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[(fe)18.6(re)18.4(nt)15.1(ia)22.2(ll)18.2(y)-320.6(e)12.8(xp)21.8(re)18.4(ss)16.3(ed)-306.4(pr)16.9(ot)15.7(e)12.7(i)0(n)18.4(s)-317.5(we)17.4(re)-310.4(i)15.4(d)0(e)16.1(n)0(t)21.4(i)0( )18.8(e)0(d)-312.7(\()12.2(Ta)16.5(b)14.6(l)0(e)-313.3(2)13.1(\).)-306.9(In)19.8(te)18.6(r-)]TJ
0 -1.2203 TD
[(es)17.8(ti)15(ng)23.8(ly)17.3(,)-445.5(m)0(a)21.9(n)0(y)-437.8(o)0(f)-433.2(t)0(h)15.1(e)12.8(se)-437.5(pr)16.9(ot)22.1(ei)15.5(ns)-434.7(ar)18.8(e)-442.5(d)0(o)19.5(w)0(n)14(-)12.2(re)18.4(gu)19.5(la)22.2(te)18.6(d)-445.6(i)0(n)-436.9(t)0(h)15.1(e)]TJ
T*
[(M6)14.3(3)13.1(1)13.1(L)-199(Tg)-184.5(b)14.6(r)0(a)18.8(i)0(n)-184(r)0(e)18.4(l)0(a)15.9(t)12.2(iv)21(e)-195.9(t)0(o)-186.6(t)12.2(ha)16.1(t)-196.5(o)0(f)-186.6(J)12.2(2)13.1(0)-195.5(Tg)-184.5(mi)17.9(c)13.4(e)0(.)-186.2(P)0(r)16.9(e)12.7(vi)14.7(ou)21.2(s)-197.3(s)0(t)23.5(u)0(d)14.6(i)0(e)21.9(s)]TJ
0 -1.2266 TD
[(sh)14.3(ow)20.9(e)12.7(d)-312.8(t)12.2(h)0(a)16.1(t)-310.3(le)21.9(ve)18.3(ls)-302(of)-300.4(th)15.1(e)12.7(s)0(e)-304.7(p)0(r)23.2(o)0(t)15.7(e)12.8(in)18.4(s)-311.1(a)0(r)18.8(e)-309.7(a)13.1(l)0(t)15(e)12.8(re)18.4(d)-312.8(i)0(n)-297.8(A)0(D)-300(a)0(n)16.1(d)-306.5(in)]TJ
0 -1.2203 TD
[(an)16.1(im)17.9(a)13.1(l)-224.8(m)15.1(o)0(d)19.5(e)0(l)15.5(s)-222.6(t)12.2(h)0(e)15.7(r)0(e)18.4(o)0(f)-211.9(\()0(2)19(\))0(.)-212(T)0(h)18.9(e)-221.2(id)18.8(en)15.7(t)12.2(i)0( )18.8(e)0(d)-211.6(p)0(r)16.9(o)0(t)15.7(e)12.8(in)18.4(s)-222.6(a)0(r)18.8(e)-221.2(in)18.4(vo)15.5(l)15.4(v)0(e)18.3(d)]TJ
T*
[(in)-329.4(en)15.7(e)12.7(r)0(g)20.2(y)-339.5(dy)17.9(sf)17.2(un)20.5(ct)19.2(io)19(n)-338.5(a)13.1(nd)-328.9(mi)17.9(to)15.7(c)13.4(h)0(o)19.1(n)0(d)18.9(r)0(i)14.7(a)13.1(l)-338.6(a)13.1(lt)15(e)12.8(r)0(a)18.8(t)0(i)15(o)0(n)19.1(s)0(,)-326.7(a)13.1(nt)15.1(io)19(xi)19.6(-)]TJ
28.0042 57.4436 TD
[(da)22.8(nt)-313.7(a)13.1(n)0(d)-309.9(c)13.4(el)15.5(lu)20.4(la)22.3(r)-323.2(d)0(e)22.4(f)0(e)18.6(n)0(s)20.6(e)0(,)-312.6(p)0(H)-304.8(r)0(e)18.4(g)0(u)19.5(l)0(a)15.9(t)12.2(io)19(n,)-309.8(li)18.2(pi)20.4(d)-319.1(a)13.1(bn)17.5(or)21.8(ma)15.6(li)18.2(t)12.2(i)0(e)21.9(s)0(,)]TJ
