post-perfusion

SD4 (Supplementary Data 4). IPA analysis of the differentially expressed targets in relation to perfusion state (post-perfusion samples vs. pre-perfusion samples, S4 Table 1- S4 Table 4). Pathway analysis of differentially expressed targets in relation to perfusion-driven IGF (S4 Table 5- S4 Table 7) and perfusion-driven DGF signature (S4 Table 8- S4 Table 10).

S4 Table 1. The list of the canonical pathways associated with reperfusion injury. S4 Table 2. The complete list of upstream regulators involved in reperfusion injury. S4 Table 3. The top networks associated with reperfusion injury. S4 Table 4. The top regulator effector network associated with reperfusion injury. S4 Table 5. The list of the canonical pathways associated with IGF pre-perfusion vs post-perfusion. S4 Table 6. The complete list of upstream regulators involved in IGF pre-perfusion vs post-perfusion. S4 Table 7. The top networks associated with IGF pre-perfusion vs post-perfusion. S4 Table 8. The list of the canonical pathways associated with DGF pre-perfusion vs post-perfusion. S4 Table 9. The complete list of upstream regulators involved in DGF pre-perfusion vs post-perfusion. S4 Table 10. The top networks associated with DGF pre-perfusion vs post-perfusion.

Canonical Pathways EIF2 Signaling Protein Ubiquitination Pathway Regulation of eIF4 and p70S6K Signaling Differential Regulation of Cytokine Production in Intestinal Epithelial Cells by IL-17A and IL-17F Differential Regulation of Cytokine Production in Macrophages and T Helper Cells by IL-17A and IL17F mTOR Signaling Aldosterone Signaling in Epithelial Cells IL-17A Signaling in Fibroblasts Glucocorticoid Receptor Signaling Granulocyte Adhesion and Diapedesis Polyamine Regulation in Colon Cancer IL-10 Signaling Role of Osteoblasts, Osteoclasts and Chondrocytes in Rheumatoid Arthritis Dolichyl-diphosphooligosaccharide Biosynthesis Complement System IL-6 Signaling Hepatic Fibrosis / Hepatic Stellate Cell Activation BMP signaling pathway Adipogenesis pathway p53 Signaling PPAR Signaling Molecular Mechanisms of Cancer B Cell Activating Factor Signaling Agranulocyte Adhesion and Diapedesis Role of Oct4 in Mammalian Embryonic Stem Cell Pluripotency April Mediated Signaling Sertoli Cell-Sertoli Cell Junction Signaling IL-17A Signaling in Gastric Cells

-log(p-value) 2.39E01 5.49E00 4.81E00 4.78E00

Ratio

z-score

4.51E-01 2.47E-01 2.74E-01 5.22E-01

-6.351 NaN -1.134 NaN

4.38E00 4.14E00 4.02E00 3.87E00 3.85E00 3.78E00 3.44E00 3.13E00 3.05E00 3.03E00 2.99E00 2.96E00 2.88E00 2.87E00 2.84E00 2.76E00 2.75E00 2.66E00 2.64E00 2.61E00 2.5E00 2.36E00 2.33E00 2.3E00

5.56E-01 2.46E-01 2.57E-01 4E-01 2.22E-01 2.43E-01 4.55E-01 2.94E-01 2.19E-01 6E-01 3.51E-01 2.5E-01 2.24E-01 2.76E-01 2.39E-01 2.55E-01 2.58E-01 1.95E-01 3.25E-01 2.17E-01 3.04E-01 3.16E-01 2.13E-01 3.6E-01

NaN 0.832 0.577 NaN NaN NaN NaN NaN NaN NaN -0.707 1.890 NaN -1.342 NaN 0.535 -2.294 NaN 0.632 NaN -1.000 0.577 NaN NaN

Toll-like Receptor Signaling Unfolded protein response Wnt/β-catenin Signaling Hypoxia Signaling in the Cardiovascular System Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid Arthritis Dendritic Cell Maturation HMGB1 Signaling Actin Nucleation by ARP-WASP Complex ILK Signaling Phosphatidylcholine Biosynthesis I CD27 Signaling in Lymphocytes GNRH Signaling Circadian Rhythm Signaling Role of Hypercytokinemia/hyperchemokinemia in the Pathogenesis of Influenza IL-1 Signaling TREM1 Signaling Hepatic Cholestasis TNFR2 Signaling Role of IL-17F in Allergic Inflammatory Airway Diseases Airway Pathology in Chronic Obstructive Pulmonary Disease Mitotic Roles of Polo-Like Kinase Role of PKR in Interferon Induction and Antiviral Response Putrescine Biosynthesis III Formaldehyde Oxidation II (Glutathione-dependent) Communication between Innate and Adaptive Immune Cells PPARα/RXRα Activation Atherosclerosis Signaling 4-1BB Signaling in T Lymphocytes Signaling by Rho Family GTPases Pathogenesis of Multiple Sclerosis

2.26E00 2.23E00 2.23E00 2.17E00 2.16E00 2.14E00 2.12E00 2.07E00 2.05E00 2.03E00 1.99E00 1.96E00 1.92E00 1.9E00 1.89E00 1.86E00 1.84E00 1.84E00 1.82E00 1.78E00 1.75E00 1.73E00 1.71E00 1.71E00 1.7E00 1.69E00 1.68E00 1.65E00 1.63E00 1.57E00

2.57E-01 2.78E-01 2.13E-01 2.62E-01 1.93E-01 2.09E-01 2.25E-01 2.68E-01 2.05E-01 5.71E-01 2.69E-01 2.17E-01 3.03E-01 2.79E-01 2.31E-01 2.4E-01 2.05E-01 3.1E-01 2.73E-01 5E-01 2.42E-01 2.75E-01 1E00 1E00 2.25E-01 1.98E-01 2.1E-01 2.9E-01 1.88E-01 4.44E-01

1.155 NaN 0.626 1.890 NaN 1.372 2.746 -1.604 2.000 NaN 0.905 0.756 NaN NaN 1.606 3.300 NaN 2.646 2.714 NaN -1.265 NaN NaN NaN NaN -0.378 NaN 1.134 -0.156 NaN

HIPPO signaling Colorectal Cancer Metastasis Signaling Acute Phase Response Signaling HGF Signaling CD40 Signaling Role of Cytokines in Mediating Communication between Immune Cells Role of IL-17A in Arthritis RANK Signaling in Osteoclasts RAR Activation TNFR1 Signaling DNA Double-Strand Break Repair by Non-Homologous End Joining Mouse Embryonic Stem Cell Pluripotency Cholecystokinin/Gastrin-mediated Signaling Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses GADD45 Signaling IL-9 Signaling NRF2-mediated Oxidative Stress Response Ephrin Receptor Signaling Wnt/Ca+ pathway fMLP Signaling in Neutrophils LPS-stimulated MAPK Signaling STAT3 Pathway Oxidative Phosphorylation Coagulation System Cell Cycle Regulation by BTG Family Proteins Aryl Hydrocarbon Receptor Signaling Factors Promoting Cardiogenesis in Vertebrates Rac Signaling

1.57E00 1.57E00 1.55E00 1.49E00 1.49E00 1.49E00 1.49E00 1.47E00 1.47E00 1.46E00 1.45E00 1.42E00 1.42E00 1.41E00 1.4E00 1.4E00 1.4E00 1.39E00 1.37E00 1.37E00 1.37E00 1.37E00 1.33E00 1.33E00 1.33E00 1.3E00 1.3E00 1.3E00

2.21E-01 1.86E-01 1.95E-01 2.1E-01 2.31E-01 2.41E-01 2.41E-01 2.16E-01 1.89E-01 2.45E-01 3.57E-01 2.11E-01 2.08E-01 2E-01 3.16E-01 2.65E-01 1.89E-01 1.9E-01 2.32E-01 2.04E-01 2.19E-01 2.19E-01 2.02E-01 2.57E-01 2.57E-01 1.93E-01 2.07E-01 2.02E-01

1.897 1.406 1.347 -0.688 0.000 NaN NaN 0.000 NaN 2.111 NaN 1.342 2.400 1.414 NaN 0.378 1.000 -0.229 2.309 -0.447 1.000 -1.500 NaN -0.333 1.342 -0.816 NaN -1.528

S4Table2. The complete list of activated and inhibited upstream regulators associated with reperfusion injury.

Upstream Regulator Activated PDGF BB TNF NFkB (complex) Salmonella enterica serotype abortus equi lipopolysaccharide lipopolysaccharide IL1B RICTOR camptothecin poly rI:rC-RNA E. coli B5 lipopolysaccharide NUPR1 TLR3 CREB1 TLR7 thapsigargin MYD88 CD 437 TREM1 salmonella minnesota R595 lipopolysaccharides RAF1

Molecule Type

Activation zscore

p-value of overlap

Mechanistic network

complex cytokine complex

7.94 7.877 7.565

2.69E-30 733 (16) 1.83E-25 847 (16) 1.90E-12 727 (13)

chemical toxicant chemical drug cytokine other chemical drug biologic drug chemical - endogenous nonmammalian transcription regulator transmembrane receptor transcription regulator transmembrane receptor chemical toxicant other chemical drug transmembrane receptor chemical - endogenous nonmammalian kinase

7.53 7.424 7.303 6.862 6.644 6.134

2.32E-16 1.04E-17 2.64E-20 3.01E-15 6.34E-13 2.39E-12

651 (18) 690 (14) 612 (13) 897 (21) 615 (13) 599 (13)

6.12 6.102 6.087 5.968 5.834 5.757 5.741 5.703 5.662

1.02E-10 7.01E-08 1.68E-07 4.21E-14 1.64E-05 1.53E-07 7.27E-10 1.11E-14 2.52E-14

573 (13) 615 (7) 434 (14) 680 (21) 415 (12) 633 (21) 594 (14) 674 (17) 576 (15)

5.644 5.621

6.71E-12 660 (14) 2.98E-08 631 (19)

ionomycin TLR2 leukotriene D4 IFNG TLR4 Ca2+ ST1926 HGF P38 MAPK TICAM1 peptidoglycan TLR9 phorbol myristate acetate IL1 ERBB2 gentamicin F2 A23187 cigarette smoke Vegf dalfampridine cyclic AMP tributyrin RELA 5-O-mycolyl-beta-araf-(1->2)-5-O-mycolylalpha-araf-(1->1')-glycerol Tlr ERK IL1A

chemical reagent transmembrane receptor chemical - endogenous mammalian cytokine transmembrane receptor chemical - endogenous mammalian chemical drug growth factor group other chemical - endogenous nonmammalian transmembrane receptor chemical drug group kinase chemical drug peptidase chemical reagent chemical toxicant group chemical drug chemical - endogenous mammalian chemical drug transcription regulator chemical - endogenous nonmammalian group group cytokine

5.614 5.575 5.571 5.539 5.483 5.454 5.43 5.359 5.342 5.297

3.91E-05 2.13E-05 1.64E-22 1.38E-14 2.05E-07 1.88E-08 1.77E-14 2.94E-09 4.42E-11 8.58E-10

734 (17) 542 (13) 547 (18) 577 (12) 600 (14) 647 (18)

5.095 5.048 5.025 5.013 4.988 4.957 4.954 4.929 4.883 4.854 4.796 4.756 4.686 4.677

5.05E-06 2.83E-06 9.29E-10 4.90E-04 2.13E-10 6.08E-07 6.50E-08 2.22E-05 2.43E-06 3.56E-07 5.13E-14 2.50E-05 7.28E-08 5.99E-11

355 (11) 522 (13) 852 (17) 670 (14) 760 (17) 611 (18) 673 (15) 611 (17) 711 (19) 490 (15) 558 (18) 683 (19) 821 (24) 749 (14)

4.667 4.65 4.632 4.63

3.39E-11 6.62E-06 5.30E-13 1.46E-05

532 (11) 527 (15) 545 (15) 582 (13)

702 (18) 547 (14) 412 (14)

CSF2 IL6 resiquimod bicuculline trovafloxacin STAT4 ERK1/2 etoposide oblimersen forskolin IL2 hydrogen peroxide SAMSN1 E. coli lipopolysaccharide MAPK14 CpG ODN 1668 kainic acid cocaine EGFR EGF CTNNB1 FGF2 SASH1 GnRH-A IL17A NRG1 Ras Pam3-Cys-Ser-Lys4

cytokine cytokine chemical drug chemical - endogenous nonmammalian chemical drug transcription regulator group chemical drug biologic drug chemical toxicant cytokine chemical - endogenous mammalian other chemical - endogenous nonmammalian kinase chemical reagent chemical toxicant chemical drug kinase growth factor transcription regulator growth factor other chemical reagent cytokine other group chemical reagent

4.624 4.592 4.567

4.65E-15 637 (16) 2.10E-07 648 (15) 7.29E-10 416 (13)

4.546 4.536 4.533 4.528 4.512 4.461 4.441 4.433 4.424 4.379

2.43E-13 1.08E-08 1.66E-11 2.16E-08 1.60E-06 9.25E-06 2.69E-13 2.40E-07 4.22E-09 1.47E-03

674 (23) 565 (12) 610 (14) 801 (17) 697 (15)

4.369 4.324 4.249 4.238 4.219 4.196 4.174 4.158 4.13 4.123 4.117 4.108 4.089 4.089 4.068

3.40E-08 5.29E-04 1.27E-05 9.70E-10 5.23E-05 6.40E-10 1.66E-12 5.02E-05 3.15E-09 1.02E-02 1.43E-15 5.29E-09 2.93E-09 2.43E-06 8.18E-07

375 (12) 447 (17) 384 (15) 625 (21) 572 (18) 699 (16) 711 (15) 759 (20) 715 (18)

627 (18) 569 (13) 719 (16) 470 (12)

581 (18) 588 (13) 581 (15) 688 (19) 396 (13)

5-fluorouracil PTPRJ Cg enterotoxin B fatty acid FOXL2 TNFSF11 TCR HIF1A methyl methanesulfonate CCL5 ECSIT PRKCE 5-azacytidine L-dopa DOCK8 deferoxamine PAF1 TNFRSF1A E. coli B4 lipopolysaccharide IGF1 imiquimod CREM IL5 carrageenan Fcer1 NFATC2 mycophenolic acid KITLG

chemical drug phosphatase complex biologic drug chemical - endogenous mammalian transcription regulator cytokine complex transcription regulator chemical toxicant cytokine transcription regulator kinase chemical drug chemical - endogenous mammalian other chemical drug other transmembrane receptor chemical toxicant growth factor chemical drug transcription regulator cytokine chemical - endogenous nonmammalian complex transcription regulator chemical drug growth factor

4.028 4.025 4.006 4 3.968 3.96 3.952 3.939 3.93 3.921 3.92 3.899 3.896 3.892 3.88 3.873 3.871 3.86 3.858 3.833 3.821 3.797 3.783 3.769

9.77E-18 1.07E-06 1.73E-06 4.44E-03 1.72E-03 3.31E-10 9.54E-09 2.92E-08 4.58E-10 1.58E-05 1.08E-08 2.69E-08 9.91E-05 2.32E-05 4.15E-03 3.48E-02 1.58E-08 7.66E-04 4.10E-04 4.99E-03 1.88E-07 5.72E-05 1.19E-07 6.35E-09

866 (22) 691 (21) 739 (18) 576 (12) 620 (17) 431 (8) 638 (16) 639 (14) 519 (16) 599 (15) 553 (16) 344 (12) 573 (18) 765 (21) 656 (17)

3.763 3.763 3.755 3.752 3.746

3.64E-09 9.94E-09 6.18E-05 5.40E-08 1.10E-05

558 (14) 678 (18) 759 (18) 487 (17) 443 (15)

480 (14) 512 (11) 461 (16) 906 (22) 408 (15) 600 (18) 755 (17)

Jnk IL12 (complex) palmitic acid PGR Ap1 MAP2K1/2 CAMP F2RL1 TAC1 doxorubicin HMGB1 Map3k7 IFN Beta MAP2K3 BMP2 reactive oxygen species F7 IL7 bee venom TRAF6 Pkc(s) MAPK8 IL17a dimer Gm-csf CD40 anisomycin MALP-2s Mapk

group complex chemical - endogenous mammalian ligand-dependent nuclear receptor complex group other g-protein coupled receptor other chemical drug transcription regulator kinase group kinase growth factor chemical toxicant peptidase cytokine chemical - endogenous nonmammalian enzyme group kinase complex group transmembrane receptor chemical - endogenous nonmammalian chemical reagent group

3.743 3.74 3.718 3.699 3.67 3.669 3.659 3.649 3.638 3.632 3.63 3.629 3.625 3.624 3.618 3.617 3.61 3.605

3.42E-10 2.54E-04 9.90E-05 2.49E-06 1.28E-05 4.99E-08 1.11E-07 4.77E-05 5.21E-03 1.14E-06 1.08E-04 3.13E-05 1.17E-04 4.60E-04 3.94E-05 3.29E-03 9.04E-08 1.37E-04

654 (17) 455 (14) 560 (14) 831 (19) 616 (15) 600 (18) 393 (15) 465 (20) 464 (18) 702 (16) 398 (16) 424 (16) 508 (13) 585 (16) 772 (19) 535 (14) 420 (17) 579 (14)

3.593 3.588 3.554 3.554 3.548 3.536 3.53

3.40E-16 1.02E-03 8.65E-10 4.18E-06 1.19E-06 2.25E-07 3.22E-07

672 (16) 344 (14) 632 (18) 777 (17) 426 (7) 597 (18) 549 (14)

3.511 3.493 3.492

2.30E-06 441 (15) 7.34E-06 372 (14) 6.05E-05 609 (19)

mitomycin C tunicamycin NfkB-RelA AGT L-glutamic acid bucladesine Tnf (family) NOD2 TBK1 CpG oligonucleotide PF4 TLR5 CHUK Pka IRF6 TGFA H2AFB3 (includes others) TRADD PPRC1 BMP6 clozapine ELK1 IL18 potassium chloride NFKBIA F2R AKT1 Ni2+ di(2-ethylhexyl) phthalate

chemical drug chemical - endogenous nonmammalian complex growth factor chemical - endogenous mammalian chemical toxicant group other kinase chemical drug cytokine transmembrane receptor kinase complex transcription regulator growth factor other other transcription regulator growth factor chemical drug transcription regulator cytokine chemical drug transcription regulator g-protein coupled receptor kinase chemical reagent chemical toxicant

3.472

4.06E-06 575 (16)

3.462 3.45 3.446 3.446 3.433 3.431 3.419 3.396 3.394 3.394 3.385 3.381 3.379 3.377 3.364 3.357 3.352 3.347 3.339 3.336 3.333 3.317 3.315 3.308 3.3 3.295 3.295 3.286

1.38E-03 9.45E-06 3.48E-07 7.51E-03 1.14E-08 1.33E-05 1.59E-08 3.04E-04 1.63E-06 1.66E-05 2.16E-03 4.35E-13 3.01E-06 3.38E-05 2.49E-04 1.94E-03 4.53E-07 4.55E-04 1.31E-02 1.92E-03 7.07E-06 2.03E-03 6.88E-09 6.76E-11 1.08E-04 3.88E-06 1.03E-04 1.16E-01

546 (14) 556 (13) 699 (23) 681 (19) 423 (15) 387 (14) 366 (14) 508 (15) 417 (17) 431 (15) 620 (11) 750 (22) 381 (14) 602 (17) 296 (7) 435 (15)

571 (13) 651 (19) 568 (14) 646 (20) 732 (15) 579 (15) 631 (17) 728 (14)

