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[(phe)12.8(nol)13.8(:ch)12.7(lor)13.9(ofo)14(rm:)12.6(iso)14(am)12.7(yl)-555.3(alc)11.5(oh)15.1(ol)-555.3(25:)13.8(24:)13.8(1,)-545.9(Tri)12.7(s\(h)14.2(ydr)14(oxy)14(-)]TJ 0 -1.1174 TD [(met)11.4(hyl)13.8(\)am)11.6(ino)13.8(me)12.7(tha)12.7(ne,)-554(eth)12.7(yle)12.7(ned)12.8(iam)17.2(ine)12.7(tet)12.6(raa)11.7(cet)11.5(ic)-556.4(aci)11.5(d,)-557.5(2-)]TJ 0 -1.1116 TD [(mer)11.6(cap)11.7(toe)12.7(tha)12.7(nol)13.8(,)-475.7(H)]TJ 7.3823 0 0 6.5614 392.4849 545.1589 Tm (2)Tj 9.843 0 0 9.843 396.17 546.803 Tm [(O,)-471.9(ace)10.5(ton)13.8(itr)13.8(ile)12.6(,)-481.5(eth)12.7(ano)18.6(l,)-477(tri)13.8(eth)12.7(yla)12.7(min)12.6(e,)]TJ -8.4437 -1.1116 TD [(hex)12.8(au)13(oro)14(iso)14(pro)14(pan)12.8(ol,)-155.5(and)-160(he)13.9(mat)11.5(oxy)14(lin)-159.1(we)13(re)-164.6(pur)14(cha)11.6(sed)-154(fro)14(m)]TJ T* [(Sig)14(ma-)11.6(Ald)13(ric)12.7(h)-450.4(\(St)14(.)-452.7(Lou)12.8(is,)-443.3(MO\))12.2(.)-452.7(Twe)10.7(en-)12.8(20)-445.7(was)-442.9(pur)14(cha)11.6(sed)]TJ 0 -1.1174 TD [(fro)14(m)-284.5(Pro)14.2(me)12.7(ga)-279.8(Cor)13(por)14(ati)12.6(on)-272.9(\()-75.9(Mad)11.9(iso)14(n,)-275.2(WI\))11.8(.)-279.9(MSD)-269.9(blo)13.9(cke)11.7(r)-283.3(A)0(,)]TJ 0 -1.1116 TD [(MSD)-483(rea)11.7(d)-490.7(buf)14(fer)-482.5(T)-491.9(\()0(4)]TJ /F8 1 Tf 9.6878 0 TD ()Tj /F3 1 Tf .5472 0 TD [(\))-490.6(wit)12.8(h)-484.9(sur)14.2(fac)11.7(tan)12.7(t,)-488.5(and)-476.8(MSD)-483(gol)13.8(d)]TJ -10.235 -1.1116 TD [(stre)17.6(pta)12.7(vid)13.8(in)-250(pla)12.7(te)-251.2(wer)12(e)-255.7(pur)14(cha)11.7(sed)-246.2(fro)14(m)-255.7(M)0(e)13(s)0(o)-255.4(S)0(a)14.1(l)0(e)-251.2(Dis)13.2(cov)12.8(ery)]TJ 0 -1.1174 TD [(\(Ro)13(ckv)12.8(ill)13.6(e,)-276.4(MD\))12.2(.)-274.1(Str)14(ata)11.5(-X)-273.7(33)]TJ /F9 1 Tf 11.9687 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(m)-278.8(pol)13.8(ym)13.9(eri)12.7(c)-278.7(and)-269.4(pro)14(tei)12.6(n)-277.6(pre)12.8(-)]TJ -12.5158 -1.1116 TD [(cip)12.7(ita)12.6(tio)13.7(n)-173.9(pla)12.7(te)13.8(s)-173.7(wer)12(e)-169.3(pur)14(cha)11.7(sed)-165.5(fro)14(m)-169.4(Phe)13(nom)12.8(ene)17.4(x)-173.9(\(To)12.8(rra)12.9(nce)11.7(,)]TJ T* [(CA\))12.1(.)-458.4(Pho)14.1(sph)14.2(ate)11.5(-bu)19.8(ffe)12.9(red)-447.9(sal)12.9(ine)-448.1(\(PB)13.1(S\),)-443.2(exp)12.8(res)13(s)-455.9(sup)14.2(ers)13(cri)12.7(pt)]TJ 0 -1.1174 TD [(qPC)13.1(R)-313.1(sup)14.2(erm)11.6(ix)-307.6(uni)13.8(ver)12.8(sal)12.9(,)-314.4(rox)-302.8(ref)12.9(ere)11.7(nc)13.9(e)-319(d)0(y)15.1(e)0(,)-311(exp)12.8(res)13(s)-311.9(sup)14.2(er-)]TJ 0 -1.1116 TD [(scr)13(ipt)-141.8(mix)12.6(,)-153.2(Rib)12.8(oG)14.2(ree)11.7(n,)-148.5(pur)14(eli)12.6(nk)-146.2(pro)-135.7(RNA)-144.3(pur)14(ic)12.8(ati)12.6(on)-146.2(kit)13.7(,)-147.4(gen)12.8(e)]TJ T* [(exp)12.8(res)13(sio)14(n)-507.9(qPC)13.1(R)-503.2(kit)13.7(,)-504.5(sim)12.8(ply)13.8(blu)13.9(e)-509.1(saf)13(est)12.9(ai)13.8(n,)-505.6(DNa)16.8(se)-504.3(I,)-499.8(and)]TJ T* [(ale)11.5(xa-)12.8(488)-233.7(wer)12(e)-249.9(pur)14(ch)13.9(ase)11.8(d)-248.8(fro)14(m)-244.2(Inv)14(itr)13.8(oge)12.8(n)-243(\(Ca)11.8(rls)14.1(bad)12.8(,)-245.3(CA\))12.1(.)]TJ 1.0137 -1.1174 TD [(MSD)-321.7(probes)-318.6(and)-315.5(qPCR)-323.1(primer)-314.3(probe)-323.4(set)-315.4(were)-324.4(purchased)]TJ -1.0137 -1.1116 TD [(from)-201.4(Integrated)-204.8(DNA)-196(Technologies)-202.3(\(Coralville,)-203.7(IA\).)-197.6(Xbridge)]TJ T* [(column)-395(\(50)]TJ /F8 1 Tf 4.9015 0 TD ()Tj /F3 1 Tf .72 0 TD [(2.1)-166.9(mm,)-394(2.5)]TJ /F9 1 Tf 5.0397 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(m\))-389.3(was)-391(purchased)-393.3(from)-391.5(Waters)]TJ -11.2141 -1.1174 TD [(\()-75.9(M)0(i)19.8(l)0(f)20.7(o)0(r)15.1(d)0(,)-298.3(M)0(A)19.1(\))0(.)-298.2(S)0(i)20.9(z)0(e)-304(e)0(x)19.7(c)0(l)19.5(u)0(s)21(i)0(o)15(n)-306.4(co)19.7(lu)20.7(mn)-302.9(\(3)20.9(00)]TJ /F8 1 Tf 17.7917 0 TD ()Tj /F3 1 Tf .7084 0 TD [(4.)18.5(6)-156.6(m)0(m)18.4(,)-308.7(3)]TJ /F9 1 Tf 4.147 0 TD (m)Tj /F3 1 Tf .5414 0 TD (m\))Tj -23.1886 -1.1116 TD [(wa)13(s)-260.1(p)0(u)20.8(r)0(c)14(h)0(a)19.7(s)0(e)19.9(d)-266(fr)20.9(om)-251.1(Se)14.1(pa)19.7(x)-260.3(T)0(e)18.5(c)0(h)19.7(n)0(o)15.1(l)0(o)20.7(g)0(i)20.7(e)0(s)19.9(,)-262.6(In)20.9(c.)-259.1(\(N)20(ew)18.8(ar)19.7(k,)-252.2(DE)18.8(\).)]TJ T* [(Na)13(no)20.8(se)19.9(p)-317.9(3)0(0)20.8(K)-313(om)19.6(eg)13.9(a)-313.3(c)0(e)18.5(n)0(t)20.7(r)0(i)15(f)0(u)20.9(g)0(a)19.7(l)-318(l)20.9(te)19.6(rs)-307.2(we)18.8(re)-308.6(pu)20.8(rc)19.7(ha)19.7(se)19.9(d)-317.9(f)0(r)20.9(o)0(m)]TJ 0 -1.1174 TD [(Pa)14.1(ll)-227.1(Co)14(rp)20.9(or)20.9(at)19.5(io)20.7(n)-243(\()0(A)20(n)0(n)-232.6(A)0(r)20(b)0(o)20.8(r)0(,)-234.9(M)0(I)20(\))0(.)-229.1(S)0(u)21(r)0(f)15.1(a)0(c)18.5(t)0(-)20.7(a)0(m)18.4(p)0(s)-232.4(8)0(0)20.8(,)-239.6(10)20.8(%)-244.1(a)0(n)19.7(d)]TJ 0 -1.1116 TD .0121 Tc [(Tri)5.1(s)-.3(-b)5.2(uf)5.3(fered)-415.2(s)5.4(al)5.1(ine)-410.6(\()-.5(TBS\))-415.2(wer)5.3(e)-416.4(pu)5.2(rch)5.2(a)-1.7(s)5.4(e)-1.7(d)-415.2(f)-.5(r)5.3(o)-.5(m)-416.4(T)4(hermo)]TJ T* 0 Tc [(Sc)14.1(ie)19.6(nt)20.7(i)20.9(c)-238.4(\()0(R)19.8(o)0(c)19.7(k)0(f)15.1(o)0(r)20.9(d)0(,)-229.2(I)0(L)19.7(\))0(.)-229.1(R)0(e)18.6(a)0(d)19.7(y)0(S)21(t)0(r)20.7(i)0(p)-227(I)0(P)15.3(G)-238.1(st)20.9(ri)20.7(ps)15.3(,)-233.8(e)0(q)19.7(u)0(i)14.9(l)0(i)20.6(b)0(r)20.9(a)0(t)19.5(i)0(o)20.7(n)]TJ 0 -1.1174 TD [(bu)15.1(ff)20.9(er)19.7(s)-208.3(I)-208.4(an)19.7(d)-208.4(I)0(I)20.9(,)-205(io)15(do)20.8(ac)18.5(et)19.5(am)18.5(id)20.7(e,)-195.8(30)15.1(%)-203.8(g)0(l)20.7(y)0(c)13.9(e)0(r)19.7(o)0(l)-198.2(s)0(o)21(l)0(u)20.7(t)0(i)20.6(o)0(n)20.8(,)-210.8(pr)20.9(ot)20.7(ei)19.5(n)]TJ 0 -1.1116 TD [(st)15.1(an)19.7(da)19.7(rd)-198(pl)14.9(ug)20.8(s,)-200.2(ov)20.8(er)19.7(la)19.5(y)-208.4(a)0(g)13.9(a)0(r)19.7(o)0(s)21(e)0(,)-201.5(p)0(r)20.9(e)0(c)18.5(a)0(s)19.9(t)-214.3(ge)19.7(l)-208.6(c)0(r)19.7(i)0(t)20.6(e)0(r)14(i)0(o)20.7(n)-208.4(8%)19.8(1)20.8(6%)]TJ T* [(Tr)13.9(is)20.9(H)20(Cl)19.7(,)-205(T)0(r)19.7(i)0(s)15.1()0(g)20.8(l)0(y)20.7(c)0(i)19.5(n)0(e)-199.2(s)0(o)21(d)0(i)20.7(u)0(m)-199.2(d)0(o)20.8(d)0(e)19.7(c)0(y)19.7(l)-208.6(su)21(lf)15(at)19.6(e)-203.8(\()0(S)15.3(D)0(S)20.1(\))-208.4(ru)20.9(nn)20.8(in)20.7(g)]TJ T* [(bu)15.1(ff)20.9(er)-314.4(10)]TJ /F8 1 Tf 3.7035 0 TD ()Tj /F3 1 Tf .5414 0 TD [(,)-326(a)0(n)19.7(d)-323.6(Br)19.8(ad)19.7(fo)20.9(rd)-313.2(to)15(ta)19.6(l)-323.8(p)0(r)20.9(o)0(t)20.7(e)0(i)19.5(n)-323.6(as)19.9(sa)19.9(y)-323.6(w)0(e)18.8(r)0(e)-320.1(p)0(u)20.8(r)0(c)19.7(h)0(a)19.7(s)0(e)19.9(d)]TJ -4.2449 -1.1174 TD [(fr)15.1(om)-291.4(Bi)19.7(o-)15.1(Ra)18.6(d)-300.6(\()0(H)20(e)0(r)14(c)0(u)19.7(l)0(e)19.6(s)0(,)-292.3(C)0(A)18.9(\))0(.)-292.5(P)0(r)15.3(o)0(t)20.7(e)0(i)19.5(n)0(a)19.7(s)0(e)-296.9(K)-301.5(an)13.9(d)-300.6(D)0(A)19.1(B)-307.4(Ch)19.8(ro)20.9(-)]TJ 0 -1.1116 TD [(ma)18.4(ge)13.9(n)-271.8(w)0(e)13(r)0(e)-268.3(p)0(u)20.8(r)0(c)19.7(h)0(a)19.7(s)0(e)19.9(d)-277.6(fr)20.9(om)-268.4(Da)18.8(ko)-267.1(\(C)14.1(ar)19.7(pi)20.7(nt)20.7(er)19.7(ia)19.6(,)-279.9(C)0(A)18.9(\))0(.)-269.4(P)0(r)21(o)0(t)20.7(e)0(i)19.5(n)]TJ T* [(Bl)13.9(oc)19.7(ki)20.7(ng)-422.7(So)21(lu)15(ti)20.6(on)-422.7(wa)18.8(s)-438.6(o)0(b)20.8(t)0(a)19.6(i)0(n)20.7(e)0(d)-423.8(f)0(r)15.2(o)0(m)-423.9(I)0(n)20.9(n)0(o)20.8(v)0(e)19.7(x)-433.1(Bi)13.9(os)21(ci)19.5(en)19.7(ce)18.5(s)]TJ 0 -1.1174 TD [(\(R)14.1(ic)19.6(hm)19.6(on)20.8(d,)-407.7(CA)18.9(\).)-407.7(Se)19.8(co)19.7(nd)20.8(ar)19.7(y)-421.6(a)0(n)19.7(t)0(i)20.6(b)0(o)20.8(d)0(y)20.8(:)-415.9(go)15.1(at)-406.7(an)19.7(ti)20.6(-r)20.9(ab)13.9(bi)20.7(t)-415.9(I)0(g)20.9(G)]TJ 0 -1.1116 TD [(\(H)14.2(RP)20(\))-479.1(w)0(a)18.8(s)-479(pu)20.8(rc)19.7(ha)19.7(se)19.9(d)-479.2(f)0(r)20.9(o)0(m)-470(J)0(a)19.9(c)0(k)13.9(s)0(o)21(n)-479.2(Im)19.6(mu)19.6(no)20.8(Re)18.6(se)19.9(ar)19.7(ch)-469.9(La)18.5(-)]TJ T* [(bo)15.1(ra)19.7(to)20.7(ry)-370.8(\(W)18.6(es)19.9(t)-375.6(G)0(r)20(o)0(v)15.1(e)0(,)-368.6(P)0(A)20.1(\))0(.)-367.4(X)0(y)20(l)0(e)19.6(n)0(e)-372(a)0(n)19.7(d)-375.5(et)19.5(hy)15.1(l)-375.6(a)0(l)19.5(c)0(o)19.7(h)0(o)20.8(l)-381.4(we)18.8(re)]TJ 0 -1.1174 TD .0175 Tc [(pu)4.9(rchased)-323.4(f)-.8(r)4.9(o)-.9(m)-324.6(B)3.9(BC)-324.4(Bio)4.9(c)3.7(hemi)4.8(cal)-323.5(\()-81.5(Mou)4.9(n)-.9(t)-323.5(V)4(er)4.9(no)4.9(n,)-320(WA\).)]TJ 0 -1.1116 TD [(Mu)4.8(ri)4.7(ne-s)5(peci)4.7(c)-560.8(alb)4.8(u)-1(min)-559.7(e)3.6(nzyme-)4.8(li)4.7(n)4.8(k)-1(ed)-565.4(i)4.7(m)-2.2(mu)4.8(no)4.8(so)4.8(rb)4.8(en)4.8(t)]TJ T* .0147 Tc [(a)-4.8(s)2.3(say)-222.5(\()2.1(EL)-4.9(ISA\))-216.7(kit)-216.9(w)-4.5(as)-222.3(purchas)]TJ 12.6483 0 TD .0131 Tc [(ed)-218.4(f)-5.2(r).5(o)-5.3(m)-219.6(Be)-6.4(th)-5.3(yl)-218.5(La)-6.4(bo)-5.3(ra)-6.4(to)-5.3(ri)-5.4(es)]TJ -12.6483 -1.1116 TD [(\()-86(M)-6.3(on)-5.4(tg)-5.4(ome)-6.5(r).4(y)-5.4(,)-433.9(T)-6.6(X)-.5(\))-5.3(.)-433.9(M)-6.3(u).4(r)-5.3(i).3(n)-5.4(e)-.8(-)-5.3(s).6(p)-5.4(eci)-5.5(c)-438.5(I)-5.3(mmu)-5.4(no)-5.4(gl)-5.5(ob)-5.4(ul)-5.5(in)-437.3(G)-6.2(,)]TJ 0 -1.1174 TD .0128 Tc [(M)-6.5(,)-537.8(and)-541.2(A)-536.3(ki)-5.7(ts)-535.3(w)-6.4(e)-1(r)-5.5(e)-536.6(pu)-5.6(rc)-6.7(ha)-6.7(se)-6.7(d)-535.5(f).2(r)-5.5(o).2(m)-536.7(e)-6.7(Bio)-5.6(s).4(c)-6.7(i).1(e)-6.7(n).2(c)-6.8(e)-536.6(\(S)-5.4(an)]TJ 0 -1.1116 TD .0173 Tc [(Di)4.6(eg)4.7(o,)-326(CA\))4.7(.)-331.7(HRG)-324.5(E)-2.3(LIS)4.8(A)-330.2(k)4.7(i)-1.2(t)-329.5(w)3.8(as)-329.2(pu)4.7(rchased)-329.4(f)4.7(ro)4.7(m)-330.6(C)3.7(lo)4.7(ud)4.7(-)]TJ T* .0127 Tc [(C)-6.7(l)0(o)-5.7(n).1(e)-283.3(C)-6.7(or)-5.6(po)-5.7(ra)-6.8(tio)-5.7(n)-282.1(\()-5.6(Hou)-5.7(s).3(t)-5.8(o).1(n)-5.7(,)-278.7(T)-6.9(X)-.8(\))-5.6(.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 313.0582 105.959 Tm 0 Tc (MAM)Tj /F8 1 Tf 6.7246 0 0 5.9768 333.9779 109.9275 Tm (-)Tj /F10 1 Tf .5564 0 TD (/)Tj /F8 1 Tf .2782 0 TD (-)Tj /F10 1 Tf 8.9663 0 0 8.9663 343.3322 105.959 Tm (MUG1)Tj /F8 1 Tf 6.7246 0 0 5.9768 369.1842 109.9275 Tm (-)Tj /F10 1 Tf .5564 0 TD (/)Tj /F8 1 Tf .2782 0 TD (-)Tj /F10 1 Tf 8.9663 0 0 8.9663 381.5432 105.959 Tm [(DKO)-332.6(breeding)]TJ -7.6381 -1.2203 TD [(and)-335.7(routine)-336.5(colony)-331.7(testing)]TJ /F3 1 Tf 9.843 0 0 9.843 323.0361 78.5763 Tm [(C57BL/6-DKO)-208.2(murine-alpha-2-macroglobulin)-212.4(\()-81.7(MAM\))]TJ /F8 1 Tf 7.3823 0 0 6.5614 541.9274 82.9417 Tm (-)Tj /F3 1 Tf .5529 0 TD (/)Tj /F8 1 Tf .2841 0 TD (-)Tj /F3 1 Tf 9.843 0 0 9.843 313.0582 67.5779 Tm [(and)-211.8(murinoglobulin)-207.2(\()-81.7(MUG1\))]TJ /F8 1 Tf 7.3823 0 0 6.5614 428.0314 72 Tm (-)Tj /F3 1 Tf .5529 0 TD (/)Tj /F8 1 Tf .2765 0 TD (-)Tj /F3 1 Tf 9.843 0 0 9.843 440.277 67.5779 Tm [(mice)-209.7(were)-209.2(obtained)-207.2(from)-212.9(the)]TJ -12.9248 -1.1116 TD [(University)-462.5(of)-457.2(California,)-461.6(San)-459.3(Francisco.)-460.1(DKO)-455.2(mice)-463.1(were)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (224)Tj 46.1699 0 TD [(SHEMESH)-334(ET)-338.7(AL.)]TJ ET endstream endobj 82 0 obj <>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 59.7543 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(generated)-348.7(by)-342(recombinan)-10.1(t)-341(DNA)-345.7(construct)-346.3(vectors)-344(targeting)]TJ 0 -1.1174 TD [(the)-396.3(MUG)-397.6(and)-401.9(MAM/MUG)-399.1(genes)-393.5(and)-401.9(were)-393.5(electroporated)]TJ 0 -1.1116 TD [(into)-407.8(embryonal)-405.2(stem)-404.1(cell)-404.4(lines,)-407.6(pups)-401.6(were)-410.7(genotyped,)-401.7(and)]TJ T* [(HE/HE)-355.4(pairs)-352.2(were)-353.2(mated)-354.8(followed)-350.9(by)-347.8(screening)-358.9(for)-348.8(homo-)]TJ T* [(zygous)-284(strains)-279.4([25,26].)-284.1(Both)-282(male)-278.8(and)-280.9(female)-282.1(breeders)-288.5(were)]TJ 0 -1.1174 TD [(setup)-438.6(as)-440.9(exclusive)-439.7(\(HO/HO)]TJ /F8 1 Tf 11.5424 0 TD ()Tj /F3 1 Tf .5529 0 TD [(HO/HO\),)-439.9(and)-442.2(\(WT/WT)]TJ /F8 1 Tf 9.803 0 TD ()Tj /F3 1 Tf .5529 0 TD (WT/)Tj -22.4513 -1.1116 TD [(WT\))-444.5(matings.)-439.8(Breeders)-445.1(and)-436.4(pups)-441.9(were)-439.5(screened)-445.2(by)-434.2(A2M)]TJ T* [(plasma)-373(concentrations.)-375(Whole)-371.9(blood)-368.5(and)-373.1(plasma)-367.2(were)-376.2(col-)]TJ 0 -1.1174 TD [(lected)-315.6(from)-305.1(mice)-313.4(at)-308.8(5)-306.4(weeks)-308(of)-307.4(age)-310.9(and)-309.7(centrifuged)-309.5(using)-310.7(a)]TJ 0 -1.1116 TD [(5415C)-283(Microcentrifuge)-293.1(to)-284.6(collect)-282.3(plasma)-286.6(\(Eppendorf,)-287.4(Ham-)]TJ T* [(burg,)-284.3(Germany\).)]TJ 1.0137 -1.1174 TD [(An)-193.1(ELISA)-187.1(specic)-195.3(for)-193.3(murine)-187.7(A2M)-189.4(was)-195.2(performed)-191.9(using)-189.8(a)]TJ -1.0137 -1.1116 TD [(singleplex)-278.5(assay)-272.4(on)-267.1(the)-275.3(luminex)-269.6(platform)-276.3(using)-270.4(a)-273(polyclonal)]TJ T* [(sheep)-278.3(anti-A2M)-276.9(captu)-8(re)-274(antibody.)-278.6(The)-276.4(standard)-276(curve)-278.5(range)]TJ T* [(was)-362.2(from)-362.7(8.9)-362.7(to)-359.4(6,500)-169.1(ng/mL,)-362.8(samples)-362.3(were)-364.7(diluted)-360.6(before)]TJ 0 -1.1174 TD [(analysis.)-296.7(Western)-294.4(blotting)-297.3(was)-293.1(used)-287.6(to)-296.1(conrm)-291(the)-292.6(165-kDa)]TJ 0 -1.1116 TD [(MAM)-386.1(subunit)-382.2(and)-384.6(180-kDa)-384.1(MUG1)-387.2(subunit.)-385.6(A)-382.1(Hyg)-384.3(qPCR)]TJ T* [(assay)-232.1(as)-227.8(a)-232.6(TaqMan)-229.9(qPCR)-230.9(targeting)-231.5(the)-229.2(selection)-232.5(cassette)-232.2(as)-227.8(a)]TJ 0 -1.1174 TD [(surrogate)-242.5(was)-241.3(used)-241.5(for)-239.4(genotyping)-242.8(us)21(in)20.7(g)-225.7(t)0(h)15(e)-226.9(fo)20.9(ll)20.6(ow)20(in)15(g)-225.7(M)0(A)19.1(M)]TJ 0 -1.1116 TD [(pr)15.1(im)19.5(er)-654.2(pr)20.9(ob)20.8(e)-664.6(s)0(e)14.1(q)0(u)20.8(e)0(n)19.7(c)0(e)18.5(s)0(:)-653(h)0(y)15.1(g)0(q)20.8(F)0(8)21(2)0(1)20.8(:)0(5)]TJ /F8 1 Tf 15.8507 0 TD ()Tj /F3 1 Tf .2419 0 TD [(CC)18.8(GC)18.9(AA)19.1(GG)19.1(AA)19.1(TC)]TJ -16.0926 -1.1116 TD [(GG)19.1(TC)18.6(AA)13.3(T3)]TJ /F8 1 Tf 5.1953 0 TD ()Tj /F3 1 Tf .2361 0 TD -.0208 Tc [(,)-680.8(h)-20.8(yg)-20.8(qR)-20.8(8)-6.8(7)-20.8(8:)-678.6(5)]TJ /F8 1 Tf 6.4278 0 TD 0 Tc ()Tj /F3 1 Tf .2419 0 TD [(GA)19.1(TC)18.6(AG)19.1(CA)18.9(AT)18.8(CG)18.9(CG)18.9(CA)18.9(TA)]TJ -12.1011 -1.1174 TD [(TG)18.8(3)]TJ /F8 1 Tf 1.8028 0 TD ()Tj /F3 1 Tf .2419 0 TD -.0208 Tc [(,)-749.9(h)-20.8(y)-5.7(g)-20.8(qp)-20.8(ro)-20.8(be)-20.8(:)-744.3(5)]TJ /F8 1 Tf 6.6755 0 TD 0 Tc ()Tj /F3 1 Tf .9791 0 TD [([V)14.2(ic)19.6(]C)19.8(AC)18.9(TA)18.8(CA)18.9(TG)18.8(GC)18.9(GT)18.8(GA)19.1(TT)18.5([M)]TJ -9.6993 -1.1116 TD [(GB)18.9(]3)]TJ /F8 1 Tf 2.1829 0 TD ()Tj /F3 1 Tf .2361 0 TD [(,)-274.1(a)0(n)19.7(d)-266(ap)13.9(ob)-255.6(qP)15.2(CR)-257.7(as)19.9(sa)14.1(y)-266(a)0(s)-262.4(a)0(n)-262.5(e)0(n)19.7(d)0(o)20.8(g)0(e)19.7(n)0(o)15.1(u)0(s)-255.4(c)0(o)13.9(n)0(t)20.7(r)0(o)20.9(l)-271.9(us)21(in)20.7(g)]TJ -2.4191 -1.1116 TD [(mA)18.7(po)20.8(bq)15.1(Fe)19.8(26)20.8(:5)]TJ /F8 1 Tf 6.1629 0 TD ()Tj /F3 1 Tf .2419 0 TD [(CG)18.9(TG)18.8(GG)19.1(CT)18.6(CC)18.8(AG)19.1(CA)18.9(TT)18.5(CT)18.6(A3)]TJ /F8 1 Tf 13.1206 0 TD ()Tj /F3 1 Tf .2419 0 TD .8271 Tc [(,m)827.1(A)845.8(p)827.1(o)847.9(b)827.1(q)]TJ -19.7673 -1.1174 TD 0 Tc [(Re)18.6(26)15.1(:5)]TJ /F8 1 Tf 2.8395 0 TD ()Tj /F3 1 Tf .2361 0 TD [(CT)18.6(GC)18.9(CT)18.6(TT)18.5(GC)18.9(GT)18.8(CC)18.8(TT)18.4(GA)19.1(G)-480(3)]TJ /F8 1 Tf 13.4028 0 TD ()Tj /F3 1 Tf .2419 0 TD -.0203 Tc [(,)-496(m)-20.3(Ap)-20.3(ob)-20.3(qp)-20.3(e)-6.4(2)-20.3(6:)-493.8(5)]TJ /F8 1 Tf 7.3206 0 TD 0 Tc ()Tj /F3 1 Tf -24.041 -1.1116 TD [([6)15.1(Fa)19.8(m])-815.5(AG)19.1(CC)18.8(AA)19.1(TG)18.8(GT)18.8(CG)18.9(GG)13.3(C)-825.8([)0(M)20(G)0(B)18.9(])-830.5(3)]TJ /F8 1 Tf 18.9955 0 TD ()Tj /F3 1 Tf 1.0771 0 TD [(se)19.9(qu)20.8(en)19.7(ce)18.5(s,)]TJ -20.0726 -1.1116 TD [(re)14(sp)21(ec)18.5(ti)20.6(ve)19.7(ly)20.7(.)