碳氢链上含有双键的不饱和脂肪酸（多烯脂肪酸）往往对健康有益已经成为人们的共识，而日常服用含有二十碳五烯酸（EPA）、二十二碳六烯酸（DHA）等ω-3脂肪酸的“深海鱼油”被认为能防止心脏病、老年痴呆症及其他衰老相关疾病。 以往研究表明，DHA能减少阿尔茨海默病 模型 小鼠大脑中 β-淀粉样蛋白形成的沉积斑，但2011年在人体中开展的临床研究却得出DHA不能缓解轻微至中度阿尔茨海默症状的结论。更有甚者，一项为期5年共有4000名平均年龄72岁老年人参与的最新研究披露， ω-3脂肪酸不能逆转老年认知力下降。 作者对这一结果的解释是，可能与服用的时机及服用的方式有关，比如发病之前的预防性服用以及直接食用海产品而不是补充剂，因为已有大量研究发现平常多吃鱼可以降低视网膜黄斑性退化（AMD）、心血管病和老年痴呆症的发病率。 据作者介绍，他们发现服用高剂量抗氧化剂和矿物质，可以减慢AMD进展速度，这为解释 ω-3脂肪酸的矛盾结论提供了一条有趣的线索。假如把 ω-3脂肪酸仅仅当做抗氧化剂，那么在已服用抗氧化剂配方的患者中再补充抗氧化剂当然看不到差异。 事实上， ω-3脂肪酸也许只能起抗氧化剂的作用，而其抗氧化效果则取决于服用的剂量和吸收的效率。若剂量足够而且吸收充分，它们应该能发挥预防恶化及缓解病情的作用。相反，因个体差异导致的吸收障碍必然影响实验结果，从而得出无效的结论。 目前对阿尔茨海默病的发病机理仍不了解，我们假定 β-淀粉样蛋白的沉积是早老性蛋白硝基化导致错误折叠的结果。假如这个假说能获得证实，那么就能合理地解释 ω-3脂肪酸对 阿尔茨海默病有效而对其他老年病低效甚至无效的研究结论。 蛋白质硝基化是由过氧化亚硝酸根负离子（ONOO - ）介导的，而 ONOO - 的形成既需要有一氧化氮（NO），也需要有超氧阴离子（ · O - ），两者在慢性炎症下可以大量产生。若此时加入抗氧化剂，就能淬灭 · O - ，使 ONOO - 无法形成，于是蛋白质硝基化被阻断， 早老性蛋白不会出现错误折叠， β-淀粉样蛋白沉积也就不再发生。 至于其他老年性疾病，并不一定涉及 蛋白质硝基化，如心血管病可能只与慢性炎症直接相关，从而导致血管损伤、粥样硬化、血压异常等症状。因此，不仅服用 ω-3脂肪酸无益，而且补充其他抗氧化剂也可能收效甚微。 由此可以得出初步结论， 此研究因在复方中同时使用了 ω-3脂肪酸和抗氧化剂，故得出 ω-3脂肪酸对于防止老年痴呆症认知力下降无效的结论并不具有说服力，有待今后进一步设计甄别实验加以澄清。 附：几篇相关报道 DHA Improves Memory and Cognitive Function in Older Adults, Study Suggests Boosting Mental Performance With Fish Oil? Omega-3 Fatty Acids Don't Improve Heart's Ability to Relax and Efficiently Refill With Blood No benefit of omega-3 supplements for cognitive decline, study shows Date:August 25, 2015 Source:NIH, National Eye Institute (NEI) Summary: While some research suggests that a diet high in omega-3 fatty acids can protect brain health, a large clinical trial found that omega-3 supplements did not slow cognitive decline in older persons. With 4,000 patients followed over a five-year period, the study is one of the largest and longest of its kind. Share: 0 0 19 10 Total shares: 29 FULL STORY NIH study raises doubt about any benefits omega-3 and dietary supplements like these may have for cognitive decline. Credit: Photo courtesy of NEI While some research suggests that a diet high in omega-3 fatty acids can protect brain health, a large clinical trial by researchers at the National Institutes of Health found that omega-3 supplements did not slow cognitive decline in older persons. With 4,000 patients followed over a five-year period, the study is one of the largest and longest of its kind. It was published today in the Journal of the American Medical Association . Contrary to popular belief, we didn't see any benefit of omega-3 supplements for stopping cognitive decline, said Emily Chew, M.D., deputy director of the Division of Epidemiology and Clinical Applications and deputy clinical director at the National Eye Institute (NEI), part of NIH. Dr. Chew leads the Age-Related Eye Disease Study (AREDS), which was designed to investigate a combination of nutritional supplements for slowing age-related macular degeneration (AMD), a major cause of vision loss among older Americans. That study established that daily high doses of certain antioxidants and minerals -- called the AREDS formulation -- can help slow the progression to advanced AMD. A later study, called AREDS2, tested the addition of omega-3 fatty acids to the AREDS formula. But the omega-3's made no difference. Omega-3 fatty acids are made by marine algae and are concentrated in fish oils; they are believed to be responsible for the health benefits associated with regularly eating fish, such as salmon, tuna, and halibut.* Where studies have surveyed people on their dietary habits and health, they've found that regular consumption of fish is associated with lower rates of AMD, cardiovascular disease, and possibly dementia. We've seen data that eating foods with omega-3 may have a benefit for eye, brain, and heart health, Dr. Chew explained. Omega-3 supplements are available over the counter and often labeled as supporting brain health. A large 2011 study found that omega-3 supplements did not improve the brain health of older patients with preexisting heart disease. With AREDS2, Dr. Chew and her team saw another opportunity to investigate the possible cognitive benefits of omega-3 supplements, she said. All participants had early or intermediate AMD. They were 72 years old on average and 58 percent were female. They were randomly assigned to one of the following groups: 1) Placebo (an inert pill) 2) Omega-3 3) Lutein and zeaxanthin (nutrients found in large amounts in green leafy vegetables) 4) Omega-3 and Lutein/zeaxanthin Because all participants were at risk for worsening of their AMD, they were also offered the original or a modified version of the AREDS formulation (without omega-3 or lutein/zeaxanthin). Participants were given cognitive function tests at the beginning of the study to establish a baseline, then at two and four years later. The tests, all validated and used in previous cognitive function studies, included eight parts designed to test immediate and delayed recall, attention and memory, and processing speed. The cognition scores of each subgroup decreased to a similar extent over time, indicating that no combination of nutritional supplements made a difference. Alzheimer's disease, which is the most common cause of dementia and affects as many as 5.1 million Americans age 65 and older in the U.S., may triple in the next 40 years. Some research has examined the potential benefits of DHA for Alzheimer's. Studies in mice specially bred to have features of the disease found that DHA reduces beta-amyloid plaques, abnormal protein deposits in the brain that are a hallmark of Alzheimer's, although a clinical trial of DHA showed no impact on people with mild to moderate Alzheimer's disease. The AREDS2 data add to our efforts to understand the relationship between dietary components and Alzheimer's disease and cognitive decline, said Lenore Launer, Ph.D. senior investigator in the Laboratory of Epidemiology and Population Science at the National Institute on Aging. It may be, for example, that the timing of nutrients, or consuming them in a certain dietary pattern, has an impact. More research would be needed to see if dietary patterns or taking the supplements earlier in the development of diseases like Alzheimer's would make a difference. * Other omega-3 fatty acids are found in plant foods such as flaxseed, walnuts, soy products, and canola and soybean oils. Specific omega-3 fatty acids from these sources were not studied. The cognitive function component of AREDS2 was supported by the NEI Intramural Research Program and contracts HHS-N-260-2005-00007-C. Additional research funds were provided by the NIH Office of Dietary Supplements; the National Center for Complementary and Integrative Health; the National Institute on Aging; the National Heart, Lung, and Blood Institute; and the National Institute of Neurological Disorders and Stroke. Story Source: The above post is reprinted from materials provided by NIH, National Eye Institute (NEI) . Note: Materials may be edited for content and length. Journal Reference : Age-Related Eye Disease Study 2 (AREDS2) Research Group. Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial . JAMA , 2015