CD14 3M-001 paclitaxel CXCR4 EIF2AK2 NFKB1 AIMP1 RIPK2 Pam3-Cys ALB IKBKB uric acid okadaic acid RNASE2 hemozoin SYK TGM2 ozone bromodeoxyuridine IL3 MTOR PGF tretinoin carbonyl cyanide m-chlorophenyl hydrazone sphingosine-1-phosphate SELPLG leukotriene C4 haloperidol MET

transmembrane receptor chemical drug chemical drug g-protein coupled receptor kinase transcription regulator cytokine kinase chemical toxicant transporter kinase chemical - endogenous mammalian chemical toxicant enzyme chemical - endogenous nonmammalian kinase enzyme chemical toxicant chemical drug cytokine kinase growth factor chemical - endogenous mammalian chemical toxicant chemical - endogenous mammalian other chemical - endogenous mammalian chemical drug kinase

3.285 3.274 3.27 3.266 3.266 3.263 3.26 3.259 3.252 3.244 3.242 3.239 3.222 3.222

9.25E-06 6.86E-03 3.50E-12 2.31E-07 3.65E-07 5.13E-08 1.79E-07 7.38E-02 2.14E-04 2.58E-02 1.34E-08 9.08E-05 1.00E-07 5.46E-03

404 (16) 276 (7) 806 (16) 504 (16) 532 (13) 732 (13) 689 (23)

3.221 3.221 3.221 3.217 3.207 3.206 3.204 3.201 3.186 3.184 3.184 3.153 3.152 3.151 3.15


457 (14) 511 (19) 606 (21) 337 (12) 736 (17) 479 (16) 687 (20) 447 (16) 824 (18) 472 (16) 560 (18) 515 (16) 668 (17)

362 (12) 627 (12) 650 (14) 578 (18) 531 (17)

614 (17)

IL-17f dimer SRC cis-urocanic acid ICAM1 TMEM173 carbamylcholine AGER CAMK4 CLEC7A CpG ODN 1826 formaldehyde N-acetylsphingosine ASCL1 stallimycin MAPK7 methylnitronitrosoguanidine ESRRA EIF2AK3 methylprednisolone NOTCH1 dinoprost STAT1 ARHGAP21 ST3-Hel2A-2 amphetamine MIF 4-hydroxytamoxifen C3 LCN2 5-hydroxytryptamine

complex kinase chemical drug transmembrane receptor other chemical drug transmembrane receptor kinase transmembrane receptor chemical reagent chemical - endogenous mammalian chemical reagent transcription regulator biologic drug kinase chemical toxicant ligand-dependent nuclear receptor kinase chemical drug transcription regulator chemical - endogenous mammalian transcription regulator other chemical reagent chemical drug cytokine chemical drug peptidase transporter chemical - endogenous mammalian

3.138 3.136 3.127 3.124 3.124 3.095 3.092 3.084 3.07 3.069 3.069 3.061 3.06 3.059 3.058 3.057 3.053 3.045 3.033 3.023 3.018 3.01 3 2.999 2.996 2.992 2.987 2.986 2.971 2.969

1.32E-05 1.20E-03 2.34E-04 1.81E-03 5.46E-03 2.33E-02 2.61E-05 1.44E-03 5.51E-04 1.14E-05 1.12E-04 1.18E-03 2.85E-02 5.52E-03 3.47E-05 3.01E-03 4.23E-02 4.09E-03 2.25E-06 1.29E-06 2.49E-04 1.85E-08 1.08E-01 5.36E-07 1.56E-03 3.74E-04 1.12E-05 8.70E-03 6.88E-04 4.41E-06

800 (18) 323 (8) 473 (16) 577 (16) 565 (17) 597 (19) 444 (18) 576 (16) 522 (20) 518 (18) 585 (13) 454 (14) 669 (20) 727 (21) 725 (16) 536 (21) 585 (19) 643 (13) 352 (9) 655 (22) 532 (16) 671 (19) 476 (19) 463 (19) 528 (19)

EGR1 phorbol esters VEGFA HSPD1 ATF4 IL12 (family) RET SB 216763 vitamin K3 IL17C NfkB1-RelA JAK2 PRKCD D-galactosamine S-(2,3-bispalmitoyloxypropyl)-cysteineGDPKHPKSF cytarabine IL21 lysophosphatidic acid LCK TLR8 MAPK3 25-hydroxycholesterol MAVS trichostatin A HNF1B 10E,12Z-octadecadienoic acid PI3K (complex) GCG S100A9

transcription regulator chemical - other growth factor enzyme transcription regulator group kinase chemical toxicant chemical drug cytokine complex kinase kinase chemical - endogenous mammalian

2.957 2.957 2.949 2.949 2.945 2.944 2.942 2.935 2.934 2.929 2.929 2.927 2.925 2.922

1.26E-09 7.41E-05 2.18E-07 1.66E-05 1.60E-04 1.83E-02 1.85E-06 2.69E-11 6.20E-03 3.01E-03 4.68E-03 1.24E-02 1.40E-07 3.38E-05

882 (18) 499 (17) 477 (16) 428 (16) 639 (20)

chemical reagent chemical drug cytokine chemical - other kinase transmembrane receptor kinase chemical reagent other chemical drug transcription regulator chemical - endogenous mammalian complex other other

2.921 2.919 2.916 2.913 2.912 2.912 2.902 2.892 2.888 2.886 2.884 2.881 2.879 2.878 2.867


444 (16)

676 (17) 558 (17) 716 (20) 648 (16) 351 (4) 498 (14) 476 (14)

688 (16) 444 (16)

504 (18) 651 (21) 830 (19) 378 (8) 480 (19) 742 (18) 719 (21) 555 (20)

RHO 3-deazaneplanocin STAT3 E. coli serotype 0127B8 lipopolysaccharide aldosterone N-acetylmuramyl-L-alanyl-D-isoglutamine NEDD9 lysophosphatidylcholine tosedostat IL17F ATF2 DPP-23 S100A8 lipoteichoic acid GC-GCR dimer TSH Pdgf Ab CHRM1 SRC (family) SN-38 3M-011 MAP3K14 BMP15 C5AR1 PTH SELP EDN1

g-protein coupled receptor chemical drug transcription regulator chemical - endogenous nonmammalian chemical - endogenous mammalian chemical - endogenous nonmammalian other chemical - other chemical drug cytokine transcription regulator chemical reagent other chemical - endogenous nonmammalian complex complex complex g-protein coupled receptor group chemical drug chemical reagent kinase growth factor g-protein coupled receptor other transmembrane receptor cytokine

2.84 2.839 2.831

6.21E-03 2.53E-02 3.32E-07 662 (15)

2.831 2.83

1.11E-03 666 (15) 9.32E-08 658 (21)

2.829 2.828 2.828 2.828 2.82 2.817 2.813 2.812

3.56E-05 1.28E-07 1.02E-04 3.75E-02 5.35E-04 1.36E-04 1.84E-03 9.88E-05

448 (15) 545 (17) 532 (16)

2.81 2.804 2.798 2.797 2.791 2.791 2.791 2.791 2.788 2.786 2.785 2.784 2.782 2.778

9.34E-07 4.52E-04 1.94E-03 1.20E-03 2.85E-05 2.58E-02 3.52E-02 6.24E-02 4.71E-03 5.38E-03 9.11E-04 3.42E-08 2.86E-07 1.93E-04

450 (14)

596 (15) 579 (15) 439 (12)

806 (21) 520 (18) 615 (19)

518 (12) 473 (12) 571 (13) 555 (18) 627 (15) 548 (14)

IL24 APP CP-55940 decitabine silicon dioxide IL15 zymosan OSM EPO BCR (complex) EPAS1 MAP3K8 TGFB1 CRH KRT17 Fibrinogen norepinephrine GH1 C5 carboplatin vinblastine DDX58 LIF TNFSF13B phorbol 12,13-dibutyrate S-nitroso-N-acetylpenicillamine SAA galactosylceramide-alpha

cytokine other chemical reagent chemical drug chemical drug cytokine chemical - endogenous nonmammalian cytokine cytokine complex transcription regulator kinase growth factor cytokine other complex chemical - endogenous mammalian growth factor cytokine chemical drug chemical drug enzyme cytokine cytokine chemical - endogenous nonmammalian chemical reagent group chemical reagent

2.778 2.774 2.772 2.759 2.756 2.753

2.78E-03 1.21E-07 2.14E-04 3.69E-08 4.52E-04 9.75E-12

589 (14) 825 (18) 698 (20) 848 (22) 707 (19) 626 (14)

2.753 2.751 2.749 2.746 2.734 2.723 2.719 2.719 2.714 2.71 2.708 2.699 2.688 2.688 2.682 2.678 2.667 2.658

2.31E-07 3.94E-06 5.83E-07 1.58E-03 4.42E-07 1.40E-04 4.35E-24 1.92E-03 1.06E-03 2.66E-06 4.51E-08 1.04E-03 6.07E-11 4.45E-03 2.04E-02 1.09E-02 1.47E-05 1.47E-04

407 (13) 624 (15) 671 (16) 549 (18) 800 (19) 568 (12) 932 (17) 546 (17)

2.648 2.641 2.637 2.632

1.06E-02 6.66E-03 677 (17) 2.33E-04 574 (16) 3.83E-02

483 (16) 631 (20) 740 (23) 721 (17) 298 (7)

578 (19) 555 (16)

STIM1 EPHB1 CXCL1 STAT PADI2 RNASE1 Lymphotoxin FN1 isoproterenol CXCL3 SMARCA4 IPMK PRKD1 CCL4 AHR Akt ssRNA40 IL31 PDX1 TLR6 MAP3K3 CEBPB monophosphoryl lipid A IRAK2 homocysteine THPO lauric acid EP300 Endothelin TRAF3IP2

ion channel kinase cytokine group enzyme enzyme complex enzyme chemical drug cytokine transcription regulator kinase kinase cytokine ligand-dependent nuclear receptor group chemical reagent other transcription regulator transmembrane receptor kinase transcription regulator chemical reagent kinase chemical - endogenous mammalian cytokine chemical - endogenous mammalian transcription regulator group other

2.63 2.621 2.621 2.621 2.621 2.621 2.619 2.618 2.614 2.607 2.605 2.596 2.596 2.595 2.594 2.593 2.586 2.586 2.585 2.583 2.581 2.577 2.576 2.572 2.571 2.565 2.563 2.556 2.556 2.552


765 (22) 448 (18) 722 (20) 388 (11) 281 (7) 503 (12) 714 (18) 532 (15) 613 (16) 790 (19)

520 (17) 783 (19) 688 (17) 574 (18) 589 (17) 780 (18) 519 (17) 754 (18) 497 (16) 370 (17) 535 (18) 471 (17) 865 (19) 657 (17)

PTPRC 8-bromo-cAMP FOXO1 IFI16 IL32 CD36 Hmgb1 PRKCA Nfat (family) LHX1 N-formyl-Met-Leu-Phe CXCL12 C5 ATP Pdgf (complex) cobalt chloride TRAF2 RHOA NRAS MAP2K4 AREG KLF6 BDNF blinatumomab IL26 CNB-001 KLK5 CARM1 GNRH hyaluronic acid

phosphatase chemical reagent transcription regulator transcription regulator cytokine transmembrane receptor transcription regulator kinase group transcription regulator chemical reagent cytokine other chemical - endogenous mammalian complex chemical reagent enzyme enzyme enzyme kinase growth factor transcription regulator growth factor biologic drug cytokine chemical reagent peptidase transcription regulator group chemical - endogenous mammalian

2.55 2.549 2.547 2.547 2.546 2.546 2.543 2.534 2.532 2.53 2.518 2.509 2.507 2.507 2.5 2.496 2.494 2.486 2.468 2.467 2.466 2.465 2.455 2.449 2.449 2.449 2.449 2.449 2.447 2.443


452 (19) 634 (18) 547 (13) 430 (16) 554 (20) 417 (15) 664 (18) 354 (13) 680 (14) 672 (17) 447 (15) 437 (16) 668 (18) 387 (17) 493 (17) 757 (18) 515 (16) 666 (21) 522 (14) 513 (7)

651 (13)

EREG quinolinic acid NR5A2 IGF1R Ccl2 STAT5B TLR1 lipoarabinomannan CSF2RA ELANE pCPT-cAMP FGFR1 IL22 Interferon alpha LILRA2 GIP ERVW-1 BMPR1A Gm21596/Hmgb1 FHIT Lh cyclopiazonic acid peroxynitrite asbestos IL6ST GRP MAPK10 BCL10

growth factor chemical - endogenous mammalian ligand-dependent nuclear receptor transmembrane receptor cytokine transcription regulator transmembrane receptor chemical - endogenous nonmammalian transmembrane receptor peptidase chemical - kinase inhibitor kinase cytokine group other other other kinase transcription regulator enzyme complex chemical - endogenous nonmammalian chemical toxicant chemical toxicant transmembrane receptor growth factor kinase transcription regulator

2.442 2.441 2.439 2.438 2.436 2.432 2.432

1.11E-04 1.18E-03 6.90E-03 4.14E-03 1.66E-04 4.12E-04 8.41E-03

855 (24) 690 (21) 777 (21) 837 (21) 584 (15) 552 (15) 329 (14)

2.429 2.429 2.428 2.428 2.426 2.426 2.425 2.425 2.425 2.425 2.425 2.424 2.423 2.416

9.45E-06 4.03E-03 3.53E-04 7.04E-04 2.14E-03 1.31E-02 2.93E-03 4.03E-03 1.32E-02 4.02E-02 2.33E-01 9.29E-03 1.99E-01 3.65E-07

573 (17) 562 (19) 641 (20) 747 (18) 471 (17)

2.416 2.415 2.412 2.412 2.41 2.409 2.409

1.32E-02 1.82E-02 3.17E-04 3.79E-02 1.04E-01 1.38E-03 549 (16) 1.74E-03 424 (15)

525 (14) 309 (7)

389 (17) 825 (20)

NOD1 ADCYAP1R1 SYK/ZAP STAT5A IL6R 4-hydroxynonenal USP7 poly dA-dT CD244 TNFSF15 FGF10 Am 580 NAMPT NR3C2 N-methyl-D-aspartate MTORC1 Pro-inflammatory Cytokine YAP1 MKNK1 mitoxantrone isopentenyl diphosphate Notch FOXC2 MAPK13 UHRF2 IRAK4 sirolimus CD40LG 4-methylnitrosoamino-1-(3-pyridinyl)-1butanone

other g-protein coupled receptor group transcription regulator transmembrane receptor chemical toxicant peptidase chemical reagent transmembrane receptor cytokine growth factor chemical toxicant cytokine ligand-dependent nuclear receptor chemical reagent complex group transcription regulator kinase chemical drug chemical - endogenous mammalian group transcription regulator kinase enzyme kinase chemical drug cytokine

2.404 2.4 2.4 2.398 2.397 2.396 2.395 2.392 2.39 2.382 2.377 2.376 2.373 2.372 2.362 2.359 2.359 2.358 2.353 2.353 2.352 2.342 2.335 2.333 2.333 2.32 2.312 2.303


chemical toxicant

2.303

1.63E-02

433 (17) 668 (21) 375 (17) 622 (18) 605 (17)

562 (19)

439 (10) 611 (18) 759 (18) 738 (22)

792 (23)

537 (18) 620 (19) 527 (17) 640 (19) 653 (14) 761 (18) 627 (15)

IL33 EZH2 RETN Mek colchicine 8-chlorophenylthio-adenosine 3',5'-cyclic monophosphate IRF5 CREBBP TBX5 MAPK1 MEF2C KNG1 ceruletide cyclophosphamide IL1R1 MAP3K1 HRAS JAK1 Smad2/3-Smad4 ponesimod TCF12 C1q manganese ZAP70 1,2-dimethylhydrazine D-sphingosine NFkB (family) MYT1 FAAH

cytokine transcription regulator other group chemical drug

2.3 2.296 2.295 2.294 2.292

1.39E-03 2.85E-06 1.09E-05 3.65E-08 2.40E-03

680 (15) 876 (26) 677 (19) 556 (18) 593 (19)

chemical - kinase inhibitor transcription regulator transcription regulator transcription regulator kinase transcription regulator other biologic drug chemical drug transmembrane receptor kinase enzyme kinase complex chemical drug transcription regulator complex chemical - endogenous mammalian kinase chemical toxicant chemical - endogenous mammalian group transcription regulator enzyme

2.291 2.291 2.288 2.286 2.284 2.281 2.278 2.267 2.266 2.258 2.257 2.249 2.238 2.236 2.236 2.236 2.236 2.236 2.236 2.236 2.236 2.236 2.236 2.236


787 (24) 534 (14) 706 (19) 494 (8) 646 (16) 328 (13) 676 (18) 563 (14) 409 (15) 580 (17) 790 (19) 202 (5) 324 (7) 696 (20) 644 (21)

dithiothreitol OGG1 domoic acid phorbol 12,13-didecanoate AVP ICOSLG/LOC102723996 quisqualic acid 8-hydroxyguanine ANKRD42 15-E2-isoketal modified phosphatidylethanolamine Ck2 FBXO42 Cd2+ STAT1/3/5 dimer NMDA Receptor Angiotensin II receptor type 1 SPHK2 CXCL2 ULBP1 11-dehydrocorticosterone FAT1 (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate p85 (pik3r) FGF19 idarubicin PCDH11Y FOXO4

chemical reagent enzyme chemical toxicant chemical toxicant other other chemical - endogenous nonmammalian chemical - endogenous mammalian transcription regulator

2.236 2.233 2.232 2.228 2.226 2.225

2.84E-01 2.18E-04 562 (14) 3.24E-03 535 (16) 5.35E-04 822 (22) 5.13E-02 8.84E-02

2.224 2.219 2.219

4.09E-05 739 (20) 2.18E-04 6.80E-04 301 (7)

chemical reagent complex other chemical toxicant complex complex group kinase cytokine transmembrane receptor chemical - endogenous mammalian other chemical - endogenous nonmammalian group growth factor chemical drug other transcription regulator

2.219 2.219 2.219 2.219 2.219 2.219 2.219 2.217 2.216 2.213 2.213 2.213

6.80E-04 3.24E-03 3.24E-03 6.27E-03 1.44E-02 6.42E-02 6.42E-02 6.27E-03 5.04E-07 1.62E-03 3.24E-03 3.24E-03

2.213 2.213 2.213 2.213 2.213 2.211

9.43E-03 1.82E-02 2.55E-02 3.16E-02 1.36E-01 2.91E-03 517 (15)

315 (7) 723 (20) 287 (7) 755 (22)

599 (16) 455 (14) 342 (12) 338 (7)

3M-002 picryl chloride zymosan A TNFSF4 titanium dioxide DRD1 tetrachlorodibenzodioxin DDX5 NANOG dichlorovinylcysteine TGFB3 2,4-dinitrofluorobenzene ITGB1BP1 irinotecan palmitoyl-Cys((RS)-2,3-di(palmitoyloxy)propyl)-Ala-Gly-OH NCF1 exenatide TEK IFNL3 HOXA9 acetic acid LUM anti-benzo(a)pyrene-diol-epoxide IL2RB NFATC1 LAT reserpine chenodeoxycholic acid

chemical reagent chemical toxicant chemical - endogenous nonmammalian cytokine chemical drug g-protein coupled receptor chemical toxicant enzyme transcription regulator chemical toxicant growth factor chemical toxicant transporter chemical drug

2.211 2.211

1.82E-02 2.91E-02

2.211 2.209 2.208 2.207 2.207 2.206 2.204 2.204 2.203 2.203 2.201 2.201

2.91E-02 5.07E-02 2.53E-02 1.38E-03 5.53E-03 1.74E-03 6.75E-04 8.02E-02 3.29E-03 1.82E-02 6.80E-04 1.44E-02

chemical reagent enzyme biologic drug kinase other transcription regulator chemical - endogenous mammalian other chemical toxicant transmembrane receptor transcription regulator kinase chemical drug chemical - endogenous mammalian