0 -1.2203 TD
[(c)13.4(h)0(o)19.1(l)0(i)18.2(n)0(e)15.7(r)0(g)20.2(i)0(c)-312.6(d)0(y)17.9(s)0(f)23.5(u)0(n)14.2(c)13.4(ti)15(on)19.1(,)-319.1(a)0(n)16.1(d)-319.1(pr)16.9(ot)22(ea)19.6(so)14.9(m)15.1(e)-322.4(fu)17.1(nc)16.3(t)12.2(i)0(o)19(n)0(,)-316.1(a)13.1(lt)15(e)12.7(r)0(a)18.8(t)12.2(io)19(ns)]TJ
0 -1.2267 TD
[(in)-519.1(st)17.2(ru)16.9(c)13.4(t)0(u)17.1(r)0(e)-519.1(a)0(n)16.1(d)-527.8(ne)15.7(ur)16.9(on)19.1(a)13.1(l)-534.7(t)12.2(r)0(a)18.8(n)0(s)20.6(m)0(i)17.9(s)0(s)16.3(i)15.4(on)19.1(,)-534(c)0(e)19.8(l)0(l)-519.2(s)0(i)14.1(g)14.6(na)16.1(li)18.2(ng)23.8(,)-534(c)13.4(el)15.5(l)]TJ
0 -1.2203 TD
[(c)13.4(y)0(c)15.3(l)0(e)21.9(,)-268.5(ta)19(u)-273.2(p)0(h)20.5(o)0(s)14.9(p)0(h)20.5(o)0(r)21.8(y)0(l)17.3(a)13.1(ti)15(on)19.1(,)-268.5(a)0(n)16.1(d)-268.6(A)]TJ
/F7 1 Tf
14.6375 0 TD
(b)Tj
/F6 1 Tf
.822 0 TD
[(pr)16.9(od)19.5(uc)18.3(t)12.2(i)0(o)19(n)0(.)]TJ
/F13 1 Tf
-15.4595 -2.4406 TD
[(Energy)-335.3(dysfunction)-334.5(and)-329.4(mitochondrial)-334.1(alterations)]TJ
/F6 1 Tf
1.1128 -1.8336 TD
[(The)-347.7(decreased)-347.9(levels)-350.4(of)-351(triose)-350.1(phosphate)-354.9(isomerase)-347.9(\(TPI\),)]TJ
-1.1128 -1.2266 TD
[(glyceraldehyde-3-phosphate)-415.9(dehydrogenase)-405(\(GAPDH\),)-411.4(and)]TJ
ET
59.754 710.079 490.167 .28351 re
f
59.754 662.343 490.167 .28345 re
f
59.754 691.086 490.167 .28345 re
f
BT
/F10 1 Tf
8.9663 0 0 8.9663 134.8724 725.7258 Tm
(Table)Tj
/F6 1 Tf
3.0603 0 TD
(1.)Tj
/F10 1 Tf
1.2519 0 TD
[(List)-331.7(of)-336.4(Proteins)-336.5(with)-331.4(Differential)-338(Levels)-333(in)]TJ
/F6 1 Tf
22.067 0 TD
(M631L)Tj
/F10 1 Tf
3.3764 0 TD
[(Transgenic)-333.7(Mice)]TJ
-21.5169 -1.1128 TD
[(Relative)-330.6(to)]TJ
/F6 1 Tf
5.9435 0 TD
(M631)Tj
/F10 1 Tf
2.7694 0 TD
[(Non-Transgenic)-341.1(controls)]TJ
/F8 1 Tf
-25.3296 -2.0423 TD
[(Protein)-11625.6(Swiss)-339.3(Prot)-332.2(no.)-1562.1(MW)-332.7(\(kDa\))-2030.6(pI)-2023.3(Peptides)-341.6(\(SC\))]TJ
