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¿´µ½²»ÉÙSCIÐÂÊÖÔÚÂÛÎÄд×÷·½Ãæ´æÔÚһЩÀ§ÄÑ£¬¶øÇÒÔÚÂÛÎÄÈóÉ«ÇóÖú¹ý³ÌÖУ¬ºÜÄÑÕÒµ½ºÏÊʵÄÈóÉ«·þÎñ¡£ ÎÒÃǵıà¼ÀÏʦÄܹ»ÎªSCIÐÂÊÖÀåÇåSCIд×÷ÖеÄһЩÎÊÌ⣻Èç¹ûÄúÊÇÐÂÊÖ£¬Èç¹ûÄúÓÐʱ¼ä£¬°´ÕÕÏÂÃæ½éÉܵķ½·¨×ÐϸÃþË÷£¬Ò²ÄÜÓÐËùÌá¸ß¡£ ÓÉÓÚ±à¼ÀÏʦÃÇÆ½Ê±¶¼±È½Ï棬ËùÒÔÖ»Äܳé¿ÕÂýµãд£¬¸Ðл´ó¼ÒµÄÖ§³Ö£¡ ÔĶÁTop Papers£¬¾ÍºÃ±È¿´¸ßÊÖ¶Ô¾ö£¬×Ðϸ´§Ä¦¡¢Áì»á¡¢²ÙÁ·£¬ÓÃÐÄÁìÂÔ¸ßÊֵļ¼ÇÉ£¬ÄãÒ²»áÂýÂý³É³¤³É¸ßÊÖ¡£ ±¾ÎÄÕë¶ÔSCIÐÂÊÖ£¬¸ßÊÖÇëÇáÅÄ£¡ Èκμ¼ÄܵÄѧϰ£¬¶¼µÃ¾¹ýÄ£·Â¡¢²ÙÁ·¡¢Êµ¼ù¡¢×ܽá¾ÑéÌå»á¡¢¸Ä½øºóÔÙʵ¼ùµÄ¹ý³Ì¡£SCIÂÛÎÄд×÷¼¼ÄÜÒ²ÊÇÈç´Ë£¡ Òª½øÐÐÄ£·ÂºÍ²ÙÁ·£¬¾Í±ØÐëҪĿµÄÃ÷È·¡£Ê×ÏÈÕÒ±¾ÁìÓò×î¸ß¼¶±ðµÄÆÚ¿¯£¬ÕÒ3-5ƪÎÄÏ××ÐϸÔĶÁ¡£ÔĶÁÒª´øÓÐÄ¿µÄÐÔ£¬¸æËß×Ô¼º£¬ÕâЩ¶«Î÷ÊÇÎÒдÎÄÕÂÒªÓõġ£ÏÈ °ÑÎÄÕÂŪ¶®£¬È»ºó×Ô¼º¼ÇÏ¿ÉÄÜÓõõ½µÄ¾äʽ¡¢Óï̬¡¢´Ê»ã¡¢¾ä×Ó¼äÁ¬´ÊµÄÓ÷¨¡£ÀýÈ磺ÔÚÕªÒªÖÐÈçºÎ×ܽṤ×÷£¬IntroductionÖÐÈçºÎ½éÉÜÏà¹Ø¹¤×÷£¬ ÈçºÎдÊÔÑé²Ù×÷²½Ö裬ÈçºÎ·ÖÎöͼ±í£¬ÈçºÎ×öͳ¼Æ·ÖÎö£¬ÈçºÎд½áÂÛ²¿·Ö¡£µ±´ø×ÅÄ£·ÂÄ¿µÄÈ¥¶ÁÎÄÏ×ʱ£¬²Å»áѧµ½Ò»µã¶«Î÷¡£ ѧµ½ÉÏÊö»ù±¾µÄ¶«Î÷Ö®ºó£¬¾Í¿ÉÒÔ¿ªÊ¼²ÙÁ·ÁË¡£SCIÎÄÕ±Ͼ¹²»ÊÇÎÄѧ×÷Æ·£¬¶ÔÓÚÓïÑÔºÍд×÷¼¼ÇɵÄÒªÇó²¢²»ÊÇÌØ±ð¸ß£¬Ñо¿¹¤×÷´´Ðµã²ÅÊÇ×î¸ù±¾µÄ¶«Î÷¡£ ֻǿµ÷Ò»µã£¬Òª´ø×ÅÄ¿µÄÈ¥¶Á¸ßµµ´ÎµÄÎÄÕ£¬ÏëÏëÈç¹ûÑо¿¹¤×÷ÊÇÎÒ×öµÄ£¬ÎÒ»áÕâôıƪ²¼¾Ö£¬ÕÒ²î¾à£¬²Å»áÓнø²½£¡ ·Ï»°ÉÙ˵£¬½ñÌ쿪ʼµÚһƪ¡£ ¸ßÊÖÇáÅÄ£¡ ÔĶÁ²ÄÁÏÑ¡Ôñ̳×ÓÄÚµÄÎÄÏס£ ¸ÐлmicroinsectÌṩ cell20120817 ¼û£ºhttps://muchong.com/bbs/viewthread.php?tid=4852008 ÏȶÁµÚ9Ò³µÄSmall-Molecule Inhibition of BRDT for Male Contraception ¿ÉÒÔºöÂÔһЩÊõÓï¡£ 1¡¢ÏÈ¿´ÌâÄ¿£º Small-Molecule Inhibition of BRDT for Male Contraception ÂÛÎÄÌâĿҪÇóÓÐ2¸ö£º¼ò½à¡¢°üÀ¨È«²¿ÖØÒªÐÅÏ¢¡£ ÌâÄ¿ÖÐ×¥ÈËÑÛÇòµÄ¾ÍÊÇÄÐÐÔ±ÜÔУ¬¶øÇÒ»¹ÊÇС·Ö×Ó£¬ÕâÑù¾Í±È½ÏÎüÒýÈË£¬ÁíÍâÌå»áһϴ˴¦½é´ÊµÄÓ÷¨¡£ 2¡¢ÔÙ¿´summary SUMMARY A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood:testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception. ÕªÒª²¿·ÖÒ»°ã½éÉÜÑо¿Ä¿±ê¡¢¹¤×÷ÄÚÈÝ¡¢Ñо¿½á¹û¼°Ñо¿ÒâÒå¡£ A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Õâ2¾ä»°¾Í½éÉÜÁËÑо¿Ä¿±êºÍ¾ßÌåµÄ¹¤×÷ÄÚÈÝ¡£ **×¢ÒâµÚÒ»¾äÖÐremains a longstanding challenge inµÄ˵·¨£¬ÔÚijÁìÓò³¤ÆÚÒÔÀ´´æÔÚµÄÌôÕ½£¬ÕâЩ¶¼ÊÇ×Ô¼º¿ÉÄÜÓõÃÉϵÄÓ÷¨¡£ µÚ2¾äÖÐexploreµÄÓ÷¨Ò²ÖµµÃ½è¼ø¡£ ºóÃæ¼¸¾ä½éÉÜÑо¿½á¹û¡£ Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. here,ÓÐʱÎÒÃÇÒ²ÓÃin the paper¡£ Õâ¾äÊdz£¼ûµÄÓ÷¨¡£ ÐèÒªÖ¸³öµÄÊÇ¡£ÉÏÃæµÄ2¾ä»°¶¼ÓÐwe×÷Ö÷ÓÕâ˵Ã÷ÏÖ´úÂÛÎÄд×÷ÒѾ³¹µ×ÅׯúÁË´óÁ¿±»¶¯Óï̬µÄ·ç¸ñ¡£ ÔÚÔçÆÚÂÛÎÄд×÷ÖУ¬ÎªÁËÌåÏÖÂÛÎĵĿ͹ÛÐÔ£¬±ÜÃâ×÷ÕßµÄÖ÷¹ÛÐÔ£¬ÂÛÎÄд×÷Öж¼´óÁ¿²ÉÓñ»¶¯Óï̬µÄд·¨¡£70Äê´úÖ®ºó£¬ÕâÖÖд·¨¾ÍÒѾ±»Åׯú£¬»Ø¹éÒÔÈËΪ±¾¡£Ñо¿¹¤×÷µÄÖØµãÊÇÑо¿Ë¼Â·£¬ÎªÊ²Ã´Òª²ÉÓÃÕâÖÖ·½·¨£¬ÎªÊ²Ã´Òª½øÐв¿·ÖµÄ·½·¨ÐÞÕý¡£ÕâЩ¶¼ÐèÒªÖ÷¶¯Óï̬¡£ ËùÒÔ´ó¼Òд×÷Öл¹ÊÇÒª´óµ¨µØÊ¹ÓÃÖ÷¶¯Óï̬£¡£¡ Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Õâ¾äµÄд·¨ÓеãÒâ˼£¬Èç¹ûÊÇÎÒд£¬ÎÒÒ»°ã¾Í»áдJQ1Õ¼¾ÝÁ˽áºÏλµã and ×èÖ¹ÁËʶ±ð×÷Óã¬ËäȻҲû´í£¬µ«ÊÇ»¹ÕæÃ»ÓÐÔ¾ä׼ȷ¡£ ½«ÖÐÎÄת»»³ÉÓ¢ÎĵĹý³ÌÖУ¬¶ÔÖ÷ÓïµÄÑ¡Ôñ·Ç³£ÌåÏÖˮƽ¡£ Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Õâ¾ä¿´ËÆÆ½µÎÞÆæ£¬Èç¹ûÊÇÎÒÀ´Ð´£¬Îҿ϶¨Ð´³ÉÁËÔÚÓÃJQ1´¦ÀíÖ®ºó£¬´óÊóÓÕµ¼ÁË¡¤¡¤¡¤¡¤£» ¿ÉÄܺóÃæµÄwithoutÓ÷¨Ò»°ãÈËÒ²²»»áÓᣠÆäʵwithoutÔÚÂÛÎÄд×÷Öо³£Óöµ½£¬±È·½ÎÒÃÇ˵ijÖÖÎïÖÊÔÚ²úÉúijÖÖÕýÃæ×÷ÓõÄʱºò£¬Ò²²»»á²úÉú¸ºÃæ×÷Ó㻳õ¼¶Ð´×÷ÕßÍùÍùÓÃwhile doing;ÆäʵÕâÀïÓÃwithoutÕýºÃ£¡ ×îºó¿´¿´×îºóÒ»¾äËêÑо¿ÒâÒåµÄ²ûÊö·½·¨ These data establish a new contraceptive that can cross the blood:testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception. These data establish a new contraceptive that ÕâÖÖÓ÷¨´ó¼Ò¶¼ÓõÃ×Å£¬ÒÔ¼°ºóÃæµÄprovidingµÄÓ÷¨¡£ ÉÏÃæÊÇд¸øSCIÐÂÊÖ¿´µÄ£¬Èç¹ûÄúÊǸßÊÖ£¬¿´¹ýÇáÅĺó¿ÉÒÔÆ®×ß¡£ ³é¿Õ»áд¶àµã¡£ ¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª ½ô½Ó×Åд 20121001 ×÷Ϊһ°ãµÄ¶ÁÕßÎÒÃǾÍÁ˽âÁË£¬Ñо¿ÄÚÈÝÊÇÒ»ÖÖС·Ö×ÓµÄÄÐÓñÜÔÐÒ©¡£°´ÕÕÕªÒªÖÐÄÚÈÝ£¬¶ÁÕß×Ô»áÌá³öÏà¹ØµÄÎÊÌ⣺ 