2.2 2.2 2.2 2.2 2.2 2.199 2.196 2.195 2.195 2.194 2.192 2.191 2.191 2.19

1.62E-03 6.27E-03 3.75E-02 5.07E-02 1.15E-01 6.60E-10 1.62E-03 5.77E-03 9.43E-03 2.91E-02 2.16E-01 2.74E-03 5.07E-02 1.21E-01

752 (21) 804 (24) 636 (17) 409 (11) 717 (20) 546 (12)

380 (14) 718 (21)

361 (11) 276 (7) 735 (18)

426 (20)

Klrk1 RIPK3 CXCL10 PLA2G10 ATM LITAF MAP2K7 NOS1 HOXA5 ITGB1 CD86 aplidine risperidone PSEN1 temozolomide SELL IL18R1 prostaglandin A2 miR-16-5p (and other miRNAs w/seed AGCAGCA) IRF8 platelet activating factor XIAP TRPM2 IFNA2 EGR3 naltrexone PLC clenbuterol

other kinase cytokine enzyme kinase transcription regulator kinase enzyme transcription regulator transmembrane receptor transmembrane receptor biologic drug chemical drug peptidase chemical drug transmembrane receptor transmembrane receptor chemical - endogenous nonmammalian

2.189 2.189 2.189 2.189 2.187 2.186 2.186 2.186 2.184 2.184 2.184 2.183 2.182 2.18 2.178 2.176 2.173

6.80E-04 3.24E-03 1.26E-02 2.09E-02 1.40E-06 6.80E-04 2.53E-02 9.67E-02 1.16E-05 1.33E-03 2.38E-03 9.50E-08 6.16E-02 3.14E-04 2.95E-02 6.80E-04 1.62E-03

2.17

2.91E-02

mature microrna transcription regulator chemical - endogenous mammalian enzyme ion channel cytokine transcription regulator chemical drug group chemical drug

2.169 2.169 2.168 2.165 2.162 2.161 2.157 2.156 2.155 2.151

9.93E-07 6.66E-06 7.27E-05 1.27E-07 9.67E-02 1.59E-04 1.08E-01 9.67E-02 2.63E-06 6.55E-05

700 (18) 401 (15)

598 (13) 470 (16)

419 (15) 569 (15) 574 (19) 722 (18) 441 (15) 359 (13)

753 (19) 393 (14) 578 (16) 530 (13)

545 (19) 505 (16)

Ins1 FGF7 apomorphine NCR1 HSP90B1 HMGA1 nickel chloride TSLP PIK3CG IFNL1 SREBF1 PTGER2 NTRK1 CYP1A1 LHX2 CYP1A2 CYP1B1 IKBKG IFNB1 CD5 Fgf MAPK12 trinitrobenzenesulfonic acid TACR1 ELAVL1 SAA1 GW501516 cephaloridine ERN1 AMH

other growth factor chemical drug transmembrane receptor other transcription regulator chemical toxicant cytokine kinase cytokine transcription regulator g-protein coupled receptor kinase enzyme transcription regulator enzyme enzyme kinase cytokine transmembrane receptor group kinase chemical reagent g-protein coupled receptor other transporter chemical drug chemical drug kinase growth factor

2.151 2.151 2.151 2.15 2.147 2.142 2.141 2.138 2.137 2.136 2.135 2.125 2.121 2.121 2.121 2.121 2.121 2.118 2.118 2.115 2.111 2.109 2.104 2.1 2.092 2.091 2.081 2.076 2.074 2.074

1.31E-03 7.58E-03 3.11E-01 5.77E-03 2.57E-01 2.68E-04 3.24E-03 2.95E-02 2.19E-02 1.76E-01 6.75E-02 1.74E-03 1.22E-03 1.08E-02 1.62E-02 2.60E-01 4.48E-01 2.27E-07 1.81E-04 7.78E-03 1.94E-03 4.88E-05 7.41E-05 1.11E-04 7.03E-07 1.26E-02 1.68E-01 1.00E+00 8.14E-03 1.62E-02

645 (23) 513 (17) 511 (18) 817 (21) 562 (17)

614 (17) 674 (22)

627 (12) 590 (14) 557 (20) 547 (19) 462 (17) 614 (19) 489 (18) 369 (11)

463 (18)

CD38 SMAD4 3-methylcholanthrene SMAD3 IL27 IL23A TNFRSF8 dibutyl phthalate TGIF1 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine RIPK1 R5020 ITGA1 tetracycline IL-1R PARP1 Hsp27 IRF7 TAZ 6,7-dinitroquinoxaline-2,3-dione sGC CAY10397 hemin MNK1/2 TLR10 Tlr12 KIDINS220 COCH psychosine CLEC6A

enzyme transcription regulator chemical toxicant transcription regulator cytokine cytokine transmembrane receptor chemical toxicant transcription regulator chemical toxicant kinase chemical reagent other chemical drug group enzyme group transcription regulator enzyme chemical reagent complex chemical reagent chemical - endogenous mammalian group transmembrane receptor other transcription regulator other chemical - endogenous mammalian transmembrane receptor

2.069 2.068 2.067 2.059 2.055 2.045 2.043 2.039 2.033 2.029 2.027 2.022 2.015 2.01 2.007 2.006 2.006 2.002 2 2 2 2 2 2 2 2 2 2 2 2


644 (20) 548 (15) 745 (16) 587 (14)

691 (19) 457 (16)

358 (15) 554 (13) 658 (23) 480 (17) 578 (17) 800 (24) 641 (24) 511 (18) 515 (19) 341 (9) 561 (20) 450 (16)

F13A1 Pdgfr IL1RL2 TSC22D1 fingolimod phosphate GPR84 U1 snRNP CTSZ NEK6 ALOX12 CHRM3 clioquinol BRD2 IL1RAP PTPRE Fgfr PPARÎ±-RXRÎ± OGT finasteride ATP7B

enzyme group transmembrane receptor transcription regulator chemical - endogenous mammalian g-protein coupled receptor complex peptidase kinase enzyme g-protein coupled receptor chemical drug kinase transmembrane receptor phosphatase group complex enzyme chemical drug transporter

Inhibited Ho BPI STX11 tranexamic acid HLA-DQ SAR-20347 belnacasan PPP5C

group transporter transporter chemical drug complex chemical - kinase inhibitor chemical drug phosphatase

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 -2 -2 -2 -2 -2 -2 -2 -2

3.71E-03 5.77E-03 491 (17) 7.74E-03 327 (9) 7.74E-03 528 (14) 1.39E-02 1.39E-02 1.39E-02 2.24E-02 2.24E-02 4.71E-02 4.71E-02 4.71E-02 6.78E-02 8.24E-02 1.04E-01 1.27E-01 1.27E-01 1.93E-01 2.69E-01 1.00E+00 1.38E-03 1.38E-03 1.38E-03 1.38E-03 3.71E-03 3.71E-03 7.74E-03 7.74E-03

581 (10) 591 (15) 421 (12) 424 (7) 342 (7) 686 (19)

pimozide calmidazolium chlorogenic acid 1'-acetoxychavicol acetate STK3 p70 S6k artesunic acid L-carnitine creatine miR-293-5p (and other miRNAs w/seed CUCAAAC) vasoactive intestinal peptide HOXC8 SNAI1 iron mir-8 telmisartan Igm cilostazol cyclosporin A DICER1 Ro31-8220 inosine LAT2 RB1 DUSP5 PAX1 RAB1B ZNF217 TNFRSF4

chemical drug chemical drug chemical drug chemical reagent kinase group chemical drug chemical - endogenous mammalian chemical - endogenous mammalian

-2 -2 -2 -2 -2 -2 -2 -2 -2

2.24E-02 3.34E-02 9.67E-02 1.27E-01 1.27E-01 1.58E-01 2.09E-01 2.09E-01 2.39E-01

mature microrna biologic drug transcription regulator transcription regulator chemical - endogenous mammalian microrna chemical drug complex chemical drug biologic drug enzyme chemical - kinase inhibitor chemical - endogenous mammalian other transcription regulator phosphatase transcription regulator other transcription regulator transmembrane receptor

-2 -2 -2 -2.016 -2.028 -2.042 -2.049 -2.065 -2.067 -2.083 -2.095 -2.104 -2.117 -2.117 -2.119 -2.121 -2.121 -2.132 -2.137 -2.138

3.01E-01 3.64E-01 1.00E+00 3.80E-06 2.94E-03 7.76E-05 4.33E-03 5.52E-04 5.46E-03 1.64E-06 1.44E-04 3.39E-06 1.94E-04 3.24E-03 3.55E-03 2.71E-03 2.60E-01 6.24E-02 1.17E-02 7.43E-02

781 (25) 455 (17) 776 (20) 407 (18) 550 (19) 597 (17) 858 (23) 569 (19) 403 (17) 726 (16) 300 (7)

aspirin BIRC5 CD3 PROC IL18BP eritoran miR-125b-5p (and other miRNAs w/seed CCCUGAG) L-histidine sulfasalazine TSC22D3 FOXG1 mir-214 Irgm1 SIRPA DTX1 AURKB vinpocetine TSC2 clarithromycin hexamethoxyflavone glaucocalyxin A polymyxin B ATG16L1 ENTPD1 ethyl pyruvate TNFAIP8L2 NR0B2 mir-373

chemical drug other complex peptidase other chemical drug

-2.144 -2.148 -2.158 -2.162 -2.162 -2.163

7.27E-06 2.53E-02 1.14E-12 2.32E-06 1.62E-03 4.09E-05

mature microrna chemical - endogenous mammalian chemical drug transcription regulator transcription regulator microrna other phosphatase transcription regulator kinase chemical drug other chemical drug chemical toxicant chemical - endogenous nonmammalian biologic drug enzyme enzyme chemical drug other ligand-dependent nuclear receptor microrna

-2.165 -2.166 -2.169 -2.17 -2.17 -2.174 -2.18 -2.182 -2.184 -2.186 -2.19 -2.195 -2.195 -2.197

1.35E-01 1.44E-02 2.91E-02 7.23E-05 2.09E-02 1.74E-03 2.03E-01 2.44E-03 4.18E-06 9.67E-02 6.80E-04 1.38E-03 6.27E-03 3.24E-03

-2.2 -2.2 -2.2 -2.2 -2.2 -2.201 -2.201 -2.205

2.18E-04 1.62E-03 3.24E-03 3.24E-03 7.95E-02 2.91E-02 1.00E+00 9.43E-03

422 (14) 685 (16) 455 (15) 507 (12) 485 (10)

588 (16) 258 (6) 542 (14) 370 (12) 305 (8) 577 (19) 536 (18) 680 (17) 495 (9) 540 (13) 569 (15) 373 (15)

522 (10)

2-aminopurine nicotinic acid grepafloxacin TPCA-1 diazepam AMBP CD200 iguratimod 6-cyano-7-nitroquinoxaline-2,3-dione PDCD4 mir-150 ZC3H12A miR-31-5p (and other miRNAs w/seed GGCAAGA) PRTN3 NKX2-3 1-palmitoyl-2-oleoylglycero-3-phosphoglycerol prazosin rabeprazole PPT1 Ighg2b astragalin NELFB metoprolol SIN3A NT5E SIRT3 Ubiquitin mir-181

chemical reagent chemical - endogenous mammalian chemical drug chemical - kinase inhibitor chemical drug transporter other chemical drug chemical reagent other microrna enzyme

-2.207 -2.211 -2.213 -2.213 -2.213 -2.213 -2.213 -2.216 -2.219 -2.219 -2.219 -2.221

7.31E-03 3.39E-01 4.09E-05 2.18E-04 6.80E-04 1.62E-03 2.43E-02 6.80E-04 5.42E-06 1.44E-02 1.39E-01 2.31E-01

623 (20)

mature microrna peptidase transcription regulator chemical reagent chemical drug chemical drug enzyme other chemical - endogenous nonmammalian other chemical drug transcription regulator phosphatase enzyme group microrna

-2.23 -2.232 -2.233 -2.236 -2.236 -2.236 -2.236 -2.236

5.29E-04 6.80E-04 3.00E-04 4.09E-05 5.91E-04 6.80E-04 1.62E-03 3.24E-03

-2.236 -2.236 -2.236 -2.236 -2.236 -2.236 -2.236 -2.238

9.43E-03 287 (7) 1.44E-02 1.44E-02 1.50E-02 5.07E-02 6.42E-02 1.39E-01 6.86E-03 546 (12)

315 (7) 395 (12) 488 (14) 625 (17) 543 (14) 247 (7)

494 (20) 575 (19) 657 (18)

298 (7)

IL10 miR-155-5p (miRNAs w/seed UAAUGCU) mir-146 ethylene glycol tetraacetic acid erythromycin TNFAIP3 thalidomide Ciap APC diphenyleneiodonium HIC1 RAE1 S100A6 verapamil ABCA1 carbon monoxide MAX 10-nitrooleate CD3E tempol bardoxolone methyl CLDN7 trans-hydroxytamoxifen L-685,458 SERCA azithromycin REST etanercept MTDH 1,2-dithiol-3-thione

cytokine mature microrna microrna chemical reagent chemical drug enzyme chemical drug group enzyme chemical reagent transcription regulator other transporter chemical drug transporter chemical - endogenous mammalian transcription regulator chemical - endogenous mammalian transmembrane receptor chemical drug chemical drug other chemical drug chemical - protease inhibitor group chemical drug transcription regulator biologic drug transcription regulator chemical reagent

-2.242 -2.272 -2.275 -2.275 -2.28 -2.281 -2.284 -2.284 -2.298 -2.306 -2.308 -2.333 -2.333 -2.333 -2.337 -2.344 -2.358 -2.36 -2.37 -2.376 -2.379 -2.393 -2.396 -2.4 -2.401 -2.401 -2.401 -2.407 -2.415 -2.417

1.53E-09 4.20E-11 5.30E-04 8.52E-03 4.52E-04 2.91E-03 4.98E-04 5.51E-04 8.50E-03 1.66E-04 1.19E-02 3.30E-04 1.04E-02 6.53E-02 3.63E-03 1.40E-04 9.04E-05 2.95E-05 1.87E-03 2.45E-02 2.46E-04 1.28E-03 1.87E-02 9.29E-03 5.42E-06 3.08E-04 1.00E+00 2.46E-04 2.54E-02 4.16E-01

636 (15) 332 (7) 427 (12) 420 (15) 563 (17) 357 (15) 444 (14) 584 (16) 663 (17) 588 (21)

644 (17) 465 (15) 107 (2) 595 (14) 505 (18) 610 (17)

739 (19) 542 (16) 631 (19) 538 (16)

DNMT1 NTN1 tocilizumab edaravone 8-oxo-7-hydrodeoxyguanosine USP18 SL 327 andrographolide resolvin D1 ubiquinone 9 cyclomaltodextrin PCSK1 W7 PPP2R5C PAEP Cdc42 FOSL1 alpha-tocopherol RPSA Sn50 peptide tetrodotoxin SIGIRR H-7 BCL6 apigenin VPRBP N,N-dimethylsphingosine tosylphenylalanyl chloromethyl ketone

enzyme other biologic drug chemical drug chemical - endogenous mammalian peptidase chemical - protease inhibitor chemical drug chemical - endogenous mammalian chemical - endogenous nonmammalian chemical drug peptidase chemical reagent other other enzyme transcription regulator chemical drug translation regulator chemical toxicant chemical drug transmembrane receptor chemical - kinase inhibitor transcription regulator chemical - endogenous nonmammalian other chemical reagent chemical - protease inhibitor

-2.418 -2.423 -2.425 -2.425 -2.433 -2.433 -2.433 -2.433 -2.438

2.47E-02 1.53E-02 1.19E-04 7.04E-04 7.04E-04 5.99E-03 1.39E-01 2.68E-01 5.90E-07

-2.449 -2.449 -2.449 -2.449 -2.449 -2.449 -2.449 -2.466 -2.556 -2.559 -2.577 -2.582 -2.586 -2.591 -2.62


-2.62 -2.621 -2.63 -2.638

8.14E-03 397 (14) 1.53E-02 3.08E-04 387 (14) 1.45E-04 618 (15)

367 (14) 551 (15) 660 (17) 542 (16)

635 (17) 522 (16) 387 (11) 725 (20) 696 (20)

593 (16) 532 (17) 485 (17) 572 (20) 390 (15) 423 (13)

MNT kaempferol nimodipine ITCH fontolizumab SOX7 pyrrolidine dithiocarbamate curcumin triptolide beta-carotene CDKN1B PP1 MEOX2 miR-34a-5p (and other miRNAs w/seed GGCAGUG) KN-62 lipoxin A4 SKIL NLRP12 calphostin C SR 144528 IL37 TRAIP KLF2 anakinra LYN mir-22 H89 CBX7 COL18A1

transcription regulator chemical toxicant chemical drug enzyme biologic drug transcription regulator chemical reagent chemical drug chemical drug chemical - endogenous mammalian kinase chemical - kinase inhibitor transcription regulator

-2.646 -2.646 -2.646 -2.646 -2.646 -2.646 -2.652 -2.658 -2.671 -2.673 -2.673 -2.674 -2.68

3.30E-04 8.09E-04 1.74E-03 2.74E-03 4.13E-03 1.69E-01 1.10E-06 5.38E-07 4.41E-04 1.54E-04 3.68E-02 5.07E-05 5.90E-07

mature microrna chemical - kinase inhibitor chemical - endogenous mammalian transcription regulator other chemical - kinase inhibitor chemical reagent cytokine enzyme transcription regulator biologic drug kinase microrna chemical - kinase inhibitor other other

-2.696 -2.72 -2.725 -2.728 -2.742 -2.743 -2.746 -2.749 -2.764 -2.767 -2.771 -2.776 -2.789 -2.803 -2.828 -2.862

7.61E-02 6.36E-05 7.57E-05 3.63E-03 7.57E-05 1.04E-03 2.32E-09 1.35E-04 2.71E-03 5.27E-06 1.16E-03 1.80E-02 2.04E-02 6.66E-06 1.84E-03 5.53E-03

390 (14) 600 (21) 615 (17)

631 (11) 561 (16) 540 (12) 562 (16) 485 (20) 565 (11)

390 (15) 713 (18) 363 (8) 645 (12) 529 (15) 528 (19) 525 (13) 377 (16) 547 (17) 580 (19)

614 (16) 527 (18)

infliximab tyrphostin AG 1478 amino acids SCD triflusal PP2/AG1879 tyrosine kinase inhibitor RCAN1 SLC13A1 AG490 ZFP36 bisindolylmaleimide I SOCS1 N-acetyl-L-cysteine Nr1h ABCG1 SOCS3 PS-1145 SP600125 Bay 11-7082 CTLA4 DACH1 GFI1 bexarotene nifedipine IL1RN SU6656 Sb202190 SFTPA1 2-amino-5-phosphonovaleric acid genistein

biologic drug chemical - kinase inhibitor chemical - endogenous mammalian enzyme chemical drug chemical - kinase inhibitor transcription regulator transporter chemical - kinase inhibitor transcription regulator chemical - kinase inhibitor other chemical drug group transporter phosphatase chemical - kinase inhibitor chemical - kinase inhibitor chemical - kinase inhibitor transmembrane receptor transcription regulator transcription regulator chemical drug chemical drug cytokine chemical toxicant chemical - kinase inhibitor transporter chemical - other chemical drug

-2.882 -2.886 -2.892 -2.912 -2.923 -2.937 -2.941 -3 -3.065 -3.078 -3.091 -3.175 -3.212 -3.218 -3.218 -3.252 -3.267 -3.284 -3.462 -3.469 -3.56 -3.596 -3.741 -3.81 -3.821 -3.843 -3.872 -3.981 -4.008 -4.018