-481.5(T)0(h)19.6(e)-486.1(A2)20(M)-480(c)0(o)19.7(l)0(o)20.7(n)0(y)-474.5(w)0(a)18.8(s)-479(ma)18.4(in)20.7(ta)13.8(in)20.7(ed)-469.9(at)-475.8(Ch)19.8(ar)19.7(le)19.5(s)]TJ T* [(Ri)19.7(ve)13.9(rs)-272.7(La)18.5(bo)20.8(ra)14(to)20.7(ri)20.7(es)-279.6(\(H)20(ol)20.7(li)20.6(st)20.9(er)14(,)-285.7(C)0(A)18.9(\))-283.3(be)19.7(fo)15.1(re)-274(de)19.7(li)20.6(ve)19.7(ry)-278.6(at)-280(IO)20(NI)20(S)]TJ 0 -1.1174 TD [(Ph)15.2(ar)19.7(ma)18.4(ce)18.5(ut)20.7(ic)19.6(al)19.5(s.)]TJ /F1 1 Tf 8.9663 0 0 8.9663 59.7543 396.3968 Tm [(In)-336.7(vivo)]TJ /F10 1 Tf 3.2753 0 TD [(study)-333.9(design)]TJ /F3 1 Tf 9.843 0 0 9.843 69.7323 379.9558 Tm [(All)-223.3(animals)-224.4(and)-223.3(procedures)-227.4(conducted)-226.6(in)-221.2(the)-223.5(study)-224.3(were)-220.7(in)]TJ -1.0137 -1.1174 TD [(compliance)-506.7(and)-505.6(approved)-500.7(by)-503.3(the)-499.9(IONIS)-508.1(Pharmaceuticals)]TJ 0 -1.1116 TD [(Institutional)-315.5(Animal)-309.6(Care)-313(and)-309.7(Use)-310.4(Committee)-315.6(\(Protocol:)-311.9(P-)]TJ T* [(0214-100019)-6.3(\).)-355.8(A)-353.3(total)-358.4(of)-359.3(40)-353.5(mixed)-359.4(gender)-360.2(C57BL/6)-356.7(mice,)]TJ 0 -1.1174 TD [(including)-339.8(20)-330.5(WT/WT)-335.1(and)-338.5(20)-330.5(MAM/MUG1)-336.8(DKO)-334.2(homozy-)]TJ 0 -1.1116 TD [(gous)-441.9(mice)-440.1(aged)-438.7(610)-442.1(weeks)-440.5(and)-442.2(weighing)-437.3(1825)-166.8(g,)-442.3(were)]TJ T* [(used.)-291(Baseline)-289.9(characteristics)-288.5(at)-285.7(study)-287.7(initiation)-289.4(are)-287.8(listed)-284.4(in)]TJ T* [(Ta)18.5(bl)14.9(e)-278.7(1)0(.)-275.2(D)0(o)20(s)0(i)20.9(n)0(g)-272.9(s)0(o)21(l)0(u)20.7(t)0(i)20.6(o)0(n)15.1(s)-277.4(of)-272.9(IO)20(N-)14.2(35)20.8(33)20.8(82)-272.9(a)-278.7(5)0(-)15.1(1)0(0)20.8(-)0(5)-272.9(m)0(e)18.4(t)0(h)20.7(o)0(x)20.8(y)0(-)]TJ 0 -1.1174 TD .0111 Tc [(eth)4.2(y)-1.5(l)-543.1(\()-82.1(MOE\))-548.7(ASO)-543.8(t)4.1(arg)4.2(e)-2.7(t)4.1(i)-1.6(ng)-542.9(S)4.4(R)-2.5(B1)-542.9(wer)4.3(e)-544.1(fo)4.2(rmulated)-542.9(in)]TJ 0 -1.1116 TD [(steri)4(l)-1.7(e)-279.2(s)-1.4(alin)4.1(e)-279.2(a)-2.8(t)-278.2(1)-1.6(,)-274.7(3)-1.6(,)-280.4(6)4.1(,)-280.4(a)-2.8(n)4.1(d)-278.1(12)-168.6(mg)4.1(/mL.)]TJ 1.0137 -1.1116 TD 0 Tc [(ION-353382)-398.6(was)-391(administered)-404(as)-394.8(a)-393.9(single)-393.7(subcutaneous)]TJ -1.0137 -1.1174 TD [(dose)-253(to)-255.8(the)-252.3(nape)-254.4(of)-249.8(the)-252.3(neck)-254.4(at)-251.2(5,)-252.2(15,)-253.3(30,)-247.5(and)-257.9(60)-163.5(mg/kg)-254.5(using)]TJ 0 -1.1116 TD [(saline)-187.5(as)-181.7(a)-180.8(dosing)-185.1(vehicle)-184.2(control)-181.9(with)-184.1(a)-186.6(dose)-178.2(volume)-187.7(of)-180.7(5)-168.1(mL/)]TJ T* [(kg.)-414.6(A)-416.7(total)-416(of)-411.1(10)-411.1(treatment)-418.2(groups)-415.3(were)-416.5(used.)-417.7(Mice)-416.7(were)]TJ 0 -1.1174 TD [(fasted)-285.3(overnight)-287.8(before)-285.3(dosing,)-280.7(while)-284.3(allowed)-287.6(water)]TJ /F7 1 Tf 21.3339 0 TD [(ad)-284.4(libi-)]TJ -21.3339 -1.1116 TD (tum)Tj /F3 1 Tf 1.8143 0 TD [(continuously,)-311.8(and)-315.5(fed)-309.7(3)-168.1(h)-312.1(postdose)-309.2(while)-313.1(maintained)-315.6(in)]TJ -1.8143 -1.1116 TD [(standard)-339.3(cages.)-340.5(Following)-339.3(72)-163.5(h)-335.2(after)-342(dosing,)-338.3(mice)-336.4(were)-335.9(eu-)]TJ 0 -1.1174 TD [(thanized)-335.1(by)-330.5(terminal)-329.5(cardiac)-335(puncture)-328(and)-332.8(cervical)-330.5(disloca-)]TJ 0 -1.1116 TD [(tion,)-347.9(with)-351.1(whole)-347.5(blood)-351.2(collected)-349(and)-350(stored)-347.5(into)-350.2(K)]TJ 7.3823 0 0 6.5614 265.6629 181.0204 Tm (2)Tj 9.843 0 0 9.843 269.3479 182.6645 Tm (EDTA-)Tj -21.2936 -1.1116 TD [(containing)-445.7(tubes)-444.3(followed)-443.1(by)-445.7(centrifugation)-445.6(at)-441.2(2,000)]TJ /F7 1 Tf 22.1864 0 TD (g)Tj /F3 1 Tf .9388 0 TD (for)Tj -23.1252 -1.1116 TD [(10)-169.2(min)-292.6(at)-297.2(4)]TJ /F8 1 Tf 4.5502 0 TD ()Tj /F3 1 Tf .3974 0 TD [(C)-295.9(t)0(o)-296.1(s)0(e)19.9(p)0(a)19.7(r)0(a)19.7(t)0(e)-274.2(p)0(l)20.7(a)0(s)14.1(m)15(a.)-276.4(Li)19.5(ve)19.7(r,)-275.2(ki)14.9(dn)20.8(ey)19.7(s,)-275(lu)20.7(ng)20.8(,)-285.7(m)0(u)19.6(s)0(-)]TJ 20.5622 57.3379 TD [(cl)19.5(e,)-224.6(an)19.7(d)-237.2(h)0(e)19.7(a)0(r)19.7(t)-237.4(fr)20.9(om)-228.1(ea)18.5(ch)-228(mi)19.5(ce)-229.1(we)18.8(re)-228(ha)19.7(rv)20.9(es)19.9(te)19.6(d)-237.2(a)0(n)19.7(d)-237.2(a)19.8(sh)-226.6(fr)20.9(oz)19.7(en)]TJ 0 -1.1174 TD [(in)-261.5(li)20.6(qu)20.8(id)-261.5(ni)20.7(tr)20.7(og)20.8(en)-262.5(an)19.7(d)-271.8(s)0(t)20.9(o)0(r)20.9(e)0(d)-262.6(a)0(t)]TJ /F8 1 Tf 12.4986 0 TD (-)Tj /F3 1 Tf .5472 0 TD (80)Tj /F8 1 Tf .9791 0 TD ()Tj /F3 1 Tf .3859 0 TD -.0193 Tc [(C)-286.4(b)-19.3(ef)-19.3(or)-19.3(e)-276.1(a)-19.3(na)-19.3(l)-5.5(y)-19.3(si)-19.3(s.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 310.8472 692.277 Tm 0 Tc [(Plasma)-333.7(and)-335.7(tissue)-330.8(exposure)-333(kinetics)-333.7(in)-336.5(DKO)-332.6(mice)]TJ /F3 1 Tf 9.843 0 0 9.843 320.8251 675.8361 Tm [(Plasma)-269.1(C)]TJ 7.3823 0 0 6.5614 358.5259 674.192 Tm (trough)Tj 9.843 0 0 9.843 380.466 675.8361 Tm [(levels)-273.9(at)-268.4(72)-169.2(h)-266(were)-272.5(evaluated)-274(for)-268.2(both)-269.5(WT/)]TJ -7.0729 -1.1116 TD [(WT)-253.3(and)-252.1(HO/HO)-256.8(groups)-254.1(using)-253.1(enhanced)-261.1(chemiluminescence)]TJ 0 -1.1174 TD [(\(ECL\)-ELISA.)-430.9(A)-428.2(calibration)-430.8(curve)-428.3(was)-431.4(setup)-427.1(from)-426(0.5)-431.8(to)]TJ 0 -1.1116 TD [(100)-164.6(ng/mL.)-316.8(Stock)-317.7(capture)-322.3(probe)-311.9(for)-320(ION-353382,)-315.6(5)]TJ /F8 1 Tf 21.0287 0 TD ()Tj /F3 1 Tf .2534 0 TD (BioTeg)Tj -21.2821 -1.1116 TD (AeAkGeGeAkAeGeTk)Tj 7.3823 0 0 6.5614 403.2566 636.3778 Tm (m)Tj 9.843 0 0 9.843 408.9825 632.0125 Tm [(CeAe,)-495.9(k)]TJ /F8 1 Tf 3.6862 0 TD (=)Tj /F3 1 Tf .72 0 TD [(cEt)-489.6(BNA)-489.9(\(3\);)-488.3(e)]TJ /F8 1 Tf 6.975 0 TD (=)Tj /F3 1 Tf .72 0 TD (MOE)Tj -22.0712 -1.1174 TD [(\(7\),)-294.7(was)-293.1(diluted)-297.2(to)-290.3(25)-169.2(nmol)-293.8(in)-296.1(10)]TJ /F8 1 Tf 13.3107 0 TD ()Tj /F3 1 Tf .8467 0 TD [(SSPE)-293.1(buffer,)-299.1(and)-292.4(100)]TJ /F9 1 Tf 8.9679 0 TD (m)Tj /F3 1 Tf .5529 0 TD (L)Tj -23.6782 -1.1116 TD [(was)-183.7(added)-186.4(to)-180.9(25)]TJ /F9 1 Tf 6.4451 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-186.6(o)0(f)-180.7(each)-186.4(plasma)-188.7(sample)-182.9(and)-183(standard)-189.6(into)-183.2(a)]TJ -6.9923 -1.1116 TD [(96-well)-401.6(PCR)-402.6(plate,)-403.2(sealed,)-405.1(and)-407.6(heated)-401.9(at)-400.9(70)]TJ /F8 1 Tf 18.529 0 TD ()Tj /F3 1 Tf .3974 0 TD [(C)-399.5(for)-400.7(30)-169.2(min)]TJ -18.9264 -1.1174 TD [(followed)-183.9(by)-186.5(cooling)-187.7(at)-187.8(room)-184.2(temperature)-191(21)]TJ /F8 1 Tf 17.331 0 TD ()Tj /F3 1 Tf .3917 0 TD [(C)-186.4(for)-187.5(15)-163.5(min)-189(and)]TJ -17.7226 -1.1116 TD [(cooled)-343.1(to)-342.1(6)]TJ /F8 1 Tf 4.6423 0 TD ()Tj /F3 1 Tf .3917 0 TD [(C)-341.9(for)-343.1(15)-169.2(min)-338.7(to)-342.1(complete)-347.9(hybridization.)-343.1(At)-343(the)]TJ -5.034 -1.1116 TD [(same)-370.6(time,)-367.6(an)-372(MSD)-367.8(gold)-373.2(streptavidin-coated)-372.7(96-well)-372.8(plate)]TJ T* [(was)-298.9(blocked)-298.2(using)-293.4(1.5)-166.9(g)-294.8(o)0(f)-295.9(blocker)-298.1(A)-295.7(dissolved)-298.9(in)-296.1(50)-169.2(mL)-298.4(of)]TJ 0 -1.1174 TD [(PBS)-297.8(with)-305(150)]TJ /F9 1 Tf 5.8173 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-301.8(added)-301.6(to)-301.8(each)-307.4(well)-300.4(and)-304(incubated)-301.7(at)-303(21)]TJ /F8 1 Tf 16.8587 0 TD ()Tj /F3 1 Tf .3974 0 TD (C)Tj -23.6263 -1.1116 TD [(for)-343.1(60)-163.5(min.)-347.9(Next,)-344.1(the)-344.4(MSD)-339(plate)-347.9(was)-345(rinsed)-341.7(for)-343.1(two)-344.1(cycles)]TJ T* [(with)-270.5(10)-169.2(mM)-269.3(phosphate)-271.4(buffer)-272.6(pH)-273.8(7.4,)-268.2(150)-170.3(mM)-269.3(NaCl,)-276(0.05%)]TJ 0 -1.1174 TD [(Tween-20)-283.9(\(PBS-T\))-280.2(washing)-286.1(buffer.)]TJ 1.0137 -1.1116 TD [(Samples)-339.3(from)-333.9(the)-338.7(PCR)-339.3(plate)-336.4(were)-341.6(mixed)-336.3(68)-337.4(times,)-339.7(and)]TJ -1.0137 -1.1116 TD (50)Tj /F9 1 Tf 1.1635 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-445.8(was)-448.6(transferred)-453.2(to)-445.8(the)-448.1(MSD)-448.4(plate)-451.6(in)-445.8(duplicate)-451.5(and)]TJ -1.7164 -1.1174 TD [(allowed)-253.1(to)-255.8(immobilize)-252.5(on)-255.6(the)-252.3(plate)-255.8(using)-253.1(shaking)-250.7(at)-256.9(500)-164.6(rpm)]TJ 0 -1.1116 TD [(at)-245.4(21)]TJ /F8 1 Tf 1.9698 0 TD ()Tj /F3 1 Tf .3974 0 TD [(C)-244(for)-245.1(30)-169.2(min.)-244.2(Plates)-245(were)-249.5(then)-247.6(rinsed)-243.8(for)-245.1(two)-246.2(cycles.)-243.9(A)]TJ -2.3672 -1.1116 TD [(preheated)-688.5(detector)-686.4(probe)-686.3(for)-688.6(ION-353382,)-690(5)]TJ /F8 1 Tf 19.871 0 TD ()Tj /F3 1 Tf .2534 0 TD (-TkGxAe-)Tj 7.3823 0 0 6.5614 310.8472 450.0849 Tm (m)Tj 9.843 0 0 9.843 316.6299 445.7196 Tm (CxTkGeAfAfGe)Tj 7.3823 0 0 6.5614 382.7338 450.0849 Tm (m)Tj 9.843 0 0 9.843 388.5164 445.7196 Tm (Ck-[Spacer]-\(NH2\)-3)Tj /F8 1 Tf 8.6684 0 TD ()Tj /F3 1 Tf .2534 0 TD .3145 Tc (,k)Tj /F8 1 Tf 1.2326 0 TD 0 Tc (=)Tj /F3 1 Tf .7142 0 TD 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[(L)-370.9(o)0(f)-365(MSD)-373.5(read)-369.6(buffer)-370.5(was)-373.8(added)-370.7(to)]TJ -9.1982 -1.1116 TD [(each)-203.7(well.)-206(Plates)-204.7(were)-203.4(read)-208.3(on)-203.8(a)-198.1(Sector)-210.5(PR)-198.9(2400)-206(MSD)-200.7(system)]TJ T* [(\()-81.7(Meso)-282.7(Sale)-283.2(Discovery\).)]TJ 1.0137 -1.1174 TD [(For)-423.6(tissue)-433.9(exposure)-431.4(kinetics,)-429.5(the)-430.8(liver)-427.4(and)-430.7(kidney)-428.4(were)]TJ -1.0137 -1.1116 TD [(weighed)-316.3(to)-313.4(50)-169.2(mg)-308.7(and)-315.5(diluted)-314.5(in)-313.4(450)]TJ /F9 1 Tf 15.1941 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-313.3(o)0(f)-313.2(homogenization)]TJ -15.747 -1.1116 TD [(buffer)-289.9(\(20)-164.5(mM)-292.3(Tris)-287.7(pH)-291.1(8,)-286.8(10)-163.5(mM)-292.3(EDTA,)-288.4(0.1)-166.9(M)-290(NaCl,)-287.5(0.5%)]TJ 0 -1.1174 TD [(NP40\))-184.7(and)-188.8(broken)-186.3(up)-186.5(by)-186.5(homogenization.)-191(A)-186.3(calibration)-188.9(curve)]TJ 0 -1.1116 TD 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6.5614 429.1086 202.9606 Tm (4)Tj 9.843 0 0 9.843 432.8503 204.6047 Tm [(OH)-228.6(\(in)-233.8(5%)-233.7(acetonitrile,)-240.8(0.1)-166.9(M)]TJ -12.3949 -1.1174 TD [(TEAB\),)-554.6(and)-557.4(2)-168.1(m)0(L)-551.8(o)0(f)-555.1(10%)-557.3(acetonitrile)-559.9(in)-555.3(0.1)-166.9(M)-554.9(TEAB.)]TJ 0 -1.1116 TD [(Samples)-489.1(were)-497.1(eluted)-487.2(with)-495.1(1.5)-166.9(mL)-488.4(of)-491.7(70%)-488.2(acetonitrile)-496.6(in)]TJ T* [(0.1)-166.9(M)-359.1(TEAB)-365.8(and)-361.6(run)-366.1(through)-359.1(a)-365.1(protein)-360.4(precipitation)-369.8(plate.)]TJ T* [(Finally,)-669.1(samples)-667.6(were)-669.9(dried)-669.1(down)-667.6(under)-669(nitrogen)-666.8(and)]TJ ET 59.754 124.894 490.167 .22675 re f 59.754 77.499 490.167 .22675 re f 59.754 106.242 490.167 .22675 re f BT /F6 1 Tf 9.845 0 0 9.845 181.1338 130.5638 Tm (Table)Tj /F3 1 Tf 3.0002 0 TD (1.)Tj /F6 1 Tf 1.2496 0 TD [(Baseline)-332.4(Characteristics)-339.1(at)-330(Study)-333.8(Initiation)]TJ /F7 1 Tf -16.5788 -1.8427 TD [(Group)-3460.7(Number)-337(per)-332.2(subtype)-2664(Age)-333.5(\(weeks\))]TJ /F8 1 Tf 22.1301 0 TD ()Tj /F9 1 Tf .7141 0 TD (s)Tj /F7 1 Tf .668 0 TD (x)Tj /F3 1 Tf 7.3837 0 0 6.5625 295.6534 116.8441 Tm (a)Tj /F7 1 Tf 9.845 0 0 9.845 325.1338 112.422 Tm [(Gender)-331.4(\(n\))-2657.7(Alpha-2-Macroglobulin)-341.3(\(mg/mL\))]TJ /F8 1 Tf 20.6617 0 TD ()Tj /F9 1 Tf .7198 0 TD (s)Tj /F7 1 Tf .668 0 TD (x)Tj /F3 1 Tf 7.3837 0 0 6.5625 546.6329 116.8441 Tm (a)Tj 9.845 0 0 9.845 59.7543 93.7701 Tm [(WT/WT)-6300.1(20)-8006.4(6.6)]TJ /F8 1 Tf 20.1261 0 TD ()Tj /F3 1 Tf .7141 0 TD [(0.36)-4768.7(11)-169(M,)-333.4(9)-335(F)-7435.1(3.470)]TJ /F8 1 Tf 20.3968 0 TD ()Tj /F3 1 Tf .7198 0 TD (0.6990)Tj -41.9568 -1.0135 TD [(HO/HO)-6550.1(20)-8006.4(6.8)]TJ /F8 1 Tf 20.1261 0 TD ()Tj /F3 1 Tf .7141 0 TD [(0)-5684.7(1)0(0)-169(M)0(,)-333.4(1)0(0)-169(F)-7435.1(0.003)]TJ /F8 1 Tf 20.3968 0 TD ()Tj /F3 1 Tf .7198 0 TD (0.0004)Tj 7.3837 0 0 6.5625 499.8613 88.1575 Tm (b)Tj 6.5633 0 0 5.8334 67.748 69.5622 Tm (a)Tj 8.7511 0 0 8.7511 70.696 65.6504 Tm [(Standard)-333.5(deviation)-331.4(of)-333.1(the)-333.3(average.)]TJ 6.5633 0 0 5.8334 67.748 60.6047 Tm (b)Tj 8.7511 0 0 8.7511 71.0362 56.6929 Tm [(Statistically)-334.1(signicant,)]TJ /F7 1 Tf 9.8342 0 TD (P)Tj /F8 1 Tf .7839 0 TD (<)Tj /F3 1 Tf .7191 0 TD (0.001.)Tj /F4 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(PK/PD)-340.1(OF)-331.2(ION-353382,)-332.4(A)-337.9(MODEL)-333.5(ASO:)-334.7(IN)-335.1(WT)-335.9(AND)-330.9(DKO)-337.5(MICE)-23255.2(225)]TJ ET endstream endobj 88 0 obj <>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 62.022 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(reconstituted)-237(to)-232.7(140)]TJ /F9 1 Tf 8.0981 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-232.7(with)-224.4(100)]TJ /F9 1 Tf 4.5156 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(mol)-223.5(EDTA)-221.6(prior)-224.4(for)-222.1(liquid)]TJ -13.7196 -1.1174 TD [(chromatographymass)-275.4(spectrometry)-277.1(\(LC-MS\))-275.5(analysis.)]TJ 1.0137 -1.1116 TD [(An)-256.5(Ag)14.2(il)14.8(en)13.9(t)-266.2(1)0(1)15.1(0)0(0)15.1(/)0(1)15(2)0(0)15.1(0)-266(HP)14.4(LC)-257.9(sy)15.3(st)15.1(em)-258(co)13.9(ns)15.3(is)15.1(ti)14.8(ng)-261.4(of)-255.6(a)-267.2(1)0(,)12.7(1)0(0)15.1(0)]TJ -1.0137 -1.1116 TD [(qu)15.1(at)13.8(er)13.9(na)13.9(ry)-238.3(pu)15.1(mp)13.8(,)-245.3(c)0(o)13.9(l)0(u)15(m)0(n)-239.6(o)0(v)15.1(e)0(r)14(,)-251.1(an)19.7(d)-248.8(a)0(u)13.9(t)0(o)15(s)0(a)14.1(m)0(p)13.9(l)0(e)13.8(r)-248.7(co)13.9(up)20.8(le)13.8(d)-248.8(t)0(o)-244.2(a)]TJ T* [(si)15.1(ng)15.1(le)-504.6(qu)15.1(ad)19.7(ru)15.1(po)15.1(le)-504.6(ma)12.7(ss)-502.9(sp)15.3(ec)12.8(tr)15(om)19.6(et)13.8(er)-504.4(\(A)14.2(gi)15(le)13.8(nt)-497.7(61)15.1(30)15.1(;)-513.8(W)0(i)18.4(l)0(-)]TJ 0 -1.1174 TD [(mi)13.7(ng)15.1(to)15(n,)-355.9(DE)13(\))-363.9(w)0(a)13(s)-363.8(us)15.3(ed)13.9(.)-360.5(A)0(n)-360.2(X)0(B)13.2(r)0(i)15(d)0(g)15.1(e)-365.1(co)13.9(lu)15(mn)-354.8(\(5)15.1(0)]TJ /F8 1 Tf 20.3894 0 TD ()Tj /F3 1 Tf .7142 0 TD [(2.)18.5(1)-162.4(m)0(m)18.4(,)]TJ -21.1036 -1.1116 TD [(2.)12.7(5)]TJ /F9 1 Tf 1.3938 0 TD (m)Tj /F3 1 Tf .5414 0 TD [(m\))-377.8(wa)13(s)-386.8(u)0(s)15.3(e)0(d)-377.7(f)0(o)15.1(r)-387(ch)19.7(ro)15.1(ma)12.7(to)15(gr)15.1(ap)13.9(hi)14.9(c)-382.4(s)0(e)14.1(p)0(a)13.9(r)0(a)14(t)0(i)14.8(o)0(n)-376.6(\()0(W)18.6(a)0(t)13.8(e)0(r)14(s)0(\))15.3(.)]TJ -1.9353 -1.1116 TD [(Th)13.9(e)-232.6(c)0(o)13.9(l)0(u)20.7(m)0(n)-228.1(t)0(e)19.5(m)0(p)13.9(e)0(r)14(a)0(t)13.8(u)0(r)15.1(e)-232.6(wa)13(s)-231.3(m)0(a)18.4(i)0(n)15(t)0(a)13.8(i)0(n)15(e)0(d)-222.2(a)0(t)-222.4(5)0(5)]TJ /F8 1 Tf 18.264 0 TD ()Tj /F3 1 Tf .3917 0 TD .2325 Tc [(Cw)232.5(i)252.3(t)232.5(h)5.5(m)232.5(o)246.3(b)232.5(i)253.2(l)232.5(e)]TJ -18.6557 -1.1174 TD 0 Tc [(ph)15.1(as)14.1(e)-186.6(A)-186.3(co)19.7(ns)15.3(is)15.1(ti)14.8(ng)-180.7(of)-175(5)-156.6(m)0(M)-177.1(T)0(r)13.9(i)0(B)13.9(u)0(t)14.9(A)0(A)-176.7(i)0(n)-180.9(2)0(0)15.1(%)-180.7(ac)12.8(et)13.8(on)15.1(it)14.8(ri)15(le)-176.3(an)13.9(d)]TJ 0 -1.1116 TD [(mo)13.8(bi)15(le)-262.7(ph)20.8(as)14.1(e)-273(B)-267.1(co)13.9(ns)15.3(is)15.1(ti)14.8(ng)-261.4(of)-261.4(5)-156.6(m)0(M)-263.5(T)0(r)13.9(i)0(B)13.9(u)0(t)14.9(A)0(A)-257.4(i)0(n)-261.5(9)0(0)15.1(%)-272.9(ac)18.5(et)13.8(o-)]TJ T* [(ni)15(tr)15(il)14.8(e.)-190(A)-203.6()0(o)15.2(w)-197.8(ra)14(te)-193.6(of)-192.2(0.)18.5(30)-152(mL)12.7(/m)13.7(in)-186.6(wa)13(s)-202.5(u)0(s)15.3(e)0(d)-193.4(a)0(t)-193.6(2)0(2)20.8(%)-203.7(B)-198(i)0(n)15(i)0(t)14.8(i)0(a)13.8(l)0(l)14.8(y)]TJ 0 -1.1174 TD [(wh)14.2(il)14.8(e)-319(r)0(a)14(m)0(p)13.8(i)0(n)15(g)-317.9(to)-313.3(80)15.1(%)-318.9(t)0(o)-313.4(6)-156.6(mi)13.7(n)-317.9(a)0(n)13.9(d)-323.6(he)19.7(ld)-313.3(fo)15.1(r)-323.6(1)0(.)18.5(5)-162.4(mi)19.5(n;)-313.4(ov)15.1(er)-314.4(a)]TJ 0 -1.1116 TD [(pe)13.9(ri)15(od)-175(of)-175(0.)18.5(2)-162.4(m)0(i)13.7(n)-179.6(th)15(e)-186.6(g)0(r)15.1(a)0(d)19.7(i)0(e)13.8(n)0(t)-175.1(r)0(e)14(t)0(u)15(r)0(n)15.1(e)0(d)-176.2(t)0(o)-175.1(i)0(n)15(i)0(t)14.8(i)0(a)13.8(l)-179.8(co)13.9(nd)15.1(it)14.8(io)15(ns)-174.8(an)13.9(d)]TJ T* [(wa)13(s)-369.5(h)0(e)13.9(l)0(d)-359.4(f)0(o)15.1(r)-369.7(on)15.1(e)-370.9(a)0(d)13.9(d)0(i)14.9(t)0(i)14.8(o)0(n)15.1(a)0(l)-360.6(m)0(i)13.7(n)0(u)15.1(t)0(e)19.6(.)