JP2017000156A - 核酸ナノ構造バーコードプローブ - Google Patents
核酸ナノ構造バーコードプローブ Download PDFInfo
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- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
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Abstract
【解決手段】少なくとも2つの蛍光標識を含む核酸ナノチューブと、前記核酸ナノチューブと結合する標的結合部分と、を含む核酸バーコードプローブ。標的を検出する方法であって、サンプルを核酸バーコードプローブと接触させるステップとして、前記核酸バーコードプローブが前記サンプル中の標的と結合する条件下で接触させるステップと、超解像技術を用いて、前記核酸バーコードプローブを含む前記サンプルをイメージングして、前記核酸バーコードプローブが前記サンプル中の標的と結合するか否かを決定するステップと、を含む方法。
【選択図】図1
Description
本出願は、「DNA NANOSTRUCTURE BARCODE PROBES」という名称で、2010年10月29日に出願された米国仮特許出願第61/408358号明細書の利益を主張する。尚、上記文献の全内容は、参照として本明細書に組み込むものとする。
本開示物には、コンピュータープログラム一覧が添付され、これは、参照として本明細書に組み込む。この付録は、6ht−v5−1color−1.json及び6ht−v6−2color−1.jsonの一覧を含むファイルprogramlisting.txtを含む。
DNAナノ構造バーコードプローブは、とりわけ、既存の分子バーコード技術が用いられるあらゆるアッセイに用いることができる。例えば、DNAバーコードプローブは、米国特許出願公開第2010/0015607号明細書に記載の方法に従って用いることができる。尚、上記文献の内容は、その全文を参照として本明細書に組み込む。
本明細書で述べるように、本発明のある態様では、バーコードプローブは、200nm(すなわち、可視光線の回折限界)未満の間隔で位置する蛍光標識領域を含む。これらの形態のいくつかでは、プローブをサンプルと接触させ、このサンプルの1つ以上の成分といったん結合したら、これを可溶性オリゴヌクレオチドに暴露するが、その各々は、上記領域の1つに特異的であり、発蛍光団で標識されている。このような可溶性の、一時的に結合するオリゴヌクレオチドは、本明細書では「イメージャー」鎖と呼ぶこともある。ある形態では、サンプル中の非結合成分は、発蛍光団担持オリゴヌクレオチドの添加前に除去する。次に、発蛍光団担持オリゴヌクレオチドとプローブ上のその補体との結合を検出するために、一連の単一微速度撮影画像又は微速度撮影動画を用いて、残るサンプル成分をイメージングすることによって、バーコードプローブの存在(及びそのバーコードに基づくその同一性)を決定する。プローブ上の補体は、本明細書では「ドッキング」鎖と呼ぶこともある。任意の所定時点で、単一発蛍光団担持オリゴヌクレオチドだけがバーコードプローブと結合するように、条件を設定する。任意の所定時点で、単一発蛍光団担持オリゴヌクレオチドだけが結合すれば、たとえ隣接領域同士の間隔が200nm未満であっても、その色同一性を決定することができる(同時に隣接領域に結合する発蛍光団がないため)。このようにして、200nm未満の間隔で隣接する「蛍光標識」領域を配置することができ、これによって、バーコードのさらに高い多様性を生み出すことができる。これらの実施形態において、蛍光標識領域は、一時的に蛍光性であるにすぎず、バーコードは、イメージャー鎖が結合しているときだけ蛍光性であることは理解すべきである。
800nmの6へリックバンドル二量体ナノチューブの3つの個別の領域を蛍光標識することによって、DNA折り紙バーコードプローブを構築した(図1)。長さ約28nmの蛍光標識領域の各々を、3つの発蛍光団の1つ(ローダミン−グリーン、Cy3又はCy5)に結合させた12のオリゴヌクレオチドで修飾した。DNA折り紙バーコードプローブは、最初の2つの標識領域同士の間隔(約460nm)を最後の2つの間隔(約270nm)より大きくして配置することによって、非対称になるように設計した。尚、対称配置を含む他の配置も本発明によって考慮されることは、理解すべきである。
前述のように、モノマーナノチューブの2つを折りたたんで、個別に蛍光標識した後、一緒にして、ナノバーコードを取得した。最終生成物をアガロースゲル電気泳動によって精製した後、全反射照明蛍光顕微鏡(TIRFM)を用いたイメージングのために、ガラススライド上に直接載せた。手短に言うと、5μLの精製ナノバーコード(約20pM)をガラススライド上に載せ、カバーガラス(No.1.5、18×18mm2、厚さ約0.17mm)で挟み、5分静置した後、Leica DM16000B TIRFMでイメージングした。各々擬色(青、緑及び赤)を割り当てた3つのチャンネルを通じて、サンプルを順次イメージングした。青色チャンネルについては、488nmレーザービームをダイクロイックミラー(430/505/575/670)で反射させ、100×対物レンズ(HCX PL APO 100×/1.47 oil CORR TIRF,Leica)を介してサンプルに照射した。放射光は、同じ対物レンズを介して収集し、同じダイクロイックミラー及び外部吸収フィルターを介してフィルタリングした後、EM−CCDカメラ(Hamamatsu C9100−02)で、800ミリ秒間積分した。緑色及び赤色チャンネルについては、励起レーザー(それぞれ561及び635nm)、吸収フィルター(それぞれ605/52及び705/72)及び露光時間(それぞれ500及び700ミリ秒)を除いて同様の設計を用いた。イメージング工程は、Leica LASソフトウエアによって自動的に制御した。画像は、Image J及び解読のためのカスタムソフトウエアにより処理した。
DNAバーコードプローブを用いて、42−ntDNAオリゴヌクレオチド標的を検出した。2つの異なる精製バーコード、すなわち、42−ntオリゴヌクレオチド標的に特異的な21−ntオリゴヌクレオチド標的捕捉部分を含む緑色、赤色、緑色(GRG)と、標的捕捉部分を含まない青色、赤色、緑色(BRG)を1:1の比で混合して、フォールディングバッファーで20pMまで希釈した。標的1に特異的なビオチンプローブ(100nM、0.2μL)と標的1(10nM、0.4μL)を100μLのバーコード混合物に添加した。100μLのバーコード混合物を含む個別の試験管に、0.2μLの標的用の100nMビオチンプローブ及び0.4μLの1×フォールディングバッファーを負の対照として添加した。上記サンプルをいずれも37℃で一晩インキュベートした後、ストレプトアビジンを塗布したカバーガラス(Xenopore)支持体を含むミクロ流体セルの個別チャンネルを介して流した。次に、両チャンネルを40μLの洗浄バッファーで(5mM Tris−HCl pH8.0、500mM NaCl)洗浄した後、前述したようにLeica TIRFMでイメージングした。各チャンネルにおいてランダムな位置で10の画像を撮影し、DNA折り紙バーコードプローブの総数を手動式でカウントした。
多重化能力をさらに増大するために、ゾーン毎の6ステープル伸長部を変更して、標識のために12の同じ蛍光オリゴヌクレオチドを用いるのではなく、2つ以下の発蛍光団の組合せを用いて、各ゾーンについてユニークな蛍光シグネチャー(擬色)を生み出すようにした。スペクトルが識別可能な3つの発蛍光団を用いたこの「二重標識」戦略によって、6つの擬色(B、R、G、BG、及びGR)が生み出された。その結果、異なるバーコードの総数は、27から63=216へと増加したが、これは、多重化能力の大きさの増大を表すものである。
約100nm間隔で配置される蛍光要素を有する幾何学的コード化超解像度バーコードを用いて、より高い空間情報密度を有するバーコードも作製した。
原理証明実験において、GRGバーコードを用いて、野生型カンジダ・アルビカンス(Candida albicans)酵母をタグ付けした。この酵母細胞を、まず、カンジダ・アルビカンス(C.albicans)に特異的なビオチン化ポリクローナル抗体と混合し、次いで、ストレプトアビジンの層を塗布した後、最後に、ビオチン化GRGバーコード(図7A)と一緒にインキュベートした。TIRF顕微鏡法によって、酵母細胞の底部表面に結合したバーコードが明らかになった(図7B、上のパネル)。不都合にも酵母細胞の平らではない細胞壁上に落下したナノチューブもあったが、いくつかのGRGバーコードは、はっきりと視覚化することができる。対照的に、非ビオチン化抗体又はバーコードを用いて酵母を処理した場合、バーコードタグ付けは全く観察されなかった(図7B、下のパネル)が、これは、バーコードと細胞表面の間に非特異的相互作用がほとんど又は全く存在しなかったことを示している。