5.52E-04 3.00E-04 4.18E-06 1.04E-03 3.30E-04 3.02E-03 1.16E-03 1.00E+00 1.36E-04 2.64E-10 3.99E-04 3.15E-05 5.49E-08 6.53E-05 1.44E-03 5.59E-04 5.93E-06 9.47E-07 8.32E-05 1.47E-02 2.14E-04 1.73E-05 6.96E-08 1.72E-05 1.30E-04 1.09E-06 3.78E-05 2.16E-10 2.28E-11 1.70E-05

772 (21) 583 (15) 546 (20) 740 (17) 356 (10) 419 (16) 448 (19) 605 (17) 579 (13) 486 (17) 584 (14) 473 (17) 695 (17) 759 (21) 467 (15) 640 (17) 550 (15) 595 (15) 485 (12) 517 (11) 592 (15) 767 (22) 490 (14) 830 (23) 568 (16) 699 (14) 743 (23) 490 (17)

MYCN actinomycin D DUSP1 SB203580 ESR1 PD98059 LY294002 U0126

transcription regulator chemical drug phosphatase chemical - kinase inhibitor ligand-dependent nuclear receptor chemical - kinase inhibitor chemical - kinase inhibitor chemical - kinase inhibitor

-4.284 -4.346 -4.619 -5.289 -5.546 -5.94 -6.434 -6.895

1.55E-22 1.37E-04 1.05E-10 1.89E-08 1.47E-07 2.43E-15 1.75E-21 9.35E-19

670 (15) 512 (15) 606 (14) 936 (21) 610 (15) 551 (13) 588 (14)

S4Table3. Networks and associated network functions associated with reperfusion injury

ID

Score 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

34 31 31 31 29 29 29 29 29 29 29 29 29 27 27 27 27 27 27 27 27 27 25

Focus Molecules 35 34 34 34 33 33 33 33 33 33 33 33 33 32 32 32 32 32 32 32 32 32 31

Top Diseases and Functions Auditory Disease, Carbohydrate Metabolism, Cell Morphology RNA Post-Transcriptional Modification, Gene Expression, Protein Synthesis Cancer, Cell Death and Survival, Organismal Injury and Abnormalities Molecular Transport, Nucleic Acid Metabolism, Small Molecule Biochemistry Cellular Function and Maintenance, Molecular Transport, Small Molecule Biochemistry Tissue Morphology, Developmental Disorder, Hereditary Disorder Post-Translational Modification, Auditory Disease, Dermatological Diseases and Conditions Auditory Disease, Hereditary Disorder, Neurological Disease Post-Translational Modification, Protein Synthesis, Neurological Disease Developmental Disorder, Hereditary Disorder, Metabolic Disease Cell-To-Cell Signaling and Interaction, Cellular Function and Maintenance, Nervous System Development and Function Carbohydrate Metabolism, Small Molecule Biochemistry, Embryonic Development Cellular Development, Cellular Growth and Proliferation, Cell Death and Survival Post-Translational Modification, Developmental Disorder, Hereditary Disorder DNA Replication, Recombination, and Repair, Small Molecule Biochemistry, Amino Acid Metabolism Developmental Disorder, Hereditary Disorder, Organismal Injury and Abnormalities RNA Post-Transcriptional Modification, Cellular Assembly and Organization, Cancer Cell Signaling, Post-Translational Modification, Protein Synthesis Cellular Development, Embryonic Development, Organismal Development Post-Translational Modification, Protein Folding, Energy Production Endocrine System Disorders, Metabolic Disease, Organismal Injury and Abnormalities Cell-mediated Immune Response, Cellular Development, Cellular Function and Maintenance Embryonic Development, Organismal Development, Cell Signaling

24 25

25 25

31 Post-Translational Modification, Cancer, Organismal Injury and Abnormalities 31 Cell-To-Cell Signaling and Interaction, Connective Tissue Development and Function, Cellular Assembly and Organization

S4Table4. Top Regulator effect network

ID 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

Consistency Score Node Total 5.196 4.903 4.69 4 4 3.881 3.881 3.873 3.75 3.75 3.75 3.606 3.5 3.479 3.474 3.474 3.464 3.357 3.333 3.333 3.333 3.333 3.333 3.333 3.328 3.328 3.328 3.328

29 28 24 18 18 19 19 17 18 18 18

Regulator Total 1 1 1 1 1 1 1 1 1 1 1

15 18 12 16 16 14 17 11 11 11 11 11 11 15 15 15 15

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

Regulators sirolimus MYCN RICTOR CCL5 CCL5 CpG oligonucleotide okadaic acid CCL5 TAC1 Tnf (family) okadaic acid miR-155-5p (miRNAs w/seed UAAUGCU) F2RL1 C5AR1 COL18A1 COL18A1 Tnf (family) RELA IL1B PF4 PGF PGF PGF TNF MIF MIF MIF okadaic acid

Target Total

Disease & Function Total 27 26 22 16 16 17 17 15 16 16 16

1 1 1 1 1 1 1 1 1 1 1

Diseases & Functions cell death of osteosarcoma cells cell death of osteosarcoma cells cell death of osteosarcoma cells recruitment of blood cells recruitment of cells activation of mononuclear leukocytes transcription of DNA recruitment of leukocytes activation of cells recruitment of neutrophils cell movement of tumor cell lines

13 16 10 14 14 12 15 9 9 9 9 9 9 13 13 13 13

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

recruitment of neutrophils activation of cells recruitment of cells growth of muscle tissue proliferation of muscle cells activation of neutrophils activation of neutrophils mobilization of neutrophils activation of neutrophils chemotaxis chemotaxis of cells homing of cells mobilization of neutrophils expression of RNA transcription transcription of RNA migration of tumor cell lines

29 30 31 32 33 34 35 36

3.317 3.317 3.317 3.317 3.317 3.317 3.317 3.317

13 13 13 13 13 13 13 13

1 1 1 1 1 1 1 1

37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57

3.317 3.317 3.317 3.317 3.317 3.182 3.182 3.182 3.182 3.182 3.182 3.175 3.175 3.175 3.175 3.175 3.175 3.175 3.175 3.175 3.162

13 13 13 13 13 10 10 10 10 10 10 14 14 14 14 14 14 14 14 14 12

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

3M-001 Ap1 IL17F IL17F IL17F IL1B MEOX2 PF4 PP2/AG1879 tyrosine kinase inhibitor TRADD ozone poly rI:rC-RNA uric acid C5AR1 C5AR1 LCN2 PF4 PGF RCAN1 5-hydroxytryptamine E. coli B4 lipopolysaccharide IFI16 Jnk NFkB (complex) TLR2 TLR2 diphenyleneiodonium lysophosphatidylcholine 3M-001

11 11 11 11 11 11 11 11

1 1 1 1 1 1 1 1

activation of cells activation of neutrophils cell movement homing of cells migration of cells mobilization of myeloid cells recruitment of phagocytes cell movement of myeloid cells

11 11 11 11 11 8 8 8 8 8 8 12 12 12 12 12 12 12 12 12 10

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

cell movement of tumor cell lines recruitment of phagocytes cell movement mobilization of myeloid cells mobilization of blood cells stimulation of cells stimulation of leukocytes activation of neutrophils stimulation of cells proliferation of connective tissue cells recruitment of cells recruitment of cells mobilization of blood cells cell movement of tumor cell lines activation of neutrophils mobilization of myeloid cells migration of muscle cells migration of smooth muscle cells activation of cells chemotaxis of cells activation of blood cells

58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87

3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.162 3.051 3.051 3.051

12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 15 15 15

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

3M-001 ALB CAMK4 CAMK4 F2R F2R F2R F7 IL17F IL17F IL1B L-glutamic acid L-glutamic acid Ni2+ Ni2+ Ni2+ Ni2+ PF4 PF4 PF4 aspirin enterotoxin B lipoarabinomannan nifedipine peptidoglycan poly rI:rC-RNA trovafloxacin COL18A1 COL18A1 carbon monoxide

10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 13 13 13

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

activation of leukocytes migration of tumor cell lines transcription transcription of RNA cell movement of tumor cell lines organization of cytoplasm organization of cytoskeleton proliferation of muscle cells activation of blood cells activation of leukocytes mobilization of granulocytes cell movement of tumor cell lines survival of organism cell movement of myeloid cells cell survival cell viability recruitment of phagocytes cell movement of neutrophils development of connective tissue development of connective tissue cells mobilization of blood cells mobilization of blood cells migration of cells recruitment of cells mobilization of myeloid cells mobilization of granulocytes recruitment of leukocytes growth of smooth muscle proliferation of smooth muscle cells cell movement of myeloid cells

88

3.024

9

89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108

3.015 3.015 3.015 3.015 3.015 3.015 3.015 3.015 3.015 3.015 3 3 3 3 3 3 3 3 3 3

13 13 13 13 13 13 13 13 13 13 11 11 11 11 11 11 11 11 18 11

109 110 111 112 113 114 115

3 3 3 3 3 3 3

11 11 11 11 11 11 11

1 CCL4 1-methyl-4-phenyl-1,2,3,61 tetrahydropyridine 1 F7 1 MKNK1 1 MKNK1 1 NLRP12 1 U0126 1 bromodeoxyuridine 1 lipoxin A4 1 quinolinic acid 1 quinolinic acid 1 AG490 1 AGT 1 CXCL2 1 ECSIT 1 ERK1/2 1 IL17A 1 IL1A 1 ITGB1 1 KLF2 1 MAP3K8 N-acetylmuramyl-L-alanyl-D1 isoglutamine 1 NfkB1-RelA 1 NfkB1-RelA 1 PP1 1 PRKCE 1 PRKCE 1 TLR3

7

1 recruitment of leukocytes

11 11 11 11 11 11 11 11 11 11 9 9 9 9 9 9 9 9 16 9

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

proliferation of connective tissue cells generation of cells expression of RNA transcription chemotaxis of cells mobilization of myeloid cells activation of cells recruitment of cells expression of RNA transcription migration of smooth muscle cells activation of neutrophils chemotaxis of cells transcription of DNA mobilization of myeloid cells mobilization of myeloid cells mobilization of myeloid cells infection of mammalia recruitment of cells migration of smooth muscle cells

9 9 9 9 9 9 9

1 1 1 1 1 1 1

migration of smooth muscle cells activation of cells migration of cells expression of RNA differentiation of bone differentiation of bone cells mobilization of neutrophils

116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2.985 2.887 2.887 2.887 2.887 2.858 2.858 2.858 2.858 2.858 2.858 2.858 2.858

11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 24 14 14 14 14 8 8 8 8 8 8 8 8

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

TREM1 TSC22D3 alpha-tocopherol carrageenan carrageenan etanercept etanercept leukotriene C4 leukotriene C4 poly rI:rC-RNA resolvin D1 resolvin D1 resolvin D1 stallimycin triflusal triflusal zymosan RET CXCR4 Ccl2 Ccl2 IL3 CXCL1 CXCL1 CXCL3 CXCL3 CXCL3 IL6 ITCH MAPK10

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 22 12 12 12 12 6 6 6 6 6 6 6 6

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

mobilization of blood cells recruitment of phagocytes migration of cells cell movement of neutrophils proliferation of muscle cells activation of mononuclear leukocytes recruitment of cells cell movement generation of cells lipolysis activation of leukocytes migration of smooth muscle cells recruitment of neutrophils activation of mononuclear leukocytes activation of leukocytes migration of cells mobilization of blood cells migration of cells activation of cells transcription transcription of RNA induction of cells activation of cells recruitment of leukocytes cell movement of myeloid cells chemotaxis of cells recruitment of neutrophils lipolysis activation of cells cell movement

146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174

2.858 2.846 2.846 2.846 2.846 2.846 2.846 2.846 2.846 2.846 2.846 2.846 2.846 2.846 2.846 2.846 2.846 2.846 2.828 2.828 2.828 2.828 2.828 2.828 2.828 2.828 2.828 2.828 2.828

8 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 10 10 10 10 10 10 10 10 10 10 10

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

PF4 C5 E. coli lipopolysaccharide IRF6 KLF6 KLF6 NfkB-RelA SASH1 TLR7 TNFAIP3 Tlr aldosterone cilostazol dinoprost fatty acid fatty acid resiquimod triptolide AIMP1 AREG AREG CD 437 CXCL10 CXCL10 E. coli B5 lipopolysaccharide FOXL2 Fcer1 IL-17f dimer IL15

6 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 8 8 8 8 8 8 8 8 8 8 8

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

differentiation of antigen presenting cells mobilization of myeloid cells mobilization of blood cells migration of tumor cell lines cell movement of neutrophils development of connective tissue cells cell movement of tumor cell lines activation of leukocytes mobilization of blood cells activation of leukocytes mobilization of blood cells differentiation of bone cells migration of cells development of connective tissue development of connective tissue proliferation of connective tissue cells mobilization of blood cells recruitment of cells mobilization of blood cells growth of smooth muscle proliferation of smooth muscle cells cell death of osteosarcoma cells activation of cells cell movement mobilization of neutrophils chemotaxis of cells mobilization of myeloid cells cell movement of tumor cell lines mobilization of neutrophils

175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190

2.828 2.828 2.828 2.828 2.828 2.828 2.828 2.828 2.828 2.828 2.828 2.828 2.828 2.828 2.828 2.828

10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

191

2.828

10

1

192

2.828

10

1

193

2.828

10

1

194 195 196

2.828 2.828 2.828

10 10 10

1 1 1

197 198 199 200

2.828 2.828 2.828 2.828

10 10 10 10

1 1 1 1

IL17C IL17C IL17a dimer IL18 IL1 IL2 IL37 IL37 IL37 IL37 IL37 IL37 MALP-2s NUPR1 PD98059 Pam3-Cys S-(2,3-bispalmitoyloxypropyl)cysteine-GDPKHPKSF S-(2,3-bispalmitoyloxypropyl)cysteine-GDPKHPKSF S-(2,3-bispalmitoyloxypropyl)cysteine-GDPKHPKSF S-(2,3-bispalmitoyloxypropyl)cysteine-GDPKHPKSF SP600125 ST1926 Salmonella enterica serotype abortus equi lipopolysaccharide TACR1 TLR5 bisindolylmaleimide I

8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

activation of leukocytes recruitment of leukocytes mobilization of blood cells mobilization of myeloid cells mobilization of myeloid cells mobilization of neutrophils activation of leukocytes migration of cells recruitment of cells stimulation of cells transcription transcription of RNA migration of smooth muscle cells stimulation of cells mobilization of neutrophils migration of smooth muscle cells

8

1 activation of leukocytes

8

1 chemotaxis of cells

8

1 migration of cells

8 8 8

1 recruitment of cells 1 mobilization of myeloid cells 1 cell death of osteosarcoma cells

8 8 8 8

1 1 1 1

mobilization of myeloid cells recruitment of leukocytes migration of smooth muscle cells differentiation of bone cells

S4Table5. The list of the canonical pathways associated with associated with perfusion driven IGF

Canonical Pathways Granulocyte Adhesion and Diapedesis Agranulocyte Adhesion and Diapedesis TREM1 Signaling Glucocorticoid Receptor Signaling IL-6 Signaling HMGB1 Signaling Differential Regulation of Cytokine Production in Macrophages and T Helper Cells by IL-17A and IL-17F

-log(pRatio value) 6.62E+00 6.15E-02 6.36E+00 5.79E-02 5.57E+00 9.21E-02 5.49E+00 4.27E-02 5.33E+00 6.90E-02 5.22E+00 6.67E-02 4.94E+00 2.22E-01

IGF-1 Signaling Role of Hypercytokinemia/hyperchemokinemia in the Pathogenesis of Influenza Airway Pathology in Chronic Obstructive Pulmonary Disease Prolactin Signaling IL-17A Signaling in Gastric Cells TNFR2 Signaling Communication between Innate and Adaptive Immune Cells

4.80E+00 4.61E+00 4.55E+00 4.46E+00 4.34E+00 4.08E+00 4.04E+00

7.07E-02 1.16E-01 3.75E-01 7.89E-02 1.60E-01 1.38E-01 6.67E-02

PPAR Signaling Colorectal Cancer Metastasis Signaling IL-17A Signaling in Fibroblasts Aryl Hydrocarbon Receptor Signaling Cholecystokinin/Gastrin-mediated Signaling IL-10 Signaling JAK/Stat Signaling

3.97E+00 3.81E+00 3.75E+00 3.73E+00 3.65E+00 3.53E+00 3.53E+00

6.45E-02 3.73E-02 1.14E-01 4.79E-02 5.66E-02 6.94E-02 6.94E-02

zscore NaN NaN 2.646 NaN 1.414 2.646 NaN 0.447 NaN NaN 0.816 NaN NaN NaN 1.633 3 NaN NaN 2.449 NaN 0.447

Role of IL-17F in Allergic Inflammatory Airway Diseases Acute Phase Response Signaling TNFR1 Signaling NRF2-mediated Oxidative Stress Response Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid Arthritis Differential Regulation of Cytokine Production in Intestinal Epithelial Cells by IL-17A and IL-17F Hepatic Fibrosis / Hepatic Stellate Cell Activation ILK Signaling IL-8 Signaling Role of Cytokines in Mediating Communication between Immune Cells Role of JAK family kinases in IL-6-type Cytokine Signaling PCP pathway HGF Signaling CD40 Signaling Pathogenesis of Multiple Sclerosis Tight Junction Signaling Erythropoietin Signaling PXR/RXR Activation p38 MAPK Signaling IL-17 Signaling Circadian Rhythm Signaling Cardiac Hypertrophy Signaling Growth Hormone Signaling Corticotropin Releasing Hormone Signaling CCR5 Signaling in Macrophages Toll-like Receptor Signaling Production of Nitric Oxide and Reactive Oxygen Species in Macrophages Role of IL-17A in Psoriasis D-myo-inositol (1,4,5,6)-Tetrakisphosphate Biosynthesis D-myo-inositol (3,4,5,6)-tetrakisphosphate Biosynthesis

3.36E+00 3.31E+00 3.18E+00 3.18E+00 3.09E+00 3.09E+00 3.08E+00 3.08E+00 3.07E+00 3.02E+00 2.98E+00 2.77E+00 2.73E+00 2.72E+00 2.65E+00 2.62E+00 2.60E+00 2.58E+00 2.58E+00 2.56E+00 2.55E+00 2.55E+00 2.54E+00 2.52E+00 2.52E+00 2.52E+00 2.39E+00 2.32E+00 2.32E+00 2.32E+00


NaN 1.134 NaN 0.816 NaN NaN NaN 2.449 2.646 NaN NaN 1 NaN NaN NaN NaN NaN NaN 0.447 NaN NaN 1.134 NaN NaN NaN NaN 2.449 NaN NaN NaN

ErbB Signaling MIF Regulation of Innate Immunity iNOS Signaling D-myo-inositol-5-phosphate Metabolism 3-phosphoinositide Degradation p53 Signaling Semaphorin Signaling in Neurons CXCR4 Signaling IL-2 Signaling Role of Osteoblasts, Osteoclasts and Chondrocytes in Rheumatoid Arthritis GADD45 Signaling Role of IL-17A in Arthritis Thrombopoietin Signaling ATM Signaling 3-phosphoinositide Biosynthesis Type I Diabetes Mellitus Signaling Role of Tissue Factor in Cancer Activation of IRF by Cytosolic Pattern Recognition Receptors Hepatic Cholestasis IL-15 Signaling ERK5 Signaling Mitotic Roles of Polo-Like Kinase Estrogen-Dependent Breast Cancer Signaling Sertoli Cell-Sertoli Cell Junction Signaling Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses ERK/MAPK Signaling IL-15 Production STAT3 Pathway Chemokine Signaling Adipogenesis pathway

2.28E+00 2.27E+00 2.19E+00 2.10E+00 2.09E+00 2.08E+00 2.05E+00 2.01E+00 2.00E+00 2.00E+00 1.99E+00 1.98E+00 1.92E+00 1.92E+00 1.92E+00 1.90E+00 1.89E+00 1.86E+00 1.85E+00 1.82E+00 1.82E+00 1.79E+00 1.77E+00 1.75E+00 1.73E+00 1.71E+00 1.70E+00 1.66E+00 1.64E+00 1.62E+00


