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[(st)11.1(r)-9(a)11.1(t)-7.9(e)-1.4(d)-364.9(a)-367.8(dec)11.1(l)-10.7(ine)-368.2(i)1.2(n)-365.3(t)-2(he)-368.2(NS)11.1(C)-373.2(p)-2.9(ool,)-371.2(d)1.8(ue)-368.2(to)-364.7(incre)11.1(a)-7.3(se)11.1(d)-377.5(p)3.4(rolif-)]TJ
T*
.0106 Tc
[(eration)-258.3(a)-1.6(nd)-258(loss)-256.3(o)-4.8(f)-255.4(self)10.6(-)-9.3(r)3.6(enewal,)-257.9(i).7(n)-5.4(d)1.3(ic)10.6(a)-7.2(t)-2.5(ing)-259.4(t)-2.5(ha)10.6(t)-267.6(F)-.1(OXOs)-262.6(ma)10.6(y)]TJ
0 -1.2266 TD
0 Tc
[(p)-14(l)-9.9(ay)-471.8(a)-461.1(c)-11.9(r)-13.3(i)-9.9(ti)-16.6(c)-11.9(a)-12.2(l)-465.1(g)-10.7(en)-22.2(er)-19.6(al)-470.9(r)-13.3(o)-9.1(l)-9.9(e)-467.8(i)-9.9(n)-465(s)-7.6(t)-13.1(em)-471.7(c)-11.9(e)-12.5(l)-9.9(l)-465.1(h)-9.7(o)-9.1(m)-10.2(e)-12.5(o)-9.1(s)-7.6(t)-13.1(a)-12.2(s)-7.6(i)-9.9(s)-14(.)-464.5(S)-11.1(u)-7.7(r)-13.3(-)]TJ
0 -1.2203 TD
[(p)-14(r)-7(i)-9.9(s)-14(i)-9.9(n)-9.7(g)-10.7(l)-9.9(y)-10.7(,)-363.3(s)-7.6(i)-9.9(m)-10.2(i)-9.9(l)-9.9(a)-12.2(r)-361.1(e)-12.5(f)-13.1(f)0(e)-19.3(c)-11.9(ts)-374.8(h)-9.7(a)-12.2(v)-7.1(e)-366.6(al)-15.7(s)-14(o)-363.2(r)-13.3(e)0(v)-19.6(c)-11.9(en)-15.9(t)-13.1(l)-9.9(y)-364.8(b)-10.7(ee)-18.8(n)-363.8(r)-13.3(e)-12.5(p)-7.7(o)-9.1(r)-13.3(te)-19.3(d)]TJ
T*
.0107 Tc
[(in)-340.4(mice)-337(decient)-337.5(for)]TJ
/F5 1 Tf
9.4591 0 TD
0 Tc
[(Fo)-16.3(x)-12.2(o)-11.9(3)]TJ
/F4 1 Tf
2.8137 0 TD
.0143 Tc
[(\(8)14.3(0\).)]TJ
-11.1599 -1.2266 TD
0 Tc
[(Over)-390.1(the)-395.8(last)-390.5(decade,)-393.2(a)-391.5(plethora)-397.3(of)-388.9(studies)-396.6(have)-389.2(demon-)]TJ
-1.1128 -1.2203 TD
[(strated)-435.3(that)-433.8(FOXOs)-433.4(play)-426.1(critical)-433.5(roles)-431.9(in)-436.9(a)-429.5(wide)-431.7(variety)-432.9(of)]TJ
T*
[(cellular)-365.4(processes,)-364.9(including)-366.9(proliferation,)-367(apoptosis,)-365.1(autop-)]TJ
0 -1.2266 TD
[(hagy,)-419.3(metabolism,)-424.5(inammation,)-421.8(differentiation,)-426.3(and)-423.2(stress)]TJ
0 -1.2203 TD
[(resistance)-458.2(\(Table)-453.4(2\).)-451.8(This)-453.8(review)-455.3(focuses)-455.3(on)-455.1(the)-459(functional)]TJ
27.9978 29.332 TD
[(consequences)-642.2(of)-629.2(FOXO)-628.1(activation)-639.2(based)-627.8(on)-632.1(our)-630.8(current)]TJ
0 -1.2203 TD
