brca1 tumor suppression occurs via heterochromatin mediatedsilencing

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  • 7/30/2019 BRCA1 tumor suppression occurs via heterochromatin mediatedsilencing

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    M]HO? tukar supprdssiaf ahhurs vio gdtdrahgrakotif kdeiotde

    si`dfhifc

    _uof ^gu?,., Cdro`e K& Roa?,.,O`dxis K& Guyfg?,.., Gaaflya Xug?,..., Fifo Uaffu?, RdtroFdedr`aj=, Jrde G& Cocd?, ofe Ifedr K& Zdrko?

    ?@omarotary aj Cdfdtihs, Ugd Xo`l Ifstitutd jar Mia`aciho Xtueids, @o N a` o, HO 9=283=Edportkdft aj Rotga`acy, tgd Fdtgdr`ofes Hofhdr Ifstitutd, Okstdreok, Ugd Fdtgdr`ofes

    Omstroht

    Kutotiafs if tukar supprdssarM]HO? `doe ta mrdost ofe!ar avoriof hofhdr& Gdrd wd sgaw tgot

    `ass ajM]HO? if kihd rdsu`ts if trofshriptiafo` edrdprdssiaf aj tgd tofedk`y rdpdotde sotd``itd

    EFO&M]HO? edjihidfhy is ohhakpofide my rdeuhtiaf aj hafedfsde EFO rdciafs if tgd cdfakdofe `ass aj umiquity`otiaf aj gistafd G=O ot sotd``itd rdpdots&M]HO? mifes ta sotd``itd EFO

    rdciafs if viva ofe umiquity`otds G=O if vitra& Dhtapih dxprdssiaf aj of G=O jusde ta umiquitif

    rdvdrsds tgd djjdhts ajM]HO? `ass, succdstifc tgotM]HO? koiftoifs gdtdrahgrakotif struhturd

    vio umiquity`otiaf aj gistafd G=O& Xotd``itd EFO edrdprdssiaf wos o`sa amsdrvde kausd ofe

    gukofM]HO? edjihidft mrdost hofhdrs& Dhtapih dxprdssiaf aj sotd``itd EFO hof pgdfahapy

    M]HO? ass if hdftrasakd okp`ijihotiaf, hd`` hyh`d hgdhlpaift edjdhts, EFO eokocd ofe

    cdfakih ifstomi`ity& Sd prapasd tgot tgd ra`d ajM]HO? if koiftoififc c`amo` gdtdrahgrakotif

    iftdcrity ohhaufts jar kofy aj its tukar supprdssar jufhtiafs&

    Mrdost hofhdr sushdptimi`ity cdfd? 'M]HO?) wos iedftijide os o gdrdeitory hofhdr

    sushdptimi`ity cdfd wgihg ifhrdosde? risl jar tgd edvd`apkdft aj mrdost ofe avoriof hofhdr if

    M]HO? kutotiaf horridrs ta os gicg os 94$ my ocd 32=& UgdM]HO? pratdif haftoifs o

    ]IFC jifcdr eakoif if tgd F+tdrkifus witg umiquitif D8 `icosd ohtivity ofe twa M]HU

    rdpdots if tgd H+tdrkifus8& M]HO? is gicg`y dxprdssde if pra`ijdrotivd hd``s ofe its `ass

    `does kast prakifdft`y ta cdfdtih ifstomi`ity ofe crawtg orrdst& Ugdsd amsdrvotiafs govd

    ikp`ihotdeM]HO? if o ku`titued aj eisporotd hd``u`or jufhtiafs, ifh`ueifc EFO eokocd

    rdpoir, hd`` hyh`d hgdhlpaift ohtivotiaf, trofshriptiafo` rdcu`otiaf, EFO rdp`ihotiaf,

    hdftrasakd jufhtiaf, W ifohtivotiaf, okafc atgdrs5& Rrdsdft`y fa ufijyifc kdhgofistih

    Harrdspafedfhd> Cdro`e K& Roa * Ifedr K& Zdrko, @omarotary aj Cdfdtihs, Ugd Xo`l Ifstitutd jar Mia`aciho` Xtueids, ?22?2 FartgUarrdy Rifds ]e&, @o Na``o, HO 9=283, Ud`&> '747)+548+5?22 dxt& ?5:=< Jox> '747) 447+3545, poaBso`l&deu, vdrkoBso`l&deu&.Ugdsd outgars haftrimutde dquo``y ta tgd warl..Hurrdft oeerdss> Edpt& aj Kdeihifd, Mdtg Isrod` Kdeiho` Hdftdr, O`mdrt Difstdif Ha``dcd aj Kdeihifd, Fdw Yarl, FY

    ...Hurrdft oeerdss> Xtdk Hd``s ofe ]dcdfdrotivd Kdeihifd, @drfdr ]dsdorhg Ifstitutd!H`dvd`ofe H`ifih, 9422 Duh`ie Ovd&, H`dvd`ofe,AG 55?94

    Ugd outgars edh`ord fa hakpdtifc jifofhio` iftdrdsts&

    _^ cdfdrotde ofe _^, FU ofe CKR koiftoifde o`` tgd LA ofiko`s& CKR ofe _^ koed tgd ifitio` gdtdrahgrakotif amsdrvotiaf& _^

    ofe OKG pdrjarkde hafjaho` kihrashapy dxpdrikdfts& CKR, _^ ofe FU pdrjarkde HgIR dxpdrikdfts& ]FO isa`otiafofe

    kihraorroy dxpdrikdfts wdrd pdrjarkde my _^, CKRofe FU& Kihraeissdhtiaf aj kurifd mroifs wdrd pdrjarkde my CKR ofe OKG

    ufedr tgd cuieofhd aj JGC& CKR edsicfde tgd G=O+umiquitif jusiaf dxpdrikdfts tgot wdrd pdrjarkde my _^, CKR ofe FU& Xotd``itd

    ]FO dxpdrikdfts wdrd edsicfde my CKR ofe _^ ofe pdrjarkde my _^, CKR ofe FU& GX dstom`isgde tgd dkmryafih fduro` stdk

    hd`` isa`otiaf ofe hu`turd& RF amtoifde, isa`otde ofe hurotde tgd h`ifiho` potidft sokp`ds, wgihg wdrd ofo`yzde my _^, CKR ofe FU&

    O`` atgdr dxpdrikdfts wdrd pdrjarkde my _^, CKR ofe FU& O`` dxpdrikdfts ofe dxpdrikdfto` edsicf wos pdrjarkde ufedr tgd

    supdrvisiaf aj IKZ& CKR, _^ ofe IKZ wratd tgd kofushript&

    FIG Rum`ih OhhdssOutgar KofushriptFoturd& Outgar kofushript< ovoi`om`d if RKH =2?= Korhg 7&

    Rum`isgde if jifo` deitde jark os>

    Foturd& < 533'38:8)> ?39?75& eai>?2&?287!foturd?283?&

    FIG+ROOu

    tgarKofushript

    FIG+ROOutgarKofushript

    FIG+ROOutgarK

    ofushript

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    jrokdwarl dxists ta tid tgd rdpartde miahgdkiho` ohtivitids ajM]HO? ta its tukar supprdssar

    jufhtiaf8&

    Gdtdrahgrakotih hdftdrs if M]HO? LA hd``s

    Gicg `dvd`s aj M]HO? dxprdssiaf govd mddf jaufe if tgd dkmryafih fduradhtaedrk4, tgd

    pastfoto` hdrdmd` uk: ofe tgd sumcrofu`or zafd aj tgd edftotd cyrus if tgd oeu`t mroif, wgihg

    ord tgd sitds aj dkmryafo` ofe oeu`t fduracdfdsis, rdspdhtivd`y& Sd ifitio``y sdt aut ta stuey

    tgd haftrimutiaf ajM]HO? ta fduro` stdk hd`` 'FXH) pra`ijdrotiaf tgraucg torcdtde ed`dtiaf

    ajM]HO? if fdstif+dxprdssifc FXHs 'Xupp`dkdftory Jic& ?o)& Os dxpdhtde, tgd `dvd`s aj

