p22

true true true true

csml-variable:Double

m26

0

false

infinite

0

unit false false false

--

Go back
470.0, 548.0
51.95501730103806, 27.709342560553637

TNFAR

--

e27

cso30:c:mRNA

cso30:i:CC_Nucleoplasm

--

true true true true

csml-variable:Double

m27

0

false

infinite

0

unit false false false

--

Go back
654.5, 1070.0
37.39471826013274, 38.0285270442028

Dibutyryl cAMP

--

e28

cso30:c:SmallMolecule

cso30:i:CC_Cytosol

--

--

p24

true true true true

csml-variable:Double

m28

0

false

infinite

0

unit false false false

--

Go back
273.0, 261.0
53.76787216148024, 30.46846089150547

NO

--

e29

cso30:c:SmallMolecule

cso30:i:CC_Cytosol

--

true true true true

csml-variable:Double

m29

0

false

infinite

0

unit false false false

--

Go back
156.87518862352903, 95.12209663264667
822.0090539293948, 1209.0383168211513

--

e3

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

--

--

--

true true true true

csml-variable:Double

m3

0

false

infinite

0

unit false true false

--

Go back
254.0, 201.0
52.53153910849454, 29.76787216148024

L-arginine

--

e30

cso30:c:SmallMolecule

cso30:i:CC_Cytosol

--

--

p29 p15 p17

true true true true

csml-variable:Double

m30

0

false

infinite

0

unit false false false

--

Go back
597.0, 164.5
30.399999999999984, 22.8

NO synthase

--

e31

cso30:c:Protein

cso30:i:CC_Cytosol

--

--

p29 p15 p17

true true true true

csml-variable:Double

m31

0

false

infinite

0

unit false false false

--

Go back
405.9428090832632, 461.1009251471825
51.47182506307823, 29.167367535744322

nitrite

--

e32

cso30:c:SmallMolecule

cso30:i:CC_Cytosol

--

p32

--

true true true true

csml-variable:Double

m32

0

false

infinite

0

unit false false false

--

Go back
303.0, 349.0
34.81967213114756, 29.016393442622952

L-citrulline

--

e33

cso30:c:SmallMolecule

cso30:i:CC_Cytosol

--

p32

--

true true true true

csml-variable:Double

m33

0

false

infinite

0

unit false false false

--

Go back
522.0, 445.0
51.724137931034484, 29.310344827586203

nitrate

--

e34

cso30:c:SmallMolecule

cso30:i:CC_Cytosol

--

p32

--

true true true true

csml-variable:Double

m34

0

false

infinite

0

unit false false false

--

Go back
677.5, 385.0
35.97825165937014, 36.58805253495268

Labile Iron atoms

--

e35

cso30:c:SmallMolecule

cso30:i:CC_Cytosol

--

p28

--

true true true true

csml-variable:Double

m35

0

false

infinite

0

unit false false false

--

Go back
156.0, 44.0
55.9125315391085, 31.683767872161482

L-NMMA

--

e36

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

--

--

p29 p15 p17

true true true true

csml-variable:Double

m36

0

false

infinite

0

unit false false false

--

Go back
290.0, 28.0
27.23076923076923, 40.84615384615385

neutralizing anti TNF-alpha antibody

--

e37

cso30:c:Protein

cso30:i:CC_Extracellular

--

--

p29 p15 p17

true true true true

csml-variable:Double

m37

0

false

infinite

0

unit false false false

--

Go back
918.5, 19.0
34.01268699110017, 49.77466388941488

L.major

--

e38

cso30:c:Cell

cso30:i:CC_Extracellular

--

--

p30

true true true true

csml-variable:Double

m38

0

false

infinite

0

unit false false false

--

Go back
188.55678757705792, 125.09117672382234
758.6458560223374, 1149.1001566387988

--

e4

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_InternalSideOfPlasmaMembrane_

--

--

--

true true true true

csml-variable:Double

m4

0

false

infinite

0

unit false true false

--

Go back
157.5, 636.0
28.76386757290068, 55.672001754001315

LPS:TLR4

--

e5

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

--

true true true true

csml-variable:Double

m5

0

false

infinite

0

unit false false false

--

Go back
297.0, 486.0
533.3807488706808, 483.71773687154877

--

e50

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearEnvelopeLumen

--

--

--

true true true true

csml-variable:Double

m50

0

false

infinite

0

unit false true false

--

Go back
354.6090939189934, 497.4634071488766
311.8837153545508, 468.81883327180907

