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The interplay of aging,genetics and environmental factors in the pathogenesis of Parkinson’s disease

Translational Neurodegeneration 2019年第1期8卷 279-289页

作者： Shirley Yin-Yu Pang Philip Wing-Lok Ho Hui-Fang Liu chi-ting leung Lingfei Li Eunice Eun Seo Chang David Boyer Ramsden Shu-Leong Ho Division of Neurology Department of MedicineQueen Mary HospitalUniversity of Hong KongHong KongPeople’s Republic of China Institute of Metabolism and Systems Research University of BirminghamBirminghamUK

Background:Parkinson’s disease(PD)is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies(LB).During the course of disease,misfoldedα-synuclein,the major constituent of LB,spreads to different regions of the brain in a prion-like fashion,giving rise to successive non-motor and motor *** is likely multifactorial,and involves interplay among aging,genetic susceptibility and environmental *** body:The prevalence of PD rises exponentially with age,and aging is associated with impairment of cellular pathways which increases susceptibility of dopaminergic neurons to cell ***,the majority of those over the age of 80 do not have PD,thus other factors in addition to aging are needed to cause *** of neurotoxins which can result in parkinsonism led to efforts in identifying environmental factors which may influence PD ***,the causality of most environmental factors is not conclusively established,and alternative explanations such as reverse causality and recall bias cannot be *** lack of geographic clusters and conjugal cases also go against environmental toxins as a major cause of *** mutations as well as common variants in genes such as SNCA,LRRK2 and GBA are associated with risk of PD,but Mendelian causes collectively only account for 5%of PD and common polymorphisms are associated with small increase in PD *** of PD has been estimated to be around 30%.Thus,aging,genetics and environmental factors each alone is rarely sufficient to cause PD for most ***:PD is a multifactorial disorder involving interplay of aging,genetics and environmental *** has implications on the development of appropriate animal models of PD which take all these factors into *** converging pathways likely include mitochondrial dysfunction,impaired autophagy,oxidative stress and neuroinflammation,which are

关键词： Parkinson’s disease Genetics Aging Environmental toxins

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LRRK2 mutant knock-in mouse models: therapeutic relevance in Parkinson’s disease

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Translational Neurodegeneration 2022年第1期11卷 790-808页

作者： Eunice Eun Seo Chang Philip Wing-Lok Ho Hui-Fang Liu Shirley Yin-Yu Pang chi-ting leung Yasine Malki Zoe Yuen-Kiu Choi David Boyer Ramsden Shu-Leong Ho Division of Neurology Department of MedicineQueen Mary HospitalUniversity of Hong KongPok Fu LamHong KongChina Institute of Metabolism and Systems Research University of BirminghamBirminghamUK.

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are one of the most frequent genetic causes of both familial and sporadic Parkinson’s disease (PD). Mounting evidence has demonstrated pathological similarities between LRRK2-associated PD (LRRK2-PD) and sporadic PD, suggesting that LRRK2 is a potential disease modulator and a thera-peutic target in PD. LRRK2 mutant knock-in (KI) mouse models display subtle alterations in pathological aspects that mirror early-stage PD, including increased susceptibility of nigrostriatal neurotransmission, development of motor and non-motor symptoms, mitochondrial and autophagy-lysosomal defects and synucleinopathies. This review provides a rationale for the use of LRRK2 KI mice to investigate the LRRK2-mediated pathogenesis of PD and implications from current findings from different LRRK2 KI mouse models, and ultimately discusses the therapeutic potentials against LRRK2-associated pathologies in PD.

关键词： Parkinson’s disease LRRK2 Knock-in mouse model Neurotransmission Motor dysfunction Autophagy Lysosome Mitochondrial dysfunction Synucleinopathy Hyperkinase activity LRRK2 inhibitor

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LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson’s disease

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Translational Neurodegeneration 2022年第1期11卷 869-882页

作者： Shirley Yin-Yu Pang Rachel Cheuk Nam Lo Philip Wing-Lok Ho Hui-Fang Liu Eunice Eun Seo Chang chi-ting leung Yasine Malki Zoe Yuen-Kiu Choi Wing Yan Wong Michelle Hiu-Wai Kung David Boyer Ramsden Shu-Leong Ho Division of Neurology Department of MedicineQueen Mary HospitalUniversity of Hong KongHong KongChina School of Biomedical Sciences Li Ka Shing Faculty of MedicineUniversity of Hong KongHong KongChina Institute of Metabolism and Systems Research University of BirminghamBirminghamUK.

Mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson’s disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagy via activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and endosomal trafficking. Mutant LRRK2 impairs chaperone-mediated autophagy, resulting in α-syn binding and oligomerization on lysosomal membranes. Mutations in GBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities. LRRK2 and GBA influence each other: GCase activity is reduced in LRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity in GBA mutant cells. Clinically, LRRK2 G2019S mutation seems to modify the effects of GBA mutation, resulting in milder symptoms than those resulting from GBA mutation alone. However, dual mutation carriers have an increased risk of PD and earlier age of onset compared with single mutation carriers, suggesting an additive deleterious effect on the initiation of PD pathogenic processes. Crosstalk between LRRK2 and GBA in PD exists, but its exact mechanism is unclear. Drugs that inhibit LRRK2 kinase or activate GCase are showing efficacy in pre-clinical models. Since LRRK2 kinase and GCase activities are also altered in idiopathic PD (iPD), it remains to be seen if these drugs will be useful in disease modification of iPD.

关键词： Parkinson’s disease Interaction LRRK2 GBA GCase Mutation Autophagy α-Synuclein

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Prostate health index can stratify patients with Prostate Imaging Reporting and Data System score 3 lesions on magnetic resonance imaging to reduce prostate biopsies

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Asian Journal of Andrology 2024年第1期26卷 20-24页

作者： John Shung-Lai leung Wai-Kit Ma Brian Sze-Ho Ho Stacia Tsun-Tsun Chun Rong Na Yongle Zhan chi-Yuen Ng chi-Ho Ip Ada Tsui-Lin Ng Yiu-Chung Lam Division of Urology Department of SurgeryQueen Mary HospitalUniversity of Hong KongHong KongChina Division of Urology Department of SurgeryPrincess Margaret HospitalHongKongChina

We aim to evaluate prostate health index as an additional risk-stratification tool in patients with Prostate Imaging Reporting and Data System score 3 lesions on multiparametric magnetic resonance *** with biochemical or clinical suspicion of having prostate cancer who underwent multiparametric magnetic resonance imaging in two tertiary centers(Queen Mary Hospital and Princess Margaret Hospital,Hong Kong,china)between January 2017 and June 2022 were ***-magnetic resonance imaging fusion biopsies were performed after prostate health index *** who only had Prostate Imaging Reporting and Data System score 3 lesions were further stratified into four prostate health index risk groups and the cancer detection rates were *** of the 747 patients,47.3%had Prostate Imaging Reporting and Data System score 3 lesions *** detection rate of clinically significant prostate cancer in this group was 15.0%.The cancer detection rates of clinically significant prostate cancer had statistically significant differences:5.3%in prostate health indexting and Data System score 3 *** could be avoided in patients with low prostate health index,with a small risk of missing clinically significant prostate cancer.

关键词： biopsy fusion biopsy magnetic resonance imaging prostate cancer prostate health index

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A Simple Embedding Method for the Laplace-Beltrami Eigenvalue Problem onImplicit Surfaces

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Communications on Applied Mathematics and Computation 2024年第2期6卷 1189-1216页

作者： Young Kyu Lee Shingyu leung Department of Mathematics The Hong Kong University of Science and TechnologyClear Water BayHong KongChina

We propose a simple embedding method for computing the eigenvalues and eigenfunctions of the Laplace-Beltrami operator on implicit *** approach follows an embedding approach for solving the surface eikonal *** replace the differential operator on the interface with a typical Cartesian differential operator in the surface *** proposed algorithm is easy to implement and *** will give some two-and three-dimensional numerical examples to demonstrate the effectiveness of our proposed approach.

关键词： Laplace-Beltrami operator Level set method Implicit representation Eigenvalues Numerical PDEs

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Changes of tropical cyclone size in three oceanic basins of the northern hemisphere from 2001 to 2021

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Frontiers of Earth Science 2024年第2期18卷 312-323页

作者： Banglin ZHANG Jeremy Cheuk-Hin leung Shengyuan LIU Jianjun XU Guangzhou Institute of Tropical and Marine Meteorology/Guangdong Provincial Key Laboratory of Regional Numerical Weather Prediction CMAGuangzhou 510640China College of Atmospheric Science Lanzhou UniversityLanzhou 730020China College of Ocean and Meteorology Guangdong Ocean UniversityZhanjiang 524088China CMA-GDOU Joint Laboratory for Marine Meteorology&South china Sea Institute of Marine Meteorology Guangdong Ocean UniversityZhanjiang 524088China