[(knowledge)-288.5(of)-281.4(regulation)-278.8(of)-281.4(transcriptional)-289(targets.)]TJ
/F3 1 Tf
0 -3.054 TD
[(Regulation)-340.6(of)-330.2(Proliferation)-337.1(Through)-338.1(Induction)]TJ
0 -1.2203 TD
[(of)-336.6(Cell)-336.8(Cycle)-329.4(Arrest)]TJ
/F4 1 Tf
1.1128 -1.8336 TD
[(On)18.9(e)-278.1(o)0(f)-262.5(t)0(h)15.1(e)-271.8(fu)17.1(nc)16.3(t)12.2(i)0(o)19(n)0(s)-270.3(i)15.4(ni)18.4(ti)15(a)13.1(l)0(l)18.2(y)-276.3(a)13.1(t)0(t)18(r)0(i)14.7(b)14.6(ut)17.1(ed)-268.5(t)12.2(o)-274.7(FO)17.8(XO)-266.5(a)13.1(c)0(t)19.2(i)0(v)21(a)0(t)19(i)0(o)19(n)]TJ
-1.1128 -1.2266 TD
[(is)-245.1(th)15.1(e)-252.8(r)0(e)18.4(g)0(u)19.5(l)0(a)22.2(t)0(i)15(o)0(n)-246.4(o)0(f)-243.5(c)0(e)19.8(l)0(l)-247.3(c)13.4(yc)15.3(l)15.4(e)-259.1(pr)23.2(og)18.1(re)18.4(ss)16.3(io)19(n)-250(\()0(F)14.1(i)0(g)23.7(.)-255.8(3)13.1(\))0(.)-250(F)14.5(OX)18(Os)-244.6(ha)16.1(ve)]TJ
0 -1.2203 TD
[(be)14.7(e)12.8(n)-180.4(sh)14.3(ow)20.9(n)-180.4(t)12.2(o)-179.8(m)0(o)18.6(d)0(u)20.9(l)0(a)15.9(t)12.2(e)-183.3(b)14.6(ot)15.7(h)-180.4(t)12.2(he)-174(G)13.9(1)0(-)19(S)-181.8(t)12.2(r)0(a)18.8(n)0(s)14.3(i)0(t)21.3(i)0(o)19(n)-180.4(a)13.1(n)0(d)-170.8(t)0(h)15.1(e)-176.9(G2)20.7(-M)]TJ
T*
[(ph)14.2(a)13.1(s)0(e)-386.9(b)0(y)-388.2(c)0(o)16.9(o)0(r)21.8(d)0(i)18.8(n)0(a)16.1(t)12.2(in)18.4(g)-396.4(e)0(x)16.9(p)0(r)23.2(e)0(s)17.8(s)0(i)14.1(o)0(n)-385.5(o)0(f)-388.9(m)0(u)20(l)0(t)21.3(i)0(p)20.4(l)0(e)-389.1(i)0(m)17.9(p)0(o)21.2(r)0(t)17.8(a)0(n)16.1(t)-392.5(ce)13.5(ll)]TJ
0 -1.2266 TD
[(cy)15.3(c)13.4(l)0(e)-294.3(r)0(e)18.4(g)0(u)19.5(l)0(a)15.9(t)12.2(or)15.5(s)-298.5([)0(r)17.8(e)0(v)18.3(i)0(e)15.5(w)0(e)23.8(d)-306.5(in)-291.5(\(3)19(8)13.1(\))0(])18(.)-306.4(Ec)23(to)15.7(pi)20.4(c)-302.8(e)0(x)16.9(p)0(r)16.9(e)12.7(ss)16.3(io)19(n)-300.6(o)0(f)-294.1(c)0(o)16.9(n)0(-)]TJ
0 -1.2203 TD
[(st)17.2(it)15(ut)23.5(iv)14.7(e)12.7(l)0(y)-311.4(a)0(c)20.2(t)0(i)15(v)0(e)-310.5(F)0(O)17.8(X)0(O)18(4)13.1(,)-325.4(i)0(n)-310.4(w)0(h)20.3(i)0(c)16.2(h)-325.9(t)12.2(h)0(e)-313.1(i)0(n)18.4(h)0(i)18.4(b)0(i)17.3(t)12.2(or)21.8(y)-326.9(p)0(h)20.5(o)0(s)21.2(p)0(h)14.2(o)0(r)21.8(y)0(-)]TJ
T*