--

e51

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearPore

--

--

--

true true true true

csml-variable:Double

m51

0

false

infinite

0

unit false true false

--

Go back
303.9528216798786, 492.4561915598872
519.4751055109239, 470.8053537517741

--

e52

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearInnerMembrane

--

--

--

true true true true

csml-variable:Double

m52

0

false

infinite

0

unit false true false

--

Go back
304.94608191986106, 493.44945179986985
517.4885850309583, 468.81883327180907

--

e53

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearLumen

--

--

--

true true true true

csml-variable:Double

m53

0

false

infinite

0

unit false true false

--

Go back
297.0, 486.0
533.3807488706808, 483.71773687154877

--

e54

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearOuterMembrane

--

--

--

true true true true

csml-variable:Double

m54

0

false

infinite

0

unit false true false

--

Go back
297.0, 486.0
533.3807488706808, 483.71773687154877

--

e55

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleus

--

--

--

true true true true

csml-variable:Double

m55

0

false

infinite

0

unit false true false

--

Go back
304.94608191986106, 493.44945179986985
517.4885850309583, 468.81883327180907

--

e56

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleoplasm

--

--

--

true true true true

csml-variable:Double

m56

0

false

infinite

0

unit false true false

--

Go back
686.3580140731968, 684.6520479965292
33.32269852674252, 30.165811297893285

--

e57

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearBody

--

--

--

true true true true

csml-variable:Double

m57

0

false

infinite

0

unit false true false

--

Go back
598.9511129547243, 823.7084815940997
94.35972279835127, 85.42038063850764

--

e58

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleolus

--

--

--

true true true true

csml-variable:Double

m58

0

false

infinite

0

unit false true false

--

Go back
297.0, 486.0
533.3807488706808, 483.71773687154877

--

e59

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearEnvelope

--

--

--

true true true true

csml-variable:Double

m59

0

false

infinite

0

unit false true false

--

Go back
469.0, 842.0
53.719723183391004, 28.65051903114187

JE

--

e6

cso30:c:mRNA

cso30:i:CC_Nucleoplasm

--

p4

--

true true true true

csml-variable:Double

m6

0

false

infinite

0

unit false false false

--

Go back
422.71484138191767, 700.9601652731513
16.891384596049047, 8.132888879579177

--

e60

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Chromatin

--

--

--

true true true true

csml-variable:Double

m60

0

false

infinite

0

unit false true false

--

Go back
422.15079023781345, 676.7059660766679
57.815242270687946, 104.0674360872383

--

e61

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearChromosome

--

--

--

true true true true

csml-variable:Double

m61

0

false

infinite

0

unit false true false

--

Go back
446.40498943429776, 744.392103369181
9.02481830566835, 9.024818305668358

--

e62

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearCentromere

--

--

--

true true true true

csml-variable:Double

m62

0

false

infinite

0

unit false true false

--

Go back
156.0, 104.1116040507567
826.2361190962304, 1170.7552388669833

--

e7

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cell

--

--

--

true true true true

csml-variable:Double

m7

0

false

infinite

0

unit false true false

--

Go back
181.0, 95.0
805.5569854171277, 1169.6687428256696

--

e8

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cell_WithoutCellWall_

--

--

--

true true true true

csml-variable:Double

m8

0

false

infinite

0

unit false true false

--

Go back
144.82356784975286, 180.56908723638705
766.0556080532334, 1102.7597431195916

--

e9

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cytoplasm

--

--

--

true true true true

csml-variable:Double

m9

0

false

infinite

0

unit false true false

--

Go back
57.0, 613.0
27.0, 27.0

p1

p1

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c1 : 1
stoichiometry:c2 : 1
stoichiometry:c3 : 1

m155666*m3961*0.1

nodelay

--

true

0

false

PMID: 1757110, 3760571, 3108379 The fact that differences in TNF-o~ release could be measured at the protein level within 4 h of addition of priming/activating signals stimulated us to begin looking at changes in expression of other early response genes at the mRNA level, especially those like c-fos, c-myc, JE and KC which are known to be induced by LPS

Go back
691.0, 795.0
26.0, 26.0

p9

p10

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c24 : 1
stoichiometry:c25 : 1

m16*0.1

nodelay

--

true

0

false

PMID: 1757110, 3497923, 2537468 Expression of both c-fos and c-jun is stimulated by TNF-alpha.

