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httpビーム X ソーサリー httpビームは赤である。 クリーチャー１体かプレイヤー１人を対象とする。httpビームをプレイするために ３つ以上の赤マナが支払われている場合、httpビームはそれにX点のダメージを与える。 『模倣』や、『迎合』、『拝借』…… …『繋がりの力』は、節度と良心の下に使われる限りは決して悪とは言い切れないの。 ──錬金術師、シーナ・タウンゼント 第32版の 1を飾ったテンプレカード。 ベーシック第１版にも収録された、強力なX点火力。 《猛火》などの他のX点火力と違って“火種”が要らず、払ったマナがそのままダメージになる。 プレイコストが赤赤赤のトリプルシンボルとしてみても良いので、赤単のデッキでないとプレイが難しく、３マナ以上がプレイするための条件なので小回りが利きにくいのが弱点か… 赤マナが３つ以上必要で２点以下の火力は打てませんが、１点の底上げは嬉しい所。 それでもマナが出るデッキでは非常に強力で、マナがそのまま火力になるのはかなり強い事である。 httpビームという昔のカードとは別のカードとして扱われる ちなみにイラストは、アトリエの錬金術師シーナが前スレ(31版)のURLをビームとして打ち出しているAAで、 フレイバーテキストは しぃのアトリエ ～モナーブルグの錬金術師～ からの拝借。 サイクル ベーシック第１版の、呪文コストにXを含むソーサリー。レア度はいずれもネ申レア。 あぼ～ん ブラウザクラッシャー チートコード httpビーム ニラの詠唱
https://w.atwiki.jp/marcher/pages/338.html
＜day3＞ 大丈夫、わたしがついてる ★ ★ ★ ★ ★ ★ 「『【被害者無事保護される】 昨日深夜二時頃東京都○○区の倉庫にて数日前に誘拐・監禁されていたと思われる男女数名が無事に発見された。 発見されたのはいずれも都内在住の○○、××、●●、△△の4名で健康状態に異常はないとのことである。 警察によると発見された現場の倉庫は現在所有する会社などはなく、放置されていた状況にあったとのことである なお現在も行方不明となっている■■については「引き続き全力を挙げて捜査に当たる」とのコメントを発表した』 やって。全然れーな達のこと書かれていないとね。当たり前っちゃけど」 「だって警察も言えないでしょ、『民間人のおかげで見つかりました』なんて」 新垣がリゾナントのカウンターに座りミルクティーを飲んでいる 「警察のメンツもあるし、そもそも私達は知られちゃいけない存在なんだから」 「そうやよ、れいな。あっしらみたいな能力者がいるってことを世間が知ったらえらいことになるでしょ」 「わかっているとよ」 れいなの前に焼き立てのトーストとハムエッグが置かれた 「でも少しくらいは書かれてもいい！って思ったことは」 「「「ない」」」 綺麗に高橋、新垣、れいなの声が揃った 「というかなんでミヤはここにいると？今日も学校じゃなかと？」 当たり前のようにカウンターでコーヒーを飲んでいる雅の姿を見ながられいなが言った 「高校生は学校行くのが仕事っちゃろ。れーなもこれから仕事やけんミヤも学校行くっちゃ！」 「・・・誰かさんのおかげでほっぺた腫れていて痛いので登校拒否しま～す、イタタ」 これみよがしにわざとらしく頬を押さえる姿にれいなはいらいらを強く感じた 「田中っち、顔に気持ち出てるから、笑おうね」 「ガキさんはいいかいな？仕事っちゃろ？」 「今日は遅刻するって連絡入れてあるから大丈夫よ。菅井店長意外と融通きくのよ♪」 久住、光井、ジュンジュン、リンリンは用事があるということで呼び出しをかけなかった しかし亀井は呼び出したにも関わらず未だに来る気配がない 「多分、今頃あの4人はニュースとかでどうやって報道されたか調べとるやろうね」 「愛佳とか学校のパソコン使って全ての新聞読んでたりしてそうだね」 新垣が読み終えた新聞を丁寧に折りたたんでカウンターテーブルの上に置いた 「あっし達があれから調べたことはやっぱり公表されていないんだね、ガキさん」 誰よりも早く起きて新聞に目を通した高橋が二人に確認の意味を込めて問いかけた 「犯人もあの男しか見つかっていないようだし警察ではまだ『捜査中』だしね」 人質となっていた人々を見つけた後、リゾナンターの８人と雅は更に建物内部を捜索した しかし他に監禁されている人は見つからず、雅の探している子、そして道重は遂に見つからなかった そのかわり建物の裏口寄りに大きな穴が壁に開いていたり、やはりその周囲にひっかき傷があるのを見つけた 周囲には壁を崩した時に出るであろう壁の破片は全く落ちておらず、掃除でもされたように綺麗になっていた 壁に刻まれたひっかき傷は他の部屋で見つかったものと同じようだった 「けっこう探したけど、結局、サユおらんかったと・・・」 昨日までは一緒に笑っていた仲間の鮮明な記憶を思い出しながられいなが悲しそうに呟く 建物を十分に探しまわってから警察に「人質を見つけた」と連絡したのはほんの数時間前のこと 唯一みつけたあの男が『犯人の一味』だとメモを残して彼女達は警察が現れる前に建物から脱出した 「警察はあのメモを残したのが誰かってことでひと騒動になってるんじゃないんですか？」 コーヒーにミルクをいれながら雅が尋ねてきた 「ん～まあ、そうかもね。でも、筆跡分からないだろうし、まさか一喫茶店のマスターがそんなことしたって思わないよ」 高橋はそんな些細なことを気にも留めていないようで鼻歌を歌いながら新垣のカップにもう一杯ミルクティーを注いだ 「愛ちゃんは相変わらず能天気だよね～ご都合主義っていうかぁ」 「ガキさん、能天気ってなにいってるがし！あっしは結構考えているんだよ」 「はいはい、そうですか」 ★ ★ ★ ★ ★ ★ れいなの言う通り、光井は図書室のパソコンや新聞で事件がどれだけ報道されているかを調べていた （・・・よかった愛佳達のことは何も書いてあらへん） 一応、新垣が記憶操作をして人質及び犯人の男の記憶からリゾナンターのことを忘れさせていた さらに雅にも記憶を『消失』させたが、何かミスをしていないかが不安だった （杞憂やったわ） 何も書かれていないことに胸をなでおろした 「愛佳、何してるの？」 声をかけられたので振り返ると同じクラスの子であった 「あ、まあ・・・ちょっと調べ物を」と答えた 「あ、これってウチらの学校の子も被害者の事件だよね！その子だけまだ見つかっていないってテレビで言ってた」 「ああ、うん、そやな」 パソコンの画面を覗き込まれてしまったので心の中で光井は小さく舌打ちをした 「なんであの子だけみつかっていないんだろうね？」 「んなこというたって愛佳もわからんし」 「別に愛佳に答え求めてるわけじゃないよｗ単なる独り言だとゆいたい」 （でも確かに何でやろ？連れ去ることになんの意味があるんやろうか？ これがダークネスの仕業やとしたら道重さんを連れ去ったんは納得がいくわ。愛佳達は邪魔もんやし でもそれ以外に何人も監禁しとったわけやし・・・あの人らにはなんの共通点なんてあらへんし・・・ それに誰も傷つけされてへんかった。あんな監禁状況にもかかわらずにや 一体誰が何のために？） 時計を目にすると次の授業時間が迫っていた 「あ、授業始まるよ、愛佳、急がないと遅刻するよ」「あ、まって」 ドタドタと音を立てて二人は急いで教室へと駆け戻った ★ ★ ★ ★ ★ ★ 亀井は自身の部屋のベッドの上にじっとしていた カーテンも開けず、部屋の電気も付けずにただ顔を膝にうずめている 何も言わないでただ暗闇を見つめてばかりで、時計の秒針のカチカチという音が響く 「エリ～いるんでしょ～お母さん、ちょっと買い物に行ってくるから！お昼は適当に作って食べてね」 階下から聴こえてくる母親の声にも反応せず亀井は無言のままだ 「・・・」 亀井の部屋は正直綺麗ではない、むしろ散らかっている でも今日は特にひどい。パジャマは脱ぎっぱなし、お菓子の空き箱は床におちている 同じ姿勢を保つのを疲れたのだろう組んでいた手をほどき、背中のほうに移動させた そして、枕元に置いていた自分の携帯を手に取った 携帯を開こうとしたが、思いとどまり再び携帯をベッドの上に置いた 「・・・」 携帯を開ければそこには親友と一緒に取ったプリクラ画像が出て来るのを知っていたからだ 変顔で撮った写真にはへたくそな文字で「二人は親友」「ずっと一緒だよ #10084;」と書かれている メール不精な亀井のもとには道重からの未返信メールが溜まっている 携帯につけられたストラップは二人で一緒に買い物に行った時におそろいで揃えたもの 眼を閉じてもいつも一緒にいたその人の顔が浮かんでくる 「・・・」 浮かんでくる顔は馬鹿見たく笑っていて悲しい自分の気持ちをより一層暗くさせる 「バカァ・・・」 グスンと鼻をすする音が静かに響いた ★ ★ ★ ★ ★ ★ 「マルシェ、昨日は悪かったね、無関係なのにあたってしまって」 後ろから声をかけられたマルシェが振り返ると保田が手に何かをもってこちらに向かって歩いてきていた 「いえ、保田さんがあんな時間にいるなんて私も驚いたんですよ。何をなさっていたんですか？」 「ん～まあ、仕事で問題が起きてな。イライラしてた。まあ、なんとかなったが・・・ それより、これ、マルシェにプレゼントというかお詫びの品かな？」 保田は紙袋ごとマルシェに渡した 「なんですか～あ、こ、これはっ！！」 眼を欄欄と輝かせてマルシェは袋の中のぶつを取り出した 「マルシェが好きだろうと思って買ってきたよ。それ食って組織のために頑張ってくれよ」 「ハイ！」 視線は手に持った大好物のおやつに向いたまま保田に元気良く返事した 「あれ、保田さん、まだいたんですか？」 そこに偶然吉澤が通りかかった 「あれ、いちゃいけないのかしら？おじゃまかしら？」 「いえいえ、決してそういうわけではないので（汗）」 慌てる吉澤に保田は優しい笑みを浮かべた 「フフフ、分かっているわよ。よし子もマルシェからお菓子もらっていいわよ」 それを聴いて今度はマルシェが固まった 「え・・・」 「そうですか～それじゃあいただきますね～マルシェ、一つ頂戴」 吉澤は袋の中から特に大きい一個を手に取った 「それじゃ、私は外に出るから３日くらい帰ってこないからボスに伝えておいてね 帰ってきたら一緒に日本酒でも飲もうね、吉澤」 「いいっすね～２，３本くらい空けちゃいましょう！マルシェも連れていきますよ」 「え、わたくしは・・・」 吉澤はそういいマルシェの大好物のお菓子をまた一つ奪い取り、困り顔のマルシェはどうしようもなかった ★ ★ ★ ★ ★ ★ 「ねえ愛ちゃん、これからサユをどうやって探すと？手掛かりとかないっちゃろ？」 帰り支度を始めた新垣を見ながられいながぽつりと呟いた 「・・・今は何もできないかもしれんね」 意外なほどあっさりと答えた高橋にれいなは驚きの表情を浮かべた 「あ、愛ちゃん？ガキさんならなんか考えもってるっちゃろ？」 新垣も高橋同様、静かに答えた 「・・・私も今は待つしかないと思う。愛ちゃんの精神感応が働かない以上今は仕方ないよ」 「そんな！二人ともサユが心配じゃなかと？こうやってれーな達がなんもできんくている時も助けを求めてるかもしれんやん！」 「・・・れいな、サユは大丈夫やよ、まだ無事やから」 先ほどとは違い確信を込めた声で高橋が口を開いた 「れいなだってわかってるはずだよ、サユが生きているってことは。『なんとなく』だろうけど そりゃわたしにも根拠があるわけではないけど、心でつながっているがし。 ガキさんがいなくなったときも、あっしがＡと戦って重傷を負った時も心を強く揺さぶられたやろ？」 「そう、それが共鳴ってことだから、田中っち大丈夫なのだ！」 新垣がれいなの肩を軽くポンと叩いて励ました 「ただ愛ちゃん、私が裏切っていたってことは言わない約束にしたよね」 「あひゃひゃひゃ・・・ガキさん、すまんの～」 笑ってごまかそうとする高橋を冷たい目で新垣が睨んだ 「それにさゆみんには『さえみさん』っていう大きな存在がいるのだ！ さゆみんにヘタなことしたらさえみさんがただじゃおかないから、すぐに私達も気付くはずだよ」 れいなはつい２日前に現れた『さえみ』の行い（VanishⅡ 一話参照）を思い出し身震いした 「さえみさんが暴れたら、すぐにわかるけど今のところそんなことはないから無事だと思っていいんじゃないかな？ 田中っち、今は祈ろう、何か手掛かりが見つかるようにってさ」 れいなは猫のエプロンの紐を強く結び直して気合を入れた 「・・・仕方ないっちゃね、サユもそこまで弱くないやろうし れーなが弱虫になっとったらサユに笑われるかもしれないと！強気でいかんといかんね！」 そんなれいなの姿を見て高橋がニヤッと笑みを浮かべた 「少しれいならしくなったね！ほら、れいな、仕込みするから手伝って」 「・・・それはサボりたいんやけど」 「「ダメ」」 年上の二人の声が見事にリゾナント 「いいなあ、仲間って」 そんな３人の姿をみた雅が羨ましそうな表情を浮かべた 「ああ、私にもああやって心配してくれる人がいればいいのに・・・それにしてもあの子はどこなんだろう」 雅はいまだ行方不明の仲間を思い浮かべ、暗い表情を浮かべた ★ ★ ★ ★ ★ ★ それから三日後、事態は急速に動き始めた・・・「ヤメテ！」という心の声とともに back →『Vanish！Ⅱ～independent Girl～』（４） next →『Vanish！Ⅱ～independent Girl～』（６）
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beatmaniaIIDX18 Resort Anthem/WEEKLY RANKING beatmaniaIIDX18 Resort Anthem TOP 新曲リスト / 新曲リスト2 / 旧曲リスト / 旧曲リスト2 / 旧曲リスト3 / 削除・AC未収録曲リスト / BEMANIフォルダ 旧曲詐称・逆詐称・個人差譜面リスト / リスト2 / リスト3 EXPERTコース / 段位認定 / WEEKLY RANKING STORYモード(第一章・第二章) / 第三章・BEGINNERモード / LEAGUEモード DELLAR / JAPAN TOUR / WORLD TOUR / MISSION 隠し要素 携帯サイト・メンバーズサイト 稼働前情報 beatmaniaIIDX18 Resort Anthem/WEEKLY RANKING [#mf40e372] WEEKLY RANKING [#j2caf750] WEEKLY RANKING 公式スペシャルサイト WEEKLY RANKING 毎週水曜日12 00 START ～ 翌週水曜日12 00 END 週 期間 GENRE TITLE ARTIST 1 10/20-10/27 TECHNO Aegis IT medalion 2 10/27-11/3 CATAL Agrave LOUNGE La Mar seiya-murai feat.David Solanes Venzala 3 11/3-11/10 BUBBLEGUM DANCE Mermaid girl Cream puff 4 11/10-11/17 ITALO HOUSE You Were The One good-cool ft. Brenda Vaughn 5 11/17-11/24 AURAL ADRENALINE 夕焼け ～Fading Day～ JAKAZiD 6 11/24-12/1 ELECTRIC STEP Destiny Sword CAPACITY GATE 7 12/1-12/8 FIDGET HOUSE Cansei de S NIK PRASTIK DANCEFLOOR 8 12/8-12/15 RESORT HOUSE WISE UP! 木之下慶行 feat.星野奏子 9 12/15-12/22 NU DISCO Golden Palms Dirty Androids 10 12/22-12/29 R Stay my side DJ Yoshitaka feat.RINA 11 12/29-1/5 CYBER WALTZ reunion Tatsh 12 1/5-1/12 WORLD/POPS おおきなこえで 猫叉Master feat.Sana 13 1/12-1/19 DANCE POP XANADU OF TWO T.Kakuta With Starving Trancer + 森永真由美 14 1/19-1/26 UPLIFTING TRANCE Programmed Sun(xac Antarctic Ocean mix) xac 15 1/26-2/2 DYSTOPIA New Castle Legions Dirty Androids 16 2/2-2/9 TECH DANCE EXTREMA PT.2 Remo-con 17 2/9-2/16 EUROBEAT 恋愛レボリューション21 -秋葉工房mix- DJ Command feat. うさ＆ともみん 18 2/16-2/23 TECHY FREEFORM ラクエン Feat.Chiharu Chonan -JAKA respect for K.S.K. Remix Remixed by JAKAZiD 19 2/23-3/2 IDM ZETA ～素数の世界と超越者～ Zektbach 20 3/2-3/9 HYPER FANTASIA Fantasia T EumlЯRA
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Market Scenario Market Research Future (MRFR) reveals that the global Virtual Classroom Industry (Virtual classroom Market)2020 is expected to touch 10 % CAGR across 2017 and 2023. By 2023. Virtual classroom in the years ahead is noted as the major cause that can contribute to the rise of the market in the years to come. The surge in demand for effective online learning environment in the pandemic is anticipated to earn high value for the virtual classroom market. the virtual classroom market can value USD 12 Bn. There are multiple causes that are expected to impact the market. However, the unprecedented demand for with the ingression of modern technologies that allows communication between a high number of people, view presentations or videos easily, and better engagement are critical as it is observed to boost customer convenience. In addition, multiple synchronous technologies, such as web conferencing, video conferencing, and web-based Voice over IP (VoIP) along with live streaming solutions are easily available. These benefits add value to virtual classroom solutions, which, in turn, can support the expansion of the virtual classroom market in the years ahead. Request a Free Sample @ https //www.marketresearchfuture.com/sample_request/4065 Competitive Outlook Skyprep (Canada), SAP SE (Germany), Oracle Corporation (US), BrainCert (US), Docebo (Italy), Brainier (US), Saba Software (US), Edvance360 (US), Bluevolt (US), and Canvas (US) are some reputed companies in the virtual classroom global market that are listed by MRFR. Segmentation The segment analysis of the virtual classroom market is done by type, service, deployment, organization size, and application. By Type based segment of the virtual classroom market are Combination of Teleconferencing, Teleconferencing, and World Wide Web among others. The Service based segments of the virtual classroom market are Professional Service, and Managed Service among others. The increased need for professional services can result in the expansion of the market in the years to come. The Deployment based segment of the virtual classroom market are On-Premises and On- Cloud. The Application based segment of the virtual classroom market are Government, Enterprise or Business Education, Healthcare, Professional Services, School College, and IT Telecommunication among others. The IT sector can earn high revenue for the virtual classroom market. The Organization Size based segment of the virtual classroom market are Large Organization, and Small and medium enterprises. The rise in the application of virtual classroom by SMEs for trainings can support the