    M]HO? pratdif ofe ]FO ord sicfijihoft`y rdeuhde if tgd mroifs ajM]HO? LA kihd 'Jics&?o

    ofe Xupp`dkdftory Jic& ?m)& Ua hgorohtdrizd tgd kutoft mroifs, wd pdrjarkde kihraorroy

    ofo`ysds ofe jaufe dviedfhd aj o`tdrde dpicdfdtih rdcu`otiaf if tgd omsdfhd ajM]HO? os

    sakd ikpriftde cdfds ord edrdcu`otde 'Xupp`dkdftory Uom`d ?)& Kast fatom`y, uprdcu`otiaf

    aj matgIcj= ofeG?9 dxprdssiaf gos mddf vdrijide my quoftitotivd ]U+RH] dxpdrikdfts

    usifc hartiho` ]FO sokp`ds 'Jic& =o)&

    Gdtdrahgrakotih hdftdrs ord gicg`y hafedfsde rdciafs aj gdtdrahgrakotif witg rdpdtitivd

    tofedk EFO, wgihg hof md visuo`izde my EORI stoififc& If fdurafs tgdsd hdftdrs ord

    portihu`or`y prakifdft& Sd ofo`yzde tgd fuh`di aj tgd kutoft mroifs my EORI stoififc ofe

    jaufe o korlde rdeuhtiaf if tgd fukmdr aj gdtdrahgrakotih jahi if tgd hd``, dspdhio``y if tgd

    pdrifuh`dor rdciaf, wgdf hakporde ta haftra` hartihds '5&77 jahi!hd`` ta ?&99 jahi!hd``)

    'Xtuedfts t+tdst,p02&2224) 'Jic& ?m)& Kardavdr, tgd sizd aj tgd gdtdrahgrakotih jahi

    oppdorde ta md `orcdr ofe eijjusd if kutoft mroifs& Ugdsd amsdrvotiafs succdst o edjdhtivd

    gdtdrahgrakotih struhturd if M]HO?+edjihidft hd``s& Ua stuey tgd foturd aj tgis edjdht, wd

    stoifde tgd fuh`di aj hartiho` hd``s witg gdtdrahgrakotif pratdif 'GR?)3, o mafo jied

    pdrihdftrih gdtdrahgrakotif ossahiotde pratdif, ofe jaufe tgotGR? `aho`izde ta

    gdtdrahgrakotih hdftdrs& Ugd fukmdr ajGR?+pasitivd jahi if kutoft hartihds wos edhrdosde

    jrak =&7: jahi!hd`` ta =&?8 jahi!hd`` 'Xtuedfts t+tdst,p02&2224) 'Jic& ?h, tap raw ofe

    Xupp`dkdftory Jic& ?h, djt pofd`)& Kardavdr, ikkufam`attifc aj hdrdmd``or sokp`ds sgawde

    tgot tgd pratdif `dvd`s aj o`` tgrddGR? pratdif isajarks 'GR?ofe) wdrd sdvdrd`y

    rdeuhde if LA ofiko`s hakporde ta haftra`s 'Xupp`dkdftory Jic& ?e)& Ugd rdprdssivd

    gistafd G? o`sa eisp`oyde omdrroft stoififc ofe wos kard eijjusd ifM]HO? kutoft hartihds

    'Xupp`dkdftory Jic& =o)& Atgdr prdviaus`y hgorohtdrizde rdprdssivd gistafds, suhg os KohraG=O? ofe gdtdrahgrakotif korldrs, suhg os gistafd G8 eikdtgy` @ys 9, eie fat oppdor ta md

    ojjdhtde myM]HO? LA 'Xupp`dkdftory Jic& =m)& Xifhd wd govd prdviaus`y sgawf tgot tgd

    M]HO? pratdif prdjdrdftio``y kafa+umiquitifotds gistafd G=O if vitra tgraucg its F+

    tdrkifo` ]IFC jifcdr7, wd ifvdsticotde wgdtgdrM]HO? is ifva`vde if gdtdrahgrakotif

    jarkotiaf tgraucg gistafd G=O umiquity`otiaf& Sd jaufe tgot tgd stoififc aj kafa+

    umiquity`otde gistafd G=O, wgihg gos rdhdft`y mddf ikp`ihotde ifpa`yhakm+kdeiotde

    si`dfhifc9, harrdspafede ta tgd gdtdrahgrakotih hdftdrs edshrimde if Jic& ?m ofe tgot tgd

    stoififc sicfo` wos rdeuhde ifM]HO? kutoft mroifs 'Jic&?h mattak raw ofe Xupp`dkdftory

    Jic&?h ricgt pofd`)& Sd vdrijide tgd hd`` outafakaus foturd aj aur amsdrvotiafs usifc

    hu`turde dkmryafih fduro` pracdfitar hd``s 'FRHs) if vitra& Udf eoys ojtdr fdurafo`

    eijjdrdftiotiaf, tgdM]HO?+edjihidft hd``s eisp`oyde o sicfijihoft rdeuhtiaf if tgd fukmdr aj

    gdtdrahgrakotih hdftdrs '3&74 jahi!hd`` vs 4&22 jahi!hd``, Xtuedfts t+tdst, p02&2224)

    'Xupp`dkdftory Jic& =h)& Uoldf tacdtgdr, tgdsd eoto strafc`y succdst tgot hd``s `ohlifcM]HO? ord ikpoirde if tgd arcofizotiaf aj gdtdrahgrakotif struhturd&

    Gdtdrahgrakotih si`dfhifc eisruptiaf

    Ua oshdrtoif tgot tgd amsdrvde gdtdrahgrakotih struhturo` edjihidfhids ord aj jufhtiafo`

    ikpartofhd, wd ifvdsticotde tgd trofshriptiafo` stotus aj lfawf si`dfhde cdfds& Edjdhts ord

    ^gu dt o`& Rocd =

    Foturd& Outgar kofushript< ovoi`om`d if RKH =2?= Korhg 7&

    FIG+ROO

    utgarKofushript

    FIG+ROOutgarKofushript

    FIG+ROOutgar

    Kofushript

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    dxpdhtde ta rdsu`t if edrdprdssiaf aj farko``y si`dfhde cdfds if gdtdrahgrakotih rdciafs?2&

    Ugd kurifd pdrihdftrih gdtdrahgrakotif hafsists aj strdthgds aj gicg`y rdpdtitivd EFO

    d`dkdfts, ifh`ueifc tgd konar ofe kifar sotd``itd rdpdots, wgihg kold up ~8$ ofe ~2&54$

    aj tgd kausd cdfakd rdspdhtivd`y??& _uoftitotivd ]U+RH] dxpdrikdfts sgawde tgot tgd

    `dvd`s aj kifar ofe konar sotd``itd trofshripts wdrd d`dvotde ?2&=+ja`e ofe =3&8+ja`e,

    rdspdhtivd`y, if tgdM]HO? kutoft hartihds, ifeihotifc o `ass aj rdprdssiaf if hafstitutivd

    gdtdrahgrakotif 'Jic& =o)& Atgdr iftdrspdrsde rdpdtitivd d`dkdfts suhg os IOR?, XIFD? ofe

    tgd @? @IFD d`dkdft wdrd `orcd`y ufojjdhtde& Ugis djjdht wos hd`` outafakaus os it wosamsdrvde if vitra if hu`turde dkmryafih FRHs 'Xupp`dkdftory Jic& 8o)& Ugd edjdhts if

    gdtdrahgrakotih rdprdssiaf ifM]HO?+edjihidft kausd hd``s hau`e md rdvdrsde my rd+

    dxprdssiaf aj gukofM]HO? usifc o dftiviro` vdhtar 'Jic& =m)& Gdtdrahgrakotif rdprdssiaf

    myM]HO? is fat ufiqud ta fduro` hd``s mdhousd ed`dtiaf ajM]HO? if jimram`osts jrak R3

    kausd rimhocds o`sa sgawde uprdcu`otiaf aj matg sotd``itd trofshripts 'Xupp`dkdftory Jic&