1¡¢×÷ΪҩÎҩÎï·Ö×Ó¶Ô¸øÒ©·½Ê½ºÜÖØÒª£¬Ð¡·Ö×Ó£¬Õâ¶Ô¸øÒ©ºÜÖØÒª£¬ËãÑо¿¹¤×÷µÄÓÅÊÆºÍ´´ÐÂÖ®´¦£» 2¡¢×÷ΪÒÖÖÆ¾«×ÓµÄÒ©Î±ØÐëÊÇ¿ÉÄæµÄ£»Èç¹ûÒÖÖÆ×÷Óò»¿ÉÄæ£¬ÄǾͳÉÁËÑ˸îÒ©ÁË£» 3¡¢¸ÃÒ©ÎïÓ°Ï췶Χ²»ÄÜÌ«´ó£¬±ØÐëÓÐÑ¡ÔñÐÔ£¬²»ÄÜÓ°ÏìÐÔ·¢Óý£¬ÓÈÆäÊÇÓ°ÏìºÉ¶ûÃÉˮƽ¡£ ¸ù¾ÝÒÔÉÏ˼¿¼£¬µÚ1µãÊÇÎÄÕµĻù±¾ÄÚÈÝ¡£ºóÃæ2µãÊÇ×÷Õß±ØÐëÖØµã½âÊÍÇå³þµÄÄÚÈÝ£¬Èç¹û×÷Õß½âÊͲ»Çå³þ£¬Õâ2µãÔÚ±à¼ÄÇÀï¾Íͨ²»¹ý£¬¹þ¹þ¡£¿´¿´ºóÃæµÄÄÚÈÝ£¬Ñ¡ÔñÐԺͿÉÄæÐÔ¶¼ÓÃÁ˳¬¹ý2Ò³¶àµÄƪ·ùºÍ¶àÕÅͼƬÀ´Á¦Ö¤¡£ ÏÈ¿´introduction£¬Õⲿ·ÖÄÚÈÝÌåÏÖ×÷ÕßµÄˮƽ£¬¶ÔÑо¿ÁìÓòµÄÕÆ¿Ø£¬ÒýÑÔ²¿·ÖдºÃÁË£¬ºÍºóÃæµÄÌÖÂÛÏàºôÓ¦£»´ËÍâÒýÑԵķ¶Î§Ò²ÐèÒª×÷ÕßÕÆ¿ØºÃ¡£ ×÷ΪsciÐÂÊÖ£¬Ò»¶¨ÒªÐ´ºÃÒýÎIJ¿·Ö£¬Èç¹ûÄãÍü¼ÇÒýÓÃijλÑо¿ÈËÔ±µÄ¹¤×÷£¬»òÕßÆÚ¿¯ÒýÓôíÎ󣬶¼ÊÇ´ó¼É¡£ÒòΪ¶¼ÊÇȦÄÚÈËÊ¿£¬ÄãÉÙÒý£¬¶àÒý£¬´µÅ££¬´ó¼ÒÐÄÀï¶¼Ã÷¾µËƵ쬻òÐíijλreviewer¾ÍÊÇÒòΪÄãûÒýÓÃËûµÄÏà¹ØÎÄÕ£¬ÐÄÀﲻˬ°¡¡£ÓÈÆäÊÇͶ¸ßµµÆÚ¿¯Ò»¶¨Òª×¢ÒâÕâµã¡£ ÀÏʵ˵£¬ÎÒ¸øÆÚ¿¯Éó²éÎÄÕÂʱ£¬ÎÒÊÇÖØµã¿´introduction£¬ÒòΪÕâÀï×îÄÑд¡£ Although ~4% of the mammalian genome encodes genes expressed in male germ cells during spermatogenesis (Schultz et al., 2003), contraceptive drugs for men have remained elusive. To date, the only drugs in clinical trials are testosterone analogs that alter endogenous androgen production, although there is a short list of other possible targets (e.g., GAPDHS) and drugs (e.g., gamendazole) (Aitken et al., 2008). This lack of contraceptive alternatives for men is partially responsible for the high rate of unplanned pregnancies, especially in teenagers, and contributes to the maternal mortality, ethical, social, and financial costs associated with abortions and deliveries to single mothers. To approach this dearth of contraceptive alternatives for men, we have undertaken to develop small molecules that could target spermatogenic-specific