expansion of the market across the review period. Regional Analysis In North America, the virtual classroom market is expected to earn high turnover due to the rise in the demand for cutting-edge technology solutions to training across corporate sectors and education sector. The high investment made by different governments to improve virtual classroom solutions is expected to support the expansion of the virtual classroom market in the years ahead. In Europe, the virtual classroom market is likely to register a high CAGR in the analysis period due to increase in the need for online training and education facilities in the pandemic. In Asia Pacific, the virtual classroom market expected to emerge due the availability of excellent digital solutions with high connectivity. The easy access to high-end digital solutions can support the expansion of the virtual classroom market in India and Japan. The existence of a high number of vendors dealing in components for virtual classroom can support the expansion of the regional market across the assessment period. The rise in the number of different educational institutions that are adopting virtual classroom solutions can support the rise of APAC virtual classroom market across the analysis period. Industry News The global Virtual Classroom Market Share Report Market Trends has been affected due to the lockdown across the regions. This pandemic situation has hampered the Virtual Classroom Market Share Report Market Growth as well as its productivity, supply chain, and others. Moreover, the global market has lost its investors due to the increasing loss for the products, supply, transportation, workforce, and others. However, in the meantime, the key market players have implied various strategic techniques to boost global market growth. Thus, to meet the global market demands, the global market increased its speed in producing more valuable products for its intended customers. Recently, the global market has stabilized its position in the global market and is expected to register a higher Virtual Classroom Market Share Report Market Size for the forecast period. Browse Full Report Details @ https //www.marketresearchfuture.com/reports/virtual-classroom-market-4065 Table of Contents 1Executive Summary 2Scope of the Report 2.1Market Definition 2.2Scope of the Study 2.2.1Research objectives 2.2.2Assumptions Limitations 2.3Markets Structure Continued…. Trending Report** https //writeonwall.com/internet-of-things-market-growth-key-players-with-product-particulars-applications-future-trend-business-growth-market-size-key-players-update-business-statistics-and-forecast-till-2030/ https //www.scutify.com/articles/2022-04-18-cash-management-system-market-size-receives-a-rapid-boost-in-economy-due-to-high-emerging-demands https //ict268262635.wordpress.com/2022/04/06/geospatial-market-major-application-third-party-usage-micro-market-pricing-analysis-and-geographical-analysis-forecast-to-2030/ https //tealfeed.com/enterprise-data-warehouse-market-analysiskey-players-hqfr7 About Market Research Future At Market Research Future (MRFR), we enable our customers to unravel the complexity of various industries through our Cooked Research Report (CRR), Half-Cooked Research Reports (HCRR), Raw Research Reports (3R), Continuous-Feed Research (CFR), and Market Research Consulting Services. 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Computer-Aided Design Market Overview Market Research Future (MRFR), in its latest report on the Global Electrical Computer-Aided Design (ECAD) Market reveals that different forces that are likely to act on it. MRFR conducted a complete analysis on the impact of COVID 19 on the electrical computer-aided design (ECAD) market. MRFR study shows that the electrical computer-aided design market can rise at 9.22% CAGR across 2018 to 2024. The electrical computer-aided design market value can escalate from exhibiting USD 1,710.1 million in 2018 to USD 2,860.3 Million by 2024. Increase in awareness about Electrical computer-aided design (ECAD) benefits, such as easy-to-use, real-time standalone, and multi-user electrical design tool that efficiently resolve electrical interconnections for complex electrical systems is expected to support the rise of the ECAD market across the analysis period. Features, such as designing circuits accurately, quickly, and with optimization of the overall design process can promote the rise of the electrical computer-aided design market in the years to come. The increase in the application of ECAD in diagram making, concurrent designing, 3D assembly, and generation of manufacturing and documentation can favor the market rise. Request a Free Sample @ https //www.marketresearchfuture.com/sample_request/8235 Competitive Analysis ALPI International Software, EPLAN Software Service, Dassault Systèmes SE, Siemens PLM, Trimble, Inc., Autodesk, Inc., Bentley Systems, Inc., IGE+XAO, and Nemetschek SE among others are some reputed providers of global electrical computer-aided design (ECAD) solutions, as listed by MRFR. Segmental Analysis The segment study of the Global Electrical Computer-Aided Design (ECAD) Market is done by Industry Type, application, component, and vertical. The Component based segments of the electrical computer-aided design market are Software and Services. The Industry Type based segments of the electrical computer-aided design market are Process Industries and Discrete Industries. The Application based segments of the electrical computer-aided design market are Plant Design, Water Treatment and Distribution System Control, Switchgear Design, Industrial Machine Controls, Rail Signaling, Mining Equipment Control, and Others. The Vertical based segments of the electrical computer-aided design market are Equipment and Machinery, Construction, Automotive, Aerospace Defense, Power Generation and Energy, Railway, Oil Gas, Equipment and Machinery, and Food Beverage among others. Regional Analysis The trends of the electrical computer-aided design (ECAD) market is studied across APAC, North America, EU, and the rest of the world. MRFR regional evaluation reveals that the electrical computer-aided design market in North America is expected to be the largest market value. North America electrical computer-aided design market can thrive at 7.94% CAGR across the forecast period and reach a valuation of 0USD 620.4 million by 2024. The rise in the adoption of electrical computer-aided design (ECAD) technology across the growing number of discrete industries is expected to support the expansion of the regional market. In addition, the rise in industrial manufacturing investments can also promote the regional market growth. In Europe, the mounting complexities of manufacturing process are creating growth scope for the electrical computer-aided design regional market. Along with, the rise in focus on environmental concerns and industrial safety can impel the expansion of the market across the review period. The rise of EU ECAD market can be attributed to increase in viability of new energy sources, and gradual rise in cost of products as fresh set of competitive designers and engineers are focused on innovation. In APAC, the rise in popularity of ECAD and other effective 3D solution to enhance manufacturing and design processes is expected to drive the regional market. Controls development costs, accelerates time-to-market, aids in increasing cash flow, improves product quality, and profit margins can boost the expansion of APAC ECAD market. Access Report Details @ https //www.marketresearchfuture.com/reports/electrical-computer-aided-design-market-8235 Table of Content 1 Executive Summary 2 Market Introduction 2.1 Definition 17 2.2 Product Considered 17 2.3 Scope of The Study 18 2.4 Market Structure 19 Continued…. Similar Report Application Management Services Market By Service-Type (System Integration, Consulting Services, Modernization Services, And Others), By Organization Size, By Deployment, And By End-Users Open Source Intelligence (OSINT) Market By Security Type (Human Intelligence, Content Intelligence, Dark Web Analysis, Link/Network Analysis, Data Analytics, Text Analytics, Artificial Intelligence, Big Data, Others), Technology (Bid Data Software, Video Analytics, Text Analytics, Visualization Tool, Cyber Security, Web Analysis, Social Media Analysis, Others), Application (Military Defense, Homeland Security, Private Sector, Public Sector, National Security, Others) List of Tables Table 1 List of Assumptions 26 Table 2 Global Electrical Computer-Aided Design (Ecad) Market, By Component, 2020–2027 (Usd Million) 35 Table 3 Software Electrical Computer-Aided Design (Ecad) Market Estimates Forecast, By Region 36 Table 4 Global Electrical Computer-Aided Design (Ecad) Market, By Services, 2020–2027 (Usd Million) 36 Table 5 Support Electrical Computer-Aided Design (Ecad) Market Estimates Forecast, By Region 37 Continued….. List of Figures Figure 1 Market Synopsis 16 Figure 2 Market Structure Global Electrical Computer-Aided Design (Ecad) Market 19 Figure 3 North America Market Size Market Share By Country (2020 Vs 2027) 20 Figure 4 Asia-Pacific Market Size Market Share By Country (2020 Vs 2027) 20 Figure 5 Europe Market Size Market Share By Country (2020 Vs 2027) 21 Continued…. About Market Research Future At Market Research Future (MRFR), we enable our clients to unravel the complexity of various industries through our Cooked Research Report (CRR), Half-Cooked Research Reports (HCRR), Raw Research Reports (3R), Continuous-Feed Research (CFR), and Market Research Consulting Services. MRFR team have supreme objective to provide the optimum quality market research and intelligence services to our clients. Our market research studies by Solutions, Application, Logistics and market players for global, regional, and country level market segments, enable our clients to see more, know more, and do more, which help to answer all their most important questions. Contact Market Research Future (Part of Wantstats Research and Media Private Limited) 99 Hudson Street, 5Th Floor New York, NY 10013 United States of America 1 628 258 0071 (US) 44 2035 002 764 (UK) Email sales@marketresearchfuture.com Website https //www.marketresearchfuture.com #market #research #industry #data #growth #trend #report #analyis #share #marketing #forecast #digital #geographic #demographic #gnews Plugin Error キーワードを入力してください。 #tech #researchreport #marketreport #futrue
