抗生素 引起 的肠道 菌 群紊乱改变了人体对疫苗的免疫力 Antibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans. 《 CELL 》杂志的论文摘要 ( Cell. 2019 Sep 5;178(6):1313-1328.) 作者： Hagan T 1 , Cortese M 1 , Rouphael N 2 , Boudreau C 3 , Linde C 3 , Maddur MS 4 , Das J 3 , Wang H 4 , Guthmiller J 5 , Zheng NY 5 , Huang M 5 , Uphadhyay AA 4 , Gardinassi L 6 , Petitdemange C 4 , McCullough MP 2 , Johnson SJ 2 , Gill K 4 , Cervasi B 4 , Zou J 7 , Bretin A 7 , Hahn M 8 , Gewirtz AT 7 , Bosinger SE 4 , Wilson PC 5 , Li S 6 , Alter G 3 , Khurana S 8 , Golding H 8 , Pulendran B 9 . 作者单位： 1 Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA. 2 Hope Clinic of the Emory Vaccine Center, Decatur, GA 30030, USA. 3 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. 4 Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, GA 30329, USA. 5 Department of Medicine, Section of Rheumatology, Knapp Center for Lupus and Immunology, University of Chicago, Chicago, IL 60637, USA. 6 Department of Medicine, Emory University, Atlanta, GA 30303, USA. 7 Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA. 8 Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. 9 Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA . Highlights ( 本论文的 亮点 ): 菌群 的缺 失会 削弱 早先未曾接种的 受试者的抗体反应 。 抗生素治疗可增强血液中的炎症信号 。 次级胆汁酸的 丢 失与 AP-1/NR4A和炎性小体 （ inflammasome ） 的激活有关 。 综合分析揭示了 菌群影响 免疫的 不同 机制 。 Graphical Abstract ( 图解摘要 ) Abstract （摘要） 新出现的证据表明， 菌 群在免疫中起着核心作用。然而，在人 体中 的因果证据很少。在这里，我们在季节性流感疫苗接种之前和之后对健康成年人使用广谱抗生素。尽管肠道细菌负荷减少了 1 万倍，细菌多样性持续减少，但抗体反应没有受到显著影响。然而，在第二 项 试验中， 在先前存在的 抗体滴度较低的受试者 中 ，在 H 1 N 1 特异性中和 活性 和结合 IgG1 和 IgA 的能力 方面存在明显的 缺损 。 此外，在这两项研究中，抗生素治疗 会 导致 ： (1) 增强炎症信号 ( 包括 AP-1/NR4A 表达 ) ，这在以前 曾在 老年人中观察到，并 观察到 树突状细胞的激活 增加 ;(2) 不同的代谢轨迹，血清次级胆汁酸减少 1000 倍，与 AP-1/NR4A 信号通路和炎性小体 （ inflammasome ） 激活高度相关。多组学 （ Multi-omics ）的 整合揭示了细菌种类和代谢表型之间的重要联系，突出 展现 了 菌群 在调节人类免疫中的关键作用。 关键词： 抗体 ; 胆汁酸 ; 基因表达分析 ; 免疫学 ; 流感 ; 代谢组学 ; 微生物群 ; 系统生物学 ; 系统疫苗 学 ; 疫苗 原文链接 ： Antibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans. Cell. 2019 Sep 5;178(6):1313-1328.e13.doi: 10.1016/j.cell.2019.08.010. 相关博文： 抗生素会减弱抗体对流感疫苗的反应 2019-12-25
STM——抗tau抗体增加血浆tau蛋白水平（Sink hypothesis？） 摘要 Tauopathies are a group of disorders in which the cytosolic protein tau aggregates and accumulates in cells within the brain, resulting in neurodegeneration. A promising treatment being explored for tauopathies is passive immunization with anti-tau antibodies. We previously found that administration of an anti-tau antibody to human tau transgenic mice increased the concentration of plasma tau. We further explored the effects of administering an anti-tau antibody on plasma tau. After peripheral administration of an anti-tau antibody to human patients with tauopathy and to mice expressing human tau in the central nervous system, there was a dose-dependent increase in plasma tau. In mouse plasma, we found that tau had a short half-life of 8 min that increased to more than 3 hours after administration of anti-tau antibody. As tau transgenic mice accumulated insoluble tau in the brain, brain soluble and interstitial fluid tau decreased. Administration of anti-tau antibody to tau transgenic mice that had decreased brain soluble tau and interstitial fluid tau resulted in an increase in plasma tau, but this increase was less than that observed in tau transgenic mice without these brain changes.Tau transgenic mice subjected to acute neuronal injury using 3-nitropropionic acid showed increased interstitial fluid tau and plasma tau. These data suggest that peripheral administration of an anti-tau antibody results in increased plasma tau, which correlates with the concentration of extracellular and soluble tau in the brain（突然之间，我已经不喜欢写中文了，还是英文原文更加有意思）. 1.在Tg小鼠和PSP患者中，抗tau抗体都增加血浆tau水平 2.HJ8.5增加过表达htau的不同小鼠的血浆tau蛋白水平 3.P301S小鼠大脑中可溶性tau显著下降 经典文章回顾 帕金森病患者的康复治疗 帕金森病患者的疾病预防和保健常识 10条老年性痴呆患者的护理常识 四条建议教老年人预防老年性痴呆 老年性痴呆患者的饮食禁忌和饮食调理 2016年阿尔茨海默病10大研究进展 2016年帕金森病10大研究进展 你对老年性痴呆症到底懂多少？ 地中海饮食最健康的神经科学分析 八种食物提高记忆力，增强脑活力！ 预防老年性痴呆症，先从这些小事做起！ 睡眠不足增加肥胖风险的神经科学解释 运动是大脑的最佳保健品 预防痴呆和脑中风，减少PM2.5是我们可以做的 益生菌也能够治疗痴呆、抑郁症和精神分离症？ 喜欢我，关注我 拉到最上方标题下，点击上方蓝字关注 搜索公众号名称：神经科学临床和基础 也请你推荐给你身边的医学朋友，感谢你~
抗体（ antibody ）指机体的免疫系统在抗原刺激下，由 B 淋巴细胞或记忆细胞增殖分化成的浆细胞所产生的、可与相应抗原发生特异性结合的免疫球蛋白。主要分布在血清中，也分布于组织液及外分泌液中。 1964 年，世界卫生组织举行专门会议，将具有抗体活性以及与抗体相关的球蛋白统称为免疫球蛋白（ Ig ），如骨髓瘤蛋白，巨球蛋白血症、冷球蛋白血症等患者血清中存在的异常免疫球蛋白以及正常人天然存在的免疫球蛋白亚单位等。因而免疫球蛋白是结构化学的概念，而抗体是生物学功能的概念。可以说，所有抗体都是免疫球蛋白，但并非所有免疫球蛋白都是抗体。抗体的生物学活性包括特异性结合抗原、激活补体、结合细胞、通过胎盘及粘膜、具有抗原性、通过与细胞 Fc 受体结合发挥多种生物效应（调理作用和抗体依赖细胞介导的细胞毒作用）等。 经典的抗体只在细胞外发挥作用，最近研究发现，细胞内也存在抗体，而且这种细胞内抗体也具有生物学作用。这一方面说明我们过去的许多知识特别是生物医学方面都是不全面的,科学经常是给我们令人吃惊方式展现新知识。 细胞受到抗原感染期间，抗体在细胞内也可以存在，并可以和广泛表达的细胞内抗体受体 TRIM21 结合。 William McEwan 等最近在人和小鼠体内发现， TRIM21 识别细胞内抗体可激活免疫信号，导致促炎因子产生、诱导抗病毒免疫反应。激活 TRIM21 的细胞内抗体可以被 DNA 或 RNA 病毒或细胞内细菌诱导，提示这一功能是和传统的各种抗原分子通过模式识别受体特异性的信号通路完全不同。也就是说发现一种新型免疫激活模式，或者说即使进入细胞内，病毒和细菌仍会引起免疫反应，不能完全避免被围剿的命运。不过这种方式应该可以通过释放细胞因子启动其他细胞参与免疫反应.这样和传统的免疫活动就可以产生对接. 个人想法：细胞外模式识别分子也包括真核细胞自身的成分，在某些非细胞坏死的病理情况下，细胞内的某些分子出现在不该出现的区域，是否可以可以启动类似的信号通路。如果是这样，将会有不少关于人类疾病发生方面的重新认识。 Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21 William A McEwan , 1 Jerry C H Tam , 1 Ruth E Watkinson , 1 Susanna R Bidgood , 1 Donna L Mallery 1 Leo C James 1 Affiliations Contributions Corresponding authors Journal name: Nature Immunology Year published: (2013) DOI: doi:10.1038/ni.2548 Received 03 October 2012 Accepted 17 January 2013 Published online 03 March 2013 Article tools Citation Reprints Rights permissions Metrics Abstract Abstract Author information Supplementary information During pathogen infection, antibodies can be carried into the infected cell, where they are detected by the ubiquitously expressed cytosolic antibody receptor TRIM21. Here we found that recognition of intracellular antibodies by TRIM21 activated immune signaling. TRIM21 catalyzed the formation of Lys63 (K63)-linked ubiquitin chains and stimulated the transcription factor pathways of NF-κB, AP-1, IRF3, IRF5 and IRF7. Activation resulted in the production of proinflammatory cytokines, modulation of natural killer stress ligands and induction of an antiviral state. Intracellular antibody signaling was abrogated by genetic deletion of TRIM21 and was restored by ectopic expression of TRIM21. The sensing of antibodies by TRIM21 was stimulated after infection by DNA or RNA nonenveloped viruses or intracellular bacteria. Thus, the antibody-TRIM21 detection system provides potent, comprehensive activation of the innate immune system independently of known pattern-recognition receptors.
