systemic-delivery-microrna-using-recombinant-adeno-associated-virus

Systemic Delivery of MicroRNA Using Recombinant Adeno-associated Virus Serotype 9 to Treat Neuromuscular Diseases in Rodents

RNA interference via the endogenous miRNA pathway regulates gene expression by controlling protein synthesis through post-transcriptional gene silencing. ...

National Institutes of Health

&#x5728;&#x5F88;&#x591A;&#x751F;&#x7269;&#xFF0C;&#x9A6C;&#x7403;&#x6FC0;&#x9176;&#x51FA;&#x73B0; M &#x9636;&#x6BB5;&#x8FDB;&#x5C55;&#x8FC7;&#x7A0B;&#x4E2D;&#x626E;&#x6F14;&#x591A;&#x4E2A;&#x89D2;&#x8272;&#x3002;&#x63D0;&#x4F9B;&#x529F;&#x80FD;&#x7684;&#x840C;&#x82BD;&#x7684;&#x65B0;&#x89C1;&#x89E3;&#x9175;&#x6BCD; polo &#x6FC0;&#x9176; Cdc5p&#x3001; &#x6211;&#x4EEC;&#x751F;&#x6210;&#x65B0;&#x578B;&#x6E29;&#x5EA6;&#x654F;&#x611F; cdc5 &#x7A81;&#x53D8;&#x682A;&#x7684;&#x8BF1;&#x53D8; C &#x672B;&#x7AEF;&#x57DF;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x8868;&#x660E;&#xFF0C;&#x5728; semipermissive &#x7684;&#x6E29;&#x5EA6;&#xFF0C;cdc5 3 &#x7A81;&#x53D8;&#x4F53;&#x8868;&#x73B0;&#x534F;&#x540C;&#x82BD;&#x4F38;&#x957F;&#x7387;&#x548C;&#x589E;&#x957F;&#x7F3A;&#x635F;&#x635F;&#x5931; HSL1&#xFF0C;&#x6B63;&#x5E38;&#x7684; G (2) /M &#x8FC7;&#x6E21;&#x7684;&#x91CD;&#x8981;&#x7EC4;&#x6210;&#x90E8;&#x5206;&#x3002;SWE1&#xFF0C;phosphorylates&#xFF0C;&#x53EF;&#x706D;&#x6D3B;&#x51FA;&#x82BD;&#x9175;&#x6BCD; Cdc28p Cdk1 &#x540C;&#x6E90;&#xFF0C;&#x635F;&#x5931;&#x6291;&#x5236; cdc5 3 hsl1Delta &#x7F3A;&#x9677;&#xFF0C;&#x5EFA;&#x8BAE; Cdc5p &#x51FD;&#x6570;&#x5728;&#x4E0A;&#x6E38;&#x7684; Swe1p &#x70B9;&#x3002;&#x6B64;&#x5916;&#xFF0C;cdc5 4 &#x548C; cdc5 7 &#x7A81;&#x53D8;&#x4F53;&#x5C55;&#x793A;&#x94FE;&#x63A5;&#x5355;&#x5143;&#x683C;&#x5F62;&#x8C8C;&#x4E0E;&#x5171;&#x4EAB;&#x7EC6;&#x80DE;&#x8D28;&#x4E4B;&#x95F4;&#x8FDE;&#x63A5;&#x7684;&#x5355;&#x5143;&#x683C;&#x673A;&#x6784;&#xFF0C;&#x8868;&#x660E;&#x7EC6;&#x80DE;&#x7684;&#x7F3A;&#x9677;&#x3002;&#x4ED4;&#x7EC6;&#x68C0;&#x67E5;&#x53D1;&#x73B0;&#x8FD9;&#x4E9B;&#x7A81;&#x53D8;&#x7684;&#x5EF6;&#x8FDF; septin &#x5927;&#x4F1A;&#x5728;&#x65E9;&#x671F;&#x82BD;&#x7AD9;&#x70B9;&#x548C;&#x7EC4;&#x7EC7;&#x677E;&#x6563; septin &#x6BCD;&#x4EB2;&#x82BD;&#x9888;&#x73AF;&#x3002;&#x6709;&#x4E1D;&#x5206;&#x88C2;&#x9000;&#x51FA;&#x7F51;&#x7EDC; &#xFF08;&#x7537;&#x5B50;&#xFF09; &#x4E2D;&#x7684;&#x7EC4;&#x4EF6;&#x5728;&#x6B63;&#x5E38;&#x80DE;&#x8D28;&#x5206;&#x88C2;&#x4E2D;&#x53D1;&#x6325;&#x4E86;&#x91CD;&#x8981;&#x4F5C;&#x7528;&#x3002;&#x4F46;&#x662F;&#xFF0C;&#x635F;&#x5931; BFA1 &#x6216; BUB2&#xFF0C;&#x8D1F;&#x76D1;&#x7BA1;&#x8005;&#x7684;&#x7537;&#x5B50;&#xFF0C;&#x672A;&#x80FD;&#x7EA0;&#x6B63;&#x8FD9;&#x4E9B;&#x7A81;&#x53D8;&#xFF0C;&#x6307;&#x793A; Cdc5p &#x4FC3;&#x8FDB;&#x72EC;&#x7ACB;&#x4E8E; Bfa1p &#x548C; Bub2p &#x7684;&#x80DE;&#x8D28;&#x5206;&#x88C2;&#x7684;&#x7EC6;&#x80DE;&#x7F3A;&#x9677;&#x3002;&#x56E0;&#x6B64;&#xFF0C;Cdc5p &#x6709;&#x52A9;&#x4E8E;&#x4F9D;&#x8D56;&#x4E8E; Swe1p &#x7684; Cdc28p/Clb &#x901A;&#x8DEF;&#x3001; &#x6B63;&#x5E38; septin &#x51FD;&#x6570;&#x548C;&#x80DE;&#x8D28;&#x5206;&#x88C2;&#x7684;&#x6FC0;&#x6D3B;&#x3002;