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- visitors 2010/5/31 PKS and NRPS release mechanisms L Du, L Lou - Natural Product Reports, 2010 - rsc.org http //www.rsc.org/publishing/journals/NP/article.asp?doi=b916096e ... Review. Nat. Prod. Rep., 2010, 27, 255 - 278, DOI 10.1039/b912037h. PKS and NRPS release mechanisms Liangcheng Du and Lili Lou. Covering up to September 2009. ... Antimicrobial natural products an update on future antibiotic drug candidates M Saleem, M Nazir, MS Ali, H Hussain, YS Lee, N … - Natural Product …, 2010 - rsc.org http //www.rsc.org/publishing/journals/NP/article.asp?doi=b916096e ... Review. Nat. Prod. Rep., 2010, 27, 238 - 254, DOI 10.1039/b916096e. Antimicrobial natural products an update on future antibiotic drug candidates Muhammad Saleem, Mamona Nazir, Muhammad Shaiq Ali, Hidayat Hussain, Yong Sup Lee, Naheed Riaz and Abdul Jabbar. ... Branch-and-Bound Algorithms for Enumerating Treelike Chemical Graphs with Given Path Frequency Using Detachment-Cut Y Ishida, Y Kato, L Zhao, H Nagamochi, T … - Journal of Chemical … - ACS Publications http //pubs.acs.org/doi/abs/10.1021/ci900447z Computational methods of enumerating chemical graphs have attained great importance in chemoinformatics since they lead to a variety of useful applications including structure determination of novel chemical compounds. Recently, Fujiwara et al. have presented an efficient branch-and-bound ... A Semantic Web Ontology for Small Molecules and Their Biological Targets JY Choi, MJ Davis, AF Newman, MA … - Journal of Chemical … - ACS Publications http //pubs.acs.org/doi/abs/10.1021/ci900461j A wide range of data on sequences, structures, pathways, and networks of genes and gene products is available for hypothesis testing and discovery in biological and biomedical research. However, data describing the physical, chemical, and biological properties of small ... Drug-and Lead-likeness, Target Class, and Molecular Diversity Analysis of 7.9 Million Commercially Available Organic Compounds Provided by 29 Suppliers A Chuprina, O Lukin, R Demoiseaux, A Buzko, … - J. Chem. Inf. …, 2010 - ACS Publications http //pubs.acs.org/doi/abs/10.1021/ci900464s A database of 7.9 million compounds commercially available from 29 suppliers in 2008−2009 was assembled and analyzed. 5.2 million structures of this database were identified to be unique and were subjected to an assessment of physical and biological properties and ... Computationally Efficient Algorithm to Identify Matched Molecular Pairs (MMPs) in Large Data Sets J Hussain, C Rea - Journal of Chemical Information and Modeling - ACS Publications http //pubs.acs.org/doi/abs/10.1021/ci900450m Modern drug discovery organizations generate large volumes of SAR data. A promising methodology that can be used to mine this chemical data to identify novel structure−activity relationships is the matched molecular pair (MMP) methodology. However, before the full potential of the ... Construction of Functional Group Reactivity Database under Various Reaction Conditions Automatically Extracted from Reaction Database in a Synthesis Design … A Tanaka, H Okamoto, M Bersohn - Journal of Chemical Information and … - ACS Publications http //pubs.acs.org/doi/abs/10.1021/ci9004332 To be able to estimate the reactivity of functional groups under certain reaction conditions, we have stored three types of data (1) data of change or destruction of the functional groups by the conditions of the reaction conditions; (2) data showing no influence of the reaction ... Prokaryotic Ubiquitin-Like Protein Provides a Two-Part Degron to Mycobacterium Proteasome Substrates KE Burns, MJ Pearce, KH Darwin - Journal of Bacteriology, 2010 - Am Soc Microbiol http //jb.asm.org/cgi/content/abstract/JB.01639-09v1 Prokaryotic ubiquitin-like protein (Pup) is a post-translational modifier that targets proteins for degradation by the mycobacterial proteasome. We show that the disordered amino-terminus of Pup is required for degradation while the Phylogeny of Gammaproteobacteria KP Williams, JJ Gillespie, BWS Sobral, EK … - Journal of …, 2010 - Am Soc Microbiol The phylogeny of the large bacterial class Gammaproteobacteria has been difficult to resolve. Here we apply a telescoping multi-protein approach to the problem for 104 diverse gammaproteobacterial genomes, based on a set of 356 protein families for the whole class, and even larger sets for each of four cohesive subregions of the tree. A role for CysJ flavin reductase in molybdenum cofactor-dependent resistance of Escherichia coli to 6-N-hydroxylaminopurine SG Kozmin, J Wang, RM Schaaper - Journal of Bacteriology, 2010 - Am Soc Microbiol Page 1. A role for CysJ flavin reductase in molybdenum cofactor- 1 dependent resistance of Escherichia coli to 6-N- 2 hydroxylaminopurine 3 4 Stanislav G. Kozmin, Jian Wang, and Roel M. Schaaper* 5 6 Laboratory of Molecular ... Open source bioimage informatics for cell biology JR Swedlow, KW Eliceiri - Trends in cell biology, 2009 - Elsevier Significant technical advances in imaging, molecular biology and genomics have fueled a revolution in cell biology, in that the molecular and structural processes of the cell are now visualized and measured routinely. Driving much of this recent development has been the advent of ... BiGG a Biochemical Genetic and Genomic knowledgebase of large scale metabolic reconstructions J Schellenberger, JO Park, TM Conrad, BØ … - BMC …, 2010 - biomedcentral.com BiGG currently contains 7 reconstructions including two versions of E. coli. There are a total of 7234 unique reactions and exchanges in the database. Exchange reactions carry metabolites from the extracellular compartment across the system boundary and are not technically part of the metabolic reconstruction. Translocation reactions carry a metabolite between compartments 2010/5/24 Multiple reciprocal adaptations and rapid genetic change upon experimental coevolution of an animal host and its microbial parasite RD Schulte, C Makus, B Hasert, NK … - Proceedings of the …, 2010 - National Acad Sciences The coevolution between hosts and parasites is predicted to have complex evolutionary consequences for both antagonists, often within short time periods. To date, conclusive experimental support for the predictions is available mainly for microbial host systems, but for only a few ... Genomic arrangement of bacterial operons is constrained by biological pathways encoded in the genome Y Yin, H Zhang, V Olman, Y Xu - … of the National Academy of Sciences, 2010 - link.aip.org It is generally known that bacterial genes working in the same biological pathways tend to group into operons, possibly to facilitate cotranscription and to provide stoichiometry. However, very little is understood about what may determine the global arrangement of bacterial genes ... Revealing strengths and weaknesses of methods for gene network inference D Marbach, RJ Prill, T Schaffter, C … - Proceedings of the …, 2010 - National Acad Sciences Numerous methods have been developed for inferring gene regulatory networks from expression data, however, both their absolute and comparative performance remain poorly understood. In this paper, we introduce a framework for critical performance assessment of methods ... Structure and function of an iterative polyketide synthase thioesterase domain catalyzing Claisen cyclization in aflatoxin biosynthesis … , JW Labonte, AG Newman, J Wong, … - Proceedings of the …, 2010 - National Acad Sciences Polyketide natural products possess diverse architectures and biological functions and share a subset of biosynthetic steps with fatty acid synthesis. The final transformation catalyzed by both polyketide synthases (PKSs) and fatty acid synthases is most often carried out by a ... How the Sequence of a Gene Can Tune Its Translation K Fredrick, M Ibba - Cell, 2010 - Elsevier Just about every molecular biologist, intentionally or not, has conducted experiments on the roles of codon usage during translation. For example, to prepare a protein of interest, a foreign gene might be expressed in a heterologous host like the bacterium Escherichia coli, but ... An Evolutionarily Conserved Mechanism for Controlling the Efficiency of Protein Translation T Tuller, A Carmi, K Vestsigian, S Navon, Y Dorfan, J … - Cell, 2010 - Elsevier Recent years have seen intensive progress in measuring protein translation. However, the contributions of coding sequences to the efficiency of the process remain unclear. Here, we identify a universally conserved profile of translation efficiency along mRNAs computed based on adaptation ... The Chemical MUPpeteer I Rodriguez - Cell, 2010 - Elsevier To face a hostile world, animals have developed a complex array of sensory systems. In vertebrates, this sensory toolbox provides such a keen selective advantage that a considerable fraction of the vertebrate genome is devoted to its development and function. The primary ... Network Modeling Identifies Molecular Functions Targeted by miR-204 to Suppress Head and Neck Y Lee, X Yang, Y Huang, H Fan, Q Zhang… - 2010 - papers.gersteinlab.org Due to the large number of putative microRNA gene targets predicted by sequence-alignment databases and the relative low accuracy of such predictions which are conducted independently of biological context by design, systematic experimental Functional analysis of human mismatch repair gene mutations identifies weak alleles and polymorphisms capable of polygenic interactions SL Martinez, RD Kolodner - Proceedings of the National …, 2010 - National Acad Sciences Many of the mutations reported as potentially causing Lynch syndrome are missense mutations in human mismatch repair (MMR) genes. Here, we used a Saccharomyces cerevisiae-based system to study polymorphisms and suspected missense mutations in human MMR ...