NaN NaN NaN NaN NaN NaN NaN 2 NaN NaN NaN NaN NaN NaN NaN 0 NaN NaN NaN NaN NaN NaN NaN NaN NaN 0.447 NaN NaN NaN NaN

IL-12 Signaling and Production in Macrophages VDR/RXR Activation Regulation of IL-2 Expression in Activated and Anergic T Lymphocytes PDGF Signaling Ceramide Signaling IL-9 Signaling Role of JAK2 in Hormone-like Cytokine Signaling Superpathway of Inositol Phosphate Compounds Systemic Lupus Erythematosus Signaling Bladder Cancer Signaling TGF-Î² Signaling Interferon Signaling Glioblastoma Multiforme Signaling Apoptosis Signaling Crosstalk between Dendritic Cells and Natural Killer Cells GÎ±q Signaling April Mediated Signaling Neuregulin Signaling Airway Inflammation in Asthma Tec Kinase Signaling Role of PKR in Interferon Induction and Antiviral Response B Cell Activating Factor Signaling SAPK/JNK Signaling Protein Kinase A Signaling UVC-Induced MAPK Signaling

1.60E+00 1.58E+00 1.55E+00 1.53E+00 1.51E+00 1.51E+00 1.51E+00 1.51E+00 1.49E+00 1.48E+00 1.48E+00 1.47E+00 1.47E+00 1.45E+00 1.44E+00 1.43E+00 1.42E+00 1.40E+00 1.40E+00 1.39E+00 1.38E+00 1.38E+00 1.38E+00 1.37E+00 1.35E+00

2.92E-02 3.80E-02 3.70E-02 3.61E-02 3.57E-02 5.88E-02 5.88E-02 2.31E-02 2.29E-02 3.45E-02 3.45E-02 5.56E-02 2.65E-02 3.37E-02 3.33E-02 2.58E-02 5.26E-02 3.23E-02 2.00E-01 2.50E-02 5.00E-02 5.00E-02 3.16E-02 1.76E-02 4.76E-02

NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN 1 NaN NaN 0 NaN NaN NaN NaN NaN NaN NaN -.134 NaN

S4Table6. The complete list of activated and inhibited upstream regulators associated with perfusion driven IGF

Upstream Regulator Activated TNF lipopolysaccharide PDGF BB phorbol myristate acetate IL1B IFNG NFkB (complex) poly rI:rC-RNA EGF Salmonella enterica serotype abortus equi lipopolysaccharide F2 CREB1 leukotriene D4 TLR3 hydrogen peroxide salmonella minnesota R595 lipopolysaccharides ERK IL6 GnRH-A IL2 E. coli B5 lipopolysaccharide

Molecule Type cytokine chemical drug complex chemical drug cytokine cytokine complex biologic drug growth factor chemical toxicant peptidase transcription regulator chemical - endogenous mammalian transmembrane receptor chemical - endogenous mammalian chemical - endogenous nonmammalian group cytokine chemical reagent cytokine chemical - endogenous nonmammalian

Activation zscore

p-value of overlap

7.078 6.713 6.565 6.071 5.881 5.774 5.721 5.636 5.273 5.246 5.019 5.007 4.982 4.753 4.736


4.681 4.656 4.645 4.518 4.516

6.09E-26 7.04E-26 2.38E-17 4.31E-28 1.20E-17

4.505

1.17E-20

P38 MAPK IL1 thapsigargin dalfampridine forskolin cisplatin bicuculline doxorubicin TLR4 CSF2 TGFB1 kainic acid TREM1 HGF TICAM1 IL3 FGF2 deferoxamine 5-O-mycolyl-beta-araf-(1->2)-5-O-mycolyl-alpha-araf-(1->1')glycerol TLR9 CD40LG ERK1/2 IL17A gentamicin TNFSF11 Jnk MYD88 IGF1

group group chemical toxicant chemical drug chemical toxicant chemical drug chemical - endogenous nonmammalian chemical drug transmembrane receptor cytokine growth factor chemical toxicant transmembrane receptor growth factor other cytokine growth factor chemical drug chemical - endogenous nonmammalian transmembrane receptor cytokine group cytokine chemical drug cytokine group other growth factor

4.492 4.486 4.485 4.472 4.443 4.427

1.08E-20 8.78E-16 4.44E-21 2.41E-35 4.28E-26 1.42E-18

4.396 4.389 4.365 4.354 4.341 4.312 4.288 4.281 4.227 4.173 4.153 4.135

7.03E-33 8.42E-20 1.62E-24 4.26E-22 1.33E-23 2.32E-21 7.50E-25 6.58E-20 1.06E-21 8.53E-15 1.89E-15 4.54E-20

4.123 4.122 4.043 4.025 4.019 4 3.993 3.962 3.944 3.903

7.57E-20 1.14E-17 1.10E-18 2.08E-16 4.18E-18 5.91E-11 1.08E-19 2.27E-22 1.45E-22 3.94E-17

ionomycin palmitic acid Tlr peptidoglycan TCR SAMSN1 IL1A STAT4 TP53 A23187 cocaine camptothecin C5 cigarette smoke Ca2+ AGT APP RELA NUPR1 TLR7 MAP2K1/2 STAT3 IL18 tunicamycin IL12 (complex) carrageenan RAF1

chemical reagent chemical - endogenous mammalian group chemical - endogenous nonmammalian complex other cytokine transcription regulator transcription regulator chemical reagent chemical drug chemical drug cytokine chemical toxicant chemical - endogenous mammalian growth factor other transcription regulator transcription regulator transmembrane receptor group transcription regulator cytokine chemical - endogenous nonmammalian complex chemical - endogenous nonmammalian kinase

3.9 3.891 3.887

2.21E-13 8.54E-14 1.25E-17

3.885 3.881 3.873 3.82 3.806 3.786 3.78 3.778 3.761 3.754 3.731 3.719 3.712 3.684 3.677 3.674 3.657 3.652 3.651 3.646

5.82E-17 2.32E-20 2.60E-16 4.68E-15 1.23E-10 3.36E-20 4.27E-15 2.91E-18 2.05E-17 4.22E-16 1.03E-17 1.57E-19 3.43E-14 3.54E-13 4.57E-21 7.44E-13 1.52E-13 3.86E-17 2.63E-17 2.62E-12

3.646 3.64

3.00E-10 2.96E-12

3.63 3.604

2.19E-20 4.95E-13

trovafloxacin MET Cg TLR2 E. coli B4 lipopolysaccharide FOXO1 IL15 lysophosphatidic acid EGR1 cyclic AMP IL5 VEGFA 5-hydroxytryptamine MAPK3 carbon tetrachloride anisomycin resiquimod CXCL12 EDN1 25-hydroxycholesterol Vegf norepinephrine OSM LIF F2R NRG1 tretinoin F7 beta-estradiol

chemical drug kinase complex transmembrane receptor chemical toxicant transcription regulator cytokine chemical - other transcription regulator chemical - endogenous mammalian cytokine growth factor chemical - endogenous mammalian kinase chemical toxicant chemical - endogenous nonmammalian chemical drug cytokine cytokine chemical reagent group chemical - endogenous mammalian cytokine cytokine g-protein coupled receptor other chemical - endogenous mammalian peptidase chemical - endogenous mammalian

3.592 3.592 3.591 3.553 3.547 3.543 3.54 3.524 3.5 3.5 3.472 3.411 3.409 3.395 3.385


3.382 3.381 3.38 3.364 3.341 3.316 3.313 3.304 3.285 3.264 3.263 3.248 3.22 3.215

8.28E-19 7.60E-15 1.61E-09 2.45E-10 5.32E-19 6.04E-15 3.38E-10 4.74E-10 3.93E-17 5.38E-13 1.39E-17 1.16E-12 3.61E-16 4.24E-32

Ap1 phorbol esters PTPRJ DOCK8 SASH1 tributyrin FOXO3 uric acid okadaic acid LEP Pkc(s) NOD2 IKBKB E. coli lipopolysaccharide 10E,12Z-octadecadienoic acid TBK1 Nfat (family) CD14 reactive oxygen species Pdgf (complex) zymosan CpG ODN 1668 MAP3K8 TAC1 CCL5 Map3k7 FOXL2 MAPK1

complex chemical - other phosphatase other other chemical drug transcription regulator chemical - endogenous mammalian chemical toxicant growth factor group other kinase chemical - endogenous nonmammalian chemical - endogenous mammalian kinase group transmembrane receptor chemical toxicant complex chemical - endogenous nonmammalian chemical reagent kinase other cytokine kinase transcription regulator kinase

3.208 3.208 3.207 3.162 3.162 3.132 3.131 3.13 3.127 3.126 3.119 3.117 3.115

2.23E-14 3.74E-12 2.73E-20 1.05E-10 1.40E-10 5.65E-11 8.14E-16 1.72E-09 1.28E-16 9.67E-11 2.39E-20 4.01E-12 5.66E-15

3.105 3.104 3.101 3.098 3.095 3.088 3.086

7.73E-11 1.41E-12 6.05E-10 7.06E-11 2.32E-13 6.25E-12 2.63E-09

3.078 3.07 3.068 3.067 3.055 3.047 3.046 3.043

1.19E-11 9.86E-12 1.17E-09 6.84E-10 7.71E-15 5.38E-13 6.03E-21 1.13E-13

AKT1 LDL L-dopa Mek IL27 MAP2K1 PAF1 Tnf (family) cis-urocanic acid F3 TGM2 ICAM1 SB 216763 MAPK8 methyl methanesulfonate PTGS2 EGFR trinitrobenzenesulfonic acid mitomycin C TGFA KITLG SMAD3 EIF2AK2 platelet activating factor PRKCE sphingosine-1-phosphate MAP3K1 IFN Beta FN1 ozone

kinase complex chemical - endogenous mammalian group cytokine kinase other group chemical drug transmembrane receptor enzyme transmembrane receptor chemical toxicant kinase chemical toxicant enzyme kinase chemical reagent chemical drug growth factor growth factor transcription regulator kinase chemical - endogenous mammalian kinase chemical - endogenous mammalian kinase group enzyme chemical toxicant

3.042 3.037 3.021 3.02 3.008 2.998 2.985 2.98 2.971 2.961 2.961 2.957 2.952 2.951 2.95 2.948 2.944 2.944 2.941 2.939 2.938 2.937 2.932 2.931 2.926 2.924 2.923 2.923 2.912 2.911


formaldehyde D-galactosamine fatty acid D-glucose thioacetamide Mapk Pam3-Cys-Ser-Lys4 CpG oligonucleotide Lh L-glutamic acid NFATC2 SRC JAK2 HIF1A CTNNB1 nitric oxide JUN oblimersen gentamicin C leukotriene C4 EP300 NFKB1 IL22 acetaminophen di(2-ethylhexyl) phthalate triamterene fenamic acid NGF TRADD MAPK14

chemical - endogenous mammalian chemical - endogenous mammalian chemical - endogenous mammalian chemical - endogenous mammalian chemical toxicant group chemical reagent chemical drug complex chemical - endogenous mammalian transcription regulator kinase kinase transcription regulator transcription regulator chemical - endogenous mammalian transcription regulator biologic drug chemical drug chemical - endogenous mammalian transcription regulator transcription regulator cytokine chemical drug chemical toxicant chemical drug chemical reagent growth factor other kinase

2.905 2.905 2.905 2.903 2.897 2.892 2.892 2.891 2.883 2.879 2.875 2.875 2.874 2.868 2.867 2.834 2.83 2.828 2.828 2.823 2.819 2.818 2.813 2.804 2.804 2.804 2.8 2.793 2.789 2.773


potassium chloride Gm-csf PDGFB DDX58 MAPK7 quinolinic acid MALP-2s MIF ELK1 BMP2 IL21 tamoxifen paclitaxel PI3K (complex) etoposide mycophenolic acid E. coli serotype 0127B8 lipopolysaccharide NFKBIA decitabine bucladesine CSF1 ARHGAP21 lomustine Ras BCR (complex) BDNF phenacetin ERBB2 EPHB1

chemical drug group growth factor enzyme kinase chemical - endogenous mammalian chemical reagent cytokine transcription regulator growth factor cytokine chemical drug chemical drug complex chemical drug chemical drug chemical - endogenous nonmammalian transcription regulator chemical drug chemical toxicant cytokine other chemical drug group complex growth factor chemical drug kinase kinase

2.769 2.769 2.768 2.763 2.76 2.758 2.735 2.733 2.728 2.725 2.722 2.721 2.719 2.717 2.715 2.714


2.707 2.705 2.677 2.659 2.658 2.646 2.646 2.645 2.639 2.637 2.63 2.623 2.621

1.67E-07 2.91E-15 8.84E-11 7.57E-19 2.53E-12 3.11E-08 5.24E-07 2.39E-09 1.68E-09 1.00E-09 2.62E-08 1.66E-11 1.43E-13

C5 ECSIT 2-bromoethylamine MAP2K4 SP1 CHRM1 PF4 3M-001 CD86 Fcer1 HMGB1 3M-011 EPAS1 BMP6 cobalt chloride IRF6 TLR5 IRF8 carbamylcholine dinoprost IL7 SMARCA4 HOXA5 aldosterone N-acetylmuramyl-L-alanyl-D-isoglutamine TGFB3 lipoteichoic acid hyaluronic acid

other transcription regulator chemical reagent kinase transcription regulator g-protein coupled receptor cytokine chemical drug transmembrane receptor complex transcription regulator chemical reagent transcription regulator growth factor chemical reagent transcription regulator transmembrane receptor transcription regulator chemical drug chemical - endogenous mammalian cytokine transcription regulator transcription regulator chemical - endogenous mammalian chemical - endogenous nonmammalian growth factor chemical - endogenous nonmammalian chemical - endogenous mammalian

2.621 2.621 2.621 2.618 2.617 2.613 2.613 2.613 2.611 2.61 2.61 2.608 2.607 2.607 2.607 2.604 2.602 2.594 2.592 2.585 2.584 2.584 2.578 2.576


2.575 2.572

1.59E-07 1.23E-05

2.569 2.565

5.24E-07 2.78E-15

IL33 F2RL1 REL imiquimod CREM CEBPB HRAS AGER IRF5 amphetamine CD40 TNFSF12 GH1 ST3-Hel2A-2 lipoarabinomannan KRT17 NEDD9 hexachlorobenzene MKNK1 CHUK GNRH NfkB-RelA crocidolite asbestos C3 ATF2 EIF2AK3 stearic acid CDK9 PRKCB

cytokine g-protein coupled receptor transcription regulator chemical drug transcription regulator transcription regulator enzyme transmembrane receptor transcription regulator chemical drug transmembrane receptor cytokine growth factor chemical reagent chemical - endogenous nonmammalian other other chemical toxicant kinase kinase group complex chemical toxicant peptidase transcription regulator kinase chemical - endogenous mammalian kinase kinase

2.563 2.562 2.56 2.552 2.548 2.546 2.531 2.525 2.515 2.512 2.504 2.493 2.454 2.449

4.72E-10 7.90E-09 2.30E-10 4.16E-10 8.11E-24 2.83E-12 3.63E-10 1.40E-10 8.82E-07 2.82E-07 6.37E-11 5.76E-06 6.56E-10 7.46E-11

2.449 2.449 2.449 2.449 2.449 2.448 2.447 2.441 2.436 2.435 2.43 2.426 2.425 2.423 2.423


PRKCA cyclopiazonic acid ELANE ATF4 C5AR1 IFI16 IRF7 GRP MAPK10 N-acetylsphingosine RETN CP-55940 sulindac sulfide IPMK 9,10-dimethyl-1,2-benzanthracene colchicine methylnitronitrosoguanidine enterotoxin B AREG bromodeoxyuridine CREBBP Pam3-Cys CpG ODN 1826 IL12 (family) Fc gamma receptor hemozoin LCN2 SYK

kinase chemical - endogenous nonmammalian peptidase transcription regulator g-protein coupled receptor transcription regulator transcription regulator growth factor kinase chemical reagent other chemical reagent chemical drug kinase chemical toxicant chemical drug chemical toxicant biologic drug growth factor chemical drug transcription regulator chemical toxicant chemical reagent group group chemical - endogenous nonmammalian transporter kinase

2.42

6.40E-09

2.416 2.416 2.415 2.415 2.414 2.412 2.41 2.409 2.408 2.407 2.402 2.402 2.401 2.401 2.401 2.4 2.397 2.395 2.395 2.394 2.392 2.39 2.39 2.385


2.382 2.379 2.377

4.32E-08 6.56E-06 6.55E-12

PTH vancomycin dopamine silicon dioxide CAMK4 GAST CD 437 Fibrinogen vinblastine PDX1 CXCR4 Pka 5-azacytidine Akt Interferon alpha TSH EPO DETA-NONOate 8-bromo-cAMP Ccl2 PIK3R1 GNRH1 bleomycin D-sphingosine Pkg CYR61 carboplatin SPIB TET2 mono-(2-ethylhexyl)phthalate

other biologic drug chemical - endogenous mammalian chemical drug kinase other chemical drug complex chemical drug transcription regulator g-protein coupled receptor complex chemical drug group group complex cytokine chemical reagent chemical reagent cytokine kinase other chemical drug chemical - endogenous mammalian group other chemical drug transcription regulator other chemical toxicant

2.376 2.376 2.376 2.375 2.375 2.369 2.367 2.366 2.359 2.355 2.353 2.346 2.345 2.344 2.34 2.324 2.319 2.3 2.269 2.263 2.243 2.243 2.242 2.236 2.236 2.236 2.236 2.236 2.236 2.236


N-formyl-Met-Leu-Phe phorbol 12,13-dibutyrate ceruletide lysophosphatidylcholine 4-methylnitrosoamino-1-(3-pyridinyl)-1-butanone TRPV4 PLC CD244 CSF1R PADI2 ANXA2 ethionine ETS2 pCPT-cAMP ADCYAP1R1 FGFR1 INHBA NOD1 CXCL3 asbestos TET1 LCK PPRC1 homocysteine AIMP1 BCL10 CAMP STAT1 IRF1

chemical reagent chemical - endogenous nonmammalian biologic drug chemical - other chemical toxicant ion channel group transmembrane receptor kinase enzyme other chemical toxicant transcription regulator chemical - kinase inhibitor g-protein coupled receptor kinase growth factor other cytokine chemical toxicant other kinase transcription regulator chemical - endogenous mammalian cytokine transcription regulator other transcription regulator transcription regulator

2.232

1.55E-05

2.23 2.229 2.228 2.225 2.224 2.219 2.219 2.219 2.219 2.219 2.219 2.219 2.216 2.213 2.207 2.205 2.204 2.201 2.2 2.2 2.2 2.2 2.196 2.195 2.194 2.193 2.191 2.191


NCR2 stallimycin trichostatin A ALB N-methyl-D-aspartate RIPK2 DDIT3 S-(2,3-bispalmitoyloxypropyl)-cysteine-GDPKHPKSF IL32 TNFSF13B MTPN STAT clozapine NfkB1-RelA TRAF6 MAP3K3 HSPD1 dibutyl phthalate FSH CLEC7A PGF TRH lauric acid IL4 NR5A2 Endothelin Ifn cyclophosphamide streptozocin Il3

transmembrane receptor biologic drug chemical drug transporter chemical reagent kinase transcription regulator chemical reagent cytokine cytokine transcription regulator group chemical drug complex enzyme kinase enzyme chemical toxicant complex transmembrane receptor growth factor other chemical - endogenous mammalian cytokine ligand-dependent nuclear receptor group group chemical drug chemical drug cytokine

