NANOTOOLS V2Long read sequence tools

Administrative User
Guide

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ADMINISTRATIVE USER GUIDELong read sequence tools

 world fusion
1-38-12 kakigara-cho nihonbashi
chuoku, Tokyo 103-0014
Phone 03.3662.0521 • Fax 03.3662.0522

Copyright (C) 2019 World Fusion Co.,LTD.
All Rights Reserved. under World Fusion Inc. No part of this documentation may be reproduced, stored, ortransmitted in any form without the prior permission of World Fusion Inc.

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インストール手順



本ツールは Linux で動作するプログラムを利用しています。
このプログラムを利用するため、初期設定が必要となります。

Linux で動作するツールは Windows10 WSL（Windows Subsystem for Linux）を利用して Windows 上で動作します。この WSL の設定と、利用するツール群のセットアップを行います。

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※ 本ツールの起動時に以下のチェックを行っています。
Step1:WSL（Windows Subsystem for Linux）が Windows 上で有効になっているか
Step2:利用するツール群を含んだ設定がされているか

このセットアップ プログラムは、本ツール起動時にチェックされ、各 Step が設定されていない場合、自動的に起動します。

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【WSL（Windows Subsystem for Linux）】の有効化
Windows10 は Linux の機能を利用するための機能があります。初期状態でこの機能は無効になっているため、ユーザが有効化する必要があります。詳しくはマイクロソフト社のページを参照してください。https://docs.microsoft.com/ja-jp/windows/wsl/install-win10

Windows 上で WSL（Windows Subsystem for Linux）が有効になって居ない場合、WSL を有効化するスクリプトを実行します。［Execute］ボタンを押下します。

Click!

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WSL を有効化するスクリプトが実行されます。実行の途中に以下の様なダイアログが表示されます。
これは Windows の機能を有効化するために管理者権限が必要となるためです。

Click!

［はい］を選択して設定を有効にします。［はい］が選択されるとコマンドプロンプト（黒いコマンドが実行されているウインドウ）が表示されます。

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コマンドプロンプトの中で処理の経過が表示されます。ＷＳＬの設定を有効にするために
Windows10 の再起動が必要になります。

現状態で Windows10 の再起を行う場合は［はい］を選択します。［はい］を選択するとWindows が再起動されます。［いいえ］を選択した場合は、別途ユーザが再起動を行うまで
WSL（Windows Subsystem for Linux）の機能が有効になりません。

※ 設定を有効にするためには Windows の再起動が必要です！

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【Ubuntu と Linux Tools】のインポート
Windows10 は Linux の機能を利用するための機能があります。本ツールは Microsoft 社が提供している Linux ディストリビューションの Ubuntu を利用しています。
詳しくは以下のマイクロソフト社のページを参照してください。https://docs.microsoft.com/ja-jp/windows/wsl/install-win10

Windows 上で WSL（Windows Subsystem for Linux）が有効になっている場合、セットアッ
プツールの Step1 は［済］のマークに変わります。

WSL が有効になり、本ツールが利用する Ubuntu とツール群がセットアップされていない場合、
Step2 を実行します。以下の様に Step2 の［Execute］ボタンを押下します

Click!

実行が開始されると、Step2 が［処理中］になります。
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Ubuntu とツール群がインポートされるには５～１０分程度（PC の性質によります）の時間が掛かります。変化が無いように見えますがしばらくお時間を見てください。

また、タスクマネージャでは以下の様なタスクが実行されています。

この機能が上位に現れます!

ディスクの IO が高くなります

正常に終了すると以下の様なダイアログが表示されます。［OK］ボタンを押下しセットアップツール
を終了します。

Click!

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【Ubuntu と Linux Tools】の削除
本ツールが利用する Linux の機能が不要になった場合は Linux の機能を削除する事が可能です。
Ubuntu の機能とともに、Windows から削除します。

セットアップツールを起動します。本ツールを解凍したフォルダと同じ場所に［WfComponentInstaller.exe］があります。このファイルをダブルクリックして起動します。

ダブルクリック!

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Click!
［Execute］ボタンを押下すると、本ツールで利用する Ubuntu を削除します。

※本ツールで利用する Ubuntu は、［Ubuntu-18.04-nanopore］として登録します。
通常、ユーザが WSL（Windows Subsystem for Linux）の Ubuntu を導入する場合は［Ubuntu18.04］として登録され、別の Ubuntu 環境として保存されています。
また、本ツールの［Ubuntu-18.04-nanopore］のインストール先は、ユーザごとに以下の場所へ
保存されます。
C:\Users\［ユーザ名］\AppData\Local\Ubuntu-18.04-nanoporeix

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Chapter

初期画面構成プログラムの実行は、NanoTools2.exe プログラム本体、もしくはショートカット をダブルクリックして開始します。

Click!

