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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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Asymptotic false discovery control of the Benjamini-Hochberg procedure for pairwise comparisons

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Science china Mathematics 2025年第1期 223-252页

作者： Weidong Liu Dennis leung Qi-Man Shao School of Mathematical Sciences Shanghai Jiao Tong University School of Mathematics and Statistics University of Melbourne Department of Statistics and Data Science SICMSouthern University of Science and Technology

In a one-way analysis-of-variance(ANOVA) model,the number of pairwise comparisons can become large even with a moderate number of *** by this,we consider a regime with a growing number of groups and prove that,when testing pairwise comparisons,the Benjamini-Hochberg(BH) procedure can asymptotically control false discoveries,despite the fact that the involved t-statistics do not exhibit the wellknown positive dependence structure required for exact false discovery rate(FDR) *** Tukey's perspective that the difference between the means of any two groups cannot be exactly zero,our main result provides control over the directional false discovery rate and directional false discovery proportion.A key technical contribution of our work is demonstrating that the dependence among the t-statistics is sufficiently weak to establish the convergence result typically required for asymptotic FDR *** analysis does not rely on conventional assumptions such as normality,variance homogeneity,or a balanced design,thereby offering a theoretical foundation for applications in more general settings.

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Polyethylene glycol fusion repair of severed sciatic nerves accelerates recovery of nociceptive sensory perceptions in male and female rats of different strains

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Neural Regeneration Research 2025年第9期20卷 2667-2681页

作者： Liwen Zhou Karthik Venkudusamy Emily A.Hibbard Yessenia Montoya Alexa Olivarez Cathy Z.Yang Adelaide leung Varun Gokhale Guhan Periyasamy Zeal Pathak Dale R.Sengelaub George D.Bittner Department of Neuroscience University of TexasAustinTXUSA Program in Neuroscience Indiana UniversityBloomingtonINUSA Department of Molecular Biosciences University of TexasAustinTXUSA

Successful polyethylene glycol fusion(PEG-fusion)of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to:(1)rapidly restore electrophysiological continuity;(2)prevent distal Wallerian Degeneration and maintain their myelin sheaths;(3)promote primarily motor,voluntary behavioral recoveries as assessed by the Sciatic Functional Index;and,(4)rapidly produce correct and incorrect connections in many possible combinations that produce rapid and extensive recovery of functional peripheral nervous system/central nervous system connections and reflex(e.g.,toe twitch)or voluntary *** preceding companion paper describes sensory terminal field reo rganization following PEG-fusion repair of sciatic nerve transections or ablations;howeve r,sensory behavioral recovery has not been explicitly explored following PEG-fusion *** the current study,we confirmed the success of PEG-fusion surgeries according to criteria(1-3)above and more extensively investigated whether PEG-fusion enhanced mechanical nociceptive recovery following sciatic transection in male and female outbred Sprague-Dawley and inbred Lewis *** nociceptive responses were assessed by measuring withdrawal thresholds using von Frey filaments on the dorsal and midplantar regions of the *** von Frey filament tests were a more reliable method than plantar von Frey filament tests to assess mechanical nociceptive sensitivity following sciatic nerve *** withdrawal thresholds of the sciatic-mediated lateral dorsal region differed significantly across strain but not *** thresholds did not change significantly from baseline in chronic Unoperated and Sham-operated *** sciatic transection,all rats exhibited severe hyposensitivity to stimuli at the lateral dorsal region of the hindpaw ipsilateral to the ***,PEG-fused rats exhibited significantly earlier return to baseline withdrawal thresholds than Negative

关键词： autophagia axotomy collateral sprouting neuropathic pain peripheral nerve repair polyethylene glycol fusion(PEG-fusion) saphenous nerve sensory neurons sex and strain Wallerian degeneration

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Development of Integrative Medicine in Hong Kong,china

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chinese Journal of Integrative Medicine 2017年第7期23卷 486-489页

作者： leung ting Hung Wendy Wong School of chinese Medicine The Chinese University of Hong Kong Hong Kong SAR China Hong Kong Institute of Integrative Medicine The Chinese University of Hong KongHong Kong SAR China

Upon reflection on the experience of integration of chinese medicine（CM）and Western medicine（integrative medicine）in the china's Mainland in recent decades,this paper aims to review the recent developments of CM a... 详细信息

关键词： integrative Mainland collaboration disciplines challenging curriculum university heritage medicines deviation

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Urocortin and cardiovascular protection

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Acta Pharmacologica Sinica 2004年第3期25卷 3-11页

作者： chi-wai LAU,Yau-chi CHAN,Suk-ying TSANG,Franky leung CHAN The chinese University of Hong Kong Hong Kong china Department of Anatomy The chinese University of Hong Kong Hong Kong china Department of Anatomy The chinese University of Hong Kong Hong Kong china Department of Anatomy The chinese University of Hong Kong Hong Kong china Department of Anatomy

Urocortin and other hypothalamus corticotropin-releasing factor (CRF) polypeptides play biologically diverse roles in the stress, cardiovascular and inflammatory responses by acting on central and peripheral CRF receptors. Urocortin shows a significantly high sequence homology to CRF, and the concurrent expression of type-2 CRF (CRF2) receptors with urocortin in the heart suggests that urocortin may play a physiological role in the cardiac function. Urocortin is thought to be the endogenous agonist producing the cardiovascular actions previously attributed to CRF. This review highlights the current novel findings on the molecular and cellular mechanisms by which urocortin may exert its cardiovascular protective action.