非直線構造のDNAナノ構造を組み立てて、より洗練されたバーコードを作製することができる。図8は、ステープル伸長部同士のハイブリダイゼーションにより(図8A、挿入図)、3つの約400nmDNAチューブを約60nmDNA環状DNAの外縁に結合させた例を示す。上記の環とナノチューブの遠端を蛍光標識することにより、蛍光顕微鏡法で明瞭に分解可能な3点星様構造が形成された。TIRF顕微鏡法及びTEM試験(図8B)から、好適に折りたたまれたバーコードの約50%が、設計通りに互いの角度120°前後で、環を取り囲む3つのナノチューブを特徴としたが、他の多くのバーコードは、環とナノチューブの間の半柔軟性二本鎖DNAリンカーのために、隣接するナノチューブの間の角度が有意に偏っていた。3つの同じ「サテライト」直線状バーコードを中心ハブと接続させる類似の設計(ここで、3つのサテライトバーコードは、共通の蛍光標識ゾーンとしてハブを共有しうる)を用いて、3倍のコード化冗長性を有するバーコードを構築することができ、これらは優れた信頼性を特徴とすると考えられる。さらに、環と突起の間(例えば、鎖交差を有する多重らせんDNA)に、より剛性のリンカーを用いて、より確実に画定されたバーコード形状を強化することも可能である。
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当業者であれば、常用の実験を用いるだけで、本明細書に記載した主題の具体的実施形態の多くの同等物を認識するか、又は確認することができるであろう。こうした同等物は、以下の特許請求の範囲に含まれるものとする。
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,1,1228],[1,1231,1,1229],[1,1232,1,1230],[1,1233,1,1231],[1,1234,1,1232],[1,1235,1,1233],[1,1236,1,1234],[1,1237,1,1235],[1,1238,1,1236],[1,1239,1,1237],[1,1240,1,1238],[1,1241,1,1239],[1,1242,1,1240],[1,1243,1,1241],[1,1244,1,1242],[1,1245,1,1243],[1,1246,1,1244],[1,1247,1,1245],[1,1248,1,1246],[1,1249,1,1247],[1,1250,1,1248],[1,1251,1,1249],[1,1252,1,1250],[1,1253,1,1251],[1,1254,1,1252],[1,1255,1,1253],[1,1256,1,1254],[1,1257,1,1255],[0,1257,1,1256],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1]],「行」:15,「番号」:1},{「ステープル_色」:[[97,1507550],[139,1507550],[181,8947848],[223,8947848],[265,8947848],[307,8947848],[349,8947848],[391,8947848],[433,8947848],[475,8947848],[517,8947848],[559,8947848],[601,8947848],[643,8947848],[685,8947848],[727,8947848],[769,8947848],[811,8947848],[853,8947848],[895,8947848],[937,8947848],[979,8947848],[1021,8947848],[1063,8947848],[1105,8947848],[1147,8947848],[1189,8947848],[1231,8947848],[1273,3355443]],「ステープル」:[[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[2,57,−1,−1],[2,58,2,56],[2,59,2,57],[2,60,2,58],[2,61,2,59],[2,62,2,60],[2,63,2,61],[2,64,2,62],[2,65,2,63],[2,66,2,64],[2,67,2,65],[2,68,2,66],[2,69,2,67],[3,69,2,68],[2,71,3,70],[2,72,2,70],[2,73,2,71],[2,74,2,72],[2,75,2,73],[2,76,2,74],[2,77,2,75],[2,78,2,76],[2,79,2,77],[2,80,2,78],[2,81,2,79],[2,82,2,80],[2,83,2,81],[1,83,2,82],[2,85,1,84],[2,86,2,84],[2,87,2,85],[2,88,2,86],[2,89,2,87],[2,90,2,88],[2,91,2,89],[2,92,2,90],[2,93,2,91],[2,94,2,92],[2,95,2,93],[2,96,2,94],[2,97,2,95],[−1,−1,2,96],[2,99,−1,−1],[2,100,2,98],[2,101,2,99],[2,102,2,100],[2,103,2,101],[2,104,2,102],[2,105,2,103],[2,106,2,104],[2,107,2,105],[2,108,2,106],[2,109,2,107],[2,110,2,108],[2,111,2,109],[3,111,2,110],[2,113,3,112],[2,114,2,112],[2,115,2,113],[2,116,2,114],[2,117,2,115],[2,118,2,116],[2,119,2,117],[2,120,2,118],[2,121,2,119],[2,122,2,120],[2,123,2,121],[2,124,2,122],[2,125,2,123],[1,125,2,124],[2,127,1,126],[2,128,2,126],[2,129,2,127],[2,130,2,128],[2,131,2,129],[2,132,2,130],[2,133,2,131],[2,134,2,132],[2,135,2,133],[2,136,2,134],[2,137,2,135],[2,138,2,136],[2,139,2,137],[−1,−1,2,138],[2,141,−1,−1],[2,142,2,140],[2,143,2,141],[2,144,2,142],[2,145,2,143],[2,146,2,144],[2,147,2,145],[2,148,2,146],[2,149,2,147],[2,150,2,148],[2,151,2,149],[2,152,2,150],[2,153,2,151],[3,153,2,152],[2,155,3,154],[2,156,2,154],[2,157,2,155],[2,158,2,156],[2,159,2,157],[2,160,2,158],[2,161,2,159],[2,162,2,160],[2,163,2,161],[2,164,2,162],[2,165,2,163],[2,166,2,164],[2,167,2,165],[1,167,2,166],[2,169,1,168],[2,170,2,168],[2,171,2,169],[2,172,2,170],[2,173,2,171],[2,174,2,172],[2,175,2,173],[2,176,2,174],[2,177,2,175],[2,178,2,176],[2,179,2,177],[2,180,2,178],[2,181,2,179],[−1,−1,2,180],[2,183,−1,−1],[2,184,2,182],[2,185,2,183],[2,186,2,184],[2,187,2,185],[2,188,2,186],[2,189,2,187],[2,190,2,188],[2,191,2,189],[2,192,2,190],[2,193,2,191],[2,194,2,192],[2,195,2,193],[3,195,2,194],[2,197,3,196],[2,198,2,196],[2,199,2,197],[2,200,2,198],[2,201,2,199],[2,202,2,200],[2,203,2,201],[2,204,2,202],[2,205,2,203],[2,206,2,204],[2,207,2,205],[2,208,2,206],[2,209,2,207],[1,209,2,208],[2,211,1,210],[2,212,2,210],[2,213,2,211],[2,214,2,212],[2,215,2,213],[2,216,2,214],[2,217,2,215],[2,218,2,216],[2,219,2,217],[2,220,2,218],[2,221,2,219],[
