約 5,939,992 件
https://w.atwiki.jp/touhoukashi/pages/5019.html
【登録タグ A IZNA サリー 曲 東方幻奏響UROBOROS弐 ~fAIRYtAILoVERdRIVE~ 魔力の雷雲】 【注意】 現在、このページはJavaScriptの利用が一時制限されています。この表示状態ではトラック情報が正しく表示されません。 この問題は、以下のいずれかが原因となっています。 ページがAMP表示となっている ウィキ内検索からページを表示している これを解決するには、こちらをクリックし、ページを通常表示にしてください。 /** General styling **/ @font-face { font-family Noto Sans JP ; font-display swap; font-style normal; font-weight 350; src url(https //img.atwikiimg.com/www31.atwiki.jp/touhoukashi/attach/2972/10/NotoSansCJKjp-DemiLight.woff2) format( woff2 ), url(https //img.atwikiimg.com/www31.atwiki.jp/touhoukashi/attach/2972/9/NotoSansCJKjp-DemiLight.woff) format( woff ), url(https //img.atwikiimg.com/www31.atwiki.jp/touhoukashi/attach/2972/8/NotoSansCJKjp-DemiLight.ttf) format( truetype ); } @font-face { font-family Noto Sans JP ; font-display swap; font-style normal; font-weight bold; src url(https //img.atwikiimg.com/www31.atwiki.jp/touhoukashi/attach/2972/13/NotoSansCJKjp-Medium.woff2) format( woff2 ), url(https //img.atwikiimg.com/www31.atwiki.jp/touhoukashi/attach/2972/12/NotoSansCJKjp-Medium.woff) format( woff ), url(https //img.atwikiimg.com/www31.atwiki.jp/touhoukashi/attach/2972/11/NotoSansCJKjp-Medium.ttf) format( truetype ); } rt { font-family Arial, Verdana, Helvetica, sans-serif; } /** Main table styling **/ #trackinfo, #lyrics { font-family Noto Sans JP , sans-serif; font-weight 350; } .track_number { font-family Rockwell; font-weight bold; } .track_number after { content . ; } #track_args, .amp_text { display none; } #trackinfo { position relative; float right; margin 0 0 1em 1em; padding 0.3em; width 320px; border-collapse separate; border-radius 5px; border-spacing 0; background-color #F9F9F9; font-size 90%; line-height 1.4em; } #trackinfo th { white-space nowrap; } #trackinfo th, #trackinfo td { border none !important; } #trackinfo thead th { background-color #D8D8D8; box-shadow 0 -3px #F9F9F9 inset; padding 4px 2.5em 7px; white-space normal; font-size 120%; text-align center; } .trackrow { background-color #F0F0F0; box-shadow 0 2px #F9F9F9 inset, 0 -2px #F9F9F9 inset; } #trackinfo td ul { margin 0; padding 0; list-style none; } #trackinfo li { line-height 16px; } #trackinfo li nth-of-type(n+2) { margin-top 6px; } #trackinfo dl { margin 0; } #trackinfo dt { font-size small; font-weight bold; } #trackinfo dd { margin-left 1.2em; } #trackinfo dd + dt { margin-top .5em; } #trackinfo_help { position absolute; top 3px; right 8px; font-size 80%; } /** Media styling **/ #trackinfo .media th { background-color #D8D8D8; padding 4px 0; font-size 95%; text-align center; } .media td { padding 0 2px; } .media iframe nth-of-type(n+2) { margin-top 0.3em; } .youtube + .nicovideo, .youtube + .soundcloud, .nicovideo + .soundcloud { margin-top 0.75em; } .media_section { display flex; align-items center; text-align center; } .media_section before, .media_section after { display block; flex-grow 1; content ; height 1px; } .media_section before { margin-right 0.5em; background linear-gradient(-90deg, #888, transparent); } .media_section after { margin-left 0.5em; background linear-gradient(90deg, #888, transparent); } .media_notice { color firebrick; font-size 77.5%; } /** Around track styling **/ .next-track { float right; } /** Infomation styling **/ #trackinfo .info_header th { padding .3em .5em; background-color #D8D8D8; font-size 95%; } #trackinfo .infomation_show_btn_wrapper { float right; font-size 12px; user-select none; } #trackinfo .infomation_show_btn { cursor pointer; } #trackinfo .info_content td { padding 0 0 0 5px; height 0; transition .3s; } #trackinfo .info_content ul { padding 0; margin 0; max-height 0; list-style initial; transition .3s; } #trackinfo .info_content li { opacity 0; visibility hidden; margin 0 0 0 1.5em; transition .3s, opacity .2s; } #trackinfo .info_content.infomation_show td { padding 5px; height 100%; } #trackinfo .info_content.infomation_show ul { padding 5px 0; max-height 50em; } #trackinfo .info_content.infomation_show li { opacity 1; visibility visible; } #trackinfo .info_content.infomation_show li nth-of-type(n+2) { margin-top 