generation-shear-adhesion-map-using-synvivo-synthetic-microvascular

Generation of Shear Adhesion Map Using SynVivo Synthetic Microvascular Networks

Cell/particle adhesion assays are critical to understanding the biochemical interactions involved in disease pathophysiology and have important ...

CFD RESEARCH CORPORATION

&#x901A;&#x8FC7;&#x590D;&#x6742;&#x7684;&#x6838;&#x5B54;&#x7684;&#x5927;&#x591A;&#x6570;&#x80DE;&#x6838;&#x80DE;&#x8D28;&#x8FDE;&#x4F53;&#x4EA4;&#x901A;&#x88AB;&#x4ECB;&#x5BFC;&#x79C9;&#x6301;&#x8F93;&#x51FA;&#x56FD;&#x5BB6;&#x6216; karyopherin &#x5BB6;&#x5EAD;&#x7684;&#x53EF;&#x6EB6;&#x6027;&#x53D7;&#x4F53;&#x3002;&#x5728;&#x8FD9;&#x6CA1;&#x6709;&#x53D7;&#x4F53;&#x7684;&#x8FD9;&#x4E00;&#x5BB6;&#x4EBA;&#x5377;&#x5165;&#x8D29;&#x8FD0;&#x5927;&#x5B97; mRNAs &#x7684; mRNA &#x51FA;&#x53E3;&#x662F;&#x552F;&#x4E00;&#x7684;&#x3002;&#x76F8;&#x53CD;&#xFF0C;&#x8BB8;&#x591A;&#x4E0D;&#x540C;&#x7684;&#x86CB;&#x767D;&#x8D28;&#x5DF2;&#x94FE;&#x63A5;&#x5230; mRNA &#x51FA;&#x53E3;&#xFF0C;&#x4F46;&#x6DB5;&#x76D6;&#x4E00;&#x5207;&#x7684;&#x6A21;&#x578B;&#x4ECD;&#x7136;&#x662F;&#x53EF;&#x671B;&#x800C;&#x4E0D;&#x53EF;&#x53CA;&#x3002;&#x4E86;&#x89E3;&#x8FD9;&#x4E9B;&#x86CB;&#x767D;&#x8D28;&#x662F;&#x5982;&#x4F55;&#x5F7C;&#x6B64;&#x4EA4;&#x4E92;&#x662F;&#x4E2D;&#x592E;&#x8FD9;&#x79CD;&#x6A21;&#x5F0F;&#x7684;&#x53D1;&#x5C55;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x96C6;&#x4E2D;&#x7275;&#x8FDE; mRNA &#x51FA;&#x53E3;&#x3001; Nup98&#x3001; Rae1/Gle2 &#x548C;&#x81EA;&#x6765;&#x6C34;&#x4E2D;&#x7684;&#x4E09;&#x4E2A;&#x86CB;&#x767D;&#x8D28;&#x4E4B;&#x95F4;&#x7684;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x3002;&#x6211;&#x4EEC;&#x5B9A;&#x4E49;&#x4E86;&#x8FD9;&#x4E9B;&#x86CB;&#x767D;&#x8D28;&#x4E4B;&#x95F4;&#x5F62;&#x6210;&#x7684;&#x4E8C;&#x5143;&#x914D;&#x5408;&#x7269;&#x3002;&#x6211;&#x4EEC;&#x627E;&#x5230; Gle2 &#x9700;&#x8981;&#x4E24;&#x4E2A;&#x7AD9;&#x70B9;&#x5185;&#x6C34;&#x9F99;&#x5934;&#xFF0C;&#x7A33;&#x5B9A;&#x7684;&#x4E92;&#x52A8;&#x3002;&#x5F15;&#x4EBA;&#x6CE8;&#x76EE;&#x7684;&#x662F;&#xFF0C;&#x800C;&#x4E0D;&#x662F;&#x4E00;&#x822C;&#x7684;&#x4EB2;&#x548C;&#x6027;&#x7684;&#x6240;&#x6709; nucleoporin FG &#x91CD;&#x590D;&#xFF0C;&#x6C34;&#x9F99;&#x5934;&#x6709;&#x6700;&#x9AD8;&#x4EB2;&#x548C;&#x529B;&#x7684;&#x7279;&#x5B9A;&#x533A;&#x57DF;&#x5185;&#x7684; Nup98&#xFF0C;GLFG &#x57DF;&#x6307;&#x793A;&#x5E76;&#x4E0D;&#x662F;&#x6240;&#x6709;&#x7684;&#x91CD;&#x590D;&#x5E8F;&#x5217;&#x5B8C;&#x5168;&#x76F8;&#x540C;&#x7684;&#x529F;&#x80FD;&#x3002;&#x6211;&#x4EEC;&#x5EFA;&#x7ACB;&#x4E86;&#x4E09;&#x5143;&#x7684;&#x590D;&#x6570;&#x53EF;&#x4EE5;&#x5F62;&#x6210;&#x901A;&#x8FC7; Gle2 &#x548C;&#x6C34;&#x9F99;&#x5934;&#x7684;&#x540C;&#x65F6;&#x7ED1;&#x5B9A;&#x5230; Nup98 &#x4E0A;&#x76F8;&#x90BB;&#x7AD9;&#x70B9;&#x3002;&#x76F8;&#x6BD4;&#x4E4B;&#x4E0B;&#xFF0C;Nup98 &#x6625;&#x98CE;&#x5F97;&#x610F;&#x4E1D;&#x9525; Gle2 &#x5177;&#x6709;&#x7EA6;&#x675F;&#x529B; &#xFF1B;&#x5F53;&#x7ED1;&#x5B9A;&#x5230; Nup98&#xFF0C;Gle2 &#x4E0D;&#x518D;&#x76F4;&#x63A5;&#x4E0E;&#x4EA4;&#x4E92;&#x6C34;&#x9F99;&#x5934;&#x3002;&#x4ECE;&#x8FD9;&#x4E9B;&#x4EA4;&#x4E92;&#xFF0C;&#x6211;&#x4EEC;&#x5EFA;&#x8BAE; Gle2 &#x53EF;&#x80FD;&#x4F1A;&#x91C7;&#x53D6;&#x884C;&#x52A8;&#xFF0C;&#x4F20;&#x9012;&#x5230; Nup98 &#x6C34;&#x9F99;&#x5934;&#x548C;&#x8FD9;&#x53EF;&#x80FD;&#x662F;&#x4E00;&#x7CFB;&#x5217;&#x590D;&#x6742;&#x7684;&#x51FA;&#x53E3;&#x4E0E; nucleoporin &#x4E4B;&#x95F4;&#x7684;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x4E2D;&#x7684;&#x7B2C;&#x4E00;&#x4E2A;&#x3002;