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Silk Stalkings Victoria Nichols?Susan Thompson? Rehabilitation Medicine The Management of Physical Disabilities Philip John Russell Nichols? Echinoderms David Nichols? Rehabilitation of the Severely Disabled Philip John Russell, etc. Nichols? Echinoderms David Nichols? Transistor Physics (Mod. Elect. Studs.) K G Nichols?E V Vernon? Transients in Electronic Engineering (Mod. Elect. Studs.) K G Nichols?E E Zepler? Transistor Physics (Science Pbs.) K G Nichols?E V Vernon? Moving the Earth Herbert Lownds Nichols? Historic Churches of New South Wales A, etc. Nichols? Psychological Care in Physical Illness Keith A Nichols? Votes and More for Women Suffrage and After in Connecticut Carole Nichols? Evolution's Captain Peter Nichols? Big Paul's School Bus Paul Nichols?William Marshall? Classic Cars Richard Nichols? Classic Corvette Richard Nichols? Benn's Media Directory, 1994 United Kingdom (Benn's Media Directory United Kingdom) Milldale Riot (Active Readers , 2nd S) Freda P Nichols? 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TEC-/- BTK-/- double mutant T cells exhibit severely impaired T cell activitity. RLK-/-ITK-/- double mutant celles exhibit severely imparired Th2 responses. Grb2(+/-) mice disrupt T cell signaling networks and development. Dendric cells and macrophages of MEK3 deficient mice have impaired IL12 production. Bam32(-/-) B cell develop normally but have impaired T-independent antibody responses in vivo. T-cell and B-cell of RAP1A deficient mice impair integrin-mediated cell adhesion. T-cell of WASP deficient mice impair the proliferaction and antigen receptor cap formation in response to anti-CD3zeta stimulation. T-cell of SHB defective mice impair the phosphorylation of LAT and consequently the activation of MAP kinase pathways. B-cell of 3BP2 (-/-) deficient mice have defective in proliferation, cell cycle progression, PLC-gamma2 phosphorylation, calcium mobilization, NF-ATp dephosphorylation, and Erk and Jnk activation in response to BCR ligation. B-cell of Vav2(-/-) deficient mice are defective in the ability to switch immunoglobulin class. T-cell of Vav1(-/-) deficient mice exhibit impaired antigen receptor signaling. Vav1(-/-)Vav2(-/-) mice exhibit greatly reduced the mature B-cells. Vav-1-/-Vav-2-/- B cells were unresponsive to BCR-driven proliferation in vitro and to thymus-indepen-dent antigen in vivo. Fyn-deficient mice exhibit a remarkably specific lymphoid defect thymocytes are refractile to stimulation through the TCR with mitogen or antigen. Lck-deficient mice show a pronounced thymic atrophy, with a dramatic reduction in the double-positive (CD4+CD8+) thymocyte population. T cell from mice deficient in LCK is required for normal signal transduction through the TCR. T cells from mice deficient in SLAP-130/Fyb show markedly impaired proliferation. B cell of chicken deficient ITK reduce IP3 generation and phospholipase C gamma 2 tyrosine phosphorylation. T cell of mice deficient ITK reduce IP3 generation and phospholipase C gamma 1 tyrosine phosphorylation. T cell of mice deficient ITK have failure of Th2 development. Mice deficient in ITK have reduced proliferative responses to MHC stimulation and to anti-TCR cross-linking Mutations in Btk cause X-linked immunodeficiency. Gads(GRAP2) has a role in thymocyte proliferaction for maturation of T-cells. Gads(GRAP2) has a role for homeostatic proliferaction in B cells. Grap negatively regulates T-cell proliferation. Gab2 is a substrate of ZAP-70 and functions as a switch molecule toward inhibition of TCR signal transuduction. B cell signaling causes tyrosine phosphorylation of Gab1, and in turn SHP2 bind to Gab1 Gab1 phosophorylation potentiate the phosphorylation of Akt, PI3K-dependent response. RasGRP1 mediates Ras activation following TCR stimulatioin. RasGRP1 and RasGRP3 induces RAS activation in B-cell to response to T-cell stimulation. Grb2-hSos1-PLCgamma1-p36/p38-ZAP70 complexes localize in the vicinity of TCR-zeta Gads(Grap2) plays an important role in T-cell signaling via its association with SLP-76 and LAT. Lck is required for normal signal transduction through the TCR. ZAP-70 plays crucial roles in T-cell activation and development. Syk triggers cellular activation in T-cell. TEC-/- BTK-/- double mutant T cells exhibit severely impaired T cell activitity. 1 J Exp Med. 2000 Dec 4;192(11) 1611-24. Severe B cell deficiency in mice lacking the tec kinase family members Tec and Btk. Ellmeier W, Jung S, Sunshine MJ, Hatam F, Xu Y, Baltimore D, Mano H, Littman DR. Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine. wilfried.ellmeier@univie.ac.at The cytoplasmic protein tyrosine kinase Tec has been proposed to have important functions in hematopoiesis and lymphocyte signal transduction. Here we show that Tec-deficient mice developed normally and had no major phenotypic alterations of the immune system. To reveal potential compensatory roles of other Tec kinases such as Bruton s tyrosine kinase (Btk), Tec/Btk double-deficient mice were generated. These mice exhibited a block at the B220(+)CD43(+) stage of B cell development and displayed a severe reduction of peripheral B cell numbers, particularly immunoglobulin (Ig)M(lo)IgD(hi) B cells. Although Tec/Btk(null) mice were able to form germinal centers, the response to T cell-dependent antigens was impaired. Thus, Tec and Btk together have an important role both during B cell development and in the generation and/or function of the peripheral B cell pool. The ability of Tec to compensate for Btk may also explain phenotypic differences in X-linked immunodeficiency (xid) mice compared with human X-linked agammaglobulinemia (XLA) patients. Publication Types Research Support, Non-U.S. Gov t PMID 11104803 [PubMed - indexed for MEDLINE] RLK-/-ITK-/- double mutant celles exhibit severely imparired Th2 responses. 1 Nat Immunol. 2001 Dec;2(12) 1183-8. Mutation of Tec family kinases alters T helper cell differentiation. Schaeffer EM, Yap GS, Lewis CM, Czar MJ, McVicar DW, Cheever AW, Sher A, Schwartzberg PL. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. The Tec kinases Rlk and Itk are critical for full T cell receptor (TCR)-induced activation of phospholipase C-gamma and mitogen-activated protein kinase. We show here that the mutation of Rlk and Itk impaired activation of the transcription factors NFAT and AP-1 and production of both T helper type 1 (TH1) and TH2 cytokines. Consistent with these biochemical defects, Itk-/- mice did not generate effective TH2 responses when challenged with Schistosoma mansoni eggs. Paradoxically, the more severely impaired Rlk-/-Itk-/- mice were able to mount a TH2 response and produced TH2 cytokines in response to this challenge. In addition, Rlk-/-Itk-/- cells showed impaired TCR-induced repression of the TH2-inducing transcription factor GATA-3, suggesting a potential mechanism for TH2 development in these hyporesponsive cells. Thus, mutations that affect Tec kinases lead to complex alterations in CD4+ TH cell differentiation. Publication Types Research Support, Non-U.S. Gov t Research Support, U.S. Gov t, P.H.S. PMID 11702066 [PubMed - indexed for MEDLINE] Grb2(+/-) mice disrupt T cell signaling networks and development. 1 Nat Immunol. 2001 Jan;2(1) 29-36. Disruption of T cell signaling networks and development by Grb2 haploid insufficiency. Gong Q, Cheng AM, Akk AM, Alberola-Ila J, Gong G, Pawson T, Chan AC. Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA. The developmental processes of positive and negative selection in the thymus shape the T cell antigen receptor (TCR) repertoire and require the integration of multiple signaling networks. These networks involve the efficient assembly of macromolecular complexes and are mediated by multimodular adaptor proteins that permit the functional integration of distinct signaling molecules. We show here that decreased expression of the adaptor protein Grb2 in Grb2+/- mice weakens TCR-induced c-Jun N-terminal kinase (JNK) and p38, but not extracellular signal-regulated kinase (ERK), activation. In turn, this selective effect decreases the ability of thymocytes to undergo negative, but not positive, selection. We also show that there are differences in the signaling thresholds of the three mitogen-activated protein kinase (MAPK) families. These differences may provide a mechanism by which quantitative differences in signal strength can alter the balance of downstream signaling pathways to induce the qualitatively distinct biological outcomes of proliferation, differentiation or apoptosis. PMID 11135575 [PubMed - indexed for MEDLINE] Dendric cells and macrophages of MEK3 deficient mice have impaired IL12 production. 1 EMBO J. 1999 Apr 1;18(7) 1845-57. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. Lu HT, Yang DD, Wysk M, Gatti E, Mellman I, Davis RJ, Flavell RA. Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. The p38 mitogen-activated protein kinase (MAPK) pathway, like the c-Jun N-terminal kinase (JNK) MAPK pathway, is activated in response to cellular stress and inflammation and is involved in many fundamental biological processes. To study the role of the p38 MAPK pathway in vivo, we have used homologous recombination in mice to inactivate the Mkk3 gene, one of the two specific MAPK kinases (MAPKKs) that activate p38 MAPK. Mkk3(-/-) mice were viable and fertile; however, they were defective in interleukin-12 (IL-12) production by macrophages and dendritic cells. Interferon-gamma production following immunization with protein antigens and in vitro differentiation of naive T cells is greatly reduced, suggesting an impaired type I cytokine immune response. The effect of the p38 MAPK pathway on IL-12 expression is at least partly transcriptional, since inhibition of this pathway blocks IL-12 p40 promoter activity in macrophage cell lines and IL-12 p40 mRNA is reduced in MKK3-deficient mice. We conclude that the p38 MAP kinase, activated through MKK3, is required for the production of inflammatory cytokines by both antigen-presenting cells and CD4(+) T cells. PMID 10202148 [PubMed - indexed for MEDLINE] Bam32(-/-) B cell develop normally but have impaired T-independent antibody responses in vivo. 1 Immunity. 2003 Oct;19(4) 621-32. Bam32 links the B cell receptor to ERK and JNK and mediates B cell proliferation but not survival. Han A, Saijo K, Mecklenbrauker I, Tarakhovsky A, Nussenzweig MC. Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021, USA. Bam32 is an adaptor protein recruited to the plasma membrane upon B cell receptor (BCR) crosslinking in a phosphoinositol 3-kinase (PI3K)-dependent manner; however, its physiologic function is unclear. To determine its physiologic function, we produced Bam32-deficient mice. Bam32(-/-) B cells develop normally but have impaired T-independent antibody responses in vivo and diminished responses to BCR crosslinking in vitro. Biochemical analysis revealed that Bam32 acts in a novel pathway leading from the BCR to MAPK/ERK Kinases (MEK1/2), MAPK/ERK Kinase Kinase-1 (MEKK1), extracellular signal-regulated kinase (ERK), and c-jun NH2-terminal kinase (JNK), but not p38 mitogen-activated protein kinase (p38). This pathway appears to be initiated by hematopoietic progenitor kinase-1 (HPK1), which interacts directly with Bam32, and differs from all previously characterized BCR signaling pathways in that it is required for normal BCR-mediated proliferation but not for B cell survival. PMID 14563325 [PubMed - indexed for MEDLINE] T-cell and B-cell of RAP1A deficient mice impair integrin-mediated cell adhesion. 1 Mol Cell Biol. 2006 Jan;26(2) 643-53. Rap1A-deficient T and B cells show impaired integrin-mediated cell adhesion. Duchniewicz M, Zemojtel T, Kolanczyk M, Grossmann S, Scheele JS, Zwartkruis FJ. Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, D-14195 Berlin, Germany. Studies in tissue culture cells have demonstrated a role for the Ras-like GTPase Rap1 in the regulation of integrin-mediated cell-matrix and cadherin-mediated cell-cell contacts. To analyze the function of Rap1 in vivo, we have disrupted the Rap1A gene by homologous recombination. Mice homozygous for the deletion allele are viable and fertile. However, primary hematopoietic cells isolated from spleen or thymus have a diminished adhesive capacity on ICAM and fibronectin substrates. In addition, polarization of T cells from Rap1-/- cells after CD3 stimulation was impaired compared to that of wild-type cells. Despite this, these defects did not result in hematopoietic or cell homing abnormalities. Although it is possible that the relatively mild phenotype is a consequence of functional complementation by the Rap1B gene, our genetic studies confirm a role for Rap1A in the regulation of integrins. PMID 16382154 [PubMed - indexed for MEDLINE] T-cell of WASP deficient mice impair the proliferaction and antigen receptor cap formation in response to anti-CD3zeta stimulation. 1 Immunity. 1998 Jul;9(1) 81-91. Wiskott-Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation. Snapper SB, Rosen FS, Mizoguchi E, Cohen P, Khan W, Liu CH, Hagemann TL, Kwan SP, Ferrini R, Davidson L, Bhan AK, Alt FW. Howard Hughes Medical Institute, Children s Hospital, Boston, Massachusetts 02115, USA. The Wiskott-Aldrich syndrome (WAS) is a human X-linked immunodeficiency resulting from mutations in a gene (WASP) encoding a cytoplasmic protein implicated in regulating the actin cytoskeleton. To elucidate WASP function, we disrupted the WASP gene in mice by gene-targeted mutation. WASP-deficient mice showed apparently normal lymphocyte development, normal serum immunoglobulin levels, and the capacity to respond to both T-dependent and T-independent type II antigens. However, these mice did have decreased peripheral blood lymphocyte and platelet numbers and developed chronic colitis. Moreover, purified WASP-deficient T cells showed markedly impaired proliferation and antigen receptor cap formation in response to anti-CD3epsilon stimulation. Yet, purified WASP-deficient B cells showed normal responses to anti-Ig stimulation. We discuss the implications of our findings regarding WASP function in receptor signaling and cytoskeletal reorganization in T and B cells and compare the effects of WASP deficiency in mice and humans. PMID 9697838 [PubMed - indexed for MEDLINE] T-cell of SHB defective mice impair the phosphorylation of LAT and consequently the activation of MAP kinase pathways. 9 Sep 24;274(39) 28050-7. Requirement of the Src homology 2 domain protein Shb for T cell receptor-dependent activation of the interleukin-2 gene nuclear factor for activation of T cells element in Jurkat T cells. Lindholm CK, Gylfe E, Zhang W, Samelson LE, Welsh M. Department of Medical Cell Biology, Box 571, Biomedicum, Uppsala University, S-75123 Uppsala, Sweden. Stimulation of the T cell antigen receptor (TCR) induces tyrosine phosphorylation of numerous intracellular proteins. We have recently investigated the role of the adaptor protein Shb in the early events of T cell signaling and observed that Shb associates with Grb2, linker for activation of T cells (LAT) and the TCR zeta-chain in Jurkat cells. We now report that Shb also associates with phospholipase C-gamma1 (PLC-gamma1) in these cells. Overexpression of Src homology 2 domain defective Shb caused diminished phosphorylation of LAT and consequently the activation of mitogen-activated protein kinases was decreased upon TCR stimulation. In addition, the Shb mutant also blocked phosphorylation of PLC-gamma1 and the increase in cytoplasmic Ca(2+) following TCR stimulation. Nuclear factor for activation of T cells is a major target for Ras and calcium signaling pathways in T cells following TCR stimulation, and the overexpression of the mutant Shb prevented TCR-dependent activation of the nuclear factor for activation of T cells. Consequently, endogenous interleukin-2 production was decreased under these conditions. The results indicate a role for Shb as a link between the TCR and downstream signaling events involving LAT and PLC-gamma1 and resulting in the activation of transcription of the interleukin-2 gene. PMID 10488157 [PubMed - indexed for MEDLINE] B-cell of 3BP2 (-/-) deficient mice have defective in proliferation, cell cycle progression, PLC-gamma2 phosphorylation, calcium mobilization, NF-ATp dephosphorylation, and Erk and Jnk activation in response to BCR ligation. 1 Mol Cell Biol. 2006 Jul;26(14) 5214-25. 3BP2 deficiency impairs the response of B cells, but not T cells, to antigen receptor ligation. de la Fuente MA, Kumar L, Lu B, Geha RS. Division of Immunology, Children s Hospital, 300 Longwood Ave., Boston, MA 02115, USA. The adapter protein 3BP2 is expressed in lymphocytes; binds to Syk/ZAP-70, Vav, and phospholipase C-gamma (PLC-gamma); and is thought to be important for interleukin-2 gene transcription in T cells. To define the role of 3BP2 in lymphocyte development and function, we generated 3BP2-deficient mice. T-cell development, proliferation, cytokine secretion, and signaling in response to T-cell receptor (TCR) ligation were all normal in 3BP2(-/-) mice. 3BP2(-/-) mice had increased accumulation of pre-B cells in the bone marrow and a block in the progression of transitional B cells in the spleen from the T1 to the T2 stage, but normal numbers of mature B cells. B-cell proliferation, cell cycle progression, PLC-gamma2 phosphorylation, calcium mobilization, NF-ATp dephosphorylation, and Erk and Jnk activation in response to B-cell receptor (BCR) ligation were all impaired. These results suggest that 3BP2 is important for BCR, but not for TCR signaling. PMID 16809760 [PubMed - indexed for MEDLINE] B-cell of Vav2(-/-) deficient mice are defective in the ability to switch immunoglobulin class. 1 Nat Immunol. 2001 Jun;2(6) 542-7. Comment in Nat Immunol. 2001 Jun;2(6) 482-4. Signal transduction through Vav-2 participates in humoral immune responses and B cell maturation. Doody GM, Bell SE, Vigorito E, Clayton E, McAdam S, Tooze R, Fernandez C, Lee IJ, Turner M. Laboratory of Lymphocyte Signaling and Development, Molecular Immunology Programme, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK. B and T lymphocytes develop normally in mice lacking the guanine nucleotide exchange factor Vav-2. However, the immune responses to type II thymus-independent antigen as well as the primary response to thymus-dependent (TD) antigen are defective. Vav-2-deficient mice are also defective in their ability to switch immunoglobulin class, form germinal centers and generate secondary immune responses to TD antigens. Mice lacking both Vav-1 and Vav-2 contain reduced numbers of B lymphocytes and display a maturational block in the development of mature B cells. B cells from Vav-1(-/-)Vav-2(-/-) mice respond poorly to antigen receptor triggering, both in terms of proliferation and calcium release. These studies show the importance of Vav-2 in humoral immune responses and B cell maturation. PMID 11376342 [PubMed - indexed for MEDLINE] T-cell of Vav1(-/-) deficient mice exhibit impaired antigen receptor signaling. 1 Nature. 1995 Mar 30;374(6521) 474-7. Defective T-cell receptor signalling and positive selection of Vav-deficient CD4+ CD8+ thymocytes. Fischer KD, Zmuldzinas A, Gardner S, Barbacid M, Bernstein A, Guidos C. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. During lymphocyte development, cellular proliferation and positive and negative selection events ensure the production of T and B lymphocytes bearing highly diverse, but self-tolerant, repertoires of antigen receptors. These processes are initiated when engagement of growth-factor receptors, or the T and B lymphocyte antigen receptors, induces tyrosine phosphorylation of specific SH2- and SH3-domain-containing cytoplasmic proteins, including Vav. Here we show that vav-/- embryonic stem cells generate only limited numbers of immature and mature T and B lymphocytes in the RAG-2 blastocyst complementation assay. Furthermore, Vav-deficient T lymphocytes showed severely impaired antigen receptor signalling. Finally, we demonstrate that Vav-dependent signalling pathways regulate maturation, but not CD4/CD8 lineage commitment, during T-cell-receptor-mediated positive selection of immature CD4+ CD8+ precursors into mature CD4+ CD8- or CD4- CD8+ T cells. PMID 7700360 [PubMed - indexed for MEDLINE] Vav1(-/-)Vav2(-/-) mice exhibit greatly reduced the mature B-cells. Vav-1-/-Vav-2-/- B cells were unresponsive to BCR-driven proliferation in vitro and to thymus-indepen-dent antigen in vivo. 1 Nat Immunol. 2001 Jun;2(6) 548-55. Comment in Nat Immunol. 2001 Jun;2(6) 482-4. Compensation between Vav-1 and Vav-2 in B cell development and antigen receptor signaling. Tedford K, Nitschke L, Girkontaite I, Charlesworth A, Chan G, Sakk V, Barbacid M, Fischer KD. Abteilung Physiologische Chemie, Universitat Ulm, Albert-Einstein-Allee 11, D-89069 Ulm, Germany. Vav-1 and Vav-2 are closely related Dbl-homology GTP exchange factors (GEFs) for Rho GTPases. Mutation of Vav-1 disrupts T cell development and T cell antigen receptor-induced activation, but has comparatively little effect on B cells. We found that combined deletion of both Vav-1 and Vav-2 in mice resulted in a marked reduction in mature B lymphocyte numbers. Vav-1(-/-)Vav-2(-/-) B cells were unresponsive to B cell antigen receptor (BCR)-driven proliferation in vitro and to thymus-independent antigen in vivo. BCR-stimulated intracellular calcium mobilization was greatly impaired in Vav-1(-/-)Vav-2(-/-) B cells. These findings establish a role for Vav-2 in BCR calcium signaling and reveal that the Vav family of GEFs is critical to B cell development and function. PMID 11376343 [PubMed - indexed for MEDLINE] Fyn-deficient mice exhibit a remarkably specific lymphoid defect thymocytes are refractile to stimulation through the TCR with mitogen or antigen. 