10px; } /** Lyrics styling **/ #lyrics { font-size 1.06em; line-height 1.6em; } .not_in_card, .inaudible { display inline; position relative; } .not_in_card { border-bottom dashed 1px #D0D0D0; } .tooltip { display flex; visibility hidden; position absolute; top -42.5px; left 0; width 275px; min-height 20px; max-height 100px; padding 10px; border-radius 5px; background-color #555; align-items center; color #FFF; font-size 85%; line-height 20px; text-align center; white-space nowrap; opacity 0; transition 0.7s; -webkit-user-select none; -moz-user-select none; -ms-user-select none; user-select none; } .inaudible .tooltip { top -68.5px; } span hover + .tooltip { visibility visible; top -47.5px; opacity 0.8; transition 0.3s; } .inaudible span hover + .tooltip { top -73.5px; } .not_in_card span.hide { top -42.5px; opacity 0; transition 0.7s; } .inaudible .img { display inline-block; width 3.45em; height 1.25em; margin-right 4px; margin-bottom -3.5px; margin-left 4px; background-image url(https //img.atwikiimg.com/www31.atwiki.jp/touhoukashi/attach/2971/7/Inaudible.png); background-size contain; background-repeat no-repeat; } .not_in_card after, .inaudible .img after { content ; visibility hidden; position absolute; top -8.5px; left 42.5%; border-width 5px; border-style solid; border-color #555 transparent transparent transparent; opacity 0; transition 0.7s; } .not_in_card hover after, .inaudible .img hover after { content ; visibility visible; top -13.5px; left 42.5%; opacity 0.8; transition 0.3s; } .not_in_card after { top -2.5px; left 50%; } .not_in_card hover after { top -7.5px; left 50%; } .not_in_card.hide after { visibility hidden; top -2.5px; opacity 0; transition 0.7s; } /** For mobile device styling **/ .uk-overflow-container { display inline; } #trackinfo.mobile { display table; float none; width 100%; margin auto; margin-bottom 1em; } #trackinfo.mobile th { text-transform none; } #trackinfo.mobile tbody tr not(.media) th { text-align left; background-color unset; } #trackinfo.mobile td { white-space normal; } document.addEventListener( DOMContentLoaded , function() { use strict ; const headers = { title アルバム別曲名 , album アルバム , circle サークル , vocal Vocal , lyric Lyric , chorus Chorus , narrator Narration , rap Rap , voice Voice , whistle Whistle (口笛) , translate Translation (翻訳) , arrange Arrange , artist Artist , bass Bass , cajon Cajon (カホン) , drum Drum , guitar Guitar , keyboard Keyboard , mc MC , mix Mix , piano Piano , sax Sax , strings Strings , synthesizer Synthesizer , trumpet Trumpet , violin Violin , original 原曲 , image_song イメージ曲 }; const rPagename = /(?=^|.*
https://w.atwiki.jp/goldkai1/pages/180.html
Unimplemented contents A few maps and cutscenes Equipment and magic are on the respective pages, and enemies are on the X and youtube, so I don't have to write about them. Character ShopCheery John's WorkdmapMaps of Farnas and other places. Sandrigal Oasis Maps of New Heinrogue Castle and other places. Maps of Sage's Tower Gate and other places Map DataDigging Camp Rune Malna Mell Nautilus Port City Keb Village Conton Ruins Farnas Warrior/Mage Temples Rob Dam Warrior Shrine Mekua Port Io Port Yuuro Port Mystery Port Sandrigal Oasis Mystery CutsceneDOUKUTU HEKIGA MADOU MEGAMI SENSHI SIP WATER Character There are a few NPCs that were never used, most of them are different colors of the characters that are implemented. Shop Cheery John's Originally sold items other than milk, more of a scripting error than unimplemented. Workdmap Maps of Farnas and other places. There was a road going right, maybe to Sandrigal Oasis? Sandrigal Oasis Why was it left unimplemented? Maps of New Heinrogue Castle and other places. I thought there was a direct line to map of the Sage's Road? Maps of Sage's Tower Gate and other places Of course, there's on this side of the map. Map Data Digging Camp Bar? Not that there's anything in particular. Rune Malna Station? Inside the large building on the left side of Map4. Is there a mistake in setting the entrance because there are NPCs? Mell Bar? I thought just flipped bar of the New Heinrogue...? Nautilus