Single-Molecule Imaging of EWS-FLI1 Condensates Assembling on DNA

The fusion genes resulting from chromosomal translocation have been found in many solid tumors or leukemia. EWS-FLI1, which belongs to the FUS/EWS/TAF15 ...

Peking University

In order to investigate the relation of lipoprotein lipase (LPL) gene polymorphism at Pvu II locus and dietary intervention predisposition in hyperlipidemia population, 436 hyperlipidemia patients were screened selected from some communities in western urban districts in Beijing, and then separated into two groups, intervention (248) and control group(188). The serum lipids profile, dietary intakes data were collected and physical examination was conducted in all subjects. Also, the LPL-Pvu II polymorphisms were analyzed by PCR-RFLP. The results showed that the total energy intake, cholesterol level and percentage of energy from dietary fat, and the serum levels of TC, LDL-C and HDL-C were significantly decreased (P < 0.05) after 6-month dietary intervention in intervention group compared with the control group. The decrease range of TC and LDL-C in carriers with LPL-Pvu II (+/+) genotype was much more than others(+/- and -/- genotypes). The results from multiple linear regression analysis showed that the susceptible factors of dietary intervention included LPL-Pvu II (+) allele, the high baseline levels of TC and LDL-C and overweight. The conclusions could be primarily drawn that the variants of LPL-Pvu II locus were important determinants of variation in serum cholesterol response to dietary change in hyperlipidemia population.

[Relations of lipoprotein lipase gene polymorphism at Pvu II locus and dietary intervention predisposition in hyperlipidemia population].

T20 &#xFF08;&#x901A;&#x7528;&#x540D;&#x79F0;&#x3001; enfuvirtide &#xFF1B; &#x65B0;&#x578B;&#x54C1;&#x724C;&#x540D;&#x79F0;&#xFF09; &#x662F;&#x6838;&#x51C6;&#x5F53;&#x524D;&#x6297;&#x9006;&#x8F6C;&#x5F55;&#x75C5;&#x6BD2;&#x836F;&#x7269;&#x96BE;&#x6CBB;&#x6027;&#x611F;&#x67D3;&#x827E;&#x6ECB;&#x75C5;&#x6BD2;&#x7684;&#x60A3;&#x8005;&#x62A2;&#x6551;&#x6CBB;&#x7597;&#x7684;&#x7B2C;&#x4E00;&#x4EE3;&#x4EBA;&#x4F53;&#x514D;&#x75AB;&#x7F3A;&#x9677;&#x75C5;&#x6BD2; (HIV) &#x878D;&#x5408;&#x6291;&#x5236;&#x5242;&#x3002;&#x7136;&#x800C;&#xFF0C;&#x7531;&#x4E8E;&#x5FEB;&#x901F;&#x5D1B;&#x8D77;&#x7684; T20 &#x6CBB;&#x7597;&#x60A3;&#x8005;&#x7684; T20 &#x6297;&#x75C5;&#x6BD2;&#x53CA;&#x5176;&#x4E34;&#x5E8A;&#x5E94;&#x7528;&#x53D7;&#x5230;&#x9650;&#x5236;&#x3002;&#x56E0;&#x6B64;&#xFF0C;T1249 &#x548C; T1144 &#x6B63;&#x5728;&#x4E3A;&#x7B2C;&#x4E8C;&#x548C;&#x7B2C;&#x4E09;&#x4EE3; HIV &#x878D;&#x5408;&#x6291;&#x5236;&#x5242;&#xFF0C;&#x5206;&#x522B;&#x4E0E;&#x6539;&#x8FDB;&#x7597;&#x6548;&#x548C;&#x836F;&#x7269;&#x62B5;&#x6297;&#x7684;&#x914D;&#x7F6E;&#x6587;&#x4EF6;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x53D1;&#x73B0; T20 T1249 &#x548C;/&#x6216; T1144 &#x7EC4;&#x5408;&#x5BFC;&#x81F4;&#x5F02;&#x5E38;&#x5F3A;&#x5927;&#x7684;&#x589E;&#x6548;&#x4F5C;&#x7528; &#xFF08;&#x7EC4;&#x5408;&#x7D22;&#x5F15; &lt; 0.01) &#x9488;&#x5BF9;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x4ECB;&#x5BFC;&#x819C;&#x878D;&#x5408;&#x7684;&#x5242;&#x91CF;&#x51CF;&#x5C11; 2 &#x5230; 3 &#x6570;&#x91CF;&#x7EA7;&#x3002;&#x9AD8;&#x5EA6;&#x70C8;&#x6027;&#x534F;&#x540C;&#x6297;&#x75C5;&#x6BD2;&#x7597;&#x6548;&#x4E5F;&#x5B9E;&#x73B0;&#x4E86;&#x5BF9;&#x611F;&#x67D3;&#x5B9E;&#x9A8C;&#x5BA4;&#x6539;&#x7F16;&#x548C;&#x4E3B;&#x8981;&#x5305;&#x62EC; T20 &#x8010;&#x53D8;&#x79CD;&#x7684;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x682A;&#x3002;&#x57FA;&#x7840;&#x7684;&#x534F;&#x540C;&#x6548;&#x5E94;&#x7684;&#x673A;&#x5236;&#x53EF;&#x5F52;&#x4E8E; T20&#x3001; T1249 &#x548C; T1144 &#x6240;&#x6709;&#x5305;&#x542B;&#x4E0D;&#x540C;&#x529F;&#x80FD;&#x57DF;&#x548C;&#x6709;&#x4E0D;&#x540C;&#x4E3B;&#x7ED1;&#x5B9A;&#x7AD9;&#x70B9;&#x4E2D; gp41 &#x7684;&#x4E8B;&#x5B9E;&#x3002;&#x4E3A;&#x6B64;&#xFF0C;&#x4ED6;&#x4EEC;&#x53EF;&#x80FD;&#x5408;&#x4F5C;&#x5DE5;&#x4F5C;&#x6765;&#x6291;&#x5236; gp41 &#x516D;&#x87BA;&#x65CB;&#x675F;&#x6838;&#x5FC3;&#x7684;&#x5F62;&#x6210;&#xFF0C;&#x4ECE;&#x800C;&#x6291;&#x5236;&#x75C5;&#x6BD2;&#x7EC6;&#x80DE;&#x878D;&#x5408;&#x3002;&#x56E0;&#x6B64;&#xFF0C;&#x8FD9;&#x4E9B;&#x7814;&#x7A76;&#x7ED3;&#x679C;&#x5F3A;&#x70C8;&#x6697;&#x793A;&#xFF0C;&#x800C;&#x4E0D;&#x662F;&#x53D6;&#x4EE3; T20&#xFF0C;&#x5B83;&#x7ED3;&#x5408;&#x4E0D;&#x540C;&#x4E16;&#x4EE3;&#x7684; HIV &#x878D;&#x5408;&#x6291;&#x5236;&#x5242;&#x53EF;&#x80FD;&#x4F1A;&#x4EA7;&#x751F;&#x5BF9; T20 &#x654F;&#x611F;&#x548C;&#x4E24;&#x79CD;&#x6297;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x682A;&#xFF0C;&#x63D0;&#x51FA;&#x65B0;&#x7684;&#x6CBB;&#x7597;&#x7B56;&#x7565;-1 &#x827E;&#x6ECB;&#x75C5;&#x6BD2;&#x611F;&#x67D3;/&#x827E;&#x6ECB;&#x75C5;&#x6CBB;&#x7597;&#x7684;&#x534F;&#x540C;&#x6D3B;&#x52A8;&#x3002;