CDC5 &#x51FD;&#x6570;&#x5728;&#x917F;&#x9152;&#x9175;&#x6BCD;&#x4E2D;&#x7684;&#x635F;&#x5931;&#x4F1A;&#x5BFC;&#x81F4; Swe1p &#x8C03;&#x63A7;&#x548C;&#x80DE;&#x8D28;&#x5206;&#x88C2; Bfa1p Bub2p &#x65E0;&#x5173;&#x7684;&#x7F3A;&#x9677;&#x3002;

In many organisms, polo kinases appear to play multiple roles during M-phase progression. To provide new insights into the function of budding yeast polo kinase Cdc5p, we generated novel temperature-sensitive cdc5 mutants by mutagenizing the C-terminal domain. Here we show that, at a semipermissive temperature, the cdc5-3 mutant exhibited a synergistic bud elongation and growth defect with loss of HSL1, a component important for normal G(2)/M transition. Loss of SWE1, which phosphorylates and inactivates the budding yeast Cdk1 homolog Cdc28p, suppressed the cdc5-3 hsl1Delta defect, suggesting that Cdc5p functions at a point upstream of Swe1p. In addition, the cdc5-4 and cdc5-7 mutants exhibited chained cell morphologies with shared cytoplasms between the connected cell bodies, indicating a cytokinetic defect. Close examination of these mutants revealed delayed septin assembly at the incipient bud site and loosely organized septin rings at the mother-bud neck. Components in the mitotic exit network (MEN) play important roles in normal cytokinesis. However, loss of BFA1 or BUB2, negative regulators of the MEN, failed to remedy the cytokinetic defect of these mutants, indicating that Cdc5p promotes cytokinesis independently of Bfa1p and Bub2p. Thus, Cdc5p contributes to the activation of the Swe1p-dependent Cdc28p/Clb pathway, normal septin function, and cytokinesis.

Loss of CDC5 function in Saccharomyces cerevisiae leads to defects in Swe1p regulation and Bfa1p/Bub2p-independent cytokinesis.

Dans de nombreux organismes kinases polo semblent jouer plusieurs r&ocirc;les au cours de la progression de la phase M. Pour apporter un nouvel &eacute;clairage sur la fonction de bourgeonnement kinase polo Cdc5p de levure, nous avons g&eacute;n&eacute;r&eacute; des mutants roman sensible &agrave; la temp&eacute;rature cdc5 par mutagen&egrave;se le domaine C-terminal. Ici, nous montrons que, &agrave; une temp&eacute;rature de semitol&eacute;rantes, le mutant cdc5-3 pr&eacute;sente un d&eacute;faut de l&#39;&eacute;longation et la croissance bourgeon synergique avec perte de HSL1, un &eacute;l&eacute;ment important pour la transition de G (2) /M normal. Perte de SWE1, qui phosphoryle et inactive la levure homologue Cdk1 Cdc28p, supprim&eacute; le d&eacute;faut hsl1Delta cdc5-3, ce qui sugg&egrave;re que les fonctions de Cdc5p &agrave; un point situ&eacute; en amont de Swe1p. De plus, les mutants cdc5-4 et cdc5-7 montrent des morphologies cellule cha&icirc;n&eacute;es avec les cytoplasmes partag&eacute;s entre les corps cellulaires connect&eacute;s, ce qui indique un d&eacute;faut sch&eacute;matiquement. Un examen attentif de ces mutants a r&eacute;v&eacute;l&eacute; retard&eacute; septin Assembl&eacute;e sur le site de bourgeons naissants et l&acirc;chement organis&eacute;e septin anneaux au niveau du col de m&egrave;re-bud. Composants du r&eacute;seau de sortie mitotique (hommes) jouent un r&ocirc;le important dans la cytokin&egrave;se normal. &Eacute;chec de la perte de BFA1 ou BUB2, r&eacute;gulateurs n&eacute;gatifs des hommes, cependant, pour rem&eacute;dier &agrave; l&#39;irr&eacute;gularit&eacute; sch&eacute;matiquement de ces mutants, indiquant que Cdc5p favorise la cytokin&egrave;se ind&eacute;pendamment de Bfa1p et Bub2p. Ainsi, Cdc5p contribue &agrave; l&#39;activation de la voie d&eacute;pendante Swe1p Cdc28p/Clb, fonction de septin normal et cytocin&egrave;se.

Perte de la fonction CDC5 dans Saccharomyces cerevisiae m&egrave;ne &agrave; d&eacute;faut de r&egrave;glement de Swe1p et de la Bfa1p/Bub2p-ind&eacute;pendant de la cytocin&egrave;se.

In vielen Organismen scheinen Polo Kinasen mehrere Rollen w&auml;hrend der M-Phase Fortschreiten zu spielen. Um neue Einblicke in die Funktion des angehende Hefe-Polo-Kinase Cdc5p, wir neuartige temperaturempfindliche cdc5 Mutanten von mutagenizing der C-terminalen Dom&auml;ne generiert. Hier zeigen wir, dass bei einer semipermissive Temperatur, cdc5-3-Mutant einen synergistischen Knospe Dehnung und Wachstum defekt mit Verlust von HSL1, eine Komponente, die wichtig f&uuml;r die normale G (2) / m &Uuml;bergang ausgestellt. Verlust von SWE1, die phosphorylates und die Knospen Hefe Cdk1 Homolog Cdc28p inaktiviert, unterdr&uuml;ckt den cdc5-3 hsl1Delta-defekt, was darauf hindeutet, dass Cdc5p an einem Punkt oberhalb der Swe1p Funktionen. Dar&uuml;ber hinaus ausgestellt cdc5-4 und cdc5-7 Mutanten angekettet Zelle Morphologien mit freigegebenen Zytoplasmen werden durch zwischen dem verbundenen Zelle angibt, einen cytokinetic defekt. Genaue Pr&uuml;fung der diese Mutanten offenbart verz&ouml;gert Septin-Versammlung am Standort beginnenden Knospe und lose organisierte Septin-Ringe am Hals Mutter-Bud. Komponenten im Netzwerk mitotische Ausfahrt (M&auml;nner) spielen wichtige Rollen in normale Zellteilung. Jedoch nicht Verlust von BFA1 oder BUB2, negativen Regulatoren der M&auml;nner, die cytokinetic M&auml;ngel an diese Mutanten, die darauf hinweist, dass Cdc5p f&ouml;rdert die Zellteilung unabh&auml;ngig von Bfa1p und Bub2p zu beseitigen. Somit tr&auml;gt Cdc5p an die Aktivierung der Swe1p-abh&auml;ngige Cdc28p/Clb Weg, normale Septin-Funktion und Zellteilung.