Go back
690.0, 1002.0
27.0, 27.0

p11

p11

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c26 : 1
stoichiometry:c27 : 1

m93221*0.1

nodelay

--

true

0

false

PMID: 1757110 In the case of c-fos, the protein product for the gene dimerises with c-jun to form the TRE binding protein complex AP-1, c-fos itself having both TRE and CRE in its promoter region.

Go back
475.0, 1067.0
26.0, 26.0

p12

p12

cso30:i:ME_Binding

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c30 : 1
stoichiometry:c31 : 1
stoichiometry:c32 : 1

m221*m46*0.1

nodelay

--

true

0

false

PMID: 1757110 In the case of c-fos, the protein product for the gene dimerises with c-jun to form the TRE binding protein complex AP-1, c-fos itself having both TRE and CRE in its promoter region.

Go back
346.0, 946.0
27.0, 27.0

p13

p13

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c28 : 1
stoichiometry:c29 : 1

m93203*0.1

nodelay

--

true

0

false

PMID: 1757110 In the case of c-fos, the protein product for the gene dimerises with c-jun to form the TRE binding protein complex AP-1, c-fos itself having both TRE and CRE in its promoter region.

Go back
691.0, 855.0
25.0, 25.0

p14

p14

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleolus

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c33 : 1
stoichiometry:c34 : 1

m18*0.1

nodelay

--

true

0

false

PMID: 1757110 TNF-o~ stimulates prolonged expression at the mRNA level contrasting with transient induction observed with the phorbol ester TPA.

Go back
530.0, 258.0
27.0, 27.0

p29

p15

cso30:i:ME_Oxidation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c35 : 1
stoichiometry:c37 : 1
stoichiometry:c73 : 1
stoichiometry:c92 : 1
stoichiometry:c95 : 1
stoichiometry:c41 : 1

m16*m30*m31*0.1

nodelay

--

true

0

false

PMID: 1757110, 2279740, 2175327 In the context of the L. major model, Liew and co-workers have shown that, in the presence of 10ng/ml LPS, recombinant TNF-et acts synergistically with interferon-3, to give maximal production of INO and antileishmanial activity. PMID: 1757110, 2999236 This was confirmed by Green and co-workers [47] who showed that neutralizing anti-TNF-a antibodies blocked production of INO and antileishmanial activity in interferon-3, primed peritoneal macrophages. PMID: 1757110, 1712077, 2432665, 3242600 In this system, L-arginine is oxidised by an inducible NADPHdependent enzyme (NO synthase) to yield L-citrulline, nitrite and nitrate, with highly reactive nitric oxide (NO) produced as an intermediate. The degree of kill correlated well with the levels of nitrites measured in the supernatants at 72 h, and inclusion of 200 #M L-NMMA, a competitive inhibitor of the L-arginine dependent pathway for the synthesis of INO, inhibited the killing

Go back
830.0, 1082.0
27.0, 27.0

p16

p16

cso30:i:ME_MetabolicReaction

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c39 : 1
stoichiometry:c38 : 1
stoichiometry:c40 : 1

m19*0.1

nodelay

--

true

0

false

PMID: 1757110 This could involve differences in down regulation of LPS or TNF-a receptors, or a cAMPdependent down regulation of TNF-o~ production. In preliminary experiments (T. I.A. Roach and J.M. Blackwell, unpublished) we have established that either addition of exogenous prostaglandin E2, or inhibition of cAMP catabolism with theophylline, reduces TNF-ot release.