&#x4EBA;&#x4F53;&#x514D;&#x75AB;&#x7F3A;&#x9677;&#x75C5;&#x6BD2; (HIV) &#x878D;&#x5408;&#x6291;&#x5236;&#x5242;&#x7684;&#x7B2C;&#x4E00;&#x6B21;&#x548C;&#x4E0B;&#x4E00;&#x4EE3;&#x7684;&#x7EC4;&#x5408;&#x8868;&#x73B0;&#x51FA;&#x9AD8;&#x5EA6;&#x70C8;&#x6027;&#x7684;&#x534F;&#x540C;&#x6548;&#x5E94;&#xFF0C;&#x5BF9; enfuvirtide &#x654F;&#x611F;&#x548C;&#x6297;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x578B;&#x682A;&#x3002;

T20 (generic name, enfuvirtide; brand name, Fuzeon) is a first-generation human immunodeficiency virus (HIV) fusion inhibitor approved for salvage therapy of HIV-infected patients refractory to current antiretroviral drugs. However, its clinical use is limited because of rapid emergence of T20-resistant viruses in T20-treated patients. Therefore, T1249 and T1144 are being developed as the second- and third-generation HIV fusion inhibitors, respectively, with improved efficacy and drug resistance profiles. Here, we found that combinations of T20 with T1249 and/or T1144 resulted in exceptionally potent synergism (combination index, <0.01) against HIV-1-mediated membrane fusion by 2 to 3 orders of magnitude in dose reduction. Highly potent synergistic antiviral efficacy was also achieved against infection by laboratory-adapted and primary HIV-1 strains, including T20-resistant variants. The mechanism underlying the synergistic effect could be attributed to the fact that T20, T1249, and T1144 all contain different functional domains and have different primary binding sites in gp41. As such, they may work cooperatively to inhibit gp41 six-helix bundle core formation, thereby suppressing virus-cell fusion. Therefore, these findings strongly imply that, rather than replacing T20, combining it with HIV fusion inhibitors of different generations might produce synergistic activity against both T20-sensitive and -resistant HIV-1 strains, suggesting a new therapeutic strategy for the treatment of HIV-1 infection/AIDS.

Combinations of the first and next generations of human immunodeficiency virus (HIV) fusion inhibitors exhibit a highly potent synergistic effect against enfuvirtide- sensitive and -resistant HIV type 1 strains.

T20 (nom g&#xE9;n&#xE9;rique, l&#x26;#39;enfuvirtide; marque, Fuzeon) est une premi&#xE8;re g&#xE9;n&#xE9;ration du virus de l&#x26;#39;immunod&#xE9;ficience humaine (VIH) inhibiteur de fusion approuv&#xE9; pour le traitement de sauvetage infect&#xE9;s par le VIH chez les patients r&#xE9;fractaires &#xE0; la antir&#xE9;troviraux actuels. Cependant, son utilisation clinique est limit&#xE9;e en raison de l&#x26;#39;&#xE9;mergence rapide de virus r&#xE9;sistants T20 T20 dans les patients trait&#xE9;s. Par cons&#xE9;quent, T1249 T1144 et sont en cours d&#x26;#39;&#xE9;laboration que les inhibiteurs de deuxi&#xE8;me et de troisi&#xE8;me g&#xE9;n&#xE9;ration fusion du VIH, respectivement, avec une efficacit&#xE9; am&#xE9;lior&#xE9;e et les profils de r&#xE9;sistance aux m&#xE9;dicaments. Ici, nous avons constat&#xE9; que des combinaisons de T20 avec T1249 et / ou T1144 abouti &#xE0; une synergie exceptionnelle puissant (indice de combinaison, &#x26;lt;0,01) contre la fusion des membranes du VIH-1 m&#xE9;di&#xE9;e par 2 &#xE0; 3 ordres de grandeur en r&#xE9;duction de la dose. Tr&#xE8;s puissante efficacit&#xE9; synergique antiviral a &#xE9;galement &#xE9;t&#xE9; r&#xE9;alis&#xE9;e contre une infection par laboratoire adapt&#xE9; et primaires du VIH-1, y compris les souches r&#xE9;sistantes T20-variantes. Le m&#xE9;canisme sous-jacent &#xE0; l&#x26;#39;effet synergique peut &#xEA;tre attribu&#xE9; au fait que T20, T1249, T1144 et contiennent tous des diff&#xE9;rents domaines fonctionnels et ont diff&#xE9;rents sites de liaison primaire de la gp41. Comme tels, ils peuvent travailler en collaboration pour inhiber la gp41 six h&#xE9;lice de formation du noyau faisceau, supprimant ainsi fusion virus-cellule. Par cons&#xE9;quent, ces r&#xE9;sultats indiquent clairement que, plut&#xF4;t que de remplacer T20, en le combinant avec des inhibiteurs de fusion du VIH de diff&#xE9;rentes g&#xE9;n&#xE9;rations peuvent produire une activit&#xE9; synergique &#xE0; la fois contre T20-sensible et r&#xE9;sistant souches VIH-1, sugg&#xE9;rant une nouvelle strat&#xE9;gie th&#xE9;rapeutique pour le traitement du VIH- 1 infection / SIDA.

