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Council for Tobacco Research

1987 Report of the Council for Tobacco Research - U.S.A., Inc. [St]

Date: 1987
Length: 100 pages
CTRMN012745-CTRMN012844
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25 Sep 1995
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Ctrmn00010849-2859

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zvr30a00

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ANDREWS OFFICE PRODUCTS CAPITOL HEIGHTS, MO (K)
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t 65100 7787 CTR HN 012746
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SnN. 111c c.Ixc..illn td /IIr I ar aM/xCn t1u11c/n by itv II luJl,r. uNly lur luw atlnlqy IL-2 hlnJlnp• 1hr.r J:Na pnNlqllcJ a rcrvaua1/1N/ .,t Ihr .lnalur,d ctN11p1.a1tN101 hlyh Jlhmly 11.-2 K. Analyad nl /hr 11.-2 hlnllinK /n.llrin, cnpl.v..•d hv k•uA1•uul lrll 111w•. 1.I111nM high :dtr/lay rccrlMlN% ttvt•:/Ir1I INIIy a llnl!/C ININI'/n. IJ/Krr dlJn tIN• I:N' :Inr/yrn /N.NCIn IM, , 1S•/NN1 vs. }t•INN>I In .'IInuJ.l, ll/NN•. /INhk't'.I 1/1 t•41Nr%%Inl!h :Ilhnlly ICa'III.N\ h•NI lk•Jrly hlNh nl /1w.a: II.~:"~In/Nh/lE (N,1 Irul. htlnr/lvCr, wIN-n 11. 2 hinJlnF'tt1 n1/tlnJl I crlla wr,s t1C r1.Knll'J nrws.•r l'INNIuNN1. that IJWIrCJ Ihe IIrOqNlrtilNl nl hlgh allin/ly h•t'CIM/II. IICCupirJ. Iwlu di.llntY /InNt'U1. Ilknliral n/1h11.r a/rrally Nkntula•1) nn thr kultCmic crlls clwld hr rnt..hn{,cJ luvJ Irntly lu r:Nh//latrkll 11. 2'I llr IltiCrllfl•I:NNNIo, Ik•flvl•tI IrIN/1 IhCVC vJflctl, Jvv911hk'11 Ja1J, p1in1 /lt Iwu II. 2 h/ntlinK prdr/n.• INllh nl which arr ralulrrJ LN h/1;h alhnlly 11.-? hintl/nr 25
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Ir•rll d\\IN 6N1•11 w1111 l yt la' (:MI' :N. mnld.ItNKI I nlrl.uN r NI v.l\/NlddhlNl Ily n111U1•lyt rl ln t Uun111Nlly 1111 lU. 11]1111wm)! lal.hNll'rJ r aryl\In.• 10 1111141 )•IVt t"1t11 1 hl\ \IINIa Illvr\III,'.Nr\ lht• 0144.1\ 111 rn 1•1rt1 n1611payt a•I ln IIN•t./py ,NI l.ta 1tl,u frl,/a:NNKI JIN1 } yt IN I iMI' :Nt u1nul.NnNl n11h1a'r/1 by dN• 1n11Uaa\/NIQ.NIN. .//N1 1I14' r11/61tIN•IbU111 IkyK/Nk•nl v.1\NMIdetIK\ Kal\ wele mpY lftl with mm-rIytcrln IK dN• IKIIIlyk'IN' 1•Iy111I1IIIIIt'/ll 11M111/I III/ •1 7lIJy\ IINII:NN:NK1:1\ I11N11IIN• 111111p'IYI/'1111 Ilr.nrll 1,11. wl•Ir )tlt luld k•\\ w•n.Itlvr I.u IIN' IrLltalnl rlh•th /11 nnrl/l'Iylerln In .I.utt.l.l. 11N ;r .u.U.l. w.'Ir .Nllv 11Nrrh.td Ir\\ \rnallvr Its tlrc Irlraaal r'hv 1\ /11 ..«Lulu um..l•nna.l. whdr Ihr 1a.1.1un1a1n 11-I.L.al..n a..NrlvhM•II/N' a1NI h1,1,111/nN' V1:1\ Ih•IKr\\a•d by SII and 11'X•. rr\Iq't'tivrly Ik\rll\Ni/]NN/n I/I ICI:Ia.11i1N1 wa\ .1ea41 :Nrdwnhlt'dulyda)lIN liMPl'ICv:11Nln\hIJllllh vUVNI11J11K\ KrLIt,11/11111Ux INll11N. t)lh. /;Ml'. IhhlltVryl avtlN AMI', 111 ddliait•ul wa\ uu.dtrrla'll hv nNlu)•Iyarlul t1N•1.111v I IIkv,UNr we\ al\./ :1\\lN ia1eJ wilh An i11Crr:+vY1 vn\INvqy 11111K a In11/.N lik• a'IIt'41\ 411 IIIW IINN'1'111f:1111NN 11t INMe11111t•(IINIIN. Illl\ Il/all':14Y1 N'n\lllY/ly NI Oliver I•nN•1 'h1111C w,l. .1.u111,Nr.I with a tka'rrav iu.yclw l:Ml' kvrl\ Ihc' INrvvN Ir\uh\ \u/•)•r.t 1h:N I II Ik'\t'It\III/.IIIINI IU n11111gIyCI'lln, \/11I1t1111 n11n11N11\\Nk', :N rl~ h INdoN•. a1N1 h1.1,K1uuN• her Inu..pKl rnn dler:p/y u1:1y hr :N tlw• h•vrl lA ayrlw 1 iMl' :1.'a uwol.l 114N1. I. 1 t w IA 1;MI' 1\ IIN' a1111111NN1 11NVI1:111N nl N•I:It:N11N1 In1I1N'ClI hy lIN' 111t1a1 .11N1 t'I14I.111NIlllll/ /k'IIrINIt'ill V:INIIIII.N/K\; ( II 11N 111r1 I1:nIh1•h InvtllYrll 111 II1l' :N I/V,11NN11.1 )•a.InvLnr a µ 1.1.r .111.1 rrL1a:NNN1 by vNhunl nllapwo\\Nk•. aa'rlykhllhur. a1NI In.t./ Itu1N• cna• IN.d..lhtv tlNlrlrnl than IINI\e nl a11n1ylyrrlln. and 441 rvthc /7M1' 611.1a Ir• :Nlnpt e.:lldly.ud..ypal lN•yahvr II:av111:u1 \IFn:1I 111 dF'ININ1 11NIutaYl tYN111.MIN.u M.dIn,1, l' K. AINhr.rn. l. W., Ka1wpNNl. K. M, Wakhnan. ti. a1Nl AlrunJ. I hnnll.d 1.1 l',ndN.v,l\/ ul:Ir 19/,Iru/:ICUk/ry 111 171 17N, h1K7 1 xhrl wtp,eNt N:IIIIKI,J )11\Nnllr\ nl IkAhh u1NI she Vrlr/.m\ Admulia/:Nnm I IINn t1N• I kyl.ublN•nl ul Ml•dici/lr• Xl:ndutd I lnlvrr\ily til1NN11 401 Mrda IIN;, StanLNd, l'A. ,11NI Ihl' Vl'll'ran\ AII11n111\II711NN1 MrlI1caI l•l•INrf, I'ak/ Allu• l'A 1)11AN I I I A I IUN ANI) ('IIAKAtTI'.KI%A'1 K-N Oi: IIIIMAN 1'I.A 11'.1.1' 1 l:l.l'l Y 11'Kl rI1:IN I11a IlY K/11)I0IMMIINI IA1tiAY ( iIyrlplr111rin 111,1 was atuanlN:Naxl in human p1:Nrk1\ by r:NlillinaourNwl\\ay u\/up ant/vra \praNit lu pl.Nrkl uknlhr:ule\ :ulll pllrllitvl rIya:Ipw.Arin Illa l:lyt/pNlNrnl III.I .IINI Klya'/pNlqrio IIh wrre i\III:NaYI lrlwn w;l\hrd p1:Nek•1\ by T1114141 X 11.1 rtu:N tNN1 II/IIUwa•II by INrI1:/r:Nlve MIIIIOIII 1111111Y'yI \nllile IN/1y:N'ryI:111111k: rrI rkY11/p11NNl' \1\ K:NINnINhnalrJ klyrlpx/Nrln Illa was lunlnr Iwnliell by allinqy chr/NU:N/ly,r.qdly /Nl I rnthl kv11n Sr1111:n11\r 411 1'wdiavl pIycnq111Mr1n llb \IN.wa•J 1N11r rfa\\rr:Nl/vNy with '"I Inhrkd KIy1:IpNlda•in Illa winK Ihc a1Ni p1:Nrl-N nwulM:nlr IK anti r.IyalpN.r h'lll III:1 :NNIMf:I 1111 :1 t'IN1111r111N111 nIh/1NINN1 r:11INN11nIWIN/.Y\\:ly Iht Cll11M\\Illn llt ylyclpxWrln Illa r rlhp+r\ was the %anlr Illr the purihrJ Klyclpxlllrul llla :uNl rIy.lpN11 1rIn111a1nTn11mX 11NIwluhdiiedpLNrkl\ /ltlhll)ap/drmlkrlvrllla11nK1ylIpN1/ 1r111111a Ily bnlNrd I114Nr1.ly\i\ I,t p1:Na•kl nlrnlManr\ 21\40 cnlnr\\rrl the \anlr rpNlpw•\ a. nN:N 1 Flya Ipxolrln I lla 1nIu1nI1/aY111I~IrIIH\ l'nINJIf1e11:JMn/1111/1,Nrly 1/. µ4 ul ad,11 FlyalpNnlcln Illa rnlptrn Ir•r Or aells •Ihr kvrl ul plytlpwtNrln Illa lklrnlulNtil by r:N11U1Un11UM1a\\,ly in INIr IYNn•IN with lil:ql/IIY.Inn'\ IhfMOhu\IIN•IU:1 .1nNNlnlr(I n. b 7'.l HI INN111.II AINI 11 was t'ht\e NI the vilue\ IIINAInt'aI by IMhrl IIN'IhINI\ ('IrInN•w\Ill, (' S , NII'N'/111IIN'\~f, S . Ik•1\IMlllt, I) • K1Ni11\).1, It , .1fNl `lhnidMl, A 11 ItnN hunlca rl Itllpoly\N A At la 921 216 22J, 1'Ix1. (1•Irr \upllllrt: Nalillnal In\Iilules tll Ikahh hr.Na thi Ikp:Irtnlrnlh Id I'hy\inklyy and MCJN'Ifle, Ibr/wlhu\t\ Kr\(•jah ('rnlrr, l'enylk I Inlvrr\Ny Ilrallh tit'/rfNr (•rmer. l'hll:Nlr1p464, a1NI Ikp:Irlnlrnl 111 14npAly. K\, Ma•JNAI k'MM1I 401 LINli. I.N1i, 1'I44n41 1.1 AS
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MY(K'AkINAI f11t11 NI KG1'.11('S SfItI)II•.I1 W1111 "I'Nlt('I.IiAK MM iNl /1( • RI S/ INAN('1• I lk' lrlr/d lkvrl q•nw nl al "I' olk la•an nclFrk•Ik' « aNl.ukc INh1K1 ywluaal,py h't Ihnnpk•• 11.0% (Nl.va6'.I llk' tllllM'll/% 1104 /k' W ha%/l' dn1l l hllk •11 rl'x':Ifl h 1•.vcn dnaF h IIk' IIx' l1I UI lIfHht.qly Icl hnlqlk•.lurvaluale r•/~hknl• l.1 l hnk.d cardNdu)•y 1• /n n. ul/.nk v. :1 I.m uunllt•r 1./ "1' NMR NIkIK% UI IK'tIOKII hran /Nl'ICIr:11NM1~ :IIN) l/I anlnl,d nNakl..d Ik .nr Jlw .1.. h•lv.' In a•n..Nkhk k J 1 he Kl~d 14 Ilk•x• tc. hn/ylk•.1. tn .I lMlr ra t f1 !n /11y. a.N.1/.11 hn a9k•rl•r111. /n rrlalilNl /n nlechanll rl tnik nuN t(unnl; van INI, I.I.MIIlI~.• 1-INMIItI/N1, .I/NI d/,rax' ININr%V %. I:!<:Inqlk\ I/I /n\IINI/r\ Ik'th1(IIM'•I in lqr•n ,nN1 l In..'J l lk••1 .Imnl•d /IMMk'I~ afC INC.[MeJ, alkl Ilkr ppllcnn.d IlN 11tllNc Ikvr1..~Nlk'lll 1% .Nl.hc-r.1 IhhuiL, n• M, Y.NnIF. M•(lo.trr, 1• 11uJlkI1, 1, and r. 11 IIr,IA 1.Idull• I I'/ ISt. Au)•no/\a•INrrnhrr 1'/K7 1111p1 •nIM•N/ AIIM•ril.ln Ih'./lt A,,Ia 1.IINM1, %lN/lhl',1\(l'fn I'rnmylvtnl,l Alldlerr• uwl IIw M.ay %unlh l C.wl IIU.1 Irl.ln lik• IT.p.nlnk'm. I/l Mk•.Ilx•/.1 .I,wI (11.rlkn/i.lty/Raq.hyvc~. Itn/vrralv 1w1 1'l Nn.ylv.Nn.l. I InLaL'Ildoa ('l INII'Al IISI \ IIF NII('I VAK MA(;NI II(' NI S()NAN('1• SI'1 ('lltl)S('tN'1' IN ('AKI )1( IV A`('I II AR 1)1.%1•ASI. 1:><tl•nvvc rc.a•arch eI11Nt. arc h•ink eupenllavlln Jevehy+ nul•kw nlaprk uc rr.u- bafkY INMK I4Irl IrlNll1/1y tnnl a n11NINIity Ih:N t'an tY n'feJ fGK /n \YlY1ChXIN'la'rl/alaln Irl hNMhelllk':/I II/nllnMl ni the heart in hrahh and Ji.ca.e InlnrrnalNN1 clNk'rrnlnK rh:1111'l'l 11I IllIIalN/hlel unlll'r JltleterM IlhyaNdnKK and (Nllhllphy'iNIh1gK ClNN111NM'1, rrlalrve chanKe in nkrhillly and iMcrxlilm ol rtN+lttuka with nlelal /paranlagnrlll'1 /,Nt., ahangr in oNrxrllular pll, and en/ynle mediated reaclnln rale, can he /lhlaned u.InK NMR .rlv pu.a lMy Irl hnlyurs lllr.e Irl hniyuet nuy 1r• nl unluNal/rlyd ml(kN lanll• nl /k•Ink•almK nr lfwr nlylk•urd/al LNw/knn.lry wkl phy.N.H/ky rhl..dlrn. M AnKrk•an )lwrn.J l.( ('arJlx ImapinK 101 2J2-2t1, hrly ly1(7 Other .ul.lant Ank•ncan II[Vfl A,MtctalNM1, rennsylvania Alhliale, and lhr Mary \oNlh I4•:.J 1'ru•1 I n•m llN 1>, ~.lnne'nl. ,.1 Anr.lfK•.,a anJ Ilnahenu.lry/lll,q.hy.it'.. Itnlvr/.ry .d I'. ur.+llv.m, . 1'Inl.ul. IL1„ , rd, 1 / 1 (Y1MI'/1KIS(1N //I A'1IIIiKOS('I.I'.KOTIC 1+A1(/NS ANI) I11)1.-I.11'll) I IiVF-I S IN MAI.Ii, I I MAI.1:, ANU fh\'flltifliK(/f~l.-IKI:A'fLl)1-1•MAI.I: MI(7i I K(/M SIRAINti (-S7111./h, IfAlJl/r, AND ('111 In /vrlk•r tr, drlcmmnl• whrllk•r Inak aml lirnak nlia•c Jlllrrcd in I IUI. hpkl kvclN lN in ,Illk•rnx IcnNic rr.l>,Nl.c NI a high /N Jk:(, we c><amlrrcJ.1 inhrrJ .ttaln% whk h drllrlyd m.ua•t•INlhlhly lu llhrr/ha knla~;('S7N1.l6, 1I/U.11/c, and ('111. Mk'c wcrc IrJ rnNm:d llNlw /N an alhrllTrnk• diet clNllaimnR 1 2S'{• chl.k'.hYl1I, IS/A• Ial• alkl 11 S'.( l IN/IN' :N'1lI I.l'\NNI 11111111\Y a1kl \//e Wrrl't(eler1111111'd aIICr 1-8 wrl'k\.m IIII• JN'1• pl•Lma 1/h1. hp/d kvrl% wrrr lklrnmrlcll al t/:uk) J wlt•Iv. Im the Jlcl. I"IN (' 1I1, Ihr uk..l a/)Irrnx•kN1.i.-rc.l.la/N .Ua/n, 111)1. lipill Icvrl. wrrr vrry hll•h arkl/kN •dlrt trll by .rt tN dlrl hlr NAI.N/c,111)1. Iq+NI kvel, wcrc intrnik•dlalr Ix•Iwrrn 11k• lNhrr Iwo./raln. Mak kvclc wcrr.igndil.nmly higher than Ihr Il•m.llr.. alkl IIk• •nIk'rur.rnk• d/r/ t an.r,l a dnlll in 11111.-Iqwll kvrl% ul 14 - 2T>:- lkpl•nllu/r. lN/ x•. IvN ('S /I/l.i(*, Ilk• I/Nh1 NIk'/11xlrnN/~ \YxYlNlhk %Iraln, 111)I. Illtk/ kvrl% wr/r law clN1y..IrrJ lu Ilk• lNhl•r Iwn .Iraln.. M•Ilc, and Irnlalrl aNl nlwmal chnw d/li IkN Jd1cr nl 111)1 l/pk/• INd (rnlalr..hllwa•J a54'; lhvrca.r in I IIN • wlk•n /rJ Ihr a11k•r,. Flvlk dk'1 ('lN IrNtl IIA1.1(/c anJ ('57111./A, tl:al..(rr/Nl<IrcateJ Icmale. rrx•/llbh•d Ilk• m,dc. IIN' 1101. IyNl1 h•vclv in n/k'a• Iln alhcr/lieenlc Jlet dillcreJ uvrr a 1 Inld r,ln/,•r a11uN1ir IIk' n/lk' ~.'rIN1111 Whrn 111)1.IKNII kvrlc werc clNnparrJ In Ihr nu/lltn•r ld adk•r..a ti•IINk- k.kNl. IN dlc kual k.kNl arra, a high degree 111 a•/Nrcl,ui.Nl wa. I.h a•Ivrd 1. - (1 45 hN k.km nlmlhl'r :IrNI -(1') I hN hMAI h•mNNI a1l'aI I h/. .ul[Fr.l. tIl)1. bpkl kvrl• arr u1qNNlan( in ik9cruupinX athcn.x•kn.a..ux•cplhlluy in nuar I'urr.•n, 11 . Ilnlnk•.• 1'. A . MAchrll, 1)., arkl Alhre, I). Alhl•nnckroa. M 215 221, 1Y117. (MIk'r x/p(NN) (':IIIIIMnIa AIIIII:III' 11f AnlCrk'an Ikarl A%%nl'Ia1NN/, Na111MaI IICan, I unF alkl Ilh.wl In.ululc cnkl NalilNUl In.llluk.r nl Ikallh I aan /lw Ilnke l.y./n McnNlrial Ke.ran:h ImINwalory, (11i1Jrcn'. 1llhpnal McJkal ('c/Nrl, ( /,J,larkl. ('A. 1 (iIiNt:l l(' ANALYSIS t/1- MIIKINIi •S"fKA/NS ('t7N1.1h) ANI) ('111//rc) •f// (Y 1N1•IKM 'ff11't MM' I41SI11( )N (1F A!h-/, A(iliNl: UI:11:KMININ( i A"1111•.K(1ti('LI:K(1SIX til IC('IiP1'I1f11.ITY 14rvi1N1o rc.ull. .urrr.1eJ that slrain. ('t7111.//Sl and C111/11c1 JillercJ in a .inKk gl•nl• IIN allK rux'knrciv.u..rplilNllly, ca1kJ Arh•! . ha.ed lNl dala Inlol rcclNn hlllaw n/1NrJ .uain. Arh I wa. Irnl:Mivrly av.iRncd b.M/klk.ulnlc I bnAcd N. Alp 2 h/1h1. /r1aNt, ac1...a h.•Iwrrn ('57111./A anJ (' Ill/lk) wrw cameJ /NN In.N.fr r 1./,r.1 whrther Ilk• Irnlal/vr n/.lp Ll„i1NN1 wa. currrcl ParcrNal vrauy, anJ /, anJ 1•, Ilrnl;a•ny werc camrnrk'd ~uxcpl/hlr ullcks IA Arb•l, hNml) m C'17N1./h, we a.wrtialaJ wilh rrlMllvety hlw kvclv n/ high lknaly hl.qlnllein IIIIM./•a1N.k>Iend in aunlul. led an whenlgl•nie JIr1; rr.i.lara allrk+ uf Arb !.re aeMN:iakJ wNh relalively high kvel..d H/)I.-chldc.ltad 1•, prnKrny have 111M. kvels that xe in(ennediate hclwern thc.e n/ the Iwu rareMal %Irain. A/nlmgIhc I-,pn/geny. Alp 2 wkt Arh d nnern•Ka1cJ. INUvId- mK clNlhrmal.ry cvkll•nl'e thal Ash l i. liai eJ lu Alp-2 an chnNnlvwNnc I I hrre mk e n'alNnhinanl I/N Alp ? a1M/ Arh I wl•rr (INMd anMNlr Ihe M1chHNINMNIK',o Ic%led, rYvInR eT
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.111 t'.11n1•ItiJ 110.11, .I1,1.illai IR'Iwl't't1 tIN'4' IW.1 )•int•. u1 S 11' ? H ISI 1 lA1 Ih: IdN'n•.hlna t6•N.Nti/l.h.\n11rh 1t:4•nddr:l/•t'IN'IN 1/•111/11h11111JN\,hylt'h1I1.11.1I11a• LI.NrNN'oN.1h wIla 11 1. a ll.n.a Iclvrd Ly t•II v,Ncal I: vct. 4.1 111)I a Ia.Ir.icluL /t'Au. id 11~1. .•I IN••1/1 .IIw.14' ..11NI 1/a 1/'.1411 LNIIY'Y11y 1'.ncrrr !! . Allal•. 1/ , II..hlw•.. 1' A, a1Nl Mdah.11, 1) IIII\IN'1/1N.1I131/N'la. ~517'N1 5111 511, 1'11(1 / NIN 1.Np1.N1 N.IhuN.ll Ilc•nl . 1 un)• •NNt I(LNltt In.lltulc:lnal ANN'IN •N111i•NI A.••. 11 INNI I/rnu tlN• 11r1N1 ( y..n N1.naNl.d Kr4•:uth I.INN:N/Ny. l'hlhhc•n . IL..INI.d M.JI..d ( 1'llilr, 1)•11.I.NaI / A qrll l. A 1ANI I)1 11 KMININI; A I111 K11\('l l KI )tiIS 511S('1 1'111t11 l1 Y ANI) 11101111 N%I 1 Y I It'l 11'K(111 IN I 1 V 1 1% IN htll 1'. I/II'h.l. Il, llt II(r.IN.Ni /111I II )I I 1, IIK /11.1hN I.L1~/11.1 IIra.IN1Nt•111 tIN11NI 11111/1l t' 11•11 ININIt/ IMNIII,II LIIaN.It.Ny tta•w \.a11,11nIN1• 4'1 1.11 \NIN'11 It'111,11i /IINI' 1/1N11 ~.Nlw •A .Nr1rJ.lllyhtl/•ha111 _`A'<tladi.lirnl.IS'.{ 1./1.•11NIII l1NdN •N 1.11 IINIcva 1. •d 111/1 .lad..l. nd dl. /r./•r Ly •IlMN1) SIM(, :IINI I/11NI .1.1NNUp Ii.NNI. Lmll /n dN' .a•11./ w Ilhm 11 wt•a t. IN .Mia 1.11:NN..,1 INlac. .Iw 11 •1. l' 111 .Na1 11A1 llra . 11111 Iq.al I. vt I. Jra Il.l.r •NI)y Jyh/lv .NN) Irw ur /a/ ,NNill k'aN•n. ,Nr Id..t 1 va d•N 11 wra 1.. I la 1•. u.iN 1..LL .d 11av I•Ia1adY1.1. JIIIcIt ntl•. w.1\ .1n.dvn'd thv 11•N1)• ICt.Nld.ul.Nd INIv•.1 .Ir.llu..l.rla.ld if.rNl (t/111 r/..IMI IIAI Il/t •IINI .11\1/ it.Nn ('S)111 rt..IINI l Illrlla• IIN• Iwn IdNn.NVIx•\ 4•gIr}•11cd .1..Inlpk Mro.G•Il.ul ILNL, ,Nal 111/ /.'t.Nnhlll•nN.n w•1. Id14'fviJ IM-Iwt't'n IIN'11/ Ihu., 111)1_ th.di.lrnd il•vl•I. 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(',1r..IK In :h'fIM11 dINI1/11hCally J~IIN'J l(.KI' a1v1/1Nrta.elt IIN' II:Nhtal hkrNl Il..w IN t II/...IININ•..N11-LIIrd INIInNNIay arla'r/c..uKKc.l Ihal t:N hylllmnm am) ('17K1' wcr: t'11111INN\Y/I 11/ rCIJ\ v,1N IILN \IIMNdI/111t/v'k', Ilhhtalll/r n 1a111yl.ll/ln at'INNI v/a ti1' 1't NK 1' 1.../a.N. I IN• IN.a.ln r.n..va..d~nn /n tlh• 1.40 .Nlw.ly. ..•rn NINNI t•t(...Wn• 1.. t iKJ1r11: .nN.1c w.l. J. 1. n.lrul.N...q•N Idl..a. wnLNN•nh ul 11h• wN.kl' IN/I INa.n IIh' IIIlIN//N' I In.l•ItCCI w;1. [IIw.Ii.IN•J /11,ininqll.INClrt'JtCtl wNht':1(NaNln 114 by 1 v:Ilhuln/•uauun 1.1 XI' an,d..ylh'. w111/1.NIlyA/11111 JnL1j!4N11.IN IN111k1th'., ]IIFrI'.h11F 111.11 6Nhy/.min Irlr./.r ILNIa N'11..N V nt•tVt'. 1% a rrt'/l'1111N/ll' Il.r IIh' l'NII:Wa.a/NN1 UI III;N t.Nlh.Ifl'nh'• 11 tlh• anw,1V NIIN...a Al NI :I/hI I!,t.11N' IIINt' alMl R:IIwJ ININI'l/1 l'\Irava..IhlNl lo tht k•wrt :nlway. Ilh• Ir.utn .u}Fr.ICJ thal :NNI ImI1NrJ abway elkncl invulvr.l MNtI V•n.INV IN9rr. ;11h1 .NIN•f IIh'th•In1.111. Jt•14n1I111p! 1N111N (MI 11 L lulhlu.k•J 111.11 IrqNdatnN/ .d .cILINy /N•tvt. in Iih klwl•r allway% t':ul Ih• v1.11at1/CJ JIN' In /IKII c11111C11t lll .ItYihc Ir•pll.k.ll:h'hvlmnt. aml (Y:KI'1 arNl al,l..Ih.'J ,1\ ht'kNlFl/ll! It. IIN• ('hhl't FrIN111111/C tIt /IN'1r V•n.111V11V 141 l'aIl'.:INIn I/N'a' I~ •INNk• C'.NN,In1//1Ip cdl...lll l/l M'IL/llvl' YnVlry /N'evtd atr x1/va1rJ by Irrll:nn alnndl .uh h.1. cll•,Nt'nt .nNAc, a•dN•1 a/hl w'hl a. wt11 r. hy hl.lunnm• +I/hl Iw.dyAlnlu iluhal uq' hINI1t l'1111.11/1'lll'RP.:u1J hK'al rrka.r..l 5P. NKA a1Nl ('GKI' 'ellt.r prplNk•. UN•n mlt•/:hl w/lh .ItY1hi IrccIM.N% nn IarytY h.uN•% k':h1NIF lu va./Nh1aLIhlN1. IN.Nr/o l' Rt1,/vN.,N/1N1 :IINI IN1NhINM.N/.IrN'INN1 M.1t11n1F, C K 1l wlJh.vK, / I Atla 1'hy.Nd./yn a St:uNllaavN',1 1(IN %f.11 157. IY/(7 (h1h•r .NppINI SwrJl.h McJlral Kevarrh ('.NaN'il, SweJi.h Tuh:N•cu ('.Nnpany• I'chllm am/ Augu.ta IlcJlu/hl. Llum/a1Nln, SweJ/.h S.N'irty ld McdIC11N•. Swrd/.h W(wL I•.nvlnNmh•nl I ulNl, a11J I1N KanJln.ka In.InuN•. I I.NU 111t 11.IcnInN•nl ul ('harN1:N'uk/Ey, K:IrlJin.Aa In.tllutc. SNN~INdo1. \wclll•n NI'.IIK(1KININ A IN ('AINAI('IN SI?NSI'flVl: NI:IIKI)NS l)1 1'/ll: (:UINIa11'tl: tN1i-K/()K MI•.tiliNIliKI('(iAN(:1•1/1: AN AUI)Illl)NAI• 1N 11 A'I IVI: MI'.I)1A I I/K 1•(1K "1111: Nl NV•( lll N.INI:KGII' I:X('1'1 A I l 1K Y P1)Sl tiYNAPI l(' 1'( ) I I:N'I IAl. 'tllc prevmr ld /lcunl4inin-A likc inunamlrtartivily in Kuitra pig Inicruw Inc• .culcrir F:Nlllia wa% tklct'ICJ by raJilNnNllllmla..ay ptlNtYhln'.. 14c1/tat/nK Ihc ani 111:11% wllh l'a1NaN 111 7/Iay. Iftult 149 t;111Y1111en1a1NN1N rtY11N'lYJ IIM nwan t .N111'IN I.t IK unlAinin A Id,r imnNlmwcx•tivl/y by KY1f• /nwu il% n111trN1 va(Ik ..1 IS11 / 11 1 hlN/l Iwt Ka/1Klnln lhr'h lovrlllrNlanrt IiyuiJ t'hnNluH/fraphy tcveakJ 1ha1 INYU../ mlu A IIAc inNlwmlrcacllvtly wa.lN•Irnp,r•mluN a, in alkhtilrl lu nrunikionl A. It•a4% tllttc. pNNhllg h/111C a1111.111h/an 1:N'hyA/nin ckdllan an111N nCUr11/N'INilk K wCtC .ICLY'IcJ, and IIKy t1t11 wert tk'111tItY) by l'a11NaN'in. I'.IIYYnlllhy\Mlh/l,`KiI t1ullN•. .Ih/wcll thal m'INnk/n/n A appINYI l'l/hl'r by .u11cr1u.Mln ur by prc..utc ej.ti•Inln cv.d,eJ a.h.w Ik•IMllal/a1NN1 in /IN• /I/a1lNlly t// Inll'rNlr Ilk]cMctK F'a11/,`ha m'utlNl. In YI/L. Neuru- INmn A eW.1.eJ tk(h11a1/~:nMN/. In IhC n1:IMlrlty UI I:ell. (c.h•J wCrt awN'I:NI'J w/dl a u/11,1II /mIt'aV' 1// I/h'IIIlNn/h' //IIN/I ft'N.tWNt Ih,wl'vl•f. Illl' te./N111.t% wl't\' llhrtyM'1/ by nM nllw.llw hY1r11r.LnIr:NNN/. Ihc tafapl/l.neJ //M wI lYrNhMulnl pMcnl/a•1 trl ntuw LI/IIn A//MIIN'tY/lk'rJIN/~N1NMIwN~ -(hINV, l(t11N/VY11.It~ItNteIIUINtMh1/u/11hyllhN c1/kltNk Nm..uplwt.a•J /11t n. unltinlm /1-imhNeJ Jrp11yt/irINN1. 'lll¢ .klw lk•prller iiatNNl clNi/cd enlwr by cR11itcINNl.ly a/llll/ed .uh.tanrc 1' ur by rc1+lNilivt .11n1u1ataN1 ul hyln/g..1rit' /r'rve% wa% ecvcr.ihly chnlinaleJ in tlrc prevrN•c ul, twuralunin A. Cl/lkt•Iwely, lwr.tlN/its wyFe•( 1h:M ecw.Arnln A hke imnwmlrrwtlvlly nl.ly enesi.l wdh %ulhlalll'c-1' Ilke imnN/nlNtal'llvily in falNakin-NlNnlvt Illtr. In IIN• Kuinca pIK pteveAehtal KanKlu amllhal lhe.inlllatny Id Ihe w9i1N1l ul ncuadulln A.NI Ihc lNlt h:aNl am/ .Id+./akt I' .N/ IIh' ININ'/ Ia/Y\ Ihe IMh\IlNhly Ihat mNl t IN.InIC//`Il ]/. 77 65100 7824