-372(Ne)13(ga)13.9(ti)14.8(ve)-360.5(po)15.1(la)13.8(ri)15(ty)-359.4(el)13.8(ec)12.8(-)]TJ T* [(tr)15(os)15.3(pr)15.1(ay)-181.9(io)15(ni)15(za)12.8(ti)20.6(on)-186.5(wa)18.8(s)-191(u)0(s)15.3(e)0(d)-181.9(w)0(i)14.1(t)0(h)-180.9(a)-192.3(sc)19.9(an)-181.9(ti)14.8(me)-183.1(of)-180.7(2)15.1(8)-162.4(m)0(i)19.5(n)-191.2(us)15.3(in)15(g)]TJ 0 -1.1174 TD -.0153 Tc [(a)-173.1(s)-15.3(ca)-15.3(n)-162.7(w)-15.3(in)-15.3(do)-15.3(w)-162.4(o)-15.3(f)-167.2(1)-15.3(,2)-15.3(00)-15.3(2)-15.3(,1)-15.3(00)-177.7(m)-15.3(/)4.2(z)-173.1(w)-15.3(it)-15.3(h)-161.6(a)-173.1(s)-15.3(p)0(r)-15.3(a)-1.3(y)-171.9(v)-15.3(ol)-15.3(ta)-15.3(ge)-173.1(o)-15.3(f)-161.5(4)-171.9(k)-15.3(V)]TJ 0 -1.1116 TD 0 Tc [(an)13.9(d)-329.4(3)0(5)-324.7(p)0(s)15.3(i)0(g)-324.9(o)0(f)-324.7(s)0(h)15.3(e)0(a)12.8(t)0(h)-324.9(g)0(a)19.7(s)-335(o)15.2(w,)-322.2(12)-152(L/)13.8(mi)13.7(n,)-321.3(33)15.1(5)]TJ /F8 1 Tf 18.6787 0 TD ()Tj /F3 1 Tf .3917 0 TD .3304 Tc [(Cd)330.4(r)345.5(y)330.4(i)345.4(n)330.4(g)5.7(g)330.4(a)344.3(s)]TJ -19.0704 -1.1116 TD 0 Tc [(o)15.2(w)-174.8(u)0(s)15.3(i)0(n)20.7(g)-173.9(a)-169.3(c)0(a)12.8(p)0(i)15(l)0(l)14.8(a)0(r)14(y)-168.1(vo)15.1(lt)14.8(ag)13.9(e)-175(o)0(f)]TJ /F8 1 Tf 12.5619 0 TD (-)Tj /F3 1 Tf .5414 0 TD [(15)15.1(0)-156.6(V)0(.)-166.7(S)0(e)14.1(l)0(e)13.8(c)0(t)-164.8(i)0(o)20.7(n)-173.9(mo)13.9(ni)15(to)20.7(ri)15(ng)]TJ -13.1033 -1.1174 TD -.0144 Tc [(w)-14.4(a)-1.4(s)-383.9(p)-14.4(er)-14.4(fo)-14.4(rm)-14.4(ed)-384.1(f)-14.4(o).7(r)-384.1(t)-14.4(he)]TJ /F8 1 Tf 9.4978 0 TD 0 Tc (-)Tj /F3 1 Tf .5414 0 TD [(5)-375.5(c)0(h)19.7(a)0(r)14(g)0(e)-366.2(s)0(t)15.1(a)0(t)13.8(e)0(,)-362.8(a)0(n)13.9(d)-369.7(ch)13.9(ro)15.1(ma)18.4(to)15(gr)15.1(am)12.7(s)]TJ -10.0392 -1.1116 TD [(we)13(re)-233.7(an)13.9(al)13.8(yz)13.9(ed)-233.7(us)15.3(in)15(g)-243(A)0(g)14.2(i)0(l)20.6(e)0(n)13.9(t)-243.1(Ch)14(em)12.7(St)15.1(at)19.5(io)15(n)-243(s)0(o)15.3(f)0(t)15(w)0(a)13(r)0(e)14(.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 62.022 489.5432 Tm [(SRB1)-338.2(mRNA)-334(knockdown)-333.3(in)-330.2(liver)-335.1(and)-335.7(other)-335.1(tissues)]TJ /F3 1 Tf 9.843 0 0 9.843 72 473.1022 Tm [(App)13.1(rox)14(im)13.7(ate)11.5(ly)-180.9(100)-153.1(mg)-182(of)-186.5(liv)13.7(er)14(,)-187.7(kid)13.8(ney)12.8(,)-187.7(hea)11.7(rt,)-178.5(je)13.8(jun)13.8(um,)-179.7(and)]TJ -1.0137 -1.1174 TD [(qua)12.8(dri)13.9(cep)11.7(s)-306.2(was)-298.9(pla)12.7(ced)-299.4(int)13.7(o)-306.4(1)0(.)12.7(5)-162.4(mL)-304.1(Epp)12.8(end)12.8(orf)-297(via)12.7(ls)-301.6(wit)12.8(h)-306.4(the)]TJ 0 -1.1116 TD [(add)12.8(iti)13.6(on)-411.1(of)-416.9(an)-412.3(equ)12.8(al)-412.4(amo)11.6(unt)-406.6(of)-416.9(cer)11.7(am)12.7(ic)-418.2(pul)13.8(ver)12.8(izi)18.3(ng)-416.9(bea)11.7(ds)]TJ T* [(fol)13.9(low)13(ed)-268.3(by)-272.9(the)-263.8(add)12.8(iti)13.6(on)-267.1(of)-272.9(1.)12.7(2)-162.4(m)0(L)-275.3(o)0(f)-267.1(Inv)14(itr)13.8(oge)12.8(n)-271.8(lys)14(is)-272.8(buf)14(fer)]TJ T* [(con)12.8(tai)12.6(nin)13.9(g)-145.1(1)0(%)-147.3(b)0(e)13.9(tam)11.5(erc)11.7(apt)12.7(oet)12.7(han)12.8(ol)14.9(.)-153.2(Sam)17.5(ple)12.7(s)-150.7(wer)12(e)-146.2(pul)13.8(ver)12.8(ize)11.5(d)]TJ 0 -1.1174 TD [(usi)14(ng)-284.4(a)-290.2(Pre)13(ce)12.8(lly)13.7(s)-288.9(2)0(4)-284.4(hig)13.8(h-t)13.9(hro)14(ugh)14(put)-279.9(tis)13.9(sue)-280.7(ho)15.1(mog)12.7(eni)12.7(zer)-282.1(for)]TJ 0 -1.1116 TD [(30)-157.7(s)-265.8(t)0(o)-267.3(uni)13.8(for)14(mi)13.7(ty)-267.3(\(Be)11.8(rti)19.5(n)-271.8(Cor)13(p,)-263.7(Ro)14(ckv)12.8(ill)13.6(e,)-264.9(MD\))12.2(,)-268.4(and)-257.9(300)]TJ /F9 1 Tf 23.131 0 TD (m)Tj /F3 1 Tf .5472 0 TD (L)Tj -23.6782 -1.1116 TD [(was)-333.4(tra)12.7(nsf)14.2(err)12.9(ed)-337.4(to)-330.6(a)-342.1(2.0)-155.4(mL)-332.9(dee)11.7(p)-340.9(96-)14(wel)11.8(l)-341(p)0(l)14.9(ate)-334.1(fol)13.9(low)13(ed)-337.4(by)]TJ 0 -1.1174 TD [(add)12.8(iti)13.6(on)-290.2(of)-290.2(300)]TJ /F9 1 Tf 6.3242 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-296(o)0(f)-290.2(70%)-286.6(eth)12.7(ano)18.6(l)-295(t)0(o)-290.3(eac)10.5(h.)-286.8(Pla)12.8(tes)-286.6(wer)12(e)-296(the)12.7(n)]TJ -6.8713 -1.1116 TD [(vor)14(tex)12.7(ed)-383.5(for)-377.6(2)-162.4(min)12.6(,)-389.3(and)-378.8(100)]TJ /F9 1 Tf 11.7383 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-388.2(o)0(f)-382.3(lys)14(ate)-380.1(was)-385.3(ad)13.9(ded)-384.6(to)-382.5(the)]TJ -12.2855 -1.1116 TD [(Pur)14.2(eLi)11.5(nk)-238.3(Pro)-239.3(96)-244.1(tot)13.7(al)-239.6(RNA)-242.2(Pur)14.2(ic)12.8(ati)12.6(on)-238.3(Fil)13.9(ter)-240.7(Pla)12.8(te.)-237.3(Sam)11.7(ple)12.7(s)]TJ 0 -1.1174 TD [(wer)12(e)-393.9(cov)12.8(ere)11.7(d)-392.8(wit)12.8(h)-392.8(Air)13(por)14(e)-393.9(tap)12.7(e)-393.9(she)13(ets)-390.3(and)-384.6(cen)11.7(tri)13.8(fug)14(ed)-389.3(for)]TJ 0 -1.1116 TD [(2)-162.4(min)-229.3(at)-233.9(3,)12.7(000)]TJ /F7 1 Tf 5.6388 0 TD (g)Tj /F3 1 Tf .4953 0 TD [(.)-239.6(The)-230.3(ow)-228.6(thr)13.9(oug)14(h)-237.2(was)-229.8(dis)14(car)11.7(de)13.9(d,)-234.9(and)-229.1(500)]TJ /F9 1 Tf 16.9969 0 TD (m)Tj /F3 1 Tf .5472 0 TD (L)Tj -23.6782 -1.1116 TD [(of)-238.3(was)12.1(h)-237.2(buf)14(fer)-234.8(I)-237.2(was)-235.5(add)12.8(ed)-233.8(to)-238.5(eac)10.5(h)-237.2(wel)11.8(l)-243.1(o)0(f)-232.6(the)-235(lt)13.9(er)-239.5(pl)15(ate)-236.1(and)]TJ T* [(cen)11.7(tri)13.8(fug)14(ed)-400.8(at)-395.2(3,0)11.6(00)]TJ /F7 1 Tf 8.2825 0 TD (g)Tj /F3 1 Tf .9043 0 TD [(fo)15.1(r)-404.2(2)-162.4(min)-396.3(wit)12.8(h)-404.3(the)-390.5(ow)-395.7(thr)13.9(oug)14(h)-404.3(dis)14(-)]TJ -9.1867 -1.1174 TD [(car)11.7(ded)12.8(,)-279.9(t)0(h)15(e)0(n)-279.8(D)0(N)13.3(ase)-276.1(I)-277.5(a)0(t)-274.2(4)0(0)-157.7(U)-278.4(per)-269.4(80)]TJ /F9 1 Tf 14.6239 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L/w)11.8(ell)-269.7(was)-270.1(add)12.8(ed)-274.1(wit)12.8(h)]TJ -15.1711 -1.1116 TD [(inc)12.7(uba)12.8(tio)13.7(n)-554(a)0(t)-550.7(roo)14(m)-555.3(tem)11.5(pe)13.9(rat)12.7(ure)-545.8(for)-550.4(15)-151.9(min)12.6(,)-556.4(fol)13.9(low)13(ed)-550.5(by)]TJ T* (500)Tj /F9 1 Tf 1.653 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-244.2(o)0(f)-244.1(w)0(a)13(s)0(h)-243.9(buf)14(fer)-234.8(I.)]TJ -1.1865 -1.1174 TD [(Pla)12.8(tes)-159.9(wer)12(e)-169.3(rec)11.7(ent)12.7(rif)13.9(uge)12.8(d)-168.1(for)-164.5(2)-162.4(m)0(i)13.7(n)-173.9(at)-164.8(3,0)11.6(00)]TJ /F7 1 Tf 16.9393 0 TD (g)Tj /F3 1 Tf .4953 0 TD [(,)-170.5(and)-165.7(750)]TJ /F9 1 Tf 3.6805 0 TD (m)Tj /F3 1 Tf .5472 0 TD .1751 Tc [(Lo)175.1(f)]TJ -22.676 -1.1116 TD 0 Tc [(was)12.1(h)-220(buf)14(fer)-211.7(II)-215.2(\(17)14(.5)-160(mL)-212(was)-212.5(buf)14(fer)-211.7(II)]TJ /F8 1 Tf 14.9061 0 TD (+)Tj /F3 1 Tf .5472 0 TD [(70)-157.7(mL)-217.7(of)-215.3(eth)12.7(ano)12.8(l\))-215.4(was)]TJ -15.4533 -1.1116 TD [(add)12.8(ed)-308.6(to)-313.4(ea)12.8(ch)-314.4(we)13(ll,)-305.4(sam)11.8(ple)12.7(s)-311.9(wer)12(e)-319(r)0(e)14(cen)11.7(tif)13.8(uge)12.8(d)-312.1(and)-309.7(an)-308.6(add)12.8(i-)]TJ 0 -1.1174 TD [(tio)13.7(nal)-338.7(750)]TJ /F9 1 Tf 4.2622 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-347.9(o)0(f)-342(was)12.1(h)-346.7(buf)14(fe)14(r)-346.6(I)0(I)-342(and)-338.5(cen)11.7(tri)13.8(fug)19.8(ati)12.6(on)-342(was)-339.2(per)12.8(-)]TJ -4.8094 -1.1116 TD [(for)14(med)-184.2(fol)13.9(low)13(ed)-187.7(by)-186.5(a)-192.3(lon)13.9(ger)-188.7(du)15.1(rat)12.7(ion)-187.7(of)-186.5(5)-162.4(min)-183.2(to)-186.6(dry)-181.8(the)-183.1(lt)13.9(er.)]TJ T* [(A)-278.4(n)0(e)13.9(w)-278.4(96-)14(wel)11.8(l)-271.9(pla)12.7(te)-268.4(was)-270.1(use)13(d,)-269.5(and)-263.6(pur)14(ie)12.9(d)-271.8(RNA)-271(wa)13(s)-277.4(elu)12.7(ted)]TJ 0 -1.1174 TD [(wit)12.8(h)-369.7(100)]TJ /F9 1 Tf 3.7899 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-370.9(o)0(f)-365(RNa)10.9(se-)13(fre)12.9(e)-370.9(H)]TJ 7.3823 0 0 6.5614 181.3606 208.4598 Tm (2)Tj 9.843 0 0 9.843 185.0456 210.0472 Tm [(O.)-362.5(Sam)11.8(ple)12.7(s)-369.5(wer)12(e)-370.9(qua)12.8(nti)13.7(tat)12.6(ed)]TJ -12.4986 -1.1116 TD [(usi)14(ng)-244.1(Rib)12.8(oGr)13.1(ee)12.8(n,)-246.4(pre)12.8(par)12.8(ed)-239.5(by)-244.1(55)]TJ /F9 1 Tf 13.3683 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-250(o)0(f)-238.3(Rib)12.8(oGr)13.1(een)]TJ /F8 1 Tf 6.543 0 TD (+)Tj /F3 1 Tf .5472 0 TD [(17.)17.4(5)-162.4(m)0(L)]TJ -21.0056 -1.1116 TD [(of)-180.7(TE)12.7(1X)-181.6(an)13.9(d)-185.4(170)]TJ /F9 1 Tf 6.9001 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-180.8(was)-172.2(add)12.8(ed)-176.2(to)-180.9(10)]TJ /F9 1 Tf 7.1939 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-180.8(o)0(f)-175(sam)11.8(ple)-171.6(int)13.7(o)-185.4(a)-180.8(cle)11.5(ar)]TJ -15.1883 -1.1116 TD [(bot)13.8(tom)-148.6(96-)14(wel)11.8(l)-156.7(pla)12.7(te)13.8(.)-158.9(A)-157.5(sta)12.9(nda)12.8(rd)-151.9(cur)12.8(ve)-153.1(was)-149.1(als)12.9(o)-156.6(pre)12.8(par)12.8(ed)-153.1(fro)14(m)]TJ 0 -1.1174 TD [(com)11.6(bin)13.8(ed)-239.5(sam)11.8(ple)-235(RNA)-236.5(fro)14(m)-244.2(1.5)11.7(6)-243(t)0(o)-244.2(2)0(0)15.1(0)-162.4(ng/)13.8(mL.)]TJ 1.0137 -1.1116 TD [(Plates)-296.8(were)-295.6(read)-300.4(using)-293.4(a)-296(uorescence)-299.8(excitation/emission)]TJ -1.0137 -1.1116 TD [(wavelength)-263.3(of)-261.4(500/525)-163.4(nm)-262.6(using)-258.9(a)-255.7(SpectraMax)-264.2(Gemini)-263.6(XPS)]TJ 0 -1.1174 TD [(plate)-486.1(reader)-488.1(with)-483.6(SoftMax)-487.8(Pro)-481.2(v5.4)-484.8(\()-81.7(Molecular)-486.8(Devices,)]TJ 0 -1.1116 TD [(Sunnyvale,)-459.1(CA\).)-457.9(RiboGreen)-457.7(data)-456.1(were)-456.8(used)-460.4(to)-451.6(normalize)]TJ T* [(RNA)-495.7(values,)-496.1(and)-494(corresponding)-494.6(samples)-494.8(were)-497.1(diluted)-493.1(to)]TJ 0 -1.1174 TD [(25)-169.2(ng/mL.)-299.5(A)-295.7(qPCR)-300.1(master-mix)-303.8(was)-298.9(prepared)-300.2(with)-299.3(the)-298.3(addi-)]TJ 0 -1.1116 TD [(tion)-269.6(of)-267.1(800)]TJ /F9 1 Tf 4.5962 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-267.2(o)0(f)-267.1(express)-268.8(superscript)-273.4(qPCR)-265.5(supermix,)-268(20)]TJ /F9 1 Tf 17.976 0 TD (m)Tj /F3 1 Tf .5529 0 TD (L)Tj -23.6782 -1.1116 TD [(of)-462.9(10)]TJ /F9 1 Tf 2.4652 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(M)-462.8(forward)-464.7(SRB1)-467.1(primer,)-461.8(20)]TJ /F9 1 Tf 12.3834 0 TD (m)Tj /F3 1 Tf .5529 0 TD .463 Tc [(Lo)463(f1)463(0)]TJ /F9 1 Tf 3.5422 0 TD 0 Tc (m)Tj /F3 1 Tf .5529 0 TD [(M)-462.8(reverse)]TJ -20.0495 -1.1174 TD [(SRB1)-242.5(primer,)-242.9(20)]TJ /F9 1 Tf 6.9635 0 TD (m)Tj /F3 1 Tf .5529 0 TD .2384 Tc [(Lo)238.4(f5)]TJ /F9 1 Tf 2.5919 0 TD 0 Tc (m)Tj /F3 1 Tf .5529 0 TD [(M)-243.9(probe,)-240.5(32)]TJ /F9 1 Tf 5.0628 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-244.2(o)0(f)-238.3(ROX)-242.2(reference)]TJ -16.2769 -1.1116 TD [(dye,)-169.2(160)]TJ /F9 1 Tf 3.5307 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-163.6(o)0(f)-169.2(express)-165.1(superscript)-169.8(mix)-165.9(for)-170.3(one)-165.7(step)-166.8(qPCR,)-165.3(and)]TJ 21.4203 67.9184 TD (388)Tj /F9 1 Tf 1.6703 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-313.3(o)0(f)-307.4(RNase)-9.5(-free)-313(H)]TJ 7.3823 0 0 6.5614 410.3999 723.5148 Tm (2)Tj 9.843 0 0 9.843 414.0849 725.1588 Tm [(O.)-310.7(Individual)-317.8(reactions)-312.9(were)-318.6(setup)]TJ -10.2638 -1.1174 TD [(into)-309.9(the)-304.1(96-well)-303.7(plate)-307.6(using)-304.9(2)]TJ /F9 1 Tf 12.1703 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-301.8(o)0(f)-307.4(sample)-303.8(RNA)-311.3(combined)]TJ -12.7232 -1.1116 TD [(with)-310.8(18)]TJ /F9 1 Tf 3.26 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-307.6(o)0(f)-307.4(master-mix)-309.6(per)-309.7(well.)-309.6(A)-307.2(standard)-310.5(cycling)-315.6(pro-)]TJ -3.8129 -1.1116 TD [(gram)-162.3(was)-160.7(used)-155.1(with)-161(an)-158.9(initial)-159.3(hold)-154.3(at)-159(50)]TJ /F8 1 Tf 15.3035 0 TD ()Tj /F3 1 Tf .3917 0 TD [(C)-157.6(for)-158.7(15)-169.2(min)-154.4(followed)]TJ -15.6952 -1.1116 TD [(by)-278.7(denaturation)-282(at)-274.2(95)]TJ /F8 1 Tf 8.582 0 TD ()Tj /F3 1 Tf .3917 0 TD [(C)-278.6(with)-276.2(a)-278.7(2-min)-271.8(hold,)-278.7(and)-275.2(40)-278.7(cycles)-275(of)]TJ -8.9736 -1.1174 TD (95)Tj /F8 1 Tf 1.0022 0 TD ()Tj /F3 1 Tf .3974 0 TD [(C)-267.1(for)-262.4(15)-169.2(s)-260.1(and)-269.4(60)]TJ /F8 1 Tf 6.8886 0 TD ()Tj /F3 1 Tf .3974 0 TD [(C)-267.1(for)-262.4(1)-168.1(min)-263.8(using)-264.6(a)-267.2(StepOnePlus)-268.5(Real-)]TJ -8.6856 -1.1116 TD [(Time)-313.4(PCR)-304.7(system)-314(and)-304(with)-310.8(v2.3)-306.2(software)-311.4(\(Applied)-310.6(Biosys-)]TJ T* [(tems,)-505.5(Carlsbad,)-510.8(CA\).)-503.9(Corresponding)-506(cycle)-504.5(threshold)-506.4(\(C)]TJ 7.3823 0 0 6.5614 546.803 646.8093 Tm (t)Tj 9.843 0 0 9.843 548.9006 648.4534 Tm (\))Tj -23.9604 -1.1174 TD [(value)-8(s)-185.2(normalized)-194.5(by)-186.5(RiboGreen)-192.8(were)-191.9(used)-189.7(to)-192.4(evaluate)-192.3(SRB1)]TJ 0 -1.1116 TD [(expression)-329.8(in)-324.9(liver,)-327.1(kidney,)-322.4(heart,)-328.1(lung,)-324.7(jejunum,)-324.8(and)-327(quad-)]TJ T* [(riceps)-8.8(.)-239.6(Percent)-241.5(SRB1)-242.5(RNA)-242.2(inhibition)-242.1(compared)-243.9(to)-244.2(the)-240.7(saline)]TJ 0 -1.1174 TD [(control)-256.8(was)-252.8(determined)-252.1(across)-256.2(all)-246.6(dose)-253(groups.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 313.0582 578.381 Tm [(Inhibitory)-336.5(effect)-335.1(liver)-335.1(exposure)-333.1(response)-333.1(PD)-335.8(model)]TJ /F3 1 Tf 9.843 0 0 9.843 323.0361 561.94 Tm [(Phoenix)-527.2(Build)-530.9(6.4.0.768)-523.8(WinNonlin)-531.8(was)-529.3(used)-523.7(for)-527.4(PD)]TJ -1.0137 -1.1116 TD [(modeling)-311(and)-309.7(simulation)-307.5(\(Certara,)-316.3(St.)-305.1(Louis,)-309.6(MO\).)-308(Data)-307.2(set)]TJ T* [(assembly)-426.8(was)-425.6(constructed)-430.3(using)-420.1(animal)-425.1(number,)-427.1(time)-421.8(\(h\),)]TJ 0 -1.1174 TD [(dose)-518(\(mg/kg\),)-513.5(liver)-513.7(concentration)-514.7(\()]TJ /F9 1 Tf 15.0098 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/g\),)-509(percent)-518.2(mRNA)]TJ -15.5627 -1.1116 TD [(inhibition)-507(compared)-508.8(to)-503.4(saline)-510.1(control)-504.4(\(%\),)-503.1(and)-505.6(knockout)]TJ T* [(status)-249.5(\(WT/WT,)-247.4(or)-238.3(HO/HO)-9.1(\).)-240.6(The)-241.8(data)-248.8(set)-240.6(was)-247.1(then)-247.6(imported)]TJ 0 -1.1174 TD [(into)-263.8(an)-262.5(inhibitory)-259.2(effect)-269.4(sigmoid)-256.7(maximum)-266.1(effect)-263.6(\(E)]TJ 7.3823 0 0 6.5614 521.0645 494.5888 Tm (max)Tj 9.843 0 0 9.843 533.8203 496.1763 Tm .2602 Tc [(\)P)260.2(D)]TJ -22.4283 -1.1116 TD 0 Tc [(model,)-253.4(whereby)-252.8(effect)-252.1(C)]TJ /F8 1 Tf 10.0852 0 TD (=)Tj /F3 1 Tf .72 0 TD .2493 Tc [(0i)249.3(sE)]TJ 7.3823 0 0 6.5614 441.8077 483.5905 Tm 0 Tc (max)Tj 9.843 0 0 9.843 457.0582 485.2345 Tm [(and)-252.1(effect)-252.1(at)-251.2(C)]TJ /F8 1 Tf 6.0477 0 TD (=)Tj /F3 1 Tf .72 0 TD (innity)Tj -21.3973 -1.1116 TD [(is)-284.4(E)]TJ 7.3823 0 0 6.5614 328.4786 472.6487 Tm (0)Tj 9.843 0 0 9.843 332.1637 474.2928 Tm [(,)-279.9(using)-281.9(the)-281.1(following)-281.9(equation:)]TJ /F7 1 Tf 4.1009 -3.0354 TD (E)Tj /F11 1 Tf .8006 0 TD ()Tj /F7 1 Tf .9388 0 TD (E)Tj /F3 1 Tf 6.8899 0 0 6.8899 395.6597 442.9416 Tm (0)Tj /F12 1 Tf 9.843 0 0 9.843 399.6282 458.2487 Tm ()Tj /F3 1 Tf .7315 -1.4054 TD (1)Tj /F11 1 Tf .6624 0 TD ()Tj ET 429.789 446.683 48.586 .39685 re f BT /F7 1 Tf 9.843 0 0 9.843 447.9306 451.1054 Tm (C)Tj /F3 1 Tf 6.8899 0 0 6.8899 454.7904 454.6771 Tm (Y)Tj /F7 1 Tf 9.843 0 0 9.843 429.7888 437.6692 Tm (C)Tj /F3 1 Tf 6.8899 0 0 6.8899 436.6487 440.5038 Tm (Y)Tj /F11 1 Tf 9.843 0 0 9.843 443.7353 437.6692 Tm ()Tj /F7 1 Tf .9331 0 TD (EC)Tj /F3 1 Tf 6.8899 0 0 6.8899 465.5621 436.1952 Tm (50)Tj 1.0697 .6254 TD (Y)Tj /F12 1 Tf 9.843 0 0 9.843 422.5889 458.2487 Tm 4.9386 Tc [()4938.6()]TJ /F3 1 Tf -11.1278 -4.2334 TD 0 Tc (whereby)Tj /F7 1 Tf 3.7381 0 TD (E)Tj /F8 1 Tf .7776 0 TD (=)Tj /F3 1 Tf .72 0 TD [(%)-290.1(saline)-285.5(inhibition)-288.1(in)-284.5(liver,)]TJ /F7 1 Tf 11.3927 0 TD (E)Tj /F3 1 Tf 7.3823 0 0 6.5614 482.74 414.9353 Tm (0)Tj /F8 1 Tf 9.843 0 0 9.843 488.0692 416.5794 Tm (=)Tj /F3 1 Tf .72 0 TD (lowest%saline)Tj -18.5002 -1.1174 TD .0184 Tc (inhibition,)Tj /F7 1 Tf 4.6423 0 TD 0 Tc (C)Tj /F8 1 Tf .8524 0 TD (=)Tj /F3 1 Tf .7372 0 TD .0185 Tc [(liver)-287.8(concentration,)]TJ /F9 1 Tf 8.4783 0 TD 0 Tc (g)Tj /F8 1 Tf .6854 0 TD (=)Tj /F3 1 Tf .7372 0 TD .0187 Tc [(hill)-282(coefcient,)-284.2(a)-.8(nd)]TJ -16.1329 -1.1116 TD .0196 Tc (EC)Tj 7.3823 0 0 6.5614 326.0409 392.9952 Tm .0299 Tc (50)Tj /F8 1 Tf 9.843 0 0 9.843 335.4519 394.6393 Tm 0 Tc (=)Tj /F3 1 Tf .7372 0 TD .0186 Tc [(concentration)-212.9(r).3(equired)-207.1(f).3(or)-212.8(50%)-213.9(inhibition.)