Original Literature | Model OverView |
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Publication
Title
Mechanism of age-associated up-regulation in macrophage PGE2 synthesis.
Affiliation
Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition ResearchCenter on Aging at Tufts University, Boston, MA 02111, USA. dayong.wu@tufts.edu
Abstract
Many physiological functions of the body change during the aging process.Dysregulated immune and inflammatory responses have been well documented in bothhumans and animals. The investigation into the cellular and molecular mechanismunderlying these disorders has provided compelling evidence that up-regulatedcyclooxygenase (COX)-2 and its product, particularly prostaglandin (PG)E2, playa critical role in the age-associated dysregulation of the immune andinflammatory responses. In particular, several studies have shown that increasedPGE2 production in old macrophages (Mphi) contributes to the suppression of Tcell function with aging. Furthermore, interventions targeted at decreasing PGE2production have been shown to enhance T cell-mediated function. COX-2 and itscatalytic products are also suggested to play a key role in age-relatedneurodegenerative diseases such as Alzheimer's and Parkinson's disease.Administration of anti-inflammatory drugs which inhibit COX activity has beenshown, by some investigators, to be beneficial in preventing and treating thesediseases. It is, thus, important to understand the underlying mechanisms ofage-related COX-2 up-regulation and to delineate the factors, which contributeto this age-related change. This review focuses on the regulation of PGE2production in murine Mphi; the age-associated changes in COX-2 expression; andits implication for certain disorders observed in the aged immune system andbrain. Increased PGE2 production has been shown to be mainly due to an increasein COX activity, which is, in turn, due to an increase in COX-2 protein and mRNAexpression. Elevated COX-2 mRNA represents a higher transcription rate ratherthan an altered stability of COX-2 mRNA. Upon stimulation, Mphi from old micegenerate more ceramide, a sphingolipid, than those from young mice. Ceramide hasbeen shown to induce, by itself, and also augment, LPS-stimulated COX-2expression and PGE2 production. Several lines of evidence indicate that thehigher ceramide levels in old Mphi are an important contributor to theage-associated up-regulation of COX-2 in Mphi. Ceramide up-regulates COX-2transcription by increasing activation of transcription factor NF-kappaB.Further understanding of molecular mechanisms involved in COX-2 up-regulationwill help in delineating fundamental age-related changes, which lead to thedevelopment of immune and neurological disorders in the aged.
PMID
15331118
|
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--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c1 : 1
stoichiometry:c2 : 1
stoichiometry:c3 : 1
stoichiometry:c4 : 1
m11*m6*0.1
nodelay
--
0
PMID: 15331118 Activation of T cells is initiated by engagement of the T cell receptor (TCR) with peptide antigen presented by the major histocompatibility complex (MHC) on antigen-presenting cells (APC).
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c33 : 1
stoichiometry:c31 : 1
stoichiometry:c28 : 1
m23*m25*0.1
nodelay
--
0
PMID:15331118 ZAP-70 subsequently phosphorylates adaptor proteins, such as the linker for activated T cells (LAT), which in turn mobilize other adaptor proteins or enzymes to amplify and to transmit signals downstream through different stages and ultimately lead to the activation of different nuclear transcription factors necessary for cytokine gene transcription.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c37 : 1
stoichiometry:c34 : 1
m28*0.1
nodelay
--
0
PMID:15331118 LAT in turn mobilize other adaptor proteins or enzymes to amplify and to transmit signals downstream through different stages and ultimately lead to the activation of different nuclear transcription factors necessary for cytokine gene transcription.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c127 : 1
stoichiometry:c35 : 1
stoichiometry:c36 : 1
m86*m26*0.1
nodelay
--
0
PMID:15331118 LAT in turn mobilize other adaptor proteins or enzymes to amplify and to transmit signals downstream through different stages and ultimately lead to the activation of different nuclear transcription factors necessary for cytokine gene transcription.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c38 : 1
stoichiometry:c39 : 1
stoichiometry:c40 : 1
m30*m29*0.1
nodelay
--
0
PMID: 15331118 The binding of LPS to its receptor CD14 at cell surface triggers its association with transmembrane protein toll-like receptor (TLR), mainly TLR2 and TLR4.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c41 : 1
stoichiometry:c42 : 1