2,222,2,220],[2,223,2,221],[−1,−1,2,222],[2,225,−1,−1],[2,226,2,224],[2,227,2,225],[2,228,2,226],[2,229,2,227],[2,230,2,228],[2,231,2,229],[2,232,2,230],[2,233,2,231],[2,234,2,232],[2,235,2,233],[2,236,2,234],[2,237,2,235],[3,237,2,236],[2,239,3,238],[2,240,2,238],[2,241,2,239],[2,242,2,240],[2,243,2,241],[2,244,2,242],[2,245,2,243],[2,246,2,244],[2,247,2,245],[2,248,2,246],[2,249,2,247],[2,250,2,248],[2,251,2,249],[1,251,2,250],[2,253,1,252],[2,254,2,252],[2,255,2,253],[2,256,2,254],[2,257,2,255],[2,258,2,256],[2,259,2,257],[2,260,2,258],[2,261,2,259],[2,262,2,260],[2,263,2,261],[2,264,2,262],[2,265,2,263],[−1,−1,2,264],[2,267,−1,−1],[2,268,2,266],[2,269,2,267],[2,270,2,268],[2,271,2,269],[2,272,2,270],[2,273,2,271],[2,274,2,272],[2,275,2,273],[2,276,2,274],[2,277,2,275],[2,278,2,276],[2,279,2,277],[3,279,2,278],[2,281,3,280],[2,282,2,280],[2,283,2,281],[2,284,2,282],[2,285,2,283],[2,286,2,284],[2,287,2,285],[2,288,2,286],[2,289,2,287],[2,290,2,288],[2,291,2,289],[2,292,2,290],[2,293,2,291],[1,293,2,292],[2,295,1,294],[2,296,2,294],[2,297,2,295],[2,298,2,296],[2,299,2,297],[2,300,2,298],[2,301,2,299],[2,302,2,300],[2,303,2,301],[2,304,2,302],[2,305,2,303],[2,306,2,304],[2,307,2,305],[−1,−1,2,306],[2,309,−1,−1],[2,310,2,308],[2,311,2,309],[2,312,2,310],[2,313,2,311],[2,314,2,312],[2,315,2,313],[2,316,2,314],[2,317,2,315],[2,318,2,316],[2,319,2,317],[2,320,2,318],[2,321,2,319],[3,321,2,320],[2,323,3,322],[2,324,2,322],[2,325,2,323],[2,326,2,324],[2,327,2,325],[2,328,2,326],[2,329,2,327],[2,330,2,328],[2,331,2,329],[2,332,2,330],[2,333,2,331],[2,334,2,332],[2,335,2,333],[1,335,2,334],[2,337,1,336],[2,338,2,336],[2,339,2,337],[2,340,2,338],[2,341,2,339],[2,342,2,340],[2,343,2,341],[2,344,2,342],[2,345,2,343],[2,346,2,344],[2,347,2,345],[2,348,2,346],[2,349,2,347],[−1,−1,2,348],[2,351,−1,−1],[2,352,2,350],[2,353,2,351],[2,354,2,352],[2,355,2,353],[2,356,2,354],[2,357,2,355],[2,358,2,356],[2,359,2,357],[2,360,2,358],[2,361,2,359],[2,362,2,360],[2,363,2,361],[3,363,2,362],[2,365,3,364],[2,366,2,364],[2,367,2,365],[2,368,2,366],[2,369,2,367],[2,370,2,368],[2,371,2,369],[2,372,2,370],[2,373,2,371],[2,374,2,372],[2,375,2,373],[2,376,2,374],[2,377,2,375],[1,377,2,376],[2,379,1,378],[2,380,2,378],[2,381,2,379],[2,382,2,380],[2,383,2,381],[2,384,2,382],[2,385,2,383],[2,386,2,384],[2,387,2,385],[2,388,2,386],[2,389,2,387],[2,390,2,388],[2,391,2,389],[−1,−1,2,390],[2,393,−1,−1],[2,394,2,392],[2,395,2,393],[2,396,2,394],[2,397,2,395],[2,398,2,396],[2,399,2,397],[2,400,2,398],[2,401,2,399],[2,402,2,400],[2,403,2,401],[2,404,2,402],[2,405,2,403],[3,405,2,404],[2,407,3,406],[2,408,2,406],[2,409,2,407],[2,410,2,408],[2,411,2,409],[2,412,2,410],[2,413,2,411],[2,414,2,412],[2,415,2,413],[2,416,2,414],[2,417,2,415],[2,418,2,416],[2,419,2,417],[1,419,2,418],[2,421,1,420],[2,422,2,420],[2,423,2,421],[2,424,2,422],[2,425,2,423],[2,426,2,424],[2,427,2,425],[2,428,2,426],[2,429,2,427],[2,430,2,428],[2,431,2,429],[2,432,2,430],[2,433,2,431],[−1,−1,2,432],[2,435,−1,−1],[2,436,2,434],[2,437,2,435],[2,438,2,436],[2,439,2,437],[2,440,2,438],[2,441,2,439],[2,442,2,440],[2,443,2,441],[2,444,2,442],[2,445,2,443],[2,446,2,444],[2,447,2,445],[3,447,2,446],[2,449,3,448],[2,450,2,448],[2,451,2,449],[2,452,2,450],[2,453,2,451],[2,454,2,452],[2,455,2,453],[2,456,2,454],[2,457,2,455],[2,458,2,456],[2,459,2,457],[2,460,2,458],[2,461,2,459],[1,461,2,460],[2,463,1,462],[2,464,2,462],[2,465,2,463],[2,466,2,464],[2,467,2,465],[2,468,2,466],[2,469,2,467],[2,470,2,468],[2,471,2,469],[2,472,2,470],[2,473,2,471],[2,474,2,472],[2,475,2,473],[−1,−1,2,474],[2,477,−1,−1],[2,478,2,476],[2,479,2,477],[2,480,2,478],[2,481,2,479],[2,482,2,480],[2,483,2,481],[2,484,2,482],[2,485,2,483],[2,486,2,484],[2,487,2,485],[2,488,2,486],[2,489,2,487],[3,489,2,488],[2,491,3,490],[2,492,2,490],[2,493,2,491],[2,494,2,492],[2,495,2,493],[2,496,2,494],[2,497,2,495],[2,498,2,496],[2,499,2,497],[2,500,2,498],[2,501,2,499],[2,502,2,500],[2,503,2,501],[1,503,2,502],[2,505,1,504],[2,506,2,504],[2,507,2,505],[2,508,2,506],[2,509,2,507],[2,510,2,508],[2,511,2,509],[2,512,2,510],[2,513,2,511],[2,514,2,512],[2,515,2,513],[2,516,2,514],[2,517,2,515],[−1,−1,2,516],[2,519,−1,−1],[2,520,2,518],[2,521,2,519],[2,522,2,520],[2,523,2,521],[2,524,2,522],[2,525,2,523],[2,526,2,524],[2,527,2,525],[2,528,2,526],[2,529,2,527],[2,530,2,528],[2,531,2,529],[3,531,2,530],[2,533,3,532],[2,534,2,532],[2,535,2,533],[2,536,2,534],[2,537,2,535],[2,538,2,536],[2,539,2,537],[2,540,