检索结果-南通市图书馆

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

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

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

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

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

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

Unveiling a novel metal-to-metal transition in LuH_(2):Critically challenging superconductivity claims in lutetium hydrides

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Matter and Radiation at Extremes 2024年第3期9卷 65-73页

作者： Dong Wang Ningning Wang Caoshun Zhang Chunsheng Xia Weicheng Guo Xia Yin Kejun Bu Takeshi Nakagawa Jianbo Zhang Federico Gorelli philip Dalladay-Simpson Thomas Meier Xujie Lü Liling Sun Jinguang Cheng Qiaoshi Zeng Yang Ding ho-kwang Mao Center for High-Pressure Science and Technology Advanced Research Beijing 100094China Beijing National Laboratory for Condensed Matter Physics and Institute of Physics Chinese Academy of SciencesBeijing 100190China Shanghai Key Laboratory of Material Frontiers Research in Extreme Environments(MFree) Shanghai Advanced Research in Physical Sciences(SHARPS)Shanghai 201203China

Following the recent report by Dasenbrock-Gammon et al.[Nature 615,244–250(2023)]of near-ambient superconductivity in nitrogendoped lutetium trihydride(LuH_(3-δ)N_(ε)),significant debate has emerged surrounding the composition and interpretation of the observed sharp resistance ***,we meticulously revisit these claims through comprehensive characterization and *** definitively identify the reported material as lutetium dihydride(LuH_(2)),resolving the ambiguity surrounding its *** similar conditions(270–295 K and 1–2 GPa),we replicate the reported sharp decrease in electrical resistance with a 30%success rate,aligning with the observations by Dasenbrock-Gammon et ***,our extensive investigations reveal this phenomenon to be a novel pressure-induced metal-to-metal transition intrinsic to LuH_(2),distinct from ***,nitrogen doping exerts minimal impact on this *** work not only elucidates the fundamental properties of LuH_(2)andLuH_(3),but also critically challenges the notion of superconductivity in these lutetium hydride *** findings pave the way for future research on lutetium hydride systems,while emphasizing the crucial importance of rigorous verification in claims of ambient-temperature superconductivity.

关键词： resistance hydride superconductivity

The hong Kong consensus statements on unresectable hepatocellular carcinoma:narrative review and update for 2021

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Hepatobiliary Surgery and Nutrition 2023年第3期12卷 366-385页

作者： Tan-To Cheung Simon Chun-ho Yu Stephen L.Chan Ronnie T.P.Poon philip Kwok Ann-Shing Lee Anna Tai Derek Tam Chin-Cheung Cheung Tak-wing Lai Nam-Hung Chia Ada Law Tracy Shum Yim-Kwan Lam Vince Lau Victor Lee Charing Chong Chung-Ngai Tang Thomas Yau Department of Surgery Queen Mary HospitalThe University of Hong KongHong KongChina Department of Imaging&Interventional Radiology Prince of Wales HospitalThe Chinese University of Hong KongHong KongChina State Key Laboratory of Translational Oncology and Department of Clinical Oncology Sir YK Pao Centre for CancerPrince of Wales HospitalThe Chinese University of Hong KongHong KongChina Department of Radiology and Imaging Queen Elizabeth HospitalHong KongChina Department of Clinical Oncology Tuen Mun HospitalHong KongChina Department of Clinical Oncology Queen Elizabeth HospitalHong KongChina Department of Surgery United Christian HospitalHong KongChina Department of Surgery Tuen Mun HospitalHong KongChina Department of Surgery Princess Margaret HospitalHong KongChina Department of Surgery Queen Elizabeth HospitalHong KongChina Department of Clinical Oncology Pamela Youde Nethersole Eastern HospitalHong KongChina Department of Clinical Oncology Princess Margaret HospitalHong KongChina Department of Medicine and Geriatrics United Christian HospitalHong KongChina Department of Radiology Queen Mary HospitalHong KongChina Department of Clinical Oncology Queen Mary HospitalThe University of Hong KongHong KongChina Department of Surgery Prince of Wales HospitalThe Chinese University of Hong KongHong KongChina Department of Surgery Pamela Youde Nethersole Eastern HospitalHong KongChina Department of Medicine Queen Mary HospitalThe University of Hong KongHong KongChina

Background and Objective:hong Kong,like many parts of Asia,faces a high burden of hepatocellular carcinoma(HCC)caused by high endemic rates of hepatitis B virus *** Kong clinicians have developed a high level of expertise in HCC treatment across surgical,transarterial,ablative,radiotherapeutic and systemic *** publication summarizes the latest evidence-based recommendations on how these modalities should be ***:In two meetings held in 2020,a multidisciplinary panel of surgeons,oncologists and interventional radiologists performed a narrative review of evidence on the management of HCC,with an emphasis on treatment of HCC not amenable to surgical *** attention was paid to new evidence published since the previous version of these statements in *** Content and Findings:The expert panel has formulated 60 consensus statements to guide the staging and treatment of unresectable *** the previous version of these statements,considerable additions have been made to the recommendations on use of targeted therapies and immunotherapies because of the large volume of new ***:Our consensus statements offer guidance on how to select HCC patients for surgical or non-surgical treatment and for choosing among non-surgical modalities for patients who are not candidates for *** particular,there is a need for more evidence to aid physicians in the selection of second-line systemic therapies,as currently most data are limited to patients with disease progression on first-line sorafenib.

