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[(and)-332.8(hypertrophic)-338.3(brain)-335.1(natriuretic)-338.6(peptide)-338.6(signaling.)]TJ
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[(Usi)5(n)-.6(g)-265.6(t)-.8(h)5.1(i)-.8(s)-271.1(i)5(so)5.1(geni)5(c)-272.5(m)3.9(o)5.1(d)-.6(el)-271.5(we)-266.7(were)-266.7(su)5.1(cces)5.3(sf)5.2(ul)5(ly)-265.6(ab)5.1(le)-266.7(to)]TJ
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[(i)-5.7(s).4(o)-5.5(l).1(a)-6.7(t).1(e)-335(a)-.9(nd)-333.8(pe)-6.7(rf)-5.5(or)-5.5(m)-329.3(t)-5.7(ra)-6.7(ns)-5.3(cr)-5.5(ip)-5.5(to)-5.5(mic)-335(a)-.9(n)-5.5(a)-.9(l)-5.7(y).2(s)-5.3(i).1(s)-333.6(o).2(n)-333.8(E)-1(V)-6.4(s)-327.9(f)-5.5(r)-5.5(o).2(m)]TJ
0 -1.1116 TD
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[(wi)4.8(ld)-334.9(t)4.8(y)4.9(pe)-336.1(\()5(W)-3.1(T\))-334.9(an)4.9(d)-334.9(H)-1.7(CM)-335.8(car)5(d)-.8(i)4.8(o)-.8(my)4.9(ocyt)4.8(es)5.1(,)-337.2(b)4.9(ot)4.8(h)-334.9(a)-2(t)-335(b)4.9(as)5.1(e-)]TJ
25.504 67.9184 TD
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[(li)4.6(ne)-497.5(and)-496.4(i)4.6(ncr)4.8(e)-2.2(ased)-496.4(co)4.7(nt)4.6(racti)4.6(o)-1(n)-496.4(f)4.8(requ)4.7(en)4.7(cy)4.7(.)-492.9(C)-2.1(o)4.7(m)-2.3(p)4.7(a)-2.2(r)4.8(i)-1.2(s)4.9(o)-1(n)4.7(s)]TJ
0 -1.1174 TD
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[(b)-5.3(e)-.7(t)-5.5(w)-.4(e)-6.5(e)-.7(n)-621.6(t).3(h)-5.3(e)-617(HC)-6.4(M)-616.8(a)-6.5(nd)-621.6(WT)-617.1(E)-6.5(V)-616.7(tr)-5.3(an)-5.3(sc)-6.5(ri)-5.5(pt)-5.5(s)-615.7(i)-5.5(de)-6.5(nt)-5.5(i)-5.2(ed)]TJ
0 -1.1116 TD
.0228 Tc
[(mu)4.4(lt)4.3(ip)4.4(le)-319.3(fu)4.4(ncti)4.3(o)4.4(n)-1.3(al)-324(p)4.4(a)-2.5(t)4.3(h)-1.3(w)3.6(a)-2.5(y)4.4(s)-323.7(aff)4.5(e)-2.5(cted)-318.1(by)-318.1(th)4.4(e)-325(p)4.4(resence)-325(o)4.4(f)]TJ
T*
.0234 Tc
[(th)5(e)-336(d)5(is)5.2(ease)-330.2(mut)4.9(a)-1.9(t)4.9(i)-.9(o)5(n)5(.)]TJ
1.0137 -1.1116 TD
0 Tc
[(Transcriptomic)-511(analysis)-500.6(of)-503.3(cellular)-502.2(mRNA)-503.7(showed)-503.8(in-)]TJ
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[(creasing)-375.1(contraction)-367.3(frequency)-370.4(had)-367.3(a)-365.1(large)-370.8(effect)-367.3(on)-365.1(meta-)]TJ
0 -1.1116 TD
[(bolic)-479.2(gene)-473.3(expression,)-477.3(which)-474.2(was)-471.7(amplied)-479(in)-468.9(the)-476.9(HCM)]TJ
T*
[(backg)-7.8(round.)-567.6(Analysis)-569.4(of)-566.6(small)-566.7(RNA)-570.5(\()]TJ
/F8 1 Tf
16.7665 0 TD
(<)Tj
/F3 1 Tf
.5529 0 TD
[(200)-567.8(nucleotides\))]TJ
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[(showed)-382.8(HCM)-380.5(hiPSC-CMs)-386.9(altered)-380(their)-381.3(loading)-383.5(of)-376.5(specic)]TJ
0 -1.1116 TD
[(snoRNAs)-326.9(into)-315.7(EVs,)-319.6(and)-321.2(responded)-317.3(to)-319.1(increased)-325.5(contraction)]TJ
T*
[(frequency)-272.5(with)-270.5(a)-273(greater)-270.4(fold)-269.4(change)-275(in)-267.3(EV)-269.2(release)-271.4(rate,)-275.2(and)]TJ
0 -1.1174 TD
[(chang)-7.8(es)-389.1(in)-388.2(small)-393.9(RNA)-392(prole.)-391.3(The)-397.3(snoRNAs)-390.3(identied)-392.6(in)]TJ
0 -1.1116 TD
[(HCM)-311.4(EVs)-304.7(at)-308.8(baseline)-306.1(and)-309.7(during)-306.2(increased)-308.2(work)-310.5(may)-305.2(have)]TJ
T*
[(potential)-392.9(signaling)-391.4(roles)-386.7(in)-388.2(post-translational)-392.3(modications)]TJ
T*
[(\(PTMs\))-480.6(and)-476.8(alternative)-483.8(splicing.)-480.1(These)-475.4(may)-478(in)-480.4(future)-474.4(be)]TJ
0 -1.1174 TD
[(used)-339.4(as)-331.5(biomarkers)-337(or)-336.2(therapeutic)-339.7(targets.)]TJ
/F6 1 Tf
9.9626 0 0 9.9626 313.0582 540.2833 Tm
[(Mater)-8.2(ials)-337.1(and)-336.9(Method)-13.6(s)]TJ
/F9 1 Tf
0 -1.673 TD
[(hiP)-9.4(SC)-334.5(line)-7.8(s)-330.8(and)-335.7(cu)-6.4(lture)]TJ
/F3 1 Tf
9.843 0 0 9.843 323.0361 505.7573 Tm
[(I)16.2(s)0(o)26.8(g)16.2(e)15(n)0(i)26.5(c)-457.3(h)16.2(i)16(PS)26.9(C)-457.1(l)16.1(i)16.1(n)16.2(es)-446.7(w)15.3(i)16(t)16.1(h)-456.1(o)16.2(r)-456.1(wi)25.6(t)16.1(h)16.2(ou)26.6(t)-456.2(t)16.1(h)16.2(e)-457.3(c)15(.)]TJ
/F4 1 Tf
18.2064 0 TD
[(A)15(C)15.2(TC)25.7(1)]TJ
/F3 1 Tf
7.3823 0 0 6.5614 531.0424 510.1794 Tm
-.017 Tc
[(G301)6.9(A)]TJ
9.843 0 0 9.843 313.0582 494.8156 Tm
0 Tc
[(mu)25.4(t)16.1(a)15(t)16(i)0(o)26.5(n)-507.9(w)15.3(e)15(re)-498.7(g)16.2(e)15(ne)25.4(r)16.2(a)15(t)16(e)0(d)-498.7(a)15(s)-507.8(p)16.2(re)25.5(v)16.2(i)16(ou)26.6(s)16.4(l)16.1(y)-513.7(d)16.2(e)15(s)16.4(cr)25.5(i)16(b)16.2(e)15(d)-513.7(i)16(n)-507.9(d)16.2(e)15(ta)25.3(i)16(l)]TJ