※インストールに関しては別途資料を参照してください。

起動すると以下の様なウインドウが表示されます。

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【機能タブ】の説明

それぞれのツールを切り替えます。

Convert タブ
MinION から出力された Fast5 形式から Fastq へ変換を行います。
この機能を利用するために nanopore コミュニティより取得する ont-guppy-cpu のインストールが必要です。

mapping タブ
リファレンスと Fastq 形式ファイルを指定し、マッピングを行います。対象の Fastq 形式ファイルは nanopore、
PacBaio、Illumina から出力されたファイルです。
マッピングツールは minimap2 を使用します。 ※https://github.com/lh3/minimap2

assemble タブ
Fastq 形式ファイルを指定し denovo assemble を行います。内部では minimap2、minasm、racon を利用したワークフローが実行されます。
※https://github.com/lh3/miniasm ※https://github.com/isovic/racon

variant タブ
リファレンスと Fastq 形式ファイルを指定し、構造変異検出を行います。内部では SVIM(Structural

Variant Identification Method using Long Reads)を使用します。
※https://github.com/eldariont/svim

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Chapter

Fast5/Fastq 変換
Nanopore MinION シーケンサから出力された Fast5 形式のファイルから
Fastq への変換を行います。ツールは guppy を使用します。
guppy は nanopore のユーザサイトよりダウンロードし、インストールします。

【Guppy Path.】の指定 必須

Click!

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[select]ボタンを押下すると、ファイル選択ウインドウが表示されます。

nanopore ユーザサイトからダウンロードし、インストールした guppy の basecaller のパスを設定します。インストール済みの ont-guppy-cpu_(バージョン)以下にある[bin]フォルダ内の【guppy_basecaller.exe】を指定します。

※ 現在は guppy_barcoder.exe のみ対応しています。 guppy_basecaller_1d2.exe を指定するとIndex ファイルが必要となり正常終了しない場合があります。

【Fast5 Directory.】の指定 必須[select]ボタンを押下すると、フォルダ選択ウインドウが表示されます。

nanopore シーケンサから出力された Fast5 形式ファイルを含むフォルダを指定します。
フォルダは複数選択が可能です。

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【more options】
guppy コマンドラインに追加するパラメータを記述します。
※現在は利用できません【Execute】ボタンを押す
必須項目が全て設定されていると、[Execute]ボタンが有効になります。ボタンを押下すると結果ファイルの出力先フォルダを選択するダイアログが表示されます。

実行可能!

出力先を選択すると処理が実行されます。
実行が正常に終了した場合、guppy の結果ファイルから PycoQC が実行されシーケンスの QCプロットが表示されます。

※https://github.com/a-slide/pycoQC

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Chapter

リファレンスマッピング

リファレンス配列に対して、指定した Fastq ファイルの塩基配列をマッピングします。
Fastq ファイルは、Illumina 、Nanopore、Pacbio の配列が適用できます。
Illumina 由来の Fastq ファイルがペアエンドの場合、自動的にペアを認識しマッピングを行います。（※ ファイル名の［_L001 _］を認識し、この文字列より前の文字列が同一の場
合、ペアエンドとみなします）

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【Reference.】の設定 必須

マッピング対象のリファレンス（fasta 形式）ファイルを選択します。［Select］ボタンを押下するとファイル選択ウインドウが表示されます。リファレンスとなる FASTA ファイルを選択します。

【Fastq File(s).】の入力 必須

マッピングする Fastq 形式ファイルを選択します。［Select］ボタンを押下するとファイル選択ウ
インドウが表示されます。複数選択された場合、選択されたファイルをマージ（結合）してから処理を行います。

【Options.】パラメータの設定

マッピング実行時にツールへ付与するオプションを指定します。

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シーケンサの選択 必須

マッピングを行う Fastq ファイルのシーケンサ種類を選択します。この選択により、minimap2
実行時のオプションが自動で選択されます。

その他

その他にパラメータを指定した場合は、[More Option(s)]へ入力します。パラメータは
minimap2 実行時に直接渡されます（不備なパラメータはエラー終了となります）。
オプション文字列は、minimap2[Manual Reference Pages]を参照してください。
※https://lh3.github.io/minimap2/minimap2.html【Execute】ボタンのクリック
必須項目が全て設定されていると、[Execute]ボタンが有効になります。ボタンを押下すると結果ファイルの出力先フォルダを選択するダイアログが表示されます。

実行可能!

出力先を選択すると処理が実行されます。
マッピングが正常に終了すると、結果フォルダが表示されます。有効な BAM ファイルが作成された
場合、IGV が起動しマッピング状態を確認する事が出来ます。
※http://software.broadinstitute.org/software/igv/

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Chapter

De Novo assemble

指定した Fastq ファイルよりコンティグを作成します。Fastq ファイルは Nanopore、Pacbioの配列が適用できます。

【Fastq File(s).】の入力 必須

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アセンブルする Fastq 形式ファイルを選択します。［Select］ボタンを押下するとファイル選択ウ
インドウが表示されます。複数選択された場合、選択されたファイルをマージ（結合）してから処理を行います。

【Options.】の設定

アセンブル実行時にツールへ付与するオプションを指定します。

シーケンサ選択 必須

マッピングを行う Fastq ファイルのシーケンサ種類を選択します。この選択により、minimap2
実行時のオプションが自動で選択されます。

対象のゲノムサイズ 必須

アセンブル結果の予測サイズ（数値）を記述します。小数点を含む数値と単位（K/M/Gなど）を含めることが可能です。

アセンブルの回数

アセンブルは minimap2-minasm-racon を繰り返実行します。繰り返しの回数を指定します。0 または空白の場合はアセンブル結果が同じになるまで繰り返します。

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【Execute】ボタンのクリック
必須項目が全て設定されていると、[Execute]ボタンが有効になります。ボタンを押下すると結果ファイルの出力先フォルダを選択するダイアログが表示されます。

実行可能!