关键词： Hepatocellular carcinoma(HCC) hong Kong guidelines consensus

Everything you always wanted to know about metallic hydrogen but were afraid to ask

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Matter and Radiation at Extremes 2020年第3期5卷 25-30页

作者： Eugene Gregoryanz Cheng Ji philip Dalladay-Simpson Bing Li Ross T.howie ho-Kwang Mao Centre for Science at Extreme Conditions and School of Physics and Astronomy University of EdinburghEdinburgh EH93FDUnited Kingdom Center for High Pressure Science and Technology Advanced Research Shanghai 201203China Key Laboratory of Materials Physics Institute of Solid State PhysicsChinese Academy of SciencesHefei 230031China

The hydrogen molecule is made from the first and lightest element in the periodic *** hydrogen gas is either compressed or cooled,it forms the simplest molecular *** solid exhibits many interesting and fundamental physical *** is believed that if the density of the solid is increased by compressing it to very high pressures,hydrogen will transform into the lightest known metal with very unusual and fascinating properties,such as room temperature superconductivity and/or *** this article,we provide a critical look at the numerous claims of hydrogen metallization and the current experimental state of affairs.

关键词： hydrogen metallic solid

MINAR1 is a Notch2-binding protein that inhibits angiogenesis and breast cancer growth

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Journal of Molecular Cell Biology 2018年第3期10卷 195-204页

作者： Rachel Xi-Yeen ho Rosana D. Meyer Kevin B. Chandler Esma Ersoy Michael Park philip A. Bondzie Nima Rahimi Huihong Xu Catherine E. Costello Nader Rahimi Department of Pathology School of Medicine Boston University Medical Campus Boston MA 02118 USA Department of Biochemistry and Center for Biomedical Mass Spectrometry School of Medicine Boston University Medical Campus Boston MA 02118 USA

内在地混乱的蛋白质(IDP )/intrinsically 未组织的蛋白质被缺乏描绘修理或稳定的第三级的结构，并且逐渐地在信号 transduction 和 transcriptional 规定与主要角色作为蛋白质的一个重要的班被认出。在这研究，我们报导鉴定和功能的描... 详细信息

内在地混乱的蛋白质(IDP )/intrinsically 未组织的蛋白质被缺乏描绘修理或稳定的第三级的结构，并且逐渐地在信号 transduction 和 transcriptional 规定与主要角色作为蛋白质的一个重要的班被认出。在这研究，我们报导鉴定和功能的描述一以前 uncharacterized 蛋白质(UPF0258/KIAA1024 ) ，主要内在地混乱的联系 Notch2 的受体 1 (MINAR1 ) 。当 MINAR1 带一个单个 transmembrane 领域和一个短细胞质的领域时，它有不与已知的蛋白质序列分享类似的一个大细胞外的领域。Uncharacteristically， MINAR1 是一高度，有将近 70% 它的氨基酸的 IDP 定序未组织。我们证明 MINAR1 身体上与 Notch2 交往，它到 Notch2 的绑定增加它的稳定性和函数。MINAR1 广泛地包括胸的上皮的房间和血容器的 endothelial 房间在各种各样的纸巾被表示。当它在房间文化并且在塞子和 zebrafish angiogenesis 建模的老鼠 matrigel 禁止 angiogenesis， MINAR1 在 angiogenesis 起一个否定作用。而且，当 MINAR1 高度在正常的人的胸被表示时，它的表示是显著地，在先进人的乳癌的 downregulated 和它在乳癌房间的重新表示禁止了肿瘤生长。我们的学习证明 MINAR1 是否定地调整乳癌细胞的 angiogenesis 和生长的 IDP。

关键词：蛋白质序列肿瘤生长癌细胞约束力乳 IDP 稳定性房间

NOISY SOUNDS! It's a Listening Affair:Jazz Aesthetic, Improvisation, and Womanism in M. NourbeSe philip's She Tries Her Tongue, Her Silence Softly Breaks

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Journal of Foreign Languages and Cultures 2021年第1期5卷 53-69,155页

作者： Thao ho Humboldt University of Berlin

Black writers adapted jazz music to“say the unsayable”or employed the“jazz aesthetic,”which includes improvisation,citation,and variation as a stylistic device to distance their literature from European forms of *** elements can also be found in *** philipp poetry collection She Tries Her Tongue,Her Silence Sofily Breaks(1988)which rigorously challenges the way language and words are *** denounces the Western ideology of non-ambiguity,dichotomies,and narration altogether by engaging the reader as jazz musicians engage their *** role did music play in the Black resistance?What is the“jazz aesthetic”and how is it incorporated into Black diasporic literature?how does jazz music create community and how did Black female musicians speak up in a rather hypermasculine jazz universe?how does philip incorporate the jazz aesthetic,improvisation,and womanist thoughts in her poems?And what is the intention of noise,dissonance,and(musical)violence?