0 -1.1116 TD
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0 -1.1174 TD
0 Tc
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0 -1.1116 TD
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/F8 1 Tf
9.1695 0 TD
0 Tc
()Tj
/F3 1 Tf
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[(Ca)180.7(n)206.1(d)-4.7(5)196.9(%)0(C)180.7(O)]TJ
7.3823 0 0 6.5614 459.3259 460.2896 Tm
0 Tc
(2)Tj
9.843 0 0 9.843 462.8408 461.9337 Tm
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[(.)-203.5(h).4(iP)-15.8(S)11.1(C)-.7(s)-201(w)-.5(er)-15.8(e)-186.2(r)-15.8(o)10.8(u).4(ti)-15.8(n)10.7(e)-.8(ly)]TJ
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0 Tc
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T*
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0 -1.1174 TD
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0 -1.1116 TD
0 Tc
[(no)26.6(l)16.1(o)16.2(gi)26.5(e)15(s)16.4(\))-248.7(e)15(v)16.2(e)15(ry)-232.6(3)-243(d)0(a)25.4(y)16.2(s)16.4(,)-245.3(a)15(n)0(d)-232.6(u)16.2(se)25.6(d)-243(b)16.2(et)25.3(w)15.3(e)15(e)15(n)-248.8(p)16.2(a)15(s)16.4(s)0(a)25.6(g)16.2(e)15(s)-248.6(2)16.2(0)-243(an)25.4(d)-243(3)16.2(0.)]TJ
/F9 1 Tf
9.9626 0 0 9.9626 313.0582 397.644 Tm
[(hiP)-9.4(SC-CM)-339.8(differ)-8(entiatio)-9.1(n)-330(and)-341.4(electrical)-343.9(stimulatio)-11.6(n)]TJ
/F3 1 Tf
9.843 0 0 9.843 323.0361 379.7857 Tm
[(Cardiomyocyte)-314.1(differentiation)-320.1(was)-310.4(performed)-312.9(by)-307.5(seeding)]TJ
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[(hiPSCs)-456.5(on)-445.7(MT)-453.6(\(Corning\)-coated)-454.3(plastic)-448(ware)-456.8(at)]TJ
/F10 1 Tf
20.7925 0 TD
(*)Tj
/F3 1 Tf
1.0022 0 TD
(2040)Tj
-21.7947 -1.1116 TD
[(thousa)-7.7(nd)-393.9(cells/cm)]TJ
7.3823 0 0 6.5614 385.5684 362.2676 Tm
(2)Tj
9.843 0 0 9.843 389.2534 357.9023 Tm
[(.)-400.8(Fresh)-392.2(E8)-400.8(was)-396.8(added)-393.7(the)-402(next)-391.6(day)-401.9(and)]TJ
-7.741 -1.1174 TD
[(the)-419.3(preconditioning)-411(step)-414.4(of)-416.9(hiPSC)-409.5(was)-419.8(performed)-416.6(the)-413.5(day)]TJ
0 -1.1116 TD
[(after,)-587.3(by)-583.9(adding)-583.9(an)-579.3(MT)-586(overlay)-586.1(\()-81.7(M)0(T)-580.3(diluted)-585.2(1:100)-581.6(in)]TJ
T*
(StemPro)Tj
/F8 1 Tf
3.4501 0 TD
()Tj
/F3 1 Tf
1.2959 0 TD
[(34-Serum)-414.2(Free)-415.5(Medium,)-410.9(SP34;)-414.3(Gibco\))-411.9(supple-)]TJ
-4.746 -1.1116 TD
[(mented)-471.1(with)-460.5(1)-168.1(ng/mL)-463.1(BMP4)-467(\(R&D\).)-467(Approximately)-468.4(16)-163.5(h)]TJ
0 -1.1174 TD
[(later,)-512.6(medium)-505.7(was)-506.2(replaced)-514.7(by)-503.3(SP34)-505.2(supplemented)-513.3(with)]TJ
0 -1.1116 TD
[(8)-168.1(ng/mL)-290.3(Activin)-292.4(A)-284.2(\(ActA;)-292(LifeTechnologies\))-296.6(and)-292.4(10)-163.5(ng/mL)]TJ
T*
[(BMP4.)-499.2(Forty-eight)-503(hours)-494.9(later,)-501.1(medium)-499.9(was)-494.7(chang)-7.8(ed)-492.9(by)]TJ
0 -1.1174 TD
[(RPMI)-714.6(supplemented)-714.9(with)-714(B27)-712.8(without)-711.7(insulin)-716.3(\()]TJ
/F8 1 Tf
21.8581 0 TD
(-)Tj
/F3 1 Tf
.5529 0 TD
(INS;)Tj
-22.411 -1.1116 TD
[(LifeTechnologie)-12.4(s\))-808.3(and)-810.8(KY0211)-809(\(R&D\))-814.9(and)-810.8(XAV939)]TJ
T*
[(\(R&D\),)-300(both)-292.5(at)-297.2(100)]TJ
/F10 1 Tf
8.1442 0 TD
(m)Tj
/F3 1 Tf
.5529 0 TD
[(M.)-293.4(These)-296.8(small)-295.9(molecules)-302.7(were)-295.6(added)]TJ
-8.6972 -1.1174 TD
[(again)-416.9(2)-415.8(days)-414.3(later,)-414.7(in)-411.3(RPMI)-415.1(supplemented)-421.2(with)-414.5(B27)-413.3(with)]TJ
0 -1.1116 TD
[(insulin)-336.2(\()]TJ
/F8 1 Tf
3.3982 0 TD
(+)Tj
/F3 1 Tf
.5529 0 TD
[(INS;)-333.5(LifeTechnologies\))-342.7(instead.)]TJ
-2.9375 -1.1116 TD
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[(Th)6.5(er)6.6(ea)5.4(fte)5.4(r).8(,)-519.9(m)-.4(e)5.4(d).8(i)6.4(u).8(m)-524.6(w)5.7(as)-523.2(ch)6.5(an)6.5(ge)5.4(d)-523.3(e)-.4(v)6.5(e)-.4(ry)-523.3(2)6.5().8(3)-523.4(d)6.5(ay)6.5(s)-528.9(b)6.5(y)]TJ
-1.0137 -1.1116 TD
.0104 Tc
[(fresh)-244.1(RPMI)]TJ
/F8 1 Tf
4.7748 0 TD
0 Tc
(+)Tj
/F3 1 Tf
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.0103 Tc
(B27)Tj
/F8 1 Tf
1.6934 0 TD
0 Tc
(+)Tj
/F3 1 Tf
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.0124 Tc
[(I)5.6(N)-1.1(S)-242(u)5.5(nt)5.4(il)-242.3(d)5.5(a)-1.4(y)-242.1(1)5.5(5)-242.1(o)-.2(f)-242.1(d)5.5(if)5.6(fer)5.6(e)-1.4(n)5.5(t)-.3(i)5.4(a)-1.4(t)5.4(i)-.3(on)5.5(,)-244.5(w)4.7(hen)]TJ