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r at i1.d/Ny rydr/11u.11. CIIt Ileal In IFN• InletNlr Inl•v'nlrric 1•rnglla nlay he Ia'rp'I.IICII by n11t INN' Irot a numtn•1 111 t kla•ly rcl.ucd I:NIIyAInm\ San,l. A. M.1, R(' ,Oan, N 1. I1N1.16N\NM N/Nh1•In1.I: nw) I nndl.•r4:. 1 Al Ncun..l/r/NC 1t1111/51 45x, 1'fx7 (hIN'/ .nlyNlu IA Il.rrtrlN•n11,1 Ilc.dlh a/wl lhmran S.•IvNC\,ow11ISAMRIK'. Au.h.an %l N•nllht Krv.n,11 I u1N1., Xwrd/.h McrIN a) I(c.t•ar1 h t INIrN d. •IINI Swt'dl.h I u'I.Iw l.. ( unlp.my I Inlo IIN• I k'l1.uhlN•nl .11 I'h.nlnx,.k.~y. L/Iyola llnlvcr.uy McJaal tcn11•1. M.ly w/NNI. II .IX'11.1/111N'111 nl ('IlnNal (1N•Inl.lfy, Kartd/n.1,11111.pqal, ti11N1h111n1. Swc. Ik'/l, :IINI IIN' I/t'1/.111nNY11 tll 1'h:Inn.NOll/yy. KaN/Inl.(,.1 In.uluk• NI lIN1)1'1 1'11111 Y ANI) NIIN /1t)HI NI RG1(' SYMI'AlIIl-al(' VA\('lIl AR ('tINIk1/1 111' 1111 ('AI NA\AI MI1l'/1%A NcunqrlwNh• Y INI'Y/ I.N'al.l. w11b MN.NIrI'n.It/11C INAI in .1 INyNd.dl/Nl ul Ill'/1V,1y 111.11 /N'rvl, in IIN• 1.11 11./%.1) 111tN -J In (1N' INI'N'll/ \IWIy. 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Id 111c n.l..J IIUh/•..1 IIN• It.al. a,1 NI'1' 11 In IlN• .u1Nr1.n tc/./1,11 r:I/IFINNI wl'rl' INlwt'vl'1 r\'IIINI•II Altl l il'M'fIt//N' trl'./IIIN'11I, wI1NI1 tk'11I1'ta'II IIN' 11.1,11 NA t'INllrlll hy JIIINI\('NMX,nwl IIN' NI'Y tlwllcnt hy Slr% ,:1 va\/q INNlrlt t/ll rt\INNIK• NI tNyvc\tlnu1L11wawa\\Idlprc.l•u/ AIh'1rl'V'rlnrN•Irl'!lhlll•nlt'Iwl/hlllt'IIw11I11Nt'}1ao}h- 1N1N 1k'IN'IVa1NNl. INfvl' \n1111/I,/111111 NII/ull:uktilu\ly Irwlut•cJ in /IN-fl•:1\l'tI INIIINII I/t NPY I I aml a mar4cJ IIIny 61.IInK VJU1lIM\IfNINNI which wa\ rwll In111N•INCd by 111M'/wlRyhl'll/d1/111N' a1NI (MIIIRJIIIIkII I IN' rC\t'r1111K uNhwcJ dt•plctwln 11/ NA wa\ Mll //IIIININI•II by Iwl'I;a11Kh11nll' Ik'nl•rv:lltlwl whlk' the It•IIININNI in tIN' /la\•/I 1IN111'lll 411 NI'Y 1.1 wa. INCVrnICJ In.•IwNlu\w/u, NI'Y clNlkllt a Mnl :Ithl'IN'/pl nN•JIatIN /ll .ynlp.nlN•IK vavul.n cllctt\ in t:/l na.r) uwnl\a I./IINIIII,NI, I. , Anl•Faf11, A,S•Ir1a. A, and I l.a.fhrr,t;, I AI hlurn,d ul Ihc /1ullawNlul Ncrvllu. Sy.tcnl 211 IM'1 1107, 1//1(7 (NtN•r .ulrywlrl SwcJl\h McJNaI Rc.c:uth ('/NIfNI). SwcJl.h Worl 1'nvu/ronw•nl•11 I u/wl. \weJl•h 1 al.xta('INUp•Iny, Wlhcry\ 1'11un11elwm• Pt•t1u..IrNt Au/;u•l,l I lclilund I'INIINIJIIINI. :nNl Ihc K:Ir//Iln\Ild In\tltulC I rnm tlw• 1>,'p.ullrKnh 1.1 INII Khlnu I arynpuk.gy :1MI 1'h:Ifn61l'l1lr.ry, K•If11I1tl\I1J /n.tnul.`t,. ~h..llll ~wr/l.'n .I/wl I h r.ntnw'n11.1 1•.It•rlnN•IIt.11 Irw1 I IJnt,d I'h.lllna I..Ly. 14.LI/.dl ,.I l,l.u tAJl.f//./ ]x 1 IN IL/'I ION 01 N/aINO1M'I'111N: Y ANI) flN nIRNA IN MI:( ;AK AK YI K'Y'I I:S: I:NIIAN('1:1) LI:V/a S IN ('I .K I AIN AI 114 /IMMItNI'. Mlt'I: • Ncur/qvpluk Iyr1/\ilk Ifwuaqh•p1i1k Y; NI'Y11. a Iwecnl VaNNUn.11N11N w11h ,1 wNk dl\n Ihu1wN1 un dN• ccnlral arwl lrnplw raI rN•rvlw..y\Icln. I Icrc wc \Iw/w d1 N Inyh k•vcL Id lal NI'Y nl/(NA :Me:IIM/ I/y1rNI n11N•rlllhl•raI hk11NI t't'II\, INNII' /11,/Ir11w, Iu/1F. alwl .pk•cn I'1/11IN'111NK1', I:wINN11MInnM1:1\Vly It.'YCdkYI hll.'h kvl•I\ ut NI'I hkl' p'p Ink•\ u1 1IN'v' n\.IN'\ (n /oN•c, dlc kvch Id ylkolc NI'Y nINNA awl InuoumNC.NUrt• IN•INNk• Jdlcrcd cwlcn\wcly hclwtrn \Ifaln% and wcrc prcally clcv.llcJ /n a•vr1,d \t/ •iul.l N/ I t. N/ H t W, arwl 11 KSII I Ih:M Ik vcklp a JIV a.r rt•x'uJdlny.lbuulan \y.lcnlw lulro\ crydN•n1aN/.u. LAc t1w ral. Ihl• N711 nNNnc .huwcJ a hlyh ./Nllcol 4.1 NI'1' nIR NA /n t1N• IN'uldN•r,ll hkNNl ccII\ :IIwI INNM /161ttuw. I111111u/w111/\IHN tN'1111C.11 .I.unwF /cvr.drd NI•1' hAc Innuulwncatlivny in laryc ccll\ nnlrldwduFlc:111y uknllil,lhk .1. nN•r•11...1 W N ytt•. In 1.01 INNN' /o:urUw aNl in 41w y/kY•n t/1 dN• N/.1l Oww1.1• .uA/n 1.Iwc..wNl ..I NI'Y /nRNA in nN•KaL•ayllty/c% m r.ll IwwN• nlarll/w :u1d N/11 nwN/v \Ilk't'/l w,1\ tIN111/11N•II by /n .tHN ItyINNh/a1NN1 IlN\l' f\\IIII\ IIwIN',111' /II,11 NI'Y 1• \yotlN•aicll n1 nN•F,/l,eylaytc\, olpdylnK Ihar NI'Y can hc a•Ica.rJ /nwn p1.In•k•1l al./ I nM I N N1 ,N :1 V,I W 11'rNNIf N•IIn IIW IIII! hk N 11I vc\%r) Jama)!c. (n :wkln lon, dN• nN rc..c u1 .pk•lu. NI'Y In lCllaln a1111N/1nnu1M /IwNI\Q .uamm aJII\ /a 111c Ir\t .ll ,IINwN/ll•III/N'• a.\INIa1cd wdh IIN•v \Irams. I/N\.INI. A. tillt:JhnF. M . Mclnlyre. K R. Lnn.Nar.C. / A1 . I.nkuulnal. 1/ , %c1/w.lry, h, 11.IAIch. 1, arwl l'c/\..NI, II I'r.MCC111n1•.Id llw• Na1NNlal Acalknly ul kICIN•c\. IItiA 1W SSRS SSN4, AuFo.11'/M1 ( NIN'1 \IIIIINNI KaM (N•n AII, 1IIC twtNh\II N:nnfa) til'll'INY' Kt'N'.1r1I1('IN11N 11, SWC111\II McdNal Rcv:w.h ('INlnril, Maynu\ IlerKvallv 1IwrN1:IhIN1, I'clfnm antl Auyu\t.l IIcdInnll\ II NIrN1:Nwwt, Swttih.h '1IIhx•.u ('INnpany, and 1•rcJnl. a1N1 InynJ Ihunoy. I /NIINI.11NN1 lilwn dN• 1 kp:muk n1. ul MrJit•al ( it•IN•lic. anJ IuronnwdnF y, IIN• IhunN•dltal ('cntrr. I IIM`\ Ila 1 Inlvt /vily• l lMl\ala,lwctkn, a/n) I kl+artnwM\ ul I I1.I/dugy a/wl 1'llarol:N 1/I Ity,y, IIN• K.Irldln.la In.111u1c, ShN:Lhlllfn, Swclkn A('1'll)NS t)1• ('Al.('/1/M ANl'A(:()NIS'11()N P{(1s• ANI) 1'l)S7'/IINI'1///NA1 I:1'/1:('111)1• NL•lIROIN:1'111)1: YON 11(/MAN IM*/1M11'RAL 111.(N)11 VIa11a.ti IN t'lIK() lhc nN•rh.un\alm u1Nk•rlyink Ihc cllnlral•hk cllcch /d /Nlatllwpwk Y IN/'Y/111 rt'L/IIINI III IIwIV• 1/t IwNallfl'nAI1/M INA) /M \n1:11I hu/na/l hI/NNI vl'\µ'I\ wl•IC \IIwIwYI /r/ rlla- NI'Yt,11/N•IIA INnfat1N1/1c11tnM\l'nN'IN'vC111i,r1•IIaIa1NI\ACICI:II/IIIIVIII',ulcrn'• Mn mll u/ aN•.+•nIC/N:ulcrlr\ NI'Y wa\ aIN1tN Slu I(I II/I/I /IwNC INdI'/l) IIL//1 NA I IN• 111•/LL111/aI t 1NIlr•N {NIC tl•\IMNNI•\ III NhY 15 M NI M 1 wcfc 1N ' 4. /7 ' M elwl 1/5 ' IWx ul Ilk fc\INNL.• cvuhcd by NA N/' M in Ilw• nw\cfucnc vc/n, rcn./l and .kt•klri /n1/a k• •rncril•\ rl:\pcl uvcly ITw NI'Y clln h vw rc rc.a1.M k1 alhcfww clwtw anaFl.n1.1\ I IN• caknlnl anlaKllrll\I ni/eJil+inc reJlkeJ Ihe cllal nl NA hu1 rw11 tIK a.raracnk tc.pNl.c 11/ NI'Y un nK.cmcric vein.. 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LLw'I Kh(:111.A fIUN OU SI,RFA(TANT Sli('RIiTION tROM ISO1.ATIiI) fYI'1:11 1'NI .I IM( M'Y I 1:` II YSUIIS I AN(T 1' Snh.t,ua r 1'• •rn ckvcn anlinll ariJ na•un111C1111Jr• aynda•an1ly InhlhilrJ rrlcav ul ~'l l ILIx1.Idl.mJyk IaJnw h/wn pulnrlnaty 1 ypc 11 cpllhchal crll. m vlun ha.al rrk av arl tckav in rcynwl.c hl the /f-alkrnaKicic awtnal. lrfiulahtlr and 12 () 1eh:wka./ Ir/ylllhllrfrll 11 ;axlalr /17'A) wrrc ./gnilia•:nNly .k•ctra.rJ In 11w prrwta•c ut .ul. .la/ac P h/h/hlluty rllrah u( .uhNancc 1' wa•rc Ia11rJ lolk/winr a I h cslr/.urr 411 pton.n y a oluur. ul I ypr It cr ll% in viltn arullr•t.1.IrJ up h/ 1 h ul lhc prcxrae .d Ihr vcrrt:IF/./cta•.. I PA a/w1 Icrhut•alinc. '111r K'„ val_K. tlw .uh.lanar I' InhthllaNl .11 I'l 111Y' rrk•ov wcrr 11/ µM llw ha.al rcka.c, 411 µM hlr I 1'A•in11uccJ rcka.c alxt S11 pM hw trrillnalnlt• nwlntcJ rcka.r. 'llrc ra•IakJ muuqla•puJr. physalarnlin aull the .L/l.k• :la uva• .ul.do{. ol .uM/:/na'c 1'. Ip( ilu'. MrI'hr'. Ma•l ay'I.uh.lara'c 1'. haJ nll .•r, nlta .1n1 udtJnlln v c11c11. /N1 .nrlaalaM trka.r whrllrer ul the prcvra-c nW ahv/w r..1 I I'A Iy Ic/blN./hlw I la•..• drla.oll{to/n Ilw' hypMlwa.lhal NI12 N•nnmal haar r, /ullp. /d .n11.1.ua r/' aar /M•. c.wry La Inhlhitnln /d .ur/ac61111 V'Crl•IaMt ItIM111mula1C1I I ylry' II tcll. J/MI .ulywwl da• .o/arlw 111.11 an ndnhnlwy .y.km aulnrihulr. lu uKJ1.lth/n1 ul .ul /:a 1.1111 yy Ia'Iawl I/.M11 I ylq• II C1/1IIN I/:II aY'II\ Kn r. W K aal Sln{!Iraln. 1•. M. Ita. huu/ra a1 Naq.hy.w a Aa'ta KK4,121 127. 1'/K6 ( Nht•r .u/q.at Anx•ta an I.unp A../lcctli/m. ('hikkcn'.11//.pllal Kc.calah i'.w1aLlulm atxt Na1nM1.J lo.ldutc% ul IkalthI hllan t1a• Ilnlrcraly u1 ('Irlciunali Mcdlral ('rnlcr. PrJialrlc.rNcwlwltn 1)Ivlaun. t'om: mnall, ()11 K17.IiAS1i (11 ~IIHS'fAN(7: p, ACI:TYL('ll(N.INI' ANh MI.77111)NINIi I:NKI.IMIALIN 11((1M Ml)llSli ('F.KI,:IIRA1. til.l('/i1: 1:1 I IiC'I.S l)1 NI('l)I INI•• \uMl uar I' Itil'1 cnharla•cJ sa'ctykla/linc (A(71) rcka.r whllr Inctha/nlnc cnkrph:lhn(Mf.K)I/cprr.vJ/t 'focvaluurlhr/'ac.tfisaAnlachanl.nllnrA( hrrkav. tllr cllr.l% ul na /wuk Iln thr dnn/1lawvlu% tcka.r /4 A('h• MI?K, arkl %P INn11 11aM1.C arrctw:J .Ipc. wcrr Invc.tiy,alavl u.inK mical.ullrt(u.Nwl Al'h tcka.c wa% lulk/wcJ by Ila• rllluud '11 Al'h 'llw prplak ark a.cJ wcrc ntra.urcd hy raJildnulaawr.l..ays A hlw a/warrHStluln ol nicnl/nc It`) 6 x 1111' M1 Ina'travJ Ihr talc ul %I11N11:1MYMIV a•k•a4' td A( 7\ :In1I SP and akcrravJ Ihc trka.c ul MI:K. A lulth .Llaa•uu:lu.al ul nalwun Itll tl>' lo' M/ .k•a•rr•a.rJ the ynlnljnctw. « k•a.c ol A('h anJ M1 K alxl IIa traM'J the %I11M1t.lla'.MIV Irk'aK' UI ti1'. I1C In{!h I/NN'•'111t.NaM 111 naldlnt• lk'/NrV1rJ Ila• rvuArJ rl•k•a.c u1 all Ihtcc. A(71. %I' anll ML•K '11a•.c nhvrvatawl. \I/Mat the hypwlM.1. Ih.d MI K a/1J SI' nl.ly Iwrlalpaa• m IlK• rrKol:ataM uI Al I11rk•a.c Ir111M la,nn '1 avah. /1 ti anJ Gnu t•• l/ V K. In Ilrnry.) (. • ('INIIore• R . ('urlk/, A C , Prlkllrr• (i . OIrltilm. K • an.l KcK.•Il. I ) lctl. ) SuA.lanar 1/ arwl NrurllAmm., Xprmgrr Vcrlag• 1+11. tSl) 1S_• IvNh 1'rIN11/Ia' 1)cp:nlna•ol nl I'F1.InnxuklKy, Vamkrhlll l/nlvctany titMlld 111 Mrdlu/a•. N.Lhvdl. • I N 117 65100 7829 Kr'
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11 \IIHA1 AN('1 I' IN IIItMAN Nil KMA ItIZt/A ANI) Mt11)IILAf I(1N (1F SI'I KM M/II11 11 Y FIY \IIII\1 AN('1: I' ANI) IIS ANIAla/NIS1'S 1•I.MUt.IN•d hnus/n .Ir rnr.lfoi..~ anJ vrlnnJl plaana werr ctlr:NlrJ LN XI' lllr Ih'INNk'. %I'11/1IN't'll/•MI\w.l.Mk'1111IN'11hy4k'lltwIJIINNn1111111N4h.;lyJINIh1..•L%ay INI. 1. t IrM ally .h/nuLnrd r.lr v,l..k trrrn. 'I l1 cv:IhlJle Itlc ruk ol SI', 11047 n111u.'IN r ul SI':uN1 twn 11' (1 pru .11 lrli ' SI' aaI I) ary', O Irp" ku" SI' welc .tlNl MYI .NI hnnl•m .Ir•/nl nH.ldny NMka /MII AI 4 INNU., 11M• MI ..I SI' br.d..1 11 S. pl' • MI yhYn/ w,l. hl)•htr Ihan Ihal .d the unlrcalrJ r.Ntu.d, by ;IIhN11 ?11'.{ . IL.wI'vl'1,IIN'AII Wa..l.'INl'.4Ylwlthlu}I1CrfINNYntralMNN1/t%I'1 'It/'M1 I1.dh\I' Jn1,/1Y.111,t.1117' N/ 11) M 1 NN tt•J4YI Ihl' M111y Jh/lw M)-SlrV I hFIM'r C1NMCnttJlnNL 111 IIM•4r anle/YMU.1. 1111' N/ 1/1' M1 dNl 111411 cttlhN ..iKnilkanl rllrlt INI dM• Mi Se' 1. AIN.wI/ 11. llM /c.14' (.1 , IIIN,II.I' by rN•/vc tell. 11 i, pnahk 111.11 SP :uNay.NN.t. arc `I' a/Mt Iht•rehy dnwn rrgul.uny tIM' ('J' ' l h,lll/lt'h I n/.. Ir11./1n/. nbly 4•rv. :1.1•1Nh./.Y•/MYN/. (+hy\N.I.1rNaI ]n1:/r.N1/.t...1 \I'. 1.r.b1 ll V K.Nh1 (.N1.rN1. V 1: In I/rnry.) 1. ,l'u1mNr.K .('IN•IIo,A C .1'rlklMr.(i ,0nrnm.K .anJKlyIdl.l) Il•d. 1%ul..t:mte 1• and Ncut..l,mm., \lwmFcr V.IIJK, 1+{+ t)9 1utl, 1'/xb. (MINr ~II/.~hNl 11 ti 1'uhha Ilr,dlh I.'rvNc 1 r1Nln 11N• 11,•p.NtnM•nl .d I 11.nn1.N.d..yy. Van.krhdl Unlve/alv tirlNN.l ol MrdN Nlc, N,Lllvlllt-, 1 N OAMAGI 111) tltl 11ItJ1 AII INIIY y AAI1N111t1i11K11 M'lltl(;AI(AI 111'IAKI %1S11 M IN Mtll/%l IIkA1N 111 Iulk\I KAIN\/I I'1 k()\II)A%I tllkl'/ I'rl'\y/1.lrllt I/l'IVt' Il'1111111.11. MIM'll.l.'(w.Lu.v. .1 Nt• 4•n.pl..• 1.1nnNldw.In/•r. •11 .uNl 11111%. InN1.1I .Ilh'IJ111N111y IUN4'r.NI1.h Ir•t..tIJJ4• M.NIV• hlaul .1Nr., ll 1 nun• Jt/rd.lr v.•ll by a K' 1I1 1'I ti M1I/l'1 J/Mt t'lIM.4'II I.. INN4Y.MI11I11.1'r..tN1•14 Cttllhllt'/l .1111'/.1 IN.mmlhNh.yualNp vCalk'tllt'/11I/L1/1C.IrutlNre,nNtmhl);h alhnNyl'Y'Iy;1/1111MrIN1- ly/la' at'N) 1/1NJkC I IN' rlnt .InIN11J1.Ny R'IrhvJt 11) .ynaplm: vc.N:k•. InN1111N' na'IVc Icnnm.lI plaau:l nNmIN;nM• in the 11n4•IN'c ot hlN.eraJl.h Itrnailla.C rc.ullrJ in a tk't fl':NC 1n 1IN' .y1Wt111N vt'.N-h' INIiNII:/INNI with a l'llrlt'ufll'IN IIMrCaM m nlNl .yn:q+lil' . Ve.l/tl' IIN'11/1Na111'.ttlKillrl'• IIII!halhnlly 1"('ly-aunrMlhulyrN• ;IriJ Iqqake Inlul/ I- Inlll .IMr. n( nMN1.C ICfCINJI CIN1l'l aMI IMNI. IINYh/1IJ.I.1/1a) t/NJ wa. mhlhltrd by (1'X JrNI'!'I , rc.IrYirvcly, Jllcr uN'uh:llMln IIN tA/nun in K' 111•1'liti hullcr clNlta/n /n$! INna'LNh.h Ih•aIaNIJ4• Su/lerurek d/.nNILl4' p.NCtll•J hNh 11K .yn;yNN' vrat k• IIN'111tKi/n1':1rMI1tICI11~•II MIIIn1Iyu~ttYl.l'.y.tl•IIIIrIN1/tIM.'lh'k'll'fNW\eIIIY'/\I.ItNN4'r:NI 1.111h'1/.{NI.14', IMNnl/lll,' I./ (IIC 111N\/hh' /I/vnivC11M'/N 1./ .//lp'r1.R/.ll' anMNl r:NlN.lt.ln II1C MN4Y.Mh.h la•naMlJ.c rrlalrJ ell..t. l l/c.c IMNVeaMh.h rrr.l.Mlav ImhMr.l IdNYJ Ii.NI. Jllllt•:Ir 1., t\ 1111t•t (C.I L.wafll. IIK' C~IMhIYl.yna(MN' vC.N k' 11M•nltNanC. •/INC tMNI . d1/11n1.uCd /N.///1 .ht l'. Ct(h1yYI N/ hIN.Cf:Mh.h ~a'ru~NIJ.C /ll. MN e><IIIMI a rCIhN InM /n cllhrr IMyl6 .N 1.1w alhNlly ("('1y aullrNlhnlyric x•NI upla{,c. 1•uw a(hnily uplalkc .ul I"l'ly ,n11UN.INnyrN :N Nt JMI I"('INd////1NNV/1M11yfN' aC1/I In1U l'IMIN'aI \IKl'. W:L IN.t alltth•d ,1171't IlNl/h•/INN. In K' 1111•1-ti wnh INN.cf:Nh.h (hY...MIaw' I.Iw at.lnlty NL1.Jr h..W i•r. /• 1.'.lu. r.) hy lip• In/•t. K rN.1 * I4Y' ~II/IIIII•111Nv IIN I/h.11MM IN•.N /a, ul•t.d.- 11 .qq. .r • tlw. t1r r/ hry•1r rN,l Inw •dhNlly uld.dr .N.• dr.1/m 1.uhl .IJlr/rnl t .y.lcnl. w11h the hiy.h al/inily Iran.pNt .y.lcm .trw•turally a.aw c/N•J wills .ynalNlc vC.ICk• nwnlhl.uM•. Ik•Ider. 1: A,•C.•t./N•n, Il., Lahha, A. anll (knnatu• 1 1'.. 11 Nr/ulhlx•ml.by InlrrnJulroal 11421141 151. , 14t17. 11uu1 dM• ('rlNa LN Nrtu.rlM•mi./ry• Itk Nalh:m S Klillr In.hlutr LN 1'.ythlattlt Kr4':Nlh, WcNJ-. LlJlal. Nrw YINA, a/Nl New YINA Unlvrfaly• IA•IaNlnw'nt..1 1(Nd "4y NI('1)IINI INUIII'1 U('IIAN(~IS IN'Illli Atl:"1'AHI)LItiM l)I til'/:('ll l(' IlKA1N 1'K1/11 IN% lIh• t•Itl•l1 rd ,N Wl' arNl tllrtNlK INt/N//N' tNI IIN' IIMIaMdl.ol ..1 .IrY /iN hratn INU1C111. W,/N t'R:11n1nt'.I by nlCa.urlnF' 1/NINIIIN:IIMM1111 IJtICkII vaI1/1C I/NU IN.NCItI • wnll Ik'n.IhMlku/c r/ annlny ld ptulrnl. revdveJ by Ket ckctaMllMNe.i. Acule arNl thronN a.Innni.tralMMlulmt.d/rlClo41UI,'/k/.'IICt N1nlln1/N 21MWr],..1' ,INII 51/11,'rAl!141 41 Illln IIN S tlay. ( A I/v1 Illl/li INN1111 i111t11:Nlll'l1 .u1M'1/t:1M•IIINIy 1) rl'llltt lYI IlM'11fIhN,11 NNI..t 1'Y'/valuK :Nhnln/.lrrrd by ;IpNUnmalt'ly 6 77i lllc re.ult% wtlh CtNtNlll' Il1..N1/N• a1h/11n/.Iq1/NN11rMIH'JIIYI a lal'1k t/I IllkrlltK'e t11t Ihl.l'IICI l UI //NIIIIIIC MI•t-an1yIJ11u/N•, a IINah11NI!JIIrINN11t' a1NJF91111.t, Jllc. 11114111 .cem 1.1 hktt'A the mhIh11NN1 .d INUIrm .ytNIN•.1.. Snlall nNrra.r. in prrMCiu cINNcM were Ilh.ervcd nl a h/rh am/ a tuw nMlk'tvlat wclyht rcltNNl n1 tiUS pnlyx'ryl:anak kel, u.cd ,o .rp;11:/1C ININCIII\ Ifnnl nt•wIMNn INam IN;Mlull twain allCr chHNIN nil•Uline aJminl]uU1Mn1, .C1C.IIvC IINrea4•• a/M1 a Ik•t-ICav' were vYn in Hka•(We harNl.. RC.ul/% afC cIN14Nl:m/ wdll .CICIUvC cllccl% ul nla'INlrlr INI the .yrNhc.iv tN dcgra11a1NN10l .pecilic twaln Ix.NCin. Jrrth.•n, ll . Banay-Sl'hwxq, M., Uunklp,l). S..1)chlcr, l:. A, antl Krnh. M li A NcunKl>,rnN'al Kc4:atch 12/21:1Y7•2t/2, 14117. 1 rlNU the ('t•nlrr /ot Nrunlnccmi.lry, lllc Nathan S. Klirlc In.hhne 1.N 1'.ya hlJorlc Kc.carrh, WuJ'. LIanJ, New Y.Nk. lihUl'.(T O1;AS('OKIIK' A('IhUN'tllli SYNAITOS/)MAI. IIPfAKI'.IN; 1'I/IMI'1", I'111IKN'AMINI:• ANI)1"('1(;AItA Vol• l'IICI't. nt nMYMh/C acid tM the .ynalMnwlmal u1Nal.e ol /'111MI•P', I'111J./ punnnr, anll I"('/(iA11A were cxan/intYl in al.nlplv N/ unJerarrMl the rnelhunl.nl ul Y.I.MhN 1N'/11 NICIWYINM 11/ MI•CI' nrwdn.N /1y 1'1111)r111amirrc uplrkr waN i/N teJ4•.1 at bw.'r kvcl./11111 and 11.1 mM) wNllkcrea.aY1 at hlRtrr kvel. (NI mM) ut .4vwhN• acNl. A.c/Nhlr rciJ inh/h11eJ 1'111M1'1" uln;/ke IK'„ - 11 1 n/M /+uNl ('Y'K ;AIIA uprali< IIC_= NI nlM/ Wa./Nlut lll axlNhir at'Nl re.NlreJ uplake u/ ('ll/Jllplmulc a/Nl /'11/M1M" ,.u1tRc.linR that arcarhic-xNl inllw'eJ lipid peroaiJ.1NN1 w.% rM11 mvnlvcJ in the ef(ect rNl upukc In a.Wlitilln h/ the plom-ihk mwAvemeM Id anliulit Ml.nl nM•, hs n/.nl% in the rn rrl'.r anCnualNN1 u/ the newnluaN'Ny rd MI•11' by A.t'.NhN' at 041. she (Ne.enl re.u1r.11NIMa/c a Jucrl e/ln'1.11 ..clNhir aciJ m Inh/hitlnR Ihe up.kr ul MI'1" /nr11111111Yn/1M'r)'M IM'Ivl' N'1/111n.11\ x x 1119
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C.•.J.rn. It : 1k-I.1cr. 1 A atwl l.apha. A h.mnal.d Ncun.\tu-n.c Kc.ratlh 17 2I/K l/ll, I'/X7 IntulllM• ('t•mcr Lw Ncut.ahl'mt\Uy, Ihc Nadun S Kltnl• In.blull• I.K 1'.yllumt ll kl'N•.Irl II, N'•:Ir11 \ W.IINI, N.'w YINII HI IIAVI( /KAI ANI )Itlt x'lll MI('A1. 1•1'1'li(1:C t/1:NI('()11Nli 1N AN MI'll' INlrllt'I II MI111~1 Mt)1N 1.111 1'AKKINS()N'ti 1)1%I'ASI: l ltn\ \ludy c%JtnuK•d tht• cllcc1.1/( nit o/inr.M hV'1RIMMIM Jl'11v/1y a1MI.n111N• h•vl•) NI 1h•II,ut/11M' ( I)A I J/NI 11\ IIN'1•IIM.1111•\ 1•.1 dlhydruR yphl•nylJarlwx td I IK )1•A(' 1; n.l IM•IIMW,It11IIn M nI/1IVA/11t IIN• \IrIJ1Um JINI..II•MI.My Inhl'rlh t.t IIIKI• IIIJI h.M1 IM't•11 la:drd with dw• tw•uart..\ut I nw•Ihyl •t t,lK•nyl 1,!, 1.6 IctrahydaM.ynclnM' (MI'1 i'/ MI'11' aty.mhl.odly 6.wctrd t1N• .p.nlJnclw. Ww/wl.ra.» :Khvdy I 2 wcck\ JtM. r nwmth. J11cr 2 tnN•ltum. u1 MPII' / N1 m1;/1K S(', 24 hr ar.ut/ in ylw,ng :wluh I 1 /IMN11I1\) JMI 4.I11111/l1• (:2 1/ uM•nllt\.ll.l/ IIK• l•IIIYI /tl nt\INI/K• lMl hnINIMNIInI W;1\ hq.6.lal , Jn ttutu,l \InnuIJ11.N1 Ot hI.NIM4.N 1// 1 min alter nw-rNlnc) h.lluwcd I/y a .klwc...ml lt•n.ul IJ\tuty Inwn S t.t 211 mm Jhrr utM•ltntn r..h•rancc lu 11K lklnc\.Jnt fllClt..1 IINtd/1N• 111'v1'Lhtvl J/ICr the 5th.L.y.d d.nly mlcatpwt\al ma•ulnrc 11/ 4 my.Ay S('. Iwn r duly / I.drr.uM t• .bJ rw.l n. t ut thy dJy M 1u 1IK• tnnlal .Imml.ll.wy cllcl I ot mlultnl• A vnulJr rlltlt .d nN.Ntnl' .NI Lnn/1w4.N 3ltlvlly wa. \ccn in mKC /rcalcJ wllh MI'1 I' I la• tl•vl•I..d 011 11'A(' JtaI I I V A in Ihk- InJtunt wcrc tcdwl•d by Jnl.wm/ !Irf In IM•.hnntn tn..4nw' uc.ne.1 •uum•J. IIN• Irvcl. ut 1)1/1'A('• IIA, an111 JA wc/r rednl yd ut Ilw' MI'I I' Ilt'•Ha•11111tp l•, IM.WP\t•1 . Jl u1l• JMI t I/I.Nlll nn allnc dnl 1HM IJUV':111;MIIIIInNWI\I1.1/14l'111/)M•7111t11M'IC\I'1• IIN'It'\I/II\\III,'I;l'\I\Ihalnn-1M1111'h.l\]II IIIIII/Cnl l' M1 I14.MIM4. V.N Ilvlty in MI' l l' Irl•J,1'.) Inn l' JINI th.11 thl\ {•Ill•l I 1\ n1N llw• 1.. .hJn).tiv in 1)A rc.clN,a :n Ihvtly ut the .trt.llum . Ju.cd by chr.uln nalwtnc Nrr.lu'n, ll , I1J\hml, A a/w/ I:qthJ• A I'harat:NldttFy Ihlncenn.try Rc NchavilN ?RI'1 2l1') 1411. 1')K7 I rluu the ('culcr Ilw Ncnnw•IKnuslry, 'Iltc Nalhan S. Kline In\tllule It.t I'\ythiaua• Re.carlh• WuJ'\ 1\/atwl, New YIMk KI•.514)NSL• (N' 111f, /11-V1a•UI'INIi NIi1IR(1MIIS('lIl-AR SYSI'IiM (1F lllli kA 1' It) NI(Y11INVANI) I111: NI'11KOIR1N'I(' IMiIT11W I KA(:M1•.N1 Al' I11/MS114 111 Re.ulls \Iwlw rwo chanye in lwitch lK Ietanic nmlracliam amplilwk hetween la within the ynMq.s tc.1r.1 N.t nicrMine tw M'l ll/MSH 4 NI InlhkeJ chanpes l, cuneJ in c/lher p.\I re.t t•r ry.\I tc•tania• Irncntuatam Nu Jd/crences were secn in mu\rlr wet wc/KM. I'up. IucaleJ wtdt ntaAme during prenatal and p.analal Ide as t•nnq.arcd /u cuntul4 ammal. l\attm -saltnc) \MwrcA \MMCr Iwltch claaraclirxt dunhunc irwliraltng a Iroae rap/d twn.h 1•tcnat..l A('lI1rMS1/ 4 111ucateJ pupa hall MMnewhat Ntngcr Iw.l.h w.tt, nn.w.rw 1.,.1n.d.dty lu Iwtp\ trc•nc.1 with 65100 7831 i r- candy la\tcr Iwitl h hall rclaratinn /intc than pultv re.-eivtng niclNlnc pt\tnatJlly lmly 1'uln IrcalrJ wrlh n1a.NUtc durnnK prenata) and ppMn•alal lilc a\ C1N111t:IR•II Ill IINIItuI anunal\ .IwtwcJ ;In IrM7l•a\C in Ietan/C l•tMMral'IMM tluralNM t/MIN'JIIIII! Jn lnywuvcJ Jl.rhtv In \a\l.uu Ictanu\ ( Illyainp rcccrvinp nicrdinc prc anJ Irntn.ually h wl .IKnth r:wllv WatrY•r IclJntr c.mlrarlNn111mes Ihao /hlr\e Itlrp% rca'crvlnF onlNUk (w..lnatJlly IN/1y Adldl I'UI. mu.ck, nlak up rd prty4mtinaMly la\I /vl+e 1/1.cr\, tmtUally hJ\, dlamy /MMIIIai lkvchtlomcnt, cnrNracuk I+ararnck•rs \mnlJr lu tlwr.c u1 \h.w typl• hlrt. Na tNur• ncty cwt clctalc thl% maluraem pnw•cs>, whtk A(' 1 t I/MSI I d III otJy hevc ht11c cllcrl J\ vcn Iwo wcch\ altcr hlrth. K I aal SnnnJ, f'. l.. ~ AnnJl.l.l Ihc New Y.n). Acatkvny tt/ Sa•icrk•es 41W:11'/ 122, May 27. 14//7 1'Hn/l the IIN.L.yy Ikp:utn.•n/, Ncw Yluk Iloivcrsily, Ncw Y/wh V. Pharmacology, Biochemistry and C ell Biology kI:V1:RS1111 F. SL()W• ll/illr-IIINI)IN(; INIIIIIffl(/N (/1• IIIIMAN 111 IKI K'Y 11: ITAS'fASI: ('hi AIJ Ala /'rmarnlwnVal Ch, was syn(hcsiicJ 'fhe clmqrNmJ mhlhn\ hu man M•w'lr•ylc ela.lasc with K. =( 11 x N1' M. 'Ibi% rdlihul» i% a reverslhf,•, sl.tw• ughl Mwhng /otuMlNlr wnh A_ = 2 x N)' M' .' k- - I 9 x N1 • s', FIK Ihc Mt1uh11rv:ItMN/ l.I c1J\un by I lI.f. by 1 t(' .= 1N/ nM. 'Iha rnhibihw ia lhc nrt.l cllee tpvc akkhylk lu kC11MN tnluhtaa ut J.crnk palcurase yet Je.erihrll. 1lurdap• R 1' . SllwK', P I and AM•lr., R. U. NNtlhl•Iml'JI arMl IlM.phy\Il'aI I(e%eart-h CtMIMMMII'aNNMm 14S(1)1, May "), N)K7. hr/wn Itw 1)cp;/nnK•nt nl anKhcntistry. Il,tah.n Ilorvct.uy Sclurtl td Mcdwtnl•. Jtwl (ir:duJlc IkpartnN•nl ol ttMw~hcmislry, (lranikis (Imvcr.uly• WJltham, MA I:X71'N111:11 IIINI)INt7 IN/tlhlll)kS 111: l'l1YMl)1RY1'SIN 'I IIA UIN I I.KAt'1 WII I/ I IcAVIN(i (iktK/1' 5(IIISII'1:% S,' S; Wc have \ynlhc.i/eJ inluhiaw\ ut chynw.lrypsin, ha\eJ un /lwKlwlcdlyl kclunl•\• that hinJ at S and S' whsiles. "Slnall" inhihilun n/ aerine Iw.Ncases• whNh have previnosly been \yrahc\veJ, rwlly inlerar/ with S wh.ites. llle parenl clMqxwlnJ 1\ Ae-leu-utn/nt t'he ('I• 1t /1) (K, = 25 x N1• M/. llris inhrhihw was nwMldw'd by sw•ce\\rvely replJclnK 11 td the -(T,11 Rmup by -('11,('H,('ONII('ll, (41, ('ll• ('ll.('()NlI It'u N11Mc (S). (l1,(l1l'()NII (tu Val(11:.1 /61, .al ('11('11 41
