IntAct European Bioinformatics Institute IntAct intact http://www.ebi.ac.uk/ http://www.ebi.ac.uk/intact/query/${ac} EBI-[0-9]+|IA:[0-9]+ INTerAction database (IntAct) provides an open source database and toolkit for the storage, presentation and analysis of molecular interactions. http://www.ebi.ac.uk/intact European Bioinformatics Institute; Wellcome Trust Genome Campus; Hinxton, Cambridge; CB10 1SD; United Kingdom http://www.ebi.ac.uk/intact/ MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. Cell death & disease 2017 imex curation Xu W., Zhang Z., Zou K., Cheng Y., Yang M., Chen H., Wang H., Zhao J., Chen P., He L., Chen X., Geng L., Gong S. genglan_2001@hotmail.com 09-May-2019: Contacted by IntAct-Help. Only protein-protein interactions imex curation human-ht_29 Homo sapiens HT-29 caucasian women with colon adenocarcinoma ht_29 HT-29 confirmed as human with IEF of AST, LDH established from the primary tumor of a 44-year-old Caucasian woman with colon adenocarcinoma in 1964; described to be heterotransplantable forming well-differentiated grade I tumors anti bait coip anti bait coimmunoprecipitation anti bait coip western blot western blot Immuno blot Immuno blot Xu W., Zhang Z., Zou K., Cheng Y., Yang M., Chen H., Wang H., Zhao J., Chen P., He L., Chen X., Geng L., Gong S. genglan_2001@hotmail.com Accepted 2018-JUN-20 AT 08:39 BST AT 08:39 BST by LIVIAP Cell death & disease 2017 Only protein-protein interactions imex curation imex curation MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. Cell death & disease 2017 imex curation Xu W., Zhang Z., Zou K., Cheng Y., Yang M., Chen H., Wang H., Zhao J., Chen P., He L., Chen X., Geng L., Gong S. genglan_2001@hotmail.com 09-May-2019: Contacted by IntAct-Help. Only protein-protein interactions imex curation human-ht_29 Homo sapiens HT-29 caucasian women with colon adenocarcinoma ht_29 HT-29 confirmed as human with IEF of AST, LDH established from the primary tumor of a 44-year-old Caucasian woman with colon adenocarcinoma in 1964; described to be heterotransplantable forming well-differentiated grade I tumors confocal microscopy confocal microscopy immunohistochemistry immunohistochemistry Xu W., Zhang Z., Zou K., Cheng Y., Yang M., Chen H., Wang H., Zhao J., Chen P., He L., Chen X., Geng L., Gong S. genglan_2001@hotmail.com Accepted 2018-JUN-20 AT 08:39 BST AT 08:39 BST by LIVIAP Cell death & disease 2017 Only protein-protein interactions imex curation imex curation MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. Cell death & disease 2017 imex curation Xu W., Zhang Z., Zou K., Cheng Y., Yang M., Chen H., Wang H., Zhao J., Chen P., He L., Chen X., Geng L., Gong S. genglan_2001@hotmail.com 09-May-2019: Contacted by IntAct-Help. Only protein-protein interactions imex curation human-293 Homo sapiens transformed primary embryonal kidney cells Human 293 Transformed human primary embryonal kidney cells. The