CDC5 Funktionsverlust in Saccharomyces Cerevisiae f&uuml;hrt zu Defekten in Swe1p Verordnung und Bfa1p/Bub2p-unabh&auml;ngige Zellteilung.

In molti organismi, le chinasi polo sembrano giocare pi&ugrave; ruoli durante la progressione M-fase. Per fornire nuove intuizioni la funzione di germogliamento lievito chinasi polo Cdc5p, abbiamo generato romanzo sensibili alla temperatura cdc5 mutanti di mutagenizing il dominio C-terminale. Qui vi mostriamo che, ad una temperatura semipermissive, il mutante di cdc5-3 esposto un difetto di crescita e allungamento bud sinergica con perdita di HSL1, una componente importante per la normale transizione G (2) m. Perdita di SWE1, che fosforila e inattiva il lievito gemmante Cdk1 omologo Cdc28p, soppresso il difetto di cdc5-3 hsl1Delta, suggerendo che Cdc5p funzioni in un punto a monte della Swe1p. Inoltre, i mutanti di cdc5-4 e 7 cdc5 esposto cella incatenato morfologie con citoplasmi condivise tra i corpi cellulari collegati, indicando un difetto cytokinetic. Attento esame di questi mutanti rivelato ritardato septin assieme al sito bud incipiente e scioltamente organizzato septin anelli al collo madre-bud. Componenti della rete di uscita mitotica (uomini) giocano un ruolo importante nella Citocinesi in normale. Tuttavia, perdita di BFA1 o BUB2, regolatori negativi degli uomini, non &egrave; riuscito a rimediare al difetto di questi mutanti, che indica che il Cdc5p promuove Citocinesi in indipendentemente da Bfa1p e Bub2p cytokinetic. Cos&igrave;, Cdc5p contribuisce all&#39;attivazione del pathway dipendente dalla Swe1p Cdc28p/Clb, septin normale funzione e Citocinesi in.

Perdita della funzione CDC5 in Saccharomyces cerevisiae porta a difetti di Swe1p regolamento e Citocinesi in Bfa1p/Bub2p-indipendente.

&#x591A;&#x304F;&#x306E;&#x751F;&#x7269;&#x3001;polo &#x30AD;&#x30CA;&#x30FC;&#x30BC; M &#x76F8;&#x306E;&#x9032;&#x884C;&#x4E2D;&#x306B;&#x8907;&#x6570;&#x306E;&#x5F79;&#x5272;&#x3092;&#x518D;&#x751F;&#x3059;&#x308B;&#x306B;&#x8868;&#x793A;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;&#x65B0;&#x9032;&#x306E;&#x6A5F;&#x80FD;&#x306B;&#x65B0;&#x305F;&#x306A;&#x6D1E;&#x5BDF;&#x3092;&#x63D0;&#x4F9B;&#x3059;&#x308B;&#x9175;&#x6BCD;&#x306E; polo &#x30AD;&#x30CA;&#x30FC;&#x30BC; Cdc5p &#x306F;&#x3001;&#x6211;&#x3005; C &#x672B;&#x7AEF;&#x30C9;&#x30E1;&#x30A4;&#x30F3;&#x306E; mutagenizing &#x306B;&#x3088;&#x3063;&#x3066;&#x5C0F;&#x8AAC;&#x306E;&#x6E29;&#x5EA6;&#x611F;&#x53D7;&#x6027; cdc5 &#x5909;&#x7570;&#x4F53;&#x3092;&#x751F;&#x6210;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F; semipermissive &#x306E;&#x6E29;&#x5EA6;&#x3067; cdc5 3 &#x5909;&#x7570;&#x76F8;&#x4E57;&#x82BD;&#x306E;&#x4F38;&#x9577;&#x3068;&#x6210;&#x9577;&#x6B20;&#x9665; HSL1&#x3001;&#x901A;&#x5E38;&#x306E; G (2)/M &#x9077;&#x79FB;&#x306B;&#x5BFE;&#x3057;&#x3066;&#x91CD;&#x8981;&#x30B3;&#x30F3;&#x30DD;&#x30FC;&#x30CD;&#x30F3;&#x30C8;&#x306E;&#x640D;&#x5931;&#x3068;&#x5C55;&#x793A;&#x3092;&#x898B;&#x308B;&#x3002;&#x640D;&#x5931;&#x306F;&#x51FA;&#x82BD;&#x9175;&#x6BCD; cdk1 &#x306B;&#x3088;&#x308B;&#x30DB;&#x30E2;&#x30ED;&#x30B0; Cdc28p &#x3092;&#x4E0D;&#x6D3B;&#x6027;&#x5316;&#x3057;&#x3001;SWE1 &#x306E; Cdc5p &#x4E0A;&#x6D41; Swe1p &#x306E;&#x6642;&#x70B9;&#x3067;&#x6A5F;&#x80FD;&#x3057;&#x3066;&#x3044;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3001;cdc5 3 hsl1Delta &#x6B20;&#x9665;&#x6291;&#x5236;&#x3002;&#x307E;&#x305F;&#x3001;cdc5 4 &#x3068; cdc5 7 &#x5909;&#x7570;&#x4F53;&#x9023;&#x9396;&#x7D30;&#x80DE;&#x306E;&#x5F62;&#x614B;&#x9593;&#x63A5;&#x7D9A;&#x3055;&#x308C;&#x305F;&#x7D30;&#x80DE;&#x4F53;&#x306F;&#x3001;&#x7D30;&#x80DE;&#x8CEA;&#x5206;&#x88C2;&#x306E;&#x6B20;&#x9665;&#x3092;&#x793A;&#x3059;&#x3001;&#x5171;&#x6709;&#x306E;&#x7D30;&#x80DE;&#x8CEA;&#x3092;&#x5C55;&#x793A;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x660E;&#x3089;&#x304B;&#x306B;&#x3053;&#x308C;&#x3089;&#x306E;&#x5909;&#x7570;&#x306E;&#x541F;&#x5473;&#x30BB;&#x30D7;&#x30C1;&#x30F3; &#x30A2;&#x30BB;&#x30F3;&#x30D6;&#x30EA;&#x521D;&#x671F;&#x82BD;&#x30B5;&#x30A4;&#x30C8;&#x3067;&#x9045;&#x5EF6;&#x3057;&#x3001;&#x30BB;&#x30D7;&#x30C1;&#x30F3; &#x30EA;&#x30F3;&#x30B0;&#x6BCD;&#x82BD;&#x9996;&#x3092;&#x3056;&#x3063;&#x304F;&#x308A;&#x6574;&#x7406;&#x3057;&#x307E;&#x3059;&#x3002;&#x6709;&#x7CF8;&#x5206;&#x88C2;&#x7D42;&#x4E86;&#x30CD;&#x30C3;&#x30C8;&#x30EF;&#x30FC;&#x30AF; &#xFF08;&#x7537;&#x6027;&#xFF09; &#x306E;&#x30B3;&#x30F3;&#x30DD;&#x30FC;&#x30CD;&#x30F3;&#x30C8;&#x6B63;&#x5E38;&#x7D30;&#x80DE;&#x8CEA;&#x5206;&#x88C2;&#x306B;&#x91CD;&#x8981;&#x306A;&#x5F79;&#x5272;&#x3092;&#x679C;&#x305F;&#x3057;&#x307E;&#x3059;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;&#x640D;&#x5931;&#x306E; BFA1 &#x307E;&#x305F;&#x306F; BUB2&#x3001;&#x8CA0;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30BF;&#x3001;&#x7537;&#x6027;&#x306E; Cdc5p Bfa1p &#x3068; Bub2p &#x3068;&#x306F;&#x7121;&#x95A2;&#x4FC2;&#x306E;&#x7D30;&#x80DE;&#x8CEA;&#x5206;&#x88C2;&#x3092;&#x4FC3;&#x9032;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3059;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x5909;&#x7570;&#x4F53;&#x306E;&#x7D30;&#x80DE;&#x8CEA;&#x5206;&#x88C2;&#x306E;&#x6B20;&#x9665;&#x3092;&#x89E3;&#x6C7A;&#x3059;&#x308B;&#x306B;&#x306F;&#x5931;&#x6557;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;Cdc5p &#x306F; Swe1p &#x306B;&#x4F9D;&#x5B58;&#x3059;&#x308B; Cdc28p/Clb &#x7D4C;&#x8DEF;&#x3001;&#x901A;&#x5E38;&#x30BB;&#x30D7;&#x30C1;&#x30F3;&#x95A2;&#x6570;&#x304A;&#x3088;&#x3073;&#x7D30;&#x80DE;&#x8CEA;&#x5206;&#x88C2;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x306B;&#x8CA2;&#x732E;&#x3057;&#x307E;&#x3059;&#x3002;