Combinaisons des premi&#xE8;res g&#xE9;n&#xE9;rations et Suivant de virus de l&#x26;#39;immunod&#xE9;ficience humaine (VIH) inhibiteurs de fusion pr&#xE9;sentent un effet tr&#xE8;s puissant synergique contre le VIH de type enfuvirtide-sensible et r&#xE9;sistant &#xE0; 1 souches

T20 (generischer Name, Enfuvirtid, Markennamen, Fuzeon) ist ein taktisches Human Immunodeficiency Virus (HIV)-Fusionshemmer zur Bergung Therapie von HIV-infizierten Patienten auf aktuelle antiretrovirale Medikamente zugelassen. Seine klinischen Einsatz ist jedoch wegen der raschen Entstehung T20-resistenter Viren bei T20-behandelten Patienten begrenzt. Daher sind T1249 und T1144 als die zweiten und dritten Generation HIV-Fusion-Inhibitoren bzw. mit verbesserter Wirksamkeit und Droge-Widerstand-Profilen entwickelt. Hier, wir fanden, dass Kombinationen von T20 mit T1249 und/oder T1144 au&szlig;ergew&ouml;hnlich starke Synergismus gef&uuml;hrt (Kombination Index, &lt; 0,01) gegen HIV-1-vermittelter Membrane Fusion von 2 bis 3 Gr&ouml;&szlig;enordnungen in Dosisreduktion. Hochwirksames synergistische antivirale Wirksamkeit wurde auch gegen eine Infektion durch Labor-angepasst und prim&auml;re HIV-1-St&auml;mme, einschlie&szlig;lich T20-resistente Varianten erreicht. Der Mechanismus zugrunde liegen der synergistischen Wirkung k&ouml;nnte darauf zur&uuml;ckzuf&uuml;hren, dass T20, T1249 und T1144 alle verschiedene funktionelle Dom&auml;nen enthalten und verschiedene prim&auml;re Bindungsstellen in gp41 haben. Als solche k&ouml;nnen sie kooperativ arbeiten hemmen gp41 sechs-Helix-B&uuml;ndel Kern Bildung, Virus-Zellfusion dadurch zu unterdr&uuml;cken. Daher diese Ergebnisse stark implizieren, dass, anstatt ersetzen T20, Kombination mit HIV-Fusion-Inhibitoren verschiedener Generationen synergistische T&auml;tigkeit gegen sowohl T20-empfindlichen und -resistente HIV-1-St&auml;mme, schl&auml;gt eine neue therapeutische Strategie zur Behandlung von HIV-1 Infektion/AIDS produzieren k&ouml;nnte.

Kombinationen der ersten und n&auml;chsten Generationen von Human Immunodeficiency Virus (HIV)-Fusion-Inhibitoren zeigen eine hochwirksame synergistische Wirkung gegen Enfuvirtid-empfindlichen und -resistente St&auml;mme von HIV-Typ 1.

T20 (generico nome, enfuvirtide; marca, Fuzeon) &egrave; un inibitore di fusione di prima generazione virus dell&#39;immunodeficienza umana (HIV) approvato per la terapia di salvataggio dei pazienti sieropositivi refrattari ai farmaci antiretrovirali corrente. Tuttavia, l&#39;utilizzo clinico &egrave; limitato a causa della rapida comparsa di virus T20-resistente in pazienti trattati con T20. Pertanto, T1249 e T1144 sono stati sviluppati come gli inibitori di fusione HIV seconda e terza generazione, rispettivamente, con profili di resistenza migliorati efficacia e droga. Qui, abbiamo trovato che combinazioni di T20 con T1249 o T1144 ha portato a sinergismo eccezionalmente potente (indice di combinazione, &lt; 0,01) contro la fusione della membrana di HIV-1-mediata da 2 a 3 ordini di grandezza nella riduzione del dosaggio. Altamente potente efficacia antivirale sinergica &egrave; stato raggiunto anche contro l&#39;infezione da ceppi di HIV-1 laboratorio-adattato e primari, incluse varianti T20-resistente. Il meccanismo alla base dell&#39;effetto sinergico potrebbe essere attribuito al fatto che T20, T1249 e T1144 contengono tutti diversi domini funzionali e hanno siti di legame primario diverso in gp41. Come tali, possono lavorare in modo cooperativo per inibire la formazione di nucleo sei-helix bundle gp41, sopprimendo quindi la fusione cellulare virus. Pertanto, questi risultati fortemente implicano che, piuttosto che sostituendo T20, combinandolo con gli inibitori di fusione HIV di diverse generazioni potrebbe produrre attivit&agrave; sinergica contro i ceppi di HIV-1 sia T20-sensibili e - resistenti, suggerendo una nuova strategia terapeutica per il trattamento dell&#39;infezione da HIV-1/AIDS.