Cell type named 293 is synonymous with HEK-293. mirna interference luciferase assay miRNA interference luciferase reporter assay miRNA interference luciferase assay tag luciferase tag visualisation by luciferase assay tag luciferase Xu W., Zhang Z., Zou K., Cheng Y., Yang M., Chen H., Wang H., Zhao J., Chen P., He L., Chen X., Geng L., Gong S. genglan_2001@hotmail.com Accepted 2018-JUN-20 AT 08:39 BST AT 08:39 BST by LIVIAP Cell death & disease 2017 Only protein-protein interactions imex curation imex curation MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. Cell death & disease 2017 imex curation Xu W., Zhang Z., Zou K., Cheng Y., Yang M., Chen H., Wang H., Zhao J., Chen P., He L., Chen X., Geng L., Gong S. genglan_2001@hotmail.com 09-May-2019: Contacted by IntAct-Help. Only protein-protein interactions imex curation human-hct116 Human colon carcinoma HCT116 cells hct116 Human colon carcinoma line HCT116 confocal microscopy confocal microscopy immunohistochemistry immunohistochemistry Xu W., Zhang Z., Zou K., Cheng Y., Yang M., Chen H., Wang H., Zhao J., Chen P., He L., Chen X., Geng L., Gong S. genglan_2001@hotmail.com Accepted 2018-JUN-20 AT 08:39 BST AT 08:39 BST by LIVIAP Cell death & disease 2017 Only protein-protein interactions imex curation imex curation MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. Cell death & disease 2017 imex curation Xu W., Zhang Z., Zou K., Cheng Y., Yang M., Chen H., Wang H., Zhao J., Chen P., He L., Chen X., Geng L., Gong S. genglan_2001@hotmail.com 09-May-2019: Contacted by IntAct-Help. Only protein-protein interactions imex curation human-ht_29 Homo sapiens HT-29 caucasian women with colon adenocarcinoma ht_29 HT-29 confirmed as human with IEF of AST, LDH established from the primary tumor of a 44-year-old Caucasian woman with colon adenocarcinoma in 1964; described to be heterotransplantable forming well-differentiated grade I tumors ch-ip chromatin immunoprecipitation assay ch-ip primer specific pcr primer specific pcr Xu W., Zhang Z., Zou K., Cheng Y., Yang M., Chen H., Wang H., Zhao J., Chen P., He L., Chen X., Geng L., Gong S. genglan_2001@hotmail.com Accepted 2018-JUN-20 AT 08:39 BST AT 08:39 BST by LIVIAP Cell death & disease 2017 Only protein-protein interactions imex curation imex curation MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. Cell death & disease 2017 imex curation Xu W., Zhang Z., Zou K., Cheng Y., Yang M., Chen H., Wang H., Zhao J., Chen P., He L., Chen X., Geng L., Gong S. genglan_2001@hotmail.com 09-May-2019: Contacted by IntAct-Help. Only protein-protein interactions imex curation human-caco2 Human Caucasian colon adenocarcinoma caco2 Human Caucasian colon adenocarcinoma anti bait coip anti bait coimmunoprecipitation anti bait coip western blot western blot Immuno blot Immuno blot Xu W., Zhang Z., Zou K., Cheng Y., Yang M., Chen H., Wang H., Zhao J., Chen P., He L., Chen X., Geng