In this study the changes of tropical cyclone(TC)size from 2001 to 2021 are analyzed based on linear and quadratic curve fittings of the National Hurricane Center(NHC)/Joint Typhoon Warning Center(JTWC)best track data,based on the radius of maximum wind(RMW)and the average radius of 34-kt wind(AR34),in three oceanic basins of the North Atlantic(NATL),the Western North Pacific(WPAC)and the Eastern North Pacific(EPAC).The computations are done separately for two categories of tropical cyclones:tropical storms(TS)and hurricanes(HT).Size changes of landfalling and non-landfalling TCs are also *** show that there is a great inter-basin variability among the changes in TC *** conclusions include:1)overall,the inner cores of TSs have become larger in all three basins,with the increasing tendencies being significant in the NATL and WAPC,while those of HTs mostly get smaller or remain similar;2)meanwhile,comparatively large inter-basin differences are observed for the TC outer core sizes,and the sizes of landfalling TCs;3)particularly,a significant decrease in landfalling HT outer core size is observed over the EPAC;4)in contrast,significant increases in landfalling TS inner core size are found over the NATL and *** presented analysis results could benefit future research about TC forecasts,storm surge studies,and the cyclone climate and its changes.

关键词： tropical cyclone storm size frequency intensity duration

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Translating bacteriophage-derived depolymerases into antibacterial therapeutics:Challenges and prospects

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Acta Pharmaceutica Sinica B 2024年第1期14卷 155-169页

作者： Honglan Wang Yannan Liu Changqing Bai Sharon Shui Yee leung School of Pharmacy the Chinese University of Hong KongHong Kong SARChina Emergency Medicine Clinical Research Center Beijing Chao-Yang HospitalCapital Medical UniversityBeijing 100020China Department of Respiratory Shenzhen University General HospitalShenzhen University Clinical Medical AcademyGuangdong 518055China

Predatory bacteriophages have evolved a vast array of depolymerases for bacteria capture and *** depolymerases are enzymes responsible for degrading diverse bacterial surface *** are exploited as antibiofilm agents and antimicrobial adjuvants while rarely inducing bacterial resistance,making them an invaluable asset in the era of antibiotic *** depolymerases have been investigated preclinically,with evidence indicating that depolymerases with appropriate dose regimens can safely and effectively combat different multidrug-resistant pathogens in animal infection ***,some formulation approaches have been developed for improved stability and activity of ***,depolymerase formulation is limited to liquid dosage form and remains in its infancy,posing a significant hurdle to their clinical translation,compounded by challenges in their applicability and *** development must address these obstacles for clinical ***,after unravelling the history,diversity,and therapeutic use of depolymerases,we summarized the preclinical efficacy and existing formulation findings of recombinant ***,the challenges and perspectives of depolymerases as therapeutics for humans were assessed to provide insights for their further development.

关键词： Phage-derived polysaccharide depolymerases Bacteriophage proteins Bacterial capsules Polysaccharide capsules Antibiotic resistance Biofilms Antibacterial therapy Antimicrobial adjuvants Combination treatment

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Spatiotemporal variations of sand hydraulic conductivity by microbial application methods

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Journal of Rock Mechanics and Geotechnical Engineering 2024年第1期16卷 268-278页

作者： Viroon Kamchoom Thiti Khattiwong Treesukon Treebupachatsakul Suraparb Keawsawasvong Anthony Kwan leung Excellent Centre for Green and Sustainable Infrastructure Department of Civil EngineeringSchool of EngineeringKing Mongkut’s Institute of Technology Ladkrabang(KMITL)Bangkok10520Thailand Department of Biomedical Engineering School of EngineeringKing Mongkut’s Institute of Technology Ladkrabang(KMITL)Bangkok10520Thailand Department of Civil Engineering Thammasat School of EngineeringThammasat UniversityPrathumthani10200Thailand Department of Civil and Environmental Engineering The Hong Kong University of Science and Technology(HKUST)Hong KongChina

