From 0c57c0df4df49bef2089340a05664610c88f45ac Mon Sep 17 00:00:00 2001 From: kilian Date: Mon, 12 Oct 2026 10:53:10 +0200 Subject: [PATCH] Dateien nach "Paper/GraphTheory" hochladen --- Paper/GraphTheory/pfadhypergraph.pdf | 17708 +++++++++++++++++++++++++ 1 file changed, 17708 insertions(+) create mode 100644 Paper/GraphTheory/pfadhypergraph.pdf diff --git a/Paper/GraphTheory/pfadhypergraph.pdf b/Paper/GraphTheory/pfadhypergraph.pdf new file mode 100644 index 0000000..0d2e1ea --- /dev/null +++ b/Paper/GraphTheory/pfadhypergraph.pdf @@ -0,0 +1,17708 @@ +%PDF-1.6 +% +3 0 obj +<< +/Length 12609 +>> +stream +/GS1 gs +BT +/F3 1 Tf +10.959 0 0 10.959 272.296 714.7841 Tm +0 0 0 rg +0 Tc +0 Tw +[(1.)-496.7(INTRODUCTION)]TJ +27.7155 0 0 27.7155 106.8094 679.0675 Tm +(S)Tj +/F7 1 Tf +9.9626 0 0 9.9626 123.137 690.9164 Tm +[(ignaling)-458.4(and)-461.5(metabo)-7.7(lic)-454.6(pathw)-8.2(ays)]TJ +/F2 1 Tf +16.4457 0 TD 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237.3165 Tm +0 Tc +[(The)-271.3(rst)-275.6(exampl)-8.7(e)-270(i)0(s)-272.9(drawn)-273.3(from)-272.3(the)-274.3(23)-269(instanc)-9.9(es)-272(in)]TJ +/F5 1 Tf +21.0493 0 TD +[(NCI-)-8.2(PID)]TJ +/F2 1 Tf +4.5069 0 TD +(where)Tj +/F5 1 Tf +-40.75 -1.2007 TD +[(Mmu)-9(nin)]TJ +/F2 1 Tf +4.0687 0 TD +[(outperf)-8.1(orms)]TJ +/F5 1 Tf +5.3377 0 TD +[(Hhugi)-7.3(n)]TJ +/F2 1 Tf +3.6306 0 TD +[(,)-432.9(a)0(s)-437(i)0(t)-433.8(nds)-435.9(a)-435(subopt)-8.5(imal)-435(hyper)-7.6(path.)-434.8(\(We)-441.1(chose)-441.1(this)-436.6(particula)-11.1(r)-429.5(instanc)-9.9(e)]TJ +-13.037 -1.195 TD +[(becau)-9.2(se)-442.7(the)-439.3(size)-443.1(of)-441.7(its)-441.5(hyperpat)-8.7(hs)-440.9(makes)-444.6(them)-443.6(reasonable)-447.5(to)-442.5(draw.\))-440.7(We)-444(note)-445.8(that)]TJ +/F5 1 Tf +35.196 0 TD +[(Acy)-9(cMILP)]TJ +/F2 1 Tf +5.2808 0 TD +[(is)-443.7(also)]TJ +-40.4769 -1.2007 TD 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+[()48.5(cAMP)-371.2(response)-366.8(eleme)-9.8(nt)-362.8(modulator)-8.3()48.5()-361.2(\(CREM\).)-367.2(Source)-9.3(s)-360.5(are)-360.7(show)-8.2(n)-359.3(acro)-8.6(ss)-356.7(the)-365.3(top)-363.6(of)-362(the)-359.7(g)-6.4(ure,)-359.2(and)-368.3(the)]TJ +T* +[(tar)-8.8(get)-331.2(is)-335.5(in)-334.3(the)-331.2(bott)-8.6(om)-329.4(rig)-7(ht)-328.6(corne)-9.4(r.)-333.2(Hypered)-9.1(ges)-335.3(drawn)-341.6(in)-328.7(a)-332.6(red)-336.1(dash)-336.1(are)-337.9(uniqu)-6.6(e)-332.6(t)0(o)]TJ +/F5 1 Tf +34.2514 0 TD +[(Mmuni)-7.3(n)]TJ +/F2 1 Tf +3.6306 0 TD +[(s)-334.8(hyper)-7.6(path,)]TJ +-37.882 -1.2007 TD +[(and)-248.8(hyper)-7.6(edges)-247.6(in)-249(a)-247.2(green)-248.4(dotted)-250.9(line)-249.4(are)-246.8(unique)-248.1(to)]TJ +/F5 1 Tf +20.7079 0 TD +(Hhugin)Tj +/F2 1 Tf +3.6306 0 TD +[(s)-243.7(hyper)-7.6(path,)-247(while)-254.1(hyperedges)-255.1(in)-243.3(a)-247.2(solid)-249.5(black)]TJ +-24.3385 -1.2007 TD +[(lin)-7.8(e)-235.9(are)-246.8(common)-241(to)-243.3(both)-239.1(hyper)-7.6(paths.)-243.2(Eight)-242.5(hyp)-8(eredges)-247.2(that)-238(are)-246.8(shared)-244.6(by)-240.5(both)-239.1(path)-7.6(ways)-243.3(have)-245.6(been)-239.9(replace)-11.5(d)]TJ +0 -1.195 TD +[(in)-260.4(the)-262.9(gure)-262.9(by)-257.6(elli)-7.4(pses,)-258(for)-262.3(simpl)-8.4(icity.)-259(All)-262.1(hyper)-7.6(edges)-264.6(denote)-261.3(bioc)-7.6(hemical)-264.4(reaction)-13.3(s)-258(except)-263.1(the)-262.9(hyperedges)]TJ +0 -1.2007 TD +[(from)-352(MA)-7.4(PK8)-352.6(to)-345.7(JUN)-352.8(and)-351.2(from)-352(MA)-7.4(PK3)-346.9(to)-351.4(JUN,)-353.2(which)-353.7(denote)-352.3(the)-354(transcrip)-9.7(tion)-350(and)-351.2(translat)-9.7(ion)-346.5(of)-350.6(JUN.)]TJ +T* +[(Ver)-10(tices)-304.3(wi)-8.2(th)-300.2(a)-309.8(gray)-308.4(ll)-302.9(denot)-8.4(e)-304.2(the)-302.7(act)-8.6(ivated)-309.6(form)-306.4(of)-305.1(a)-304.2(prot)-7.8(ein.)-303.1(Note)-313.1(that)-306.3(stoichiom)-10.3(etry)-305.5(of)-305.1(the)-308.4(reactions)-316.8(is)]TJ +T* +[(no)-7.2(t)-231.1(consi)-9.6(dered)-242.7(in)-237.6(our)-237.6(hyperpat)-8.7(h)-234.1(formul)-9.1(ation,)-239.1(so)-241.7(this)-237.4(hyper)-7.6(path)-235.2(is)-238.8(valid,)-244.8(even)-239.9(though)-240.7(two)-236.6(copi)-7.6(es)-237.8(of)-236.8(NFAT)-9.9(C2)]TJ +T* +[(are)-337.9(neede)-9.2(d)-336.5(i)0(n)-334.3(the)-336.9(nal)-336.9(reaction.)]TJ +ET +q +429.732 0 0 138.274 74.438 583.994 cm +/Im3 Do +Q +BT +/F3 1 Tf +8.9663 0 0 8.9663 74.0976 568.0062 Tm +[(FIG.)-246.3(2.)]TJ +/F2 1 Tf +4.0277 0 TD +[(Comparison)-247.5(of)-248.2(hyperpaths)-248(whose)-244.7(target)-246.5(is)-244.5(the)-245.2(NFATC2/CREM)-252.3(complex.)-245.8(Sources)-250.4(are)-246.2(shown)-248.6(across)-247.2(the)-245.2(top)-242.8(of)]TJ +-4.0277 -1.2203 TD +[(the)-416(gure,)-408.7(and)-411.9(the)-409.6(target)-410.9(is)-408.9(in)-414(the)-409.6(bottom)-407(right)-412.9(corner.)