    8m)& XifhdM]HO? is o tukar supprdssar if mrdost hofhdr wd fdxt cdfdrotde kihd gormarifc o

    kokkory c`ofe spdhijih ed`dtiaf ajM]HO? ofe ofo`yzde tgd iftdcrity aj gdtdrahgrakotif

    my q]U+RH] 'Jic& =h)& Ugd rdsu`t edkafstrotde tgot `ohl ajM]HO? if kokkory c`ofes

    jrak :+wddl a`e vircif jdko`ds, eisruptde gdtdrahgrakotih sotd``itd EFO si`dfhifc os wd``

    os ikpriftdeG?9 dpicdfdtih rdcu`otiaf, hafsistdft witg aur jifeifcs ifM]HO? fu`` mroifs

    'Jic& =o)&

    Ugd si`dfhifc aj hafstitutivd gdtdrahgrakotif my M]HO? is o`sa fat `ikitde ta kausd hd``s,os sotd``itd trofshripts jrak gukof Gd@o hd``s wdrd uprdcu`otde upaf dxprdssiaf aj of

    sg]FO torcdtifcM]HO? 'Xupp`dkdftory Jic& 5o)& Xiki`or`y, rdhafstitutiaf aj tgd gukof

    M]HO?+edjihidft hd`` ifd, GHH?983, witg o rdtravirus dxprdssifc wi`etypdM]HO?

    rdprdssde tgd dxprdssiaf aj sotd``itd EFO trofshripts omaut =2+ja`e 'Jic& =e)& Ua edtdrkifd

    wgdtgdr tgd F+tdrkifo` ]IFC eakoif aj M]HO? is ikpartoft jar tgd gdtdrahgrakotih

    si`dfhifc jufhtiaf, wd rdhafstitutde GHH?983 hd``s witg ditgdr o potgacdfihM]HO? kutoft

    edvaie aj umiquitif `icosd ohtivity 'U83], lfawf ta hafjdr ifhrdosde hofhdr risl) ar o

    pa`ykarpgih vorioft 'Z??O, ifeistifcuisgom`d jrak wi`etypd)& Ugd U83] kutoftM]HO?

    joi`de ta rdprdss sotd``itd trofshripts wgdrdos tgd Z??O rdprdssde tgd sotd``itd trofshripts ta

    of dxtdft siki`or ta wi`etypdM]HO? 'Jic& =e)& Ugd `ohl aj rdprdssivd ohtivity wos fat eud ta

    rdeuhde mifeifc aj MO]E?, tgd foturo` gdtdraeikdrih portfdr aj M]HO?, os matg

    pa`ykarpgih ofe kutoft ikkufaprdhipitotdeMO]E? siki`or`y 'Xupp`dkdftory Jic& 5m)& Ua

    jurtgdr vdrijy tgd ifva`vdkdft aj tgd D8+`icosd ohtivity ajM]HO?, wd ossdssde tgd djjdhts ajMO]E? lfahleawf af sotd``itd EFO trofshriptiaf sifhd tgd gdtdraeikdrizotiaf mdtwddf

    M]HO? ofeMO]E? is rdquirde jar tgd aptiko` D8 `icosd ohtivity7,?=& Dxprdssiaf aj of

    sg]FO ocoifstMO]E? d`dvotde tgd sotd``itd EFO trofshriptiaf if tgdM]HO? rdhafstitutde

    GHH?983 hd``s mut fat if tgd GHH?983 hd``s wgdrdM]HO? is omsdft ofe tgd sotd``itd rdpdot

    trofshriptiaf is o`rdoey edrdprdssde 'Xupp`dkdftory Jic& 5h)& Ugdsd rdsu`ts jrak hu`turde

    gukof hd``s ord hafsistdft witg eoto amtoifde jrak tgd M]HO? edjihidft kausd mroifs,

    jimram`osts ofe kokkory c`ofes if wgihg sotd``itd EFO trofshript ifeuhtiaf wos amsdrvde&

    Kardavdr, it oppdors tgot umiquitif D8 `icosd ohtivity ajM]HO? is dssdftio` jar its ra`d if

    cdfd si`dfhifc if hafstitutivd gdtdrahgrakotif&

    M]HO? ofe gdtdrahgrakotif rd`otiafsgip

    Ua coif o kdhgofistih ifsicgt ifta tgd ra`d aj M]HO? if koiftoififc gdtdrahgrakotifstruhturd, wd jirst ifvdsticotde ijM]HO? eirdht`y ossahiotds witg tgd hafstitutivd

    gdtdrahgrakotih rdciaf if viva& Hgrakotif ikkufaprdhipitotiaf 'HgIR) dxpdrikdfts sgawde

    tgotM]HO? wos ifedde dfrihgde af konar ofe kifar sotd``itd EFO 'Jic& =d) if kausd hd``s

    ofe af voriaus sotd``itd sdqudfhds if Gd@o hd``s 'Xupp`dkdftory Jic& 5e)&

    ^gu dt o`& Rocd 8

    Foturd& Outgar kofushript< ovoi`om`d if RKH =2?= Korhg 7&

    FIG+ROO

    utgarKofushript

    FIG+ROOutgarKofushript

    FIG+ROOutgar

    Kofushript

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    Sd fdxt tdstde wgdtgdrM]HO? ifj`udfhde gistafd umiquity`otiaf if viva& Ugd rdsu`ts aj

    HgIR dxpdrikdfts sgawde tgot umiquity`otde gistafd G=O wos dfrihgde if matg konar ofe

    kifar sotd``itd rdciafs wgdf hakporde witg o gistafd G8 oftimaey 'Jic& =j)& Gawdvdr, tgis

    sotd``itd rdciaf dfrihgkdft wos omracotde if tgd omsdfhd ajM]HO?, ifeihotifc tgotM]HO?

    iftdcrity is dssdftio` jar tgd ohhuku`otiaf aj umiquity`+gistafd G=O ot sotd``itd rdpdots if

    viva& Aur eoto o`sa sgaw tgot umiquity`+gistafd G=O is dfrihgde ot tgd sotd``itd rdciafs aj tgd

    kausd cdfakd ta o crdotdr dxtdft tgof ot atgdr iftdrspdrsde rdpdots suhg os @IFD? 'eoto fat

    sgawf) succdstivd aj o eistifht gdtdrahgrakotif& IjM]HO? is ifedde tgd umiquitif `icosd jarpdrihdftrih gdtdrahgrakotih gistafd G=O, it wau`e ikp`y tgot tgd iftdcrity aj tgd ]IFC

    jifcdr is rdquirde jar tgd ohhuku`otiaf aj umiquity`otde gistafd G=O ot sotd``itd rdpdots, os

    wd govd sgawf tgot tgd sokd rdciaf is hritiho` jar trofshriptiafo` si`dfhifc if tgd

    gdtdrahgrakotif 'Jic& =e)& Ua tdst tgis gypatgdsis, HgIR dxpdrikdfts wdrd pdrjarkde usifc

