Nature:难怪阿尔茨海默病那么难治!科学家发现AD患者神经元存在数千种APP基因变体,颠覆科学家的认知

2018-11-25 奇点糕 奇点网

不得不说活得长就是好,活得久了什么都能见到,大脑这个人体最复杂的器官一次又一次刷新我们的认知,谁能想到呢,神经元竟然比其他体细胞都“技高一筹”,竟然还会只有免疫细胞才会的基因重组!

不得不说活得长就是好,活得久了什么都能见到,大脑这个人体最复杂的器官一次又一次刷新我们的认知,谁能想到呢,神经元竟然比其他体细胞都“技高一筹”,竟然还会只有免疫细胞才会的基因重组!

本周《自然》杂志刊登了一篇来自Sanford Burnham Prebys医学发现研究所(SBP)的最新科研成果,研究者们终于确定大脑神经元存在基因重组现象,特别是研究所关注的与阿尔茨海默病(AD)有关的淀粉样蛋白前体蛋白(APP)基因,竟然能够产生数千种变体!

一方面,这个新发现说明屡战屡败的β淀粉样蛋白理论或许并未走错;另一方面,APP的基因重组与逆转录机制有关,结合HIV感染者几乎不得AD的现实,或许逆转录酶抑制剂是AD的一个可能的新疗法!

就算不谈对疾病的意义,光是发现神经元也会基因重组这个事情就够神奇的了,难怪有科学家评论这项研究是“近年来分子生物学领域最大的发现之一”、“里程碑式的研究”。


通讯作者Jerold Chun

以前我们写到光遗传学的时候曾经为大家介绍过,人的大脑是一个十分复杂的器官,神经元之间异质性非常高,高到两个相邻的神经元甚至可能具有完全不同的功能。是什么让神经元有了“七十二变”的能力呢?科学家最初给出的猜测就是,基因重组。

想必大家了解的基因重组发生在生殖细胞中,其实体细胞也会这个绝技,比如说免疫细胞,准确来说就是产生抗体的B细胞,为了高效生产抗体,它编码抗体可变区的基因就可以通过重组形成新的DNA分子。

那神经元到底会不会这个技能呢?科学家们虽然发现了神经元中的基因镶嵌现象,也确定了不少重组模式,但是从没有在特定的基因上证实重组的存在。

于是这次研究者们就把目光放在了APP基因上,这个基因表达的淀粉样蛋白前体蛋白经过分泌酶水解,产生的就是具有神经毒性的β淀粉样蛋白肽和蛋白沉淀,也就是阿尔茨海默病的病理因素之一。散发性阿尔茨海默病(SAD)患者和唐氏综合症患者都存在APP拷贝数增加的问题,可见APP基因应该对病理进展有作用。


APP基因在21号染色体上,它的拷贝数也和唐氏综合症有关

当分析来自AD患者大脑的神经元时,研究者检测到了完整的APP基因,也检测到了几个已知与疾病有关的变体,不过奇怪的时,他们发现了更多的预料之外的变体基因。

这些基因和以前报道过的变体都不同,很多都表现出中部外显子丢失,两端外显子连接在一起,其中很常见的一类是3号外显子和16号外显子的连接(R3/16)。研究者把这些变体叫做gencDNA。

但是这似乎是APP特有的现象,另外一种与AD有关的基因早老蛋白1(PSEN1)就没有发现这样的变体。


APP的各种gencDNA

对比AD患者和健康人的神经元,差别很惊人。来自5名AD患者的96424个神经元中,共检测到了6299种独特的APP序列,包括45种外显子连接;同样来自5名健康人的162248个神经元中,则只发现了1084种独特的APP序列,只有20种外显子连接。

来自AD患者的gencDNA不单单是数量上有近六倍的碾压,其中还有11种已经被证实与AD的家族性发病有关了!而这些变化在非神经元细胞中是不存在的。

研究者把部分gencDNA的表达产物拿到体外与细胞培养,证实了某些gencDNA产物是有生物毒性的。

研究者还在AD小鼠模型中进行了检测,发现随着年龄的增长,小鼠脑中也出现了越来越多的gencDNA,同样,在非神经元细胞中也不存在这样的变化。


无论数量还是种类,AD患者的APP gencDNA都远超正常人

那这些gencDNA是怎么来的呢?

看看这些gencDNA的长相,缺内含子,还有细胞特异性的亚型,感觉很像经过剪接的RNA。研究者猜测,说不准这些gencDNA就是从RNA来的,经过逆转录才成了今天的样子!