Port City Mystery Map There was supposed to be a quest? Keb Village Where Yuuta was Version with open door to basement. Basement Where it was supposed to be used when the pattern was to save Yuuta's family. Conton Ruins Remnants of the unimplemented quest There's this line that comes in DISC 1, it looks like this one was to be the Keb Village. Farnas 2nd floor of inn So-so, it's well made. Warrior/Mage Temples Mysterious object It looks like the connection was where the Guard are - here - Warrior Shrine. Rob Dam Mystery Map1 It leads here from the Dam, you can faintly see the road. Mystery Map2 Map1 - here - at the waterfall, maybe you wanted to express the water flowed... Before the altar When DISC1, they say this, i didn't get a key in DISC2 either. Warrior Shrine Before Entrance When DISC1, they say this. Mekua Port Mystery Map Mystery. Io Port Entrance Usually stays closed. Yuuro Port Entrance Usually stays opened. Mystery Port Wharf Baroa is there, and when talk to him, he'll change where going.There are three destinations New Heinrogue Castle, Old Heinrogue Castle, and Mekua Port.But they won't ride me to Mekua unless complete the statue. Sandrigal Oasis Panoramic view It's a sophisticated pun on the words "Everything that happens twice will surely happen a third time." (nido aru koto ha sando aru) and Sandrigal (sandorua) Indoor All the data for this Oasis is not set up. Indoor I think the frame-like objects in the live-action picture are the four audition winners at the time, as has been said. Indoor The Indoor rest Indoor is Indoor nothing 室内 special. Mystery Mystery I don't know anything about this. Cutscene DOUKUTU Looks like the Sacred Beast Shrine? HEKIGA The location is a mystery, and these gods don't appear in the game. MADOU It's not a place worth showing in a cutscene. MEGAMI It's not a place worth (omit) SENSHI It's not a (omit) SIP The same sound effects as in the Rob Dam's cutscene are played.Maybe they were talking about this happening while traveling by ship, and then an emergency evacuation from there to the Kuuba Port.Then it's not hard to see why the ship is sinking at the far end of Kuuba Port. WATER Camera angles are needlessly elaborate.
https://w.atwiki.jp/boare/pages/119.html
Release Note Release Date 14 Jun, 2009 Notes Cadencii requires ".NET Framework Runtime(version 2.0 or later)". Installer of this rumtime is available from the link below. .NET Framework Runtime Download .NET Framework 3.5 SP1 Cadencii can be launched with the latest version of mono. This enable you to use Cadencii with many platforms supported by mono. (Note Several functions using VOCALOID2 VSTi are not available in this case.) Mono is available from the link mono download Download Cadencii version 2.1.0 (603KB) CadenciiSDK version 2.0 (455KB) How to get source codes Source code is available on SourceForege.JP. Please follow the instruction below for checking out the SourceForge.JP s SVN repository. svn checkout -r 255 http //svn.sourceforge.jp/svnroot/cadencii/branches/2.0 ./ These svn command is for checiking out "THIS" version of Cadencii. In order to get the latest source codes, please remove "-r" option.
https://w.atwiki.jp/boare/pages/250.html
English 日本語 Release Note Release Date 2 Jul., 2010 Notes Cadencii requires ".NET Framework Runtime(version 2.0 or later)". Installer of this rumtime is available from the link below. .NET Framework Runtime Download .NET Framework 3.5 SP1 Cadencii can be launched with the latest version of mono. This enable you to use Cadencii with many platforms supported by mono. (Note Several functions using VOCALOID2 VSTi are not available in this case.) Mono is available from the link mono download Download Cadencii version 3.0.22 (1.7MB) Get codes Source code is available on SourceForege.JP. Please follow the instruction below for checking out the SourceForge.JP s SVN repository. svn checkout -r 1088 http //svn.sourceforge.jp/svnroot/cadencii/Cadencii/branches/3.0 ./ These svn command is for checiking out "THIS" version of Cadencii. In order to get the latest source codes, please remove "-r" option.