/F6 1 Tf
6.7246 0 0 5.9768 391.8046 701.4045 Tm
(a)Tj
8.9663 0 0 8.9663 421.0015 697.436 Tm
(P)Tj
6.7246 0 0 5.9768 426.2739 701.4045 Tm
(b)Tj
/F8 1 Tf
8.9663 0 0 8.9663 455.8109 697.436 Tm
[(Fold)-333.9(change)]TJ
/F6 1 Tf
6.7246 0 0 5.9768 499.5211 701.4045 Tm
(c)Tj
8.9663 0 0 8.9663 516.4723 697.436 Tm
(p)Tj
/F8 1 Tf
.5944 0 TD
(-Value)Tj
/F6 1 Tf
6.7246 0 0 5.9768 545.8392 701.4045 Tm
(d)Tj
8.9663 0 0 8.9663 59.7543 678.6707 Tm
[(Hsp90)-336.8(B1)-11522.9(P08113)-4349.1(92.42)-2688.2(4.59)-3536(4)-328.3(\(8\))-3541.3(5.00e)]TJ
/F11 1 Tf
6.7246 0 0 5.9768 430.1857 682.6392 Tm
(-)Tj
/F6 1 Tf
.725 0 TD
(06)Tj
8.9663 0 0 8.9663 468.17 678.6707 Tm
(2.28)Tj
/F12 1 Tf
1.7514 0 TD
([)Tj
/F6 1 Tf
4.3755 0 TD
(0.035)Tj
-51.6772 -1.1128 TD
[(Proteasome)-341.4(subunit)]TJ
/F7 1 Tf
9.1176 0 TD
(b)Tj
/F6 1 Tf
.5501 0 TD
[(,)-331.7(type)-334.9(2)-2775.3(Q9R1P3)-3902.1(22.89)-2688.2(6.61)-3536(1)-328.3(\(2\))-3541.3(3.00e)]TJ
/F11 1 Tf
6.7246 0 0 5.9768 430.1857 672.6613 Tm
(-)Tj
/F6 1 Tf
.725 0 TD
(04)Tj
8.9663 0 0 8.9663 468.17 668.6927 Tm
(1.65)Tj
/F12 1 Tf
1.7514 0 TD
(Y)Tj
/F6 1 Tf
4.3755 0 TD
(0.019)Tj
5.9774 0 0 5.3127 67.748 654.1227 Tm
(a)Tj
7.9702 0 0 7.9702 70.7527 650.551 Tm
[(The)-262.3(number)-268.1(of)-268(peptide)-263.1(sequences)-269.1(identi ed)-263.1(by)-268.8(nanospra)10.3(y)-273.1(ESI-MS/)13.1(MS)-271.5(of)-268(tryptic)-266.2(peptides.)-265.8(The)-269.4(total)-267.5(number)-261(of)-275.1(MS/MS)-259.1(spectral)-268.4(counts)-263(is)]TJ
-1.3799 -1.1239 TD
[(indicated)-326.9(in)-334.9(parenthe)10.4(sis.)]TJ
5.9774 0 0 5.3127 67.748 636.151 Tm
(b)Tj
7.9702 0 0 7.9702 71.0362 632.636 Tm
[(The)-333.5(probabilit)13(y)-330(o)0(f)-339.1(a)0(n)-329.3(incorrect)-326.1(identi cation)-325.2(associate)11.4(d)-334.9(with)-332.2(each)-327.7(protein)-330.6(identi c)12.4(ation)-330.5(using)-331.7(the)-330.9(SEQUEST)-327.3(search)-323.3(alogorithm.)]TJ
5.9774 0 0 5.3127 67.748 627.1935 Tm
(c)Tj
7.9702 0 0 7.9702 70.3559 623.6786 Tm