-414.7(Hyperedges)-414.1(drawn)-410.5(in)-407.7(dashed)-414.1(red)-408.2(are)-410.6(unique)-414.5(to)]TJ +/F5 1 Tf +43.6597 0 TD +(Mmunin)Tj +/F18 1 Tf +3.623 0 TD +(s)Tj +-47.2827 -1.2203 TD +[(hyperpath,)-294.5(hyperedges)-297(in)-287.6(dotted)-298.4(green)-289.5(are)-296.8(unique)-288(to)]TJ +/F5 1 Tf +21.4157 0 TD +(Hhugin)Tj +/F18 1 Tf +3.623 0 TD +[(s)-293.7(hyperpath,)-294.5(and)-291.8(hyperedges)-290.7(in)-293.9(solid)-291.3(black)-290.9(are)-296.8(common)]TJ +-25.0387 -1.2266 TD +[(to)-331.8(both)-330.9(hyperpaths.)-333.2(Eight)-334.2(hyperedges)-328.6(that)-337.3(are)-328.4(shared)-334.5(by)-327.8(both)-330.9(hyperpaths)-336.6(have)-331.7(been)-331.7(replaced)-334.9(by)-327.8(ellipses.)-334.4(Hyperedges)]TJ +0 -1.2203 TD +[(from)-354.5(MAPK8)-357.5(to)-350.8(JUN)-354.1(and)-348.7(from)-354.5(MAPK3)-357.5(to)-350.8(JUN)-354.1(denote)-353.7(transcription)-356.1(and)-348.7(translation)-354.5(of)-355.7(JUN.)-350.7(Vertices)-359.9(with)-350.8(gray)-357.1(ll)]TJ +T* +[(denote)-334.7(the)-340.1(activated)-333.5(form)-335.6(of)-330.4(a)-337(protein.)]TJ +/F3 1 Tf +9.9626 0 0 9.9626 74.0976 737.4045 Tm +[(12)-7.2(16)-26741.4(KRIEG)-9.3(ER)-334.5(AN)-9.4(D)-334.8(KECE)-8.6(CIOGLU)]TJ +ET + +endstream +endobj +58 0 obj +<< +/Length 68313 +/Subtype /Image +/Filter /DCTDecode +/BitsPerComponent 8 +/ColorSpace /DeviceRGB +/Width 895 +/Height 288 +/Type /XObject +>> +stream +Adobed   + + + +       +  + s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& 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+WLZ].I[;9Kku3#т*1Uz4/ڀI-yk QaM#E4QS<2jwփkͧumAJ(a fvpbQ,$b:n[l5/+\w7(̑L*"2CN0T8Z5k8ӑc%6oYRH:`.5Kz Z~ҟDYтqu?*Yo埒.yv.rC"1 +6Ovz>DN'_28WKUj1W[^[\y3󽠿-2kkMJ] A9R ~>bUӱ>dKʷWz->ףI??cοBo,0j$qji4TX4-y#RߙZӤ0z?9n]1MF/{ 3D`]EC} +[8APwv*U??6?%lUeKͻ,+idZ%Տ/bD*ABcʾd䫿=OzG'wQ ? komjPHh܋ +)?*D 34Z\g#P99Ph*Q/eZɥY*UثWb]v* UتQtJ hdCJ16 2,0ʓd' ŔV !~f~pOȉy./L0}Rckj?n)ds:yu~:F_b v)|R10)3H|0y+5~cɴ>M2>O%|lZ-tHK@ +W<//n {ٖZטeSmoJOt_:XQy/̭H-H`q(* $eAS\HhU_MѼޔ:~WI+ʡk1?,UR~mjGjjy$#RAVT>^/%y[Z]Ӣc㑇I!{SUثWb]v*UثWb]v*UثWb]v*UثWb]v*،UIO/uhHbyn4Y.XQ^l5$G4~>D8p"e_0]Lzl2yʠoEX1uѓIɇhie+klW_OJed1x7cc##PjCCWb W SfT&1K ~LJo=kb&{Lx|cF9|6̱=G?Dmy'R򅧗oYuKuJmOGl>=ve &u]~%+m|RDa?n3dj8AO6#SZYm."yOF il%?̲xWãZƯlϣ0]3QMaw DT<.?IIQ4E9q#h'b;)g`:4b_4~ #z~Xયs+$#=g& Ҹ_8Ewƛ[o/#ryYwVq XSP<yDݤyV$MOY+Qby4ͽ<1<=wwI4˳IYRAs߂8 ɧĤ+$^oJKmPpd//|Z<#0hdѹU իn_#V~aߣ>ڏ%O1D#UR&;+jLqd<ic)[譴.!>Ej?,T;ju[O(1u+?TOt5R~ONlERPlǞ FCnl =k~bl$eMz6 zjÔ)X)4s:dL~Tu{rmB]cxُ9os~#=Ozw7;v*UثWb]v*%~{y{?emqc)a  %MIqTZ#%H[ի_2_Z#%H[ի_2_Z#%H[ի_2_Z#%H[ի_2_Z#%H[ի_2_Z#%H[ի_2_Z#%H[ի_2_^k*n OǶ*~B~pK[9NG?ӏ28w7?ex1?揓Q-#4?514|N<_N?_G^.y~ :edt)jȜ)'^~㏚i.*h_:{vkۆO!qW{Na4-Nˆr?ISUثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb] + +endstream +endobj +61 0 obj +<< +/Length 10321 +>> +stream +/GS1 gs +BT +/F2 1 Tf +9.9626 0 0 9.9626 117.5811 512.277 Tm +0 0 0 rg +0 Tc +0 Tw +[(Each)-273.9(hyper)-7.6(path)-275.1(cont)-7.6(ains)-276.2(hyperedges)-283.6(from)-272.3(the)-274.3(fol)-7(lowing)-275.8(four)-274.5(NCI-)-10(PID)-274.9(pathwa)-9.2(ys:)-273.7()48.5(Calcium)-281.5(signaling)-279.9(in)]TJ +-1.0015 -1.2007 TD +[(the)-268.6(CD4)]TJ +/F9 1 Tf +7.4718 0 0 6.641 141.3354 504.7369 Tm +(+)Tj +/F2 1 Tf +9.9626 0 0 9.9626 148.1385 500.3148 Tm +[(TCR)-267.6(path)-7.6(way,)45.8()-270.2()48.5(RAS)-269(sign)-7(aling)-272.9(in)-266.1(the)-268.6(CD4)]TJ +/F9 1 Tf +7.4718 0 0 6.641 327.118 504.7369 Tm +(+)Tj +/F2 1 Tf +9.9626 0 0 9.9626 333.9211 500.3148 Tm +[(TCR)-267.6(path)-7.6(way,)45.8()-270.2()48.5(JNK)-270.2(sign)-7(aling)-267.2(in)-271.7(the)-268.6(CD4)]TJ +/F9 1 Tf +7.4718 0 0 6.641 511.7668 504.7369 Tm +(+)Tj +/F2 1 Tf +9.9626 0 0 9.9626 518.5133 500.3148 Tm +(TCR)Tj +-41.2451 -1.2007 TD +[(pathwa)-9.1(y,)47.3()-241.7(and)-243.1()54.2()0(N)-7.4(ongenotro)-7.7(pic)-245.8(androgen)-245(sign)-7(aling.)42.7()-236.1(T)0(h)-7(e)-241.6(hyperpat)-8.7(hs)-241.7(show)-241.5(CREM)-247.6(repr)-8.8(essing)-244.8(the)-240.2(act)-8.6(ivated)]TJ +T* +[(form)-289.4(of)-282.3(NFA)-9.4(TC2)-285.7(before)-290.9(formi)-8.4(ng)-286.1(a)-281.4(ter)-8.8(nary)-285.7(comp)-8.4(lex)-285.7(with)-285.7(NFA)-9.4(TC2)-285.7(and)-288.6(its)-287.8(DNA)-287.2(binding)-289.7(sites,)-292.7(resulting)-293.3(in)]TJ +T* +[(the)-450.7(attenua)-10.5(tion)-452.4(of)-453.1(transcrip)-9.7(tion)-452.4(of)-447.4(T)-450.1(help)-7.6(er-1-sp)-8.6(ecic)-455(cytokine)-459.1(genes)-452.4(in)-453.8(human)-453(med)-7.6(ullary)-452(thymocy)-7.7(tes)]TJ +0 -1.195 TD +[(\(Bodor)-337.6(and)-339.8(Habener)-10.9(,)-330.4(1998\).)]TJ +/F5 1 Tf +1.0015 -1.2007 TD +(Hhugin)Tj +/F2 1 Tf +3.6306 0 TD +[(s)-488.4(hyper)-7.6(path)-491.3(contain)-8.7(s)-485.7(1)0(3)-490.9(hyper)-7.6(edges)-8.6(,)-484.1(while)]TJ +/F5 1 Tf +19.069 0 TD +[(Mmu)-9(nin)]TJ +/F2 1 Tf +3.6363 0 TD +[(s)-488.4(hyper)-7.6(path)-491.3(contain)-8.7(s)-485.7(1)0(1)-490.9(hyper)-7.6(edges,)]TJ +-27.3374 -1.2007 TD +[(which)-239.9(is)-233.1(o)-6.5(ptimal.)