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[(hiP)4.6(S)-1.2(C-CM)-290.2(were)-290.5(repl)4.3(at)4.3(ed,)-285.9(a)-2.5(n)4.4(d)-289.3(kept)-289.4(in)-289.3(RPMI)]TJ
/F8 1 Tf
18.3619 0 TD
0 Tc
(+)Tj
/F3 1 Tf
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.0131 Tc
(B27)Tj
/F8 1 Tf
1.6991 0 TD
0 Tc
(+)Tj
/F3 1 Tf
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.0069 Tc
[(IN)-6.6(S)-293.5(f)-5.7(or)]TJ
/F10 1 Tf
-21.334 -1.1116 TD
0 Tc
(*)Tj
/F3 1 Tf
1.0137 0 TD
[(1)-6.9(0)-312.1(d)-12.6(a)-8(y)-12.6(s)-311.9(wh)20(en)-279.8(el)13.8(ec)18.5(tr)20.7(ic)19.6(al)-285.7(st)20.9(im)19.5(ul)20.7(at)19.5(io)20.7(n)-294.8(a)0(n)19.7(d)-289.1(ex)13.9(os)21(om)19.6(e)-290.2(i)0(s)15.1(o)0(l)20.7(a)0(t)19.5(i)0(o)20.7(n)]TJ
-.864 -1.1116 TD
[(as)14.1(sa)19.9(ys)-324.6(we)18.8(re)-331.6(pe)19.7(rf)20.9(or)20.9(me)18.4(d.)-327.1(El)19.5(ec)18.5(tr)15(ic)19.5(al)-326(pa)19.7(ci)19.5(ng)-330.5(of)-324.7(th)20.7(e)-336.3(h)0(i)14.9(P)0(S)21.2(C)0(-)19.8(C)0(M)18.9(s)]TJ
0 -1.1174 TD
[(wa)13(s)-271.6(p)0(e)19.7(r)0(f)20.9(o)0(r)15.1(m)0(e)18.4(d)-271.8(wi)19.8(th)-267.3(co)19.7(nd)20.8(it)20.6(io)20.7(ns)-267(of)-261.4(1)-156.6(V)0(/)14.1(2)-156.6(Hz)18.8(,)-274.1(i)0(m)19.5(p)0(u)20.8(l)0(s)20.9(e)-278.7(du)20.8(ra)19.7(ti)20.6(on)]TJ
0 -1.1116 TD
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/F9 1 Tf
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[(EV)-341(isolatio)-10.3(n)-330(and)-335.7(c)-6.5(haracte)-6.9(rization)]TJ
/F3 1 Tf
9.843 0 0 9.843 323.0361 111.3448 Tm
[(The)-564.4(conditioned)-567.8(media)-562.1(was)-563.8(centrifuged)-568.7(at)-562.2(300)]TJ
/F4 1 Tf
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(g)Tj
/F3 1 Tf
1.0598 0 TD
(for)Tj
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[(10)-169.2(min,)-342.2(200)]TJ
/F4 1 Tf
5.1607 0 TD
(g)Tj
/F3 1 Tf
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[(for)-337.3(10)-169.2(min,)-336.4(and)-338.5(10,000)]TJ
/F4 1 Tf
9.6993 0 TD
(g)Tj
/F3 1 Tf
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[(for)-343.1(30)-163.5(min)-338.7(at)-343.3(room)]TJ
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[(temperatur)-10.2(e.)-305.2(The)-310.9(resulting)-310.7(supernatant)-315.2(was)-310.4(concentrated)-313(by)]TJ
T*
[(Vivaspin-20)-532.6(\(100)-528.5(MWCO\))-528.9(protein)-527.5(concentration)-531.9(column)]TJ
0 -1.1174 TD
[(\(Sigma)-348.8(Aldrich\))-345.1(following)-345.2(the)-344.4(manufacturers)-349.4(directions)-347.6(to)]TJ
0 -1.1116 TD
[(a)-336.3(total)-335.4(volume)-337.4(of)-330.5(500)]TJ
/F10 1 Tf
9.0888 0 TD
(m)Tj
/F3 1 Tf
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(L.)Tj
/F6 1 Tf
8.9663 0 0 8.9663 62.022 749.6502 Tm
(1216)Tj
47.6684 0 TD
[(JAMES)-333.5(ET)-338.7(AL.)]TJ
ET
endstream
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/GS1 gs
BT
/F3 1 Tf
9.843 0 0 9.843 69.7323 725.1588 Tm
0 0 0 rg
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0 Tw
[(Th)4.9(e)-353.3(c)-2(o)4.9(n)-.8(cen)4.9(t)-.9(rated)-352.2(s)-.6(up)4.9(er)5(nata)]TJ
11.4906 0 TD
.0123 Tc
[(nt)-351.8(was)-351.5(a)-1.5(pp)5.4(li)5.3(ed)-351.7(t)5.3(o)-357.4(a)-352.8(q)5.4(EVor)5.5(i-)]TJ
-12.5043 -1.1174 TD
.0119 Tc
[(gin)5(a)-1.9(l)-438.6(\()-.7(7)5(0)-167.7(n)5(m)-1.9(\))-438.4(s)-.5(ize)-445.4(e)3.9(xclu)5(sio)5(n)-444.2(chro)5(mato)5(gr)5.1(ap)5(hy)-444.2(\()5.1(S)-.6(EC\))-438.4(c)-1.9(o)5(l)-.8(-)]TJ
0 -1.1116 TD
[(umn)-755.1(a)-1.8(n)5.1(d)-755.1(EVs)-754.9(i)5(sol)5(a)-1.8(t)5(e)-1.8(d)-755.1(a)4(ccor)5.2(din)5.1(g)-755.1(t)5(h)-.6(e)-756.3(m)3.9(an)5.1(uf)5.2(actur)5.2(e)-1.8(r)5.2()-.6(s)]TJ
T*
.0097 Tc
[(dire)-4.1(ction.)-368.1(T)-4.1(h)2.8(e)-372.7(r)-2.9(esulting)-365.8(EV)-3.8(s)-371.3(w)]TJ
13.0688 0 TD
.0132 Tc
[(er)6.4(e)-369.2(s)6.5(ub)6.3(je)5.2(ct)-362.4(to)-362.3(wes)6.5(t).5(e)5.2(r).6(n)-362.3(b).6(l)6.2(o).6(t)]TJ
-13.0688 -1.1116 TD
.0122 Tc
[(an)5.3(aly)5.3(s)-.2(i)5.2(s)-265.2(o)5.3(f)-259.6(tet)5.2(r)-.4(aspani)5.2(n)-259.6(m)-1.6(ark)5.3(e)-1.6(r)-259.6(C)-1.4(D9,)-261.9(c)4.2(yt)5.2(oso)5.3(l)-.5(i)5.2(c)-260.8(mark)5.3(er)-259.6(Al)5.2(ix,)]TJ
0 -1.1174 TD
[(an)5.3(d)-276.9(a)-278(Go)5.3(lg)5.3(i)-277(m)-1.6(ark)5.3(e)-1.6(r)-276.8(n)5.3(egati)5.2(v)-.4(e)-278(c)4.2(on)5.3(tr)5.4(ol)-277(GM13)5.3(0.)-273.5(In)-276.9(b)5.3(r)-.4(i)5.2(e)-1.6(f,)-273.5(EVs)]TJ