[(The)-333.5(fold)-329(change)-327.5(in)-327.8(spot)-333.1(density)-327.4(from)-331(M631L)-323.5(Tg)-330.7(mice)-329(compared)-320.1(with)-332.2(M631)-330(NTg)-326.7(controls.)-330.8(The)-326.4(arrow)-329.3(indicates)-322.9(the)-330.9(direction)-327.1(of)-339.1(change.)]TJ
5.9774 0 0 5.3127 67.748 618.2361 Tm
(d)Tj
7.9702 0 0 7.9702 71.3763 614.7211 Tm
(The)Tj
/F8 1 Tf
1.9703 0 TD
(P)Tj
/F6 1 Tf
.6046 0 TD
[(-value)-325.5(associated)-323.5(with)-332.2(fold)-329(change)]TJ
5.9774 0 0 5.3127 214.4125 618.2361 Tm
(c)Tj
7.9702 0 0 7.9702 219.685 614.7211 Tm
[(calculated)-328.6(using)-324.6(a)-332.2(Students)]TJ
/F8 1 Tf
12.7396 0 TD
(t)Tj
/F6 1 Tf
.3201 0 TD
(-test.)Tj
/F8 1 Tf
2.4327 0 TD
(n)Tj
/F11 1 Tf
.7184 0 TD
(=)Tj
/F6 1 Tf
.7184 0 TD
[(10)-330.2(for)-331.1(M631L)-323.5(Tg,)]TJ
/F8 1 Tf
8.0094 0 TD
(n)Tj
/F11 1 Tf
.7184 0 TD
(=)Tj
/F6 1 Tf
.7113 0 TD
[(5)-332.2(for)-331.1(M631)-330(NTg.)]TJ
-45.4316 -1.131 TD
[(ESI,)-270.5(electrospra)8.8(y)-273.1(ionization;)-267.1(Leu/L,)-270(leucine;)-270.6(Met/M,)-266.2(methionine)8.3(;)-276.4(MS,)-270.5(mass)-275.5(spectrom)11(etry;)-270.8(MW,)-274.2(molecul)11.9(ar)-274.4(weight;)-271.5(NTg,)-268.7(non-transg)9.5(enic;)-275.3(P,)]TJ
-1.003 -1.1239 TD
[(probability)-324.2(of)-332(type)-334.1(I)-328.5(error;)-331.7(pI,)-332(isoelectri)10.4(c)-338.3(point;)-328.9(SC,)-328.7(spectral)-325.3(counts;)-333.1(Tg,)-329.6(transgen)9.9(ic.)]TJ
ET
q
1 i
311.301 474.803 m
549.468 474.803 l
549.468 283.238 l
311.301 283.238 l
W n
q
238.167 0 0 191.565 311.301 283.238 cm
/Im3 Do
Q
Q
BT
/F9 1 Tf
8.9663 0 0 8.9663 310.8472 266.5133 Tm
[(FIG.)-570.8(3.)-1001.4(Pro)17.2(teom)14.4(ics)-517.5(was)-517.3(used)-510.6(to)-517(iden)13(tif)11(y)-522.9(prot)16.7(eins)-514.4(fro)13.1(m)]TJ
0 -1.1128 TD
[(bra)15.8(ins)-211.4(of)-207.5(J20)-208.4(Tg)-211(and)-207.8(M6)14.1(31L)-210.7(Tg)-211(mi)12(ce)-213.8(wit)11.7(h)-218(dif)14.8(fere)12.2(nti)15(al)-215(lev)14.6(els.)]TJ
/F6 1 Tf
T*