proteins that have been shown to be essential for both spermatogenesis and fertility in mammals. One such contraceptive target is the testis-specific and bromodomain- containing protein BRDT. µÚÒ»¶Î¶¼Ãâ²»ÁËË×Ì×£¬½²Ëß±¾Ñо¿¹¤×÷µÄÒâÒ壬³£¼ûÌ×·¶¼ÊÇ£ºÓë±¾Ñо¿ÓйصŤ×÷ºÍÑо¿³É¹ûºÜÉÙ¼û£¬±¾Ñо¿ºÜnb£¬¹¤×÷Óд´Ð¡£ÏÂÃæ×Ðϸ·ÖÎöµÚÒ»¶Î£¬×÷ÕßÈçºÎ´µÅ££¬Ê¹ÓÃÁËʲô´Ê»ãºÍ¾äʽ¡£ Although ~4% of the mammalian genome encodes genes expressed in male germ cells during spermatogenesis (Schultz et al., 2003), contraceptive drugs for men have remained elusive. µÚÒ»¾äÖÐÓÐ2¸öµØ·½ÖµµÃÌá³ö£¬Ò»¸öÊÇ~4% ÊǿƼ¼ÂÛÎÄÖг£Óõģ¬~Ï൱ÓÚaboutµÄÒâ˼£»µÚ2¸öµØ·½ÊÇhave remained elusive£¬ÄÐÓñÜÔÐÒ©»¹Ã»ÕÒµ½£¬»¹²»Çå³þ¡£ Õâ¾äÎÒÃÇÒ²ÓõÃ×Ű¡£¬¸Ï¿ìÄóöС±Ê¼Ç±¾¼ÇÏ¡£ÕâÊÇ´µÅ£Éñ¾ä°¡£ºÈç¹ûÄãÒª±íʾǰÈËÔÚijÑо¿ÁìÓò»¹ÊÇÒ»Çî¶þ°×£¨have remained elusive£©£¬¶øÄãµÄÑо¿¹¤×÷Ôò¿ª´´ÁËоÖÃæ£¨providing a lead compound targeting the male germ cell for contraception. ÕªÒª²¿·Ö×îºóÒ»¾ä£©¡£ Õâλ×÷ÕߺÜÅ£²æ£¬¼ÌÐøÒý¾¾Ýµä£¬±ÉÊÓÒ»ÏÂǰÈ˵Ť×÷£¬¿´ÏÂÒ»¾ä¡£ To date, the only drugs in clinical trials are testosterone analogs that alter endogenous androgen production, although there is a short list of other possible targets (e.g., GAPDHS) and drugs (e.g., gamendazole) (Aitken et al., 2008). To dateµÄÓ÷¨½Ï³£¼û£¬sciÐÂÊÖÒ²ÓõÃ×Ű¡¡£ È»ºó£¬×÷Õß»¹²»Íü¼ÌÐø´Ó˼Ïë²ãÃæÉÏ·ÖÎöһϣ¬ÎªÊ²Ã´Ç°È˵Ť×÷ÕâÃ´Ë®ÄØ£¿ ÔÀ´ÊÇÒòΪÓÐһЩ¹¤×÷ÔÚ¼¼Êõ²ãÃæÉÏ»¹Ã»¸ã¶¨£¬¿´¿´×÷ÕßÊÇÔõô±íÊöµÄ¡£ This lack of contraceptive alternatives for men is partially responsible for the high rate of unplanned pregnancies, especially in teenagers, and contributes to the maternal mortality, ethical, social, and financial costs associated with abortions and deliveries to single mothers. This lack ofÕâÖÖÓ÷¨Ò²ÊǺܳ£¼ûµÄ£¬Äã¾ø¶ÔÓõÃ×Å£¬lackÕâ¸ö´Ê±È½ÏÆæ¹Ö£¬´ó¼Ò¿ÉÒÔ×Ðϸ²é²é¡£´ËÍâis