[(la)15.9(t)12.2(i)0(o)19(n)-300.6(si)20.4(t)12.2(e)0(s)-285.7(a)0(r)18.8(e)-297.1(mu)20(ta)19(te)18.6(d,)-284.1(in)18.4(du)20.9(ce)13.5(s)-292.2(a)-296.7(G1)-282.8(ce)19.8(ll)-291.6(c)13.4(y)0(c)21.6(l)0(e)-288(a)0(r)18.8(r)0(e)18.4(s)0(t)-286.3(i)0(n)-285.1(A)0(1)18.1(4)13.1(,)]TJ
T*
[(U2)18.1(OS)17.4(,)-173.6(a)13.1(nd)-164.5(J)12.2(u)0(r)16.9(k)14.6(at)-164.4(ce)19.8(ll)18.2(s,)-162.3(wh)20.3(ic)22.5(h)-174.1(i)0(s)-162.9(d)0(e)22.4(p)0(e)17.7(n)0(d)18.9(e)0(n)15.7(t)-171.2(on)-157.9(ex)16.9(pr)16.9(e)12.7(s)0(s)16.3(i)0(o)19(n)-167.8(of)-161.3(th)15.1(e)]TJ
0 -1.2266 TD
[(ce)13.5(ll)-310.6(c)13.4(y)0(c)15.3(l)0(e)-306.9(i)0(n)18.4(h)0(i)18.4(b)0(i)17.3(t)12.2(or)-313.3(p2)18.1(7)-322(\()12.2(61)19.9(\).)-313.2(Th)18.9(e)-322.4(c)13.4(el)15.5(l)-319.7(c)13.4(yc)15.3(le)-313.3(i)15.4(s)-323.8(re)18.4(gu)19.5(la)22.2(te)18.6(d)-325.5(b)14.6(y)-320.6(t)0(h)15.1(e)]TJ
0 -1.2203 TD
[(co)16.9(or)15.5(di)25.1(na)16.1(t)12.2(e)0(d)-312.7(a)13.1(ct)19.2(iv)21(at)19(io)19(n)-319.5(o)0(f)-306.7(m)0(u)20(l)0(t)15(i)0(p)20.4(l)0(e)-306.9(c)0(y)15.3(c)13.4(li)18.2(n)]TJ
/F9 1 Tf
17.6472 0 TD
(=)Tj
/F4 1 Tf
.4995 0 TD
[(C)12.5(D)0(K)14.8(s)0(,)-307.7(w)0(h)20.3(i)0(c)16.2(h)-313.2(ph)14.2(os)21.2(-)]TJ
-18.1468 -1.2203 TD
[(ph)14.2(or)21.8(yl)17.3(a)13.1(t)0(e)-183.7(a)0(n)16.1(d)-192.7(re)18.4(g)14.6(u)0(l)14.1(a)13.1(te)-183.7(mu)20.1(lt)21.3(ip)14.1(le)-180.5(su)16.3(b)14.6(s)0(t)17.2(r)0(a)18.8(t)0(e)18.6(s)-191(th)15.1(a)13.1(t)-196.5(a)13.1(r)0(e)-184(e)0(s)17.8(s)0(e)17.8(n)0(t)21.4(i)0(a)15.9(l)-193.2(f)12.2(o)0(r)]TJ
0 -1.2266 TD
[(ce)13.5(ll)-171.5(cy)21.6(cl)16.2(e)-183.3(p)0(r)16.9(o)0(g)24.4(r)0(e)18.4(s)0(s)16.3(i)0(o)19(n)0(.)-177(p)0(2)24.4(7)-182.9(is)-175.6(a)-182.9(m)0(e)15.2(m)15.1(be)14.7(r)-184.1(o)0(f)-174(t)12.2(he)-174(Ci)15.3(p)]TJ
/F9 1 Tf
20.6127 0 TD
(=)Tj
/F4 1 Tf
.4995 0 TD
[(Ki)18.9(p)-184.7(f)0(a)19(m)0(i)17.9(l)0(y)-172.3(o)0(f)]TJ
-21.1122 -1.2203 TD
[(CD)17.4(K)-319(i)0(n)18.4(h)0(i)18.4(b)14.6(it)15(or)21.8(s)-317.5(t)0(o)15.7(g)0(e)21(t)0(h)15.1(e)12.8(r)-316.8(w)0(i)20.1(t)0(h)-307.4(p)0(2)18.1(1)-315.7(an)16.1(d)-312.8(p)0(5)18.1(7)-315.7(an)16.1(d)-312.8(b)0(i)17.3(n)0(d)18.9(s)-317.5(t)12.2(o)-318.9(bo)18.1(t)12.2(h)]TJ
T*
[(cy)15.3(c)13.4(l)0(i)18.2(n)-294.2(an)16.1(d)-293.9(C)12.5(DK)-282.4(su)16.3(bu)19.5(ni)18.4(ts)-286.3(in)18.4(hi)18.4(b)14.6(i)0(t)15(i)0(n)18.4(g)-288.9(th)15.1(e)-290.7(a)0(c)20.2(t)0(i)15(v)0(i)21(t)0(i)21.3(e)0(s)-285.7(o)0(f)-287.8(c)0(y)21.6(c)0(l)16.2(i)0(n)-285.1(D)0(-)23.4(,)]TJ