Nup98&#x3001; Rae1/Gle2 &#x548C;&#x6C34;&#x9F99;&#x5934;&#x7684; RNA &#x51FA;&#x53E3;&#x86CB;&#x767D;&#x8D28;&#x4E4B;&#x95F4;&#x7684;&#x590D;&#x6742;&#x5730;&#x5C42;&#x3002;

Most nucleocytoplasmic traffic through the nuclear pore complex is mediated by soluble receptors of the importin/exportin or karyopherin family. mRNA export is unique in that no receptor of this family has been implicated in trafficking of the bulk of mRNAs. Instead, many diverse proteins have been linked to mRNA export, but an all-encompassing model remains elusive. Understanding how these proteins interact with each other is central to the development of such a model. Here, we have focused on the interactions between three proteins implicated in mRNA export, Nup98, Rae1/Gle2, and TAP. We have defined the binary complexes that form among these proteins. We find that Gle2 requires two sites within TAP for stable interaction. Strikingly, rather than a general affinity for all nucleoporin FG repeats, TAP has highest affinity for a specific region within the GLFG domain of Nup98, indicating that not all repeats are identical in function. We have established that the ternary complex can form through simultaneous binding of both Gle2 and TAP to adjacent sites on Nup98. In contrast, Nup98 competes with TAP for Gle2 binding; when bound to Nup98, Gle2 no longer interacts directly with TAP. From these interactions, we propose that Gle2 may act to deliver TAP to Nup98 and that this may represent the first in a series of interactions between an export complex and a nucleoporin.

Complex formation among the RNA export proteins Nup98, Rae1/Gle2, and TAP.

La plupart du trafic nucl&#xE9;ocytoplasmique par le complexe du pore nucl&#xE9;aire est m&#xE9;di&#xE9;e par des r&#xE9;cepteurs solubles de la importine / exportin ou karyoph&#xE9;rine famille. l&#x26;#39;exportation d&#x26;#39;ARNm est unique en ce sens qu&#x26;#39;aucun r&#xE9;cepteur de cette famille a &#xE9;t&#xE9; impliqu&#xE9;e dans le trafic de la majeure partie des ARNm. Au lieu de cela, de nombreuses prot&#xE9;ines diff&#xE9;rentes ont &#xE9;t&#xE9; li&#xE9;s &#xE0; l&#x26;#39;ARNm &#xE0; l&#x26;#39;exportation, mais un mod&#xE8;le qui englobe tout reste insaisissable. Comprendre comment ces prot&#xE9;ines interagissent les uns avec les autres est un &#xE9;l&#xE9;ment central pour le d&#xE9;veloppement d&#x26;#39;un tel mod&#xE8;le. Ici, nous nous sommes concentr&#xE9;s sur les interactions entre trois prot&#xE9;ines impliqu&#xE9;es dans l&#x26;#39;exportation d&#x26;#39;ARNm, NUP98, Rae1/Gle2 et TAP. Nous avons d&#xE9;fini des complexes binaires qui forment entre ces prot&#xE9;ines. Nous constatons que Gle2 n&#xE9;cessite deux sites au sein de TAP pour une interaction stable. &#xC9;tonnamment, plut&#xF4;t que d&#x26;#39;une affinit&#xE9; g&#xE9;n&#xE9;rale pour toutes les r&#xE9;p&#xE9;titions FG nucl&#xE9;oporine, TAP a la plus forte affinit&#xE9; pour une r&#xE9;gion sp&#xE9;cifique dans le domaine de la GLFG NUP98, indiquant que tous les r&#xE9;p&#xE9;titions sont identiques en fonction. Nous avons &#xE9;tabli que le complexe ternaire peut se former par liaison simultan&#xE9;e de deux Gle2 et TAP &#xE0; des sites adjacents sur NUP98. En revanche, NUP98 en concurrence avec TAP pour Gle2 contraignant; lorsqu&#x26;#39;il est li&#xE9; &#xE0; NUP98, Gle2 plus interagit directement avec TAP. De ces interactions, nous proposons que Gle2 peut agir pour offrir &#xE0; TAP NUP98 et que cela peut repr&#xE9;senter le premier d&#x26;#39;une s&#xE9;rie d&#x26;#39;interactions entre un complexe d&#x26;#39;exportation et un nucl&#xE9;oporine.