-240.5(Notably,)-238.9(hyper)-7.6(edges)-241.9(unique)-236.7(to)]TJ +/F5 1 Tf +19.6609 0 TD +[(Mmun)-8.2(in)]TJ +/F2 1 Tf +3.6306 0 TD +[(s)-238(hyper)-7.6(path)-235.2(only)-239.1(use)-238.6(vertices)-242.1(that)-238(are)-241.1(common)-241(to)]TJ +-23.2914 -1.2007 TD +[(both)-335.9(hyper)-7.6(paths,)-340(further)-340.2(simplifyin)-8.3(g)-330.8(it,)-337.5(and)-334.1(mak)-7.6(ing)-335.1(it)-337.1(a)-332.6(more)-340.4(likely)-339(pathway)-9.9(.)]TJ +/F8 1 Tf +10.959 0 0 10.959 117.5811 392.7117 Tm +[(The)-492.7(phosphorylated)-488.9(p53)-496.9(tetramer.)]TJ +/F2 1 Tf +9.9626 0 0 9.9626 285.2787 392.7117 Tm +[(Th)-7(e)-509(secon)-8.6(d)-512.9(exampl)-8.7(e)-514.7(was)-515.7(chosen)-515.8(from)-517(the)-519(22)-513.7(instances)-520.9(in)]TJ +/F5 1 Tf +-17.8342 -1.2007 TD +[(React)-7.3(ome)]TJ +/F2 1 Tf +5.1784 0 TD +[(with)-342.6(no)-337.3(acycli)-9.8(c)-338.3(hyper)-7.6(path,)-338(on)-343(which)]TJ +/F5 1 Tf +15.3929 0 TD +[(AcycM)-7.3(ILP)]TJ +/F2 1 Tf +5.1784 0 TD +[(nds)-339.2(no)-343(solution.)-340.3(We)-341.6(note)-343.3(that)-340.4(the)-342.6(heuris-)]TJ +-25.7497 -1.2007 TD +(tic)Tj +/F5 1 Tf +1.343 0 TD +[(Hhug)-8.2(in)]TJ +/F2 1 Tf +3.9663 0 TD +[(also)-338.8(nds)-339.2(an)-333.4(optim)-7.2(al)-330.4(h)-6.5(yperpath)-338.8(for)-336.3(this)-339.8(particular)-343.9(instance.)]TJ +-4.3077 -1.195 TD +[(Figure)-437.1(3)-433.2(show)-8.2(s)-434.4(the)-433.6(optim)-7.2(al)-432.9(hyper)-7.6(path)-434.4(ret)-8.8(urned)-434.4(by)]TJ +/F5 1 Tf +21.755 0 TD +[(Mmu)-9(nin)]TJ +/F2 1 Tf +3.6363 0 TD +[(,)-432.9(which)-439.1(capture)-9.7(s)-434.4(the)-433.6(phospho)-6.5(ryl)-7(ation)-437.9(of)]TJ +-26.3928 -1.2007 TD +[()48.5(cellula)-10.3(r)-258.8(tumor)-262.5(antigen)-264.8(p53)46.2()-258.8(\(TP53\))-263.6(by)-257.6()48.5(AMPK)-9.1(-related)-265.6(protei)-8.2(n)-256.8(kinase)-262.5(5)47.7()-258.8(\(ARK5\))-9.7(,)-256.5(causing)-268.9(its)-259.4(activation.)]TJ +T* +[(Source)-9.3(s)-269.4(are)-275.3(show)-8.2(n)-268.2(acro)-8.6(ss)-271.4(the)-274.3(top)-272.5(of)-276.6(the)-274.3(gure,)-274.6(and)-277.2(the)-274.3(target)-277.4(is)-272.9(in)-271.8(the)-274.3(bottom)-275.4(righ)-7.8(t)-271(corner.)-274.2(Th)-7(e)-270(hyper)-7.6(edges)]TJ +T* +[(in)-351.4(dotted)-353.3(b)-6.5(lue)-348.3(repr)-8.8(esent)-352.8(tran)-9.6(scription)-8.7(/translati)-11.1(on)-348.7(events,)-359.6(and)-351.2(the)-354(hyper)-7.6(edge)-353.7(in)-351.4(red)-353.2(show)-8.2(s)-349.1(the)-354(cycle)-359.1(in)-351.4(the)]TJ +T* +[(hyper)-7.6(path,)-406.3(whe)-8(re)-403.6(a)-406.6(node)-408.9(in)-408.3(the)-405.2(head)-410.7(of)-407.5(the)-410.9(red)-404.4(hyper)-7.6(edge)-410.7(is)-403.8(in)-408.3(the)-405.2(tail)-411.5(of)-407.5(an)-407.3(earlier)-412.8(hyperedge)-412.5(in)-408.3(the)]TJ +T* +[(hyper)-7.6(path.)]TJ +1.0015 -1.2007 TD +[(This)-530.3(hyper)-7.6(path)-531.1(show)-8.2(s)-525.5(the)-536.1(transcrip)-9.7(tion)-532.1(and)-533.3(translation)-538.3(of)-527(k)-6.5(e)0(y)-526.8(prot)-7.8(eins)-532.3(involved)-536.9(in)-527.8(the)-530.4(format)-10.9(ion)]TJ +-1.0015 -1.2007 TD +[(of)-401.8(a)-395.2(com)-7.6(plex)-400.2(with)-405.2(the)-399.5(TP5)-7(3)-399.1(homotetra)-10.1(mer.)-402.6(Once)-403.2(this)-402.4(comple)-8.7(x)-399.1(i)0(s)-398.1(formed)-8.1(,)-398.7(ARK5)-402.6(is)-403.8(activate)-10.2(d)-399.1(b)0(y)-399.9(phos-)]TJ +0 -1.195 TD +[(phorylat)-9.7(ion,)-301.3(allowing)-304.6(it)-303(to)-300.2(direct)-10(ly)-300.2(phospho)-6.5(rylate)-305.9(p53)-298.2(\(H)-7.4(ou)-297.4(et)-302(al.,)-302.7(2011\),)-302.1(act)-8.6(ivating)-305.6(p53)-298.2(and)-305.7(allowing)-304.6(it)-303(to)]TJ +0 -1.2007 TD +[(assist)-339.8(in)-334.3(DNA)-338.4(dam)-7.6(age)-335.9(repair)-9.2(.)]TJ +1.0015 -1.2007 TD +[(This)-445(exam)-10.2(ple)-445(from)]TJ +/F5 1 Tf +8.4789 0 TD +[(React)-7.3(ome)]TJ +/F2 1 Tf +5.2865 0 TD +[(has)-449.1(more)-448.5(than)-445.8(1,600)-447.3(h)-6.5(yperedges)-453.6(in)-442.5(the)-450.7(doubly-r)-7.1(eachable)-456(subgraph,)]TJ +-14.767 -1.2007 TD +[(making)-280.1(it)-274.5(one)-277.2(of)-276.7(the)-274.3(largest)-279.4(instanc)-9.9(es.)-278(It)-273.7(is)-272.9(als)-8(o)-273.9(one)-277.2(of)-271(the)-280(longer)-278.6(cycles)-281.3(for)-273.7(any)]TJ +/F5 1 Tf +32.476 0 TD +[(Reac)-8.1(tome)]TJ +/F2 1 Tf +5.1158 0 TD +[(instanc)-9.9(e,)-276.1(with)]TJ +-37.5918 -1.2007 TD +[(three)-410.5(hyper)-7.6(edges)-412.6(involved)-411.7(in)-408.3(the)-405.2(cycle.)-410.7(Int)-7(erestingl)-10.5(y,)-405.2(even)-410.7(thoug)-6.6(h)-404.8(this)-408.1(is)-403.8(a)-406.6(lar)-8.8(ge)-407.3(instance,)-411.2(no)-411.2(alternat)-10.3(e)]TJ +T* +[(hyper)-7.6(paths)-333.9(exis)-8.8(t)-333.6(that)-334.7(reach)-341.2(the)-336.9(target)-340(for)-336.3(this)-334.1(instanc)-9.9(e.)]TJ +/F8 1 Tf +10.959 0 0 10.959 117.5811 177.5054 Tm +[(The)-461.6(BMP7/BMPR2/BMPR1)6(A/SMAD6/SMURF1)-462.4(complex.)]TJ +/F2 1 Tf +9.9626 0 0 9.9626 386.192 177.5054 Tm +[(The)-481.9(third)-483.6(exam)-10.2(ple)-479.2(was)-487.2(also)-486.8(chosen)]TJ +-27.9634 -1.195 TD +[(from)-414.6(the)-410.9(22)-411.3(instances)-418.5(in)]TJ +/F5 1 Tf +10.6925 0 TD +[(Rea)-9(ctome)]TJ +/F2 1 Tf +5.2524 0 TD +[(whe)-8(re)-409.3(all)-413.6(source-s)-10.3(ink)-409.1(hyper)-7.6(paths)-413.6(are)-411.9(cyclic)-9.8(,)-410.1(hence)]TJ +/F5 1 Tf +21.5956 0 TD +[(Mmun)-8.2(in)]TJ +/F2 1 Tf +4.0403 0 TD +(out-)Tj +-41.5808 -1.2007 TD +(performs)Tj +/F5 1 Tf +3.9549 0 TD +[(AcycM)-7.3(ILP)]TJ +/F2 1 Tf +4.8427 0 TD +[(.)