-209.4(Uniform)]TJ -3.0123 -1.1116 TD [(weighting)-460.7(u).1(sing)-460.7(initial)-460.8(p).1(arameter)-5.6(s/bounds)-454.7(with)-460.6(Nelder)]TJ 0 -1.1174 TD 0 Tc [(Me)13(ad)-268.3(mi)19.5(ni)14.9(mi)19.5(za)18.5(ti)20.6(on)-272.9(wa)18.8(s)-283.1(u)0(s)21(e)0(d)19.7(,)-285.6(an)19.7(d)-283.3(E)0(C)]TJ 7.3823 0 0 6.5614 462.5573 371.055 Tm -.0162 Tc (50)Tj 9.843 0 0 9.843 472.6487 372.6991 Tm 0 Tc [(va)19.7(lu)20.7(es)-273.9(fo)20.9(r)-283.3(b)0(o)20.8(t)0(h)-273(W)0(T)17.4(/)]TJ -16.2136 -1.1116 TD [(WT)-264.8(an)19.7(d)-271.8(H)0(O)19.1(/)0(H)19.8(O)-272.7(co)19.7(ho)20.8(rt)20.7(s)-271.6(w)0(e)18.8(r)0(e)-262.5(c)0(o)19.7(m)0(p)19.6(a)0(r)19.7(e)0(d)19.7(.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 313.0582 334.5448 Tm (Immunohistochemistry)Tj /F3 1 Tf 9.843 0 0 9.843 323.0361 318.1038 Tm [(Fo)26.8(r)16.2(m)0(a)24.2(l)16.1(in)-175.1()16.3(x)0(e)25.4(d)-185.4(pa)25.4(r)16.2(a)0(f)25.5()0(n)-174.8(s)16.4(e)15(c)0(t)25.3(i)0(o)26.5(n)16.2(s)-191(o)16.2(f)-185.4(m)15(ur)26.6(i)16.1(n)0(e)-176.1(l)16.1(iv)26.5(e)15(r)-185.4(we)24.6(re)-176.1(c)15(u)16.2(t)-185.5(a)0(n)25.4(d)]TJ -1.0137 -1.1116 TD [(se)25.6(ct)25.3(i)16.1(o)0(n)26.6(e)0(d)-147.4(a)15(t)-156.7(4)]TJ /F9 1 Tf 5.3623 0 TD (m)Tj /F3 1 Tf .5414 0 TD [(m)15(,)-153.2(an)25.4(d)-156.6(s)16.4(li)26.3(de)25.4(s)-156.4(w)15.3(er)25.5(e)-157.8(d)16.2(ri)26.5(ed)-147.4(o)16.2(v)16.2(e)0(r)25.5(n)0(i)26.5(g)16.2(ht)-146.3(i)16.1(n)-156.6(a)15(n)-156.6(ov)26.6(e)15(n)-156.6(se)25.6(t)]TJ -5.9037 -1.1116 TD [(to)-491.9(5)16.2(0)]TJ /F8 1 Tf 2.2405 0 TD ()Tj /F3 1 Tf .3859 0 TD [(C)15.2(.)-504.5(T)15(h)16.2(e)-503.3(s)16.4(li)26.3(de)25.4(s)-502(w)15.3(er)25.5(e)-503.4(t)16(he)25.4(n)-502.2(d)16.2(ep)25.4(a)15(r)0(a)25.5(f)0()26.8(n)16.2(iz)25.3(e)15(d)-502.2(wi)25.6(t)16.1(h)-502.2(xy)26.6(l)16.1(e)0(n)25.4(e)]TJ -2.6264 -1.1174 TD [(tr)26.5(ea)24.3(t)16.1(m)0(e)24.2(n)16.2(t)-513.8(f)16.2(or)-497.5(1)16.2(0)-156.6(m)15(i)16.1(n)-513.7(f)16.2(o)16.2(l)0(l)26.3(o)0(w)25.7(e)15(d)-513.7(b)16.2(y)-507.9(1)0(0)26.6(0)0(%)-498.6(e)15(th)26.5(y)16.2(l)-513.8(a)15(l)16.1(co)25.4(ho)26.6(l)-508.1(f)0(o)26.6(r)]TJ 0 -1.1116 TD [(10)-140.4(m)15(i)0(n)26.5(,)-233.8(95)26.6(%)-232.5(e)0(t)25.3(h)16.2(yl)-221.2(a)15(l)0(c)25.3(o)0(h)26.6(o)16.2(l)-237.4(f)16.2(or)-221(6)-150.8(m)0(i)25.2(n)16.2(,)-233.8(a)0(n)25.4(d)-231.5(ri)26.5(ns)26.8(ed)-222.2(w)15.3(i)0(t)26.3(h)-231.5(wa)24.6(te)25.3(r)-231.5(f)0(o)26.6(r)]TJ T* [(2)-156.6(m)15(i)16(n)0(.)-171.6(E)15(n)16.2(d)0(o)26.6(g)0(e)25.4(n)16.2(ou)26.6(s)-185.2(p)16.2(e)15(r)0(o)26.6(x)16.2(id)26.5(as)25.6(e)-180.8(w)0(a)24.6(s)-179.5(qu)26.6(en)25.4(c)15(h)0(e)25.4(d)-179.6(pl)26.5(ac)24.3(i)16.1(n)0(g)-169.2(t)16.1(he)-170.4(sl)26.7(i)16(d)0(e)25.4(s)]TJ T* [(in)-290.3(3)16.2(%)-301.7(hy)26.6(dr)26.6(o)16.2(g)0(e)25.4(n)-300.6(pe)25.4(r)16.2(o)0(x)26.6(i)0(d)26.5(e)-301.8(f)16.2(o)0(r)-290.2(1)16.2(5)-156.6(m)15(i)16(n)0(.)-286.8(S)0(l)26.6(i)0(d)26.5(e)15(s)-306.2(w)15.3(e)15(r)0(e)-291.3(t)16.1(he)25.4(n)-300.6(r)16.2(in)26.5(se)25.6(d)]TJ 0 -1.1174 TD [(wi)25.6(th)-134.8(1)]TJ /F8 1 Tf 2.373 0 TD ()Tj /F3 1 Tf .7027 0 TD -.0158 Tc [(TBS)-160.7(f)-15.8(o)10.8(r)-160.9(5)-172.4(m)-.8(in)-166.6(and)-166.6(t).3(re)-15.8(a)8.5(t)-15.8(e)9.5(d)-160.9(wi)-15.8(t)10.5(h)-166.6(Pro)-15.8(t)10.7(e)-15.8(i)9.5(na)-15.8(s)9.8(e)-162.1(K)-167.5(for)-166.6(5)-166.6(m)-.8(i)-15.8(n)-150.6(at)]TJ -3.0757 -1.1116 TD 0 Tc [(ro)26.6(om)-435.4(t)16.1(e)0(m)24.2(p)16.2(er)25.5(a)15(t)0(u)26.5(r)0(e)25.5(.)-446.9(S)16.3(l)0(i)26.3(d)0(e)25.4(s)-444.4(we)24.6(r)16.2(e)-451.5(r)16.2(i)0(n)26.5(s)16.4(ed)-435.3(a)15(g)0(a)25.4(i)0(n)-434.3(w)15.3(it)26.3(h)-444.6(T)0(B)24.4(S)-444.4(an)25.4(d)]TJ T* [(bl)26.5(oc)25.4(k)16.2(e)0(d)-435.3(w)15.3(i)16.1(t)0(h)-434.3(p)16.2(ro)26.6(t)16(e)0(i)25.3(n)-444.6(bl)26.5(o)16.2(c)0(k)25.4(i)0(n)26.5(g)-444.6(s)16.4(o)0(l)26.5(u)0(t)26.5(i)16.1(on)-434.2(f)16.2(o)0(r)-428.4(2)0(0)-140.4(m)15(in)-434.3(a)15(t)-444.7(ro)26.6(o)16.2(m)]TJ 0 -1.1174 TD [(te)25.3(m)15(p)0(e)25.4(r)0(a)25.5(t)16(ur)26.6(e.)-224.6(Sl)26.6(i)16.1(d)0(e)25.4(s)-237(we)24.6(r)16.2(e)-238.4(re)25.5(r)16.2(i)0(n)26.5(s)0(e)25.6(d)-237.2(w)15.3(i)0(t)26.3(h)-237.2(T)15(B)0(S)25.7(,)-239.6(a)15(n)16.2(d)-237.2(p)0(r)26.6(i)0(m)25.2(a)15(ry)-226.8(a)15(n)16.2(ti)26.3(-)]TJ 0 -1.1116 TD [(bo)26.6(dy)-267.1(\()16.2(R)0(a)24.4(b)16.2(bi)26.5(t)-283.5(a)15(n)16.2(t)0(i)26.3(-)0(A)25.8(S)16.3(O)-284.2(A)15.3(n)16.2(t)0(i)26.3(b)0(o)26.6(d)16.2(y\))-267.1(wa)24.6(s)-277.4(a)0(d)25.4(d)16.2(ed)-268.3(a)15(t)-283.5(1)16.2(:)0(1)26.5(0)16.2(,)13.9(0)0(0)26.6(0)-277.6(an)25.4(d)]TJ T* [(in)26.5(cu)25.4(b)16.2(a)0(t)25.3(e)0(d)-199.2(o)16.2(ve)25.4(rn)26.6(i)16(g)0(h)26.6(t)-214.3(a)15(t)-208.6(4)]TJ /F8 1 Tf 9.3653 0 TD ()Tj /F3 1 Tf .3801 0 TD [(C)15.2(.)-210.8(Sl)26.6(id)26.5(e)15(s)-214(w)15.3(e)0(r)25.5(e)-209.6(re)25.5(ri)26.5(n)16.2(s)0(e)25.6(d)-214.2(w)15.3(i)0(t)26.3(h)-208.4(TB)24.4(S)-208.3(a)0(n)25.4(d)]TJ -9.7454 -1.1174 TD [(go)26.6(at)-130.2(a)15(n)0(t)26.5(i)16.1(-r)26.7(ab)25.4(b)16.2(i)0(t)-129.2(s)0(e)25.6(c)15(on)26.6(d)16.2(a)0(r)25.5(y)-139.3(an)25.4(ti)26.3(b)16.2(o)0(d)26.6(y)-139.3(wa)24.6(s)-139.1(a)0(d)25.4(d)0(e)25.4(d)-139.3(a)15(t)-145.2(1)16.2(:)16(20)26.6(0)-139.3(d)0(i)26.5(l)0(u)26.5(t)16(io)26.5(n,)]TJ 0 -1.1116 TD [(an)25.4(d)-156.6(i)16(nc)25.4(u)16.2(b)0(a)25.4(t)0(e)25.3(d)-150.8(fo)26.6(r)-156.6(3)16.2(0)-156.6(m)15(i)16.1(n)-156.6(a)15(t)-156.7(r)16.2(o)0(o)26.6(m)-152.1(te)25.3(m)15(p)0(e)25.4(r)0(a)25.5(t)16(ur)26.6(e)-157.8(\()16.2(RT)24.4(\))16.2(.)-153.2(Sl)26.6(id)26.5(e)15(s)-156.4(w)15.3(e)0(r)25.5(e)]TJ T* [(re)25.5(ri)26.5(ns)26.8(e)15(d)-179.6(w)15.3(i)0(t)26.3(h)-179.6(T)15(B)15.2(S,)-165.6(a)15(n)0(d)-163.5(D)15.3(AB)-165.4(Ch)25.6(r)16.2(o)0(m)25.4(a)15(ge)25.4(n)-179.6(w)15.3(a)15(s)-179.5(a)15(p)0(p)26.6(l)0(i)26.3(e)15(d)-179.6(f)16.2(or)-163.4(5)-156.6(m)15(i)16.1(n)]TJ 0 -1.1174 TD [(at)-297.2(R)15.2(T)15(,)-302.9(r)0(i)26.5(n)0(s)26.8(e)0(d)-291.3(i)0(n)-290.3(H)]TJ 7.3823 0 0 6.5614 384.8314 141.1653 Tm (2)Tj 9.843 0 0 9.843 388.403 142.7527 Tm [(O)-301.5(f)0(o)26.6(r)-306.3(3)-150.8(m)15(in)26.5(,)-302.9(a)0(n)25.4(d)-306.4(c)15(o)0(u)26.6(n)16.2(te)25.3(rs)26.8(ta)25.3(i)16.1(n)0(e)25.4(d)-306.4(b)16.2(y)-306.4(h)16.2(e)0(m)24.2(a)15(-)]TJ -7.6546 -1.1116 TD [(to)26.5(xy)26.6(l)16.1(i)0(n)-226.9(i)16(nc)25.4(ub)26.6(a)15(t)0(i)26.3(o)0(n)-226.8(f)16.2(o)16.2(r)-243(3)16.2(0)-150.8(s,)-229(f)16.2(o)16.2(l)0(l)26.3(o)0(w)25.7(e)15(d)-237.2(b)0(y)-226.8(a)-238.4(H)]TJ 7.3823 0 0 6.5614 480.8125 130.1669 Tm (2)Tj 9.843 0 0 9.843 484.3841 131.811 Tm [(O)-238.1(r)0(i)26.5(n)0(s)26.8(e)-238.4(fo)26.6(r)-237.2(1)-156.6(m)15(i)16(n,)]TJ -17.4058 -1.1116 TD [(ac)24.3(id)-134.8(a)15(l)16.1(co)25.4(ho)26.6(l)-145.2(r)0(i)26.5(n)16.2(se)-135.6(f)16.2(o)0(r)-134.6(1)-150.8(s,)-131(H)]TJ 7.3823 0 0 6.5614 413.9715 119.2252 Tm (2)Tj 9.843 0 0 9.843 417.5432 120.8692 Tm [(O)-146(r)16.2(i)16.1(n)0(s)26.8(e)-146.3(fo)26.6(r)-145.1(3)-156.6(m)15(i)16.1(n,)-131.2(95)26.6(%)-146.1(e)0(t)25.3(h)16.2(yl)-134.8(a)15(l)0(c)25.3(o)16.2(ho)26.6(l)]TJ -10.6151 -1.1116 TD [(fo)26.6(r)-237.2(2)-156.6(m)15(i)16.1(n,)-223.4(1)16.2(0)0(0)26.6(%)-238.3(e)15(t)0(h)26.5(y)16.2(l)-237.4(a)0(l)25.3(c)15(oh)26.6(o)16.2(l)-237.4(fo)26.6(r)-237.2(3)-150.8(mi)25.2(n)16.2(,)-239.6(a)15(n)16.2(d)-237.2(x)0(y)26.6(l)16(en)25.4(e)-238.4(f)16.2(or)-226.8(2)-150.8(m)15(in)26.5(.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 313.0582 84.0189 Tm [(To)15.2(ta)23.7(l)-199.3(p)0(l)17.6(a)0(s)21.4(m)0(a)-189.4(p)0(r)18.8(o)14.6(te)17.3(in)-191.1(b)14.6(i)0(n)17.6(d)0(i)17.6(n)0(g)-185.9(a)0(n)22.8(d)-200.4(pr)18.8(ot)23.7(ei)17.6(n)-200.4(b)14.6(in)17.6(di)17.6(ng)-185.9(pr)18.8(o)21.4(li)18.7(ng)]TJ /F3 1 Tf 9.843 0 0 9.843 323.0361 67.5779 Tm [(An)-723(ultraltration)-721(method)-723.3(with)-725.5(a)-716.5(nuclease-dependent)]TJ -1.0137 -1.1174 TD [(hybrid)-6.7(ization)-471.2(ELISA)-469.4(was)-471.7(used)-466.1(to)-468.9(determine)-475.6(total)-467.8(protein)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (226)Tj 46.1699 0 TD [(SHEMESH)-334(ET)-338.7(AL.)]TJ ET endstream endobj 93 0 obj <>stream LDCNMC+AdvP4C4E46 wrOC18C19AdvP4C4E46 kSmPfHH5B9"ݷ}}||"^9 tbgmx1 web}gH5g9<"88aa^9{+;PWB> ( ||MO=B3^s587 4,# endstream endobj 96 0 obj <>stream hbd`ab`ddqquvL) 0q6q57+iW <~OI102,b񟁕)bW|j+_,:qҲ+7s,\9  z}~3u5H5,l_Z%bzݴߓuKO_>{|9S8~Ne{Vy~~m+kmfZk~a./=S;V]1~r@?5T,~B fPwWZKKwOm|JA.0 W endstream endobj 98 0 obj <>stream hT=o w~ǫ:2G M{R~v'`rH .x>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 59.7543 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(binding)-451.5(differences)-454.3(between)-455.7(sample)-453.6(types.)-447.8(The)-449.2(degree)-453.6(of)]TJ 0 -1.1174 TD [(plasma)-205.9(protein)-204.9(binding)-198(differences)-206.7(was)-201(evaluated)-210.7(using)-201.3(ION-)]TJ 0 -1.1116 TD [(353382)-409.8(at)-400.9(both)-407.7(5)-404.3(and)-407.6(150)]TJ /F9 1 Tf 11.1508 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/mL)-404.4(in)-405.5(WT/WT)-410(and)-407.6(HO/HO)]TJ -11.7037 -1.1116 TD [(fresh)-472.9(plasma.)-468.6(Nanosep)-477.3(\(30K\))-467.1(lters)-474.2(were)-468.3(pretreated)-476.6(with)]TJ T* (300)Tj /F9 1 Tf 1.6703 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-180.8(o)0(f)-186.5(0.5%)-186.3(Tween-80)-186(and)-188.8(incubated)-186.5(at)-187.8(room)-184.1(temperature)]TJ -2.2232 -1.1174 TD [(for)-291.2(15)-169.2(min)-292.6(followed)-293.3(by)-284.4(centrifugat)-10.2(ion)-285.7(at)-291.5(12,000)]TJ /F7 1 Tf 19.3181 0 TD (g)Tj /F3 1 Tf .7891 0 TD [(for)-291.2(10)-169.2(min)]TJ -20.1071 -1.1116 TD [(to)-370.9(minimize)-371.1(nonspecic)-371.4(binding.)-374.3(Retained)-370.7(volume)-372(was)-368(re-)]TJ T* [(moved)-295.9(by)-290.2(rinsing)-295.7(the)-292.6(membrane)-291.2(twice)-296.9(with)-293.5(300)]TJ /F9 1 Tf 19.6464 0 TD (m)Tj /F3 1 Tf .5529 0 TD .2903 Tc [(Lo)290.3(f)-5.6(H)]TJ 7.3823 0 0 6.5614 285.6188 646.8093 Tm 0 Tc (2)Tj 9.843 0 0 9.843 289.3605 648.4534 Tm (O,)Tj -23.3268 -1.1174 TD [(followed)-293.3(by)-284.4(the)-286.8(addition)-292.6(of)-284.4(300)]TJ /F9 1 Tf 13.0227 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-284.5(o)0(f)-284.4(a)-290.2(300)]TJ /F9 1 Tf 4.4177 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/mL)-289.2(aqueous)]TJ -18.5463 -1.1116 TD [(solution)-383.4(of)-376.5(ION-420476)-375.6(as)-383.3(a)-376.6(separate)-382(ASO)-379.3(with)-379.9(no)-376.6(cross-)]TJ T* [(reactivity)-458.5(to)-457.3(ION-353382)-456.2(to)-457.3(further)-458.2(minimize)-457.5(nonspecic)]TJ 0 -1.1174 TD [(binding.)-541.3(Filters)-533(were)-543.2(incubated)-537.8(at)-533.4(room)-535.5(temperatur)-10.2(e)-532.2(for)]TJ 0 -1.1116 TD [(10)-169.2(min)-281.1(and)-280.9(centrifuged)-286.5(at)-280(12,000)]TJ /F7 1 Tf 13.351 0 TD (g)Tj /F3 1 Tf .7833 0 TD [(for)-279.7(10)-169.2(min.)]TJ -13.1206 -1.1116 TD [(Recovery)-381.9(testing)-377.7(was)-379.5(performed)-376.2(to)-376.7(correct)-379.9(for)-377.6(any)-378.8(non-)]TJ -1.0137 -1.1116 TD [(specic)-350.8(binding)-342(and)-344.3(evaluated)-343.1(at)-343.3(250)-170.3(ng/mL,)-339.8(and)-344.3(three)-347.7(ali-)]TJ 0 -1.1174 TD [(quots)-546.9(of)-549.3(300)]TJ /F9 1 Tf 5.7597 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-549.5(o)0(f)-549.3(ION-353382)-548.4(were)-549(placed)-551.6(into)-546.1(three)]TJ -6.3126 -1.1116 TD [(pretreated)-384.5(lters)-376.3(and)-378.8(centrifuged)-378.7(at)-377.9(12,000)]TJ /F7 1 Tf 17.6881 0 TD (g)Tj /F3 1 Tf .8755 0 TD [(for)-377.6(7)-162.4(min.)-376.7(Ul-)]TJ -18.5635 -1.1116 TD [(traltrate)-245.2(\(ltered\))-236.9(samp)-12.4(l)-7(e)-13.8(s)-248.6(w)-7.7(e)-13.8(r)-6.8(e)-249.9(c)-8(o)-12.6(l)-7(l)-12.7(e)-8(c)-13.8(t)-12.7(e)-8(d)-248.8(i)-7(n)-248.8(a)-8(d)-12.6(d)-6.9(i)-12.7(t)-7(i)-12.7(o)-12.6(n)-243(t)-12.7(o)-243(t)-12.7(h)-6.9(e)]TJ 0 -1.1174 TD .0129 Tc [(ini)5.9(t).2(i)5.9(a)-.9(l)-333.9(s).5(a)4.9(m)-.9(p)6(l).2(es)-333.6(an)6(d)-339.5(a)4.9(ss)6.2(aye)4.9(d)-333.8(by)-333.8(EC)5(L-E)4.9(L)4.9(I).3(SA)-334.6(to)-333.8(ob)6(ta)4.9(in)-333.8(pe)4.9(r-)]TJ 0 -1.1116 TD .0117 Tc [(cent)-415.7(reco)4.8(very.)-412.2(Two)-415.6(c)-2.1(o)4.8(n)-.9(cen)4.8(t)-1(ra)]TJ 12.6829 0 TD .0123 Tc [(ti)5.3(ons)5.6(,)-417.3(i)5.3(nclud)5.4(i)-.4(n)5.4(g)-415(bo)5.4(th)-415(5)-415(a)4.3(nd)]TJ -12.6829 -1.1116 TD .0126 Tc (150)Tj /F9 1 Tf 1.6991 0 TD 0 Tc (m)Tj /F3 1 Tf .5645 0 TD .0119 Tc [(g)5(/)-.8(mL)-485.7(of)-484.5(ION-)5.1(35)5(338)5(2,)-481.1(were)-485.7(pr)5.1(ep)5(ared)-484.5(in)-484.5(1)5(.)-3(2)-162(m)3.8(L)-485.7(o)-.7(f)]TJ -2.2636 -1.1174 TD .0121 Tc [(who)5.2(l)-.6(e)-278.1(p)5.2(lasma)-278.1(fro)5.2(m)-278.2(W)3(T/)5.1(WT)-278.2(and)-277(H)4.4(O/)5.1(HO)-277.8(mice.)-273.6(S)-.3(pi)5.1(ked)-277(o)-.5(l)5.1(i)-.6(-)]TJ 0 -1.1116 TD [(gon)5.1(ucleoti)5(d)-.6(e)-168.8(d)-.6(id)-167.6(no)5.1(t)-173.5(e)-1.8(x)5.1(c)-1.8(eed)-173.4(1)5.1(.5%)-174.5(o)5.1(f)-173.4(t)-.7(h)5.1(e)-174.6(p)5.1(l)-.7(as)5.3(ma)-168.8(vol)5(ume,)-170(and)]TJ T* .011 Tc [(plasma)-336.8(pH)-336.5(was)-335.5(n)4.1(ear)-335.6(p)-1.6(h)4.1(y)-1.6(si)4(ol)4(ogi)4(cal)-335.8(l)-1.7(evels)-335.5(b)-1.6(etween)-335.7(7.3)-335.7(a)3(nd)]TJ 0 -1.1174 TD .013 Tc [(7.5.)-203.5(Sa)5(mp)6.1(les)-206.8(w)5.3(er)6.2(e)-208.1(i).3(n)6.1(c)-.8(ub)6.1(at)6(ed)-207(a)5(t)-207.1(37)]TJ /F8 1 Tf 13.8118 0 TD 0 Tc ()Tj /F3 1 Tf .4089 0 TD .0128 Tc [(C)-208.2(f)6(or)-207.1(30)-161.1(mi)5.8(n)-207.2(f).2(o)5.9(r)-207.1(bin)5.9(d).2(i)5.8(ng,)]TJ -14.2207 -1.1116 TD [(an)5.8(d)-310.9(t)5.7(hr)5.9(ee)-306.3(aliq)5.8(uo)5.8(ts)-305(o)12.7(f)-277.5(3)12.7(0)33.5(0)]TJ /F9 1 Tf 10.4827 0 TD 0 Tc (m)Tj /F3 1 Tf .5414 0 TD [(L)-301.8(w)0(e)18.8(r)0(e)-285.6(p)0(l)20.7(a)0(c)18.5(e)0(d)-291.3(i)0(n)-290.3(t)0(h)20.7(r)0(e)19.7(e)-296(pr)15.1(et)19.5(re)19.7(at)19.5(ed)]TJ -11.0241 -1.1116 TD [(l)15.1(te)19.6(rs)-330.3(an)19.7(d)-340.9(c)0(e)18.5(n)0(t)20.7(r)0(i)20.7(f)0(u)20.9(g)0(e)19.7(d)-340.9(at)-331.8(12)20.8(,0)18.5(00)]TJ /F7 1 Tf 12.9017 0 TD (g)Tj /F3 1 Tf .8409 0 TD [(fo)20.9(r)-340.9(7)-156.6(mi)19.5(n)-340.9(f)0(o)20.9(r)-340.9(co)19.7(ll)20.6(ec)18.5(ti)20.6(on)-330.5(of)]TJ /F9 1 Tf -13.7427 -1.1116 TD (*)Tj /F3 1 Tf .9907 0 TD [(20)20.8(%)-169.2(o)0(f)-157.7(i)0(n)20.7(i)0(t)20.6(i)0(a)19.5(l)-168.3(pl)20.7(as)19.9(ma)-160.1(vo)20.8(lu)20.7(me)]TJ /F9 1 Tf 11.5194 0 TD (*)Tj /F3 1 Tf .9849 0 TD (60)Tj /F9 1 Tf 1.1462 0 TD (m)Tj /F3 1 Tf .5472 0 TD -.0204 Tc [(L)-184(o)-20.4(f)-178.1()-20.4(lt)-20.4(ra)-20.4(te)-20.4(.)-181.6(A)-20.4(li)-20.4(qu)-20.4(ot)-20.4(s)-178(o)-20.4(f)]TJ -15.1883 -1.1174 TD 0 Tc [(ul)14.9(tr)20.7(a)19.8(lt)20.6(ra)19.7(te)19.5(s)-167.9(a)0(n)19.7(d)-168.1(in)20.7(it)20.6(ia)19.6(l)-168.3(p)0(l)20.7(a)0(s)19.9(m)0(a)-160.1(w)0(e)18.8(r)0(e)-153.1(a)0(s)14.1(s)0(a)19.9(y)0(e)19.7(d)-162.4(by)-157.7(EC)18.6(L-)19.7(EL)18.5(IS)21(A)-169(t)0(o)]TJ 0 -1.1116 TD [(qu)15.1(an)19.7(ti)20.6(ta)19.6(te)19.5(%)-376.5(b)0(o)20.8(u)0(n)20.8(d)-375.5(an)19.7(d)-375.5(u)0(n)20.8(b)0(o)20.8(u)0(n)20.8(d)-375.5(AS)20.1(O)-376.3(i)0(n)-365.2(s)0(a)19.9(m)0(p)19.6(l)0(e)19.6(s)0(.)