L., Gong S. genglan_2001@hotmail.com Accepted 2018-JUN-20 AT 08:39 BST AT 08:39 BST by LIVIAP Cell death & disease 2017 Only protein-protein interactions imex curation imex curation gene_hk2 gene gene human Homo sapiens Human smad3_human Mothers against decapentaplegic homolog 3 SMAD3 MADH3 SMAD family member 3 JV15-2 protein protein human Homo sapiens Human MSSILPFTPPIVKRLLGWKKGEQNGQEEKWCEKAVKSLVKKLKKTGQLDELEKAITTQNVNTKCITIPRSLDGRLQVSHRKGLPHVIYCRLWRWPDLHSHHELRAMELCEFAFNMKKDEVCVNPYHYQRVETPVLPPVLVPRHTEIPAEFPPLDDYSHSIPENTNFPAGIEPQSNIPETPPPGYLSEDGETSDHQMNHSMDAGSPNLSPNPMSPAHNNLDLQPVTYCEPAFWCSISYYELNQRVGETFHASQPSMTVDGFTDPSNSERFCLGLLSNVNRNAAVELTRRHIGRGVRLYYIGGEVFAECLSDSAIFVQSPNCNQRYGWHPATVCKIPPGCNLKIFNNQEFAALLAQSVNQGFEAVYQLTRMCTIRMSFVKGWGAEYRRQTVTSTPCWIELHLNGPLQWLDKVLTQMGSPSIRCSSVS DIP protein P84022 original sequence version: 57 DIP protein P84022 original sequence version: 112 DIP protein P84022-1 original sequence version: 146 DIP protein P84022-1 original sequence version: 111 46DF5E8B371321AC hif1a_human Hypoxia-inducible factor 1-alpha ARNT-interacting protein Member of PAS protein 1 Basic-helix-loop-helix-PAS protein MOP1 HIF1A MOP1 BHLHE78 PASD8 PAS domain-containing protein 8 Class E basic helix-loop-helix protein 78 protein protein human Homo sapiens Human MEGAGGANDKKKISSERRKEKSRDAARSRRSKESEVFYELAHQLPLPHNVSSHLDKASVMRLTISYLRVRKLLDAGDLDIEDDMKAQMNCFYLKALDGFVMVLTDDGDMIYISDNVNKYMGLTQFELTGHSVFDFTHPCDHEEMREMLTHRNGLVKKGKEQNTQRSFFLRMKCTLTSRGRTMNIKSATWKVLHCTGHIHVYDTNSNQPQCGYKKPPMTCLVLICEPIPHPSNIEIPLDSKTFLSRHSLDMKFSYCDERITELMGYEPEELLGRSIYEYYHALDSDHLTKTHHDMFTKGQVTTGQYRMLAKRGGYVWVETQATVIYNTKNSQPQCIVCVNYVVSGIIQHDLIFSLQQTECVLKPVESSDMKMTQLFTKVESEDTSSLFDKLKKEPDALTLLAPAAGDTIISLDFGSNDTETDDQQLEEVPLYNDVMLPSPNEKLQNINLAMSPLPTAETPKPLRSSADPALNQEVALKLEPNPESLELSFTMPQIQDQTPSPSDGSTRQSSPEPNSPSEYCFYVDSDMVNEFKLELVEKLFAEDTEAKNPFSTQDTDLDLEMLAPYIPMDDDFQLRSFDQLSPLESSSASPESASPQSTVTVFQQTQIQEPTANATTTTATTDELKTVTKDRMEDIKILIASPSPTHIHKETTSATSSPYRDTQSRTASPNRAGKGVIEQTEKSHPRSPNVLSVALSQRTTVPEEELNPKILALQNAQRKRKMEHDGSLFQAVGIGTLLQQPDDHAATTSLSWKRVKGCKSSEQNGMEQKTIILIPSDLACRLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN DIP protein Q16665 original sequence version: 94 DIP protein Q16665 original sequence version: 98 DIP protein Q16665-1 original sequence version: 102 DIP protein Q16665 original sequence version: 102 DIP protein Q16665 original sequence version: 127 DIP protein Q16665 original sequence version: 120 DIP protein Q16665 original sequence version: 169 DIP protein Q16665 original sequence version: 174 DIP protein Q16665-1 original sequence version: 174 DIP protein Q16665-1 original sequence version: 191 DIP protein Q16665 original sequence version: 191 DIP protein Q16665 original sequence version: 179 DIP protein Q16665 original sequence version: 150 DIP protein Q16665 original sequence version: 156 DIP protein Q16665 original sequence version: 177 ABD4F7DAA135BE2D gene_hif1a gene gene human Homo