stoichiometry:c43 : 1
m31*m33*0.1
nodelay
--
0
PMID: 15331118 The binding of LPS to its receptor CD14 at cell surface triggers its association with transmembrane protein toll-like receptor (TLR), mainly TLR2 and TLR4.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c44 : 1
stoichiometry:c45 : 1
stoichiometry:c128 : 1
m31*m35*0.1
nodelay
--
0
PMID: 15331118 The binding of LPS to its receptor CD14 at cell surface triggers its association with transmembrane protein toll-like receptor (TLR), mainly TLR2 and TLR4.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c46 : 1
stoichiometry:c47 : 1
stoichiometry:c48 : 1
m34*m37*0.1
nodelay
--
0
PMID: 15331118 MyD88, a cytoplasmic adaptor protein, responds to CD14/TLR stimulation by recruiting IRAK.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c49 : 1
stoichiometry:c50 : 1
stoichiometry:c51 : 1
m36*m37*0.1
nodelay
--
0
PMID: 15331118 MyD88, a cytoplasmic adaptor protein, responds to CD14/TLR stimulation by recruiting IRAK.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c52 : 1
stoichiometry:c53 : 1
stoichiometry:c54 : 1
m32*m39*0.1
nodelay
--
0
PMID: 15331118 MyD88, a cytoplasmic adaptor protein, responds to CD14/TLR stimulation by recruiting IRAK.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c55 : 1
stoichiometry:c56 : 1
stoichiometry:c57 : 1
m38*m39*0.1
nodelay
--
0
PMID: 15331118 MyD88, a cytoplasmic adaptor protein, responds to CD14/TLR stimulation by recruiting IRAK.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c5 : 1
stoichiometry:c6 : 1
stoichiometry:c7 : 1
m11*m14*0.1
nodelay
--
0
PMID: 15331118 Activation of T cells is initiated by engagement of the T cell receptor (TCR) with peptide antigen presented by the major histocompatibility complex (MHC) on antigen-presenting cells (APC) or anti-receptor antibodies.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c58 : 1
stoichiometry:c59 : 1
m40*0.1
nodelay
--
0
PMID: 15331118 MyD88, a cytoplasmic adaptor protein, responds to CD14/TLR stimulation by recruiting IRAK which leads to IRAK activation.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c60 : 1
stoichiometry:c62 : 1
stoichiometry:c61 : 1
m43*m42*0.1
nodelay
--
0
PMID: 15331118 TRAF6 is phosphorylated and recruited to IRAK.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c63 : 1
stoichiometry:c64 : 1
stoichiometry:c65 : 1
m44*m42*0.1
nodelay
--
0
PMID: 15331118 TRAF6 is phosphorylated and recruited to IRAK.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c66 : 1
stoichiometry:c67 : 1
m41*0.1
nodelay
--
0
PMID: 15331118 MyD88, a cytoplasmic adaptor protein, responds to CD14/TLR stimulation by recruiting IRAK which leads to IRAK activation.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c68 : 1
stoichiometry:c70 : 1
stoichiometry:c69 : 1
m43*m46*0.1
nodelay
--
0
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c71 : 1
stoichiometry:c72 : 1
stoichiometry:c73 : 1
m44*m46*0.1
nodelay
--
0
PMID: 15331118 TRAF6 is phosphorylated and recruited to IRAK.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c74 : 1
stoichiometry:c78 : 1
stoichiometry:c75 : 1
m48*m71*0.1
nodelay
--
0
PMID: 15331118 Several tentative molecules have been suggested to relay the signal to IKK complex downstream of TRAF6. NF-¦ÊB-inducing kinase (NIK) is one of these molecules.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c76 : 1
stoichiometry:c79 : 1
stoichiometry:c77 : 1
m70*m45*0.1
nodelay
--
0
PMID: 15331118 Several tentative molecules have been suggested to relay the signal to IKK complex downstream of TRAF6. NF-¦ÊB-inducing kinase (NIK) is one of these molecules.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c80 : 1
stoichiometry:c82 : 1
stoichiometry:c81 : 1
m63*m49*0.1
nodelay
--
0
PMID: 15331118 IKK is a major kinase responsible for the phosphorylation of I¦ÊB.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c83 : 1
stoichiometry:c84 : 1
stoichiometry:c85 : 1
m64*0.1
nodelay
--
0
PMID: 15331118 Phosphorylated I¦ÊB is eventually degraded, leaving the NF-¦ÊB dimer free and translocate to nucleus
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c8 : 1
stoichiometry:c11 : 1
stoichiometry:c9 : 1
m16*m15*0.1
nodelay
--
0
PMID: 15331118 Occupancy of the TCR triggers activation of Src family protein tyrosine kinases Fyn and Lck.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c86 : 1
stoichiometry:c87 : 1
m66*0.1
nodelay
--
0
PMID: 15331118 Phosphorylated I¦ÊB is eventually degraded, leaving the NF-¦ÊB dimer free and translocate to nucleus
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c88 : 1
stoichiometry:c89 : 1
stoichiometry:c90 : 1
m67*m68*0.1
nodelay
--
0
PMID: 15331118 NF-¦ÊB binds to the promoter region of COX-2 gene
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c91 : 1
stoichiometry:c93 : 1
stoichiometry:c92 : 1
m70*m47*0.1
nodelay
--
0