出力先を選択すると処理が実行されます。
実行が正常に終了するとアセンブル結果のサマリーが表示されます。

アセンブル結果 表示例

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Chapter

構造変異解析

指定したリファレンスと Fastq ファイルよりバリアント検出を行います。Fastq ファイルはNanopore、Pacbio が対応しています。

【Reference.】の設定 必須

構造変異の検出対象リファレンス（fasta 形式）ファイルを選択します。［Select］ボ
タンを押下するとファイル選択ウインドウが表示されます。リファレンスとなる FASTA ファイ
ルを選択します。

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【Fastq File(s).】の入力 必須

構造変異を検出する Fastq 形式ファイルを選択します。［Select］ボタンを押下するとファイル
選択ウインドウが表示されます。複数選択された場合、選択されたファイルをマージ（結合）してから処理を行います。

【Options.】の設定

構造変異検出の実行時にツールへ付与するオプションを指定します。

シーケンサの選択 必須

構造変異検出を行う Fastq ファイルのシーケンサ種類を選択します。この選択により、
minimap2 実行時のオプションが自動で選択されます。
マッピングツールの選択 必須

マッピングに使用するアライメントツールを選択します。構造変異を含むシーケンスリードのアライメントには NGMLR を推奨しています。

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配列クオリティの閾値（数値 ）マッピング結果からバリアント検出を行う際に、Fastq クオリティ(Phread Score)の閾値を指定します。

【Execute】ボタンのクリック
必須項目が全て設定されていると、[Execute]ボタンが有効になります。ボタンを押下すると結果ファイルの出力先フォルダを選択するダイアログが表示されます。

実行可能!

出力先を選択すると処理が実行されます。
処理が正常に終了すると、結果フォルダが表示されます。有効な BAM ファイルが作成された場
合、IGV が起動しマッピング状態を確認する事が出来ます。
※http://software.broadinstitute.org/software/igv/

また、検出結果が有効な場合に SVIM が出力するレポートを表示します。

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※ 初めてマッピングおよび構造変異解析の結果を表示する際に、以下の様なダイアログが表示されることがあります。
この場合、[Microsoft HTML アプリケーション ホスト]（通常は表示の際に選択されています）
を選択し、[OK]ボタンを押下してください。
結果表示に HTA(HTML Application)を利用しているために表示されます。

選択して OK を押す!

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1. IGVゲノムブラウザの起動
Nano Toolsに付属のIGVを
NanoTools2/bin/IGV_Winにあるigv.batをダブルクリックしてIGVゲノムブラウザを立ち上げます。
2．ゲノム情報の取り込み
IGVのメニューから
Genomes->Load Genome From Serverをクリックして生物種を選択し、ゲノム配列とアノテーションを取得します。
3．BAMファイルの表示
IGVのメニューから
File->Load from Fileをクリックして.bamファイルをIGVに取り込みます。
.bamファイルはNanoToolのVariant解析結果出力先フォルダに作成されています。
4．構造変異検出部位のゲノムブラウザでの表示
IGVのメニューから
File->Load from Fileをクリックして.bedファイルをIGVに取り込みます。
.bedファイルはNanoToolのVariant解析結果出力先フォルダに作成されており、イベントの種類ごとに作成されています(e.g del.bed, dup_tan_dest.bed)。

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Acknowledgement

Chapter

Nano Tool 2.0 have benefited greatly from the use of open source software.
We specifically acknowledge, with thanks the producers below.
minimap2

https://github.com/lh3/minimap2

ライセンス The MIT License
miniasmhttps://github.com/lh3/miniasm

ライセンス The MIT License
racon
https://github.com/isovic/racon

ライセンス The MIT Licensesvim
https://github.com/eldariont/svim

ライセンス GNU General Public License v3.0
https://github.com/eldariont/svim/blob/master/LICENSEIGV （Integrative Genomics Viewer）
http://software.broadinstitute.org/software/igv/home
https://github.com/igvteam/igv/

ライセンス The MIT License
http://software.broadinstitute.org/software/igv/Credits

samtools
https://github.com/samtools/samtools

ライセンス The MIT/Expat License

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ngmlr
https://github.com/philres/ngmlr

ライセンス The MIT License
pycoQC
https://github.com/a-slide/pycoQC

ライセンス GNU General Public License v3.0

本ソフトウエアで付属の外部ソフトウエアを実行するにあたり、外部モジュール（.dll）より呼び出して実行しています。この dll は以下の URL にて公開しています。
https://github.com/WorldFusion/WfComponent18

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The MIT/Expat License
Permission is hereby granted, free of charge, to any person obtaining a copyof this software and associated documentation files (the "Software"), to deal
in the Software without restriction, including without limitation the rights
to use, copy, modify, merge, publish, distribute, sublicense, and/or sellcopies of the Software, and to permit persons to whom the Software isfurnished to do so, subject to the following conditions:
The above copyright notice and this permission notice shall be included in
all copies or substantial portions of the Software.
THE SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR
IMPLIED, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF MERCHANTABILITY,
FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT. IN NO EVENT SHALLTHE AUTHORS OR COPYRIGHT HOLDERS BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER
LIABILITY, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING
FROM, OUT OF OR IN CONNECTION WITH THE SOFTWARE OR THE USE OR OTHERDEALINGS IN THE SOFTWARE.