http://nature.bio1000.com/neuroscience/201406/333.html 期刊名： Nature Communications 日期：2014-06-16 DOI：10.1038/ncomms5159 标签： 星形胶质细胞 GABA 海马齿状回神经元 摘要 : 日前，由宾夕法尼亚州立大学生物系Verne M. Willaman 冠名主任教授陈功博士带领的研究团队，发现星形胶质细胞中高浓度的 GABA是通过其特有的GABA转运体进行释放，导致海马齿状回神经元受到过度的 GABA 抑制作用，从而不能像正常神经细胞一样发放动作电位，从而导致记忆下降。相关文章发表于2014年6月13日的《自然-通讯》杂志上。 日前，由宾夕法尼亚州立大学生物系Verne M. Willaman 冠名主任教授陈功博士带领的研究团队，发现星形胶质细胞中高浓度的 GABA是通过其特有的GABA转运体进行释放，导致海马齿状回神经元受到过度的 GABA 抑制作用，从而不能像正常神经细胞一样发放动作电位。相关文章发表于2014年6月13日的《自然-通讯》杂志上。 近年来失败的临床试验多以淀粉样蛋白作为靶向分子而设计药物。淀粉样蛋白在大脑中形成老年斑，毒杀大脑内神经细胞,现已成为诊断阿尔茨海默氏症的公认标准之一。然而从源头上减少淀粉样蛋白并不能有效地治疗老年痴呆症,需要新思路。“目前，我们实验室和国际上许多其他研究组的研究方向开始转向寻找新的药物靶点，开发诊断和治疗阿尔兹海默病的新方法”，陈功教授解释到。 “最近我们发现，在死于阿尔茨海默氏症的患者大脑中，有异常高浓度的一种抑制性神经递质，”陈教授说。他领导的研究小组发现，神经递质GABA(γ-氨基丁酸)在大脑海马齿状回的应激性星形胶质细胞里有大量聚集。海马齿状回是大脑的核心区域，是通往海马的门户，与大脑学习和记忆密切相关。在健康大脑中，正常星形胶质细胞具有支持神经元并连接大脑血管的功能。“我们的研究表明，阿尔茨海默氏症患者的应激性星形胶质细胞中有着高浓度的GABA，可能是一种新型的生物标志物。我们希望通过进一步的研究，使这一发现能成为阿尔茨海默病的新的诊断工具和进行针对性治疗的新靶点”，陈教授说。 陈功教授的博士后组员吴政博士开发了一种新的实验分析方法来评价正常小鼠和阿尔茨海默病转 基因 模型小鼠(AD 小鼠)大脑中神经递质浓度的差异。我们对AD 小鼠的研究显示，海马内高浓度的GABA 与其学习记忆障碍有明确关联，陈功教授说。他的实验室发现星形胶质细胞中高浓度的 GABA是通过其特有的GABA转运体进行释放，导致海马齿状回神经元受到过度的 GABA 抑制作用，从而不能像正常神经细胞一样发放动作电位。而神经细胞发放正常的动作电位，是学习记忆的重要基础。因此,星形胶质细胞特异性GABA转运体也是该研究中发现的新型药物靶点。 更重要的是,我们通过抑制星形胶质细胞的 GABA 转运体，减少应激性星形胶质细胞的GABA 释放，从而降低AD小鼠脑内的GABA抑制，结果发现AD小鼠的记忆能力增强了。这个结果令我们非常兴奋和鼓舞，因为这或许可以解释为什么以往那些只针对淀粉样蛋白的药物临床试验都以失败而告终。一种可能的解释是，虽然这些药物可以有效地减少淀粉样蛋白的沉积，但淀粉样蛋白可能是阿尔茨海默氏症的诱因，却不一定是终极原因。其触发的一系列下游信号通路的改变，如我们发现的过度GABA 抑制，并不能通过简单的降低淀粉样蛋白而改善。我们认为减少老年痴呆症患者大脑海马内的过度抑制，可能会是一种新型疗法。最终的成功治疗老年痴呆症的方案可能是一种同时作用于几个靶点的鸡尾酒疗法,陈教授总结说。 除了陈功教授，该研究团队还包括来自宾夕法尼亚州立大学的博士后吴政，博士研究生郭梓园和来自埃默里大学的Marla Gearing. 原文摘要： Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzhiemer’s disease model Zheng Wu, Ziyuan Guo, Marla Gearing Gong Chen Amyloid plaques and tau tangles are common pathological hallmarks for Alzheimer’s disease (AD); however, reducing Aβ production failed to relieve the symptoms of AD patients. Here we report a high GABA (γ-aminobutyric acid) content in reactive astrocytes in the dentate gyrus (DG) of a mouse model for AD (5xFAD) that results in increased tonic inhibition and memory deficit. We also confirm in human AD patient brains that dentate astrocytes have a high GABA content, suggesting that high astrocytic GABA level may be a novel biomarker and a potential diagnostic tool for AD. The excessive GABA in 5xFAD astrocytes is released through an astrocyte-specific GABA transporter GAT3/4, and significantly enhances tonic GABA inhibition in dentate granule cells. importantly, reducing tonic inhibition in 5xFAD mice rescues the impairment of long-term potentiation (LTP) and memory deficit. Thus, reducing tonic GABA inhibition in the DG may lead to a novel therapy for AD.
长期便秘是老年人智力下降的罪魁祸首，有80%左右的老年便秘者易患老年痴呆症。 正常情况下，人体肠道内的细菌能将没有被消化的蛋白质分解成氨、吲哚、硫化氢和组织胺等有毒物质，这些有毒物质生成后可通过大便排出体外。而便秘患者由于不能正常排出这些有毒物质，久而久之，体内就会大量积累有毒物质。当体内的有毒物质积累到一定程度并超过肝脏的解毒能力时，就会随着血液循环慢慢进入大脑，损害人们的中枢神经系统，成为老年人智力下降的罪魁祸首。尤其是老年人进食量相对减少，消化功能也相对较差，代谢机能呈明显衰退的趋势，因此，老年人长期便秘极易引发老年痴呆症。 老年人便秘一般可分为痉挛性便秘和无力性便秘。痉挛性便秘大多是由于所进食物中含有香料和纤维过量而引发的，这类老年便秘患者应注意多吃些少渣的半流质食物，如牛奶、米粥、蛋汤和软米饭等，能够有效避免或减轻便秘症状。无力性便秘者大多是因为所进食物中脂肪含量不够、缺乏蔬菜水果和饮水不足引发的，这类老年便秘患者应多食用有渣食物，如粗粮、青菜、豆制品和含维生素B1比较多的食物等，以增加身体对纤维的摄入量，促进肠道蠕动，从而缓解便秘症状。易患便秘的老年人，要养成早起空腹饮一杯水、就寝前喝一杯酸奶的好习惯，对预防便秘能起到一定的作用。 http://www.gopubmed.org/web/gopubmed/1?WEB0an1r0evyz8lI5I1I00h001000j100300.y constipation AND Dementia 108 documents semantically analyzed 1 2 Top Years Publications 2009 14 2007 8 2010 7 2004 7 2001 7 2006 6 2005 6 2008 5 2003 4 1997 4 2002 3 1999 3 2000 3 1996 3 1994 3 1998 2 1995 2 1991 2 1988 2 1986 2 1 2 1 2 Top Countries Publications USA 34 United Kingdom 8 Japan 7 Netherlands 5 Spain 4 Germany 3 Italy 3 Australia 3 Sweden 2 New Zealand 2 Belgium 1 Czech Republic 1 Taiwan 1 Croatia 1 Turkmenistan 1 Austria 1 Portugal 1 France 1 China 1 Finland 1 1 2 1 2 3 Top Cities Publications Tokyo 4 Nijmegen 4 Rochester, MN, USA 3 Milwaukee 3 London 3 Boston 3 Valladolid 2 Atlanta 2 Auckland, New Zealand 2 Chicago 2 Brussels 1 Heidelberg 1 Spokane 1 Guildford 1 Dresden 1 Naples 1 Prague 1 Ume 1 San Diego 1 Los Angeles 1 1 2 3 1 2 3 4 5 Top Journals Publications J Am Med Dir Assoc 4 Eur J Clin Nutr 3 Drug Aging 3 J Clin Psychiat 3 Am J Gastroenterol 3 Am J Geriatr Pharmacother 2 Mayo Clin Proc 2 J Nutr Health Aging 2 Age Ageing 2 Movement Disord 2 Arch Intern Med 2 Int J Geriatr Psychiatry 2 J Clin Gastroenterol 2 Nurs Times 2 Tijdschr Gerontol Geriatr 2 Rinsho Shinkeigaku 2 Ned Tijdschr Geneeskd 2 Wien Med Wochenschr 2 J Am Geriatr Soc 2 Rev Med Brux 1 1 2 3 4 5 1 2 3 ... 55 Top Terms Publications Constipation 108 Humans 102 Dementia 92 Aged 71 Patients 60 Aged, 80 and over 32 Alzheimer Disease 26 Nursing 24 Nurses 24 Adult 23 Diagnosis 22 Parkinson Disease 22 Depression 20 Middle Aged 20 Nursing Homes 19 Prevalence 17 Comorbidity 17 Evaluation Studies as Topic 17 Risk Factors 17 Pharmaceutical Preparations 17 1 2 3 ... 55 1 2 3 ... 17 Top Authors Publications Van Weel C 3 Koopmans R 3 Van den Hoogen H 3 Kovch C 2 Noonan P 2 Cuellar L 2 De Luis D 2 Aller R 2 Izaola O 2 Terroba M 2 Lyman P 2 Volicer L 2 Lane P 2 Panke J 2 Kiely D 2 Jesudason V 2 Furner S 2 Lhle M 1 Reichmann H 1 Schneider C 1 1 2 3 ... 17