2.19 2.19 2.189 2.189 2.189 2.188 2.186 2.185 2.184 2.183 2.18 2.18 2.179 2.178 2.177 2.176 2.176 2.176 2.174 2.172 2.169 2.169 2.161 2.158 2.158 2.157 2.155 2.154 2.144 2.138


BMP4 nitrofurantoin IGF1R EZH2 PLG S100A9 NFYA methapyrilene histamine Ifn gamma methamphetamine cycloheximide IFNA2 ESR2 IL6R Insulin tert-butyl-hydroquinone IKBKG NEK6 misoprostol NTRK1 tosedostat Collagen type I PIN1 seocalcitol SYVN1 ciprofibrate

growth factor chemical drug transmembrane receptor transcription regulator peptidase other transcription regulator chemical drug chemical - endogenous mammalian complex chemical drug chemical reagent cytokine ligand-dependent nuclear receptor transmembrane receptor group chemical reagent kinase kinase chemical drug kinase chemical drug complex enzyme chemical drug transporter chemical drug

2.138 2.137 2.133 2.129 2.129 2.128 2.121 2.121 2.108 2.088 2.078 2.058 2.056 2.047 2.036 2.021 2.016 2.005 2 2 2 2 2 2 2 2 2

8.75E-07 5.52E-08 4.19E-05 2.17E-11 2.26E-04 2.69E-10 6.05E-10 1.07E-05 2.74E-14 6.14E-05 6.96E-08 1.44E-27 9.37E-07 8.62E-12 2.36E-13 1.05E-12 2.23E-06 1.44E-10 3.79E-07 5.25E-06 2.04E-05 7.28E-05 1.21E-04 6.79E-04 1.02E-03 1.91E-02 2.46E-02

Inhibited U0126

chemical - kinase inhibitor

-6.13

4.18E-40

PD98059 LY294002 SB203580 2-amino-5-phosphonovaleric acid SP600125 CD3 SFTPA1 miR-155-5p (miRNAs w/seed UAAUGCU) wortmannin Hdac triamcinolone acetonide DACH1 KLF2 N-acetyl-L-cysteine Sb202190 DUSP1 bexarotene curcumin SU6656 COL18A1 actinomycin D Bay 11-7082 genistein Alpha catenin Nr1h herbimycin geldanamycin IL1RN VIP

chemical - kinase inhibitor chemical - kinase inhibitor chemical - kinase inhibitor chemical - other chemical - kinase inhibitor complex transporter mature microrna chemical - kinase inhibitor group chemical drug transcription regulator transcription regulator chemical drug chemical - kinase inhibitor phosphatase chemical drug chemical drug chemical toxicant other chemical drug chemical - kinase inhibitor chemical drug group group chemical - kinase inhibitor chemical - endogenous nonmammalian cytokine other

-5.758 -5.305 -4.415 -4.246 -4.179 -3.681 -3.643 -3.642 -3.543 -3.31 -3.293 -3.274 -3.25 -3.198 -3.158 -3.1 -3.087 -2.991 -2.975 -2.952 -2.928 -2.889 -2.863 -2.861 -2.777 -2.775

9.36E-25 5.65E-37 1.93E-18 8.60E-23 3.20E-19 2.35E-12 2.47E-19 1.08E-11 9.75E-13 6.70E-17 3.38E-14 3.24E-15 1.18E-08 3.67E-10 2.19E-09 1.10E-15 3.52E-08 1.81E-12 2.08E-12 2.39E-08 5.77E-13 4.16E-10 2.45E-12 3.33E-13 1.19E-05 1.79E-09

-2.711 -2.706 -2.653

1.31E-05 1.06E-11 5.66E-14

MEOX2 ACOX1 apigenin FOSL1 baicalein tyrphostin AG 1478 Sn50 peptide Ro31-8220 LYN carbon monoxide amino acids resolvin D1 bisindolylmaleimide I NS-398 CD28 AG490 DUSP5 iron CGS 21680 THRA PP1 tosylphenylalanyl chloromethyl ketone CORT pyrrolidine dithiocarbamate triptolide bardoxolone methyl calphostin C SERCA

transcription regulator enzyme chemical - endogenous nonmammalian transcription regulator chemical - endogenous nonmammalian chemical - kinase inhibitor chemical toxicant chemical - kinase inhibitor kinase chemical - endogenous mammalian chemical - endogenous mammalian chemical - endogenous mammalian chemical - kinase inhibitor chemical reagent transmembrane receptor chemical - kinase inhibitor phosphatase chemical - endogenous mammalian chemical reagent ligand-dependent nuclear receptor chemical - kinase inhibitor chemical - protease inhibitor other chemical reagent chemical drug chemical drug chemical - kinase inhibitor group

-2.646 -2.646

1.52E-08 1.12E-04

-2.635 -2.622

9.63E-08 1.50E-16

-2.607 -2.6 -2.597 -2.587 -2.581 -2.575 -2.56 -2.549 -2.513 -2.508 -2.499 -2.481 -2.449 -2.449 -2.433 -2.433 -2.425 -2.423 -2.418 -2.417 -2.417 -2.406 -2.404 -2.401


sulforafan SOCS3 sirolimus losartan potassium docosahexaenoic acid prazosin nimodipine USP18 MNT GPX1 mir-146 tempol edaravone GADD45A ZFP36 CEP-1347 Go 6976 ENTPD1 PS-1145 2-aminopurine ADA nifedipine triflusal ABCG1 pentobarbital fingolimod RCAN1 APOE NLRP12 SOCS1

chemical drug phosphatase chemical drug chemical drug chemical drug chemical drug chemical drug peptidase transcription regulator enzyme microrna chemical drug chemical drug other transcription regulator chemical drug chemical - kinase inhibitor enzyme chemical - kinase inhibitor chemical reagent enzyme chemical drug chemical drug transporter chemical drug chemical drug transcription regulator transporter other other

-2.398 -2.353 -2.317 -2.297 -2.268 -2.236 -2.236 -2.236 -2.236 -2.236 -2.226 -2.216 -2.213 -2.213 -2.207 -2.207 -2.205 -2.2 -2.2 -2.2 -2.2 -2.2 -2.198 -2.196 -2.192 -2.19 -2.186 -2.182 -2.18 -2.177


luteolin thalidomide H-7 silibinin SCD NR3C1 KN-62 TSC2 lipoxin A4 BCL6 Ciap THRB diphenyleneiodonium PRDM1 pyridoxamine 8-oxo-7-hydrodeoxyguanosine N,N-dimethylsphingosine cyclomaltodextrin Sod SIN3A ITCH RNF20 L-tryptophan FASN kaempferol FBXO32 daidzein INSIG1 miR-30c-5p (and other miRNAs w/seed GUAAACA)

chemical - endogenous nonmammalian chemical drug chemical - kinase inhibitor chemical drug enzyme ligand-dependent nuclear receptor chemical - kinase inhibitor other chemical - endogenous mammalian transcription regulator group ligand-dependent nuclear receptor chemical reagent transcription regulator chemical - endogenous mammalian chemical - endogenous mammalian chemical reagent chemical drug group transcription regulator enzyme enzyme chemical - endogenous mammalian enzyme chemical toxicant enzyme chemical drug other mature microrna

-2.176 -2.17 -2.169 -2.158 -2.153 -2.142 -2.138 -2.135 -2.126 -2.126 -2.116 -2.111 -2.092 -2.067 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2

1.59E-07 1.28E-07 5.17E-07 1.04E-05 2.64E-07 5.73E-27 3.90E-12 4.67E-08 6.15E-06 1.01E-05 2.00E-08 1.34E-08 2.98E-10 1.18E-08 4.59E-08 6.27E-07 1.46E-06 2.10E-06 3.96E-06 4.40E-06 5.25E-06 8.72E-06 1.10E-05 2.04E-05 3.46E-05 3.74E-03 4.24E-03 7.42E-03 9.33E-03

PKD1

ion channel

-2

S4Table7. Networks and associated network functions associated with perfusion driven IGF

Focus Score Molecules

ID 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

27 27 25 25 21 19 19 15 13 12 12 12 10 10 7 2 2 2 2

Top Diseases and Functions 17 17 16 16 14 13 13 11 10 9 9 9 8 8 6 1 1 1 1

Cell Death and Survival, Carbohydrate Metabolism, Molecular Transport Humoral Immune Response, Protein Synthesis, Neurological Disease Neurological Disease, Post-Translational Modification, Cellular Compromise Gastrointestinal Disease, Inflammatory Disease, Inflammatory Response Cell Morphology, Nervous System Development and Function, Neurological Disease Infectious Diseases, Organismal Development, Cardiovascular Disease Gene Expression, Cell Cycle, Connective Tissue Development and Function Hereditary Disorder, Neurological Disease, Organismal Injury and Abnormalities Organismal Injury and Abnormalities, Gene Expression, Cell Cycle Connective Tissue Disorders, Immunological Disease, Inflammatory Disease Cell-mediated Immune Response, Cellular Development, Cellular Function and Maintenance Neurological Disease, Small Molecule Biochemistry, Cellular Development DNA Replication, Recombination, and Repair, Neurological Disease, Cell-mediated Immune Response Cellular Compromise, Cellular Growth and Proliferation, Organismal Development Cellular Movement, Hematological System Development and Function, Immune Cell Trafficking Cell Death and Survival, Cellular Movement, Nervous System Development and Function Cellular Assembly and Organization, Cellular Function and Maintenance, Cancer Organismal Injury and Abnormalities, Reproductive System Disease

4.19E-02

S4Table8. The list of the canonical pathways associated with associated with perfusion driven DGF

Canonical Pathways Granulocyte Adhesion and Diapedesis Agranulocyte Adhesion and Diapedesis Differential Regulation of Cytokine Production in Intestinal Epithelial Cells by IL-17A and IL-17F Differential Regulation of Cytokine Production in Macrophages and T Helper Cells by IL-17A and IL-17F HMGB1 Signaling Glucocorticoid Receptor Signaling Role of Cytokines in Mediating Communication between Immune Cells Role of Hypercytokinemia/hyperchemokinemia in the Pathogenesis of Influenza TREM1 Signaling Communication between Innate and Adaptive Immune Cells Hepatic Fibrosis / Hepatic Stellate Cell Activation Atherosclerosis Signaling Unfolded protein response Cholecystokinin/Gastrin-mediated Signaling IL-6 Signaling PPAR Signaling IL-17A Signaling in Gastric Cells IL-10 Signaling NRF2-mediated Oxidative Stress Response Aryl Hydrocarbon Receptor Signaling IL-17A Signaling in Fibroblasts Retinoic acid Mediated Apoptosis Signaling Acute Phase Response Signaling p53 Signaling

-log(p-value) Ratio 1.29E+01 1.12E-01 1.14E+01 1.00E-01 1.13E+01 3.91E-01 8.87E+00 3.89E-01 8.38E+00 1.08E-01 6.92E+00 6.05E-02 6.43E+00 1.48E-01 5.98E+00 1.63E-01 5.28E+00 1.05E-01 4.73E+00 8.89E-02 4.56E+00 5.88E-02 4.51E+00 7.20E-02 4.22E+00 1.11E-01 4.22E+00 7.55E-02 3.94E+00 6.90E-02 3.75E+00 7.53E-02 3.59E+00 1.60E-01 3.53E+00 8.33E-02 3.31E+00 5.00E-02 3.26E+00 5.48E-02 3.02E+00 1.14E-01 2.89E+00 7.81E-02 2.82E+00 4.68E-02 2.82E+00 6.12E-02

zscore NaN NaN NaN NaN 3.464 NaN NaN NaN 2.828 NaN NaN NaN NaN 2.828 1.414 -1.89 NaN NaN 0.816 NaN NaN 2.236 1.414 NaN

GADD45 Signaling

2.78E+00

1.58E-01 NaN

JAK/Stat Signaling Role of IL-17F in Allergic Inflammatory Airway Diseases Toll-like Receptor Signaling Production of Nitric Oxide and Reactive Oxygen Species in Macrophages Sertoli Cell-Sertoli Cell Junction Signaling Chemokine Signaling ILK Signaling Prolactin Signaling IL-8 Signaling Type I Diabetes Mellitus Signaling iNOS Signaling VDR/RXR Activation Graft-versus-Host Disease Signaling Airway Pathology in Chronic Obstructive Pulmonary Disease CXCR4 Signaling Semaphorin Signaling in Neurons Aldosterone Signaling in Epithelial Cells ErbB Signaling Altered T Cell and B Cell Signaling in Rheumatoid Arthritis Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid Arthritis Pathogenesis of Multiple Sclerosis Tight Junction Signaling TNFR2 Signaling ATM Signaling Dendritic Cell Maturation IL-12 Signaling and Production in Macrophages PCP pathway IGF-1 Signaling

2.66E+00 2.64E+00 2.61E+00 2.59E+00 2.59E+00 2.59E+00 2.57E+00 2.56E+00 2.56E+00 2.54E+00 2.54E+00 2.49E+00 2.47E+00 2.37E+00 2.37E+00 2.35E+00 2.34E+00 2.33E+00 2.29E+00 2.28E+00 2.27E+00 2.27E+00 2.24E+00 2.18E+00 2.12E+00 2.10E+00 2.08E+00 2.07E+00


0.447 2 NaN 2.828 NaN 2.236 2.828 0.447 2.828 0.816 NaN NaN NaN NaN 2.449 NaN NaN NaN NaN NaN NaN NaN NaN NaN 2.646 NaN 1 0

Estrogen-Dependent Breast Cancer Signaling Interferon Signaling Role of IL-17A in Psoriasis Colorectal Cancer Metastasis Signaling Erythropoietin Signaling Role of PKR in Interferon Induction and Antiviral Response CCR5 Signaling in Macrophages Leukocyte Extravasation Signaling p38 MAPK Signaling Cyclins and Cell Cycle Regulation Germ Cell-Sertoli Cell Junction Signaling Systemic Lupus Erythematosus Signaling MSP-RON Signaling Pathway

1.99E+00 1.98E+00 1.95E+00 1.93E+00 1.93E+00 1.86E+00 1.84E+00 1.82E+00 1.78E+00 1.77E+00 1.75E+00 1.68E+00 1.67E+00

5.97E-02 8.33E-02 1.54E-01 3.32E-02 5.71E-02 7.50E-02 5.41E-02 3.43E-02 4.27E-02 5.13E-02 3.68E-02 3.21E-02 6.38E-02

LXR/RXR Activation TNFR1 Signaling Cell Cycle: G2/M DNA Damage Checkpoint Regulation Hepatic Cholestasis Neuregulin Signaling IL-2 Signaling Role of IL-17A in Arthritis Actin Nucleation by ARP-WASP Complex Role of JAK1, JAK2 and TYK2 in Interferon Signaling Glioma Invasiveness Signaling Role of JAK family kinases in IL-6-type Cytokine Signaling Protein Ubiquitination Pathway HGF Signaling CD40 Signaling phagosome formation Tec Kinase Signaling

1.63E+00 1.62E+00 1.62E+00 1.61E+00 1.52E+00 1.49E+00 1.47E+00 1.47E+00 1.44E+00 1.43E+00 1.40E+00 1.33E+00 1.32E+00 1.31E+00 1.31E+00 1.28E+00


NaN NaN NaN 2.828 NaN NaN NaN 2 1.342 -2 NaN NaN NaN 1.342 NaN NaN NaN 1 NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN 2

Role of Tissue Factor in Cancer 4-1BB Signaling in T Lymphocytes PXR/RXR Activation Airway Inflammation in Asthma Renin-Angiotensin Signaling IL-17 Signaling Role of MAPK Signaling in the Pathogenesis of Influenza 14-3-3-mediated Signaling Growth Hormone Signaling Role of Osteoblasts, Osteoclasts and Chondrocytes in Rheumatoid Arthritis STAT3 Pathway Corticotropin Releasing Hormone Signaling IL-9 Signaling Role of JAK2 in Hormone-like Cytokine Signaling Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses Signaling by Rho Family GTPases April Mediated Signaling Hereditary Breast Cancer Signaling Ceramide Signaling B Cell Activating Factor Signaling FXR/RXR Activation Type II Diabetes Mellitus Signaling TGF-Î² Signaling UVC-Induced MAPK Signaling Molecular Mechanisms of Cancer UVA-Induced MAPK Signaling Apoptosis Signaling Crosstalk between Dendritic Cells and Natural Killer Cells MIF Regulation of Innate Immunity Death Receptor Signaling

1.27E+00 1.24E+00 1.22E+00 1.21E+00 1.20E+00 1.20E+00 1.20E+00 1.19E+00 1.19E+00 1.18E+00 1.17E+00 1.17E+00 1.16E+00 1.16E+00 1.13E+00 1.10E+00 1.08E+00 1.07E+00 1.04E+00 1.04E+00 1.02E+00 1.02E+00 1.01E+00 1.01E+00 9.93E-01 9.88E-01 9.88E-01 9.77E-01 9.73E-01 9.56E-01


NaN NaN NaN NaN 2 NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN 2.449 NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN

Regulation of Actin-based Motility by Rho IL-1 Signaling Hematopoiesis from Pluripotent Stem Cells Estrogen Biosynthesis Glioblastoma Multiforme Signaling GÎ±q Signaling CD27 Signaling in Lymphocytes Hematopoiesis from Multipotent Stem Cells UVB-Induced MAPK Signaling HIF1Î± Signaling Tetrapyrrole Biosynthesis II Pancreatic Adenocarcinoma Signaling LPS/IL-1 Mediated Inhibition of RXR Function Calcium Transport I Thrombopoietin Signaling Sphingosine-1-phosphate Signaling Induction of Apoptosis by HIV1 EGF Signaling Huntington's Disease Signaling Activation of IRF by Cytosolic Pattern Recognition Receptors Role of JAK1 and JAK3 in Î³c Cytokine Signaling ERK5 Signaling Cell Cycle: G1/S Checkpoint Regulation Hypoxia Signaling in the Cardiovascular System Mitotic Roles of Polo-Like Kinase IL-17A Signaling in Airway Cells Remodeling of Epithelial Adherens Junctions phagosome maturation PI3K/AKT Signaling Agrin Interactions at Neuromuscular Junction



NaN NaN NaN NaN 1 1 NaN NaN NaN NaN NaN NaN 2 NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN

IL-3 Signaling GDNF Family Ligand-Receptor Interactions mTOR Signaling T Helper Cell Differentiation Neurotrophin/TRK Signaling PI3K Signaling in B Lymphocytes Endoplasmic Reticulum Stress Pathway LPS-stimulated MAPK Signaling Renal Cell Carcinoma Signaling RAR Activation GNRH Signaling D-myo-inositol (1,4,5,6)-Tetrakisphosphate Biosynthesis D-myo-inositol (3,4,5,6)-tetrakisphosphate Biosynthesis Adipogenesis pathway Zymosterol Biosynthesis HER-2 Signaling in Breast Cancer Polyamine Regulation in Colon Cancer Role of Lipids/Lipid Rafts in the Pathogenesis of Influenza Heme Biosynthesis II Fatty Acid Î±-oxidation Role of BRCA1 in DNA Damage Response IL-22 Signaling Tumoricidal Function of Hepatic Natural Killer Cells Estrogen-mediated S-phase Entry Integrin Signaling Regulation of IL-2 Expression in Activated and Anergic T Lymphocytes PDGF Signaling Epithelial Adherens Junction Signaling IL-15 Production Allograft Rejection Signaling



NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN 2 NaN NaN NaN NaN NaN

Bladder Cancer Signaling D-myo-inositol-5-phosphate Metabolism 3-phosphoinositide Degradation RANK Signaling in Osteoclasts eNOS Signaling Cardiac Hypertrophy Signaling SAPK/JNK Signaling Telomerase Signaling Circadian Rhythm Signaling Coagulation System Cell Cycle Regulation by BTG Family Proteins 3-phosphoinositide Biosynthesis T Cell Receptor Signaling NF-ÎºB Signaling CDK5 Signaling Antigen Presentation Pathway Complement System Role of NFAT in Regulation of the Immune Response Glioma Signaling Inhibition of Angiogenesis by TSP1 Cholesterol Biosynthesis I Cholesterol Biosynthesis II (via 24,25-dihydrolanosterol) Cholesterol Biosynthesis III (via Desmosterol) RhoGDI Signaling Transcriptional Regulatory Network in Embryonic Stem Cells Inhibition of Matrix Metalloproteases Salvage Pathways of Pyrimidine Ribonucleotides PPARÎ±/RXRÎ± Activation Thyroid Cancer Signaling Regulation of the Epithelial-Mesenchymal Transition Pathway



NaN NaN NaN NaN NaN 2 NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN

Endothelin-1 Signaling Androgen Signaling G-Protein Coupled Receptor Signaling Melanoma Signaling ERK/MAPK Signaling Docosahexaenoic Acid (DHA) Signaling Role of Oct4 in Mammalian Embryonic Stem Cell Pluripotency Neuroprotective Role of THOP1 in Alzheimer's Disease Thrombin Signaling PKCÎ¸ Signaling in T Lymphocytes Xenobiotic Metabolism Signaling CD28 Signaling in T Helper Cells Axonal Guidance Signaling Estrogen Receptor Signaling P2Y Purigenic Receptor Signaling Pathway Role of CHK Proteins in Cell Cycle Checkpoint Control Lymphotoxin Î² Receptor Signaling Superpathway of Inositol Phosphate Compounds ErbB2-ErbB3 Signaling Nur77 Signaling in T Lymphocytes Regulation of Cellular Mechanics by Calpain Protease cAMP-mediated signaling Heparan Sulfate Biosynthesis (Late Stages) Relaxin Signaling IL-15 Signaling Glutamate Receptor Signaling Role of PI3K/AKT Signaling in the Pathogenesis of Influenza Antiproliferative Role of Somatostatin Receptor 2 Calcium-induced T Lymphocyte Apoptosis Heparan Sulfate Biosynthesis



NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN NaN

Caveolar-mediated Endocytosis Signaling Small Cell Lung Cancer Signaling Pyridoxal 5'-phosphate Salvage Pathway Ephrin B Signaling Role of Wnt/GSK-3Î² Signaling in the Pathogenesis of Influenza IL-4 Signaling BMP signaling pathway Leptin Signaling in Obesity GPCR-Mediated Integration of Enteroendocrine Signaling Exemplified by an L Cell

2.18E-01 2.15E-01 2.15E-01 2.11E-01 2.08E-01 2.04E-01 2.04E-01 2.01E-01 1.98E-01

S4Table9. The complete list of activated and inhibited upstream regulators associated with perfusion driven DGF

Upstream Regulator Activated lipopolysaccharide TNF IL1B PDGF BB phorbol myristate acetate NFkB (complex) poly rI:rC-RNA IFNG IL2 Salmonella enterica serotype abortus equi lipopolysaccharide P38 MAPK IL6

Activation z-score

p-value of overlap

chemical drug cytokine cytokine complex chemical drug complex biologic drug cytokine cytokine

7.73 7.287 6.724 6.222 6.109 6.083 5.885 5.859 5.484

1.92E-31 1.57E-35 6.07E-37 1.27E-32 1.87E-20 3.97E-25 2.16E-24 3.03E-21 1.09E-21

chemical toxicant group cytokine

5.445 5.361 5.233

1.67E-26 2.72E-25 6.18E-19

Molecule Type

1.37E-02 1.35E-02 1.35E-02 1.33E-02 1.32E-02 1.30E-02 1.30E-02 1.28E-02 1.27E-02

NaN NaN NaN NaN NaN NaN NaN NaN NaN

ERK F2 CREB1 CSF2 hydrogen peroxide IL1 MYD88 TNFSF11 leukotriene D4 salmonella minnesota R595 lipopolysaccharides TLR3 RELA E. coli B5 lipopolysaccharide tretinoin 5-O-mycolyl-beta-araf-(1->2)-5-O-mycolylalpha-araf-(1->1')-glycerol cisplatin ERK1/2 thapsigargin EGF kainic acid Ca2+ TLR9 TGFB1 IL1A

group peptidase transcription regulator cytokine chemical - endogenous mammalian group other cytokine chemical - endogenous mammalian chemical - endogenous non-mammalian transmembrane receptor transcription regulator chemical - endogenous non-mammalian chemical - endogenous mammalian chemical - endogenous non-mammalian chemical drug group chemical toxicant growth factor chemical toxicant chemical - endogenous mammalian transmembrane receptor growth factor cytokine

5.13 5.125 5.099 4.997

3.68E-26 2.99E-20 2.68E-28 1.89E-22

4.997 4.891 4.876 4.79

6.21E-19 2.81E-13 9.54E-21 3.65E-18

4.787

4.02E-32

4.786 4.772 4.738

4.68E-24 1.41E-18 2.68E-19

4.736

6.71E-18

4.66

1.29E-08

4.656 4.622 4.619 4.589 4.586 4.525

1.22E-23 2.09E-16 4.18E-19 9.40E-23 3.04E-21 1.89E-18

4.458 4.451 4.377 4.345

4.88E-19 8.76E-17 5.42E-21 1.86E-12

cocaine TLR4 peptidoglycan TICAM1 AGT IL17A dalfampridine EGR1 Jnk IL3 doxorubicin TLR7 GnRH-A bicuculline E. coli B4 lipopolysaccharide CD40LG gentamicin SMARCA4 IL5 camptothecin NUPR1 cigarette smoke OSM FOXO1 IKBKB carbon tetrachloride STAT4 palmitic acid

chemical drug transmembrane receptor chemical - endogenous non-mammalian other growth factor cytokine chemical drug transcription regulator group cytokine chemical drug transmembrane receptor chemical reagent chemical - endogenous non-mammalian chemical toxicant cytokine chemical drug transcription regulator cytokine chemical drug transcription regulator chemical toxicant cytokine transcription regulator kinase chemical toxicant transcription regulator chemical - endogenous

4.341 4.315

1.28E-16 1.60E-18

4.314 4.302 4.287 4.248 4.243 4.24 4.234 4.234 4.232 4.228 4.172

5.37E-19 4.70E-20 3.25E-12 1.68E-19 5.07E-27 2.21E-21 4.04E-21 3.96E-15 2.47E-16 2.68E-16 7.66E-24

4.165 4.162 4.156 4.133 4.119 4.105 4.094 4.082 4.052 3.961 3.957 3.944 3.93 3.922 3.919


mammalian Ap1 RAF1 IL18 IL4 FGF2 IGF1 TLR2 Vegf TP53 carrageenan Tlr Cg PTGS2 CXCL12 EDN1 E. coli lipopolysaccharide MAP2K1/2 APP SMAD3 resiquimod D-glucose CD40 EPO forskolin acetaminophen KITLG

complex kinase cytokine cytokine growth factor growth factor transmembrane receptor group transcription regulator chemical - endogenous non-mammalian group complex enzyme cytokine cytokine chemical - endogenous non-mammalian group other transcription regulator chemical drug chemical - endogenous mammalian transmembrane receptor cytokine chemical toxicant chemical drug growth factor

3.916 3.912 3.898 3.883 3.84 3.84 3.828 3.816 3.81

1.32E-14 1.01E-12 9.17E-12 5.38E-15 1.09E-14 2.26E-12 2.95E-12 4.44E-11 7.37E-18

3.786 3.766 3.762 3.706 3.678 3.67

2.74E-19 3.96E-13 7.53E-13 5.45E-13 8.64E-11 1.68E-10

3.669 3.657 3.655 3.648 3.646

4.39E-14 2.22E-14 4.89E-11 1.03E-19 4.53E-17

3.637 3.627 3.614 3.576 3.541 3.537

5.51E-12 7.94E-12 5.01E-13 6.72E-29 3.30E-11 9.81E-08

A23187 bleomycin TCR ionomycin IL15 PTPRJ Pam3-Cys-Ser-Lys4 CTNNB1 CSF1 methyl methanesulfonate TREM1 anisomycin IL7 trinitrobenzenesulfonic acid trovafloxacin SAMSN1 lysophosphatidic acid TAC1 Interferon alpha Tnf (family) FOXL2 PAF1 MET LEP Nfat (family) C5 AGER 5-hydroxytryptamine

chemical reagent chemical drug complex chemical reagent cytokine phosphatase chemical reagent transcription regulator cytokine chemical toxicant transmembrane receptor chemical - endogenous non-mammalian cytokine chemical reagent chemical drug other chemical - other other group group transcription regulator other kinase growth factor group cytokine transmembrane receptor chemical - endogenous mammalian

3.525 3.51 3.493 3.491 3.487 3.464 3.413 3.403 3.401 3.396 3.394

5.89E-10 8.01E-11 6.50E-11 1.32E-07 3.53E-14 2.92E-14 7.88E-13 1.70E-04 1.59E-12 1.85E-15 1.37E-18

3.392 3.377 3.369 3.357 3.357 3.353 3.351 3.342 3.316 3.311 3.302 3.302 3.284 3.268 3.258 3.257


3.255

5.31E-10

CpG ODN 1668 CCL5 trichostatin A enterotoxin B MAP2K1 hemozoin CHUK Pdgf (complex) PI3K (complex) TNFRSF1A S100A9 Ras HIF1A IFI16 AKT1 PDX1 IL12 (complex) 10E,12Z-octadecadienoic acid PF4 NGF okadaic acid NFATC2 TGFB3 EIF2AK2 MAPK14 mitomycin C CpG oligonucleotide IRF8

chemical reagent cytokine chemical drug biologic drug kinase chemical - endogenous non-mammalian kinase complex complex transmembrane receptor other group transcription regulator transcription regulator kinase transcription regulator complex chemical - endogenous mammalian cytokine growth factor chemical toxicant transcription regulator growth factor kinase kinase chemical drug chemical drug transcription regulator

3.239 3.232 3.226 3.212 3.211

1.70E-12 1.27E-13 9.50E-12 4.20E-11 2.38E-12

3.204 3.203 3.191 3.187 3.181 3.181 3.169 3.134 3.131 3.13 3.13 3.118

5.90E-15 5.26E-14 6.82E-12 5.49E-17 4.26E-17 7.72E-09 1.98E-11 4.27E-13 1.34E-09 2.55E-08 1.73E-07 1.96E-08

3.112 3.107 3.099 3.097 3.092 3.081 3.078 3.078 3.077 3.073 3.071

3.44E-09 7.93E-14 6.67E-11 1.09E-13 2.35E-10 3.82E-07 1.96E-12 1.69E-11 2.09E-09 3.59E-09 4.80E-09

decitabine SRC HGF L-glutamic acid deferoxamine HMGB1 tunicamycin GH1 lipoarabinomannan SELPLG zymosan BMP6 Mek MAPK3 thioacetamide reactive oxygen species TNFSF12 IL17a dimer PGR MIF CD14 TGM2 IFNA2 F7 ATF4 cyclic AMP

chemical drug kinase growth factor chemical - endogenous mammalian chemical drug transcription regulator chemical - endogenous non-mammalian growth factor chemical - endogenous non-mammalian other chemical - endogenous non-mammalian growth factor group kinase chemical toxicant chemical toxicant cytokine complex ligand-dependent nuclear receptor cytokine transmembrane receptor enzyme cytokine peptidase transcription regulator chemical - endogenous

3.07 3.067 3.065

2.20E-11 1.37E-06 2.84E-19

3.045 3.036 3.013

2.37E-07 1.04E-12 1.13E-10

3.01 3.01

2.14E-10 2.10E-07

3 3

4.67E-14 1.22E-10

2.985 2.985 2.98 2.975 2.975 2.97 2.968 2.966

2.15E-12 1.16E-07 1.02E-09 2.05E-11 4.24E-05 1.22E-11 1.36E-06 2.88E-12

2.964 2.962 2.956 2.949 2.947 2.945 2.943 2.94

7.52E-07 7.70E-12 3.26E-11 8.69E-05 9.45E-09 9.00E-11 8.40E-08 3.55E-11

mammalian JAK2 TLR5 IL27 AGN194204 CpG ODN 1826 FN1 F2R IL6R VEGFA MAP3K8 NOD2 LCN2 MALP-2s platelet activating factor LDL ELK1 formaldehyde D-galactosamine uric acid beta-estradiol TBK1 Ifn gamma SRF CREBBP

kinase transmembrane receptor cytokine chemical drug chemical reagent enzyme g-protein coupled receptor transmembrane receptor growth factor kinase other transporter chemical reagent chemical - endogenous mammalian complex transcription regulator chemical - endogenous mammalian chemical - endogenous mammalian chemical - endogenous mammalian chemical - endogenous mammalian kinase complex transcription regulator transcription regulator

2.935 2.934 2.931 2.931 2.93 2.929

1.26E-05 3.79E-10 2.12E-13 1.48E-04 1.76E-09 1.56E-07

2.928 2.926 2.926 2.923 2.922 2.921 2.919

1.48E-09 4.99E-11 1.21E-09 2.35E-09 6.79E-14 4.12E-08 1.07E-11

2.916 2.913 2.909

9.59E-09 3.67E-21 3.82E-13

2.905

2.31E-11

2.905

3.79E-11

2.904

3.72E-12

2.887 2.876 2.851 2.847 2.835

6.23E-31 1.49E-11 1.24E-06 1.49E-12 3.70E-11

MAPK8 IFNB1 NEDD9 DOCK8 SASH1 leukotriene C4 EIF2AK3 TRADD oblimersen di(2-ethylhexyl) phthalate NRG1 C5AR1 Ccl2 PRKCA AIMP1 bromodeoxyuridine carbamylcholine imiquimod IL32 HSPD1 EP300 N-acetylmuramyl-L-alanyl-D-isoglutamine Mapk TRAF6 Gm-csf dinoprost

kinase cytokine other other other chemical - endogenous mammalian kinase other biologic drug chemical toxicant other g-protein coupled receptor cytokine kinase cytokine chemical drug chemical drug chemical drug cytokine enzyme transcription regulator chemical - endogenous non-mammalian group enzyme group chemical - endogenous mammalian

2.832 2.83 2.828 2.828 2.828

3.79E-10 2.48E-08 8.02E-09 1.58E-06 1.97E-06

2.821 2.816 2.813 2.813 2.804 2.801

2.12E-12 2.55E-06 8.94E-10 2.29E-07 3.06E-07 1.33E-14

2.791 2.791 2.787 2.784 2.781 2.777 2.775 2.774 2.772 2.77

3.57E-08 2.65E-07 3.25E-10 2.12E-12 1.97E-07 1.27E-08 2.37E-09 9.59E-09 2.20E-10 2.81E-08

2.766 2.76 2.76 2.759

1.36E-08 2.26E-09 1.97E-07 9.59E-09

2.759

3.31E-06

SP1 etoposide E. coli serotype 0127B8 lipopolysaccharide cyclophosphamide PGF ozone phorbol esters CREM hyaluronic acid CXCR4 S100A8 IL21 STAT3 NFKB1 methylprednisolone NFKBIA FOXO3 bucladesine KRT17 gentamicin C MKNK1 CAMP NfkB-RelA ATP F3 ETS2

transcription regulator chemical drug chemical - endogenous non-mammalian chemical drug growth factor chemical toxicant chemical - other transcription regulator chemical - endogenous mammalian g-protein coupled receptor other cytokine transcription regulator transcription regulator chemical drug transcription regulator transcription regulator chemical toxicant other chemical drug kinase other complex chemical - endogenous mammalian transmembrane receptor transcription regulator

2.745 2.74

3.09E-13 5.57E-09

2.74 2.739 2.736 2.735 2.729 2.728

4.91E-08 2.70E-06 2.12E-12 4.59E-10 1.16E-07 1.66E-20

2.726

3.14E-11

2.726 2.72 2.715 2.714 2.712 2.703 2.7 2.691 2.677 2.646 2.646 2.646 2.642 2.638

1.89E-08 2.39E-10 6.99E-06 1.08E-17 1.51E-15 2.84E-08 6.05E-14 2.25E-11 5.88E-18 4.92E-08 9.58E-06 2.03E-04 1.00E-12 6.36E-09

2.63 2.63 2.63

1.97E-10 8.60E-06 8.60E-06

triamterene IGF1R homocysteine PRKCE IL-17f dimer C5 MTPN ICAM1 fenamic acid CCL3 3M-001 ERBB2 IL17F TNFRSF8 stallimycin tamoxifen norepinephrine GLI1 PRKCD CAMK4 GNRH1 ETS1 aldosterone F2RL1 silicon dioxide fatty acid

chemical drug transmembrane receptor chemical - endogenous mammalian kinase complex other transcription regulator transmembrane receptor chemical reagent cytokine chemical drug kinase cytokine transmembrane receptor biologic drug chemical drug chemical - endogenous mammalian transcription regulator kinase kinase other transcription regulator chemical - endogenous mammalian g-protein coupled receptor chemical drug chemical - endogenous mammalian

2.63 2.63

1.31E-05 1.86E-04

2.627 2.625 2.621 2.621 2.621 2.619 2.619 2.613 2.613 2.608 2.605 2.6 2.598 2.595

5.04E-07 9.54E-08 5.37E-10 5.37E-10 5.43E-05 3.79E-11 1.76E-05 3.21E-10 2.32E-07 7.57E-10 2.92E-08 7.71E-06 1.10E-06 2.01E-06

2.587 2.586 2.583 2.583 2.583 2.582

1.16E-10 8.84E-03 9.14E-12 6.29E-08 4.86E-06 3.30E-08

2.582

6.73E-04

2.581 2.577

2.65E-07 3.19E-10

2.575

1.39E-05

Fibrinogen MAPK7 methylnitronitrosoguanidine quinolinic acid Pam3-Cys JUN Lh tributyrin STAT5A LIF 5-azacytidine nitrofurantoin Map3k7 TGFA PLG NFYA PIK3R1 ANGPT2 Pka RETN Fcer1 RET C3 paclitaxel 25-hydroxycholesterol BCR (complex) ARHGAP21 SPIB cardiotoxin

complex kinase chemical toxicant chemical - endogenous mammalian chemical toxicant transcription regulator complex chemical drug transcription regulator cytokine chemical drug chemical drug kinase growth factor peptidase transcription regulator kinase growth factor complex other complex kinase peptidase chemical drug chemical reagent complex other transcription regulator chemical - other

2.574 2.573 2.571

6.29E-11 3.41E-12 3.81E-08

2.565 2.561 2.553 2.552 2.55 2.547 2.543 2.538 2.538 2.535 2.535 2.533 2.53 2.53 2.53 2.518 2.499 2.497 2.482 2.463 2.458 2.455 2.449 2.449 2.449 2.449

4.32E-08 2.81E-07 3.06E-15 2.93E-07 4.72E-09 4.47E-08 2.54E-12 6.92E-06 3.06E-05 3.35E-12 3.11E-09 2.55E-05 1.49E-11 1.14E-08 1.70E-05 2.30E-15 4.93E-11 5.15E-12 3.43E-13 4.64E-07 9.18E-19 5.02E-16 1.82E-07 1.11E-05 4.93E-04 9.38E-03

mono-(2-ethylhexyl)phthalate calcitriol Ni2+ crocidolite asbestos sulindac sulfide cuprizone phenacetin 9,10-dimethyl-1,2-benzanthracene ALB topotecan EPHB1 SP3 2-bromoethylamine cis-urocanic acid BMP2 CXCL3 lysophosphatidylcholine CHRM1 ATF2 PPRC1 CCND1 PIK3CG PRKCB cobalt chloride CRH potassium chloride haloperidol MAP2K4 colchicine

chemical toxicant chemical drug chemical reagent chemical toxicant chemical drug chemical toxicant chemical drug chemical toxicant transporter chemical drug kinase transcription regulator chemical reagent chemical drug growth factor cytokine chemical - other g-protein coupled receptor transcription regulator transcription regulator transcription regulator kinase kinase chemical reagent cytokine chemical drug chemical drug kinase chemical drug