Combinazioni delle generazioni prime e successiva di inibitori di fusione del virus dell&#39;immunodeficienza umana (HIV) mostrano un effetto sinergico altamente potente contro i ceppi sensibili enfuvirtide e - resistenti HIV tipo 1.

T20&#xFF08;&#x4E00;&#x822C;&#x540D;&#x3001;&#x30A8;&#x30F3;&#x30D5;&#x30E5;&#x30FC;&#x30D3;&#x30EB;&#x30BF;&#x30A4;&#x30C9;&#x3001;&#x30D6;&#x30E9;&#x30F3;&#x30C9;&#x540D;&#x3001;Fuzeon&#xFF09;&#x306F;&#x3001;&#x73FE;&#x5728;&#x306E;&#x6297;&#x30EC;&#x30C8;&#x30ED;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x85AC;&#x306B;&#x4E0D;&#x5FDC;&#x6027;&#x306E;HIV&#x611F;&#x67D3;&#x60A3;&#x8005;&#x306E;&#x30B5;&#x30EB;&#x30D9;&#x30FC;&#x30B8;&#x7642;&#x6CD5;&#x306E;&#x305F;&#x3081;&#x306B;&#x627F;&#x8A8D;&#x3055;&#x308C;&#x305F;&#x6700;&#x521D;&#x306E;&#x4E16;&#x4EE3;&#x306E;&#x30D2;&#x30C8;&#x514D;&#x75AB;&#x4E0D;&#x5168;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#xFF08;HIV&#xFF09;&#x306E;&#x878D;&#x5408;&#x963B;&#x5BB3;&#x5264;&#x3067;&#x3042;&#x308B;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;&#x305D;&#x306E;&#x81E8;&#x5E8A;&#x4F7F;&#x7528;&#x304C;&#x3042;&#x308B;&#x305F;&#x3081;T20&#x6295;&#x4E0E;&#x60A3;&#x8005;&#x306B;&#x304A;&#x3051;&#x308B;T20&#x8010;&#x6027;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x306E;&#x6025;&#x901F;&#x306A;&#x51FA;&#x73FE;&#x306E;&#x5236;&#x9650;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;T1249&#x3068;T1144&#x306F;&#x3001;&#x6539;&#x826F;&#x306E;&#x6709;&#x52B9;&#x6027;&#x3068;&#x85AC;&#x5264;&#x8010;&#x6027;&#x30D7;&#x30ED;&#x30D5;&#x30A1;&#x30A4;&#x30EB;&#x3067;&#x3001;&#x305D;&#x308C;&#x305E;&#x308C;&#x3001;&#x7B2C;&#x4E8C;&#x3068;&#x7B2C;&#x4E09;&#x4E16;&#x4EE3;&#x306E;HIV&#x878D;&#x5408;&#x963B;&#x5BB3;&#x5264;&#x3068;&#x3057;&#x3066;&#x958B;&#x767A;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;T1249&#x3001;&#x304A;&#x3088;&#x3073;/&#x307E;&#x305F;&#x306F;T1144&#x3068;T20&#x306E;&#x7D44;&#x307F;&#x5408;&#x308F;&#x305B;&#x306F;&#x6E1B;&#x91CF;&#x306E;&#x5927;&#x304D;&#x3055;&#x306E;2&#x301C;3&#x6841;&#x306B;&#x3088;&#x308B;HIV-1&#x5A92;&#x4ECB;&#x819C;&#x878D;&#x5408;&#x306B;&#x5BFE;&#x3057;&#x3066;&#x975E;&#x5E38;&#x306B;&#x5F37;&#x529B;&#x306A;&#x76F8;&#x4E57;&#x52B9;&#x679C;&#xFF08;&#x7D44;&#x307F;&#x5408;&#x308F;&#x305B;&#x306E;&#x30A4;&#x30F3;&#x30C7;&#x30C3;&#x30AF;&#x30B9;&#x3001;&#x26;lt;0.01&#xFF09;&#x3092;&#x3082;&#x305F;&#x3089;&#x3057;&#x305F;&#x3053;&#x3068;&#x304C;&#x308F;&#x304B;&#x3063;&#x305F;&#x3002;&#x975E;&#x5E38;&#x306B;&#x5F37;&#x529B;&#x306A;&#x76F8;&#x4E57;&#x7684;&#x306A;&#x6297;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x52B9;&#x679C;&#x306F;&#x3001;&#x5B9F;&#x9A13;&#x5BA4;&#x9069;&#x5FDC;&#x3057;&#x3001;T20&#x8010;&#x6027;&#x5909;&#x7570;&#x4F53;&#x3092;&#x542B;&#x3080;&#x4E3B;&#x8981;&#x306A;HIV-1&#x682A;&#x306B;&#x3088;&#x308B;&#x611F;&#x67D3;&#x306B;&#x5BFE;&#x3057;&#x3066;&#x9054;&#x6210;&#x3055;&#x308C;&#x305F;&#x3002;&#x76F8;&#x4E57;&#x52B9;&#x679C;&#x306E;&#x6839;&#x5E95;&#x306B;&#x3042;&#x308B;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x306F;T20&#x3001;T1249&#x3001;T1144&#x3068;&#x306F;&#x3001;&#x3059;&#x3079;&#x3066;&#x306E;gp41&#x306E;&#x5185;&#x306E;&#x5225;&#x306E;&#x4E3B;&#x8981;&#x306A;&#x7D50;&#x5408;&#x90E8;&#x4F4D;&#x3092;&#x5225;&#x306E;&#x6A5F;&#x80FD;&#x30C9;&#x30E1;&#x30A4;&#x30F3;&#x304C;&#x542B;&#x307E;&#x308C;&#x3066;&#x304A;&#x308A;&#x3001;&#x6301;&#x3063;&#x3066;&#x3044;&#x308B;&#x3068;&#x3044;&#x3046;&#x4E8B;&#x5B9F;&#x306B;&#x8D77;&#x56E0;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x308B;&#x3002;&#x3053;&#x306E;&#x3088;&#x3046;&#x306B;&#x3001;&#x5F7C;&#x3089;&#x306F;gp41&#x306E;6&#x30D8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x30D0;&#x30F3;&#x30C9;&#x30EB;&#x30B3;&#x30A2;&#x5F62;&#x6210;&#x3092;&#x6291;&#x5236;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x308B;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x306E;&#x7D30;&#x80DE;&#x878D;&#x5408;&#x3092;&#x963B;&#x5BB3;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x5354;&#x8ABF;&#x3057;&#x3066;&#x52D5;&#x4F5C;&#x3059;&#x308B;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x77E5;&#x898B;&#x306F;&#x3001;&#x5F37;&#x304F;&#x7570;&#x306A;&#x308B;&#x4E16;&#x4EE3;&#x306E;HIV&#x878D;&#x5408;&#x963B;&#x5BB3;&#x5264;&#x3068;&#x305D;&#x308C;&#x3092;&#x7D44;&#x307F;&#x5408;&#x308F;&#x305B;&#x308B;&#x3053;&#x3068;&#x306B;&#x3088;&#x308A;&#x3001;HIV-&#x306E;&#x6CBB;&#x7642;&#x306E;&#x305F;&#x3081;&#x306E;&#x65B0;&#x3057;&#x3044;&#x6CBB;&#x7642;&#x6226;&#x7565;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3001;&#x4E21;&#x65B9;&#x306E;T20&#x3068;&#x5C0F;&#x6587;&#x5B57;&#x3092;&#x533A;&#x5225;&#x3057;&#x3001;&#x8010;&#x6027;HIV-1&#x682A;&#x306B;&#x5BFE;&#x3057;&#x3066;&#x76F8;&#x4E57;&#x4F5C;&#x7528;&#x3092;&#x751F;&#x307F;&#x51FA;&#x3059;&#x304B;&#x3082;&#x3057;&#x308C;&#x306A;&#x3044;&#x304C;&#x3001;&#x3080;&#x3057;&#x308D;T20&#x3092;&#x7F6E;&#x304D;&#x63DB;&#x3048;&#x308B;&#x3088;&#x308A;&#x3082;&#x3001;&#x3068;&#x3044;&#x3046;&#x3053;&#x3068;&#x3092;&#x610F;&#x5473;1&#x611F;&#x67D3;&#x75C7;/ AIDS&#x3002;