http://news.sciencenet.cn/htmlnews/2010/9/237369.shtm 厦门大学生物医学研究院 张云武 教授和 许华曦 教授所领导的福建省神经退行性疾病及衰老研究重点实验室团队，最新鉴定出一个可以抑制老年痴呆症发病的小鼠新基因。这项成果目前已被《人类分子遗传学》（ Human Molecular Genetics ）接受并提前在网上发表。 http://hmg.oxfordjournals.org/content/19/19/3835.abstract?sid=d32374f2-3e48-4b71-94ed-14aee3383ad5 Title: A functional mouse retroposed gene Rps23r1 reduces Alzheimer's beta-amyloid levels and tau phosphorylation . PMID: 19914182 Related Articles Authors: Zhang, Y , et.al. Journal: Neuron , Vol. 64 (3): 328-40 , 2009 Snippet: Here, we identify a mouse gene Rps23r1 that originated through retroposition of ribosomal protein S23. Affiliation: Institute for Biomedical Research, Xiamen University, Xiamen , China . http://www.gopubmed.org/web/gopubmed/1?WEB09o7ocq82oxxsIjI1I00h001000j100500001002000001200301011000606 983 documents semantically analyzed Top Years Publications 2009 508 2008 176 2007 89 2006 76 2005 31 2010 26 2004 22 2002 14 2001 10 2003 9 1995 5 1999 4 2000 4 1996 3 1998 3 1994 1 1993 1 1980 1 1 2 Top Countries Publications USA 314 Japan 76 China 69 Germany 61 Spain 59 United Kingdom 51 Italy 31 Canada 28 Australia 26 Sweden 23 South Korea 21 Switzerland 18 Belgium 18 France 17 Israel 15 Netherlands 13 Russia 9 Portugal 8 Chile 8 Slovakia 8 1 2 1 2 3 ... 14 Top Cities Publications New York City 44 Madrid 43 Wuhan 33 Irvine 25 London 20 Baltimore 18 Seoul, South Korea 16 Los Angeles 15 Beijing, China 13 Sydney 12 Tokyo 12 Leipzig 10 Barcelona 9 Cambridge 9 Huddinge 9 Boston 9 Chicago 8 Leuven 8 Montreal 8 Bratislava 8 1 2 3 ... 14 1 2 3 ... 16 Top Journals Publications J Alzheimers Dis 71 J Neurosci 40 J Neurochem 35 J Biol Chem 31 Curr Alzheimer Res 29 Biochem Biophys Res Commun 24 Acta Neuropathol 23 Neurobiol Dis 21 Neurobiol Aging 21 Neurosci Lett 20 Febs Lett 20 Proc Natl Acad Sci U S A 17 J Med Chem 13 Am J Pathol 12 J Neurosci Res 11 Neuroscience 11 J Cell Mol Med 11 Brain Res 11 Eur J Neurosci 11 Biochim Biophys Acta 10 1 2 3 ... 16 1 2 3 ... 250 Top Authors Publications Avila J 23 Iqbal K 20 Wang J 16 Grundkeiqbal I 16 La Ferla F 15 Hernandez F 13 Oddo S 10 Wang Q 10 Goetz J 10 Takashima A 10 Gong C 9 Liu F 9 Perry G 9 Lucas J 8 Novk M 8 Li H 6 Ishiguro K 6 Perez M 6 Dickson D 5 Tian Q 5 1 2 3 ... 250 1 2 3 ... 274 Top Terms Publications Alzheimer Disease 853 Humans 692 Animals 672 Proteins 636 tau Proteins 593 Phosphorylation 525 Mice 445 Amyloid beta-Protein 429 phosphorylation 412 Neurons 408 hyperphosphorylation 342 Neurofibrillary Tangles 305 Phosphotransferases 288 Brain 269 tau protein binding 268 Mice, Transgenic 266 Pathology 260 Amyloid beta A4 protein 259 Transgenes 238 Senile Plaques 223 1 2 3 ... 274
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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 10.98wnt 20.98caspase 30.97estrogen receptor alpha 40.97differentially expressed gene 50.96clusterin 60.96statin 70.96ap180 80.96bax 90.95apoe 100.95parkin 110.95paraoxonase 120.94nf kappab 130.94stat3 140.94smad2 150.94chaperone 160.94ikappab 170.94apolipoprotein e 180.93abeta 190.93c1q 200.93megalin 210.93homeobox gene 220.93cdna library 230.93bcl-2 240.93egr-1 250.93candidate gene 260.92galanin 270.91pten 280.91cjd 290.91c1qb 300.90genome wide 310.89erk 320.89nurr1 330.89metallothionein 340.89apoj 350.89smac 360.88tnfalpha 370.88calpain 380.87han 390.86tgf beta1 400.86estrogen receptor 410.85apolipoprotein a i 420.85apoptotic gene 430.85hdl 440.85p53 tumor suppressor 450.85apolipoprotein a 460.84n cadherin 470.84leptin 480.82th1 490.82cd34 500.82transcription factor 510.81hif-1alpha 520.80vitronectin 530.80b myb 540.79hydrocephalus 550.78pro apoptotic gene 560.77cdna 570.77ldl 580.76antiapoptotic gene 590.75gene associated 600.74heat shock protein 610.72apolipoprotein c 620.72cytokine 630.71gene family 640.71platelet activation 650.71tgf beta 660.67hdl cholesterol level 670.67nf 680.67novel gene 690.65isoform 700.65hsp70 710.65c fos 720.64serial analysis gene 730.63gene symbol 740.63lipoprotein receptor gene 750.63protein kinase 760.63hsp27 770.62reduced expression 780.61promoter 790.61cadherin 800.60pick 810.58apo 820.56dft 830.55transglutaminase 840.51abl 850.50gene human chromosome 860.49lecithin cholesterol acyltransferase 870.48src 880.48cpg 890.46olfactory 900.45p2y 910.44senescence 920.43myelin basic protein 930.43gene involved 940.42glucocorticoid receptor 950.42gene expressed 960.42amyotrophic lateral sclerosis 970.41gene apolipoprotein 980.41interleukin 990.403'-untranslated region 1000.38afm 1010.37channel gene 1020.36gene encode a 1030.35proteoglycan 1040.35apolipoprotein f g 1050.35cell cycle progression 1060.35trail 1070.34glutathione s transferase 1080.34associated protein 1090.33proteolysis 1100.33genomic 1110.32fibroblast growth factor 1120.31ornithine decarboxylase 1130.31new gene 1140.31homodimer 1150.31tumor necrosis factor 1160.31receptor gene 1170.30analysis gene 1180.30tumor suppressor 1190.30domain 1200.30gst 1210.29p53 1220.28p21 1230.28topoisomerase 1240.27retinal degeneration 1250.27sh 1260.26myc 1270.26fc 1280.25repressor 1290.24fas 1300.24map 1310.24acyltransferase 1320.24beta1 1330.24c9 1340.23protease 1350.23phospholipase 1360.23androgen receptor 1370.23hip 1380.23raby 1390.23hnk-1 1400.21bb 1410.21retinoic acid induced 1420.20cholesterol 1430.20lipoprotein lipase 1440.19kinase 1450.18rt 1460.17cholesterol acyltransferase gene 1470.16pcr 1480.16gene human 1490.15integrin beta 1500.15gene transfer 1510.15ligand 1520.15epidermal growth factor 1530.14fos 1540.14gene a 1550.14programmed cell death 1560.12ms 1570.12iron 1580.11spatial 1590.11islet 1600.11inositol 1610.11twin 1620.11complement component 1630.10hiv 1640.10gh 1650.09diabetes mellitus 1660.08pro 1670.08conductance 1680.08b12 1690.08inducible 1700.08transferrin 1710.07gene 1720.07egf 1730.07von willebrand factor 1740.06fab 1750.06cycle gene 1760.06atherosclerosis 1770.06locus 1780.06lens 1790.06hydrolase 1800.06mitochondrial 1810.06nervous 1820.06variant 1830.05integrin 1840.05spin 1850.05alpha2 1860.05snail 1870.05prostate cancer 1880.04proteinase 1890.04lipase 1900.04death 1910.04beta2 1920.04beta3 1930.04saa 1940.04diabetes 1950.04d3 1960.03haptoglobin 1970.03pur 1980.03histone 1990.03p2 2000.03double 2010.03family 2020.03node 2030.03igg 2040.03novel 2050.03lacking 2060.03trait 2070.02gamma 2080.02milk 2090.02damage 2100.02bypass 2110.02signal 2120.02thrombin 2130.02mice 2140.02rna 2150.02decarboxylase 2160.02b103 2170.02elastin 2180.02myocardial infarction 2190.01tert 2200.01adp 2210.01synergistic 2220.01gal 2230.01old 2240.01key 2250.01fragment 2260.01genome 2270.01fat 2280.01lack 2290.01apoprotein 2300.01impact 2310.01protein 2320.01e coli 2330.01fibrinogen 2340.01ca2 2350.01inhibitor 2360.01plasma protein 2370.01transferase 2380.01leaf 2390.01receptor 2400.01abnormal 2410.01alpha 2420.01insulin 2430.01beta 2440.01albumin 2450.01rd 2460.01oh 2470.00gap 2480.00breast cancer 2490.00rest 2500.00glycoprotein a 2510.00hypertension 2520.00germ 2530.00bulb 2540.00sera 2550.00gel 2560.00vein 2570.00leg 2580.00ds 2590.00early 2600.00polypeptide 2610.00not 2620.00xx 2630.00fusion 2640.00retinal pigment epithelium 2650.00juice 2660.00art 2670.00reductase 2680.00limb 2690.00cat 2700.00sea 2710.00poly 2720.00co 2730.00asthma 2740.00glycoprotein 2750.00atp 2760.00giant 2770.00weight 2780.00alga 2790.00beta chain 2800.00cord 2810.00genic 2820.00tree 2830.00tran 2840.00amino acid sequence 2850.00tyr 2860.00hare 2870.00or 2880.00eye 2890.00fiber 2900.00ir 2910.00mdl 2920.00enhancement 2930.00ray 2940.00activity 2950.00pig 2960.00cycle 2970.00glass 2980.00lethal 