[The use of a range of years within a copyright notice in this distribution
should be interpreted as being equivalent to a list of years including thefirst and last year specified and all consecutive years between them.
For example, a copyright notice that reads "Copyright (C) 2005, 2007-2009,2011-2012" should be interpreted as being identical to a notice that reads"Copyright (C) 2005, 2007, 2008, 2009, 2011, 2012" and a copyright noticethat reads "Copyright (C) 2005-2012" should be interpreted as being identicalto a notice that reads "Copyright (C) 2005, 2006, 2007, 2008, 2009, 2010,2011, 2012".]19

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# GNU GENERAL PUBLIC LICENSE**Version 3, 29 June 2007**
Copyright (C) 2007 Free Software Foundation, Inc. <http://fsf.org/>
Everyone is permitted to copy and distribute verbatim copiesof this license document, but changing it is not allowed.
## Preamble
The GNU General Public License is a free, copyleft license forsoftware and other kinds of works.
The licenses for most software and other practical works are designed
to take away your freedom to share and change the works.By contrast,
the GNU General Public License is intended to guarantee your freedom toshare and change all versions of a program--to make sure it remains free
software for all its users.We, the Free Software Foundation, use the
GNU General Public License for most of our software; it applies also to
any other work released this way by its authors.You can apply it toyour programs, too.
When we speak of free software, we are referring to freedom, notprice.Our General Public Licenses are designed to make sure that you
have the freedom to distribute copies of free software (and charge forthem if you wish), that you receive source code or can get it if you
want it, that you can change the software or use pieces of it in new
free programs, and that you know you can do these things.
To protect your rights, we need to prevent others from denying youthese rights or asking you to surrender the rights.Therefore, you havecertain responsibilities if you distribute copies of the software, or if
you modify it: responsibilities to respect the freedom of others.
For example, if you distribute copies of such a program, whether
gratis or for a fee, you must pass on to the recipients the same
freedoms that you received.You must make sure that they, too, receiveor can get the source code.And you must show them these terms so theyknow their rights.
Developers that use the GNU GPL protect your rights with two steps:(1) assert copyright on the software, and (2) offer you this License
giving you legal permission to copy, distribute and/or modify it.

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For the developers' and authors' protection, the GPL clearly explainsthat there is no warranty for this free software.For both users' andauthors' sake, the GPL requires that modified versions be marked aschanged, so that their problems will not be attributed erroneously toauthors of previous versions.
Some devices are designed to deny users access to install or run
modified versions of the software inside them, although the manufacturer
can do so.This is fundamentally incompatible with the aim ofprotecting users' freedom to change the software.The systematic
pattern of such abuse occurs in the area of products for individuals touse, which is precisely where it is most unacceptable.Therefore, wehave designed this version of the GPL to prohibit the practice for those
products.If such problems arise substantially in other domains, westand ready to extend this provision to those domains in future versionsof the GPL, as needed to protect the freedom of users.
Finally, every program is threatened constantly by software patents.
States should not allow patents to restrict development and use ofsoftware on general-purpose computers, but in those that do, we wish to
avoid the special danger that patents applied to a free program could
make it effectively proprietary.To prevent this, the GPL assures thatpatents cannot be used to render the program non-free.
The precise terms and conditions for copying, distribution andmodification follow.
## TERMS AND CONDITIONS
0. Definitions.
"This License" refers to version 3 of the GNU General Public License.
"Copyright" also means copyright-like laws that apply to other kinds ofworks, such as semiconductor masks.
"The Program" refers to any copyrightable work licensed under thisLicense.Each licensee is addressed as "you"."Licensees" and"recipients" may be individuals or organizations.
To "modify" a work means to copy from or adapt all or part of the workin a fashion requiring copyright permission, other than the making of an
exact copy.The resulting work is called a "modified version" of the21

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earlier work or a work "based on" the earlier work.
A "covered work" means either the unmodified Program or a work basedon the Program.
To "propagate" a work means to do anything with it that, without
permission, would make you directly or secondarily liable forinfringement under applicable copyright law, except executing it on acomputer or modifying a private copy.Propagation includes copying,
distribution (with or without modification), making available to the
public, and in some countries other activities as well.
To "convey" a work means any kind of propagation that enables otherparties to make or receive copies.Mere interaction with a user througha computer network, with no transfer of a copy, is not conveying.
An interactive user interface displays "Appropriate Legal Notices"to the extent that it includes a convenient and prominently visible
feature that (1) displays an appropriate copyright notice, and (2)tells the user that there is no warranty for the work (except to theextent that warranties are provided), that licensees may convey thework under this License, and how to view a copy of this License.If
the interface presents a list of user commands or options, such as amenu, a prominent item in the list meets this criterion.
1. Source Code.
The "source code" for a work means the preferred form of the work
for making modifications to it."Object code" means any non-source
form of a work.
A "Standard Interface" means an interface that either is an official
standard defined by a recognized standards body, or, in the case ofinterfaces specified for a particular programming language, one thatis widely used among developers working in that language.
The "System Libraries" of an executable work include anything, otherthan the work as a whole, that (a) is included in the normal form of
packaging a Major Component, but which is not part of that Major
Component, and (b) serves only to enable use of the work with that
Major Component, or to implement a Standard Interface for which an
implementation is available to the public in source code form.A"Major Component", in this context, means a major essential component