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IIN' I/Nhl CIICYI/vC innrNl :Ia/NI a1N111NN1INN11.I 411.J1 Inh11/n.K. l•1n ht• I.h1.InN•J h.Nn tIN• :IlnuN/ :ICMI 47t1U1'1M'C 1,1 (N.Nt•111 In1111NItN• Irnlt•rl.dl, It ,I/N) AI•rlrt, N lI 1h.NIN•nu.llv `h•11/d 4477. 11/K7 f 111N•1 u/yNNI N.d1un.J In.tllult•. Id I(r.dlh 1 IINn 11N• f;/.NIu,N. 1\•I..Ntrllt•n/ nl hl.n ht•nn.try, (trrntk•1. I Inlvt•r.uy, Wrlth.lul. MA I I IIIIKII)1 MI IHA111) n("IIVAIIIIN 01 (:IIINI'A I'IG NI.lI1Klq'IIII 1 In yuuN e I/IF IK rN.NN•,11 rK ntn.l•hJ. N.II :11 .1 t/Nw t'/11ri11/N11.I •IINWt' S nIM rht NrJ J tk.4• Ik•Ila'INIt•11t, .hl.lyt'.I .1n11 4/./.IIIN'I) ,nI1t.111.N1 ul NA111'lI uanlav Illdll.- m hunlau rN ull.y.h/l.. In INg lt•1L. Ilu, lr.r-uv w.1. /nJa•ry•/Nh•nt .•I rn11:Nt•11 J./t cak luln I uR1 ` IhNNt'4 Cnl y dN'J.I/ll'l/N•nl. IMIN :ItC1I •IINI p IIINNIIk• IIN.'IIIJICII t1Nwk•r illC t'ICv:11/1M 111 IIN• h•vt'I ot 1 y/u...hl t•IIt 111111 l1Nnt't11rOt11M I'rcltc:NNN•NI n/ nrlun. plul% wilhlrlln.4.lntms hk.AcJ IIINNnk /KI.nN.ll•d:ntlv:/uon..l NA111'l1.la1J.14•. f1n/1t11hn1,' 111.11 N.11- .11n1111./ul.n wa, nn•tll.ll!'tl by :1 (: I111Nt•In wlnCh 1% a IN•flu.a. 4nu1 .uh.lralc N•1F tl/curJl.lI1111111Ck'V.IIUNIM:N1/14'l1.NIVCUIIIN'IuRln I/lNNlltan.l.l.d N:11' .hllll/l.lll'll tl'11. t.* a IIINNNk' Irl't' IIN'IIIIIIII. .IIIY't/aNk' rt'It'a4' Ik't II/N'II :/IN1 t•1I cnnn Irvch lhln/n/.IN•tl low fl'.INN14' I/I low IIC.w11v:11C1I. IIINKIIk' INl'.III/I/ILIIt'J 1,'111//C:1 IIII! IICIIIt111/h1I• 111 :/ 4YINNI:Ify .1111N/I:/IIIM wllll IIINN)N/I /IlYt1.1.1IC :NCI•Nt• II'MAI IN IMrI Ixu 1'hC• wa% cNhwr un.lllctl/•d by 111e INcvnN/% t•hrlknFr wnh N.11' 11'MA1lN auynlrnaJ hy N Illlr chtnNN:Nlir prlNllk 1 In p.cJk•I It/11n :Iativa1i1n1 ul NAI)1'II /1\NI•LC. 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IN/Ir t'/VIh111141N•Iln II'(+I. tNll IN+1 by >•IhlNtlln, la'I:1I t'aIl ]rrulll• a1N1 71 v.nl.'tv Id yn/wlh LNtr.t..N Elyt.q+nwcm.t lly Jay. 12-11 nl .cll t'uhu/r• whrn IIk IN.q cun+N l rll. o1.NmrJ lo Le. erylht.~(+Ia.1.. .INt'/lic MINImF n1 ukrJly IkchlN J In Ih1..luJy. lNlnl•m ('l lt I h.+vc hrcn Lu1.At•J in .Idlicirnl INlnly N+ ah./r:N/t•/vr llN• IIMNI+IM.h./'v LI ItN' V' Llll' l.'It~ ..n1I In ~uI/N KM nullt(N't\ NI n1~.a~11f\ ~(\'l Ilit h11MI1111~ .d I it ~aw•NL1, K. Ao+nv. \ N. K.+n.. 1 ti, Ik..yprl.• li N• Sawycr• S,(itN~, l~ I) , :IIMI ( I+111. ( I IIN• I..urn.Jl.l l'hnN.J Invr.11/•./IMNI11/I 110 IM.• Auku,ll)R7 / hfN•r .urjwN1 Vcl.•ran. AII1111111%1r•IIMNI Ml'Jll.ll kr~a•atl h 1•aml.:/al N:nNN1.11 In.t1- lul.•...1 I Ic.1111/ I r.+o111N• Ik•p.ntnN•nl...l M+-dN Inc ,/rNI 1'•.dN.h.Fy, VJIMI.•rh1I1 It/11verNty tiIIMNII ul Mc.IN1•w. ,nNl Vclrl.+u. A.Inunl.ll•NNNI M.JN.d ('cnlcl• Na.hvrllc• IN. a1N1 IfN• 1.4111% 11.q.lln% ( hN .,l.q•t t. ul. /. 11.JunM.1. MI1 l"1 ()NIN(:1/1 KAI '1'kIt)N KI.1.A11 I11'Kt)II IN' ll)NA K.II plnNl tc1:NCJ pllacm 11'rPI l I)NA h)~ IN'r'/l t kNNYI JMI VYIIMnI'rJ ( 1NnIM11 vNl /+l du% a I/NA wuh t 11NA Ir/NU hunc/n• ham.trl, :IINI allwv intlir•rk•% r*NcuN•ly layh I+Nlvtv,1/1.N1 I,IINN/t'1S•,i 1 Ilx 1{cJurrJ paftul ra1 1'tl' p•.%rar.: 1a1 a hiyhly t'IN1V'IVeJ rl'rNNI 1+N111N1yll 44 ta'f+t'hlfvl' 4'111N9Ni•\ In wh,lt L INt•luulahly a11 ralr.NC1 Inl.n IMNn:un. 1h/ a hyJ/+y+IN.hN: tt:ul.nN•IUhrplw JlNUaln. (a•1 a luyhly ch:wKa•J IrE/un whN'h .INwkl %1.+11/11r1/1tN.1/K traMlt•r• IIII a M/Ih1:1/N1aI t'yl/y1la%InN' tkNll•JIII Iwhn'II a'.NII:11//~ AII 4.1 1IN' IMNN'1N11r/ v111/vr 11/Ih1/1111NNN afMl a II/~.`h IN+MNNINNI U/ CIN1%rt v:11 wr %II)KIItu1NN1%l. :11NI Irl a hydr/q+IN+hN' C•ICrnliou.. 1)Id and N.Nt1N•tn bkw analy..•. .u/•rr\I a 111/11k'J t•tIN-nN/1.1 I'tI' in ral II%NN•% anti I/NIN a/r Ihdt I'11' ryNrl%MN+ Iv tk•t a'.Ll•J ul 11N M:un JN/ lny tl+r alulr ph.l%r rr.pNl.r .y.lrnln al/y / lul rr•uh. ti/NI WIyNNI 1.1IIN; rM~IMN11I1:11 I'11' ma hll,'hty l'+NlMrvrll, fMK111aI CrIl/1lat nla•nlhralN' 1N+NC111 1+1 r.vnll.d 1 c11dNN//•h I/n1.IM.w11I hN.I1.~K I WN-IN/r1. whN'h Inay 11a' t/e1N„/IIYI /ll hhllliaf a/11yh+Nl Il+rnl J% a Il•WI1 l/) ahINMn1aI 11hNeNln1,' 1/.M. Y t' . l l4c.. Y. LNt+. I•. .1.:Illiry. A . W.N., (' , Rult.Nl. 11) • anJ (•lu«•. n. f: .1 t.dw.~.dsn. I,•..•ly.an•n ~ tl 11 1 p/ 1 r.l P/N7 ( hIN•t .IqqNw1 NalnNlal In.lilulrs ol Flcallh. 1'r/Nll thp t 1a'11:11111N'/11 u) 1'atIN/1+IKy, ScINNA,d' MeJN'ita• llnlvrr.ily ol ('ahlurnla. S:n I'r:11N /V it 1111; MA1l1K N11('11(ri11N:'fK11MK)SIMIAI'ASI:IN-Nl1('I.IiAR S(A1•Ii)1.1) IS h1ti1IN("f 1'ROM A("IIN 11N• nclpN nIN kna,k IriplNn(dl:uav ul rallivrr nw-k:u .rallnitl, a 46 AI ) INlqrul IINN/FIN I.+I+:IIIN 11~11t' In IIIN"kYN'y1/111I hnlN KNA IIa/1lkN'aINNI, 1\ tI111//K'I It1+/11111111111- IMduKN ally 1.k'n11Ih'II ..:IIIuIJ aa•Im al Wrllcrn h11M1• ha. a .ub.laMially lhllctrnl amnM. ,N NI tvNlqN../hlNl. :uNl 11. rn/yn1a1N• athv//y i. rNll a11av'la•J by anli-aa'11n an/l f+1+11N'\. I1111\, :JIIMMII!h tilC CIN11raChll' Ilrnll'In at'/ln 1% IINInJ in na'k•rr v'a11ulJ a/N/ nlMw.lt. HI /nlrr,Nl wqll KNA, i1 i./NM u.aN'I:N/•J wilh Ihr nu.ktil.itk h/pM+.lAlalra• :N hv/ly 1/1 %1N II INl'I..Ir:11NNN. ('luN•l.m. /: A . I:Ni,ry. A . BuUl+n. 1.. aal Snlut'kkr. Ii, A. 1'ap.•rmknt:J ('t:ll Rr.carch 1hTSS4 SA2• 1'1)((.. ( hIN•/ .ujoiNN1 1 I S 1'uhlia' I lealth h•rvicr, Rr.eara'h ('art•rt / k•vr kqNIN•nl Aw:uJ. alMl AI:NIrInN' \ru:Nt: Aw:nJ. Ilnivrr.ity td ('alll+lrnia. S..•. Ura/la'LCn I tlNn Ihc I kpartnw nt nl 1':IItN+k+Ky• StINNJ uf Mrtlicolc, (/nivrr.ily ul l'aliluln/a• San I r1/N Lt o. i 1'ARLY IIYIY)MI:IilY1.Al'K)N t11' 2'-(/ K11K1S1: M1/11:T11:S IN III'I'A I( N'Y'l l: (•Y 1/ )1M.AIMK' k11kri(1MA1. RNA IININ:k1./1:S 'I Illi 1'kt111 IN SYNl lll':Ilt' 1N•.1•1i('1' 1'klN)ll(1:1) IfY ('('1, . (',IrINN/1rlf,N'hhNNk• 1('(Y,) IrralnlrM 11( t:N. prlrlucr.:m carly /k/ccl in nlrlhyla- INIn ul hcp:Nurylr rlhl+aNlu1 RNA, whKh INrur% rNncurtrnlly wilh a tk•tra'1 m 111c pfldcm.yltllN•lacap,N'1/y11//M/INCIIrItMWNIK~ /~le(t'1,-i1Nlw•rJnlrlhytalNNllklrcl 1\ %I1Y11N LN Ihr 2' t) r/fMhr INh1INw. BIII a a'tlffryNNNlln1,' InnINMNlll:ll incrra.r In m'(: hav' nN'Ihyi:dNN11Nl'//h /n /'r1Y! IInkler111lMhylill.•J r1h+/Vn11aI .uhunil. 1tRNA1 IaNn l•('/, Irr alavl prrlur:NNNI% t'an 1t nk thylalad /n .vn.. its a tuut'h F rc:Nrr r slr Ill lhan (1Nhl• II/MII l'I+n11111 INl'I+:/ta1NN1%• a1N1 rn IY/I11 nN'lhytalNN1 IC%IIN'l.'l IIKIt Iu1N'INN1:11 cap.w Uy !n rtlr.r nN•111vIrInN1 ut IrraLvl riMwun:ll.uhunN.lwhich rraaNr. IuminNl:d cap:Nity/ IN'rur. :w '' (/ rltN..a• pwNillm (larXrly t7 tc%wlw.) In c.NNf..1• rn rur., nN•Ihy1.NNNl.d tv«Itl.+l ntN../Nna/ whun/l. (whiah Jn}s tNN allral /INN INNIa) a.NVny/ /rlNl'4'1Nl h:/M' /IN'IhyLNMNI A% IIIY), \/ll'% 111,164,111 Mfr YI+II:npnlly nIl'II/yl,Na•J /n Ut•.nrJ Itrrpx:NNNI. w IYIi. Ml'l11y1JINN1/aIpllNthyI:11NN11/1 2'-l/ tltNlv.ilr./n IRNA rap+vJ IMI IlN' N/r1aCr UI t'y1.1111:a11111t- r/tN.MN1/:1I luhunN% nWy rtlNa•M•nl iNl I/nINN1aM trII111d1 oN.•a'han/.n/ /nr cINllndilnK pnMeln .yMhra% in quic.ren/ hep:N/wyte.. arNl a apprJr. Ihal lY'1, Jlaupl% pr.ncln .ynlllca% by InhihilinR Ihc 2'-(1 nlNt.e nlelhylalNN1 ('LrN'...n. G A . M.NIhN1a1J. I R. anJ WINI, ('. 11. '111e )nurnal nl ('rtl 1tM.hqry 1111. 7115 711• AuKum 1'p{7 '/~/K '/ 4
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4 NIN'/ .ulqrnl 11 S I'nhllt I k:Jdl St•rvMt alN/ Kc.caf\ h('atccr Ikvt•IlKmlcnl AwcnJ I f.N111IN' Ih'11..r1/t11'/N Ut I'.IIINd.q•y. `.INN.I nI M\YIN IIN•. I/n/va'rmly..l ('.IIIIIMn1a. %an 11.nN 1..1. INIKAI 1111II AK ('AI ( IIIM 11l)MI OSIASISI)IIKIN(:11Y1)KMIiN I'1 Kl /\Iltl IN/I IKY 11) l 111.111K1:1) I'IMK11, ('H1 1 ti I1M• t•/1r\t ul ra1N..mr .•t ulluucJ PtNK11, cc11. h+ 1111. .NI InlrurNhJ.u Ircr a Jl. wal l/('.1' LI N.I. Invl•.nE..ll'.I ur/1v/nK t1M• Inlrarellnlar tlwwrv c1u tak lunll IM•L. UN "1~1nn ~.• ~l'J I• rnlv IrINn :/(IIMU.nn.ACly IS/1 nM In ~-2 yM nvcr a t1uM' clwlv 111.11 w'•t\ %1/1Ntrlv J6•1rlNknl .N1 Ihl' a1NM l•INr.dNM 111 110. u\[tl ('s x N' ' In 5• 111 'M / Mlrr 1 yM..ua .d (' INKI t, \ t'll. l.l S K IU ' M//11., (Jlnn ? wa.lulty .:dur:ltcJ It•Iwcrn 1%.I/MI 11/ nun t•a1N..u1C I hnint( Ihl. 11nM•. IN/ a(.(I:/rCnl thanl,'f In Ihc fall nl capldlMa- U.NI Id •t'a ' Ir.Mn 11M• r.u.MCltular nM•d/uln.INlkl 11c .klrrteJ. wh.vc+% m lrll. prl•L..Nkd w/lll •/'./• rM'1 "l-./ w.l. knt IaMn 11K a•a•11..11 a prcalrr ratr than tlNwld. M\•a.urCnM•w. Id 1.d.[1 \PllulJr \.Ja'nUll hv at.Nnl: ah.IN)+lu.n yt•al/alallpy lIN1tInIM•J 111.0 Ihrtt• wa, a IM•1 la.d ul \•J. lum Ir.Nn IIM• \ cll. Ju11nF Iln In.l pl nnn AI Ii11M' IrNw. •JS nnn •dh•t ralr/.nrr M. I111 t1M• lulhl...1 t•.IrJ.a•Ilut,lt 'V.l J/MI flct Intr:MClhdJr ('a' '. Nr' Iwl K r.q/N11v uM rc.l•rJ 11.111 IN1N•.1.N I I 1) t J1.Jr.h.w by Ihi rcll. vclrlrJ (IINn ./lw.ut K nun 1t I- t/ . Ilt ' M 11 t 1 1.. /1 O nnn .d S 11 . NI ' M WIN•1/ IIN' 1.N.J '/':1' '• MlllCrlllt' l.Ip.N /IV d IIN• ()11u1 ' I« .1 w•1\ v.IrM•J by I/lt I\'JV/ll/! 1IM' IIW.I1111t .d mlr.Mtlhd.N frun _` by /.K InIJ 11 1• III ) h• III JnN.I IM'r \t'II). IIK fdlC.ll 11v.11 Il :1 I, wJ. lk•INc.vJ Ly .NJy I (1 14.1.1 Inlluwlnr rtq.~urc tu 5 mM 111). 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INlly Inlr:McllNl:a t ak /unl 1. mv.dvcJ ul 111r SIIIM•4 l'vt'lllv /K\ Ilr a'INM/MII/IJIIIIy Wllh gY1hv 11MNI.IMJIIgical \IclnFc• tl. IIM• Id:1V11:1 /IM•I/IIN:11M', aIMI I111JIIy• (I) /1M.'vl• l'vC11I\ INClrlk b... 4.1 n11t•y/lty ..t 11N• 1.I.1%1/1a /IM'/11IN:nA a• a IR•rnM'./h/hly h:/nM•r Ilv•h.11.1' A.Illn.l/:/w••U It ,S.hraul.la/trr•1 11 •SLIJr•1. A•SIMarr.K (:..11N1 ( .N 1/LIIN'. C 1. , )uurn:J.lt l'c111JJr I'hy.NduFy 12'/ IS(. thh• 1'I1tG 1 NIN r•ulqral 1/ % 1'u1.6. 11r.dth \rr.a c I n.... d.. 1/. 1•..1..« ... . 1 I..u......../.•, . \...Iq•. / Lnn ..u.l N. .. .a.1. I.NnNl..h..u 1.1 L.n. . t .... 1. 1. . , ./ .. .. 1 ...... ... ..1 1 .1.1...a.. \,n l lu l•. IN t'll K( ) S Il 11/11:5 / M' I Il1MAN M(/N( )('Y Il : MIGK A'1'I/ /N M'Kt )SS 1'.NI11/1111'1 111h1 IN KINIY/NSI: Ill LI:I/K/IIKII:NI: It, ANt) I Atl 1 I 1:11 I'lll. KrlJtlvclv 11nk' 1. Aw/wn a1MNN IIMNMM'y1C a•r111rIJ1NN1 1140811 Illr vawulJlu/r IN ./tvwn t1M• LM h.r. t11a1 1rFuI:Nr Ih1.In Iili..lwly, a huln //1 tn t lu.• nMNkl 1.1 a I.hM1MI \t\4•) W.1II w:1\ U4'J LN l'ta/11111a1N11/111 11MNMM'yN Iran\a/MLMINIt:1I uNFr.wlNl I1111hlhtJt Vl'In \'INIINIM'I1.1I Cl'I/% wf/l' 1'//lwn /1/ \'INIn11Cln'y IMI a11111N41 t'.NI/Ktllvt• II%%IM'.:IIMII11111L11111MMMq•yla'% Wl'rC%1111N1Ia1tYI1111r11N%1IW 11MMM11ayC11/1ta•NIMNIti L.IIM' lIM•oM..Inr:MiJ/N. k11d.dIM•/IC It, IN IMCI-Ixu 1'IM. 1h1• pattern and 1/1nc t/tlu\a ut 1/MMMM yll• mlFratuNl wac .mnl:n 1iw Ihe twu alwnMd:Mlir lal:r/ws. bl tMNh \a.r.. a/yNUtunJlcty 411 . SIM.t ./1 tiM• allhcrcnl nNNNM'ylr% cxlenikcl.inglc aw nmluplr p.cwl.. IIIMI. 1nM/ dN• alMral a•tM6NIKhal.urlarc. lln% inik•nling tK•havwn was alal l.ha•rvrJ In IIN' ah%.'IM't• 1.1 l IN'tINN.M'tM' I:Il11M\ 11 Wa\ MN al1r.'la'\I by Ilw oMVhum IMI'r/,l.l:cy'./ /N IIM'tINNI uI IIMMMM'ylt• 14/LNNN1. Na'Ytflqllnl. ala/ Ji.playcJ Ihi. helb:.vNN• Mn INlly :ItMNN I1:III J\ IIIJI/Y IN'11111.f.111I1 a\ 11MMM0.-yk'v Iwk•IIN/I 1IM• CIMhMIM:haI \U/Ial'C I IN' 111M'1'r/ty IIt IIM' \'INII.tIM'111/11/1.•111a1/M\/ /Illal'1 aN IIM' IIMNNM'ytC\ /faVl'f KJ the 1/MMMJ.IyI•/ WIM'111IN' 11MNMMIII'\ ICaI-IMYI Ihe IYIVII .nrlaa'c 1,1 IIh t•IMkNIM'hunl. they In'y1M'INly wrJy\•J I1M•NLCIvc. IM•Iwa•cn 11M• ba.al .urlxr ld dlr rd41111c1ntul arM11t. ha.al lanlwa I hr nMNMMyh•% tIM•11 InV:Nk•II 11M.' ha.al lawnw a1M1 atranwl:NrJ m Ihe cunlMV tlvr 11•%uC. In rC.IMNI%C (n tMNll I MaYLCU-I'IM' :nMI ICU1.1Aril'rMt It„ 11MNMM'ylC Inl)!I:aNNI i aa1.n.111C cIM11A1M•Iwnl hCpan a.ratly a. NI llMnulr. 'llll' avr/a~'e Ia1c 1/1 :Mcunwl.aaN1 /n IIM7 pNMM•c11v1' (1..1M1 (>tal.l'J al M/ mmull'.: :/nll by fd1 num/1C.• 2S• IS'X n) Iln.• nNNNM•ylr% had tlavl'rv1J r1M 11MNMIIayIY. AIIIKO\1111a1CIy Iwlt It/1hll'l It11M'% 71% /1/.111y IIMNNM yk'\ (/aVl'IY\I Ihl' a'IMkNIM.'i/11111 UIMhf .'t1/NII1NNIV /lt t IM'/IMNa\/\ :fN II/Nk't l/NMh (/INI\ 111 l IM91N1{.IIIN VIv IN 1a1MI1N1/11111`IJIMMI. IIN'Vl' \IwIN ISIn11vNk llh h:N/v I/N U1Nk7- N:nM1/111: Ihl' ININ'l'v\ 1.( IIMMMM: ytl' 1111~'fa1NM11NM //) IIM' IIkMMI\Irt'altl a1Ml lay IIM• (11/lwla IIINI I/M tIN .FIMIy UI ttM•Ir ddlCn•INia1MM1 i/llu n/aa•rullhal!l'% /11 1IK t'tM/MYt/VC It..IM• MIKlNlrlv. l i• 1'ullc.• Ii . 1'awklw4i• N., and ('runN•r• 1[ It, Aa1crM'an IINIrnA nI I'allN/klgy 127.1S7-1h7, 11187. I ltlkl .uplMNl Nati/Nlal In.lilule.ld (lralth a1M) Ncw YIKL II.JrI A..IwialNm 1•LNII Illl' I1\'(KIf111Kn1 UT AnalaNlly :IIMI ('cll NN•h.ry, Slalr IInlvcr.ily u1 New YINk• Ihlwn.tatl• Mr.IMJI ('cntrr• ItuNlllyn• arNl Ia1.NaNNy 491 l'cllul.n 1'l1y.Md./yy a/Nl IlwlMUNlhlry•'11M• K.NI,a•Iclkr Ilnlvar.ity• Ncw YIwk. 'I lili I•1•1/-lT (11• NIA/TKUI't11I. 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Lt thl• Ir.lllx•at a/wl d Ihe y1./Lacr.ll \Il'lll MINN IIIN, hlll M.lh.ln/vo wl're .•ha•rvcd 1n (N•nrlN•ral lunl: I1y IINI 1r.1.1 ndra/NN11r.:J 101 .Nk• v.lgal by,lunn l.w•t•tl I lhv rea..• in ( Y iKP 1111111u1wxl•:/l llVl• nl•rvc- n) IIN• q•.d.urr.d hull• •11MI INIIIN III/, w11INN11 alhYhllg Ihl• IIIINnk: rlwucnl in Ilw: tt,laha••1 I rlt V.1r,1) lly.lolNt a1..1 uwlulcd a markeJ inaea.e in MNh 11w• inlrn.ny ul •Lllnlnlr a1w) 1n1111h1•1 oI 1'l iKI' I/III1111111N1•:nilvl• l•n1/11Cr1IK' .•a•II% in Ihl• htng We llwwlulk.• th.N /'(;KP InnInllNNe.wtrv/ly i. 11N•ali/eJ in fNwh nervc lllxC% anJ erwhN rlna•.cllw arnl /. a..oclalcd Ilrun'rpally with the alfcrenl(K•o.INy) Inncrvali.rl ul thc rc.pnatlNy tr;Ir1 Ihr rpl+arcM ahanFc% in the ('GKP /11/111UnINcal•hve en.l.t"IIw.' celllrpN11,11NN1I./IL/winK.:q/.aicln IrcaluN•n1:ItrI vagal hkalnNl %uFkevl1ha11he.c aa•II• ulay It• undrr rw•urlwl,d udluerN•c ('.Nhrut, A• SINm1.+1/. 1) K, Mul.krry, I' K, K.Nlril;ll J•(;hatcl, M A, Irrrnrhl, l; , It1.wNn. S K. anlt /'..G/4. / A( . Nrur..,c/en.•e 1W'1 M11 627. 191116 ()ther upNNt ('anlcr Ke.carch Cam(+a/Kn I rlNn 11k Ik•partlnenl% ul Ih.nlchemiary anll MeJicine• Kuyal /'n.1gnNluate Mel'iral `11N111I, I /NNkN1, I' nF IJIN) 65100 7849 1 I111 I KI 1• KM)I('AI. ('IIPMISIKY (If (•1(;AK1:7•IT SMIIKIi ANI) I IIIi INAI'I1VAIlt)N(/1 ALPIIA 11'KO"Ili1NASliINIllItll(1K ('/y.ucne .nw.kc clo he .cparalcJ IMI/ ra% phase .nwlkc alrl blr. :uw/1NNl1 phav. a.NN./•n vcry 1u1•h l INNrnn.Nnwl. 411 In•c r:wlical. 'I:It caxNam..l:lhk t:Nhcal, that a./n It• .d...•rved J/ra•l lly I.y rkrllr.wl .pln re.+lnalK-l: 11:SK1 (;a% ph./.c .nM/kc cl•INam. N'.MIIVeI':11ItNl alwlutyl:en-.cnlrlrJr:wha•a1.Ih:Ncan/wNIk/lhvtvcJJua•cllyhyl.~K INN cau Lr Ilh.crvcd u./nF tlk 1•tiK yxn-lrap nr•Ihlwl. I IK I,a /,whl.d 1. Nk?nnlil•al :In a lluinlNw.• I/y11rltlnilNNla• x•/nN1111rwxll' inll•raa t1no! .y.lrm In a Ilrw owd.•t ular we/rIN• IStry nuuit. 7he tar radia•al can R cl.lr:K'IeJ mlu w.nrl, anll du..w11N'1 NI% 1.11 I.NhI"aI \y%klll rl•IhMY•sUUyI.•l•n IU \n(Il•r11;NkL• inwl hy1111/rl•11 IN•/UlNki 711NI :IIMI lal•IIy/l•% Ilrc alnvctcilln IN hyJnTCn IwrullMk lu Ibc hyilrotyl r•w11.:J Ayal•.NI. Wd1uwN1m ul dle lar rallia•al. Ihl:rehxc, nick 1)NA. 1;:/% tlh•IK VnN.k,C l In,/%1% //1 V1141II, t\;/Chvl' tallN'ak /hal %Ixlull/ havl• hlelnlN % /N uwN II A•.% th;llt 1NN• V'l INNI I•aralbt/l:ally• Mnwcvcr, lhc a1..crveJ blrhnrc Id rxllcal. 1/1 1•a. I/II:IN' \nNlkl' /% :1hIN/1 hvc /llm. l11 ratNNlah/c thl%, w{,• have \UI,•14'mhYl that r:w/11,d.:111• l'/N11/111wN1%Iy INllllln•CII m1!aV phaVl• NlMlkl• hy rcaClMNIs, Ihal arC \/III/IJr 111 tlN/.c 111.21 Itf ur In .nNry; l hl. view 401 /he r:Nhcyl a heoli.lry /d Kac ph:l.c .nw.kc .aFrc.t% th:N l ly:uetp• .nNlkc 1% an NI ), rich .nw/r If/Nh 1// Jemnnaralr Ihal amnNIK. Ida• Inlaura• IN Mav- l:m chlpha'ale Ilr raJiral chl•nn.lry ll/ ya.•pha.c .nlllkc. arwl al.u I..Ix..v/dr a nvInl :nwt trr Irec nwwkrlnl cipatcuc.nMlhc, we have Jcvchq+cd a.inlpkz IINNh'I .y.tMn ()tlr IIwtICI awla.h nl Iniaann% 111 nNriC nlli.k INO/ anl/ ia~(Ncnc at kvl'I% IIL11 t/11111/l' IINhV' in l•//,`arl•Ila• anMll,e. I ha• rcactiun.lN N(1 and LlqNrrle In air INIIII/N7• II/IttIQC\ IN /•NI/falV Ihad arl' vnlually n/CnIN aI In IIw1VC In l•/4art•lll• .nNlke (;.1. I+Iwv a•Irarrllc .oN•4c inacllvalc% alpha l IxlNeina.c in/nhiwl /all'I/ m a hl(Illaaa INltl•VV t'INNIVnn~• IN a IaVI reaa'IMN/ IUIkUwI•lI by a]ktlw teal'1/INl /hat 1N'l'lll• Lvrr .a•ver.ll Aay. I Iw: la.l tcxlNln ik la+.crveJ nnly when Irc.h .nw/Ac 1. INllbhkvl IhnNyh a Mdlcr clNl/:unm~ all'1 '1hc .Wlw trtK•lilln is uha.rvcJ hlNh using Irc.h Fa% phav .nwlke ;ulll u.uly prevew.ly ptrl+aravl awla•Iw. a•ataa h nl .nwlke '11w; N/ I/ an I IM.IxI•Ill' //wwki'I VY%IC•11 aIN1111a1'hvall'V alpl, alw) al.a by a hqdcl.ia• IxIN-c.. vely ailndar In Ib 11/.fw rvaJ /IN I a. pha.e c/Karcllc.InllAc /1 nlnnhat nl .uh.lamr.• nl...l nl.lahly a/11111a•%• ;IMINh1V :w IJ, alwl lhwd..wh:u g1ul:Nhel/k, /x/NCai all'/ ;1g:1111\I /naa'l1V,nNw\ by cll.'arcilC .Iilnke lYv..r, W A I'11ItIw111aty I:nlrhy..ma aal l'rulcldy.i. W) 192. 1'/l(6. 1 Nlw•r .upNxl. N:NNNI:II IIIVlltutea nl I/l•:Ihh a/wI NatNMal I'INIn1IalNln I/N ('anlY'1 Re vat.h. I:tlwn dle 1(wNlynanln'. In.hlule, lawi.iana State Univct.ny, Na11N1 KINIrc 1 1/. 1111KIN(K'I I'lUKS Kh(;IU.A11i C11K1;A("IAN'1 SY.(•KI:TION I•K(1M KAT 1\1 N A 11:11 ALVIa)LAK 'fYl'li 11(la.l ti 1. Rat i.ulrlcJ alve.drr l)pe 11 cella wen ut/1vcJ 1n eR.lrninl: 1he ellea•1 n/ /xrr/ne slw pyrintiJine anak,lruc. Ixl secrclan nf pllmlx..ry wr(aclarN. 2 ATP plNCnlly .Ii1no/:.1eJI'111 plwrylhalNlyklw/llnell'111 1'(•I.ecrelNlninaliml:•.nJJnve Jepawknl nunnrr llrc cllecl n1 A'1 P wy./wNeJ by Iwlc hllur 11f exphure.nJ Iletv.leJ I.N /hrec hlNlrs. 'llw: 1•.(•.Ia'INKen11a1wx111nwh/a-M1,' //) Ihe /Ilatlnnll rta(Illn{e) hN A I I•-Irwluwell 127