&#x51FA;&#x82BD;&#x9175;&#x6BCD;&#x306B;&#x304A;&#x3051;&#x308B; CDC5 &#x6A5F;&#x80FD;&#x306E;&#x55AA;&#x5931;&#x306F;&#x3001;Swe1p &#x898F;&#x5236;&#x304A;&#x3088;&#x3073; Bfa1p/Bub2p-&#x72EC;&#x7ACB;&#x306E;&#x7D30;&#x80DE;&#x8CEA;&#x5206;&#x88C2;&#x306E;&#x6B20;&#x9665;&#x306B; &#x3057;&#x307E;&#x3059;&#x3002;

&#xB9CE;&#xC740; &#xC0DD;&#xBB3C;&#xC5D0;&#xC11C; &#xD3F4;&#xB85C; kinases M &#xC0C1; &#xC9C4;&#xD589; &#xD558;&#xB294; &#xB3D9;&#xC548; &#xC5EC;&#xB7EC; &#xC5ED;&#xD560;&#xC744; &#xB098;&#xD0C0;&#xB0A9;&#xB2C8;&#xB2E4;. &#xC2E0;&#xC9C4;&#xC758; &#xAE30;&#xB2A5;&#xC5D0; &#xB300; &#xD55C; &#xC0C8;&#xB85C;&#xC6B4; &#xD1B5;&#xCC30;&#xB825;&#xC744; &#xC81C;&#xACF5; &#xD558;&#xAE30; &#xC704;&#xD574; &#xD6A8; &#xBAA8; &#xD3F4;&#xB85C; &#xB2C8; Cdc5p, C &#xD130;&#xBBF8;&#xB110; &#xB3C4;&#xBA54;&#xC778; mutagenizing &#xD558; &#xC5EC; &#xC18C;&#xC124; &#xC628;&#xB3C4; &#xBBFC;&#xAC10;&#xD55C; cdc5 &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xC0DD;&#xC131; &#xD588;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC5EC;&#xAE30; &#xC6B0;&#xB9AC;&#xAC00;, semipermissive &#xC628;&#xB3C4;&#xC5D0;&#xC11C; cdc5 3 &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; HSL1, &#xC815;&#xC0C1;&#xC801;&#xC778; G (2) /M &#xC804;&#xD658;&#xC5D0; &#xB300; &#xD55C; &#xC911;&#xC694; &#xD55C; &#xAD6C;&#xC131; &#xC694;&#xC18C; &#xC190;&#xC2E4; &#xC2DC;&#xB108;&#xC9C0; &#xBC84;&#xB4DC; &#xC2E0;&#xC7A5; &#xBC0F; &#xC131;&#xC7A5; &#xACB0;&#xD568; &#xC804;&#xC2DC; &#xBCF4;&#xC5EC;&#xC90D;&#xB2C8;&#xB2E4;. Phosphorylates&#xB294; &#xC2E0;&#xC9C4; &#xD6A8; &#xBAA8; Cdk1 &#xCCB4; cdc28p&#xC740; swe1&#xC758; &#xC190;&#xC2E4; Cdc5p swe1p&#xC758; &#xC0C1;&#xB958; &#xC9C0;&#xC810;&#xC5D0;&#xC11C; &#xC791;&#xB3D9; &#xD558;&#xB294; &#xAC83;&#xC744; &#xC81C;&#xC548; &#xD558;&#xB294; cdc5 3 hsl1Delta &#xACB0;&#xD568;&#xC744; &#xD45C;&#xC2DC; &#xB418;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4;. &#xB610;&#xD55C;, cdc5 4, cdc5-7 &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; cytokinetic &#xACB0;&#xD568;&#xC744; &#xB098;&#xD0C0;&#xB0B4;&#xB294; &#xC5F0;&#xACB0; &#xB41C; &#xC140; &#xBC14;&#xB514; &#xC0AC;&#xC774; &#xACF5;&#xC720; cytoplasms&#xC640; &#xC5F0;&#xACB0; &#xB41C; &#xC140; &#xBB38;&#xBC95;&#xACFC; &#xC804;&#xC2DC;. &#xBC1D;&#xD600; &#xC774;&#xB7EC;&#xD55C; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774;&#xC758; &#xC815;&#xBC00; &#xAC80;&#xC0AC;&#xC640; &#xCD08;&#xAE30; &#xC0C8;&#xC2F9; &#xC0AC;&#xC774;&#xD2B8;&#xC5D0;&#xC11C; septin &#xC5B4;&#xC148;&#xBE14;&#xB9AC; &#xC9C0;&#xC5F0; &#xB290;&#xC2A8;&#xD558;&#xAC8C; septin &#xBC18;&#xC9C0; &#xC5B4;&#xBA38;&#xB2C8; &#xBC84;&#xB4DC; &#xBAA9;&#xC5D0; &#xC870;&#xC9C1;. Mitotic &#xCD9C;&#xAD6C; &#xB124;&#xD2B8;&#xC6CC;&#xD06C; (&#xB0A8;&#xC790;)&#xC758; &#xAD6C;&#xC131; &#xC815;&#xC0C1;&#xC801;&#xC778; cytokinesis&#xC5D0;&#xC11C; &#xC911;&#xC694; &#xD55C; &#xC5ED;&#xD560;&#xC744; &#xD55C;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, BFA1 &#xB610;&#xB294; BUB2, &#xB124;&#xAC70;&#xD2F0;&#xBE0C; &#xB808; &#xADE4; &#xB808;&#xC774; &#xD130;, &#xC0AC;&#xB78C;&#xC758; &#xC190;&#xC2E4; Cdc5p cytokinesis Bfa1p &#xBC0F; Bub2p &#xB3C5;&#xB9BD;&#xC801;&#xC73C;&#xB85C; &#xCD09;&#xC9C4;&#xC744; &#xB098;&#xD0C0;&#xB0B4;&#xB294; &#xC774;&#xB7EC;&#xD55C; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774;&#xC758; cytokinetic &#xACB0;&#xD568;&#xC744; &#xD574;&#xACB0; &#xD558;&#xC9C0; &#xBABB;&#xD588;&#xC2B5;&#xB2C8;&#xB2E4;. &#xB530;&#xB77C;&#xC11C;, Cdc5p Swe1p &#xC885;&#xC18D; Cdc28p/Clb &#xD1B5;&#xB85C;, &#xC815;&#xC0C1;&#xC801;&#xC778; septin &#xD568;&#xC218; &#xBC0F; cytokinesis&#xC758; &#xD65C;&#xC131;&#xD654;&#xC5D0; &#xAE30;&#xC5EC; &#xD55C;&#xB2E4;.

Bfa1p/Bub2p-&#xB3C5;&#xB9BD; cytokinesis&#xC640; Swe1p &#xADDC;&#xC815;&#xC5D0; Saccharomyces cerevisiae&#xC5D0; CDC5 &#xAE30;&#xB2A5;&#xC758; &#xC190;&#xC2E4; &#xB9AC;&#xB4DC;.

En muchos organismos, quinasas polo parecen desempe&ntilde;ar m&uacute;ltiples funciones durante la progresi&oacute;n de la fase M. Para ofrecer nuevas perspectivas sobre la funci&oacute;n del florecimiento levadura quinasa polo Cdc5p, generamos mutantes novela cdc5 sensibles a la temperatura de mutagenizing el dominio c-terminal. Aqu&iacute; mostramos que, a una temperatura de semipermissive, el mutante cdc5-3 exhibi&oacute; un defecto de crecimiento y alargamiento de bud sin&eacute;rgica con p&eacute;rdida de HSL1, un componente importante para la transici&oacute;n de G (2) /M normal. P&eacute;rdida de SWE1, que fosforila y desactiva la levadura de florecimiento Cdk1 hom&oacute;logo Cdc28p, suprimi&oacute; el defecto cdc5-3 hsl1Delta, sugiriendo que la Cdc5p funciona en un punto aguas arriba del Swe1p. Adem&aacute;s, los mutantes cdc5-4 y 7-cdc5 exhiben morfolog&iacute;as celulares encadenados con citoplasmas compartidas entre los cuerpos celulares conectados, lo que indica un defecto cytokinetic. Examen minucioso de estos mutantes revelada hab&iacute;a retrasado Asamblea septin en el sitio de bot&oacute;n incipiente y libremente organizados septin anillos en el cuello de la madre-bud. Componentes de la red de salida mit&oacute;tica (hombres) desempe&ntilde;an papeles importantes en la citocinesis normal. Sin embargo, la p&eacute;rdida de BFA1 o BUB2, reguladores negativos de los hombres, no remediar el defecto cytokinetic de estos mutantes, indicando que Cdc5p promueve la citocinesis independientemente de Bfa1p y Bub2p. As&iacute;, Cdc5p contribuye a la activaci&oacute;n de la v&iacute;a Swe1p-dependiente Cdc28p/Clb, funci&oacute;n septin normal y citocinesis.