-330.4(Aga)-8(in)]TJ +/F5 1 Tf +3.3688 0 TD +[(Hhugi)-7.3(n)]TJ +/F2 1 Tf +3.9663 0 TD +[(is)-335.5(optimal)-337.6(on)-337.3(these)-335.7(as)-340.2(well.)]TJ +-15.1312 -1.2007 TD +[(Figure)-385.9(4)-376.3(show)-8.2(s)-377.5(the)-382.4(optim)-7.2(al)-381.7(hyperpat)-8.7(h)-376.3(found)-387.1(by)-377.1(both)]TJ +/F5 1 Tf +22.472 0 TD +[(Mmu)-9(nin)]TJ +/F2 1 Tf +4.0118 0 TD +(and)Tj +/F5 1 Tf +1.8324 0 TD +[(Hhugi)-7.3(n)]TJ +/F2 1 Tf +4.0118 0 TD +[(for)-381.8(this)-379.7(exampl)-8.7(e,)-378.5(whi)-9(ch)]TJ +-33.3296 -1.2007 TD +[(represe)-10.1(nts)-268(a)-270(sign)-7(aling)-272.9(path)-7.6(way)-269.8(resu)-8(lting)-273.9(in)-266.1(the)-274.3(degra)-9.4(dation)-273.7(of)-271(the)-268.6()48.5(bone)-275(morph)-9.3(ogenetic)-273.1(p)-6.5(rotein)-269.9(rece)-10.4(ptors)44.4()]TJ +T* +[(\(BMPR2)-318.7(and)-311.4(BMPR)-8(1A\))-309.8(in)]TJ +/F5 1 Tf +11.4096 0 TD +(Reactome)Tj +/F2 1 Tf +5.1499 0 TD +[(\()-82.4(Mura)-8.8(kami)-312.7(et)-307.7(al.,)-314.1(2003\).)-313.5(Sources)-312.9(are)-315.1(shown)-316.2(across)-314.1(the)-308.4(top)-312.3(of)-310.8(the)]TJ +-16.5595 -1.2007 TD +[(gure,)-274.6(and)-271.5(the)-268.6(target)-271.7(is)-272.9(in)-266.1(the)-274.3(bottom)-269.7(rig)-7(ht)-266.1(corne)-9.4(r.)-264.9(Th)-7(e)-264.3(part)-277(of)-265.3(the)-274.3(nal)-268.6(hyper)-7.6(edge)-274.1(shown)-270.7(with)-274.3(a)-270(dotted)-273.7(line)]TJ +T* +[(represe)-10.1(nts)-239.6(PPM1A)-241.4(acting)-241.3(as)-243.5(a)-235.9(positive)-245(regulator)-247.5(of)-236.8(the)-240.2(reaction.)-247(The)-237.2(cycle)-245.3(in)-237.6(this)-237.4(hyper)-7.6(path)-240.9(is)-238.8(shown)-242.2(in)-237.6(red,)]TJ +T* +[(and)-243.1(represe)-10.1(nts)-245.2(the)-245.8(phospho)-6.5(rylation)-245.8(and)-248.8(subsequent)-249.7(dephos)-7.6(phorylat)-9.7(ion)-244.1(of)-242.5()48.5(Mothers)-251.1(against)-248.9(decapent)-10.3(aplegic)]TJ +0 -1.195 TD +[(homo)-6.6(log)-335.1(1)47.7()-332.8(\(SMAD)-9.1(1\).)]TJ +ET +q +429.732 0 0 134.419 107.887 587.849 cm +/Im4 Do +Q +BT +/F3 1 Tf +8.9663 0 0 8.9663 107.6031 571.8613 Tm +[(FIG.)-328.5(3.)]TJ +/F2 1 Tf +4.1036 0 TD +[(Shortest)-331.4(hyperpath)-323.2(to)-325.5(the)-327.4(phosphorylated)-332.3(p53)-321(tetramer.)-332.9(Sources)-326.3(are)-328.4(shown)-324.5(across)-329.3(the)-327.4(top)-325(of)-330.4(the)-321.1(gure,)-332.9(and)]TJ +-4.1036 -1.2203 TD +[(the)-340.1(target)-347.7(is)-339.3(in)-344.5(the)-340.1(bottom)-343.8(right)-343.3(corner.)-338.8(The)-342.2(hyperedges)-347.6(in)-344.5(dotted)-342.6(blue)-339.6(represent)-342.1(transcription/translation)-353.7(events.)-338.8(The)]TJ +T* +[(hyperedge)-296.3(in)-293.9(red)-294.4(creates)-292.3(a)-292.8(cycle)-299.7(in)-293.9(the)-289.5(hyperpath,)-294.5(as)-293.5(node)-297.6(STK11)-290.1(in)-293.9(its)-298.6(head)-293.7(occurs)-290.2(in)-293.9(the)-295.8(tail)-297.1(of)-292.5(a)-292.8(prior)-291.3(hyperedge)-296.3(in)]TJ +0 -1.2266 TD +[(the)-333.8(hyperpath.)]TJ +/F3 1 Tf +9.9626 0 0 9.9626 107.6031 737.4045 Tm +[(SHOR)-7.6(TEST)-340.8(HYPERPA)-13.6(THS)-334.1(IN)-336.7(DIRE)-11.1(CTED)-339(HYPE)-9.3(RGRAPH)-11.8(S)-13560.6(1217)]TJ +ET + +endstream +endobj +62 0 obj +<< +/Length 69226 +/Subtype /Image +/Filter /DCTDecode +/BitsPerComponent 8 +/ColorSpace /DeviceRGB +/Width 895 +/Height 280 +/Type /XObject +>> +stream +Adobed   + + + +      +  + s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& +EFVU(eufv7GWgw8HXhx)9IYiy*:JZjzm!1AQa"q2#BRbr3$4CS%cs5DT +&6E'dtU7()󄔤euFVfvGWgw8HXhx9IYiy*:JZjz ?N*UثU;{[y..eX`K,*& YalnA}n܈B3D}r}w1XI ?^?~f_̓`k&jt?^?~̿'?L)H2NԙxR?W2d+[b "$gȬ{KsPv=PY+#RI7R>_nSV=>ysCm.&kImrӧ*fF-,,mɣ.4yiXG%yQma?fMNbr=;-0W\^?7#L?q̍S ?O~֟[0*_A{(?B^\?4cď>az٥uݬfX2}bjB / ثWbsankĕ?I駓p6ӗQs;uI<ZOͼ'ͪ\ Ge(S i̮79+Geo/O~ַo,Xṋ ޝG)}QGcvQk>fUwͷVU>1b HQrq;+fUثWb k_ѴKCw^Ggo4cYj"d 0Zƥ<{ }˲P7j?O#`y o_DIjCI %~@1:_$gͣ:-bM$ʵS#t̿/\.-"CXlsR(jMIe;v*UثWb]v*UثWb]v*UĀ*vXAv\w5).]_,ˆd\#Ş nG55ml=>x + +}/ 2}&c 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+[(for)-302.1(ubiqu)-6.6(itinati)-9.6(on)-297.4(and)-305.7(degradat)-10.5(ion)-301(both)-301.7(by)-297.4(SMA)-7.4(D1)-301.4(and)-305.7(the)-302.7(complex)-305.4(of)-299.4(SMA)-7.4(D6)-301.4(and)-300()48.5(SMA)-10.1(D-spec)-9.5(ic)-302(E3)]TJ +T* +[(ub)-7.2(iquitin)-335.1(protei)-8.2(n)-330.8(ligase)-344.9(1)47.7()-332.8(\(SMURF)-9.9(1\).)]TJ +1.0015 -1.2007 TD +[(This)-410.8(particula)-11.1(r)-406.8(example)-409.6(show)-8.2(s)-406(how)-404.6(even)-410.7(a)-406.6(short)-413.8(hyperpat)-8.7(h)-404.8(can)-409.9(be)-407.3(fairly)-408.5(involved)-7.7(,)-404.4(b)0(y)-405.6(shar)-8(ing)-403.4(man)-7.6(y)]TJ +-1.0015 -1.2007 TD +[(vert)-9.6(ices)-306.5(among)-310.7(its)-304.9(hyperedges)-312.1(in)-305.9(various)-309(way)-8(s.)-303.9(While)-309.6(this)-305.7(hyper)-7.6(path)-303.5(has)-306.9(only)-307.4(ve)-304.9(hy)-7.2(peredges,)-310.9(most)-306.4(have)]TJ +T* +[(tail)-7.4(s)-275.1(and)-271.5(heads)-281.7(with)-274.3(multipl)-8.5(e)-275.7(vertices,)-282.3(and)-271.5(hence)-282.3(would)-278(likely)-276.4(not)-278.2(be)-270.8(capt)-9.4(ured)-274.3(correct)-11.7(ly)-271.7(by)-274.7(ordinar)-8.1(y)-273.9(graph-)]TJ +T* +[(based)-344.3(methods)-8.9(.)]TJ +/F8 1 Tf +10.959 0 0 10.959 74.0976 390.1039 Tm +[(4.5.)