sapiens Human mrna_hif1a mrna hypoxia inducible factor 1 alpha subunit mrna messenger rna mRNA mrna human Homo sapiens Human ATTTGAAAACTTGGCAACCTTGGATTGGATGGATTCATATTTCTTAGTATAGAAGTTCTTGATATAACTGAAAAATTAAGTTAAACACTTAATAAGTGGTGGTTACTCAGCACTTTTAGATGCTGTTTATAATAGATGACCTTTTCTAACTAATTTACAGTTTTTTGAAAGATAACTGAGAGGTTGAGGGACGGAGATTTTCTTCAAGCAATTTTTTTTTTCATTTTAAATGAGCTCCCAATGTCGGAGTTTGGAAAACAAATTTGTCTTTTTAAAAGAAGGTCTAGGAAACTCAAAACCTGAAGAATTGGAAGAAATCAGAATAGAAAATGGTAGGATAAGTTCTGAACGTCGAAAAGAAAAGTCTCGAGATGCAGCCAGATCTCGGCGAAGTAAAGAATCTGAAGTTTTTTATGAGCTTGCTCATCAGTTGCCACTTCCACATAATGTGAGTTCGCATCTTGATAAGGCCTCTGTGATGAGGCTTACCATCAGCTATTTGCGTGTGAGGAAACTTCTGGATGCTGGTGATTTGGATATTGAAGATGACATGAAAGCACAGATGAATTGCTTTTATTTGAAAGCCTTGGATGGTTTTGTTATGGTTCTCACAGATGATGGTGACATGATTTACATTTCTGATAATGTGAACAAATACATGGGATTAACTCAGTTTGAACTAACTGGACACAGTGTGTTTGATTTTACTCATCCATGTGACCATGAGGAAATGAGAGAAATGCTTACACACAGAAATGGCCTTGTGAAAAAGGGTAAAGAACAAAACACACAGCGAAGCTTTTTTCTCAGAATGAAGTGTACCCTAACTAGCCGAGGAAGAACTATGAACATAAAGTCTGCAACATGGAAGGTATTGCACTGCACAGGCCACATTCACGTATATGATACCAACAGTAACCAACCTCAGTGTGGGTATAAGAAACCACCTATGACCTGCTTGGTGCTGATTTGTGAACCCATTCCTCACCCATCAAATATTGAAATTCCTTTAGATAGCAAGACTTTCCTCAGTCGACACAGCCTGGATATGAAATTTTCTTATTGTGATGAAAGAATTACCGAATTGATGGGATATGAGCCAGAAGAACTTTTAGGCCGCTCAATTTATGAATATTATCATGCTTTGGACTCTGATCATCTGACCAAAACTCATCATGATATGTTTACTAAAGGACAAGTCACCACAGGACAGTACAGGATGCTTGCCAAAAGAGGTGGATATGTCTGGGTTGAAACTCAAGCAACTGTCATATATAACACCAAGAATTCTCAACCACAGTGCATTGTATGTGTGAATTACGTTGTGAGTGGTATTATTCAGCACGACTTGATTTTCTCCCTTCAACAAACAGAATGTGTCCTTAAACCGGTTGAATCTTCAGATATGAAAATGACTCAGCTATTCACCAAAGTTGAATCAGAAGATACAAGTAGCCTCTTTGACAAACTTAAGAAGGAACCTGATGCTTTAACTTTGCTGGCCCCAGCCGCTGGAGACACAATCATATCTTTAGATTTTGGCAGCAACGACACAGAAACTGATGACCAGCAACTTGAGGAAGTACCATTATATAATGATGTAATGCTCCCCTCACCCAACGAAAAATTACAGAATATAAATTTGGCAATGTCTCCATTACCCACCGCTGAAACGCCAAAGCCACTTCGAAGTAGTGCTGACCCTGCACTCAATCAAGAAGTTGCATTAAAATTAGAACCAAATCCAGAGTCACTGGAACTTTCTTTTACCATGCCCCAGATTCAGGATCAGACACCTAGTCCTTCCGATGGAAGCACTAGACAAAGTTCACCTGAGCCTAATAGTCCCAGTGAATATTGTTTTTATGTGGATAGTGATATGGTCAATGAATTCAAGTTGGAATTGGTAGAAAAACTTTTTGCTGAAGACACAGAAGCAAAGAACCCATTTTCTACTCAGGACACAGATTTAGACTTGGAGATGTTAGCTCCCTATATCCCAATGGATGATGACTTCCAGTTACGTTCCTTCGATCAGTTGTCACCATTAGAAAGCAGTTCCGCAAGCCCTGAAAGCGCAAGTCCTCAAAGCACAGTTACAGTATTCCAGCAGACTCAAATACAAGAACCTACTGCTAATGCCACCACTACCACTGCCACCACTGATGAATTAAAAACAGTGACAAAAGACCGTATGGAAGACATTAAAATATTGATTGCATCTCCATCTCCTACCCACATACATAAAGAAACTACTAGTGCCACATCATCACCATATAGAGATACTCAAAGTCGGACAGCCTCACCAAACAGAGCAGGAAAAGGAGTCATAGAACAGACAGAAAAATCTCATCCAAGAAGCCCTAACGTGTTATCTGTCGCTTTGAGTCAAAGAACTACAGTTCCTGAGGAAGAACTAAATCCAAAGATACTAGCTTTGCAGAATGCTCAGAGAAAGCGAAAAATGGAACATGATGGTTCACTTTTTCAAGCAGTAGGAATTGGAACATTATTACAGCAGCCAGACGATCATGCAGCTACTACATCACTTTCTTGGAAACGTGTAAAAGGATGCAAATCTAGTGAACAGAATGGAATGGAGCAAAAGACAATTATTTTAATACCCTCTGATTTAGCATGTAGACTGCTGGGGCAATCAATGGATGAAAGTGGATTACCACAGCTGACCAGTTATGATTGTGAAGTTAATGCTCCTATACAAGGCAGCAGAAACCTACTGCAGGGTGAAGAATTACTCAGAGCTTTGGATCAAGTTAACTGAGCTTTTTCTTAATTTCATTCCTTTTTTTGGACACTGGTGGCTCATTACCTAAAGCAGTCTATTTATATTTTCTACATCTAATTTTAGAAGCCTGGCTACAATACTGCACAAACTTGGTTAGTTCAATTTTGATCCCCTTTCTACTTAATTTACATTAATGCTCTTTTTTAGTATGTTCTTTAATGCTGGATCACAGACAGCTCATTTTCTCAGTTTTTTGGTATTTAAACCATTGCATTGCAGTAGCATCATTTTAAAAAATGCACCTTTTTATTTATTTATTTTTGGCTAGGGAGTTTATCCCTTTTTCGAATTATTTTTAAGAAGATGCCAATATAATTTTTGTAAGAAGGCAGTAACCTTTCATCATGATCATAGGCAGTTGAAAAATTTTTACACCTTTTTTTTCACATTTTACATAAATAATAATGCTTTGCCAGCAGTACGTGGTAGCCACAATTGCACAATATATTTTCTTAAAAAATACCAGCAGTTACTCATGGAATATATTCTGCGTTTATAAAACTAGTTTTTAAGAAGAAATTTTTTTTGGCCTATGAAATTGTTAAACCTGGAACATGACATTGTTAATCATATAATAATGATTCTTAAATGCTGTATGGTTTATTATTTAAATGGGTAAAGCCATTTACATAATATAGAAAGATATGCATATATCTAGAAGGTATGTGGCATTTATTTGGATAAAATTCTCAATTCAGAGAAATCATCTGATGTTTCTATAGTCACTTTGCCAGCTCAAAAGAAAACAATACCCTATGTAGTTGTGGAAGTTTATGCTAATATTGTGTAACTGATATTAAACCTAAATGTTCTGCCTACCCTGTTGGTATAAAGATATTTTGAGCAGACTGTAAACAAGAAAAAAAAAATCATGCATTCTTAGCAAAATTGCCTAGTATGTTAATTTGCTCAAAATACAATGTTTGATTTTATGCACTTTGTCGCTATTAACATCCTTTTTTTCATGTAGATTTCAATAATTGAGTAATTTTAGAAGCATTATTTTAGGAATATATAGTTGTCACAGTAAATATCTTGTTTTTTCTATGTACATTGTACAAATTTTTCATTCCTTTTGCTCTTTGTGGTTGGATCTAACACTAACTGTATTGTTTTGTTACATCAAATAAACATCTTCTGTGGACCAGGCAAAAAAAAAAAAAAAAAAAAAAA gene_mct4 gene gene human Homo sapiens Human hsa-mir-1-3p microRNA hsa-miR-1-3p mirna micro rna micro RNA micro-RNA micro-rna mirna miRNA human Homo sapiens Human UGGAAUGUAAAGAAGUAUGUAU hsa_mir_1_3p-mrna_hif1a-1 3 11 regulator target regulator target regulator target modulator target neutral component neutral component over-expressed over expressed level over-expressed living cell living cell engineered engineered tag luciferase tag luciferase tag undetermined undetermined sequence position undetermined undetermined undetermined sequence position undetermined r.2799_2802delinstaag mutation decreasing mutation decreasing interaction hotspot hotspot mutation decreasing certain certain sequence position certain certain certain sequence position certain ATTC TAAG I couldn' t find the other mutated site in this refseq entry, nor in the other one, so I did not add it. 13 predetermined predetermined participant predetermined tag luciferase tag visualisation by luciferase assay tag luciferase regulator regulator modulator regulator neutral component neutral component over-expressed over expressed level over-expressed living cell living cell engineered engineered physical association physical association Fig4 A, B down-regulates quantity by destabilization hif1a-smad3-1 1 8 unspecified role unspecified role prey prey living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level 9 unspecified role unspecified role bait bait living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level physical association physical association Fig 4G hif1a-smad3-2 1 8 unspecified role unspecified role bait bait living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level 9 unspecified role unspecified role prey prey