2,538],[2,541,2,539],[2,542,2,540],[2,543,2,541],[2,544,2,542],[2,545,2,543],[1,545,2,544],[2,547,1,546],[2,548,2,546],[2,549,2,547],[2,550,2,548],[2,551,2,549],[2,552,2,550],[2,553,2,551],[2,554,2,552],[2,555,2,553],[2,556,2,554],[2,557,2,555],[2,558,2,556],[2,559,2,557],[−1,−1,2,558],[2,561,−1,−1],[2,562,2,560],[2,563,2,561],[2,564,2,562],[2,565,2,563],[2,566,2,564],[2,567,2,565],[2,568,2,566],[2,569,2,567],[2,570,2,568],[2,571,2,569],[2,572,2,570],[2,573,2,571],[3,573,2,572],[2,575,3,574],[2,576,2,574],[2,577,2,575],[2,578,2,576],[2,579,2,577],[2,580,2,578],[2,581,2,579],[2,582,2,580],[2,583,2,581],[2,584,2,582],[2,585,2,583],[2,586,2,584],[2,587,2,585
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行」:15,「番号」:2},{「ステープル_色」:[[84,1507550],[126,1507550],[168,8947848],[210,8947848],[252,8947848],[294,8947848],[336,8947848],[378,8947848],[420,8947848],[462,8947848],[504,8947848],[546,8947848],[588,8947848],[630,8947848],[672,8947848],[714,8947848],[756,8947848],[798,8947848],[840,8947848],[882,8947848],[924,8947848],[966,8947848],[1008,8947848],[1050,8947848],[1092,8947848],[1134,8947848],[1176,8947848],[1218,8947848],[1260,3355443]],「ステープル」:[[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[4,56,3,57],[3,56,3,58],[3,57,3,59],[3,58,3,60],[3,59,3,61],[3,60,3,62],[3,61,3,63],[3,62,3,64],[3,63,3,65],[3,64,3,66],[3,65,3,67],[3,66,3,68],[3,67,3,69],[3,68,2,69],[2,70,3,71],[3,70,3,72],[3,71,3,73],[3,72,3,74],[3,73,3,75],[3,74,3,76],[3,75,3,77],[3,76,3,78],[3,77,3,79],[3,78,3,80],[3,79,3,81],[3,80,3,82],[3,81,3,83],[3,82,−1,−1],[−1,−1,3,85],[3,84,3,86],[3,85,3,87],[3,86,3,88],[3,87,3,89],[3,88,3,90],[3,89,3,91],[3,90,3,92],[3,91,3,93],[3,92,3,94],[3,93,3,95],[3,94,3,96],[3,95,3,97],[3,96,4,97],[4,98,3,99],[3,98,3,100],[3,99,3,101],[3,100,3,102],[3,101,3,103],[3,102,3,104],[3,103,3,105],[3,104,3,106],[3,105,3,107],[3,106,3,108],[3,107,3,109],[3,108,3,110],[3,109,3,111],[3,110,2,111],[2,112,3,113],[3,112,3,114],[3,113,3,115],[3,114,3,116],[3,115,3,117],[3,116,3,118],[3,117,3,119],[3,118,3,120],[3,119,3,121],[3,120,3,122],[3,121,3,123],[3,122,3,124],[3,123,3,125],[3,124,−1,−1],[−1,−1,3,127],[3,126,3,128],[3,127,3,129],[3,128,3,130],[3,129,3,131],[3,130,3,132],[3,131,3,133],[3,132,3,134],[3,133,3,135],[3,134,3,136],[3,135,3,137],[3,136,3,138],[3,137,3,139],[3,138,4,139],[4,140,3,141],[3,140,3,142],[3,141,3,143],[3,142,3,144],[3,143,3,145],[3,144,3,146],[3,145,3,147],[3,146,3,148],[3,147,3,149],[3,148,3,150],[3,149,3,151],[3,150,3,152],[3,151,3,153],[3,152,2,153],[2,154,3,155],[3,154,3,156],[3,155,3,157],[3,156,3,158],[3,157,3,159],[3,158,3,160],[3,159,3,161],[3,160,3,162],[3,161,3,163],[3,162,3,164],[3,163,3,165],[3,164,3,166],[3,165,3,167],[3,166,−1,−1],[−1,−1,3,169],[3,168,3,170],[3,169,3,171],[3,170,3,172],[3,171,3,173],[3,172,3,174],[3,173,3,175],[3,174,3,176],[3,175,3,177],[3,176,3,178],[3,177,3,179],[3,178,3,180],[3,179,3,181],[3,180,4,181],[4,182,3,183],[3,182,3,184],[3,183,3,185],[3,184,3,186],[3,185,3,187],[3,186,3,188],[3,187,3,189],[3,188,3,190],[3,189,3,191],[3,190,3,192],[3,191,3,193],[3,192,3,194],[3,193,3,195],[3,194,2,195],[2,196,3,197],[3,196,3,198],[3,197,3,199],[3,198,3,200],[3,199,3,201],[3,200,3,202],[3,201,3,203],[3,202,3,204],[3,203,3,205],[3,204,3,206],[3,205,3,207],[3,206,3,208],[3,207,3,209],[3,208,−1,−1],[−1,−1,3,211],[3,210,3,212],[3,211,3,213],[3,212,3,214],[3,213,3,215],[3,214,3,216],[3,215,3,217],[3,216,3,218],[3,217,3,219],[3,218,3,220],[3,219,3,221],[3,220,3,222],[3,221,3,223],[3,222,4,223],[4,224,3,225],[3,224,3,226],[3,225,3,227],[3,226,3,228],[3,227,3,229],[3,228,3,230],[3,229,3,231],[3,230,3,232],[3,231,3,233],[3,232,3,234],[3,233,3,235],[3,234,3,236],[3,235,3,237],[3,236,2,237],[2,238,3,239],[3,238,3,240],[3,239,3,241],[3,240,3,242],[3,241,3,243],[3,242,3,244],[3,243,3,245],[3,244,3,246],[3,245,3,247],[3,246,3,248],[3,247,3,249],[3,248,3,250],[3,249,3,251],[3,250,−1,−1],[−1,−1,3,253],[3,252,3,254],[3,253,3,255],[3,254,3,256],[3,255,3,257],[3,256,3,258],[3,257,3,259],[3,258,3,260],[3,259,3,261],[3,260,3,262],[3,261,3,263],[3,262,3,264],[3,263,3,265],[3,264,4,265],[4,266,3,267],[3,266,3,268],[3,267,3,269],[3,268,3,270],[3,269,3,271],