Formation complexe entre les prot&#xE9;ines &#xE0; l&#x26;#39;exportation, les ARN NUP98 Rae1/Gle2, et TAP

Die Komplexbildung zwischen den RNA-Export-Proteine &#x200B;&#x200B;Nup98, Rae1/Gle2 und TAP.

Maggior parte del traffico nucleo-citoplasmatici attraverso il poro nucleare complesso &egrave; mediata da recettori solubili della importin/exportin o famiglia karyopherin. esportazione del mRNA &egrave; unico in quanto nessun recettore di questa famiglia &egrave; stato implicato nel traffico della maggior parte dei mRNAs. Invece, molte proteine diverse sono state collegate all&#39;esportazione del mRNA, ma un totalizzante modello resta sfuggente. Comprendere come queste proteine interagiscono con a vicenda &egrave; centrale per lo sviluppo di tale modello. Qui, ci siamo concentrati sulle interazioni fra tre proteine implicate nell&#39;esportazione del mRNA, Nup98, Gle2/Rae1 e rubinetto. Abbiamo definito i binari complessi che si formano tra queste proteine. Troviamo che Gle2 richiede due siti all&#39;interno del rubinetto per interazione stabile. Sorprendentemente, piuttosto che un generale affinit&agrave; per tutte le nucleoporin FG ripete, TAP ha pi&ugrave; alta affinit&agrave; per una regione specifica all&#39;interno del dominio GLFG di Nup98, che indica che non tutte le ripetizioni sono identici nella funzione. Abbiamo stabilito che il complesso ternario pu&ograve; formare tramite l&#39;associazione simultanea di entrambi Gle2 e rubinetto a siti adiacenti su Nup98. Al contrario, Nup98 compete con rubinetto per l&#39;associazione Gle2; Quando associato a Nup98, Gle2 non interagisce direttamente con rubinetto. Da queste interazioni, proponiamo che Gle2 pu&ograve; agire per consegnare il rubinetto a Nup98 e che questo potrebbe rappresentare il primo di una serie di interazioni tra un&#39;esportazione complessa e un nucleoporin.

Formazione di complessa tra le proteine di esportazione di RNA Nup98, Gle2/Rae1 e rubinetto.