https://w.atwiki.jp/projectdiva_ac/pages/741.html
ファインダー(DSLR remix - re edit) 基本情報 作曲・作詞・編曲 kz(livetune) http //livetune.syncl.jp/ イラスト redjuice http //redjuicegraphics.com/ 初音ミクwiki http //www5.atwiki.jp/hmiku/pages/144.html EASY NORMAL HARD EXTREME EX EXTREME レベル FT 2 4 5 7 7.5 無印 2 4 5 6 - ノート数 281 344 421 463 482 BPM 130 ランキング HARD http //miku.sega.jp/arcade/ranking/ranking_find_hard.html EX http //miku.sega.jp/arcade/ranking/ranking_find_extreme.html EEX http //miku.sega.jp/arcade/ranking/ranking_find_ex_extreme.html 備考 2ndからの移植 3DS「Project mirai」にも収録されている 動画 EASY 評価:PERFECT モジュール:ミコ Player:らいあ NORMAL 評価:PERFECT モジュール:エールダンジュ Player:とりこ 評価:PERFECT モジュール:みやび Player:らいあ HARD 評価:PERFECT モジュール:パウダー Player:みそら>ヮ<からあげ 評価:PERFECT モジュール:初音ミク 蝶 Player:らいあ EXTREME 評価:PERFECT モジュール:スピリチュアル Player:まふスピ♪@Key♪ 評価:PERFECT モジュール:メイコ スイムウェアB Player:アラーキー 評価:PERFECT モジュール:初音ミク 蝶 Player:らいあ EX EXTREME 評価:PERFECT モジュール:パウダー Player:おがたつ 評価:PERFECT モジュール:鏡音レン 凰月 Player:めかひすい@なまねぎ ※ボタン音なし 攻略 コメント これ難しくてできんとは決して言わんが☆6ではないだろう…最後の方?の同位置○すっごい押しにくい。 -- (名無しさん) 2011-11-04 00 54 34 確かに間奏の一点集中○押しはコンボブレイクしやすいかも。僕の場合は目押しで叩いて繋いだ。 -- (OSX@X1) 2011-11-04 14 40 26 かなりcool判定甘いと思う。あまり上手じゃない俺でもHでF8。EでF1だった -- (名無しさん) 2011-11-05 19 14 01 目押しゲーだね、これ。 -- (名無しさん) 2011-11-05 21 35 31 EXTREME 間奏サビ前の ○の連続重ねノーツは、ミクの声(残響)にあわせるといいですよ。 -- (名無しさん) 2011-11-14 04 43 36 2ndのノリでやったら重ね○は乗り切ったのに、「このまま」以降でミスしまくった -- (名無しさん) 2011-11-20 23 57 14 NORMALのノート数追加。ついでに動画も。見てみたらNも相変わらずのリズム難。あれができればHもできる…かな? -- (名無しさん) 2011-11-28 00 15 43 2ndは歌詞に合わせてある アーケードはメロディーに合わせてある ここだけの違い。 あとさすがファインダーという曲名だけあってfineが多いんダーおや、だれかry -- (名無しさん) 2012-01-16 02 21 35 6詐欺であって7弱ぐらいのレベルかな -- (名無しさん) 2012-03-23 06 09 17 ↑2 ごめん、つっこむのめんどくさい -- (名無しさん) 2012-03-23 06 09 48 名前 コメント すべてのコメントを見る
https://w.atwiki.jp/gamemusicbest100/pages/10547.html
メイプルストーリー 機種:PC 作曲者: 発売元:ネクソン 発売年:2003年 概要 ネクソンのMMORPG。 20年以上の歴史があるためBGMの総数は膨大。メイプルストーリーのBGMデータベース「MapleStory Music」には1000曲以上登録されている。 収録曲(サウンドトラック順) 曲名 作・編曲者 補足 順位 「MapleStory OST The BLACK」収録曲 Start The Adventure The Tune of The Azure Light The Fantastic Thinking Lacheln The Illusion City Floral Life Raindrop Flower Funny Time Maker Dimension Library The Bard of Snowfield The Aurora Way Back Home Nowhere The Black Heaven Dancing With The Moon Fighting PinkBeen The Shattered Time Heroes of Maple Theme Endless Journey Promise of Heaven When The Morning Comes 第10回883位第14回998位 The Cygnus Garden The Queen’s Garden Fly to The Moon The Temple of Time Login 「MapleStory OST Ark」収録曲 Evening Primrose Verdel Town Verdel Dungeon Doomsday Recollecting Memories A Place Where Life Begins Cotaminated Sea Le Temple du Miroir Mirror Cage The Bloody Cage 「MapleStory OST Snowdrift Lodge」収録曲 God of Brain Dice Master Primrose Peaceful Life Downhill Ride Melting Snow 「MapleStory OST NOVA」収録曲 Savage Terminal Hunting Ground Mr.Hazard Outlaw Of The Lonely Island Way Back Home Forgotten Names Nowhere Asylum Crystal Academia Death Of Asylum Illium Rebirth Asylum (Piano Ver.) Swamp Of Memory, Moras Memory of Kritias 「MapleStory OST BEYOND」収録曲 Eluna Express Song of Naty Pioneer Headquater Off the beaten path Weight of the Soul 「アルカナ」収録曲 The Tune of the Azure Light (Orchesta Ver.) Shadow of Incongruity The Tune of the Azure Light (Gleam Ver.) 