Go back
454.0, 298.0
27.0, 27.0

p29

p17

cso30:i:ME_Oxidation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c36 : 1
stoichiometry:c42 : 1
stoichiometry:c74 : 1
stoichiometry:c93 : 1
stoichiometry:c96 : 1
stoichiometry:c43 : 1

m5*m30*m31*0.1

nodelay

--

true

0

false

PMID: 1757110, 2279740, 2175327 In the context of the L. major model, Liew and co-workers have shown that, in the presence of 10ng/ml LPS, recombinant TNF-et acts synergistically with interferon-3, to give maximal production of INO and antileishmanial activity. PMID: 1757110, 2999236 This was confirmed by Green and co-workers [47] who showed that neutralizing anti-TNF-a antibodies blocked production of INO and antileishmanial activity in interferon-3, primed peritoneal macrophages. PMID: 1757110, 1712077, 2432665, 3242600 In this system, L-arginine is oxidised by an inducible NADPHdependent enzyme (NO synthase) to yield L-citrulline, nitrite and nitrate, with highly reactive nitric oxide (NO) produced as an intermediate. The degree of kill correlated well with the levels of nitrites measured in the supernatants at 72 h, and inclusion of 200 #M L-NMMA, a competitive inhibitor of the L-arginine dependent pathway for the synthesis of INO, inhibited the killing

Go back
761.0, 353.0
29.0, 29.0

p18

p18

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c45 : 1
stoichiometry:c48 : 1
stoichiometry:c44 : 1

m25*0.1

nodelay

--

true

0

false

PMID: 1757110, 3917283, 2112157 Previous studies have shown, for example, that L. donovani is a potent stimulator of prostaglandin E2 synthesis in BALB/ c (Lsh s) macrophages, and that preinfection of macrophages selectively diminishes IL-1 (but not TNF-ot) production.

Go back
777.0, 257.0
29.0, 29.0

p19

p19

cso30:i:ME_MetabolicReaction

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c46 : 1
stoichiometry:c47 : 1

m23*0.1

nodelay

--

true

0

false

PMID: 1757110, 3917283, 2112157 Previous studies have shown, for example, that L. donovani is a potent stimulator of prostaglandin E2 synthesis in BALB/ c (Lsh s) macrophages, and that preinfection of macrophages selectively diminishes IL-1 (but not TNF-ot) production.

Go back
371.0, 663.0
25.0, 25.0

p2

p2

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c4 : 1
stoichiometry:c5 : 1

m5*0.1

nodelay

--

true

0

false

PMID: 1757110, 3760571, 3108379 The fact that differences in TNF-o~ release could be measured at the protein level within 4 h of addition of priming/activating signals stimulated us to begin looking at changes in expression of other early response genes at the mRNA level, especially those like c-fos, c-myc, JE and KC which are known to be induced by LPS

Go back
526.0, 630.0
27.0, 27.0

p20

p20

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c51 : 1
stoichiometry:c50 : 1

m26*0.1

nodelay

--

true

0

false

PMID: 1757110, 1707920 More recently, Descoteaux and co-workers have shown that parasite-derived lipophosphoglycan (LPG) stimulates rapid expression of both c-fos and TNF-a genes

Go back
754.0, 742.0
27.0, 27.0

p20

p21

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c49 : 1
stoichiometry:c52 : 1

m26*0.1

nodelay

--

true

0

false

PMID: 1757110, 1707920 More recently, Descoteaux and co-workers have shown that parasite-derived lipophosphoglycan (LPG) stimulates rapid expression of both c-fos and TNF-a genes

Go back
574.0, 518.0
27.0, 27.0

p22

p22

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c53 : 1
stoichiometry:c54 : 1

1.0*0.1

nodelay

--

true

0

false

PMID: 1757110 LPG induced a rapid down-modulation of TNF-a receptors but did not impair stimulation of expression of c-fos by the cAMP analogue, dibutyryl cAMP.

Go back
858.0, 750.0
27.0, 27.0

p23

p23

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c55 : 1
stoichiometry:c56 : 1

m27*0.1

nodelay

--

true

0

false

PMID: 1757110 LPG induced a rapid down-modulation of TNF-a receptors but did not impair stimulation of expression of c-fos by the cAMP analogue, dibutyryl cAMP.

Go back
557.0, 841.0
27.0, 27.0

p24

p24

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c57 : 1
stoichiometry:c58 : 1

m28*0.1

nodelay

--

true

0

false

PMID: 1757110 LPG induced a rapid down-modulation of TNF-a receptors but did not impair stimulation of expression of c-fos by the cAMP analogue, dibutyryl cAMP.