PMID: 15331118 Several tentative molecules have been suggested to relay the signal to IKK complex downstream of TRAF6. NF-¦ÊB-inducing kinase (NIK) is one of these molecules.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c94 : 1
stoichiometry:c95 : 1
m69*0.1
nodelay
--
0
PMID: 15331118 NF-¦ÊB binds to the promoter region of COX-2 gene and initiates the transcription.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c96 : 1
stoichiometry:c97 : 1
m72*0.1
nodelay
--
0
PMID: 15331118 The resulting mRNA of COX-2 encodes synthesis of COX-2 enzyme.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c98 : 1
stoichiometry:c99 : 1
stoichiometry:c100 : 1
m73*m74*0.1
nodelay
--
0
PMID: 15331118 COX-2 catalyzes metabolism of AA to PGH2 which is further isomerized to PGE2.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c101 : 1
stoichiometry:c102 : 1
m75*0.1
nodelay
--
0
PMID: 15331118 COX-2 catalyzes metabolism of AA to PGH2 which is further isomerized to PGE2
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c103 : 1
stoichiometry:c105 : 1
stoichiometry:c104 : 1
m77*m79*0.1
nodelay
--
0
PMID: 15331118 Ceramide is a sphingolipid second messenger generated from the hydrolysis of membrane sphingomyelin under the action of sphingomyelinase (SMase).
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c106 : 1
stoichiometry:c109 : 1
stoichiometry:c107 : 1
m80*m36*0.1
nodelay
--
0
PMID: 15331118 Mitogen-activated protein kinase (MAPK) intermediates such as extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinases (JNK), and p38 are involved in LPS- as well as ceramide-induced COX-2 gene expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c110 : 1
stoichiometry:c111 : 1
m81*0.1
nodelay
--
0
PMID: 15331118 Mitogen-activated protein kinase (MAPK) intermediates such as extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinases (JNK), and p38 are involved in LPS- as well as ceramide-induced COX-2 gene expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c12 : 1
stoichiometry:c15 : 1
stoichiometry:c13 : 1
m18*m13*0.1
nodelay
--
0
PMID: 15331118 Occupancy of the TCR triggers activation of Src family protein tyrosine kinases Fyn and Lck.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c112 : 1
stoichiometry:c116 : 1
stoichiometry:c113 : 1
m82*m34*0.1
nodelay
--
0
PMID: 15331118 Mitogen-activated protein kinase (MAPK) intermediates such as extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinases (JNK), and p38 are involved in LPS- as well as ceramide-induced COX-2 gene expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c114 : 1
stoichiometry:c115 : 1
m83*0.1
nodelay
--
0
PMID: 15331118 Mitogen-activated protein kinase (MAPK) intermediates such as extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinases (JNK), and p38 are involved in LPS- as well as ceramide-induced COX-2 gene expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c118 : 1
stoichiometry:c120 : 1
stoichiometry:c119 : 1
m84*m34*0.1
nodelay
--
0
PMID: 15331118 Mitogen-activated protein kinase (MAPK) intermediates such as extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinases (JNK), and p38 are involved in LPS- as well as ceramide-induced COX-2 gene expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c122 : 1
stoichiometry:c123 : 1
m85*0.1
nodelay
--
0
PMID: 15331118 Mitogen-activated protein kinase (MAPK) intermediates such as extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinases (JNK), and p38 are involved in LPS- as well as ceramide-induced COX-2 gene expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c124 : 1
stoichiometry:c125 : 1
m78*0.1
nodelay
--
0
PMID: 15331118 ceramide stimulates by itself and also potentiates LPS-induced PGE2 production and COX-2 expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c129 : 1
stoichiometry:c131 : 1
stoichiometry:c130 : 1
m63*m78*0.1
nodelay
--
0
PMID: 15331118 Ceramide alone was a weak inducer of NF-¦ÊB activation.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c126 : 1
stoichiometry:c133 : 1
stoichiometry:c132 : 1
m84*m36*0.1
nodelay
--
0
PMID: 15331118 Mitogen-activated protein kinase (MAPK) intermediates such as extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinases (JNK), and p38 are involved in LPS- as well as ceramide-induced COX-2 gene expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c121 : 1
stoichiometry:c135 : 1
stoichiometry:c134 : 1
m80*m34*0.1
nodelay
--
0
PMID: 15331118 Mitogen-activated protein kinase (MAPK) intermediates such as extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinases (JNK), and p38 are involved in LPS- as well as ceramide-induced COX-2 gene expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c108 : 1
stoichiometry:c137 : 1
stoichiometry:c136 : 1
m82*m36*0.1
nodelay
--
0