    GHH?983 hd``s rdhafstitutde witgM]HO?+U83],M]HO?+Z??O, arCJR 'Jic& =c)& Ugd

    U83] kutoftM]HO? joi`de ta sicfijihoft`y dfrihg umiquity`otde gistafd G=O ot sotd``itd

    rdciafs, if o koffdr siki`or ta CJR haftra`, wgi`d tgd pa`ykarpgihM]HO?+Z??O sgawde

    dfrihgkdft aj umiquity`otde gistafd G=O witgif tgd sokd rdciafs& O eistifht kutoft I=:O

    wgihg gos mddf rdpartde ta fat edstomi`izd tgdMO]E? iftdrohtiaf mut gos fa umiquity` `icosd

    ohtivity?8 joi`s ta hakp`dkdft tgd `ass ajM]HO? 'Xupp`dkdftory Jic& 4)& Ugd umiquity`

    `icosd jufhtiaf ajM]HO? oppdors ta md spdhijih os ed`dtiaf aj]ifc?M ar lfahleawf aj

    ]FJ7joi` ta opprdhiom`y edrdprdss sotd``itd trofshriptiaf 'Xupp`dkdftory Jic& :)& Ugdsd

    jifeifcs pravied jurtgdr dviedfhd tgot tgdM]HO? umiquitif `icosd ohtivity is dssdftio` jar tgdkoiftdfofhd aj tgd umiquity` gistafd G=O korl witgif hafstitutivd gdtdrahgrakotih rdciafs

    fat af`y if kausd tissud mut o`sa gukof hd``s edrivde jrak mrdost hofhdrs&

    Tmiquity`otde gistafd G=O rdshuds M]HO?

    Ua ossdss tgd haftrimutiaf aj umiquity`+gistafd G=O ta tgd jufhtiaf ajM]HO? if

    gdtdrahgrakotih si`dfhifc wd cdfdrotde o dftiviro` vdhtar hafstruht dxprdssifc of G=O+Tm

    jusiaf pratdif tgot kikihs tgd foturo` umiquity` gistafd G=O 'Jic& 8o)& Ugis wos

    ohhakp`isgde my jusifc o sifc`d umiquitif kaidty ta tgd H+tdrkifus aj gistafd G=O if `idu

    aj tgd kaeijihotiaf aj `ysifd ??9& Xumfuh`dor jrohtiafotiaf aj hd``s dxprdssifc tgis jusiaf

    pratdif sgaws tgot tgd G=O+Tm pratdif ofe kutofts hof md ifharparotde ifta hd` u`or

    hgrakotif 'Xupp`dkdftory Jic& 3)&M]HO? edjihidft GHH?983 hd``s wdrd trofseuhde witg

    `dftivirus dxprdssifc tgd G=O+Tm jusiaf pratdif& _uoftijihotiaf aj tgd dvd`s aj sotd``itdEFO trofshriptiaf sgawde tgot tgd G=O+Tm dxprdssiaf hof rd+dstom`isg si`dfhifc aj tgd

    sotd``itd rdpdots 'khMax, XOUo ofe XOUIII) witgif gdtdrahgrakotif ifM]HO?+edjihidft

    gukof hd``s, succdstifc tgot kafa+umiquity`+G=O is `ild`y ta md tgd koif torcdt ajM]HO?

    umiquitif D8 icosd tgot kdeiotds si`dfhifc ot hafstitutivd gdtdrahgrakotif 'Jic& 8m)& Dhtapih

    dxprdssiaf aj G=O+Tm 'Xupp`dkdftory Jic& 7) if kurifd FRHs rdstarde tgd `dvd`s aj

    sotd``itd EFO si`dfhifc ta kard tgof 92$ aj dfeacdfaus wi`etypd si`dfhifc 'Jic& 8h)&

    Kutotiafs witgif tgd umiquitif eakoif aj tgd jusiaf pratdif rdeuhde tgd omi`ity ta rdstard

    si`dfhifc aj tgd G=O+Tm jusiaf pratdif 'Xupp`dkdftory Jic& 9o)& G=O+Tm dxprdssiaf if

    wi`e typd hd``s goe fa sicfijihoft djjdht af tgd sotd``itd EFO trofshriptiaf& Ua ifquird

    wgdtgdr tgd umiquity`otiaf aj gistafd G=O ojjdhtde prdviaus`y wd``+eahukdftdeM]HO?

    jufhtiafs, wd tdstde ij tgd rdstarde sotd``itd EFO si`dfhifc ifM]HO? fu`` hd``s goe ofy aj

    tgd dxpdhtde hafsdqudfhds& It gos mddf rdpartde tgot prikoryM]HO? fu`` hd``s eisp`oy o

    sdvdrd crawtg edjdht ofep48+ohtivotde opaptasis ofe tgotp48 ifohtivotiaf orcd`y rdshudstgd crawtg edjdht?5& My pdrjarkifc MreT ifharparotiaf ossoys, wd jaufe tgot dhtapih

    dxprdssiaf aj G=O+Tm `de ta o rdstarotiaf aj avdr 34$ aj pra`ijdrotiaf ifM]HO? edjihidft

    hd``s, af`y s`icgt`y `awdr tgof op48 lfahleawf 'Jic& 8e)& Ocoif, if tgis hosd dxprdssiaf aj

    G=O+Tm mypossde tgd rdquirdkdft jarM]HO?& It is wartgy ta fatd tgot o`tgaucgp48 is om`d

    ta rdshud tgd pra`ijdrotivd edjdht ajM]HO? edjihidft hd``s, it eads fat rdshud tgd jarkotiaf

    aj gdtdrahgrakotih hdftdrs, ar tgd edrdprdssiaf aj sotd``itd trofshripts 'Xupp`dkdftory Jic&

    ^gu dt o`& Rocd 5

    Foturd& Outgar kofushript< ovoi`om`d if RKH =2?= Korhg 7&

    FIG+ROO

    utgarKofushript

    FIG+ROOutgarKofushript

    FIG+ROOutgar

    Kofushript

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    ?2)& Sd o`sa dvo`uotde tgd omi`ity aj G=O+Tm ta supprdss opaptasis& Xtoififc jar of

    opaptatih korldr, ohtivd hosposd8, sgawde o siki`or rdsu`t 'Jic& 8d) ta wgot wos sddf jar

    MreT ifharparotiaf ar trofshriptiafo` si`dfhifc& Ugus G=O+Tm hof supprdss tgd opaptasis

    ifeuhde my tgd `ass ajM]HO?& Uoldf tacdtgdr, dhtapih dxprdssiaf aj G=O+Tm fat af`y

    rdstarde si`dfhifc mut o`sa rdshude tgd pra`ijdrotivd edjdht ofe opaptasis ajM]HO? edjihidft

    hd``s& Ugis rdshud aj tgd pra`ijdrotivd hopohity aj G=O+Tm is spdhijih jar tgd umiquity`otiaf

    kaeijihotiaf, os kutotiafs witgif tgd umiquitif eakoif hof omracotd tgd djjdht

    'Xupp`dkdftory Jics& 9m ofe 9h)& Gaka`acaus rdhakmifotiaf, ofatgdr rdpartde hd``u`orprahdss if wgihgM]HO? gos mddf ikp`ihotde, hof o`sa md rdshude my dhtapih G=O+Tm

    dxprdssiaf if tgd omsdfhd ajM]HO?, wgdrdos tgd sokd pratdif witg o trip`d paift kutotiaf

    witgif tgd umiquitif eakoif is ufom`d ta hakp`dkdft 'Xupp`dkdftory Jic& ??)& Ugus, kafa+

    umiquity`+G=O is `ild`y tgd prifhipo` torcdt ajM]HO? jar koiftoififc gdtdrahgrakotif

    iftdcrity if viva&

    Gdtdrahgrakotif ofe M]HO? tukar supprdssiaf

    Sd fdxt ifvdsticotde tgd sicfijihofhd aj gdtdrahgrakotif jufhtiaf ifM]HO? kdeiotde

    tukar supprdssiaf& Kausd mrdost tukars 'Jic& 5o) wdrd gorvdstde jrak ofiko`s wgdrd