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1111 IY' vv Ii•hl,n w.l. (1111 aM t A1/1' w.1. J1..1 .11rNrnl v11r1.q•uFur IIN \ut1.1.1.an .t'.111h.o, hal AhIF' I/aI JMk'IhNl/1r II,aI INI %I/•adll.tnl rl/a 11111 \I/rl.lt1.1111 V'l1t'IN•11 .11 1,.11.Yn11.111.N1. _'N1pM IIN'I( _I.N AI)PIINhN(lI''11' I'('4't/l'INN1W,1\ 2t11al.1 I I/1lli / IN1111a' .11aI1N11//11.I/1N' Illa I.'..Iak'\ I I I I'.1:11'• ('11'. 1'1 PI N•l'K'r\.n1111N'.I 1.61 11N-h . I1.'l l/NI I 11114 V'11.1aN1 All INIIIIN' I/NI (Iy11111NI11N' II/I.IM/\Ilhala'\ l'1.111/1•,i,l \/I•I/lllt .11111% .tl//•ItN 111,YI 1 I II I'1 ' 4'l ll'INNI, h111 Wl'rr 11NNI1 Ia'\\ Ir.Ir111 Ih.ll A I I' I tN' I(' .w.•11•1I1' U/pM (:11' IIr1pM ('11• ?uI/1M.111' IINipM % Nt,da'/ N I.IIt'11\IIlh.qdl.llnl.' 11/1 yA) .1 P, IN1111aN1'It/1N :IIILIF/N11\lI. INLIN.na1h11/1/N/ pht .1 (1 .NII.'Ih\.IN.N ./1t1.11'1N11l1) 1hN IIh/,N111'Ih:11'In IIII IlM• a)NI.\1.11•LI/NII/I a,lalNlnll IatN1n1rJ I\11' taJu.rd I III PC aYrclaNl InNtl L.d.drd (vlr (1 .rll. (, I Ia'4' 11./1./ IN..\ Nlr .-. hIr1N. I,N Il't'11LII/IMI .II .In1.Nian1 vt rrh.m Il..nt •d.r.,l.ll I%Ir I) . r11. I.v Ina1n.. cld,.r H/, r. 1%, H.ald 1ary'I,i,NI I A1 I(1m.11 1,Nao.1) ..I I'11.Inn.h N'1 1Kt 1'11. I'/Nr. I/lla 1.alyr.u A na th .al I my' A.\.r 1.1t1ut1. ('hddu n\ 11,1.1./1.11 Kl•\r.1N It ( INUtul.d/..o .In,/ N.IU,Nt.ll Iu.ldulr. d I I..JIh I L.nl llh 11. I..nlnN nl,/1 t'. Jl.dl l. \. 1 havc•r.dy .d ( 11N au1•Ifl Mrdl. al ('l nlrr. ('na la 1/.111 /111 MI•A\IIKI MI NI /11 IN11 K\IKAN111 K/1%\ I INA I HI1)111 N(•Y ANI) 1/IS1 AN( 1 111 I H'I I N IN I I KK111'I Il IN\ IN I/N ^ 1\IY /\1 11 11) .1,%'.N I KIAtI I 11\ 1 t'%./ 1K,\I 1 N nNl / NI AR 1•t I H•\vlI ll 1 1 1 14.111 IIII11/Nla•n./1 P..N.IICIn Ir.al t•1u.1..IL. nu,.d1. r,111 IINA 1.. I.NIn .10/•Ir .I/.nhl .aMI1N1\:11NI1/11l'1\11.1111I, lIh111/l.ll./,." 11nt.. 4 1,•" 1.161, I.NIILNhN11\ III~i,N.I. r N11I1 1/'I.IIN'IINNr1111.11aM1..I.Ml,kdp..N.d.lt wlhnll'I A,.IIh'N I1NA,/1....1 :NaNt, /Nl\1.1n1 I)NA aadct ult•.1 nal.anlo) m1. 1.11.nh1.1..•• hnk•.ur Irvr/vl.l% Ihda Is 1JI JINI \./.Ih' Il'.11I1IY IIt'I1'IIIYI (1 M,1• IaN IN't\'l1.I1N1' IY„NLIr lulk•IctlnnN•.1,1•\ l/ok Irrqla•INy In Ir/1ydnlN'/N' I)NA IIIN1/1Ia' 111.14\ f ul 1)NA •palyd I.rlr\ hnk,lgr We h.lvr /k•rlvrd J\1.Nt\IN dI Irt.1111t11 11/ i.1h 11IJIr l tl/\\ hnk IrcyuetN y a1 11lleJ tlFhl a•.pl \nlr :NNI vNlJldr ~1'1 Wr •Ialw hrrr Ihc11.\, IIN unna) .hyr ld IIN rmvc Ik\. nIN•tl br 111 / J\ a In/N 1aN111I 11'1. /\ pr111NN111N1aI 11/ A/, • IIN' wl'IgII/ avl'ral!e I/N1h'r1/I:11 writ!III u1 nl.k Ircr I1NA Ihr .n/.. IIIIk Irl'111M'INy aI Jlly'1') can flr.IrtrtnNllrJ h..m 4, a IINi\1:1111 IIN':1\nlt'1I IIN I/NA 11I klNlw/ll At, al 11tw 1r11N\~Iltlka)!l' I III% Il'Ia1N111/\ v:11111 IIN 1)NA 1.1 INy nadr.uLN wcrKhl dl\InIN11aN1 In eu(x•rtnlrnl. wllh unihNni knl•111 I/NA• In I LIU•\ hllk IrYl11N•rliry) nNlra.rJ In \nlqth• IIr1yNNlNln Itn 1P' IIt1.N1 :I/aI /r\1/11111N1 1'IMIINIIN /r.14' l/In1IIII chyr.lyd ph:trr A I)NA natlr.ak% have Jlv /clr h'11t•111\ .% I.N t•,NI/ W.1\ It1..lwNINN1,1I/11 AI• /II the IW111IN'hll evl'n IlaNll't111N' Ila•trt 111.11 wt'1/!III IIt\IIIINIINNI I/I the tr\IININN1 IIJFIIN'lll\ w:N \krWl'11 N w,l\ 111111NNINN1.Il llt A/• a1aI Ilt 1IN' IIh'tI1.11111N.1e1 ul•Ir weil•hl l.t \IN•.nrd crllolar 1)NA ovct J wl.k tany.• /U\o. Wt' 11N11N1 11N' IJ.\ w:1\ IIIN':Ir wlth r11N1\Ilrr //) .rllular 11NA Ilt y r:Nha1//N1 .\ r:111 tlN•/chNC h• n\rJ 111 . JL IIIJIr I.. Illr avrr./Kr dt\lanrc hrlwern mlrnlqaaNl. 1i the 111.1d.1r IIr11. M.II.a... N.tn.l k•••• I' At /ln.. b..n..n. .'/n '/ 'rrH .•rNri I'eY7 ( )Ihrr \nplrNt the Skln Caln•cr hlwnJaleNl and Nalidhal In.lihlle% nl 1lralltl 14491" Ihr I aINNa11Ny /.N Invc\tigalive IkrnululoKy,111c R/N:kcfnccr I lntvrr.dy, New YINk I)NA RI 1'All( IN YII Kt) I/NA IrpJn rrla•\ Ironl !{., h,'ri.lria ,.dr, yra.t arNl Inan have rrcendy Ik•rn . LNN•J I IN'r/l/y/lN'\ q'\INNI\lttk fIN IIINM1Nr7N'llva111N1• tna.'Ir111NIC e111'1\NM rl'ItAtl a1Nl IIYIN,IhlnalaNl Iathuc1/1aan/N1rrlla/rinF r,/hhavl'Ih•rnlN/rl(n•dlnhlNlNh.'rlll•ny11/Nn If1'/N'l1C,lIIy l'll/!/IN'1'll'.I \1/:1111\ Ca/lylnt,' thl' CINtI'\INNNII/II,' Kl'11l'\ llli. pap•r /k.. nlr•\ IIh' 11\.'/ININtINt/1N1 /INI IN//IINJINNI nl I)NA pIMIII/Iya\r /lt(NN/Nl':NIIVa1n11t r11/y11N'I wlnt 11 oa d1.Nr. IdNa..rrvrr.Jl ,d pynNlNlnly dmN'rv :NNI t1/ AII(' cu /nIN'Ira.r whll II na',11JIr. 11N• /cna.v,J ./I Ity1//11NI11N' II/nN1\ r. wa•11 a\ ha.r whhni. ruu\r,l hy 111r 111.a/1N Ily UI 1 Ia'nlN JI t-,Ip Ilat/!rn\ I)NA ItINNolya\l' Wa\ f111f//hYI I/1 INNIN/Kl'IN'lly INNII a\UJ/o dtJl nvr11N1ahNr. t1N• cn/ynNr by a Ixl1N 111 (SIMN). '1111: pllrih.til rn/ynk Iu1\ a hIlll' I.IhN /h/r 11/111N' tll 11\ l'11rIN1a1111NNr\, the 1•^I) Ip•ntral nNlll•al In a111I/1NN1. II I.NH:111h :1 YYINNI .'II//N/M.ItINNr 11/ urlk/NtWll \IrIN1u1e. 1'111tt/tlya\e ININI\ wnh hlyh 1 alllnny II/c111N•r IIINIhIr lN .InKk~\h:MIlIr11 hNA rlNNaulinK ~IYnmNl/tll' JIIIN•r\ Ma /aw Iu u1NL1a1J4r11 1)NA 1(y /uvr.UK:1/inK IIk activllres anll :Ih\rdlMe actam y+rttrJ ul rN/ynN• INrlwwatilln\.INNalninK 1•/11),,,.1•AUII•,:aNl FAI)11. wa• have 111t1ai/N•d \1uNIK - l'vNh'IKl' 111.14 11(rNl rRt8:11NN1 with 11111 S(11) 1n11 ,he l'n/y11N• IIIN1:Nr\ an a•kcUun 146 pyu/n/dla• dn/w r.1u Krnrralc a Jullrr arlNm whN-h tall:qr.e.lu /wl/ pyr1n11ilhnr. wlth pNN'INt1/1anl rrtll//l nl the l'/1Y'Ir11/11111he /:hNN/N1111MKr whinc cnahlr\ IIw rn/yNlr lu ann ovrt 'IIN• plnr rn/ynr rcpair. 2 4 JlnKrm ntin', in aKr.r•nlyd wilh thr rn 1•/r.w va11M% ol J S du1N•r\ olm'. AIIC esrinlwka.c wa% terlln.Uluk•J Ir11m irNlivilluJlly INNdN•d \uhl/nn\, the IIvrA, llvtN a1Nl Ilvl(' pn/lcinv. llle Ihrer \uhuni(\ JI. Ia11 a\\/t11.11rt) in VIInINNI INN a\\l•nlhk tN1 the \ull\Irall'. The l'n/y/lll• h1/NI\ Iu 111r 1)NA Lovr 1lq11at.Nr the Ilrle rIN11a1n/nK the Janul,'CI/ nurlf.MiJel%) anal renNwr.Ihr IIaNhIn'II hJ.r\ by hyJr111ynnK IIN• N/h (tIN.y1/NNhc.tct INNNI S' irNl the Jth rN tth rlNl\f11NMIN'\Il'1 INNNI V t,1111e Il:lnlaptil ha.c. llw eRCirnrcka.e .h1ev nll/ Nun uvrt /n the ah.rlN'r IIt NIIIdn/nal /xnN. In the Ilrr.elw•e o/ ()NA p111ynlcra.e 1, hchra.c /1 :NNI I)NA IIy,1.r, A'11' arN1 4AN 1 l'\• IIN'r/vynlc ellriv. Ja11uK.d rwckrllil/c. rlrar t1M in w1•u ratr 11/ 12 1/ 24 JInN•r% lnln •1 a1Nl clNUpkle trpalr ld the danuKcll 1)Nn is I/.Fnrvcd S.m,to• A. I'INNIIININ'IMnli\Iry aM) I'IMIIl11N11~thy~N.'~ SU/IIII : M/1 115, 14N1. OIINI \t/MNN1 Nat11uu1 In.Ulute.Id Heallh. 1 rINn11N Ilnvrr.nyld NINIh('aruliru.S.Iaatluf MrJl.ine.lA'parlnN•mu11(c.NiN•IIIp IIy• ( 11.qN'111/11 RP.1'AIR O1• N MIiI IIYI. N' NffRO N NIIRUS(K7IIANII)INI! INUU('1'.h 1)NA 1)/1MA(:1'. RY /11((' /iX('INII(•I.IiASIi F.'1, h,•n. hw r.•!1 ha. .evrral uverlappinR 1)NA repan pathw.ly whN h:N / In clNNrrl /u rlnllmJlr IIN• 1)NA JJnuKe caavd by a Ihvrr.c anay ul IAIy\Nal and I ,x 124 65100 7850
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.IN•mltal ayr/n. IlK• AH(• c.a'inllclcav whr.h i\ cnclnlral by dK u.'rA. ur.ll. .In.1 u. r( • yrlN•\ uK alcnr.l.•Ih thc uw 1\n.n aMl cta t.um \Irpl ul nua Irdi,k rRrr.ilMt rrp.m 1 r.1,Imlwcdly. IIn, rcpau p•Id.way ha\ Ix•rn a.\unKd tu• he active a/•aln\I I)NA :wIJua,\ 111.11 cau.r mara IK•In.J dl.torlu/n. Iu,klrnMnc Ihc kvrl nl Irlwal,k•hw/ndy n• qulrcJ llw rrl..ynannt aMl n•pan by AI1(• c.unul k•a.r, wc havr a•valu:lltJ Ilw• adr \Irrtr \IK•t thl ny u/ thl, rniynM by u\mg UNA damagrd by N nla•thyl N' nlu.. Pr n/11u\I.)'IWIII/IItM• Alt( t'R,IIIInkaK nK-r.td mcthylated I)NA rn rnrn In a d.l\r ,klr•rwk•nl m•,nlw•r m:1 rl•.K InMI lhat wa\ A I h lkla•Illk'nt aMI \IM•l /In' I/K 1hr IuLy rr„In.tllnlra a•n.yoK• h/ n,.• \ual/r, wtrh varlllu\ alkylall,wt rrp:ur lk•la n•nt Inut.,ct\ nNln •Itr,l a/,n thr a•alntN /r.lV• 11,Irtla /ratrll In Ihe rellair nl 1)NA ll.l/ll•11'r n111n1 r,l hy N ok•/hvl N' nll/u N nluu.u)•u,,n+lhnr V,ut ILII/t.M• It .nMl.Cun.u., A Lnnn.J..l ll.nlrrluhp.ry Ih•N'/ 1,d/1 t.15, I'rhruary IV1(7. /)Ihct .oly+nl Nah.al.l) In.l/tutc. /d Ilralth I rU1111Ih' I/.'I•.1t111N'/ll •11 /lum hcml.lry. t In/vct\Ily ul N•n+h (•.Ilulln.l Sa1Mr/1..1 Ma•h l,M•, 1 h.,l.•1 11,11 INVI SIItiA1Il)Nt)1 HI'N/ul..h'1•kl NI /:I I11tIN AI)UlI("IS Ihr n.nurr •d 11% .n1Jn.1. 1•nrln'.11.Iw1',•n Irtv.•IIIlpyrrlr• 1111'1 aM) FL•hln wa\ Invr\tly.nrll In ./nnn..1. tlr.n1 d wnh I 1I1111' M•rldl. ah..n Icvrl. un Fh.hln wrrr ,k'ta•t lonxd by i.Nhn.wl/\Ity nN'J•dtl'nM•nl• \IMr 111• Irtr.w•h a.ln Iha• ttk:1Y•1I IHNII tr•u /,•I•I (Pyq•tx• dl•d clr•.uk• ItNMllht••t INI•tr/ll .nl•I I)NA hy.l.,d ur.nmcut, l'Ldan..uuph•. wrlr uc•urd w1111.a 1.1. lelr.lvJ tr/r.a•I. v'p.ualr.l by III'1 (• rMl qu•mtdalyd by ..InuI lattun.,wnmo4 lit •..LInH•n. k.Q rrlr.lvJ m.dcrl,ll w•1\ nru.u/rd /n a.uuqt•Illlvr rnrynN ho/.rd mmwlw,..•Ihrnl .L..Iv 11 1 1\A/ u.mr rntdlwrln', wlnah ra•tuFnvc I11' Iclt,nd\ 11.,41% uwv.utrow•nl. /Mlraalr Ihrl l.nly 2'3 .11 hnulxl r,whu,wuvdy .•nikl lu rl k,lu•ll a. Itra• IlP Irur:Md. ('hr.r \IMIIC\ IMINaIe 111.11 hl•IIN.II.lpyrenr a1n'1 cl*/udc olay MII he Ihr III./IIM Ilh•17h„hlt ul 111' mvutvrll in pl..hm huwlml;. Wallm, 11 ,)rlltr, A M aMl Grnrrlfa, R M. (•arx•rr 1x11rr. IS 114 1•1h, 1'/117. 1 nMn Ihr ('anccr t•cntcr/ln\lulue I.f (':•nrrt Kc.carch, (•Idumhia llnrvcr.ity, New Ylnll. S AI)I:NIriYI. 1. MliII111)NINI: MI'1)fAll 1) PN/.YMAI1(• MIiIIIYI.A111)NS IN 1111• 1'1 A%MA MI MIIKANI•S ut• 1111-. III/MAN IK111•I1l)HLASI' lo ttvcnl yr:u., .evrral eniytn:mr rcxlNlnm mcalralrJ by S alk•me.yl lL nw•Ihulnun• (SAM) havc hcrn,k\crllx•.I //1 thc\e. Ial \lepwlv c,.nvet.M•n ul nlcnl M.IM 1•IM..MI..hdyk therndaminr 11•1' / u. ph••.phwtrllyl N nlclhyktharllllanrok 11'MI• / ll'1 Ihvldn•y•lldqa•1N 1\M'thylt1.1/1IC1.IM'\II'Mf (aM1111•/tb1 /1'1 AU I I.v 1•..A. ul , atlr.. yuw'IhvL,.r 11'., \1 . .../ ..... n. . . . ...1 . ... .. / .... .. ..I. /•, 1 .n. a ..1....L.., lu. 11.~ L..r. 11•A(•MI have rra•rlveal c,m\iJrrahle allcotnln 1r•cause they have hren intphcatcd in vvrral crllular /unrtnat\ aMl in hin\ignal tran\ler aanl\\ rncmMana•. Inhlhm,m lul SAM nlcdlaltll rniynK• rcacti/m\ in iMact human placcmal vr11om ha\ lkprr..a•ll 1hr .i, uvr ulNakr ld all+ha-arnlMaiadwlyria• acnl/AlII1 by thi% li\.ue. AnuM, aan) ulNalc \y\trm. arc kM.wn la hr kKalvcJ in Ihe pla\nla mcmhranc. lhcrrhucI thr p1a\nwl nlcmhranr ul tlr• hutnan Ir111+IwIMa.1 wa% prrp:urJ and SAM-nKJlatcJ nwthylau,.n\ wrtr \nIJIrJ t.o a•valualr a. 141 whlah nne 401 Ihe ahuvr rniyarc% mIy111 play a adr tu da•Ixr\\rnF 11k Allt upt:dc. 1hc pla\Ina nk•mhranc ad the huntan lull lrrm placenlal villu% wa\ prcpartJ by ral.d1a11un ul mn'ruvdll Inlm.yncyliMnK+lwllda.l aMl lldlcrcnhal cenlrilugatnm AI {,al•Iw• I,lu.y,hata.r aMl S'.nuckMlJa.c atr markcr rniynko faK plarcnlal•\url:lcc uw ud+rarr•. 11M u:Lirvtllr. wttr rnricheJ hy ahlwl 2t lukl in /he pla.ma nrvnlwaM a. a1Nlry,•nrJ tn 1hr vdlu% h.wtr.genalc- The pla.una memhranc Clnl/atlKll clVylllr .y\ICnI. whl. h IlnoK•J 1'M1:11'MT 1: K_ 4•. µM, p11 rM+llnwm 8.G/ anJ 1'( • 1I'M 1 11 K_ •_11 tl M, p111hHmnun 11/ 5) PM'1' 1 wa. enrw'hcd nl lhe pla.rm menthranc I'art /.1 tIk• I'Ml' II /ah,w14/PR I wa\.IduhlliicJ and pr.\/hly krN JurinF Ihc Incparalnln.d dk plr\nla uk•nlManc Iivcn thrn, 1'M'1' II wa. al.wl 4thmc. NaN ol 1'M 1 I fhr aa uvna•. ul 1'l •M .uw/ l Al'M wrrc con.iJrrahly ktwa•r in the lda\nla mclnhranr Ihan IM/\c in Iha• vllln\ IMn/N,/!rn,/lr I hr\r /nvrVl/,'WNIII\ NI~`~•r\I (hal hli\/IUI IIKlnhfaM• 111M1\I1IN/II/N.I N nM•thylatnnt rlay% a\Ignlli.'nw nde In Ihr u1+lake uf anuM/ aa'al. by Ihr hllnl./n tnlrlnA.L.\t Tran.n•n/ x'cunudalwln ld 1'MI: in Ihc mcnlhranc Irpal Inlayer Juwmg plw.ydulllpnl N nw drylatnnl lnay aher mrulhranc QuiJdy whwfi, in lurn, m1lurMr\ Ihc lalrral nucnrlt\plracmcM aMl alirnmenl ul annMe acaf canln .yarm\ in thr IM•m hranr aMl thco tnlrr-•Linln% with amiMt ac/J.. Ilanlwcll. S 1.L aMl Sa,nv. B V R. Tn.llhlllda.t R/:.car.h 2:YS•120, 14117. (Nha•t \ul.ltlnt 11 S Public Ilcallh Servia•c and 1'hamtaa'eulical Manulaclurcr. A\\.r'1- al u MI I'1 nl l klat 1,1/1. I I•nnll the I)r11:n1/11l•M ol 1'hannanrklogy. VanJcrMlt llniver\Ily tich,r,l 411 MrJl.irr, Na\hvllk, '/ N Rf.CI/)NA1. ANI)11IfFI: .KkNT1A1• SIiNSIl1VITY (N' (IMNILI('(/1'I.AI•I:NfAI. VAS(•1N.A•fIIKhT() 3•IIYI)Kl1XYIKYI•fAMINIi, NI(Y)'1'INF, ANI) 1:111Y1. AL(`(NNN. I'trlu.i,m ul human placcnla in rinu Joc. M11 Ir•nna Ji.unyui\hiny il+ \itc% a.l va.rular rr\i\1aMC IharaLwe, lrclKally cul slnpc rd la/ unlMlw'al, IM 1Mr1/MN', aMI la) villu\ \trnl artrnr. wa•tr cnamirlrt111rc Iheir .rrnillvlty h. S 11'1', mcdlnt, aM/ clhyl ak•nM+/11i1/)111 rn Ktrh% hicarlrwlaNr hullrt Ip11 7 4. 17••(•1 In Iht•.r prrparab,nt\, /n.rra.rll va\culm ra•.r•tanrc 1\ /Mha'ateal by /M'ra'a\CII /l•n\MM1 1M 111n1L:N1nM1 u1 II1t va.rul•n \Irql\ Ilw•.a• e.ltnnterqa gave Ihc lulk/wlng tc\uh.: IcU S/11 wa\ vrry IMllenl hn a'a1/Vn4• l/nNral InM\ nI un11nINJI, th111nMK, aMl villu..Itm 1U(•., N•1, 47. aM11t11 nM, ta•./t•a tlvrly / arrrua) anlra; (h) nKalhnc IMkKrl) aYMNraI'INM\ m u111h1I/a /I, chlni/lnic and vdlu..lcm artcrial Nrillc (li('., 2.4, ). ~, anJ 2.1 mM, rc.lta uvrly /. a 1 1if/)11//1 S Itu 2 IMX•, v/v) h:MI111/1QRM1aI ellerh.Ml WIIINhI'aI ant/ rIMMp/11N' a/ter/aI .rrnK M. 1/% e/lca•t /m umhth.vl arltria) .trip\ wa, mmimal runlra.1nln.ln Ilal cldny ` I11' wa\ k\e rl/rrlrvr ut 11K umlwln'aI arlen:d .Irip. Incuralca/ with 1:11111 Atr•In I 111 1 .• /
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In :nWili/N1, JdlcrcM/ MrJ arll. wc u\nAIIv (NNIIIIILNN'.M 1MIIV \hlwly JIVNI1111,', :IINI INIIIg Ith• IIA IC \yNl'//1/IN• Invl•\II',1hN O\Y:IIIY N'k'l I\ I/N' II/\NNI ININIINI\ I14I nNNI Id/N1IIy /I/Yhh' Sint•c M/\ hl•hcvcJ Ihal h•\\ Ih.m 1'X U1 dN• uu11.111N•It'r/.Ilaly/N1\ uluhulrly rIVf f1.Q hl d1v111u1I,' hy1wN1 l LNIC\, 11 1\ IrN.J.k• IhJI hy 1/\Ing I1A 1 w•Icl IhN1/N/c nl:ly u/:Nlvctlcnlly 1N:N IIN• la•ulll\ aI•.in.l Illr r.INC..i.Nl 461 d111crcululcJ h/nl1NN1 mNl L/w:nJ n hiyhly a•h•tlcJ \uhv1 I u/11N•1 nNNI•. /I/I/INN'I:Ihly uI III\NNI 1111NIIIt'la Ir.x .//lyl•kNll] t•fII x.pkcn cc11.11. /aN IN•lc\ \:Inly JlNntnanl II ha. 1N•t•n /llwrvt•J Ih:ll nNNl.r cell\ :uc ra\N•t lu tr./n\11Nm 11W auuaNl./hly dlJn huncm acll\ 'fhl\ a'INIW hi an ctplanalinn ttw wlty hN.ua• u/yrhNnJ acll\ luvJ 1.. \pkcn tcll\ Fruw well. wIN•rca% hu/n+n /nyt'kNlu lrll\ lu.cJ l.t .plcrn l lal. tk. INN t I1, I lil
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I Inally. rrc,Nnhin,lnl I/NA Irthm,luyN•. may utter prnm,.r ut thr hyhrnJiNna 11.•ht 1 L In n ul rrLNtrd Iurn tN,nal nnmurw,yhdwlm IN,NIuttN,n allct Irau.kclw,n „t .t LNN•d IIIII11111N1~ II~fN1I111 FrtN•. tn IYn,f,INNJ .'rllv II Itan.IatNM I,I unnnta,l'h.Mdm y.•/w•. 4.111 fN• :N „NUpI1.IN•J tN+ h:N tt•tal M,vt t'cll., Ihrn laryr v'•dr INtNIu, twm ul hun,.ln nwNwN hmndl ,w,lJtMwllr. nlay fN•l'.•nN• Cl INN,nINa11y Ilwwc It•:rahlr Sb.n . I W In 11,Ina1• A II a1wl Ihr.brut. Y IrdtNN/ Mrtlwrl. ut IlylNtd,.n1.1 I,N/nrlnM. I1N• I lum.u,a i'rr.., 1'IN 7. Ih• /0 75 1/11N•r .a1qNN1 N.It1, N1./I tt It•na C I-,N/ntl:llt,M1 and NatNN1aI ('JMl•r I,1%tltlllr. I I. NIt IIN' ,i1 (i•n Ilwdl.gy antl An:NtNny, Thr Ilnivt•,•ny „1 lcta. Ilralih Xt p•n. r 1'rulr/ ..I I)•dL,, AI 1 1)\ 11 K Il' AN11 N(1N AI 1 f IS11 K I(' I I 1K M% (11 R Al I.1 V FR I 1I11)K(1)(Y I MI I111•1 (e11I1 AKYI ('()I N/YMI. A KI'I)U('IASI. I)t111 KI NIIAI INIIIIIIIHtNt/l A/ IIVIIY 11Y AI)1.N(1\INI. `' MI 1N1/1'l 111MP1111 S' 1 tl I'l l(/\I•1 H)1( I I(/111 A,I1•fw,VIN• 2' IINIrN11,h.I,IdN, S' Jqdw~•t+IMNIf\,4' 11' AUI' K11./ t%a%Inhlur.d .ut :db,F u/ NA111'll whw1, wa1 rrlrwtrJ f~,a~u,rt'hnvcly inhibit IK/„ 21 7 µM).uh.hl Ivrd r:d hvrr I hydalay I„N•Ihytylul,uyl.,r'vynw• A/I IM(: (,oAI rcJa tav Ih.w cvcf, nuul,aNnfl IIMt: (•,,A trthNlav, wh,tIt u U,w IhN,l .,NNt•nltauunv ctlu',u% alht.lrta' t,nqrnN•., 1, tNdy /wNNly Inh,hnrtl by 1' AI)1' RIh Kt„ • SSI/ µM ,N 4 S IoM (NI11 lir:whl]I %h/ll ,-I 11N' /111lHNtNt,.11 Il•11/Nta%l' I/Iw,Iftl% a M,n :Ilhr%tCEN hNllt by IIM'rl•a\I/Ir rh11a1hnNtl• (( itllll IN1lC nlratNNN rC,uht•lI in a hlt,'hCr InhlhltllNt by I' A)1' K111 I I/Nh'f IIN'4' CtNMI11N~0~, Ill vaI1N•\ hN P AI )1' Rd, were 16S pM aml S 1 pM :It'! mM arwl 27 fnM (:%I1. rr•prttlvrly 1 hr I:nRevt t.hanlec in Ihc Jrytre t,l Inhd,uNN, by P Al)I' Klb wa. t/h•.•rvcd wtdnn thc 11/ mM raugr ld (LCII Ily a•,Nqra.t, Irrrir thaw va,lutNhicJ IIMG l•nA rrdulla.r, whtth J,K. 11411 J1.play alht.ICrN pnh+rntr•. 1• tra,ldy mlfibllyd by P AI)1' Klh, even when a..ayrJ al a Wtw clNw'enlfa/NNI,d (iSII IK1., M1yMa/4 SInMl7S111 A..ay,nklhr.uluhilvclltnhNla.rinllk INrvrNr.d IIN'IC:/~rJ IIIN,I ~1NKrnIIatNM Il•~UII~ In a IIIIMN JlY fl'a~r /n IIIC a11(yrl'/M KI hN I' AI )1' Kth 112 pM al 17 InM GXI11 Mf.r.w'mal 1aMG ('nA rcrlu.la.e 1. alh,.trrrcally al'uv:Ncll by varN,u• mN k,dNk •. Whrn:x'llvaln/ hy NAI )II, ItN• rniywr 1• cllcctivrly Iuh,Mtr.I Ly 1' A111' Klh even al a4.t-mM /iS11 ctNN•rntraMMNt 1Kt„" 17S µM in thr INt•W'/Nr 1,1 IIM/ pM NAI)I11 lhr.r re.ult..ury*Nt a pt,qN,.al th.N thwd lklknth•nt ar.lut tNNt nl CniynN dl.ultah•1%) oN IN1NI1r11 /,t an 1IhNICEN' :N /IV,11tN lu tl t'aml' 11NIhN tn,n,nn,d lhanyl', tn 11N• nuul,mNnal ft•ductaSC pnacln Ilul ahrf I1w pr,1(rrlN•. ,d n. .:d.dyttc NAhI'l/ hnN11nM vlte(vl Rullclmrn. I a/N).Shc/ hrrr, f. IrN,m.d nl I Ip,d Rrvcanh .`1112N M1S, 1')Mh. I n•m dw• Iyr1'.u1nN•M „/ ItwN fN•nu.uy. (;c,Nlrc S WLC 1 acully 4.11 lir Sk sent c., fcl Av,v I l,uv~ r.-1v l.l.w I I %I/.I:/)F 'fllli 111KF(7lNG MOIITY AT('ARItuN t()I;('Y'IY/S1NIi ANI)1N1: Al'IIVI l Y/H' IIIIMAN 1)NA (('Yl'()SINI:•SIMI:f1IYt:lKAN11 I:KAtiI: MII 11NA% in wh/ah l':IttNNI S 111 rat'h J1.1t1{yCytNhlle rCmNI1N.' in rNk .tranJ i% rlpl:Ned wtth a hu1Ly ytt,up ate very KINN) .uhdratr. IrN hwN:m I)NA Icyh,.mr St nN'thyltfan.lrra.r K:nr rnhanlenlrM.ld up l0 35 luh) are lANaincd lkpcnllmF nn the .vr 411 tiN• nN,N•Iy at (' 5(br cniynk allN•:N% tqqunally.,tilcd lu.cn.r a rnrlhyl Krnup t1/,NN' %1Lt/NI at Ihl. INmrhtm AlL]I/rIC lkn]Ity I,Ya1hCn1 allaly]l'\ llI IIK JNIfIhu111N1 uI /IN•IIIyI ~I,NIIN i11,1,ht•,I t,1 S-ItrJ('yd ur SItK'yJ .ub.ututcll 1)NA revral that tIN•.c yuNlp. a•rvc tu dnrlt dN• cniynr to mNhylalr Ihl: tm.uh.lhulcd strand. 11.Irdy, I A, IIaArr. I) )., Newman. 1:. M, tinwrr., I,. ('., (MrNtman, M f, arNl 1NNfh. N .1 1t/.Nhcnntal .nul Ih,y,hyNlaI RCKarih (•1N11111UNKattnn% 145111-146152, May 24, 11197 ( hIN•t .ull.Nt N,IINmaI In.titwrv ul Iicalth 1•rwrl dN' 1)Ivi.NN,.,.t Surgrry ant) I'rdlalrn'., ('ily ul (lupr Nale,n,d MrJla':d ('rntrf • Ihr.ulr, ('A, arN/ I)%•parutN'ul .4 Iliuh.Fical Sl'wnrr., Mulecu6lr ISNduyy XrtINNI, lhnvrraly „1 CINnIKrn (:Illhlfll/a, IAh Ant!l•k\ I111 IN/1.1t1 N('1:1)F lllt: Jt•tKi MItiPA1R //N 1111: A(TIVI1'Y (11•'I Ill•. IIUMAN 1)NA ICY I(ISINI'•-S1MIi111Y1:CRANS1i:KAS1: Syndw•tic uhg,NkuS ynucklwiJr% cvmlaininK a Jf•vK: uti.p:nr a1 a.rntr,dly lu cn1rJ tl(I,t Y i/ du1N•r art• mrthylalal at a nNNktalc r:Nr by hty,hly IwtllirJ hulnan I/NA (cv1,N//N• SInN•IIIyltranAl•r:,v lli C. 2 1 1.17). ') hr prr.cncr ol a mr.pairrrl dl ut rNk .tr,nNl rnlhN'rtl dN• cnrymc to prrlcfrnhally utrthyl:Nr thr uplN..itr .IrarNl 11aLrr, 1) 1, Itatdy,l'. A. rnJ Snruh. S. S. IrN4'hl•nIK:II an1l Ihlqlhy\K'aI Rclc:nl'h ('1Nn11Wnrt'a1Ntn% 14(N21 S'Nr(412, July 11, N)%7. (Mhrr .uplNNt: N.lu,mal In.blule.ld Ih:alth. 1•rlNn Ihl• 1)lviaun at Sury.rry, ('ity tll IhM>< NalitNtal Medical ('entcr, Ihwnc, CA SIRII('IUNAI.(/K(:AN17.A7'I(1N ANI)I)NA MIil1IYI,All11N 1'ATII:KNIN(7 W I I I IIN '1111: Ml 111S1: 1.1 1'AMII .Y Wr h:wr .Iu.IN•J .IaMc Jdlcrrn.Y. in palcrm ut 1)NA mclhylau,Nl .crn in Ihr repratrd.ryurrN•e. nl nN,u.e cellc. A chN1eJ I1 M1-Ma.e pa/r (raKott•rn ol nww.e rrlN•u livr 1)NA /pl•1 11/ wr% u.cJ >t% a pr/d+e in S.wthern hM/11inK ealN'rrmcnl. M,NIV• y,lcrn atwl 1.12111 Iynq,fNNnu 1)NA N+I+rareP ub hc rNxmally methylatrd aN Il/r/ll .nc. pa,hrd hy Ih/. v.tlN rN c Pr 1erNt rrythn.kukrmia crll, aml Sp2 crll l)NA MNh .howrd an rMwNtu:d halNlu,y paurrn in ll1w111 J,Kc.1. IlytNwhiNN,n rn vtu h- NN•faph,lw• l'MMINNtNIM~ %tw,Wr,I I/Iat 1N.dN•d.ey1N•IN r% werr M.,ally rmer.IN•rad ahnq' dle arn,. 1 1S