经过实验,研究者确定了两个gencDNA产生的必要条件:一是内源性逆转录酶的活性,二是过氧化氢导致的DNA链断裂。考虑到逆转录过程实际上很“粗糙”,研究者认为这导致了更多不同的基因变异。



那么这或许就能够解释为什么这么多年来针对β淀粉样蛋白的临床试验屡屡失败了。通讯作者Jerold Chun做了个很妙的比喻,如果把DNA看作是一种语言,那么APP基因就是一个单词,现在科学家发现一个单词可以产生数千个我们从来都不认识的单词——那么原本针对某种单一蛋白的治疗方法不起效也就不足为奇了。

这应该是件好事,至少这么多年来朝向β淀粉样蛋白所作的努力并不是完全白费的。

另一方面,逆转录酶作用的发现意味着目前已被FDA批准的抗逆转录病毒疗法或许可以用于治疗AD。流行病学数据也给了这个观点有力的支持,HIV感染者极少患AD——事实上首个共病病例2016年才出现。

Chun认为,在当前对AD束手无策的情况下,考虑到HIV药物普遍很安全,尽早开始相关的临床研究也未尝不可。

《自然》同期配发的评论对这个观点倒是比较谨慎,认为在进一步确定APP gencDNA产生机制和与AD的关系之前,谈治疗还为时尚早。

《科学》杂志评论对这项研究给了很高的赞誉,多名科学家认为这是“多年来分子生物学领域最大的发现之一”,“是一项具有里程碑意义的研究”。

神经元细胞的基因重组可能不仅限于APP基因,既然健康神经元也存在重组,那么这很可能是一种神经元保持多样性的独特方式,以便提供更加丰富的大脑功能;未来更多的研究或许也可以延伸到帕金森等更多的脑部疾病。

原始出处:Ming-Hsiang Lee, Benjamin Siddoway, Gwendolyn E. Kaeser, et al. Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature. 21 November 2018