&#x6838;&#x819C;&#x5B54;&#x8907;&#x5408;&#x4F53;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x307B;&#x3068;&#x3093;&#x3069;&#x306E;&#x6838; - &#x7D30;&#x80DE;&#x8CEA;&#x306E;&#x30C8;&#x30E9;&#x30D5;&#x30A3;&#x30C3;&#x30AF;&#x306F;&#x3001;&#x30A4;&#x30F3;&#x30DD;&#x30FC;&#x30C1;&#x30F3;/ exportin&#x307E;&#x305F;&#x306F;&#x30AB;&#x30EA;&#x30AA;&#x30D5;&#x30A7;&#x30EA;&#x30F3;&#x5BB6;&#x65CF;&#x306E;&#x53EF;&#x6EB6;&#x6027;&#x53D7;&#x5BB9;&#x4F53;&#x306B;&#x3088;&#x3063;&#x3066;&#x5A92;&#x4ECB;&#x3055;&#x308C;&#x308B;&#x3002; mRNA&#x306E;&#x8F38;&#x51FA;&#x306F;&#x3001;&#x3053;&#x306E;&#x5BB6;&#x65CF;&#x306E;&#x306A;&#x3044;&#x53D7;&#x5BB9;&#x4F53;mRNA&#x306E;&#x30D0;&#x30EB;&#x30AF;&#x306E;&#x4EBA;&#x8EAB;&#x58F2;&#x8CB7;&#x306B;&#x95A2;&#x4E0E;&#x3055;&#x308C;&#x3066;&#x3044;&#x306A;&#x3044;&#x3068;&#x3044;&#x3046;&#x70B9;&#x3067;&#x3001;&#x30E6;&#x30CB;&#x30FC;&#x30AF;&#x3067;&#x3042;&#x308B;&#x3002;&#x4EE3;&#x308F;&#x308A;&#x306B;&#x3001;&#x591A;&#x304F;&#x306E;&#x591A;&#x69D8;&#x306A;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306F;&#x3001;&#x8F38;&#x51FA;&#x3092;mRNA&#x306B;&#x30EA;&#x30F3;&#x30AF;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x304C;&#x3001;&#x3059;&#x3079;&#x3066;&#x306E;&#x5305;&#x62EC;&#x7684;&#x306A;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x306F;&#x3001;&#x3068;&#x3089;&#x3048;&#x3069;&#x3053;&#x308D;&#x306E;&#x306A;&#x3044;&#x307E;&#x307E;&#x306B;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306F;&#x4E92;&#x3044;&#x306B;&#x5BFE;&#x8A71;&#x3059;&#x308B;&#x65B9;&#x6CD5;&#x3092;&#x7406;&#x89E3;&#x3059;&#x308B;&#x3053;&#x3068;&#x306F;&#x3001;&#x305D;&#x306E;&#x3088;&#x3046;&#x306A;&#x30E2;&#x30C7;&#x30EB;&#x306E;&#x958B;&#x767A;&#x306E;&#x4E2D;&#x5FC3;&#x3068;&#x306A;&#x308A;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;3 mRNA&#x306E;&#x8F38;&#x51FA;&#x306B;&#x95A2;&#x4E0E;&#x3059;&#x308B;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x3001;NUP98&#x3001;Rae1/Gle2&#x3001;&#x3068;TAP&#x3068;&#x306E;&#x9593;&#x306E;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x306B;&#x7126;&#x70B9;&#x3092;&#x5F53;&#x3066;&#x3066;&#x3044;&#x308B;&#x3002;&#x6211;&#x3005;&#x306F;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306E;&#x9593;&#x3067;&#x30D0;&#x30A4;&#x30CA;&#x30EA;&#x5F62;&#x5F0F;&#x306E;&#x8907;&#x5408;&#x4F53;&#x3092;&#x5B9A;&#x7FA9;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005;&#x306F;Gle2&#x304C;&#x5B89;&#x5B9A;&#x3057;&#x3066;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x306E;&#x305F;&#x3081;&#x306E;TAP&#x5185;&#x306E;2&#x3064;&#x306E;&#x30B5;&#x30A4;&#x30C8;&#x304C;&#x5FC5;&#x8981;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x898B;&#x3064;&#x3051;&#x308B;&#x3002;&#x9A5A;&#x304F;&#x3079;&#x304D;&#x3053;&#x3068;&#x3067;&#x306F;&#x306A;&#x304F;&#x3001;&#x3059;&#x3079;&#x3066;&#x306E;&#x30CC;&#x30AF;&#x30EC;&#x30AA;&#x30DD;&#x30EA;&#x30F3;FG&#x306E;&#x7E70;&#x308A;&#x8FD4;&#x3057;&#x306E;&#x305F;&#x3081;&#x306E;&#x4E00;&#x822C;&#x7684;&#x306A;&#x89AA;&#x548C;&#x6027;&#x3088;&#x308A;&#x3082;&#x3001;TAP&#x306F;&#x3001;&#x3059;&#x3079;&#x3066;&#x306E;&#x7E70;&#x308A;&#x8FD4;&#x3057;&#x306F;&#x3001;&#x95A2;&#x6570;&#x304C;&#x540C;&#x4E00;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3059;&#x3001;NUP98&#x306E;GLFG&#x30C9;&#x30E1;&#x30A4;&#x30F3;&#x5185;&#x306E;&#x7279;&#x5B9A;&#x306E;&#x9818;&#x57DF;&#x306B;&#x5BFE;&#x3057;&#x3066;&#x6700;&#x3082;&#x9AD8;&#x3044;&#x89AA;&#x548C;&#x6027;&#x3092;&#x6301;&#x3063;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005;&#x306F;&#x3001;&#x4E09;&#x5143;&#x8907;&#x5408;&#x4F53;&#x306F;&#x3001;&#x4E21;&#x65B9;&#x306E;Gle2&#x306E;&#x540C;&#x6642;&#x7D50;&#x5408;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x5F62;&#x6210;&#x3057;&#x3001;NUP98&#x306B;&#x96A3;&#x63A5;&#x3057;&#x305F;&#x90E8;&#x4F4D;&#x306B;&#x30BF;&#x30C3;&#x30D7;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x3053;&#x3068;&#x3092;&#x78BA;&#x7ACB;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x5BFE;&#x7167;&#x7684;&#x306B;&#x3001;NUP98&#x304C;Gle2&#x7D50;&#x5408;&#x306E;&#x305F;&#x3081;&#x306E;TAP&#x3068;&#x7AF6;&#x5408;&#x3059;&#x308B;&#x3002;NUP98&#x306B;&#x30D0;&#x30A4;&#x30F3;&#x30C9;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x5834;&#x5408;&#x306B;&#x306F;&#x3001;Gle2&#x306F;&#x3082;&#x306F;&#x3084;TAP&#x3068;&#x76F4;&#x63A5;&#x5BFE;&#x8A71;&#x3057;&#x307E;&#x305B;&#x3093;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x304B;&#x3089;&#x3001;&#x6211;&#x3005;&#x306F;Gle2&#x306F;NUP98&#x306B;TAP&#x3092;&#x63D0;&#x4F9B;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x3001;&#x3053;&#x308C;&#x306F;&#x8F38;&#x51FA;&#x8907;&#x96D1;&#x3067;&#x30CC;&#x30AF;&#x30EC;&#x30AA;&#x30DD;&#x30EA;&#x30F3;&#x306E;&#x9593;&#x306E;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x306E;&#x30B7;&#x30EA;&#x30FC;&#x30BA;&#x306E;&#x4E2D;&#x3067;&#x6700;&#x521D;&#x306B;&#x8868;&#x73FE;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x4F5C;&#x7528;&#x3057;&#x3046;&#x308B;&#x3053;&#x3068;&#x3092;&#x63D0;&#x6848;&#x3059;&#x308B;&#x3002;

&#x8907;&#x96D1;&#x306A;RNA&#x30A8;&#x30AF;&#x30B9;&#x30DD;&#x30FC;&#x30C8;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;NUP98&#x3001;Rae1/Gle2&#x306E;&#x4E2D;&#x3067;&#x5F62;&#x6210;&#x3057;&#x3001;TAP