Go back
833.0, 545.0
30.0, 30.0

p26

p26

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c64 : 1
stoichiometry:c66 : 1
stoichiometry:c68 : 1
stoichiometry:c91 : 1
stoichiometry:c65 : 1

m93309*m5*0.1

nodelay

--

true

0

false

PMID: 1757110, 2999236 The LPS itself acts as a potent stimulator of TNF-ct release, which may then form an autocrine loop acting back on the macrophage. PMID: 1757110 This could involve differences in down regulation of LPS or TNF-a receptors, or a cAMPdependent down regulation of TNF-o~ production. In preliminary experiments (T. I.A. Roach and J.M. Blackwell, unpublished) we have established that either addition of exogenous prostaglandin E2, or inhibition of cAMP catabolism with theophylline, reduces TNF-ot release.

Go back
533.0, 369.0
29.0, 29.0

p28

p28

cso30:i:ME_Nitrosylation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c61 : 1
stoichiometry:c62 : 1
stoichiometry:c63 : 1

m29*m62266*0.1

nodelay

--

true

0

false

PMID: 1757110, 3745439, 2451695, 2497225 NO mediates L-arginine dependent tumour cyo tostasis during co-culture with interferon-7 and LPS activated macrophages, possibly via nitrosylation reactions which remove labile iron atoms from Fe-S prosthetic groups of aconitase and complexes I and II of the mitochondrial electron transport system

Go back
496.0, 198.0
27.0, 27.0

p29

p29

cso30:i:ME_Oxidation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c75 : 1
stoichiometry:c77 : 1
stoichiometry:c78 : 1
stoichiometry:c79 : 1
stoichiometry:c94 : 1
stoichiometry:c76 : 1

m30*m31*m13*0.1

nodelay

--

true

0

false

PMID: 1757110, 2279740, 2175327 In the context of the L. major model, Liew and co-workers have shown that, in the presence of 10ng/ml LPS, recombinant TNF-et acts synergistically with interferon-3, to give maximal production of INO and antileishmanial activity. PMID: 1757110, 2999236 This was confirmed by Green and co-workers [47] who showed that neutralizing anti-TNF-a antibodies blocked production of INO and antileishmanial activity in interferon-3, primed peritoneal macrophages. PMID: 1757110, 1712077, 2432665, 3242600 In this system, L-arginine is oxidised by an inducible NADPHdependent enzyme (NO synthase) to yield L-citrulline, nitrite and nitrate, with highly reactive nitric oxide (NO) produced as an intermediate. The degree of kill correlated well with the levels of nitrites measured in the supernatants at 72 h, and inclusion of 200 #M L-NMMA, a competitive inhibitor of the L-arginine dependent pathway for the synthesis of INO, inhibited the killing

Go back
375.0, 731.0
25.0, 25.0

p2

p3

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c7 : 1
stoichiometry:c6 : 1

m5*0.1

nodelay

--

true

0

false

PMID: 1757110, 3760571, 3108379 The fact that differences in TNF-o~ release could be measured at the protein level within 4 h of addition of priming/activating signals stimulated us to begin looking at changes in expression of other early response genes at the mRNA level, especially those like c-fos, c-myc, JE and KC which are known to be induced by LPS

Go back
789.0, 465.0
30.0, 30.0

p30

p30

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c80 : 1
stoichiometry:c82 : 1
stoichiometry:c67 : 1
stoichiometry:c90 : 1
stoichiometry:c81 : 1

m93309*m38*0.1

nodelay

--

true

0

false

PMID:1757110 In this case, the parasite (L. major) itself acted as the stimulus for TNF-a release by the macrophage. PMID: 1757110 This could involve differences in down regulation of LPS or TNF-a receptors, or a cAMPdependent down regulation of TNF-o~ production. In preliminary experiments (T. I.A. Roach and J.M. Blackwell, unpublished) we have established that either addition of exogenous prostaglandin E2, or inhibition of cAMP catabolism with theophylline, reduces TNF-ot release.

Go back
858.0, 442.0
27.0, 27.0

p31

p31

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c83 : 1
stoichiometry:c85 : 1
stoichiometry:c69 : 1
stoichiometry:c71 : 1
stoichiometry:c84 : 1

m23*m93309*0.1

nodelay

--

true

0

false

PMID: 1757110 The magnitude of this response was enhanced in macrophages preinfected with L. donovani amastigotes, suggesting again that the parasite itself may act as a trigger for TNF-ct production/release. PMID: 1757110 This could involve differences in down regulation of LPS or TNF-a receptors, or a cAMPdependent down regulation of TNF-o~ production. In preliminary experiments (T. I.A. Roach and J.M. Blackwell, unpublished) we have established that either addition of exogenous prostaglandin E2, or inhibition of cAMP catabolism with theophylline, reduces TNF-ot release.