「アフターランド」収録曲 The World of Paradox Can You Read My Thoughts? The Dancing Weathercock Bottoms Up! The World of Paradox(Night Ver.) Can You Read My Thoughts? (Night Ver.) The Dancing Weathercock (Night Ver.) Bottoms Up! (Night Ver.) (Bonus Track) Frenzy Winter 「地球防衛本部」収録曲 Go, Go! Rangers! Dances With Aliens The Vecuum Cleaner Lovers in The Afternoon (Bonus Track) 「MAPLESTORY SYNPHONY IN BUDAPEST」収録曲 When The Morning Comes The Cygnus Garden Start The Adventure The Tune Of Azure Light The Raindrop Flower The Queen's Garden The Fantastic Thinking The Black Heaven The Shattered Time Dancing With The Moon An Eternal Breath (Vocal EUNTO) AN Eternal Breath (Inst.) 「アーケインリバー」収録曲 The Lake of Oblivion The Cave of Peace Volcanic Mountain Expedition to Chew Chew Island Welcome to Chew Chew Lacheln, the City of Dreams Shattered Time Phantasmal Woods Dream Fragments 「MMF」収録曲 Bad Guys Maple Island Ariant Time Temple Kinesis 「Maplestory Hi-Five」収録曲 Hi-FIve MapleStory Mashup 「ヒドゥンテイルズ」収録曲 Frozen Heart The Shadow of Chaos Greeting of the Death Angel 「メイプル探偵団」収録曲 Stellar Detectives Mission Invasion 「Masteria Through Time」収録曲 An Eternal Breath Jungle Pursuit War For The Castle An Eternal Breath (Instrumental) 「軍団長デミアン」収録曲 The Tragic Fate of Demian Corrupted Blood 「キノコ神社異聞録」収録曲 Legend of Zipang Living Again Zipang Hero Tengu's Trial Legend of Zipang (Sad Version) Legend of Zipang (Sillence Version) その他 Deep Sea 第12回918位 Fantasia 泣き曲260位 Above the Treetops 2000年~2007年135位
https://w.atwiki.jp/boare/pages/149.html
Release Note Release Date 27 Sep., 2009 Notes Cadencii requires ".NET Framework Runtime(version 2.0 or later)". Installer of this rumtime is available from the link below. .NET Framework Runtime Download .NET Framework 3.5 SP1 Cadencii can be launched with the latest version of mono. This enable you to use Cadencii with many platforms supported by mono. (Note Several functions using VOCALOID2 VSTi are not available in this case.) Mono is available from the link mono download Download Cadencii version 2.3.5 (641KB) How to get source codes Source code is available on SourceForege.JP. Please follow the instruction below for checking out the SourceForge.JP s SVN repository. svn checkout -r 491 http //svn.sourceforge.jp/svnroot/cadencii/branches/2.3 ./ These svn command is for checiking out "THIS" version of Cadencii. In order to get the latest source codes, please remove "-r" option.
https://w.atwiki.jp/boare/pages/153.html
Release Note Release Date 27 Sep., 2009 Notes Cadencii requires ".NET Framework Runtime(version 2.0 or later)". Installer of this rumtime is available from the link below. .NET Framework Runtime Download .NET Framework 3.5 SP1 Cadencii can be launched with the latest version of mono. This enable you to use Cadencii with many platforms supported by mono. (Note Several functions using VOCALOID2 VSTi are not available in this case.) Mono is available from the link mono download Download Cadencii version 3.0.2 (1015KB) How to get source codes Source code is available on SourceForege.JP. Please follow the instruction below for checking out the SourceForge.JP s SVN repository. svn checkout -r 496 http //svn.sourceforge.jp/svnroot/cadencii/branches/3.0 ./ These svn command is for checiking out "THIS" version of Cadencii. In order to get the latest source codes, please remove "-r" option.