红斑狼疮抗体可用作攻击DNA修复缺陷的癌症新疗法 发布：2012/10/25 来自：生物探索 阅读数： 664 导读 《科学--转化医学》24日刊登的一篇研究报告称，系统性红斑狼疮抗体会使癌细胞对化疗变得更为敏感。这是耶鲁大学医学院、耶鲁大学癌症中心及加州大学等研究机构共同参与的一项研究。这些结果提示，该抗体可用来作为一种攻击DNA修复有缺陷的癌细胞的新疗法 《科学--转化医学》24日刊登的一篇研究报告称，系统性 红斑狼疮 抗体会使癌细胞对 化疗 变得更为敏感。系统性 红斑狼疮 是一种自身免疫系统疾病，它会攻击身体自身的健康细胞和组织。这些发现是人们第一次证明狼疮抗体可潜在地用于治疗癌症。 系统性红斑狼疮是一种影响全世界5百多万人的自身免疫性疾病。这项研究可帮助解释在罹患狼疮的患者中有着意想不到的 乳腺癌 、 卵巢癌 和 前列腺癌 的低发病率。 这是耶鲁大学医学院、耶鲁大学癌症中心及加州大学等研究机构共同参与的一项研究。James Hansen及其同事在实验室中确认了一种叫做3E10的狼疮抗体可使卵巢肿瘤对放疗敏感。狼疮抗体是通过穿透细胞并附着于DNA从而打乱了修复DNA所需的细胞机器而发挥作用的。在没有修复DNA的能力时，细胞对像放疗等损伤DNA的疗法会变得更为敏感。 令人意外的是，该抗体本身（无需放疗或 化疗 ）可杀灭DNA修复有缺陷的像 乳腺癌 、 卵巢癌 或 前列腺癌 等的癌细胞。 这些结果提示，该抗体可用来作为一种攻击DNA修复有缺陷的癌细胞的新疗法，但同时又不会伤害正常细胞。另外，用于本研究的这种抗体已经作为一种狼疮疫苗，在人体的临床试验中通过了测试并被认为是安全的。 Targeting Cancer with a Lupus Autoantibody . James E. Hansen, Grace Chan, Yanfeng Liu, Denise C. Hegan, Shibani Dalal1, Eloise Dray, Youngho Kwon, Yuanyuan Xu, Xiaohua Xu, Elizabeth Peterson-Roth, Erik Geiger, Yilun Liu, Joseph Gera, Joann B. Sweasy, Patrick Sung, Sara Rockwell, Robert N. Nishimura, Richard H. Weisbart and Peter M. Glazer Abstract： Systemic lupus erythematosus (SLE) is distinct among autoimmune diseases because of its association with circulating autoantibodies reactive against host DNA. The precise role that anti-DNA antibodies play in SLE pathophysiology remains to be elucidated, and potential applications of lupus autoantibodies in cancer therapy have not previously been explored. We report the unexpected finding that a cell-penetrating lupus autoantibody, 3E10, has potential as a targeted therapy for DNA repair–deficient malignancies. We find that 3E10 preferentially binds DNA single-strand tails, inhibits key steps in DNA single-strand and double-strand break repair, and sensitizes cultured tumor cells and human tumor xenografts to DNA-damaging therapy, including doxorubicin and radiation. Moreover, we demonstrate that 3E10 alone is synthetically lethal to BRCA2-deficient human cancer cells and selectively sensitizes such cells to low-dose doxorubicin. 文献链接 ： Targeting Cancer with a Lupus Autoantibody. 相关热点 张学军团队又发现5个红斑狼疮易感基因 1月10日 Nature 杂志生物学精选 全基因组测序助推常规巴氏检测法敏锐诊断肿瘤 英国10年研究数据支持缩短乳腺癌放疗 2012年乳腺癌讨论会公布5项乳腺癌新发现
【文献导读】 恶性肿瘤的常见疗法不外乎放疗、化疗和手术治疗，其中放化疗是不能区分正常细胞与肿瘤细胞（无靶向性）的全细胞“绝杀”，采取的战略战术是“宁可错杀三千也不能放走一个”！因此，放化疗的毒副作用非常明显也十分严重，而这种残酷折磨对于患者本人或家属来说都是难以忍受的。 那么，有没有只杀肿瘤细胞的药物呢？答案是肯定的，那就是免疫治疗药物。同样是抗癌药物，免疫药物的靶向性高，因而毒副作用很低。例如，针对肿瘤细胞表面特有抗原（正常细胞无）设计的抗体，可以通过非常专一的抗原-抗体结合反应识别肿瘤细胞并与之结合。假如让抗体携带肿瘤杀伤药物，那么它就能直达靶标杀死肿瘤细胞，而不会伤及正常细胞。这种抗体-药物复合物就是多年前曾经轰动一时的“生物导弹”。 2010年美国FDA批准了一种叫做Sipuleucel-T的肿瘤疫苗上市，商品名为Provenge，用于前列腺癌的治疗。这个肿瘤疫苗可以刺激患者本身的免疫细胞，让它们能有效攻击前列腺癌细胞。2011年，FDA又批准另一种药物ipilimumab（商品名为Yervoy）上市，用于黑色素瘤治疗。这个药物靶向细胞毒T淋巴细胞抗原4（CTLA-4），恢复T细胞杀死黑色素瘤细胞的功能。 可惜该药物没有选择性，既能杀死肿瘤细胞，也能杀死正常细胞。 本月2号，New England Journal of Medicine发表了一篇描述抗PD-1抗体用于肿瘤治疗的临床一期实验结果的研究论文，Nature在本月6号的“焦点新闻”栏目中还专门撰文予以介绍。所谓PD-1是“程序性细胞死亡1”（programmed cell death 1）膜蛋白，它与T细胞受体一样位于T细胞表面。肿瘤细胞上相应的PD-1配基（PD-1L）可与T细胞上的PD-1像“锁”和“钥匙”那样“契合”，从而“封锁”了T细胞的免疫应答，使T细胞无法行使杀伤肿瘤细胞的功能，这也许就是肿瘤细胞得以逃避机体免疫监视的重要原因。 给肿瘤患者注射抗PD-1抗体后，就使被束缚的T细胞被解救出来。根据客观应答（肿瘤缩小或消失）的评价，在全部236名肿瘤患者中，非小细胞肺癌的应答率为18%，黑色素瘤的应答率是28%，肛门细胞癌的应答率是27%。31人中有20人的应答有效期可持续一年以上。在17名PD-L1阴性肿瘤患者中，无一有客观应答；在25名PD-L1阳性肿瘤患者，9人有客观应答。 这项实验的一个重大突破在于首次将有效率提高到接近30%，而以往的疗效一般在10%以下。不过，这个药物还是存在一定的副作用（11%），在用药过程中，有3人（1%）因肺部炎症而死亡。因此，有人正在尝试用抗PD-1L抗体代替抗PD-1抗体，以避免严重的副作用。 New Engl J Med 论文下载链接： http://www.nejm.org/doi/full/10.1056/NEJMoa1200690 Nature 评论下载链接： http://www.nature.com/news/antibody-alarm-call-rouses-immune-response-to-cancer-1.10784
由于忙于经营自己的实验也很少来科学网逛了，今天做完实验喘口气上来逛逛。 western blotting（WB）可以说是实验中用的最多的技术，因此关于WB的操作和经验的文章也是一搜一箩筐，本人算上这次实验总共也不过做了几次完整的WB，而这次做的也是一种全新的蛋白，但是本人却一次拿到结果，虽然结果没有说一丁点杂带和背景也没有，但还是很说的过去的。听很多人也见很多人抱怨wb难做，甚至拿到一个漂亮结果要几个星期甚至几个月，但是本人觉得做个WB真的没有想象中那么难，本人三天就拿到了结果，当然有一点点运气的成分，比如一抗二抗的浓度一次性选择了较佳的比例，但是即使不是用的最佳比例，但只要从高开始探索还是能拿到结果的。wb最重要的就是抗体和蛋白了（抗体不灵敏，提取的蛋白含量很高也可能没有结果，而提取的蛋白中不含要检测的蛋白那么再灵敏的抗体也是无济于事），如果有一个好的抗体和没有问题的蛋白那么不出结果是很没有道理的。除了这两方面，其他做不出结果的原因可总结到一点：操作不认真，不仔细。从配胶到转膜到显影，这些都是有点机械化的过程，只要肯动动脑子，对拿到结果影响不大。 如果认认真真的操作还没有结果，那还是考虑换抗体和蛋白吧，因为只要这两个东西是好的，不出结果真的没道理。
RNA酶和核酸配基，单链寡核酸链具有高级三维结构，既能够与蛋白质等特异性结合，也能够作为酶高效催化生物与化学反应。Aptamer与蛋白质结合的强度和特异性均不亚于单克隆抗体，而且SELEX 筛选技术使得Aptamer的筛选非常容易而快速，相对单克隆抗体的制备要简单得多，因此Aptamer在临床诊断及治疗方面具有广泛的应用前景。 Aptamer 适体；核酸识体；适配子 Aptamers are single-stranded oligonucleotides with a length of tens of nucleotides and single stranded DNA aptamers have a very highly ordered tertiary structure,which allows them to form stable and specific complex with different targets such as protein,nucleic acid. 可用于定量检测目标蛋白，其亲和性及专一性与单克隆抗体有一拼，且半衰期较长，不易变性，稳定性也较好。由于其属于核酸，在DNA检测方面的发展也可以运用于此。 下面介绍一下跟aptamer有关的一个比较有趣的东西，叫做Riboswitch。很多aptamer在没有ligand结合的时候是没有稳定的高级结构的，但当ligand存在时就会折叠成紧密的三级结构。于是有人把某种小分子的aptamer插在E.coli mRNA的核糖体结合位点（Ribosome binding site, RBS） 和起始密码子之间，当小分子不存在时，核糖体能顺利读过aptamer区域，翻译蛋白质；但当小分子存在时，apatmer区域紧密折叠。使得核糖体不能顺利读过，抑制了蛋白质的翻译。这是完全人工构造的翻译水平的调控模型。实际上有很多natural的riboswitch的例子，作用机理多种多样，但大多出现在5'UTR，而且都是利用小分子与mRNA上aptamer区域的相互结合改变RNA结构，从而调节翻译或转录中止。Yale的Ronald Breaker就是因为发现了这些自然的riboswitch而扬名利万，最近两年风光无限。我老板有一个rotation project，就是把ATP aptamer（可以区分ATP和ADP/AMP）构造成riboswitch，后面接上报告基因，实时反映细胞内的能荷。但好像还没人愿意做这个项目。我正在酝酿中的一个project也是利用人工riboswitch来对一些蛋白进行engineering，现在还在可行性验证阶段，呵呵。 小型RNA分子因為被發現可控制基因表現，近幾年來受到科學家們的注意。然而另一種RNA能夠偵測一些小分子的量來幫助細胞運作更為順暢，並且可以藉由細胞本身的需要來改變基因的表現與否。 耶魯大學分子學家Ronald Breaker與他的研究團隊發堀出這些具有多項能力的RNA分子--稱之為riboswitch—而這些riboswitch就是指由特定的mRNA結合住所謂的代謝分子 (metabolite)，藉由改變mRNA的形狀來啟動基因的表現與否，而這些代謝分子的產生是經由一些基因藉由感受代謝分子的量多量少來調節的。先前都假定有一個特定的蛋白質來結合住代謝分子並且啟動下游的基因的表現或抑制，而過去Breaker和其他大學的研究學者一樣花了相當大的精神與時間來找尋這個蛋白質，但卻都徒勞無功。然而有一個理由讓他們都找不到的原因就是這個神秘的蛋白質是一個真實的mRNA，而並非是一個蛋白質。 在這次的會議中，Breaker報告一個細菌的riboswitch，並且將發表在Nature上。這個riboswitch可以調節glucosamine的量 (這是一個可以幫助細菌形成細胞壁的物質) ，這個riboswitch也是一個ribozyme，可以利用切開RNA來調控基因的表現，當細胞中glucosamine的量高時，代謝分子會結合住mRNA並誘使mRNA來切斷他自己，但是奇怪的是mRNA切的位置是不會轉譯成蛋白質的區域，然而還是可以破壞基因的表現，Breaker也不知道為什麼。不過Breaker的研究是受到肯定的，而這樣的機關也可以在真菌和植物中發現，Breaker進一步計畫開始找尋動物中這樣的機關存在。
http://www.gopubmed.org/web/gopubmed/1?WEB0slirnuhkrhkfIoI1I00f01000j10040001rl 2F5 and 4E10 and HIV HIV-1 94 of 104 documents semantically analyzed Top Years Publications 2009 26 2008 18 2007 17 2006 11 2005 10 2004 6 2001 4 2003 1 1996 1 Top Countries Publications USA 54 France 7 Netherlands 6 China 4 Spain 4 Austria 4 South Africa 3 Switzerland 3 Canada 2 Germany 2 Portugal 1 India 1 Thailand 1 Israel 1 Taiwan 1 1 2 Top Cities Publications Durham 9 Boston 8 New York 6 Amsterdam 6 Bethesda 5 Seattle 4 Frederick 4 Wien 4 Beijing 3 Paris 3 Jo'anna 3 Bilbao 3 Zrich 3 Rockville 2 Grenoble 2 Atlanta 2 Madison 1 Irvine 1 Toronto 1 San Francisco 1 1 2 1 2 Top Journals Publications J Virol 34 Virology 9 Aids 7 Proc Natl Acad Sci U S A 3 Vaccine 3 Curr Hiv Res 3 Aids Res Hum Retrov 3 Bing Du Xue Bao 2 J Immunol 2 Biochemistry-us 2 J Biol Chem 2 Plos One 1 Mucosal Immunol 1 Chembiochem 1 Biochemistry 1 Microbes Infect 1 Biochim Biophys Acta 1 Febs Lett 1 Retrovirology 1 Faseb J 1 1 2 1 2 3 ... 32 Top Terms Publications HIV-1 94 Antibodies 92 antigen binding 92 Viruses 78 Epitopes 72 Humans 72 Antibodies, Monoclonal 70 gp41 67 HIV 65 HIV Antibodies 58 HIV Envelope Protein gp41 55 Neutralization Tests 55 Vaccines 54 Vaccination 54 HIV Infections 40 Amino Acid Sequence 37 Immunization 36 Immunity 35 Peptides 32 Membranes 32 1 2 3 ... 32 1 2 3 ... 29 Top Authors Publications Katinger H 19 Stiegler G 17 Burton D 8 Kunert R 7 Vcelar B 6 Zwick M 6 Montefiori D 5 Wang M 5 Joos B 4 Binley J 4 Liao H 3 Yu H 3 Zhang M 3 Morris L 3 Mehandru S 3 Markowitz M 3 Armbruster C 3 Ruprecht R 3 Haynes B 3 Alam S 3 1 2 3 ... 29 http://www.sciencenet.cn/htmlnews/2009/11/225107.shtm 研究发现两种抗体对抗艾滋病毒机制 为艾滋病疫苗的研制指明新方向 美国杜克大学医学中心研究人员发现了两种强力抗体2F5和4E10阻断艾滋病病毒（HIV）感染的机制。该发现为研制新的、更有效的艾滋病疫苗指出了一个新方向。相关研究刊发在美国《国家科学院院刊》（ PNAS ）上。 美国杜克大学医学中心人类疫苗研究所的S穆尼尔阿拉姆博士和哈佛医学院的儿科助理教授陈兵（音译）博士一起，对两种对抗HIV的潜在强力抗体2F5和4E10进行了研究。这两种抗体十分罕见，属于广效性中和抗体，它们能够阻断若干不同的HIV毒株。HIV有其致命的薄弱之处，即所谓的病毒外层包膜近侧区。在这一区域靠近病毒包膜的一部分外蛋白质层，会在细胞融合和感染过程中短暂开放，从而使病毒有几分钟的时间暴露在抗体面前。而这两种抗体正是利用这个机会与病毒绑定，从而阻断HIV。 但要控制病毒感染，还面临着这样的问题：在艾滋病病毒感染者中，这两种抗体十分罕见，而目前的试验性疫苗还不能产生这些抗体。此外，这类抗体的机会之窗也十分狭窄。 病毒目标区域只开放几分钟也许只有15分钟甚至更短。阿拉姆博士说，除非抗体与目标十分接近，并做好了准备，否则就不会起作用。这意味着我们要设计出新型疫苗，可诱导更多的这类抗体，让它们在感染的最初阶段即投入战斗。 2F5和4E10都具有很长的、一圈一圈的蛋白质片段，这些片段具有疏水性，这意味着它们容易被脂质吸引。研究人员发现，抗体要成功对接到HIV的外膜区域，有赖于抗体可依附在HIV外层类脂包膜上，而这些包膜中就含有脂质。 该研究团队已开始设计一种含有脂质成分的疫苗。该论文的合著者、人类疫苗研究所主任巴顿海恩斯指出，在这些中和抗体的所有功能中，病毒粒子脂质反应性作用给他们的研究提供了一个关键性切入点，即免疫系统需要看到什么才会产生这类抗体。他们基于这些发现而设计出的新型疫苗，目前已开始进行动物试验。 更多阅读 美国《国家科学院院刊》发表论文摘要（英文） http://www.pnas.org/content/early/2009/11/10/0908713106.abstract?sid=407af014-6a89-4988-8d04-144fece8b253 Role of HIV membrane in neutralization by two broadly neutralizing antibodies S. Munir Alam a , 1 , 2 , Marco Morelli b , c , 1 , S. Moses Dennison a , Hua-Xin Liao a , Ruijun Zhang a , Shi-Mao Xia a , Sophia Rits-Volloch b , d , Li Sun e , Stephen C. Harrison a , d , f , Barton F. Haynes a and Bing Chen b , f , 2 + Author Affiliations a Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710; b Laboratory of Molecular Medicine, Children's Hospital, d Howard Hughes Medical Institute, and f Department of Pediatrics, Harvard Medical School, 320 Longwood Avenue, Boston, MA 02115; c Program in Virology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115; and e Xiamen Amoytop Biotech Company, Ltd., 330 Wengjiao Road, Xiamen, Fujian, China 361022 1 S.M.A. and M.M. contributed equally to this work. Edited by Peter Cresswell, Yale University School of Medicine, New Haven, CT, and approved October 2, 2009 (received for review August 3, 2009) Abstract Induction of effective antibody responses against HIV-1 infection remains an elusive goal for vaccine development. Progress may require in-depth understanding of the molecular mechanisms of neutralization by monoclonal antibodies. We have analyzed the molecular actions of two rare, broadly neutralizing, human monoclonal antibodies, 4E10 and 2F5, which target the transiently exposed epitopes in the membrane proximal external region (MPER) of HIV-1 gp41 envelope during viral entry. Both have long CDR H3 loops with a hydrophobic surface facing away from the peptide epitope. We find that the hydrophobic residues of 4E10 mediate a reversible attachment to the viral membrane and that they are essential for neutralization, but not for interaction with gp41. We propose that these antibodies associate with the viral membrane in a required first step and are thereby poised to capture the transient gp41 fusion intermediate. These results bear directly on strategies for rational design of HIV-1 envelope immunogens.