P&eacute;rdida de funci&oacute;n CDC5 en Saccharomyces cerevisiae conduce a defectos en la regulaci&oacute;n de Swe1p y citocinesis Bfa1p/Bub2p-independiente.

Temporal aspects of intracellular calcium signaling are particularly important in activity-dependent regulation of gene expression in neurons. This review traces calcium-dependent intracellular signaling from the membrane to the nucleus in response to action-potential firing, and considers how specific genes are regulated by specific patterns of impulse firing. Modes of calcium influx, calcium-dependent protein kinases, transcription factors, individual genes, and genomic analysis are examined, with particular emphasis on the importance of temporal aspects of calcium dynamics in regulating these processes.

Temporal integration of intracellular Ca2+ signaling networks in regulating gene expression by action potentials.

Changes in gene expression associated with different forms of synaptic plasticity in rat hippocampus were investigated. Microarray analysis revealed differential expression of hundreds of genes 30 min after synaptic or antidromic stimulation in different patterns. Results of selected genes were verified by LightCycler RT-PCR. Synaptic activation in a theta burst protocol, which induced long-term potentiation (LTP), increased the mRNA abundance of BDNF-exon 1, but antidromic stimulation in the presence of CNQX, APV, and MCPG (to block glutamatergic synapses) decreased the level of mRNA of this transcript, as did 1 Hz synaptic stimulation. The opposite regulation of this BDNF transcript after firing of the postsynaptic neuron, coincidently or uncorrelated with synaptic firing, is consistent with the effects of BDNF on synaptic transmission, suggesting possible involvement in strengthening and weakening CA1 synapses after correlated versus uncorrelated firing of the postsynaptic neurons with its synaptic inputs. Possible involvement of transcriptional regulation of BDNF in the conversion of early-phase LTP to late-phase LTP are discussed in the context of previous studies by Dudek & Fields (Proc. Natl. Acad. Sci. USA 99: 3962-3967) showing that this conversion can be induced by antidromic stimulation of CA1 neurons in the absence of excitatory synaptic activity.

Gene expression in the conversion of early-phase to late-phase long-term potentiation.

Mechanisms by which tumor cells evade detection by the host's immune system are thought to play a role in progression to malignancy, but this has not been investigated in the context of neurofibromatosis type 1 (NF1). NF1 is an autosomal dominant disorder, in which aggressive peripheral nerve tumors, known as malignant peripheral nerve sheath tumors (MPNSTs), develop in 5-10% of patients. Large scale gene expression profiling of a MPNST-derived cell line, T265, and normal human Schwann cells (hSCs) identified a large group of immune function genes down-regulated in T265 cells. Here we report that the aberrant expression of immune system related genes extends beyond MHC class I and II genes in T265 cells to include a transcription factor (MHC2TA) and other critical components of the antigen processing and presentation apparatus. TAP1, the transporter-activator protein that loads peptide antigens onto MHC class I molecules, is down-regulated, and CD74, a chaperone protein whose function is in processing and transport of MHC class II molecules, is down-regulated and alternatively spliced to produce an RNA transcript not evident in normal human Schwann cells. These findings reveal multiple molecular pathways and at least two cellular mechanisms acting to reduce the normal immune system molecules involved in antigen processing and presentation in cells derived from a peripheral nerve sheath tumor. Acquiring a "silent" immune signature may be a critical step in the progress towards malignancy in MPNSTs.

Immune system evasion by peripheral nerve sheath tumor.

cDNA microarrays were utilized to identify abnormally expressed genes in a malignant peripheral nerve sheath tumor (MPNST)-derived cell line, T265, by comparing the mRNA abundance profiles with that of normal human Schwann cells (nhSCs). The findings characterize the molecular phenotype of this important cell-line model of MPNSTs, and elucidate the contribution of Schwann cells in MPNSTs. In total, 4608 cDNA sequences were screened and hybridizations replicated on custom cDNA microarrays. In order to verify the microarray data, a large selection of differentially expressed mRNA transcripts were subjected to semi-quantitative reverse transcription PCR (LightCycler). Western blotting was performed to investigate a selection of genes and signal transduction pathways, as a further validation of the microarray data. The data generated from multiple microarray screens, semi-quantitative RT-PCR and Western blotting are in broad agreement. This study represents a comprehensive gene-expression analysis of an MPNST-derived cell line and the first comprehensive global mRNA profile of nhSCs in culture. This study has identified ~900 genes that are expressed abnormally in the T265 cell line and detected many genes not previously reported to be expressed in nhSCs. The results provide crucial information on the T265 cells that is essential for investigation using this cell line in experimental studies in neurofibromatosis type I (NF1), and important information on normal human Schwann cells that is applicable to a wide range of studies on Schwann cells in cell culture.

Transcriptional profiling in an MPNST-derived cell line and normal human Schwann cells.

Myelination is a highly dynamic process that continues well into adulthood in humans. Several recent gene expression studies have found abnormal expression of genes involved in myelination in the prefrontal cortex of brains from patients with schizophrenia and other psychiatric illnesses. Defects in myelination could contribute to the pathophysiology of psychiatric illness by impairing information processing as a consequence of altered impulse conduction velocity and synchrony between cortical regions carrying out higher level cognitive functions. Myelination can be altered by impulse activity in axons and by environmental experience. Psychiatric illness is treated by psychotherapy, behavioral modification, and drugs affecting neurotransmission, raising the possibility that myelinating glia may not only contribute to such disorders, but that activity-dependent effects on myelinating glia could provide one of the cellular mechanisms contributing to the therapeutic effects of these treatments. This review examines evidence showing that genes and gene networks important for myelination can be regulated by functional activity in axons.

Regulation of myelin genes implicated in psychiatric disorders by functional activity in axons.

