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基因密码神来之笔,重磅流感活疫苗诞生记——专访北大药学院长周德敏教授

2018-01-10 佚名 学术经纬

然而,免疫探索之路依然任重道远。流感病毒是最容易影响普通人健康的病原体之一,而小小的流感病毒所导致的恐慌和威胁,也从未停下过侵扰人类的脚步。至今,治疗流感尤其是重症患者的药物疗效依然有限,流感疫苗仍是普通人群最应关注的预防手段。

疫苗诞生之前的历史,是一部战争与瘟疫交织的历史。数千年来,人类在微生物面前,常常扮演着一个被动迷茫的弱者。许多致命病原体的攻击,更让死神像秋风扫落叶一般,戕害无数手无寸铁的生灵。当历史的车轮驶向近代的地平线,天花疫苗终于横空出世。从中国的人痘接种术,到英国的牛痘接种法在全球推广,世界各地千百年来反复爆发的天花病毒,终于在几十年前被人类彻底消灭。此后,脊灰糖丸、卡介苗、乙肝疫苗等相继推广,也在不同程度上抑制了致命病毒和细菌,疫苗的防范普及由此为人类医学发展史掀开了崭新的篇章。


▲图片来源:波士顿儿童医院网站

然而,免疫探索之路依然任重道远。流感病毒是最容易影响普通人健康的病原体之一,而小小的流感病毒所导致的恐慌和威胁,也从未停下过侵扰人类的脚步。至今,治疗流感尤其是重症患者的药物疗效依然有限,流感疫苗仍是普通人群最应关注的预防手段。北大药学院长周德敏带领团队利用密码子扩展技术,通过修改病毒基因编码和多重诱导病毒突变实验,研制出一种全新复制缺陷型活病毒流感疫苗,彻底突破了减毒、灭活、亚单位片段等传统疫苗的研发模式,该成果也被《科学》杂志列为去年全球十大科学突破之一。这种高效、低风险、抗突变的疫苗模式,不仅是人类震慑流感病毒的希望,更为我们最终攻克其他痼疾带来革命性曙光。

周德敏教授1996年完成北医大与日本筑波大学联合培养博士课程,之后在Scripps研究所师从Peter G. Schultz教授进行博士后训练,现任国家973“基于基因密码子扩展的蛋白质标记新方法”首席科学家,以及天然药物及仿生药物国家重点实验室系主任,并于2017年12月获得药明康德生命化学研究奖杰出成就奖。


▲周德敏教授(左)与张礼和(右)院士

密码子扩展术:全抗原活疫苗不是神话

·传统疫苗存在着感染风险、接种效果不佳、难以应对病毒突变等多种挑战。您团队研制出的全新流感疫苗如何克服这些挑战,并体现出独特优势?

周德敏教授:传统疫苗分为减毒、灭活、亚单位、载体疫苗等种类。常见的减毒疫苗注射到人体之后,病原体仍可以在体内复制,如果遇上抵抗力低下的宿主则可能恢复毒力。传统灭活疫苗不会导致接种者感染,但病毒蛋白结构在灭活过程中一旦被破坏,则可能难以达到理想的接种效果。某些亚单位流感疫苗采用病毒表面少量膜蛋白片段,其接种效果有时也差强人意。

流感病毒基因由八个片段组成,每个片段都包含上百个密码子。我们的技术要点概括起来非常简洁:就是将某些基因位点的密码子修改为终止密码子(三碱基UAG),即在天然细胞的环境内,使病毒在关键基因位点停止翻译蛋白质,从而成为失去传代能力。因此这种全抗原疫苗完整保存了病毒的结构和感染力,可以在接种人体内诱导高效的免疫应答,但是无法复制的病毒对人体造成的风险则降到最低。


▲流感病毒(图片来源:NIH官网)

流感病毒表面的包膜会分布了大约500个血凝素刺突(HA)和100个神经氨酸酶刺突(NA)。这两类刺突都属于糖蛋白,每一个刺突理论上都可能突变,所以高突变率是疫苗研发的严峻挑战。为了应对挑战,我们最大可能性模拟了诱导病毒基因突变的内外环境:即模拟人体内部多种免疫通路,以及模拟达菲、金刚烷、干扰素等常用抗病毒药物的外部化学环境,让弱流感病毒疫苗实现多种负反馈性的耐药性突变。目前我们已经证实了弱流感疫苗甚至可应用于预防强流感。

·过去曾有学者通过其他技术制备复制缺陷型病毒疫苗,但转基因病毒仍存在恢复为野生型病毒的风险。密码子扩展技术如何防止病毒通过基因突变恢复丢失蛋白,并实现疫苗疗效的迭代升级?