Affinity （亲和力） : the strength of binding of one epitope to a monovalent antibody, such as Fab fragment, and is expressed in terms of the association constant, Ka . 亲和力 为一个抗原表位与单价抗体结合的能力，用 Ka 表示 (M -1 ,1/moles per liter) ，值越大表示亲和力越大，可高达 10 12 M -1 。室温时，大部分抗原抗体相互作用可于 1h 内达到平衡，但在 4 度时却要更长时间（ over night ）才能达到平衡。 Avidity （亲合力） ： a measure of the contribution of multivalent interactions to the stability of the antigen-antibody complex. 一个抗体分子与整个抗原之间的结合强度。 区别联系 ： 低 affinity （亲和力） 的抗体也许不适合进行 免疫沉淀 ，但往往可以于 免疫组化 实验中得到很好的结果，这正是由于其高 Avidity （亲合力）。 然而与蛋白的 低 affinity （亲和力） 交叉 反应也可在免疫组化技术中造成许多麻烦。 Specificity( 特异性 ) ： 由于抗体识别抗体相对较小的区域，故由于抗原分子之间结构有相关性的话，抗体偶尔识别其它抗原的现象也就不奇怪了。免疫组化不容易验证抗体的特异性，一般要用 IP 或 WB 来验证。 下面用一表来描述特异性在各种免疫化学反应中的区别： 技术 交叉反应 注意事项 评 价 免疫染色 普遍 较难识别，因为证实抗原一致性的辅助方法有困难 两个无关抗体的对照很重要 免疫沉淀 偶尔 区别交叉反应和相关性很重要 需设立好的对照 免疫印迹 普遍 容易识别，因为根据抗原分子的大小可鉴定 免疫亲和纯化 偶尔 应该避免使用交叉反应抗体 上表引自： http://www.uscnlife.cn/web/page/news5927.htm
http://news.sciencenet.cn/htmlnews/2009/10/224489.shtm 查新信息分析和知识发现结论： 经检索1966 - 2009年的美国PUBMED数据库和欧洲EMBESE数据库，检索到相关文献6篇，未检索到与该课题的研究内容相同的文献报道。Extracellular histones are major mediators of death in sepsis的研究成果具有新颖性。与该研究课题相关的100篇文献（PUBMED数据库）计量分析可以看出文献的国家、城市、作者、期刊、年代和研究主题的分布情况（见信息分析报告）；还可以看到研究的历史演变和趋势（见GOPUBMED信息分析平台）。对Extracellular histones与 sepsis进行知识发现分析，发现211个主题（关键词）具有相关性，可以作为科研的参考。 科学家发现止血抗体 可有效控制外伤所致内出血 美国研究人员发现一种抗体，可有效控制由外伤导致的严重内出血。它有望为挽救在车祸、枪击等事件中受伤人员的生命提供新途径。 组蛋白毒性 俄克拉何马医学研究基金会一个研究小组发现，外伤导致大出血主要由名为组蛋白的蛋白质破坏血管组织膜造成，新发现的特殊抗体可抑制组蛋白破坏作用，控制内出血。 研究人员发现组蛋白在患败血症老鼠的血液中含量很高，并在随后对灵长类动物和人类的研究中发现同样事实。 组蛋白一般存在于细胞核中，环绕脱氧核糖核酸（DNA）并起到维持DNA双螺旋形态的重要作用。但是，当细胞由于外伤或疾病受损，原本位于细胞核中的组蛋白就会释放到血液中，吞噬血管组织膜，造成血管损伤。 研究小组认为，这导致内出血和身体组织中体液聚积，威胁生命。 研究带头人、心血管生物学家查尔斯埃斯蒙说：当意识到组蛋白的毒性时，我们立刻投入到寻找阻止它们破坏性作用（的物质）的工作中去。 研究报告10月25日发表于《自然医学》（ Nature Medicine ）杂志网络版。 老鼠有抗体 这种可抗阻组蛋白的特殊抗体被称为单克隆抗体，由美国天普大学研究人员马克莫内斯蒂耶发现。 单克隆抗体最早在一只患有自身免疫病的老鼠体内发现。在患有自身免疫病的患者体内也已发现单克隆抗体，但目前尚不清楚为何这些患者细胞核内会有这种抗体存在。 研究人员在患有败血症的老鼠身上试验单克隆抗体，结果显示抗体确实能阻止组蛋白的毒副作用，老鼠恢复健康。 埃斯蒙说，所有哺乳动物体内的组蛋白类似，因为它们是身体的基本组成部分。因此，老鼠体内的单克隆抗体对人类应同样有效。下一步研究将针对灵长类动物和人类。 止血防衰竭 对因简易炸弹袭击受伤的士兵、枪击受害者和忍受外伤痛苦的患者而言，这一发现为救治他们打开了一扇新门，埃斯蒙说，当患者大出血时，单克隆抗体能防止多器官衰竭。 埃斯蒙认为组蛋白的存在可以看作进化过程中的适应表现。 数百万年前，人和动物生病后，并非死于心脏病或车祸，而是死于传染病他说，我们相信细胞核中的组蛋白正是免疫系统最后一道防线。 俄克拉何马医学研究基金会主席斯蒂芬普雷斯科特说，遭受一处外伤的患者往往还要遭受多次致命性继发损伤，单克隆抗体的发现同时给人们研究这一问题提供了线索。 如果能搞清楚如何控制初次损伤，或许就能阻止经常随后产生的多米诺效应，他说。 更多阅读 《自然医学》发表论文摘要（英文） http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.2053.html Nature Medicine Published online: 25 October 2009 | :10.1038/nm.2053 :10.1038/nm.2053 Extracellular histones are major mediators of death in sepsis Jun Xu 1 , Xiaomei Zhang 2 , Rosana Pelayo 3 , Marc Monestier 4 , Concetta T Ammollo 1 , Fabrizio Semeraro 1 , Fletcher B Taylor 1 , Naomi L Esmon 1 , Florea Lupu 1 Charles T Esmon 1 , 2 Abstract Hyperinflammatory responses can lead to a variety of diseases, including sepsis 1 . We now report that extracellular histones released in response to inflammatory challenge contribute to endothelial dysfunction, organ failure and death during sepsis. They can be targeted pharmacologically by antibody to histone or by activated protein C (APC). Antibody to histone reduced the mortality of mice in lipopolysaccharide (LPS), tumor necrosis factor (TNF) or cecal ligation and puncture models of sepsis. Extracellular histones are cytotoxic toward endothelium in vitro and are lethal in mice. In vivo , histone administration resulted in neutrophil margination, vacuolated endothelium, intra-alveolar hemorrhage and macro- and microvascular thrombosis. We detected histone in the circulation of baboons challenged with Escherichia coli , and the increase in histone levels was accompanied by the onset of renal dysfunction. APC cleaves histones and reduces their cytotoxicity. Co-infusion of APC with E. coli in baboons or histones in mice prevented lethality. Blockade of protein C activation exacerbated sublethal LPS challenge into lethality, which was reversed by treatment with antibody to histone. We conclude that extracellular histones are potential molecular targets for therapeutics for sepsis and other inflammatory diseases. Top of page Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. Howard Hughes Medical Institute, Oklahoma City, Oklahoma, USA. Immunology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. Temple Autoimmunity Center, Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA. http://www.embase.com/search/results Neutrophil-derived circulating free DNA (CF-DNA/NETs): A potential prognostic marker for posttraumatic development of inflammatory second hit and sepsis Margraf S. , Lgters T. , Reipen J. , Altrichter J. , Scholz M. and Windolf J. Shock 2008 30 :4 (352-358) Go to publisher for the full text The release of neutrophil extracellular traps (NETs) has been identified as a novel immune response in innate immunity. Neutrophil extracellular traps are composed of neutrophil-derived circulating free DNA (cf-DNA), histones , and neutrophil cytoplasm-derived proteins such as proteases. Here, we studied the putative predictive value of plasma cf-DNA/NETs for the development of sepsis and mortality after multiple trauma. In a prospective pilot study with 45 multiple trauma (Injury Severity Score 16) patients, cf-DNA was directly quantified in plasma. Blood samples were sequentially obtained daily from admission to our Trauma Center until day 10. Because of limited intensive care unit (ICU) stay of less than 3 days, 8 patients have been excluded, resulting in 37 patients that were evaluated. Time kinetics of cf-DNA/NETs was compared with C-reactive protein (CRP), interleukin (IL) 6, leukocyte counts, and myeloperoxidase. The severity of the injury was calculated on the basis of the Injury Severity Score, as well as Multiple Organ Dysfunction Score, Sequential Organ Failure Assessment, and Simplified Acute Physiology Score II on ICU. Initially high cf-DNA/NETs values (800 ng/mL) with recurrent increased values between days 5 to 9 were associated with subsequent sepsis , multiple organ failure, and death . In conjunction with cf-DNA/NETs, IL-6 was significantly elevated after admission. However, the development of a second hit was not indicated by IL-6. In contrast to cf-DNA/NETs, no difference in CRP kinetics was observed between patients with and without development of sepsis . Circulating free DNA/NETs kinetics rather followed kinetics of Multiple Organ Dysfunction Score, Sepsis -related Organ Failure Assessment, leukocyte counts, and partially of myeloperoxidase. Circulating free DNA/NETs seems to be a valuable additional marker for the calculation of injury severity and/or prediction of inflammatory second hit on ICU. However, a large clinical trial with severely injured patients should confirm the prognostic value of neutrophil-derived cf-DNA/NETs. Copyright 2008 by the Shock Society. Associated Links Drug Index Terms C reactive protein (endogenous compound), DNA (endogenous compound), interleukin 6 (endogenous compound), myeloperoxidase (endogenous compound) Non-drug Index Terms adolescent , adult , aged , article , clinical article , controlled study , enzyme kinetics , female , hospitalization , human , inflammation , injury scale , intensive care unit , leukocyte count , male , mortality , multiple trauma , neutrophil , prognosis , sepsis Author Keywords Inflammation, Multiple organ failure, Multiple trauma, NETs, Neutrophils, SIRS Correspondence Address Scholz M. : Klinik fr Unfall- und Handchirurgie, Heinrich-Heine-Universitt Moorenstr. 5 , 40225 Dsseldorf , Germany . Author Addresses Margraf S. : Department of Thoracic and Cardiovascular Surgery, Johann Wolfgang Goethe University , Frankfurt am Main , Germany . Lgters T. , Reipen J. , Altrichter J. , Scholz M. , Windolf J. : Department of Trauma and Hand Surgery, Heinrich-Heine University , Dsseldorf , Germany . Scholz M. : Klinik fr Unfall- und Handchirurgie, Heinrich-Heine-Universitt Moorenstr. 5 , 40225 Dsseldorf , Germany . Copyright MEDLINE is the source for part of the citation data of this record Additional Information Abbreviated Journal Title Shock ISSN 10732322 CODEN SAGUA Source Type Journal Source Publication Date October 2008 Item Type Article Pages 352-358 Country of Author Germany Country of Source United States Language of Article English Language of Summary English MEDLINE PMID 18317404 EMBASE Accession Number 2008488897 Number of References 35 Cited by in Scopus 5 CAS Registry Numbers C reactive protein ( 9007-41-4 ) DNA ( 9007-49-2 ) Back to results Record 2 Related Articles | Add to Clipboard | Email Record Beneficial suicide: Why neutrophils die to make NETs Brinkmann V. and Zychlinsky A. Nature Reviews Microbiology 2007 5 :8 (577-582) Go to publisher for the full text Neutrophils are one of the main types of effector cell in the innate immune system and were first shown to effectively kill microorganisms by phagocytosis more than 100 years ago. Recently, however, it has been found that stimulated neutrophils can also produce extracellular structures called neutrophil extracellular traps (NETs) that capture and kill microorganisms. This Progress article gives an overview of the structure, function and generation of NETs, and their role in infections. Associated Links Drug Index Terms deoxyribonuclease (endogenous compound), histone (endogenous compound), histone H2A (endogenous compound), hydrogen peroxide (endogenous compound), protein kinase C (endogenous compound), reactive oxygen metabolite (endogenous compound), reduced nicotinamide adenine dinucleotide phosphate oxidase (endogenous compound) Non-drug Index Terms antimicrobial activity , article , bacterial virulence , cell death , chemical structure , chromatin , chronic granulomatous disease , fertilization , fungus , Gram negative bacterium , Gram positive bacterium , granulocyte , human , infection control , innate immunity , intracellular killing , necrotizing fasciitis , neutrophil , neutrophil chemotaxis , nonhuman , phagocytosis , preeclampsia , priority journal , sepsis , Streptococcus pneumoniae Correspondence Address Brinkmann V. : Microscopy Core Facility, Max Planck Institute for Infection Biology Charitplatz 1 , 10117 Berlin , Germany . Author Addresses Brinkmann V. : Microscopy Core Facility, Max Planck Institute for Infection Biology, Charitplatz 1 , 10117 Berlin , Germany . Zychlinsky A. : Department of Cellular Microbiology, Max Planck Institute for Infection Biology Charitplatz 1 , 10117 Berlin , Germany . Copyright MEDLINE is the source for part of the citation data of this record Additional Information Abbreviated Journal Title Nat. Rev. Microbiol. ISSN 17401526 CODEN NRMAC Source Type Journal Source Publication Date August 2007 Item Type Article Pages 577-582 Country of Author Germany Country of Source United Kingdom Language of Article English Language of Summary English Publisher Item Identifier NRMICRO1710 MEDLINE PMID 17632569 EMBASE Accession Number 2007348090 Number of References 39 Cited by in Scopus 33 CAS Registry Numbers deoxyribonuclease ( 37211-67-9 ) histone ( 9062-68-4 ) hydrogen peroxide ( 7722-84-1 ) protein kinase C ( 141436-78-4 ) reduced nicotinamide adenine dinucleotide phosphate oxidase ( 9032-22-8 ) http://www.gopubmed.org/web/gopubmed/1?WEB01wpyt85j5itedI5bI1I00f01000j10040001rl Title: Extracellular histones are major mediators of death in sepsis . PMID: 19855397 Related Articles Authors: Xu, J , Zhang, X , Pelayo, R , Monestier, M , Ammollo, C T , Semeraro, F , Taylor, F B , Esmon, N L , Lupu, F , Esmon, C T Journal: Nat Med , 2009 Abstract: Hyperinflammatory responses can lead to a variety of diseases, including sepsis . We now report that extracellular histones released in response to inflammatory challenge contribute to endothelial dysfunction, organ failure and death during sepsis . They can be targeted pharmacologically by antibody to histone or by activated protein C ( APC ). Antibody to histone reduced the mortality of mice in lipopolysaccharide (LPS), tumor necrosis factor ( TNF ) or cecal ligation and puncture models of sepsis . Extracellular histones are cytotoxic toward endothelium in vitro and are lethal in mice. In vivo, histone administration resulted in neutrophil margination, vacuolated endothelium, intra-alveolar hemorrhage and macro- and microvascular thrombosis. We detected histone in the circulation of baboons challenged with Escherichia coli, and the increase in histone levels was accompanied by the onset of renal dysfunction. APC cleaves histones and reduces their cytotoxicity. Co-infusion of APC with E. coli in baboons or histones in mice prevented lethality. Blockade of protein C activation exacerbated sublethal LPS challenge into lethality, which was reversed by treatment with antibody to histone. We conclude that extracellular histones are potential molecular targets for therapeutics for sepsis and other inflammatory diseases. Affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City , Oklahoma , USA . Wikipedia: Age-specific death rate , Antibodies , Baboon , Benign neoplasm , Bleeding , Blood poisoning , Cancer , Case fatality rate , DAEC , Death Rate , Death rates , EAEC , EIEC , E Coli , Endothelium , Enteroinvasive Escherichia coli , Escherichia , Escherichia Coli , Hemorrhage , Histone , Histone H1 , Histone H3 , Histone H4 , Histone H5 , House Mouse , House mice , Laboratory mice , Laboratory mouse , Ligation , Ligature , Lipopolysaccharides , Mice , Mortality , Mouse , Mus , Mus domesticus , Mus musculus , Mus musculus domesticus , Necrosis , Neoplasm , Neutrophil , Papio , Polymorphonuclear leukocyte , Protein C , Proteins , Puncture , Savanna Baboon , Sepsis , Septicemia , Severe sepsis , Therapeutic , Thrombosis , Thrombus , Treatment , Tumor , Tumor necrosis factors , Vacuole Title: Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones . PMID: 16530522 Related Articles Authors: Pollicino, T , Belloni, L , Raffa, G , Pediconi, N , Squadrito, G , Raimondo, G , Levrero, M Journal: Gastroenterology , Vol. 130 (3): 823-37 , 2006 Abstract: BACKGROUND AIMS: HBV covalently closed circular DNA (cccDNA), the replicative intermediate responsible for persistent HBV infection of hepatocytes, is the template for transcription of all viral mRNAs. Nuclear cccDNA accumulates as a stable episome organized into minichromosomes by histone and nonhistone proteins. In this study we investigated, by a newly developed sensitive and specific assay, the relationship between viral replication and HBV chromatin assembly, transcription, and interaction with viral and cellular regulatory proteins. METHODS: To achieve this aim we coupled a quantitative chromatin immunoprecipitation (ChIP) technique to an established method that allows the amplification of virion-encapsidated HBV genomes after transfection of linear HBV DNA into human hepatoma HuH7 cells. The cccDNA-ChIP technique was also applied to study HBV minichromosome transcriptional regulation in liver tissue from HBV-infected patients. RESULTS: The use of anti-acetyl- H4 /-H3 specific antibodies to immunoprecipitate transcriptionally active chromatin revealed that HBV replication is regulated by the acetylation status of the cccDNA-bound H3/ H4 histones . Class I histone deacetylases inhibitors induced an evident increase of both cccDNA-bound acetylated H4 and HBV replication. Finally, histones hypoacetylation and histone deacetylase 1 recruitment onto the cccDNA in liver tissue correlated with low HBV viremia in hepatitis B patients. CONCLUSIONS: We developed a ChIP-based assay to analyze, in vitro and ex vivo, the transcriptional regulation of HBV cccDNA minichromosome. Our results provide new insights on the regulation of HBV replication and identify the enzymatic activities that modulate the acetylation of cccDNA-bound histones as new therapeutic targets for anti-HBV drugs. Affiliation: Laboratory of Gene Expression, Fondazione A. Cesalpino, University of Rome La Sapienza, Rome , Italy . Pubmed MeSH: Adult , Aged , DNA, Viral , Enzyme Inhibitors , Hepatitis B, Chronic , Humans , Middle Aged Wikipedia: Acetylation , Animal virus , Antibodies , B-DNA , B virus , Carcinoma, hepatocellular , Cercopithecine herpesvirus 1 , Chromatin , Circular DNA , Client , Co-immunoprecipitation , DNA , Deoxyribonucleic Acid , Double-stranded DNA , Drugs , Episome , Genome , Genomics , Hepatitis , Hepatitis B , Hepatitis B Virus , Hepatitis virus , Hepatocellular carcinoma , Hepatocyte , Hepatoma , Herpes B Virus , Herpesvirus simiae , Histone , Histone H1 , Histone H3 , Histone H4 , Histone H5 , Histone deacetylase , Immunoprecipitation , Liver cells , Messenger RNA , Monkey B virus , Patient , Plasmid , Poly(A) tail , Proteins , Therapeutic , Tissue , Transfection , Treatment , Viremia , Virus Title: Susceptibility to programmed cell death in T-lymphocytes from septic patients: a mechanism for lymphopenia and Th2 predominance. PMID: 12927795 Related Articles Authors: Roth, G A , Moser, B , Krenn, C G , Brunner, M , Haisjackl, M , Almer, G , Gerlitz, S , Wolner, E , Boltz-Nitulescu, G , Ankersmit, H J Journal: Biochem Biophys Res Commun , Vol. 308 (4): 840-6 , 2003 Abstract: Sepsis causes lymphopenia which is inversely correlated with patient survival. The role of apoptosis-specific immune-activation and activation-induced cell-death in sepsis is incompletely understood. Fifteen septic patients and 20 healthy controls were included. T-cell proliferation was measured by thymidine uptake. Apoptosis and cell phenotype were determined by FACS. sTNFR1, sCD95, interleukin-1beta converting enzyme (sICE), and interleukin (IL)-10 were measured by ELISA. PHA and CD3-driven T-cell proliferation were significantly decreased in septic patients. The percentages of CD3(+) and CD4(+) T cells and CD19 (+) B cells were significantly reduced. Percent memory T-cells (CD45RO(+)) and cells undergoing apoptosis (CD95(+)/ annexin-V (+)) were significantly increased in sepsis . Moreover, sCD95, sTNFRI, and ICE were significantly increased. Anti-CD3 antibody triggering induced a 56% increase of CD4 T-cell death in septic patients vs. 7.5% in controls relative to IgG. Serum level of IL-10 , a Th2 cytokine, was enhanced. These findings strongly suggest that in septic patients Th1 T-cells are selectively susceptible to undergo apoptosis. This observation provides an additional pathophysiological concept in the genesis of Th2 dominance. Affiliation: Department of Surgery, General Hospital of Vienna Medical School, Vienna , Austria . Pubmed MeSH: Adult , Aged , Annexin A5 , Antigens, CD19 , Antigens, CD3 , Antigens, CD45 , Antigens, CD95 , Cell Division , Cell Separation , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Histones , Humans , Interferon Type II , Interleukin-10 , Middle Aged , Th2 Cells Wikipedia: Antibodies , Apoptosis , B-Cell , B-lymphocyte , B Cells , B Lymphocytes , Blood Serum , Blood poisoning , Cell death , Client , Cytokines , Enzymes , IgG , IgG1 , IgG2 , IgG3 , IgG4 , Immunoglobulin G , Interleukin , Lymphocytopenia , Lymphopenia , Patient , Phenotype , Sepsis , Septicemia , Serum , Severe sepsis , T-Cell , T-lymphocyte , T Lymphocytes , T cells Title: The Felty syndrome: a case-matched study of clinical manifestations and outcome, serologic features, and immunogenetic associations. PMID: 1969604 Related Articles Authors: Campion, G V , Maddison, P J , Goulding, N J , James, I E , Ahern, M J , Watt, I S , Sansom, D M Journal: Medicine (Baltimore) , Vol. 69 (2): 69-80 , 1990 Abstract: Thirty-two patients with the Felty syndrome, defined by the presence of rheumatoid arthritis, splenomegaly, and neutropenia, have been studied in comparison with 32 patients with rheumatoid arthritis matched for age, sex, and disease duration, and 9 patients with rheumatoid arthritis and idiopathic neutropenia. Patients with the Felty syndrome had severe destructive arthritis, which progressed during follow-up despite little evidence of objective synovitis, and a higher frequency of extra-articular manifestations, including vasculitis. Bacterial infection tended to occur in patients with the lowest neutrophil count but continued to occur in some despite normalization of the WBC. Prognosis was poor and 8 deaths occurred, predominantly from sepsis . Serologic features were prominent. High titers of IgG rheumatoid factor and circulating immune complexes characterized patients with persistent neutropenia. A family history of rheumatoid arthritis was more common in patients with the Felty syndrome. The association with HLA DR4 was very strong; in addition there was an increased frequency of the DQw3 variant, 3b, suggesting that HLA Class II genes in linkage with DR4 may contribute to disease expression. Affiliation: Bath Institute for Rheumatic Diseases, U.K . Pubmed MeSH: Adult , Antibodies , Antibodies, Antinuclear , Follow-Up Studies , HLA-DQ Antigens , HLA-DR Antigens , Histones , Humans , Polymorphism, Restriction Fragment Length Wikipedia: Angiitis , Antigen-antibody complex , Arthritis , Arthritis, rheumatoid , Bacterial Infections , Bacterial infection , Blood poisoning , Cistron , Class II gene , Client , Enlarged spleen , Felty's Syndrome , Felty syndrome , Gene , Genetic material , IgG , IgG1 , IgG2 , IgG3 , IgG4 , Immune complex , Immunity , Immunization , Immunogenetic , Immunoglobulin G , Neutropenia , Neutrophil , Patient , Polyarthritis , Polymorphonuclear leukocyte , Prognosis , Rheumatoid Arthritis , Rheumatoid factor , Sepsis , Septicemia , Severe sepsis , Splenomegaly , Syndrome , Synovitis , Variolation , Vasculitides , Vasculitis http://www.gopubmed.org/web/gopubmed/1?WEB01wpyt85j5itedI5kI1I00f01000j10040001rl statistics 1 2 Top Years Publications 2004 14 2009 9 2008 9 2001 7 2007 7 2002 6 2006 5 1996 5 1997 5 2005 5 1991 4 2003 4 2000 4 1995 3 1992 3 1998 3 1999 3 1990 1 1989 1 1993 1 1 2 1 2 3 ... 