https://w.atwiki.jp/tiger/pages/4.html
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]
https://w.atwiki.jp/elvis/pages/1149.html
World Civilizations 1500 to the Present David Peck? Don at War Sir David Hunt? Environmental Burden Measures David Hunt Wharncliffe Companion to Preston David Hunt "Times" Yearbook of World Affairs Sir David Hunt? "Times" Yearbook of World Affairs Sir David Hunt? Environmental Management Systems (Environmental Training Packages S.) David HuntSara Lambton? Pictorial Supplement to LMS Locomotive Profile Number 6 David HuntFred James?R.J. Essery?John Jennison?David Clarke? Around the Twist David Hunt Equivalency Potential Values to Estimate Environmental Burden Measures for Water in Respect of Acidification,Oxygen Demand and Eutrophication David Hunt Oribatid Mites Glen Hunt?Roy Norton?John Kelly?Matthew Colloff?Sue Lindsay?Mike Dallwitz?David Walter? Midland Engines David HuntBob Essery?Fred James? For Those Who Hunt the Wounded Down David Adams Richards? Pictorial Supplement to LMS Locomotive Profile No. 8 John Jennison?Fred James?David HuntR.J. Essery? Possible Environmental Burden Measures for Water David Hunt Leyland (Pocket Images) David HuntWilliam Waring? Possible Environmental Burden Measures for Hazardous Substances David Hunt A Gateway to Verse David Elliott?Birgit Hunt? Treasure Hunt in the Jungle (Math Adventures) David Clemson?Wendy Clemson? Normandy Campaign Robert Hunt?David Mason? Early Farming Communities in Scotland (British Archaeological Reports (BAR)) David Hunt Triad (A New Playwrights' Network Quality Publication) Anthony Hunt?David Welsh?Leonard Morley? Pocket Tales Brown Level 4 Beast Hunt Jillian Powell?David Lupton? Chemistry Activities and Teachers' Notes for GCSE Andrew Hunt?David Lewis?etc.? Footprints in Cyprus Sir David Hunt? National Hunt Statistics David Ikerrin? Magnolias and Their Allies David Hunt Silent Mills David Hunt Midland Engines David HuntBob Essery?Fred James? Pieces Of Stone David Hunt Leeds Countryside Strategy Steven Derek Hunt?David John Feeney? Now the Dust Has Settled David HuntFreddie de Butts? Band 16 Easy Order Pack (Longman Book Project) Mick Gowar?Nicholas Orme?Geraldine McCaughrean?Dennis Hamley?Wendy Body?Andrew Bylo?Hemesh Alles?Norman Bancroft Hunt?Miranda Gray?David Sim? Midland Record Special David Hunt James Hunt Against All Odds Eoin Young?David Hodges? James Hunt Against All Odds Eoin Young?David Hodges? Horse Profiles for the National Hunt David Peat? Genetic Basis of Development (Tertiary Level Biol. S) Alistair D Stewart?David M Hunt? Oxford Reading Tree Robins Pack 1 The Old Vase Roderick Hunt?David Parkins? Hospice And Palliative Care in Africa A Review of Developments And Challenges Michael Wright?David Clark?Jennifer Hunt?Thomas Lynch? Illustrated Guide to the Trees of Peru T.D. Pennington?C. Reynel?A. Daza?Rosemary Wise? Monster Hunt Wendy Newsham? Seed-diversity in the Cactaceae Subfamily Cactoideae (Succulent Plant Research S.) Wilhelm Barthlott?David Hunt On the Spot Sir David Hunt? Selected Topics in KS3 Maths David HuntJanet Chadwick? Manu's Beetles (Living Earth) David Hunt The Stream (Living Earth) David Hunt Guide to Oklahoma Museums David C. Hunt? Art of the Old West Paul Rossi?David Hunt Minutes of Proceedings Giles Radice?David HuntGreat Britain? The Catch (Living Earth) David Hunt The Competent Speaker William W. Neher?Paul J. Sandin?David H. Waite? Field Experiences 328, 428, and 450 David Meckley? The Human Muscle System A Programmed Instruction Manual David Engerbreston? The Tender Traps David HuntSteve Evans?David Thompson?David Saunders? The Life Death of a Family Farm David Howard Day? Experiments in General Chemistry James David Wicks? Sistemas de Gestion Medioambiental David HuntCatherine Johnson? PC Lan Systems for Law Firms Emphasis on Planning and Selection Process (A Planning Reference Guide) David G. Baker?Steve L. Falkin? The Believable Organization An Introduction to Communications Management Herbert W. Jackson?Ralph R. Smith?David L. Dollar? I Can Do All Things Conquering Your Goliaths David