0 -1.1116 TD
.012 Tc
[(an)5.1(d)-369.2(c)4(el)5(ls)-363.3(were)-364.6(resu)5.1(spend)5.1(e)-1.8(d)-363.5(i)-.7(n)-363.5(R)4.1(IPA)-364.3(b)5.1(uff)5.2(er)-363.4(su)5.1(pp)5.1(lemented)]TJ
T*
.0071 Tc
[(w)-6.4(i).1(t)-5.6(h)-483.6(pr)-5.5(ot)-5.6(e)-6.7(a)-.9(s)-5.3(e)-479(i)-5.6(n).2(h)-5.5(i)-5.6(bi)-5.6(to)-5.5(r)-483.5(c)-.9(o)-5.5(c)-.9(k)-5.5(t).1(a)-6.7(i).1(l)-483.7(\()-5.5(Pr)-5.5(om)-6.7(eg)-5.5(a\))-5.5(.)-480.1(P)-5.4(ro)-5.5(t)-5.6(e)-.9(i)-5.6(n)-477.8(c)-6.7(o).2(n)-5.5(-)]TJ
0 -1.1174 TD
.0134 Tc
[(ce)5.4(ntr)6.6(a)-.4(t)6.4(i).7(o)6.5(n)-333.3(wa)5.4(s)-338.8(d)6.5(et)6.4(er)6.6(mi)6.4(ne)5.4(d)-333.3(b).8(y)-333.3(t)]TJ
12.9881 0 TD
.0118 Tc
[(h)4.9(e)-336(Qu)4.9(bi)4.8(t)-335(pro)4.9(tein)-334.9(assay)-334.9(\()-.8(I)5(n)-.8(-)]TJ
-12.9881 -1.1116 TD
.0122 Tc
[(vit)5.2(r)-.4(o)5.3(g)-.4(en\),)-377.1(and)-380.6(2)5.3(0)]TJ
/F10 1 Tf
7.4646 0 TD
0 Tc
(m)Tj
/F3 1 Tf
.5645 0 TD
.0132 Tc
[(g)-379.6(o)6.3(f)-385.3(p)6.3(rot)6.2(ei)6.2(n)-385.3(p)6.3(er)-379.5(EV)-380.4(sa)5.2(mp)6.3(le)-380.7(a)5.2(n).6(d)-379.6(1).6(0)]TJ
/F10 1 Tf
15.1999 0 TD
0 Tc
(m)Tj
/F3 1 Tf
.5645 0 TD
(g)Tj
-23.7933 -1.1116 TD
.0132 Tc
[(pe)5.2(r)-494.7(c)-.6(e)5.2(l).5(l)-494.9(s)6.5(am)5.1(pl)6.2(e)-495.9(w)-.3(e)5.2(r).6(e)-490.2(s).8(ep)6.3(ar)6.4(at)6.2(ed)-494.7(b)6.3(y)-494.7(SD)5.5(S-)6.4(PAG)5.5(E)-495.9(o)6.3(n)-494.8(10)6.3(%)]TJ
0 -1.1174 TD
.0122 Tc
[(pol)5.2(yacr)5.4(yl)5.2(amid)5.3(e)-266.5(g)5.3(el)5.2(s)-265.2(\()5.4(Bi)5.2(oRad\))5.4(.)-261.9(Pr)5.4(ot)5.2(ein)5.3(s)-259.4(wer)5.4(e)-260.8(trans)5.5(f)-.4(erred)-265.4(t)5.2(o)]TJ
0 -1.1116 TD
.012 Tc
[(nit)5(r)-.6(o)5.1(c)-1.8(ell)5(u)-.6(lo)5.1(se)-335.8(membr)5.2(a)-1.8(n)5.1(e)-335.8(us)5.3(in)5.1(g)-334.7(t)-.7(he)-330.1(Bi)5(oRad)-334.7(Tran)5.1(sb)5.1(lo)5.1(t)-334.8(T)-1.8(u)5.1(r)-.6(-)]TJ
T*
[(bo)-328.8(Sy)5.2(stem.)]TJ
1.0137 -1.1116 TD
0 Tc
[(Membranes)-516.4(were)-514.4(blocked)-511.3(for)-510.1(1)-168.1(h)-507.9(in)-509.2(5%)-510.1(\(w/v\))-513.3(bovine)]TJ
-1.0137 -1.1174 TD
[(serum)-456.9(albumin)-453.9(\(BSA\))-456.4(in)-451.6(TBST.)-454.6(Primary)-453.5(antibodies)-457(were)]TJ
0 -1.1116 TD
[(incubated)-336.2(for)-331.5(18)-169.2(h)-329.4(a)0(t)-331.8(4)]TJ
/F8 1 Tf
9.2962 0 TD
()Tj
/F3 1 Tf
.3974 0 TD
[(C)-330.4(a)0(t)-331.8(a)-330.6(1:1,000)-332.7(dilution)-331.9(in)-336.4(3%)-331.6(\(w/v\))]TJ
-9.6936 -1.1116 TD
[(BSA)-546.5(in)-543.7(TBST)-549.1(as)-544.6(follows:)-545.5(CD9)-546.6(\(D801A\),)-548.5(Alix)-541.2(\(3A49\),)]TJ
0 -1.1174 TD
[(and)-597.7(GM130)-594.8(\(D6B1\))-601.7(\(Cell)-595.4(Signaling\).)-597.5(Membranes)-602.8(were)]TJ
0 -1.1116 TD
[(washed)-343.7(three)-342(times)-342(in)-336.4(TBST)-341.7(for)-337.3(10)-169.2(min,)-336.4(followed)-339.4(by)-342(a)-336.3(60-)]TJ
T*
[(min)-453.9(incubation)-457.2(with)-454.8(either)-452.7(HRP-conjugated)-458.6(anti-rabbit)-458.4(or)]TJ
0 -1.1174 TD
[(anti-mouse)-544.5(secondary)-543.1(antibody)-540.1(\(Cell)-537.8(Signaling\))-542.3(at)-539.1(room)]TJ
0 -1.1116 TD
[(temperature.)-315.4(Membranes)-309.1(were)-312.8(washed)-309.1(three)-307.4(times)-307.5(in)-307.6(TBST)]TJ
T*
[(for)-700.2(10)-163.5(min,)-699.3(followed)-696.5(by)-699.1(incubation)-699.1(with)-696.7(Clarity)-701.4(ECL)]TJ
0 -1.1174 TD
[(\(BioRad\))-461.4(and)-453.7(visualization)-461.8(using)-454.7(the)-459.6(BioRad)-453.5(GelDoc)-460.1(Go)]TJ
0 -1.1116 TD
[(Imaging)-338.5(System.)]TJ
1.0137 -1.1116 TD
.0255 Tc
[(The)-322.3(s)1.6(iz)-5.6(e)-316.6(a).2(nd)-315.4(concentration)-321.2(o)1.4(f)-321.1(E).2(Vs)-321(was)-321(d)1.4(ete)-5.6(r)1.4(mined)-321.2(b)1.4(y)]TJ
-1.0137 -1.1116 TD
.0245 Tc
[(e)-6.6(l).2(ectrop)-5.4(hores)-5.2(i).2(s)-391.1(a)-.8(nd)-391.3(Bro)-5.4(w)-.5(nian)-391.3(moti)-5.5(on)-391.3(analys)-5.2(is)-391.1(usi)-5.5(n).4(g)-391.3(l).2(a-)]TJ
0 -1.1174 TD
[(s)-5.2(e)-.8(r)-512.2(s).6(cat)-5.5(tering)-518(microsc)-6.6(opy)-512.2(and)-512.2(t)-5.5(he)-513.4(resul)-5.5(ting)-512.2(E)-.8(Vs)-517.8(were)]TJ
0 -1.1116 TD
.0255 Tc
[(a)-5.6(l)1.2(so)-459.4(characterized)-459.4(by)-459.4(nanosight)-465.3(and)-459.4(t)1.2(ransmission)-459.4(e)-5.6(lec-)]TJ
T*
.0245 Tc
[(t)-5.5(ron)-650.5(micros)-5.2(copy)-650.5(and)-650.5(t).2(he)-651.6(Nan)-5.4(o).4(sigh)-5.4(t)-644.9(L)-.8(M1)-5.4(0)-644.7(\()-86(Mal)-5.5(v).4(ern)]TJ
0 -1.1174 TD
[(P)-5.2(a)-.8(nalyt)-5.5(i).2(cal\).)]TJ
1.0137 -1.1116 TD