关键词： urocortin corticotropin-releasing hormone vascular smooth muscle heart vasodilaion second messenger system protein kinases

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Fatal thrombotic complications of hepatic cystic compression of the inferior vena: A case report

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World Journal of Gastroenterology 2005年第11期11卷 1728-1729页

作者： ting-Kai leung chi-Ming Lee Hsin-chi Chen Department of Diagnostic Radiology

Of 5% of patients who develop liver cysts, only 10-15%of them come for medical attention, typically because of dull right upper quadrant pain, abdominal bloating or early satiety. We treated a 77-year-old female with a rare complication of inferior vena cava thrombosis. The patient expired due to septic shock and multiple organ failure.

关键词： Liver cyst Inferior vena cava thrombosis Non-parasitic cyst Cellulitis IVC compression Sepsis

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Anatomic and technical skill factor of gastroduodenal complication in post-transarterial embolization for hepatocellular carcinoma: A retrospective study of 280 cases

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World Journal of Gastroenterology 2005年第10期11卷 1554-1557页

作者： ting-Kai leung chi-Ming Lee Hsin-chi Chen Department of Diagnostic Radiology

AIM: To reduce the possibility of gastroduodenal complications. The purpose of this retrospective study was to survey the literature and compare and discuss the incidence of post-transarterial embolization (TAE)gastroduodenal ***: We found reports describing 280 cases of hepatocellular carcinoma with TAE procedures done during the past 4 years and selected all of them for our *** these cases, 86 were suspected of suffering gastroduodenal complications within one month of postTAE treatment. Fifteen of these cases were proved by pan-endoscopy to have gastroduodenal erosions or ulcerations. We reviewed the angiographic pictures in patient records to evaluate the possibility that anatomic and technical skill factors could explain the ***: Amongst the 15 cases, 9 were primary lesions of the antrum and prepylorus; 4 had duodenal ulcer or erosions; 2 had mid-body lesions; none showed a lesion at the fundus or cardia region. Three cases had not received TAEs using our ideal method, and may be associated with possible regurgitation of gel-foam pieces into the right or left gastric arteries. Two cases involved sub-selective embolization at a distal point on the hepatic artery; one case was found by angiography to have complete occlusion of the celiac ***: Comparing our results with past cases of post-TAE gastroduodenal complications, we surmise that our relatively low incidence (5.3%) of gastric complications might be explained by our concerted efforts to improve our technical skills in multi-sequential, selective and superselective approaches to the embolization of tumor vessels.

关键词： Post-TAE complication Transarterial embolization Gastroduodenal complication

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chinese topical herbal medicine gives additive effect on pharmaceutical agent on fracture healing

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Journal of Traditional chinese Medicine 2019年第6期39卷 853-860页

作者： Siu Wing Sum Shiu Hoi ting Shum Wai ting Ko Chun Hay Lau Clara Bik San Hung leung Kim leung Ping Chung Institute of chinese Medicine The Chinese University of Hong KongShatinNew TerritoriesHong Kong China State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants The Chinese University of Hong KongShatinNew TerritoriesHong Kong China Department of Orthopaedics and Traumatology The Chinese University of Hong KongShatinNew TerritoriesHong Kong China

OBJECTIVE:To investigate the efficacy on the combination of oral strontium ranelate(Sr R)with a topical chinese herbal paste on facilitation of fracture ***:An open fracture was created at the mid-shaft of the right tibia of rat.A herbal pastecalled CDR containing Honghua(Flos Carthami),Chuanxuduan(Radix Dipsaci Asperoidis)and Dahuang(Radix Et Rhizoma Rhei Palmati)was *** rats were treated with either CDR topically on the fracture site,or Sr R orally,or their *** turnover biochemical markers in serum were *** of the fracture was analyzed using micro-CT after 14 and 28 d,followed by histomorphometrical ***:Micro-computed tomography analysis revealed that the combined treatment of CDR with600 mg/g Sr R significantly increased the total callus density,mineralized callus volume fraction,mineralized callus mineral content and mineralized callus density of the callus after 28 d of *** result was consistent with the histomorphometrical analysis on the osteoid *** of biochemical markers showed that the combined treatments reduced the bone resorption that occurs temporarily after ***:This study demonstrated that the combined treatment of oral Sr R and topical CDR is effective to promote fracture healing by their additive effect on promoting bone formation and retarding bone resorption.

关键词： Fracture healing Osteogenesis Bone resorption Medicine,chinese Traditional Integrative medicine Strontium ranelate

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