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(kernel, window system, and so on) of the specific operating system(if any) on which the executable work runs, or a compiler used to
produce the work, or an object code interpreter used to run it.
The "Corresponding Source" for a work in object code form means all
the source code needed to generate, install, and (for an executablework) run the object code and to modify the work, including scripts tocontrol those activities.However, it does not include the work's
System Libraries, or general-purpose tools or generally available freeprograms which are used unmodified in performing those activities but
which are not part of the work.For example, Corresponding Source
includes interface definition files associated with source files forthe work, and the source code for shared libraries and dynamicallylinked subprograms that the work is specifically designed to require,
such as by intimate data communication or control flow between those
subprograms and other parts of the work.
The Corresponding Source need not include anything that users
can regenerate automatically from other parts of the Corresponding
Source.
The Corresponding Source for a work in source code form is thatsame work.
2. Basic Permissions.
All rights granted under this License are granted for the term of
copyright on the Program, and are irrevocable provided the statedconditions are met.This License explicitly affirms your unlimited
permission to run the unmodified Program.The output from running acovered work is covered by this License only if the output, given its
content, constitutes a covered work.This License acknowledges yourrights of fair use or other equivalent, as provided by copyright law.
You may make, run and propagate covered works that you do notconvey, without conditions so long as your license otherwise remains
in force.You may convey covered works to others for the sole purposeof having them make modifications exclusively for you, or provide youwith facilities for running those works, provided that you comply withthe terms of this License in conveying all material for which you do
not control copyright.Those thus making or running the covered works
for you must do so exclusively on your behalf, under your direction
and control, on terms that prohibit them from making any copies of23

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your copyrighted material outside their relationship with you.
Conveying under any other circumstances is permitted solely under
the conditions stated below.Sublicensing is not allowed; section 10
makes it unnecessary.
3. Protecting Users' Legal Rights From Anti-Circumvention Law.
No covered work shall be deemed part of an effective technologicalmeasure under any applicable law fulfilling obligations under article
11 of the WIPO copyright treaty adopted on 20 December 1996, orsimilar laws prohibiting or restricting circumvention of suchmeasures.
When you convey a covered work, you waive any legal power to forbid
circumvention of technological measures to the extent such circumvention
is effected by exercising rights under this License with respect tothe covered work, and you disclaim any intention to limit operation or
modification of the work as a means of enforcing, against the work's
users, your or third parties' legal rights to forbid circumvention oftechnological measures.
4. Conveying Verbatim Copies.
You may convey verbatim copies of the Program's source code as you
receive it, in any medium, provided that you conspicuously andappropriately publish on each copy an appropriate copyright notice;keep intact all notices stating that this License and any
non-permissive terms added in accord with section 7 apply to the code;
keep intact all notices of the absence of any warranty; and give allrecipients a copy of this License along with the Program.
You may charge any price or no price for each copy that you convey,
and you may offer support or warranty protection for a fee.
5. Conveying Modified Source Versions.
You may convey a work based on the Program, or the modifications to
produce it from the Program, in the form of source code under theterms of section 4, provided that you also meet all of these conditions:a) The work must carry prominent notices stating that you modified
it, and giving a relevant date.

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U S E RG U I D Eb) The work must carry prominent notices stating that it isreleased under this License and any conditions added under section 7.
This requirement modifies the requirement in section 4 to"keep intact all notices".
c) You must license the entire work, as a whole, under thisLicense to anyone who comes into possession of a copy.This
License will therefore apply, along with any applicable section 7
additional terms, to the whole of the work, and all its parts,
regardless of how they are packaged.This License gives nopermission to license the work in any other way, but it does notinvalidate such permission if you have separately received it.
d) If the work has interactive user interfaces, each must display
Appropriate Legal Notices; however, if the Program has interactive
interfaces that do not display Appropriate Legal Notices, yourwork need not make them do so.
A compilation of a covered work with other separate and independentworks, which are not by their nature extensions of the covered work,
and which are not combined with it such as to form a larger program,in or on a volume of a storage or distribution medium, is called an"aggregate" if the compilation and its resulting copyright are notused to limit the access or legal rights of the compilation's users
beyond what the individual works permit.Inclusion of a covered workin an aggregate does not cause this License to apply to the otherparts of the aggregate.
6. Conveying Non-Source Forms.
You may convey a covered work in object code form under the termsof sections 4 and 5, provided that you also convey themachine-readable Corresponding Source under the terms of this License,
in one of these ways:a) Convey the object code in, or embodied in, a physical product(including a physical distribution medium), accompanied by theCorresponding Source fixed on a durable physical medium
customarily used for software interchange.
b) Convey the object code in, or embodied in, a physical product(including a physical distribution medium), accompanied by a25