responsible for ºÍcontributes toµÄÓ÷¨Ò²ºÜ³£¼û¡£¼Çס¸±´Êpartially¡¢especiallyµÄÓ÷¨£¬³õѧÕßÒªÌØ±ð×¢Ò⸱´ÊºÍÁ¬´ÊµÄÓ÷¨¡£ ×¢ÒâºóÃæµÄdeliveriesÊÇÃû´Ê£¬²»ÊǶ¯´ÊµÚÈýÈ˳ÆÐÎʽ¡£ ºóÃæ2¾ä»°Õýʽ¿ªÊ¼´µÅ£ To approach this dearth of contraceptive alternatives for men, we have undertaken to develop small molecules that could target spermatogenic-specific proteins that have been shown to be essential for both spermatogenesis and fertility in mammals. One such contraceptive target is the testis-specific and bromodomain- containing protein BRDT. To approach this dearth of contraceptive alternatives for men, ΪÁ˽â¾öȱ·¦ÄÐÐÔ±ÜÔз½·¨µÄÀ§¾³£¬To approach£¬ÖµµÃÄóöС±Ê¼Ç±¾¼ÇÏÂÀ´¡£ ÎÒÃǽô½Ó×Å¿´¿´ºóÃæµÄд·¨£¬Á¬ÓÃ2¸ö¶¨ÓڴӾ䣬˵ʵ»°£¬Õâ¾ä»°Ò»°ãÈËÕæÐ´²»À´°¡¡£ To approach this dearth of contraceptive alternatives for men, develop small molecules that could target spermatogenic-specific proteins that have been shown to be essential for both spermatogenesis and fertility in mammals. Ò»°ã˼·£ºÎªÁË£¨to ...£©£¬ÒòΪspermatogenic-specific proteinÊÇÉú³É¾«×Ó±ØÐëµÄ£¬ËùÒÔÎÒÃÇÕë¶ÔÕâÖÖµ°°×ÖÊÉè¼ÆÁËÒ»ÖÖС·Ö×ÓÒ©Îï¡£ ÓÃ1¸ö´Ó¾ä£ºÎªÁË£¨to ...£©£¬ÎÒÃÇdevelop small molecules to target spermatogenic-specific proteins that (´Ó¾ä). ÔÙÒªÌáÉý¾ÍÊÇÔ¾äµÄÓÃ2¸ö´Ó¾äÁË¡£ дӢÎľä×ÓµÄʱºò£¬²»Äܰ´ÕÕ×Ô¼ºµÄÖÐÎıí´ïÒâ˼À´×éÖ¯Ó¢Îľä×Ó¡£ ¶øÊÇÓ¦¸Ã°´ÕÕ¾ä×ӳɷÖÂß¼½á¹¹£¬×éÖ¯¾ä×Ó£¬ÀýÈçÉÏÃæµÄС·Ö×Ó¿ÉÒÔ×÷ΪdevelopµÄ±öÓ»¹¿ÉÒÔ×÷ΪtargetµÄÖ÷Ó¶øºóÃæµ°°×ÖÊ¿ÉÒÔ×÷ΪtargetµÄ±öÓ»¹¿ÉÒÔ×÷ΪÁíÒ»·ÝÄÚÈݵÄÖ÷ÓȻºóÒ»»·Ì×Ò»»·£¬À´×éÖ¯ÓïÑÔ¡£ µ±È»²»ÊÇ˵¾ä×ÓÔ½¸´ÔÓÔ½ºÃ£¬Èç¹ûÄÜ׼ȷ¡¢±í´ïÇå³þµØ±í´ïÒâ˼£¬µ±È»ÊÇÓüòµ¥¾ä×îºÃ¡£µ«Êǵ±ÄãÓöµ½²»ºÃ×éÖ¯ÓïÑÔµÄʱºò£¬ÍùÍùÊÇÒª½èÖú´Ó¾äµÄÓ÷¨µÄ¡£ ÕâÖÖÅׯúÖÐÎÄÔ¾äÍâÐΣ¬°´ÕÕ¾ä×ӳɷ֡¢Âß¼½á¹¹À´×éÖ¯Ó¢Îľä×ӵķ½·¨»áʹµÃÄúµÄÓ¢ÎÄд×÷ÌáÉýÒ»¸ö²ã´Î¡£ ´ó¼Ò¶¼Ôø¾Ñ§¹ý¸÷ÖִӾ䣬Ҳ¶¼ÄÜ¿´¶®´Ó¾ä£¬µ«ÊÇÔÚʵ¼ÊµÄд×÷ÖÐÒªÔËÓúôӾ䣬¾ÍÒªÀí½â´Ó¾äµÄ±¾ÖÊ£¬´Ó¾äÊÇÐÞÊιØÏµ£¬ÊµÖÊÊÇÂß¼¹ØÏµ¡£ ÀýÈ磺״Óï´Ó¾äÖУ¬ÐÞÊβ¿·ÖΪºóÃæ¾ä×ÓµÄ×´Ó¶¨Óï´Ó¾äµÄÐÞÊιØÏµ£¬ÔÚÐÎʽÉÏÒ²ÊÇÂß¼¹ØÏµ¡£ ÖйúÈËÒ»°ã¶ÔÂß¼¹ØÏµ»¹ÊDZȽÏÃô¸ÐµÄ£¬ÀûÓÃÂß¼¹ØÏµÀ´×éÖ¯Ó¢Îľä×Ó¡£ ÒòΪÕâµã¶ÔÓÚSCIÐÂÊÖÀ´Ëµ±È½ÏÖØÒª£¬ËùÒÔÎÒ¶à˵¼¸¾ä¡£ Õâ¾ÍºÃ±È×öÊýѧӦÓÃÌâ¡£ ¶ÁСѧ5Äê¼¶µÄʱºò£¬¾³£»á×ö¸÷ÖÖ¸´ÔÓ¹ØÏµµÄÓ¦ÓÃÌ⣬½âÌâ¹ý³Ì¾ÍÊǵ¹ÍÆ£¬ÓÃÀ¨ºÅºÍ¸÷ÖÖËãʽд³öËùÇó½á¹ûµÄ±í´ïʽ£»ÕâÖÖÇó½â¹ý³ÌµÄÈ·ºÜÉËÈË¡£ µÈÎÒÃǵ½Á˳õÖеÄʱºò£¬ÎÒÃÇѧÁ˺¯Êý£¬Ñ§ÁË·½³Ì×飬ÎÒÃÇÔٻعýÍ·À´¿´ÕâÖÖÓ¦ÓÃÌ⣬ÎÒÃǶ¼»áºÜ̹Ȼ£¬¾õµÃºÜ¼òµ¥¡£ µ±ÄúÕÆÎÕÁ˺¯ÊýºÍ·½³Ì×éµÄ˼Ïë·½·¨£¬ÔÙ¸´ÔÓµÄÓ¦ÓÃÌâ¶¼ÊÖµ½ÇÜÄᣠÎÒÃÇдӢÎľä×ÓµÄʱºòÒ²ÊÇÈç´Ë£¬µ±ÄãÕÆÎÕ´Ó¾äÐÞÊιØÏµµÄ±¾ÖÊÊÇÂß¼¹ØÏµµÄʱºò£¬È»ºó½«ÕâÖÖ˼Ïë»ý¼«Ö÷¶¯µØÔËÓÃÔÚÓ¢Îľä×ӽṹ×éÖ¯µÄ¹ý³ÌÖУ¬¸÷ÖÖËùνµÄÄѾä×Ó£¬¶¼»á±È½Ï¼òµ¥¡£ ÕâÖÖÉî¿ÌÀí½â¡°´Ó¾äÐÞÊιØÏµµÄ±¾ÖÊÊÇÂß¼¹ØÏµ¡±µÄ˼Ï룬¾ÍÊÇÓ¦¶ÔÊýѧӦÓÃÌâµÄº¯Êý·½·¨ºÍ·½³Ì×é˼Ï룬SCIÐÂÊÖÃÇ£¬ºÃºÃÌå»á£¬²¢ÔÚʵ¼Êд×÷ÖмÓÒÔÁé»îÔËÓã¬Äã»á¸Ðµ½Ó¢ÎÄд×÷ÆäʵûÄÇôÄÑ¡£ ³æÓѵĹÄÀø£¬ÈÃÎÒÊܳèÈô¾ª£¬ËäȻƽʱ¹¤×÷ÒµÎñºÜ棬ÎÒÈÔ»á¼ÌÐø¼Ó½ô¸úÌû¡£ ¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª¡ª ½ô½Ó×Åд 20121005 ÉÏÃæ´µÍêÅ£ÁË£¬½ô½ÓמͱØÐë½²Çå³þ×Ô¼ºµÄÑо¿Ë¼Â·¡£ ¿ÆÑеÄÈÎÎñ¾ÍÊÇ̽Ë÷±¾Öʺͽâ¾öÎÊÌ⣬ËùÒÔÑо¿ÂÛÎÄÖеÄ˼·ÊǺÜÖØÒªµÄ£¬Ëµ´ó°×»°£¬¾ÍÊǽ²Çå³þÄãÊÇÈçºÎÏëµ½²ÉÓúÎÖÖ·½·¨À´×öÄãµÄÑо¿¹¤×÷µÄ£¬Ò»°ã˼·¾ÍÊÇ»ùÓÚһЩǰÈËÑо¿ÄÚÈÝ£¬ÒÔ¼°×Ô¼ºµÄÑо¿ÄÚÈÝ£¬¾ß±¸ÁË̽Ë÷ijÖÖ±¾ÖÊ»ò½â¾öij¸öÎÊÌâµÄ¿ÉÄÜÐÔ£¬ËùÒÔÎÒ²úÉúÁËij¸ö˼·¡£ ´Ë´¦½â¾öÎÊÌâµÄ˼·¾ÍÊÇ´´Ðµ㡣introductionµÄÖØµã¾ÍÔÚÓÚ½²Çå³þ×Ô¼ºµÄÑо¿Ë¼Â·£¬¶ø²»ÊǼòµ¥µØÂÞÁÐÏà¹ØµÄÑо¿ÄÚÈÝ¡£ ÎÒÃÇ¿´¿´ÕâÆªÎÄÕµÄÑо¿Ë¼Â·ÊÇÈçºÎÕ¹¿ªµÄ¡£ Ê×ÏÈÊÇÇ°ÃæÒѾ½²¹ýµÄintroductionµÚÒ»¶Î£¬×÷Õß¹Ø×¢µ½ÄÐÐÔ±ÜÔÐÒ©µÄÑо¿¼¸ºõÊǿհס£ È»ºóÏÂÃæÒ»¶Î·Ç³£ÖØÒª£¬Ï൱ÌåÏÖ×÷ÕßµÄˮƽ¡£ÎÒÃÇÖØµã¿´introductionµÚ2¶ÎµÄ×îºó2¾ä£º Genetic studies of BRDT have demonstrated that selective deletion of the BRDT(1)-encoding region is sufficient to confer sterility in homozygous hypomorphic male mice (Shang