1 Cell. 1992 Sep 4;70(5) 751-63. Defective T cell receptor signaling in mice lacking the thymic isoform of p59fyn. Appleby MW, Gross JA, Cooke MP, Levin SD, Qian X, Perlmutter RM. Howard Hughes Medical Institute, Department of Immunology, University of Washington, Seattle 98195. Considerable evidence supports the hypothesis that the nonreceptor protein tyrosine kinase p59fyn participates in signal transduction from the T cell receptor (TCR). To examine this hypothesis in detail, we have produced mice that lack the thymic isoform of p59fyn but retain expression of the brain isoform of the protein. fynTnull mice exhibit a remarkably specific lymphoid defect thymocytes are refractile to stimulation through the TCR with mitogen or antigen, while peripheral T cells, following what appears to be a normal maturation sequence, reacquire significant signaling capabilities. These data confirm that p59fynT plays a pivotal role in TCR signal transduction and demonstrate that additional developmentally regulated signaling components also contribute to TCR-induced lymphocyte activation. PMID 1516132 [PubMed - indexed for MEDLINE] Lck-deficient mice show a pronounced thymic atrophy, with a dramatic reduction in the double-positive (CD4+CD8+) thymocyte population. 1 Nature. 1992 May 14;357(6374) 161-4. Comment in Nature. 1993 Jan 21;361(6409) 213. Profound block in thymocyte development in mice lacking p56lck. Molina TJ, Kishihara K, Siderovski DP, van Ewijk W, Narendran A, Timms E, Wakeham A, Paige CJ, Hartmann KU, Veillette A, et al. Ontario Cancer Institute, University of Toronto, Canada. The protein Lck (p56lck) has a relative molecular mass of 56,000 and belongs to the Src family of tyrosine kinases. It is expressed exclusively in lymphoid cells, predominantly in thymocytes and peripheral T cells. Lck associates specifically with the cytoplasmic domains of both CD4 and CD8 T-cell surface glycoproteins and interacts with the beta-chain of the interleukin-2 receptor, which implicates Lck activity in signal transduction during thymocyte ontogeny and activation of mature T cells. Here we generate an lck null mutation by homologous recombination in embryonic stem cells to evaluate the role of p56lck in T-cell development and activation. Lck-deficient mice show a pronounced thymic atrophy, with a dramatic reduction in the double-positive (CD4+CD8+) thymocyte population. Mature, single-positive thymocytes are not detectable in these mice and there are only very few peripheral T cells. These results illustrate the crucial role of this T-cell-specific tyrosine kinase in the thymocyte development. PMID 1579166 [PubMed - indexed for MEDLINE] T cell from mice deficient in LCK is required for normal signal transduction through the TCR. 1 Cell. 1992 Aug 21;70(4) 585-93. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Straus DB, Weiss A. Howard Hughes Medical Institute, Department of Medicine, University of California, San Francisco 94143. Signaling through the T cell antigen receptor (TCR) results both in rapid increases in tyrosine phosphorylation on a number of proteins and in the activation of the phosphatidylinositol pathway. It is not clear how stimulation of the TCR leads to these signaling events. Mutants of the Jurkat T cell line have been previously isolated that fail to show increases in calcium following receptor stimulation. Analysis of one of these mutants, JCaM1, which is defective in the induction of tyrosine phosphorylation, revealed a defect in the expression of functional lck tyrosine kinase. The lack of lck activity was caused in part by a splicing defect. Expression of the lck cDNA in JCaM1 restores the ability of the cell to respond to TCR stimulation. These results indicate that lck is required for normal signal transduction through the TCR. PMID 1505025 [PubMed - indexed for MEDLINE] T cells from mice deficient in SLAP-130/Fyb show markedly impaired proliferation. 1 Science. 2001 Sep 21;293(5538) 2263-5. Coupling of the TCR to integrin activation by Slap-130/Fyb. Peterson EJ, Woods ML, Dmowski SA, Derimanov G, Jordan MS, Wu JN, Myung PS, Liu QH, Pribila JT, Freedman BD, Shimizu Y, Koretzky GA. The Abramson Family Cancer Research Institute, Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. SLAP-130/Fyb (SLP-76-associated phosphoprotein or Fyn-binding protein; also known as Fyb/Slap) is a hematopoietic-specific adapter, which associates with and modulates function of SH2-containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76). T cells from mice lacking SLAP-130/Fyb show markedly impaired proliferation following CD3 engagement. In addition, the T cell receptor (TCR) in SLAP-130/Fyb mutant cells fails to enhance integrin-dependent adhesion. Although TCR-induced actin polymerization is normal, TCR-stimulated clustering of the integrin LFA-1 is defective in SLAP-130/Fyb-deficient cells. These data indicate that SLAP-130/Fyb is important for coupling TCR-mediated actin cytoskeletal rearrangement with activation of integrin function, and for T cells to respond fully to activating signals. PMID 11567141 [PubMed - indexed for MEDLINE] B cell of chicken deficient ITK reduce IP3 generation and phospholipase C gamma 2 tyrosine phosphorylation. 1 J Exp Med. 1996 Jul 1;184(1) 31-40. A role for Bruton s tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2. Takata M, Kurosaki T. Department of Oncology and Immunology, Wyeth-Ayerst Research, Pearl River, New York 10965, USA. Defects in the gene encoding Bruton s tyrosine kinase (Btk) result in a disease called X-linked agammaglobulinemia, in which there is a profound decrease of mature B cells due to a block in B cell development. Recent studies have shown that Btk is tyrosine phosphorylated and activated upon B cell antigen receptor (BCR) stimulation. To elucidate the functions of this kinase, we examined BCR signaling of DT40 B cells deficient in Btk. Tyrosine phosphorylation of phospholipase C (PLC)-gamma 2 upon receptor stimulation was significantly reduced in the mutant cells, leading to the loss of both BCR-coupled phosphatidylinositol hydrolysis and calcium mobilization. Pleckstrin homology and Src-homology 2 domains of Btk were required for PLC-gamma 2 activation. Since Syk is also required for the BCR-induced PLC-gamma 2 activation, our findings indicate that PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions. PMID 8691147 [PubMed - indexed for MEDLINE] T cell of mice deficient ITK reduce IP3 generation and phospholipase C gamma 1 tyrosine phosphorylation. 1 J Exp Med. 1998 May 18;187(10) 1721-7. T cell receptor-initiated calcium release is uncoupled from capacitative calcium entry in Itk-deficient T cells. Liu KQ, Bunnell SC, Gurniak CB, Berg LJ. Program of Immunology, Division of Medical Sciences, Harvard University, Boston, Massachusetts 02115, USA. Itk, a Tec family tyrosine kinase, plays an important but as yet undefined role in T cell receptor (TCR) signaling. Here we show that T cells from Itk-deficient mice have a TCR-proximal signaling defect, resulting in defective interleukin 2 secretion. Upon TCR stimulation, Itk-/- T cells release normal amounts of calcium from intracellular stores, but fail to open plasma membrane calcium channels. Since thapsigargin-induced store depletion triggers normal calcium entry in Itk-/- T cells, an impaired biochemical link between store depletion and channel opening is unlikely to be responsible for this defect. Biochemical studies indicate that TCR-induced inositol 1,4,5 tris-phosphate (IP3) generation and phospholipase C gamma1 tyrosine phosphorylation are substantially reduced in Itk-/- T cells. In contrast, TCR-zeta and ZAP-70 are phosphorylated normally, suggesting that Itk functions downstream of, or in parallel to, ZAP-70 to facilitate TCR-induced IP3 production. These findings support a model in which quantitative differences in cytosolic IP3 trigger distinct responses, and in which only high concentrations of IP3 trigger the influx of extracellular calcium. PMID 9584150 [PubMed - indexed for MEDLINE] T cell of mice deficient ITK have failure of Th2 development. 1 Immunity. 1999 Oct;11(4) 399-409. Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells. Fowell DJ, Shinkai K, Liao XC, Beebe AM, Coffman RL, Littman DR, Locksley RM. Department of Medicine, University of California San Francisco 94143, USA. Naive Itk-deficient CD4+ T cells were unable to establish stable IL-4 production, even when primed in Th2-inducing conditions. In contrast, IFNgamma production was little affected. Failure to express IL-4 occurred even among cells that had gone through multiple cell divisions and was associated with a delay in the kinetics and magnitude of NFATc nuclear localization. IL-4 production was restored genetically by retroviral reconstitution of Itk or biochemically by augmenting the calcium flux with ionomycin. In vivo, Itk-deficient mice were unable to establish functional Th2 cells. Development of protective Th1 cells was unimpeded. These data define a nonredundant role for Itk in modulating signals from the TCR/CD28 pathways that are specific for the establishment of stable IL-4 but not IFNgamma expression. PMID 10549622 [PubMed - indexed for MEDLINE] Mice deficient in ITK have reduced proliferative responses to MHC stimulation and to anti-TCR cross-linking 1 Immunity. 1995 Dec;3(6) 757-69. Altered T cell receptor signaling and disrupted T cell development in mice lacking Itk. Liao XC, Littman DR. Department of Microbiology and Immunology, University of California, San Francisco 94143-0414, USA. Itk is a T cell protein tyrosine kinase (PTK) that, along with Btk and Tec, belongs to a family of cytoplasmic PTKs with N-terminal pleckstrin homology domains. Btk plays a critical role in B lymphocyte development. To determine whether Itk has an analogous role in T lymphocytes, we used gene targeting to prepare mice lacking expression of Itk. Such animals had decreased numbers of mature thymocytes, an effect most clearly observed in mice expressing T cell receptor (TCR) transgenes. Mature T cells from Itk-deficient mice had reduced proliferative responses to allogeneic MHC stimulation and to anti-TCR cross-linking, but responded normally to stimulation with phorbol ester plus ionomycin or with IL-2. These results provide genetic evidence that Itk is involved in T cell development and also suggest that Itk has an important role in proximal events in TCR-mediated signaling pathways. PMID 8777721 [PubMed - indexed for MEDLINE] Mutations in Btk cause X-linked immunodeficiency. 1 Semin Immunol. 1998 Aug;10(4) 309-16. Btk function in B cell development and response. Satterthwaite AB, Li Z, Witte ON. Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90095-1662, USA. Mutations in Bruton s tyrosine kinase (Btk) result in the B cell immunodeficiencies XLA in humans and Xid in mice. Both the maintenance of peripheral B cell numbers and their response to B cell antigen receptor (BCR) crosslinking depend on Btk. Btk integrates signals from multiple cell surface receptors, including BCR and G-protein coupled receptors. These Btk dependent signals control B cell proliferation and survival by mediating Ca2+ flux, activating JNK and p38 and inducing cell cycle regulatory genes. Publication Types Review PMID 9695187 [PubMed - indexed for MEDLINE] Gads(GRAP2) has a role in thymocyte proliferaction for maturation of T-cells. 1 Science. 2001 Mar 9;291(5510) 1987-91. Requirement for the SLP-76 adaptor GADS in T cell development. Yoder J, Pham C, Iizuka YM, Kanagawa O, Liu SK, McGlade J, Cheng AM. Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110, USA. GADS is an adaptor protein implicated in CD3 signaling because of its ability to link SLP-76 to LAT. A GADS-deficient mouse was generated by gene targeting, and the function of GADS in T cell development and activation was examined. GADS- CD4-CD8- thymocytes exhibited a severe block in proliferation but still differentiated into mature T cells. GADS- thymocytes failed to respond to CD3 cross-linking in vivo and were impaired in positive and negative selection. Immunoprecipitation experiments revealed that the association between SLP-76 and LAT was uncoupled in GADS- thymocytes. These observations indicate that GADS is a critical adaptor for CD3 signaling. PMID 11239162 [PubMed - indexed for MEDLINE] Gads(GRAP2) has a role for homeostatic proliferaction in B cells. 1 Eur J Immunol. 2005 Apr;35(4) 1184-92. Expression and function of the adaptor protein Gads in murine B cells. Yankee TM, Draves KE, Clark EA. Department of Immunology, University of Washington, Seattle, USA. tyankee@kumc.edu Nearly all hematopoietic receptors are dependent on adaptor proteins for the activation of downstream signaling pathways. The Gads adaptor protein is expressed in many hematopoietic tissues, including bone marrow, lymph node, and spleen. Using intracellular staining, we detected Gads protein in a number cells, including B cells, T cells, NK cells, monocytes, and plasmacytoid DC, but not in macrophages, neutrophils, or monocyte-derived DC. In the B cell compartment, Gads was first expressed after immature B cells leave the bone marrow and was down-regulated after B cell antigen receptor (BCR) ligation. Female Gads(-/-) mice had increased numbers of splenic B cells, as compared to female Gads(+/+) mice, suggesting a role for Gads in B cell homeostasis. Although B cell production and turnover of splenic B cell subsets appeared normal in Gads(-/-) mice, homeostatic proliferation was significantly impaired in Gads(-/-) B cells. Whereas BCR ligation can induce apoptosis in wild-type transitional stage 1 (T1) B cells, Gads(-/-) T1 B cells were resistant to BCR-induced apoptosis. Gads(-/-) B cells also showed increased BCR-mediated calcium mobilization. We conclude that Gads may have a negative regulatory role in signaling through survival pathways, and is necessary for normal homeostatic proliferation in B cells. PMID 15761845 [PubMed - indexed for MEDLINE] Grap negatively regulates T-cell proliferation. 1 Mol Cell Biol. 2002 May;22(10) 3230-6. Grap negatively regulates T-cell receptor-elicited lymphocyte proliferation and interleukin-2 induction. Shen R, Ouyang YB, Qu CK, Alonso A, Sperzel L, Mustelin T, Kaplan MH, Feng GS. Program in Signal Transduction Research, The Burnham Institute, La Jolla, California 92037, USA. Grb-2-related adaptor protein (Grap) is a Grb2-like SH3-SH2-SH3 adaptor protein with expression restricted to lymphoid tissues. Grap(-/-) lymphocytes isolated from targeted Grap-deficient mice exhibited enhanced proliferation, interleukin-2 production, and c-fos induction in response to mitogenic T-cell receptor (TCR) stimulation, compared to wild-type cells. Ectopic expression of Grap led to a suppression of Elk-1-directed transcription induced by the Ras/Erk pathway, without having effects on gene expression mediated by Jnk and p38 mitogen-activated protein kinases. Together, these data suggest that Grap, unlike Grb2, acts as a negative regulator of TCR-stimulated intracellular signaling by downregulating signal relay through the Ras/Erk pathway. PMID 11971956 [PubMed - indexed for MEDLINE] Gab2 is a substrate of ZAP-70 and functions as a switch molecule toward inhibition of TCR signal transuduction. 1 J Biol Chem. 2001 Nov 30;276(48) 45175-83. Epub 2001 Sep 25. Docking protein Gab2 is phosphorylated by ZAP-70 and negatively regulates T cell receptor signaling by recruitment of inhibitory molecules. Yamasaki S, Nishida K, Hibi M, Sakuma M, Shiina R, Takeuchi A, Ohnishi H, Hirano T, Saito T. Molecular Genetics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan. To maintain various T cell responses and immune equilibrium, activation signals triggered by T cell antigen receptor (TCR) must be regulated by inhibitory signals. Gab2, an adaptor protein of the insulin receptor substrate-1 family, has been shown to be involved in the downstream signaling from cytokine receptors. We investigated the functional role of Gab2 in TCR-mediated signal transduction. Gab2 was phosphorylated by ZAP-70 and co-precipitated with phosphoproteins, such as ZAP-70, LAT, and CD3zeta, upon TCR stimulation. Overexpression of Gab2 in Jurkat cells or antigen-specific T cell hybridomas resulted in the inhibition of NF-AT activation, interleukin-2 production, and tyrosine phosphorylation. The structure-function relationship of Gab2 was analyzed by mutants of Gab2. The Gab2 mutants lacking SHP-2-binding sites mostly abrogated the inhibitory activity of Gab2, but its inhibitory function was restored by fusing to active SHP-2 as a chimeric protein. A mutant with defective phosphatidylinositol 3-kinase binding capacity also impaired the inhibitory activity, and the pleckstrin homology domain-deletion mutant revealed a crucial function of the pleckstrin homology domain for localization to the plasma membrane. These results suggest that Gab2 is a substrate of ZAP-70 and functions as a switch molecule toward inhibition of TCR signal transduction by mediating the recruitment of inhibitory molecules to the TCR signaling complex. PMID 11572860 [PubMed - indexed for MEDLINE] B cell signaling causes tyrosine phosphorylation of Gab1, and in turn SHP2 bind to Gab1 Gab1 phosophorylation potentiate the phosphorylation of Akt, PI3K-dependent response. 1 J Biol Chem. 2001 Apr 13;276(15) 12257-65. Epub 2001 Jan 22. The Gab1 docking protein links the b cell antigen receptor to the phosphatidylinositol 3-kinase/Akt signaling pathway and to the SHP2 tyrosine phosphatase. Ingham RJ, Santos L, Dang-Lawson M, Holgado-Madruga M, Dudek P, Maroun CR, Wong AJ, Matsuuchi L, Gold MR. Departments of Microbiology and Immunology and Zoology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. B cell antigen receptor (BCR) signaling causes tyrosine phosphorylation of the Gab1 docking protein. This allows phosphatidylinositol 3-kinase (PI3K) and the SHP2 tyrosine phosphatase to bind to Gab1. In this report, we tested the hypothesis that Gab1 acts as an amplifier of PI3K- and SHP2-dependent signaling in B lymphocytes. By overexpressing Gab1 in the WEHI-231 B cell line, we found that Gab1 can potentiate BCR-induced phosphorylation of Akt, a PI3K-dependent response. Gab1 expression also increased BCR-induced tyrosine phosphorylation of SHP2 as well as the binding of Grb2 to SHP2. We show that the pleckstrin homology (PH) domain of Gab1 is required for BCR-induced phosphorylation of Gab1 and for Gab1 participation in BCR signaling. Moreover, using confocal microscopy, we show that BCR ligation can induce the translocation of Gab1 from the cytosol to the plasma membrane and that this requires the Gab1 PH domain as well as PI3K activity. These findings are consistent with a model in which the binding of the Gab1 PH domain to PI3K-derived lipids brings Gab1 to the plasma membrane, where it can be tyrosine-phosphorylated and then act as an amplifier of BCR signaling. PMID 11278704 [PubMed - indexed for MEDLINE] RasGRP1 mediates Ras activation following TCR stimulatioin. RasGRP1 and RasGRP3 induces RAS activation in B-cell to response to T-cell stimulation. 1 Immunol Lett. 2006 May 15;105(1) 77-82. Epub 2006 Feb 20. The role of RasGRPs in regulation of lymphocyte proliferation. Coughlin JJ, Stang SL, Dower NA, Stone JC. Department of Biochemistry, University of Alberta, Edmonton, Alta., Canada T6G 2H7. RasGRP1 links TCR signaling to Ras in T cells, while both RasGRP1 and RasGRP3 link BCR signaling to Ras in B cells. T cells deficient in RasGRP1 have defective proliferative responses as do B cells deficient in both RasGRP1 and RasGRP3, confirming the importance of Ras activation in lymphocyte proliferation. While aged Rasgrp1-/- mice develop late-onset autoimmunity characterized by splenomegaly and the presence of anti-nuclear antibodies (ANA), the additional loss of RasGRP3 expression inhibits this phenotype. We show here that the autoimmunity in Rasgrp1-/- mice is T cell dependent. Compared to wildtype, Rasgrp1-/- T cells induce greater in vitro B cell proliferation that is due, at least in part, to increased production of interleukin-4 (IL-4). Rasgrp1 Rasgrp3 double mutant B cells are less responsive to this T cell stimulation. The reduced double mutant B cell proliferative response was paralleled by decreased induction of cyclin D2 upon stimulation with IL-4 and anti-IgM. Taken together these results suggest that double mutant mice fail to generate autoimmunity due to their decreased B cell cyclin D2 accumulation, and thus proliferation, in response to the elevated levels of IL-4 produced by mutant T cells. PMID 16530850 [PubMed - indexed for MEDLINE] Grb2-hSos1-PLCgamma1-p36/p38-ZAP70 complexes localize in the vicinity of TCR-zeta 1 J Biol Chem. 1995 Aug 4;270(31) 18428-36. Ligation of the T-cell antigen receptor (TCR) induces association of hSos1, ZAP-70, phospholipase C-gamma 1, and other phosphoproteins with Grb2 and the zeta-chain of the TCR. Nel AE, Gupta S, Lee L, Ledbetter JA, Kanner SB. Department of Medicine, UCLA School of Medicine 90024, USA. Signaling by the T-cell antigen receptor (TCR) involves both phospholipase C (PLC)-gamma 1 and p21ras activation. While failing to induce Shc/Grb2 association, ligation of the TCR/CD3 receptor in Jurkat T-cells induced hSos1-Grb2 complexes. In addition to hSos1, Grb2 participates in the formation of a tyrosine phosphoprotein complex that includes 145-, 95-, 70-, 54-, and 36-38-kDa proteins. p145 was identified as PLC-gamma 1 and p70 as the protein tyrosine kinase, ZAP-70. Although of the same molecular weight, p95 was not recognized by an anti-serum to p95 Vav. The SH2 domains of Grb2 and PLC-gamma 1 were required for the formation of this protein complex. In anti-CD3-treated cells, Grb2 redistributed from the cytosol to a particulate cell compartment along with p36/p38, ZAP-70, and PLC-gamma 