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A 1':NII I/NNIN' lhr.NIN-IN1N' Ihl' IyNA %rllul'11Ce Ilf 11x 11111 hra• pipn m.rn in IM• tI, NN•w:1.lA•1rr1n11N•d.:ll.q+y.dlllcK.cyurrNrulI Iwa.h.uta/allt.S'rrNl Wrl\Iny r.l. rn1N nl. N./nF A11 t.nbIUNR'~ IIINII ItI'~ I 1(N t/lllltl'lI IIK CINollll t11N1 UI :/ n41/1 I-N 1hl.( ( 1 ;( /1 \lll'' at IIN' 1' t'rNI 1-I the 11NNIV I I IanNly -(la• 1muN•IhyLNcd dlp('( ( :1:) .nl'. In \Il `,11N) I/Il'INt l l'II, l1«1ht Ihl'/1 I\ ]l%IrrN 111111N/Iy11NNphlr rrfN'.dr.l.cqnrlN r within I 1, h1111M~1..FIN/. l/1 dN• rcyaNl yl.lnnrd by IIAMS .NNI K Snlcr IIN•rr nr yVl'1•1I IINN/':I/NI 1/1N1'% A l':Nt11it 11N' ttA/!I1N•nt\ VYn In:11/11N.N1/~/1'r:111M, IIN'%I' w lI1N•INl•% mo.l /Me-M'%% d 1u11MN1 11N•IhY101NM1 %tdlr it nuny rr/N«ItK I1r'711/N/~ /~In /rltr.111N1nr.nNhNU/11vIMn1N•Ihyl.ln/N//dcrnalnwhlamdlrad 1 I.qyrat.lart•aSl,lhlr l h.n.a 1rrl.ul ui a•vc1.d t/ 11 InNayrv I hr.c IrndlnE..uKFc.t lh.u . rn.nn I I Llnuhr. Ir-r..l llmn«N/:dlnr. 110.01 /w•Innt aml Irthafw "ire dll/crrnllal I)NA uN•Ihyl.Itu1N1 101 r.1:d~h.IN d t rll IlrN ;q•r. Ildlr•rp, M I' , I'1/1N11'IINIII, ti I, Kb.ak, I JMI .Snlr/b, J.S IIN' IINIIII•II Id Nndlq'L.d ('hrnu.lry Z6:1:11 11167 111716. Aul•u•1 IS• 1'/N7 / NIN•r %NIMMNt N,I11.N1.1) In.lnulr% ul /lcahh I r/N111IK I)IV1%N«I, /1I SIIlprry :IrNI IINdl.yy, ('Iry l-i Ihyu NatNm.d MrdN'aI ('rNtrr, 1111.Ntr, ('A. ,NNI Ih•p.ulnr'nl nl I'rJljlnl., Ilnlvcr.ny Ill Cal/hNnr•1 al I.... AnFrlr., %l IN.-11it Ml IIN I/N' 1111MAN 1)NA I('YIII%INI SIMI IIIYI IRANCI I KASf %I I.1'("flVl'.I.Y MI'IIIYI.A11'S 1)111'11 X I>NA ('t/NIAININGMISI'AIIt\ IM INl•.r/Nr /11 Ihr (''(' 1n1.p.ur ul .1 J.'blN•d duplrs ullp.A-./tvltlNh'.NNk t'r. h,Na'rlI ItN1.111•N /ly tl.N'/ vic e../ •Ilh.n,dc IIN hlyhly INUdIrJ hwu•In 1/NA nN•dlylu•ul. It'I.IM• AI1:IIv,1% l/I Irlll,la'1I Il'.N 1/1N1 INlAI1N 1% 'IN-wrII 111,11 Ilse ('1 1111\h,llt :N IrI) .11 :1 uNlhyl.Inlm:Nlr/+1,N" In 111,11 it w:1. n.r/l r.1plJly IIIrlhylatrJ Ilse mY'•(7 ha.c p:nr ala/ rn1/.NN rd the 1:111,N /ly 0.1 Ilse 11I1F1«Il'11tynIN IrIMNk 11/ V•IV1' a\ a Wh%lr.nr IIN Ilse rIVV/1N• 11uMrvi•r. Ihl. ~uloplrNlrm:uy h.IN• Il,ln wa. hNnNl Iu:N1 a% a"U/rihyl:ll/. n 111tr111N ' I hit 1%, Ilse INl'N'/N r UI Ilse /11 C/n INIr Strami nN11N rd Ilse rmynNr 111 r:lpldly nN•Ihy1.11r cN Ilse cyNNnN• tcadur lm Ilse I~I+INI.dr •Ita1N) in an :NI/,N l'll) (''( i h]K 11,nr Snudl. S 1, Itardy, I' A:mrl Nakct, I/ 1 Nul Icll Al NI. Kr.rarrh IS1171 blllrr blrl(., 1'qS7 I/1IN't mIIyNNI Nr1nNl.d In.plulr. ul Ih':dlh ( ruln 111r I)v1.NN1 ul SIrrycry, ('ity ul 111hr N:nNNlal MrJaal ('rnlcr, I)uatlr, ('A '1 A1' AN'I I(:1'N 1(1KM1 1)1SI11.1•II)/? 1-INKI-I) HOMOt)IMY.Rti Inlrrkuk/n 2111 21 i. rr•fNlmlhk (IN .tmlulalinR T•ccll pndilcratinn via mlcr:N - INN/ wlrh./t•t dn . InFh alhn/ty menllxarlc rrrr p111r. AIIINwyh an 11. 2 binding pmll•rn he.IN•rn Nw•IdlhrJ by vlrturr ot qc tc:N'nvny with a rrNNNlchNlsl annMNly Iha1 rlNnpele. w1111 11 2 liN hu«hn/t L/nl/ 1•N /, Ihr tlmqplrlr :/nll (NCl Ilc %rnN Illrr nl IIIININNILI II. 2 /'., rlw~.l. 1. Iltl Nnlnnwu I .. '11'II/N' II//lIN'1 IIN• 1 uln/«1\IINNI --1 11 .2/r1-rfNIN\, IYN/I 11. 2 il.rlt anll and l,N- wcre u.cd av IigarNl.l,u adaxh uK InlNaoe pnMrm. IlN analyvl% hywiahunllhNkcyl.ull.llc/pdycN'rylanlilk Krlrk.1alptNNr.1.IN:d1.Nlti(!,/1'Al~l'1 A vculrly ol ra/.•rtnN•nlal allhnl:l.hrv yahl tr.Nll% imlw•:Nmg Uu111N: l x antlyrn, wln. Is nuKr.n.•. 1../ .ulylr prolrm nn NalANISl1,/PA(il: ulafl7 IIYIuI'1/1r. l'lNNI/1NNN, 1% almo r1tNl'\Y'lI J% II1%11II11k linked INNINIIhnll•r\ :nNI 1/11l!4N111'r\ I-.It:IrnIrN.YI urllkr rNNnrlI1N IIIF /111NI/1aN1%, INNII :a'tlv:Nrll INIr11t:lI hnllldn I ccll% rtaf.rll IirN-./nnn pallrnt, wllh :NI1d1 1 1 rl/ knka•nua l11( I I 1112, M 1• 11 r.prc..'I:N' anhprn INNINrhnlcn IM• HIS INNII in ,11kI/1NN1 a111NNNNnI't% IA/, 54 (NMI) I'1N/11a/NN1//1 Ilse /h\Nllak IMNMI 1\ M/t a l1NIV qlN /Nr ul 11N' cRlt•1nIN olal pnrrdurc% uvd w Lldalr Ihr pr.Arin% lllr an3lva•• rn.l. IIIINh :/% NI1911N:1i rr%uttN are uM,urN•d when t1N• rcccpNw pnNCmc arc rlrhnalyd rnl t'AIrdl h'lI /11 Ilse IMryMl' Uf N l•1I/yI/14t1'InlN/r IN 11r1•pire1l IIK ckCtto111NNCV% 1/1 (/N' :/hN'IN'l' ul IN':N /ll'1IJ111rdINN/ ACl'/KII1111[Iy, IIa'H• /1/NI//1~\ f11NM IU I-al' anh);l•n a..." / L/lnl/7 wIlI1 11N'It /N('hYl'nINIIy I hl' 11hy\Mlhl~a' NI!n1IN'JrN l' I/I INN/NNI//11rr :/MI uhl'll IIN•/11N//1.IIN//1, r%INY1JIty :1\ 11 tl'IJtI•\ IIIt1a• IIN111:11aN1 UI h/l!halhnlly II.- 2 Il'l'l't/11N~, 1\ /Nl'V'lllly 111/klN/wn K:IIa, K J/NI .Smnlr, K. A ISar IN•uN.uy 2h 161 54 51trJ• 1487. ( MIN•r .u/MNN1 NalNlrlal ('a1N'rr In.lllulc aml 1:11 Lilly ('arplNata.n 1'rlNn Ilse (k•punnN•M ul McdlrNlr, I):Irt11NN/111 Ml'IIIr:1I til INNIl, IIAn11vl'r, NII '1111i IN17:K1.I:IIKIN 2 KI?Clil?(N(-• /(/N('I'K)NM. (Y/NSI•.U(11'N('IiS O1• 11 X 111M(1I .L('ULAK S"hKI/('l ( IKI: Ihgh allinny 11.•2-R binding re.ult. /ral/n an excclMwmal lypr uf llNll+l•rallvr inlrraclNln between 1wu 11•-2 hialmK pr111cm. Icmrcd a aml /t. When cq+rr..cd NI rrlhrr nn the rcll .utlarc, lhcv 1wn diNinlt chainm hwm a tauw'uv•rkni kirk tUC hyM/d nYY'IM/N l'IN1111kR Ihal etp11Nh a ra1Nd aMMN'Ia1N111 tAle l'/N11t11Wtell by Ihl' Il« (t l haln arNl a.f,lw .11..11.•ualilwl rale rharalkri.IN' hK tllr p75 ii chain '1-hr 1,75 n chanl../Fnal c.•11 Kn.wlh, w/N'nv.Ihr pSS I1 chain.INl/y Iacdllalr t) ••2 binding by .crv/ng a% hcll«•r hlrNlmK .nr.. havrmy rN/ di.crrnihk.iFnalink tuk Ihrmvlvca. '11N• umquc IwN d.Nlal InlqdiralilNl. r/l Ih/..IrlNtural lK~,'arIVa1NN1 irNlic:NC that Ih/% c1N111rranvr hulN/h•a'uI.N anankcnN•M n•/kl t% a yrra'ral nlrt hant.m by which 11N• c/b, w•m•y ul •lnrlacr trcrlw.Nt can la cnh.nNrd matkl•Jly Wang. 11.-M. a1N/ Smnh, K. A )oumal o( l:yrrinN•ntal Medicine 1(16.NISS N/hV, (khlhrr 19117 (Ahrr .IIMNNt. Nalalnal ('anCrt In%l/lulc a1NI I'.II LIIIy CINIMMa1NH1 Fmnl lhr Ikpannlrnl l-1 MrdNinc, 1)arlnNNllh MrJrcal S.'hlNd, /IatNlvcr, NII 117 I Ih 65100 7854
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IN I I N1.1 IIKIN ' IAIMIINI MSSA1' USIN( *.MON(K'I t)NAI. AN ItHOI)11-.S I1.11.',It•//.l ,l'1•V11v1' .11NI tl'(NIRIt/l Ihla' 111 / / 11111N.a,\Jy I1N Intrth'l/{.111 2 (II !). 1w.. II ' Il'•N 1IVl' I/NNNR LNLII Jn111b11I1C\ 11)M< I JtNI l)MS 51 wrrr c11.Ir.Rtrrvr.l l•al: n ./.. Iv (1N• nn1y1R 11 .` huNI/nF t hJr.N Irll,lN +u1 I)M\ I atNt I )MS S wrr.• r.Id.NtrJ I.1 I..n./nN t..n 11 '/.nnIN/N.J...ly th•n 1, a•n,ll/vr tn 11111M n/unlN a/Nl hllllt:nt 11 ? t 1SIt Iq•/u111, :InR a.d•Ir I..IhNh r.Nhul..d.hNl JINIrII/yln.ttlC Ih•IeltµN1• 111N11C,NIIIy •1v./1L1Itll• t...N1h'1 Ldh•/eb.nr% flud.l. K C .mJ \nrrlh A A Ilw/ lr.hn.d.q•y J'/NI 'tRr,, N..vrn/hrt 14Rh. ()IIN•1 aqy.Nt N,Ih..n.d ('./rlll•t IILUtulr atNi I:II I,/IIy ('IN)RN:Ih.111 I l..m tlN• I i. p.utuN•nt .d MrJn /nr• I t•nulNNUh McJIt Jl 1/ Mh.l, IIa/R.vrr, NI I IN11'R1 I t1KIN ! AtuN(K'I t)NAI ANIIH()I)Y AI•fINIIY AI)%ORI'11()N 1111 I/(1IIl AI HlH 1(11 111N1)IN(;KINI 1I('S 1()K I)1'IIMAI. IMAt11N/)AI )SI )KI'1 II IN Wlth t1N• rC:Nly Jv.ldahllny ul nhNNR LNI,d Jn11h.NhC% rCJ.tlvl• with an Ca1l'mivC .I.ra 11/11111.1 .Inrt/•P/l.. /II/111urN1.111m/1y .Nhn11NµM ILIV lR'l ININ' IINNC w11h'Iy ./11~.111 Jl./r lIN IN1.1.In pur/hl.A/.N/ IL.wrvlr, 1'/vl'11 4'VI /dI IINNNR LNIA1 JIIIIhIRIM, rl':Iltivr wlth IIN' .:n1N• .Inu/•cn. an..t Invc•U{•.dar. ILLr I.•und 111.11 ..n1v a Icw aat1MRIN•. ue uvlul I.N ,UINI I.IIJw• nnvuun.elh191v .1/11J/•. n I.n/dh .111..n n...N.hn/•Iy, lo nllkl II..Ic•1.'/ IIIIIN' IIN' ~..11.11/N't.'/,..I /1h.n.R LNLII.1111./w.I~ .11111r•111h11hI1n/• I1N.,1 IIII/rN1.11111.N l'Itl't Ilva uomutN.,llhluly J.L.NIMUm. r.1111I111/111//1 .11N/ L/IN IN h/rIJInF .'.IR'r111N nh w. /l• IN•1/.NUN•A u.nly //NhnL/t.IrJ unetl. u\nl ` ill '1 •/. .Inlq•rn .uR1 L.ut .h11. Irn1 II ` Ie.NUvr uwNNNhmal :In111RRhr. IIN' .11111Ih~lµ, wt•/1• LNI/NI 1.1 ddlr/ I.nnl,ody wuh Ir•IR•tl la tlMn I.ItN•ul 1.11NI111C llwr,µti•rNtN,-.It 1r'l11 ' IRNIINI W two ul IIN'V' a11111NN1NV vrry 1.qN.lly, wlnlr It I1NN11N11U IIN• .dIN•r 1wu nNNr .hlwly WIN•n h/rNlmy w.l. Iw r11NnR d al •1 ( '• thr l'aI111I1M111/11 1I/,MR 1•/111N1 CINNIant\ hy a1I t11 1IR' :In11hIRI/lY Ikt rrJN'lt Ihlr 141 a nµwr ItlirAt•tl fMal/Mlg:111/NI I.t thC /Ii..IRiatllNl ratr Ih•m the :KMwIa luNl ratr IhIwCvCr, JI •I"(' Ihe a\MR'IJInM1 tall'\ UI the Iw1/ %hlw-reaChve :In11IRNIµ'% IRV anK rraulkd +11 nl ukrdly dlal rllN /rM alhmty aJ./1qN11n1 JIJ nIw Ilcrut Ity com pJnwNl. 14m h11th Id Iht•.r anllhlrhr., elliclrnl rrnwwal uf II. 2 clndJ hr 11hl:utK•d 11 :µI,.N).Ulnl w:1, IR tIIMIIN'1I a1 A7'(', I1Hw/Ik/I IIK 11 11 1 / 111n Ilow rJle wa, all/n,IlY1 :IlY1N 11 . Inf' t1111N• 11 2 a..IR/anlm rate K/rtl•t7a t/N1.NkraNIN1% aL11dn-1a/CJ 11.2 all.urhtluNl tll /111\I//rC, II Iw111N IIFNI' nMNNt 111n.11 atltlhlNhr\ II. 2 IIIIIIIII/MI:NIMNIMNM cINrI'I•nr1l wlth 1111' d„IR ta1N111 1.11t'% Id the irNlrvidu.d an/1fRRIN•.. ta/lN•r th.ln Ihr cyu11/fNlanl huNlluy..N/.la1N. Ihr.r tr.uh. IrNINJlr Ih.11/tN' /1N1\I I/IIlRN6m1 pwJnlacl I.N a•1 hIN•nt .dbmly :NI,INI111.N1 1% thr a.,ml•IINN/ rJle tINNt7n1 lit A111N111N1, the /1•,ult. I.1N,nIKQ IINIn.1/C Ihal nNNwRI1NL11 JrIt/1RRNr% may ddlcr m:IrACJIy a. /rI;J/J. Ihelr &nN•1/t hutabnF .hJIJ. N•n.iN., and thal atl jnu1NRllr% ran .rrvr a^ e11rc11vc nn/11u' na.NlaNhrnt., IN..vNkd their anlirrn MrRImF ahrrxleri.Nc% atr Lrnlwn I1u.61• K l JIN1 1.na//- K A Lnun.11 d InulNmnl../•h ..1 MI'Ih.RhW. ) 17 ?dN. 1'//16 1 ( hIN•r ursfNNI Na1nIn:11 ('arN•rt Inahulr anl) Y.11 Lilly ('INplwatlon. I r.Nn thl• Ih•p:uulKnl of MrJla'irlr, 1)annNlulh Mrdlaal tiaiNN+l, IIJINIvrr, NII RI.VI RSIHII IlY l)F GI 1 ti(N.IN/A('1IN IN'II:KA('Il/)N IN MA('kl /l'l1AC1•S- IiVll)1•N('li /)f ('a" 1)1'.1'IiNI/1iNT ANI) ('a ' INUI1'1'.NI)1:N1• 1'A-111WAYS R:IpiJ :nNl rrvrr.ihk a.vcmbly /If an arlin m.11t/t in the Itripllrral cyluplaan 1% a.w-c1:u1•J with the nN+11k lunt•/i/w1% ul m•rulmahan phar/acylr.l/) AIdNN/yh.cn.un a)qNn.1. I1rIR1111 r a Iran.Irn1 rl,r m Ihr mlralYllular ('a" c/1nCro/ra111N1 whNIl (Mr1 rlk. 1IN' IN14•1 III k11111R'ytl' at'Iin a„Cn/t1ly a1Ml nNN/hly, it /\ aIN1 :yhlarrnl IhJI Iru1,IR yie :N 1111 a\N•111t.Iy a1N/ a\MN'/all'II IIN/venlrnt\ aan JIVI Ia1lC Illal'e /11 MNIN l':IV'\ wllh.µn a Ikll•1 t.lhk I/N tt'aM• m(1M l'y1./411N' ('a ' k vrl '1 hrrel/we, hr.uk. ('a" , an •whhtNNl.II .11'/L11 1. nnPlN:nral (1M the Iegula1NM UI at1Un a.vnlhly a%Mll'/alelf with ku1.R-ylr nNNlhty ( i.Iw11u1. a('a" -Mrwlmg prdr/n a/ nl:aumahan ku4.N ytr. ar11111thrr ce11,./. a INIh'lll IINNIula11N /It at'tln hlanll'nt kngth arnl 1,'rI:ItN111. In t111• rreKM'C 11l tllN'tIN/N11J1 ('a ' t'INµ•rnlraluln, INndICJ LYIv111n1 kvrm al'tln h1anICM. and rCn1a/M hlNnll) 111 tw11 .l.lm uwwNNllrr. at Iln laa(,'nlwin~,' ct1111111hC .evrrell IflanlCntc whrre /1 h/11a1% hutlN•r exlllanKe /•1 /INNNNnrrm a11hr end 11 the.e e11e.Y% were revrr+lhk. Kr1.l.lln a1Nd11• in a1NNrr1 wdh dhrr actin-Alnlhnp IlnNc/m, reFulalc the a/:Nr ul INdynu'niatuN1/1/ arun /n re-,IRNI,e 111 than/[e\ in Ihe Cy/11M1111' ('a" cunceMralilln 1luwevrr• whl•rca. Iln INrNhnK u/ purillcd Kckr/1/n N/ alain i% hiKh/y ('a" •drpctNknl. n 1. /Nlly partlrlly ra'vcrvJ in vrr..n hy a M/werinF n/ Ihe calcium cllrN•eMratutn 'Ille •r.Mhtilln ul Ille a'ak lulll chrlaNlt 1:(:TA t/1 the 2:1 al'Im/ ,I'eIM111n CIIf1411CR IIrr/Nlt\ IMly tN1e 111 t111• Iw11 hlNlnl/ al'lIM 11/11mcq'lales rewhinR in a 1:1 wUn/grlwllin ctNllpk>< which I% inrarahk /d .evennl; artin IilanlerN% even thllulth the c/lml+ku can hhu'A the la.t Kruw/ng end ul at hn Idrnk IN% II aMNhef I/KChani<m, tMll tllrlYYly /nvtllvlnl,' l'hanl,'C% in ('a" l'lltnYn- tratnln, wa% ahk III IIi.f11Ci71e the 1:(if A-re,4.lant xlin/~,'cl..dln clm/(111•t, q w/luhl .uyKr.t that Rr1.111in has a rrMral n11e a% a regulahlr ol Ihr aclin maulm rn 1•nv1 ('halNlnnirr, l' , Yin. It. 1.L anl/ Sar.vel, I'. I'. hlurnal ul I:.III•rinlenlal Medieinr 1hS:97-hlb, lanuaty 191(7. t Ahrr suplN.n N:dilNlal Inaitulec of Ikahh. 1•nMn the Ilrn1au1111ky (Mn111/ry IInN, Ma.aa1-hu.etl. (enrral IILylital, aml Ikpan nlrnl ld McJlalnr, IlarvarJ Mrlhcal 5rhl.d, HmNIn 1'1/1.Y1'/11)S1'11111N1)XI'111N•. Mil 1 I I I:S ANh 1'1/1.Y1'lll/~l'11/lIN/)\l lllll l'1lN1AININ(7 Vlall'I.I:SI)ISJIK'IA'11:1.NIxK7/.N/)I/5/:1'LS/)I IN Al'lIN ('()MIM 1'.Xl:S ANI) I•kl)M/)fl? M'fIN ASSI:MIILY I Itt1M 1111. 1 A% I GKt)WIN(: IiNI) l)FACIIN 1•ILAMIiNIS HI.(K'KU) HY GI:1.%O1.IN 7TN• ('a" aetivalrtl aclin MnJinR prutein Fel.ulin reKulale% actun Id:.nlrut knplh by .rvermK IwchNllxll lilrmenl, anll by hinllinK.rtin trwml/arcr., ./alahvulg n111 h•/ IIN Ihltu a..emhly /nta hlamenl. t:rIw11/n hirlllv NI ph!mpha1/Jy11/N1ala1, I,S h/.pM., phate wnh lun%,-y1K•nt InluhltuNl ul n. Idanlt'nl .evetlnR a111vlty atNl dl.•IN ii I la 119
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171N1 u/ I(:IA rr.i.IJnt au/npklc\ m:Mk with rahhll mJlrlrylhJl!C I.r humJn 111.1\r11.1 hn .uNI r..Id111 nwa Ic :M llul I hl. \tully (auvNlc% evrak•nrc Il/r an r1nc1.N Ul.n A 1•rhuhn wldl IdN1.l41.rhdvha..d/d nNMMq+IN..phalr 11'l/'1 J% wrll .1. I'll'. JINI lu/tb•/ Ik•\t rtl\•\ IIN'n l•Ih•t 1\ nn Fll\1/11t1'\ 1111M 1NN1 11.a11 ptM.\pIMN1N1\IINk\ cntllptrtrly Jl. ..y1.nc I(:lA Inva.ul\r uMNI nlxr.q+lcllr.ytlry,l.\mic yrlwhn xun loalpk•a \ .11N1111IIIh/1 ~,'eIN.1n/'\ yY.'flnl• :Nllvlly IIN• mJlCnlll/l)e nl mh/hlbuwl tkl\•IN1..Ir.NiFly 1.11 Illl' Ilhy\N •11 \1.111' 111 IIN' lahl/\111NNIM1\IINk'\• hl'Ing IIIJtlllll.tl Itl INl'h•Ir:1111M\ II1.11 1..n1Ja/ .wl•Ill nnlrllc. ..1 1'n1a•r Ilt/lt(Ird PIP lIr I'II'•. AKErrI`Jtll.n ul 1'11' In I'11' ala rllr. by /IIV•111•/M t AII.MI\ 1q In\Iltlla a'11t MInK71a1r11K Ihl'Ir /11t1M111NJ1//N11/1a1 Vl•'.1 a Ir\ ..ml.nttay •NIN'1 LIN.ydNd/pal\ Ik•rlc./v% hu/ Jllcs 11411 rhmmJlr 11N• mh/hqlny IN.ry.'ttlr. td lla IrdY111N..pINInN•.Ihlk\ 1ta' prrvra'c n/ Kl•Iv.lm lun/y udubn. IIN• /I/V•1L'//l l•IILNI IINIINI'/I,11•FrrrJH.mlll l'll'. nlarlka PIP.InclMnhm•NaNI wnh I(:1 A m./allv•11r\ Krhnlnl uNllrlulr. lh•It hh~l, IIM• Ia.1 rrrlwinK 1•tNl /.1 :Mltn 1r1.a1N'n/\• /IN•Irl.y .N l.•1rl./luy Jt 11/1 IS.IyIIN'r//.11NM1 kcKulallltn /1/ RcL/d/n Ly IIN nll/.a l llNl.lr /IN•\M'/1/•1-I\t .1 •I/N11M1IVIItM1~I11NMINN11/111'\ Jllltw\ IIy lIN' IIM/IIJILM1111 M•Vri,111I11It 1 ral /•I Lnhn N tt/1 tnll•rnN•JI•I/r% wnh III\IIIN I IUM IaMaI INIry\'/tlt'\ Ih•d Inay Ir• al v/dvt•d at t h./1q•.•. In IIN' .Ldr 1./ 11y1rydJ\ont a tln Ildlowlnpll'l) \IInMILdNNI ).Inna•v. 1' A . hJ.l. K. l la. 11 1. arNl 1r..t..'l. I!' IIN• G.IU/1J11.1 (I/n1uFN.011 'Iw•Iln.try !h?I:S/1?1!% 1211h• ScINt•nllx•t S. 1997 t)tIM•r .alryM.nt 11 % I'ahht Ila•.d/h %rrv/.r• Whlt.dcr IlcJlth XtIrINC•. I'11'NI. J/NI AnN•IIl J/1 11.,ut A...V /•Wl.n 1nnt111N Ilcnl./adn/•~ IbNnl.q'y Ilnll, M.H\.Mh11N'IhtN/N'1.11IIn\plt.d. •aNl I)a'p:ul nN•ol lll Mc.ht uN•. IL/r..a.l MI d1a.J \ah.w.l H.•.tl.n Mt11)1tl A11/1Nt11 t:1'1S(r1 IN I1IN( 1k/N 11Y I'11()SI'IIAIII)YI.IN(1SIlcll. 4•S III\I'lhMl'11A11: 11N• al lln InlMlln/! Iwnlc/n pcla/lin rryunr\ mirdlnM+IJr c/1ra'cntrJlBln\ OI cJl. 111411 NN•\ /o N'w•1 7a tln IIIA/ll'nt\. t1/11111rINIJIr /t\ h11MImy,1u thr cnll ol the /dana'nI Jnrnl a1 IN.MIMMI• Ihr IIIIIvIIa•II1.111rM ll/ IIMNNn/MYa' :Illin mt11 hl.//llrnt\ Ill'1:1u\c tfaMil'nl uNtrJ\t•\ in hl/lh lntlalrIlalJr /('a' I :nM1 aalln IMt1ynICr1/JINIn Jl•c/Nnllany IIIr.cIhllJr rc•pm.c tulrrtJln.lunuli, It hn.Itnn.uFyc.1cl11h:N gl•I\uhn rrKalalc.lhr rrvcr\Ihlr a..c/uhly 1/1 al"Iln 1i1Jn1rn1\ that aCC11n111J11ar\ ]uCh cCllular alltvalMNN 11131 Idllrr rvNk•IK'r WL'R'c\I\ thJl Ihl'K aalvltic. d1 nlll rlcc'tl inrrcj+rll cyaqda\nuc /('a" I alNl 111.01 laar al'hn I,'l'IMIIIII t-/qnllkRl'\ LMnI in IIK INc\rlKe nI ('a" in WIIP• fl'IIMWJt /1) Ill•C ( b" riMl\l•.111.NL IJ1nN1 ld INlly tMM• ol Iw.11N1n/Nl ilctln nMMNlnll'r\ Ir/Mn rclVtlnl J/N) IIa• Ic\ultanl hr/l•uy l/wlqlk><c. cJnlNl/ .rvrr al•I/n bIJnN•nl. '11h• /inlhng tb.n tt•tlul•uKt•I\Idal a1u1.'INUpkRr\lanlt•dl.\tK/alell\ultkr\t\Ih,Nat'i' /IMk•hl'INkYII rry/datam Id Kl I\ulm JL/. tti. w. / Irrr we \h11w Ihal • IIIIC 111e lh\Mtl 1.16411144 Iwl•hlu/ aa I/n uNnplrac\. hlN..hl/audylnMl\dld 4.S h/.plMtyahJlc. whKh urak•rpur% rJpIJ tM/n uvrr durulK crll .tlnndJtam. \tr/M1Fly /nhlhlt\ Ihr allin lilanlrnl .cvrrmg Ilroprrta•. nl prl...hn• mlahll\ k.\ .a.wlFly Ihr nwlcranp ability ol thl% prldl•m a1N1 rc.aNr. Ihr irdcnrl•J hu 1d.luN'/n .rvl.ln/• :atrvUy 1/. MrI\Idln al'tm c.NnpkRC\ / u.nw • 1' A .I.r \r.-... I I I' N.ao.. t'\./ p.•, . ...1 t..... .•. ' I .. t ( )qhrr .u19Nnt 1 I S ('uhlic I lcallh tirrviar Jnll Wh11JAcr l lrallh S. K rlcc. I'unJ I'11N1111N' I11'111:11Uh.ry (hN~a111Ky (lnn, MJ.vMho.cn\ (:rrw•ral I11.\lalal. a1Nl Ik1a111 nN•nl ul Mrthl ua•• 11:1rvard Mcdical tilhIN/1. (t/i\NIn. I I III/kl \t'1 N('I: kA I It/ IMA(:IN(: MI('It/)1('()l'Y ll:Ml'OkAI. 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Ir.Iy//N'f~1/I1MrNIY/1N'1.11NIIl/t'III1an11M/aINI~I:1/Ilu/1N11NC~UMNCWN I.cllyrm•ra /NNI I IIf1I1C111NNt', lIk' /I,11.1 lM'llkNl~lf:lll' 1h,n ,11/11 2 /NNIN1h/1!y 11111%1 CRI%I hl'Iwl'l'/l IIK I%, IN1111f WN% :1tN111N' ://1/1/Y11 INr V'/111111• t l'II INIIN/1:11NN11I \IIh(Nr%MN a111v11Y 1\ II/ Ilr 14'Ik•fJ/lYI Wl' +IN.,I1,It.k (l'll/C IIN' ltlltl'1,'n11Jt F\'IN'IN te%llklNNl\ thal /4/vl'1n 11N' nN1u.1NNl ld I... c11.111.n , IN11u,4 •u1qNr••NNl ld r lllk•r f. c11 tN It cc11 fr•.INNI.e• I tk• ,1,11.1 ~I//,''l',11I1.11 ahINN//;I1 I I frl,'NNI rIN I%h'II F`CIN' 11r1N11111% l.N/t111I IlN' IIkI1k11N111 :I/NI t'Ill'l IhN 1111:1M'% 111 \II(IINI'\,lN ll'It Jl tlr/ty J% IIN•JWtrll tNl I l'CII fl'%IIIN14'%. IIIC \Iltlptr, %N111UI It ll•II Il•%IkInV'% :IpMa/ lltlfCC/N1trl/Ih'tlhy I A 1,`t'fIC 11HNI11lh 1'u+ahk cclloLlr uwlllanlan. 111.11 Illlghl r.pl:lln Ihr.r IltkhnK. arr d1.u.v11 KawJ..ll,i. 11 .%np/.,., K . 111anNNkl. It , Minalni, M, anti !)nr/. M t:. 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(IIN• lallCl atC ttll•.u1u:1111y IrJlnvr wu11 l1k• I% a I1/rl clw.N / hl huNl I I itlN•r:kvnK nNlk. ulr alNl I./ lnhlhd antu/•t•n INr.rnla (NNI /u I. fCll. Slkil anli NINIlyllir rca/!l't11. wctc /Nt'parC/l al'Jln.l I,cll r.•JCt1vf IIMNNk IINLII JIIII I• J1NI.1111/ II'anIlMNhc• I Ik' I'taa' )• II:11•IIN'll-/lI IIk•N' a1111 I/I11NyIal rrJyrnl% hla ArJ I'.lclt Im11NINln IlN• inh/1NINN1 wa. haphNylt .tt•l I1N: Jnll ul.yq+rd 111 t1N• II IcyaNl I I1C 11/111 NINIIy11N' ant111111hr] hhk INYI IIk[ rrtMtatNNl .u1 '1.,• I. . J1NI l.. crll. I1N' lrII11I:11 1,111!CI I/I Iilr hI1N I.InIg aCllv/ly /IIrlI1:Ur1I by IIN'N anb /dNNVpk :II/IIINNIk'~ 1\ ,I /II,N f11l.h,lt'r. Ihl\ wa\ ~Ik/wll hy 11\Inl,' a l'IINNII I11al1,lllI1:11'r I1yINNI1N11J Illk' hN 1NN11 I% IIkI1kINN1 a/N1 JhM111NNN11/I an111NN1y Jlhvlty IIN' l'.NIIh1/NVI II,IIJ N11MkN1 IIN• , INk t'tN 111.11 m.Nnq.hJrr. cttNC.. 11 IntctxiinK ,k/rrnunant. 111.61 Jr.• t1'%INNI%IhII' IIN I% l'l•II IMIIN'/N111 KJwa.aA/• 11 . 7upl,u, K., I)/JnNIrNl, Il , Min:uni, M, and 111../. Af F 11K 11NU/ad ol Inulwnldly;y 11M171 2(MI1 2(Ndl, Allrlf 1, 1'aN7. (NIN'1 %IIIIINNI N,aNNI•11 In.hlulr% nl 11.'ahh ( rulll dN I kp.ntuk m ld 1'adN/hlpy,llJrv:aJ MrJia al Sl hlNd, llmhln, :Im11 k•p,uulk•nt a,l MN rulNUla} y a/kl tolNwnllh.gy, /Ulrrt I.w.IC/n ('ulleyr ul MrJN ule, •I M• Ilnm. • NY I IINt'Il11NAI AN/11.1'StS (11• ('l (1N1i1) MA('KOI91A(il: 1I1•IIKIIx)MnS V IN11Il(' I N 1N ()I• SI U'PKI•.SS(Nt 'I ('1'1.1. KIiS1't 1NSI;.S It ha^ hrcn .uyyr.trll Ih:lt n1:N•rlq+hagr like acrc.alry crllk atr n/vulvcJ in .up (1fC%%1N I l rK I I%I I/kI1N'INNI I P Iur1111•t analy/C IIII% h%111', Wl• 1lhtal/k•lI ~l•Vl'f aI l LNKII o/:Nllhllclge hyMNAnna crll linr% by vwnat/r a•rll /u.i,Nl nl thr /rlaltlqdlarc 1unNlr 1'1NKI/, ul 11I1A/2 Ill !'1 IlriKill wnh ylknic a1NlrtrM rcll. 1./ ('KH nlNc /11 2'1 %1•vl'faI l hNN II I11N'%1hy11Jy.YI IIK V r1111/I,`N'aI an1l I/Ml'INM:II l'II:Af:N'h'tlt`IN'~ L) 11/J1111 p11J1.•r. Wr cvaluJtcd Ihr atN111y ul thr.r hyllrNhlnw.l,1 itkhN•r dIUJ,N,k•r /N cl/r. NN ('. 1 I v,l 1u vlqllNr%% Ihr ru.Nar/ wM%tlivily rryNln.r akaiMl Ihc Icqllrn 4 hydru.y I in/.lphcnyl :NVlyl l NI'/. In c/1Mra.1 N1111r ryrrMal l' 1KIt1), wNl lwu .N/nt nlJC/lydr,lyc hyMNMNIM., lNN• nLN•ulllhaler hy11ti111Nl1a ehlnr, ICr111CJ (f 1, wllrn f.N11uKa1CJ wllh NI', InIhNT1I I%, wh/Ch %1/M11C%N'II,',IMaIY ]Cn\/hvny fCNkN11r5 al,'a1Mt NI' hu1 INy t INI-1/, .IN1wtnK that Ihr 1'.. wcrc alNycrn .yN•rilir. Ma1 tophaKc hytMN11N11a (11 l'IN/hI %/AY 111 t ally ImhN r f., al1ivily in rilhtY 11 -2', 11 2', ur 1) 2'/11 2' hr/crl//yFoa.1N1.1. 1 hu., /o:11•r,11111:11,'r hyMkhl/lla hl IwIN~IMlnally r/tlNl'NIYI n1a1/N htu,N/Nnlla//hllity %INl/l/lrst• trl:arJ n•.uicbny ,klcrminaln., atNl thr /u.wln wilh ccll. It/Nn a 11 2' /l/acwy.ha)r ,11N11N l'alINYI a IIIM (IMMI:II r1N11111C111C111a1NN1 ,t( II• 2Y-eCIallYl, I\ I/N11N-111t. ' t'h•IIN'/N• 'Ihr I,'l•/N•INIr.tr/11uN1 F'uw•rn111I,' MNIUI•INNI nl 1'., wa..,Nllnllh•ll hy 1,`rrwv Ihat nwlyll'J 1.,1 I/crNNl Iu11M•1 nkwr, N/' clNlpl~al.•d n1:NnllllUl~~r hyfNNllNlla 61,•,NdJ vIVr J. a t:nVfl I/N rIN It.11NN/ IlI %IIl/I1re%MN fr%INNIVY ahl'f :NIIII/nh/ta1NN1/11 1 1'• IN/I INd I I'• /r.lrk Ic,l .U(MNr.vN (J. hN .'lllr Ilala•ul,'9r.l thJl /Ilalr,llfhar,• hy1NN111n1a% rrlN,•w•nl a nN•a/l. L/,h.vl 1 Ik•N•r1T,•IlC/ly within Ihr n/a111111haKe INMIU1JINln. '11N• 41.0141 aIN. Nlylly Ilul thr I I dciclnlmanl% ryNr..cJ nn /uxn1I1h1/[r~ Irllfrwnl a III,'afN) IIN (IN• Jn11Fl'n rccrpaN /d T.. KawJ•aki, I/ , Marthl• (' A, Ik•hiJJ, 7., Ilan, M, Nll/na, T, Mlnaan. M, anll 1)In/. At F: 14S