Go back
453.0, 389.0
29.0, 29.0

p32

p32

cso30:i:ME_MetabolicReaction

cso30:i:CC_Cytosol

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c86 : 1
stoichiometry:c87 : 1
stoichiometry:c88 : 1
stoichiometry:c89 : 1

m29*0.1

nodelay

--

true

0

false

PMID: 1757110, 1712077, 2432665, 3242600 In this system, L-arginine is oxidised by an inducible NADPHdependent enzyme (NO synthase) to yield L-citrulline, nitrite and nitrate, with highly reactive nitric oxide (NO) produced as an intermediate.

Go back
379.0, 791.0
25.0, 25.0

p2

p4

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

e5

e6

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c8 : 1
stoichiometry:c9 : 1

m5*0.1

nodelay

--

true

0

false

PMID: 1757110, 3760571, 3108379 The fact that differences in TNF-o~ release could be measured at the protein level within 4 h of addition of priming/activating signals stimulated us to begin looking at changes in expression of other early response genes at the mRNA level, especially those like c-fos, c-myc, JE and KC which are known to be induced by LPS

Go back
411.0, 583.0
25.0, 25.0

p2

p5

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c10 : 1
stoichiometry:c15 : 1
stoichiometry:c11 : 1

m5*m13*0.1

nodelay

--

true

0

false

PMID: 1757110, 3760571, 3108379 The fact that differences in TNF-o~ release could be measured at the protein level within 4 h of addition of priming/activating signals stimulated us to begin looking at changes in expression of other early response genes at the mRNA level, especially those like c-fos, c-myc, JE and KC which are known to be induced by LPS PMID: 1757110 Priming with 33 units/ml interferon-3, along with l0 ng/ml LPS induced much higher levels of KC

Go back
50.0, 374.0
27.0, 27.0

p6

p6

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c12 : 1
stoichiometry:c13 : 1
stoichiometry:c14 : 1

m1639*m12*0.1

nodelay

--

true

0

false

PMID: 1757110 Priming with 33 units/ml interferon-3, along with l0 ng/ml LPS induced much higher levels of KC

Go back
598.0, 662.0
27.0, 27.0

p7

p7

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c16 : 1
stoichiometry:c17 : 1
stoichiometry:c18 : 1

m14*m15*0.1

nodelay

--

true

0

false

PMID: 1757110 For c-fos, differences in expression are observed within 20min following stimulation with PMA plus ionophore. In this case, however, resistant macrophages down-regulate expression from a higher baseline level while susceptible macrophages show enhanced expression over the 20-min time course.

Go back
1047.0, 795.0
25.0, 25.0

p8

p8

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c19 : 1
stoichiometry:c20 : 1
stoichiometry:c21 : 1

m230*m17*0.1

nodelay

--

true

0

false

PMID: 1757110, 3497923, 2537468 Expression of both c-fos and c-jun is stimulated by TNF-alpha.

Go back
599.0, 731.0
26.0, 26.0

p9

p9

cso30:i:ME_GeneExpression

cso30:i:CC_Nucleoplasm

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c22 : 1
stoichiometry:c23 : 1

m16*0.1

nodelay

--

true

0

false

PMID: 1757110, 3497923, 2537468 Expression of both c-fos and c-jun is stimulated by TNF-alpha.

