,So orf oems erans,o imrteerosrtatsnun is ietnhmsgo evI' LYAAWS eugrsdltg ..tw.ih boalpyrb auceesb I sant'w thaugt it lewl so rvnee relyal dernlea ,ti sjut leenrda oeghnu rof erevhwat x.mae I utjs donuf tish boo tgrhhou BICN dna tsi S!FCNTITAA stI' romf 2100 so mhtgi be d,lo tbu it wsa taegr. oYu nca rescha rgtuhoh eth kboo dna dnif eht hrta.cpes I ttpeyr hcmu utsj tenw rhuotgh lal fo het rtsenarminetorut arhtep.c sishton.w7t9okN/blb.pKn9ic/wm.n0B/wh:/1vog/.

My imna a:wt a-luGmtaasyekaet = amojr itteracyxo rutinnsarmeoe.rtt wTo yestp fo pe1sretr:c)o bromc,petoiat tmso of ciwhh are yintpcrspea Gi hhcwi asdel to rddeecsae MAND oeprtecr avytiitc dna irsk of ixxtcot,ocieiyit ro yapstptisonc qG coprester thta laed to iarcnees +N,a ,+K nda eedsacedr mlaauttge ecsusa ootedpnariilza nda dsrienaec Mg++ idlpeneacstm dan NAMD treecpro yatitvci nda riks fo ,ttcxicytooeiix nad )2 oiocrnitpo lsahcenn luicndnig DANM and APnaMkia/teA asnehcn,l hchwi lal lwloa ncoisnfeipc toiacn u,lifxn tub onyl DNAM lwslao Ca++ ulxinf (and olny in a gotvael petndeend rmaenn reatf fietcnisfu pdniolaziatero sah ilcdesdpa teh iihnotbri +g+M ino in the )enhnla.c

BGAA and icgenyl = ibintrohiy sstr.enrtroiatemun 1) AGBA-A dna GBAA-C = ocoiipnotr sehlcann that lade ot luefx fo -Cl, adn sdeeitp hist gsnciua apnidz,teaoriol eth ruonne itsll astys oelwb gsrtien poit.leant A-AGAB bndigin ites orf r,abebtruasit dss,otier A,BGA dna oocitrxnip = dsiien erpo fo nal.nche G-BAAA bidnign etsi of esbeiazdpzieonn = eutodsi fo erop of hnca.lne )2 ecnilyG clnneha si a very iraisml -Cl fxlue ecanh.nl )3 A-ABGB is a otmtaoepcibr nenlcah atht actasitev iG daenigl ot eeddrcesa AMcP hwchi saetvctai ffxuel +K asencnlh adn ihtiibsn C+a+ ifnlxu celnanhs anidgel to tolraezyiprino.aph

iginoeBc anemsi = isohtaenelccam mnpoiead n(acooniodtri of dbyo meetnvm,o aewrd,r ioto,nmatvi i,nneocmtrere)f nirnierephpoen ls,e(ep lesuwkfnea,s anito,etnt idnfeeg arv,ebioh eneerniphip (loswet ocorctantinen ni C,N)S uspl noietonrs (,epsle ekwafse,unls pneosdies,r axneiy,t uas)ean adn atsnmihei (,alrusao i,onetantt reyllga, uetiss a,gaemd and amy nelcuinef odolb rnabi ofw)l. O,yslobiuv lal of itsh si ni tiiodnad ot ergirecnad nmeturriiossnoasn and ,glhitf hftig,r dan thifg eo.nseprs

ATP nda etorh uinerps = tyioxrteac snirims,tsnoa orcees-aedl thiw rtohe oca-lelullsmme eett.snnitarmrsour nonAeedsi nis't ayslscialcl oceirdnesd a trtmtsanroriunee ceaubes it t'ins otrlesdsr/eeead in +C+a eedendptn nmrna,e ubt deerivd mofr PTA efboer ihganv an oyticxtrae npleaito.t

tnAycoelicelh = omjra uortretsirmteann idevvoln ni rormsiotieannsnus aiv mauncisr adn icnicotin orsre.epct

ePiptde ttaertnisnrsrumeo = onmloymc reeesdla sa epeporiptd grrela cropsrersu tath rae edvecla yb pescicif esmenzy taht were in teh msae esatttremrirunno eicvlse puon lrsee.ea ieFv psyet = riu/bangt ,spdetiep diopio ppestedi, yitrauitp t,ppides tahcliahypmo iasernegl e,mrnosho dna thseo not eiildas.fcs paEsxlme = ersurocpr htat evsgi reis ot secnbasut P sc,oipmapu(hp oernxteo,c nda ITG dna lresaede mfro amlls metidear SNP C fibesr that irnamtst nipa nda rmaptueerte tfaiioonnm,r uefowprl yhpis,tevnoe bdetiiihn yb diipoo esi)d,ptpe nonnriukie A, opnreeeutpid ,K dan petuoeindrpe m,mgaa nda odopii pideetsp ugcldinni aplnt lladoskia i(ekl i,orpneh)m ishtcynet idioop diravv,eetsi nda neo,dprnihs op,nihndrys dan lns.ahknipee nI rlngaee iopdoi ieeptspd ear snadpreests i..e( aelgiansa msm)ecin,ha vielvond in ocxmepl asrhoiveb ase(lux ,rnitaaotct bessgsia/rgiesmuivsve ,bsvaeroih) and piceiamdtl ohh(gtu ont ei)vntideif in taicyhcrpsi drser.odsi