-502(Accuracy)-330.9(of)-331.2(pathway)-330.7(inference)]TJ +/F5 1 Tf +9.9626 0 0 9.9626 84.0755 372.1322 Tm +[(Mmun)-8.2(in)]TJ +/F2 1 Tf +3.9549 0 TD +[(recovers)-329.6(know)-7(n)-319.4(annotat)-8.7(ed)-322(pathwa)-9.1(ys)-321.4(from)]TJ +/F5 1 Tf +17.3789 0 TD +[(Reac)-8.2(tome)]TJ +/F2 1 Tf +5.167 0 TD +[(typicall)-9.3(y)-319.4(with)-325.5(very)-325.5(high)-324.5(accuracy)-11.3(.)-319(For)]TJ +-27.5024 -1.195 TD +[(the)-382.4(followi)-8.1(ng)]TJ +/F8 1 Tf +5.8897 0 TD +[(pathway)-384.5(infere)-9.2(nce)]TJ +/F2 1 Tf +7.9042 0 TD +[(experiment)-12.6(s,)-377.9(we)-377.1(formed)-389.4(new)-377.9(problem)-385.3(instanc)-9.9(es)-380.1(for)-376.1(a)-378.1(sma)-8.8(ll)-376.9(number)-381.7(of)]TJ +-13.7939 -1.2007 TD +[(kn)-7.2(own)-421.6(p)-6.5(athways)-432.2(in)]TJ +/F5 1 Tf +8.57 0 TD +(Reactome)Tj +/F2 1 Tf +4.8427 0 TD +[(:)-418.9(nam)-7.6(ely,)-428.3(all)-425(ten)-427.9(pathwa)-9.1(ys)-423.8(from)-425.9(the)-427.9(22)-422.6(instanc)-9.9(es)-425.6(with)-427.9(only)-426.9(cyclic)-430.9(hy-)]TJ +-13.4126 -1.2007 TD +[(perpa)-9.4(ths)-262.3(whe)-8(re)-267.1(the)-262.9(target)-271.7(appears)-269.9(in)-266.1(only)]TJ +/F8 1 Tf +16.8554 0 TD +(one)Tj +/F2 1 Tf +1.7129 0 TD +[(annot)-8.4(ated)]TJ +/F5 1 Tf +4.1769 0 TD +[(Reac)-8.2(tome)]TJ +/F2 1 Tf +5.1044 0 TD +[(path)-7.6(way)]TJ +/F11 1 Tf +7.4718 0 0 6.641 385.455 340.7243 Tm +({)Tj +/F2 1 Tf +9.9626 0 0 9.9626 391.8046 336.3023 Tm +[(\(and)-268.6(hence)-270.9(there)-268.2(is)-267.2(a)-264.3(unique)]TJ +/F8 1 Tf +-31.8898 -1.2007 TD +(true)Tj +/F2 1 Tf +1.9519 0 TD +[(path)-7.6(way)-338.1(that)-334.7(produc)-8.3(es)-334.6(the)-336.9(target\).)-343.1(This)-336.9(gave)-336.7(ten)-336.9(instanc)-9.9(es)-334.6(for)-336.3(the)-336.9(infere)-9.2(nce)-335.9(experiment)-12.6(.)]TJ +-.9503 -1.2007 TD +[(For)-362(each)-361.2(instanc)-9.9(e,)-355.7(g)-6.5(iven)-360.4(by)-354.3(a)-361.1(partic)-10(ular)]TJ +/F5 1 Tf +16.827 0 TD +[(Rea)-9(ctome)]TJ +/F2 1 Tf +5.2012 0 TD +[(path)-7.6(way)]TJ +/F8 1 Tf +3.7615 0 TD +(P)Tj +/F10 1 Tf +6.9738 0 0 6.9738 347.1306 316.0062 Tm +()Tj +/F2 1 Tf +9.9626 0 0 9.9626 351.0991 312.3779 Tm +[(,)-358.9(the)-359.6(input)-362.2(hyper)-7.6(graph)]TJ +/F8 1 Tf +9.5487 0 TD +(G)Tj +/F2 1 Tf +1.0755 0 TD +[(cont)-7.6(ains)]TJ +/F8 1 Tf +3.7102 0 TD +(all)Tj +/F2 1 Tf +-42.1385 -1.2007 TD +[(vert)-9.6(ices)-460.1(and)-459.3(hyperedges)-465.7(from)]TJ +/F5 1 Tf +12.9289 0 TD +[(React)-7.3(ome)]TJ +/F2 1 Tf +4.8427 0 TD +[(;)-453.1(the)]TJ +/F8 1 Tf +2.4242 0 TD +(sources)Tj +/F2 1 Tf +3.5111 0 TD +[(consist)-464.6(of)-453.1(all)-459.2(vertic)-10(es)-459.7(in)]TJ +/F8 1 Tf +10.8234 0 TD +(G)Tj +/F2 1 Tf +1.1779 0 TD +[(with)-456.4(no)-456.8(inco)-7.6(ming)]TJ +-35.7082 -1.2007 TD +[(hy)-7.2(peredges)-384.5(in)]TJ +/F8 1 Tf +6.1116 0 TD +(G)Tj +/F2 1 Tf +.7227 0 TD +[(,)-376(and)-379.7(all)-385.2(vertices)-384.3(in)-379.9(path)-7.6(way)]TJ +/F8 1 Tf +12.2973 0 TD +(P)Tj +/F10 1 Tf +6.9738 0 0 6.9738 270.822 292.0818 Tm +()Tj +/F2 1 Tf +9.9626 0 0 9.9626 278.5889 288.4535 Tm +[(with)-382.4(no)-377.1(incomi)-9.7(ng)-377.1(hyper)-7.6(edges)-384.2(from)-380.4(within)]TJ +/F8 1 Tf +17.9423 0 TD +(P)Tj +/F10 1 Tf +6.9738 0 0 6.9738 463.4644 292.0818 Tm +()Tj +/F2 1 Tf +9.9626 0 0 9.9626 467.4329 288.4535 Tm +[(;)-379.1(and)-379.7(the)]TJ +/F8 1 Tf +-39.481 -1.2007 TD +[(targ)-7(ets)]TJ +/F2 1 Tf +3.1013 0 TD +[(are)-315.1(all)-311.2(vertic)-10(es)-311.8(in)]TJ +/F8 1 Tf +7.3977 0 TD +(P)Tj +/F10 1 Tf +6.9738 0 0 6.9738 184.8755 280.1196 Tm +()Tj +/F2 1 Tf +9.9626 0 0 9.9626 191.9621 276.4913 Tm +[(with)-314.1(no)-314.5(outgoing)-318.9(hyperedges)-317.7(from)-317.8(within)]TJ +/F8 1 Tf +17.3107 0 TD +(P)Tj +/F10 1 Tf +6.9738 0 0 6.9738 370.5448 280.1196 Tm +()Tj +/F2 1 Tf +9.9626 0 0 9.9626 374.5133 276.4913 Tm +[(.)-313.4(Across)-321.9(these)-312.9(ten)-314.1(instanc)-9.9(es,)-317.9(the)]TJ +-30.1542 -1.195 TD +[(nu)-7.2(mber)-448.5(of)-447.4(hyper)-7.6(edges)-452.4(in)-448.2(pathwa)-9.1(y)]TJ +/F8 1 Tf +14.8922 0 TD +(P)Tj +/F10 1 Tf +6.9738 0 0 6.9738 228.5858 268.1574 Tm +()Tj +/F2 1 Tf +9.9626 0 0 9.9626 237.033 264.5858 Tm +[(has)-449.1(range)-453.2([2)-171.3(98],)-448.5(with)-450.7(median)-452.6([14)-172(17].)-448.5(We)-449.7(note)-451.5(that)-454.2(all)-447.8(these)]TJ +-16.3546 -1.2007 TD +[(instanc)-9.9(es)-334.6(now)-342(contain)]TJ +/F8 1 Tf +9.3723 0 TD +[(multipl)-8.9(e)-332.6(targets)]TJ +/F2 1 Tf +6.4189 0 TD +(.)Tj +-14.7897 -1.2007 TD 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93.9401 204.7747 Tm +[(from)-505.6(the)-501.9(cycle)-501.3(that)-505.4(would)-505.6(not)-500.1(normal)-8.9(ly)-499.4(qualify)-504(as)-499.6(sourc)-8.8(es)-499.6(\(since)-503.5(thes)-8.8(e)-497.6(vertic)-10(es)-499.6(have)-501.7(inco)-7.6(ming)]TJ +-1.9917 -1.2007 TD +[(hy)-7.2(peredges\).)