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written offer, valid for at least three years and valid for as
long as you offer spare parts or customer support for that productmodel, to give anyone who possesses the object code either (1) acopy of the Corresponding Source for all the software in the
product that is covered by this License, on a durable physicalmedium customarily used for software interchange, for a price nomore than your reasonable cost of physically performing thisconveying of source, or (2) access to copy theCorresponding Source from a network server at no charge.
c) Convey individual copies of the object code with a copy of thewritten offer to provide the Corresponding Source.This
alternative is allowed only occasionally and noncommercially, andonly if you received the object code with such an offer, in accord
with subsection 6b.
d) Convey the object code by offering access from a designatedplace (gratis or for a charge), and offer equivalent access to theCorresponding Source in the same way through the same place at nofurther charge.You need not require recipients to copy theCorresponding Source along with the object code.If the place tocopy the object code is a network server, the Corresponding Source
may be on a different server (operated by you or a third party)
that supports equivalent copying facilities, provided you maintainclear directions next to the object code saying where to find theCorresponding Source.Regardless of what server hosts theCorresponding Source, you remain obligated to ensure that it isavailable for as long as needed to satisfy these requirements.
e) Convey the object code using peer-to-peer transmission, provided
you inform other peers where the object code and Corresponding
Source of the work are being offered to the general public at nocharge under subsection 6d.
A separable portion of the object code, whose source code is excluded
from the Corresponding Source as a System Library, need not be
included in conveying the object code work.
A "User Product" is either (1) a "consumer product", which means any
tangible personal property which is normally used for personal, family,or household purposes, or (2) anything designed or sold for incorporation
into a dwelling.In determining whether a product is a consumer product,
doubtful cases shall be resolved in favor of coverage.For a particular

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product received by a particular user, "normally used" refers to atypical or common use of that class of product, regardless of the statusof the particular user or of the way in which the particular user
actually uses, or expects or is expected to use, the product.A productis a consumer product regardless of whether the product has substantialcommercial, industrial or non-consumer uses, unless such uses represent
the only significant mode of use of the product.
"Installation Information" for a User Product means any methods,
procedures, authorization keys, or other information required to installand execute modified versions of a covered work in that User Product froma modified version of its Corresponding Source.The information must
suffice to ensure that the continued functioning of the modified object
code is in no case prevented or interfered with solely because
modification has been made.
If you convey an object code work under this section in, or with, or
specifically for use in, a User Product, and the conveying occurs aspart of a transaction in which the right of possession and use of theUser Product is transferred to the recipient in perpetuity or for a
fixed term (regardless of how the transaction is characterized), theCorresponding Source conveyed under this section must be accompaniedby the Installation Information.But this requirement does not apply
if neither you nor any third party retains the ability to install
modified object code on the User Product (for example, the work has
been installed in ROM).
The requirement to provide Installation Information does not include arequirement to continue to provide support service, warranty, or updates
for a work that has been modified or installed by the recipient, or for
the User Product in which it has been modified or installed.Access to a
network may be denied when the modification itself materially andadversely affects the operation of the network or violates the rules andprotocols for communication across the network.
Corresponding Source conveyed, and Installation Information provided,in accord with this section must be in a format that is publicly
documented (and with an implementation available to the public insource code form), and must require no special password or key for
unpacking, reading or copying.
7. Additional Terms.

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"Additional permissions" are terms that supplement the terms of thisLicense by making exceptions from one or more of its conditions.
Additional permissions that are applicable to the entire Program shallbe treated as though they were included in this License, to the extent
that they are valid under applicable law.If additional permissions
apply only to part of the Program, that part may be used separately
under those permissions, but the entire Program remains governed bythis License without regard to the additional permissions.
When you convey a copy of a covered work, you may at your option
remove any additional permissions from that copy, or from any part ofit.(Additional permissions may be written to require their own
removal in certain cases when you modify the work.)You may place
additional permissions on material, added by you to a covered work,
for which you have or can give appropriate copyright permission.
Notwithstanding any other provision of this License, for material you
add to a covered work, you may (if authorized by the copyright holders ofthat material) supplement the terms of this License with terms:a) Disclaiming warranty or limiting liability differently from theterms of sections 15 and 16 of this License; orb) Requiring preservation of specified reasonable legal notices orauthor attributions in that material or in the Appropriate Legal
Notices displayed by works containing it; orc) Prohibiting misrepresentation of the origin of that material, or
requiring that modified versions of such material be marked inreasonable ways as different from the original version; ord) Limiting the use for publicity purposes of names of licensors or
authors of the material; ore) Declining to grant rights under trademark law for use of sometrade names, trademarks, or service marks; orf) Requiring indemnification of licensors and authors of thatmaterial by anyone who conveys the material (or modified versions ofit) with contractual assumptions of liability to the recipient, for
any liability that these contractual assumptions directly impose on
those licensors and authors.

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All other non-permissive additional terms are considered "further
restrictions" within the meaning of section 10.If the Program as you
received it, or any part of it, contains a notice stating that it isgoverned by this License along with a term that is a further
restriction, you may remove that term.If a license document contains
a further restriction but permits relicensing or conveying under thisLicense, you may add to a covered work material governed by the termsof that license document, provided that the further restriction does
not survive such relicensing or conveying.
If you add terms to a covered work in accord with this section, youmust place, in the relevant source files, a statement of theadditional terms that apply to those files, or a notice indicatingwhere to find the applicable terms.
Additional terms, permissive or non-permissive, may be stated in theform of a separately written license, or stated as exceptions;the above requirements apply either way.
8. Termination.
You may not propagate or modify a covered work except as expressly
provided under this License.Any attempt otherwise to propagate or
modify it is void, and will automatically terminate your rights under
this License (including any patent licenses granted under the thirdparagraph of section 11).
However, if you cease all violation of this License, then yourlicense from a particular copyright holder is reinstated (a)provisionally, unless and until the copyright holder explicitly andfinally terminates your license, and (b) permanently, if the copyrightholder fails to notify you of the violation by some reasonable means
prior to 60 days after the cessation.
Moreover, your license from a particular copyright holder isreinstated permanently if the copyright holder notifies you of theviolation by some reasonable means, this is the first time you havereceived notice of violation of this License (for any work) from thatcopyright holder, and you cure the violation prior to 30 days after
your receipt of the notice.
Termination of your rights under this section does not terminate thelicenses of parties who have received copies or rights from you under29