0 Tc
[(Finally,)-525.2(EVs)-529.3(were)-525.9(visualized)-527.3(by)-520.6(transmission)-528(electron)]TJ
-1.0137 -1.1116 TD
[(microscopy)-602(for)-590.7(ultrastructural)-602.1(characterization.)-599.9(EV)-597.5(SEC)]TJ
0 -1.1174 TD
[(elutes)-400.7(were)-399.2(xed)-391.3(at)-395.2(a)-399.7(1:1)-395.1(ratio)-392.8(in)-399.7(4%)-394.9(\(v/v\))-391.5(paraformalde-)]TJ
0 -1.1116 TD
[(hyde)-443.3(\(PFA\))-443.7(in)-434.3(cacodylate)-449.1(buffer)-439.7(for)-441(18)-169.2(h.)-436.5(The)-443.4(xed)-437.4(EVs)]TJ
T*
[(were)-871.5(seeded)-868.1(onto)-862.7(0.1%)-866(poly-)]TJ
/F7 1 Tf
14.117 0 TD
(l)Tj
/F3 1 Tf
.5011 0 TD
[(-lysine-treated)-868.1(carbon/)]TJ
-14.6181 -1.1116 TD
[(formvar)-251.9(slot)-246.4(grids)-247.3(\(EM)-247.3(resolution\))-249.6(and)-246.4(embedded)-249.7(for)-245.1(30)-169.2(min)]TJ
0 -1.1174 TD
[(at)-493.1(room)-495.2(temperature.)-493.9(The)-489.5(grids)-495(were)-491.4(washed)-493.4(twice)-498.5(with)]TJ
0 -1.1116 TD
[(distilled)-351.3(water)-348.6(and)-350(stained)-344.2(with)-351.1(1%)-343.1(aqueous)-349.7(uranyl)-347.7(acetate)]TJ
T*
[(and)-401.9(left)-403.2(to)-399.7(air)-407.7(dry.)-398.4(Transmission)-408.1(electron)-404.2(microscopy)-400.4(was)]TJ
0 -1.1174 TD
[(carried)-282(out)-268.4(\(T)-274.1(100KEV;)-275.7(FEI)-275(Tecnai)-276.4(Biotwin-12\))-279.3(with)-270.5(a)-278.7(side)]TJ
0 -1.1116 TD
[(mount)-335.2(megaview)-337.1(III)-337.3(camera.)]TJ
/F9 1 Tf
9.9626 0 0 9.9626 59.7543 238.8472 Tm
[(RNA)-339.2(isol)-8.6(ation)-337.4(and)-335.7(bioi)-7.8(nformat)-7.5(ics)-335.5(analysis)]TJ
/F3 1 Tf
9.843 0 0 9.843 69.7323 221.0456 Tm
.0075 Tc
[(R)-6.1(N)-.2(A)-363.1(w)-.2(a)-6.3(s)-362(ex)-5.1(tr)-5.1(ac)-6.3(te)-6.3(d)-362.2(u).6(s)-4.9(i).5(n)-5.1(g)-356.5(t)-5.2(h)-5.1(e)-357.6(m)-6.3(iR)-6.1(Ne)-6.3(as)-4.9(y)-362.2(m)-.6(iR)-6.1(N)-6(A)-357.3(i)-5.2(s).8(o)-5.1(l).5(a)-6.3(-)]TJ
-1.0137 -1.1174 TD
.012 Tc
[(tio)5.1(n)-334.7(m)-1.8(i)5(n)-.6(i)-334.8(k)-.6(i)5(t)-334.8(\(Qi)5(a)-1.8(g)5.1(e)-1.8(n)5.1(\))-.6(.)-337(R)4.1(NA)-335.5(was)-334.5(prepared)-340.4(f)5.2(or)-334.6(sequ)5.1(en)5.1(cin)5.1(g)]TJ
0 -1.1116 TD
.0123 Tc
[(usi)5.3(n)-.3(g)-489.9(t)5.3(he)-491.1(NEBNext)-490(l)5.3(ib)5.4(rar)5.5(y)-489.9(pr)5.5(ep)5.4(ar)5.5(ati)5.3(o)-.3(n)-489.9(k)5.4(it)5.3(s)-489.7(f)-.3(o)5.4(r)-489.9(the)-485.3(c)-1.5(ell)]TJ
T*
[(lin)5.4(es)-374.5(an)5.4(d)-380.5(t)-.4(h)5.4(e)-381.6(NEBNex)5.4(t)-380.6(L)4.2(ow)-375.6(Inp)5.4(ut)-374.8(lib)5.4(rary)-380.5(p)5.4(r)-.3(eparat)5.3(io)5.4(n)-380.5(k)5.4(it)]TJ
T*
.0114 Tc
[(for)-335.2(t)4.4(h)-1.2(e)-336.4(E)3.4(V)-336.1(s)-1(amp)4.5(l)-1.3(es)-335.1(\(New)-336.1(Engl)4.4(an)4.5(d)-335.3(B)-2.2(i)4.4(o)-1.2(l)4.4(a)-2.4(b)4.5(s)-1(\).)-331.8(Th)4.5(e)-336.4(R)-2.2(NAseq)]TJ
0 -1.1174 TD
.0117 Tc
[(was)-329(c)-2.1(arri)4.7(ed)-323.5(ou)4.8(t)-329.3(a)-2.1(t)-323.6(t)-1(he)-324.6(Bart)4.7(s)-329(G)-1.8(eno)4.8(m)-2.1(e)-330.4(C)3.8(en)4.8(tr)4.9(e)-330.4(\()-.9(Queen)-323.5(M)-1.8(ary)]TJ
0 -1.1116 TD
.0071 Tc
[(U)-6.4(n).2(i)-5.6(v)-5.5(er)-5.5(si)-5.6(t)-5.6(y)-276.2(of)-276.2(L)-6.7(o).2(n)-5.5(d)-5.5(o).2(n)-5.5(\))-276.2(u)-5.5(s).4(i)-5.6(n).2(g)-276.2(t)-5.6(h)-5.5(e)-277.4(Ne)-6.7(xt)-5.6(Se)-6.7(q)-276.2(5)-5.5(00)-276.2(H)-6.4(i)-5.6(gh)-276.2(O)-6.4(u).2(t)-5.6(p)-5.5(ut)]TJ
T*
.0119 Tc
[(Ru)5(n)-236.9(\()5.1(15)5(0)-236.9(c)3.9(ycles\))-231.1(for)-231.1(all)-231.2(s)-.5(amp)5(l)-.8(es)5.2(.)-233.4(T)-1.9(h)5(e)-232.3(sequencin)5(g)-236.9(d)5(at)4.9(a)-232.3(w)-1.6(er)5.1(e)]TJ
0 -1.1174 TD
.0071 Tc
[(a)-6.7(n).2(a)-6.7(l)-5.6(yz)-6.7(ed)-310.8(u)-5.5(s).4(i)-5.6(n)-5.5(g)-310.8(a)-311.9(pi)-5.6(pe)-6.7(li)-5.6(n)-5.5(e)-311.9(co)-5.5(ns)-5.3(is)-5.3(t)-5.6(i).1(n)-5.5(g)-310.8(of)-316.5(Fa)-6.7(st)-5.6(QC)-311.8(f)-5.5(o)-5.5(r)-310.8(qu)-5.5(al)-5.6(i)-5.6(t).1(y)]TJ
0 -1.1116 TD
.0131 Tc
[(co)6.2(ntr)6.3(o).5(l)6.1(,)-445.3(Sk)6.2(ew)5.4(er)-443([)6.3(2).5(8)6.2(])-448.7(f)6.3(o).5(r)-443(r)6.3(ea)5.1(d)-443(t).4(ri)6.1(mm)5(in)6.2(g,)-439.6(Hi)6.1(Sa)5.1(t2)-443([2)6.2(9])-443(f)6.3(o).5(r)]TJ
T*
.0122 Tc
[(read)-622.5(al)5.2(ig)5.3(nmen)5.3(t)-628.4(\()5.4(to)-622.5(GRch)5.3(38)-622.5(bu)5.3(il)5.2(d\))5.4(,)-624.8(S)-.3(t)5.2(r)-.4(in)5.3(gTie)-623.6([)5.4(30])-622.4(f)5.4(o)-.4(r)]TJ
0 -1.1174 TD
.0132 Tc
[(tra)5.2(n).6(s)6.5(c)-.6(r)6.4(i).5(pt)-281.8(qu)6.3(an)6.3(ti)6.2(ca)5.2(t).5(i)6.2(o).6(n)6.3(,)-284(an)6.3(d)-287.4(D)5.5(ESe)5.2(q).6(2)-281.6([).6(3)6.3(1).6(])-281.6(a)-.6(n)6.3(d)-287.4(Sn)6.3(ak)6.3(em)5.1(ak)6.3(e)]TJ