-353.5(We)-347.3(tried)-348.8(to)-345.7(choose)-350.8(for)-342(thes)-8.8(e)-344(new)-349.4(source)-347.1(vertic)-10(es)-345.9(those)-345.3(that)-351.8(would)-346.2(minimi)-8.5(ze)-346.5(the)-348.3(number)-347.6(of)]TJ +T* +[(reac)-10.4(tions)-278(that)-277.8(coul)-7.6(d)-273.9(now)-279.4(be)-276.5(bypass)-8.7(ed,)-276.8(sinc)-8.8(e)-275.7(these)-278.8(new)-281.2(sourc)-8.8(es)-277.7(could)-275.8(n)-6.5(o)0(w)-272.9(b)0(e)-282.2(i)0(n)-277.4(the)-274.3(tail)-280.6(of)-276.6(a)-275.7(hyp)-8(eredge)-279.4(in)-277.4(a)]TJ +0 -1.195 TD +[(hy)-7.2(perpath)-338(before)-342.2(being)-338.4(reached)-338.8(in)-340(the)-336.9(head)-336.7(of)-333.6(a)-332.6(pri)-7(or)-333.6(hyper)-7.6(edge.)]TJ +ET +q +429.732 0 0 163.956 74.438 558.312 cm +/Im5 Do +Q +BT +/F3 1 Tf +8.9663 0 0 8.9663 74.0976 542.3243 Tm +[(FIG.)-353.7(4.)]TJ +/F2 1 Tf +4.1289 0 TD +[(Shortest)-350.4(hyperpath)-348.5(to)-350.8(the)-346.4(BMP7/BMPR2/BMPR1A/SMAD6/SMURF1)-354.1(complex.)-353.3(Sources)-345.2(are)-353.7(shown)-349.8(across)]TJ +-4.1289 -1.2203 TD +[(the)-295.8(top)-293.4(of)-292.5(the)-295.8(gure,)-294.9(and)-291.8(the)-295.8(target)-290.8(is)-295.1(shown)-292.9(at)-296.3(the)-295.8(bottom.)-289.8(The)-297.9(portion)-291.8(of)-292.5(the)-295.8(nal)-293.9(hyperedge)-290(in)-293.9(dotted)-298.4(red)-294.4(represents)]TJ +T* +[(PPM1A)-333.8(acting)-338.7(as)-331.4(a)-337(positive)-334.2(regulator)-336.2(of)-330.4(the)-340.1(reaction.)-333.1(The)-335.9(hyperedges)-335(in)-331.8(red)-338.7(form)-329.3(a)-337(cycle)-337.6(in)-331.8(the)-333.8(hyperpath.)]TJ +ET +q +1 i +74.098 153.808 m +504.51 153.808 l +504.51 69.902 l +74.098 69.902 l +W n +0 0 0 RG +1 J 1 j .454 w 10 M []0 d +q 1 0 0 1 74.098 153.808 cm 0 0 m +490.677 0 l +S +Q +Q +BT +/F11 1 Tf +6.7246 0 0 5.9768 84.0755 143.6031 Tm +({)Tj +/F2 1 Tf +8.9663 0 0 8.9663 87.4771 139.6346 Tm +[(These)-338.5(ten)-340.1(benchmark)-337.8(pathways)-344.6(are)-341.1(identied)-339.9(by)-340.5(the)-333.8(following)-342.4(names:)-339.4()54.8(Glycogen)-339.2(Synthesis,)51.2()-337.2()54.8(Hydrocarboxylic)]TJ +-1.4922 -1.1128 TD +[(Acid-Binding)-367(Receptors,)55.5()-362.5()54.8(Interleukin-37)-361.4(Signaling,)49.5()-356.2()54.8(Proton/Oligopeptide)-367.7(Cotransporters,)56.2()-362.5()54.8(Regulation)-360.3(of)-362(Com-)]TJ +0 -1.1065 TD +[(plement)-436.6(Cascade,)46()-432.1()54.8(Sphingolipid)-434.6(Metabolism,)53.4()-438.4()61.1(Tolerance)-443.8(by)-435.3(Mtb)-433.2(to)-433(Nitric)-434.8(Oxide)-437.3(Produced)-438.4(by)-435.3(Macrophages,)55.7()]TJ +0 -1.1128 TD +[()54.8(Transport)-339.2(of)-330.4(Small)-338.9(Molecules,)51.7()-330.9()54.8(Triglyceride)-336.7(Catabolism,)49.4()-330.9(and)-336.1()54.8(Uncoating)-336.4(of)-330.4(the)-333.8(Inuenza)-333.3(Virion.)53.5()]TJ +/F19 1 Tf +6.7246 0 0 5.9768 84.0755 103.8047 Tm +({)Tj +/F2 1 Tf +8.9663 0 0 8.9663 87.4771 99.7795 Tm +[(For)-334.8(all)-331.5(ten)-340.1(instances,)-338.7(the)-333.8(specic)-336.4(vertices)-337.6(that)-337.3(were)-337.6(added)-337.5(to)-338.2(the)-333.8(source)-334.5(set)-341.3(are)-334.8(listed)-335.2(in)-338.2(le)]TJ +/F5 1 Tf +38.0513 0 TD +(supplementary_)Tj +-39.5435 -1.1065 TD +(sources)Tj +/F2 1 Tf +4.4893 0 TD +(on)Tj +/F5 1 Tf +1.2583 0 TD +(Mmunin)Tj +/F2 1 Tf +3.623 0 TD +[(s)-255.7(website,)-263.5(identied)-257.7(by)-258.3(their)-257.2(Pathway)-260.2(Commons)-262.5(ID.)-254.4(This)-262.3(includes)-256.8(both)-261.3(vertices)-261.8(that)-255.1(contain)-262.4(no)]TJ +-9.3706 -1.1128 TD +[(incoming)-307.3(hyperedges)-303.3(from)-304(within)-303.3(the)-302.1(known)-304.4(pathway)]TJ +/F8 1 Tf +22.3262 0 TD +(P)Tj +/F10 1 Tf +6.2762 0 0 6.2762 279.7794 83.1118 Tm +()Tj +/F2 1 Tf +8.9663 0 0 8.9663 283.4078 79.8803 Tm +[(,)-306.4(and)-304.5(vertices)-306(added)-299.6(to)-306.5(establish)-305.7(reachability)-307(of)-298.8(an)-304.9(otherwise)]TJ +-23.3442 -1.1128 TD +[(unreachable)-342.1(cycle.)]TJ +/F3 1 Tf +9.9626 0 0 9.9626 74.0976 737.4045 Tm +[(12)-7.2(18)-26741.4(KRIEG)-9.3(ER)-334.5(AN)-9.4(D)-334.8(KECE)-8.6(CIOGLU)]TJ +ET + +endstream +endobj +66 0 obj +<< +/Length 88423 +/Subtype /Image +/Filter /DCTDecode +/BitsPerComponent 8 +/ColorSpace /DeviceRGB +/Width 895 +/Height 342 +/Type /XObject +>> +stream +Adobed   + + + +     V +  + s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& +EFVU(eufv7GWgw8HXhx)9IYiy*:JZjzm!1AQa"q2#BRbr3$4CS%cs5DT +&6E'dtU7()󄔤euFVfvGWgw8HXhx9IYiy*:JZjz ?imv +4GrP,E_ .qNumFٸM̯HsGO!#oV3Ա _F_'i7Ӈ5?1پϖuZN5eqƐuHkӇ5 +O5D^?>kXԱ 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G8l}  |}oCyFJM "=a?I/è>\Cɧ.ϟ>*촧W,DlO?[MftȪ>myZ7!_%q<? }>~dL@Ls~̺BK55GeVR ~xqh>e6ߒI.եծVvޥĞ܎ʿUS)=Ón-/Mci?2?ھ|_|H>>0d>|#cw6||a|jG~?m#Id ?F!'CW?ϟ;7ySoO'̇?wn14O?_>/Mci?2?ھ|_|H>>0d>|#cw6||a|jG~d{[K-XMbEj:q/өtqb +W$g׆"8?