C. Evans? Chemistry in Microscale Book 1 David Ehrenkranz?John J. Mauch? A History of Preston North End Football Clubs David Hunt Magicians Tale A Novel David Hunt Dangerous Supplements (Law Social Theory) Peter Fitzpatrick?Anthony Carty?Peter Goodrich?Yifat Hachamovitch?Alan Hunt?Carol Smart?David Sugerman?Alan Thomson? Introduction to Criminal Justice An Annotated Outline and Workbook David Falcone?Lois Guyon? Fundamental Computer Skills Fengqi Lai?David R. Hofmeister? Experimental Biological Science An Introductory Lab Manual David R. Caprette? Basic Theory and Experiments in Physics Diego Castano?David Simon? Microchemistry Laboratory Experiments David Ehrenkranz? Vascular Plant Taxonomy Dirk R. Walters?David J. Keil? Advanced Public Speaking David H. Waite?Paul J. Sandin?William W. Neher? The World of Science David Brodie?Ann Fullick?Andrew Hunt?David Sang?Mary Whitehouse? Discrete Mathematics and the Art of Proof David Reimer? Physics for Engineering Technology Jack Prince?David Sacher? Computers in the Classroom David H. Jonassen? Confessions of a Scilly Birdman David Hunt Physical Geography Laboratory Manual Exercises in Atmospheric And Earth Surface Processes David Shankman? Political Concepts An Introduction David A. Freeman? Life Science for Elementary Educators I David Rudge? Confessions of a Scilly Birdman David Hunt From Start to Studio A Practical Approach to Photography David J. Wolfe?Christian Waits? Genetics with Budgerigars David M. Hunt? LMS Locomotive Profiles David HuntR.J. Essery?Fred James? Einer bricht aus. Der Weg eines Hindus von Krishna zu Christus David Hunt Midland Engines David HuntR.J. Essery?Fred James? Purple Secret John C.G. Rohl?Martin Warren?David Hunt Instructional Technology An Introduction to the Technologies of Instruction/Lab Manual David C. Byrum? Leyland (Archive Photographs) David HuntWilliam Waring?William Warring? Managing Safety the Systems Way David Smith?Geoff Hunt?Clive Green? The World of Science David Brodie?Ann Fullick?Andrew Hunt?David Sang?Mary Whitehouse? Readings, Skills, and Activities for Teacher Support Programs Nancy G. Mims?David S. Carr? Chemistry in Microscale David Ehrenkranz? Como Fomentar LA Participacion De Voluntarios (Spanish - Volunteers) David Tenenbaum? Preston David Hunt Programmieren mit Ruby. Mit umfassender Referenz David Thomas?Andrew Hunt? David and Goliath (Now I Can Read Bible Stories) Rhona Pipe?Stephen Walsh? Study Guide for Introductory Genetics E. David Peebles? David Livingstone (Heroes of the Faith) Robert Van De Weyer? David Livingstone Heroes of Faith Hunt? Basic Mathematical Skills for College Students David E. Boliver? Introduction to Astronomy, Preliminary Edition David Carico? David's Adventure with the Giant (A Bible Flap-book) Peter Mills? First Aid and Cpr Manual David M. White? Democracy 2500? Questions and Challenges (Colloquia and Conference Papers, No. 2) Ian Morris?Kurt Raaflaub?David Castriota? Merry the Lamb Meets David Linda Parry?Alan Parry? The Power to Manage Barry Spicer?Robert Bowman?David Emanuel?Alister Hunt? David Questions Coloring Puzzles (Your Favourite Sticker Books) Hunt and Thorpe? At Home with Oxford Reading Tree (Oxford Reading Tree) Alex Brychta?Roderick Hunt?Jan Brychta?Joe Wright?David Parkins? Clarisworks 4.0 for Secondary School Teachers David Caverly? Physical Geography Lab Manual Exercises in Atmospheric David Shankman? A How to Guide to Basic Programming David Y. Wen? Oxford Reading Tree Stages 8-11 Jackdaws Anthologies Pack (10 Books, 1 of Each Title) (Oxford Reading Tree) Rod Hunt?Michael Poulton?David Oakden? Oxford Reading Tree Stage 4 More Sparrows Storybooks Lucky the Goat (Oxford Reading Tree) Rod Hunt?David Parkins? Strategic Management Kenya-A Book of Cases David M. Hunt?Peter Gufwoli? Astronomy for the Masses Astronomy 1100 Lab Manual David Lamp? Oxford Reading Tree Stage 4 More Sparrows Storybooks Mosque School (Oxford Reading Tree) Rod Hunt?David Parkins? Oxford Reading Tree Stage 4 More Sparrows Storybooks Yasmin and the Flood (Oxford Reading Tree) Rod Hunt?David Parkins? Social Enterprise