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lIN• 1.IUn1.11 .II lnunulN.k.'y 11717) 21JS 2151, (kl..lrt 1• 1996 ( Irflr/ .ulq..ft N.aNm.tl IIn./11utr. 4.1 11c.d111 I l.trn t11.• 1% I.n/1111t•nl ul 1'.ulN.k.Ey, Ilafv.ud Mcd/.al SthlNd, 11uJ.ro NhW ('l/N( 1.1'Iti IN ANllItlq)Y SIKI/('IIIKI: In thia lI.q11rr wc h.lvc aulluw•tl a ncw .lali.lw'a) analy.i. ul dw• anuh.ly .u1N tu/c .1% /1 11'1.IIl'% lu il% :In1/Ft n IqMI1nI,' allll I/Ml•IaliMMl in 111t //II/IWIM' M'IwtMl. Wuh Ihl. dI.INn•NI1 wc Irl.qrnvc ct•rt,ml utl:Nc xac.ahk arca.ld Ihc IK nN.lr.uk• whnh l'\fNl',% Nh..tyrN Ik•IClnnn.lnl. IIw.C I11NN1y1l 11k-1Crmmm~,' Kl•/•NNI%(II1K)ttvl'II.111/1t .1 I.NF'l' t•\h'IU W 1111 /Mt•VNMI,Iy /k•hm•.1 11.11q.kmt•Iw.uy tk'Ie1//11111nr It').'NMs t( 11K,1 111111Ih./11'/I I/I INLvNhl//• l IM11.M I fY\NkN'% hM lhl' arN11•l'n 1'.~ry'11/ttl'111.111LN.1 tnl NINNy Int vIpM•la t• a•)•N/n% atc in t•.tt•IkM aKtrcnlt•m with IlK flreda ov.1 kt':aNlll .d It 1K. I hc c.L/hh.tlnn-/tN .d II /K. 1.•.Nl. /u /11l• lkwckqlntc nl nl a nt•w t Ln1 cIM td 11k• rnhla.ly \11111lutt' IIIIN INN/ ft'I.1INN0111t,/tNI 111t/vNk\ ath'Itl•1 fatNMlak I.M /n111nnM/ IINN111L111My .I/yN1t,N tll•\ h.14'tI IMI tlll' uV' 111 ./n111u.1p•. A/NylK•r ,Nlv.lnl.q•c .d t/u Iwty..vJ mulnpk• varl./hk .ur/:KC nwtdl•I rclntc% tu a ft'ItNM /ILIINMI t.l fMt'vNNI% 4/Cw\.M1/1M• aIIIItwNIy %1lU1I111C with I/NMkI\ t11 an //II/IIIIIIt• 111'IwtNf, Atl.Mlhtl/•l..llti•.c vN-w.lh.-mIr1.Nn.wlul1w./l.aw.wc.w ••It•/nak- lbnwknF ~/ll'~ W.MIItf IIJY.' h. Ll/.l' f•1.N l' t11/1tnF IN'/W.N~ IIIII'LN INNN K\ItMrv111r IIM• It'mflt ILM I.N :1 In111I11/F• %I/l' IL 1\- l1MN .lvl• :IINI hN ./n NINM.yh' I.t tr' f1f11tr11'lY1• .IIk.W\ Itt INI/L1 .1 hl'nl'/ IIN/1ly IIIdt IIN11k'I LM IIN' 111111111M• /N•IwIN• A, .IlIN14'Illll'Ml•t1I IIIIN. wC I.t.•IM .N' 111 :Ih.1/NkN11I11' NILMyI\• IfI//111N1I1.1•y ..I Ah2 .III.11:1 Iq'1.1, F,1111111.1 .IINI 1'INIIINI Anhl.-r. ll alNl Klt•tK•t I n1nNm.• ( In Sirrluvany/• A . M.olrcr. I' (1 .nNl I.nuall. It W Ird. I Anllhtwhc.. 1'I.rluul I'11hI1%hln/! ( .NIMM:111/M1, I'/N7• 111 II I) 1 NIN•r .uly11a1 Anw•/ll,lo ('.m. rr C.r /rly .nNl ('cnlrr lar AIM.IItv1 M.dr.ulrl 14..LIpy :I/NI I111/111// N.It.I• y 1140111 Ihc IA•p.ulnlrld ..1 M..Ic.ul:/f inulnnNlluyy• Ku.wcll /'alA Mclluwl:d In.ululr. ItalLlla, NY Il1M(/K SI'L('I11(' 11)1O1YIM' VA(•('INI S 11 ANAI YSIS O1 1111. IIIMOK KI-.I.A11.1)NIiTWOKK KI•.SI'ONSI-. INI)lltTI) IIY I111• IIIMt)K ANI) NY IN11 KNAL IMA(;i: ANIIt:1 NS IAh?I11 In thi..lu.ly t11.• 1Un11N .flCailic II11n1unC rc%IMM.e Irn1UlC1I by i1CNllall•d (Utulr .cll. 11 IaUf(:/I./ anJ IIy Jn11 NINNyh antlMMhc% wa% analyicd Iht' all/l NINa)Iw antlt,.hc) t Ah? t wclc n1,Nk• aprin.t tIN• p.v:Nufx• l1f a nM1/Nw L.nal afntlunNw anutwldy 111('111h.11 f1l..I,'m/a•. a IunNM a../K1a1PJ ../NIrrn whil'h f/l/..-rPa1] with thr ItNNI.e In:mnnaly Innl.w vnu% cfN tldkd cnvchqu• Flyaqantcm 52 1 wtt Ah2• 21-1(/ antl IPA, IMIINI•tI NIL.tyfll'% t•tlMl•\V'1I by Ihf nNN114I1t11aI ant1tu11MN an1lMMhe\ II(') atool 2112 ( yNd.nN 1.cll.. Fc/N•r.ucd by mummvalitln with /r.alh:Netl lunww t'ell.• ly.c 21 111 end tA•1 byhnJ..m./ . r11. 1 unhcltn.Nr. unnlunv./llun wl/h Ah2 /frlutcs tunNV .It- c11H ty111tnslt 'I IynqllNtcytc..'flk frcyucrlcy of IuuNll reatbvc cyht(uar 11y/nplNt t'ytc wa% kNltwl 1., Ir ./Inll.lt in mll•c mmwnvcd wldl Ah2 tlr ur:Nhalcd lunwlf 101% wIk•ncR.lnnlll•d:d thc 1•1 .•.... kvcl 11'ttwcvcr. tlnly 21:I/I Intlutc.In/NC.4vc 111111111 nny aya/n.l tlk Kluwlh u1 1 12111r(:%1. tunrw t•etl.. llw tkpklNal ul a 1.114 • I lcll p1111/1,NNn11run1 21•II/ Ifnnn/nC mlCe wa% hlurMl /u inCfeaa• Ihe e//cCtivcnc.. PI (fan.lft trd 1.'t'II% (11 11NIIN'e IIIhIh1//1N11/I (UIINN I,'tltwlh I IIC inability nt lM In IMItN"l' a/N1 1NU1Nw •nununny cledd 1.c a'orlcl:dell wnh Illc p/t•.cloce of a ptq>,11:Na1n t,l I y/.' rcFul.lhay I tcll. ('Illkcbvcly, thr.e rc.ultaklnlln.lrate Ihc exi.ICac t/l a rcy.ul.lalry Iw•Iw11tk cluna.llmg Ihc l•ilflrc\\NNI t)t Cllt•1111V1' lunwlr iulnwnNy Our fr.ulh tknwal %h.llc Ih:N 4'ICl II.NI Ut hIn1I111l! 31(e•rt•Ialtyl W /llay IMII he a\II,'nliN•ant t•fllt'rIJ ItN (ln' tk•vckqa/u•m Id :In nlNqyrc vaccine. A Itltcr n/rk•r.larwlinp td Ihe rcKulauwy Intcl..< INNh IIMhhtYl by an/l IIINMyhe% is Ile{Yklf I/N the tk\II,'n tlt t•I/lY't/vt' a11111u11NN I/III//tlnlNhl'1 d11y . Kryth.nN/llurl, S, Sal•ki. Y•(lwn, 1 1• Inhc• il., Fuji, 11.• and A..hl.-r• ll Itw• /ouln.d Id Iuullu/Ntlugy 11'N11 271 1)R, luly 1, 1487. t N1N•r %I/I.It1Nt AtIN'flt'a// ('anlt•r ti1qll•ly :nMI (l1C N:AMM7I ('ant•cr Inaltutc 1-tunl tlw• Iklwrtnrol nl Mnkculx Imulua/k.yy. Ka.wcll Park Ml'IIMNIaI I/N//nllt', Itnll.do, NY I I IN( "I K1NA1. ANALYSIti (11= T('1?I.1. NIIItS1:TS ANI) ('1.()NFti IN IIIIMAN KI-NAI. AL1.(xiKAl'f Rlal•.('1•1()N Wc Ilrcvitlu.ly rcllllttetl dnt i% wav rlnvihk Iu prllpa;alc aruvaleJ Ikl/atr-.I+1•cdlc I' IynqdNlt ytc. htwn hNlp.y U.wc d Mulwn fefu) a1k+Rra1(% unik'Iktnng a•pINMk\ 401 rcN•.INIn I Iw• ability 0 Inlefk•ukal 2 In ooI//INIIaIe Ihvl\111f1 Of NN'II /11 tY W. at Ilvah•11 I (ymplNrytc.lc/.llttn rnnfirmcJ by adr•f. hllfn tlcafl, lung, and iivct pr.dl.. Whlk 11 i% a k:lr Ih:N 11n•tl' 1% t•MN h/11CM IIN R'kva/N 1/1MMlr yft•t'iIN' 11t11111cf7Nlve aMt Cy1dIt111C T IynqllNtylc% in fcKtimg praflc, il iv InIpIf/aM Nl /nvc.ligatc IIk /nM.hanl.Inm by whw h J:unaKc 1% u/tinulcly /ncJialcd Whlk thrfc ie eva/cnce /11•u cyuMuac tcllk tan nlrthalc t1a11uFX. ININ'f r,9/MIfIV IMVe l'111IIhaNIIYf tlle l'11Mf11NNNN1% uI 11t•I111•F/ImhN'Pr .nt.v1% ul c•ru.mg rcNclNln vla a.k IaycJ type hypcrv n.ipv/ly bkc rcatlNtn '1'n cv,du alc /ht' t'tt111r11N11NM Itt uw6vlJllal cell .uh.cl., wc have u.cJ a ccll NMt•f lu c11fN 11 (1)J•, ('ItR•, a/NI a ptI11/t:NNln /d (I. 2 n'y111n.NVe (YH•/R• ccll. I.NUwI wplun tlw• } I:IIe. llK.c .ul..cl% wcre asaval hlt Jluww faytlgnilnln Iu lurthcr uur untk Ltanllmr 4,1 dK• /ntlt'c.. 4.1 tktlwlf rcrnymlwM by IynyllNw'y1c% pfc.cfll att Ihe .i/c. Id IL.IN• Inlary Ju/ln4 rcp•.INIn I lw•Ie wa. IcaJily Jrlcrlahk tklnllr yr•rlficlly with rc.lwct a/ pr1,1/1 Cf:1/NNl ln MY'tMMl:lty MI .K It~ h1Ah (1)4 •:wNl ('1)R' ~Irtc.l wMel.. hut anly Iht• a/rtc,l t'1)u• tcll. wctc .I+.vdaally cyltNu11lc. 'Ihr (1)4'I('1)11• t•cll.I:IrkcJ Junlw .pruht IUnt'INN1 III alkl1tN111• wl' have Inl'Ilaft'tI tklrlrV Irlwll hllllhnl,' IIIIu1N1m UI Iy1t/111wp y/l'% .•MaincJ It.nn hN/p.y tl.alc. 1Lr cklnal analy.c% ia11ca1cJ a fwuntauK-c.l cnnt hnw•lu IIw tklnllf..llt•ci8r IynqlMltry/es within Ihe prall hlMh hchwe vKmhcanl rn v/h.. x•Ict INNI (t'l/Nnnl,' wa% /Ifflofnlell within 411 hlqf\ aller CUIIuR /n11/71NM1) and ahcf 1w.s wccl,.ld Krltwlh in 11. 2. SlcpKa/, M• Htlyle. 1. A• Rcfkr, 1: 1• Irary• (' P.('tdvin, R 11 ,('u.nm, A It , anJ A'rrnn l, ! ! 144% 65100 7859 147
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Iten./dlnl.Nw+o I4+NCt•Jlny. NNI).1•)4 197. Irhnlary 1'/R7 I hlw•t .n1MwN1 N.NItN1.J IN.tNUtc% ill Ilcrhh a1w) Mrrt 11 ul I)iow•. 11.0111 tlw• Ih•p.111//N•nt. +d 1'.IrM+h.Ky a/w1 Sulycry. M.L.:whu.cN. Grnct,d Il+t.pu.J. I1...1+N1 1 Wt 1('( q/1k 1 1 l 1W ('Y II )MI IR Y ANI) 17IN('TN)NAI. ANAI.YSIS (11 I N MI'II/ K'1' I 1 % ( 111 I URI 1) 1/t( )M IIUMAN I(1'.NAI. AI 1.1 K:RAI-1 S If)1 NIII I('A1111N 111 A ll Il 1' 1- S11H1•l)IM/LAII(Nd I lw• 14w•Maylr u1 I lynydwes'ylr .uh.M% prc.cM in tcna) hwy..N•..Iw/wrNF :w NN• s rllnlar ;Jl..yr./ll /cp't tu+Nl in .n I+:NL•/N..m t y11...1.Yrne have h'rn 1 h.w:N /c1 vcd In vru hv ulmnnwyt Iu./J l.a' .6unlnK, aMl ahrr c.lun.wNl rn rrh.. ln ml. rkukrn 1111 11 by Iwa t../.Y Il+.w t v/uow Iry• .+Nllng• aMt IuM IN/nal analya. Altct K h1 d1 .lay. ul .Yr.In tYhu/c• Irqh 1.•u I' (1'11.11 adl 1cu 2' I(Y)111 .uh,cl% were 1/N1rw1 In t•.w1/ t u1NUC• u1..1.11w11t1.N var/t•.1 Irnul ll I' h/ S O, whlch wa. Mw.1gndwatNly JNlcrrnt d1:1N /lw• rc.u11.1.1 /n vrY unowlwyK to.Nlav .I:IIntnK ul dw uncldlurcJ hwy+.y I IIC cuhnlyd tell.wrlcalnw+.t.Jllcu 4' 1('1)111.e11.1N'rf. • J1.whnhc.prc..rJlhcat'IIv,NNN1 n1,Irkcr.l)/(II11'<- • h1.Yw111w•11 21(•1)?SlrctephY11YS. t 41 11N•l.cu I'crll.wotc 1at1•11y 1 eu x 1'IIY) • h/. wlw-tc.1^ a n11MNlly ill the la•u 1' ccllc wcre 1.•u IS' 1(l)1111N+'( ' 41 1)ulya.m.1111tattwYl+tlNlt•Icu 1' /clL.t,uncJltNlcu 71x'<- • (b/ I ulw b+Nw1 :In,dyv% ill I AIN plnrlN•J I ru 1 1' .IMI I cu ! 1 p1yNIL/111M. 1M11 calcd Ih.N Itiu11 .ul.vt% pruL1.1.NcJ in rc.1+N1.r a+ 1•tah tW+MN rntlgrn. /n a tmacJ Iytnldwt ytc re.N nun t Ml k t.uNl IN+.Int ed 11 .' t hJv Nw 1 cu 2 1 I~yNILm~.n tk nwY1 ~Ir:111'lI t1+NMN ry•cdN t v1+N++cu .w N.+IV A IIU/NN .uhlry.d.+h..n ul r.N h t ul/Nlc wt'rt• M+th Ia'n 1' aMl I cu 1' 1: 1/'11 1 ru 1 I+r11. h+NN.YN• hny+.y wrn• INII1111•d t11 IMYIMy!t'M'Ity t'MI M'R I• aMI wt'11• I+N/1NI 11+f.INf- IIw- I t cll .Inu(•ru rcerIM+N t+NUplrt lt1('1)1/W1 tl'•I.cu •1 /.hutM+tdlct•+u+u1.NldlvnNwrtcawl/•.•nl I/1111K161 Ilw• Irn 2' 1' ccll.tlcnhcrtc•IrNwti•Jmt1w•k11 H.MN.Iw+wctlatly.yNw++tlc.:Ip:1.Ny 11N• I.clt 2' 1' ccllN wcre cap.Ihlc Id 11. _v INII MN Inlt•IIt'IINI r INIwI1N1/.M1 N+NM ul tIN• IN1nIN d culturc% tkawYldr:.ecJ NK :N uvuy A.uh.ct ul ehc IN/r11N J I cu 2' 1' t cll. lu.t leu 2' JunnK 1 Iu 1 wk in culuue• aMl Iwtanlc Iwu-2 U . Ihc.c .tuJle% provNle evNkrN'e Ihal dK ccll% that Inhletale renal alt..rnlt. JurinR reoccti+m /M Iwk alltyx+. Idcrauvc Ivnry+lw.kme pnNhN inK t'elh n/ 1YNh I xo 2' anJ (xu• 1' vuh.ch. T1w• I w•u 2' I ccll% are a1..1 hlKhly cyt.wt+.ic agaln.l tMNwN IynqlMlcytec, iMlicatmK the prc. eM'c nl hclla'r rnJepeMknt cyNNuaic l'('ell. A nNMN (wyN/Ia1NM ill LeY 2' 1' T cell• Iha1 Ih) tN+l cRprcv.IkIMN .peclhc IurIc1NN1 war ala/ itknlrlted. Prcllcr. l: I• l'n/vin, R It. • 1 rary• C. I' , Ilnyk, I. A. • Tuainn,1-. V, Laiaa+vN.• A 1,('n.inli. A H• arwl A'Yrnn 1, I T. (M• hNn11aI uI InInluMdlyry I171')) 2x2I 1N111• NVve1/lhtr 1• P1xh. 1 AIN•r .uly++Nt NrINNUI In.Ntulca nl I lcalth. Match uf Ihnlc.. Shrlner'. 11urn. In.ri lulc, l/c. N.n 1)N kln.nn. 11 S 1'uhhc I lcalth ScrvNe, MeJlcal Kc.carch ('t.uM"11 ('an a1I:1, a/wI ('111161 Med/cjl IltcnJ I mm Ilx Innnamy.atlw+lt.ry 1 trNt ++( tlw• Ikpannlcm o( Pa1M/1+y[y• aMl Trancplanl.INtm I lnd +.1 NN I:r1N Ld Cta/•I+.d \rlvn c, Ma..ax hu.ett. (:crlrral 11o.plt.ul, aM1 1Iatvald MrJN.d \+ b..d I1...1..n 1 1:XCRA('IIR(1M1)SUMAI. hNA S1111SfKAll•.\ IN I'KI: If ('Ii1.IS IINI)Iik(;() INVI'R11(IN l1K I)11.1:111)N A'1 IMMUNIKiI.I)IqI1.IN V•IU/1 1OININ(: 1NiNA1 t tirerN•rK•c% rM Iw1NIK unnmMlyhd,uhn variahk /MNruinm ate kMtwn lo he a..cn1 bkJ laNn vnrl:d+lr t V 1. Jlvcr.Ny 11)). aMl pnn/nK /1/ v'ynw•nt. hy .rtc .pccncivtct.NN hlnrawYl We INCwtll J M'M/IIYI '/IIYI' :Nwl rapl.l awly LN V 1U1 1 rt'elNUhmale.n Ih:11 N.r. pl:l.rnld I)NA t1.111.w•Iltly mlr.whNrJ Irtln Iraa.l.Nnwd prc-N tcll., aM1 IkuwNl.h,Nr. IILN IIk /YCtN1/1MIn:dNN11% Nwkrl9Nh•nt 111 a11y 1111nh1e 1'IInN1wNIN11aI l'INIII'tt. 1t'41N'/NY% \NIIIt h'III lu fINNt1111N' NYYN11hIt1:NNM1 \Ill'% :Yt' l IY11:11/k tI w/lh/n Ihl' K4 :I/N1 •11 Iy+ II.I/lk iny• reyt•tilvcly. 111c mur//1c 1,1 aMl V,I K yrIIM.•nl%, wI111I1/11CI1Nk IIK k/w/W11Iw•IN./ nN•r /wN1d11Mt V 11/1 1 pNnmy %lynalc 1)l'k•INNI aMI /nvl'f~NM1 tll'Cl/r :Jt ctN111+atahlt• InY11N'M N•• 1111m, V( I)1 I IIYMIIh111:NNM 111:1y Ir rl'LNlvely 1/1wIImllve tn 11N• I+yw+lul• Nal anallycnNln +d .Nr., a/w1 evcrN..N IIN' twn M.Vt•I IN1N'INN1% INtwlw'cd hy Uw• tl':w 1NN1 /Iiay IN' a 1 N111hYI Ik.v', 1 1: , Ll+la., AI R. •(iclkn. M., :Nwl Mtiuuthl• K ('rll 441 77S.7111. )wk 14, 1'1R7 / hhcr .Iry11.+Yt N:NwNlal ('anccr In.lilulc. I:aun IM• I.ahlNalury 401 Mtlkcular Hi11111py, Na1NN1:111n.INu1e ol 1)I:Ihclcc and Utgc.- llvt• aM1 KNlnry Ih.cax'., Na11wN1a11n.1Nute. u/ Ikalth, Ne+Ika/a• MI) INiVIi11)I'MUNI'AI. S rA(;I: ti1M:('lhl('ITY (N' T{II: I.YMIM1()II) V(I)Il NI:( Y)MIIINA I1//N AC") I VI'1'Y Wc havc csanllneJ Ihe level ul immwMlKWllwliw ~ene V(I))! rea'umhinatNN1 xirv • ity in a mnuhcr ul cell line, derived InNn Iyn1111w/id Ir M/nlynlplwlial IlneaKc.. Ihc a..:ly we cN/pluye.l u.ct e.Irachr.NMlwNlul I)NA trt .uhNrale amt thereby avuNl% d/1/N'ullle5 awq'iak•J with Ihe W[ n( l'/KtNIMMNH7/Ily /MeKraled .uh.lratc.. lhe rc cINllhinatilNl aclivNy .kcrea.ex during R-IyrnplN/wllkvchqNlrrN 11 i% hr4hca at the carlie.l.laKe..t( r..uanlncJ It-cell dd/ereml:NNN1 ard Ihen lall% pnlgrerv/vcly, rcat 11 inR untk/cti'Iahk kvcl% at Ihr noture N crll .IaKc. 'lllc aclivqy i, alw prcant /n nndlilYacnu:dp/1gcni1/N.ulmycMNJcellcaMlin/xe•1'celLhulMNm:aureTcell. Nu a1lrvNy wa\ In11MI in %Cveral MNIhCNWN11NNe1K' cell Itne• 1(el'11111hIn,1/NN1 wa\ MY'n INIly anwN/p wh.Nalc nw+kY"uk. which haJ replN:aled in Ihc cukarytNN ccl1. \cvtv.d p+..+hk nNe11Ne1 NNNt. trl Ihr% rcwll ae Ji.c'u..ed. I rrlrrr, M R.• Ilc..e. 1. E . Mvuua•hi• K• anJ (ielkrt• M (knccQe /)evehy+nrnt 1 751-761, 19117. (Aher.ulywNt. NalwYlal ('arxer In.ululc and NatilNUl In.lNUte% u( Ikalth FnNnthe I.ahINaNYy o/ Mnktulat Itinh.Ry• Nanalal (n.lNule ill I)lahctet and I)1Kr% live and Kidney I/1.ca.e., hcthe..la, MI) Itx 149 65100 7860
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NI KVI S ANI)1111- ('!I'fAN1:1/11S A1.1.1'RGY HI'.Al' (111N IN MAN PI /\\INI I INVIn vl MI NI tN %I N\INtY N1111NN•11•I11n \ IN 1111 11 ANI NI AI INnd I hl• t'11r1 1\ ..1 IIN ,1) l:11M.IIl In Iq1'IrrJInKM tN111K l•UI:ItIrINI\ Irlltle fl•\(NN1\l• tt'.N- 11.N/1111I1N'r.I hy.1Ik'll'l'n t'tlMnltrl' ••r al/ll IKI. wrrr \tlNhctl /n lnen Atu1c rnp.•la, .11 IIN' I111111./11 ~I,/11 (n t.11N.11t /11 t,111\t'II :/ htlnllnl,' \rll\a1NN1 antl a t ICall UI II:IrC rl':N I IM/ Mn 114, wIN'.II /t-11MNIw I/ILNI tl'llt•alr.l •NIIINr11\IfY1NNl lhl•\C 11\:II fC.N1NN1\ 1/1 la(/\all'lll 1l1\J(>I.ra1C1I I IN' ll,llt't.Nn111NN'n1 AMI1M• Whll•t'llv'C /la'h/n~.Cn\a111N11/I Ihra'lllalN'• N/\ allrtky trJ.tnm t.. tJ1 ,INIyrU In.CM11Vl•1) /1l•OINI\ // i1111 II,'I: /n INNI alll'fl!N IN'r\.NI\ wrtr Iht•n /n.111,rJly rc•t11N.•tl fwo wrel\ af/er cap\airin pfclrratnlrnl /1,r IIJtr rr \INNIN• III .1Ik'r/'rl/ W.1\ M11 \lyn/haanlly ch:Nl/,'l'lI a'1NIII,arC1i /.1111r 11NNru1 tr.1t111N1, .Np)•r•tlnl• a/rvrrvhk' rll,•ll ut avp\alun IrcalnlrM 'Ihc wht•;d aoaqnNN•nl 111 11N• ,dlr//•y IN anll 1/•I Il•:N INNI Wa\, IN.wCYr1, n11t I/I/IIII't1tYll by CAI„aN/n INl'IIr.1111M'111, I/NIN IIInl! Ih,ll IIN' w)N•aI •IMI Ilatr a/NIII\Nlrnl\ ate CYnNeII by IIIIhYCfM /IN't h,ln/.nl\ 11 1\ t+NN IINk'II 111J1 1,11N,IN 111 V'n\/llvt• V'nvNy rN'rvC\ LfC 11/ /n11NN/Alt'l• I/N 1!N• honl•m t111d/N'INN I1111I1' It'\INNIy /rat1NM InI/1Nrd by alktRcn empl\utr 'IhN\, .cctNN:JIv tt'Ir.IV' UI IIM•,IL/hN., NN h J\ (•1 iRl' IN Ix hykinin\ Irl/rn .cnwxy /lrrve MarN'IN•\. Inay I.NII/1lNllr /I. IIIr II,/rr •,NIIIrNN•nI l.t lhl\ /l'aIINNI I uflhl•IIINKI' thl• 11l IIInK Y'n\:1 11N1 N•rUlv tt/1N• ,h•1.•INk•nl 11. ,, I,If/,'r ra1C111 Ln ta1/.aNm vn\N/vr rN•rvC. ll/lwa•.rr, 491.ntV IN'IVr..IV•1111.. h.lvr Ic\• rntp.tt.ullr Il.t 1hr whral rra.u/N1, / r., 11w IN,.1.•IN t•aU.w.l.Jlan, rf.INInV• I untlt.l•NI, I• I Nndlv'.c, I M Anl•}rld, A, an,l %rHC/.lrlNn, 4) Anr/ry a: 211 !%, 1'/N ) IhIN•r .1qq.Nt %wrd,.h M.'Ihtrl 11rvJlth l',wnld. Swrdl.h Wlak (nvIt..nnN•tn1 I uod. Swr/l/\h I Lh,N.../ ,Nnp,my. • Pl'tll/\,In1) A11gu\IY I Ir1II1/ML I111NI, a1NI lhr Itaro 11114.1 In.mulr 1'r1/ol Iha• I1t•p.utnN•nt\ ol (ho thNN/ latyny./l.l)sy aMI Ih/N:N'N Mrdi./rlc• KJrlfin.la Ib\pual. a1N1 Ikp:Irt11N•nt ul 1'hann.N/111,) y. Karuhn.ka In\mulc. ti11NUN/hn. Swr. Ikn 1'.XI'KIiSSI()N (W 1111MAN ly(i StIll(•I.ASSIiS lluman imnNltNtyh.h/din (3 IIX(il ran tlc Ilivilktl Intu hlur .ohclas.r\ Ihal are .clrcUvrly r.ptr\.a•11 I tN m.larlrr, cathllhylhale anliKrn\ prelrlr/ulally Chr/l Ik(72 an1ltNNhr\• >whl•rra\ prldc/n antlXcn\ n\ually cIN:11 1K(it anll ILd71 1:hN•idallnK ,IK M.11//)!N'alha\NOI IIK V•h't11Yel•tI1R\V.N1/1111NV'I«(i\IItKIa\4\1\IIIIINN1:1111HIINIf UMk•r.laM/1nF' NItl1111nINll'/NKM1l•\ aMI It IynlptNlcyle IkvrhqNlN•nt *f// invr\//J!alr a'IInN a1/n1/11NIa1N"r t/I IRl i.I/IM I:1\\ /h'hl N nl'/r\, a vCn\/llvr iMI \ItY'Iha i\\ay IIa\ 17ah'/l Ilt•vl•k111C111/N II'( i\Uhl1a.K\ 11\In/.' 11anN'IC C/NNCIMfa1NM /IINNCN CM'C InIn1UM.a\\ay. 1'er1NNlnary t ImNal .11NIN'. h:avl• a1rr:Nly .IN1Wn /hn/ Inlrl'INN1 ININIr NNIIvN11/aI\ Ohrn have .rkv llvr IKI i? \u1N I./\. /k /i1ae1N y Nunnal kvr/% ul 1X( i2, IIUWrvef, Ikl MI f11lC INn an InU11utNMk•ht Ir/N y UI Ihe Inll•C1N.n IIf/Nle /nlhvldual\ IYraua' aN11C in/livltlnal\ 1..1v.' n..nn.ll lr.. 1..d 1/•1 •uN LLU•l and Irr INaNty tr.pN,avc I.I,/nnyrn\/11 hal lr/lr Il....l..u .n.r..,l /.......nh-,.nr nw.4'1...111., 11.G•.r1.yoN•nlIlavl•fx•cn Iwlynl.c\ n/uI1q1Ir hllral!a•S and Iq/11M,\c\ Ihal a It a•cll can raplc\\ INlly ..Nllr ly(i \ult L/\a•\ 11 ha\ hrrn 1/1utN! hy u.lhat anti 1'(• arN/1NNlir\ arr nN/\Ily (rl i2 w/lh ./NNr II,•( iI, :11N1111,11 Ilar V IC)YIM /It 11,'( il anl/ atNl 1'(' anutNNly 1\ ddlrfrnl Iflnn lhal ul 1140 a1111IM1,Iy lhlt IIINIIIIg• 11NYr111t1•, \I/I,'~,'C\l.lha( N aYII\ Iq/NIUI'llll' a1N/I•t• a1111MNIN'\ alr (mll}rny ul n1,1/Nlr arlte\Iral 11 ccll that ha. vl/l•ce\\ively \wnt•INVI• hul 1wu nwkpl m Iknl .uN'r.lfal It lcll\ ('t•Ihaar .hNlir\ u\ing p,lyakNlal acllvahN\ al\t/ \uFyr\I 1hJ1 rryul.utNy nN•% h.m1\1m lur 11,•( il a1Nl 11.•( i 1 atr Jil/crcnl INNn IFNIV Id Ir( i2 anll IFl'4 WIN•1/1IN• Iwn IlNltk'Ik arr tallen 1n1!CIhe1, we IaY1N IIIe /IlUhlllnl•agl• tNll• hrlll'1 IIIJ111IA' .In L• h • /! IN a/!r nnr Nld,m, Af Il, Slull, M(i- and ShacAcl/twtl, 1/. (i. Ann:d\ NI ('hnlcal a1MI I.ahIN:111ny SCirnCl• 17111 IKt.14(., 1997. 1 hht•/ \Npp,Nt 1'uhlN tlralth Srrvia•r. I t.NntlN• 1)Iv/\NNInI 1:/14N.NINy MCJit'/nr• 1)Cpar(nN•n11d I'a1Md//gy, •alltl l)/vl\NNIO1 hdrl b/Nl\ 1 h.a•av\, I k•paltuw nl ot ISvli,lttia'\. W a\h/ngNNl Umvr/ aly St MNd ul MrJ /t/1K, ~I I!NII\ ('()N('t:.N1KA'11/)NS (/1' ANTIR(n)Ih,S IN pA1N1:1) MA'f1iKNA1. ANI) INI'AN7 SI'1(A N1:1/111UNS1111''1-O IK(i S1111(Y.ASS 1'rrvNlu..1o,IN•\ rlNUl>.•IrinR 1R( i%uhcla\a a.rN-rnlraleln\ in r1 NA atNl lualrrnal .rra have IININ'alcll tha 1r(i, i\ Iranyatloll acr/N.. dIr plaa•crwa lo a laraa•r ca1rlN Ih,ln 1. IK( i.. 'I IN pl/r)r,.r ul llur .Il/dy wa.1n euNnl/lc Ihr relalNln\hip ha•Iwrrn 11N• uanyllwt ol 1K( i, an111F•( i. a1N1111e IranyNlA n(.prc//il: aMtlNNhc.111a1 arc rrlallvcly re\1riclrJ Iu a 11:1fllt'1/Iar \III4Ia\\, rlthrr 11,'(i, nf 1g(i,. 'lllr c11rN'rMralNNIC a1I (IMaI .CIUnI 1I,'(i, a1N1 Ioi. and tMl.r n/ IK(i anll A•Ianus Iutt/1iJ (1T/ arN) a1Ni•Knwp A.ItrINlNalaCal carM/• hylhalr /(iA(•) werr /Ilca.urr// in .N/ pairrll nul/rrnal anll c11rJ .cta. 1'rrvilNa \lulhri have \IN/wn Ihal an1/ -rr in adahx in Ixtvklminantty 1r(i,. whrrra% anti (iM• /% prr tkNnlnan/1y Il.di,. lhr nlran cllrll/lnak•mal conrcnlralnln ra1N1m nl Ild:, antl anll I•1 wrrl: \innl:Ir 11.77 111 S(, and 1 93 • 1/67, rrylra'livrly), INN JdlrtcJ .iKniln'anlly 11'' I/ IKN/11 (nun IIN/\c of IK(:, anll aMt17A(• /1/.44 • 11 19 arNl 1.111 • Il dS, te\p•r- llvrlyl. Wca•INlhrnwJlhedi/1crc11ceina•/rlllnlalernalrtlncenlralilNlralal\o11K(i,alN/ IK(i, an1lfNNllr\ by nlca.urinK (K(0, anl/ IK(i, an1lMNhe. %pcrihr l//f llarnt.q•htlu. tnlfurn:er type c Cap\Idar pllywr•charuk; the nlran l•IN/I/Ina1l•Inal IYNICenIfalNN1 ra1N1 /l/ he( i, arlh I lih 1'S wa\ \iKnilicam/y hiKhrr Ilun Iha( „I /K( i, atwi- I l/h 1'S 12 11/11 K 1 alNnparrJ w/lh O•At •/) 1V,1' z 11(/11 lhe.. tewh\ IdIN ate Ih N plal'rOI%I IfamlNNt UI I/!(i a/111lNNIh•. 1\ rl•IJ/Ctl ln IhClf \IItM•Ia\,; a•IN11111h1/NN1 I:inMNn, M S,(harN.//, 1) M.. N.Ihn1, M f/ ,(juinn. A., and Sh"rII1NJ, 1' (i '111r 11NIrn:d ul PeJialria•. 1111517111 7119. Nl/venlhrr 19117. (hher \uMNlrl: U S Public Ileahh Service. hr11n11hc 1:Jward Ma111tNirlNh Ikpar(menl nf PcJiNr/cs and the 1)Ivi\i.Nl nl 1 atNNa /ILy MrJN Inc, 1 kpaltmcM o/ !'a11Nd11Ky. W a\hinl;tlN. l ini ver\il y SaMN,I ul McdN Nlc • and the UIv1.NN1 nt InkllNw\ I)Lea.r\, (1NIJren'.Ihl.p/u/, SI I.w1\, M(/ 1~1 65100 7861 1~~