&#x30D2;&#x30C8;&#x514D;&#x75AB;&#x4E0D;&#x5168;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#xFF08;HIV&#xFF09;&#x878D;&#x5408;&#x963B;&#x5BB3;&#x5264;&#x306E;&#x6700;&#x521D;&#x3068;&#x6B21;&#x306E;&#x4E16;&#x4EE3;&#x306E;&#x7D44;&#x307F;&#x5408;&#x308F;&#x305B;&#x306F;&#x3001;&#x30A8;&#x30F3;&#x30D5;&#x30E5;&#x30FC;&#x30D3;&#x30EB;&#x30BF;&#x30A4;&#x30C9;&#x3068;&#x5C0F;&#x6587;&#x5B57;&#x3092;&#x533A;&#x5225;&#x3057;&#x3001;&#x8010;&#x6027;HIV&#x30BF;&#x30A4;&#x30D7;1&#x682A;&#x306B;&#x5BFE;&#x3057;&#x3066;&#x975E;&#x5E38;&#x306B;&#x5F37;&#x529B;&#x306A;&#x76F8;&#x4E57;&#x52B9;&#x679C;&#x3092;&#x767A;&#x63EE;&#x3059;&#x308B;

T20 (&#xC77C;&#xBC18; enfuvirtide, &#xC774;&#xB984;, &#xBE0C;&#xB79C;&#xB4DC; &#xC774;&#xB984;, Fuzeon)&#xB294; HIV &#xAC10;&#xC5FC; &#xD658;&#xC790;&#xC758; &#xD604;&#xC7AC; &#xD56D; &#xB808;&#xD2B8;&#xB85C; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xC57D;&#xD488;&#xC744; &#xB0B4; &#xD654; &#xAD6C;&#xC870; &#xCE58;&#xB8CC;&#xC5D0; &#xB300; &#xD55C; &#xC2B9;&#xC778; 1 &#xC138;&#xB300; &#xC778;&#xAC04; &#xBA74;&#xC5ED; &#xACB0;&#xD54D; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; (HIV) &#xC735;&#xD569; &#xC5B5;&#xC81C;&#xC81C;. &#xADF8;&#xB7EC;&#xB098;, &#xC784;&#xC0C1; &#xC6A9;&#xB3C4; T20 &#xCE58;&#xB8CC; &#xD658;&#xC790; T20 &#xB0B4;&#xC131; &#xBC14;&#xC774;&#xB7EC;&#xC2A4;&#xC758; &#xAE09;&#xC18D; &#xD55C; &#xCD9C;&#xD604; &#xB54C;&#xBB38;&#xC5D0; &#xC81C;&#xD55C; &#xB429;&#xB2C8;&#xB2E4;. &#xB530;&#xB77C;&#xC11C;, T1249 &#xBC0F; T1144 &#xAC1C;&#xBC1C; &#xB418; &#xACE0; &#xC788;&#xB2E4; &#xB450;&#xBC88;&#xC9F8; &#xADF8;&#xB9AC;&#xACE0; &#xC81C; 3 &#xC138;&#xB300; &#xC5D0;&#xC774;&#xC988; &#xC735;&#xD569; &#xC5B5;&#xC81C;&#xC81C;&#xB85C; &#xAC01;&#xAC01; &#xD5A5;&#xC0C1; &#xB41C; &#xD6A8;&#xB2A5; &#xBC0F; &#xC57D;&#xBB3C; &#xC800;&#xD56D; &#xD504;&#xB85C; &#xD30C;&#xC77C;. &#xC5EC;&#xAE30;, &#xC6B0;&#xB9AC;&#xAC00; &#xB9E4;&#xC6B0; &#xAC15;&#xB825;&#xD55C; &#xC131;&#xBD84; &#xADC0;&#xCC29;&#xB418; T20 t1249&#xC640; t1144&#xC758; &#xC870;&#xD569;&#xC744; &#xBC1C;&#xACAC; (&#xC870;&#xD569; &#xC778;&#xB371;&#xC2A4; &lt; 0.01) 2 ~ 3 &#xBCF5;&#xC6A9;&#xB7C9; &#xAC10;&#xC18C;&#xC5D0; &#xBE44;&#xAD50; &#xD558; &#xC5EC; HIV 1 &#xC911;&#xC7AC; &#xB9C9; &#xD4E8;&#xC804;&#xC5D0; &#xB300; &#xD55C;. &#xB9E4;&#xC6B0; &#xAC15;&#xB825;&#xD55C; &#xC2DC;&#xB108;&#xC9C0; &#xD56D; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xD6A8;&#xB2A5; &#xB610;&#xD55C; T20 &#xB0B4;&#xC131; &#xBCC0;&#xC885;&#xC744; &#xD3EC;&#xD568; &#xD558; &#xC5EC; &#xC2E4;&#xD5D8;&#xC2E4;&#xC5D0; &#xC801;&#xC751; &#xD558; &#xACE0; &#xAE30;&#xBCF8; HIV 1 &#xC885;&#xC790;&#xB85C; &#xAC10;&#xC5FC;&#xC5D0; &#xB300; &#xD55C; &#xB2EC;&#xC131; &#xD588;&#xB2E4;. &#xC2DC;&#xB108;&#xC9C0; &#xD6A8;&#xACFC; &#xAE30;&#xBCF8; &#xBA54;&#xCEE4;&#xB2C8;&#xC998; T20, T1249, &#xBC0F; T1144 &#xBAA8;&#xB450; &#xD3EC;&#xD568; &#xD558;&#xB294; &#xB2E4;&#xB978; &#xAE30;&#xB2A5; &#xB3C4;&#xBA54;&#xC778; &#xBC0F; &#xB2E4;&#xB978; &#xAE30;&#xBCF8; &#xBC14;&#xC778;&#xB529; &#xC0AC;&#xC774;&#xD2B8; gp41&#xC5D0; &#xC0AC;&#xC2E4;&#xC5D0; &#xAE30; &#xC778;&#xD560; &#xC218; &#xC788;&#xC5C8;&#xB2E4;. &#xC774;&#xC640; &#xAC19;&#xC774; &#xADF8;&#xB4E4;&#xC740; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xC138;&#xD3EC; &#xC735;&#xD569;&#xC744; &#xC5B5;&#xC81C; &#xD568;&#xC73C;&#xB85C;&#xC368; gp41 6 &#xB098;&#xC120; &#xBC88;&#xB4E4; &#xCF54;&#xC5B4; &#xD615;&#xC131;&#xC744; &#xC5B5;&#xC81C; &#xD558;&#xAE30; &#xC704;&#xD574; &#xD611;&#xB825; &#xC791;&#xC5C5; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xB530;&#xB77C;&#xC11C;, &#xC774;&#xB7EC;&#xD55C; &#xACB0;&#xACFC; &#xAC15;&#xB825; &#xD558; &#xAC8C;, &#xC758;&#xBBF8; &#xBCF4;&#xB2E4;&#xB294; &#xC5D0;&#xC774;&#xC988;-1 &#xAC10;&#xC5FC;/&#xC5D0;&#xC774;&#xC988; &#xCE58;&#xB8CC;&#xC5D0; &#xB300; &#xD55C; &#xC0C8;&#xB85C;&#xC6B4; &#xCE58;&#xB8CC; &#xC804;&#xB7B5;&#xC744; &#xC81C;&#xC548; &#xBAA8;&#xB450; T20 &#xBBFC;&#xAC10;&#xD558;&#xACE0;-&#xB0B4;&#xC131; HIV 1 &#xBCC0;&#xC885;&#xC5D0; &#xB300; &#xD55C; &#xC2DC;&#xB108;&#xC9C0; &#xD65C;&#xB3D9; &#xC0DD;&#xC131; &#xB420; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xB2E4;&#xB978; &#xC138;&#xB300;&#xC758; &#xC5D0;&#xC774;&#xC988; &#xC735;&#xD569; &#xC800; &#xD574;&#xC81C; &#xACB0;&#xD569; T20 &#xAD50;&#xCCB4;.

&#xC778;&#xAC04; &#xBA74;&#xC5ED; &#xACB0;&#xD54D; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; (HIV) &#xC735;&#xD569; &#xC5B5;&#xC81C;&#xC81C;&#xC758; &#xCCAB; &#xBC88;&#xC9F8; &#xBC0F; &#xB2E4;&#xC74C; &#xC138;&#xB300;&#xC758; &#xC870;&#xD569; enfuvirtide &#xAD6C;&#xBD84; &#xBC0F;-&#xB0B4;&#xC131; HIV 1 &#xD615; &#xBCC0;&#xC885;&#xC5D0; &#xB300; &#xD55C; &#xB9E4;&#xC6B0; &#xAC15;&#xB825;&#xD55C; &#xC2DC;&#xB108;&#xC9C0; &#xD6A8;&#xACFC; &#xC804;&#xC2DC; &#xD569;&#xB2C8;&#xB2E4;.