-367.2(F)0(o)21(r)-375.4(to)20.7(ta)19.6(l)]TJ T* [(pl)14.9(as)19.9(ma)-263.8(pr)20.9(ot)20.7(ei)19.6(n)-271.8(b)0(i)20.7(n)0(d)20.8(i)0(n)20.7(g)0(,)-263.7(E)0(C)18.6(L)0(-)19.7(E)0(L)18.5(I)0(S)21(A)-272.7(wa)18.8(s)-271.6(p)0(e)19.7(r)0(f)15.1(o)0(r)20.9(m)0(e)18.4(d)-271.8(wi)19.8(th)-261.5(th)20.7(e)]TJ 0 -1.1174 TD [(sa)14.1(m)15(e)-261.4(me)18.4(th)20.7(od)-249.9(as)-256.6(de)19.7(ta)19.6(il)20.6(ed)-251(fo)20.9(r)-260.2(t)0(i)20.6(s)0(s)15.5(u)0(e)-251(e)0(x)19.7(p)0(o)20.8(s)0(u)21(r)0(e)-251(k)0(i)20.7(n)0(e)19.7(t)0(i)20.6(c)0(s)14.1(.)]TJ 1.0137 -1.1116 TD [(Protein)-250.8(binding)-249.9(proling)-250.8(was)-247.1(performed)-249.5(by)-249.9(size)-248.6(exclu)-8(sion)]TJ -1.0137 -1.1116 TD [(chromatogr)-8.9(aphy)-287.8(\(SEC\))-284(using)-287.7(ION-407988)-294.9(\(alexa-488)-291(uor-)]TJ 0 -1.1174 TD [(escently)-404(labeled)-403.1(version)-400.4(of)-399.6(ION-3553382\))-400.8(to)-399.7(interact)-404.3(with)]TJ 0 -1.1116 TD [(proteins)-298(present)-292.2(in)-290.3(nontreated)-297(WT/WT)-294.8(and)-292.4(HO/HO)-297.1(plasma.)]TJ T* [(The)-397.3(high-performance)-397.9(liquid)-387.1(chromatogr)-8.9(aphy)-391.5(\(HPLC\))-389.6(and)]TJ T* [(detector)-479.1(components)-475.3(included)-472.2(a)-474.6(G1332A)-469.1(1100)-470.9(series)-475.2(de-)]TJ 0 -1.1174 TD [(gasser,)-230.8(G1311A)-221.5(1000)-223.3(series)-227.5(quaternary)-227.7(pump,)-222.2(G1367A)-227.2(1100)]TJ 0 -1.1116 TD [(series)-480.9(autosampler,)-475.3(G1321A)-474.9(1200)-476.7(series)-475.2(uorescence)-478.3(de-)]TJ T* [(tector,)-323.6(G1315A)-319.4(1100)-321.2(series)-325.4(diode)-317.8(array,)-322.2(and)-321.2(a)-319(G1316)-323.2(1100)]TJ 0 -1.1174 TD [(se)14.1(ri)20.7(es)-291.2(co)19.7(lu)20.7(mn)-291.4(co)19.7(mp)19.6(ar)14(tm)25.2(en)13.9(t,)-286.9(al)19.5(l)-306.5(a)0(c)18.5(q)0(u)20.8(i)0(r)20.7(e)0(d)-291.3(f)0(r)20.9(o)0(m)-291.4(A)0(g)14.2(i)0(l)20.6(e)0(n)19.7(t)-300.7(Te)18.5(ch)19.7(-)]TJ 0 -1.1116 TD [(no)15.1(lo)20.7(gi)20.7(es)-469.7(\(W)18.6(il)20.6(mi)19.5(ng)20.8(to)15(n,)-465.3(DE)18.8(\).)-471(Ba)18.6(ck)19.7(gr)15.1(ou)20.8(nd)-468.7(en)19.7(do)20.8(ge)19.7(no)20.8(us)-474.3(u)21(o-)]TJ T* [(re)14(sc)19.9(en)19.7(ce)-384.7(wa)13(s)-392.6(o)0(b)20.8(t)0(a)13.8(i)0(n)20.7(e)0(d)-383.5(b)0(y)-388.1(i)0(n)20.7(c)0(u)19.7(b)0(a)13.9(t)0(i)20.6(n)0(g)-382.3(5)0(0)]TJ /F9 1 Tf 16.5764 0 TD (m)Tj /F3 1 Tf .5472 0 TD .3922 Tc [(Lo)392.2(f)4.1(p)392.2(l)412.9(a)392.2(s)412.1(m)392.2(aw)392.2(i)412(t)392.2(h)]TJ -17.1236 -1.1174 TD 0 Tc (50)Tj /F9 1 Tf 1.1462 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-324.8(o)0(f)-318.9(P)0(B)20(S)0(,)-315.4(i)0(n)-313.3(a)0(d)13.9(d)0(i)20.7(t)0(i)20.6(o)0(n)-313.2(t)0(o)-319.1(a)-324.8(se)14.1(pa)19.7(ra)19.7(te)-314.5(sa)14.1(mp)19.6(le)-314.5(of)-318.9(0.)24.3(5)]TJ /F9 1 Tf 20.1244 0 TD (m)Tj /F3 1 Tf .5472 0 TD .3249 Tc [(mo)324.9(f)]TJ -22.3649 -1.1116 TD 0 Tc [(Al)14.1(ex)19.7(a-)19.7(48)20.8(8-)20.9(la)19.5(be)19.7(le)19.6(d)-444.6(A)0(S)20.1(O)-439.7(in)-428.5(PB)20(S)-438.7(t)0(o)-434.3(d)0(e)19.7(t)0(e)19.6(r)0(m)19.7(i)0(n)20.7(e)-440(th)20.7(e)-440(r)0(e)14(t)0(e)19.6(n)0(t)20.7(i)0(o)20.7(n)]TJ T* [(ti)14.8(m)15(e)-273(of)-261.4(th)20.7(e)-273(l)0(a)19.5(b)0(e)19.7(l)0(.)]TJ 1.0137 -1.1174 TD [(To)-233.8(st)20.9(ud)20.8(y)-248.8(t)0(h)20.7(e)-244.2(pr)20.9(ot)20.7(ei)19.5(n)-243(b)0(i)20.7(n)0(d)20.8(i)0(n)20.7(g)-243(ch)19.7(ar)19.7(ac)18.5(te)19.6(ri)20.7(st)26.7(ic)19.6(s)-248.6(o)0(f)-232.6(t)0(h)20.7(e)-249.9(AS)20.1(O)-243.9(b)0(e)19.7(-)]TJ -1.0137 -1.1116 TD [(tw)19.8(ee)18.5(n)-248.8(s)0(a)19.9(m)0(p)25.4(l)0(e)19.5(s)0(,)-240.5(5)0(0)]TJ /F9 1 Tf 7.4012 0 TD (m)Tj /F3 1 Tf .5414 0 TD [(L)-244.2(o)0(f)-238.3(a)-249.9(1.)18.5(0)]TJ /F9 1 Tf 4.0145 0 TD (m)Tj /F3 1 Tf .5357 0 TD [(M)-249.7(o)0(f)-238.3(I)0(O)20(N)0(-)20(4)0(0)20.8(7)0(9)20.8(8)0(8)-238.3(w)15.3(as)-239.3(sp)21(ik)20.7(ed)]TJ -12.4928 -1.1116 TD [(in)20.7(to)-140.6(50)]TJ /F9 1 Tf 2.828 0 TD (m)Tj /F3 1 Tf .5414 0 TD .0118 Tc [(L)-140.2(o)11.8(f)-128.6(b)11.8(o)32.6(t)11.8(h)-128.8(W)11.8(T)34.9(/)11.8(W)30.3(T)-140.2(a)11.8(n)31.5(d)-139(H)11.8(O)30.9(/)11.8(H)37.4(O)-145.7(p)4.9(l)-.9(asma.)-158.7(I)-.8(n)-162.1(a)3.8(dd)4.9(it)4.8(ion)4.9(,)-164.4(t)4.8(o)]TJ -3.3694 -1.1116 TD .0131 Tc [(stu)6.2(d).5(y)-425.7(t)6.1(he)-426.9(A)5.4(S).6(O)-426.6(b).5(i)6.1(n).5(d)6.2(i).4(ng)-425.7(d)6.2(i).4(s)6.4(p).5(la)5.1(ce)5.1(me)5.1(nt)6.1(,)-428.1(a)-426.9(n)6.2(onl)6.1(ab)6.2(el)6.1(ed)-425.7(A)5.4(S).7(O)]TJ 0 -1.1174 TD .0123 Tc [(\(ION-)5.5(353)5.4(38)5.4(2\))-230.7(was)-230.5(p)5.4(rep)5.4(a)-1.5(r)5.5(e)-1.5(d)-230.7(a)4.3(nd)-230.7(2)5.4(5)]TJ /F9 1 Tf 14.6642 0 TD 0 Tc (m)Tj /F3 1 Tf .5587 0 TD .2442 Tc [(Lo)231.6(f)7(a)0(2)231.6(.)235(0)]TJ /F9 1 Tf 4.0836 0 TD 0 Tc (m)Tj /F3 1 Tf .5587 0 TD .0069 Tc [(M)-237(s)-5.5(ol)-5.8(ut)-5.8(i)-5.8(o)0(n)]TJ -19.8652 -1.1116 TD .0124 Tc [(was)-178.6(a)4.4(dd)5.5(ed)-173(t)5.4(o)-173(25)]TJ /F9 1 Tf 6.543 0 TD 0 Tc (m)Tj /F3 1 Tf .5645 0 TD .186 Tc [(Lo)173.4(fa)5.2(2)173.4(.)176.8(0)]TJ /F9 1 Tf 3.9108 0 TD 0 Tc (m)Tj /F3 1 Tf .5587 0 TD .0126 Tc [(M)-173.7(s).2(ol)5.6(ut)5.6(io)5.7(n)-172.8(o)12.6(f)-145.1(I)12.6(O)32.6(N)12.6(-)32.6(4)12.6(0)27.7(7)12.6(9)33.4(8)12.6(8)33.4(,)-152.1(b)12.6(o)33.4(t)12.6(h)]TJ -11.577 -1.1116 TD 0 Tc [(sp)15.3(ik)20.7(ed)-279.8(in)15(to)-278.8(50)]TJ /F9 1 Tf 5.8288 0 TD (m)Tj /F3 1 Tf .5414 0 TD -.0197 Tc [(L)-315.7(o)-19.7(f)-304.1(p)-19.7(la)-19.7(sm)-19.7(a.)-311.1(A)-19.7(l).1(l)-314.7(s)-19.7(am)-19.7(p)-28.9(l)-38.2(e)-39.2(s)-337.4(w)-38.9(e)-39.2(r)-38(e)-344.5(i)-38.2(n)-38.1(c)-39.2(u)-38.1(b)-38.1(a)-39.2(t)-38.2(e)-39.2(d)-337.6(a)-39.2(t)]TJ -6.3702 -1.1174 TD .0184 Tc (37)Tj /F8 1 Tf 1.0367 0 TD 0 Tc ()Tj /F3 1 Tf .4147 0 TD .0183 Tc [(C)-387(f)0(or)-385.9(30)-167.1(min)-386(b)-.1(efore)-387.1(a)-1.2(nalysis)-385.8(b)-.1(y)-386(H)-.9(PLC-SEC.)-388.3(An)-386(iso-)]TJ -1.4514 -1.1116 TD .0186 Tc [(cratic)-358(method)-356.9(was)-356.7(s).4(etup)-356.9(using)-356.9(a)-358(ow)-352(r)-5.5(ate)-358(o).2(f)-356.8(1).2(.0)-161(mL/min)]TJ T* .0183 Tc [(with)-155.6(PBS)-155.4(a)-1.2(s)-161.2(t)-.2(he)-156.7(mobile)-156.7(phase)-156.7(us)-5.6(ing)-155.6(a)-1.2(n)-155.6(\()0(300)]TJ /F8 1 Tf 17.6765 0 TD 0 Tc ()Tj /F3 1 Tf .7315 0 TD .0196 Tc [(4.6)-165.8(mm,)-150.9(3)]TJ /F9 1 Tf 4.1815 0 TD 0 Tc (m)Tj /F3 1 Tf .5702 0 TD .0196 Tc (m\))Tj -23.1598 -1.1174 TD .0187 Tc [(SEC)-282.9(c)-.8(olumn,)-278.5(with)-281.9(a)-277.3(2).3(5)]TJ /F9 1 Tf 9.924 0 TD 0 Tc (m)Tj /F3 1 Tf .5702 0 TD .0187 Tc [(L)-283.1(i).2(njection)-276.1(volume)-283.1(a)-.8(nd)-281.9(a)-277.3(20-min)]TJ -10.4942 -1.1116 TD 0 Tc [(r)-18.3(u)-18.4(n)-18.4(t)-18.5(i)-18.5(m)-19.6(e)-19.5(.)-827.1(F)-18.2(l)-18.5(u)-18.4(o)-18.4(r)-18.3(e)-19.5(s)-18.2(c)-19.5(e)-19.5(n)-18.4(c)-13.8(e)-825.9(e)-19.5(x)-18.4(c)-19.5(i)-18.5(t)-18.5(a)-19.5(t)-18.5(i)-18.5(o)-18.4(n)-18.4(/)-18.5(em)18.5(is)20.9(si)20.9(on)-785.5(wa)18.8(ve)13.9(le)19.6(ng)20.8(th)20.7(s)]TJ T* -.0204 Tc [(w)-20.4(e)-1.6(r)-20.4(e)-398.1(s)-20.4(e)-.5(t)-401.8(t)-20.4(o)-397.1(4)-20.4(95)-20.4(/5)-20.4(19)-177(n)-20.4(m)-.8(,)-404(w)-20.4(it)-20.4(h)-397.1(e)-20.4(nd)-20.4(og)-20.4(en)-20.4(ou)-20.4(s)-396.8(b)-20.4(ac)-20.4(kg)-20.4(ro)-20.4(un)-20.4(d)-397()-20.4(uo)-20.4(-)]TJ 0 -1.1174 TD 0 Tc [(re)14(sc)19.9(en)19.7(ce)-292.5(of)-295.9(pl)20.7(as)19.9(ma)-292.6(sa)19.9(mp)19.6(le)19.6(s)-306.2(s)0(u)21(b)0(t)20.7(r)0(a)14(c)0(t)19.5(e)0(d)-291.3(o)-12.6(u)-6.9(t)-323.8(o)-12.6(f)-323.6(t)-7(h)-12.6(e)-324.8(c)-8(h)-12.6(r)-6.8(o)-12.6(m)-8.1(a)-13.8(t)-7(o)-12.6(-)]TJ 0 -1.1116 TD .0124 Tc [(gram)-249.1(t)-.3(o)-247.9(e)4.4(xp)5.5(lo)5.5(re)-249(AS)5.7(O-)5.6(pro)5.5(tein)-247.9(b)5.5(i)-.3(nd)5.5(in)5.5(g)-247.9(i)-.3(nt)5.4(er)5.6(actio)5.5(ns)5.7(.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 310.8472 725.7825 Tm 0 Tc [(Total)-331.1(protein,)-333.7(albumin,)-339.3(immunoglobulins,)]TJ 0 -1.2203 TD [(and)-329.4(HRG)-337.5(quantitation)]TJ /F3 1 Tf 9.843 0 0 9.843 320.8251 698.3998 Tm [(Total)-307.6(protein)-314.4(content)-309.8(from)-310.8(WT/WT)-312.1(and)-309.7(HO/HO)-314.4(samples)]TJ -1.0137 -1.1174 TD (\()Tj /F7 1 Tf .3341 0 TD (n)Tj /F8 1 Tf .6624 0 TD (=)Tj /F3 1 Tf .72 0 TD [(7)-283.3(each\))-285.4(was)-281.6(assaye)-9.7(d)-277.6(using)-287.7(a)-278.7(Bradford)-287.4(Total)-284.6(Protein)-285.4(As-)]TJ -1.7164 -1.1116 TD [(say)-217.4(with)-212.9(samples)-218.4(diluted)-222.4(to)-215.4(t)-215.3(a)-215.4(curve)-215.1(range)-220.9(of)-215.3(1.510)]TJ /F9 1 Tf 21.5586 0 TD (m)Tj /F3 1 Tf .5529 0 TD (g/mL)Tj -22.1115 -1.1116 TD [(using)-391.3(an)-395(absorbance)-395.6(wavelength)-395.8(of)-393.8(595)-170.3(nm.)-392.8(Albumin,)-393.7(Im-)]TJ 0 -1.1174 TD [(munoglobulin)-504.4(G,)-500.7(M,)-506.5(and)-505.6(A,)-500.7(and)-505.6(HRG)-507.2(were)-502.9(assayed)-511.9(by)]TJ 0 -1.1116 TD [(murine-specic)-286.1(ELISA)-279.3(kits.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 310.8472 619.6534 Tm [(Plasma)-333.7(proteome)-332.9(ngerprinting)-335.7(by)-332.7(isoelectric)]TJ 0 -1.2203 TD [(focusing)-333.4(and)-329.4(SDS-PAGE)]TJ /F3 1 Tf 9.843 0 0 9.843 320.8251 592.2708 Tm [(The)-524(same)-531.9(volume)-527.5(\(60)]TJ /F9 1 Tf 9.7109 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L\))-527.5(from)-529.7(WT/WT)-525.2(and)-528.6(HO/HO)]TJ -11.2775 -1.1116 TD [(murine)-348.9(plasma)-355.7(samples)-350.8(was)-356.5(mixed)-347.9(with)-351.1(180)]TJ /F9 1 Tf 18.529 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-347.9(o)0(f)-347.8(binding)]TJ -19.0819 -1.1116 TD [(buffer)-324.5(followed)-327.9(by)-324.7(albumin/IgG)-326.8(removal.)-325.8(A)-324.5(200)]TJ /F9 1 Tf 20.0092 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-324.8(diluted)]TJ -20.5622 -1.1174 TD [(mixture)-350.2(containing)-347.8(50)]TJ /F9 1 Tf 9.227 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-347.9(o)0(f)-347.7(depleted)-346.6(plasma)-349.9(was)-350.7(added)-353.4(to)]TJ -9.78 -1.1116 TD (150)Tj /F9 1 Tf 1.6646 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-445.8(o)0(f)-445.7(two-dimensional)-453.2(rehydration)-446.6(media)-452.7(per)-442.2(sampl)-7.8(e)]TJ -2.2175 -1.1116 TD [(and)-298.2(loaded)-302.8(onto)-298.3(a)-296(11-cm)-301.6(ReadyStrip)-302.4(IPG)-297.7(for)-302.7(separation)-302.5(be-)]TJ 0 -1.1174 TD [(tween)-383.2(pH)-389(3)-381.2(and)-384.6(10)-388.1(for)-383.4(16)-169.2(h.)-378.9(Isoele)-8.8(ctric)-382.4(focusing)-390(was)-385.3(per-)]TJ 0 -1.1116 TD [(formed)-193.2(by)-198(a)-192.3(rapid)-196.8(ramp)-196.8(at)-193.6(200)-170.3(V)-192(for)-193.3(the)-200.4(rst)-194.2(step,)-193.2(followed)-201.1(by)]TJ T* [(a)-215.4(gradual)-223.3(ramp)-219.9(to)-215.4(8,000)-169.1(V)-215.1(t)0(o)-221.2(1)-162.4(h)-220(and)-217.6(maintained,)-221.1(followed)-224.2(by)]TJ 0 -1.1174 TD [(a)-376.6(hold)-373.2(at)-377.9(1,500)-163.3(V)-376.3(using)-374.1(a)-376.6(Protean)-378.6(i12)-377.8(IEF)-372.9(Cell)-375.5(\(Bio-Rad\).)]TJ 0 -1.1116 TD [(Following)-333.6(isoelectric)-339.6(focusing,)-335.9(the)-332.9(second)-337(dimension)-334.9(SDS-)]TJ T* [(polyacrylamide)-488.2(gel)-476.9(electrophoresis)-487.7(\(PAGE\))-487.4(was)-483.2(prepared)]TJ 0 -1.1174 TD [(using)-702.4(a)-704.9(precast)-708(8%16%)-705.7(Tris-HCl)-708.8(gel)-701.5(of)-704.9(dimensions)]TJ 0 -1.1116 TD (13.3)Tj /F8 1 Tf 1.918 0 TD ()Tj /F3 1 Tf .7142 0 TD [(8.7)-166.9(cm)-327.1(\(width)]TJ /F8 1 Tf 5.7539 0 TD ()Tj /F3 1 Tf .72 0 TD [(length\))-320.1(and)-327(run)-320.1(at)-326(150)-164.6(V)-324.5(constant)-328(for)]TJ -9.1061 -1.1116 TD [(110)-164.6(min)-402.1(using)-402.9(a)-405.4(Bio-Rad)-408.5(model)-399.7(PWSPL-4)-408.1(electrophoresis)]TJ T* [(power)-341.6(supply.)-338.3(The)-339.7(gel)-338.7(was)-345(then)-339.8(stained)-338.4(by)-342(coomassie)-342.7(blue)]TJ 0 -1.1174 TD [(staining)-298.1(using)-299.2(SimplyBlue)-296.9(SafeStain)-301.3(with)-299.3(imaging)-298.3(acquired)]TJ 0 -1.1116 TD [(by)-405.4(an)-406.5(ImageQuant)-408.4(LAS)-408.4(4000)-407.6(system)-406.2(\(GE)-408.5(Healthcare)-415.4(Bio)]TJ T* [(Sciences,)-327.7(Marlborough,)-328.7(MA\).)-325.3(Relevant)-330.4(bands)-323.3(were)-330.1(excised)]TJ 0 -1.1174 TD [(and)-298.2(characterized)-304.9(by)-295.9(LC-MS)-296.4(based)-301.4(on)-295.9(coverage,)-299.1(number)-302.7(of)]TJ 0 -1.1116 TD [(unique)-278.6(peptides,)-285.3(molecular)-285.6(weight,)-283(and)-280.9(isoelectric)-282(point.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 310.8472 349.1716 Tm [(Statistical)-336.1(analysis)]TJ /F3 1 Tf 9.843 0 0 9.843 320.8251 332.7306 Tm [(Statistical)-511.4(signicance)-512(between)-513.3(samples)-506.3(was)-512(evaluated)]TJ -1.0137 -1.1116 TD [(using)-506.5(analysis)-506.3(of)-509(variance)-508.9(and)-511.3(Students)]TJ /F7 1 Tf 17.9012 0 TD (t)Tj /F3 1 Tf .2822 0 TD [(-test.)-511.2(Mean)-508.7(of)]TJ -18.1834 -1.1116 TD [(replicate)-239.5(measurements)-238.9(\()]TJ /F7 1 Tf 10.0104 0 TD (n)Tj /F8 1 Tf .6681 0 TD (=)Tj /F3 1 Tf .7142 0 TD [(4\))-238.3(per)-234.8(group)-235.9(with)-230.2(corresponding)]TJ -11.3927 -1.1174 TD [(standard)-183.8(deviation)-191.2(values)-181.7(was)-189.5(used)-183.9(to)-186.6(plot)-183.2(the)-183.1(gures.)-189.4(Sample)]TJ 0 -1.1116 TD [(group)-281.9(differences)-293.1(less)-281.8(than)]TJ /F7 1 Tf 11.1565 0 TD (P)Tj /F8 1 Tf .7776 0 TD (<)Tj /F3 1 Tf .72 0 TD [(0.05)-283.2(were)-289.8(determined)-286.7(as)-285.4(sta-)]TJ -12.6541 -1.1116 TD [(tistically)-284.6(signicant.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 310.8472 254.0409 Tm (Results)Tj /F10 1 Tf 0 -1.8336 TD [(Plasma)-333.7(and)-335.7(tissue)-330.8(PKs)]TJ /F3 1 Tf 9.843 0 0 9.843 320.8251 221.159 Tm [(Pl)20.9(as)14.1(ma)-453.8(tr)15(ou)15.1(gh)-451.5(AS)14.4(O)-462.7(c)0(o)19.7(n)0(c)13.9(e)0(n)13.9(t)0(r)15(a)0(t)13.8(i)0(o)15(n)0(s)-451.3(w)0(e)13(r)0(e)-452.6(d)0(e)13.9(t)0(e)19.5(r)0(m)13.9(i)0(n)15(e)0(d)-452.6(b)0(y)]TJ -1.0137 -1.1116 TD [(EC)18.6(L-)13.9(EL)12.7(IS)15.3(A,)-172.4(wh)14.2(il)14.8(e)-180.8(l)0(i)14.8(v)0(e)13.9(r)-179.6(an)13.9(d)-185.4(k)0(i)20.7(d)0(n)15.1(e)0(y)-176.2(A)0(S)14.4(O)-180.5(co)13.9(nc)13.9(en)13.9(tr)15(at)19.5(io)14.9(ns)-174.8(we)13.1(re)]TJ T* [(de)13.9(te)19.6(rm)13.9(in)15(ed)-314.4(by)-313.2(LC)12.9(-M)20(S)-323.5(a)0(t)-314.5(7)0(2)-152(h)-317.9(fo)15.1(ll)14.8(ow)14.2(in)14.9(g)-317.9(s)0(i)15.1(n)0(g)15.1(l)0(e)-314.5(s)0(.)18.7(c)0(.)-316.7(d)0(o)15.1(s)0(e)-314.2(a)0(d)19.7(-)]TJ 0 -1.1174 TD [(mi)13.7(ni)20.7(st)15.1(ra)14(ti)14.8(on)-272.9(of)-272.9(IO)20(N-)14.2(35)15.1(33)15.1(82)15.1(.)-279.9(L)0(o)13.9(g)-277.6(tr)15(an)13.9(sf)15.3(or)15.1(me)18.4(d)-277.6(p)0(l)14.9(a)0(s)14.1(m)0(a)-275.3(C)]TJ 7.3823 0 0 6.5614 530.9857 186.633 Tm [(tr)22.7(ou)17(gh)]TJ 9.843 0 0 9.843 310.8472 177.3354 Tm [(va)13.9(lu)15(es)-314.2(ar)14(e)-324.8(l)0(i)14.8(s)0(t)15.1(e)0(d)-314.4(i)0(n)-313.4(F)0(i)15.1(g)0(.)-315.6(1)0(A)14.2(,)-320.2(wi)14.1(th)-319.1(er)14(ro)20.9(r)-323.6(b)0(a)13.9(r)0(s)-318.8(r)0(e)14(p)0(r)15.1(e)0(s)14.1(e)0(n)19.7(t)0(i)14.8(n)0(g)-319(t)0(h)20.7(e)]TJ 0 -1.1116 TD [(st)15.1(an)13.9(da)19.7(rd)-146.2(de)13.9(vi)14.9(at)19.5(io)15(n)-150.8(f)0(r)15.1(o)0(m)-141.7(\()]TJ /F7 1 Tf 9.7166 0 TD (n)Tj /F8 1 Tf .6566 0 TD (=)Tj /F3 1 Tf .7142 0 TD [(4\))-140.4(an)13.9(im)13.7(al)13.8(s.)-142.6(Pl)15.1(as)14.1(ma)-142.8(co)13.9(nc)19.7(en)13.9(tr)15(at)13.8(io)15(ns)]TJ -11.0874 -1.1174 TD [(of)-249.8(AS)14.4(O)-261.2(s)0(p)15.3(a)0(n)13.9(n)0(e)13.9(d)-260.3(fr)15.1(om)-251.1(a)-261.4(r)0(a)13.9(n)0(g)15.1(e)-261.4(of)-249.8(1.)12.7(8)15.1(22)15.1(.2)-148.5(ng)15.1(/m)13.7(L)-261.5(a)0(c)18.5(r)0(o)15.1(s)0(s)-255.2(d)0(o)15.1(s)0(e)]TJ 0 -1.1116 TD [(gr)15.1(ou)15.1(ps)15.3(.)-158.9(A)-157.5(do)15.1(se)14.1(-d)15.1(ep)13.9(en)13.9(de)13.9(nt)-152.1(up)15.1(ta)19.6(ke)-158.9(an)19.7(d)-162.4(A)0(S)14.4(O)-163.2(ex)19.7(po)15.1(su)15.3(re)-153.1(in)-152.1(pl)14.9(as)14.1(ma)]TJ T* [(we)13(re)-176.1(ob)15.1(se)14.1(rv)15.1(ed)-176.2(ac)12.8(ro)15.1(ss)-180.4(th)15(e)-186.6(5)0(,)-177.3(1)0(5)15.1(,)-182(30)15.1(,)-187.7(a)0(n)13.9(d)-185.4(60)-152(mg)19.6(/k)15(g)-185.4(d)0(o)15.1(s)0(e)-181.7(c)0(o)13.9(h)0(o)20.8(r)0(t)15(s)0(.)]TJ 0 -1.1174 TD [(Sl)15.1(op)15.1(es)-170.2(fr)15.1(om)-170.5(th)15(e)-180.8(l)0(i)14.8(n)0(e)19.7(a)0(r)14(i)0(z)13.8(e)0(d)-170.4(l)0(o)15(g)0(-)15.1(t)0(r)15(a)0(n)13.9(s)0(f)15.3(o)0(r)15.1(m)0(e)12.7(d)-179.6(C)]TJ 7.3823 0 0 6.5614 483.7038 120.8692 Tm [(tr)22.7(ou)17(gh)]TJ 9.843 0 0 9.843 504.3967 122.5133 Tm [(va)13.9(lu)15(es)-170.2(we)13.1(re)]TJ -19.6636 -1.1116 TD [(1.)18.5(02)-175(an)19.7(d)-179.6(0)0(.)12.7(6)0(9)-169.2(f)0(o)15.1(r)-179.6(WT)17.4(/W)12.7(T)-180.8(a)0(n)13.9(d)-179.6(HO)19.1(/H)14.1(O)-180.5(t)0(y)15(p)0(e)13.9(,)-176.2(re)14(sp)15.3(ec)12.8(ti)14.8(ve)13.9(ly)15(,)-176.2(w)0(i)14.1(t)0(h)]TJ T* [(co)13.9(ef)19.7(c)14.1(ie)13.8(nt)-676.2(of)-670.3(de)13.9(te)13.8(rm)13.9(in)20.7(at)13.8(io)15(n)-680.7(\()0(R)]TJ 7.3823 0 0 6.5614 443.792 104.9953 Tm (2)Tj 9.843 0 0 9.843 447.4203 100.6299 Tm .6807 Tc [(\)v)680.7(a)694.6(l)680.7(u)695.7(e)680.7(s)9.4(\()]TJ /F8 1 Tf 4.5444 0 TD 0 Tc (>)Tj /F3 1 Tf .5414 0 TD [(0.)12.7(99)15.1(\).)