0 -1.1116 TD
[([32)6.3(])-339.2(t).5(o)-339.2(c)-.6(a)5.2(l).5(c)5.2(u).6(l)6.2(a)-.6(t)6.2(e)-346.2(d)6.3(i).5(f)6.4(f).6(e)5.2(r).6(en)6.3(ti)6.2(al)-339.4(e)5.2(xpr)6.4(es)6.5(sio)6.3(n).6(.)-341.6(P)6.5(at)6.2(hw)5.5(ay)-339.2(an)6.3(al)6.2(ys)6.5(is)]TJ
T*
.0115 Tc
[(was)-703.6(c)3.5(on)4.6(ducted)-698(u)-1.1(si)4.5(ng)-698(PANTHE)]TJ
14.117 0 TD
.7106 Tc
[(RV)697.1(1)703.7(6)698(.)701.4(0)1.1(C)697(l)703.6(a)696.8(s)703.9(s)698.2(i)697.9()703.9(c)696.8(a)702.6(t)697.9(i)703.6(o)698(n)]TJ
-14.117 -1.1174 TD
.0091 Tc
[(System)-425.2(\(w)-4.4(ww)-4.4(.panth)]TJ
8.5013 0 TD
.0111 Tc
[(erd)4.2(b)-1.5(.or)4.3(g)-1.5(\))4.3(.)-424.3(Vol)4.1(c)-2.7(ano)-416.2(p)-1.5(l)4.1(o)-1.5(ts)-416(were)-417.4(gener-)]TJ
-8.5013 -1.1116 TD
.0132 Tc
[(at)6.2(ed)-327.7(usi)6.2(n).6(g)-327.7(V)-.3(o)6.3(l).5(c)5.2(a)-.6(N)5.5(o).6(se)5.2(R.)]TJ
/F6 1 Tf
9.9626 0 0 9.9626 310.8472 725.0455 Tm
0 Tc
(Results)Tj
/F9 1 Tf
0 -1.673 TD
[(Transcr)-7.5(iptomi)-9.1(c)-330.8(analysi)-9.3(s)-330.8(o)0(f)-339.2(HCM)-337.2(hiPS)-9.2(C-CM)-340(model)]TJ
/F3 1 Tf
9.843 0 0 9.843 320.8251 690.5195 Tm
[(Skin-punch)-559.3(biopsies)-557(were)-566.3(previously)-559.4(obtained)-558.6(from)-558.5(a)]TJ
-1.0137 -1.1116 TD
[(48-year)-309.5(old)-308.7(male)-313.4(patient)-315.7(carrying)-310.7(the)-309.9(c.)]TJ
/F4 1 Tf
16.1675 0 TD
(ACTC1)Tj
/F3 1 Tf
7.3823 0 0 6.5614 499.5211 683.9431 Tm
[(G301)-9.1(A)]TJ
9.843 0 0 9.843 524.296 679.5778 Tm
(HCM-)Tj
-21.6853 -1.1116 TD
[(causing)-349.8(mutation)-357.2(and)-350(reprogrammed)-358.9(to)-347.9(hiPSCs)-352.8(under)-352.2(ethi-)]TJ
0 -1.1174 TD
[(cal)-368.6(consent)-367.1(by)-370.8(labs)-368.4(in)-365.2(Nottingham)-371.8(\(REC)-370.5(ref:09/H0408/74\))]TJ
0 -1.1116 TD
[([26].)-272.7(Isogenic)-270.2(WT)-270.6(controls)-275(were)-272.5(generated)-279.6(for)-268.2(these)-272.7(hiPSCs)]TJ
T*
[(using)-397.1(a)-393.9(footprint-free)-398.1(PiggyBac-based)-401(CRISPR/Cas9)-402.9(strat-)]TJ
T*
[(egy)-344.3([27].)-341.8(Di)19.8(ff)20.9(er)13.9(en)19.7(ti)20.6(at)19.5(io)20.7(n)-335.2(o)0(f)-324.7(t)0(h)20.7(e)0(s)19.9(e)-330.6(hi)14.9(PS)21.2(C)-330.4(l)0(i)14.8(n)0(e)19.7(s)-329.2(to)-324.9(hi)20.7(gh)-324.7(pu)20.8(ri)20.7(ty)]TJ
0 -1.1174 TD
(\()Tj
/F8 1 Tf
.3225 0 TD
(>)Tj
/F3 1 Tf
.5414 0 TD
[(90)20.8(%)]TJ
/F10 1 Tf
2.0389 0 TD
(a)Tj
/F3 1 Tf
.5414 0 TD
[(-a)19.7(ct)19.5(in)15(in)]TJ
/F8 1 Tf
7.3823 0 0 6.5614 374.2298 618.1794 Tm
(+)Tj
/F3 1 Tf
9.843 0 0 9.843 378.1983 613.814 Tm
[(\))-225.7(c)0(a)18.5(r)0(d)20.9(i)0(o)15(m)0(y)19.6(o)0(c)19.7(y)0(t)20.7(e)0(s)-216.3(\()0(h)20.9(i)0(P)20.9(S)0(C)14.2(-)0(C)19.8(M)0(s)20.1(\))-225.7(pr)20.9(od)20.8(uc)19.7(ed)-216.5(an)]TJ
-6.8425 -1.1116 TD
[(in)-388.2(vi)20.7(tr)20.7(o)-404.3(m)0(o)19.6(d)0(e)19.7(l)-398.6(in)-388.2(wh)20(ic)13.8(h)-398.5(t)0(h)20.7(e)-399.7(mu)19.6(ta)19.6(nt)-388.2(ce)12.8(ll)20.6(s)-398.3(d)0(i)20.7(s)0(p)15.3(l)0(a)19.5(y)0(e)19.7(d)-398.5(ch)19.7(ar)19.7(ac)18.5(-)]TJ
T*
[(te)19.6(ri)20.7(st)20.9(ic)-372.1(HC)18.9(M)-376.4(p)0(h)20.8(e)0(n)19.7(o)0(t)20.7(y)0(p)15.1(e)0(s)-366(w)0(h)20(e)0(n)-366.2(c)0(o)13.9(m)15(pa)13.9(re)19.7(d)-375.5(w)0(i)19.8(t)0(h)-365.2(t)0(h)15(e)-376.6(is)20.9(og)20.8(en)19.7(ic)]TJ
0 -1.1174 TD
[(co)19.7(nt)20.7(ro)20.9(l)-260.4(l)0(i)20.6(n)0(e)-251([)0(2)20.9(6)0(,)18.5(3)0(3)20.8(])0(.)-246.4(A)-255.4(su)15.3(mm)24.1(ar)14(y)-254.5(o)0(f)-249.8(t)0(h)20.7(e)0(s)19.9(e)-255.7(HC)13.2(M)-255.4(p)0(h)20.8(e)0(n)19.7(o)0(t)20.7(y)0(p)15.1(e)0(s)-245.1(i)0(s)]TJ
0 -1.1116 TD
[(gi)20.7(ve)19.7(n)-542.5(i)0(n)-532.2(S)0(u)21(p)0(p)20.8(l)0(e)13.8(m)0(e)18.4(n)0(t)20.7(a)0(r)19.7(y)-542.5(Fi)20.9(g.)-534.4(S1)21(,)-544.8(w)0(i)19.8(t)0(h)-532.2(H)0(C)18.9(M)-543.4(hi)20.7(PS)21.2(C-)19.8(CM)18.9(s)]TJ
T*
[(di)20.7(sp)21(la)19.6(yi)14.9(ng)-290.2(in)20.7(cr)14(ea)18.5(se)19.9(d)-300.6(a)0(r)14(r)0(h)20.9(y)0(t)20.7(h)0(m)19.6(i)0(a)19.5(s)0(,)-292.3(h)0(y)15.1(p)0(e)19.7(r)0(c)19.7(o)0(n)20.8(t)0(r)20.7(a)0(c)18.5(t)0(i)14.8(l)0(i)20.6(t)0(y)20.7(,)-302.9(ca)18.5(lc)19.6(iu)14.9(m)]TJ
0 -1.1174 TD
[(dy)20.8(sr)21.1(eg)19.7(ul)15(at)19.5(io)20.7(n,)-315.6(an)19.7(d)-323.6(i)0(n)20.7(e)0(f)19.7()0(c)19.8(i)0(e)19.5(n)0(t)-313.4(e)0(n)19.7(e)0(r)14(g)0(y)-313.2(m)0(e)18.4(t)0(a)19.6(b)0(o)20.8(l)0(i)20.6(s)0(m)19.8(.)]TJ