[(Rep)13.5(rese)10.8(ntat)15.1(ive)-200.2(2D-)11.3(gel)-197.5(imag)13.9(es)-203.5(of)-199.3(the)-199.8(prot)13.7(eins)-197.8(iso)11.3(late)15.6(d)-205.3(from)-197.5(the)]TJ
T*
[(bra)14.3(in)-443.2(of)]TJ
/F9 1 Tf
4.0214 0 TD
(\(A\))Tj
/F6 1 Tf
1.8589 0 TD
[(J2)12.7(0)-448.4(T)0(g)-437.4(and)]TJ
/F9 1 Tf
5.4693 0 TD
(\(B\))Tj
/F6 1 Tf
1.7451 0 TD
[(M631)15.3(L)-445.6(T)0(g)-443.7(mic)12.3(e.)-439.1(Diff)13.1(erent)14.6(ial)12.4(ly)]TJ
-13.0947 -1.1065 TD
[(expr)14.9(esse)16.5(d)-382.4(pro)14.1(tein)-367.7(spot)13.1(s)-380.7(i)0(n)-373.6(M63)14.8(1L)-375.6(Tg)-374.2(mic)12.3(e)-379.3(are)-366.8(labe)11.6(led)-366.8(with)]TJ
0 -1.1128 TD
[(pro)14.1(tein)-462.5(ide)12.5(nti c)15.6(atio)12.7(ns)-466.3(obt)11.3(aine)12.6(d)-470.9(from)-463.1(pro)14.1(teom)11.9(ics)-465.7(usi)12.8(ng)-469.4(na-)]TJ
T*
[(nos)11.5(pray)-575(ESI-)14.9(MS/M)13.6(S)-592.8(anal)19.3(yses)-582.3(and)-581.3(dat)16(abas)14.2(e)-587.9(sea)11.9(rchi)12.1(ng.)-579.8(1,)]TJ
T*
[(Bra)15.8(in)-215.6(acid)-207.7(sol)11.4(ubl)16(e)-221.2(pro)14.1(tein)-209.6(1)-214.5(\(BAS)15.6(P1\))11.3(;)-217.9(2)0(,)-211.1(V-ty)10.8(pe)-209.9(prot)13.7(on)-214.8(ATPa)13.7(se)]TJ
0 -1.1065 TD
[(sub)11.9(unit)-268(B)-281.2(\(VAT)17.6(B2\);)-271.5(3,)-274.3(ATP)-271.3(synt)15.7(hase)-269.7(sub)11.9(unit)]TJ
/F7 1 Tf
19.7401 0 TD
(a)Tj
/F6 1 Tf
.7777 0 TD
[(mito)14.6(cho)13.5(ndri)14.7(al)]TJ
-20.5178 -1.1128 TD
[(\(AT)14.1(P)]TJ
/F7 1 Tf
2.2762 0 TD
(a)Tj
/F6 1 Tf
.4932 0 TD
[(\);)-313.2(4,)-312.2(ATP)-309.3(synth)12.3(ase)-310.5(sub)11.9(unit)]TJ
/F7 1 Tf
11.9629 0 TD
(a)Tj
/F6 1 Tf
.4995 0 TD
[(,)-312.7(mito)14.6(chon)10.1(dria)18.5(l)-319.7(\(ATP)]TJ
/F7 1 Tf
9.3073 0 TD
(a)Tj
/F6 1 Tf
.4932 0 TD
[(\);)-313.2(5,)]TJ
-25.0324 -1.1128 TD
[(Gly)12.3(cer)12.8(ald)12.9(ehyd)14.6(e-3-)12.3(pho)11.5(spha)13.4(te)-702.2(dehy)14.6(drog)14.4(enas)14.9(e)-708.1(\(GA)12(PDH\))15.8(;)-704.8(6)0(,)]TJ
T*
[(Volt)15.7(age-)14.7(depe)14.8(ndent)-244.1(anion)12.7(-se)11(lect)15.8(ive)-250.8(chan)13.4(nel)-253.4(pro)14.1(tein)-247.6(1)-258.8(\(VDA)12.9(C-)]TJ
0 -1.1065 TD