2.449 2.447 2.438 2.436 2.435 2.433 2.433 2.433 2.433 2.428 2.425 2.425 2.425 2.423 2.423 2.418 2.415

1.37E-02 1.23E-09 2.96E-07 7.96E-07 2.12E-05 4.33E-08 9.64E-06 9.64E-06 1.27E-05 5.49E-09 5.31E-10 3.68E-09 2.40E-05 1.67E-07 4.98E-04 1.91E-08 2.90E-11

2.415 2.415 2.414 2.414 2.413 2.412 2.408 2.406 2.405 2.405 2.404 2.401

2.29E-09 4.06E-09 1.45E-05 4.77E-03 1.11E-05 4.31E-06 1.97E-04 7.71E-06 2.80E-10 5.25E-04 5.19E-05 2.59E-06

HOXA5 seocalcitol GATA1 GATA4 sphingosine-1-phosphate JAK1 Akt Il3 CD244 TLR8 STAT BDNF NR3C2 IL12 (family) lipoteichoic acid RNASE2 CLEC7A N-methyl-D-aspartate SYK L-dopa chenodeoxycholic acid IL33 PTH SREBF1 AR

transcription regulator chemical drug transcription regulator transcription regulator chemical - endogenous mammalian kinase group cytokine transmembrane receptor transmembrane receptor group growth factor ligand-dependent nuclear receptor group chemical - endogenous non-mammalian enzyme transmembrane receptor chemical reagent kinase chemical - endogenous mammalian chemical - endogenous mammalian cytokine other transcription regulator ligand-dependent nuclear receptor

2.4 2.4 2.4 2.4

8.87E-08 7.00E-05 7.69E-04 1.19E-02

2.399 2.396 2.392 2.391 2.39 2.387 2.382 2.381

5.97E-08 8.07E-10 5.02E-12 1.60E-05 7.22E-11 1.27E-05 1.90E-07 7.37E-11

2.378 2.377

4.58E-07 5.95E-04

2.374 2.372 2.368 2.367 2.359

6.34E-08 3.80E-06 2.96E-07 1.65E-05 3.79E-10

2.348

2.87E-03

2.346 2.345 2.327 2.31

4.33E-04 4.52E-07 4.04E-11 2.59E-03

2.306

1.67E-04

REL methamphetamine vinblastine 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine MAPK1 diethylstilbestrol Pkc(s) tert-butyl-hydroquinone dextran sulfate ST3-Hel2A-2 KLK5 NTRK1 H2AFB3 (includes others) hexachlorobenzene TBX5 OGG1 Notch GNRH ceruletide N-formyl-Met-Leu-Phe IRF1 YAP1 clozapine 8-hydroxyguanine ACVR1C DPP-23 dimethylnitrosamine ELANE

transcription regulator chemical drug chemical drug

2.298 2.279 2.279

3.15E-10 1.31E-08 6.32E-07

chemical toxicant kinase chemical drug group chemical reagent chemical drug chemical reagent peptidase kinase other chemical toxicant transcription regulator enzyme group group biologic drug chemical reagent transcription regulator transcription regulator chemical drug chemical - endogenous mammalian kinase chemical reagent chemical toxicant peptidase

2.276 2.27 2.269 2.265 2.247 2.244 2.236 2.236 2.236 2.236 2.236 2.236 2.233 2.233 2.233 2.229 2.226 2.226 2.224 2.222

1.09E-07 3.22E-13 2.42E-04 7.73E-13 4.45E-06 2.87E-06 9.84E-08 1.71E-06 5.04E-06 3.40E-04 5.71E-04 1.12E-03 1.34E-09 2.19E-06 7.98E-06 5.04E-06 1.34E-04 2.47E-03 1.28E-03 7.81E-04

2.219 2.219 2.219 2.219 2.219

1.34E-09 1.71E-06 2.29E-06 1.45E-05 2.98E-05

D-fructose phenylbutazone EIF4E thyroid hormone pCPT-cAMP TACR1 SRC (family) FOXO4 PSEN1 Raf CSF1R cyclopiazonic acid Lymphotoxin RORC CEBPB picryl chloride IL-1R fluoxetine 2,4-dinitrofluorobenzene S-(2,3-bispalmitoyloxypropyl)-cysteineGDPKHPKSF TET1 cytarabine N-acetylsphingosine isotretinoin

chemical - endogenous mammalian chemical drug translation regulator chemical - endogenous mammalian chemical - kinase inhibitor g-protein coupled receptor group transcription regulator peptidase group kinase chemical - endogenous non-mammalian complex ligand-dependent nuclear receptor transcription regulator chemical toxicant group chemical drug chemical toxicant chemical reagent other chemical drug chemical reagent biologic drug

2.219 2.219 2.219

1.34E-04 7.24E-04 5.93E-03

2.219

6.33E-03

2.216

5.42E-08

2.216 2.216 2.215 2.214 2.213 2.213

1.24E-06 1.27E-05 1.11E-05 3.01E-06 6.32E-07 6.32E-07

2.213 2.213

8.86E-07 2.29E-06

2.213 2.211 2.211 2.207 2.207 2.203

8.71E-05 3.04E-13 4.14E-07 2.96E-07 2.87E-04 1.24E-06

2.2 2.2 2.2 2.2 2.2

1.71E-06 5.04E-06 1.32E-04 1.68E-04 1.87E-03

TLR6 PDGFB CP-55940 NfkB1-RelA 4-methylnitrosoamino-1-(3-pyridinyl)-1butanone AMH CYR61 IL17C LAMA5 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene EPAS1 ssRNA40 CXCL10 TNFSF13B amphetamine MAP2K5 Ifn vancomycin NR1I3 DDX58 TRH MAP2K3 LCK dimethyl sulfoxide IFN alpha/beta dopamine cycloheximide

transmembrane receptor growth factor chemical reagent complex

2.198 2.197 2.196 2.196

5.04E-06 4.68E-05 5.28E-06 1.21E-05

chemical toxicant growth factor other cytokine other chemical toxicant transcription regulator chemical reagent cytokine cytokine chemical drug kinase group biologic drug ligand-dependent nuclear receptor enzyme other kinase kinase chemical drug group chemical - endogenous mammalian chemical reagent

2.196 2.194 2.19 2.19 2.186 2.186 2.183 2.183 2.183 2.183 2.182 2.182 2.178 2.178

2.98E-05 1.21E-05 5.28E-06 2.12E-05 1.24E-06 7.39E-03 4.76E-07 1.71E-06 9.88E-06 3.09E-04 8.43E-07 3.93E-06 1.48E-06 8.42E-06

2.177 2.174 2.169 2.166 2.16 2.158 2.156

7.39E-03 4.84E-04 6.30E-05 1.76E-05 2.52E-05 2.00E-05 2.49E-03

2.156 2.14

7.70E-03 5.67E-24

PTPRC CXCL2 CCL11 allopurinol PARP1 Ins1 progesterone NOTCH1 RIPK2 NFKBIB SPP1 KLF6 STAT1 STAT5B PTGER2 DETA-NONOate EGFR CD38 IL12B SELP prostaglandin E2 Growth hormone nitric oxide KRAS 6,7-dinitroquinoxaline-2,3-dione ANKRD42

phosphatase cytokine cytokine chemical drug enzyme other chemical - endogenous mammalian transcription regulator kinase transcription regulator cytokine transcription regulator transcription regulator transcription regulator g-protein coupled receptor chemical reagent kinase enzyme cytokine transmembrane receptor chemical - endogenous mammalian group chemical - endogenous mammalian enzyme chemical reagent transcription regulator

2.14 2.138 2.138 2.138 2.128 2.118

6.32E-07 4.19E-12 9.59E-09 7.06E-06 1.59E-07 5.80E-06

2.105 2.089 2.083 2.078 2.077 2.068 2.058 2.058

4.98E-10 2.87E-06 1.93E-05 1.69E-07 3.21E-09 1.41E-11 2.41E-12 9.27E-08

2.055 2.048 2.038 2.027 2.025 2.024

3.86E-06 5.52E-09 4.92E-18 2.65E-03 1.89E-08 4.77E-12

2.023 2.022

5.23E-25 3.53E-07

2.016 2.003 2 2

7.84E-10 2.11E-07 1.34E-09 6.58E-07

U1 snRNP TGFB2 Pdgfr

2 2 2

1.30E-06 3.28E-06 3.84E-06

tridecanoic acid Ikb ALOX12 Pdgf Ab CARM1 RNASE1 RNF31 nitroarginine BRD2 tosedostat carboplatin RETNLB ISL1

complex growth factor group chemical - endogenous mammalian group enzyme complex transcription regulator enzyme enzyme chemical reagent kinase chemical drug chemical drug other transcription regulator

2 2 2 2 2 2 2 2 2 2 2 2 2

3.84E-06 5.04E-06 5.97E-06 5.19E-05 6.30E-05 9.86E-05 1.19E-04 3.16E-04 3.40E-04 4.15E-04 2.90E-03 1.33E-02 2.00E-02

Inhibited prazosin belnacasan PPT1 RNF20 USP18 ENTPD1 kaempferol ethylenediaminetetraacetic acid ITCH fontolizumab chelerythrine NFIL3

chemical drug chemical drug enzyme enzyme peptidase enzyme chemical toxicant chemical drug enzyme biologic drug chemical drug transcription regulator

-2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2

2.69E-07 6.58E-07 1.30E-06 1.71E-06 1.71E-06 2.32E-06 9.88E-06 1.27E-05 3.14E-05 4.07E-05 8.06E-05 1.43E-04

JAK inhibitor I bisindolylmaleimide CR1L SIN3A andrographolide paricalcitol GPX1 alefacept miR-199a-5p (and other miRNAs w/seed CCAGUGU) losartan potassium BAPTA-AM MEOX2 KLF2 SOX2 THRB rottlerin alvocidib carbon monoxide mifepristone PP2/AG1879 tyrosine kinase inhibitor pentoxifylline resolvin D1 luteolin

chemical - kinase inhibitor chemical - kinase inhibitor other transcription regulator chemical drug chemical drug enzyme biologic drug mature microrna chemical drug chemical reagent transcription regulator transcription regulator transcription regulator ligand-dependent nuclear receptor chemical toxicant chemical drug chemical - endogenous mammalian chemical drug chemical - kinase inhibitor chemical drug chemical - endogenous mammalian chemical - endogenous non-mammalian

-2

1.70E-04

-2 -2 -2 -2 -2 -2 -2

2.35E-04 5.35E-04 5.71E-04 6.03E-04 7.57E-04 1.66E-03 4.10E-03

-2 -2.053 -2.079 -2.1 -2.116 -2.121

9.60E-03 2.90E-04 9.10E-16 6.32E-10 1.68E-08 1.04E-06

-2.121 -2.126 -2.134

3.24E-04 3.63E-07 9.35E-05

-2.138 -2.147

3.05E-08 3.19E-11

-2.156 -2.156

2.70E-06 6.30E-05

-2.157

2.38E-11

-2.166

4.21E-05

CD28 miR-30c-5p (and other miRNAs w/seed GUAAACA) SIGIRR triflusal valsartan triptolide CGS 21680 pentobarbital H-7 NR4A1 SERCA infliximab eplerenone thioctic acid 3-aminobenzamide fasudil ARRB2 JAG2 candesartan epigallocatechin-gallate DICER1 herbimycin rabeprazole ubiquinone 9 cyclomaltodextrin Sod

transmembrane receptor

-2.177

6.71E-10

mature microrna transmembrane receptor chemical drug chemical drug chemical drug chemical reagent chemical drug chemical - kinase inhibitor ligand-dependent nuclear receptor group biologic drug chemical drug chemical drug chemical toxicant chemical drug other growth factor chemical drug chemical drug enzyme chemical - kinase inhibitor chemical drug chemical - endogenous non-mammalian chemical drug group

-2.177 -2.183 -2.183 -2.183 -2.184 -2.186 -2.192

9.70E-03 8.86E-07 2.29E-06 1.06E-04 4.64E-07 6.30E-05 4.14E-07

-2.194

7.20E-06

-2.195 -2.2 -2.2 -2.2 -2.2 -2.207 -2.213 -2.216 -2.216 -2.219 -2.22 -2.22

4.00E-03 1.34E-09 6.89E-06 2.52E-05 4.68E-05 4.14E-07 1.19E-04 6.45E-10 9.35E-05 1.87E-04 2.07E-18 7.68E-10

-2.224 -2.236

6.24E-08 4.65E-09

-2.236 -2.236 -2.236

4.65E-09 2.69E-07 6.15E-07

PAEP DUSP5 beta-carotene fish oils sulforafan apigenin PTGER4 Hdac dexamethasone TNFAIP3 thalidomide amino acids APOE spironolactone IL37 PP1 TRAIP anakinra minocycline lipoxin A4 INSIG1 TSC22D3 Go 6976 SU6656

other phosphatase chemical - endogenous mammalian chemical drug chemical drug chemical - endogenous non-mammalian g-protein coupled receptor group chemical drug enzyme chemical drug chemical - endogenous mammalian transporter chemical drug cytokine chemical - kinase inhibitor enzyme biologic drug chemical drug chemical - endogenous mammalian other transcription regulator chemical - kinase inhibitor chemical toxicant

-2.236 -2.236

1.71E-06 3.03E-06

-2.236 -2.236 -2.258

7.21E-05 2.55E-04 2.33E-06

-2.287

1.97E-08

-2.305 -2.331 -2.351 -2.362 -2.371

1.35E-09 1.50E-14 1.95E-21 1.11E-05 7.97E-08

-2.372 -2.378 -2.391 -2.393

1.22E-08 1.39E-08 3.08E-04 7.29E-09

-2.393 -2.401 -2.401 -2.404

5.28E-06 8.87E-08 4.96E-07 8.45E-05

-2.412 -2.414 -2.419

6.30E-09 1.37E-03 6.32E-10

-2.425 -2.433

2.59E-06 2.23E-06

MAX cilostazol MNT IRF9 baicalein iron HOXA10 ACOX1 tyrphostin AG 1478 IL1RN bexarotene NS-398 nifedipine FOSL1 Sn50 peptide mir-8 LYN ABCG1 NLRP12 calphostin C sirolimus etanercept vitamin E VIP actinomycin D Ro31-8220

transcription regulator chemical drug transcription regulator transcription regulator chemical - endogenous non-mammalian chemical - endogenous mammalian transcription regulator enzyme chemical - kinase inhibitor cytokine chemical drug chemical reagent chemical drug transcription regulator chemical toxicant microrna kinase transporter other chemical - kinase inhibitor chemical drug biologic drug chemical drug other chemical drug chemical - kinase inhibitor

-2.433 -2.434 -2.449 -2.449

7.38E-05 3.80E-06 6.27E-08 2.23E-06

-2.449

1.27E-05

-2.449 -2.449 -2.449

3.78E-05 1.38E-03 7.51E-03

-2.468 -2.478 -2.53 -2.55 -2.557 -2.562 -2.581 -2.592 -2.599 -2.603 -2.607

9.54E-08 1.73E-12 2.33E-06 4.06E-09 1.72E-08 1.40E-16 6.89E-06 1.31E-05 4.19E-08 6.29E-08 1.55E-07

-2.607 -2.613 -2.619 -2.63 -2.646 -2.724

9.58E-06 6.51E-08 4.92E-08 7.71E-06 4.98E-08 1.11E-11

-2.744

3.57E-08

GFI1 miR-16-5p (and other miRNAs w/seed AGCAGCA) ZFP36 HMOX1 CORT DACH1 Nr1h SOCS3 diphenyleneiodonium COL18A1 triamcinolone acetonide SOCS1 Sb202190 Bay 11-7082 SFTPA1 pyrrolidine dithiocarbamate AG490 curcumin CD3 bisindolylmaleimide I wortmannin Alpha catenin DUSP1 2-amino-5-phosphonovaleric acid N-acetyl-L-cysteine

transcription regulator

-2.758

1.64E-06

mature microrna transcription regulator enzyme other transcription regulator group phosphatase chemical reagent other chemical drug other chemical - kinase inhibitor chemical - kinase inhibitor transporter chemical reagent chemical - kinase inhibitor chemical drug complex chemical - kinase inhibitor chemical - kinase inhibitor group phosphatase chemical - other chemical drug

-2.772 -2.774 -2.78 -2.781 -2.789 -2.804 -2.847 -2.949 -2.969 -2.994 -3.012

2.75E-03 9.75E-18 4.48E-09 2.90E-09 1.27E-08 2.87E-04 4.57E-12 1.61E-08 1.13E-06 4.86E-09 1.17E-12

-3.085

1.76E-11

-3.099 -3.168 -3.18

1.24E-09 3.63E-16 1.90E-12

-3.205 -3.213 -3.236

4.06E-09 1.27E-15 2.95E-09

-3.253

2.68E-08

-3.366 -3.405 -3.449 -3.883 -4.002

9.16E-15 1.88E-08 5.82E-17 6.88E-15 3.36E-13

miR-155-5p (miRNAs w/seed UAAUGCU) SP600125 SB203580 LY294002 U0126 PD98059

mature microrna chemical - kinase inhibitor chemical - kinase inhibitor chemical - kinase inhibitor chemical - kinase inhibitor chemical - kinase inhibitor

-4.022

4.08E-12

-4.814

1.23E-21

-4.94

4.05E-22

-5.698

1.01E-29

-6.303

1.94E-42

-6.533

8.92E-29

S4Table10. Networks and associated network functions associated with perfusion driven DGF

ID

Score 1 2 3 4 5 6 7 8 9 10 11 12 13

37 28 26 24 24 22 20 17 17 15 15 15 13

Focus Molecules

Top Diseases and Functions 23 19 18 17 17 16 15 13 13 12 12 12 11

Neurological Disease, Post-Translational Modification, Protein Folding Cellular Growth and Proliferation, Endocrine System Disorders, Organismal Injury and Abnormalities Connective Tissue Disorders, Respiratory Disease, Inflammatory Response Cellular Movement, Hematological System Development and Function, Immune Cell Trafficking Cell Cycle, Cellular Development, Cell-To-Cell Signaling and Interaction Neurological Disease, Cardiovascular Disease, Cell Death and Survival Organismal Injury and Abnormalities, Gene Expression, Cell Cycle Cellular Development, Cellular Growth and Proliferation, Hematological System Development and Function Cell Death and Survival, Nervous System Development and Function, Amino Acid Metabolism Cellular Compromise, Endocrine System Disorders, Organ Morphology Cell Morphology, Cellular Assembly and Organization, Cellular Development Cell Cycle, Cellular Development, Cellular Growth and Proliferation Neurological Disease, Cell Cycle, Cellular Growth and Proliferation

14 15 16 17 18 19 20 21 22 23 24 25

13 13 13 13 12 10 7 2 2 2 2 2

11 11 11 11 10 9 7 1 1 1 1 1

Cellular Movement, Hematological System Development and Function, Immune Cell Trafficking Cancer, Endocrine System Disorders, Gastrointestinal Disease Cancer, Dermatological Diseases and Conditions, Organismal Injury and Abnormalities Embryonic Development, Tissue Morphology, Molecular Transport Cellular Assembly and Organization, Developmental Disorder, Skeletal and Muscular Disorders Cell-To-Cell Signaling and Interaction, Cellular Movement, Hematological System Development and Function Cancer, Cellular Movement, Organismal Injury and Abnormalities Cellular Assembly and Organization, Cellular Function and Maintenance, Cancer Inflammatory Disease, Inflammatory Response, Organismal Injury and Abnormalities Organismal Injury and Abnormalities, Reproductive System Disease

post-perfusion

post-perfusion

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