-672.6(Do)20(se)14.1(-)]TJ -18.9609 -1.1174 TD [(pr)15.1(op)15.1(or)15.1(ti)20.6(on)15.1(al)-182(pl)14.9(as)14.1(ma)-177.4(C)]TJ 7.3823 0 0 6.5614 396.5101 88.0441 Tm [(tr)15(ou)17(g)16.2(h)0(s)]TJ 9.843 0 0 9.843 420.0944 89.6314 Tm [(we)13(re)-176.1(ob)15.1(se)14.1(rv)15.1(ed)-176.2(fo)15.1(r)-191.1(W)0(T)17.4(/)0(W)12.7(T)0(,)-178.5(w)0(h)14.2(i)0(l)14.8(e)]TJ -11.0989 -1.1116 TD [(sl)15.1(ig)15(ht)14.9(ly)-232.7(le)13.8(ss)-232.2(th)15(an)-233.8(do)15.1(se)-239.3(pr)20.9(op)15.1(or)15.1(ti)14.8(on)15.1(al)-233.9(in)-238.5(HO)19.1(/H)14.1(O)-243.9(m)0(i)13.7(c)0(e)12.8(.)]TJ 1.0137 -1.1116 TD [(Exposure)-195.3(of)-198(ASO)-195(in)-198.2(tissue,)-201.1(including)-195.8(both)-200.4(liver)-197(and)-194.5(kidney)]TJ -1.0137 -1.1116 TD [(evaluations,)-324.5(is)-318.9(described)-318.6(in)-319.1(Fig.)-323.5(1B)-320(and)-315.5(C.)-322.3(Dose-dependent)]TJ /F4 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(PK/PD)-340.1(OF)-331.2(ION-353382,)-332.4(A)-337.9(MODEL)-333.5(ASO:)-334.7(IN)-335.1(WT)-335.9(AND)-330.9(DKO)-337.5(MICE)-23255.2(227)]TJ ET endstream endobj 105 0 obj <>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 62.022 336.1889 Tm 0 0 0 rg 0 Tc 0 Tw [(uptake)-567.8(was)-569.6(observed)-563.8(for)-567.7(groups)-565.1(across)-567.2(the)-569(dose)-564.1(range.)]TJ 0 -1.1116 TD [(Concentrations)-221.7(of)-215.3(ASO)-212.2(in)-215.4(the)-211.9(liver)-220(spanned)-217.2(a)-215.4(range)-215.1(from)-212.9(2)-214.2(t)0(o)]TJ 0 -1.1174 TD (16)Tj /F9 1 Tf 1.1692 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/g,)-191.2(with)-189.8(higher)-192.2(exposure)-195.2(levels)-193.3(in)-192.4(kidney)-192.2(ranging)-187.5(from)-195.6(7)]TJ -1.7222 -1.1116 TD [(to)-330.6(33)]TJ /F9 1 Tf 2.2751 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/g)-326(across)-331.1(dose)-333.7(groups.)-326.6(Log)-327(transformat)-9.9(ions)-326.9(of)-324.7(liver)]TJ -2.828 -1.1116 TD [(uptake)-239.5(revea)-9(led)-235(slightly)-245.3(less)-241.5(than,)-239.5(but)-239.6(near)-242.8(dose)-241.5(proportional)]TJ 0 -1.1174 TD [(liver)-387(uptake,)-381.1(with)-385.7(slopes)-387.6(of)-382.3(0.84)-381.1(and)-384.6(0.80,)-384.6(\(R)]TJ 7.3823 0 0 6.5614 250.4692 285.7889 Tm (2)Tj /F8 1 Tf 9.843 0 0 9.843 255.8551 281.3669 Tm (>)Tj /F3 1 Tf .7142 0 TD [(0.99\),)-385.6(for)]TJ -20.4066 -1.1116 TD [(WT/WT)-369.7(and)-367.3(HO/HO)-372(mice,)-368.6(respectivel)-11.2(y.)-367.4(The)-368.5(same)-364.9(assess-)]TJ T* [(ment)-329.5(in)-324.9(kidney)-330.4(revealed)-330.3(less)-327.9(than)-328.2(dose)-327.9(proportional)-331.5(kidney)]TJ T* [(exposure)-310.4(with)-305(slopes)-312.8(of)-307.4(0.50)-306.2(and)-304(0.55,)-309.7(\(R)]TJ 7.3823 0 0 6.5614 230.0598 252.907 Tm (2)Tj /F8 1 Tf 9.843 0 0 9.843 235.4456 248.5417 Tm (>)Tj /F3 1 Tf .7142 0 TD [(0.98\),)-310.7(for)-302.7(WT/)]TJ -18.3331 -1.1174 TD [(WT)-380(and)-378.8(HO/HO,)-381.2(respectively.)-384.3(Kidney)-377.4(to)-376.7(liver)-381.3(ratios)-376.4(were)]TJ 0 -1.1116 TD [(between)-467.2(2)-467.6(and)-465.2(5)-461.9(across)-463.5(dose)-466.1(groups,)-464.8(and)-465.2(ratios)-468.6(between)]TJ T* [(groups)-305.9(were)-312.8(superimposable)-313.7(and)-309.7(near)-306.2(identical)-313.4(with)-305(no)-307.5(sta-)]TJ 0 -1.1174 TD [(tistically)-284.6(signicant)-284.1(differences.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 62.022 182.7779 Tm [(PD)-335.8(effect)-335.1(following)-331.1(ASO)-340.3(treatment)]TJ /F3 1 Tf 9.843 0 0 9.843 72 166.3369 Tm [(PD)-550.1(effect)-557.3(was)-552.3(evaluated)-556.2(by)-555.1(measuring)-554.8(SRB1)-553.5(mRNA)]TJ -1.0137 -1.1174 TD [(knockdown)-455.5(in)-451.6(both)-448(WT/WT-)-457.1(and)-453.7(HO/HO-derived)-458.1(organs)]TJ 0 -1.1116 TD [(and)-263.7(comparing)-267(treated)-264.8(animal)-269.6(expression)-266.5(to)-261.5(the)-263.8(saline)-262.4(dosed)]TJ T* [(control.)-438.8(Following)-437.2(treatment,)-438.9(the)-436.6(PD)-434.9(effect)-436.4(of)-434.1(ASOs)-437.8(was)]TJ T* [(signicantly)-418.9(different)-421.3(across)-417.4(various)-412(tissues,)-420.9(including)-414.6(the)]TJ 0 -1.1174 TD [(liver,)-327.1(heart,)-328.1(kidney,)-322.4(quadriceps,)-328.9(jejunum,)-324.8(and)-327(lung)-321.3(\(Fig.)-324.6(2\).)]TJ 0 -1.1116 TD [(Control)-469.8(saline)-469.8(mRNA)-469.2(expression)-473.8(levels)-469.8(are)-466.4(listed)-468.7(with)-472.1(a)]TJ T* [(dashed)-383.1(bar)-378.8(representative)-384.2(of)-376.5(0%)-377.6(target)-377.8(knockdown)-380.6(\(no)-377.6(ef-)]TJ 0 -1.1174 TD [(fect\).)-316.6(Clear)-320(differences)-321.9(between)-317.5(tissues)-319.6(were)-318.6(observed)-316.2(with)]TJ 0 -1.1116 TD [(the)-574.8(most)-575.8(evident)-580.5(effect)-580.4(in)-572.5(liver,)-580.5(in)-572.5(addition)-574.8(to)-578.3(notable)]TJ T* [(knockdown)-334.5(in)-330.6(the)-327.1(kidney)-330.4(and)-332.8(heart,)-333.9(with)-328.1(minimal)-334.3(effect)-332.7(in)]TJ 25.504 28.3896 TD [(the)-321.4(jejunum)-315.6(and)-315.5(lung.)-313.2(A)-313(dose-depend)-9.6(ent)-315.6(PD)-313.9(effect)-315.4(was)-316.2(ob-)]TJ 0 -1.1116 TD [(served)-365.8(in)-365.2(the)-361.7(liver)-364(ranging)-366.1(from)-362.7(16%)-361.5(to)-365.2(93%)-361.5(inhibition)-363(of)]TJ 0 -1.1174 TD [(target)-446.9(expres)-8.7(sion.)-439.8(By)-446.7(expression)-450.8(levels)-446.7(alone,)-443.4(statistically)]TJ 0 -1.1116 TD [(signicant)-364.7(differences)-362.2(\()]TJ /F7 1 Tf 9.6878 0 TD (P)Tj /F8 1 Tf .7833 0 TD (<)Tj /F3 1 Tf .7142 0 TD [(0.01)-358.1(to)]TJ /F7 1 Tf 3.2485 0 TD (P)Tj /F8 1 Tf .7833 0 TD (<)Tj /F3 1 Tf .7142 0 TD [(0.05\))-359.1(were)-358.9(observed)]TJ -15.9313 -1.1116 TD [(betwe)-8.8(en)-222.2(WT/WT)-225.7(and)-223.3(HO/HO)-222.2(mice,)-224.6(with)-224.4(1.3-,)-223.2(1.7-,)-223.2(2.0-,)-223.2(and)]TJ 0 -1.1174 TD [(1.9-fold)-287.7(enhanced)-289.9(efcacies)-291.9(for)-285.5(the)-286.8(HO/HO)-285.6(subtype)-291(at)-285.7(dose)]TJ 0 -1.1116 TD [(levels)-285.5(of)-278.6(5,)-281(15,)-282.1(30,)-282.1(and)-280.9(60)-163.5(mg/kg.)]TJ 1.0137 -1.1116 TD [(In)-376.5(addition,)-382.4(at)-377.9(higher)-382.2(ranging)-377.6(dose)-379.8(groups,)-378.4(ION-353382)]TJ -1.0137 -1.1116 TD [(was)-316.2(more)-317.8(efcacious)-320.7(in)-313.3(4/4)-314.5(other)-312(minor)-312.1(tissues)-319.6(for)-314.3(HO/HO)]TJ 0 -1.1174 TD [(mice.)-195.8(A)-186.3(more)-191.1(subtle)-192.1(pattern)-188.8(of)-186.5(improved)-195.6(PD)-187.2(for)-187.5(HO/HO)-193.4(mice)]TJ 0 -1.1116 TD [(was)-264.3(evident)-258(across)-261.9(all)-258.2(other)-254.4(tissues)-262(and)-257.9(at)-256.9(the)-258(15)-169.2(mg/kg)-260.3(dose)]TJ T* [(in)-324.9(the)-321.4(heart,)-316.6(and)-321.2(60)-169.2(mg/kg)-317.9(dose)-322.2(in)-319.1(kidney,)-322.4(HO/HO)-325.9(had)-321.2(sta-)]TJ 0 -1.1174 TD [(tistically)-394.1(signicant)-393.5(improved)-391.4(PD)-388.8(differences)-396.8(compared)-387.9(to)]TJ 0 -1.1116 TD [(WT/WT)-283.3(\()]TJ /F7 1 Tf 4.0203 0 TD (P)Tj /F8 1 Tf .7833 0 TD (<)Tj /F3 1 Tf .72 0 TD [(0.05\).)-276.2(Kidney,)-282.9(heart,)-282.1(quadriceps,)-282.8(jejunum,)-284.5(and)]TJ -5.5236 -1.1116 TD [(lung)-292.5(knockdown)-288.4(across)-290.7(dose)-287.6(groups)-294.4(was)-287.4(from)-287.8(17%)-292.4(to)-284.6(39%,)]TJ 0 -1.1174 TD [(5%)-383.4(to)-376.7(25%,)-382.2(0%)-383.4(to)-376.7(22%,)-382.2(0%)-377.6(to)-382.5(25%,)-376.4(and)-384.6(0%)-377.6(to)-382.5(20%,)-376.4(re-)]TJ 0 -1.1116 TD [(spectively.)-208.2(Using)-207.9(an)-204.9(inhibitory)-207.3(effect)-206(liver)-202.7(exposure)-206.7(response)]TJ T* [(PD)-682.6(model)-681.9(revealed)-687.4(a)-676.1(near)-686.3(2.0-fold)-679.3(enhanced)-681.6(efcacy)]TJ T* (\()Tj /F7 1 Tf .3341 0 TD (P)Tj /F8 1 Tf .7833 0 TD (<)Tj /F3 1 Tf .72 0 TD [(0.05\))-243.9(for)-245.1(HO/HO)-251(mice)-250(with)-247.4(simulated)-249.8(liver)-243(EC)]TJ 7.3823 0 0 6.5614 517.1526 137.3102 Tm (50)Tj 9.843 0 0 9.843 526.9605 138.9543 Tm (values)Tj -21.7314 -1.1174 TD [(equivalent)-504.5(to)-497.7(5.49)]TJ /F8 1 Tf 7.885 0 TD ()Tj /F3 1 Tf .72 0 TD [(0.95)-496.3(and)-499.8(2.85)]TJ /F8 1 Tf 6.111 0 TD ()Tj /F3 1 Tf .72 0 TD [(0.33)-496.3(\(Fig.)-497.3(3\).)-500.9(Model)]TJ -15.436 -1.1116 TD [(parameters)-287.5(are)-282.1(listed)-284.4(in)-278.8(Table)-285.6(2.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 313.0582 95.074 Tm (Immunohistochemistry)Tj /F3 1 Tf 9.843 0 0 9.843 323.0361 78.6331 Tm .0218 Tc [(IHC)-268.3(w)-3.2(as)-272.8(p)3.4(e)2.3(rf)3.5(or)3.5(med)-273(t)3.3(o)-273(e)2.3(val)3.3(u)-2.3(at)3.3(e)-274.2(A)2.6(S)3.6(O)-273.9(d)3.4(i)-2.5(s)3.6(t)-2.5(r)3.5(i)3.3(bu)3.4(t)3.3(i)-2.5(o)3.4(n)-273(i)3.3(n)-273(t)3.3(h)3.4(e)]TJ -1.0137 -1.1116 TD .019 Tc [(m)-6.4(ous)-4.9(e)-507.4(l).5(i)-5.3(v).6(er)-512(of)-506.2(b)-5.1(o).6(th)-512(WT/WT)-513.2(a)-.5(nd)-506.2(H)-6(O)-.2(/H)-6(O)-507.1(m)-.6(ic)-6.3(e.)-508.6(Cl)-5.3(ear)]TJ T* .0186 Tc [(m)-6.8(o).2(rp)-5.5(hol)-5.7(ogy)-287.8(rel)-5.7(a)-.9(te)-6.7(d)-282(t).1(o)-287.8(t).1(he)-288.9(liv)-5.5(er)-282(i)-5.7(s)-281.8(ob)-5.5(ser)-5.5(v).2(ed)-5.5(,)-284.3(i).1(nc)-6.7(lud)-5.5(i).1(ng)-287.8(the)]TJ ET q 1 i 191.622 732.019 m 552.189 732.019 l 552.189 366.69 l 191.622 366.69 l W n q 360.926 0 0 365.329 191.622 366.69 cm /Im1 Do Q Q BT /F5 1 Tf 9.845 0 0 9.845 62.022 645.5621 Tm 0 Tc [(FIG.)-647.7(1.)]TJ /F3 1 Tf 4.4283 0 TD [(Pla)13.1(sma)]TJ /F5 1 Tf 3.4321 0 TD (\(A\))Tj /F3 1 Tf 1.3705 0 TD [(,)-562(liv)19.7(er)]TJ /F5 1 Tf -9.2309 -1.0077 TD (\(B\))Tj /F3 1 Tf 1.3187 0 TD [(,)-458.3(and)-453.3(kid)14.1(ney)]TJ /F5 1 Tf 5.7758 0 TD (\(C\))Tj /F3 1 Tf 1.837 0 TD [(PKs)-446.9(of)]TJ -8.9315 -1.0135 TD [(ION)12.7(-35)14.3(338)14.3(2)-398.3(i)0(n)-399.5(W)0(T)12(/WT)-398.1(an)14.1(d)]TJ T* [(HO/)12.5(HO)-320.3(mi)14(ce.)-318.7(Mi)14.3(ce)-321(wer)12.3(e)-324.6(a)0(d)14.1(-)]TJ 0 -1.0077 TD [(min)13(ist)14.1(ere)12(d)-329.2(a)-336.2(sin)14.3(gle)-321(dos)14.5(e)-330.4(sub)14.5(-)]TJ 0 -1.0135 TD [(cut)13(ane)12(ous)-417.4(in)15.1(jec)11.8(tio)14(n)-427.1(a)0(t)-423.7(5)0(,)-419(15,)]TJ T* [(30)21.1(,)-153.1(a)0(n)19.9(d)-145(60)-151.7(m)15.1(g)0(/)15.1(k)0(g)21.1(.)-147.3(Cu)20.1(rv)21(es)-141.2(we)19.1(re)]TJ T* -.0196 Tc [(l)-19.6(o)1.3(g)-204.9(t)-19.6(ra)-19.6(ns)-19.6(fo)-19.6(rm)-19.6(ed)-204.9(a)-19.6(n).3(d)-204.9(l)-19.6(in)-19.6(ea)-19.6(ri)-19.6(ze)-19.6(d)]TJ 0 -1.0077 TD 0 Tc [(to)-284.3(de)14.1(te)19.7(rm)19.9(in)20.9(e)-295.9(d)0(o)21.1(s)0(e)-290.9(p)0(r)21.1(o)0(p)21.1(o)0(r)21.1(t)0(i)20.7(o)0(n)21.1(-)]TJ 0 -1.0135 TD [(al)19.7(it)20.7(y.)-177.1(A)-180.3(t)0(o)20.9(t)0(a)19.7(l)-185.4(of)-174.7(fo)21(ur)-174.7(mi)19.7(ce)-171.3(we)19.1(re)]TJ T* [(us)21.2(ed)-412(pe)14.1(r)-421.4(g)0(r)21.1(o)0(u)21.1(p)-421.4(pe)19.9(r)-421.4(d)0(o)21.1(s)0(e)14.3(,)-418(in)20.9(-)]TJ T* [(cl)19.7(ud)21.1(in)20.9(g)-565.3(a)-560.7(sa)20(li)20.7(ne)-556(co)19.9(nt)20.9(ro)21(l)-559.7(f)0(o)21(r)]TJ 0 -1.0077 TD [(ea)18.7(ch)-435(ty)20.9(pe)19.9(.)-441(A)0(l)20.1(l)-438.8(sa)14.3(mp)19.9(le)19.7(s)-438.5(w)0(e)19.1(r)0(e)]TJ 0 -1.0135 TD [(co)19.9(ll)20.7(ec)18.7(te)13.9(d)-381.1(7)0(2)-151.7(h)-381.1(fo)15.3(ll)20.7(ow)20.2(in)20.9(g)-386.8(d)0(o)21.1(s)0(-)]TJ T* [(in)20.9(g.)-228.9(Pl)21.1(as)14.3(ma)-228.9(C)]TJ 7.3837 0 0 6.5625 115.9937 504.4534 Tm [(tr)30.5(ou)24.9(gh)]TJ 9.845 0 0 9.845 137.1968 506.0975 Tm [(wa)19.1(s)-236.9(e)0(v)19.9(a)0(l)19.7(u)0(-)]TJ -7.6358 -1.0077 TD [(at)19.7(ed)-187.4(by)-180.5(EC)18.9(L-)19.9(EL)18.7(IS)21.2(A,)-189.5(an)19.9(d)-191(l)0(i)20.7(v)0(e)19.9(r)]TJ 0 -1.0135 TD .0131 Tc [(an)6.3(d)-275.8(k).6(id)6.3(ne)5.2(y)-281.6(s)6.5(am)5.2(pl)6.2(es)-275.6(we)5.2(re)-277(as)6.5(-)]TJ T* .0101 Tc [(sayed)-601.3(b)-2.4(y)-595.5(L)-3.6(C-MS.)-597.9(L)-3.6(C-MS,)]TJ T* .012 Tc [(li)5.1(qu)5.2(id)-202.1(ch)5.2(romatog)5.2(raphy)5.2(mas)5.4(s)]TJ 0 -1.0077 TD .0072 Tc [(s)-5.1(p).4(e)-6.5(c)-.7(t)-5.5(r)-5.3(om)-6.5(et)-5.5(ry)-5.3(;)-420.1(P).6(K)-6.1(s).6(;)-420.1(p)-5.3(ha)-6.5(rm)-6.5(a-)]TJ 0 -1.0135 TD .0119 Tc [(co)5.1(ki)5(netics.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm 0 Tc (228)Tj 46.1699 0 TD [(SHEMESH)-334(ET)-338.7(AL.)]TJ ET endstream endobj 107 0 obj <>stream AdobedC        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[(assayed)-454.3(by)-451.5(murine-specic)-458.9(ELISA.)-455.5(Total)-451.6(protein)-452.6(concen-)]TJ 0 -1.1116 TD [(tration)-389.4(in)-382.5(plasma)-384.5(samples)-391.1(\()]TJ /F7 1 Tf 11.3524 0 TD (n)Tj /F8 1 Tf .6624 0 TD (=)Tj /F3 1 Tf .72 0 TD [(7)-387(per)-384.6(type\))-386.9(was)-385.3(similar)-384.6(and)]TJ -12.7347 -1.1116 TD [(comparable)-569.9(\(54.6)]TJ /F8 1 Tf 7.4991 0 TD ()Tj /F3 1 Tf .72 0 TD [(20.7)-559.7(and)-563.2(50.4)]TJ /F8 1 Tf 6.2378 0 TD ()Tj /F3 1 Tf .72 0 TD [(13.4)-168(mg/mL\))-563.3(between)]TJ -15.1768 -1.1174 TD [(WT/WT)-231.4(and)-223.3(HO/HO)-228(mice)-232.7(\(Table)-229.1(4\).)-224.5(Total)-227(albumin)-229.2(was)-224(also)]TJ 0 -1.1116 TD [(comparable)-287.7(\(46.5)]TJ /F8 1 Tf 7.2169 0 TD ()Tj /F3 1 Tf .72 0 TD [(7.5)-282.1(and)-280.9(39.8)]TJ /F8 1 Tf 5.178 0 TD ()Tj /F3 1 Tf .72 0 TD [(9.8)-166.9(mg/mL\))-281.1(between)-282.9(WT/)]TJ -13.8348 -1.1116 TD [(WT)-253.3(and)-252.1(HO/HO.)-254.5(Total)-250(IgG)-257.6(was)-252.8(determined)-252.1(to)-250(be)-256.8(107)]TJ /F8 1 Tf 21.8235 0 TD ()Tj /F3 1 Tf .72 0 TD (8.74)Tj -22.5435 -1.1174 TD [(and)-615(116)]TJ /F8 1 Tf 3.7265 0 TD ()Tj /F3 1 Tf .72 0 TD (11.00)Tj /F9 1 Tf 2.4133 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/mL,)-615.2(total)-611.8(IgM)-608.9(was)-615.7(21.48)]TJ /F8 1 Tf 12.3488 0 TD ()Tj /F3 1 Tf .72 0 TD [(9.49)-611.5(and)]TJ -20.4815 -1.1116 TD (21.74)Tj /F8 1 Tf 2.4191 0 TD ()Tj /F3 1 Tf .72 0 TD [(9.67,)-188.7(total)-191.4(IgA)-194.2(was)-195.2(12.64)]TJ /F8 1 Tf 10.0795 0 TD ()Tj /F3 1 Tf .7142 0 TD [(5.27)-196.8(and)-188.8(18.24)]TJ /F8 1 Tf 6.0016 0 TD ()Tj /F3 1 Tf .72 0 TD [(9.07,)-188.7(and)]TJ -20.6543 -1.1116 TD [(HRG)-351.7(was)-350.7(19.1)]TJ /F8 1 Tf 6.2723 0 TD ()Tj /F3 1 Tf .72 0 TD [(2.2)-351.2(and)-350(9.39)]TJ /F8 1 Tf 5.3162 0 TD ()Tj /F3 1 Tf .72 0 TD [(1.35,)-350(each)-353.5(for)-348.8(WT/WT)-352.4(and)]TJ -13.0285 -1.1174 TD [(HO/HO,)-283.3(respectively,)-286.4(at)-280(\()]TJ /F7 1 Tf 10.4135 0 TD (n)Tj /F8 1 Tf .6681 0 TD (=)Tj /F3 1 Tf .72 0 TD [(7\))-278.6(samples)-281.7(per)-286.7(type.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 62.022 84.2456 Tm [(Plasma)-333.7(proteome)-332.9(ngerprinting)]TJ /F3 1 Tf 9.843 0 0 9.843 72 67.8047 Tm [(By)-302.7(two-dimensional)-309.2(gel)-304.1(electrophoresis,)-312.5(using)-299.2(isoelectric)]TJ -1.0137 -1.1116 TD [(focusing)-199.9(in)-198.2(the)-194.7(rst)-200(dimension)-196.7(followed)-201.1(by)-198(SDS-PAGE)-196.4(in)-198.2(the)]TJ 25.504 37.8528 TD [(second)-365.8(dimension,)-355.6(a)-359.4(clear)-360.4(separation)-365.9(of)-359.3(major)-359.3(plasma)-361.4(pro-)]TJ 0 -1.1116 TD [(teins)-283.2(was)-275.8(observed.)-279.3(Major)-278.4(banding)-279.7(patterns)-281.9(between)-277.1(sample)]TJ 0 -1.1174 TD [(types)-444.3(were)-445.3(observed)-442.9(\(Fig.)-445.5(6\).)-437.6(The)-443.4(presence)-445.2(of)-445.7(signicant)]TJ 0 -1.1116 TD [(isoforms)-263.1(near)-254.4(a)-261.4(molecular)-256.8(weight)-262.3(range)-255.5(of)-255.6(150)-170.3(kDa)-253(at)-262.7(a)-255.7(near)]TJ T* [(physio)-6.5(logical)-321.5(isoelectric)-328.1(pH)-325.6(was)-321.9(conrmed)-329(to)-324.9(be)-320.1(A2M)-321.9(iso-)]TJ 0 -1.1174 TD [(forms.)-211.5(Bands)-209.1(representing)-212.5(ID13)-207.9(were)-209.2(A2M)-206.7(related,)-210.7(and)-206.1(ID4)]TJ 0 -1.1116 TD [(was)-402.6(identied)-398.4(as)-400.6(transferrin)-400.3(precursor.)-401.3(More)-398.1(minor)-398.5(differ-)]TJ T* [(ences)-227.7(between)-225.3(expression)-226.2(levels)-227.9(of)-221(much)-225.7(smaller)-224.4(protein)-228(and)]TJ T* [(peptides)-287.7(can)-282.1(also)-282(be)-279.8(observed)-281.6(as)-285.4(outlined.