2990.00da 3000.00sense 3010.00sex 3020.00region 3030.00block 3040.00term 3050.00care 3060.00non 3070.00mass 3080.00defense 3090.00men 3100.00phosphate 3110.00fish 3120.00base 3130.00total 3140.00l m 3150.00calm 3160.00cyst 3170.00dog 3180.00coat 3190.00male 3200.00line 3210.00spp 3220.00mis 3230.00fate 3240.00secretion 3250.00est 3260.00skin 3270.00ac 3280.00ph 3290.00minor 3300.00elongated 3310.00santa 3320.00pi 3330.00red 3340.00membrane 3350.00sp 3360.00ectopic 3370.00b 3380.00mode 3390.00phase 3400.00modification 3410.00area 3420.00iv 3430.00benign 3440.00tube 3450.00large 3460.00wave 3470.00mid 3480.00group 3490.00man 3500.00past 3510.00face 3520.00low 3530.00t 3540.00delta 3550.00cell 3560.00time 3570.00i 3580.00neo 3590.00disorganization 3600.00pre Restrict by semantic categories? job id # 8256 started Sun Jan 24 08:29:11 2010 Max_citations: 50000 Stoplist: /var/www/html/arrowsmith_uic/data/stopwords_pubmed Ngram_max: 3 8256 Search ARROWSMITH A A_query_raw: CLU AND PICALMSun Jan 24 08:30:08 2010 A query = CLU AND PICALM started Sun Jan 24 08:30:08 2010 A query resulted in 3 titles 8256 Search ARROWSMITH C 8256 Select from History ARROWSMITH C C_query_raw: CLU AND PICALM Sun Jan 24 08:30:29 2010 C: CLU AND PICALM 3 A: pubmed_query_A 3 AC: ( CLU AND PICALM ) AND ( CLU AND PICALM ) 3 8256 Search ARROWSMITH A A_query_raw: CLU OR PICALMSun Jan 24 08:30:55 2010 A query = CLU OR PICALM started Sun Jan 24 08:30:55 2010 A query resulted in 937 titles 8256 Search ARROWSMITH C C_query_raw: Alzheimer's disease Sun Jan 24 08:31:10 2010 C: Alzheimer's disease 68994 A: pubmed_query_A 937 AC: ( CLU OR PICALM ) AND ( Alzheimer's disease ) 67 C query = Alzheimer's disease started Sun Jan 24 08:31:10 2010 C query resulted in 50000 titles A AND C query resulted in 67 titles 3744 B-terms ready on Sun Jan 24 08:34:32 2010 Sem_filter: Genes Molecular Sequences, and Gene Protein Names 360 B-terms left after filter executed Sun Jan 24 08:40:07 2010 B-list on Sun Jan 24 08:41:21 2010 1 wnt 2 caspase 3 estrogen receptor alpha 4 differentially expressed gene 5 clusterin 6 statin 7 ap180 8 bax 9 apoe 10 parkin 11 paraoxonase 12 nf kappab 13 stat3 14 smad2 15 chaperone 16 ikappab 17 apolipoprotein e 18 abeta 19 c1q 20 megalin 21 homeobox gene 22 cdna library 23 bcl-2 24 egr-1 25 candidate gene 26 galanin 27 pten 28 cjd 29 c1qb 30 genome wide 31 erk 32 nurr1 33 metallothionein 34 apoj 35 smac 36 tnfalpha 37 calpain 38 han 39 tgf beta1 40 estrogen receptor 41 apolipoprotein a i 42 apoptotic gene 43 hdl 44 p53 tumor suppressor 45 apolipoprotein a 46 n cadherin 47 leptin 48 th1 49 cd34 50 transcription factor 51 hif-1alpha 52 vitronectin 53 b myb 54 hydrocephalus 55 pro apoptotic gene 56 cdna 57 ldl 58 antiapoptotic gene 59 gene associated 60 heat shock protein 61 apolipoprotein c 62 cytokine 63 gene family 64 platelet activation 65 tgf beta 66 hdl cholesterol level 67 nf 68 novel gene 69 isoform 70 hsp70 71 c fos 72 serial analysis gene 73 gene symbol 74 lipoprotein receptor gene 75 protein kinase 76 hsp27 77 reduced expression 78 promoter 79 cadherin 80 pick 81 apo 82 dft 83 transglutaminase 84 abl 85 gene human chromosome 86 lecithin cholesterol acyltransferase 87 src 88 cpg 89 olfactory 90 p2y 91 senescence 92 myelin basic protein 93 gene involved 94 glucocorticoid receptor 95 gene expressed Start A-Literature C-Literature B-list Filter Literature AB literature B-term BC literature CLU OR PICALM bax Alzheimer's disease 1: Interleukin-6 affects cell death escaping mechanisms acting on Bax- Ku70- Clu sterin interactions in human colon cancer progression.2009 Add to clipboard 2: Clu sterin inhibits apoptosis by interacting with activated Bax. 2005 Add to clipboard 3: Chronic beta-adrenoreceptor stimulation in vivo decreased Bcl-2 and increased Bax expression but did not activate apoptotic pathways in mouse heart.2004 Add to clipboard 1: Peripheral blood mononuclear cells from mild cognitive impairment patients show deregulation of Bax and Sod1 mRNAs.2009 Add to clipboard 2: Age-related differences in NFkappaB translocation and Bcl-2 /Bax ratio caused by TNFalpha and Abeta42 promote survival in middle-age neurons and death in old neurons.2008 Add to clipboard 3: 2007 Add to clipboard 4: Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis.2007 Add to clipboard 5: Alzheimer's amyloid beta-peptide (1-42) induces cell death in human neuroblastoma via bax/ bcl-2 ratio increase: an intriguing role for methionine 35.2006 Add to clipboard 6: 2006 Add to clipboard 7: Fragment 31-35 of beta-amyloid peptide induces neurodegeneration in rat cerebellar granule cells via bax gene expression and caspase-3 activation. A crucial role for the redox state of methionine-35 residue.2006 Add to clipboard 8: Induction of Bcl-2 and Bax was related to hyperphosphorylation of tau and neuronal death induced by okadaic acid in rat brain.2005 Add to clipboard 9: Blockade of ionotropic glutamate receptors produces neuronal apoptosis through the Bax- cytochrome C-caspase pathway: the causative role of Ca2+ deficiency.2003 Add to clipboard 10: 2003 Add to clipboard 11: Atypical antipsychotics attenuate neurotoxicity of beta-amyloid(25-35) by modulating Bax and Bcl-X(l/s) expression and localization.2003 Add to clipboard 12: Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons.2002 Add to clipboard 13: Co-involvement of mitochondria and endoplasmic reticulum in regulation of apoptosis: changes in cytochrome c, Bcl-2 and Bax in the hippocampus of aluminum-treated rabbits.2001 Add to clipboard 14: GDNF protects against aluminum-induced apoptosis in rabbits by upregulating Bcl-2 and Bcl-XL and inhibiting mitochondrial Bax translocation.2001 Add to clipboard 15: Expression of apoptosis related proteins: RAIDD, ZIP kinase, Bim/BOD, p21, Bax, Bcl-2 and NF-kappaB in brains of patients with Down syndrome.2001 Add to clipboard 16: Amyloid beta-induced neuronal death is bax- dependent but caspase-independent.2000 Add to clipboard 17: E2F1 mediates death of B-amyloid-treated cortical neurons in a manner independent of p53 and dependent on Bax and caspase 3.2000 Add to clipboard 18: Differential distribution of presenilin-1, Bax, and Bcl-X(L) in Alzheimer's disease and frontotemporal dementia.1999 Add to clipboard 19: Age-related hippocampal changes in Bcl-2 :Bax ratio, oxidative stress, redox-active iron and apoptosis associated with aluminum-induced neurodegeneration: increased susceptibility with aging.1999 Add to clipboard 20: Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer's disease .1998 Add to clipboard 21: Bcl-2 and Bax protein expression in Alzheimer's disease .1998 Add to clipboard 22: Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus.1997 Add to clipboard http://news.sciencenet.cn//htmlnews/2010/1/227529.shtm 科学家发现阿尔茨海默氏症相关基因 为潜在治疗和基因筛选开辟新领域 科学家发现了两种阿尔茨海默氏症相关基因。 