T20 (nombre gen&#xE9;rico, la enfuvirtida, nombre de la marca, Fuzeon) es una primera generaci&#xF3;n de virus de la inmunodeficiencia humana (VIH) inhibidor de la fusi&#xF3;n aprobado para el tratamiento de rescate de los pacientes infectados por VIH resistentes a los f&#xE1;rmacos antirretrovirales actuales. Sin embargo, su uso cl&#xED;nico es limitada debido a la r&#xE1;pida aparici&#xF3;n de T20-T20 virus resistentes en los pacientes tratados. Por lo tanto, T1249 y T1144 est&#xE1;n siendo desarrollados como los inhibidores de la fusi&#xF3;n de segunda y tercera generaci&#xF3;n-VIH, respectivamente, con una eficacia mejorada y perfiles de resistencia a los medicamentos. Aqu&#xED;, hemos encontrado que las combinaciones de T20 con T1249 y / o T1144 result&#xF3; en sinergismo excepcionalmente potente (&#xED;ndice de combinaci&#xF3;n, &#x26;lt;0,01) en contra de la fusi&#xF3;n de membranas del VIH-1-mediada por 2 a 3 &#xF3;rdenes de magnitud en la reducci&#xF3;n de la dosis. Muy potente eficacia antiviral sin&#xE9;rgico tambi&#xE9;n se logr&#xF3; contra la infecci&#xF3;n por el laboratorio adaptado y primaria del VIH-1, incluyendo cepas resistentes a T20 variantes. El mecanismo que subyace el efecto sin&#xE9;rgico puede atribuirse al hecho de que T20, T1249, T1144 y todos contienen diferentes dominios funcionales y tienen diferentes sitios primarios de uni&#xF3;n en la gp41. Como tales, pueden trabajar en cooperaci&#xF3;n para inhibir la gp41 seis-h&#xE9;lice formaci&#xF3;n del n&#xFA;cleo paquete, suprimiendo as&#xED; el virus de la fusi&#xF3;n de c&#xE9;lulas. Por lo tanto, estos resultados implican que, en lugar de sustituir T20, la combinaci&#xF3;n con inhibidores de la fusi&#xF3;n del VIH de diferentes generaciones pueden producir actividad sin&#xE9;rgica contra ambos T20-sensible y resistente a las cepas de VIH-1, lo que sugiere una nueva estrategia terap&#xE9;utica para el tratamiento del VIH- una infecci&#xF3;n / SIDA.

Las combinaciones de las primeras generaciones y Siguiente del Virus de Inmunodeficiencia Humana (VIH), inhibidores de la fusi&#xF3;n exhibir un efecto sin&#xE9;rgico muy potente contra el VIH enfuvirtida tipo sensible y resistente-1 cepas

This study aims to determine the up-to-date prevalence of overweight and obesity, the distributions of body weight perception and weight loss practice in Beijing adults.

Prevalence of overweight and obesity and weight loss practice among Beijing adults, 2011.

Broadly neutralizing antibodies (NAbs) against the CD4 binding site of HIV gp120 (CD4bs) have provided important information for vaccine design. In this study, we combined deep sequencing and single memory B cell sorting to isolate CD4bs-directed NAbs from a Chinese HIV-1-infected elite neutralizer. We first performed 454 pyrosequencing to capture the IGHV1, IGKV, and IGLV germline gene families. IGHV1-2*02, the heavy chain germline V gene (VH) of the CD4bs-directed bNAb VRC01, was found to have a relatively low somatic mutation rate. When an identity/divergence plot was used to interrogate the 454 sequencing data, no VRC01-like sequences were found within the dataset. We next used a pair of CD4bs-specific probes (RSC3/ΔRSC3) to sort the B cells from this Chinese donor and identified a CD4bs-directed Ab that showed limited neutralization capability. Interestingly, the VH gene of this weak NAb belongs to the IGHV5-51 lineage, with a somatic mutation rate of 7.99 %. Our study thus demonstrates that CD4bs-directed NAbs can be produced by rearrangement from other VH genes, such as IGHV5-51 in this donor, rather than IGHV1-2*02. The 454 sequencing data and NAb obtained from this study will provide useful insights into the CD4bs-directed B-cell response during HIV-1 infection as well as the diversity of neutralizing antibodies. 

Study of antibody repertoires to the CD4 binding site of gp120 of a Chinese HIV-1-infected elite neutralizer, using 454 sequencing and single-cell sorting.

Homologous recombination is an important DNA repair pathway that plays key roles in maintaining genome stability. Escherichia coli RecA is an ATP-dependent DNA-binding protein that catalyzes the DNA strand exchange reactions in homologous recombination. RecA assembles into long helical filaments on single-stranded DNA, and these presynaptic complexes are responsible for locating and pairing with a homologous duplex DNA. Recent single molecule studies have provided new insights into RecA behavior, but the potential influence of ATP in the reactions remains poorly understood. Here we examine how ATP influences the ability of the RecA presynaptic complex to interact with homologous dsDNA. We demonstrate that over short time regimes, RecA presynaptic complexes sample heterologous dsDNA similarly in the presence of either ATP or ATPγS, suggesting that initial interactions do not depend on ATP hydrolysis. In addition, RecA stabilizes pairing intermediates in three-base steps, and stepping energetics is seemingly unaltered in the presence of ATP. However, the overall dissociation rate of these paired intermediates with ATP is ∼4-fold higher than with ATPγS. These experiments suggest that ATP plays an unanticipated role in promoting the turnover of captured duplex DNA intermediates as RecA attempts to align homologous sequences during the early stages of recombination.