周德敏教授:我们团队完成了对弱流感病毒的全基因扫描,有的基因位点密码子修改为UAG容易导致该病毒返祖,但是我们也发现了不容易导致返祖的基因位点,将3个以上这样的位点密码子修改为UAG,则病毒不再出现突变回野生型病毒的风险。在小鼠实验阶段,我们将把1000个野生流感病毒注入10只小鼠鼻腔,10天之后老鼠全部死亡;把1亿个加装UAG病毒的疫苗注入小鼠体内,10天后小鼠保持健康且体内可检测到相关病毒的“全抗原“。

我们的文章投递到《科学》杂志之后,有一个编委成员表示,尚未发病的流感病毒携带者,如果不慎接种这类新型疫苗是否会产生不良反应?没想到这个提问,竟然促使我们实现了从预防性疫苗到治疗性疫苗的飞跃!众所周知,多数疫苗为预防性疫苗;治疗性疫苗所针对的人群存在不同程度的免疫禁忌、免疫无能或者免疫耐受。所以要研发治疗性疫苗,必须通过更为巧妙的方式改造靶抗原的结构和组合,使其相似又相异于预防性疫苗的靶抗原,从而有效打破和逆转患者的免疫耐受状态。


▲密码子指导蛋白质翻译(图片来源:维基百科)

我们发现随着病毒基因密码子突变为UAG的位点增多,小鼠患病后再接种相应的病毒疫苗,则清除野生病毒的能力逐渐提升。当疫苗内病毒基因密码子突变为UAG的位点达到4个,患病小鼠接种该疫苗之后则体内不会在检测到野生流感病毒。原来,野生病毒受到疫苗中转基因病毒的质粒侵染,也被迫带上了UAG这个终止密码子的枷锁!这样的疫苗研制方法不仅对于临床有重要的转化价值,更有利于病毒学的基础研究:通过体外培养,我们是否能够预测出一种病毒究竟能产生多少种突变?每一种基因突变与环境之间具体有怎样的联系?

神奇细胞系:非天然氨基酸合成工厂

·您团队研制的全新疫苗如果接种在哺乳动物体内,病毒无法实现细胞内复制。那么该病毒如何实现在体外的大规模制备,并最终投入临床转化和市场应用呢?

周德敏教授:在天然细胞中,病毒利用宿主细胞内的天然氨基酸合成蛋白质、进行复制,需要相应的天然转运RNA(tRNA)和氨酰-tRNA合成酶(aaRS)。而天然细胞内并没有能与UAG这个密码子匹配的转运RNA,所以UAG才会扮演终止密码子的角色。因此经过基因改造的活病毒疫苗,才不会在接种人群细胞内中复制。

然而终止密码子其实只是一个相对的概念。如果我们在模式细胞内整合加入特殊的基因,使该细胞表达能够与UAG匹配的转运RNA,则UAG将不再是终止密码子。然后我们再在模式细胞内整合加入特定氨酰-tRNA合成酶基因,则转基因病毒便可以在特殊的细胞环境内,启动UAG密码子,并利用非天然氨基酸合成蛋白质、完成复制。


▲特殊细胞株培养复制缺陷型病毒(图片来源:周德敏课题组)

我们耗费两年时间才成功培养出特殊细胞系,这恰恰是实现密码子扩展技术的关键步骤,也是我们能够大规模制备这种复制缺陷型病毒的核心技术。经过最初的环境适应,这种细胞系目前长势良好。作为完美的病毒包装载体,这个特殊细胞系具有重大的理论研究价值,我们还将探索其基因组、转录组测序特征,研究基因修饰细胞与正常生物体细胞之间的区别。

·基因密码子扩展技术在您研究的其他方向中,还有哪些重要的应用?