A D M I N I S T R A T I V E

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this License.If your rights have been terminated and not permanently
reinstated, you do not qualify to receive new licenses for the samematerial under section 10.
9. Acceptance Not Required for Having Copies.
You are not required to accept this License in order to receive or
run a copy of the Program.Ancillary propagation of a covered work
occurring solely as a consequence of using peer-to-peer transmission
to receive a copy likewise does not require acceptance.However,nothing other than this License grants you permission to propagate or
modify any covered work.These actions infringe copyright if you do
not accept this License.Therefore, by modifying or propagating acovered work, you indicate your acceptance of this License to do so.
10. Automatic Licensing of Downstream Recipients.
Each time you convey a covered work, the recipient automaticallyreceives a license from the original licensors, to run, modify andpropagate that work, subject to this License.You are not responsible
for enforcing compliance by third parties with this License.
An "entity transaction" is a transaction transferring control of anorganization, or substantially all assets of one, or subdividing anorganization, or merging organizations.If propagation of a covered
work results from an entity transaction, each party to thattransaction who receives a copy of the work also receives whatever
licenses to the work the party's predecessor in interest had or could
give under the previous paragraph, plus a right to possession of theCorresponding Source of the work from the predecessor in interest, if
the predecessor has it or can get it with reasonable efforts.
You may not impose any further restrictions on the exercise of therights granted or affirmed under this License.For example, you may
not impose a license fee, royalty, or other charge for exercise ofrights granted under this License, and you may not initiate litigation(including a cross-claim or counterclaim in a lawsuit) alleging thatany patent claim is infringed by making, using, selling, offering for
sale, or importing the Program or any portion of it.
11. Patents.
A "contributor" is a copyright holder who authorizes use under this30

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License of the Program or a work on which the Program is based.The
work thus licensed is called the contributor's "contributor version".
A contributor's "essential patent claims" are all patent claims
owned or controlled by the contributor, whether already acquired orhereafter acquired, that would be infringed by some manner, permitted
by this License, of making, using, or selling its contributor version,
but do not include claims that would be infringed only as aconsequence of further modification of the contributor version.For
purposes of this definition, "control" includes the right to grant
patent sublicenses in a manner consistent with the requirements ofthis License.
Each contributor grants you a non-exclusive, worldwide, royalty-freepatent license under the contributor's essential patent claims, tomake, use, sell, offer for sale, import and otherwise run, modify andpropagate the contents of its contributor version.
In the following three paragraphs, a "patent license" is any express
agreement or commitment, however denominated, not to enforce a patent(such as an express permission to practice a patent or covenant not tosue for patent infringement).To "grant" such a patent license to a
party means to make such an agreement or commitment not to enforce apatent against the party.
If you convey a covered work, knowingly relying on a patent license,
and the Corresponding Source of the work is not available for anyone
to copy, free of charge and under the terms of this License, through apublicly available network server or other readily accessible means,then you must either (1) cause the Corresponding Source to be soavailable, or (2) arrange to deprive yourself of the benefit of thepatent license for this particular work, or (3) arrange, in a mannerconsistent with the requirements of this License, to extend the patent
license to downstream recipients."Knowingly relying" means you haveactual knowledge that, but for the patent license, your conveying thecovered work in a country, or your recipient's use of the covered workin a country, would infringe one or more identifiable patents in thatcountry that you have reason to believe are valid.
If, pursuant to or in connection with a single transaction or
arrangement, you convey, or propagate by procuring conveyance of, acovered work, and grant a patent license to some of the parties
receiving the covered work authorizing them to use, propagate, modify

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or convey a specific copy of the covered work, then the patent license
you grant is automatically extended to all recipients of the covered
work and works based on it.
A patent license is "discriminatory" if it does not include within
the scope of its coverage, prohibits the exercise of, or isconditioned on the non-exercise of one or more of the rights that are
specifically granted under this License.You may not convey a covered
work if you are a party to an arrangement with a third party that isin the business of distributing software, under which you make payment
to the third party based on the extent of your activity of conveying
the work, and under which the third party grants, to any of theparties who would receive the covered work from you, a discriminatory
patent license (a) in connection with copies of the covered work
conveyed by you (or copies made from those copies), or (b) primarily
for and in connection with specific products or compilations that
contain the covered work, unless you entered into that arrangement,or that patent license was granted, prior to 28 March 2007.
Nothing in this License shall be construed as excluding or limiting
any implied license or other defenses to infringement that mayotherwise be available to you under applicable patent law.
12. No Surrender of Others' Freedom.
If conditions are imposed on you (whether by court order, agreement orotherwise) that contradict the conditions of this License, they do not
excuse you from the conditions of this License.If you cannot convey a
covered work so as to satisfy simultaneously your obligations under thisLicense and any other pertinent obligations, then as a consequence you may
not convey it at all.For example, if you agree to terms that obligate you
to collect a royalty for further conveying from those to whom you convey
the Program, the only way you could satisfy both those terms and thisLicense would be to refrain entirely from conveying the Program.
13. Use with the GNU Affero General Public License.
Notwithstanding any other provision of this License, you havepermission to link or combine any covered work with a work licensed
under version 3 of the GNU Affero General Public License into a single
combined work, and to convey the resulting work.The terms of thisLicense will continue to apply to the part which is the covered work,
but the special requirements of the GNU Affero General Public License,32

