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The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies:a review

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Translational Neurodegeneration 2017年第1期6卷 245-255页

作者： shirley Yin-Yu pang Kay-Cheong Teo Jacob Shujui Hsu Richard Shek-Kwan Chang Miaoxin Li Pak-Chung Sham Shu-Leong Ho Division of Neurology Department of MedicineQueen Mary HospitalUniversity of Hong KongHong KongPeople’s Republic of China Centre for Genomic Sciences University of Hong KongHong KongPeople’s Republic of China Department of Medical Genetics Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouPeople’s Republic of China Key Laboratory of Tropical Disease Control(SYSU) Ministry of EducationGuangzhouPeople’s Republic of China

The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping *** does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same *** advent of next generation sequencing(NGS)has allowed for a system-wide,unbiased approach to identify all gene variants in the genome *** the plethora of new genes being identified,genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia(SCA),hereditary spastic paraplegia(HSP)and Charcot-Marie-Tooth disease(CMT)has become widely *** has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson’s disease(PD)and amyotrophic lateral sclerosis(ALS).The observation of pleiotropy has emerged,with mutations in the same gene giving rise to diverse phenotypes,which further increases the complexity of phenotype-genotype *** mechanisms of pleiotropy include different downstream effects of different mutations in the same gene,presence of modifier genes,and oligogenic *** directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms,translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies,and ultimately finding disease-modifying therapies for neurodegenerative disorders.

关键词： Next generation sequencing Neurodegenerative diseases Genetics Pleiotropy

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

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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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Sustainability and Active Transportation at Universities: Case Study of Fort Garry Campus, University of Manitoba in Winnipeg, Canada

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Journal of Geoscience and Environment Protection 2025年第1期13卷 103-120页

作者： Parinaz Joneidi Shariat Zadeh shirley Thompson Natural Resource Institute University of Manitoba Winnipeg Canada

The environmental and health implications of Active Transportation (AT) strategies at the University of Manitoba’s Fort Garry campus in Canada were investigated, focusing on walking, biking, and public transit use of students and staff. We analyzed connectivity, planning, and campus-city integration through mapping, observation, and transportation plan analysis. We found large gaps in connectivity of AT routes within the campus, a lack of AT planning, and poor AT city-campus integration, which explain why AT is decreasing rather than increasing, undermining sustainability on campus. Investing in biking, walking, and bus infrastructure and programs can be a practical, educational, and economical solution to negative environmental, safety, and health impacts posed by vehicles. Universities like the University of Manitoba (UM) have the potential to be leaders in creating an AT ecosystem that mitigates climate change through transportation and turns around the global problem of youth inactivity.

关键词： Active Transportation Sustainability Planning Environment Accessibility Connectivity

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Review:Mechanisms of inherited cancer susceptibility

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2008年第1期9卷 1-4页

作者： shirley HODGSON Department of Cancer Genetics St Georges HospitalUniversity of LondonLondon SW17 OREUK

A small proportion of many cancers are due to inherited mutations in genes,which result in a high risk to the indi-vidual of developing specific cancers. There are several classes of genes that may be involved: tumour suppressor genes,onco-genes,genes encoding proteins involved in DNA repair and cell cycle control,and genes involved in stimulating the angiogenic pathway. Alterations in susceptibility to cancer may also be due to variations in genes involved in carcinogen metabolism. This review discusses examples of some of these genes and the associated clinical conditions caused by the inheritance of mutations in such genes.

关键词： Cancer Inherited mutations DNA repair Tumour suppressor gene Oncogenes

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Diffusive transport of two charge equivalent and structurally similar ruthenium complex ions through graphene oxide membranes

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Nano Research 2015年第4期8卷 1128-1138页

作者： Michael Coleman Xiaowu (shirley) Tang Department of Chemistry 200 University Ave West Waterloo Ontario N2L 3G1 Canada Waterloo Institute for Nanotechnology 200 University Ave West Waterloo Ontario N2L 3G 1 Canada

Here, we report a study of ion transport across graphene oxide （GO） membranes of various thicknesses, made by vacuum filtration of GO aqueous solutions. The diffusive transport rates of two charge-equivalent ruthenium complex ions Ru（bpy）3^2＋ and Ru（phen）32% with a sub-angstrom size difference, are distinguishable through GO membranes and their ratio can be a unique tool for probing the transport-relevant pore structures. Pore and slit-dominant hindered diffusion models are presented and correlated to experimental results. Our analysis suggests that ion transport is mostly facilitated by large pores （larger than 1.75 nm in diameter） in the relatively thin GO membranes, while slits formed by GO stacking （less than 1.42 nm in width） become dominant only in thick membranes. By grafting PEG molecules to the lateral plane of GO sheets, membranes with enlarged interlayer spacing were engineered, which showed drastically increased ion transport rates and lower distinction among the two ruthenium complex ions, consistent with the prediction by the slit-dominant steric hindered diffusion model.