and Community-based Care Richard Lewis?Peter Hunt?David Carson? Practical Selling Selling, Sold! David Seigel? Walton-le-Dale David Hunt Carving Wildlife in Wood Complete Patterns and Instructions for 20 Exciting Projects (Woodcarvers Favorite Patterns, Book 4) George Lehman?David Hunt Business Law A Comprehensive Cpa Law Review David A. Minars? CITES Cactaceae Checklist David Hunt Caterina Cornaro, Queen of Cyprus David HuntIro Hunt? Qualitative Analysis An Introduction David Moseley? A History of Preston David Hunt The Manhattan Hunt Club John Saul?David Daoust? Farben der Nacht David Hunt Experiments in General Chemistry A Laboratory Manual Coordinated With Video Briefing Tapes James David Wicks? Historic Gardens in Cornwall David HuntDouglas Ellory Pett? Farben der Nacht. David Hunt The Law, Society and Business M. David Wertheimer? A Beginner's Guide to the Isu Vax Computer David W. Bachmann?Roger W. Bachmann? Your Career Choices, Chances, Changes David Borchard?John Kelly?Nancy Weaver? Astronomy for the Masses Astronomy 1100 Lab Manual David Lamp? Living with Dyspraxia Mary Colley?David Hunt Public Speaking for Everyone David Lambkin? Study Package to Accompany Making Connections, Achieving Success, Understanding Others Kathy Matthews?David King?Frank Pintozzi?Michael Redd? Geh nicht zurueck David Hunt Geh nicht zurueck. David Hunt Principles of Animal Growth and Development David Gerrard? Outlook The Earth David V. McCalley? A Programmed Instruction Manual of the Human Muscle System David L. Engerbretson? The New RHS Dictionary Manual of Cacti and Succulents David HuntMark Griffiths? We're Going on a Lion Hunt David Axtell? Taking Charge for the Good Life The Personal Health Manual David H. Chenoweth? College Survival Handbook A Program for Success David A. Hurwitz? The Samford Connection Amanda Welch Borden?David Little? The What If Bible Andrew Bianchi?David Mostyn? The Performing Arts an Audience's Perspective David P. Hirvela? Introduction to Computer Concepts Concepts of Structured Design David M. Harris? California Vegetation V. L. Holland?David Keil?V.L. Holland?David J. Keil? Make Your Meetings Count! How Storyboarding With Ideas Can Help Your Work Team Plan, Solve Problems, Make Better Decisions Durward Humes?Gary W. Thompson?David G. Noyes? Write for Success A Guide to Effective Technical and Professional Writing David H. Klein?Jean H. Klein? Study Guide for Introductory Genetics E. David Peebles? Managing in the Postmodern World America's Revolution Against Exploitation David M. Boje?Robert F. Dennehy? From Bakersfield to Beale Street A Regional History of American Rock 'n' Roll David Stuart?Ryan Sheeler? Economics of Food and Agriculture David Debertin? For Those Who Hunt the Wounded Down David Adams Richards? Photographic Regional Atlas Of Bone Disease A Guide To Pathologic And Normal Variation In The Human Skeleton Robert W. Mann?David R., Ph.D. Hunt? Lab Research in Psychology David Eckerman? Lectures in Fundamentals of Biology A Foundation in the Essential Concepts of Modern Biology David Williams? Treasure Hunt in the Jungle (Math Adventures) David Clemson?Wendy Clemson? Chemistry in Microscale David Ehrenkranz? Physics Lab Skills Manual David Newton? Main Line Diesel Electric Nos. 10000 and 10001 (LMS Locomotive Profiles) David Hunt A Handbook for Introduction to Criminal Justice Lois Guyon?David Falcone? Light Inquiry and Insights An Inquirybased Physics Course David Schuster? Managing in the Postmodern World Welcome to the Greenback Company America's Revolution Against Exploitation David M. Boje?Robert F. Dennehy? Responsibilities of the Professional Educator Patricia A. Williams?Jerry C. McGee?David L. Henderson? Course Guide for Communication 4-110 Fundamentals of Speech David Burns? A World of Weather Fundamentals of Meteorology Jon M. Nese?Lee M. Grenci?David J. Mornhinweg?Timothy W. Owen? The "Hunt for the Royal Handbag" David Wood? Property Companies (Industry Accounting Auditing Guides) David HuntDudley Hilton? Joining Together Group Theory and Group Skills David W. Johnson?Frank P. Johnson?