The spatiotemporal distributions of microbes in soil by different methods could affect the efficacy of the microbes to reduce the soil hydraulic *** this study,the specimens of bio-mediated sands were prepared using three different methods,***,mixing,and pouring a given microbial so-lution onto compacted sand *** hydraulic conductivity was measured by constant-head tests,while any soil microstructural changes due to addition of the microbes were observed by scan-ning electron microscope(SEM)and mercury intrusion porosimetry(MIP)*** amount of dextran concentration produced by microbes in each type of specimen was quantified by a *** show that dextran production increased exponentially after 5-7 d of microbial settling with the supply of culture *** injection and mixing methods resulted in a similar amount and uniform dis-tribution of dextran in the *** pouring method,however,produced a nonuniform distri-bution,with a higher concentration near the specimen *** the supply of culture medium discontinued,the dextran content near the surface produced by the pouring method decreased dramatically due to high competition for nutrients with foreign *** dextran concentration was negatively and correlated with hydraulic conductivity of bio-mediated soils exponentially,due to the clogging of large soil pores by *** hydraulic conductivity of the injection and mixing cases did not change significantly when the supply of culture medium was absent.

关键词： Bio-mediated soil Dextran Hydraulic conductivity Leuconostoc mesenteroides Microbial application Microstructure

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RepDNet:A re-parameterization despeckling network for autonomous underwater side-scan sonar imaging with prior-knowledge customized convolution

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Defence Technology（防务技术） 2024年第5期35卷 259-274页

作者： Zhuoyi Li Zhisen Wang Deshan Chen Tsz leung Yip Angelo P.Teixeira Department of Logistics and Maritime Studies The Hong Kong Polytechnic UniversityChina State Key Laboratory of Maritime Technology and Safety Wuhan University of TechnologyChina School of Transportation and Logistics Engineering Wuhan University of TechnologyChina National Engineering Research Center for Water Transport Safety Wuhan University of TechnologyChina Centre for Marine Technology and Ocean Engineering(CENTEC) Instituto Superior TecnicoUniversidade de LisboaPortugal

Side-scan sonar(SSS)is now a prevalent instrument for large-scale seafloor topography measurements,deployable on an autonomous underwater vehicle(AUV)to execute fully automated underwater acoustic scanning imaging along a predetermined ***,SSS images often suffer from speckle noise caused by mutual interference between echoes,and limited AUV computational resources further hinder noise *** approaches for SSS image processing and speckle noise reduction rely heavily on complex network structures and fail to combine the benefits of deep learning and domain *** address the problem,Rep DNet,a novel and effective despeckling convolutional neural network is *** DNet introduces two re-parameterized blocks:the Pixel Smoothing Block(PSB)and Edge Enhancement Block(EEB),preserving edge information while attenuating speckle *** training,PSB and EEB manifest as double-layered multi-branch structures,integrating first-order and secondorder derivatives and smoothing *** inference,the branches are re-parameterized into a 3×3 convolution,enabling efficient inference without sacrificing *** DNet comprises three computational operations:3×3 convolution,element-wise summation and Rectified Linear Unit *** on benchmark datasets,a real SSS dataset and Data collected at Lake Mulan aestablish Rep DNet as a well-balanced network,meeting the AUV computational constraints in terms of performance and latency.

关键词： Side-scan sonar Sonar image despeckling Domain knowledge Re-parameterization

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Modelling smear effect of vertical drains using a diameter reduction method

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Journal of Rock Mechanics and Geotechnical Engineering 2024年第1期16卷 279-290页

作者： Zhichao Shen Siau Chen chian Siew Ann Tan Chun Fai leung School of Marine Science and Engineering South China University of TechnologyGuangzhouChina Department of Civil and Environmental Engineering National University of SingaporeSingapore

Vertical drains are used to accelerate consolidation of clays in ground improvement *** zones exist around these drains,where permeability is reduced due to soil disturbance caused by the installation *** solution is widely used in practice to consider the effects of drain discharge capacity and smear on the consolidation *** this study,a computationally efficient diameter reduction method(DRM)obtained from the Hansbo solution is proposed to consider the smear effect without the need to model the smear zone *** by analytical and numerical results,a diameter reduction factor is analytically derived to reduce the diameter of the drain,while achieving similar solutions of pore pressure dissipation profile as the classical full model of the smear zone and *** the DRM,the excess pore pressure u obtained from the reduced drain in the original un-disturbed soil zone is accurate enough for practical applications in numerical *** performance of DRM is independent of soil material *** also show equally accurate performance of DRM under conditions of multi-layered soils and coupled radial-vertical groundwater flow.

关键词： Consolidation Vertical drain Smear effect Pore pressure Soil improvement

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