27 Top Authors Publications Taylor F 9 Remick D 6 Esmon C 5 Bolgos G 5 Newcomb D 3 Wollenberg G 3 Ferrell G 3 Jansen P 3 De Jong I 3 Hack C 3 Okajima K 3 Call D 2 Cunha F 2 Chang A 2 Catlett R 2 Zhang L 2 Chang A 2 Wang P 2 Chaudry I 2 Lee H 2 1 2 3 ... 27 1 2 3 ... 59 Top Terms Publications Sepsis 90 Animals 71 Tumor Necrosis Factor-alpha 64 Necrosis 64 Neoplasms 61 Mice 56 Lipopolysaccharides 53 Proteins 50 Cytokines 45 Mortality 44 Ligation 42 Punctures 40 Tumor Necrosis Factors 38 tnf-alpha 38 Escherichia coli 37 Wounds and Injuries 33 Escherichia 33 tnf 31 tumor necrosis factor 31 Neutrophils 30 1 2 3 ... 59 Top Countries Publications USA 29 Netherlands 3 France 2 South Korea 1 Turkey 1 Italy 1 Top Cities Publications Oklahoma City 5 Ann Arbor 4 Indianapolis 2 Boston 2 Bethesda 2 New Orleans 2 Amsterdam 2 Jinju 1 Philadelphia 1 Ankara 1 East Lansing 1 Lille 1 Seattle 1 Orlans 1 Chicago 1 Denver 1 Kansas City, KS, USA 1 Gainesville 1 Baltimore 1 Milan 1 1 2 Top Journals Publications Infect Immun 5 J Immunol 4 Shock 3 Blood 3 Surgery 2 Crit Care Med 2 J Trauma 2 Mol Pharmacol 1 World J Surg 1 Maturitas 1 Plos One 1 J Pharmacol Exp Ther 1 J Lab Clin Med 1 Ann Surg 1 Jama-j Am Med Assoc 1 Am J Pathol 1 J Thromb Haemost 1 J Infect Dis 1 J Biol Chem 1 J Surg Res 1 1 2 http://arrowsmith.psych.uic.edu/cgi-bin/arrowsmith_uic/edit_b.cgi?refresh=TID=407 Start A-Literature C-Literature B-list Filter Literature A-query: Extracellular histones C-query: sepsis The B-list contains title words and phrases (terms) that appeared in both the A and the C literature. 2 articles appeared in both literatures and were not included in the process of computing the B-list but can be viewed here . The results of this search are saved under id # 407 and can be accessed from the start page after you leave this session. There are 1541 terms on the current B-list ( 211 are predicted to be relevant), which is shown ranked according to predicted relevance. The list can be further trimmed down using the filters listed in the left margin. To assess whether there appears to be a biologically significant relationship between the AB and BC literatures for specific B-terms, please select one or more B-terms and then click the button to view the corresponding AB and BC literatures. Use Ctrl to select multiple B-terms. Rank Prob B-term 10.98paclitaxel 20.97ubiquitin proteasome 30.97akt 40.97ubiquitin proteasome pathway 50.97fludarabine 60.96cox-2 70.96proteasome 80.96inflammatory cytokine 90.96c ebp 100.95mapk 110.95mitogen activated protein 120.95histone deacetylase inhibitor 130.95cyclooxygenase-2 140.95caspase-3 150.95enterococcus faecalis 160.94a2a receptor 170.94mkp-1 180.94lipopolysaccharide binding 190.94erk1 200.94ebp 210.94statin 220.93hcv 230.93role nitric oxide 240.93jnk 250.93stat5 260.93adenosine a2a receptor 270.93cytokine release 280.93extracellular signal regulated 290.92a2a 300.92il-8 310.92signal regulated kinase 320.92il-10 330.92microvascular endothelial cell 340.91microvascular endothelial 350.91cytarabine 360.91map kinase 370.91endothelin-1 380.91tyk2 390.90kinase signaling 400.90nf kappab 410.90endothelial cell apoptosis 420.90vegf 430.90extracellular trap 440.89caspase-3 activation 450.89serum amyloid 460.89neutrophil extracellular trap 470.88histone deacetylase 480.88protein kinase pathway 490.88nitric oxide synthase 500.88activated protein kinase 510.88regulated kinase 520.87extracellular signal 530.87human cytomegalovirus 540.87kinase pathway 550.87ubiquitin 560.86assist device 570.86enterococcus 580.85olanzapine 590.85mapk activation 600.85protein kinase signaling 610.85ribosomal rna gene 620.84smad3 630.84nucleosome 640.84mapk pathway 650.84erk 660.83proteomic 670.83tnfalpha 680.82poly adp 690.82coactivator 700.82activated protein 710.81sp1 720.80interferon alfa 730.80neuronal nitric oxide 740.80matrix metalloproteinase 750.79anthrax 760.79metalloproteinase-9 770.78alfa 780.78nuclear factor 790.78small cell 800.77cyclooxygenase-2 cox-2 810.77il-10 promoter 820.77microarray analysis 830.77clozapine 840.77t helper 850.77celecoxib 860.77induce apoptosis human 870.76ap-1 nf kappab 880.76jun n terminal 890.76cardiomyocyte 900.76tyrosine phosphorylation 910.75rna gene 920.75matrix metalloproteinase-9 930.75human endothelial 940.75il-8 expression 950.74irf-2 960.74human endothelial cell 970.74c jun 980.74cytomegalovirus 990.74th2 1000.73feline leukemia virus 1010.72chromatin remodeling 1020.72transcriptional activation 1030.72ifn 1040.71cell apoptosis 1050.71feline leukemia 1060.71group a streptococcus 1070.70reactive oxygen 1080.70p300 1090.68leishmania major 1100.67stent 1110.66alfa therapy 1120.66n terminal kinase 1130.66liver transplantation 1140.66apoptosis human 1150.66chronic liver disease 1160.66mapk dependent 1170.65serine phosphorylation 1180.65oxidative stress 1190.64chronic liver 1200.64downregulation 1210.64surface protein 1220.64acute myelogenous leukemia 1230.63alternatively spliced human 1240.63a streptococcus 1250.63ap-1 1260.63apoptotic 1270.63cytokine 1280.63antimicrobial activity 1290.62taxol paclitaxel 1300.62transactivation 1310.61hepatocellular 1320.61kinase activation 1330.61kinase mitogen 1340.60alternatively 1350.60replicon 1360.60s6 kinase 1370.59interferon alfa therapy 1380.59mitogen 1390.59cyclin dependent 1400.59transactivation domain 1410.58valproic acid 1420.58nf 1430.58liver disease 1440.57transcriptional regulation 1450.57protein tyrosine kinase 1460.57apoptosis acute 1470.57rat hepatocyte culture 1480.57hiv 1490.56lupus nephritis 1500.56kappab 1510.56c fos 1520.55mek 1530.55kinase mitogen activated 1540.55pkc 1550.54protein kinase activation 1560.54anthrax lethal toxin 1570.54leukotriene b4 1580.53activation erk1 1590.52myeloid leukemia 1600.51fos c jun 1610.51erk signaling 1620.51neural stem cell 1630.51apoptosis 1640.51taxol 1650.51tissue inhibitor metalloproteinase 1660.51gene variant 1670.50hypertonic 1680.50antimicrobial agent 1690.50receptor expression 1700.50histone h1 1710.49biomarker 1720.49promyelocytic 1730.48transcriptional response 1740.48signal regulated protein 1750.48erk activation 1760.48signaling cascade 1770.47cell activation 1780.47metalloproteinase 1790.47down regulation 1800.47nuclear receptor 1810.47promoter region 1820.47renal injury 1830.47dendritic cell 1840.47proximal tubular epithelial 1850.46killing neutrophil 1860.46tissue inhibitor 1870.46erk phosphorylation 1880.46apoptosis induced 1890.45gene encoding 1900.45autophagy 1910.45natural killer 1920.45candida 1930.45dna methyltransferase inhibitor 1940.44aortic endothelium 1950.44innate immunity 1960.43transcription factor 1970.42factor gene 1980.42induced platelet 1990.42amyloid p component 2000.41microarray 2010.41heparan sulfate 2020.41glycogen synthase 2030.40timp-3 2040.40serum amyloid p 2050.40induce apoptosis 2060.40kinase mediate 2070.40streptococcus 2080.40rat mesangial cell 2090.39contractility 2100.39laminin 2110.39heat shock 2120.39src 2130.39kinase-1 2140.38myelogenous leukemia 2150.38host defense 2160.38glycohydrolase 2170.38gene expression 2180.37tyrosine kinase 2190.37mapk cascade 2200.37tnfalpha induced 2210.37expression pattern 2220.37leukotriene 2230.37density lipoprotein receptor 2240.37induced apoptosis 2250.37vitronectin 2260.37endothelium 2270.36antimicrobial 2280.36c fos c 2290.36colonic epithelial 2300.36stem cell 2310.36ifn beta 2320.35hepatocellular carcinoma 2330.35rna level 2340.35growth factor-1 2350.35histone 2360.35nitric oxide 2370.35mouse model 2380.35insulin growth factor-1 2390.34glucocorticoid 2400.33chlamydia 2410.33signal transduction pathway 2420.33lung epithelial 2430.33protein kinase a 2440.33lung epithelial cell 2450.33mesangial cell 2460.33basic fibroblast growth 2470.33differentially regulated 2480.33aortic 2490.33kinase signaling cascade 2500.32tubular epithelial cell 2510.32signal pathway 2520.32lung fibroblast 2530.32muscle glycogen 2540.32promoter methylation 2550.31shigella 2560.31polymerase 2570.31ribosomal rna 2580.31histone dna 2590.31transcriptional 2600.31myosin heavy chain 2610.31peritoneal 2620.30innate 2630.30vitamin d receptor 2640.30candida albican 2650.30microvascular 2660.29plasminogen 2670.29expression gene 2680.29myeloid 2690.29proapoptotic 2700.29cell cycle arrest 2710.29transplantation 2720.29cntf 2730.29dendritic 2740.29protein kinase c 2750.29jun 2760.28h3 2770.28synergistically 2780.27mitogenic activity 2790.27mycobacterium 2800.27signaling pathway 2810.27copd 2820.27spliced 2830.26platelet derived 2840.26mediated lysis 2850.26phagocyte 2860.26bronchial carcinoma 2870.26endothelial cell 2880.26stimulate protein 2890.25extracellular matrix 2900.25reactive oxygen species 2910.25therapy multiple 2920.25inducible 2930.25transcriptional induction 2940.25fibroblast growth factor 2950.24rat pineal gland 2960.24mek erk 2970.24induced cell death 2980.24transforming growth factor 2990.23immunoglobulin 3000.23dexamethasone 3010.23pkb 3020.23immediate early 3030.23expression induced 3040.22therapy multiple myeloma 3050.22injury induced 3060.22tat 3070.22shigella flexneri 3080.22xenograft 3090.22dependent protein kinase 3100.22acetylation 3110.22parp-1 