大量资金的投入终于在对阿尔茨海默氏症的研究中取得了突破。在这项最大型的研究中，科学家发现了两个能够增加人体向最常见形式的阿尔茨海默氏症发展的基因。研究人员指出，这项国际研究在了解阿尔茨海默氏症的发展趋势方面取得了进展，并为潜在治疗和基因筛选的进一步研究开辟了新的领域。 全球有数百万人饱受阿尔茨海默氏症之苦，仅在英国就大约有417000人罹患此病。阿尔茨海默氏症最初由德国精神病学家阿诺斯阿尔茨海默所定义，是一种影响大脑的身体疾病。在致病过程中，类淀粉斑和神经纤维在脑结构中发展，导致脑细胞死亡。阿尔茨海默氏症患者的大脑中同时还缺少某些重要的化学物质。这些化学物质参与了大脑内信息的传输。 这项研究对16000人的脱氧核糖核酸（DNA）进行了为期两年的分析，结果显示，CLU和PICALM基因在阿尔茨海默氏症发展风险中发挥了直接作用。之前，只有一种基因APOE4被确认为潜在风险因素。 该研究成果的主要作者、英国加的夫市医学研究理事会新旗舰研究中心的Julie Williams博士说：这项研究改变了我们对于最普遍形式的阿尔茨海默氏症的可能成因的了解，并且为发现治疗方法提供了新的导向。如果能够战胜这两种基因的有害影响，我们估计将减少20%的人罹患阿尔茨海默氏症的可能性。 医学研究理事会首席执行官LeszekBorysiewicz说：为神经变性疾病进行资助是我们的优先工作项目，并且医学研究理事会对该创新研究领域的投资对揭示出阿尔茨海默氏症之谜是非常关键的。这项研究在阿尔茨海默氏症的诊断道路上迈出了一大步，并且使很多受此病折磨的人的生活得到了改善。阿尔茨海默氏症研究信托基金的开发总监Marie Janson博士补充说：这些空前的发现是资助者和科学家等共同合作的结果。 《科学时报》 (2010-1-22 A4 国际) 更多阅读 英法科学家发现老年痴呆症相关三个基因 http://news.sciencenet.cn/htmlnews/2009/9/223102.shtm 英法科学家发现老年痴呆症相关三个基因 这是16年来首次找到老年痴呆症与基因有关联的新证据 英国和法国的研究人员发现了与阿尔茨海默症（俗称老年痴呆症）有关的3个基因。 据英国广播公司报道，这是16年来研究人员首次找到阿尔茨海默症与基因有关联的新证据。过去唯一找到的和一般老年痴呆症有关的基因APOE4一直是研究的焦点。 在最新的研究中，英法科学家对两万人的染色体样本进行了分析，发现了CR1、CLU和PICALM三个基因与阿尔茨海默症之间的关系。 报道称，CLU和PICALM基因都有保护大脑的功能。研究人员说，如果基因有变异，不仅可能失去保护大脑的功能，甚至保护者还有可能成为攻击者。 这项研究成果发表在最新出版的《自然遗传学》杂志上。它将促使科学家重新审视现在的有关阿尔茨海默症病因的理论。此外，研究成果还有助于医学界研发新的诊断、治疗手段。 英国阿尔茨海默研究基金会将这项新发现称为向前迈出了一大步。 据估计，全世界共有3000万阿尔茨海默症患者。而这一数字还将继续增长。 更多阅读 《自然遗传学》发表论文摘要（英文） http://www.nature.com/ng/journal/v41/n10/abs/ng.440.html Nature Genetics 41 , 1088 - 1093 (2009) Published online: 6 September 2009 | Corrected online: 28 September 2009 | :10.1038/ng.440 :10.1038/ng.440 There is an Erratum (October 2009) associated with this Letter. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease Denise Harold 1 , 45 , Richard Abraham 1 , 45 , Paul Hollingworth 1 , 45 , Rebecca Sims 1 , Amy Gerrish 1 , Marian L Hamshere 1 , Jaspreet Singh Pahwa 1 , Valentina Moskvina 1 , Kimberley Dowzell 1 , Amy Williams 1 , Nicola Jones 1 , Charlene Thomas 1 , Alexandra Stretton 1 , Angharad R Morgan 1 , Simon Lovestone 2 , John Powell 3 , Petroula Proitsi 3 , Michelle K Lupton 3 , Carol Brayne 4 , David C Rubinsztein 5 , Michael Gill 6 , Brian Lawlor 6 , Aoibhinn Lynch 6 , Kevin Morgan 7 , Kristelle S Brown 7 , Peter A Passmore 8 , David Craig 8 , Bernadette McGuinness 8 , Stephen Todd 8 , Clive Holmes 9 , David Mann 10 , A David Smith 11 , Seth Love 12 , Patrick G Kehoe 12 , John Hardy 13 , Simon Mead 14 , Nick Fox 15 , Martin Rossor 15 , John Collinge 14 , Wolfgang Maier 16 , Frank Jessen 16 , Britta Schrmann 16 , Hendrik van den Bussche 17 , Isabella Heuser 18 , Johannes Kornhuber 19 , Jens Wiltfang 20 , Martin Dichgans 21 , 22 , Lutz Frlich 23 , Harald Hampel 24 , 25 , Michael Hll 26 , Dan Rujescu 25 , Alison M Goate 27 , John S K Kauwe 28 , Carlos Cruchaga 27 , Petra Nowotny 27 , John C Morris 27 , Kevin Mayo 27 , Kristel Sleegers 29 , 30 , Karolien Bettens 29 , 30 , Sebastiaan Engelborghs 30 , 31 , Peter P De Deyn 30 , 31 , Christine Van Broeckhoven 29 , 30 , Gill Livingston 32 , Nicholas J Bass 32 , Hugh Gurling 32 , Andrew McQuillin 32 , Rhian Gwilliam 33 , Panagiotis Deloukas 33 , Ammar Al-Chalabi 34 , Christopher E Shaw 34 , Magda Tsolaki 35 , Andrew B Singleton 36 , Rita Guerreiro 36 , Thomas W Mhleisen 37 , 38 , Markus M Nthen 37 , 38 , Susanne Moebus 39 , Karl-Heinz Jckel 39 , Norman Klopp 40 , H-Erich Wichmann 40 , 41 , 42 , Minerva M Carrasquillo 43 , V Shane Pankratz 44 , Steven G Younkin 43 , Peter A Holmans 1 , Michael O'Donovan 1 , Michael J Owen 1 Julie Williams 1 Top of page We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E ( APOE ) locus (most significant SNP, rs2075650, P = 1.8 10 -157 ) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ ) gene (rs11136000, P = 1.4 10 -9 ) and 5' to the PICALM gene (rs3851179, P = 1.9 10 -8 ). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 10 -10 , odds ratio = 0.86; rs3851179, P = 1.3 10 -9 , odds ratio = 0.86). Top of page Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK. National Institute for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, Kings College, London, UK. Department of Neuroscience, Institute of Psychiatry, Kings College, London, UK. Institute of Public Health, St. James Hospital and Trinity College, Dublin, Ireland. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. Mercer's Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland. Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK. Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK. Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK. Clinical Neuroscience Research Group, Greater Manchester Neurosciences Centre, University of Manchester, Salford, UK. Oxford Project to Investigate Memory and Ageing, University of Oxford, John Radcliffe Hospital, Oxford, UK. Dementia Research Group, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK. Department of Molecular Neuroscience and Reta Lilla Weston Laboratories, Institute of Neurology, London, UK. MRC Prion Unit, UCL Institute of Neurology, London, UK. Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK. Department of Psychiatry, University of Bonn, Bonn, Germany. Institute of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Department of Psychiatry, Charit Berlin, Berlin, Germany. Department of Psychiatry and Psychotherapy, University of Erlangen-Nrnberg, Erlangen, Germany. Landschaftsverband Rheinland-Hospital Essen, Department of Psychiatry and Psychotherapy, University Duisburg-Essen, Essen, Germany. Institute for Stroke and Dementia Research, Klinikum der Universitt Mnchen, Munich, Germany. Department of Neurology, Klinikum der Universitt Mnchen, Munich, Germany. Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Laboratory of Neuroimaging Biomarker Research, Trinity College, University of Dublin, Dublin, Ireland. Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany. Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. Department of Biology, Brigham Young University, Provo, Utah, USA. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium. Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium. Memory Clinic and Department of Neurology, Ziekenhuis Netwerk Antwerpen Middelheim, Antwerpen, Belgium. Department of Mental Health Sciences, University College London, London, UK. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, London, UK. Third Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. Department of Genomics, Life Brain Center, University of Bonn, Bonn, Germany. Institute of Human Genetics, University of Bonn, Bonn, Germany. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany. Institute of Epidemiology, Helmholtz Zentrum Mnchen, German Research Center for Environmental Health, Neuherberg, Germany. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universitt, Munich, Germany. Klinikum Grosshadern, Munich, Germany. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA. Division of Biomedical Statistics and Informatics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA. These authors contributed equally to this work. Correspondence to: Julie Williams 1 e-mail: williamsj@cardiff.ac.uk Correspondence to: Michael J Owen 1 e-mail: owenmj@cardiff.ac.uk * NOTE: In the version of this article initially published, the name of the first author of reference 12 was stated incorrectly in the reference list. The correct reference is: Lambert, J.-C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet. advance online publication, doi:10.1038/ng.439 (6 September 2009). The error has been corrected in the HTML and PDF versions of the article. MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated. REVIEWS Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses Nature Reviews Neuroscience Review (01 Oct 2008) See all 4 matches for Reviews NEWS AND VIEWS Alzheimer?s disease beyond APOE Nature Genetics News and Views (01 Oct 2009) RESEARCH Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease Nature Genetics Letter (01 Oct 2009) Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease Nature Genetics Letter (01 Feb 2009) Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies Nature Genetics Article (01 Nov 2009) See all 53 matches for Research
http://www.sciencenet.cn/htmlpaper/20099895997607248.shtm 发现老年痴呆症相关三个基因 英国和法国的研究人员发现了与阿尔茨海默症（俗称老年痴呆症）有关的3个基因。 据英国广播公司报道，这是16年来研究人员首次找到阿尔茨海默症与基因有关联的新证据。过去唯一找到的和一般老年痴呆症有关的基因APOE4一直是研究的焦点。 在最新的研究中，英法科学家对两万人的染色体样本进行了分析，发现了CR1、CLU和PICALM三个基因与阿尔茨海默症之间的关系。 报道称，CLU和PICALM基因都有保护大脑的功能。研究人员说，如果基因有变异，不仅可能失去保护大脑的功能，甚至保护者还有可能成为攻击者。 这项研究成果发表在最新出版的《自然遗传学》杂志上。它将促使科学家重新审视现在的有关阿尔茨海默症病因的理论。此外，研究成果还有助于医学界研发新的诊断、治疗手段。 英国阿尔茨海默研究基金会将这项新发现称为向前迈出了一大步。 据估计，全世界共有3000万阿尔茨海默症患者。而这一数字还将继续增长。 http://www.nature.com/ng/journal/vaop/ncurrent/abs/ng.440.html Nature Genetics Published online: 6 September 2009 | :10.1038/ng.440 :10.1038/ng.440 Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease Denise Harold 1 , 45 , Richard Abraham 1 , 45 , Paul Hollingworth 1 , 45 , Rebecca Sims 1 , Amy Gerrish 1 , Marian L Hamshere 1 , Jaspreet Singh Pahwa 1 , Valentina Moskvina 1 , Kimberley Dowzell 1 , Amy Williams 1 , Nicola Jones 1 , Charlene Thomas 1 , Alexandra Stretton 1 , Angharad R Morgan 1 , Simon Lovestone 2 , John Powell 3 , Petroula Proitsi 3 , Michelle K Lupton 3 , Carol Brayne 4 , David C Rubinsztein 5 , Michael Gill 6 , Brian Lawlor 6 , Aoibhinn Lynch 6 , Kevin Morgan 7 , Kristelle S Brown 7 , Peter A Passmore 8 , David Craig 8 , Bernadette McGuinness 8 , Stephen Todd 8 , Clive Holmes 9 , David Mann 10 , A David Smith 11 , Seth Love 12 , Patrick G Kehoe 12 , John Hardy 13 , Simon Mead 14 , Nick Fox 15 , Martin Rossor 15 , John Collinge 14 , Wolfgang Maier 16 , Frank Jessen 16 , Britta Schrmann 16 , Hendrik van den Bussche 17 , Isabella Heuser 18 , Johannes Kornhuber 19 , Jens Wiltfang 20 , Martin Dichgans 21 , 22 , Lutz Frlich 23 , Harald Hampel 24 , 25 , Michael Hll 26 , Dan Rujescu 25 , Alison M Goate 27 , John S K Kauwe 28 , Carlos Cruchaga 27 , Petra Nowotny 27 , John C Morris 27 , Kevin Mayo 27 , Kristel Sleegers 29 , 30 , Karolien Bettens 29 , 30 , Sebastiaan Engelborghs 30 , 31 , Peter P De Deyn 30 , 31 , Christine Van Broeckhoven 29 , 30 , Gill Livingston 32 , Nicholas J Bass 32 , Hugh Gurling 32 , Andrew McQuillin 32 , Rhian Gwilliam 33 , Panagiotis Deloukas 33 , Ammar Al-Chalabi 34 , Christopher E Shaw 34 , Magda Tsolaki 35 , Andrew B Singleton 36 , Rita Guerreiro 36 , Thomas W Mhleisen 37 , 38 , Markus M Nthen 37 , 38 , Susanne Moebus 39 , Karl-Heinz Jckel 39 , Norman Klopp 40 , H-Erich Wichmann 40 , 41 , 42 , Minerva M Carrasquillo 43 , V Shane Pankratz 44 , Steven G Younkin 43 , Peter A Holmans 1 , Michael O'Donovan 1 , Michael J Owen 1 Julie Williams 1 We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E ( APOE ) locus (most significant SNP, rs2075650, P = 1.8 10 -157 ) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ ) gene (rs11136000, P = 1.4 10 -9 ) and 5' to the PICALM gene (rs3851179, P = 1.9 10 -8 ). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 10 -10 , odds ratio = 0.86; rs3851179, P = 1.3 10 -9 , odds ratio = 0.86). Top of page Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK. National Institute for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, Kings College, London, UK. Department of Neuroscience, Institute of Psychiatry, Kings College, London, UK. Institute of Public Health, St. James Hospital and Trinity College, Dublin, Ireland. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. Mercer's Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland. Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK. Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK. Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK. Clinical Neuroscience Research Group, Greater Manchester Neurosciences Centre, University of Manchester, Salford, UK. Oxford Project to Investigate Memory and Ageing, University of Oxford, John Radcliffe Hospital, Oxford, UK. Dementia Research Group, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK. Department of Molecular Neuroscience and Reta Lilla Weston Laboratories, Institute of Neurology, London, UK. MRC Prion Unit, UCL Institute of Neurology, London, UK. Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK. Department of Psychiatry, University of Bonn, Bonn, Germany. Institute of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Department of Psychiatry, Charit Berlin, Berlin, Germany. Department of Psychiatry and Psychotherapy, University of Erlangen-Nrnberg, Erlangen, Germany. Landschaftsverband Rheinland-Hospital Essen, Department of Psychiatry and Psychotherapy, University Duisburg-Essen, Essen, Germany. Institute for Stroke and Dementia Research, Klinikum der Universitt Mnchen, Munich, Germany. Department of Neurology, Klinikum der Universitt Mnchen, Munich, Germany. Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Laboratory of Neuroimaging Biomarker Research, Trinity College, University of Dublin, Dublin, Ireland. Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany. Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. Department of Biology, Brigham Young University, Provo, Utah, USA. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium. Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium. Memory Clinic and Department of Neurology, Ziekenhuis Netwerk Antwerpen Middelheim, Antwerpen, Belgium. Department of Mental Health Sciences, University College London, London, UK. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, London, UK. Third Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. Department of Genomics, Life Brain Center, University of Bonn, Bonn, Germany. Institute of Human Genetics, University of Bonn, Bonn, Germany. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany. Institute of Epidemiology, Helmholtz Zentrum Mnchen, German Research Center for Environmental Health, Neuherberg, Germany. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universitt, Munich, Germany. Klinikum Grosshadern, Munich, Germany. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA. Division of Biomedical Statistics and Informatics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA. These authors contributed equally to this work. Correspondence to: Julie Williams 1 e-mail: williamsj@cardiff.ac.uk Correspondence to: Michael J Owen 1 e-mail: owenmj@cardiff.ac.uk 原文请见： Genome-wide association study identifies variants 信息分析平台： http://www.gopubmed.org/web/gopubmed/2?WEB016o3080s6rvr5I2fI1I00d000j10040001rl 相关文献计量分析结果（43 documents analyzed） Top Years Publications 2000 6 2005 5 1996 5 1994 4 1998 3 1995 3 1992 3 2006 2 2004 2 2002 2 1999 2 2009 1 2008 1 2001 1 1993 1 1991 1 1990 1 Top Countries Publications USA 26 Japan 6 Canada 3 Switzerland 2 Sweden 2 Spain 2 Austria 1 1 2 Top Cities Publications Los Angeles 8 New York 4 St. Louis 3 Tokyo 3 Gothenburg 2 Boston 2 Montreal 2 Lausanne 1 Minneapolis 1 Sun City 1 Graz 1 Majadahonda 1 Fukuoka 1 Cleveland 1 New Haven 1 San Francisco 1 Chicago 1 Kyoto 1 Geneva 1 Sapporo 1 1 2 1 2 Top Journals Publications J Biol Chem 3 Brain Res 3 Acta Neuropathol 3 Neurobiol Aging 2 P Natl Acad Sci Usa 2 Microsc Res Techniq 2 Ann Ny Acad Sci 2 Exp Neurol 2 Neurochem Int 1 Alz Dis Assoc Dis 1 Brain Pathol 1 Neurotox Res 1 Eur J Cell Biol 1 Subcell Biochem 1 J Mol Neurosci 1 Neurobiol Dis 1 J Gastrointest Surg 1 Am J Pathol 1 Brit J Ophthalmol 1 Nippon Ronen Igakkai Zasshi 1 1 2 1 2 3 ... 9 Top Authors Publications Finch C 7 Oda T 4 Johnson S 4 Pasinetti G 4 Ghiso J 3 Frangione B 3 Holtzman D 3 Matsubara E 3 Rozovsky I 3 Choi-Miura N 3 Blennow K 2 Davidsson P 2 Calero M 2 Rostagno A 2 Parsadanian M 2 Zlokovic B 2 Wisniewski K 2 Morgan T 2 Osterburg H 2 Poirier J 2 1 2 3 ... 9 1 2 3 ... 34 Top Terms Publications Alzheimer Disease 43 Clusterin 40 Humans 38 Glycoproteins 38 Molecular Chaperones 38 Proteins 28 Apolipoproteins 23 lipid transporter activity 23 Senile Plaques 19 Animals 18 Amyloid beta-Protein 18 Brain 16 Apolipoproteins E 16 Immunohistochemistry 15 Aged 14 Nerve Tissue Proteins 13 apolipoprotein j 13 Neurons 12 Peptides 12 clusterin 12 1 2 3 ... 34 Top Terms Publications apolipoprotein E receptor activity 12 Tissues 11 Mice 11 apoj 11 apolipoprotein E binding 10 Hippocampus 9 RNA, Messenger 9 apoe 9 pathogenesis 8 Patients 8 Aged, 80 and over 8 hippocampus development 7 Gene Expression 7 Genes 7 cerebrospinal fluid secretion 7 Antibodies 7 antigen binding 7 Neurites 7 neuron projection 7 apolipoprotein e 7 1 2 3 4 ... 34 Top Terms Publications Up-Regulation 6 Mice, Transgenic 6 Cerebrospinal Fluid 6 Peptide Fragments 6 Middle Aged 6 Blotting, Western 6 Brain Chemistry 6 Neurofibrillary Tangles 6 Lipoproteins 6 Astrocytes 6 Amyloid 6 Membranes 5 membrane 5 Rats 5 Enzyme-Linked Immunosorbent Assay 5 Neuroglia 5 Complement Membrane Attack Complex 5 catabolic process 5 Adult 5 Metabolism 5 1 2 3 4 5 ... 34 Top Terms Publications metabolic process 5 Antibodies, Monoclonal 5 Oxidative Stress 5 Oxides 5 Lipids 5 Cerebral Cortex 5 Amyloid beta-Protein Precursor 5 sgp-2 5 Serum 5 Sulfates 5 gene expression 4 Population Groups 4 Dementia 4 Complement System Proteins 4 Microscopy 4 Cells, Cultured 4 Alleles 4 Amino Acids 4 Base Sequence 4 Microglia 4 1 2 3 4 5 6 ... 34 知识发现平台： http://arrowsmith.psych.uic.edu/cgi-bin/arrowsmith_uic/edit_b.cgi?refresh=TID=4780 Start A-Literature C-Literature B-list Filter Literature A-query: Alzheimer Disease C-query: PICALM The B-list contains title words and phrases (terms) that appeared in both the A and the C literature. 1 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 # 4780 and can be accessed from the start page after you leave this session. There are 191 terms on the current B-list ( 20 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 10.99caspase 20.99clathrin assembly protein 30.99alternative splicing 40.99clathrin assembly 50.98ap180 60.97clathrin 70.97expression profiling 80.97gene expression profiling 90.94genome wide 100.93calpain 110.93protein ap180 120.85associated alzheimer disease 130.84wide association study 140.81cdna 150.76genome wide association 160.75clathrin mediated 170.74genetic susceptibility 180.73associated alzheimer 190.69upregulation 200.66overexpression 210.64association study 220.55endocytic 230.21mouse model 240.15ethnic difference 250.15protein family 260.10splicing 270.09nucleation 280.06hybridisation 290.06iron metabolism 300.04ethnic 310.04molecular signature 320.03association study identify 330.03alzheimer disease 340.02mutation 350.02alzheimer 360.02gene expression 370.01encoding a 380.01cleavage 390.01trafficking 400.00assembly 410.00endocytosis 420.00inositol 430.00coated pits 440.00encode a 450.00knee 460.00potential role 470.00genomic 480.00protein rat 490.00neuronal 500.00gene 510.0011q23 520.00gst 530.00signature 540.00subcellular localization 550.00chromosomal inversion 560.00expression 570.00genetic 580.00truncated 590.00molecular 600.00stem cell 610.00hematopoietic 620.00auditory 630.00event 640.00encoding 650.00family 660.00novel 670.00profiling 680.00susceptibility 690.00mouse 700.00chromosomal 710.00mice 720.00abnormality 730.00purification 740.00lymphoid 750.00variant 760.00role truncated 770.00potential 780.00cell free 790.00impact 800.00protein 810.00e coli 820.00osteoarthritis 830.00difference 840.00phospholipid 850.00member 860.00regulator 870.00stem 880.00inositol phospholipid 890.00model 900.00monocytic 910.00iron 920.00suggest a 930.00association 940.00structural organization 950.00functional 960.00inversion 970.00genome 980.00structural 990.00coli 1000.00nucleocytoplasmic 1010.00formation 1020.00fusion protein 1030.00regulatory 1040.00wild 1050.00mechanism 1060.00subtype 1070.00protein localization 1080.00cell line 