[3,270,3,272],[3,271,3,273],[3,272,3,274],[3,273,3,275],[3,274,3,276],[3,275,3,277],[3,276,3,278],[3,277,3,279],[3,278,2,279],[2,280,3,281],[3,280,3,282],[3,281,3,283],[3,282,3,284],[3,283,3,285],[3,284,3,286],[3,285,3,287],[3,286,3,288],[3,287,3,289],[3,288,3,290],[3,289,3,291],[3,290,3,292],[3,291,3,293],[3,292,−1,−1],[−1,−1,3,295],[3,294,3,296],[3,295,3,297],[3,296,3,298],[3,297,3,299],[3,298,3,300],[3,299,3,301],[3,300,3,302],[3,301,3,303],[3,302,3,304],[3,303,3,305],[3,304,3,306],[3,305,3,307],[3,306,4,307],[4,308,3,309],[3,308,3,310],[3,309,3,311],[3,310,3,312],[3,311,3,313],[3,312,3,314],[3,313,3,315],[3,314,3,316],[3,315,3,317],[3,316,3,318],[3,317,3,319],[3,318,3,320],[3,319,3,321],[3,320,2,321],[2,322,3,323],[3,322,3,324],[3,323,3,325],[3,324,3,326],[3,325,3,327],[3,326,3,328],[3,327,3,329],[3,328,3,330],[3,329,3,331],[3,3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6ht−v6−2color−1.jsonの一覧:
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1],[2,670,2,672],[2,671,2,673],[2,672,2,674],[2,673,2,675],[2,674,2,676],[2,675,2,677],[2,676,2,678],[2,677,2,679],[2,678,2,680],[2,679,2,681],[2,680,2,682],[2,681,2,683],[2,682,2,684],[2,683,2,685],[2,684,2,686],[2,685,2,687],[2,686,2,688],[2,687,2,689],[2,688,2,690],[2,689,2,691],[2,690,2,692],[2,691,2,693],[2,692,2,694],[2,693,2,695],[2,694,2,696],[2,695,2,697],[2,696,2,698],[2,697,2,699],[2,698,2,700],[2,699,2,701],[2,700,2,702],[2,701,2,703],[2,702,2,704],[2,703,2,705],[2,704,2,706],[2,705,2,707],[2,706,2,708],[2,707,2,709],[2,708,2,710],[2,709,2,711],[2,710,2,712],[2,711,2,713],[2,712,2,714],[2,713,2,715],[2,714,2,716],[2,715,2,717],[2,716,2,718],[2,717,2,719],[2,718,2,720],[2,719,2,721],[2,720,2,722],[2,721,2,723],[2,722,2,724],[2,723,2,725],[2,724,2,726],[2,725,2,727],[2,726,2,728],[2,727,2,729],[2,728,2,730],[2,729,2,731],[2,730,2,732],[2,731,2,733],[2,732,2,734],[2,733,2,735],[2,734,2,736],[2,735,2,737],[2,736,2,738],[2,737,2,739],[2,738,2,740],[2,739,2,741],[2,740,2,742],[2,741,2,743],[2,742,2,744],[2,743,2,745],[2,744,2,746],[2,745,2,747],[2,746,2,748],[2,747,2,749],[2,748,2,750],[2,749,2,751],[2,750,2,752],[2,751,2,753],[2,752,2,754],[2,753,2,755],[2,754,2,756],[2,755,2,757],[2,756,2,758],[2,757,2,759],[2,758,2,760],[2,759,2,761],[2,760,2,762],[2,761,2,763],[2,762,2,764],[2,763,2,765],[2,764,2,766],[2,765,2,767],[2,766,2,768],[2,767,2,769],[2,768,2,770],[2,769,2,771],[2,770,2,772],[2,771,2,773],[2,772,2,774],[2,773,2,775],[2,774,2,776],[2,775,2,777],[2,776,2,778],[2,777,2,779],[2,778,2,780],[2,779,2,781],[2,780,2,782],[2,781,2,783],[2,782,2,784],[2,783,2,785],[2,784,2,786],[2,785,2,787],[2,786,2,788],[2,787,2,789],[2,788,2,790],[2,789,2,791],[2,790,2,792],[2,791,2,793],[2,792,2,794],[2,793,2,795],[2,794,2,796],[2,795,2,797],[2,796,2,798],[2,797,2,799],[2,798,2,800],[2,799,2,801],[2,800,2,802],[2,801,2,803],[2,802,2,804],[2,803,2,805],[2,804,2,806],[2,805,2,807],[2,806,2,808],[2,807,2,809],[2,808,2,810],[2,809,2,811],[2,810,2,812],[2,811,2,813],[2,812,2,814],[2,813,2,815],[2,814,2,816],[2,815,2,817],[2,816,2,818],[2,817,2,819],[2,818,2,820],[2,819,2,821],[2,820,2,822],[2,821,2,823],[2,822,2,824],[2,823,2,825],[2,824,2,826],[2,825,2,827],[2,826,2,828],[2,827,2,829],[2,828,2,830],[2,829,2,831],[2,830,2,832],[2,831,2,833],[2,832,2,834],[2,833,2,835],[2,834,2,836],[2,835,2,837],[2,836,2,838],[2,837,2,839],[2,838,2,840],[2,839,2,841],[2,840,2,842],[2,841,2,843],[2,842,2,844],[2,843,2,845],[2,844,2,846],[2,845,2,847],[2,846,2,848],[2,847,2,849],[2,848,2,850],[2,849,2,851],[2,850,2,852],[2,851,2,853],[2,852,2,854],[2,853,2,855],[2,854,2,856],[2,855,2,857],[2,856,2,858],[2,857,2,859],[2,858,2,860],[2,859,2,861],[2,860,2,862],[2,861,2,863],[2,862,2,864],[2,863,2,865],[2,864,2,866],[2,865,2,867],[2,866,2,868],[2,867,2,869],[2,868,2,870],[2,869,2,871],[2,870,2,872],[2,871,2,873],[2,872,2,874],[2,873,2,875],[2,874,2,876],[2,875,2,877],[2,876,2,878],[2,877,2,879],[2,878,2,880],[2,879,2,881],[2,880,2,882],[2,881,2,883],[2,882,2,884],[2,883,2,885],[2,884,2,886],[2,885,2,887],[2,886,2,888],[2,887,2,889],[2,888,2,890],[2,889,2,891],[2,890,2,892],[2,891,2,893],[2,892,2,894],[2,893,2,895],[2,894,2,896],[2,895,2,897],