周德敏教授:地球上绝大多数生物体内的蛋白质翻译过程,由61个密码子和3个终止密码子执行,其中61个密码子产生20种天然氨基酸,并组成无数种不同的蛋白质。密码子扩展技术,旨在将生物体内闲置的终止密码子变身为有义密码子,从而让生物体合成出含有更多种类氨基酸的蛋白。非天然氨基酸最重要的作用是实现蛋白质定点修饰和标记。天然蛋白质由20种氨基酸进行排列组合,但能进行化学交联反应的氨基酸种类却很少,常用的结合位点为赖氨酸。多数蛋白质含有多个赖氨酸位点,如果需要对蛋白质进行偶联,则修饰物/标记物可能会被随机结合在任意一个赖氨酸位点。若某个蛋白质包含具有特殊反应活性的非天然氨基酸,则偶联反应会发生在特定氨基酸位点,从而实现可控的精准修饰。

我们利用这一技术已实现腺相关病毒(AAV)的非天然氨基酸定点标记及靶向修饰,有望催生新一代的靶向基因疗法。AAV病毒宿主范围广、病原性低、携带的治疗基因表达期长,是基因疗法常用的转染载体之一。 利用非天然氨基酸标记方法,可以进一步提升AAV病毒的细胞特异性、减少其对靶细胞之外的感染风险,从而提升转染效率。我们还是将终止密码子引入AAV病毒,并让其在模式细胞中表达出包含非天然氨基酸的蛋白质,从而使蛋白质可以定点定量引入多种修饰分子。


▲AAV病毒生命周期(图片来源:美国微生物协会网站)

我们选择脑胶质瘤为该疗法研究对象,通过让AAV病毒载体表达出环形RGD(精氨酰-甘氨酰-天冬氨酸)分子,引导病毒靶向整合素高表达的脑胶质瘤细胞。另外AAV病毒基因组还整合了HSV-TK(单纯疱疹病毒胸苷激酶)自杀基因,所以这种疗法大大提升了靶向杀伤脑胶质瘤细胞的能力。目前细胞实验阶段已经结束,我们将在下一阶段启动动物实验模型。

整合酶基因裂变:艾滋病疫苗研发的新靶标

·您目前在研的疫苗主要覆盖哪些疾病?未来您的团队还有哪些具体的研究发展方向?

周德敏教授:在疫苗研究领域,我目前主要是研发弱流感疫苗以预防其他重型流感,之后我们还会继续开发H1N1、H3N2、H5N1、H7N8型流感疫苗。除此之外,我们还会利用同样的方式研发EV71型手足口病、非典、埃博拉病毒疫苗。这些都是游离复制型病毒的疫苗,即病毒基因组以游离质粒方式自行复制,而不整合入宿主细胞基因组。

同时我们也已经启动了针对整合型病毒疫苗的研制,整合型病毒包括HIV等逆转录病毒。而HBV(乙肝病毒)、HPV(人乳头瘤病毒)等既可以游离态复制,也可整合到宿主细胞基因组并导致高危的癌变风险。这类病毒疫苗研发的靶标,是病毒整合入宿主基因组所需要的整合酶:我们在整合酶蛋白基因编码的特殊位点加上终止密码子,则整合酶无法翻译表达,这类病毒便无法整合进入宿主基因组,从而杜绝疫苗在人体内导致感染的风险。尽管这类病毒突变速率较快,但我们相信依据游离复制型疫苗的研发经验,我们有希望找到重大疾病的有效预防手段。


▲引起艾滋病的HIV通过整合酶,进入人体细胞基因组(图片来源:美国卫生部网站)

·在多年的学习和科研过程中,您有幸遇到国内外名师的指导。在科学精神的传承中,您有哪些特别的感触?