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IIIIA1nN AN'Illp/l)II S T/) 1'II()51'II/K'11(N INE IgG ANII I'(' ANIIIt(11)Il..ti 1-X1'KI Sfi* RI C I KI(•I I I1 NIIMItUKS 1/FV ANU (' KL(M1Nti Wl• f\:IIII/rNYI IIM IF( i WtM IJ%% CINn(+IKIIpN/ JrNI INII'ICtl//t hN u.mR 1/1H .ry•c- Ir. NrIK Ictncrn.,l netur,llly rNl umnK hum:m IR(i JnhMrbcc that hlrNl pM+.pINN.M.htlc tI'( ) :IrMI I.NItN/ IIIrIV I t'vNkrNC IIN fl'%IrK'Iell e.INc%%ll+n nI IMNII V aMl l' rtr11M\ an"tuk t1N•v antltNiallc. In trN+.t uNlwldu:llc, thc 1ctMype n/ tIN•v IK(: anll 1'(' an111Nt1 N•% wa. INl,n,mly I/•/:! IIUWCvI't, M'rUn1 InMI vNllc IMI/vNIUak l'INIIaU1t't) %IFntln',1f1( :Nnl-un1. M I1•1:1 JrHI ll•(: I an11 lY' anutNNbcc We aIN+ ItN/MI tI1:11 1n IMI1v11h/a) 4'rJ, ,11111 I'(' :/IIIItM4IN'\ a/l' ItJ1M it hN1aI, a\ t)l'nMNn\Ita(el/ by rC%lrN ttYl \hly tr1NyINc h:,nctn\ A t1N• Jnfl I'(' anhlwwhc. Ilw• II Y palMrn t/l Ihccc anU1NNIn•c wcrc LN tM• nN+.t p,lrt 11nnI1N' ltN c:N II //NIIvNIUJI In clNlK ccta, t•crtaln aMi-1'(' anttlwNlN•c wdh IvN•kl'trlr I.nntl t/l hJ.N pl1 LNrrrl P(' ctNquyalc•d In hnv+ne ccnun alMllnln IIY' IISA ) ttit Jld 11421111041 prN•Nlnwn,N t.l (' tatlNdlythalc hcannK 1'(' Iklcrmin:mtc• In twt, inohvldu•d., wl' //N1111I Ih,11 IIN' 1I4't t/111y11t•% thlt IMNn11I tNJy 1`(' H\A wt•rr n/ Iht• 1'1:1 IdN (.Lc 1 Jkt•n 11-gc11N•t, IIN•.r hrNlrnKc Jc/rNNl.trJll• IhJI within Imhvldu.d .crJ, hanl.ul :u td.t.l N•.1.+ 1'( ' Jrr yullr rr.n r% trJ In L.Ih V arNl (' rryaNl c.prccvN.n. a/Nl lu/tlw•rnr Nr. dN'a• V ,11h1 ( 11'1'NNI~ 1.1 1111111.411 I/.' I+IJy fNN rJMhN11Iy a\NKIJte Sl.•ll, M(i , I/nlc., I) I-. . Shalkcll.NJ, 1' (7 , Sltnth, 1) S, aml Nuhm. At ll IIN' 1-Nlrn.d ul Ihnmun.d--yy 111111111 1125 1111. M:ly IS. 19147 1 N1a•r .uly.Nt 1I \ 1•ul•ht 1Il•.dth C,•1 va t• I ulm IIN M.Jlnw \1 .11 11N , 1 h.IFrN..nt ('r~.hl.l.) )rvlaan, SI L.INn., Ml ), I/mvcr.ny ul ALIhJmJ, Huaunl•hJnl, lk pJ/arN'nl /d I't-J/JnN.arn1I)IVl.ulnul l.atwwat.Ny MrJI I/tN•, I).•LJrtnu•rn M 1'.dhu.1-yv, W,1.1nn1•lun Ill//vl'/\/ly tiIINM+I ut MI•dNnN•, SI I lNn., MI / 511111'I /I'( II.A I H INS I II H I YMI•11( K'Y Il'.S IN GI KMINAL (•1•.N I I.KS Wdh two+ nl•w /INNNthNIJI Jn1tIMMht'\ arNl 11uw eytlNlklry, we tk11tN•d 1)ncc ~Illl~rl(111LIII/N1\ a/1N/ny II lt'II\ t•\(+It',%m)r h1lMl/n/,' %ne% hN (N•a/N11 aFF,'IUllnltl 1/ Y, It ccllc 411 tIN• ycrnlmal ccnlctl (hrc /INNNNLNIa) atqllrN/y 451151 hlrNlk gNoINqri:N..yl CCI:N11111C I hl• It Iy1111+IN4 yIC\ hIn1I1t1g 5115 IIavC INIMhn/,' \/IC\ hN hl'arWt :1)tl'iNli/uN INI dN• .orlatc atNl ea1NC•. /Nlly .uwll anwnmlc Id .1r1) and c1pM When IcclcJ a/taulcl a patxl ol H tcll hIN•.. tmly (lurkldc 1rnq+INNna ccllc wcrc SI15' . M/NCnver, ltlc 5115' ccllc havC I•nl•t'r :IVI•L/Fl• cl/t'c aMI :1 1Jryc IcN•urNl uf tNUldctaltnr ccll. lhc tNIN•r IIMNN\/IN1aIA11111rMIy111K~1)h/1Ml~a'NIIMM/1111dt•/n I.ympINKylccMrNhnE11K2t:nc SItS anli IINhNh' I.cll..nltt a cu111.qwIJblN/ ol H ccll. In rtNllracl lo SIIS' ccll., lln I IK 11 ' arwl pl anut al•1_Iaumn p+auvc H l l'II~ e.(If( ~~ a):Itl t' a1tMNIM /I c1yM I IN•cc Iw/..uhphNlLrhlnlc /.1 Kcrnunal tTMI•tC :NC 1I01M1 IIINII IIN• /',CIt11mal CI'/llCr H tcll cuhlNMwlJU..n c.INCC•Iny 1ht l'1>2 ( tllla.l _`1 anl/rcn '111c (•1)! 1' H ccll. arc SIIS aml c.lNt'.v an n/lrrnwd/,dc kvcl u1 IIK21 antl" In adllnltNl, ('1121' H ccll. arr atc Inl•hly vJrrJhlr ro rNlndti•t, wlN•tlaw dN• tNqqnNtl+N1c o) 11K: 1' alNl 5115' tl•11c reI..l/vcly .IJldc 1.1.•, l: (.MJ Il...u.•. I A, Mu.taun I• , I)avlc, I M, Alley. l' 1) ,owl Mrlltrl, Al 11 Ih. 1....... .1../1......... .,1../.+ 11•hlt 'IN1 'P+.1 (A1.drr 1. 1'IN) t ( Xhcr .u/qrM 11 S Puhlic 1lcalth Setvice and the PnK'ter and (:amhlc l'lNnprny 1•rolu thl• 1 kpartrlN•nl ul Pa11Nr/r+Ny. I)Iv1wM nl LaIMNal/Ny Mf1ht'IrM, an1l IIN.' 1)t'tqll- nN•nt ul Mn n"l+i"h+9y arNl ImnwrN4uKy. WachlnRhNl limvcr.ny St-IwNrl 411 MrdltNw. SI 1-ro/., M(1, arNl (kpart/ncnl ot ('ell HM4t+Ky and Anal+Nny, /lnivcr.ny ol Ala- ha/ua, ItltminFbanl AN ANAI /XiY 111:1'WI:.I:N h/:TAI. IIAPIYX:1.()HIN ANI) A I'()11:N-1 IMMI IN(/SI /1'1'KI•.l'tiAN i IN (•AN('!:K (n .I+dc o1 11N• nunN•n+u% rcplNtc Ilwln•alinK the ptccenrc ut hunwN.l /nlnnlal.up- /Nl'%%/vl' I,It 1-N% /n t J/lt't'r t+atll•nt%• INIIy a It•w nt IIIN%I' Ia11/M\ havl• IN'l'/1141h IN'111N aIIy akublN d I ur11K rnwNC. tfN•it n+k a% cllavIivc inulwnnctry+INecau. tn rnYo It•ul,l/n% lu IK c.1Jh11.lw•J (/ur L/INN NtNy hac slknlllk 111u I.rdJte arN/ nk nlll y thc nlapN InlumtN+ c1y.INC.avc 1:«1.N ul Iht• n1a11KnaM c/1u.Nlnc Iktivavl /n+lu uvarlan ald lunl:.arkrr palw•u/. We havc INCvNNnly IkmINl.IralcJ Ihal the Af•52,IMM1 IIII//Iu1NNUIMNI'%NVI' Lh'HN /v+lak'tl Ir/N111IN.' aK11CV 1INMI nI an nvaflan carlct'r /ta111•111 /III11h11C11 I.kh•ak•ut UNnNl1h' nY1nNIK% II1 1•IIYr arltl rn PI(IIr rltl'Iu11/nl,' IIIC In111MINN1 nI I. tltN•1/1//1; Ih11N, /hlc Io1nmlN.wplNC.avc Iac11N waz n:NmJ "wpNC.avc I:-rrccphN" IS1 K1 (hN lutrrm .1NIdy IkNNNlclrala•. Iha1 Ihic %1•.R lachN purilictl InNn n+ahynanl c11u.NN/. dl•rlvctl /rt+nl uv:ulan, lung, llr hea11:NN/ neck cantct palirn/o h:Nl :1 1YN1//1NN1 t'IN111Nb rN•nl whl. h Jlc.r a I:NrJ cyually inln M, Ut•/MNI 42,IMM I(ntl I T,IMk/ 1'),1 M 11 uN1ic1/c.IN1 vNlaun tllNkcyl cn11:NC pdyat•tylanNlk gcl ekv(nMttNNcclv utNlrr v/KrNtN/c rrdu.'/ng t'INMIIIhNh 1111'l'111q•IU111NI III IIK'~C Iwn l'INII/MMICM\ h1Ih/wC1I by a I/II/IhYI an111M1 aCNI vyucmrllrlclnull:tlinnrcvcaleJlhrxtwutymyNNklN.h+havcN IcrminalamirNlat'N1 V VIN'11t't'\ NknlN:d 1u IIk (S anJ a,.ahunilc n/ awnul aJull hapa+l;hllan luulluall•kr- IIty1111Nt'NV 1+) 1I•.K u\Inl,' a INllyl•IlNlal aMNCtWII (n nC1Nlalal tYN1I h11NNI Ik/1MNINrah'l1 that \I K, nnl/kc tNNtnal hyllopltthin, h^ >,Mw'cr ckrtnyfMNCUr /INd»Irly Ihan dlr INNIII:II alhd( haplH.l;hlhm. Wcactn hhll(inK analy.ic ol til•K xparalt•tl .In cldw/u tMNlra'yI cul/:uc INdyal'rylantilk Nclclrctr1y11NNCCil wNlcr.kn:durinK rINN)ItNNIC IadcJ Iu ret'nl!nlic a nNNNw hNUl aM/hlNly Jnt•c/cJ yt•t•ilica/ly h/ SI:K I luwcvcr,lhic nNNNI t'hNlal anlih.Nly ct.lucivcly rcac/cJ wnh /he Yf:R %eparaleJ hy an analyli.al p+lyatry Ialunlc Kcl cka'trIhANNtcix Kcl wr/cr nlNNknalurmF c/NNlilitm, whik awnlal :Nhdt hal>tul;Mlhmc rN pufllicJ INN Iknaturtvl ha1N.+KMlhin nMalnwl lnNU Ilrc acJnlc n/abKnanl tlunl ac 51•.N all Ia1kJ 1n n•a1:1 with Ihis a/NtINNly. lhuc. SIiN alyx•arc 111 IN•as an a111I11NN1a) t'/NU11M'/v111G11 Iv allk'M In nlNllla/ a11YN hal+ltll,'htllln SIIKI' (hc tiI'.N a%w/'II ac IIM nc/NIJ1aI h:NNuKhrhin hac al k ac1 NM11u NMM/-InW ruNNC pNCM mumuw..nlhNa c clve arliv/ly Ihan thc rNNlnal adult ha1MnK1111Nn• Ihlc atkldMN+al cpltal+l•LI INCU•nt m SI K may It• rc.INNl.lhk ttN Ilw• (NMCnI ilnminn+.uMNCCCwc pahK•rty ul \I.K ' ()h, N A, Vl•ry, 1) 1. . Walkcr, 1., Num, S., :NNI lu, S-T ('anl'cr Kc.carch 47.511(1 5126, (kttlher 1, 19117. (Nhcr cuylrM. Nt.tilNlrl Incblulcs o/ /lcallhI hnwn Ihc /)cpJnnk nt 401 Micnd+NAt+gy and Atlhnlic ('cntcr, H/NtIN1 I IniYcr\Ily `t IMFII ut MedNUI., NJtnk Army Kcccarlh('enlcr, NMitk, MA, anll IlcpJnnN'1u.,1 Mr.h c/ne, lulh Ilmvct.uy XtIn.A lol Mr.lnrulc, 1lucttNl 1~~ ISt 65100 7862
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1)NI' I'11Y('O1111.11'K(/I1:INS, 1'1.1111k/-S('hNl AN'rIGI:NS lY) SI1111Y 1)l NAMI(' I'kI1P1 k I ll ti( N AN71(:I-N IF1 k1 t'GI•11/k ('UMI'I I• XI-.St)N klll. 2111 kA I MAti 1 l'1-1 I ti' In k111. '11 t rJt mnansal ma.t trlls, tlx anrslmLing nl crl) sutlacr IkL• rc.elw.w l ooq,k Rrs by rnuluvJlrnl :mtuKcns unnatcs a 4•qucm•r u( rt•spNr.rs kaJmr tu dl•- )~trnul•rn.ar W. hJVr ,kvcl.ryr•J J I:andy .d Jmru.qdamJ /UNI') a,.n~uy:MrJ Ilu,acs lrnt .oMr);rns 1., .UNly 11ynJ111N' nN'In14Jnl' CYCIMS a\4K'/atrll wnh t1w•sr IrsINN/4'\ I y.vl /- , uaq,s ,m rIN• t,1,yt.,hJyM.Mrms. It pbyat,rythnn atN/ (' Iohyclsyanrnt wrrr 1.dr•Ih'.I wuh 1)NI', yrc6hny Ihaar4-rnt cnayuFalt•s Ihat cauv tla• frka4' nl 1'111 4 f.,1.Nnn hum Jnh I1N1' lyl: ptnra•J klt1. 2H 1 tclls. Thc hirNhny u/ lhrsr antrFrn. a1 h•1 rr, rlM,a t.NrM.lrar% was uh4•rvrJ by Ilmaescrncr micnr4 r,l+y anJ yuaauhrJ hy Il..w % yfi.uN•tuy Irk uhJtNat wnh I µK/ml l)NI',.-H ph)n'urrythrm stumdatcs mJUnrnm .I.'t9JINJ:,1aN1I,.N,II)'I'. ~•Illn•/IPJCrII• I/rNlrrtlK4'l'.aNI11Na1~,J1>fa.,~/111•MCIyn'.I/II)' uwdrl olcs a.l I)NI', 11 Lh1..,-tythnn arr IvNtml lu•t tcll at ryuddarum I/N' ratr JrNt t' ucnt .d ann1Y'n hlnlllnl! JINI Ut antll'rn \IInnllJtl•,I nkYhal,a n'It'Jw lllt'h'J4' tit hJr..l If) .N II1t' I INN r1111ah.,a.nNl 1)NI' la.MCrn r.Ma,.d IIK tlwrr4'cnt t.mlul!atrs is rrdtN r.l \.•4 trlnNr .t.q.% nmrNd,.,h•ly wIN•n ncc rNmlhNwc4rnl naawrval.•n1 atMr4cn. I)NI' ly 4tN•. rs :NLkJ t.. ,1.'t:rJnuLamF ccll su.lx n.N,ns UNI' lysmr al4„rrsplJacs wtI N r 1rN,IN1•Illt/l'i'ItWI11'/I.NI.tCJllllrnl~'thrtlf\Innnatr% Jltl'rnalltlvJlt9MintIF`Cn Il.,wcvcr. IlN• Ahrhty ..t 1 tNl' Ivv.N• w d.yd:w r.ar1:N c h.rrnJ UNI',. It phyl rr•ryllhnn Inau lyl'. Il'„'INM l IN111,lrars ,k•% rcJ4•. IN..Ktrsw.•ly wnh Inar I rcJtuw•nt with Jthy,k.. yt., tlrnl.nat H JrNI a'vcr.d JnJh.):. 111.11 INrvrut Jnlt/:rn s/nnulJlrJ 1' :wtUn Js.cnddy rn 11.11k t'% 4't'fl'1/.N1 .11NI,1rI./y. lla• Irrn•Mh.Nr .d Jnnycn 14, Ms I/N1' lysmr rrsislJU1 hN,n 1'vt.a tr.da.w ta•.MON'ut al... p•nnus dN• l.w/• rangc nv,vruw•n/ n1 Jnnycu rn1., surl.,, r ..q,. I1J4•J 1NI IIN'4' Ih.11 4'tfl•INMI I\ Irnl'Frrc.l by lh. :NI ,.1 a•, cIN.N t n...hnl,,ny .N by .1 IINMt IIVr.1 f . %t n.Vl .I.Mr ul IIN• t n,..Im1.rJ ,mUyrn 1/' tlv.'IN.N I,NOIdr. Wr I,r/hr.4' Inr1IN'1 III./1 ./IInF1'n .nnnd•MrJ 1' a.bn Jsrruhly l.N, I/IlNMr% 11t IIN• 1rJA%rn.N1 UI Jn11Krn Ipl .r. r1a.N ..Nnldc.cs I.. a I)NI' Iy.nN• rra.oot LNn, 111.00 J+n•s rNM uq'yrr s.ltrlNNr I w.. Ir,..d.lc- nN•.hJm4,.. I.r Ihr u.uf.no,n It, 1)NI' Iy4tN• rr.r.IJrNr .ur J.4a.4d %l•J}•r.wc. I (' . IlrJnon. (: (i , MJrlm, ) (' . I)Jvrs, 11 1) . .aNl O!nv'r. I Af (-yMmN•try /l 297 2'tt, I'1M7 (hIN•t .ulMNat AnN•rNJn ('Jntrr t/N'N'ly. NJIN,/1JI In%fltl/ll'% ol Ilrallh aml lI S 1>, p.uu,N ru ..I 1'rN-rFy I nNn dN• Ik•pJftna'rM .,1 1'Jtholoyy. (lmvl-rsity 4.1 New McRi.u, kh.Nd n( MrJ,cn r. AIINNIaI'f11/N'. :nNI I 1147 Slrrrwrs Ihvr.N,n, 1.,.. AlanNrs N:In,mal LatNaal.Ky, I us AI•mN,s. NM, ,ual l)rhJrtnN•rnl al 1'alla,h,l y, t LatraNrOr 11Mt hlvN lk MrJN J1 ('rnt.•r, IlarNwrr, Nil A k1)1 1•. 1 t tk 111C1 AM1NI 11'1'f 11 111 ?) KI'('fPlllll IIININN(: IN I'K( /1111(' 111)N ( II I I II•. I.YMI'll( IKINI . S( lUIH1 I: IMMI/NI•. kl -'-11't)Ntil. SI1I'rkl•s.I/K IsIK%t \.daMr unnm,n• n••I.•o4• .uMNrs4N 1SIKS1 Is an Inu,alm,.a(qNl•sslvc (a.Nrln IN.rheld l.v 11.1011.411 •m.I tnO11tIN' •111,IN.'~NN .r11% allrvalrJ by a v.aN•ly ul at7rnls Ill•. .n...' Iu.leuN$N• 1,... 1. ,n @. IwNtr.I N..n I/../N' 'UIlNr"•N l-PII%. IIN' IwnNhll/ty 111.11 11 a14t inJar-eJ SIRS Iu.Nlucli.m was invesliRala•J Iluman IynydwN: ytcs IrcatcJ wMh N) ' M fitslJrmnc hK kss Ih:m I hr reka.rJ a sup,rr.arve .nha•Jncc irMO a•ulturr snlN•t- nalants that was physitally. IunctirMaHy and anliRrnN.dly stmJn lo human SIRS ('rmctalmr anJ randiJrnc, slructurally Jidinct hislarmnr lypc 11111 2) nvcpl,M antal;o- ms1., (+revrntrJ lu.tanune-intlw-cd SIKS pnalaclirm. In lurthcr erlrrrrmrM., w~res- .i,at u/ htmran pdycHmal (KM 1'1(' ayarnats by (im A aml intcrlraM,s, .uhstarwrs t1u1 allw:MC Ihc SIRS p:Mhway, was inhibita•J by 11 2 rcrrpUK anlal;tarisl.. Acliva/hwt ot IyrnlAwK ylrs tn Ia.wluce SIRS by ( iMt A/w mlcrlrnms was bMn•YrJ by cimehJnK ..r ramlalmr '1 hrsr J:Ma tknaalaratc thM luralucti.at .d 3IkS is iralurcJ by hi.tamnw•, anJ rarsr tlr (rrssJ,drt y that I I: recqNnr hiraling nuy play a nrk in the SIR S palhwJy Srhn.q.r.t ll W. AarK. T M. anJ Kr,hy, R K. l1M• 1.Nnn:J ol hnmumd..ry 114(i)./INS-11Y/1, Aurus1 15, 1'1RT. (Ahrr .nptwwl N•MNarJl ('arwcr In.hlutr. I-nan thl• 1 kpJrtur•nt u/ 1'JIM,L.Ry, )rwish lhspilal tul SI I AN/I\, arNl I)r11Jn1nMnl%U1 I'rlhUlr/l'\ arNl I'Jlh„I..gy, Walh/nghal (/nlvCr%My Sth1arl „I MCJN'nK• tit I_..wrs I LYMI'll()MA M111N:1 C It1k H('1:1.1. A('iIVn111)N ANIy lY)t.l•kAN(T ' Ill ('LL1. ('Y('1.1: I)1'.1'1'NI)IiN('li Ii)1( Nf(iAl IVI: %1(iNA1.1.INGU1' WI'.III 211 11 I•YM1M1()MA ('I:LI.S IIY ANTI-µ 11 has IKt'tNtK incrca.inKly a~weM Iha/ H lyntltlwanas (auviJr cl.ara/ nark•L /.w antiKrn srot•cfic IynrydaM'ylrs and hK thc analysis u/1aMh prsilive anJ nr/:anvc 4gna1 hnl; m 11('cll.. In:NIJMiun, aMl-Ir, rCal,'CMs hare IK'Cn uNYI hr n111nN' an1l~Cnlh,Irl.,~rrl in thl•n inlrrat liwar wMh It ccll recrphK, al a p,lycMMtal kvel Wr have hcrn slwlywl: Ihc rllrch t.1 atni IK on a KnaM rrl umyue It rell Iymplamlas av oNNk'Is La cMIN•r hdrn,krna rn tmrnumTrnic signalling. (Ira'.uch hne, W111 211, has been aarwn to hr rr:MlJy mbrhitrJ in i1s Rrnwth by anli 1p reaKrnts We craNirnKtil thr .ensitrvMy .d Ihts tmr 1u yruwth tnhdnlear hy anli •µ anJ anti M rraprMs, aral drtr rnutK J ns linrlw s, yK•a'ilra'ity, anJ site ul lhr hMr'k in 1he cell cyck N the ( i,/S aMrrlace, la thr. rrpat, we have rnrMhrJ W I•.111 211 lynq,laana a•ellk a1 variuu. INanlv m(:,1n S and analyicJ Un c11rcN..1 anh µ un pn.prrs.Na+lhnwph S phasr (hu Jala suyKca 1hJt crMrc:J rvcnls lrcur rarly m( i, aral arc uniyurly xespive lo owalulatinn by antu µ'I la•v tnNhrs IN,w will alh,w, .rn.Mrvr nwJrcular ay,ltnrarhe% towarrh :ur unJrraaralrng ul H l rll .rynJl Irng, as well as na•IM.Is lu rrRulatr lynp,laana Krnwth l•.r a. S..Nr, I) W., LrvnJt, 1) . 1'cnncll, C. A., anJ KenK, 1' l.,urnal ul lixprnnwntal McJicinc IM.ISf+ IM, July 1486. ()Ihcr suplNat' 1I.N 1'uhlir 11ta11b Servire anJ the Irukemia titti'n•ty ul AnN•raa hrom Ihe ImnarnnhtFy and 1:> perimeMal'IlrctareWKS llnM., (lmver.ity ,rf R,n ccstrt ('arwa ('enter, k.Nhr.ar, NY. ISS Itd 65100 7863
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Ik.•lM'/N) u1F .NI 1hc .INacc •11 AI' alx//Ir lypc 111 11K INlddcf:Nivc a/Nlulu% p/uv/Jc.l /01 ccll. 11M•v J./la hevc hlrn JLI:u..eJ in thc cunlcnl ul 'f-cell :rilv:unx/ .S.qwwl. M l. . Ilurt, Y. 1.. ('llcrian, S., Kaplan. A. M., aal Uianl:ult.icln• T ('cllulaf lnununlllu):y 141% 171•11lh, 1997. ( )Ilnr wlpalrl 7uh:lcru a11J I IcaUh Rcx •rrch In.111u1c. I r/Nn Ihl• 1 k•paftnlcnt o1 McJN'aI MicnlhilJugy a1N11nunulNdugy, Univcl.ny Id Kcn (lNl.y MI'JN'.1I ('CnN'f• I l'AIIII!1/N1, :nNI Illr UIIn1a1Nd.Iky Kc.car.h Iinl], Slt•IFlIU (llnir. 1'ICc Uulvcf.uy ul Wc.t Ik•/lio, Wc.l (a•nu:my. V 1 I. fi pidemiology til 1.1 RI'W)K'11i1) AL(•t)IIUt. I/Sl:: A I l)Nt7lll/1)INAL S"fIIUY 1)I' I:!N)•1 AI)111.Iti lhr Inlcrnal valNhly uf 11x qucvlhNlv xl ak.dN/1 u.e in 11n ylK.lu.nn:ufc. w./v aaa.vC.l by l Jlt'ul.in/l~,' 111C INt11an1Na111//nt lala./cnt feplft. Nl yLLJnNI y JntllfcylMn. y u/ .k.JNd utc ON•..c hyufc. welc /0 1'M I.a Iwt'r 11 6'lf•, wun 11 M'f•. ynul. I I'A .nJ I%x 159 65100 7865
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ul 1'/MI lur hrrr /1 1'i., wIM• 11 R'f- aMl plrlt.ll 77 Tn a..e.% thr thange% ol Jlr.•hnI 04• LNn ru.up% wrre I.NnN•d 1111rr1.NJlcr. /21 .Nla4..n:d .hudt•r., 111 nNNkralr Ihl/ll.l'h JMl l.1/ IKJVy JrlnLcr. 1 hr tNl IwNnl\ hM 1,'rlMl(1% wl're I, 41MI a1NI'NM/ gr Iln% ..I a1l..In.I p't nNNdh I IN• .Llhddy ld JIu.INd ctm.uoqwu.n by .ea ic dl.played in Ihr -t Jhk•. 1 au.l 2 Wl/h Iu11..w t/rnI %1a yl•.Ir% it wa\ I.NIINI IhYt Illrfe were MN any rr/narkJhh'th:InF!r\ in I1N' INalr1//t11NN..I ddlrh•nt Kf.Nlh% tll JrlnklnK 111e1r Jl.lnhlm.Nl werr /IrJrly 4/nliJf /n INdh apN .U..nn:ufr. I IN' 'tJhlllly ul ah'111M/1 CINI~nn11MNN1 wJ% :1\4•\\t'II Ily a INn1N/1 uqt dlr IN.yNNtum ..I IN..I..IINI~ \Iay/nl,• m the \a111r l'IM\111111N11M1 t-Jtl'r1Ny tlUfllll• IIK hJl..w pla Rc4r11% wrlr Ihat 6S');• a.1 rluk•. SlayrJ in thrir clln.u111ptNNly all'/`IN y M 111a1' .hFhllyuwwrlhJnll'.i nN.vrJlaahlghrrcalegtwyatlJl7'1i•nNIvrJlualnwr/cJlry.Ny \umlJfly. 7M'>:. ..I IrnlJle, frnlalnrd in Ihe vme caleKnry whdr aplNUalnlJtrly '/'xX uN.vrd 1u a hll•IN•r a aleg.Ny and 12'll• nN.veJ lu a luwer talt•I:.ny AIIMNI/,' II1l• 1(YLNJh'r%, a thJ11/,'e 111 %tart tlflnflml,' ak'IiIN/I t'Jn IN' uh.rrvl•J urN• IhuJ /d ulJk' /rrl.walrr..n 1'I7S heKJn u.InR variJhk% anrwnt% n) aka•INd Junnp tIN• hdl.aw Np Nr•nly IIN' .JnN• nlm/l.rr /d /MhvNluJl% u4nR al. nlN.l al Starr 1 J/d MM .,tuJ, .Ja.dN.l JI XIJpr 11 At J t.M4'ynrMr Ihr "nrn/arr n/ Illak IrrlMJlrr% rcnl•mNd M.Nly IIN• .•u1N•,'1 1'a in 1o1S aMt 111 7'>; in 1991 Renurf<ahlr t hangr. arr JL.. LNUNl culNaqr IN•:wy m.da• Jr/nkrr., hall u/ Ihrln cu1 tklwn Iheu a1t•aANd tun.NlnlNlol by nl.wlng ta.lha• luwrr t cNrF.Nlrv JonnK IIN• hdl..w up Ituwevrr, %nt/u11a1N•..u%ly alnN..t IIN• ..ulw• mml ilN•t .,1 m.Ja . Inw.veJ 1. 1 Iln /NVV •v Jr ink rnr p.Nlp Imm the k awrr cnn+ulnp 111N1 l,lla'IYMN'• A/IMN111 Itll' Ia'nl.lk'1 Ihr .anN• hrlNl% t Jn 1x• .,h.rrveJ, nvcr !IYfiM ul lrra.talrr. In 1'17S wrn• alnn1/ng :da.dNrt in 1'1M/ aMl .wa-f pl'( ol Irrt.qalen tu 1')MI wrte Jrult,ulr altadNd rn 1'/15 IIw (Nn1.Nnnn u/ Ire1.H.J..ru IMrca4•J Jurlng t11r lulk.w up Irunl 2( 1'1 tu :11 K'x AIINNI/• L'lll•IIa' IMJvy Jnul,rr., cuN/Fhly RIYI frJwtr111N•/r JIInk111F by 1'/lll 1)1 tlNr4• wh., wan• IN•.Ivy Jnnl.er. ul I'!n1 uvt't 11Yt. wl•tr MM ul lhr.alry..ry nl 1'11 S I)r.pdr thr4' t tl.anfc. Ir•twrrn Jdlrrrnl l.mwmlNlnn )[h/111N a/MN11,' IN.Ih K xl'%, Ihrrr wrre t.nly IIIIINN lh.wKr• un ttN• d1.IrdNmmrs Id Jh..hnf l'.Nhu111111NM1 IN'Iwt•rn SIJyr. 1 alN) 11 R.NUamw, K• Ru4•. R 1, Ka/uNr, 1• Krr.lrmw.r, M, langmvalni.t, 11 , and S•uuJ. S AludNd /4 AltnlNrlban Sulhd 16110 62 1. 19117. (Mhrr .uppprt I Imll•h f.wMlalaul nf AkldNll SluJiec and U S. Na1NN+al In.hlutr tNl Alc.dNd Ahu.r and AkadN.h.m. Fawn the Ik•partn/ent 401 Nlblir Ileallh, I lnlvrraty uf Ilrlcmki,llrl.inl.i,FinlanJ, aMl I/Nlulu Ilnivrra/]y• 1(LN.nlinxhm St K'IAI ANI1(71.N1 11(' INI I 111.N('1 S l)N IIRINKIN(: 1'A'1'f1:RNX l ll• AI)t11 1' Mt N A.% I I.II/Y 111• Sh(II PINNISII I WIN 11R/)IIII:RS I lleran hlt al nwhlplr reFrca.iaNl an.dy.ra nl yllrallnnnairr Jau rrpNtrJ by male Iwm. rn t1N• 1.nm.h I wIn 1 1aNM were u4'II 1/1 Cv:1I11aIe KeM'lll' a1N1 MK IaI IIIIINrM'rNNI u~~• ,.n.l Jla..r nt .d, I IN• .n...1..r.1~ n J/INLIn/: I.Jlll•/n\ I/I (wln IN.Mher\ /\ 11'Ia/ral /.. d,. I~..1....... ..1 ./... .....1 .n/...w...u. ..wl nr.ra.i~/•.da .. Iw.nm a/e rn nNNr h.,p. .a ... ..~ . . H... .r. . .1.~. . ....d..t.l, r. c......•a. .INw 1/..N IIN- (vu.nr. 4.1 611 /m1-rJt 1nNl ul luft•nrll Jl lwlnm t'anlNlt :Nt-aNNN l.w IIN•II grralri .r(tN1.1/~Ily 111411111k /111' pJ1ta•11t. Wl' I.NN ILL1k' III:11 Fl'nrlll' VJfIJIN"r 4rt11I11J111Iy C.Nllrlhula'% I~.IN.~NILIINNI h:n1.IMr In (tN• IIr11M•rlty. tlnJlttlly, a1Nl lk•n.lty ul 4N'lal Jrlnl,lNr KaprNa, ), AUa~1'Ilap.- AI . L:IIIgmvalnNl, 11 R.NnalNw, K, S•una. S, aM/ Ru.r• R 1 Ah.dNd A Ah..h.dl.nl Suppi 1 111 177, P/M7 O11 :•r .u1qNN1 I In1u.h F.N/Mfali.Nl Lw A1riAN.1 SIMhr., l..hn li. 1-ag:lrty Inlrrn:w.N1•d ('a•nlrl u/ dN• 11 S , N:/u.NIJl In.Unur% o/ I IrJlth, •uNl IlN• 1/ S Na(/unJl Inanulr on AItnINd A/N14• JINI Alc.dwdl4n I/. Nn 11N• I h•parulN•nl nl I'uhlN I h•alth, I Inrvrr.ny.d I lrl.mki, I Ir1.InA 1, I-mi:md. .uNl 1)a•p.nlnNO1..1 1'.y.h..1..)•y. hwh•Ina Ilnlvrr.ny, 11kN.nnnFlun (K'('lIRR1 N('L OI RIII:IIMA'1U11) AR"111RI11S IN A NA'11ONWIUf S1:R11•S 1)1 7WINS I IN• nJlN.nwNk• I inni.h Twin ('.IFNNI wa% linked wnh the Sit faa•.. In.urJMr Rrpl.lrr .NI Ihr hJ4% nl thr unitple Nk'1111h1'a1NM1 nu1/11Kt a%%l/,•M'II hi r:ah Ptlrol.h ulvrn 'I Ik .Iwly vrlr. nw1.i.1rJ u/ d117 nwnNliy~,tMa• 1 MY.1 aMl'1I62 JvyF.da 11)LI .anw Y NYI Iwl/l 11:11f% hMNn IaeI1Mr I'/5R a1NI ahvr In 1975 AltnlytIN9, 2(.1 auhK•rl. In Ihr 4:rN•% h:NI IIM' 111!h11t1 tell•Ivr Irrt' InellNalNMl IIK fllrumatnNl ar(hr1t/V IRA) utMk'f 11N• SICi,ntr. In.ur,lntr Aa•1 IhaN ruvrt. Ihr rnlirr 1•/nni.h ppyN11J1Nm fhe p•urw14• t.NkawJJMr IN•ICrrual..e IlN RA wa.12. \ in MZ Iwm% wNl I S in 1)/ Iwul. '1 he agr :uNl va adlu.IrJ rJIN/ ul nh.rrvrJ prt rapeclrJ nurnh.n 4111 1M'twJJM p:ur.lrclJ/lvr rl.l.l wa. R(/ lur M% pair% a.N1 1/ hw 1)% poir. 'Illr.e /IYurr% arr k.wrr Ihan Ih14• IMt•vNNNIy 1t'(NK(l•aI tM IwIM hu1 1Y1111//Nlh/e wdh tr.u11. InMU /alndy .luahr. aNl dlr 1•'rM•IN' t'IN11111KIr nl ..1 RA. AINI, K., K.aRr/n•n.., At . Twwninrn• 1, anJ KaprN/, 1 )twrnal td Rlleumalobgy 1)15/ MMJ 402• 1'111b. (hhrr .upplw1 Siyritl luvhu.l-.wntl:NitN1 uf Finland. from Ihe NataNlal Ih/hhr Ikalth InUitu/r, Ilrl.inki, UinlaMl, arNl IkpannN•nt ul Ibhllc liralth tiaN•nrr. Ilnivrf.i(y td Ilrl.mki. 1 SNl)RIN(i AS A RItiK I A(`fOR 1OR 11('IIAI:MI(' Ill'ARI Ut11•AtiF ANI) S'1 R1)K1: IN MI:N 1hM al4N.•Ia11.N1 u/ .Mwing with i4h:N•mK• hrart Jivare aMl .uule wa../uJIrJ pnr.pt r/rvrly in 11MN nw n alti•J 11/ h'/ '1 hr okn wrrr a.krJ, In a yM .u.Ntna/rr 4•nl tu Ihrm, wIN•llKr dN•y .MNrJ IcrhlulJlly, Ifry1N•mly, .wca4amJlly, tw nrvrr tec..rJ. :nNl ak :uh a rrldN a1r. were t hl•aked l.u 1he nritl Ihrre yrar. /n r.lJhl..h I..w nlJny 1.l I/N.' nKn J.'vt't..(la•J 14h,N'1,/1l 11N:Ir1/l14'a4'.N a/./1it' IlN' 11111111N•/\ w.•rl• I•t'/ /'•• 1 161