&#xBCF5;&#xC7A1; &#xD55C; &#xD575; &#xACF5; &#xD1B5;&#xD574; &#xB300;&#xBD80;&#xBD84;&#xC758; nucleocytoplasmic &#xD2B8;&#xB798;&#xD53D; importin/exportin &#xB610;&#xB294; karyopherin &#xAC00;&#xC871;&#xC758; &#xC218;&#xC6A9; &#xC131; &#xC218;&#xC6A9; &#xCCB4;&#xC5D0; &#xC758;&#xD574; &#xC911;&#xC7AC;&#xC785;&#xB2C8;&#xB2E4;. mRNA &#xC218;&#xCD9C;&#xC774;&#xC774; &#xAC00;&#xC871;&#xC758; &#xC218;&#xC6A9; &#xCCB4; &#xC544;&#xBB34; Mrnas&#xC758; &#xB300;&#xBD80;&#xBD84;&#xC758; &#xC778;&#xC2E0; &#xB9E4;&#xB9E4;&#xC5D0; &#xC5F0;&#xB8E8; &#xB418;&#xC5B4; &#xC788;&#xB2E4;&#xB294; &#xC810;&#xC5D0;&#xC11C; &#xB3C5;&#xD2B9;&#xD569;&#xB2C8;&#xB2E4;. &#xB300;&#xC2E0;, &#xB9CE;&#xC740; &#xB2E4;&#xC591; &#xD55C; &#xB2E8;&#xBC31;&#xC9C8; mRNA &#xC218;&#xCD9C; &#xD558;&#xC9C0;&#xB9CC; &#xBAA8;&#xB450; &#xD3EC;&#xAD04;&#xC5D0; &#xC5F0;&#xACB0; &#xB41C; &#xBAA8;&#xB378; &#xC560;&#xB9E4; &#xB0A8;&#xC544; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774; &#xB2E8;&#xBC31;&#xC9C8;&#xC774; &#xC11C;&#xB85C; &#xC0C1;&#xD638; &#xC791;&#xC6A9; &#xD558;&#xB294; &#xBC29;&#xC2DD;&#xC744; &#xC774;&#xD574; &#xD558;&#xB294; &#xAC83;&#xC785;&#xB2C8;&#xB2E4; &#xC774;&#xB7EC;&#xD55C; &#xBAA8;&#xB378; &#xAC1C;&#xBC1C;&#xC758; &#xC911;&#xC2EC;. &#xC5EC;&#xAE30;, &#xC6B0;&#xB9AC;&#xB294; 3 &#xAC1C;&#xC758; &#xB2E8;&#xBC31;&#xC9C8; mRNA &#xB0B4;&#xBCF4;&#xB0B4;&#xAE30;, Nup98, Rae1/Gle2 &#xBC0F; &#xC218;&#xB3D7;&#xBB3C;&#xC5D0; &#xC5F0;&#xB8E8; &#xAC04;&#xC758; &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC5D0; &#xC9D1;&#xC911; &#xD588;&#xB2E4;. &#xC774; &#xB2E8;&#xBC31;&#xC9C8; &#xB4E4;&#xC744; &#xAD6C;&#xC131; &#xD558;&#xB294; &#xC774;&#xC9C4; &#xB2E8;&#xC9C0; &#xC815;&#xC758; &#xD588;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; Gle2 &#xC548;&#xC815;&#xC801;&#xC778; &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC5D0; &#xB300; &#xD55C; &#xD0ED; &#xB0B4;&#xC5D0;&#xC11C; &#xB450; &#xAC1C;&#xC758; &#xC0AC;&#xC774;&#xD2B8;&#xB97C; &#xD544;&#xC694; &#xCC3E;&#xC73C;&#xC2ED;&#xC2DC;&#xC624;. &#xAE30; &#xB9C9;&#xD788;&#xAC8C;, &#xBAA8;&#xB4E0; nucleoporin FG&#xC5D0; &#xB300; &#xD55C; &#xC77C;&#xBC18;&#xC801;&#xC778; &#xC120;&#xD638;&#xB3C4; &#xBC18;&#xBCF5; &#xBCF4;&#xB2E4;&#xB294; &#xD0ED; &#xAC00;&#xC7A5; &#xB192;&#xC740; &#xC120;&#xD638;&#xB3C4;&#xAC00;&#xC9C0;&#xACE0; Nup98, GLFG &#xB3C4;&#xBA54;&#xC778; &#xB0B4;&#xC5D0;&#xC11C; &#xD2B9;&#xC815; &#xC9C0;&#xC5ED;&#xC5D0; &#xB300; &#xD55C; &#xBAA8;&#xB4E0; &#xBC18;&#xBCF5;&#xC740; &#xB3D9;&#xC77C; &#xD568;&#xC218;&#xC5D0;&#xC11C; &#xB098;&#xD0C0;&#xB0B4;&#xB294;. 3 &#xC9C4; &#xBCF5;&#xC7A1; &#xD55C; nup98&#xC5D0; &#xC778;&#xC811; &#xD55C; &#xC0AC;&#xC774;&#xD2B8;&#xC5D0; Gle2 &#xBC0F; &#xD0ED; &#xB3D9;&#xC2DC; &#xBC14;&#xC778;&#xB529;&#xC744; &#xD1B5;&#xD574; &#xD615;&#xC131;&#xD560; &#xC218; &#xC124;&#xB9BD; &#xD588;&#xC2B5;&#xB2C8;&#xB2E4;. Nup98 Gle2 &#xBC14;&#xC778;&#xB529;&#xC5D0;; &#xD0ED;&#xACFC; &#xACBD;&#xC7C1; &#xD558;&#xB294; &#xBC18;&#xBA74;, nup98&#xC5D0; &#xBC14;&#xC778;&#xB529;&#xB41C; &#xACBD;&#xC6B0; gle2&#xB294; &#xB354; &#xC774;&#xC0C1; &#xD0ED;&#xACFC; &#xC9C1;&#xC811; &#xC791;&#xC6A9; &#xD569;&#xB2C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC5D0;&#xC11C; &#xC6B0;&#xB9AC;&#xB294; Gle2 Nup98 &#xD0ED; &#xD558; &#xACE0;&#xC774; &#xBCF5;&#xC7A1; &#xD55C; &#xC218;&#xCD9C; &#xACE0;&#xB294; nucleoporin &#xAC04;&#xC758; &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC758; &#xC2DC;&#xB9AC;&#xC988;&#xC758; &#xCCAB; &#xBC88;&#xC9F8;&#xB97C; &#xB098;&#xD0C0;&#xB0B4;&#xB294; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xC804;&#xB2EC; &#xD558;&#xAE30; &#xC704;&#xD574; &#xD589;&#xB3D9; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xC81C;&#xC548; &#xD569;&#xB2C8;&#xB2E4;.