周德敏教授:我在国内的研究生课程中师承张礼和院士,学习药物全合成和天然产物合成。但老师站得高看得远,他很早就认识到生物制药发展的潜力,所以建议我进行日语培训。之后我有幸前往日本接受博士联合培养计划,并学习分子生物学。在日本我的进步很快,将生物和化学的界限打通,许多曾经困扰自己的问题豁然开朗,在1年半的时间里就在《JACS》、《PNAS》杂志上发表了好几篇重要论文。

正是有了跨界的知识积累,帮助我将不同领域的新技术组合,然后再产生自己的原创性突破。突破需要找到方法,更需要有敢于突破的勇气。面对失败的实验,不应该气馁或质疑自己,而应当坚持创新的想法,并且在失败中看到机遇。也许前人也遇到过同样的失败,却没有从中汲取成功的灵感,所以我们应当珍惜这样反败为胜的机遇。回国之前我曾在药企工作,负责过一个shRNA文库建设项目,当时我发现依据某一权威论文的数据进行实验却反复出现问题,我并未因无法重复权威实验而气馁,相反经过长时间实验和反复推敲,发现这篇论文中的关键环节错误,之后也有其他学者发表纠错论文证实了自己的想法。所以只要坚持对基础科学深入研究,一定能从失败中找到原因并产生新的发现。


▲ 周德敏教授课题组(从左到右):徐欢、司龙龙、周德敏教授、张礼和院士

优秀的老师教会我如何做人、做科研,而今作为博导和院系主管,我也希望将科研精神传承下去。另外我认为在实验课题的推进过程不能急功近利,3-5年的时间很正常;而对研究生的培养也不局限于传授知识,而是要给予同学们充分的主动权;和年轻学生在一起工作,我会让自己保持开放的心态,而不是墨守陈规,这样才能发挥名校优秀学生的聪明才智,让整个团队在攻克科学难题的道路上不断实现新的突破,为人类健康带来更多福祉。