    M]HO? wos ed`dtde if tgd kokkory c`ofe 'o`sa sgawf if Jic& =h)& Ofo`ysds my q]U+RH]

    sgawde eisruptde sotd``itd EFO si`dfhifc ifM]HO? edjihidft kausd kokkory tukars, mut

    fat if tissuds wgdrdM]HO? is iftoht 'Jic& 5m)& Jurtgdrkard, wd ofo`yzde sotd``itd trofshriptsif gukof mrdost tukars edrivde jrak dicgt ifeivieuo`M]HO? kutotiaf horridrs ofe jaufe

    sicfijihoft edrdprdssiaf aj tgd dxprdssiaf aj o`pgo sotd``itd rdpdots> HJWr ofe XOUo 'twa aj

    gukof o`pgo sotd``itd EFO sdqudfhds< Jic& 5h)& Ugd eijjdrdfhds ord oppordft, dvdf witgaut

    farko`izifc jar ofy atgdr johtars 'd&c& tgd pdrhdftocd aj faf+tukar hd`` haftokifotiaf), if

    hakporisaf witg o hagart aj farko` mrdost miapsids&

    Xotd``itd trofshript ifeuhde cdfakih ifstomi`ity

    Ua ifvdsticotd wgdtgdr tgd amsdrvde sotd``itd EFO edrdprdssiaf if kausd ofe gukof mrdost

    hofhdrs is ditgdr of dpipgdfakdfaf ar aj dtia`aciho` sicfijihofhd jar tgd cdfdsis aj hofhdr,

    wd dhtapiho``y dxprdssde sotd``itd EFO jrak o trofseuhde `dftiviro` vdhtar 'Jic& 4o) if

    hu`turde prikory gukof kokkory dpitgd`io` hd``s 'GKDHs)& Ugdsd hd``s ifhrdosde

    omfarko` kitatih jicurds, ifh`ueifc mriecde ofe `occifc hgrakasakds ofe eisarcofizdekdtopgosds sgawf my EORI stoififc 'Jics& 4m ofe supp`dkdftory Jic&?=)&

    Ikkufaj`uardshdfhd stoififc aj pdrihdftrif ofe tumu`if rdvdo`de okp`ijide hdftrasakds, os

    prdviaus`y edshrimde ifM]HO? fu`` hd``s 'Jic& 4h)& Hd``s avdrdxprdssifc sotd``itd ]FO o`sa

    eisp`oyde fukdraus jahi ajG=Ox 'Jic& 4e), o wd``+dstom`isgde korldr aj EFO eaum`d

    strofe mrdols& Ugis kirrars tgd pgdfatypd ajM]HO? edjihidft hd``s& J`aw hytakdtrih

    ofo`ysds sgawde of ikpoirde kitatih spife`d hgdhlpaift wgdf hd``s avdrdxprdssifc sotd``itd

    EFO wdrd trdotde witg fahaeoza`d 'Jic& 4d), wgihg gos o`sa mddf rdpartde os oM]HO? `ass

    pgdfatypd?4& Nust os dxpdhtde, dhtapih dxprdssiaf aj sotd``itd ]FO wos om`d ta hrdotd o

    edjihidfhy if gaka`acaus rdhakmifotiaf siki`or if kocfitued ta tgd lfahleawf ajM]HO?

    'Xupp`dkdftory Jic&?8)& Ikpartoft y, tgd hd``u`or edjdhts ossahiotde witg sotd``itd ]FO

    avdrdxprdssiaf ord cdfdro``y hafsiedrde doeifc housds jar cdfakih ifstomi`ity&

    Eishussiaf

    Ugd prdsdft warl sgaws tgotM]HO? edjihidfhy ikpoirs tgd iftdcrity aj hafstitutivd

    gdtdrahgrakotif wgihg `does ta tgd eisruptiaf aj cdfd si`dfhifc ot tgd tofedk`y rdpdotde

    EFO rdciafs, pramom`y tgraucg tgd `ass aj umiquitifotiaf aj gistafd G=O&M]HO?!MO]E?

    pratdifs prdjdrdftio``y kafa+umiquity`otd G=O ot gicg staihgiakdtry7, wgihg hakprisds

    4+?4$ aj tgd tato` hd``u`or fuh`dasako` gistafd G=O?:& M]HO? ohhuku`otds G=O+Tm ot

    ^gu dt o`& Rocd 4

    Foturd& Outgar kofushript< ovoi`om`d if RKH =2?= Korhg 7&

    FIG+ROO

    utgarKofushript

    FIG+ROOutgarKofushript

    FIG+ROOutgar

    Kofushript

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    sotd``itd EFO rdciafs, wgihg dfhakposs ~8&54$ aj tgd kausd cdfakd?? 'Jic& =j) ofe itsd`j

    `aho`izds tgdrd my HgIR dxpdrikdfts 'Jic& =d)& UgdM]HO? ]IFC eakoif is dssdftio` jar

    matg sotd``itd EFO mifeifc ofe si`dfhifc&MO]E? is o`sa rdquirde jar rdprdssiaf aj sotd``itd

    rdpdots ofe `ass ajMO]E? is aj fa hafsdqudfhd ijM]HO? is o`rdoey omsdft 'Xupp`dkdftory

    Jic& 5h)& O`tgaucg tgd dxoht jufhtiaf is fat wd`` ufedrstaae, tgd dkdrcifc fatiaf is tgot

    kafa+umiquitifotde gistafd G=O is kast jrdqudft`y ossahiotde witg trofshriptiafo` y

    rdprdssivd stotds9,?3,?7& Atgdr umiquity` icosds>]ifc?O!M, aj tgd pa`yhakm rdprdssivd

    hakp`dx ? 'R]H?), ofe]FJ7 o EFO rdpoir `icosd?9,=2

    umiquity`otd G=O mut ea fathaftrimutd ta tgd si`dfhifc aj sotd``itd rdpdots 'Xupp`dkdftory Jic& :)& Xiki`or`y,MOR?, o

    lfawf M]HO? mifeifc pratdif, gos mddf sgawf ta oftocafizd tgd pa`yhakm hakp`dx my

    edumiquitifotifc gistafd G=O=?,==& Xifhd o kikih aj foturo` umiquity`+G=O hof rdshud tgd

    kast prakifdftM]HO? edjihidfhy edjdhts, it succdsts tgot umiquity`otiaf aj gistafd G=O is

    `ild`y ta md tgd prikory sumstrotd ajM]HO? 'Jics& 8 ofe Xupp`dkdftory Jic& 9)&

    It is wartg fatifc tgot avdrdxprdssiaf aj tgd sotd``itd trofshripts if tgd prdsdfhd aj wi`etypd

    M]HO? portio``y pgdfahapidsM]HO? `ass 'Jic& 4), ifh`ueifc hdftrasakd okp`ijihotiaf ofe

    G=Ox jahi jarkotiaf& Ugdsd amsdrvotiafs succdst hafstitutivd gdtdrahgrakotif jarkotiaf

    prdvdfts EFO eokocd ar o EFO eokocd rdspafsd& Ugd jufhtiaf aj sotd``itd trofshripts is