关键词： graphene oxide ion transport hindered diffusion nanofluidics

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Large non-pedunculated colorectal polyp management: The elephant in the room

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World Journal of Gastroenterology 2024年第25期30卷 3126-3131页

作者： shirley X Jiang Neal Shahidi Department of Medicine University of British ColumbiaVancouver V6Z 2K5BCCanada

Minimally invasive innovations have transformed *** to colorectal cancer(CRC),there has been a shift towards less invasive surgical techniques and use of endoscopic resection as an alternative for low risk T1 *** role of endoscopic resection is however much more extensive:It is now considered the first line management strategy for most large(≥20 mm)non-pedunculated colorectal polyps,the majority of which are *** is due to the well-established efficacy,safety,and cost-effectiveness of endoscopic techniques compared to *** endoscopic modalities now exist with distinct risk-benefit profiles and their outcomes are further improved by site-specific technical modifications,auxiliary techniques,and adverse event miti-gation *** capacity continues to evolve with emerging endoscopic techniques and expanding applications,particularly in the confines of a multi-disciplinary setting.

关键词： Cancer Colonoscopy Endoscopy Polyp Endoscopic mucosal resection Endoscopic submucosal dissection

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Beyond Well-being: The Quest for Wholeness and Purpose in Education

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ECNU Review of Education 2020年第3期3卷 542-555页

作者： Dennis shirley Lynch School of Education and Human Development Boston College

Purpose:This article develops a critique of contemporary understandings and practices related to well-being in *** proposes a fuller development of wholeness and purpose that supplements and goes beyond the new well-being ***/Approach/Methods:This article draws upon a document analysis of conceptual and policy frameworks related to *** builds its critique of well-being with reference to a qualitative study consisting of 222 interviews with educators in the Canadian province of Ontario with regard to their understandings of *** includes references to the research and development work in the U.S.,Germany,and ***:The inclusion of well-being in policy agendas is an important step forward in the field of educational change,but this indication of progress is in danger of being reified through simplistic understandings of life satisfaction and other frameworks that evade the complexity of human *** and purpose are concepts that include but also go beyond well-being that should be addressed by ***/Value:Most of the criticisms of the new well-being agenda in educational policies and research simply assume its status as a summum bonum for human *** essay acknowledges the importance of well-being but expands beyond it to define wholeness and purpose as an alternative set of constructs with their own independent integrity that should not simply be subsumed into current well-being agendas.

关键词： Educational change educational policy purpose well-being wholeness

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Corrupted Infrastructure： Imperialism and Environmental Sovereignty in Shanghai, 1873-1911

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Frontiers of History in China 2015年第3期10卷 428-456页

作者： shirley Ye Depa15maent of History University of Birmingham Edgbaston B 15 2TT UK

The introduction of Western science in order to change physical and operational aspects of Shanghai＇s Huangpu River had been debated by Qing and Western officials since almost the beginning of its history as a Treaty Port. At stake in those debates was the perception of the river＇s proper use： as a natural barrier for military defense, or as a conduit for global trade. After the Western powers unified to militarily suppress the Boxer Uprising in 1900, they attained their long-awaited goal of the right to transform the river for global trade as part of Article 11 of the Boxer Protocol： the Junpuju （or Huangpu Conservancy Board） was created and authorized by the central government to make the Huangpu River navigable for shipping vessels. Although the Junpuju continued the ethos of earlier extra-bureaucratic organizations established during the Self-Strengthening Movement, after 1901 the organization bore the authority of the central government. During the era of the New Policies, Qing officials were intent on revising the original terms of river conservancy so that they would be more favorable to Chinese sovereignty. At the same time, imperialist rivalries among the Western powers ruptured the apparent unity of the earlier alliance during the suppression of the Boxer Uprising. Before long, Western corruption in the Huangpu River dredging was brought to the attention of Qing officials, who deftly used it to recover Qing control over certain parts of the body of the river.

关键词： Boxer Protocol corruption infrastructure Gu Hongming Huangpu River new policies Self-Strengthening Sino-French War

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