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  1. [GetPortalCommentsPageByObjectIdResponse(id=2078833, encodeId=aa2320e883383, content=<a href='/topic/show?id=f48865242bb' target=_blank style='color:#2F92EE;'>#活疫苗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=65242, encryptionId=f48865242bb, topicName=活疫苗)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e4aa106, createdName=crystal0562, createdTime=Mon May 28 23:09:00 CST 2018, time=2018-05-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1703289, encodeId=1c671e032899a, content=<a href='/topic/show?id=dba720e31b7' target=_blank style='color:#2F92EE;'>#专访#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=103, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=20731, encryptionId=dba720e31b7, topicName=专访)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=070a30497323, createdName=flyingeagle87, createdTime=Fri Mar 30 22:09:00 CST 2018, time=2018-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1811265, encodeId=e02918112650f, content=<a href='/topic/show?id=e78b8e542bb' target=_blank style='color:#2F92EE;'>#药学院#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=87542, encryptionId=e78b8e542bb, topicName=药学院)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a0802500050, createdName=肉我只吃一口, createdTime=Tue Oct 02 04:09:00 CST 2018, time=2018-10-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=278916, encodeId=0a052e8916a8, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6d551998554, createdName=1e1c07bdm01(暂无匿称), createdTime=Tue Jan 16 06:47:59 CST 2018, time=2018-01-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1549265, encodeId=87a6154926515, content=<a href='/topic/show?id=f7879600061' target=_blank style='color:#2F92EE;'>#重磅#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=67, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=96000, encryptionId=f7879600061, topicName=重磅)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=3acc14121561, createdName=xxxx1054, createdTime=Fri Jan 12 14:09:00 CST 2018, time=2018-01-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277503, encodeId=5d352e75030d, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=119, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Thu Jan 11 10:04:47 CST 2018, time=2018-01-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277381, encodeId=88ba2e73819f, content=好好好好好好好好, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/29/bbc5cc0eed9b8d17623d2fd49dbdf19a.jpg, createdBy=79522135794, createdName=yjs木玉, createdTime=Thu Jan 11 05:21:44 CST 2018, time=2018-01-11, status=1, ipAttribution=)]
  2. [GetPortalCommentsPageByObjectIdResponse(id=2078833, encodeId=aa2320e883383, content=<a href='/topic/show?id=f48865242bb' target=_blank style='color:#2F92EE;'>#活疫苗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=65242, encryptionId=f48865242bb, topicName=活疫苗)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e4aa106, createdName=crystal0562, createdTime=Mon May 28 23:09:00 CST 2018, time=2018-05-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1703289, encodeId=1c671e032899a, content=<a href='/topic/show?id=dba720e31b7' target=_blank style='color:#2F92EE;'>#专访#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=103, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=20731, encryptionId=dba720e31b7, topicName=专访)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=070a30497323, createdName=flyingeagle87, createdTime=Fri Mar 30 22:09:00 CST 2018, time=2018-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1811265, encodeId=e02918112650f, content=<a href='/topic/show?id=e78b8e542bb' target=_blank style='color:#2F92EE;'>#药学院#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=87542, encryptionId=e78b8e542bb, topicName=药学院)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a0802500050, createdName=肉我只吃一口, createdTime=Tue Oct 02 04:09:00 CST 2018, time=2018-10-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=278916, encodeId=0a052e8916a8, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6d551998554, createdName=1e1c07bdm01(暂无匿称), createdTime=Tue Jan 16 06:47:59 CST 2018, time=2018-01-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1549265, encodeId=87a6154926515, content=<a href='/topic/show?id=f7879600061' target=_blank style='color:#2F92EE;'>#重磅#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=67, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=96000, encryptionId=f7879600061, topicName=重磅)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=3acc14121561, createdName=xxxx1054, createdTime=Fri Jan 12 14:09:00 CST 2018, time=2018-01-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277503, encodeId=5d352e75030d, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=119, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Thu Jan 11 10:04:47 CST 2018, time=2018-01-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277381, encodeId=88ba2e73819f, content=好好好好好好好好, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/29/bbc5cc0eed9b8d17623d2fd49dbdf19a.jpg, createdBy=79522135794, createdName=yjs木玉, createdTime=Thu Jan 11 05:21:44 CST 2018, time=2018-01-11, status=1, ipAttribution=)]
  3. [GetPortalCommentsPageByObjectIdResponse(id=2078833, encodeId=aa2320e883383, content=<a href='/topic/show?id=f48865242bb' target=_blank style='color:#2F92EE;'>#活疫苗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=65242, encryptionId=f48865242bb, topicName=活疫苗)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e4aa106, createdName=crystal0562, createdTime=Mon May 28 23:09:00 CST 2018, time=2018-05-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1703289, encodeId=1c671e032899a, content=<a href='/topic/show?id=dba720e31b7' target=_blank style='color:#2F92EE;'>#专访#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=103, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=20731, encryptionId=dba720e31b7, topicName=专访)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=070a30497323, createdName=flyingeagle87, createdTime=Fri Mar 30 22:09:00 CST 2018, time=2018-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1811265, encodeId=e02918112650f, content=<a href='/topic/show?id=e78b8e542bb' target=_blank style='color:#2F92EE;'>#药学院#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=87542, encryptionId=e78b8e542bb, topicName=药学院)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a0802500050, createdName=肉我只吃一口, createdTime=Tue Oct 02 04:09:00 CST 2018, time=2018-10-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=278916, encodeId=0a052e8916a8, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6d551998554, createdName=1e1c07bdm01(暂无匿称), createdTime=Tue Jan 16 06:47:59 CST 2018, time=2018-01-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1549265, encodeId=87a6154926515, content=<a href='/topic/show?id=f7879600061' target=_blank style='color:#2F92EE;'>#重磅#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=67, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=96000, encryptionId=f7879600061, topicName=重磅)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=3acc14121561, createdName=xxxx1054, createdTime=Fri Jan 12 14:09:00 CST 2018, time=2018-01-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277503, encodeId=5d352e75030d, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=119, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Thu Jan 11 10:04:47 CST 2018, time=2018-01-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277381, encodeId=88ba2e73819f, content=好好好好好好好好, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/29/bbc5cc0eed9b8d17623d2fd49dbdf19a.jpg, createdBy=79522135794, createdName=yjs木玉, createdTime=Thu Jan 11 05:21:44 CST 2018, time=2018-01-11, status=1, ipAttribution=)]