0 -1.2266 TD
[(E-)15.5(,)-300.1(a)0(n)16.1(d)-300.2(A-)17.1(C)12.5(D)0(K)-295.1(c)0(o)16.9(m)15.1(pl)14.1(e)12.8(x)0(e)16.9(s)-298.5([r)17.8(ev)18.3(ie)15.5(we)23.8(d)-306.5(i)15.4(n)-306.9(\()12.2(8\))19(].)-294.2(Us)16.3(e)-303.4(o)0(f)-287.8(p)0(r)16.9(o)0(m)18.6(o)0(t)22(e)0(r)]TJ
0 -1.2203 TD
[(lu)14.1(c)13.4(i)0(f)15(e)12.8(ra)18.8(se)-418.5(re)18.4(po)21.2(rt)17.8(er)-417.9(as)18.1(sa)18.1(ys)-416.7(de)16.1(mo)18.6(ns)20.6(tr)17.8(a)13.1(t)0(e)18.6(d)-433(t)12.2(h)0(a)16.1(t)-424.1(p2)18.1(7)-429.5(e)12.7(xp)15.5(re)18.4(ss)22.7(io)19(n)]TJ
T*
[(wa)17.8(s)-368(r)0(e)24.7(g)0(u)13.2(l)15.4(at)19(ed)-357(t)12.2(h)0(r)14.9(o)0(u)21.2(g)0(h)-355.6(d)0(i)18.8(r)0(e)18.4(c)13.4(t)-367.2(F)0(O)17.8(X)14.7(O4)16.4(-)12.2(m)0(e)15.2(d)0(i)18.8(a)13.1(te)18.6(d)-363.4(t)0(r)17.8(a)13.1(ns)14.3(c)13.4(r)0(i)14.7(p)0(t)23.5(i)0(o)19(n)]TJ
0 -1.2266 TD
[(\(6)19(1\))19(.)-319.1(C)0(y)20.7(t)0(o)15.7(k)0(i)17.3(n)0(e)22(s)-317.5(ar)18.8(e)-322.4(r)0(e)18.4(g)14.6(ul)14.1(a)13.1(t)0(o)15.7(r)0(s)-305.5(o)0(f)-313.1(p)0(r)23.2(o)0(l)19(i)0(f)15(e)12.8(ra)18.8(ti)21.3(on)-316(a)13.1(n)0(d)-309.9(s)0(u)16.3(r)0(v)23.8(i)0(v)14.7(a)13.1(l)-319.7(o)0(f)]TJ
0 -1.2203 TD
[(he)15.7(ma)21.9(to)15.7(po)21.2(ie)15.5(t)12.2(i)0(c)-300(c)13.4(el)15.5(ls)-295.7(an)16.1(d)-306.5(c)13.4(yt)14.1(ok)24.4(in)18.4(e)-309.7(d)0(e)16.1(p)0(r)23.2(i)0(v)14.7(a)13.1(ti)21.3(on)-303.3(wi)20.1(ll)-297.9(of)22(te)18.6(n)-313.2(r)0(e)24.7(s)0(u)16.3(l)0(t)]TJ
ET
q
358.485 0 0 163.162 62.249 569.31 cm
/Im1 Do
Q
BT
/F6 1 Tf
8.9663 0 0 8.9663 432.6802 721.9841 Tm
[(FIG.)-596.1(1.)-995.1(The)-594.8(DNA)-589.4(binding)]TJ
0 -1.1128 TD
[(domain)-529.1(is)-524.5(highly)-527.9(conserved)]TJ
0 -1.1065 TD
[(within)-576.5(the)-578.4(FOXO)-571.4(transcrip-)]TJ
0 -1.1128 TD
[(tion)-349.8(factor)-346.5(family.)]TJ
/F4 1 Tf
8.6371 0 TD
(Alignment)Tj
-8.6371 -1.1128 TD
[(of)-338.4(the)-332.5(amino)-335.6(acid)-334.1(sequence)-338.2(of)]TJ
0 -1.1065 TD
[(the)-800.4(DNA)-805.8(binding)-797.1(domains)]TJ
0 -1.1128 TD
[(of)-629.2(FOXO1,)-624.2(FOXO3,)-630.5(FOXO4,)]TJ
T*
[(FOXO6,)-940.3(and)-935.4(DAF-16.)-945.4(The)]TJ