ATP hydrolysis Promotes Duplex DNA Release by the RecA Presynaptic Complex.

Targeting the PI3K pathway is a promising strategy for treating prostate cancers with PTEN-loss. However, current anti-PI3K therapies fail to show long lasting  effects. We find that not only the PI3Kα- and PI3kβ-isoforms, but also PI3Kδ, are associated with the epithelial-mesenchymal transition (EMT), a critical process distinguishing indolent from aggressive prostate cancer. This suggests that cotargeting PI3Kα/β/δ could preempt the rebound activation of the parallel pathways induced by α- or β-isoform-selective inhibitor and prevent EMT. Indeed, BAY1082439, a new selective PI3Kα/β/δ inhibitor, is highly effective  in inhibiting null prostate cancer growth and preventing EMT in the mutant  metastatic model. The anti-PI3Kδ property of BAY1082439 further blocks B-cell infiltration and lymphotoxin release, which are tumor microenvironment factors that promote castration-resistant growth. Together, our data suggest a new approach for the treatment of prostate cancer by targeting both tumor cells and tumor microenvironment with PI3Kα/β/δ inhibitor. .

Cotargeting the Cell-Intrinsic and Microenvironment Pathways of Prostate Cancer by PI3Kα/β/δ Inhibitor BAY1082439.

Generation of single-stranded DNA (ssDNA) is required for the template strand formation during DNA replication. Replication Protein A (RPA) is an ssDNA-binding protein essential for protecting ssDNA at replication forks in eukaryotic cells. While significant progress has been made in characterizing the role of the RPA-ssDNA complex, how RPA is loaded at replication forks remains poorly explored. Here, we show that the  protein regulator of Ty1 transposition 105 (Rtt105) binds RPA and helps load it at replication forks. Cells lacking Rtt105 exhibit a dramatic reduction in RPA loading at replication forks, compromised DNA synthesis under replication stress, and increased genome instability. Mechanistically, we show that Rtt105 mediates the RPA-importin interaction and also promotes RPA binding to ssDNA directly , but is not present in the final RPA-ssDNA complex. Single-molecule studies reveal that Rtt105 affects the binding mode of RPA to ssDNA These results support a model in which Rtt105 functions as an RPA chaperone that escorts RPA to the nucleus and facilitates its loading onto ssDNA at replication forks.

Rtt105 functions as a chaperone for replication protein A to preserve genome stability.

Phase separation of proteins/nucleic acids to form non-membrane organelles is crucial in cellular gene-expression regulation. However, little is known about transcriptional regulator phase separation and the underlying molecular mechanism. Vernalization 1 (VRN1) encodes a crucial transcriptional repressor involved in plant vernalization that contains two B3 DNA-binding domains connected by an intrinsic disorder region (IDR) and nonspecifically binds DNA. We found that the Arabidopsis VRN1 protein undergoes liquid-liquid phase separation (LLPS) with DNA that is driven by multivalent protein-DNA interactions (LLPS), and that both B3 domains are required. The distribution of charged residues in the VRN1 IDR modulates the interaction strength between VRN1 and DNA, and changes in the charge pattern lead to interconversion between different states (precipitates, liquid droplets, and no phase separation). We further showed that VRN1 forms puncta in plant cell nuclei, suggesting that it may stabilize the vernalized state by repressing gene expression through LLPS.

Mechanism of DNA-Induced Phase Separation for Transcriptional Repressor VRN1.

The vast majority of eukaryotes possess two DNA recombinases: Rad51, which is ubiquitously expressed, and Dmc1, which is meiosis-specific. The evolutionary origins of this two-recombinase system remain poorly understood. Interestingly, Dmc1 can stabilize mismatch-containing base triplets, whereas Rad51 cannot. Here, we demonstrate that this difference can be attributed to three amino acids conserved only within the Dmc1 lineage of the Rad51/RecA family. Chimeric Rad51 mutants harboring Dmc1-specific amino acids gain the ability to stabilize heteroduplex DNA joints with mismatch-containing base triplets, whereas Dmc1 mutants with Rad51-specific amino acids lose this ability. Remarkably, RAD-51 from , an organism without Dmc1, has acquired "Dmc1-like" amino acids. Chimeric  RAD-51 harboring "canonical" Rad51 amino acids gives rise to toxic recombination intermediates, which must be actively dismantled to permit normal meiotic progression. We propose that Dmc1 lineage-specific amino acids involved in the stabilization of heteroduplex DNA joints with mismatch-containing base triplets may contribute to normal meiotic recombination.

Defining the influence of Rad51 and Dmc1 lineage-specific amino acids on genetic recombination.

Abnormally formed FUS/EWS/TAF15 (FET) fusion oncoproteins are essential oncogenic drivers in many human cancers. Interestingly, at the molecular level, they also form biomolecular condensates at specific loci. However, how these condensates lead to gene transcription and how features encoded in the DNA element regulate condensate formation remain unclear. Here, we develop an in vitro single-molecule assay to visualize phase separation on DNA. Using this technique, we observe that FET fusion proteins undergo phase separation at target binding loci and the phase separated condensates recruit RNA polymerase II and enhance gene transcription. Furthermore, we determine a threshold number of fusion-binding DNA elements that can enhance the formation of FET fusion protein condensates. These findings suggest that FET fusion oncoprotein promotes aberrant gene transcription through loci-specific phase separation, which may contribute to their oncogenic transformation ability in relevant cancers, such as sarcomas and leukemia.

Zhi Qi

Center for Quantitative Biology,
Peking-Tsinghua Center for Life Sciences,
Academy for Advanced Interdisciplinary Studies,
Center for Quantitative Biology, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies

Peking University

Single-Molecule Imaging of EWS-FLI1 Condensates Assembling on DNA