l,lOrave ernsstirmnutotear = ypet yp:est leaculmlsm-loe tnirtetmrass and een,ptosieupdr eehwr llml-euacmlosse tmtsinrstaer rea aetrsf nda mdtaeie idarp tanycpsi rsnintsiaosm e.i(. orgndnae SSN tigfhfglrt/g/ihitfh kquic ens,epos)r ehrew sa tseuippodneer (gnaol tihw ciobilgo nseima nad meso sllma ouellcem msrntestt)ria ear rsewlo nad aetedmi la,gdura orpldnoeg mr.nnresnssaouioti

meoS resuipct: trwaaoshsh.ne.rp_t.odve/tmehi//_or:tiabpnpnd_ikiouuwvmfunl/setmtp/wteurceredek, bweirAg/r3salc2h1gupat2ol-82c4r6gw/1b-fpG11aoeernhue/3a1Ps8gp/-Bi//fTlB-soot-init46rdp45e36-uf3ada.0eAit6teasrr:iR0fe0re70reds-ctmsg/adh9pe-cn.b0wb, adn ;itpsdiwi.fl-ut/gabgeo5aw1sel3wedasa/:agcUfxb-ee-traee-/5gmprt2r-in10-0dd9&/bf/dhe=-hl-2eb36a#w./fbn_41xt8l61g.a=7nh

ouhTg stn.oeuiq

laRlec ttha ieMntenam sihr'zleaem( g)udr is a DAMN ecRretpo Ansoattign that phsle eeptvrn etccixtoxyoit yb oiBclgkn +aC2 yetrn. shTt'a how I rmermbee siht.

• )A AAAB-G cseetorpr tel -lC ni
• B) Gleciyn si ueds in eth painls odcr sa na tbinriihoy arnmtnru;erotiset aosl slet -Cl in
• C nad )E cbtpMorteaio emagttula crtrposee rea -niprteoG opcudle
• fTeeohr,er hte yonl itgnh thta udclo etl 2+Ca ni si MDNA rpsroteec

NAMD rocerpset ni tshi csae aer nebig sedu ofr nlgo term oitonntaipet wtihin hte rbian nad uot fo all of hetre hsoecci noyl thsi terrpoec suse +aC

uoY acn eanwrs by posrecs fo ni.tilienamo miipe"tovCte ct"aoernisnti amsek uyo tikhn ylsttiamuor .NT rsosC tuo GABA nad l.yicgen nI het eorxtc os maal.tegtu otoatiMecbpr dwuol mnea erste'h odcesn esergsmens oevnlvid dna the creetorp dlowu ton airttsmn malcu.ic ceHne .NAMD

dues ni nolg mret aonitentiopt uae,n(lgag ,ryemmo) aMy loas lypa a roel ni geen apnsotiinrtrc ni roesunn

1) DAMN is a mtluGetaa rtceerpo yu)st pe2b APAM is a tuyspeb of NAMD taht is tyaliilin dtcaivtea by tlgtmauae esal3ee) r MNDA etorcepsr era fnodu aner MAPA ecoetrspr btu are ont tadtiavce by wol leelvs fo gumaetatl erselea eud ot a Mg noi n’kb‘licgo hte e4h can)nl uqFeernt tnAoic potialnte g;—t& mtlonuiaist fo MPAA g—&;t izeldrpeaos sotp icypanst onnrue ;g—&t veoglat tdenpeedn gM bolkc fo ANDM corprete eovmrde )5 lfxniu fo Ca rhuhtog DANM &g;t— uecssa neve emro MAPA rptcrseeo to eb tserdine oint eth ebmmeran O(NT:E PAMA si svsierpneo to Ca adn )almae6ttg) u esBcuae trehe are ermo rseectpor to ndpreos to ,it het lcle si rmoe pnisvroees to uegaamtlt

lal the hosert a ectivntioneopm encsi heyt heva iiepfcscfyiepccitis( ns)dl,iag MNAD is the lyon e(eenvnnecilceohts iecpttvoime oc,r)rptee ahs a daignl esti nda ac , na nda .ec.hm.gne cevotptmiei