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 313.0582 314.3621 Tm (Discussion)Tj /F3 1 Tf 9.843 0 0 9.843 323.0361 297.9212 Tm [(ASOs)-218.9(offer)-219.7(signicant)-215(advantages)-223(as)-216.3(a)-215.4(modern)-216.3(therapeutic)]TJ -1.0137 -1.1116 TD [(delivery)-287.8(platform)-287.9(and)-286.7(continue)-282.1(to)-284.6(mature)-286.7(for)-285.5(various)-285.3(targets)]TJ T* [(in)-324.9(numerous)-322(preclinical)-328.3(and)-321.2(clinical)-323.8(development)-322.4(programs)]TJ 0 -1.1174 TD [([27].)-313(To)-308.7(be)-308.6(effective,)-317.7(ASOs)-311.1(must)-305.1(be)-314.4(well)-306.2(absorb)-7.5(ed,)-306.3(distrib-)]TJ 0 -1.1116 TD [(uted,)-469.9(and)-465.2(ultimately)-470.2(transported)-469.5(into)-465.4(productive)-468.6(compart-)]TJ T* [(ments)-249.7(to)-250(reach)-245.1(the)-246.5(target)-251.1(site)-247.5(of)-249.8(action)-245.3(such)-247.3(as)-250.8(the)-246.5(cytoplasm)]TJ T* [(and)-269.4(nucleus.)-266.8(Yet)-264.7(ASO)-269.8(delivery)-264.8(is)-267.1(challenging)-269.4(in)-267.3(many)-266(ways)]TJ 0 -1.1174 TD [(as)-423.6(a)-417(signicant)-422.3(portion)-416.9(of)-416.9(ASO)-419.6(distributes)-422.3(to)-417(the)-419.3(nonpro-)]TJ 0 -1.1116 TD [(ductive)-194.6(compartments)-197.8(and)-194.5(is)-192.2(endocytosed)-194.1(into)-194.7(lysosomes)-196.2(and)]TJ T* [(endosomes,)-362.1(where)-354.3(it)-353.8(is)-353.5(hydrolyzed)-359(and)-355.8(metabolized)-358.2(before)]TJ 0 -1.1174 TD [(reach)-9(ing)-279.9(the)-281.1(intended)-282.1(target.)]TJ 1.0137 -1.1116 TD [(Clearly)-443.3(dened)-440.8(mechanisms)-442.9(for)-441(ASO)-436.9(uptake)-441(have)-444.5(per-)]TJ -1.0137 -1.1116 TD [(sisted)-376.3(as)-371.8(a)-370.9(major)-370.9(challenge,)-369.6(and)]TJ /F7 1 Tf 13.6793 0 TD [(in)-370.9(vitro)]TJ /F3 1 Tf 3.4155 0 TD [(systems)-372.5(are)-374.2(often)]TJ -17.0948 -1.1174 TD [(limit)-7.3(ed)-251(in)-250(their)-254.6(ability)-257.1(to)-250(predict)]TJ /F7 1 Tf 13.1379 0 TD [(in)-255.8(vivo)]TJ /F3 1 Tf 2.9662 0 TD [(outcomes)-254.2(often)-254.4(with)]TJ -16.1041 -1.1116 TD [(poor)-534.3(correlation)-528.5([2833].)-529.5(Seemingly)-531.9(major)-532.1(discrepancies)]TJ T* [(exist)-461.8(with)-460.5(unclear)-460.6(outcomes,)-459.2(yet)-453.8(we)-459.3(suspect)-459(and)-459.5(conrm)]TJ 0 -1.1174 TD [(hepat)-8(ocyte)-295.9(surface)-293.2(proteins)-298(such)-299.1(as)-291.2(A2M)-298.8(could)-294.8(be)-291.4(involved)]TJ 0 -1.1116 TD [(in)-365.2(major)-359.3(shuttling)-361.6(events)-366(related)-362.8(to)-359.4(productive)-364.9(and/or)-365(non-)]TJ T* [(productive)-255.5(uptake)-251([34].)-249.7(A)-249.6(signicant)-249.5(amount)-251(of)-249.8(studies)-250.7(have)]TJ T* [(comprehens)-9.8(ively)-421.6(described)-422.2(the)-419.3(PKs)-424.3(and)-419.2(biodistribution)-420.3(of)]TJ 0 -1.1174 TD [(ASOs,)-487.3(yet)-476.9(insight)-486(into)-477(mechanisti)-10.2(c)-480.3(differences)-483.1(related)-483.7(to)]TJ 0 -1.1116 TD [(major)-284.5(serum)-278.4(protein)-279.8(knockout)-280.8(models)-279.6(is)-278.6(lacking.)-278.7(Therefore,)]TJ T* [(we)-246.1(sought)-242.7(to)-244.2(evaluate)-249.9(the)-240.7(hypothesis)-248.2(that)-242(knocking)-246.3(out)-245.3(A2M)]TJ ET q 1 i 191.622 732.019 m 552.189 732.019 l 552.189 559.559 l 191.622 559.559 l W n q 360.926 0 0 172.46 191.622 559.559 cm /Im3 Do Q Q BT /F5 1 Tf 9.845 0 0 9.845 62.022 687.1746 Tm [(FIG.)-342.5(3.)]TJ /F3 1 Tf 4.1231 0 TD [(In)15.3(hi)15.1(bi)15.1(to)15.1(ry)-324.5(ef)14.1(fe)14.1(ct)-331.6(li)20.7(-)]TJ -4.1231 -1.0135 TD .024 Tc [(ver)-570.1(e)-1.2(xpos)-5.6(ure)-565.5(r)-5.8(e)-1.2(spo)-5.8(n)0(se)-565.5(PD)]TJ 0 -1.0077 TD -.0275 Tc [(mo)-5.5(de)-6.6(l)-356.9(f).3(o)-5.5(r)-356.7(IO)-6.3(N-)-5.5(353)-5.5(38)-5.5(2)-356.7(t).1(a)-6.6(r).3(g)-5.5(e)-.9(t-)]TJ 0 -1.0135 TD -.0273 Tc [(i)-5.4(n).5(g)-310.5(S)-5.1(RB)-6.3(1.)-312.8(L)-6.4(i).3(ve)-6.4(r)-310.5(c)-6.4(on)-5.3(cen)-5.3(tr)-5.3(at)-5.4(ion)]TJ T* .358 Tc [(i)379.9(s).1(p)380(l)385.6(o)380(t)385.6(t)385.6(e)378.9(do)380(nt)379.9(h)385.8(e)]TJ /F7 1 Tf 6.8815 0 TD 0 Tc (x)Tj /F3 1 Tf .4204 0 TD -.0233 Tc [(-axi)4.3(s,)-383.7(whi)4.3(l)4.3(e)]TJ -7.3018 -1.0135 TD -.0274 Tc [(p)-5.4(e)-.8(rc)-6.5(en)-5.4(t)-305(i)-5.5(nhi)-5.5(bi)-5.5(ti)-5.5(on)-310.6(com)-6.5(p).4(a)-6.5(r).4(ed)-310.6(to)]TJ 0 -1.0077 TD [(s)-5.3(a)-.9(li)-5.6(ne)-334.9(co)-5.5(nt)-5.6(ro)-5.5(l)-328.1(i)-5.6(s)-327.8(p)-5.5(lo)-5.5(tt)-5.6(ed)-333.7(on)-333.7(th)-5.5(e)]TJ /F7 1 Tf 0 -1.0135 TD 0 Tc (y)Tj /F3 1 Tf .4204 0 TD -.0239 Tc [(-axi)3.7(s)-364.5(t)3.7(o)-364.6(o)3.9(bt)3.7(ai)3.7(n)-364.6(s)4.1(imu)3.9(l)-2(ated)-364.6(an)3.9(d)]TJ -.4204 -1.0135 TD -.0271 Tc [(p)-5.1(r).7(ed)-5.1(ic)-6.2(ted)-310.3(E)-.5(C)]TJ 7.3837 0 0 6.5625 111.685 605.8203 Tm -.0316 Tc (50)Tj 9.845 0 0 9.845 121.6062 607.4644 Tm -.0277 Tc [(va)-6.8(lue)-6.8(s)-304.9(f)-5.7(o).1(r)-305.1(b)-5.7(oth)]TJ -6.0522 -1.0135 TD -.0268 Tc [(WT)-5.9(/WT)-334.2(a)-5.9(nd)-338.8(HO/)-4.9(HO)-5.6(.)]TJ ET 62.022 523.842 490.167 .28345 re f 62.022 476.447 490.167 .22675 re f 62.022 505.19 490.167 .22681 re f BT /F6 1 Tf 9.845 0 0 9.845 86.2866 539.4896 Tm 0 Tc (Table)Tj /F3 1 Tf 3.0002 0 TD (2.)Tj /F6 1 Tf 1.2496 0 TD [(Pharmacodynamic)-334.8(Model)-333.7(Parameters)-332.7(After)-335.2(a)-334.8(Single)-335.2(Subcutaneous)-332.6(Dose)-338.4(of)]TJ /F3 1 Tf 35.2768 0 TD [(\(0,)-333.6(5,)-332.6(15,)-333.6(30,)]TJ /F6 1 Tf -33.3305 -1.0135 TD (and)Tj /F3 1 Tf 2.05 0 TD (60)Tj /F6 1 Tf 1.169 0 TD (mg/kg)Tj /F3 1 Tf 2.6029 0 TD (\))Tj /F6 1 Tf .668 0 TD (of)Tj /F3 1 Tf 1.3302 0 TD (ION-353382)Tj /F6 1 Tf 5.4418 0 TD [(in)-331.6(Both)-334.2(Wild-Type)-335.7(and)-337.8(Homozygous)-334.1(Mice)]TJ /F7 1 Tf -21.9228 -1.837 TD [(Dose)-334(group)-5826.7(Observations)-337.3(\()]TJ /F3 1 Tf 16.5904 0 TD (N)Tj /F7 1 Tf .7198 0 TD (\))Tj /F3 1 Tf 6.1559 0 TD (E)Tj /F7 1 Tf 7.3837 0 0 6.5625 299.1117 509.7825 Tm (0)Tj 9.845 0 0 9.845 306.085 511.4266 Tm [(\(%\))-5820.1(Gamma)-335.6(\()]TJ /F9 1 Tf 11.1428 0 TD (g)Tj /F7 1 Tf .501 0 TD 5.8229 Tc [(\)E)5822.9(C)]TJ 7.3837 0 0 6.5625 493.9085 509.7825 Tm 0 Tc (50)Tj 9.845 0 0 9.845 504.6235 511.4266 Tm (\()Tj /F9 1 Tf .334 0 TD (m)Tj /F7 1 Tf .5471 0 TD (g/g\))Tj /F8 1 Tf 1.9522 0 TD ()Tj /F7 1 Tf .8811 0 TD (SE)Tj /F3 1 Tf -48.6712 -1.9003 TD [(WT/WT)-10215.9(20)-9135(102.1)-7562.5(1.33)-8511.7(5.49)]TJ /F8 1 Tf 45.7459 0 TD ()Tj /F3 1 Tf .7198 0 TD (0.95)Tj -46.4657 -1.0135 TD [(HO/HO)-10465.9(20)-9636(99.8)-7561.5(1.34)-8511.7(2.85)]TJ /F8 1 Tf 45.7459 0 TD ()Tj /F3 1 Tf .7198 0 TD (0.33)Tj 7.3837 0 0 6.5625 536.655 487.1054 Tm (a)Tj 6.5633 0 0 5.8334 70.0157 468.5101 Tm (a)Tj 8.7511 0 0 8.7511 72.9637 464.5983 Tm [(Statistically)-334.1(signicant,)]TJ /F7 1 Tf 9.8342 0 TD (P)Tj /F8 1 Tf .7839 0 TD (<)Tj /F3 1 Tf .7126 0 TD (0.05.)Tj /F9 1 Tf -11.6675 -1.0236 TD (g)Tj /F3 1 Tf .4988 0 TD [(,)-333.1(hill)-334.9(coefcient;)-329.8(E)]TJ 6.5633 0 0 5.8334 141.959 454.2235 Tm (0)Tj 8.7511 0 0 8.7511 145.2472 455.6408 Tm [(,)-333.1(lowest%saline)-336.1(inhibition;)-329.4(EC)]TJ 6.5633 0 0 5.8334 254.6645 454.2235 Tm (50)Tj 8.7511 0 0 8.7511 261.2409 455.6408 Tm 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[(gr)21.1(ee)-655(of)-652.7(bi)20.9(nd)21.1(in)20.9(g)-663.2(d)0(i)20.9(f)0(f)21(e)0(r)19.9(e)0(n)19.9(c)0(e)18.7(s)]TJ T* [(be)19.9(tw)20.1(ee)18.7(n)-536.5(n)0(o)21.1(n)0(t)20.9(r)0(e)19.9(a)0(t)19.7(e)0(d)-527.2(W)0(T)17.7(/)0(W)18.7(T)]TJ T* -.0155 Tc [(an)6.5(d)-327.5(HO/)6.4(HO)-328.3(sa)5.4(mp)6.5(les)6.7(.)-329.8(Th)6.5(e)-328.6(a)-.4(d)6.5(-)]TJ 0 -1.0077 TD .6632 Tc [(d)639.2(i)633.2(t)639(i)639(o)639.2(no)639.2(f0)639.2(.)636.8(5)]TJ /F9 1 Tf 6.1444 0 TD 0 Tc (m)Tj /F3 1 Tf .5759 0 TD .0249 Tc [(m)-639.5(o).9(f)-638.3(I).9(ON-)]TJ -6.7202 -1.0135 TD 0 Tc [(35)21.1(33)21.1(82)-387.8(wa)19.1(s)-398.2(u)0(s)21.2(e)0(d)-389(t)0(o)-388(d)0(i)20.9(s)0(p)21.2(l)0(a)19.7(c)0(e)]TJ T* [(pr)21.1(ot)20.9(ei)13.9(n-)21.1(bo)21.1(un)21.1(d)-323.5(A)0(S)20.4(O)0(.)]TJ ET 62.022 184.422 490.167 .28342 re f 62.022 87.194 490.167 .28348 re f 62.022 155.792 490.167 .28348 re f BT /F6 1 Tf 9.845 0 0 9.845 73.3039 190.148 Tm (Table)Tj /F3 1 Tf 3.0002 0 TD (4.)Tj /F6 1 Tf 1.2496 0 TD [(Selected)-335.8(Protein)-330.4(Quantitation)-338.5(Comparing)-335.4(Wild-Type)-335.7(and)-332(Double-Knockout)-336(Control)-337(Plasma)]TJ /F7 1 Tf -5.3958 -2.8562 TD [(Assayed)-338.3(protein)]TJ 10.7512 1.0135 TD [(No.)-334.6(of)-330.4(samples)]TJ 1.3705 -1.0135 TD [(per)-332.2(type)]TJ 7.5034 1.0135 TD [(WT/WT)-335(\()]TJ /F13 1 Tf 3.6394 .0058 TD ()Tj /F7 1 Tf -.023 -.0058 TD (x)Tj /F8 1 Tf .6162 0 TD ()Tj /F9 1 Tf .7198 0 TD (s)Tj /F7 1 Tf .668 0 TD (x\))Tj -4.1404 -1.0135 TD (\(mg/mL\))Tj 7.7107 1.0135 TD [(HO/HO)-336.7(\()]TJ /F13 1 Tf 3.7488 .0058 TD ()Tj /F7 1 Tf -.023 -.0058 TD (x)Tj /F8 1 Tf .6104 0 TD ()Tj /F9 1 Tf .7198 0 TD (s)Tj /F7 1 Tf .668 0 TD (x\))Tj -4.1922 -1.0135 TD (\(mg/mL\))Tj 7.7625 1.0135 TD [(CD1)-338.8(control)]TJ .8407 -1.0135 TD (\(mg/mL\))Tj 7.0657 1.0135 TD (DKO/WT)Tj .9099 -1.0135 TD (ratio)Tj /F3 1 Tf -46.9264 -1.8946 TD [(Immunoglobulin)-333.4(G)-5754.6(7)-6335.4(0.107)]TJ /F8 1 Tf 22.7981 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.009)-3859.8(0.116)]TJ /F8 1 Tf 8.5226 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.039)-4533.5(0.810)-5236.1(1.08)]TJ -32.7604 -1.0135 TD [(Immunoglobulin)-333.4(M)-5587.6(7)-5840.2(0.0215)]TJ /F8 1 Tf 22.7981 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.009)-3358.8(0.0217)]TJ /F8 1 Tf 8.5226 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.009)-4533.5(0.024)-5236.1(1.01)]TJ -32.7604 -1.0135 TD [(Immunoglobulin)-333.4(A)-5754.6(7)-5840.2(0.0126)]TJ /F8 1 Tf 22.7981 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.005)-3358.8(0.0182)]TJ /F8 1 Tf 8.5226 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.009)-4533.5(0.029)-5236.1(1.44)]TJ -32.7604 -1.0135 TD [(HRG)-11442.1(7)-5840.2(0.0191)]TJ /F8 1 Tf 22.7981 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.002)-3358.8(0.0093)]TJ /F8 1 Tf 8.5226 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.001)-4533.5(0.011)-5236.1(0.49)]TJ -32.7604 -1.0077 TD [(Albumin)-9983.1(7)-6836.4(46.5)]TJ /F8 1 Tf 22.7981 0 TD ()Tj /F3 1 Tf .7198 0 TD [(7.5)-5355(39.8)]TJ /F8 1 Tf 8.5226 0 TD ()Tj /F3 1 Tf .7198 0 TD [(9.8)-6161.2(70)-5858.4(0.86)]TJ -32.7604 -1.0135 TD [(Total)-335.9(protein)-8243.2(7)-6836.4(54.6)]TJ /F8 1 Tf 22.7981 0 TD ()Tj /F3 1 Tf .7198 0 TD [(20.7)-4855(50.4)]TJ /F8 1 Tf 8.5226 0 TD ()Tj /F3 1 Tf .7198 0 TD [(13.4)-5661.2(45)-5858.4(0.92)]TJ 8.7511 0 0 8.7511 70.0157 75.4016 Tm [(Values)-299.2(are)-308.4(listed)-299.7(as)-301.7(the)-307.4(mean)]TJ /F8 1 Tf 12.0951 0 TD ()Tj /F3 1 Tf .7191 0 TD [(standard)-306.2(deviations,)-298.9(CD1)-305.7(murine)-300(plasma)-301(was)-309.3(used)-299.4(as)-301.7(a)-304.5(positive)-303.9(control,)-302.7(DKO/WT)-305.7(is)-299.3(the)-300.9(ratio)-308.8(of)-300.7(results)]TJ -13.7276 -1.0236 TD [(obtained)-333.9(from)-333.4(DKO)-333.7(homozygous)-328.8(mice)-337.4(to)-333.3(wild)-332(type.)]TJ .9134 -1.0236 TD [(DKO,)-329.9(double)-336.3(knockout;)-331.5(HRG,)-330.1(histidine-rich)-338(glycoprotein.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (232)Tj 46.1699 0 TD [(SHEMESH)-334(ET)-338.7(AL.)]TJ ET endstream endobj 129 0 obj <>stream AdobedC       @ s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& 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[(type)-236.1(exhibited)-243(twofold)-233.4(enhanced)-243.9(pharmacological)-242.8(activity)-236.3(in)]TJ T* [(the)-252.3(liver.)-252.2(IHC)-252.8(staining)-252.1(in)-255.8(mouse)-249.6(liver)-254.6(revealed)-255.5(less)-253(profound)]TJ 0 -1.1174 TD [(nonparenchymal)-384.3(kupffer)-383.2(cell)-381.4(uptake)-383.4(for)-377.6(homozygous)-387.6(mice)]TJ 0 -1.1116 TD .0125 Tc [(wi)5.5(th)-288.1(min)5.6(o)-.1(r)-288.1(q)-.1(u)5.6(a)-1.3(l)5.5(itati)5.5(ve)-289.3(d)5.6(i)-.2(ff)5.7(er)5.7(ences)-287.9(i)5.5(n)-288.1(A)-1(S)5.8(O)-289(dis)5.8(t)-.2(ri)5.5(bu)5.6(ti)5.5(on.)-284.7(No)]TJ T* .0119 Tc [(majo)5(r)-519.1(p)5(ro)5(tei)4.9(n)-519.1(b)5(i)-.8(n)5(d)-.7(in)5(g)-519.1(d)5(if)5.1(fer)5.1(e)-1.9(n)5(c)-1.9(es)-518.9(b)5(e)-1.9(tween)-519.1(g)5(ro)5(ups)-513.1(were)]TJ 0 -1.1174 TD .0116 Tc [(ob)4.7(served.)-533.2(Two-)4.8(dimen)4.7(s)-.8(i)4.6(onal)-536.8(g)]TJ 12.7635 0 TD .0131 Tc [(el)-535.3(e)5.1(l).4(e)5.1(c)-.7(tr)6.3(op)6.2(hor)6.3(es)6.4(is)-535(r)6.3(e)-.7(ve)5.1(al)6.1(ed)]TJ -12.7635 -1.1116 TD .0122 Tc [(band)5.3(ing)-213.5(d)5.3(iff)5.4(e)-1.6(r)5.4(e)-1.6(nces)-213.3(wi)5.2(th)-213.5(di)5.2(fferi)5.2(ng)-213.5(pr)5.4(otein)-213.5(e)-1.6(x)5.3(p)-.4(r)5.4(e)-1.6(ss)5.5(ion)-213.5(l)5.2(evels)]TJ T* [(related)-277(t)5.1(o)-277(A)-1.4(2M)-277.9(i)5.1(s)-.3(of)5.3(or)5.3(ms.)]TJ 1.0137 -1.1174 TD 0 Tc [(Our)-436.1(investigations)-444.2(depict)-435.4(A2M)-442.8(as)-435.1(an)-441.1(important)-438.9(plasma)]TJ -1.0137 -1.1116 TD [(protein)-308.6(involved)-309.7(in)-307.6(ASO)-310.1(transport,)-308.3(wh)20(ic)19.6(h)-294.8(i)0(n)15()0(u)21(e)0(n)19.7(c)0(e)18.5(s)-294.6(su)21(bc)13.9(el)19.5(-)]TJ T* [(lu)20.7(la)19.6(r)-421.5(u)0(p)20.8(t)0(a)13.8(k)0(e)-412.3(a)0(n)19.7(d)-421.6(di)20.7(st)20.9(ri)20.7(bu)20.8(ti)14.8(on)-411.1(of)-411.1(AS)20.1(Os)20.2(.)-423.9(T)0(a)18.5(k)0(e)19.7(n)-421.6(to)20.7(ge)19.7(th)20.7(er)19.7(,)-423.9(t)0(h)20.7(e)]TJ T* [(re)19.7(su)21(lt)14.8(s)-381(o)0(f)-370.8(t)0(h)20.7(i)0(s)-370.8(w)0(o)20(r)0(k)-370.8(p)0(r)20.9(o)0(v)20.8(i)0(d)20.7(e)-382.4(va)19.7(lu)20.7(ab)19.7(le)-372.1(in)20.7(si)15.1(gh)20.8(t)-381.4(a)0(n)19.7(d)-381.2(re)19.7(ve)19.7(al)-372.1(th)20.7(e)]TJ 0 -1.1174 TD [(ap)19.7(pl)20.7(ic)19.5(ab)13.9(il)20.6(it)20.6(y)-208.4(o)0(f)-198(t)0(h)20.7(i)0(s)-203.7(m)15(od)15.1(el)-199.3(to)-198.2(sc)19.9(re)19.7(en)-199.2(ot)20.7(he)13.9(r)-208.4(A)0(S)20.1(O)0(s)-198.7(w)0(i)19.8(t)0(h)-198.2(a)0(l)19.5(t)0(e)13.8(r)0(n)20.9(a)0(t)19.5(e)]TJ 0 -1.1116 TD [(ch)19.7(em)18.5(is)20.9(tr)15(ie)19.5(s)-311.9(f)0(o)20.9(r)-312.1(ev)19.7(al)13.8(ua)19.7(ti)20.6(ng)-301.7(me)18.4(ch)19.7(an)19.7(is)20.9(ti)14.8(c)-313.3(d)0(i)20.7(f)0(f)20.9(e)0(r)19.7(e)0(n)19.7(c)0(e)18.5(s)-317.7(in)-301.8(up)20.8(ta)19.6(ke)19.7(,)]TJ T* [(an)19.7(d)-271.8(f)0(o)20.9(r)-271.8(de)19.7(si)20.9(gn)-261.4(of)-261.4(AS)20.1(Os)-262.1(wi)19.8(th)-261.5(re)19.7(du)20.8(ce)18.5(d)-271.8(b)0(i)20.7(n)0(d)20.8(i)0(n)20.7(g)-271.8(to)-261.5(A2)20(M.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 514.9416 Tm (Acknowledgments)Tj /F3 1 Tf 9.843 0 0 9.843 72 498.5006 Tm [(The)-230.3(authors)-227.6(kindly)-231.5(thank)-231.4(Ethan)-232.6(Weiss)-227.5(of)-232.6(the)-229.2(University)-232.1(of)]TJ -1.0137 -1.1116 TD [(California)-296.9(San)-286.5(Francisco)-295.4(for)-291.2(providing)-292.4(the)-286.8(double-knockout)]TJ 0 -1.1174 TD [(mice)-255.8(and)-257.9(for)-256.7(project)-257.9(support;)-256.5(Ezio)-254.6(Petrella,)-263.6(Alex)-254.2(Perieteanu,)]TJ 0 -1.1116 TD [(and)-257.9(Colin)-260.2(Barry)-261.1(of)-261.4(SGS)-263(Pharmaceuticals)-266.6(for)-256.7(their)-260.3(assistance)]TJ T* [(with)-454.8(immunoassa)-9.8(ys)-451.3(and)-459.5(protein)-458.4(characterizations;)-466.1(Andrea)]TJ 0 -1.1174 TD [(Benoit)-210.7(and)-211.8(Rajeev)-212.9(Dhawan)-212.3(of)-209.5(Charles)-212.6(River)-215.2(Laboratories)-213.7(for)]TJ 0 -1.1116 TD [(breeding)-270.4(and)-263.7(colony)-267.1(conrmations;)-265.6(Xiaokun)-269.1(Xiao)-265.8(and)-263.7(Gene)]TJ T* [(Hung)-287.5(of)-290.2(Ionis)-287.6(Pharmaceuticals)-295.4(for)-291.2(their)-289.1(support)-284.1(with)-293.5(histol-)]TJ 0 -1.1174 TD [(ogy)-308.6(assessments;)-316.7(Robert)-314.2(Saunders)-316(of)-307.4(Ionis)-310.7(Pharmaceuticals)]TJ 0 -1.1116 TD [(for)-481.3(his)-487.1(administrative)-487.1(assistance.)-491.1(They)-484.8(would)-484.6(like)-483.9(to)-480.4(ac-)]TJ T* [(knowledge)-284(and)-280.9(thank)-283.3(Donna)-278.2(Sipe)-282(and)-280.9(the)-281.1(vivarium)-282.1(staff)-283(for)]TJ T* [(animal)-517.3(husbandry.)-509.6(They)-513.6(would)-513.4(also)-512.4(like)-512.7(to)-514.9(thank)-513.7(Tracy)]TJ 0 -1.1174 TD [(Reigle)-206.1(of)-209.5(Ionis)-201.2(Pharmaceuticals)-214.8(for)-204.8(her)-206(kind)-206.1(support)-203.4(and)-206.1(help)]TJ 0 -1.1116 TD [(with)-282(graphics)-281.7(and)-280.9(formatting.