1.0137 -1.1116 TD
[(T)15(o)-531(de)19.7(te)19.6(rm)19.6(in)20.7(e)-532.2(i)0(f)-514.9(t)0(h)15(e)-526.4(HC)18.9(M)-526.1(p)0(h)15.1(e)0(n)19.7(o)0(t)20.7(y)0(p)20.8(e)0(s)-521.5(s)0(e)19.9(e)0(n)-516(w)0(i)14.1(t)0(h)20.7(i)0(n)-514.9(t)0(h)20.7(e)]TJ
-1.0137 -1.1116 TD
[(ce)18.5(ll)20.6(ul)20.7(ar)-521.7(mo)19.6(de)19.7(l)-531.1(c)0(o)19.7(u)0(l)20.7(d)-531(be)-516(an)13.9(al)19.5(yz)19.7(ed)-516(at)-521.9(an)-521.7(ex)19.7(pr)20.9(es)19.9(si)15.1(on)-514.8(le)13.8(ve)19.7(l,)]TJ
0 -1.1174 TD
[(tr)20.7(an)19.7(sc)19.9(ri)15(pt)20.7(om)19.6(ic)-216.6(an)19.7(al)19.5(ys)15.3(is)-215.2(wa)18.8(s)-225.5(p)0(e)19.7(r)0(f)15.2(o)0(r)20.9(m)0(e)18.4(d)-225.7(on)-215.3(th)20.7(e)-226.9(c)0(e)18.5(l)0(l)20.6(u)0(l)14.9(a)0(r)-216.4(m)0(R)18.6(N)0(A)19.1(.)]TJ
0 -1.1116 TD
[(He)18.8(re)-239.5(we)-234.6(fo)15.1(un)20.8(d)-243(1)0(2)15.1(7)-243(ge)19.7(ne)13.9(s)-242.8(w)0(e)18.8(r)0(e)-239.5(d)0(y)20.8(s)0(r)15.3(e)0(g)19.7(u)0(l)20.7(a)0(t)19.5(e)0(d)-239.5(b)0(e)19.7(t)0(w)19.8(e)0(e)18.5(n)-248.8(th)20.7(e)-249.9(W)0(T)]TJ
T*
[(an)19.7(d)-375.5(H)0(C)18.9(M)-376.4(hi)14.9(PS)21.2(C-)19.8(CM)18.9(s)-375.3(\()0(S)15.3(u)0(p)20.8(p)0(l)20.7(e)0(m)18.5(e)0(n)19.7(t)0(a)19.6(r)0(y)-370.8(F)0(i)20.9(g)0(.)-367.4(S)0(1)21(b)0(\))20.9(.)-377.8(Of)-365.9(th)15(es)19.9(e,)]TJ
T*
[(70)20.8(%)-503.3(o)0(f)-491.7(g)0(e)19.7(n)0(e)19.7(s)-502(we)18.8(re)-492.9(as)19.9(so)15.3(ci)19.5(at)19.6(ed)-492.9(wi)19.8(th)-491.9(co)19.7(nt)20.7(ro)15.1(ll)20.6(in)20.7(g)-502.2(m)0(e)18.4(t)0(a)19.5(b)0(o)20.8(l)0(i)20.6(c)]TJ
0 -1.1174 TD
[(pr)20.9(oc)19.7(es)19.9(se)14.1(s,)-303.8(in)20.7(di)20.7(ca)18.5(ti)14.8(ng)-301.7(th)20.7(e)-319(b)0(a)19.7(c)0(k)19.7(g)0(r)20.9(o)0(u)15.1(n)0(d)-301.7(p)0(r)15.1(e)0(s)19.9(e)0(n)19.7(c)0(e)-304(o)0(f)-307.4(t)0(h)20.7(e)-319(di)20.7(se)19.9(as)14.1(e)]TJ
0 -1.1116 TD
[(mu)19.6(ta)19.5(ti)20.6(on)-388.1(le)19.6(ad)13.9(s)-398.3(t)0(o)-388.2(g)0(l)20.7(o)0(b)20.8(a)0(l)-389.4(a)0(l)19.6(t)0(e)13.8(r)0(a)19.7(t)0(i)20.6(o)0(n)20.8(s)-398.3(in)-388.2(me)18.4(ta)19.6(bo)15.1(li)20.6(c)-399.7(p)0(r)20.9(o)0(c)19.7(e)0(s)19.9(s)0(e)14.1(s)0(,)]TJ
T*
[(co)19.7(ns)21(is)20.9(te)13.8(nt)-313.4(wi)19.8(th)-313.4(th)20.7(e)-324.8(o)0(b)20.8(s)0(e)19.9(r)0(v)15.1(e)0(d)-308.6(e)0(n)13.9(e)0(r)19.7(g)0(y)-313.2(d)0(e)19.7(p)0(l)20.7(e)0(t)19.5(i)0(o)20.7(n)-323.6(ph)15.1(en)19.7(ot)20.7(yp)20.8(e.)]TJ
1.0137 -1.1174 TD
[(Of)-440.8(importance,)-439.9(pathway)-448.8(analysis)-443(conrmed)-444.2(the)-436.6(disease)]TJ
-1.0137 -1.1116 TD
[(mutation)-495.4(had)-499.8(led)-499.9(to)-497.7(disruption)-500.8(of)-497.5(known)-496(HCM)-501.4(pathway)]TJ
T*
[(genes)-341.7(\(Fig.)-336.1(1\).)-339.7(Of)-337.1(interest,)-343(multiple)-340(genes)-341.7(within)-336.2(this)-338.5(path-)]TJ
0 -1.1174 TD
[(way)-397(were)-405(shown)-397.8(to)-399.7(have)-404.2(isoforms)-401.4(with)-397.2(increased)-406.1(and)-401.9(de-)]TJ
0 -1.1116 TD
[(creased)-403.8(expression,)-408.1(indicating)-405.5(the)-402(HCM)-403.5(mutant)-400.9(lines)-404.2(may)]TJ
T*
[(alter)-336.4(the)-332.9(expression)-335.6(of)-336.2(alternative)-339.8(spliced)-332.6(variants.)]TJ
1.0137 -1.1116 TD
-.0158 Tc
[(Tog)-15.8(e)9.6(ther)-258.8(this)-258.6(analy)-15.8(s)11(is)-258.6(conrmed)-258.8(the)-265.7(H)-.5(CM)-259.7(phenotypes)-258.6(s).6(een)]TJ
-1.0137 -1.1174 TD
-.0159 Tc
[(within)-305(the)-300.4(cell)-15.9(u)10.6(lar)-299.2(m)-.9(odel)-305.1(c)-.9(orrespon)-15.9(d)10.7(e)-.9(d)-299.2(w)-.6(ith)-305(a)-.9(ltered)-305(t).2(ranscript)]TJ
0 -1.1116 TD
[(expression,)-255.6(and)-259(t)0(his)-253.1(c)-1(ou)-16(l)10.5(d)-253.2(be)-254.4(ident)-16(i)10.3(ed)-253.2(t).1(hrough)-259(bioinformatics)]TJ
T*
[(analysis.)-503.1(T)-.9(he)-502(presence)-502(o).3(f)-500.8(t).2(he)-496.2(c)-15.9(.)]TJ
/F4 1 Tf
13.3798 0 TD
-.0154 Tc
(ACTC1)Tj
/F3 1 Tf
7.3823 0 0 6.5614 471.2881 344.2393 Tm
-.0189 Tc
(G301A)Tj
9.843 0 0 9.843 497.14 339.8739 Tm
-.0157 Tc
[(mutati)-15.7(o)10.8(n)-494.8(had)]TJ
-18.9264 -1.1174 TD
[(altered)-633(g).6(enes)-627(within)-633(the)-634.1(d).6(ened)-627.2(H)-.3(CM)-633.9(pathway)-627.2(\().6(KEGG)]TJ
0 -1.1116 TD
[(pathway)-431.6(h).4(sa05410\),)-428.2(wit)-15.8(h)-415.5(diff)-15.8(e)9.7(r).4(ential)-426(i)-15.8(s)10.9(oform)-427.1(ex)-15.8(p)10.8(r).4(ession,)-428.2(as)]TJ
T*
-.0159 Tc