关键词： improvisation jazz aesthetic African American poetry womanism politics of listening

Mitochondrial neuronal uncoupling proteins:a target for potential disease-modification in Parkinson’s disease philip

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Translational Neurodegeneration 2012年第1期1卷 11-19页

作者： WL ho Jessica WM ho Hui-Fang Liu Danny HF So Zero HM Tse Koon-ho Chan David B Ramsden Shu-Leong ho Division of Neurology Department of MedicineUniversity of Hong KongPokfulamHong Kong SARChina School of Medicine and School of Biosciences University of BirminghamBirminghamUK Research Centre of Heart BrainHormone and Healthy Aging(HBHA)University of Hong KongPokfulamHong Kong SARChina

This review gives a brief insight into the role of mitochondrial dysfunction and oxidative stress in the converging pathogenic processes involved in Parkinson’s disease(PD).Mitochondria provide cellular energy in the form of ATP via oxidative phosphorylation,but as an integral part of this process,superoxides and other reactive oxygen species are also *** free radical production contributes to oxidative *** have evolved to handle such stress via various endogenous anti-oxidant *** such family of proteins is the mitochondrial uncoupling proteins(UCPs),which are anion carriers located in the mitochondrial inner *** are five known homologues(UCP1 to 5),of which UCP4 and 5 are predominantly expressed in neural *** a series of previous publications,we have shown how these neuronal UCPs respond to 1-methyl-4-phenylpyridinium(MPP+;toxic metabolite of MPTP)and dopamine-induced toxicity to alleviate neuronal cell death by preserving ATP levels and mitochondrial membrane potential,and reducing oxidative *** also showed how their expression can be influenced by nuclear factor kappa-B(NF-B)signaling pathway specifically in ***,we previously reported an interesting link between PD and metabolic processes through the protective effects of leptin(hormone produced by adipocytes)acting via UCP2 against MPP+-induced *** is increasing evidence that these endogenous neuronal UCPs can play a vital role to protect neurons against various pathogenic stresses including those associated with *** expression,which can be induced,may well be a potential therapeutic target for various drugs to alleviate the harmful effects of pathogenic processes in PD and hence modify the progression of this disease.

关键词： uncoupling proteins mitochondria Parkinson??s disease ATP oxidative stress neuroprotection

Potent and conditional redirected T cell killing of tumor cells using Half DVD-Ig

在线全文

维普期刊数据库

学校读者我要写书评

暂无评论

Protein & Cell 2018年第1期9卷 121-129页

作者： philip D. Bardwelll Matthew M. Staron Junjian Liu Qingfeng Tao Susanne scesney Gail Bukofzer Luis E. Rodriguez Chee-ho Choi Jennifer Wang Qing Chang Feng Dong Cherrie Donawho Jieyi Wang Christine M. Grinnell Edit Tarcsa Charles Hutchins Tariq Ghayur Jijie Gu Foundational Immunology AbbVie Bioresearch Center Worcester MA 01605 USA Global Preclinical Safety AbbVie Bioresearch Center Worcester MA 01605 USA Oncology Discovery AbbVie Inc. North Chicago IL 60064 USA DMPK-BA AbbVie Bioresearch Center Worcester MA 01605 USA Research and Development AbbVie Inc. North Chicago IL 60064 USA Torque Therapeutics Inc. Cambridge MA 02142 USA Innovent Bioloqics Inc. Suzhou China Lyvgen Biopharma Shanghai 201203 China

Novel biologics that redirect cytotoxic T lymphocytes （CTLs） to kill tumor cells bearing a tumor associated antigen hold great promise in the clinic. however, the ability to safely and potently target CD3 on CTL toward tumor associated antigens （TAA） expressed on tumor cells remains a challenge of both technology and biol- ogy. Herein we describe the use of a Half DVD-Ig format that can redirect CTL to kill tumor cells. Notably, Half DVD-Ig molecules that are monovalent for each speci- ficity demonstrated reduced non-specific CTL activation and conditional CTL activation upon binding to TAA compared to intact tetravalent DVD-Ig molecules that are bivalent for each specificity, while maintaining good drug like properties and appropriate PK properties.

关键词： DVD-Ig Half DVD-Ig Halt'body epidermal growth factor receptor redirected T-cell cytotoxicity rCTL