PMID: 15331118 Mitogen-activated protein kinase (MAPK) intermediates such as extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinases (JNK), and p38 are involved in LPS- as well as ceramide-induced COX-2 gene expression.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c117 : 1
stoichiometry:c139 : 1
stoichiometry:c138 : 1
m16*m13*0.1
nodelay
--
0
PMID: 15331118 Occupancy of the TCR triggers activation of Src family protein tyrosine kinases Fyn and Lck.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c16 : 1
stoichiometry:c18 : 1
stoichiometry:c17 : 1
m20*m17*0.1
nodelay
--
0
PMID: 15331118 Occupancy of the TCR triggers activation of Src family protein tyrosine kinases Fyn and Lck, which mediate the phosphorylation of immunoreceptor tyrosine-based activation motifs on CD3-¦Æ.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c10 : 1
stoichiometry:c14 : 1
stoichiometry:c140 : 1
m15*m18*0.1
nodelay
--
0
PMID: 15331118 Occupancy of the TCR triggers activation of Src family protein tyrosine kinases Fyn and Lck.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c19 : 1
stoichiometry:c20 : 1
stoichiometry:c21 : 1
m19*m20*0.1
nodelay
--
0
PMID: 15331118 Occupancy of the TCR triggers activation of Src family protein tyrosine kinases Fyn and Lck, which mediate the phosphorylation of immunoreceptor tyrosine-based activation motifs on CD3-¦Æ.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c23 : 1
stoichiometry:c141 : 1
stoichiometry:c24 : 1
m22*m21*0.1
nodelay
--
0
PMID: 15331118 Occupancy of the TCR triggers activation of Src family protein tyrosine kinases Fyn and Lck, which mediate the phosphorylation of immunoreceptor tyrosine-based activation motifs on CD3-¦Æ. This leads to the recruitment and activation of ZAP-70.
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
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1,
--
cso30:c:InputAssociation
threshold
--
0
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--
cso30:c:InputAssociation
threshold
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cso30:c:InputAssociation
threshold
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cso30:c:OutputProcess
threshold
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--
cso30:c:InputProcess
threshold
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--
cso30:c:InputAssociation
threshold
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cso30:c:OutputProcess
threshold
--
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--
cso30:c:InputAssociation
threshold
--
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cso30:c:InputProcess
threshold
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--
cso30:c:InputAssociation
threshold
--
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--
cso30:c:InputProcess
threshold
--
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--
cso30:c:InputAssociation
threshold
--
0
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--
cso30:c:OutputProcess
threshold
--
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cso30:c:InputAssociation
threshold
--
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--
cso30:c:OutputProcess
threshold
--
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cso30:c:InputProcess
threshold
--
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--
cso30:c:OutputProcess
threshold
--
0
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--
cso30:c:InputAssociation
threshold
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--
cso30:c:OutputProcess
threshold
--
0
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--
cso30:c:InputAssociation
threshold
--
0
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--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
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--
cso30:c:InputAssociation
threshold
--
0
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--
cso30:c:OutputProcess
threshold
--
0
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--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
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--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
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--
cso30:c:InputProcess
threshold
--
0
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--
cso30:c:OutputProcess
threshold
--
0
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--
cso30:c:OutputProcess
threshold
--
0
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--
cso30:c:InputProcess
threshold
--
0
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--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
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--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:InputProcess
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--
cso30:c:OutputProcess
threshold
--
0
1,
--
cso30:c:InputAssociation
threshold
--
0
1,
--