[(well)-333.9(as)-333.6(the)-334.9(dysregulation)-333.8(o).3(f)-333.7(g).3(lobal)-333.9(metabolic)-334.9(pro)-15.9(c)9.5(e)-.9(sses.)]TJ
/F9 1 Tf
9.9626 0 0 9.9626 310.8472 282.6708 Tm
0 Tc
[(Altered)-340(EV)-335.3(signa)-10.3(ling)-337.9(in)-334(HCM)]TJ
/F3 1 Tf
9.843 0 0 9.843 320.8251 264.8125 Tm
[(Fo)21(ll)20.6(ow)20(in)20.7(g)-294.8(t)0(h)20.7(e)-290.2(co)19.7(n)15.2(rm)19.6(at)19.6(io)20.7(n)-289.1(o)0(f)-284.4(c)0(h)19.7(a)0(r)19.7(a)0(c)18.5(t)0(e)19.6(r)0(i)15(s)0(t)20.9(i)0(c)-280(H)0(C)13.2(M)-290(ce)18.5(ll)20.6(ul)20.7(ar)]TJ
-1.0137 -1.1116 TD
[(ge)19.7(ne)-372(ex)19.7(pr)20.9(es)19.9(si)15.1(on)-370.8(in)-370.9(th)20.7(e)-382.4(m)0(u)19.6(t)0(a)19.6(n)0(t)-370.9(h)0(i)20.7(P)0(S)15.4(C)0(-)19.8(C)0(M)18.9(s)0(,)-373(w)0(e)-372.9(n)0(e)19.7(x)0(t)-371(s)0(o)21(r)0(t)-370.9(t)0(o)]TJ
T*
[(de)19.7(te)19.6(rm)19.6(in)20.7(e)-370.9(w)0(h)20(e)0(t)13.8(h)0(e)19.7(r)-369.7(th)20.7(er)19.7(e)-370.9(w)0(a)13(s)-369.5(al)19.5(te)19.6(re)19.7(d)-375.5(t)0(r)20.7(a)0(n)19.7(s)0(c)19.9(r)0(i)20.7(p)0(t)-365.2(c)0(a)18.5(r)0(g)20.9(o)-369.7(wi)19.8(th)20.7(in)]TJ
0 -1.1174 TD
[(EV)18.8(s)-288.9(r)0(e)14(l)0(e)19.6(a)0(s)19.9(e)0(d)-285.6(b)0(y)-278.7(H)0(C)18.9(M)-295.7(hi)20.7(PS)21.2(C-)19.8(CM)18.9(.)-291.4(E)0(V)18.8(s)-294.6(re)19.7(le)19.6(as)14.1(ed)-279.8(in)20.7(to)-284.6(cu)19.7(lt)20.6(ur)15.1(e)]TJ
0 -1.1116 TD
[(me)18.4(di)20.7(um)-326(by)-330.5(hi)20.7(PS)15.4(C-)19.8(CM)18.9(s)-340.7(w)0(e)18.8(r)0(e)-331.6(i)0(s)20.9(o)0(l)20.7(a)0(t)19.5(e)0(d)-331.7(a)0(f)19.7(t)0(e)19.5(r)-340.9(24)-146.2(h)-340.9(u)0(s)21(i)0(n)20.7(g)-340.9(SE)19.8(C.)]TJ
T*
[(Th)19.6(es)19.9(e)-537.9(p)0(h)20.8(y)0(s)21(i)0(c)19.5(a)0(l)-527.6(p)0(r)20.9(o)0(p)20.8(e)0(r)14(t)0(i)20.6(e)0(s)-527.3(w)0(e)18.8(r)0(e)-527.5(c)0(h)19.7(a)0(r)19.7(a)0(c)18.5(t)0(e)19.6(r)0(i)20.7(z)0(e)18.5(d)-536.7(us)21(in)20.7(g)-536.7(n)0(a)19.7(n)0(o)20.8(-)]TJ
T*
[(pa)19.7(rt)20.7(ic)19.6(le)-418.2(tr)20.7(ac)18.5(ki)20.7(ng)-416.9(an)19.7(al)19.5(ys)21(is)-416.8(\(N)20(TA)18.8(\),)-413.4(tr)20.7(an)19.7(sm)19.8(is)15.1(si)20.9(on)-416.9(el)19.5(ec)18.5(tr)20.7(on)-411.1(mi)19.5(-)]TJ
0 -1.1174 TD
[(cr)19.7(os)21(co)19.7(py)20.8(,)-383.6(a)0(n)19.7(d)-381.2(we)18.8(st)20.9(er)14(n)-381.2(b)0(l)20.7(o)0(t)20.7(s)-381(to)-370.9(de)19.7(te)19.5(rm)19.6(in)15(e)-382.4(t)0(h)20.7(e)-382.4(qu)20.8(al)19.5(it)20.6(y)-381.2(o)0(f)-370.8(t)0(h)20.7(e)]TJ
0 -1.1116 TD
[(EV)-269.2(is)20.9(ol)20.7(at)19.5(io)20.7(ns)-272.7(an)19.7(d)-277.6(t)0(h)20.7(a)0(t)-268.4(t)0(h)20.7(e)-278.7(pr)15.1(o)21(le)19.5(s)-277.4(c)0(o)19.7(r)0(r)20.9(e)0(s)14.1(p)0(o)20.8(n)0(d)20.8(e)0(d)-268.3(t)0(o)-267.3(e)0(x)19.7(o)0(s)21(o)0(m)19.6(e)0(s)]TJ
T*
[(an)19.7(d)-323.6(s)0(m)19.8(a)0(l)19.5(l)0(e)19.6(r)-323.6(EV)18.8(s)-323.4(\()0(S)21(u)0(p)20.8(p)0(l)14.9(e)0(m)24.2(e)0(n)13.9(t)0(a)19.5(r)0(y)-313.2(F)0(i)20.9(g)0(.)-309.8(S)0(2)15.2(\))0(.)]TJ
1.0137 -1.1174 TD
-.0216 Tc
[(The)-260(i).2(s)-5.2(o).3(la)-6.6(ted)-258.8(E)-6.6(Vs)-258.7(we)-6.6(re)-260(pr)-5.4(oce)-6.6(sse)-6.6(d)-258.8(f).4(or)-258.8(t)-5.5(r).4(an)-5.4(sc)-6.6(rip)-5.4(t).2(om)-6.6(ic)-260(an)-5.4(aly)-5.4(s).5(is)]TJ
-1.0137 -1.1116 TD
[(\(F)-5.3(ig.)-255.4(2).3(\).)-255.4(Bi)-5.5(olo)-5.4(g).3(ic)-6.6(al)-253.2(pr)-5.4(oce)-6.6(s).5(s)-252.9(e)-.8(n)-5.4(r).4(ic)-6.6(hme)-6.6(n).3(t)-253.2(a)-.8(na)-6.6(lys)-5.2(i).2(s)-252.9(w)-6.3(as)-252.9(con)-5.4(duc)-6.6(ted)]TJ
T*
[(us)-5.3(ing)-356.9(P)-5.4(an)-5.5(the)-6.7(r)-356.8(to)-356.9(d)-5.5(e)-.9(te)-6.7(rmi)-5.6(n).2(e)-358(t)-5.6(he)-358(nu)-5.5(mbe)-6.7(r)-356.8(of)-356.8(g)-5.5(e)-.9(ne)-6.7(s)-356.7(p).2(e)-6.7(r)-356.8(fu)-5.5(nct)-5.6(i).1(on)]TJ
0 -1.1174 TD
-.0178 Tc
[(p)4.1(a)3(th)4.1(way)-462.4(p)4.1(r)4.2(e)-2.8(s)4.3(e)3(nt)-462.5(i)4(n)-462.4(EVs)-462.2(p)4.1(ro)4.1(du)4.1(ced)-456.6(f)-1.6(r)4.2(o)4.1(m)-463.6(e)3(it)4(h)4.1(e)-2.8(r)-462.4(t)4(h)4.1(e)-463.6(WT)-463.6(an)4.1(d)]TJ
0 -1.1116 TD
-.0216 Tc
[(HCM)-611.1(h).3(i)-5.5(P).5(S)-5.3(C)-.7(-C)-6.4(Ms)-610(\(F)-5.3(ig.)-612.5(2).3(B\))-5.4(.)-606.8(O)-6.3(f)-604.4(t)-5.6(he)-611.3(fu)-5.4(nct)-5.6(i).2(on)-5.4(al)-610.3(pa)-6.6(thw)-6.3(a)-.8(ys)]TJ
T*
[(ide)-6.6(n).3(t)-5.6(i).2(e)-6.6(d,)-243.9(cat)-5.6(aly)-5.4(tic)-242.7(a)-6.6(c)-.8(ti)-5.5(vit)-5.5(y)-241.6(and)-241.6(b)-5.4(ind)-5.4(i).2(n)-5.4(g)-241.6(wer)-5.4(e)-242.7(the)-242.7(t)-5.6(wo)-241.6(pa)-6.6(thw)-6.3(a)-.8(ys)]TJ
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