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It+2 or•n rn(r+rtcJ a Iu.Nwy ..1 :uq'ina I+t't Iul1. ++r IItv+4.t111/:11 Illl.l/t IN+It I tN IIMIt11111' Il'I.IIIVe rl\l. 1/1 14h:q'/11/a IN',Irt t1/4'.I4' IY'Iw+'t'It 11.0110141.11111101 /ICqIN•nt 4NNt'1\ JtMI nt+n %nlMm wll% ( N/ INS1. /+a nN•n w1dNNlt I+rc vNNt. /a h:N•nut IN•.Nt d/va.c 2 7? Ip- 111/S1 \m•u1n/• 4•cnl. w(+r .11r+N n1/.11 tk•tcnnar•ml 111914 at 14 h.N•tnti IN',Ir/ tI14'.11 •.I/NI .1r++Ar K..+1.Ntun A1 K,q+nu. I, la•Ltlrvl. I. I'.1rt+lN•n, M. 11.•tltI.A.t. K..NNI \.uNt \ 111111,11 MrJ.+,11 hwln.d ?'rJ IA 1'1• l.Ntu.Ny 1, 1'/N7 ( hlh•1 .ulyral I'.tavu Nurtn/ 1 +NIrNL11N+n 1 11N11 tIN• I A'/+.1/1//N'ill +/1 I'uh1N Ilc.dlh_ 14nlvcrvly ul I Irl.lnl.1. Ilrl4nll• 1+nLirNl 1 Ku.4r rn'rnt. At . K.qxlo, 7.,1'Jrtincn• M. • Ianginvainut,ll . SJrna, S• Rita. II , J/NI IIc/1,1/1J. K P.yt IuJlrt.l I t-noi. J\apidclncnlum 115.1?O, 14N6 IY+NII Ilta' I)t'1+;Ill/lN'tU ul 1'11hhr 1lcaIlh SCN'M'c, llnlvl'raly ul 11rl.mh/, Ilrl.ln6/• I 1111:IIN1 1t1 Sl(;N ANI) tAM/9 ING(•(/NSII)1'KAI7t1NS, KIiSl4)NSIi KAIfS, ANI) RI 1'KI SI'NIA IIVI NI:SS IN A I INNISII'1 WIN 1•AMILY SIUI)Y K/ll.h/lh ttunlN+y+l lll twin p:/h•nIY. thei/ .I+It114•. 7MI Chlklrt•n. 1+1-/a•r :1 H+IN/J uNl 1h•.dd\• %.t1111+IN11• tk•VI,'/1 IIN Il•%a'A/aIt 1/11Y'IN•IN' CIINk'IIINII/t4'y I•J/nQlc. ul twutm tk 41!N., a llt uNHCnl 4ulw Id 11t. .JU11d1111; 111t1h/l•/11\ IIIJI ArNC WIN /t /1Nk.•Ita•/Nk•Ilt II.NA 4'I• art• atnnl.nkd. tuNl IIM•v ak•.ign. pruvak unNluc evalualaan% ul nt,dcrn:.l /nlhlcnac., :1.4Ntd11Yt• /It.lU/lg JINI X II/IltO/!e. Ilnlttr1U11a1a'Iy• a•/IIININ':Il %I1NIIl•% alI IJIIIIIN'% ++I Iw111 p:ncul% h:lvc hlt•n hmllctl hy rclalivcly .null .antptr% anNl Ivy .a•II vk•aNtm M:IV. Inllln4a ut J•ac/ta/nurcnl ol IamdN'% I/tNn v/duoteaY twin rcocINnc• A 1•Iryc alNl rclxcvnlauvc rulN+rt nl nNllNt/yrtMN' a1MI Jvyptqn• Iwnt p,ucnl.• a1r:Iw111ttNt/ a IMMNII:NNN1 IIJNYI twin rCl,'I%Ify• I+fUY11/C% lhe /MMI/IIJI %AIn(1I/11l: 11.1UN' /ar twin lanuly rc.ca/ch. •fhtI paper nvicw> l1k %;mtpling con.Nk•f:uN+n% nak•llyln4 11w inu1J11:1Ullly %IINIy hdrC1l tN111N I'111f11-11 1 wln ('u1N111 :11N1 a•vJI11Jh'% (M' fa'1Nl•Ne11/allvr rta•.% td dk .alnpk•J Iwtnc. Spnu.c% antl a11oN t-hlklfco I/uver IN yc;lr.l ul 2 lb pJlr% ul 1w1u.• a1NNu equally Jivwk•al by KcrNk•f ;aul iyrualy• were cvalladcd by a Iwn6d arN•.1Nlnn:ure 111411101411121 reyNllt.c rJIC. ctcwyk•al Rt+'.(. atxd rn 464 /11 dtc 472 nul lcs I:IIIt1IN% ('/}I 1'{•), A1 Itihl tMle nll'nahcf OI /IIe Iwln*\ liN11/Iy C1N11111CIa'II 1IIl' qIN•.NtNt- lu/re 11w• .://npk•tl Iwin.• aekcled llw Iccurwbly lu nuttnliic .lau.tN'al puwcl al dk• uM;nnavl dala• wa•rr Mlr.nlly reprc.cnlalivc /d nnn .clrclral Iwln% dlJwn Inml Ihe (*111NK1. 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I9 B J (p J AD 1 t/WAKI) 1 1 1 I I /'n 1/ , 1) Cr 1•/.•1....•/ •.1 1 6• n•..nv Iln.rrr.dY u/ JAY A 1.1•.VY. M It A.v.lale /'Ndc.\.u nI MeJn /nr Kc vJ..h l4.\/aulr. 1',LNCr Ka•..'.n.h 61.r/ luh•, I/Nrverv/y .,1 / ahl.xm.. \• Ix.•1 ..I Ma'JN InC, Swn I/Jn. IN 1. 1'A1/1 11 11'WIC. M 11 G'nNN (.•.1WCr in IILNIpJIh•J..*y. K..y•J Ib /orr.nlualc MrJNa) SaMwJ• 11•unu./ \.n.111 I L..IxIJI. 1.NNMNI, I nl'IJ/NI AVI kIl l A 1 It 1111W, M 1) I hJnnun.lA•~./nllt•d..l l'.I/M.Lq'y. Y.Jr Iln/rehny S.IN..I.d Mr•h.NN'- NcNIIJ v.•n (') iKVIN) (IINIK,1'nll ul IINw 1u•Inl.lty. I hll.rtalv •d RLnrN'.. IJ. SI 1'JUl VAt I K11 K I INIK:KI'N. 1'11 I) I.INN Ill•4•Ir\In•1 N.11n.n.J l.uacr In.lr 1N1r. I/a•IIN'.JJ. Mt) 1 %11 N// I INI1\I 11/, M 1) . i'/1 I/ SI h..rph-. lh..pllal krvarlh 1 JMx.I NNy, SI ILul. MN K11111 K 1 11 I INNI 1/., Iht i) A\.a lalr Pruk~wN.d t 6cnu\try, lhIVCr ./Iy xl VCnluNlt. 1lurl/nplue. I AIIIAN I LI/1N1.11 I, 1'II 11 14x1f'.vN ../ NNwIN-nu.uy, IIn.NNI 111.1 v.Lt\uy W Ihwd nl Me.IN Inc. (1u.NN1 111 Klil Kl i. 111MIIAKI/• M 1) . M I' 11 Alhlulc. l'Jn.cr kl•v'JI. h LLutuN•. N. w I nrlJnJ IR•.N.wN•..Ilxyn•.I• n 1 1' 14 /N/:, 1'tl 11 nw.•r R.AewN ul 1'h.un/,N.clup)~ Xlah• I .Ity ui luwa /o11rp.• .J M.•JN nN IuwJ /uy I:I~XINA 1 1 tING1 NI•('K1 k A.\.w /Jle /'IxIC.vN ..1 I-1larnla Nh.Ry, Ilmre/\dy ul \.xllh Alahrrnu ( u/ RI, •IN In••. Mnl•.Ir luh ('1 AY111N/; 11N1C11, M 1) , 1•N 1) IIa.Nnr\ 1'lulc\\.N .d McJl.nn: alw/ 1'a IM.hp•v. lln/ver.Ny x1 S.w11N•rn('ahl.Nw/a 5aMv•I ul R1cJN uw. 1- Aurc/e. IM/NAI 1111 I I/lIK1A. M 11 A.\.n/•M. ('/.d..\.N nl MrJla/ne, t'.Nnell Ilnlra•LNy McJ1a.J ( SJh-Fe. Nrw Y.N•,. K/ 1NAI 11 11 1 1 U 11(:. 1'tl 1) /'lul.•...N a1N1 I1. ,NI . I R'palNlw'nl ul MN n. haJ•p•Y a1N1 6u/mm~dxF . 1.SU MrJl.al 1.'n/.1. Nr. INh•an.• I X K I NNI I/1 MI K K 11.1 1\ NI'l l. M 1) , 4 1/,11 1) 1'ILIC\MN I 11N'IIN/• nl I'JIINJx y YINI l'I1..n.r11•N McJ/•a1 lldlrKc .•~ S.Nwlh 1'aa1mJ. ( h.u/r.t.m 1 /tKIK I A MA/'lll k• /'/11) A..LIa/N IY.dc.vx ..I Iplanluaculua) Ilnnn.lry. Ihuvc/aly ul i'a1d.Nma, ~aw 1 raN.lv.. IK/WAki/X MAKI K. M O A...w lah• 1'a.la•\..x ./1 Neutuh/pr. M.wnl \Inal %. h•wd nl McJn , Na•w Y.wk INI S MANI)I.. Ihl 11 A\\/\Iaw/ 1'r/de\4N .A I/N./n•nN\Ny, ('n hu1dN l l/mvelvly ( 'NIkKe /d 1'hya. taw\ 1i Su1pe.N1\. Ncw Y.NL NIIIN 11 MAN111N 1), 1N 1) M I) I'I.JC\MN a1NI I hn'aNN, IK-pYf/NNYM N/ Pi IM4..Ky anJ /Nal 1)/aklN/u., NCw h•tvcy ('..IR•ye .d McdN /nc atlll I ltnll.lry. ),.ay ('ny 1)AV11)1: MANN. 1'/11) A.wwlalc 1'udc..IN ul /'hanlua'1/1..Fy, 'I.mpk Itnlvcr.ay S.INIIJ nl 1'hartwaly• 1p1da1h•Ipllla I kANK AK 1111/K MANNIN(i, M 1) A.\/\tanl IYolcvvN /A IN..kuw. anJ (iynct..M1ry• W.Nllcn \ I11..~w171• IJ.. Anr.•h•v ('INUNyrliwlva•raty rd .~.wllnrn ('aht•Nnw M.•Jna1 l'cnlcl. I..w AnRckv 11)IIN 1' MANI15. M 11 In.trwlw 1// VIr.J•.ry +uNl /Ia11c/N.h.~y, :Aa•JNaI l'..IIcRc .I tiul/lh ('Jr.J/wa. 1'hn k\la+. KI('11AR1/ A MAKKIIAM. M 1/ A..1.1aM 1'tnle.vlw.d McJN Ine alNLd M/ .y.d/N.11.Ry and IIIITYnIJx y, Ihc /cwl.h Iluyxtd u1 SI 1.wl., SI C..wlv. Mt1 197 ('IIkIX1/M'l11 K M MAKl IN. M 11 A..h1aM I'ru/ewN IA MrJn/na JIN11). IaYNn, Ihal\NNI .J III/IYINxI\ Ihv'JV•,_ h•Nlw 11.111 ('.Jh•p.• ..1 M..Iwlnr, 1.IV-y l lly. NJ k kllSSl'1.1 MAk1/N. M 1) 1'L.IcwN .4 R1rJN I/n•. an.1 MN n•hN•Ix('v a1N11uuuu/NJ..Ky. IlayhN t'o11cFc nl M. J/ •IIw•. Ihw\Nxl. KL-GINAI l)G MAS(KV. M i) . 1'u 1) I'Ixil•\VN a/Ni l'IIaNNUn. I1\'I.:n111N'lll .•1 1'a1/NJ1.Ky, Ihulvet.lly ul I llah ('ull. l•r •d McdN I/w•, %.JI I.aRc ('Ny MAMIN kUS1 Akl'1I INC1111111. W.+.cdcr. MA IK1NA11) 1 MA5tiAk/1• M 1) A\Mn 1•we 1'/nIl•\MN ..1 MrJn /nc •/~.•• xk•a Wa\h/nKl.ln I/Nlva•/.11~y, \.INwJ ..1 MrJv a1M•, Wa\INNF•Nq, I) \ l'l1A1t1.1'S Me AK /lll/K. 1'll 1) (INlvc/.ay I/callh R.•rv/.a•.. /I:uvarJ lhnvrtaly, 1'aN/hlnlpa•• MA ('l1AKI J'.S MI l'AN IS, /ht 1) A.vr ta/e 1't.Je...N ul %ud.. Nxrdl l'aln l/lla Slale l'ulh•pe ~aMNJ ..1 A/•INUItNIr, kakoKh /i/:KA1/) li MI('LI:AKN, 1'/t I1 I)I/lyhN, IN\I/IwIC I.N I/ChavnNJl / n•IK) IC\, I1C11iN111KM .u/ 1'\y.INlluyr Ibnvcr .Ny Id 1'.d.NaJ.. kluwJ .J 1'h:u/luay. 111whkt. A/•AN (' Me 1.A1K:111 IN. /ht 1) I+taYWC/ In IINp'IN•NN\tly anJ IlNplhy.u., 1lnlver.sly, /d I'r•nnvylvana X.INNJ •J M.JN tta. 1'lldalklpMa 111:NKY (' M/t:111•, IN . M 1) ItA.Nnr /k.J. IAparlnwnl ../ 1'a1h.J..py, •w/aawa 11a1c I Iwlvcl.Ny %'aINw11/N MrJ N'Iwc. Ne.(hkan. IIPNKY 1) M/ IN1'11511, M 1) /4nk.vN.J MrJa'Nlc anll 1)/rc./.N, ('J/ Juwavcu/ar I aMN.NNy, Iblc Ilmv.'nny McJN al l'cnlet, I/urha.u, N/' II/KIM• A M.IVI;K, M 1) A..1/. INt /hale.vN.d I'a1h•.h.ry, MeJI. al ('.JkFe.A tilwlh Catuhna. (-halc\h.e 111WAKI) MI KIiG, M 1) 11..IevvN arN) A.Ilnlt l'harlnan. Ih•pa/l Irw•/w .11 V./lu.h~~.•~, McJnvl /'ollaK.• ..1 %.NNh ('NNhna, l 11Nh'\r.M
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GF(/R(L/i li M/1(1RM 1) , 19t 11 Ihrtch., Rn.weil 1'ark Mcnwwral hntr lulr, 11ur1a1..• NY KI NNI:TtI M M(1CER, M 1) A-r.lanl Ptolc%4w.d Mcdtcinc, tiawKc In..n UmrNaty McJna/ SaM.d, Wa.h .url.m. 1 K' 111/K11 Y 11F . Ml)II I.Y, M 11 IS..It•.4w ul Mtdwlnt aoJ 1>na•at.H. I ardw. Kr.p.uhwy I .1r.w•n.uv. Ihuvrr ..Ir ..1 \uulha'rn 1aldwm.r \a h•.d ul h/. J .. .na . I .•. Anra tr. 111Mt/N1) ANIIIIINY MIIKI'l1Y M It . A.4..ale 1•r.dr.4n ul Hw..Ulnln. a.wl Mrd.. uK. l/w/ulm~ 11.uPlur. I lnr.rn.ly G h.«d .d MrJ...nr, 1latlu.wwc. Me 1 W111 1AM S MIINKAY, Sr 1) Sennn SIaII 4.Itnll%l• Ihc lat4.n I.aM, rahry, Hat IlarMw, ME IAY A NA111i1., M 1) 1'r../cww td McJamc. 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LAH(MtAT(KtY (/at RwIRt, TN I RAN/ (MSI'll. 1'n 1) 1'uAc.4w ui /~.armxula.Ry, IkaJ, Scar.n .m 11ww M•rnn al 1'hann.a nh.Fy • 1lnwer. • .Ity .A Mav, Marni, Wt%t (.rtmany 1• WII LIAM 1NtK, M I) A.4R•ulc 1•a.Ir.ww .A Pa/M.h.Ry Ilntvct- %ily n1 Mannnha, WmmltR• ManiM.ha• ('anaJa 171)NAI.1) M PA(li, WI 1) I•nJt\4w Id I'hy.nA.qey and IAret•pw, In. .Inwc Lw l'tilulx Rr.cra'h,lleirclaly u/ NctMa%ha. I .Ina.dn. KI'.NN1'1111•AN1UN, PII D Ihrcahu, I)tparlrnrM .d M..ktiular HMd• nKy, Ikahh Rt.carih, Inc . K.natll Part Ihvl.n.n, 1101131.1. NY. ALIII R 1' N PAI .MI:R, H1 () • A.aNad 1'rulc.4a tr/ 1•atMd..Rr, (lmvcr .Ny.J I nlrJn. 1 tdrJ.., I H1 K//11i MARIIi PANl311(/RN, M S A..rdaM h.wwl Tcafim.h.rel and Itchner• I7\'rautnrM nI 1'..wl \a tcn.Y and leclwwirty. Ilmw•r.Ny d ('ahl.wma, I)aa. KNIN W PARKI K, M 1) A.4.aalc PnAt.4w .4 1'a1h..Mrry, t/nivrt.ny .d 4w/lw•rn ('a1J..ma 'atwwA ta Mt•Jr'wtc. I u. Anptk. MARY \11 ANNX 1•AR\III I:Y, Itit 11 1:1)WARI) W W'.I.IKAN, M 1) (llaeman, 1)cparlmeM of Pharmxoh.Fy .nd I:yurimcelal Thtra~euln-., 11u.ww VnSrersNy Schm.l nl MeJN'rne, N...h.n R()R1S M PITI?KL/N, M 1). A..IS1aM PnJc.aw ul Mcdlcrnc. Scalww M Rheumahrh.fy-t'hma'allmmua.A.gr. Ilntvct.dy tA ( aldmnu ScMwd ul Mnh cinc, San 1'rancl.co. IM:NNtS R M:TERSI:N• Pn 1) 14..Ic%aw ut PAatnucoh.Ry. Ilnlvcr.ily ul (•trMwadn Sch.wrl tA Pharmaay. 11rwWcr CARI• W PII'.Kt7:, M 1) . Ptt 1) I41Ars4N, I)a•parlnw•M\ ..1 1'atlwJ..Ky and Mlp.i.n.h.gy-lmmum•h.gy, Wa.h.nrhw I/mvcr.ny S.'Mwd tJ M.Jtunc. Ihrcahr, t•a1MJ..~r aml latwwanny MrJ..rne, Ihe kwl.h 11'..InIr11A S1 l..wl., \t I•.wr., Mt ). MAI•('(11•M C. PIKI:, PII 1) 14u1e.ww n1(lwrunumly MrJiane aa/14 dta/tn•s, I /auvcnny.J \.wllw•tn l'althrnu Stlwn.l td Medianc• 1... Anltek. 1)TAKAR 1 1414 1•AK, M 11 , Pn 1) liaa'wivc IAtca.K. Ih.vct McJw:al Rc. .ear.h ('cnler, Inr., Ih.ver, IH•. M(AtKIS POI LARI), 1•a 1) /htcr/.w, L.IwnJ Lalwaa.wy. Ihnrcr.ny 411 NtMrc Uarnc•, N.Ntc Uamc• IN C. M P(NMI:RAT• Pa I) Ihrct irr nl Hi..M.Rn al Kc.cata lA, Pa.a.kna hwndaluwl LM McJla al Rc4•arth, 1'a.a dcna• C'A S H 1'RAI)IIAN, M 1) , 14/1) hu/csuu .4 ('halmav..InKy, 1lurarJ I/nl rct.Ny (•.AkRc• ../ MtJn rnc• W a.hmRhw. IK. 11 R PRATT TIK/MAS, M 1) 14../c\4u Iq Pa1MJ..Ky and Ikan. MrJwd ('dkRc td Gwth l'aulma, l Tark.wm 1•111K'1iS5 A~,INSIRIIMI{NI\ (Y/MW IRA 1NM/ 1lnwilyn, NY 11 KAt 1) A Mt1t'111 I I 1'tl 11 A....ul• /'.••/•..•w ••1 An...•rny W ).r \Ld• 1 t..•,• .,,1. \. 1....1 •.1 AI• •h• ur- 11 hv•••1 MI A.a.lan1/1.JtwM.AAn.aanr in(MnlelrK~ ll.lumMa I'nnvenllr ('nl anJ l:y~nc..d..ley4 kKe ..( I'hr.w tan. & 11wKc.wt.. New Ytrt HLNI)N'111 1/ 1'Alll 1. 1) V M A.4w lalc 11.Jr.4n nl 1•allw.h.Fy. Ru.h Rr.hyk'nan G 1 uke'. MeJw al l'rnler, / lu• tap.. MAkTIN S I'Rl)1/1-1., it 1/ S (lntl• 141wlmrwt n/ (hal Pa1Mdn~y• Nc.rrt ('Ny Ilnynlal. Ncrratt. N/ WII t.IAM A PIIYt/K. 1'u 1) Noyd PuJc.vr .d l'htnn.lry. (aw.4ana S/a1c (ImvcfsNy, Hal.wf K.wKc IKv 1xx
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M1l'11A1I S RAHCIIN• M 1) Ke..vlah C..ann.1, I alwwallwy al ('alh.J h.l•h N.nl.rul l'anarr In.tnlwr. HrIM~.Ja. RI)NAI I) 1 RA%MI/C\I N. I'll 1) A...w late AJluna t 1•r.•Ir.vw. Ik•ParlnwM% ul Ilm.mwlNy anJ I nvu..nnlrMal Ma11• Ilnc. Ilm.cr.wy .d ldd.wnlA lldkKc o( MeJp n.•, Irvule. ('A WAI II k R1 1NSl'11• M 1) A..+•a.alr 1•ndc...y .4 ( Lnk al Mrdn /ne. Nrw Yo11 1 Imvrr.rty %. M.J ol MrJw nw, anJ Nl'1/ kr.rat.lb Cr/vMr, (:.Jdwaltt Mrnrwul (In.Pt.J, Na•w 1.w1 I IMI)111Y I kl GAN. M 1/ Pr.Ar..ar .4 Mrdn.nr. 1)ncal.w. 1)IVl.n.e 1•1 ('A1,In.vaN tlLlr 14.ta.r.. 1'/J6 orr ul Mr11N/M' a/wI (A'M..Ir~ .4 Naw Irr.cy, Nrw Ir/.. y Ma Ja al \, IrrA, NcwarA WII I IAM 1114.11 \I)N M I) /'H.Ir.wa a/r1/-hauro.n, 1lrrahmrnl .4 M.JnaI IMN.•h•rv• M,.1.a.1 (•.•Ihrr .J V///'m.a, Kn lan/•.nal 1 YNNI M k111) M 1) W.dl•.n h I'r.dr..•. „1 Patfw•1••ry /In.A•J M.Ja al \a Iw.•1 1/.•.b•n 1 h.u.n..n 1 h' P.u/uw nl .d 1'wdnd.• ~ 1 h./Jla n. II••qn IIIINARI A RI IMANN, M 1) 1'u.lr.vq Id M.J/. nn, Ilahncn.ann MaJr a.11/'ad1YKc a1N1 11•..I..lal. IT/I.Wa If.h/A 111!1NRI-Ml11.1)1) Ix)NNI I1..1'u 1) I'nn..ryl kcvar. h A...•aalr. 11Ar varJ h1l'dNal %.M.J, InvC•I/ra1.M, ('eMr/ l.w 11h.r1 kc.caah, Hn.lam /tHIN E RI PINC•. M 1) A..r.(aM Ihrr.hw. Wchh Warlrl I.~nK In.INWr: A..rc ralc I'role.•Iw u~ Mcdl ./Ile, ltllIVC/•/1y .4 (lJ.wMh/ Ikahh S./ rmc% ('rnlcl, I k•nvr r R()HI RT RI?SNk'K, M 1) A\M\ lalc Pn•k•%.rw u/ Rfl1r.alwuve MrJ n Im•. I lnwrr.ay u1 l'a1111wma McJn al CcMCt, San Ihcral Ill•R11I•kT Y RI YNU11)S, M 1) 1't.dc...w u( McJl.lnr. 1kw/, ILlnraary %ecn••n. Yale I/n/vrr.ny S. h.rJ ••1 MeJ/. ./nr, New /laven, 1'1 141141 ANI) 1 kl YNtN 11\, M tl A..../.M Pa.t....v ..1 I'.d•.d..rv 1 h,.vrr a. ..1 1.. \...../.....,.w VI('f1)k RI('11AKIri, M 1) ( hw•1 n1 Xurprry. Prc.hyl.•n.m k1rJ/, A1 ( 'a•Mer, San I /.aK La.. VIR(:INIA 1. KI('IIMI)N/). 1•11 1) Rr.car.h A..awlNr, 1•aa/lK N•wlh..r.l kc.car.h I.InM1:Nnm, %ralrk. W.\ ARNIS RI('111'1,RS, 1`I/ 1) A...¢ul.• ('ruk...w..l l',nlr.hlrv • I lmvrr sny o/ ~rwlM•ru l'aldlwnu S. MrJ ul Mc.l . iainc. la.. Anra•Irs W11.LIS If RIh%I:N, 1'/l 1) Sennw HnhhrnlNl, I lir kn•n.-. Itlvl .nw1, 111 K.•vvah 1n.twWC, I hn ara 1)ANIH H k11 KIN. Pn 1) Ava./anl Pu•/r.v.w J 1 llrnoa .J lhe R.r\elrlla•r (lmver.ny, Nrw V•n\ R 11 RH:Ik1N. M 1) 1'Y.Jc.+.w ..I 1'a1h..h.Ky. llmvrr..ty .J Tc>ta. McJn:a/ Hramh, (:alvr.tlr. SYI)NIY1' K1111NI11R17.Pnla 1'wh•.4w a.l 11.wlcn•.h.py. Ilmva•r.ny ol %.WIIw'In 1 ahl,Nnla, I In Anl•a Ir• I111:1NU k111(1kIS,I'u1) kr.rAa h Sa wnrl.l. ('/ly ul I I.qw- Rr.raa h /n./nurr. I h.al/r. ( A III N\I1N H RI)P. M 1/ A...wutc I'r•Jc•ww ad Surra•ry . /'hwI, ('a/dlaa Sw •a•ly. Ilnlvcr.uy ad (.Id.wma \aMrd a.l ~cdn.nc. San I ruwl..la a()SI.PII tl R(N:/:R%. M 1) lhdy Nanle ul lc.u. Ihr.(w1al, GaJ.akn, Al.. RUH/:R"f (' R(KAN, M 1) As4Rta/c Pa//csMw uI PatlnllaakZ anal Pc dultlc., S/ lawl. llnwcr.ny hiral n( Mcdn Ine; A.wt ialc 1'a1hlJlryel.l, l'al.bnal (iknmin Mcnuwal 11u.lnlal hw ( hllalrra, SI 1 Iwrs, M( / ('11AR11:S 1. R(1SIi, Pu I) ('IInN' Ihrel'hM, I)IIC.11w, N.rmaovc A/t (np Stuwlr, Vrlrran. AJ/wrn/.l.aln.n (hN Pa//rM ( hnN, Iln.hw/ H)IIN A R//SY('kANS, 1•u 1) Aswrcrale Ptnlc%..w .J 1'bxnla.nl•.Ry, Medical CnikRe n/ VlrRmla. Vupnu t'.wnnw.nwcahh I /n.vrmly, kn hnr.m/ 11 111( M R(1CC. 1Y/1) N. .r.a h A..•. ulr 1 hr R.. trlrlla. l lrn 1 )/)IIN R RI)WLANI)S, Pu 1) Stal/ tian•ML1, Saulhwca Rc.ench tn.U- lulc, San Anlunn., l% H1•NIAMIN A k1IHIN, 1'(1 1) A..LIaM Ik.dc.,.w.J Puhlm: Ileakh, Hay• IIw 1lnlvct.ny ('aJkke..t MeJlclne,l/nu. LM R/1NA1.1) P KIININ, PII 1). 11aAr...w 401 1'hnmx'ola.Py, Mcdical ('IJ Irpe .4 VlrpMl., KKhnwwnl. I/I:NKY I kllt\I-.K, M I) Prr.nknl, Thr ku%,cl1 1•Iwnlalnw/, Inw., Slalcn I.land, NY W l' k11SS11 I, M 1) llnlvcr.dy 4.1 Ir.a. Medic.) ('cnlcr, 11,w.h.n WAYNI• 1. RYAN. Prl 1) 11.Ae...w /11 Hu.hcnu.lrr, Ilnivenily .d Nrhra.(a ('.J1cRc 1/1 Madicrnc. ()maha 1'I 11:k 1 SAI 1\1WKY, M 1) , 1'hl l) IIraJ, hwrnavr 1 rca/meM ('cnlet. Sainl I...rph Ilu.lwlal, Hwhank, ('A. I•AI11• SAI : f MAN, Ih/ 1) A..Ltanl W..Ic...w .11 Hi.whrnMUty .rnl Nutnlwln, 11Mvcr.dy.J Srwlhcrn('aldd• nu S.hawd u/ McJ.loc, lan AnKclrs. MAIIkK'1: S SI:(:AL. M 1) ('hnw d Pt.dc•vw u/ McJrclnc. 1 u11.11M vcrvly Sr1u.J.d Medn.nc. Uara.w. IA• ~rarlmrnl ol Inhalaunn I hcr apy. 11o.1.r. l'ny Huynlal, Hn.h.n ('ARI. C. SELTLI:K, 1h( 1). I/.wwwary Re.eanh A.wlriae. PeaM.ly Mu.ewn, Ilarvard Ilmvcr.uy, l'aM txnlKe. MA. 1L1 K'1t 1 SI : V I:R1, h1 1). Ihtcchw and Dean. In.lilwc u/ Analomy am/ 1'a1M.M.opy. blvl\nM ul ('amc. Kr %tar.h, Ilmvervly ul 1'crvRla, 1'cruKla, 11 aly ('11AR1 ES R SIIAW. M 1) l'Mc/. Scclnln ol MrJ.. al (:rnrna •. M 1) Amkt..ws Ihr%Iw/1I and 1n11Mw hn1/11NC, Padcva.w 4.1 Hnd•IKy. Ihc l/nrvcr.qy ad 1 c.as al 11.w.l.wr ('HARLESI:. SIII:RW/KN). M 1) As.r%lanl Pt.Aes..w ul RadnlhlKy. Ilmver %ny .d kaLhc.lcr S. Mw.l nl MrJK Inr and Iknl/.lry, Rrwhcarr, NY S111)11 S11111A1 A, M 1) . PII I) 14.Jcsaaw Id 1lhawwl:nul•.Fy. l/nwcraUy ul Ilawail S.hInA.J MrJnrnc, IlawnJulu NRAIIMI P SANI. t'11 1). 1kad,1'ralrrn Hntihrmi.uy, S.wlhcrn Rc• .carch In.leulc, HnnminlCham, At.. I II .Rll'll 1/ Sl'11A1:PP1, M.I) IhrccMw u1 Nrwnpharrnac.Ih.Kr. Mav+n I(e.carah Inai/We. W.wces(er, MA X)Rl:1:N l/ Sl'111Ja:1:1., M 1).. PH 1). 11n/eWw anJ lbawnlan, I)ePalmeM d Sur~trry, lulanc llnivcrsily ScAlwll u) McJnlnc, Nrwa Ihkan., I.A. ALVIN R S('lIMII)T, PII 1). Il.rcchM .d ( inmKl/nR, Tdu Universwy, Mcdhwd, MA. IAKINI S('lIMt1)f, M 1)., P(1 1) AvN/.l.nlPnJc~..wuIHNK'helwiMry (hvi- .nn1.J Iln.l.~(N./ ~r/cmcs, Sldc 1lnwcr .ny u1 Nrw Y.wk N Slnny Hnrd, lnwly 1h..IR ISAA(' S('HOtIR, 1) 1) S., Pw 1)., D S/'. Ikan, Ilnrvetslly d Illimwa Cu/kRe at IkMlslry. ('hlcaRa Sl RIIM'S ('I INI(' ANO RESEARCII It)IINI)Al l()N I a (hJ1a, /'A 1:1:RA1.1) SIIKLAR, 1) 1) S. ( bark. A Btac\cll Itole...w rl( ()ral 1'a Ih..h.Ry:llcad. 1)cParuncnl al Ihal Mrah• tlnr aml ()ral Pa1MA..Ky, IlxvarJ S.Mwd nl I)eM1I Me111\1nc, H.NNM 1)AVII)1.. SIMON. M 1). IwNnwhw.n IMctnal MeJicine. ('in.'rnnan ( irneeal Ih..plaI. ('In. raaau.1)H E?RIK SKIN/IN/, M 1) (lwel. 1)clwlmcnl nt Neun.hryty. Hrylcb- lerK 1hnPrlal, CnPcnhaRen, I Rnmar\ Kl)III:RT ) SKLAREsW, Pu I) Reser.h Aswra/e Ptrdes..w ul 1'a1MJ r.Fy. New YrwR 1lmvct.ay Re.ran.h Scr vn'e, (:oWwalrr Mennwlal 1loyulal, R.u..e.ell h•and, NY NIK111AN 11 Sl.(MNIi, Pn 1) PYdcwwd Hn.nc47m/.uy, lhc Iln/vrraly IA ('cnncs.ee l'cnlrr 1.r Ilr 11.v1d. S./ ences, McqlMs HAN(K'll SL(Nt, Pn I) AxYKla/e P!n(cfMw .d /luman Gcnr/ias. Saalikr ScIw.A nl Mcdwlnc, let Aviv 1lnlvcraly, Tel Aviv. lan-1 1 a 1 191 ~
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TI11 OIK)K1 A SI I)I KIN, 141 1) A..Ll..nl 1'r..lr..w .4 1'harmx.dryy, Ihr\r I/mvrr.nr M.'Jual ('.•nlr., IAn ham, N(' I:I l)R/:1 W SMI 1// MS. MO A.wul.• In 1'.aMd..Ky. N..Ihwc•ICtn IIn1..r.rtv MrJ...1 \.h.w.l, 1 hn•.Ku 1)I NNI%M SM1111. I'n 1) A..Llaul 1'r..Icwa ..I 14.d.~taal S.t emcv, Wrlk.k'y l'..1kFc• Welk.ley, MA (31 NI. M SMitll, 1'u 1/ A\vlNant R..Ir.vw ul /'.y.MJ..ry. Ilar vaJ MrJr. al \. M..1, Ma..an ha.r•nv (kn rr,11Ilo.bn 1 11('ll.l: SM1111 WI 1) I'L.IC\VN .•1 Itnahenn.lrr I)artrmnNh Mr.lnal Sah...l, 1lamrvcr. NII 10111% A S111 1111 , M 1) lllan.he 1• 1 rvy Ih.l.nrur./n•J %rr.nc Ptr.la•\va, Prulr\..a ul McJn/nc. Ouc. hu. Rr\c+r.h I/PId I.h.w.awyI fcml.k (lmvct\IIy /lcahh \. n•mcv ( rnlcr, 1'hJ. .h•Ipbu SIII.I.I)ON (' SI)MMI.kS M 1) Ihre.hw..1 IAIra.Iwlr.• I ea.. 11d11/o. pItal.(lrnk .11'u.lr...a u/ /'•nlwd..py• 1 0 IanAna I Ilnva•t.n ( 1.11cKc ul ITy\n r.n. A `YtRt.N1.. Na•w ?.uk 1 RNI ST S//NI)111 IMhR. Ihl 1) Awti lalc 1•rnlr.\.w ol Ib.n Iw ou.lry •('.J kFc.d I.nr.lty, Sl.tr Unlver.uy.d New Ynth, tiylxu.r t M SONNI R(NIN, Pa 1) 1hv11nrut.hcJ Scrrnc PruIc.vw u( Y.ad I.gy, Ilnhana Ilnlrfr\Ny, I(kaN111nRItM1 SAM SORI)1'. Pn 1) Ik,ul. IlrP.nlmrM 401 Ma.r.Inn.kaular ( Tww1.11~, Ihr In.l8u1.• l.u ('.ncer Ke .fu.h, 1'h11nk•IPh1a S/III111W1.SI KI SI'AR( 111NSTIf111U. San AM.+Ia., I X 1)AVIIyM \I•AIN. M 1) I/nrvhn, Ih'p.rn.wn1 0l Palh..l.ryty• The IIr...Wak Il...pa.l 1.n1.r, 11u.ilyn, NY AI 1 t ANI N k\I-4 u M M It .A..•.LM 1•..d..,. ..I 1•..L.uw. Ilutr 14u....... M. •1.. .1 1 . a... I..../..n. Nl I RI III RI('K I STARI•. M 1) 1'rolr\v.a..l Nuln/mn. Il.rvuJ Ilmvet.ny S.M.d ul Puhln 1k.11h. 11.n1..n NORMAN (' SfA11R, M 1) 1•tnkwa .A Phy\~nl..ly, ('..Ja.v... al.n kevx.h In.hlulr. Ilmver.Ny .J l ahlor n.a. San FrancI..u (:I:INIGI: W SM1 1-11RS, M 11 /4vuxiMC tn 1•.d.d..ry. N..Ihw..lrrn Ilntver\ny MeJn.l SaMad. l harF.. JACK P STRI)NG. M 1) A.vM'talc Pt.dcv..a nl I'.IM.k.yy I. .u1.r ana Sla/r Ilnlrrr.ny S.lard..1 M.•J. nr•, Ncw llrkan\ MARION R 51/1./lll R(:1 R, M 1) Ih.ac\va aml l'hanman• 1kPannwnl .d Iklrnal.AnR] am/ SyPlnk.h.Ry. New Y.aL Ilmvtsrnlqr Relkvue MeJwal ('rnlrr. NY. R1 NAT(1 TAGIIIKI• /hl 1) A...a1ac 1'Ldr.wa.J 1•.y.Md..Ky. (;t.nl u.nr S.M.d .4 IIu.Inr\\ AJmms.n.uh.a., ILrvatJ I/nlvct.ny. Nu.h.n I)AVII) W TAI MMG1:, M 1) Ihrr.hN, Wrh(. WamK IunR /n.blulc. 1lmvrt.lly uI 0nkNMk. MrJn.1 I rnlct• I h-nver LYNN M TAIIS%I(i, M 1) - Awrlale Prulr.vN aml Avvnlale ('hau man. Ih•nalmw•n1 al 1'cJlatn\• Aana.a Ikahh 1.Irmr\ ('rMrr• I wwnl MAR(' 1). TIIAMI %. M I) Senna kevearch I elk.w, Mayn ( TmK aml I,wnJalnat, R.oi hc\ICr• MN ('ARIN.INN R1:1N.1.1. TIN)MAS. M I) Ihnk\S4w I:rrlctitw .uI Mc.h.u.r. Ihr k.hn\ (hq•~In\ Ilmvcr\Ily Sah.wd u/ Mr.h clnr, Naltlnnwc• MI) )1 kl)Mli P IIII IMAS, Pit 1) I'r..IC.Nn .d Sant6mry 1 nKlnrcnny. 11m vcr\Ny nt l'ald.nnl., 11r1\rlcy /AMIS 1: P 11)MAN, 1•tu 1) lhnkw.t and /h.nnun. 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