living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level physical association physical association Fig 4G, H fig 4 H should show that mir-1 inhibits the binding, but what I see is that it inhibites the binding of smad3 with the antibody hif1a-smad3-3 2 9 unspecified role unspecified role neutral component neutral component physiological level physiological level endogenous level endogenous endogenous endogenous level fixed cell fixed cell 8 unspecified role unspecified role neutral component neutral component physiological level physiological level endogenous level endogenous endogenous endogenous level fixed cell fixed cell colocalization colocalization Fig 4 F hif1a-smad3-4 4 9 unspecified role unspecified role neutral component neutral component physiological level physiological level endogenous level endogenous endogenous endogenous level fixed cell fixed cell 8 unspecified role unspecified role neutral component neutral component physiological level physiological level endogenous level endogenous endogenous endogenous level fixed cell fixed cell colocalization colocalization Fig 4 F hif1a-smad3-5 6 8 unspecified role unspecified role prey prey living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level 9 unspecified role unspecified role bait bait living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level physical association physical association Fig 4G smad3-hif1a-1 6 8 unspecified role unspecified role bait bait living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level 9 unspecified role unspecified role prey prey living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level physical association physical association Fig 4G, H fig 4 H should show that mir-1 inhibits the binding, but what I see is that it inhibites the binding of smad3 with the antibody smad3-gene_mct4-1 5 13 inhibitor inhibitor neutral component neutral component purified purified 8 unspecified role unspecified role bait bait living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level 12 unspecified role unspecified role prey prey living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level association association Fg 5A smad3-gene_hk2-1 5 13 inhibitor inhibitor neutral component neutral component purified purified 8 unspecified role unspecified role bait bait living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level 7 unspecified role unspecified role prey prey living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level association association Fg 5A smad3-gene_hif1a-1 5 13 inhibitor inhibitor neutral component neutral component purified purified 10 unspecified role unspecified role prey prey living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level 8 unspecified role unspecified role bait bait living cell living cell physiological level physiological level endogenous level endogenous endogenous endogenous level association association Fg 5A