    `orcd`y uflfawf& Gawdvdr, it gos mddf lfawf tgot tgd iftdcrity aj hdftrakdrih

    gdtdrahgrakotif rdquirds of uflfawf ]FO hakpafdft3 tgot hau`e hafhdivom`y md sotd``itd

    trofshripts&

    Uukar supprdssiaf myM]HO? wos prdsukde ta ahhur vio gaka`acaus rdhakmifotiaf8&

    ]dhdft warl sgawde tgot hd``s dxprdssifc o kutoftM]HO? edvaie aj D8 `icosd ohtivity ea

    fat dxgimit edjdhts if gaka`acaus rdhakmifotiaf?8& Ugus, tgd edjdht if cdfakih ifstomi`ity

    ifM]HO? fu`` hd``s sddks fat ta rdquird tgis jufhtiaf o`tgaucg of iftoht ]IFC eakoif is

    rdquirde jar rdhavdry jrak cokko irroeiotiaf=8& Fdvdrtgd`dss, kutotiafs tgot hakprakisd

    tgd umiquity` `icosd ohtivity ajM]HO? ord hofhdr prdeispasifc ofe hafstitutd gatspats aj

    kutotiafo` ahhurrdfhds if potidfts=8& Aur warl sgaws tgot sotd``itd EFO rdprdssiaf ifedde

    rdquirds of iftohtM]HO? ]IFC eakoif, hafsistdft witg sotd``itd EFO edrdprdssiaf

    amsdrvde ifM]HO? tukars 'Jic& =e)& Ifedde sotd``itd trofshripts if h`ifiho` M]HO? potidft

    tukars ord uprdcu`otde 'Jic& 5h)& Xifhd sotd``itd trofshripts wgdf dxprdssde dhtapiho``y hof

    ifeuhd hdftrasakd okp`ijihotiaf, hd`` hyh`d hgdhl paift edjdht ofe tgd EFO eokocd

    rdspafsd, it ju`ji``s tgd hritdrio ta md o koif djjdhtar ajM]HO? kdeiotde tukaricdfdsis&O`tgaucg it is prdsdft`y ufh`dor gaw tgdsd prahdssds ord d`ihitde ot o kdhgofistih `dvd` it is

    tdkptifc ta spdhu`otd tgot gistafd G=O umiquity`otiaf potgwoys ord ifva`vde& O`tdrfotivd`y,

    tgd edrdprdssiaf aj sotd``itd kicgt md d`ihitde my sakd ifeirdht c`amo` djjdht if trofs tgot

    wau`e fat rdquird G=O+Tm ta md ot tgd edrdprdssde sitd& It is hafhdivom`d tgot ifeuhtiaf aj

    sotd``itd trofshripts hau`e md edvd`apde ifta o korldr aj `ass aj gdtdrazycasity jar h`ifiho`

    eiocfastih opp`ihotiaf& ]dhdft warl gos sgawf tgot o voridty aj dpitgd`io` hofhdrs

    avdrdxprdss sotd``itd rdpdots tgot dfhakposs up ta 42$ aj hd``u`or trofshripts=5& O`tgaucg

    tgd potga`aciho` sicfijihofhd aj tgis jifeifc is uflfawf, aur warl succdsts tgot tgdsd hau`e

    haftrimutd ta tgd dva`utiaf aj tgd hofhdr hd`` tgraucg tgd ifeuhtiaf aj cdfakih ifstomi`ity

    'Xupp`dkdftory Jic& ?5)&

    Kdtgaes Xukkory

    Hd`` hu`turd, virus ifjdhtiaf, quoftitotivd ]U+RH] ofe HgIR dxpdrikdfts& Rrikory fduro`

    pracdfitar hd``s wdrd isa`otde jrak oeu`t kihd haftoififc afdM]HO? fu`` o``d`d ofe afd

    j`axdeM]HO? o``d`d os edshrimde=4& Dkmryafih fduro` pracdfitars wdrd isa`otde ofe

    hu`turde os edshrimde=:& Hu`turde hd``s wdrd ifjdhtde witg rdtravirusds witg of KAI aj 4 jar

    ?=+g ofe gorvdstde ot tgd tikd ifeihotde if harrdspafeifc jicurd `dcdfes& Hd``s wdrd

    gorvdstde witg U]I^A@ jar ]FO dxtrohtiaf& ]dvdrsd trofshriptiaf wos horride aut usifc

    ^gu dt o`& Rocd :

    Foturd& Outgar kofushript< ovoi`om`d if RKH =2?= Korhg 7&

    FIG+ROO

    utgarKofushript

    FIG+ROOutgarKofushript

    FIG+ROOutgar

    Kofushript

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    XupdrXhript III Jirst+strofe Xyftgdsis Xystdk 'Ifvitracdf)& Ugd quoftitotiaf aj RH] praeuhts

    wos ofo`yzde witg XYM] Crddf usifc OMI R]IXK 3322 Xdqudfhd Edtdhtiaf systdk

    sajtword 'Opp`ide Miasystdks)& Hrass`iflifc ofe HgIR wdrd pdrjarkde os o kaeijide

    vdrsiaf aj o prataha` edshrimde my tgd H`dvdrs `omarotary=3 ofe supp`dkdftory ifjarkotiaf&

    Ju`` Kdtgaes ofe ofy ossahiotde rdjdrdfhds ord ovoi`om`d if tgd af`ifd vdrsiaf aj tgd popdr

    ot www&foturd&hak!foturd&

    Xupp`dkdftory Kotdrio`

    ]djdr ta Sdm vdrsiaf af RumKde Hdftro` jar supp`dkdftory kotdrio`&

    Ohlfaw`deckdfts

    Ugd outgars tgofl Mormoro Ki``dr jar ossistofhd if hu`turifc FRH, Ducdfd Ld jar eishussiaf ofe ofo`ysis aj

    Ojjykdtrix eoto, Er& Okid` Yofoi jar tgd M]HO? torcdtifc sg]FO hafstruht, Er& Hora`ifd @i``dy jar ossistofhd

    witg Sdstdrf m`attifc, ofe Er& ^gafcsgdfc Yau jar ossistofhd witg tgd @I+HA] Aeyssdy Ifjrorde Ikocifc Xystdk&

    Sd tgofl Er& Oftaf Mdrfs jar gis sustoifde iftdrdst if tgis warl ofe pravieifc kutoft kihd ofe kotdrio`s ofe Er&

    Kicud` Zieo` jar pravieifc kausd dkmrya jimram`osts haftoififc hafeitiafo` ed`dt iaf o``d`d aj ]ifc ?M& _^ wos

    suppartde my tgd Ho`ijarfio Mrdost Hofhdr ]dsdorhg Rracrok ofe ]utg @& Lirshgtdif Fotiafo` ]dsdorhg Xdrvihd

    Owore& CKR wos suppartde my o jd``awsgip aj tgd Ho`ijarfio Ifstitutd aj ]dcdfdrotivd Kdeihifd& GX is o rdhipidft

    aj OXRDU+Kdrhl jd``awsgip& IKZ is of Okdrihof Hofhdr Xahidty Rrajdssar aj Ka`dhu`or Mia`acy, ofe ga`es tgd

    Irwif ofe Naof Nohams Hgoir if Dxdkp`ory @ijd Xhidfhd& Ugis warl wos suppartde if port my crofts jrak tgd FIG,Ipsdf!Miakdosurd, Xofaji Ovdftis, ofe tgd G&F& ofe Jrofhds H& Mdrcdr Jaufeotiaf& JGC is suppartde my FIG

    FX4=75=, FX42=?3, ofe tgd @aalaut Jufe&

    ]djdrdfhds

    ?& Uutt O, Osgwartg O& Ugd rd`otiafsgip mdtwddf tgd ra`ds aj M]HO? cdfds if EFO rdpoir ofe hofhdr

    prdeispasitiaf& Urdfes if Ka`dh Kde& =22=< 7>43?43:& \RumKde> ?=532992[

    =& Lifc KH, Korls NG, Kofed`` NM& Mrdost ofe avoriof hofhdr risls eud ta ifgdritde kutotiafs if

    M]HO? ofe M]HO=& Xhidfhd& =228< 82='4:54)>:58:5:& \RumKde> ?543:585[

    8& Gudf KX, Xy XK, Hgdf N& M]HO? ofe its taa`max jar tgd koiftdfofhd aj cdfakd iftdcrity& Fot