3120.21myoblast 3130.21ldl 3140.21virus felv 3150.21ribosomal 3160.21keratinocyte 3170.20interferon 3180.20erk activity 3190.20dna binding 3200.20dna methylation 3210.20lethal toxin 3220.19growth factor beta 3230.19human lung epithelial 3240.19baculovirus 3250.19tumor angiogenesis 3260.19infection mycobacterium 3270.19chemotactic factor 3280.19zymosan 3290.18chemiluminescence 3300.18chronic myeloid leukemia 3310.18mesangial 3320.18mb 3330.18phorbol 3340.18na k atpase 3350.18autoimmunity 3360.18n methyl d-aspartate 3370.18selenomethionine 3380.18platelet derived growth 3390.18norepinephrine 3400.17proteoglycan 3410.17stem 3420.17nephritis 3430.17mouse macrophage 3440.17endothelial 3450.17escherichia 3460.17kinase not 3470.17gastric carcinoma 3480.17effect dexamethasone 3490.16chromatin remodelling 3500.16oxidative 3510.16sequestration 3520.16regulated protein 3530.15protein tyrosine 3540.15colonic epithelial cell 3550.15cell signaling 3560.15nad glycohydrolase 3570.15escherichia coli 3580.15thyroid hormone 3590.15regulated protein kinase 3600.15c2c12 3610.15rat cortical 3620.15oxide 3630.15kinase a 3640.14dependent protein 3650.14antinuclear 3660.14naturally infected 3670.14dnase 3680.14chromatin modification 3690.14chronic myeloid 3700.14coli 3710.14pyrophosphatase 3720.14kinase phosphatase 3730.14adhesion 3740.13lipopolysaccharide 3750.13suppress tumor 3760.13gene regulation 3770.13signal transduction 3780.13derived growth factor 3790.13nuclear protein 3800.13induced apoptotic 3810.13promoter a 3820.13glutamate uptake 3830.13control viral 3840.12biotinidase 3850.12induction mkp-1 3860.12patient systemic lupus 3870.12glioblastoma 3880.12metallothionein 3890.12translational 3900.12spontaneously 3910.12chemotactic 3920.12alpha chronic 3930.12rat peritoneal 3940.12bronchial epithelial 3950.12colonic 3960.12induced cytotoxicity 3970.12related gene 3980.12epidermal growth factor 3990.11trichostatin a 4000.11bacterial toxin 4010.11fos 4020.11cell regulate 4030.11platelet 4040.11osteosarcoma 4050.11immunity 4060.11phosphodiesterase 4070.11macrophage 4080.11histone protein 4090.11neuroprotective 4100.11subunit gene 4110.11integrin 4120.10microtubule 4130.10raw 4140.10clone 4150.10killer 4160.10vitamin d 4170.10multiple myeloma 4180.10leukemia 4190.10amyloid 4200.10selective inhibitor 4210.10erk pathway 4220.10response stress 4230.10necrosis 4240.10platelet surface 4250.10hcc 4260.10norepinephrine induced 4270.10neutrophil 4280.10dna damage 4290.09angiogenesis 4300.09heavy chain 4310.09retinoblastoma 4320.09rat hepatic 4330.09stably 4340.09viral 4350.09lymphocyte patient 4360.09opsonized 4370.08arsenite 4380.08down regulate 4390.08rat hepatocyte 4400.08kinase regulate 4410.08cell cycle progression 4420.08renal 4430.08assay cell 4440.08na k 4450.08shock 4460.08repression 4470.08mitogenic signal 4480.08pineal gland 4490.08repress 4500.08weight 4510.08bacteria 4520.08mitogenic 4530.08mycobacterium tuberculosis 4540.08matrix protein 4550.08methyltransferase 4560.07murine 4570.07leishmania 4580.07multiple signaling pathway 4590.07factor receptor 4600.07myocardium 4610.07pathogen 4620.07blood leukocyte 4630.07protein degradation 4640.07protein kinase 4650.07genomic 4660.07astrocyte 4670.07phorbol ester 4680.07leukocyte 4690.07proteinuria 4700.07effect interferon 4710.07pluripotent 4720.07potential role 4730.07promoter 4740.07cardiac 4750.07faecalis 4760.07density lipoprotein 4770.07cell death 4780.07replication 4790.07skeletal muscle 4800.07survival 4810.07p90 4820.07phagocytosis 4830.07human skeletal muscle 4840.07mapk ap-1 4850.07activation mapk 4860.07cell contact 4870.07assist 4880.07pro 4890.06myosin 4900.06mediate 4910.06eukaryotic 4920.06rna polymerase 4930.06gene expression human 4940.06lung 4950.06proximal tubular 4960.06h1 4970.06recombinant 4980.06lipoprotein 4990.06expression human 5000.06fold 5010.06thyroid 5020.06sodium butyrate 5030.06expression epithelial 5040.06glycogen 5050.06small interference rna 5060.06hepatocyte 5070.06gene rat 5080.06ligation 5090.06pig 5100.06h4 5110.05nanoparticle 5120.05transcription 5130.05insulin growth 5140.05specific gene expression 5150.05evolutionary 5160.05transporter 5170.05effect growth hormone 5180.05isoprenoid 5190.05lethal 5200.05low dose 5210.05hepatic 5220.05kidney 5230.05human lung 5240.05protein dna 5250.05alpha1 5260.05atpase 5270.05regulated gene 5280.05casein 5290.05apoptotic death 5300.05inflammatory 5310.05glomerular 5320.05gene transcription 5330.05implanted cardiac 5340.05factor-1 5350.05mek erk signaling 5360.04sodium channel 5370.04high throughput 5380.04regulation c 5390.04cell induction 5400.04low density lipoprotein 5410.04human recombinant 5420.04quercetin 5430.04defense 5440.04epigenetic 5450.04megakaryocyte 5460.04low density 5470.04cartilage 5480.04myofibroblastic 5490.04expression gene encoding 5500.04trend 5510.04target gene 5520.04smooth muscle cell 5530.04epigenetic regulation 5540.04calcium activated 5550.04oxygen 5560.04expression 5570.04cue 5580.04butyrate 5590.04recruitment 5600.04chromatin 5610.04hormone signaling 5620.04stimulating hormone 5630.04dexamethasone inhibit 5640.04protein phosphatase 5650.03response inflammatory stimuli 5660.03escape 5670.03death 5680.03protein rat 5690.03threonine 5700.03culture 5710.03cell adhesion 5720.03inflammation 5730.03bacterial 5740.03atherosclerosis 5750.03adp 5760.03mrna 5770.03progression 5780.03hepatoma 5790.03human platelet 5800.03induced cell 5810.03smooth muscle 5820.03reactive 5830.03device 5840.03onset 5850.03albican 5860.03suppress tumor growth 5870.03protein peptide 5880.03diabetes 5890.03exercise 5900.03expression a 5910.03porcine 5920.03coronary 5930.03new strategy 5940.03thyroidal 5950.03pituitary 5960.03cell surface receptor 5970.03differentially 5980.03rapidly 5990.03factor beta 6000.03schizophrenia 6010.03dephosphorylation 6020.03n methyl 6030.03tuberculosis 6040.03permeation 6050.03pancreatic cancer 6060.03feline 6070.02avian 6080.02hippocampal 6090.02muscle cell 6100.02oncogene 6110.02immunogenic 6120.02biochemical characterization 6130.02hydroxamic acid 6140.02assay 6150.02cocaine 6160.02smooth 6170.02oocyte 6180.02persistence 6190.02mammalian cell 6200.02clinically 6210.02alzheimer 6220.02gamma1 6230.0225-dihydroxyvitamin d 6240.02resistance 6250.02immune 6260.02group a 6270.02methylation 6280.02novel 6290.02kinase activity 6300.02killing 6310.02mycobacteria 6320.02human blood leukocyte 6330.02na 6340.02cell cycle 6350.02systemic lupus 6360.02gene expression induced 6370.02serine 6380.02rna 6390.02decrease 6400.02systemic lupus erythematosus 6410.02heat 6420.02cell inhibition 6430.02calcium dependent 6440.02regulation gene 6450.02pediatric 6460.02receptor mediated 6470.02growth factor receptor 6480.02hydrogen peroxide induced 6490.02n terminal 6500.02species 6510.02myeloma 6520.02binding protein 6530.02cytotoxicity 6540.02broad 6550.02melanoma 6560.02drug abuse 6570.02plasticity 6580.02liver 6590.02mice 6600.02nad 6610.02cell binding 6620.02regulator 6630.02related protein 6640.02novel histone 6650.02dose 6660.02activation 6670.02nonmuscle myosin 6680.02growth arrest 6690.021-mediated 6700.02signalling pathway 6710.02patient systemic 6720.02molecular mechanism 6730.02associated protein 6740.02nocturnal 6750.02induced down regulation 6760.02prolactin 6770.02inhibition rat 6780.01adult rat 6790.013t3-l1 6800.01dopamine 6810.01epidermal 6820.01lymphoid 6830.01purification 6840.01leukemia virus 6850.01leukocyte platelet 6860.01glycolytic enzyme 6870.01decarboxylase 6880.01tumor cell line 6890.01glutamate 6900.01anticancer 6910.01channel 6920.01weapon 6930.01cell shape 6940.01induce expression 6950.01gene induction 6960.01systemic 6970.01silencing 6980.01directly 6990.01relationship cell 7000.01modulate host 7010.01brain region 7020.01injury 7030.01domain 7040.01tyrosine 7050.01endogenous 7060.01moth 7070.01acetyltransferase 7080.01memory 7090.01bronchial 7100.01cell fate 7110.01thymus 7120.01confer 7130.01cell role 7140.01transcription mrna 7150.01mrna abundance 7160.01targeting 7170.01growth differentiation 7180.01peptide 7190.01mast cell 7200.01colon cancer 7210.01locus 7220.01growth hormone 7230.01carcinoma cell 7240.01increase 7250.01epithelial cell 7260.01naturally 7270.01map 7280.01collagen synthesis 7290.01molecule 7300.01protein 7310.01phase 7320.01independent 7330.01signaling 7340.01host cell 7350.01modulate 7360.01trap 7370.01reverse 7380.01alkaline phosphatase 7390.01inhibitory 7400.01chain gene 7410.01constitutive 7420.01yeast 7430.01virus 7440.01inhibitor 7450.01long lasting 7460.01dermal 7470.01cultured human 7480.01export 7490.01cold shock 7500.01animal model 7510.01molecular 7520.01role epigenetic 7530.01effect growth 7540.01fibroblast 7550.01profound 7560.01gastric 7570.01rat brain 7580.01cell growth 7590.01production 7600.01pancreatic 7610.01human placenta 7620.01role histone 7630.01liver cell 7640.01mammal 7650.01hydrogen peroxide 7660.01mitochondrial 7670.01protection 7680.01histamine 7690.01alpha 7700.01phospholipid 7710.01suppressor 7720.01acute 7730.01protein kinase activity 7740.01ras 7750.01airway 7760.01pathogenesis 7770.01cell surface protein 7780.01attenuation 7790.01encoding 7800.01glucose 7810.01major 7820.01glial 7830.01mediated gene 7840.01model 7850.01cell distinct 7860.01bystander 7870.01lupus erythematosus 7880.01ischemic 7890.01multiple 7900.00isolation characterization 7910.00tubular 7920.00inflammatory site 7930.00peroxide 7940.00stimulating 7950.00carboxyl terminal 7960.00cellular gene 7970.00cell surface 7980.00induced increase 7990.00phosphatase 8000.00messenger 8010.00regulatory 8020.00nude 8030.00human blood 8040.00gene human 8050.00transduction 8060.00homolog 8070.00stress 8080.00leukemia cell line 8090.00cell wall 8100.00increased 8110.00lymphocyte 8120.00kinase 8130.00|--kinase m 8140.00critical 8150.00helper 8160.00insulin 8170.00aggregation 8180.00infection 8190.00promastigote 8200.00leukemia cell 8210.00association 8220.00breast cancer 8230.00pp1 8240.00cascade 8250.00death renal 8260.00element 8270.00strategy 8280.00homologous 8290.00retinal 8300.00regulation tissue 8310.00infected 8320.00lysis 8330.00single 8340.00group 8350.00lupus 8360.00camp 8370.00colon 8380.00therapeutic 8390.00blood 8400.00arrest 8410.00adult 8420.00goat 8430.00boar 8440.00fatty acid 8450.00altered expression 