  4. [GetPortalCommentsPageByObjectIdResponse(id=2078833, encodeId=aa2320e883383, content=<a href='/topic/show?id=f48865242bb' target=_blank style='color:#2F92EE;'>#活疫苗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=65242, encryptionId=f48865242bb, topicName=活疫苗)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e4aa106, createdName=crystal0562, createdTime=Mon May 28 23:09:00 CST 2018, time=2018-05-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1703289, encodeId=1c671e032899a, content=<a href='/topic/show?id=dba720e31b7' target=_blank style='color:#2F92EE;'>#专访#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=103, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=20731, encryptionId=dba720e31b7, topicName=专访)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=070a30497323, createdName=flyingeagle87, createdTime=Fri Mar 30 22:09:00 CST 2018, time=2018-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1811265, encodeId=e02918112650f, content=<a href='/topic/show?id=e78b8e542bb' target=_blank style='color:#2F92EE;'>#药学院#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=87542, encryptionId=e78b8e542bb, topicName=药学院)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a0802500050, createdName=肉我只吃一口, createdTime=Tue Oct 02 04:09:00 CST 2018, time=2018-10-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=278916, encodeId=0a052e8916a8, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6d551998554, createdName=1e1c07bdm01(暂无匿称), createdTime=Tue Jan 16 06:47:59 CST 2018, time=2018-01-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1549265, encodeId=87a6154926515, content=<a href='/topic/show?id=f7879600061' target=_blank style='color:#2F92EE;'>#重磅#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=67, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=96000, encryptionId=f7879600061, topicName=重磅)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=3acc14121561, createdName=xxxx1054, createdTime=Fri Jan 12 14:09:00 CST 2018, time=2018-01-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277503, encodeId=5d352e75030d, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=119, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Thu Jan 11 10:04:47 CST 2018, time=2018-01-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277381, encodeId=88ba2e73819f, content=好好好好好好好好, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/29/bbc5cc0eed9b8d17623d2fd49dbdf19a.jpg, createdBy=79522135794, createdName=yjs木玉, createdTime=Thu Jan 11 05:21:44 CST 2018, time=2018-01-11, status=1, ipAttribution=)]
  5. [GetPortalCommentsPageByObjectIdResponse(id=2078833, encodeId=aa2320e883383, content=<a href='/topic/show?id=f48865242bb' target=_blank style='color:#2F92EE;'>#活疫苗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=65242, encryptionId=f48865242bb, topicName=活疫苗)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e4aa106, createdName=crystal0562, createdTime=Mon May 28 23:09:00 CST 2018, time=2018-05-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1703289, encodeId=1c671e032899a, content=<a href='/topic/show?id=dba720e31b7' target=_blank style='color:#2F92EE;'>#专访#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=103, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=20731, encryptionId=dba720e31b7, topicName=专访)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=070a30497323, createdName=flyingeagle87, createdTime=Fri Mar 30 22:09:00 CST 2018, time=2018-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1811265, encodeId=e02918112650f, content=<a href='/topic/show?id=e78b8e542bb' target=_blank style='color:#2F92EE;'>#药学院#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=87542, encryptionId=e78b8e542bb, topicName=药学院)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a0802500050, createdName=肉我只吃一口, createdTime=Tue Oct 02 04:09:00 CST 2018, time=2018-10-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=278916, encodeId=0a052e8916a8, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6d551998554, createdName=1e1c07bdm01(暂无匿称), createdTime=Tue Jan 16 06:47:59 CST 2018, time=2018-01-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1549265, encodeId=87a6154926515, content=<a href='/topic/show?id=f7879600061' target=_blank style='color:#2F92EE;'>#重磅#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=67, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=96000, encryptionId=f7879600061, topicName=重磅)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=3acc14121561, createdName=xxxx1054, createdTime=Fri Jan 12 14:09:00 CST 2018, time=2018-01-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277503, encodeId=5d352e75030d, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=119, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Thu Jan 11 10:04:47 CST 2018, time=2018-01-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277381, encodeId=88ba2e73819f, content=好好好好好好好好, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/29/bbc5cc0eed9b8d17623d2fd49dbdf19a.jpg, createdBy=79522135794, createdName=yjs木玉, createdTime=Thu Jan 11 05:21:44 CST 2018, time=2018-01-11, status=1, ipAttribution=)]
    2018-01-12 xxxx1054
  6. [GetPortalCommentsPageByObjectIdResponse(id=2078833, encodeId=aa2320e883383, content=<a href='/topic/show?id=f48865242bb' target=_blank style='color:#2F92EE;'>#活疫苗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=65242, encryptionId=f48865242bb, topicName=活疫苗)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e4aa106, createdName=crystal0562, createdTime=Mon May 28 23:09:00 CST 2018, time=2018-05-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1703289, encodeId=1c671e032899a, content=<a href='/topic/show?id=dba720e31b7' target=_blank style='color:#2F92EE;'>#专访#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=103, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=20731, encryptionId=dba720e31b7, topicName=专访)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=070a30497323, createdName=flyingeagle87, createdTime=Fri Mar 30 22:09:00 CST 2018, time=2018-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1811265, encodeId=e02918112650f, content=<a href='/topic/show?id=e78b8e542bb' target=_blank style='color:#2F92EE;'>#药学院#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=87542, encryptionId=e78b8e542bb, topicName=药学院)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a0802500050, createdName=肉我只吃一口, createdTime=Tue Oct 02 04:09:00 CST 2018, time=2018-10-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=278916, encodeId=0a052e8916a8, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6d551998554, createdName=1e1c07bdm01(暂无匿称), createdTime=Tue Jan 16 06:47:59 CST 2018, time=2018-01-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1549265, encodeId=87a6154926515, content=<a href='/topic/show?id=f7879600061' target=_blank style='color:#2F92EE;'>#重磅#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=67, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=96000, encryptionId=f7879600061, topicName=重磅)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=3acc14121561, createdName=xxxx1054, createdTime=Fri Jan 12 14:09:00 CST 2018, time=2018-01-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277503, encodeId=5d352e75030d, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=119, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Thu Jan 11 10:04:47 CST 2018, time=2018-01-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277381, encodeId=88ba2e73819f, content=好好好好好好好好, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/29/bbc5cc0eed9b8d17623d2fd49dbdf19a.jpg, createdBy=79522135794, createdName=yjs木玉, createdTime=Thu Jan 11 05:21:44 CST 2018, time=2018-01-11, status=1, ipAttribution=)]
    2018-01-11 明月清辉