et al., 2007), and a recently published genome-wide association study of idiopathic male infertility identified single-nucleotide polymorphisms of BRDT as significantly associated with oligozoospermia or azoospermia in European men (Aston et al., 2010). These insights establish a compelling rationale to target BRDT for a contraceptive effect. Ç°ÃæÒ»¾äÊǺͲ¢Áи´ºÏ¾ä£¬½²¸ö2²ãÒâ˼¡£ µÚ1²ãÒâ˼£ºÒÅ´«Ñ§Ñо¿±íÃ÷Ñ¡ÔñÐÔɾ³ýBRDT(1)±àÂëÇø¿ÉÒÔµ¼Ö²»Óý¡£ µÚ2²ãÒâ˼£ºÏÈÌìÄÐÐÔ²»Óý¼²²¡µÄÈ«»ùÒò×鹨ÁªÑо¿È·ÈÏÁËBRDTµÄµ¥ºËÜÕËá¶à̬ÐÔºÍÅ·ÖÞÄÐÐÔµÄÉÙ¾«×ÓÖ¢ºÍÎÞ¾«×ÓÖ¢ÏÔÖøÏà¹Ø¡£ ÆäÖÐÖµµÃÐÂÊÖѧϰµÄÓ¢ÎÄ£ºhave demonstrated that£¬confer£¨Ìå»áºÍattribute to µÄ²»Í¬£©£¬identified £¬as significantly associated with£¨ÏÔÖøÏà¹Ø£©£¬ÒÔ¼°²¢Áи´ºÏ¾äµÄд·¨¡£ ±¾ÈËÒ²²»ÊÇÕâ·½ÃæµÄר¼Ò£¬²éѯÁËһϡ£ºÍÎÒÒ»Ñù²»¶®µÄ£¬¿ÉÒÔ¿´¿´ÕâÀï¡£ ¹ØÓÚSNPÓëGWAS£¨Genome Wide Association study£©µÄһЩÏë·¨ https://www.dxy.cn/bbs/topic/16400551 ÔÚÕâÀï¸Ðл¶¡ÏãÔ°µÄlorry_zgf¡£ ÔÙ¿´ºóÃæÒ»¾ä£¬Õâ¾äÊǹؼü¡£These insights establish a compelling rationale to target BRDT for a contraceptive effect. ÕâЩ¹ÛµãΪ½«BRDT×÷ΪÄÐÐÔ±ÜÔÐÄ¿±êÎïÌṩÁËÒ»ÖÖcompelling˼·¡£ ˵ʵ»°£¬Õâλ×÷ÕßµÄ˼ά»¹ÊǺÜÌøÔ¾µÄ£¬ ½âÊÍһϣºÒòΪBRDTºÍÄÐÐÔ²»Óý¹ØÏµ·Ç³£ÃÜÇУ¬ËùÒԾͿÉÒÔ°ÑÕâ¸ö»ùÒò×÷ΪÄÐÐÔ±ÜÔÐÒ©µÄ×÷Óðбꡣ Õâ¾ÍÊÇÈ˼ҵÄÑо¿µÄÆðµãºÍ×÷ÕߵĻù±¾Ïë·¨£¬ÉÏÊöÎÄÏ×Ò²ÊÇΪÁË˵Ã÷×÷ÕßµÄÑо¿Ë¼Â·¶øÒýÓõ쬶ø²»Êǽö½ö¼òµ¥µØÂÞÁÐÏà¹ØµÄÑо¿¹¤×÷¡£ These insights establish a compelling rationale to target BRDT for a contraceptive effect. Õâ¾ä»°ÖµµÃÄóöС±Ê¼Ç±¾¼ÇÏ£¡£¡ ÕâµãÏë·¨»¹ÊǺܶàÈ˶¼Óе쬵«ÊǾßÌåÔõô×ö¡£Õâ¾ÍÒª¿´×÷Õß±¾È˵ÄÑо¿»ù´¡ÁË£¬ÏÂÃæ×÷Õß»á½éÉÜ×Ô¼ºµÄÑо¿»ù´¡£¬È»ºóÌá³öʵÏÖÉÏÊöÏë·¨µÄ·½·¨£¬ÕâÑùµÄ»°£¬Ë¼Â·ÄÇÊǷdz£Çå³þ¡£ ÎÒÓÐÏë·¨£¬ÎÒÓлù´¡£¬ËùÒÔÎÒ¾ÍÕâô×öÁË¡£Õâ¾ÍÊÇÕû¸öintroductionµÄ˼·¡£ ÔÙ¿´introductionµÚÈý¶Î£º Recently, we established the feasibility of targeting human bromodomains