Nup98, Rae1/Gle2, TAP RNA &#xC218;&#xCD9C; &#xB2E8;&#xBC31;&#xC9C8; &#xAC00;&#xC6B4;&#xB370; &#xBCF5;&#xC7A1; &#xD55C; &#xD615;&#xC131;.

La mayor parte del tr&#xE1;fico nucleocytoplasmic a trav&#xE9;s del complejo del poro nuclear est&#xE1; mediado por los receptores solubles de la importina / o exportina carioferina familia. exportaci&#xF3;n ARNm es &#xFA;nico en que no hay receptores de esta familia se ha implicado en el tr&#xE1;fico de la mayor parte de los ARNm. En cambio, muchas diversas prote&#xED;nas se han relacionado con el ARNm de exportaci&#xF3;n, sino un modelo que lo abarca todo sigue siendo dif&#xED;cil de alcanzar. La comprensi&#xF3;n de c&#xF3;mo estas prote&#xED;nas interact&#xFA;an unos con otros es fundamental para el desarrollo de este modelo. Aqu&#xED;, nos hemos centrado en las interacciones entre las tres prote&#xED;nas implicadas en la exportaci&#xF3;n del ARNm, Nup98, Rae1/Gle2 y TAP. Hemos definido los complejos binarios que forman entre estas prote&#xED;nas. Encontramos que Gle2 requiere de dos sitios dentro de TAP para la interacci&#xF3;n estable. Sorprendentemente, en lugar de una afinidad general para todas las repeticiones nucleoporin FG, TAP tiene mayor afinidad por una regi&#xF3;n espec&#xED;fica dentro del dominio de GLFG Nup98, lo que indica que no todas las repeticiones son id&#xE9;nticas en funci&#xF3;n. Hemos establecido que el complejo ternario pueden formar a trav&#xE9;s de la uni&#xF3;n simult&#xE1;nea de dos Gle2 y TAP a los sitios adyacentes en Nup98. Por el contrario, Nup98 compite con TAP para Gle2 vinculante, cuando se une a Nup98, Gle2 no interact&#xFA;a directamente con TAP. A partir de estas interacciones, se propone que Gle2 puede actuar para entregar TAP para Nup98 y que esto puede representar la primera de una serie de interacciones entre un complejo de exportaci&#xF3;n y una nucleoporin.

Formaci&#xF3;n de complejos entre las prote&#xED;nas y ARN de exportaci&#xF3;n Nup98 Rae1/Gle2, y TAP

Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting approximately 1% of the adult population worldwide, with an estimated heritability of 60%. To identify genes involved in RA susceptibility, we investigated the association between putative functional single-nucleotide polymorphisms (SNPs) and RA among white individuals by use of a case-control study design; a second sample was tested for replication. Here we report the association of RA susceptibility with the minor allele of a missense SNP in PTPN22 (discovery-study allelic P=6.6 x 10(-4); replication-study allelic P=5.6 x 10(-8)), which encodes a hematopoietic-specific protein tyrosine phosphatase also known as "Lyp." We show that the risk allele, which is present in approximately 17% of white individuals from the general population and in approximately 28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with Csk, potentially altering these proteins' normal function as negative regulators of T-cell activation. The minor allele of this SNP recently was implicated in type 1 diabetes, suggesting that the variant phosphatase may increase overall reactivity of the immune system and may heighten an individual carrier's risk for autoimmune disease.

A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.

Stimulation of mature T cells activates a downstream signaling cascade involving temporally and spatially regulated phosphorylation and dephosphorylation events mediated by protein-tyrosine kinases and phosphatases, respectively. PTPN22 (Lyp), a non-receptor protein-tyrosine phosphatase, is expressed exclusively in cells of hematopoietic origin, notably in T cells where it represses signaling through the T cell receptor. We used substrate trapping coupled with mass spectrometry-based peptide identification in an unbiased approach to identify physiological substrates of PTPN22. Several potential substrates were identified in lysates from pervanadate-stimulated Jurkat cells using PTPN22-D195A/C227S, an optimized substrate trap mutant of PTPN22. These included three novel PTPN22 substrates (Vav, CD3epsilon, and valosin containing protein) and two known substrates of PEP, the mouse homolog of PTPN22 (Lck and Zap70). T cell antigen receptor (TCR) zeta was also identified as a potential substrate in Jurkat lysates by direct immunoblotting. In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22.

Identification of substrates of human protein-tyrosine phosphatase PTPN22.

To examine the effects of social support role (i.e., recipient versus provider) and experimentally manipulated closeness on men's and women's cortisol responses during an acute stress paradigm.