    谢谢分享.学习了

    0

  7. [GetPortalCommentsPageByObjectIdResponse(id=2078833, encodeId=aa2320e883383, content=<a href='/topic/show?id=f48865242bb' target=_blank style='color:#2F92EE;'>#活疫苗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=65242, encryptionId=f48865242bb, topicName=活疫苗)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e4aa106, createdName=crystal0562, createdTime=Mon May 28 23:09:00 CST 2018, time=2018-05-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1703289, encodeId=1c671e032899a, content=<a href='/topic/show?id=dba720e31b7' target=_blank style='color:#2F92EE;'>#专访#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=103, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=20731, encryptionId=dba720e31b7, topicName=专访)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=070a30497323, createdName=flyingeagle87, createdTime=Fri Mar 30 22:09:00 CST 2018, time=2018-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1811265, encodeId=e02918112650f, content=<a href='/topic/show?id=e78b8e542bb' target=_blank style='color:#2F92EE;'>#药学院#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=87542, encryptionId=e78b8e542bb, topicName=药学院)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a0802500050, createdName=肉我只吃一口, createdTime=Tue Oct 02 04:09:00 CST 2018, time=2018-10-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=278916, encodeId=0a052e8916a8, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6d551998554, createdName=1e1c07bdm01(暂无匿称), createdTime=Tue Jan 16 06:47:59 CST 2018, time=2018-01-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1549265, encodeId=87a6154926515, content=<a href='/topic/show?id=f7879600061' target=_blank style='color:#2F92EE;'>#重磅#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=67, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=96000, encryptionId=f7879600061, topicName=重磅)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=3acc14121561, createdName=xxxx1054, createdTime=Fri Jan 12 14:09:00 CST 2018, time=2018-01-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277503, encodeId=5d352e75030d, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=119, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Thu Jan 11 10:04:47 CST 2018, time=2018-01-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=277381, encodeId=88ba2e73819f, content=好好好好好好好好, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/29/bbc5cc0eed9b8d17623d2fd49dbdf19a.jpg, createdBy=79522135794, createdName=yjs木玉, createdTime=Thu Jan 11 05:21:44 CST 2018, time=2018-01-11, status=1, ipAttribution=)]
    2018-01-11 yjs木玉

    好好好好好好好好

    0

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