Go back
72.46077228077336, 561.0

c1

c1

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
186.0, 601.0933219616422

c10

c10

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
433.0, 608.0

c11

c11

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
68.90577222238119, 321.0

c12

c12

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
82.87008539214536, 301.0

c13

c13

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
77.0, 389.0

c14

c14

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
187.0, 412.0

c15

c15

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
632.7527000989086, 562.0

c16

c16

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
632.9975895783581, 665.0

c17

c17

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
507.69219158112656, 680.0

c18

c18

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
1062.8834522085988, 723.0

c19

c19

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
90.7839864320407, 574.0

c2

c2

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
980.0, 826.1754418849364

c20

c20

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
984.4994021760781, 813.0

c21

c21

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
632.6992808929201, 750.172803196775

c22

c22

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
507.75650936697343, 717.9587144866094

c23

c23

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
724.9262285231786, 811.0839286869304

c24

c24

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
635.995971802363, 805.2538403746781

c25

c25

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
619.0, 820.0

c26

c26

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
578.9898505738666, 1009.4028496087664

c27

c27

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
370.5777087639997, 728.0

c28

c28

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
373.0, 968.0

c29

c29

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
84.0, 632.0

c3

c3

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
444.0, 1020.0

c30

c30

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
505.52380597346, 1023.0

c31

c31

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
501.0, 1086.0

c32

c32

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
723.3186260823085, 876.2307448471452

c33

c33

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
634.5587425737733, 819.5807090991433

c34

c34

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
558.7329764398, 291.4497235615411

c35

c35

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
186.0, 331.120768121685

c36

c36

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
307.0, 222.0

c37

c37

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
860.9995717523051, 1093.0

c38

c38

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
853.029062765764, 1016.0

c39

c39

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
186.0, 665.0

c4

c4

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
822.0872722011422, 1109.0

c40

c40

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
334.99844739330433, 272.0

c41

c41

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
307.0, 230.0

c42

c42

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
334.8251141788001, 283.66360695139844

c43

c43

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
790.0, 369.0

c44

c44

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
685.0, 389.48928855010814

c45

c45

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
812.8652281794084, 127.0

c46

c46

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
757.1159660434203, 213.85994340570036

c47

c47

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
792.9581207450804, 132.0

c48

c48

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
781.1976917271486, 278.0

c49

c49

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
396.0, 680.0

c5

c5

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
503.05701381977434, 657.0

c50

c50

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
559.5107474838611, 278.0

c51

c51

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
692.7677168938225, 737.9137853216664

c52

c52

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
604.4977358353469, 277.0

c53

c53

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
529.6039626014052, 536.0

c54

c54

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
522.0, 576.0

c55

c55

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
879.0, 777.0

c56

c56

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
580.1951186300456, 875.3342495826046

c57

c57

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
498.16915575016554, 734.8277478227349

c58

c58

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
400.0, 749.0

c6

c6

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
327.0, 288.0

c61

c61

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
568.1702509923432, 288.0

c62

c62

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
562.0, 386.0

c63

c63

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
685.0, 579.53863057437

c64

c64

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
863.0, 570.0

c65

c65

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
186.0, 563.2219666236251

c66

c66

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
806.6130776922869, 498.9527377529024

c67

c67

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
849.3305726138997, 578.9863168146724

c68

c68

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
872.092998110995, 472.99891877278736

c69

c69

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
186.0, 669.0

c7

c7

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
888.9976239974144, 450.0

c71

c71

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
558.6062289543274, 187.0

c73

c73

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
486.801212467863, 187.0

c74

c74

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
307.0, 212.16927426324855

c75

c75

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
334.6462320697756, 216.0

c76

c76

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
530.5476811172091, 181.0

c77

c77

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
187.0, 223.89090422003193

c78

c78

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
317.0, 59.0

c79

c79

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
186.0, 673.0

c8

c8

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
677.0, 502.036566992757

c80

c80

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
819.0, 493.0

c81

c81

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
811.320059162263, 69.0

c82

c82

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
882.7549575953628, 141.0

c83

c83

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
882.0, 469.0

c84

c84

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
681.0, 475.44373704107113

c85

c85

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
320.0, 291.0

c86

c86

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
345.72427717759115, 371.08219645656806

c87

c87

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
442.6438064345119, 418.0

c88

c88

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
482.0, 414.0

c89

c89

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
404.0, 810.0

c9

c9

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
822.9767323821561, 452.0

c90

c90

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
866.6209477762922, 461.0

c91

c91

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
317.0, 60.0

c92

c92

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
317.0, 69.0

c93

c93

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
212.0, 73.0

c94

c94

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
211.0, 76.0

c95

c95

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back
202.0, 76.0

c96

c96

cso30:c:InputInhibitor

--

true true true true

cso30:c:InputInhibitor

threshold

--

0

1,

--

Go back