[2,896,2,898],[2,897,2,899],[2,898,2,900],[2,899,2,901],[2,900,2,902],[2,901,2,903],[2,902,2,904],[2,903,2,905],[2,904,2,906],[2,905,2,907],[2,906,2,908],[2,907,2,909],[2,908,2,910],[2,909,2,911],[2,910,2,912],[2,911,2,913],[2,912,2,914],[2,913,2,915],[2,914,2,916],[2,915,2,917],[2,916,2,918],[2,917,2,919],[2,918,2,920],[2,919,2,921],[2,920,2,922],[2,921,2,923],[2,922,2,924],[2,923,2,925],[2,924,2,926],[2,925,2,927],[2,926,2,928],[2,927,2,929],[2,928,2,930],[2,929,2,931],[2,930,2,932],[2,931,2,933],[2,932,2,934],[2,933,2,935],[2,934,2,936],[2,935,2,937],[2,936,2,938],[2,937,2,939],[2,938,2,940],[2,939,2,941],[2,940,2,942],[2,941,2,943],[2,942,2,944],[2,943,2,945],[2,944,2,946],[2,945,2,947],[2,946,2,948],[2,947,2,949],[2,948,2,950],[2,949,2,951],[2,950,2,952],[2,951,2,953],[2,952,2,954],[2,953,2,955],[2,954,2,956],[2,955,2,957],[2,956,2,958],[2,957,2,959],[2,958,2,960],[2,959,2,961],[2,960,2,962],[2,961,2,963],[2,962,2,964],[2,963,2,965],[2,964,2,966],[2,965,2,967],[2,966,2,968],[2,967,2,969],[2,968,2,970],[2,969,2,971],[2,970,2,972],[2,971,2,973],[2,972,2,974],[2,973,2,975],[2,974,2,976],[2,975,2,977],[2,976,2,978],[2,977,2,979],[2,978,2,980],[2,979,2,981],[2,980,2,982],[2,981,2,983],[2,982,2,984],[2,983,2,985],[2,984,2,986],[2,985,2,987],[2,986,2,988],[2,987,2,989],[2,988,2,990],[2,989,2,991],[2,990,2,992],[2,991,2,993],[2,992,2,994],[2,993,2,995],[2,994,2,996],[2,995,2,997],[2,996,2,998],[2,997,2,999],[2,998,2,1000],[2,999,2,1001],[2,1000,2,1002],[2,1001,2,1003],[2,1002,2,1004],[2,1003,2,1005],[2,1004,2,1006],[2,1005,2,1007],[2,1006,2,1008],[2,1007,2,1009],[2,1008,2,1010],[2,1009,2,1011],[2,1010,2,1012],[2,1011,2,1013],[2,1012,2,1014],[2,1013,2,1015],[2,1014,2,1016],[2,1015,2,1017],[2,1016,2,1018],[2,1017,2,1019],[2,1018,2,1020],[2,1019,2,1021],[2,1020,2,1022],[2,1021,2,1023],[2,1022,2,1024],[2,1023,2,1025],[2,1024,2,1026],[2,1025,2,1027],[2,1026,2,1028],[2,1027,2,1029],[2,1028,2,1030],[2,1029,2,1031],[2,1030,2,1032],
[2,1031,2,1033],[2,1032,2,1034],[2,1033,2,1035],[2,1034,2,1036],[2,1035,2,1037],[2,1036,2,1038],[2,1037,2,1039],[2,1038,2,1040],[2,1039,2,1041],[2,1040,2,1042],[2,1041,2,1043],[2,1042,2,1044],[2,1043,2,1045],[2,1044,2,1046],[2,1045,2,1047],[2,1046,2,1048],[2,1047,2,1049],[2,1048,2,1050],[2,1049,2,1051],[2,1050,2,1052],[2,1051,2,1053],[2,1052,2,1054],[2,1053,2,1055],[2,1054,2,1056],[2,1055,2,1057],[2,1056,2,1058],[2,1057,2,1059],[2,1058,2,1060],[2,1059,2,1061],[2,1060,2,1062],[2,1061,2,1063],[2,1062,2,1064],[2,1063,2,1065],[2,1064,2,1066],[2,1065,2,1067],[2,1066,2,1068],[2,1067,2,1069],[2,1068,2,1070],[2,1069,2,1071],[2,1070,2,1072],[2,1071,2,1073],[2,1072,2,1074],[2,1073,2,1075],[2,1074,2,1076],[2,1075,2,1077],[2,1076,2,1078],[2,1077,2,1079],[2,1078,2,1080],[2,1079,2,1081],[2,1080,2,1082],[2,1081,2,1083],[2,1082,2,1084],[2,1083,2,1085],[2,1084,2,1086],[2,1085,2,1087],[2,1086,2,1088],[2,1087,2,1089],[2,1088,2,1090],[2,1089,2,1091],[2,1090,2,1092],[2,1091,2,1093],[2,1092,2,1094],[2,1093,2,1095],[2,1094,2,1096],[2,1095,2,1097],[2,1096,2,1098],[2,1097,2,1099],[2,1098,2,1100],[2,1099,2,1101],[2,1100,2,1102],[2,1101,2,1103],[2,1102,2,1104],[2,1103,2,1105],[2,1104,2,1106],[2,1105,2,1107],[2,1106,2,1108],[2,1107,2,1109],[2,1108,2,1110],[2,1109,2,1111],[2,1110,2,1112],[2,1111,2,1113],[2,1112,2,1114],[2,1113,2,1115],[2,1114,2,1116],[2,1115,2,1117],[2,1116,2,1118],[2,1117,2,1119],[2,1118,2,1120],[2,1119,2,1121],[2,1120,2,1122],[2,1121,2,1123],[2,1122,2,1124],[2,1123,2,1125],[2,1124,2,1126],[2,1125,2,1127],[2,1126,2,1128],[2,1127,2,1129],[2,1128,2,1130],[2,1129,2,1131],[2,1130,2,1132],[2,1131,2,1133],[2,1132,2,1134],[2,1133,2,1135],[2,1134,2,1136],[2,1135,2,1137],[2,1136,2,1138],[2,1137,2,1139],[2,1138,2,1140],[2,1139,2,1141],[2,1140,2,1142],[2,1141,2,1143],[2,1142,2,1144],[2,1143,2,1145],[2,1144,2,1146],[2,1145,2,1147],[2,1146,2,1148],[2,1147,2,1149],[2,1148,2,1150],[2,1149,2,1151],[2,1150,2,1152],[2,1151,2,1153],[2,1152,2,1154],[2,1153,2,1155],[2,1154,2,1156],[2,1155,2,1157],[2,1156,2,1158],[2,1157,2,1159],[2,1158,2,1160],[2,1159,2,1161],[2,1160,2,1162],[2,1161,2,1163],[2,1162,2,1164],[2,1163,2,1165],[2,1164,2,1166],[2,1165,2,1167],[2,1166,2,1168],[2,1167,2,1