What's closeness got to do with it? Men's and women's cortisol responses when providing and receiving support.

Activation of the B-cell antigen receptor (BCR) signaling pathway contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. Herein we describe a selective and irreversible Btk inhibitor, PCI-32765, that is currently under clinical development in patients with B-cell non-Hodgkin lymphoma. We have used this inhibitor to investigate the biologic effects of Btk inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. In mice with collagen-induced arthritis, orally administered PCI-32765 reduced the level of circulating autoantibodies and completely suppressed disease. PCI-32765 also inhibited autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Btk. Active site occupancy of Btk was tightly correlated with the blockade of BCR signaling and in vivo efficacy. Finally, PCI-32765 induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway.

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy.

Hepatitis B virus (HBV) vaccination is recommended for individuals with hepatitis C virus (HCV) infection given their shared risk factors and increased liver-related morbidity and mortality upon super-infection. Vaccine responses in this setting are often blunted, with poor response rates to HBV vaccinations in chronically HCV-infected individuals compared to healthy subjects. In this study, we investigated the role of T cell immunoglobulin mucin domain-3 (Tim-3)-mediated immune regulation in HBV vaccine responses during HCV infection. We found that Tim-3, a marker for T cell exhaustion, was over-expressed on monocytes, leading to a differential regulation of IL-12/IL-23 production which in turn TH17 cell accumulation, in HCV-infected HBV vaccine non-responders compared to HCV-infected HBV vaccine responders or healthy subjects (HS). Importantly, ex vivo blockade of Tim-3 signaling corrected the imbalance of IL-12/IL-23 as well as the IL-17 bias observed in HBV vaccine non-responders during HCV infection. These results suggest that Tim-3-mediated dysregulation of innate to adaptive immune responses is involved in HBV vaccine failure in individuals with chronic HCV infection, raising the possibility that blocking this negative signaling pathway might improve the success rate of HBV immunization in the setting of chronic viral infection.

Tim-3 alters the balance of IL-12/IL-23 and drives TH17 cells: role in hepatitis B vaccine failure during hepatitis C infection.

KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K(+) current (I Kr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing I Kr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (I Kv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients' genotypes) mostly corrected the changes in I Kv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing I Kr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease I Kr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient.

Mechanistic Basis for Type 2 Long QT Syndrome Caused by KCNH2 Mutations that Disrupt Conserved Arginine Residues in the Voltage Sensor.

KCNH2 encode le canal de Kv11.1, qui dirige le redresseur retard&eacute; rapidement activation k actuel (I Kr) au coeur. KCNH2 mutations causent syndrome du QT long type 2 (LQT2), ce qui augmente le risque d&#39;arythmies ventriculaires mortelles. LQT2 mutations devraient pour prolonger le potentiel d&#39;action cardiaque (AP) en r&eacute;duisant je Kr au cours de la repolarisation. Kv11.1 contient plusieurs acides amin&eacute;s basiques conserv&eacute;es dans le quatri&egrave;me segment transmembranaire (S4) de la sonde de tension qui sont importants pour le canal normal traite et blocage. Cette &eacute;tude visait &agrave; d&eacute;terminer l&#39;ou les m&eacute;canismes par lequel LQT2 mutations conserv&eacute;es r&eacute;sidus arginine dans S4 (R531Q, R531W ou R534L) alt&eacute;rer la fonction Kv11.1. Buvardage de Western de cellules HEK293 transitoirement exprimant R531Q, R531W ou R534L a propos&eacute; que seulement R534L inhib&eacute;e Kv11.1 trafic. Tension de serrage des exp&eacute;riences ont montr&eacute; que les R531Q ou R531W modifi&eacute; radicalement activation du courant (I Kv11.1) Kv11.1, inactivation, r&eacute;cup&eacute;ration d&#39;inactivation et d&eacute;sactivation. Coexpression de type sauvage (pour imiter les g&eacute;notypes du patient) corrige principalement les changements j&#39;ai Kv11.1 d&#39;activation et l&#39;inactivation, mais cin&eacute;tique de d&eacute;sactivation ont &eacute;t&eacute; encore plus rapide. Des simulations informatiques en utilisant un mod&egrave;le de AP ventriculaire humain ont montr&eacute; que l&#39;acc&eacute;l&eacute;ration des taux de d&eacute;sactivation &eacute;tait suffisant pour prolonger l&#39;AP, mais ces effets sont minimes par rapport &agrave; la simple r&eacute;duction je Kr. Ce sont les premi&egrave;res donn&eacute;es pour d&eacute;montrer que co-exprimant type sauvage permet de corriger la dysfonction d&#39;activation et l&#39;inactivation caus&eacute;e par des mutations &agrave; un r&eacute;sidu de d&eacute;tection de tension critique dans Kv11.1. Nous concluons que certaines mutations Kv11.1 pourraient acc&eacute;l&eacute;rer la d&eacute;sactivation pour provoquer LQT2 mais que la dur&eacute;e d&#39;AP ventriculaire est beaucoup plus sensible aux mutations qui diminuent je Kr. Probablement, ceci explique pourquoi la plupart des mutations LQT2 sont non-sens ou d&eacute;ficient en trafic.

Base m&eacute;caniste pour Syndrome du QT Long Type 2 caus&eacute;e par des Mutations de KCNH2 que r&eacute;sidus d&#39;Arginine conserv&eacute; perturber dans le capteur de tension.