[(1\);)-388.6(7,)-394.4(Glu)15.3(tathi)17.9(one)-391.8(S-tr)12.5(ansf)14.3(era)12.5(se)-393.2(Mu)-398.5(1)-391.5(\(GST)11.9(M1\);)-387.4(8,)-394.5(Pe)11.4(ptid)10.6(yl-)]TJ
0 -1.1128 TD
[(pro)14.1(lyl)-207.5(cis-)14.4(tran)14.9(s)-216.3(iso)11.4(mera)15(se)-216.2(1)-214.5(\(Pi)13.6(n-1\))15.1(;)-217.9(9)0(,)-211.1(P)0(e)11.4(ptid)10.6(yl-p)15.5(rol)12(yl)-210.3(cis-)14.4(tra)12(ns)]TJ
T*
[(iso)11.4(mer)14.5(ase)-392.7(1)-391.5(\(Pin)10.2(-1)12.7(\);)-395.4(10,)-387.6(Ubi)15.9(quiti)18.3(n-co)13.1(njug)11.2(atio)12.7(n)-395.4(enzy)18.1(me)-389.5(E2)-160.6(N)]TJ
0 -1.1065 TD
[(\(EB)12.5(E2N\))16(;)-597.3(11,)-583.6(Pho)11.4(spha)13.4(dit)12(ylet)10.7(han)12.7(ola)13.2(mine)-586.1(bind)17.3(ing-)13.5(prot)13.7(ein)-588.5(1)]TJ
0 -1.1128 TD
[(\(PE)14.1(BP-1)14.6(\);)-401.7(12)13.6(,)-401.3(Car)12.3(boni)11.2(c)-397.6(anhy)14.6(dras)14.4(e-2)-391.9(\(CA)10.6(2\);)-394.9(13,)-394(Pho)11.5(sph)12.9(oglu)13.2(-)]TJ
T*
[(com)13(uta)11.3(se)-431.2(1)-435.8(\(PG)12.1(M1\);)-425.3(14,)-425.6(Sup)11.4(erox)13.4(ide)-430.1(di)12.4(smut)11.9(ase)-430.7([Mn])15.8(,)-432.9(mito)14.6(-)]TJ
T*
[(cho)13.5(ndr)11.9(ial)-234.2(\(SO)10.7(D2\))11.3(;)-243.2(1)0(5)13.6(,)-243.2(Trio)15.3(se)-235.2(pho)11.5(spha)13.4(te)-240.6(iso)11.4(mer)14.5(ase)-234.7(\(TP)14.1(I\).)-233.1(ATP,)]TJ
0 -1.1065 TD
[(aden)13.2(osi)11.3(ne)-370(trip)12.9(hos)11.5(phat)14.2(e.)-369.5(\(To)-373(se)11.4(e)-379.3(thi)11.6(s)-374.4(illu)13.3(stra)17(tion)-364.2(in)-373.6(colo)10.6(r)-373.8(the)]TJ
0 -1.1128 TD
[(rea)12.5(der)-364(is)-358.9(refe)11.7(rre)11.3(d)-369.7(t)0(o)-363.6(the)-364.2(web)-360(ver)11.3(sio)11.4(n)-370.1(o)0(f)-363.6(this)-362.8(art)12(icl)12.6(e)-372.9(a)0(t)-360.4(www)]TJ
T*
[(.li)15.3(eber)14.1(tpub)11.4(.co)14(m/a)12.6(rs.\))]TJ
/F5 1 Tf
-28.0042 77.228 TD
[(IMPORTANCE)-337.1(OF)-337.5(A)]TJ
/F14 1 Tf
9.5033 0 TD
(b)Tj
/F5 1 Tf
.4995 0 TD
[(-RESIDENT)-335.9(METHIONINE)-337.8(IN)-335.1(AD)-334.4(PATHOGENESIS)-19083.2(1509)]TJ
ET
endstream
endobj
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