T*
[(localization)-761.1(of)-755.7(the)-756.2(three)]TJ
/F8 1 Tf
12.513 0 TD
(a)Tj
/F4 1 Tf
.4995 0 TD
(-)Tj
-13.0126 -1.1065 TD
[(helices)-845.5(\(H1,)-843.8(H2,)-843.4(and)-840.5(H3\),)]TJ
0 -1.1128 TD
(three)Tj
/F8 1 Tf
2.839 0 TD
(b)Tj
/F4 1 Tf
.5501 0 TD
[(-strands)-629.8(\(S1,)-621(S2,)-620.6(and)]TJ
-3.3891 -1.1128 TD
[(S3\),)-463(and)-461.2(two)-466.4(wing-like)-461.1(loops)]TJ
T*
[(\(W1)-485.9(and)-486.4(W2\))-479.5(is)-485.4(indicated)-489.8(at)]TJ
0 -1.1065 TD
[(the)-800.4(top.)-797.9(DAF-16,)-793.7(abnormal)]TJ
0 -1.1128 TD
[(dauer)-674.7(formation)-681.4(protein)-676(16;)]TJ
T*
[(FOXO,)-333.8(Forkhead)-334.3(box)-338.1(O.)]TJ
/F6 1 Tf
-5.2227 -40.8018 TD
[(FIG.)-577.1(2.)-1001.4(Regulation)-574.5(of)-574.2(FOXOs)-583.3(is)-575.1(con-)]TJ
0 -1.1065 TD
[(served)-543.9(between)]TJ
/F12 1 Tf
7.9163 0 TD
[(Ca)21.3(en)15.3(o)14.6(r)0(h)13.9(a)14.6(bd)20.7(it)17.8(is)-524.6(el)19.2(eg)20.2(an)16.5(s)]TJ
/F4 1 Tf
10.3822 0 TD
(,)Tj
/F12 1 Tf
-18.2985 -1.1128 TD
[(Dr)16.9(o)14.5(s)0(o)15.3(p)14.6(hi)14.1(l)12.2(a)-428.1(me)13.4(l)12.2(a)0(n)22.8(o)0(g)15(a)14.5(st)19(er)]TJ
/F6 1 Tf
11.1536 0 TD
-.0204 Tc
[(,)-453.3(a)-20.4(nd)-453.4(m)-20.4(a)-1.2(m)-8(m)-20.4(al)-20.4(s.)]TJ
/F4 1 Tf
-11.1536 -1.1128 TD
0 Tc
[(Ac)18.3(t)12.2(i)0(v)14.7(a)13.1(t)12.2(i)0(o)19(n)-376.4(of)-370(t)12.2(h)0(e)-370(i)0(n)18.4(s)0(u)22.6(l)0(i)18.2(n)-376.4(re)18.4(c)13.4(e)0(p)17.7(t)0(o)15.7(r)-373.8(\(D)17.1(AF)19.5(-)12.2(2)0(\))]TJ
T*
[(a)13.1(c)0(t)19.2(i)0(v)14.7(a)13.1(te)18.6(s)-639.9(P)0(I)21.8(3)0(K)-628.3(\()12.2(AG)18.8(E-)15.5(1)13.1(\))-639.1(re)18.4(su)22.6(lt)15(i)15.4(n)0(g)-627.4(i)0(n)-626.6(t)0(h)15.1(e)]TJ
0 -1.1065 TD
-.0139 Tc
[(fo)-13.9(rm)-13.9(a)8(t)-13.9(i)7.4(o)-13.9(n)-513.2(o)-13.9(f)-510.3(P)-13.9(I)7.9(P)]TJ
6.7246 0 0 5.9768 454.1668 155.3952 Tm
0 Tc
(3)Tj
8.9663 0 0 8.9663 457.455 156.926 Tm
[(.)-502.4(T)0(h)18.9(e)0(s)17.8(e)-505.7(ph)20.6(os)14.9(ph)20.6(or)21.8(yl)17.3(a)13.1(t)0(e)18.6(d)]TJ
-7.9858 -1.1128 TD
[(li)18.2(pi)20.4(ds)-535.4(f)12.2(o)0(r)15.5(m)-541.3(do)19.5(ck)21.6(in)18.4(g)-548.2(s)0(i)20.4(t)12.2(es)-538.7(f)12.2(o)0(r)-534.6(P)0(D)16.2(K)0(1)-533.5(a)13.1(nd)]TJ
T*
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