169],[2,1168,2,1170],[2,1169,2,1171],[2,1170,2,1172],[2,1171,2,1173],[2,1172,2,1174],[2,1173,2,1175],[2,1174,2,1176],[2,1175,2,1177],[2,1176,2,1178],[2,1177,2,1179],[2,1178,2,1180],[2,1179,2,1181],[2,1180,2,1182],[2,1181,2,1183],[2,1182,2,1184],[2,1183,2,1185],[2,1184,2,1186],[2,1185,2,1187],[2,1186,2,1188],[2,1187,2,1189],[2,1188,2,1190],[2,1189,2,1191],[2,1190,2,1192],[2,1191,2,1193],[2,1192,2,1194],[2,1193,2,1195],[2,1194,2,1196],[2,1195,2,1197],[2,1196,2,1198],[2,1197,2,1199],[2,1198,2,1200],[2,1199,2,1201],[2,1200,2,1202],[2,1201,2,1203],[2,1202,2,1204],[2,1203,2,1205],[2,1204,2,1206],[2,1205,2,1207],[2,1206,2,1208],[2,1207,2,1209],[2,1208,2,1210],[2,1209,2,1211],[2,1210,2,1212],[2,1211,2,1213],[2,1212,2,1214],[2,1213,2,1215],[2,1214,2,1216],[2,1215,2,1217],[2,1216,2,1218],[2,1217,2,1219],[2,1218,2,1220],[2,1219,2,1221],[2,1220,2,1222],[2,1221,2,1223],[2,1222,2,1224],[2,1223,2,1225],[2,1224,2,1226],[2,1225,2,1227],[2,1226,2,1228],[2,1227,2,1229],[2,1228,2,1230],[2,1229,2,1231],[2,1230,2,1232],[2,1231,2,1233],[2,1232,2,1234],[2,1233,2,1235],[2,1234,2,1236],[2,1235,2,1237],[2,1236,2,1238],[2,1237,2,1239],[2,1238,2,1240],[2,1239,2,1241],[2,1240,2,1242],[2,1241,2,1243],[2,1242,2,1244],[2,1243,2,1245],[2,1244,2,1246],[2,1245,2,1247],[2,1246,2,1248],[2,1247,2,1249],[2,1248,2,1250],[2,1249,2,1251],[2,1250,2,1252],[2,1251,2,1253],[2,1252,2,1254],[2,1253,2,1255],[2,1254,2,1256],[2,1255,2,1257],[2,1256,2,1258],[2,1257,2,1259],[2,1258,2,1260],[2,1259,2,1261],[2,1260,2,1262],[2,1261,2,1263],[2,1262,2,1264],[2,1263,2,1265],[2,1264,2,1266],[2,1265,2,1267],[2,1266,2,1268],[2,1267,2,1269],[2,1268,2,1270],[2,1269,2,1271],[2,1270,3,1271],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1]],「番号」:2,「行」:15},{「ステープル_色」:[[42,3355443],[84,8947848],[126,8947848],[168,8947848],[210,8947848],[252,8947848],[294,13369344],[336,13369344],[378,8947848],[420,8947848],[462,8947848],[504,8947848],[546,8947848],[588,8947848],[630,8947848],[672,8947848],[714,8947848],[756,89
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[5,1065,5,1063],[5,1066,5,1064],[5,1067,5,1065],[5,1068,5,1066],[5,1069,5,1067],[5,1070,5,1068],[5,1071,5,1069],[5,1072,5,1070],[5,1073,5,1071],[5,1074,5,1072],[5,1075,5,1073],[5,1076,5,1074],[5,1077,5,1075],[5,1078,5,1076],[5,1079,5,1077],[5,1080,5,1078],[5,1081,5,1079],[5,1082,5,1080],[5,1083,5,1081],[5,1084,5,1082],[5,1085,5,1083],[5,1086,5,1084],[5,1087,5,1085],[5,1088,5,1086],[5,1089,5,1087],[5,1090,5,1088],[5,1091,5,1089],[5,1092,5,1090],[5,1093,5,1091],[5,1094,5,1092],[5,1095,5,1093],[5,1096,5,1094],[5,1097,5,1095],[5,1098,5,1096],[5,1099,5,1097],[5,1100,5,1098],[5,1101,5,1099],[5,1102,5,1100],[5,1103,5,1101],[5,1104,5,1102],[5,1105,5,1103],[5,1106,5,1104],[5,1107,5,1105],[5,1108,5,1106],[5,1109,5,1107],[5,1110,5,1108],[5,1111,5,1109],[5,1112,5,1110],[5,1113,5,1111],[5,1114,5,1112],[5,1115,5,1113],[5,1116,5,1114],[5,1117,5,1115],[5,1118,5,1116],[5,1119,5,1117],[5,1120,5,1118],[5,1121,5,1119],[5,1122,5,1120],[5,1123,5,1121],[5,1124,5,1122],[5,1125,5,1123],[5,1126,5,1124],[5,1127,5,1125],[5,1128,5,1126],[5,1129,5,1127],[5,1130,5,1128],[5,1131,5,1129],[5,1132,5,1130],[5,1133,5,1131],[5,1134,5,1132],[5,1135,5,1133],[5,1136,5,1134],[5,1137,5,1135],[5,1138,5,1136],[5,1139,5,1137],[5,1140,5,1138],[5,1141,5,1139],[5,1142,5,1140],[5,1143,5,1141],[5,1144,5,1142],[5,1145,5,1143],[5,1146,5,1144],[5,1147,5,1145],[5,1148,5,1146],[5,1149,5,1147],[5,1150,5,1148],[5,1151,5,1149],[5,1152,5,1150],[5,1153,5,1151],[5,1154,5,1152],[5,1155,5,1153],[5,1156,5,1154],[5,1157,5,1155],[5,1158,5,1156],[5,1159,5,1157],[5,1160,5,1158],[5,1161,5,1159],[5,1162,5,1160],[5,1163,5,1161],[5,1164,5,1162],[5,1165,5,1163],[5,1166,5,1164],[5,1167,5,1165],[5,1168,5,1166],[5,1169,5,1167],[5,1170,5,1168],[5,1171,5,1169],[5,1172,5,1170],[5,1173,5,1171],[5,1174,5,1172],[5,1175,5,1173],[5,1176,5,1174],[5,1177,5,1175],[5,1178,5,1176],[5,1179,5,1177],[5,1180,5,1178],[5,1181,5,1179],[5,1182,5,1180],[5,1183,5,1181],[5,1184,5,1182],[5,1185,5,1183],[5,1186,5,1184],[5,1187,5,1185],[5,1188,5,1186],[5,1189,5,1187],[5,1190,5,1188],[5,1191,5,1189],[5,1192,5,1190],[5,1193,5,1191],[5,1194,5,1192],[5,1195,5,1193],[5,1196,5,1194],[5,1197,5,1195],[5,1198,5,1196],[5,1199,5,1197],[5,1200,5,1198],[5,1201,5,1199],[5,1202,5,1200],[5,1203,5,1201],[5,1204,5,1202],[5,1205,5,1203],[5,1206,5,1204],[5,1207,5,1205],[5,1208,5,1206],[5,1209,5,1207],[5,1210,5,1208],[5,1211,5,1209],[5,1212,5,1210],[5,1213,5,1211],[5,1214,5,1212],[5,1215,5,1213],[5,1216,5,1214],[5,1217,5,1215],[5,1218,5,1216],[5,1219,5,1217],[5,1220,5,1218],[5,1221,5,1219],[5,1222,5,1220],[5,1223,5,1221],[5,1224,5,1222],[5,1225,5,1223],[5,1226,5,1224],[5,1227,5,1225],[5,1228,5,1226],[5,1229,5,1227],[5,1230,5,1228],[5,1231,5,1229],[5,1232,5,1230],[5,1233,5,1231],[4,1233,5,1232],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1],[−1,−1,−1,−1]],「番号」:5,「行」:16}],「名称」:「2010年8月21日(土)16:08:47GMT−0400」}
Claims (34)
- 標的を検出する方法であって、以下:
サンプルを核酸バーコードプローブと接触させるステップ、及び
前記核酸バーコードプローブが、前記サンプル中の1つ以上の成分と結合するか否かを決定するステップを含み、
前記核酸バーコードプローブと前記サンプルの1つ以上の成分との結合が、前記サンプル中の標的の存在を示し、また、前記核酸バーコードプローブが、標的結合部分と、少なくとも2つの蛍光標識領域とを含む核酸ナノ構造を含む、方法。 - 前記サンプルの1つ以上の成分と結合した前記核酸バーコードプローブの蛍光標識領域の色及び/又は配向に基づいて、標的を識別するステップをさらに含む、請求項1に記載の方法。
- 前記核酸バーコードプローブが、前記サンプル中の1つ以上の成分と結合するか否かが、前記核酸バーコードプローブを、可溶性の、一時的に結合する発蛍光団担持オリゴヌクレオチドと接触させるステップを含む、請求項1又は2に記載の方法。
- 前記核酸バーコードプローブが、安定に結合した発蛍光団担持オリゴヌクレオチドを含む、請求項1又は2に記載の方法。
- 標的を検出する方法であって、
前記標的が核酸バーコードプローブと結合するのに十分な条件下で、前記標的を核酸バーコードプローブと接触させるステップ;
前記標的と結合していない材料から前記標的を分離するステップ;及び
前記標的と結合した前記核酸バーコードプローブの存在を検出するステップを含み、
前記核酸バーコードプローブが、標的結合部分と、少なくとも2つの蛍光標識領域とを含む核酸ナノ構造を含む、方法。 - 前記標的と結合した前記核酸バーコードプローブの蛍光標識領域の色及び/又は配向に基づいて、前記標的を識別するステップをさらに含む、請求項5に記載の方法。
- 前記標的と結合した前記核酸バーコードプローブの存在を検出するステップが、前記核酸バーコードプローブを、可溶性の、一時的に結合する発蛍光団担持オリゴヌクレオチドと接触させるステップを含む、請求項5又は6に記載の方法。
- 前記核酸バーコードプローブが、安定に結合した発蛍光団担持オリゴヌクレオチドを含む、請求項5又は6に記載の方法。
- サンプルと、
少なくとも2つの蛍光標識領域を有する核酸ナノ構造を含む核酸バーコードプローブ
を含む組成物であって、前記核酸ナノ構造上の前記蛍光標識領域の各々の位置は、前記蛍光標識のパターンが、前記蛍光標識領域による可視光線の発光に基づいて決定可能であるようにする、組成物。 - 前記核酸ナノ構造が、スカフォールド鎖と複数のステープル鎖を含む、請求項9に記載の組成物。
- 前記蛍光標識領域が、蛍光標識ステープル鎖を含む、請求項9又は10に記載の組成物。
- 前記蛍光標識ステープル鎖が、(a)スカフォールド鎖にハイブリダイズしたステープルドメインと(b)ハンドルドメインとを含む、請求項11に記載の組成物。
- 前記ハンドルドメインが、発蛍光団標識オリゴヌクレオチドにハイブリダイズしている、請求項12に記載の組成物。
- 前記核酸ナノ構造が、DNAナノ構造である、請求項9〜13のいずれか一項に記載の組成物。
- 前記DNAナノ構造がナノチューブである、請求項14に記載の組成物。
- 前記核酸ナノ構造が、少なくとも3つの蛍光標識領域又は少なくとも4つの蛍光標識領域を含む、請求項9〜15のいずれか一項に記載の組成物。
- 前記少なくとも3つ又は少なくとも4つの蛍光標識領域の配向が、前記蛍光標識領域同士の非対称間隔に基づいて決定可能である、請求項16に記載の組成物。
- 前記蛍光標識領域の各々が、前記他の蛍光標識領域の中心から少なくとも約50nm又は少なくとも約100nmに位置する中心を有する、請求項9〜17のいずれか一項に記載の組成物。
- 前記蛍光標識領域の各々が、前記他の蛍光標識領域の中心から少なくとも約200nmの地点に位置する中心を有する、請求項9〜18のいずれか一項に記載の組成物。
- 前記蛍光標識領域の各々の前記中心が、あらゆる他の蛍光標識領域の中心から少なくとも約250nmに位置する、請求項9〜19のいずれか一項に記載の組成物。
- 前記核酸ナノ構造が、標的結合部分をさらに含む、請求項9〜20のいずれか一項に記載の組成物。
- 前記標的結合部分が、一本鎖核酸である、請求項21に記載の組成物。
- 前記標的結合部分が、抗体である、請求項21に記載の組成物。
- 前記標的結合部分が、タンパク質又はペプチドである、請求項21に記載の組成物。
- 標的核酸を識別する方法であって、以下:
前記標的核酸が核酸バーコードプローブと結合するような条件下で、前記標的核酸を請求項9〜24のいずれか一項に記載の核酸バーコードプローブと接触させるステップ;
前記標的核酸と結合していない材料から前記標的核酸を分離するステップ;及び
前記標的核酸と結合した前記核酸バーコードプローブの存在を検出するステップを含む、方法。 - 標的タンパク質又は細胞を識別する方法であって、以下:
前記標的タンパク質又は細胞が核酸バーコードプローブと結合するような条件下で、前記標的タンパク質又は細胞を請求項9〜24のいずれか一項に記載の核酸バーコードプローブと接触させるステップ;
前記標的タンパク質又は細胞と結合していない材料から前記標的タンパク質又は細胞を分離するステップ;及び
前記標的タンパク質又は細胞と結合した前記核酸バーコードプローブの存在を検出するステップを含む、方法。 - 標的タンパク質又は細胞を識別する方法であって、以下:
前記標的タンパク質又は細胞が核酸バーコードプローブと結合するような条件下で、前記標的タンパク質又は細胞を請求項9〜24のいずれか一項に記載の核酸バーコードプローブと接触させるステップ;
前記標的タンパク質又は細胞と結合していない材料から前記標的タンパク質又は細胞を分離するステップ;及び
前記標的タンパク質又は細胞と結合した前記核酸バーコードプローブの存在を検出するステップを含む、方法。 - 標的を検出する方法であって、以下:
サンプルを請求項9〜24のいずれか一項に記載の核酸バーコードプローブと接触させるステップ、及び
前記核酸バーコードプローブが、前記サンプル中の1つ以上の成分と結合するか否かを決定するステップを含み、
前記核酸バーコードプローブと前記サンプル中の1つ以上の成分との結合が、前記サンプル中の標的の存在を示す、方法。 - 前記接触ステップの後、前記核酸バーコードプローブに結合していないサンプル中の成分を除去するステップをさらに含む、請求項28に記載の方法。
- 前記標的が、核酸、タンパク質、ペプチド、若しくは細胞、又はこれらの組合せである、請求項28又は29に記載の方法。
- 前記核酸バーコードプローブの存在が、蛍光顕微鏡によって検出される、請求項25〜30のいずれか一項に記載の方法。
- 前記核酸バーコードプローブの存在が、前記核酸バーコードプローブを電界に暴露することなく、検出される、請求項25〜30のいずれか一項に記載の方法。
- 核酸バーコードプローブの集団であって、各プローブが、少なくとも2つの蛍光標識領域と標的結合部分を有する核酸ナノ構造を含み、
前記核酸ナノ構造上の前記蛍光標識領域の各々の前記位置は、前記核酸バーコードプローブの蛍光標識のパターン及び前記結合部分の同一性が、前記蛍光標識領域による可視光線の発光に基づいて決定可能であるようにする、核酸バーコードプローブの集団。 - 前記蛍光標識領域の各々が、他の蛍光標識領域の中心から少なくとも約50nm、少なくとも約100nm、少なくとも約200nm、又は約250nmに位置する中心を有する、請求項33に記載の集団。
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US10876971B2 (en) | 2020-12-29 |
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