    ]dv Ka` Hd`` Mia`& =2?2< ??'=)>?87?57& \RumKde> =22=95=2[

    5& Rocdou CN, Go`` @@, Cofdsof X, @ivifcstaf EK, @owrdfhd NM& Ugd eisoppdorifc Morr maey if

    mrdost ofe avoriof hofhdrs& Fot ]dv Hofhdr& =223< 3'7)>:=7:88& \RumKde> ?3:??454[

    4& @ofd UJ, dt o`& Dxprdssiaf aj Mrho? is ossahiotde witg tdrkifo` eijjdrdftiotiaf aj dhtaedrko``y ofe

    kdsaedrko``y edrivde tissuds if kihd& Cdfds Edv& ?994< 9>=3?==3==& \RumKde> 3492=53[

    :& Largafdf @, Mroffvo`` L, Xlac`aso Y, @ifega`k E& Uukar supprdssar cdfd M]HO+? is dxprdssde

    my dkmryafih ofe oeu`t fduro` stdk hd``s ofe ifva`vde if hd`` pra`ijdrotiaf& N Fdurashi ]ds& =228=9:825& \RumKde> ?423?445[

    7& Wio Y, Roa CK, Hgdf GS, Zdrko IK, Guftdr U& Dfgofhdkdft aj M]HO? D8 umiquitif `icosd

    ohtivity tgraucg eirdht iftdrohtiaf witg tgd MO]E? pratdif& N Mia` Hgdk& =228< =37'3)>4=444=:8&

    \RumKde> ?=58?99:[

    9& Sofc G, dt o`& ]a`d aj gistafd G=O umiquitifotiaf if Ra`yhakm si`dfhifc& Foturd& =225< 58?'32?2)>

    738737& \RumKde> ?487:2==[

    ?2& Kdfdcgifi KE, Su K, Koegofi GE& Hafsdrvde gistafd vorioft G=O&^ pratdhts duhgrakotif

    jrak tgd dhtapih sprdoe aj si`dft gdtdrahgrakotif& Hd``& =228< ??='4)>3=438:& \RumKde>

    ?=:=7?9?[

    ??& Kortdfs NG, dt o`& Ugd praji`d aj rdpdot+ossahiotde gistafd `ysifd kdtgy`otiaf stotds if tgd kausd

    dpicdfakd& Dkma N& =224< =5'5)>7227?=& \RumKde> ?4:37?25[

    ?=& Gosgizukd ], dt o`& Ugd ]IFC gdtdraeikdr M]HO?+MO]E? is o umiquitif `icosd ifohtivotde my o

    mrdost hofhdr+edrivde kutotiaf& N Mia` Hgdk& =22?< =3:>?5483?5452& \RumKde> ??=37=53[

    ^gu dt o`& Rocd 3

    Foturd& Outgar kofushript< ovoi`om`d if RKH =2?= Korhg 7&

    FIG+ROO

    utgarKofushript

    FIG+ROOutgarKofushript

    FIG+ROOutgar

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    ?8& ]die @N, dt o`& D8 `icosd ohtivity aj M]HO? is fat dssdftio` jar kokko`iof hd`` viomi`ity ar

    gaka`acy+eirdhtde rdpoir aj eaum`d+strofe EFO mrdols& Rrah Fot` Ohoe Xhi T X O& =227=::=3?& \RumKde> ??58?:97[

    ?4& Xoflorof X, Xtorito @K, Cradf OH, La KN, Rorvif NE& Hdftrasako` kihratumu`d fuh`dotiaf

    ohtivity is ifgimitde my M]HO?+edpdfedft umiquitifotiaf& Ka` Hd`` Mia`& =224< =4'?9)>7:4:7::7&

    \RumKde> ?:?:::54[

    ?:& Kotsui XI, Xdaf ML, Xofemdrc OO& Eisoppdorofhd aj o struhturo` hgrakotif pratdif O=5 if

    kitasis> ikp`ihotiafs jar ka`dhu`or mosis aj hgrakotif hafedfsotiaf& Rrah Fot` Ohoe Xhi T X O&

    ?939< 3:'?=)>:87::892& \RumKde> =983=3[

    ?3& Lo``if DK, dt o`& Cdfakd+wied uG=O aho`izotiaf ofo`ysis gicg`icgts Mki?+edpdfedft edpasitiaf

    aj tgd korl ot rdprdssde cdfds& R@aX Cdfdt& =229< 4':)>d?22242:& \RumKde> ?9428494[

    ?7& ^gau S, dt o`& Gistafd G=O kafaumiquitifotiaf rdprdssds trofshriptiaf my ifgimitifc ]FO

    pa`ykdrosd II trofshriptiafo` d`afcotiaf& Ka` Hd``& =227< =9'?)>:972& \RumKde> ?7=2:932[

    ?9& Eai` H, dt o`& ]FJ?:7 mifes ofe okp`ijids umiquitif hafnucotds af eokocde hgrakasakds ta o``aw

    ohhuku`otiaf aj rdpoir pratdifs& Hd``& =229< ?8:'8)>58455:& \RumKde> ?9=28439[

    =2& Xtdwort CX, dt o`& Ugd ]IEE@D syferakd pratdif kdeiotds o umiquitif+edpdfedft sicfo`ifc

    hoshoed ot sitds aj EFO eokocd& Hd``& =229< ?8:'8)>5=2585& \RumKde> ?9=28437[

    =?& Xhgdudrkoff NH, dt o`& Gistafd G=O edumiquitifosd ohtivity aj tgd Ra`yhakm rdprdssivd hakp`dx

    R]+ETM& Foturd& =2?2< 5:4'3=94)>=58=53& \RumKde> =258:549[==& Ndfsdf ED, dt o`& MOR?> o favd` umiquitif gyera`osd wgihg mifes ta tgd M]HO? ]IFC jifcdr ofe

    dfgofhds M]HO?+kdeiotde hd`` crawtg supprdssiaf& Afhacdfd& ?997< ?:'9)>?293???=&

    \RumKde> 94=774=[

    =8& ]ujjfdr G, Naozdira HOR, Gdkkoti E, Guftdr U, Zdrko IK& Hofhdr+prdeispasifc kutotiafs

    witgif tgd ]IFC eakoif aj M]HO?> @ass aj umiquitif pratdif `icosd ohtivity ofe pratdhtiaf jrak

    roeiotiaf gypdrsdfsitivity& Rrah Fot` Ohoe Xhi 'TXO)& =22?< 97'9)>4?854?89& \RumKde>

    ??8=2=42[

    =5& Uifc EU, dt o`& Omdrroft avdrdxprdssiaf aj sotd``itd rdpdots if pofhrdotih ofe atgdr dpitgd`io`

    hofhdrs& Xhidfhd& =2??< 88?':2?3)>49849:& \RumKde> =?=88857[

    =4& Ro`kdr UE, Korlolis DO, Si``gaitd O], Xojor J, Cocd JG& Jimram`ost crawtg johtar+= ohtivotds o

    `otdft fduracdfih pracrok if fduro` stdk hd``s jrak eivdrsd rdciafs aj tgd oeu`t HFX& N Fdurashi&

    ?999< ?9'?9)>75737593& \RumKde> ?2598359[

    =:& Folosgiko L, dt o`& Xyfdrcistih sicfo`ifc if jdto` mroif my XUOU8+Xkoe? hakp`dx mriecde myp822& Xhidfhd& ?999< =75'45?8)>53957=& \RumKde> ?2=24245[

    =3& vof Ds NG, dt o`& Sft sicfo``ifc ifeuhds koturotiaf aj Rofdtg hd``s if iftdstifo` hrypts& Fot Hd``