1. Part of the Grb2 complex associated with the particulate compartment could be extracted with Nonidet P-40, while the rest was Nonidet P-40 insoluble. In both the detergent-soluble and -insoluble fractions, Grb2 coimmunoprecipitated with the zeta-chain of the TCR. Taken together, these results indicate that anti-CD3 induces Grb2-hSos1-PLC-gamma 1-p36/p38-ZAP70 complexes, which localize in the vicinity of TCR-zeta. PMID 7629168 [PubMed - indexed for MEDLINE] Gads(Grap2) plays an important role in T-cell signaling via its association with SLP-76 and LAT. 1 Curr Biol. 1999 Jan 28;9(2) 67-75. The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. Liu SK, Fang N, Koretzky GA, McGlade CJ. Department of Medical Biophysics, University of Toronto, The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Research Institute, 555 University Ave, Toronto, Ontario M5G 1X8, Canada. BACKGROUND The adaptor protein Gads is a Grb2-related protein originally identified on the basis of its interaction with the tyrosine-phosphorylated form of the docking protein Shc. Gads protein expression is restricted to hematopoietic tissues and cell lines. Gads contains a Src homology 2 (SH2) domain, which has previously been shown to have a similar binding specificity to that of Grb2. Gads also possesses two SH3 domains, but these have a distinct binding specificity to those of Grb2, as Gads does not bind to known Grb2 SH3 domain targets. Here, we investigated whether Gads is involved in T-cell signaling. RESULTS We found that Gads is highly expressed in T cells and that the SLP-76 adaptor protein is a major Gads-associated protein in vivo. The constitutive interaction between Gads and SLP-76 was mediated by the carboxy-terminal SH3 domain of Gads and a 20 amino-acid proline-rich region in SLP-76. Gads also coimmunoprecipitated the tyrosine-phosphorylated form of the linker for activated T cells (LAT) adaptor protein following cross-linking of the T-cell receptor; this interaction was mediated by the Gads SH2 domain. Overexpression of Gads and SLP-76 resulted in a synergistic augmentation of T-cell signaling, as measured by activation of nuclear factor of activated T cells (NFAT), and this cooperation required a functional Gads SH2 domain. CONCLUSIONS These results demonstrate that Gads plays an important role in T-cell signaling via its association with SLP-76 and LAT. Gads may promote cross-talk between the LAT and SLP-76 signaling complexes, thereby coupling membrane-proximal events to downstream signaling pathways. PMID 10021361 [PubMed - indexed for MEDLINE] Lck is required for normal signal transduction through the TCR. 1 Cell. 1992 Aug 21;70(4) 585-93. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Straus DB, Weiss A. Howard Hughes Medical Institute, Department of Medicine, University of California, San Francisco 94143. Signaling through the T cell antigen receptor (TCR) results both in rapid increases in tyrosine phosphorylation on a number of proteins and in the activation of the phosphatidylinositol pathway. It is not clear how stimulation of the TCR leads to these signaling events. Mutants of the Jurkat T cell line have been previously isolated that fail to show increases in calcium following receptor stimulation. Analysis of one of these mutants, JCaM1, which is defective in the induction of tyrosine phosphorylation, revealed a defect in the expression of functional lck tyrosine kinase. The lack of lck activity was caused in part by a splicing defect. Expression of the lck cDNA in JCaM1 restores the ability of the cell to respond to TCR stimulation. These results indicate that lck is required for normal signal transduction through the TCR. PMID 1505025 [PubMed - indexed for MEDLINE] ZAP-70 plays crucial roles in T-cell activation and development. Syk triggers cellular activation in T-cell. 1 Mol Cell Biol. 1998 Mar;18(3) 1388-99. Genetic evidence for differential coupling of Syk family kinases to the T-cell receptor reconstitution studies in a ZAP-70-deficient Jurkat T-cell line. Williams BL, Schreiber KL, Zhang W, Wange RL, Samelson LE, Leibson PJ, Abraham RT. Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA. T-cell antigen receptor (TCR) engagement activates multiple protein tyrosine kinases (PTKs), including the Src family member, Lck, and the Syk-related PTK, ZAP-70. Studies in ZAP-70-deficient humans have demonstrated that ZAP-70 plays crucial roles in T-cell activation and development. However, progress toward a detailed understanding of the regulation and function of ZAP-70 during TCR signaling has been hampered by the lack of a suitable T-cell model for biochemical and genetic analyses. In this report, we describe the isolation and phenotypic characterization of a Syk- and ZAP-70-negative somatic mutant derived from the Jurkat T-cell line. The P116 cell line displays severe defects in TCR-induced signaling functions, including protein tyrosine phosphorylation, intracellular Ca2+ mobilization, and interleukin-2 promoter-driven transcription. These signaling defects were fully reversed by reintroduction of catalytically active versions of either Syk or ZAP-70 into the P116 cells. However, in contrast to ZAP-70 expression, Syk expression triggered a significant degree of cellular activation in the absence of TCR ligation. Transfection experiments with ZAP-70-Syk chimeric proteins indicated that both the amino-terminal regulatory regions and the carboxy-terminal catalytic domains of Syk and ZAP-70 contribute to the distinctive functional properties of these PTKs. These studies underscore the crucial role of ZAP-70 in TCR signaling and offer a powerful genetic model for further analyses of ZAP-70 regulation and function in T cells. PMID 9488454 [PubMed - indexed for MEDLINE]
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O.C.U.編 BARINDEN｜NEW MILGAN｜MENASA｜GREY ROCK｜FREEDOM｜PESETA｜BELTCHKA｜OCU FRONTBASE｜FORT MONUS｜SOLEIT｜CARRIER CAMP｜RUPIDIS BARINDEN バリンデン 備考 Shop ショップ Military office 軍オフィス Mission02 Bar 酒場 マスター / うそつきハッシュ / ヒゲ男のムッサー / ひとり言のベレッタ Colosseum 闘技場 対戦相手 Sazaland / Rudensky / Jorg / Alexander / Were Wolf / Adam / Jimmy / Demon.V 賭け金 100 / 200 / 300 Shop Shop Colosseum Shop ▼Mission02～▼ Weapon Grip｜Shoulder Parts Body｜Arm L｜Arm R｜Legs｜Computer｜Back Pack Item Item Weapon Grip New 名称 価格 AT DF Hit Range Weight Bullet Type 備考 回×攻 防 的 射程 重 弾 タイプ New SIEGE シージュ MG 180 5× 2 － 78 1（1-1） 8 － Short（近） New SIEGER ズィーガー ライフル 180 1×10 － 78 1（1-1） 8 － Short（近） ZIEGER ショップ目次へ Shoulder New 名称 価格 AT DF Hit Range Weight Bullet Type 備考 回×攻 防 的 射程 重 弾 タイプ No item なし ショップ目次へ｜上へ Parts Body New 名称 価格 DF HP Engine Weight Inter 備考 防 HP 出 重 内蔵武器 New ZENITH ゼニス ボディ 340 11 33 130 24 None New ZOLA 3A ゾラ3A ボディ 340 11 30 140 22 None ZOLA-3A New PAVOT パボット ボディ 340 11 36 120 26 None PABOTTE ショップ目次へ Arm L New 名称 価格 DF HP Hit Weight Inter 備考 防 HP 的 重 内蔵武器 New ZENITH ゼニス アーム 160 14 24 60 18 PUNCH（格） New ZOLA 3A ゾラ3A アーム 160 15 22 62 16 PUNCH（格） ZOLA-3A New PAVOT パボット アーム 160 13 25 58 20 PUNCH（格） PABOTTE ショップ目次へ Arm R New 名称 価格 DF HP Hit Weight Inter 備考 防 HP 的 重 内蔵武器 New ZENITH ゼニス アーム 160 14 24 60 18 PUNCH（格） New ZOLA 3A ゾラ3A アーム 160 15 22 62 16 PUNCH（格） ZOLA-3A New PAVOT パボット アーム 160 13 25 58 20 PUNCH（格） PABOTTE ショップ目次へ Legs New 名称 価格 DF HP Engine Move Weight Type 備考 防 HP 出 移 重 種類 New ZENITH ゼニス レッグ 260 13 26 0 12 20 ノーマル New ZOLA 3A ゾラ3A レッグ 260 14 24 0 14 18 ノーマル ZOLA-3A New PAVOT パボット レッグ 260 12 27 0 12 22 ノーマル PABOTTE ショップ目次へ Computer New 名称 価格 Fight Short Long Agility 備考 格 近 遠 回避 New АДС アエス BD-068 160 0 30 2 0 New Zera ゼラ ZR-06St 160 8 8 8 8 New РНЁНС ロゴス RG-0404 160 14 7 9 2 ショップ目次へ Back Pack New 名称 価格 Item Range Engine Weight 備考 アイテム 射程 出 重 No item なし ショップ目次へ｜上へ Item Item New 名称 価格 解説 備考 New Repair S リペアー S 50 HPを50回復する リペア S ショップ目次へ｜上へ Shop ▼Mission02～▼ ※ミッションが進行すると、商品は追加されていく Weapon Grip｜Shoulder Parts Body｜Arm L｜Arm R｜Legs｜Computer｜Back Pack Item Item Weapon Grip New 名称 価格 AT DF Hit Range Weight Bullet Type 備考 回×攻 防 的 射程 重 弾 タイプ New SIEGE シージュ MG 180 5× 2 － 78 1（1-1） 8 － Short（近） New SIEGER ズィーガー ライフル 180 1×10 － 78 1（1-1） 8 － Short（近） ZIEGER ショップ目次へ Shoulder New 名称 価格 AT DF Hit Range Weight Bullet Type 備考 回×攻 防 的 射程 重 弾 タイプ No item なし ショップ目次へ｜上へ Parts Body New 名称 価格 DF HP Engine Weight Inter 備考 防 HP 出 重 内蔵武器 New ZENITH ゼニス ボディ 340 11 33 130 24 None New ZOLA 3A ゾラ3A ボディ 340 11 30 140 22 None ZOLA-3A New PAVOT パボット ボディ 340 11 36 120 26 None PABOTTE New INNOVA イノーヴァ 11400 75 600 1400 270 None 2周目以降 ショップ目次へ Arm L New 名称 価格 DF HP Hit Weight Inter 備考 防 HP 的 重 内蔵武器 New ZENITH ゼニス アーム 160 14 24 60 18 PUNCH（格） New ZOLA 3A ゾラ3A アーム 160 15 22 62 16 PUNCH（格） ZOLA-3A New PAVOT パボット アーム 160 13 25 58 20 PUNCH（格） PABOTTE ショップ目次へ Arm R New 名称 価格 DF HP Hit Weight Inter 備考 防 HP 的 重 内蔵武器 New ZENITH ゼニス アーム 160 14 24 60 18 PUNCH（格） New ZOLA 3A ゾラ3A アーム 160 15 22 62 16 PUNCH（格） ZOLA-3A New PAVOT パボット アーム 160 13 25 58 20 PUNCH（格） PABOTTE ショップ目次へ Legs New 名称 価格 DF HP Engine Move Weight Type 備考 防 HP 出 移 重 種類 New ZENITH ゼニス レッグ 260 13 26 0 12 20 ノーマル New ZOLA 3A ゾラ3A レッグ 260 14 24 0 14 18 ノーマル ZOLA-3A New PAVOT パボット レッグ 260 12 27 0 12 22 ノーマル PABOTTE ショップ目次へ Computer New 名称 価格 Fight Short Long Agility 備考 格 近 遠 回避 New АДС アエス BD-068 160 0 30 2 0 New Zera ゼラ ZR-06St 160 8 8 8 8 New РНЁНС ロゴス RG-0404 160 14 7 9 2 ショップ目次へ Back Pack New 名称 価格 Item Range Engine Weight 備考 アイテム 射程 出 重 No item なし ショップ目次へ｜上へ Item Item New 名称 価格 解説 備考 New Repair S リペアー S 50 HPを50回復する リペア S ショップ目次へ｜上へ Colosseum PILOT MACHINE WEAPON MACHINE DATAName Level Skill Name HP Body Body AT（回×攻）or＜DF＞ Bullet Type Fight State Fight Exp. Fight L. Arm L. Grip Short Short Short R. Arm R. Grip Long Long Long Legs L. Shoulder Agility Agility Agility Move R. Shoulder Total Sazaland 2 －－－－－－－－－－－－－－－ Scarlet devil 24 －－－ 11 9 50 25 F-1 TONFA 1×13 － Fight（格） 4 9 100 19 RAPTOR 4× 3 － Short（近） 0 9 30 18 －－－ 22 9 20 16 －－－ 37 Rudensky 2 －－－－－－－－－－－－－－－ GUST 21 －－－ 0 9 100 16 GUST MG 3× 4 － Short（近） 9 9 50 16 GUST MG 3× 4 － Short（近） 0 9 100 34 －－－ 18 9 100 17 －－－ 27 Jorg 4 －－－－－－－－－－－－－－－ CARM 24 －－－ 30 9 50 22 F-3 HAND ROD 1×34 － Fight（格） 0 9 150 22 TENDUS PUNCH 1× 8 － Fight（格） 30 10 400 21 －－－ 24 9 100 12 SUN OWL 3×14 3 Long（遠） 84 Alexander 4 －－－－－－－－－－－－－－－ TENDUS 27 －－－ 34 10 300 22 F-1 TONFA 1×13 － Fight（格） 0 9 100 22 F-3 HAND ROD 1×34 － Fight（格） 0 9 100 24 －－－ 26 9 200 13 －－－ 60 Were Wolf 6 －－－－－－－－－－－－－－－ ZOLA-3A 30 －－－ 7 9 150 16 GUST MG 3× 4 － Short（近） 6 9 150 24 ZENITH PUNCH 1× 9 － Fight（格） 0 12 850 24 －－－ 25 9 150 19 －－－ 38 Adam 7 －－－－－－－－－－－－－－－ PABOTTE 36 －－－ 9 10 450 25 CEMETERY 4× 5 － Short（近） 16 10 300 25 PABOTTE PUNCH 1×10 － Fight（格） 7 10 500 27 PIZ-3 1×10 3 Long（遠） 30 10 350 12 －－－ 62 Jimmy 8 －－－－－－－－－－－－－－－ ZENITH 33 －－－ 14 10 400 24 ZENITH PUNCH 1× 9 － Fight（格） 0 10 400 25 GALVO PUNCH 1×11 － Fight（格） 24 11 700 26 BONE 2×14 3 Long（遠） 34 10 400 13 －－－ 72 Demon.V 9 －－－－－－－－－－－－－－－ GALVO 42 －－－ 36 11 600 24 F-3 HAND ROD 1×34 － Fight（格） 0 12 900 24 TEMPEST PUNCH 1×12 － Fight（格） 0 10 400 30 WS-20 ＜9＞ － Shield（盾） 42 10 300 14 －－－ 78 上へ