KCNH2 codifica per il canale di Kv11.1, che conduce rapidamente attivazione ritardato raddrizzatore K(+) corrente (I Kr) nel cuore. KCNH2 mutazioni causano tipo 2 sindrome del QT lungo (LQT2), che aumenta il rischio di aritmie ventricolari letali. LQTS2 mutazioni sono previsti per prolungare il potenziale d&#39;azione cardiaco (AP) riducendo I Kr durante la ripolarizzazione. Kv11.1 contiene diverse conservate amminoacidi basici nel quarto segmento transmembrana (S4) del sensore di tensione che sono importanti per il canale normale traffico e gating. Questo studio ha cercato di determinare i meccanismi comprendono da cui LQTS2 mutazioni a conservano residui di arginina in S4 (R531Q, R531W o R534L) alterano la funzione Kv11.1. Analisi Western blot di cellule HEK293 transitoriamente esprimendo R531Q, R531W o R534L ha suggerito che solo R534L inibito Kv11.1 traffico. Tensione di serraggio esperimenti hanno mostrato che R531Q o R531W notevolmente alterata attivazione corrente (I Kv11.1) Kv11.1, inattivazione, recupero da inattivazione e disattivazione. Coexpression di tipo selvatico (per simulare i genotipi dei pazienti) per lo pi&ugrave; corretti i cambiamenti che Kv11.1 attivazione ed inattivazione, ma cinetica di disattivazione erano ancora pi&ugrave; veloce. Simulazioni computazionali utilizzando un modello di AP ventricolare umano ha dimostrato che accelerare i tassi di disattivazione &egrave; stata sufficiente a prolungare l&#39;AP, ma questi effetti sono state minime rispetto al vantaggio riducendo I Kr. Questi sono i primi dati per dimostrare che coexpressing wild type pu&ograve; correggere la disfunzione attivazione ed inattivazione causata da mutazioni in un residuo di rilevazione della tensione critica in Kv11.1. Possiamo concludere che alcune mutazioni Kv11.1 potrebbero accelerare la disattivazione per causare LQTS2, ma che la durata di AP ventricolare &egrave; molto pi&ugrave; sensibile alle mutazioni che riducono I Kr. Questo probabilmente spiega perch&eacute; la maggior parte delle mutazioni LQTS2 sono sciocchezze o deficit di traffico.

Base meccanicistica per la sindrome del QT lungo tipo 2 causata da mutazioni KCNH2 quello conservato arginina residui di interferire nel sensore di tensione.

Discrete gold nanoparticles with diameters between 2 and 3 nm show remarkable properties including enhanced catalytic behavior and photoluminescence. However, tunability of these properties is limited by the tight size range within which they are observed. Here, we report the synthesis of discrete, bimetallic gold-copper nanoparticle alloys (diameter ≅ 2-3 nm) which display photoluminescent properties that can be tuned by changing the alloy composition. Electron microscopy, X-ray photoelectron spectroscopy, inductively coupled plasma mass spectrometry, and pulsed-field gradient stimulated echo (1)H NMR measurements show that the nanoparticles are homogeneous, discrete, and crystalline. Upon varying the composition of the nanoparticles from 0% to 100% molar ratio copper, the photoluminescence maxima shift from 947 to 1067 nm, with excitation at 360 nm. The resulting particles exhibit brightness values (molar extinction coefficient (ε) × quantum yield (Φ)) that are more than an order of magnitude larger than the brightest near-infrared-emitting lanthanide complexes and small-molecule probes evaluated under similar conditions.

Photoluminescent gold-copper nanoparticle alloys with composition-tunable near-infrared emission.

Treatment manuals are currently the most common way treatments are disseminated to practicing clinicians, although little is known about the rates with which practicing therapists incorporate these manuals into their practice. In light of a widely acknowledged research-practice gap, understanding how often therapists are using manuals is important for shaping future dissemination efforts. This study collected data on rates of manual use among a national sample of mental health clinicians representative of those likely to be targeted in dissemination efforts (N = 756), as well as predictors of use. Results indicated that few clinicians (< 10%) routinely incorporated manuals into their practice, although most employed them to some degree. Predictors of manual use included greater openness to new treatments, younger age, and a cognitive-behavioral treatment orientation (ps < .05). Implications for future dissemination efforts are discussed.

Article	Year
Complex formation among the RNA export proteins Nup98, Rae1/Gle2, and TAP. The Journal of biological chemistry\| PubMed ID: 12637516	2003
A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. American journal of human genetics\| PubMed ID: 15208781	2004
Identification of substrates of human protein-tyrosine phosphatase PTPN22. The Journal of biological chemistry\| PubMed ID: 16461343	2006
What's closeness got to do with it? Men's and women's cortisol responses when providing and receiving support. Psychosomatic medicine\| PubMed ID: 19661188	2009
The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 20615965	2010
Tim-3 alters the balance of IL-12/IL-23 and drives TH17 cells: role in hepatitis B vaccine failure during hepatitis C infection. Vaccine\| PubMed ID: 23499521	2013
Mechanistic Basis for Type 2 Long QT Syndrome Caused by KCNH2 Mutations that Disrupt Conserved Arginine Residues in the Voltage Sensor. The Journal of membrane biology\| PubMed ID: 23546015	2013
Photoluminescent gold-copper nanoparticle alloys with composition-tunable near-infrared emission. Journal of the American Chemical Society\| PubMed ID: 23548041	2013
Who's using treatment manuals? A national survey of practicing therapists. Behaviour research and therapy\| PubMed ID: 23973815	2013

Ashley M. Smith

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