8460.00damage 8470.00citrate 8480.00initiation 8490.00epsilon 8500.00expression cell 8510.00non 8520.00i protein 8530.00low 8540.00bursa 8550.00therapy 8560.00key regulator 8570.00bone related 8580.00ovarian 8590.00dysregulation 8600.00synthase 8610.00liver disease effect 8620.00specific gene 8630.00tissue specific gene 8640.00regulate 8650.00embryonic 8660.00inhibitory activity 8670.00abuse 8680.00cell proliferation 8690.00early 8700.00antimicrobial protein 8710.00phosphoprotein 8720.00tissue specific 8730.00epithelial 8740.00phosphorylation 8750.00carcinoma 8760.00related 8770.00stimuli 8780.00nickel 8790.00ligand 8800.00lysine 8810.00human breast 8820.00metastasis 8830.00mda 8840.00striatum 8850.00mitochondria 8860.00skeletal 8870.00trail 8880.00embryo 8890.00growth factor 8900.00arthritis 8910.00hydrogen 8920.00new paradigm 8930.00ex 8940.00metal 8950.00global 8960.00alkaline 8970.00rat liver cell 8980.00potassium 8990.00modulating 9000.00expression rabbit 9010.00placenta 9020.00cell line 9030.00methionine 9040.00induced release 9050.00nucleotide 9060.00augment 9070.00species specific 9080.00stimulation a 9090.00tolerance 9100.00modulation 9110.00protamine 9120.00old 9130.00responsiveness 9140.00hormone secretion 9150.00vulnerability 9160.00vitamin 9170.00not 9180.00interact 9190.00time 9200.00level 9210.00fragment 9220.00regulate constitutive 9230.00heritability 9240.00activating 9250.00characterization antimicrobial 9260.00response 9270.00regulation rat 9280.00salt 9290.00high 9300.00assembly 9310.00media 9320.00carbon 9330.00melanoma cell 9340.00poly 9350.00essential role 9360.00adenosine 9370.00breast 9380.00human cancer 9390.00clinical 9400.00nicotinamide 9410.00spatial 9420.00cortical 9430.00lysate 9440.00proliferation 9450.00redistribution 9460.00irradiation 9470.00matrix 9480.00spiny 9490.00suppress 9500.00asthma 9510.00augmentation 9520.00disease 9530.00neuron 9540.00c rat 9550.00visual 9560.00mcf 9570.00cytoplasmic 9580.00senescence 9590.00antibody 9600.00extracellular 9610.00crucial 9620.00neoplastic 9630.00atp 9640.00immature 9650.00rat liver 9660.00exert 9670.00cancer therapy 9680.00transformation 9690.00radiation 9700.00heavy 9710.00repair 9720.00potent 9730.00deprivation 9740.00high affinity 9750.00c terminal 9760.00impair 9770.00integrative 9780.00dextran 9790.00defense mechanism 9800.00feed 9810.00chicken 9820.00ester 9830.00phenotypic 9840.00arterial 9850.00production human 9860.00patient 9870.00receptor 9880.00toxin 9890.00cell lead 9900.00fibrosis 9910.00long 9920.00collagen 9930.00or 9940.00activated 9950.00mammalian 9960.00variant 9970.00growth related 9980.00gene a 9990.00identify 10000.00potential 10010.00neuronal 10020.00ageing 10030.00nuclear 10040.00role 10050.00active 10060.00dna 10070.00|--dna alkylating agent 10080.00nonmuscle 10090.00stress associated 10100.00gene 10110.00specification 10120.00cancer 10130.00receptor dependent 10140.00composition 10150.00neuropathology 10160.00joint 10170.00sustained 10180.00neural 10190.00mediated inhibition 10200.00contact 10210.00transport 10220.00intracellular bacteria 10230.00density 10240.00kill bacteria 10250.00exogenous 10260.00class i 10270.00muscle 10280.00cell a 10290.00growth inhibition 10300.00chain 10310.00hela 10320.00alpha a 10330.00link 10340.00host 10350.00basal 10360.00a novel class 10370.00change gene expression 10380.00mediated signalling 10390.00immune complex 10400.00phenotype 10410.00sulfate 10420.00alpha beta 10430.00induce 10440.00analysis identify 10450.00stability 10460.00articular 10470.00conditioning 10480.00modification protein 10490.00force 10500.00structure 10510.00silica 10520.00ex vivo 10530.00set 10540.00influence dna 10550.00intracellular 10560.00lead 10570.00smoker 10580.00progressive 10590.00cold 10600.00gene activation 10610.00inhibition 10620.00alter 10630.00promote 10640.00delta 10650.00associated gene 10660.00subtype 10670.00behavioral 10680.00gate 10690.00net 10700.00maturation 10710.00recognition 10720.00signal 10730.00protein a 10740.00inhibit 10750.00cultured 10760.00collagenase 10770.00enhance 10780.00key 10790.00dependent manner 10800.00universal 10810.00chromosome 10820.00receptor expressing 10830.00extracellular effect 10840.00correct 10850.00clinical implication 10860.00bone 10870.00genetic 10880.00encoded 10890.00developmental 10900.00landscape 10910.00cell level 10920.00gland 10930.00tetraploidy 10940.00inhibition human 10950.00differentiation 10960.00signalling 10970.00immediate 10980.00annual 10990.00transient 11000.00binding 11010.00truth 11020.00cycle 11030.00screen 11040.00terminal 11050.00low molecular 11060.00shape 11070.00widespread 11080.00methyl 11090.00cell induced 11100.00pharmacological 11110.00class 11120.00cat 11130.00osteogenesis 11140.00distal 11150.00alteration 11160.00isolation 11170.00target 11180.00uptake 11190.00sodium 11200.00non specific 11210.00localization 11220.00ice 11230.00increased replication 11240.00metabolic 11250.00proximal 11260.00molecular regulation 11270.00toxicity 11280.00hormone 11290.00rheumatoid arthritis 11300.00line 11310.00experience 11320.00essential 11330.00rheumatoid 11340.00particle 11350.00identification 11360.00epithelial cell a 11370.00bind 11380.00biology 11390.00occupancy 11400.00degradation 11410.00lymphoid cell 11420.00expression related 11430.00versus 11440.00m phase 11450.00paucity 11460.00intermediate 11470.00protein human 11480.00secretion 11490.00brain response 11500.00pigment 11510.00anti 11520.00small 11530.00definition 11540.00impaired 11550.00bovine 11560.00biosynthesis 11570.00family 11580.00cellular 11590.00relation leukocyte 11600.00deregulation 11610.00disrupt 11620.00site 11630.00transforming 11640.00pathway 11650.00lineage 11660.00possible role 11670.00rest 11680.00factor-1alpha 11690.00wall 11700.00vesicle 11710.00release 11720.00swimming 11730.00surface 11740.00coordinately 11750.00inhibitor human 11760.00calcium 11770.00phosphorylated 11780.00granule 11790.00conversion 11800.00complex a 11810.00kill 11820.00intact 11830.00region 11840.00prevent 11850.00sensitive 11860.00cation 11870.00improve 11880.00delayed 11890.00mouse 11900.00mediated 11910.00ecto 11920.00molecular phenotypic 11930.00whole 11940.00receptor a 11950.002b 11960.00factor inhibit 11970.00activate 11980.00cortex 11990.00intense 12000.00conservation 12010.00structural 12020.00natural 12030.00subcellular 12040.00organization 12050.00brain 12060.00molecular mechanism mediating 12070.00basic 12080.00cell vitro 12090.00oxidase 12100.00affecting 12110.00derivative 12120.00regulated 12130.00purification characterization 12140.00symposium 12150.00growth 12160.00manner 12170.00specific activation 12180.00deposition 12190.00synthesis 12200.00oxidized 12210.00reduced 12220.00regulation 12230.00two human 12240.00putative 12250.00role early 12260.00reduction 12270.00phosphatase activity 12280.00specific 12290.00activation following 12300.00module 12310.00metabolism 12320.00d2 12330.00stimulation 12340.00ability 12350.00vivo 12360.00switch 12370.00incorporation 12380.00expressing 12390.00excitation 12400.00tumor 12410.00program 12420.00cell treated 12430.00current 12440.00cellular protection 12450.00complex 12460.00absence 12470.00hormonal 12480.00reduced growth 12490.00cell inhibited 12500.00ultrastructural 12510.00potentiate 12520.00selective 12530.00associate 12540.00determine 12550.00interaction tumor 12560.00deficiency 12570.00occurrence 12580.00modification 12590.00tissue 12600.00chronic 12610.00acidic 12620.00behavior 12630.00interaction 12640.00constitutive inducible 12650.00number 12660.00biochemical 12670.00enzyme 12680.00moderately 12690.00spreading 12700.00disorder 12710.00involve 12720.00express 12730.00effect sodium 12740.00derived 12750.00leading 12760.00preimplantation 12770.00subunit 12780.00compound 12790.00spontaneous 12800.00suppressed 12810.00molecular weight 12820.00common 12830.00vitro ex vivo 12840.00turned inside 12850.00differential 12860.00paradigm 12870.00dependent 12880.00share common 12890.00differential involvement 12900.00auto 12910.00lining 12920.00serum 12930.00treated 12940.00dynamic 12950.00germinal 12960.00property 12970.00based 12980.00form 12990.00cooperation 13000.00beta 13010.00fatty 13020.00involvement 13030.00oncogenic 13040.00factor 13050.00altered protein 13060.00domain c 13070.00presence 13080.00attachment 13090.00coordination 13100.00bulb 13110.00status 13120.00primary 13130.00loss 13140.00rat 13150.00instability 13160.00lasting 13170.00component 13180.00abundance 13190.00action 13200.00implication 13210.00chick 13220.00induce a 13230.00require 13240.00sperm 13250.00expression require 13260.00rabbit 13270.00homogeneous 13280.00required 13290.00specificity 13300.00increased activity 13310.00discovery 13320.00agent 13330.00induce sustained 13340.00trigger 13350.00mean 13360.00regulated human 13370.00technique 13380.00following 13390.00convergence 13400.00inhibited 13410.00opposing 13420.00architecture 13430.00formation 13440.00acid synthase 13450.00october 13460.00remodeling 13470.00one 13480.00induced 13490.00malignant 13500.00novo 13510.00matrix a 13520.00possible 13530.00disease effect 13540.00sequela 13550.00down 13560.00accelerated 13570.00mechanism 13580.00protein role 13590.00blocking 13600.00drug 13610.00cell differentiation 13620.00facilitate 13630.00forward 13640.00animal 13650.00acid 13660.00stimulate 13670.00allow 13680.00phosphate 13690.00accessibility 13700.00affinity 13710.00precursor 13720.00associated 13730.00different 13740.00cell 13750.00metabolite 13760.00pattern 13770.00attachment site 13780.00information 13790.00two 13800.00hereditary 13810.00normal 13820.00albican yeast 13830.00relation 13840.00mediating 13850.00chicken embryo 13860.00activation chronic 13870.00analysis 13880.00primary culture 13890.00h1 a 13900.00medium 13910.00related multiple 13920.00spatial effect 13930.00killed 13940.00regulating 13950.00relationship 13960.00biochemical morphological 13970.00control 13980.00development 13990.00part 14000.00chromium 14010.00coupled 14020.00survival function 14030.00responsible 14040.00limited 14050.00modulated 14060.00induced a 14070.00function 14080.00human 14090.00substrate 14100.00dependence 14110.00breakdown 14120.00fate 14130.00activity 14140.00linked 14150.00released 14160.00required normal 14170.00reciprocal 14180.00acid derivative 