with acetyl-lysine competitive small molecules (Filippakopoulos et al., 2010). Ê×ÏÈÎÒÃÇÐγÉÁËÒ»ÖÖÓÃacetyl-lysineÖØ¸´Ð¡·Ö×ÓÀ´×÷ÓÃÓÚhuman bromodomainµÄ·½·¨¡£ È»ºó½ô½Ó׎²ËßJQ1¶ÔBRDTµÄ ÒÖÖÆ×÷ÓᣠÔÙ¿´introductionµÚËĶΣº ×÷Õß½ô½Ó×ÅÏêϸ½éÉÜÕâÖÖÒÖÖÆÐ§¹û£¬a dose- and time-dependent inhibitory effect £¨×¢ÒâÕâÖÖÓ÷¨£© complete and reversible contraceptive effect in males without adversely affecting testosterone levels or mating behaviors and without prompting obvious teratogenic effects in offspring. ×¢Òâ´Ë´¦2¸öwithoutÁ¬Óã¬ÓÃandÁ¬½ÓµÄÓ÷¨¡£ ¿´introductionµÚËĶÎ×îºóÒ»¾ä These results indicate that targeting a developmental epigenetic reader protein with an orally bioavailable small molecule can modulate male fertility for a contraceptive effect. ÕýÊÇ»ùÓÚÕâÖÖÒÖÖÆÐ§¹û£¬ËùÒԾͿÉÄÜÌṩÕâÖÖ¿Ú·þµÄÄÐÐÔ±ÜÔÐС·Ö×ÓÒ©Îï¡£ µ½ÁËÕâÀ×÷ÕßµÄ˼·¿ÉνÊÇË®µ½Çþ³É£¡ ¿´ÁËÉÏÃæµÄintroduction£¬¶ÔÓÚÒ»°ãµÄSCIÐÂÊÖÀ´Ëµ£¬ÎÒÃǸÃÈçºÎÀ´Ð´ÄØ£¿ ÔÚÏÖʵÖУ¬´ó¼Ò¶¼ÊÇΪÁËÖ°³Æ¡¢Ñ§Î»À´·¢±íÎÄÕ£¬¹Ø×¢Ñо¿ÊֶΣ¬Ñо¿·½·¨ºÍÑо¿ÄÚÈÝ£¬ÍùÍùºöÂÔÁËÑо¿ÏîÄ¿µÄ±¾Éí¡£ÄÄÀïÊÇÇ°ÑØÈȵ㣬ÄÄЩÊÇз½·¨£¬ÎÒÒ²À´Ñо¿Ò»Ï£¬Åªµã´óÏîÄ¿¡£ 03Äê·ÇµäÖ®ºó£¬¹úÄÚij¸öÑо¿Ëù£¬±¾À´Ñо¿Ö²Îﲡ¶¾µÄ£¬¶¼¸Äµ½Ñо¿·Çµä²¡¶¾ÁË£¬ÉêÇëÁ˺ܶàÏîÄ¿¡£ÆäÖвî±ðÀÏ´óÁË£¬¶¼ÊÇΪÁËÏîÄ¿ºÍÇ®¡£ ÈÃÎÒÃÇÔÙÀ´»Ø¹ËһϿÆÑеÄÈÎÎñ£º¿ÆÑеÄÈÎÎñ¾ÍÊÇ̽Ë÷±¾Öʺͽâ¾öÎÊÌ⣬¿ÆÑÐÐèÒª¶ÔÕæÏàµÄ¿ÊÇóºÍ¶Ôδ½âÎÊÌâµÄ˼¿¼£¬Õâ±¾ÊǷdz£ÐèÒªÈÈÇéµÄ¹¤×÷£¬¿Éϧ¶¼ÈùúÈË×ö³ÉÁËÏîÄ¿£¬ÉÙÁË˼¿¼£¬Ö»Ê£Ä£·ÂºÍ²ÙÁ·¡£ Ñо¿¹¤×÷µÄÄѵãÔÚÓÚ´´Ð£¬ÓÐÁË´´Ð£¬¾Í»áÓкÃ˼·¡£ ºÜ¶àÈ˵ÄÑо¿¹¤×÷Ö»ÊÇÑ¡ÓÃÁËеÄÑо¿²ÄÁÏ£¬»òÕß·½·¨ÉԼӸĽø¡¢ÉõÖÁÊÇÎÞÒâÒåµÄÖØ¸´£¬ÎÄÖйØÓÚÑо¿Ë¼Â·µÄ½éÉÜÒ²Ö»ÄÜ˵£¬¹ØÓÚÕâ·½ÃæµÄÑо¿ºÜÉÙ£¬ËùÒÔÎÒ×öÁË¡£ÕâÑù½²ÕæµÄºÜ²Ô°×¡£ ºÜ¶àÈË˵£¬ËµÁ˰ëÌ죬»¹ÊDz»½â¾öÎÊÌâ¡£ÔÛ²»ÄÜ×ö·ßÇֻ࣬±§Ô¹£¬²»Ìá³ö½â¾öÎÊÌâµÄ·½°¸¡£ ÏÖʵÖУ¬ÏîÄ¿ÊÇÓÉÀÏʦ¶¨µÄ£¬ÊÜÏÞÓÚÑо¿»ù´¡ºÍÊÔÑéÊֶΣ¬ÈçºÎÕÒ´´ÐµãÄØ£¿ 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