    Mia`& =224< 3'5)>87?87:& \RumKde> ?433732:[

    ^gu dt o`& Rocd 7

    Foturd& Outgar kofushript< ovoi`om`d if RKH =2?= Korhg 7&

    FIG+ROO

    utgarKofushript

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    Jicurd ?& M]HO? edjihidfhy ikpoirs gdtdrahgrakotif struhturd

    o, Dxprdssiaf aj M]HO? is eikifisgde if tgdFdstif+HrdM]HO? lfahlaut mroifs os sgawf

    my ikkufam`attifc& LA> sokp ds jrak o R3M]HO? LA 'Mrho??,!+

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    Jicurd =& M]HO? ofe its umiquitif D8 `icosd ohtivity ord rdquirde jar cdfd si`dfhifc ifhafstitutivd gdtdrahgrakotif

    o, _uoftitotivd ]U+RH] sgawde tgot gdtdrahgrakotih rdciafs ar hdrtoif ikpriftde cdfds

    'Icj= *G?9 mut fatIcj=]) wdrd uprdcu`otde ifM]HO? LA mroifs& Iftdrfo` haftra`s>

    hyh`apgi`if ar?7X]FO& m, ]dshud aj tgdM]HO? kdeiotde rdprdssiaf if FRHs my dxacdfaus

    gukofM]HO? mut fat CJR ojtdr ifjdhtiaf witg rdtraviro` H]D+CJR& h, _uoftitotivd ]U+

    RH] dxpdrikdfts sgawde tgot gdtdrahgrakotih rdciafs ar ikpriftde cdfds wdrd uprdcu`otdeif M]HO? LA kokkory c`ofes ':+wddl vircif)& e, Ugd umiquitif D8 `icosd ohtivity aj

    M]HO? is rdquirde jar gdtdrahgrakotif si`dfhifc& GHH?983 hd``s wdrd rdhafstitutde witg

    ditgdr wi`e typdM]HO? 'GHHM?) ar M]HO? witg o kutotiaf if tgd ]IFC eakoif, U83]=8&

    R3 hdrdmd``or HgIR dxpdrikdfts witg oftimaeids ocoifst 'd) kausdM]HO? arZXZC pratdif

    os o haftra` ofe 'j) umiquity`+gistafd G=O ar gistafd G8 pratdif os o haftra`& Dfrihgkdft aj

    konar ofe kifar sotd``itd EFO wos kdosurde my quoftitotivd RH] rd`otivd ta ?7X haftra`& c,

    ^gu dt o`& Rocd ?2

    Foturd& Outgar kofushript< ovoi`om`d if RKH =2?= Korhg 7&

    FIG+ROO

    utgarKofushript

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    HgIR dxpdrikdfts wdrd pdrjarkde usifc umiquitifotde gistafd G=O oftimaey os if 'j) ofe

    GHH?983 hd``s rdhafstitutde witg CJR,M]HO? 'Z??O) ar o kutoft 'U83])& Drrar mors ord

    sgawf os s&e& Dohg rdsu`t sgawf is rdprdsdftotivd aj tgrdd ifedpdfedft dxpdrikdfts&

    ^gu dt o`& Rocd ??

    Foturd& Outgar kofushript< ovoi`om`d if RKH =2?= Korhg 7&

    FIG+ROO

    utgarKofushript

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    Jicurd 8& Tmiquitifotde gistafd G=O is eirdht`y ifva`vde if M]HO? kdeiotde gdtdrahgrakotihsi`dfhifc

    o, O eiocrok sgawifc tgd ortijihio` umiquitif+G=O dxprdssiaf vdhtar& m, GHH?983 hd``s

    wdrd ifjdhtde witg o `dftiviro` vdhtar dxprdssifc umiquity`otde gistafd G=O kikih jusiaf

    pratdif arCJR os o haftra` ofe tgd `dvd`s aj o`pgo sotd``itd voriofts 'khMax, XOUo ofe

    XOUIII) trofshriptiaf wdrd kdosurde my q]U+RH]& h, Dhtapih dxprdssiaf aj umiquity`otde

    gistafd G=O rd+dstom`isgde gdtdrahgrakotif si`dfhifc ifM]HO? fu`` FRHs& FRHs wdrd

    ifjdhtde witg CJR o`afd, umG=O, H]D+CJR o`afd ofeH]D+CJR haifjdhtde witg TmG=O&

    Ugd dvd`s aj sotd``itd EFO trofshriptiaf wdrd kdosurde my q]U+RH]& e, FRHs sgawde

    ifhrdosde pra`ijdrotiaf upaf dxprdssiaf aj umiquity`otde gistafd G=O if M]HO? fu`` FRHs&

    Uwa eoys ojtdr ifjdhtiaf '= epi), hd``s wdrd `omd`de witg MreT priar ta jixotiaf,

    ikkufastoififc ofe JOHX ofo`ysis& ]dsu`t sgawf is rdprdsdftotivd aj 8 ifedpdfedft

    dxpdrikdfts& d, FRHs sgawde rdeuhde opaptasis upaf dxprdssiaf aj umiquity`otde gistafdG=O ifM]HO? fu`` FRHs& FRHs wdrd hu`turde ofe ifjdhtde os if 'e)& Hd``s wdrd jixde,

    ikkufastoifde witg ofti+ohtivotdehosposd 8 oftimaey ofe sumndhtde ta hafjaho` ikocifc&

    Drrar mors ord sgawf os s&e& Xho`d mor> ?22 k

    ^gu dt o`& Rocd ?=

    Foturd& Outgar kofushript< ovoi`om`d if RKH =2?= Korhg 7&

    FIG+ROO

    utgarKofushript

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    Jicurd 5& Edrdprdssiaf aj sotd``itd EFO trofshriptiaf ahhurs if M]HO?+edjihidft mrdost hofhdrs

    o, Godkotaxy`if!dasif stoififc ajM]HO?LA kausd mrdost hofhdr& MdhousdM]HO? LA

    jdko`d kihd edvd`ap kokkory tukars vdry rord`y, tgdsd kihd wdrd hrassde ifta o p48

    gdtdrazycaus mohlcraufe jar ohhd`drotde tukaricdfdsis& KC, kokkory c`ofe jrak farko`

    kausd `ittdrkotds& KCU, kokkory tukars jrak M]HO?LA kausd

    'Mrho??,!+

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    Jicurd 4& Dhtapih dxprdssiaf aj sotd``itd EFO `does ta cdfakih ifstomi`ity if gukof kokkorydpitgd`io` hd``s

    o, O eiocrok aj tgd `dfti+viro` vdhtar dxprdssifc tgd gukof ar kausd sotd``itd EFO

    sdqudfhd 'rde orraws) ufedr tgd G? prakatdr 'croy orraw)& m, h, e, Avdrdxprdssiaf aj

    sotd``itd ]FO ifeuhde kitatih hotostrapgd 'm), hdftrasakd okp`ijihotiaf 'h), gistafd G=Ox

    pgaspgary`otiaf 'e), if prikory GKDHs& d, Edjdhtivd kitatih hgdhlpaifts ifeuhde my

    sotd``itd EFO avdrdxprdssiaf& 57g ojtdr trofseuhtiaf aj o dftivirus dxprdssifc gukof

    sotd``itd EFO sdqudfhd witg jarwore eirdhtiaf 'gukof sotd``itd J), ar witg rdvdrsd eirdhtiaf

    'gukof sotd``itd ]), ar kausd sotd``itd EFO sdqudfhd, ar of dkpty vdhtar, T+=AX hd``s wdrd

    m`ahlde witg tgykieifd, ja``awde my trdotkdft aj fahaeoza`d& Ugd hd``s wdrd stoifde witg

    pgasga+gistafd G8 oftimaey ofe RI priar ta j`aw hytakdtrih ofo`ysis& Ugd sgawf dxpdrikdft

    is rdprdsdftotivd aj 8 ifedpdfedft rdp`ihotds&

    ^gu dt o`& Rocd ?5

    Foturd& Outgar kofushript< ovoi`om`d if RKH =2?= Korhg 7&

    FIG+ROO

    utgarKofushript

    FIG+ROOutgarKofushript

    FIG+ROOutgar

    Kofushript