Leukemia inhibitory factor (LIF) promotes the survival of oligodendrocytes both in vitro and in an animal model of multiple sclerosis, but the possible role of LIF signaling in myelination during normal development has not been investigated. We find that LIF(-/-) mice have a pronounced myelination defect in optic nerve at postnatal day 10. Myelin basic protein (MBP)- and proteolipid protein (PLP)-positive myelin was evident throughout the optic nerve in the wild-type mice, but staining was present only at the chiasmal region in LIF(-/-) mice of the same age. Further experiments suggest that the myelination defect was a consequence of a delay in maturation of oligodendrocyte precursor cell (OPC) population. The number of Olig2-positive cells was dramatically decreased in optic nerve of LIF(-/-) mice, and the distribution of Olig2-positive cells was restricted to the chiasmal region of the nerve in a steep gradient toward the retina. Gene expression profiling and cell culture experiments revealed that OPCs from P10 optic nerve of LIF(-/-) mice remained in a highly proliferative immature stage compared with littermate controls. Interestingly, by postnatal day 14, MBP immunostaining in the LIF(-/-) optic nerve was comparable to that of LIF(+/+) mice. These results suggest that, during normal development of mouse optic nerve, there is a defined developmental time window when LIF is required for correct myelination. Myelination seems to recover by postnatal day 14, so LIF is not necessary for the completion of myelination during postnatal development.

Leukemia inhibitory factor regulates the timing of oligodendrocyte development and myelination in the postnatal optic nerve.

The developing and mature central nervous system contains neural precursor cells expressing the proteoglycan NG2. Some of these cells continuously differentiate to myelin-forming oligodendrocytes; knowledge of the destiny of NG2(+) precursors would benefit from the characterization of new key functional players. In this respect, the G protein-coupled membrane receptor GPR17 has recently emerged as a new timer of oligodendrogliogenesis. Here, we used purified oligodendrocyte precursor cells (OPCs) to fully define the immunophenotype of the GPR17-expressing cells during OPC differentiation, unveil its native signaling pathway, and assess the functional consequences of GPR17 activation by its putative endogenous ligands, uracil nucleotides and cysteinyl leukotrienes (cysLTs). GPR17 presence was restricted to very early differentiation stages and completely segregated from that of mature myelin. Specifically, GPR17 decorated two subsets of slowly proliferating NG2(+) OPCs: (i) morphologically immature cells expressing other early proteins like Olig2 and PDGF receptor-α, and (ii) ramified preoligodendrocytes already expressing more mature factors, like O4 and O1. Thus, GPR17 is a new marker of these transition stages. In OPCs, GPR17 activation by either uracil nucleotides or cysLTs resulted in potent inhibition of intracellular cAMP formation. This effect was counteracted by GPR17 antagonists and receptor silencing with siRNAs. Finally, uracil nucleotides promoted and GPR17 inhibition, by either antagonists or siRNAs, impaired the normal program of OPC differentiation. These data have implications for the in vivo behavior of NG2(+) OPCs and point to uracil nucleotides and cysLTs as main extrinsic local regulators of these cells under physiological conditions and during myelin repair.

Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during oligodendrocyte differentiation.

Homeostatic mechanisms are required to control formation and maintenance of synaptic connections to maintain the general level of neural impulse activity within normal limits. How genes controlling these processes are co-coordinately regulated during homeostatic synaptic plasticity is unknown. MicroRNAs (miRNAs) exert regulatory control over mRNA stability and translation and may contribute to local and activity-dependent posttranscriptional control of synapse-associated mRNAs. However, identifying miRNAs that function through posttranscriptional gene silencing at synapses has remained elusive. Using a bioinformatics screen to identify sequence motifs enriched in the 3'UTR of rapidly destabilized mRNAs, we identified a developmentally and activity-regulated miRNA (miR-485) that controls dendritic spine number and synapse formation in an activity-dependent homeostatic manner. We find that many plasticity-associated genes contain predicted miR-485 binding sites and further identify the presynaptic protein SV2A as a target of miR-485. miR-485 negatively regulated dendritic spine density, postsynaptic density 95 (PSD-95) clustering, and surface expression of GluR2. Furthermore, miR-485 overexpression reduced spontaneous synaptic responses and transmitter release, as measured by miniature excitatory postsynaptic current (EPSC) analysis and FM 1-43 staining. SV2A knockdown mimicked the effects of miR-485, and these effects were reversed by SV2A overexpression. Moreover, 5 d of increased synaptic activity induced homeostatic changes in synaptic specializations that were blocked by a miR-485 inhibitor. Our findings reveal a role for this previously uncharacterized miRNA and the presynaptic protein SV2A in homeostatic plasticity and nervous system development, with possible implications in neurological disorders (e.g., Huntington and Alzheimer's disease), where miR-485 has been found to be dysregulated.

MicroRNA regulation of homeostatic synaptic plasticity.

The family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients.

Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.

The myelin sheath on vertebrate axons is critical for neural impulse transmission, but whether electrically active axons are preferentially myelinated by glial cells, and if so, whether axo-glial synapses are involved, are long-standing questions of significance to nervous system development, plasticity and disease. Here we show using an in vitro system that oligodendrocytes preferentially myelinate electrically active axons, but synapses from axons onto myelin-forming oligodendroglial cells are not required. Instead, vesicular release at nonsynaptic axo-glial junctions induces myelination. Axons releasing neurotransmitter from vesicles that accumulate in axon varicosities induces a local rise in cytoplasmic calcium in glial cell processes at these nonsynaptic functional junctions, and this signalling stimulates local translation of myelin basic protein to initiate myelination. 

Nonsynaptic junctions on myelinating glia promote preferential myelination of electrically active axons.

Spinal and bulbar muscular atrophy (SBMA) is a currently untreatable adult-onset neuromuscular disease caused by expansion of a polyglutamine repeat in the androgen receptor (AR). In SBMA, as in other polyglutamine diseases, a toxic gain of function in the mutant protein is an important factor in the disease mechanism; therefore, reducing the mutant protein holds promise as an effective treatment strategy. In this work, we evaluated a microRNA (miRNA) to reduce AR expression. From a list of predicted miRNAs that target human AR, we selected microRNA-298 (miR-298) for its ability to downregulate AR mRNA and protein levels when transfected in cells overexpressing wild-type and mutant AR and in SBMA patient-derived fibroblasts. We showed that miR-298 directly binds to the 3'-untranslated region of the human AR transcript, and counteracts AR toxicity in vitro. Intravenous delivery of miR-298 with adeno-associated virus serotype 9 vector resulted in efficient transduction of muscle and spinal cord and amelioration of the disease phenotype in SBMA mice. Our findings support the development of miRNAs as a therapeutic strategy for SBMA and other neurodegenerative disorders caused by toxic proteins.

MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy.

In a recent study of the pathophysiology of mild, blast-induced traumatic brain injury (bTBI) the exposure of dissociated, central nervous system (CNS) cells to simulated blast resulted in propagating waves of elevated intracellular Ca(2+). Here we show, in dissociated human CNS cultures, that these calcium waves primarily propagate through astrocyte-dependent, purinergic signaling pathways that are blocked by P2 antagonists. Human, compared to rat, astrocytes had an increased calcium response and prolonged calcium wave propagation kinetics, suggesting that in our model system rat CNS cells are less responsive to simulated blast. Furthermore, in response to simulated blast, human CNS cells have increased expressions of a reactive astrocyte marker, glial fibrillary acidic protein (GFAP) and a protease, matrix metallopeptidase 9 (MMP-9). The conjoint increased expression of GFAP and MMP-9 and a purinergic ATP (P2) receptor antagonist reduction in calcium response identifies both potential mechanisms for sustained changes in brain function following primary bTBI and therapeutic strategies targeting abnormal astrocyte activity.

Blast shockwaves propagate Ca(2+) activity via purinergic astrocyte networks in human central nervous system cells.

Action-potential-induced LTD (AP-LTD) is a form of synaptic plasticity that reduces synaptic strength in CA1 hippocampal neurons firing antidromically during sharp-wave ripples. This firing occurs during slow-wave sleep and quiet moments of wakefulness, which are periods of offline replay of neural sequences learned during encoding sensory information. Here we report that rapid and persistent down-regulation of different mRNA transcripts of the BDNF gene accompanies AP-LTD, and that AP-LTD is abolished in mice with the BDNF gene knocked out in CA1 hippocampal neurons. These findings increase understanding of the mechanism of AP-LTD and the cellular mechanisms of memory consolidation.

BDNF mRNA abundance regulated by antidromic action potentials and AP-LTD in hippocampus.

Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by severe, often fatal muscle weakness due to loss of motor neurons. SMA patients have deletions and other mutations of the  () gene, resulting in decreased SMN protein. Astrocytes are the primary support cells of the CNS and are responsible for glutamate clearance, metabolic support, response to injury, and regulation of signal transmission. Astrocytes have been implicated in SMA as in in other neurodegenerative disorders. Astrocyte-specific rescue of SMN protein levels has been shown to mitigate disease manifestations in mice. However, the mechanism by which SMN deficiency in astrocytes may contribute to SMA is unclear and what aspect of astrocyte activity is lacking is unknown. Therefore, it is worthwhile to identify defects in SMN-deficient astrocytes that compromise normal function. We show here that SMA astrocyte cultures derived from mouse spinal cord of both sexes are deficient in supporting both WT and SMN-deficient motor neurons derived from male, female, and mixed-sex sources and that this deficiency may be mitigated with secreted factors. In particular, SMN-deficient astrocytes have decreased levels of monocyte chemoactive protein 1 (MCP1) secretion compared with controls and MCP1 restoration stimulates outgrowth of neurites from cultured motor neurons. Correction of MCP1 deficiency may thus be a new therapeutic approach to SMA. Spinal muscular atrophy (SMA) is caused by the loss of motor neurons, but astrocyte dysfunction also contributes to the disease in mouse models. Monocyte chemoactive protein 1 (MCP1) has been shown to be neuroprotective and is released by astrocytes. Here, we report that MCP1 levels are decreased in SMA mice and that replacement of deficient MCP1 increases differentiation and neurite length of WT and SMN-deficient motor-neuron-like cells in cell culture. This study reveals a novel aspect of astrocyte dysfunction in SMA and indicates a possible approach for improving motor neuron growth and survival in this disease.

Article	Year
Loss of CDC5 function in Saccharomyces cerevisiae leads to defects in Swe1p regulation and Bfa1p/Bub2p-independent cytokinesis. Genetics\| PubMed ID: 12586693	2003
Temporal integration of intracellular Ca2+ signaling networks in regulating gene expression by action potentials. Cell calcium\| PubMed ID: 15820391	2005
Gene expression in the conversion of early-phase to late-phase long-term potentiation. Annals of the New York Academy of Sciences\| PubMed ID: 16154938	2005
Immune system evasion by peripheral nerve sheath tumor. Neuroscience letters\| PubMed ID: 16406348	2006
Transcriptional profiling in an MPNST-derived cell line and normal human Schwann cells. Neuron glia biology\| PubMed ID: 16429615	2004
Regulation of myelin genes implicated in psychiatric disorders by functional activity in axons. Frontiers in neuroanatomy\| PubMed ID: 19521541	2009
Leukemia inhibitory factor regulates the timing of oligodendrocyte development and myelination in the postnatal optic nerve. Journal of neuroscience research\| PubMed ID: 19598242	2009
Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during oligodendrocyte differentiation. The Journal of biological chemistry\| PubMed ID: 21209081	2011
MicroRNA regulation of homeostatic synaptic plasticity. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 21697510	2011
Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia. JAMA neurology\| PubMed ID: 25751282	2015
Nonsynaptic junctions on myelinating glia promote preferential myelination of electrically active axons. Nature communications\| PubMed ID: 26238238	2015
MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy. Molecular therapy : the journal of the American Society of Gene Therapy\| PubMed ID: 26755334	2016
Blast shockwaves propagate Ca(2+) activity via purinergic astrocyte networks in human central nervous system cells. Scientific reports\| PubMed ID: 27162174	2016
BDNF mRNA abundance regulated by antidromic action potentials and AP-LTD in hippocampus. Neuroscience letters\| PubMed ID: 27760383	2016
Decreased Motor Neuron Support by SMA Astrocytes due to Diminished MCP1 Secretion. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 28450545	2017

Philip R. Lee

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