ҿOMcv*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb]v*UثWb_ + +endstream +endobj +67 0 obj +<< +/Length 613 +/Subtype /Type1C +/Filter /FlateDecode +>> +stream +h,Rn1MmPH +tTH޻cl}ܻDODOEG@edx3>> +stream +/GS1 gs +BT +/F2 1 Tf +9.9626 0 0 9.9626 117.5811 715.4644 Tm +0 0 0 rg +0 Tc +0 Tw +[(This)-450.7(resulted)-450.8(in)-448.2(a)-446.4(d)0(o)-7.2(ubly-reacha)-10.9(ble)-450.7(subgraph)-454.9(contain)-8.7(ing)-448.9(up)-445.4(to)-448.2(3,600)-447.3(hyper)-7.6(edges)-452.4(for)-450.1(some)-447.7(p)-6.5(athway)]TJ +-1.0015 -1.195 TD +[(infere)-9.2(nce)-364.4(instances,)-367.6(whi)-9(ch)-361.8(is)-364(more)-363.2(than)-366.1(double)-367.6(the)-359.7(siz)-8(e)-361.1(o)0(f)-362(this)-362.6(subgr)-7(aph)-362.6(for)-364.7(any)-362.6(of)-362(our)-362.8(previ)-10.3(ous)-362(single-)]TJ +0 -1.2007 TD 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TD +[(s)-337.9(running)-344.6(time)-340.8(to)-338.2(three)-344.1(features)-342.6(of)-343.1(the)-340.1(instances)-342.1(for)-345.2(the)-340.1(pathway)-343.9(inference)-343.3(exper-)]TJ +-14.157 -1.2203 TD +[(iment.)-254.7(The)-247.4(three)-249.3(features)-254(are:)-249.8(\(a\))-252.8(size)-248.4(of)-248.2(the)-251.6(doubly-reachable)-251.5(edge)-255.8(set,)-249.3(\(b\))-250.3(shortest)-245.5(hyperpath)-253.7(length,)-250.7(and)-247.5(\(c\))-252.8(number)-245.9(of)]TJ +T* +[(targets.)-281.7(Red)-277.6(discs)-284.6(mark)-278.5(the)-276.9(four)-281.5(instances)-278.8(with)-281.3(high)-274(running)-281.4(time,)-274.2(while)-283.2(blue)-276.4(triangles)-281.9(mark)-278.5(the)-276.9(six)-281.9(instances)-278.8(with)-281.3(low)]TJ +T* +[(running)-338.3(time.)]TJ +ET +74.098 199.559 430.413 .51024 re +f +74.098 71.206 430.413 .51022 re +f +74.098 181.134 430.413 .51024 re +f +74.098 152.787 430.413 .51024 re +f +74.098 133.398 430.413 .51022 re +f +BT +/F7 1 Tf +8.9663 0 0 8.9663 186.1795 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+[(We)-313.2(found)-318.8(that)-317.6(the)-314.1(distanc)-9.9(e-based)-321.2(cuts,)-316.5(head-)-9.4(hitting)-318(constra)-9.2(ints,)-317.4(and)-317.1(tail-coveri)-11.7(ng)-314.5(constraint)-11.3(s)-309.3(cont)-7.6(ribute)]TJ +-1.0015 -1.195 TD +[(the)-376.7(most)-374.7(to)-374.2(a)-372.4(reas)-9.8(onable)-375.1(runni)-8.6(ng)-371.4(time)-8.2(,)-370.3(a)0(s)-374.4(their)-377.3(absen)-8.6(ce)-375(causes)-382.2(a)-372.4(huge)-374.7(slowdow)-11.5(n.)-371(In)-373.4(reali)-9.2(ty,)-374.6(rather)-379.1(than)]TJ +0 -1.2007 TD +[(literally)-435.9(excludi)-8.7(ng)]TJ +/F8 1 Tf +7.9554 0 TD +(all)Tj +/F2 1 Tf +1.4909 0 TD +[(distanc)-9.9(e-based)-435(cuts,)-430.3(to)-425.4(ensur)-8.8(e)-423.7(that)-431.5(the)-427.9(cutti)-8.2(ng-plane)-435.5(algorithm)-432.2(terminat)-12.1(es)-425.6(\(giv)-7.8(en)]TJ +-9.4463 -1.2007 TD +[(enough)-296.6(ti)-7.1(me\))-294.1(we)-297.5(mus)-7(t)-293.7(replace)-301.7(the)-297.1(distance-b)-10.3(ased)-298(cuts)-299(with)-297(the)-297.1(sing)-7(le)-296.3(cut)]TJ +/F8 1 Tf +30.0518 0 TD +(C)Tj +/F9 1 Tf +1.03 0 TD +(=)Tj +/F10 1 Tf +.882 0 TD +(f)Tj +/F8 1 Tf +.5008 0 TD +(s)Tj +/F10 1 Tf +.387 0 TD +(g)Tj +/F2 1 Tf +.5008 0 TD +[(.)-296.3(Our)-298.4(impleme)-10.1(ntation)-299.9(of)]TJ +/F5 1 Tf +-33.3523 -1.2007 TD +[(Mmuni)-7.3(n)]TJ +/F2 1 Tf +3.8639 0 TD +[(in)-237.6(fact)-239(starts)-238.2(with)-240.1(this)-237.4(single)-235(cut,)-240.5(but)-238.4(once)]TJ +/F5 1 Tf +16.8156 0 TD +[(Hhug)-8.1(in)]TJ +/F2 1 Tf +3.8696 0 TD +[(terminates)-244.2(in)-237.6(parallel,)-238.3(all)-237.2(of)-236.8(the)-240.2(distance-b)-10.3(ased)]TJ +-24.549 -1.2007 TD +[(cuts)-424.2(are)-428.9(then)-428.7(compute)-9.5(d)-421.9(and)-425.2(suppl)-7.8(ied)-422.3(to)-425.4(the)-427.9(cutting-plane)-438(algorithm.)-432.5(For)-424.6(many)-423.8(of)-424.6(the)-427.9(easier)-431.3(instanc)-9.9(es,)]TJ +/F5 1 Tf +T* +[(Hhugi)-7.3(n)]TJ +/F2 1 Tf +4.046 0 TD +[(does)-415.7(not)-420.5(actually)-423.8(terminate)-424.3(before)]TJ +/F5 1 Tf +14.7613 0 TD +[(Mmuni)-7.3(n)]TJ +/F2 1 Tf +3.6306 0 TD +[(,)-415.8(i)0(n)-414(which)-422(case)-419.3(the)-416.6(distanc)-9.9(e-based)-423.6(cuts)-418.5(never)-419.1(get)]TJ +-22.4378 -1.2007 TD +[(added,)-263.8(even)-262.7(whe)-8(n)-256.8(they)-263.7(are)-263.9(not)-261.1(deliberat)-11.1(ely)-257.2(excl)-9.4(uded.)-261.3(For)-259.6(the)-262.9(harder)-268.2(instances,)-265.2(howe)-8.8(ver,)-262.5(the)-262.9(distance-b)-10.3(ased)]TJ +T* +[(cuts,)-344.9(head-hitt)-9.3(ing)-340.8(constra)-9.1(ints,)-340.2(and)-339.8(tail)-7.4(-covering)-347.2(constra)-9.1(ints)-339.8(are)-343.6(all)-339.7(neces)-10.4(sary)-343.8(for)]TJ +/F5 1 Tf +32.9824 0 TD +(Mmunin)Tj +/F2 1 Tf +3.9663 0 TD +[(to)-340(nish)-342.7(within)]TJ +-36.9487 -1.195 TD +[(24)-297.4(hours)-7(.)-296.3(For)-293.7(the)-302.7(easier)-300.4(instanc)-9.9(es,)-300.8(exclusio)-10.7(n)-296.7(o)0(f)-293.7(the)-302.7(head-hitt)-9.3(ing)-295.3(constra)-9.2(ints)-300(has)-301.2(the)-297.1(most)-300.7(impact,)-302.1(as)-300.4(shown)]TJ +0 -1.2007 TD +[(by)-331.6(the)-336.9(larg)-9.6(est)-332.4(increas)-10.9(e)-332.6(i)0(n)-334.3(med)-7.6(ian)-336.9(running)-340.1(time)-338.2(and)-334.1(itera)-9.2(tion)-332.9(count)-8.4(.)]TJ +1.0015 -1.2007 TD +[(To)-428.1(dete)-9.4(rmine)-435(the)-427.9(eff)-8(ect)-429.7(on)-434(running)-431.2(time)-435(of)-430.3(the)-433.6(cuttin)-9(g-plane)-434.8(inequal)-8.7(ities)-430.5(that)-437.2(are)-434.6(source-)-435.2(and)-430.9(sink)-7(-)]TJ +-1.0015 -1.2007 TD +[(augment)-9.5(ed)-344.7(distanc)-9.9(e-based)-349.6(cuts)-8.8(,)-341.8(w)0(e)-348.7(replace)-11.5(d)]TJ +/F5 1 Tf +18.5 0 TD +[(Mmun)-8.2(in)]TJ +/F2 1 Tf +3.6306 0 TD +[(s)-346.1(gener)-9.4(al)-347.5(separation)-351.7(algo)-7.6(rithm)-344.9(with)-348.2(the)]TJ +/F8 1 Tf +16.8099 0 TD +[(trivia)-10.2(l)]TJ +/F2 1 Tf +2.8054 0 TD +[(on)-7.2(e)]TJ +-41.7459 -1.2007 TD +[(that)-357.5(at)-353.2(each)-361.2(itera)-9.2(tion)-355.7(just)-356.9(nds)-356.3(the)-354(set)]TJ +/F8 1 Tf +16.0189 0 TD +(R)Tj +/F2 1 Tf +.9674 0 TD +[(of)-356.3(vertices)-361.6(reac)-10.4(hable)-357.3(from)]TJ +/F8 1 Tf +11.1933 0 TD +(s)Tj +/F2 1 Tf +.7398 0 TD +[(along)-361.2(the)-354(active)-362.6(hyperedges)-363.3(of)-356.3(the)]TJ +-28.9194 -1.2007 TD +[(current)-482.2(solution)]TJ +/F8 1 Tf +7.0278 0 TD +(x)Tj +/F10 1 Tf +6.9738 0 0 6.9738 182.0976 551.7353 Tm +()Tj +/F2 1 Tf +9.9626 0 0 9.9626 186.0661 548.1069 Tm +[(,)-472.7(and)-476.4(only)-478.1(adds)-472.7(the)-479.2(single)-479.7(cut)]TJ +/F8 1 Tf +13.4923 0 TD +(C)Tj +/F9 1 Tf +1.03 0 TD +(=)Tj +/F8 1 Tf +.8877 0 TD +(R)Tj +/F2 1 Tf +1.0869 0 TD +[(to)-476.6(the)-473.5(ILP.)-476(We)-478.2(found)-478.1(that)-471.3(usin)-7(g)-473.1(this)-476.4(trivial)]TJ +-24.3726 -1.2007 TD +[(separat)-10.9(ion)-374.9(algori)-8.2(thm)-372.8(and)-379.7(exclu)-10.1(ding)-375.7(the)-376.7(target)-10(-production)-383.8(constra)-9.1(int)-377.7(had)-374(little)-378.7(eff)-8(ect)-378.5(on)-377.1(running)-380(time)-378.1(for)]TJ +T* 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+[(to)-334.3(nd)-337.2(an)-333.4(optim)-7.2(al)-336.1(hyperpat)-8.7(h,)-331.2(likel)-8.2(y)-330.8(becau)-9.2(se)-334.6(fewer)-339.6(cut-)-9.6(based)-338.6(inequal)-8.7(ities)-333.7(are)-337.9(added)-343.1(at)-336.1(each)-338.5(iteration.)]TJ +/F8 1 Tf +10.959 0 0 10.959 117.5811 464.4282 Tm +[(4.6.2.)-497(Including)-327.6(constraint)-337.3(classes.)]TJ +/F2 1 Tf +9.9626 0 0 9.9626 285.2787 464.4282 Tm +[(For)-339.2(the)-336.9(secon)-8.6(d)-336.5(inclusion)-342.5(exper)-9.4(iment,)-339.4(we)-343(rst)-338.2(ranked)-340.2(the)-342.6(con-)]TJ +-17.8342 -1.2007 TD +[(straint)-348.6(classes)-347.1(by)-343(their)-343.2(effect)-346.7(on)-343(running)-345.8(time)-343.9(\(from)-343.3(greates)-10.9(t)-339.3(effect)-346.7(to)-340(least\))-346.9(based)-344.3(on)-343(the)-342.6(outc)-7.6(ome)-343.3(of)-339.3(the)]TJ +T* 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TD +[(is)-335.5(open,)-335.3(and)-339.8(will)-333.9(requi)-10.3(re)-335.3(a)-332.6(much)-338.4(different)-340.6(desi)-8.8(gn)-331.6(than)-337.7(our)-334.3(curr)-8.8(ent)-336.9(one.)]TJ +/F8 1 Tf +10.959 0 0 10.959 117.5811 679.6345 Tm +[(Incorporati)7.8(ng)-251.9(negative)-249.3(regulation.)]TJ +/F2 1 Tf +9.9626 0 0 9.9626 280.1763 679.6345 Tm +[(More)-247.8(directly)-247.6(relevan)-9.8(t)-242.5(t)0(o)-243.3(computa)-9.5(tional)-242.3(biolog)-10.1(y)-239.8(i)0(s)-244.5(incorporat)-9.3(ing)]TJ +-17.322 -1.2007 TD +[(negativ)-8.7(e)-372.4(regulat)-10.7(ion)-374.9(when)-373(n)-6.4(ding)-375.7(shortes)-8.6(t)-367.7(h)0(y)-7.2(perpaths.)-380.2(A)]TJ +/F8 1 Tf +23.6044 0 TD +[(negativ)-8.7(e)-372.4(regulat)-8.1(or)]TJ +/F2 1 Tf +7.944 0 TD +[(is)-375.4(a)-372.4(molecu)-8.7(le)-376(that)-374.6(inhibi)-7.2(ts)-375.4(a)]TJ +-31.5484 -1.2007 TD 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+[(Collecting)-425.3(benchmark)-434.4(hypergraph)8.1(s.)]TJ +/F2 1 Tf +9.9626 0 0 9.9626 289.5306 498.2739 Tm +[(Our)-446.4(experiment)-12.6(s)-440.1(evaluat)-10.5(ing)-443.2(the)-445(cutting-plane)-455.1(approach)-451.6(im-)]TJ +-18.261 -1.195 TD +[(plemen)-8.7(ted)-382.4(by)]TJ +/F5 1 Tf +5.9523 0 TD +[(Mmu)-9(nin)]TJ +/F2 1 Tf +4.0118 0 TD +[(in)-379.9(Sect)-8.6(ion)-380.6(4.5)-383.2(suggest)-382.2(it)-7(s)-377.5(hardest)-384.7(instanc)-9.9(es)-380.1(ari)-8.8(se)-380.1(from)-380.4(grow)-9(th)-379.9(in)-379.9(the)-382.4(size)-386.2(of)-379.1(the)]TJ +-9.9642 -1.2007 TD +[(doubl)-6.6(y-reachable)-371.2(subgraph.)-364.2(While)-366.5(compreh)-8.7(ensive)-364.9(evaluation)-368.4(of)]TJ +/F5 1 Tf +26.6261 0 TD +[(Mmun)-8.2(in)]TJ +/F2 1 Tf +3.9891 0 TD +[(over)-365.3(all)-356.7(sing)-7(le-target)-365.9(instanc)-9.9(es)]TJ +-30.6152 -1.2007 TD 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+[(\(in)-439.5(cont)-7.6(rast)-443.2(to)-442.5(simulat)-8.7(ed)-441.5(instances)-446.9(from)]TJ +-26.37 -1.2007 TD +[(rando)-7.6(m)-311.6(hyper)-7.6(graph)-314.9(generat)-9.7(ors)-312.7(which)-319.6(can)-318.8(lack)-316.7(the)-314.1(challengin)-9.9(g)-313.7(structure)-322.7(of)-310.8(real)-318.7(instanc)-9.9(es\))-314.5(besides)-321.3(cellular)]TJ +T* +[(reaction)-354.7(networ)-9.3(ks,)-350.2(for)-353.4(evaluating)-357(shortes)-8.6(t)-350.6(hyperpat)-8.7(h)-347.9(solvers)-8.6(,)-347.5(that)-351.8(contain)-355.9(harder)-353.5(struct)-9.4(ure)-347.5(\(suc)-8(h)-347.9(a)0(s)-351.6(larger)]TJ +0 -1.195 TD +[(doubl)-6.6(y-reachable)-502(subgr)-7(aphs\))-8.8(,)-489.8(and)-499.2(naturally)-498.7(ari)-8.8(se)-493.9(from)-494.2(appl)-7.6(ications)-502.8(needing)-501.1(solution?)-501.8(Collecting)-505(such)]TJ +0 -1.2007 TD 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