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section 13, concerning interaction through a network will apply to the
combination as such.
14. Revised Versions of this License.
The Free Software Foundation may publish revised and/or new versions of
the GNU General Public License from time to time.Such new versions will
be similar in spirit to the present version, but may differ in detail toaddress new problems or concerns.
Each version is given a distinguishing version number.If theProgram specifies that a certain numbered version of the GNU General
Public License "or any later version" applies to it, you have theoption of following the terms and conditions either of that numberedversion or of any later version published by the Free Software
Foundation.If the Program does not specify a version number of the
GNU General Public License, you may choose any version ever publishedby the Free Software Foundation.
If the Program specifies that a proxy can decide which futureversions of the GNU General Public License can be used, that proxy's
public statement of acceptance of a version permanently authorizes you
to choose that version for the Program.
Later license versions may give you additional or different
permissions.However, no additional obligations are imposed on any
author or copyright holder as a result of your choosing to follow alater version.
15. Disclaimer of Warranty.
THERE IS NO WARRANTY FOR THE PROGRAM, TO THE EXTENT PERMITTED BYAPPLICABLE LAW.EXCEPT WHEN OTHERWISE STATED IN WRITING THE COPYRIGHTHOLDERS AND/OR OTHER PARTIES PROVIDE THE PROGRAM "AS IS" WITHOUT WARRANTY
OF ANY KIND, EITHER EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO,
THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULARPURPOSE.THE ENTIRE RISK AS TO THE QUALITY AND PERFORMANCE OF THE PROGRAM
IS WITH YOU.SHOULD THE PROGRAM PROVE DEFECTIVE, YOU ASSUME THE COST OF
ALL NECESSARY SERVICING, REPAIR OR CORRECTION.
16. Limitation of Liability.
IN NO EVENT UNLESS REQUIRED BY APPLICABLE LAW OR AGREED TO IN WRITING

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WILL ANY COPYRIGHT HOLDER, OR ANY OTHER PARTY WHO MODIFIES AND/OR CONVEYS
THE PROGRAM AS PERMITTED ABOVE, BE LIABLE TO YOU FOR DAMAGES, INCLUDING ANYGENERAL, SPECIAL, INCIDENTAL OR CONSEQUENTIAL DAMAGES ARISING OUT OF THE
USE OR INABILITY TO USE THE PROGRAM (INCLUDING BUT NOT LIMITED TO LOSS OF
DATA OR DATA BEING RENDERED INACCURATE OR LOSSES SUSTAINED BY YOU OR THIRDPARTIES OR A FAILURE OF THE PROGRAM TO OPERATE WITH ANY OTHER PROGRAMS),EVEN IF SUCH HOLDER OR OTHER PARTY HAS BEEN ADVISED OF THE POSSIBILITY OF
SUCH DAMAGES.
17. Interpretation of Sections 15 and 16.
If the disclaimer of warranty and limitation of liability provided
above cannot be given local legal effect according to their terms,
reviewing courts shall apply local law that most closely approximatesan absolute waiver of all civil liability in connection with theProgram, unless a warranty or assumption of liability accompanies acopy of the Program in return for a fee.
END OF TERMS AND CONDITIONS
How to Apply These Terms to Your New Programs
If you develop a new program, and you want it to be of the greatest
possible use to the public, the best way to achieve this is to make itfree software which everyone can redistribute and change under these terms.
To do so, attach the following notices to the program.It is safest
to attach them to the start of each source file to most effectively
state the exclusion of warranty; and each file should have at least
the "copyright" line and a pointer to where the full notice is found.
{one line to give the program's name and a brief idea of what it does.}
Copyright (C) {year}{name of author}
This program is free software: you can redistribute it and/or modify
it under the terms of the GNU General Public License as published by
the Free Software Foundation, either version 3 of the License, or(at your option) any later version.
This program is distributed in the hope that it will be useful,
but WITHOUT ANY WARRANTY; without even the implied warranty of
MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE.See the
GNU General Public License for more details.

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You should have received a copy of the GNU General Public Licensealong with this program.If not, see <http://www.gnu.org/licenses/>.
Also add information on how to contact you by electronic and paper mail.
If the program does terminal interaction, make it output a short
notice like this when it starts in an interactive mode:{project}Copyright (C) {year}{fullname}
This program comes with ABSOLUTELY NO WARRANTY; for details type show w.
This is free software, and you are welcome to redistribute it
under certain conditions; type show c' for details.
The hypothetical commands show w' and show c' should show the appropriate
parts of the General Public License.Of course, your program's commands
might be different; for a GUI interface, you would use an "about box".
You should also get your employer (if you work as a programmer) or school,
if any, to sign a "copyright disclaimer" for the program, if necessary.
For more information on this, and how to apply and follow the GNU GPL, see<http://www.gnu.org/licenses/>.
The GNU General Public License does not permit incorporating your program
into proprietary programs.If your program is a subroutine library, you
may consider it more useful to permit linking proprietary applications withthe library.If this is what you want to do, use the GNU Lesser General
Public License instead of this License.But first, please read
<http://www.gnu.org/philosophy/why-not-lgpl.html>.

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