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  4. 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    2019-05-20 liye789132251
  5. [GetPortalCommentsPageByObjectIdResponse(id=1816881, encodeId=c6a6181688147, content=<a href='/topic/show?id=17b59e77626' target=_blank style='color:#2F92EE;'>#阿尔茨#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97776, encryptionId=17b59e77626, topicName=阿尔茨)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Bnia2EtH2IvyBtniaWHPQOYAicsN3IAL1ZuPV7qyALcdCiawRJdEiafMxWTxzERQW7eeKg8HfCKCRK2CJicy073C4RJg/132, createdBy=464b2500186, createdName=ms1948154235210413, createdTime=Wed Aug 21 02:22:00 CST 2019, time=2019-08-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1817904, encodeId=8645181e9048f, content=<a href='/topic/show?id=4c9f9e777ac' target=_blank style='color:#2F92EE;'>#阿尔茨海#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, createdName=12498da4m32(暂无昵称), createdTime=Wed Apr 17 01:22:00 CST 2019, time=2019-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1802581, encodeId=d5111802581a6, content=<a href='/topic/show?id=acfae485578' target=_blank style='color:#2F92EE;'>#科学家发现#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=74855, encryptionId=acfae485578, topicName=科学家发现)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e572480, createdName=旅苦化文_208, createdTime=Sat Dec 22 09:22:00 CST 2018, time=2018-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1883441, encodeId=57af188344132, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Mon May 20 15:22:00 CST 2019, time=2019-05-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470258, encodeId=598d14e02583d, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Tue Nov 27 14:22:00 CST 2018, time=2018-11-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1631023, encodeId=6a3d163102384, content=<a href='/topic/show?id=16152686be' target=_blank style='color:#2F92EE;'>#APP基因#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2686, encryptionId=16152686be, topicName=APP基因)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=dc5521636944, createdName=chaojitidian, createdTime=Tue Nov 27 14:22:00 CST 2018, time=2018-11-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=353727, encodeId=969d353e27b3, content=学习了,期待有更好进展!, beContent=null, objectType=article, channel=null, level=null, likeNumber=51, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=92722485194, createdName=12468634m81暂无昵称, createdTime=Mon Nov 26 18:54:55 CST 2018, time=2018-11-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=353715, encodeId=ecde353e152c, content=怪不得呢??, beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKibA62IFMeUJEmSyIe8DvYFeERuOsfrRd8iano7nENqQU1dRR3tqeQOUL3eqgYgEZRT2t2iaEsib0JEw/132, createdBy=66771693911, createdName=易水河, createdTime=Mon Nov 26 16:11:18 CST 2018, time=2018-11-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=353687, encodeId=5c2b35368e87, content=学习了谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTLbTp9nZtjwVrSZNxAXbAicnKQWnic2eBdJUQYhxO36XdkstSicr7FVF8p5ReH4omtmsbnLdvZLiaJJ1A/132, createdBy=8bff2327056, createdName=kafei, createdTime=Mon Nov 26 09:21:18 CST 2018, time=2018-11-26, status=1, ipAttribution=)]
  6. [GetPortalCommentsPageByObjectIdResponse(id=1816881, encodeId=c6a6181688147, content=<a href='/topic/show?id=17b59e77626' target=_blank style='color:#2F92EE;'>#阿尔茨#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97776, encryptionId=17b59e77626, topicName=阿尔茨)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Bnia2EtH2IvyBtniaWHPQOYAicsN3IAL1ZuPV7qyALcdCiawRJdEiafMxWTxzERQW7eeKg8HfCKCRK2CJicy073C4RJg/132, createdBy=464b2500186, createdName=ms1948154235210413, createdTime=Wed Aug 21 02:22:00 CST 2019, time=2019-08-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1817904, encodeId=8645181e9048f, content=<a href='/topic/show?id=4c9f9e777ac' target=_blank style='color:#2F92EE;'>#阿尔茨海#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, createdName=12498da4m32(暂无昵称), createdTime=Wed Apr 17 01:22:00 CST 2019, time=2019-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1802581, encodeId=d5111802581a6, content=<a href='/topic/show?id=acfae485578' target=_blank style='color:#2F92EE;'>#科学家发现#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=74855, encryptionId=acfae485578, topicName=科学家发现)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e572480, createdName=旅苦化文_208, createdTime=Sat Dec 22 09:22:00 CST 2018, time=2018-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1883441, encodeId=57af188344132, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Mon May 20 15:22:00 CST 2019, time=2019-05-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470258, encodeId=598d14e02583d, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Tue Nov 27 14:22:00 CST 2018, time=2018-11-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1631023, encodeId=6a3d163102384, content=<a href='/topic/show?id=16152686be' target=_blank style='color:#2F92EE;'>#APP基因#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2686, encryptionId=16152686be, topicName=APP基因)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=dc5521636944, createdName=chaojitidian, createdTime=Tue Nov 27 14:22:00 CST 2018, time=2018-11-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=353727, encodeId=969d353e27b3, content=学习了,期待有更好进展!, beContent=null, objectType=article, channel=null, level=null, likeNumber=51, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=92722485194, createdName=12468634m81暂无昵称, createdTime=Mon Nov 26 18:54:55 CST 2018, time=2018-11-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=353715, encodeId=ecde353e152c, content=怪不得呢??, beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKibA62IFMeUJEmSyIe8DvYFeERuOsfrRd8iano7nENqQU1dRR3tqeQOUL3eqgYgEZRT2t2iaEsib0JEw/132, createdBy=66771693911, createdName=易水河, createdTime=Mon Nov 26 16:11:18 CST 2018, time=2018-11-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=353687, encodeId=5c2b35368e87, content=学习了谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTLbTp9nZtjwVrSZNxAXbAicnKQWnic2eBdJUQYhxO36XdkstSicr7FVF8p5ReH4omtmsbnLdvZLiaJJ1A/132, createdBy=8bff2327056, createdName=kafei, createdTime=Mon Nov 26 09:21:18 CST 2018, time=2018-11-26, status=1, ipAttribution=)]
  7. [GetPortalCommentsPageByObjectIdResponse(id=1816881, encodeId=c6a6181688147, content=<a href='/topic/show?id=17b59e77626' target=_blank style='color:#2F92EE;'>#阿尔茨#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97776, encryptionId=17b59e77626, topicName=阿尔茨)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Bnia2EtH2IvyBtniaWHPQOYAicsN3IAL1ZuPV7qyALcdCiawRJdEiafMxWTxzERQW7eeKg8HfCKCRK2CJicy073C4RJg/132, createdBy=464b2500186, createdName=ms1948154235210413, createdTime=Wed Aug 21 02:22:00 CST 2019, time=2019-08-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1817904, encodeId=8645181e9048f, content=<a href='/topic/show?id=4c9f9e777ac' target=_blank style='color:#2F92EE;'>#阿尔茨海#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, createdName=12498da4m32(暂无昵称), createdTime=Wed Apr 17 01:22:00 CST 2019, time=2019-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1802581, encodeId=d5111802581a6, content=<a href='/topic/show?id=acfae485578' target=_blank style='color:#2F92EE;'>#科学家发现#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=74855, encryptionId=acfae485578, topicName=科学家发现)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e572480, createdName=旅苦化文_208, createdTime=Sat Dec 22 09:22:00 CST 2018, time=2018-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1883441, encodeId=57af188344132, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Mon May 20 15:22:00 CST 2019, time=2019-05-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470258, encodeId=598d14e02583d, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Tue Nov 27 14:22:00 CST 2018, time=2018-11-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1631023, encodeId=6a3d163102384, content=<a href='/topic/show?id=16152686be' target=_blank style='color:#2F92EE;'>#APP基因#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2686, encryptionId=16152686be, topicName=APP基因)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=dc5521636944, createdName=chaojitidian, createdTime=Tue Nov 27 14:22:00 CST 2018, time=2018-11-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=353727, encodeId=969d353e27b3, content=学习了,期待有更好进展!, beContent=null, objectType=article, channel=null, level=null, likeNumber=51, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=92722485194, createdName=12468634m81暂无昵称, createdTime=Mon Nov 26 18:54:55 CST 2018, time=2018-11-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=353715, encodeId=ecde353e152c, content=怪不得呢??, beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKibA62IFMeUJEmSyIe8DvYFeERuOsfrRd8iano7nENqQU1dRR3tqeQOUL3eqgYgEZRT2t2iaEsib0JEw/132, createdBy=66771693911, createdName=易水河, createdTime=Mon Nov 26 16:11:18 CST 2018, time=2018-11-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=353687, encodeId=5c2b35368e87, content=学习了谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTLbTp9nZtjwVrSZNxAXbAicnKQWnic2eBdJUQYhxO36XdkstSicr7FVF8p5ReH4omtmsbnLdvZLiaJJ1A/132, createdBy=8bff2327056, createdName=kafei, createdTime=Mon Nov 26 09:21:18 CST 2018, time=2018-11-26, status=1, ipAttribution=)]
    2018-11-26 12468634m81暂无昵称