14190.00work 14200.00low molecular weight 14210.00alternative 14220.00additional 14230.00replication inhibition 14240.00altered 14250.00accelerated vitro 14260.00pretreated 14270.00demonstration 14280.00morphological 14290.00distinct 14300.00cortex a 14310.00coupling 14320.00purified 14330.00enzymic 14340.00facilitate activation 14350.00mechanism regulating 14360.00express a 14370.00system 14380.00pathogenesis systemic 14390.00mixed 14400.00determination 14410.00g i 14420.00activation n 14430.00well 14440.00pathway inhibition 14450.00involved 14460.00interrelationship 14470.00effect 14480.00processing 14490.00mechanism gene 14500.00response multiple 14510.00highlight 14520.00transformed 14530.00study 14540.00characterization 14550.00a class 14560.00factor stimulate 14570.00related factor 14580.00human mouse 14590.00activity a 14600.00species induced 14610.00interference 14620.00development mouse 14630.00induction 14640.00remodelling 14650.00involving 14660.00visualization 14670.00accessory 14680.00acid induce 14690.00inhibitor decrease 14700.00trend study 14710.00capture 14720.00symposium october 14730.00non specific resistance 14740.00inverted 14750.00requirement 14760.00induced activated 14770.00disrupted 14780.00line clinical 14790.00vivo effect 14800.00vivo animal 14810.00factor effect 14820.00cycling 14830.00regulatory mechanism 14840.00interaction alpha 14850.00select 14860.00implanted 14870.00identify a 14880.00containing 14890.00induction human 14900.00relevance 14910.00new 14920.00share 14930.00living 14940.00effect mechanism 14950.00dynamic change 14960.00situ 14970.00vi 14980.00induce profound 14990.00facilitated 15000.00vitro interaction 15010.00opposite 15020.00recognition a 15030.00assess 15040.00consequence 15050.00alleviated 15060.00suggesting 15070.00reflected 15080.00vitro 15090.00mammary 15100.00current trend 15110.00preceded 15120.00suitability 15130.00evidence 15140.00selecting 15150.00issue 15160.00branching 15170.00dose dependence 15180.00providing 15190.00contribution 15200.00goes 15210.00expanded 15220.00process 15230.00inside 15240.00phospho 15250.00influence 15260.00depending 15270.00role a 15280.00level determine 15290.00transition 15300.00region a 15310.00part a 15320.00developing 15330.00change 15340.00state 15350.00vitro inhibition 15360.00framework 15370.00a spontaneous 15380.00programming 15390.00critical factor 15400.00effect induced 15410.00characteristic Restrict by semantic categories? Start A-Literature C-Literature B-list Filter Literature Semantic Filters This filter can be used to focus your search on B-terms that belong to certain semantic categories by selecting them below. You may also expand categories by clicking on the corresponding + button, and select from the subcategories. Activities Behaviors Anatomy Chemicals Drugs Concepts Ideas Devices Disorders Genes Molecular Sequences, and Gene Protein Names Geographic Areas Living Beings Objects Occupations Organizations Phenomena Physiology Procedures Keep B-terms that do not exist in the medical thesaurus Start A-Literature C-Literature B-list Filter Literature AB literature B-term BC literature Extracellular histones mitogen activated protein sepsis 1: Genomic instability and histone H3 phosphorylation induction by the Ras -mitogen activated protein kinase pathway in pancreatic cancer cells.2009 Add to clipboard 2: Chromatin modification of the trefoil factor 1 gene in human breast cancer cells by the Ras /mitogen-activated protein kinase pathway.2006 Add to clipboard 3: High throughput identification of potential Arabidopsis mitogen-activated protein kinases substrates.2005 Add to clipboard 4: Involvement of histone H3 (Ser10) phosphorylation in chromosome condensation without Cdc2 kinase and mitogen-activated protein kinase activation in pig oocytes.2004 Add to clipboard 1: Losartan prevents sepsis -induced acute lung injury and decreases activation of nuclear factor kappaB and mitogen-activated protein kinases.2009 Add to clipboard 2: Liver X receptor agonist GW3965 dose-dependently regulates lps-mediated liver injury and modulates posttranscriptional TNF-alpha production and p38 mitogen-activated protein kinase activation in liver macrophages.2009 Add to clipboard 3: Inhibition of Nuclear Factor-kappaB and p38 Mitogen-Activated Protein Kinase Does Not Always Have Adverse Effects on Wound Healing.2009 Add to clipboard 4: Cytokine-induced epithelial permeability changes are regulated by the activation of the p38 mitogen-activated protein kinase pathway in cultured Caco-2 cells.2008 Add to clipboard job id # 407 started Tue Oct 27 06:20:47 2009 Max_citations: 50000 Stoplist: /var/www/html/arrowsmith_uic/data/stopwords_pubmed Ngram_max: 3 407 Search ARROWSMITH A A_query_raw: Extracellular histonesTue Oct 27 06:21:04 2009 A query = Extracellular histones started Tue Oct 27 06:21:05 2009 A query resulted in 275 titles 407 Search ARROWSMITH C C_query_raw: sepsis Tue Oct 27 06:21:18 2009 C: sepsis 102054 A: pubmed_query_A 275 AC: ( Extracellular histones ) AND ( sepsis ) 2 C query = sepsis started Tue Oct 27 06:21:19 2009 C query resulted in 50000 titles A AND C query resulted in 2 titles 1541 B-terms ready on Tue Oct 27 06:24:24 2009 Sem_filter: Chemicals Drugs 363 B-terms left after filter executed Tue Oct 27 06:28:48 2009 Sem_filter: Phenomena 8 B-terms left after filter executed Tue Oct 27 06:31:05 2009 Viewed B-terms Tue Oct 27 06:31:18 2009 tyrosine phosphorylation Sem_filter: Genes Molecular Sequences, and Gene Protein Names 1 B-terms left after filter executed Tue Oct 27 06:32:14 2009 Sem_filter: Disorders 1 B-terms left after filter executed Tue Oct 27 06:32:29 2009 C_query_raw: sepsis Tue Oct 27 06:34:41 2009 C: sepsis 102054 A: pubmed_query_A 275 AC: ( Extracellular histones ) AND ( sepsis ) 2 C query = sepsis started Tue Oct 27 06:34:42 2009 C query resulted in 50000 titles A AND C query resulted in 2 titles 1541 B-terms ready on Tue Oct 27 06:35:29 2009 Viewed B-terms Tue Oct 27 06:36:03 2009 inflammatory cytokine Viewed B-terms Tue Oct 27 06:36:33 2009 mitogen activated protein B-list on Tue Oct 27 06:37:41 2009 1 paclitaxel 2 ubiquitin proteasome 3 akt 4 ubiquitin proteasome pathway 5 fludarabine 6 cox-2 7 proteasome 8 inflammatory cytokine 9 c ebp 10 mapk 11 mitogen activated protein 12 histone deacetylase inhibitor 13 cyclooxygenase-2 14 caspase-3 15 enterococcus faecalis 16 a2a receptor 17 mkp-1 18 lipopolysaccharide binding 19 erk1 20 ebp 21 statin 22 hcv 23 role nitric oxide 24 jnk 25 stat5 26 adenosine a2a receptor 27 cytokine release 28 extracellular signal regulated 29 a2a 30 il-8 31 signal regulated kinase 32 il-10 33 microvascular endothelial cell 34 microvascular endothelial 35 cytarabine 36 map kinase 37 endothelin-1 38 tyk2 39 kinase signaling 40 nf kappab 41 endothelial cell apoptosis 42 vegf 43 extracellular trap 44 caspase-3 activation 45 serum amyloid 46 neutrophil extracellular trap 47 histone deacetylase 48 protein kinase pathway 49 nitric oxide synthase 50 activated protein kinase 51 regulated kinase 52 extracellular signal 53 human cytomegalovirus 54 kinase pathway 55 ubiquitin 56 assist device 57 enterococcus 58 olanzapine 59 mapk activation 60 protein kinase signaling 61 ribosomal rna gene 62 smad3 63 nucleosome 64 mapk pathway 65 erk 66 proteomic 67 tnfalpha 68 poly adp 69 coactivator 70 activated protein 71 sp1 72 interferon alfa 73 neuronal nitric oxide 74 matrix metalloproteinase 75 anthrax 76 metalloproteinase-9 77 alfa 78 nuclear factor 79 small cell 80 cyclooxygenase-2 cox-2 81 il-10 promoter 82 microarray analysis 83 clozapine 84 t helper 85 celecoxib 86 induce apoptosis human 87 ap-1 nf kappab 88 jun n terminal 89 cardiomyocyte 90 tyrosine phosphorylation 91 rna gene 92 matrix metalloproteinase-9 93 human endothelial 94 il-8 expression 95 irf-2 96 human endothelial cell 97 c jun 98 cytomegalovirus 99 th2 100 feline leukemia virus 101 chromatin remodeling 102 transcriptional activation 103 ifn 104 cell apoptosis 105 feline leukemia 106 group a streptococcus 107 reactive oxygen 108 p300 109 leishmania major 110 stent 111 alfa therapy 112 n terminal kinase 113 liver transplantation 114 apoptosis human 115 chronic liver disease 116 mapk dependent 117 serine phosphorylation 118 oxidative stress 119 chronic liver 120 downregulation 121 surface protein 122 acute myelogenous leukemia 123 alternatively spliced human 124 a streptococcus 125 ap-1 126 apoptotic 127 cytokine 128 antimicrobial activity 129 taxol paclitaxel 130 transactivation 131 hepatocellular 132 kinase activation 133 kinase mitogen 134 alternatively 135 replicon 136 s6 kinase 137 interferon alfa therapy 138 mitogen 139 cyclin dependent 140 transactivation domain 141 valproic acid 142 nf 143 liver disease 144 transcriptional regulation 145 protein tyrosine kinase 146 apoptosis acute 147 rat hepatocyte culture 148 hiv 149 lupus nephritis 150 kappab 151 c fos 152 mek 153 kinase mitogen activated 154 pkc 155 protein kinase activation 156 anthrax lethal toxin 157 leukotriene b4 158 activation erk1 159 myeloid leukemia 160 fos c jun 161 erk signaling 162 neural stem cell 163 apoptosis 164 taxol 165 tissue inhibitor metalloproteinase 166 gene variant 167 hypertonic 168 antimicrobial agent 169 receptor expression 170 histone h1 171 biomarker 172 promyelocytic 173 transcriptional response 174 signal regulated protein 175 erk activation 176 signaling cascade 177 cell activation 178 metalloproteinase 179 down regulation 180 nuclear receptor 181 promoter region 182 renal injury 183 dendritic cell 184 proximal tubular epithelial 185 killing neutrophil 186 tissue inhibitor 187 erk phosphorylation 188 apoptosis induced 189 gene encoding 190 autophagy 191 natural killer 192 candida 193 dna methyltransferase inhibitor 194 aortic endothelium 195 innate immunity 196 transcription factor 197 factor gene 198 induced platelet 199 amyloid p component 200 microarray 201 heparan sulfate 202 glycogen synthase 203 timp-3 204 serum amyloid p 205 induce apoptosis 206 kinase mediate 207 streptococcus 208 rat mesangial cell 209 contractility 210 laminin 211 heat shock 212 src 213 kinase-1 214 myelogenous leukemia 215 host defense 216 glycohydrolase 217 gene expression 218 tyrosine kinase 219 mapk cascade 220 tnfalpha induced 221 expression pattern
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