1090.00suggest 1100.00leukemia 1110.00polypeptide 1120.00fusion 1130.00cat 1140.00calm 1150.00reveal 1160.00deletion 1170.00p2 1180.00binding 1190.00aberration 1200.00lattice 1210.00role 1220.00depletion 1230.00lymphoid myeloid 1240.00interactor 1250.00sex 1260.00fish 1270.00alternative 1280.00localization 1290.00expression functional 1300.00protein alter 1310.00disease 1320.00coat 1330.00neuropathy 1340.00line 1350.00interaction 1360.00expressed 1370.00metabolism 1380.00alter subcellular 1390.00subcellular 1400.00minor 1410.00identify 1420.00alter subcellular localization 1430.00alter 1440.00coexpression 1450.00comp 1460.00liver 1470.00organization 1480.00membrane 1490.00rare 1500.00wide 1510.00subtype specific 1520.00study 1530.00specific 1540.00myeloid 1550.00simultaneous 1560.00traffic 1570.00free 1580.00transformation 1590.00property 1600.00acute 1610.00involve 1620.00evidence 1630.00rat 1640.00conserved 1650.00regulatory mechanism 1660.00metabolism abnormality 1670.00reconstitution 1680.00comparative 1690.00lymphoma 1700.00cell 1710.00coated 1720.00responsible 1730.00characteristic a 1740.00multi 1750.00infant 1760.00child 1770.00purified 1780.00rat liver 1790.00effect 1800.00new 1810.00mediated 1820.00associated 1830.00suggest a potential 1840.00result 1850.00produced 1860.00rare event 1870.00characterisation 1880.00unusual 1890.00characteristic 1900.00influence 1910.00directing Restrict by semantic categories? 发现的新知识单元： job id # 4780 started Wed Sep 9 05:21:34 2009 Max_citations: 50000 Stoplist: /var/www/html/arrowsmith_uic/data/stopwords_pubmed Ngram_max: 3 4780 Search ARROWSMITH A A_query_raw: Alzheimer Disease Wed Sep 9 05:22:05 2009 A query = Alzheimer Disease started Wed Sep 9 05:22:05 2009 A query resulted in 50000 titles 4780 Search ARROWSMITH C C_query_raw: PICALM Wed Sep 9 05:22:18 2009 C: PICALM 27 A: pubmed_query_A 50928 AC: ( Alzheimer Disease ) AND ( PICALM ) 1 C query = PICALM started Wed Sep 9 05:22:18 2009 C query resulted in 27 titles A AND C query resulted in 1 titles 191 B-terms ready on Wed Sep 9 05:24:57 2009 B-list on Wed Sep 9 05:27:33 2009 1 caspase 2 clathrin assembly protein 3 alternative splicing 4 clathrin assembly 5 ap180 6 clathrin 7 expression profiling 8 gene expression profiling 9 genome wide 10 calpain 11 protein ap180 12 associated alzheimer disease 13 wide association study 14 cdna 15 genome wide association 16 clathrin mediated 17 genetic susceptibility 18 associated alzheimer 19 upregulation 20 overexpression 21 association study 22 endocytic 23 mouse model 24 ethnic difference 25 protein family 26 splicing 27 nucleation 28 hybridisation 29 iron metabolism 30 ethnic 31 molecular signature 32 association study identify 33 alzheimer disease 34 mutation 35 alzheimer 36 gene expression 37 encoding a 38 cleavage 39 trafficking 40 assembly 41 endocytosis 42 inositol 43 coated pits 44 encode a 45 knee 46 potential role 47 genomic 48 protein rat 49 neuronal 50 gene 51 11q23 52 gst 53 signature 54 subcellular localization 55 chromosomal inversion 56 expression 57 genetic 58 truncated 59 molecular 60 stem cell 61 hematopoietic 62 auditory 63 event 64 encoding 65 family 66 novel 67 profiling 68 susceptibility 69 mouse 70 chromosomal 71 mice 72 abnormality 73 purification 74 lymphoid 75 variant 76 role truncated 77 potential 78 cell free 79 impact 80 protein 81 e coli 82 osteoarthritis 83 difference 84 phospholipid 85 member 86 regulator 87 stem 88 inositol phospholipid 89 model 90 monocytic 91 iron 92 suggest a 93 association 94 structural organization 95 functional 96 inversion 97 genome 98 structural 99 coli 100 nucleocytoplasmic 101 formation 102 fusion protein 103 regulatory 104 wild 105 mechanism 106 subtype 107 protein localization 108 cell line 109 suggest 110 leukemia 111 polypeptide 112 fusion 113 cat 114 calm 115 reveal 116 deletion 117 p2 118 binding 119 aberration 120 lattice 121 role 122 depletion 123 lymphoid myeloid 124 interactor 125 sex 126 fish 127 alternative 128 localization 129 expression functional 130 protein alter 131 disease 132 coat 133 neuropathy 134 line 135 interaction 136 expressed 137 metabolism 138 alter subcellular 139 subcellular 140 minor 141 identify 142 alter subcellular localization 143 alter 144 coexpression 145 comp 146 liver 147 organization 148 membrane 149 rare 150 wide 151 subtype specific 152 study 153 specific 154 myeloid 155 simultaneous 156 traffic 157 free 158 transformation 159 property 160 acute 161 involve 162 evidence 163 rat 164 conserved 165 regulatory mechanism 166 metabolism abnormality 167 reconstitution 168 comparative 169 lymphoma 170 cell 171 coated 172 responsible 173 characteristic a 174 multi 175 infant 176 child 177 purified 178 rat liver 179 effect 180 new 181 mediated 182 associated 183 suggest a potential 184 result 185 produced 186 rare event 187 characterisation 188 unusual 189 characteristic 190 influence 191 directing 通过知识发现选择新的研究课题： 1. 老年痴呆症与白血病的研究 2. 白血病与 PICALM 基因的研究 Alzheimer Disease leukemia PICALM Start A-Literature C-Literature B-list Filter Literature AB literature B-term BC literature Alzheimer Disease leukemia PICALM 1: 2005 Add to clipboard 2: Chronic lymphocytic leukemia presenting with symptomatic central nervous system involvement.2002 Add to clipboard 3: Expression of the cytokine leukemia inhibitory factor and pro-apoptotic insulin-like growth factor binding protein-3 in Alzheimer's disease.2002 Add to clipboard 4: Immunohistochemistry and in situ hybridization of T-cell acute lymphoblastic leukemia -associated antigen 1 in human brain tissues.1999 Add to clipboard 5: Expression of adult T cell leukemia -derived factor in human brain and peripheral nerve tissues.1998 Add to clipboard 6: A monoclonal antibody to common acute lymphoblastic leukemia antigen (neutral endopeptidase) immunostains senile plaques in the brains of patients with Alzheimer's disease.1991 Add to clipboard 1: The CALM-AF10 fusion is a rare event in acute megakaryoblastic leukemia .2007 Add to clipboard 2: Acute monocytic leukemia with coexpression of minor BCR-ABL1 and PICALM -MLLT10 fusion genes along with overexpression of HOXA9.2006 Add to clipboard 3: Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia .2006 Add to clipboard 4: Effect of clathrin assembly lymphoid myeloid leukemia protein depletion on clathrin coat formation.2005 Add to clipboard 5: A novel chromosomal inversion at 11q23 in infant acute myeloid leukemia fuses MLL to CALM, a gene that encodes a clathrin assembly protein.2003 Add to clipboard 6: Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic.1999 Add to clipboard
标签: 老年痴呆症