    学习了,期待有更好进展!

    0

  8. [GetPortalCommentsPageByObjectIdResponse(id=1816881, encodeId=c6a6181688147, content=<a href='/topic/show?id=17b59e77626' target=_blank style='color:#2F92EE;'>#阿尔茨#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97776, encryptionId=17b59e77626, topicName=阿尔茨)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Bnia2EtH2IvyBtniaWHPQOYAicsN3IAL1ZuPV7qyALcdCiawRJdEiafMxWTxzERQW7eeKg8HfCKCRK2CJicy073C4RJg/132, createdBy=464b2500186, createdName=ms1948154235210413, createdTime=Wed Aug 21 02:22:00 CST 2019, time=2019-08-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1817904, encodeId=8645181e9048f, content=<a href='/topic/show?id=4c9f9e777ac' target=_blank style='color:#2F92EE;'>#阿尔茨海#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, createdName=12498da4m32(暂无昵称), createdTime=Wed Apr 17 01:22:00 CST 2019, time=2019-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1802581, encodeId=d5111802581a6, content=<a href='/topic/show?id=acfae485578' target=_blank style='color:#2F92EE;'>#科学家发现#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=74855, encryptionId=acfae485578, topicName=科学家发现)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e572480, createdName=旅苦化文_208, createdTime=Sat Dec 22 09:22:00 CST 2018, time=2018-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1883441, encodeId=57af188344132, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Mon May 20 15:22:00 CST 2019, time=2019-05-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470258, encodeId=598d14e02583d, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Tue Nov 27 14:22:00 CST 2018, time=2018-11-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1631023, encodeId=6a3d163102384, content=<a href='/topic/show?id=16152686be' target=_blank style='color:#2F92EE;'>#APP基因#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2686, encryptionId=16152686be, topicName=APP基因)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=dc5521636944, createdName=chaojitidian, createdTime=Tue Nov 27 14:22:00 CST 2018, time=2018-11-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=353727, encodeId=969d353e27b3, content=学习了,期待有更好进展!, beContent=null, objectType=article, channel=null, level=null, likeNumber=51, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=92722485194, createdName=12468634m81暂无昵称, createdTime=Mon Nov 26 18:54:55 CST 2018, time=2018-11-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=353715, encodeId=ecde353e152c, content=怪不得呢??, beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKibA62IFMeUJEmSyIe8DvYFeERuOsfrRd8iano7nENqQU1dRR3tqeQOUL3eqgYgEZRT2t2iaEsib0JEw/132, createdBy=66771693911, createdName=易水河, createdTime=Mon Nov 26 16:11:18 CST 2018, time=2018-11-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=353687, encodeId=5c2b35368e87, content=学习了谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTLbTp9nZtjwVrSZNxAXbAicnKQWnic2eBdJUQYhxO36XdkstSicr7FVF8p5ReH4omtmsbnLdvZLiaJJ1A/132, createdBy=8bff2327056, createdName=kafei, createdTime=Mon Nov 26 09:21:18 CST 2018, time=2018-11-26, status=1, ipAttribution=)]
    2018-11-26 易水河

    怪不得呢??

    0

  9. 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    2018-11-26 kafei

    学习了谢谢

    0

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Nature:APP基因的点突变可降低患老年痴呆几率

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