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| 1 | Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection显示文摘Missense mutations in Leucine-Rich Repeat Kinase 2(LRRK2)cause the majority of familial and some sporadic forms of Parkinson’s disease(PD).The hyperactivity of LRRK2 kinase induced by the pathogenic mutations underlies neurotoxicity,promoting the development of LRRK2 kinase inhibitors as therapeutics.Many potent and specific small-molecule LRRK2 inhibitors have been reported with promise.However,nearly all inhibitors are ATP competitive—some with unwanted side effects and unclear clinical outcome—alternative types of LRRK2 inhibitors are lacking.Herein we identify 5′-deoxyadenosylcobalamin(AdoCbl),a physiological form of the essential micronutrient vitamin B12 as a mixed-type allosteric inhibitor of LRRK2 kinase activity.Multiple assays show that AdoCbl directly binds LRRK2,leading to the alterations of protein conformation and ATP binding in LRRK2.STD-NMR analysis of a LRRK2 homologous kinase reveals the contact sites in AdoCbl that interface with the kinase domain.Furthermore,we provide evidence that AdoCbl modulates LRRK2 activity through disrupting LRRK2 dimerization.Treatment with AdoCbl inhibits LRRK2 kinase activity in cultured cells and brain tissue,and prevents neurotoxicity in cultured primary rodent neurons as well as in transgenic C.elegans and D.melanogaster expressing LRRK2 disease variants.Finally,AdoCbl alleviates deficits in dopamine release sustainability caused by LRRK2 disease variants in mouse models.Our study uncovers vitamin B12 as a novel class of LRRK2 kinase modulator with a distinct mechanism,which can be harnessed to develop new LRRK2-based PD therapeutics in the future. | Adam Schaffner Xianting Li Yacob Gomez-Llorente Emmanouela Leandrou Anna Memou Nicolina Clemente Chen Yao Farinaz Afsari Lianteng Zhi Nina Pan Keita Morohashi Xiaoluan Hua Ming-Ming Zhou Chunyu Wang Hui Zhang Shu G.Chen Christopher J.Elliott Hardy Rideout Iban Ubarretxena-Belandia Zhenyu Yue | 2019 | Cell Research2019，29，4： | 7 |
| 2 | Graded Blood Pressure Reduction in Hypertensive Outpatients Associated With Use of a Device to Assist With Slow Breathing显示文摘 | William J.Elliott Joseph L.Izzo William B.White Douglas R.Rosing Christopher S.Snyder ArielaAlter BenjaminGavish Henry R.Black | 2007 | The Journal of Clinical Hypertension2007，，10： | 1 |
| 3 | Characterization of agonist‐induced endothelium‐dependent vasodilatory responses in the vascular bed of the equine digit显示文摘 | Y.BERHANE S. R.BAILEY C.PUTIGNANO J.ELLIOTT | 2007 | Journal of Veterinary Pharmacology and Therapeutics2007，，1： | 1 |
| 4 | Are Chlorthalidone and Hydrochlorothiazide Equivalent Blood‐Pressure‐Lowering Medications?显示文摘 | NitinKhosla Dave Y.Chua William J.Elliott George L.Bakris | 2007 | The Journal of Clinical Hypertension2007，，6： | 1 |
| 5 | Market rewards associ-ated with patterns of increasing earnings显示文摘 | Barth M J.Elliott M.Finn | | 0，，： | 1 |
| 6 | 美国为何比欧洲更快复苏显示文摘美国对银行融资的依赖度相对较低,美国银行比欧洲银行的资本雄厚,同时美国对金融系统中的问题反应迅速。 | 道格拉斯·艾略特(Douglas J.Elliott) 张远岸(译) | 2013 | 中国改革2013，，6： | 0 |
| 7 | 如何获取存储高投资回报率显示文摘众所周知,在当前的企业信息系统中,一些新型的应用、无法预料的业务需求、加上信息传递和访问渠道的增多,使得企业需要存储的数据信息量呈爆炸性增长。应对这些问题,是一项艰巨而又昂贵的工作,尤其是存储及处理大量重要的商业信息。对于存储,很多信息系统决策者已经认识到了它的重要性。但是,高昂的花销却让决策者“瞻前顾后”、左右为难。如何才能制订一个最合适的规划呢?IBM存储产品部副总裁Frank J.Elliott为我们展示了他的分析。 | Frank J.Elliott | 2003 | 中国计算机用户2003，，5： | 0 |
| 8 | Local tips, global impact: community-driven measures as avenues of promoting inclusion in the control of neglected tropical diseases: a case study in Kenya显示文摘Background:Neglected tropical diseases(NTDs)affect poor populations with little or no’’political voice’to influence control activities.While most NTDs have interventions that work,the biggest challenge remains in delivering targeted interventions to affected populations residing in areas experiencing weak health systems.Despite the upward development trends in most countries of sub-Saharan Africa(SSA),the healthcare worker to population ratio remains exceptionally low,with some areas not served at all;thus,there is a need to involve other personnel for school and community-based healthcare approaches.Nonetheless,the current community-based programs suffer from inconsistent community participation due to a lack of coordinated response,and an expanded intervention agenda that lacks context-specific solutions applicable to rural,urban,and marginalized areas.Methods:This research investigated the capacity of local communities to address the burden of NTDs.Informed by the social theory of human capability,the research collected primary qualitative data by conducting key informant interviews and focus group discussions of people infected or affected by NTDs.The interview data were collected and transcribed verbatim for thematic analysis using Nvivo version 12.Results:Our findings reveal,first,a need for intersectoral collaboration between governments and affected populations for inclusive and sustainable NTD solutions.Second,a’’bottom-up’approach that enhances capacity building,sensitization,and behaviour change for improved uptake of NTD interventions.Third,the enforcement of Public Health Legislative Acts that mandates the reporting and treatment of NTDs such as leprosy.Fourth,the establishment of support groups and counseling services to assist persons suffering from debilitating and permanent effects of NTDs.Conclusions:Our research demonstrates the importance of human agency in encouraging new forms of participation leading to the co-production of inclusive and sustainable solutions against NTDs. | Elizabeth A.Ochola Diana M.S.Karanja Susan J.Elliott | 2022 | Infectious Diseases of Poverty2022，11，4： | 0 |
| 9 | 上海离国际金融中心有多远显示文摘上海在建设国际金融中心方面的机遇显而易见。 | 道格拉斯·艾略特(Douglas J.Elliott) | 2011 | 中国改革2011，，11： | 0 |
| 10 | 美国为何比欧洲更快恢复显示文摘欧洲金融系统面临严重问题,而美国金融系统相对平静。为什么美国的状况较好?这预示着怎样的未来? | 道格拉斯·艾略特(Douglas J.Elliott) 张远岸(译) | 2013 | 新世纪周刊2013，，20： | 0 |
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