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 332.107 Tm [(Author)-338.7(Disclosure)-330.4(Statement)]TJ /F3 1 Tf 9.843 0 0 9.843 72 315.666 Tm [(All)-643.8(authors)-648.1(are)-644.9(employees)-648.1(of)-641.5(Ionis)-644.7(Pharmaceuticals,)]TJ -1.0137 -1.1116 TD [(Carlsbad,)-286.2(California.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 280.8 Tm (References)Tj /F3 1 Tf 9.2951 0 0 9.2951 66.6708 264.7558 Tm [(1.)-500.4(Chaudhuri)-317(L.)-313.2(\(1993\).)-310.6(Human)-317.1(alpha)]TJ 6.9712 0 0 6.196 212.0314 263.1685 Tm (2)Tj 9.2951 0 0 9.2951 215.5464 264.7558 Tm [(-macroglobulin)-311.8(and)-315.7(its)]TJ -14.7662 -1.1284 TD [(biological)-336.9(signicance.)-336.5(Indian)-336.2(J)-334.7(Exp)-331.7(Biol)-333.6(9:723727.)]TJ -1.2503 -1.1223 TD .0171 Tc [(2)17.1(.)-483.3(Abe)-420.3(K)-2.9(,)-422.1(K)-417.7(Yamam)5.2(o)-1.3(to)-422.2(an)4.8(d)-422.2(H)-423.8(Sin)4.8(ohara.)-422.1(\()2.4(19)4.8(89\).)-422.1(P)1.9(rot)5.3(e)-5.5(i)5.3(n)-1.3(-)]TJ 1.2503 -1.1284 TD .0182 Tc [(ase)-535.1(i).3(n)5.9(h)-.2(ib)5.9(ito)5.9(ry)-530.9(sp)5.9(ect)6.4(r)-2.6(u)5.9(m)-536.5(o)5.9(f)-539.3(m)6.3(o)-.2(u)5.9(s).7(e)-535.1(m).2(urin)5.9(og)5.9(lob)5.9(u)-.2(li)6.4(n)-537(a)1.7(nd)]TJ /F9 1 Tf 0 -1.1223 TD 0 Tc (a)Tj /F3 1 Tf .5672 0 TD .0143 Tc [(-m)-3.7(acr)-6.5(og)-4.1(l)-3.6(o)2(b)-4.1(u)2(l)-3.6(i)-3.6(n)2(.)-339.5(J)-332.6(Bi)-3.6(oc)-8.3(hem)-339.2(4)2(:)-3.6(5)-4.1(64)-4.1(5)-4.1(6)-4.1(8)2(.)]TJ -1.8176 -1.1284 TD 0 Tc [(3.)-500.4(Rehman)-501.6(AA,)-503.7(H)-501.8(Ahsan)-499.7(and)-504.8(FH)-498.8(Khan.)-506.6(\(2013\).)-499.6(Alpha-2-)]TJ 1.2503 -1.1223 TD [(macroglobulin:)-528.5(a)-528.9(physiological)-531.7(guardian.)-529.8(J)-523.8(Cell)-533(Physiol)]TJ 0 -1.1284 TD (8:16651675.)Tj -1.2503 -1.1223 TD .0217 Tc [(4)21.7(.)-478.7(Overbergh)-344.4(L)1.4(,)-344.3(C)-343.1(Hilliker,)-344.3(K)-339.9(L)-4.7(orent,)-344.3(FV)-346(Leuven)-344.4(and)-338.3(V)-4.4(D)]TJ 1.2503 -1.1284 TD .0226 Tc [(Berg)4.2(he.)-410.5(\()1.8(19)4.2(94)4.2(\).)-416.6(Id)4.2(ent)4.7(i)-1.4(cat)]TJ 11.4788 0 TD .0217 Tc [(ion)-411.5(o)-2.8(f)-407.7(f)-5.2(our)-413.8(g)3.3(ene)5.2(s)-416.7(coding)-411.5(for)]TJ -11.4788 -1.1223 TD .0238 Tc [(is)6.2(ofo)5.4(r)-3.1(m)5.8(s)-402.4(o)5.4(f)-399.5(mu)5.4(rin)5.4(o)-.7(g)5.4(l)-.2(ob)5.4(ul)5.9(in)5.4(,)-403.2(t)5.9(he)-395.3(mo)5.4(no)5.4(meric)-395.3(m)-.3(ou)5.4(se)]TJ /F9 1 Tf 22.5428 0 TD 0 Tc (a)Tj /F3 1 Tf .5733 0 TD .0245 Tc (2-)Tj -23.1161 -1.1284 TD .0216 Tc [(mac)5.1(r)-5.3(oglobulin:)-350(characteri)]TJ 10.9664 0 TD .0197 Tc [(zat)-4.3(io)-4.8(n)-346.4(o)-4.8(f)-348.7(t)-4.3(he)-350.6(ex)-4.8(on)-4.8(s)-351.6(c)-2.9(od)-4.8(in)-4.8(g)-346.4(f)-1.1(o)-4.8(r)]TJ -10.9664 -1.1223 TD .024 Tc [(th)5.6(e)-334.1(b)5.6(ait)-329.3(r)3.2(egi)6.1(o)-.5(n)5.6(.)-329.8(Gen)5.6(o)-.5(m)6(i)0(cs)-329(3:)6.1(53)5.6(0)5.6(53)5.6(9.)]TJ -1.2503 -1.1284 TD 0 Tc [(5.)-500.4(Leu)11.8(ven)-559.7(FV,)-559.9(S)-570.3(Tor)13.7(re)11.5(ken)13.7(s,)-566.6(L)-569.3(Ove)12.1(rbe)11.3(rgh)15.5(,)-573.4(K)-568.9(Lor)13.7(ent)14.2(,)-567.3(B)0(D)]TJ 1.2503 -1.1223 TD [(Str)13.2(oop)17.9(er)-147.1(and)-138.8(HVD)-145.4(Ber)12.7(ghe)13.7(.)-146.5(\(19)15.5(92\))15.5(.)-152.5(The)-140.7(pri)16.1(mar)11.8(y)-146.5(seq)14.6(uen)13.7(ce)-149(and)]TJ 0 -1.1284 TD [(th)12.5(e)-321.5(s)0(u)12.8(buni)18.3(t)-316.7(s)0(t)13.4(ruc)11.3(tu)12.5(re)-311.8(of)-313.7(mo)12.3(use)]TJ /F9 1 Tf 12.6071 0 TD (a)Tj /F3 1 Tf .5489 0 TD [(-2-)19.3(macr)13.5(ogl)18.4(obul)18.3(in,)-304.7(ded)13.7(uced)]TJ -13.156 -1.1223 TD [(fro)13.2(m)-365.7(prot)16(ein)-357.8(sequ)14.4(en)13.8(cing)-358(of)-362.5(the)-363.9(iso)13.2(lat)14.8(ed)-364.3(sub)12.7(uni)18.4(ts)-364.8(and)-364.5(fr)13.4(om)]TJ 0 -1.1284 TD [(mo)12.3(lecu)16(lar)-238.2(clo)14.2(ni)12.5(ng)-244.3(of)-240.5(th)12.5(e)-248.3(c)0(D)12.2(NA.)-241.4(Eur)-230.3(J)-249.3(Bio)13.7(che)15.6(m)-243.7(1:3)12.3(193)17.7(27.)]TJ -1.2503 -1.1223 TD [(6.)-500.4(Hudson)-428.5(NW,)-433.2(JM)-425.6(Kehoe)-431.6(and)-431.6(PH)-431.7(Koo.)-429(\(1987\).)-426.4(Mouse)]TJ /F9 1 Tf 24.3359 0 TD (a)Tj /F3 1 Tf .555 0 TD (-)Tj -23.6406 -1.1284 TD [(macroglobulin.)-333.8(Biochem)-336.5(J)-334.7(3:837845.)]TJ 25.7571 70.9158 TD [(7.)-500.4(Armstrong)-359.4(PB)-355.6(and)-352.3(JP)-349.9(Quigley.)-359.5(\(1999\).)]TJ /F9 1 Tf 17.7061 0 TD (a)Tj /F3 1 Tf .5489 0 TD (2-macroglobulin:)Tj -17.0047 -1.1223 TD [(an)-565.6(evolutionarily)-571(conserved)-570.4(arm)-561.6(of)-569.8(the)-565.2(innate)-563.2(immune)]TJ 0 -1.1284 TD [(system.)-337.8(Dev)-335.6(Comp)-334.3(Immunol)-331.3(45:375390.)]TJ -1.2503 -1.1223 TD [(8.)-500.4(Wu)-291.3(SM,)-289.2(DD)-290.1(Patel)-285.3(and)-291.3(SV)-285.3(Pizzo.)-292.1(\(1998\).)-286.2(Oxidized)-290.6(alpha2-)]TJ 1.2503 -1.1283 TD [(macroglobulin)-437.4(\(alpha2M\))-433.9(differentially)-433.5(regulates)-435.1(receptor)]TJ 0 -1.1223 TD [(binding)-256(by)-256.5(cytokines/growth)-255.4(factors:)-262.2(implications)-256(for)-255.1(tissue)]TJ 0 -1.1284 TD [(injury)-343.6(and)-340.1(repair)-342.7(mechanisms)-346.3(in)-341.3(inammation.)-339.8(J)-340.8(Immunol)]TJ 0 -1.1223 TD (8:43564365.)Tj -1.2503 -1.1284 TD [(9.)-500.4(Petersen)-536(CM.)-522.8(\(1993\).)-530.1(Alpha)-530.5(2-macroglobulin)-531.5(and)-523.1(preg-)]TJ 1.2503 -1.1223 TD [(nancy)-509.3(zone)-503(protein.)-506.6(Serum)-503.7(levels,)-507.5(alpha2-macroglobulin)]TJ 0 -1.1284 TD [(receptors,)-377(cellular)-368.1(synthesis)-373.8(and)-364.5(aspects)-371.1(of)-368.6(function)-372.5(in)-365.7(re-)]TJ 0 -1.1223 TD [(lation)-338.8(to)-329.1(immunology.)-335(Dan)-335.6(Med)-333.3(Bull)-339.7(4:409446.)]TJ -1.7505 -1.1284 TD [(10.)-500.5(Hope)-616.3(C,)-621(J)-615.3(Mettenburg,)-614.2(SL)-621.1(Gonias,)-615.2(ST)-615(DeKosky,)-617.5(MI)]TJ 1.7505 -1.1284 TD [(Kamboh)-664.9(and)-657.3(CT)-659.6(Chu.)-657.9(\(2003\).)-658.2(Functional)-663.7(analysis)-659.3(of)]TJ 0 -1.1223 TD (plasma)Tj /F9 1 Tf 3.4095 0 TD (a)Tj /F3 1 Tf .5489 0 TD [(2-macroglobulin)-568.1(from)-559.8(Alzheimers)-566.9(disease)-566.3(pa-)]TJ -3.9584 -1.1284 TD [(tients)-252.5(with)-251.1(the)]TJ /F7 1 Tf 5.9407 0 TD (A2M)Tj /F3 1 Tf 2.1957 0 TD [(intronic)-249.9(deletion.)-251.9(Neurobiol)-252.2(Dis)-250.6(3:504)]TJ -8.1364 -1.1223 TD (512.)Tj -1.7505 -1.1284 TD [(11.)-500.5(Kovacs)-406.4(DM.)-397.7(\(2000\).)]TJ /F9 1 Tf 10.7164 0 TD (a)Tj /F3 1 Tf .555 0 TD [(2-Macroglobulin)-403.1(in)-396.2(late-onset)-404.1(Alz-)]TJ -9.5209 -1.1223 TD [(heimers)-341.7(disease.)-334.6(Exp)-331.7(Gerontol)-337.5(4:473479.)]TJ -1.7505 -1.1284 TD [(12.)-500.5(LaMarre)-458.6(J,)-450.7(GK)-448.7(Wollenberg,)-454.6(SL)-450.3(Gonias)-450.4(and)-449.9(MA)-452.5(Hayes.)]TJ 1.7505 -1.1223 TD [(\(1991\).)-707(Cytokine)-704.3(binding)-707.4(and)-706.1(clearance)-705.3(properties)-707.8(of)]TJ 0 -1.1284 TD (proteinase-activated)Tj /F9 1 Tf 8.3377 0 TD (a)Tj /F3 1 Tf .5489 0 TD [(2-macroglobulins.)-244.2(Lab)-244.4(Invest)-243.8(1:314.)]TJ -10.6371 -1.1223 TD [(13.)-500.5(Nezu)-413.1(T,)-416.8(N)-410.4(Hosomi,)-409.3(S)-411.7(Aoki,)-410.3(K)-416.5(Deguchi,)-413.1(H)-410.4(Masugata,)-414.2(N)]TJ 1.7505 -1.1284 TD [(Ichihara,)-371.7(H)-361.6(Ohyama,)-364.3(T)-361.9(Ohtsuki,)-366.6(M)-365.3(Kohno)-362.2(and)-364.5(M)-359.2(Matsu-)]TJ 0 -1.1223 TD [(moto.)-444.9(\(2013\).)-444.7(Alpha2-macroglobulin)-446(as)-442.8(a)-443.5(promising)-440.3(bio-)]TJ 0 -1.1284 TD [(marker)-342.8(for)-346.6(cerebral)-345.3(small)-337.9(vessel)-342.4(disease)-346.7(in)-341.3(acute)-342.1(ischemic)]TJ 0 -1.1223 TD [(stroke)-335.3(patients.)-336.4(J)-334.7(Neurol)-337.8(10:26422649.)]TJ -1.7505 -1.1284 TD [(14.)-500.5(Annapoorani)-385.4(P,)-375.2(PS)-384.2(Dhandapany,)-381.7(S)-375.1(Sadayappan,)-381.1(S)-381.2(Rama-)]TJ 1.7505 -1.1223 TD [(samy,)-381.7(A)-379.9(Rathinavel)-377(and)-376.7(GS)-382.9(Selvam.)-377.2(\(2006\).)-377.6(Cardiac)-380(iso-)]TJ 0 -1.1284 TD [(form)-657.4(of)-655.2(alpha-2)-651.6(macroglobulina)-661.6(new)-652.7(biomarker)-659.9(for)]TJ 0 -1.1223 TD [(myocardial)-466.2(infarcted)-468.8(diabetic)-463.4(patients.)-464.5(Atherosclerosis)-468(1:)]TJ 0 -1.1284 TD (173176.)Tj -1.7505 -1.1223 TD [(15.)-500.5(Ho)-349.5(AS,)-346.4(CC)-351.4(Cheng,)-345.3(SC)-349.5(Lee,)-352.4(ML)-349.1(Liu,)-343.4(JY)-348.6(Lee,)-352.4(WM)-345.5(Wang)]TJ 1.7505 -1.1284 TD [(and)-395(CC)-400.2(Wang.)-393.5(\(2010\).)-395.9(Novel)-396.3(biomarkers)-396.9(predict)-394.8(liver)-396.4(-)]TJ 0 -1.1223 TD [(brosis)-342.4(in)-335.2(hepatitis)-342(C)-340.4(patients:)-342(alpha)-337.9(2)-341.7(macroglobulin,)-339.9(vita-)]TJ 0 -1.1284 TD [(min)-261.7(D)-264(binding)-256(protein)-262.6(and)-260.8(apolipoprotein)-266.6(AI.)-260.4(J)-255.4(Biomed)-265(Sci)]TJ 0 -1.1223 TD (17:58.)Tj -1.7505 -1.1284 TD [(16.)-500.5(Yu)-276.3(RZ,)-275.4(TW)-274.9(Kim,)-275.5(A)-276.2(Hong,)-276.7(TA)-272.1(Watanabe,)-284.1(HJ)-269.3(Gaus)-279.9(and)-273(RS)]TJ 1.7505 -1.1223 TD [(Geary.)-379.1(\(2007\).)-371.5(Cross-species)-373.6(pharmacokinetic)-377.1(comparison)]TJ 0 -1.1284 TD [(from)-401.2(mouse)-400.1(to)-402.3(man)-400.7(of)-399.1(a)-400.8(second-generation)-404.3(antisense)-401.4(oli-)]TJ 0 -1.1223 TD [(gonucleotide,)-275(ISIS)-273.3(301012,)-275.4(targeting)-272.6(human)-272.9(apolipoprotein)]TJ 0 -1.1284 TD [(B-100.)-337.3(Drug)-333.8(Metab)-337.2(Dispos)-335.6(3:460468.)]TJ -1.7505 -1.1223 TD [(17.)-500.5(Geary)-354.6(RS,)-349.6(TA)-345.3(Watanabe,)-351.2(L)-349.7(Truong,)-352.8(S)-344.6(Freier,)-351.8(EA)-351.4(Lesnik,)]TJ 1.7505 -1.1284 TD [(NB)-244.5(Siou,)-237.8(H)-233.5(Sasmor,)-240.8(M)-237.3(Manoharan)-247.3(and)-236.4(AA)-241.3(Levin.)-238.1(\(2001\).)]TJ 0 -1.1223 TD -.0212 Tc [(Pharmacokinetic)-275.6(p)-3(roperties)-270.5(o)-3(f)-273.7(2)]TJ /F8 1 Tf 12.3144 0 TD 0 Tc ()Tj /F3 1 Tf .2318 0 TD -.0211 Tc (O-\(2-methoxyet)Tj 6.1541 0 TD (hyl\)-modied)Tj -18.7003 -1.1284 TD .0119 Tc [(oligo)5.7(nucleoti)11.9(d)-6.1(e)-340.1(a)1.5(nalog)5.7(s)-341.1(in)-335.9(rats)11.9(.)-347.3(J)-335(Ph)5.7(armacol)-335.3(E)-2.3(x)5.7(p)-342(Ther)-338.2(3:)]TJ T* .0123 Tc [(890)6.1(897.)]TJ -1.7505 -1.1223 TD 0 Tc [(18.)-500.5(Tse)-591.2(MT.)-593.1(\(2013\).)-591.1(Regulatory)-589.2(watch:)-595.2(antisense)-590.4(approval)]TJ 1.7505 -1.1284 TD [(provides)-335.6(boost)-334.7(to)-335.2(the)-333.4(eld.)-336.5(Nat)-335(Rev)-332.7(Drug)-333.8(Discov)-334.5(12:179.)]TJ -1.7505 -1.1223 TD [(19.)-500.5(Crooke)-500.1(ST.)-499.2(\(1999\).)-499.6(Molecular)-502.3(mechanisms)-498.8(of)-502.7(action)-496.1(of)]TJ 1.7505 -1.1284 TD [(antisense)-340.4(drugs.)-331.6(Biochem)-336.5(Biophys)-333.7(Acta)-339.4(1:3144.)]TJ -1.7505 -1.1223 TD [(20.)-500.5(Bennett)-391.2(CF)-392.2(and)-382.8(EE)-394.4(Swayze.)-390.1(\(2010\).)-383.7(RNA)-392.6(targeting)-388.5(ther-)]TJ 1.7505 -1.1284 TD [(apeutics:)-371.2(molecular)-374.5(mechanisms)-370.7(of)-368.6(antisense)-370.9(oligonucleo-)]TJ 0 -1.1223 TD [(tides)-643.3(as)-644(a)-644.8(therapeutic)-647.2(platform.)-642.8(Annu)-642.6(Rev)-643.7(Pharmacol)]TJ 0 -1.1284 TD [(Toxicol)-335.3(50:259293.)]TJ -1.7505 -1.1223 TD [(21.)-500.5(Chan)-375.5(JH,)-379.2(S)-375.1(Lim)-373.4(and)-376.7(WS)-373.5(Wong.)-377.1(\(2006\).)-377.6(Antisense)-374.3(oligo-)]TJ 1.7505 -1.1284 TD [(nucleotides:)-480.8(from)-480.5(design)-479.4(to)-475.4(therapeutic)-482.6(application.)-475.5(Clin)]TJ 0 -1.1223 TD [(Exp)-337.8(Pharmacol)-335.3(Physiol)-331.2(33:533540.)]TJ -1.7505 -1.1284 TD [(22.)-500.5(Geary)-360.7(RS,)-349.6(D)-355.5(Norris,)-353.4(R)-352.6(Y)0(u)-355.6(and)-352.3(CF)-355.6(Bennett.)-354.7(\(2015\).)-353.2(Phar-)]TJ 1.7505 -1.1223 TD [(macokinetics,)-412.1(biodistribution)-402.7(and)-407.2(cell)-404.3(uptake)-405.2(of)-405.2(antisense)]TJ 9.2951 0 0 9.2951 329.329 97.5118 Tm [(oligonucleotides.)-340.6(Adv)-331.4(Drug)-333.8(Deliv)-340.8(Rev)-332.7(87:4651.)]TJ -1.7505 -1.1223 TD [(23.)-500.5(Campbell)-610.5(ZT)-601.8(and)-608.5(M)-603.2(Wickens.)-604(\(2015\).)-603.3(Probing)-603.4(RNA-)]TJ 1.7505 -1.1284 TD [(protein)-549.2(networks:)-550.2(biochemistry)-546.2(meets)-550.1(genomics.)-544.5(Trends)]TJ 0 -1.1223 TD [(Biochem)-336.5(Sci)-336.3(3:157164.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (234)Tj 46.1699 0 TD [(SHEMESH)-334(ET)-338.7(AL.)]TJ ET endstream endobj 142 0 obj <>stream /GS1 gs BT /F3 1 Tf 9.2951 0 0 9.2951 59.7543 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(24.)-500.5(Valacchi)-445.4(G,)-447(C)-438(Sticozzi,)-448.1(Y)-440.9(Lim)-440.5(and)-443.8(A)-447(Pecorelli.)-444.4(\(2011\).)]TJ 1.7505 -1.1223 TD [(Scavenger)-480.8(receptor)-475.3(class)-476.4(B)-474.6(type)-473.9(I:)-471.7(a)-474(multifunctional)-478.7(re-)]TJ 0 -1.1284 TD [(ceptor.)-340.5(Ann)-331.4(NY)-332.8(Acad)-339.9(Sci)-330.2(1229:E1E7.)]TJ -1.7505 -1.1223 TD [(25.)-500.5(Umans)-267.5(L,)-258.3(L)-264.3(Serneels,)-261.6(L)-264.3(Overbergh,)-260(L)-264.3(Stas)-262.4(and)-260.8(FV)-260.9(Leuven.)]TJ 1.7505 -1.1283 TD (\(1999\).)Tj /F9 1 Tf 3.2753 0 TD (a)Tj /F3 1 Tf .5489 0 TD [(2-Macroglobulin-)-362.9(and)-358.4(murinoglobulin-1-decient)]TJ -3.8242 -1.1223 TD [(mice.)-367.9(A)-367.7(mouse)-369.6(model)-369.9(for)-364.9(acute)-366.5(pancreatitis.)-377.6(Am)-361.3(J)-371.3(Pathol)]TJ 0 -1.1284 TD (3:983993.)Tj -1.7505 -1.1223 TD [(26.)-500.5(Umans)-328.5(L,)-331.5(L)-325.3(Serneels,)-334.8(L)-325.3(Overbergh,)-327.1(K)-331.1(Lorent,)-325.9(FV)-328(Leuven)]TJ 1.7505 -1.1284 TD [(and)-254.7(VD)-253.5(Berghe.)-260.4(\(1995\).)-249.6(Targeted)-261.4(inactivation)-255.5(of)-252.7(the)-254.1(mouse)]TJ /F9 1 Tf 0 -1.1223 TD (a)Tj /F3 1 Tf .555 0 TD [(2-macroglobulin)-336.3(gene.)-332.3(J)-334.7(Biol)-333.6(Chem)-338.5(34:1977819785.)]TJ -2.3055 -1.1284 TD [(27.)-500.5(Sharma)-331.2(VK,)-326.8(RK)-329.9(Sharma)-325.1(and)-327.9(SK)-328(Singh.)-326.4(\(2014\).)-328.9(Antisense)]TJ 1.7505 -1.1223 TD [(oligonucleotides:)-626.8(modications)-619.9(and)-614.6(clinical)-621.4(trials.)-620.9(Med)]TJ 0 -1.1284 TD [(Chem)-338.5(Commun)-334.2(10:14541471.)]TJ -1.7505 -1.1284 TD [(28.)-500.5(Beltinger)-527.4(C,)-517.3(HU)-521.9(Saragovi,)-526.6(RM)-516.7(Smith,)-520.6(L)-520.5(LeSauteur,)-526.8(N)]TJ 1.7505 -1.1223 TD [(Shah,)-465.2(L)-465.6(DeDionisio,)]TJ /F7 1 Tf 9.1245 0 TD [(et)-461.4(al.)]TJ /F3 1 Tf 2.6898 0 TD [(\(1995\).)-463(Binding,)-468.3(uptake,)-466.2(and)]TJ -11.8142 -1.1284 TD [(intracellular)-471.8(trafcking)-461.5(of)-466.2(phosphorothioate-modied)-465.3(oli-)]TJ 0 -1.1223 TD [(godeoxynucleotides.)-340.2(J)-334.7(Clin)-333.6(Invest)-335.3(4:18141823.)]TJ -1.7505 -1.1284 TD [(29.)-500.5(Crooke)-573.3(RM,)-565.5(MJ)-572(Graham,)-574(ME)-568.7(Cooke)-570.8(and)-565.8(ST)-572.3(Crooke.)]TJ 1.7505 -1.1223 TD [(\(1995\).)-365.4(In)-362.5(vitro)-361.7(pharmacokinetics)-370.3(of)-362.5(phosphorothioate)-364.2(an-)]TJ 0 -1.1284 TD [(tisense)-281(oligonucleotides.)-273.5(J)-273.7(Pharmacol)-280.4(Exp)-270.7(Ther)-277.4(1:462473.)]TJ -1.7505 -1.1223 TD [(30.)-500.5(Bijsterbosch)-623.7(MK,)-617.2(M)-615.4(Manoharan,)-619.4(ET)-620.1(Rump,)-621(RLA)-618.6(De)]TJ 1.7505 -1.1284 TD [(Vreueh,)-275.5(R)-273.3(van)-279.1(Veghel,)-272.6(KL)-278.2(Tival,)]TJ /F7 1 Tf 13.8087 0 TD [(et)-272.3(al)]TJ /F3 1 Tf 1.781 0 TD [(.)-274.5(\(1997\).)-274(In)-271(vivo)-274.5(fate)]TJ -15.5896 -1.1223 TD [(of)-380.8(phosphorothioate)-388.6(antisense)-383.1(oligodeoxynucleotides:)-387.8(pre-)]TJ 0 -1.1284 TD [(dominant)-558.8(uptake)-563.7(by)-555.3(scavenger)-562.4(receptors)-566(on)-555.3(endothelial)]TJ 0 -1.1223 TD [(cells.)-336.5(Nucleic)-337.3(Acids)-334.4(Res)-337.9(16:32903296.)]TJ -1.7505 -1.1284 TD [(31.)-500.5(Butler)-480.7(M,)-475.2(RM)-474(Crooke,)-475.8(MJ)-474.4(Graham,)-476.4(KM)-476.9(Lemonidis,)-480.8(M)]TJ 1.7505 -1.1223 TD [(Lougheed,)-328.7(SF)-323.2(Murray,)]TJ /F7 1 Tf 9.5941 0 TD [(et)-321.1(al)]TJ /F3 1 Tf 1.8359 0 TD [(.)-323.3(\(2000\).)-322.7(Phosphorothioate)-330.5(oli-)]TJ -11.43 -1.1284 TD [(godeoxynucleotides)-193.7(distribute)-193.9(similarly)-187.2(in)-188.8(class)-195.9(A)-184.7(scavenger)]TJ 0 -1.1223 TD [(receptor)-457(knockout)-450(and)-456(wild-type)-452.9(mice.)-453.3(J)-456.7(Pharmacol)-451.2(Exp)]TJ 0 -1.1284 TD [(Ther)-271.3(2:489496.)]TJ -1.7505 -1.1223 TD 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