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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 | Spatial and temporal variation of groundwater recharge in shallow aquifer in the Thepkasattri of Phuket,Thailand显示文摘Whether groundwater resources can be sustainably utilized is largely determined and characterized by hydrogeological parameters.Estimating the groundwater recharge is one of the essential parameters for managing water resources and protecting water resources from contamination.This study researched the spatial and temporal variation of groundwater recharge in the Thepkasattri sub-district through integrating chloride mass balance(CMB)and water table fluctuation(WTF)methods.The chloride content of representative rainfall and groundwater samples was analyzed.Besides,WTF method was adopted from groundwater level data from 2012 to 2015.According to the CMB method,the mean recharge was estimated to be 1172 mm per year,accounting for 47%of the annual rainfall.Moreover,the estimated recharge from the WTF method took 26%of annual rainfall in 2015.The recharge was underestimated according to the WTF method,because of the uncertainty in specific yield estimates and the number of representative wells in the study area.Moreover,the correlation between rainfall and water table fluctuation data indicated the positive linear relationship between two parameters.The spatial recharge prediction indicated that recharge was higher(1200-1400 mm/yr)in the eastern and western catchment,while that in the central floodplains was between 800 mm/yr and 1100 mm/yr.In addition,low recharge value between 450 mm/yr and 800 mm/yr was observed in the south-west part of Thepkasattri.The spatial variation of recharge partly reflects the influences of land use and land cover of the study area. | Yacob T Tesfaldet Avirut Puttiwongrak Tanwa Arpornthip | 2020 | Journal of Groundwater Science and Engineering2020，8，1： | 3 |
| 3 | Delibera- ting on Low Carbon Development 显示文摘 | Yacob Mulugetta Frauke Urban | 2010 | Energy Policy2010，38，12： | 1 |
| 4 | International innovations in optical finishing 显示文摘 | YACOBS S D | 2004 | SPIE2004，5523，： | 1 |
| 5 | Costs and benefits analysis of Aquilaria species on plantation for agarwood production in Malaysia显示文摘 | Mamat M F Yacob M R Fui L H Rdam A | 2010 | International Journal of Business and Social Science2010，1，2： | 1 |
| 6 | Radiation effects on the thermal boundary layer flow over a moving plate with convective boundary condition显示文摘 | Ishak A Yacob N A Bachok N | 2011 | Meccanica2011，46，4： | 1 |
| 7 | Assessing relative soil moisture with remote sensing data:theory, experimental validation, and application to drought monitoring over the North China Plain显示文摘 | Su Z B Yacob A Wen J | 2003 | Physics and Chemistry of the Earth2003，28，： | 1 |
| 8 | Citral is a new inducer ofcaspase - 3 in tumor cell lines 显示文摘 | Nativ D Yacob W Margalit K ef al | 2005 | Planta Medica2005，71，： | 1 |
| 9 | Baseline Study of Methane Emission from Open Digesting Tanks of Palm Oil Mill Effluent Treatment显示文摘 | Yacob S Hassan M A Shirai Y | 2005 | Chemosphere2005，59，11： | 1 |
| 10 | Privatizafion of state - owned enterprises and the law: Issues and problenxs显示文摘 | Yacob Haile Marlam | 1993 | (7)1993，，7： | 1 |
| 11 | ESR Study of Electron Trapped on Activated Carbon by KOH and ZnCl2 Activation显示文摘 | Yacob A. Rahim Siam N. Aqmar Dasril R.S. Dewi | 2010 | 材料科学与工程(中英文版)2010，4，3： | 1 |
| 12 | Assessing relative soil moisture with remote sensing data:theory,experimental validation, and application to drought monitoring over the North China plain显示文摘 | Su Z Yacob A Wen J | 2003 | Physics and Chemistry of the Earth2003，，28： | 1 |
| 13 | International innovations in optical finishing显示文摘 | YACOBS S D | 2004 | SPIE2004，5523，： | 1 |
| 14 | Can we treat hydraulic frac-turing flowback with a conventional biological process? The case of guar gum显示文摘 | Lester Y Yacob T Morrissey I | 2014 | Environmental Science & Technology Letters2014，1，1： | 1 |
| 15 | Assessing relative soil moisture with remote sensing data theory, experimental validation, and application to drought monitoring over the North China plain显示文摘 | SU Z YACOB A WEN J | 2003 | Physics and Chemistry of the Earth2003，，28： | 1 |
| 16 | Dexmedetomidine-ketamine sedation during upper gastrointestinal endoscopy and biopsy in a patient with Duehenne muscular dystrophy and egg allergy 显示文摘 | Raman V Yacob D Tobias JD | 2012 | Int J Crit Illn Inj Sci2012，2，1： | 1 |
| 17 | Prevalence of pain- predominant functional gastrointestinal disorders and somatic symptoms in patients with anxiety or depressive disorders 显示文摘 | Yacob D Di Lorenzo C Bridge JA | 2013 | J Pediatr2013，163，3： | 1 |
| 18 | Assessing relative soil moisture with remote sensing data: Theory, experimental validation, and application to drought monitoring over the North China plain显示文摘 | Su Z Yacob A | 2003 | Physics and Chemistry of the Earth2003，，28： | 1 |
| 19 | Deliberating on low carbon development显示文摘 | Yacob Mulugetta Frauke Urban | 2010 | Energy Policy2010，，12： | 1 |
| 20 | Radiation effects on the thermal boundary layer flow over a moving plate with con- vective boundary condition 显示文摘 | Ishak A Yacob N A Bachok N | 2011 | Meecanica2011，46，4： | 1 |
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