Dr Zhi-dong Zhou, Ph.D & M.D - National Neuroscience Institute - Associate Principle Investigator

Dr Zhi-dong Zhou

Ph.D & M.D

National Neuroscience Institute

Associate Principle Investigator

Singapore | Singapore

Main Specialties: Molecular Genetic Pathology, Neurology, Neuropathology, Pharmacology

Additional Specialties: Chinese

ORCID logohttps://orcid.org/0000-0003-0251-4163


Top Author

Dr Zhi-dong Zhou, Ph.D & M.D - National Neuroscience Institute - Associate Principle Investigator

Dr Zhi-dong Zhou

Ph.D & M.D

Introduction

I am graduated as a medical doctor in 1991 and had 5 years of postgraduate clinical training in internal medicine in China. Subsequently he acquired my Ph.D from Chinese Academy of Science, Shanghai Branch and started me research career in Singapore on pathogenesis and therapy related to dopamine (DA) neuron degeneration in Parkinson's disease (PD). Later he joined the National Neuroscience Institute (NNI) as a member of the Singapore National PD Translational Bench to Bedside team and continue to work on translational researches on pathogenesis and therapy against DA neuron degeneration in PD. Currently, I am an Associate Principle Investigator in charge of the Translational Therapeutics Laboratory of NNI and an Assistant Professor at Duke-NUS, NBD as well as a PI of NMRC and SHF grants.

Currently we are searching for and identifying novel key molecular targets related to DA neuron dgeneration in PD, which will be validated in multiple DA cells, C elegan, Drosophila and mice PD models. Second, we are performing high-throughput screening studies to identify new therapeutic chemical pre-drugs to protect mitochondria functions and promote DA neurons survival from chemical libraries using DA cells and transgenic animal PD models. Third, we are studying and identifying new biomarkers which can enhance PD diagnosis and therapy. Our translational researches target to uncover the pathogenesis and DA neuron degeneration in PD and develop new diagnosis and therapeutic strategies, which can finally improve our life quality and benefit PD patients.

Primary Affiliation: National Neuroscience Institute - Singapore , Singapore

Specialties:

Additional Specialties:

Research Interests:


View Dr Zhi-dong Zhou’s Resume / CV

Education

Sep 2009
National University of Singapore
Post-Doctor training on Neuroscience
Neuroscience
Mar 2003
Shanghai Branch, Chinese Academy of Science
Ph.D. in Biochemistry
Aug 1996
the First People's Hospital of Nantong City
Post-graduate clinical training in Internal Medicine
Sep 1991
Nantong Medical University
Bachelor of Medicine
Medicine

Experience

Oct 2018
Long service award (10 years).
NNI
Dec 2013
NMRC Transition Award 2013
PI
Dec 2013
Therapeutic effects and molecular mechanism of polyphenols in black tea and neuroprotection in Parkinson's Disease. NMRC Project no. NMRC/CNIG/1093/2012.
PI
4 years project
Nov 2013
Iron species induced dopaminergic neuron degeneration in Drosophila, a sporadic Parkinson's disease animal model. SHF grant no. NRS13/004
PI
3 years project
Aug 2013
Therapeutic effects and molecular mechanism of polyphenols in black tea and neuroprotection in Parkinson's Disease. NMRC Project no. NMRC/CNIG/1093/2012.
PI
3 years project

Publications

22Publications

382Reads

51Profile Views

61PubMed Central Citations

Pathophysiological mechanisms linking F-box only protein 7 (FBXO7) and Parkinson's disease (PD).

Mutat Res 2018 Oct - Dec;778:72-78. Epub 2018 Oct 17.

Department of Research, National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore; Department of Neurology, Singapore General Hospital, Outram Road, 169608, Singapore; Signature Research Program in Neuroscience and Behavioural Disorders, Duke-NUS Medical School, 8 College Road, 169857, Singapore. Electronic address:

Mutations of F-box only protein 7 (FBXO7) gene are associated with a severe form of autosomal recessive juvenile Parkinson's disease (PD) (PARK15) with clinical features of Parkinsonian-Pyramidal syndrome (PPS). FBXO7 is an adaptor protein in SCF ubiquitin E3 ligase complex that recognizes and mediates degradative or non-degradative ubiquitination of substrates. The FBXO7 protein can regulate cell cycle, proliferation, mitochondrial and proteasome functions via interactions with multiple target proteins. Five PARK15-linked FBXO7 gene mutations and several PD-associated single nucleotide polymorphisms (SNP) have been identified so far. WT FBXO7 proteins possess dual protective and deleterious functions, whereas PARK15-linked FBXO7 mutants are toxic. FBXO7 is a stress response protein and stress challenges can promote translocation of FBXO7 protein from nucleus into mitochondria and even form deleterious protein aggregate in mitochondria. FBXO7 mutants aggravate protein aggregation in mitochondria and inhibit mitophagy. The pathological mechanisms concerning FBXO7-relevant protein aggregation, mitochondria impairment, reactive oxygen species (ROS) generation and mitophagy modulation in PARK15 pathogenesis are highlighted and discussed in the current review.

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http://dx.doi.org/10.1016/j.mrrev.2018.10.001DOI Listing
April 2019
14 Reads
6.081 Impact Factor

Molecular targets for modulating the protein translation vital to proteostasis and neuron degeneration in Parkinson's disease.

Transl Neurodegener 2019 4;8. Epub 2019 Feb 4.

1Department of Research, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433 Singapore.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body formation in affected brain areas. The detailed pathogenic mechanisms underlying the selective loss of dopaminergic neurons in PD are unclear, and no drugs or treatments have been developed to alleviate progressive dopaminergic neuron degeneration in PD. However, the formation of ?-synuclein-positive protein aggregates in Lewy body has been identified as a common pathological feature of PD, possibly stemming from the consequence of protein misfolding and dysfunctional proteostasis. Proteostasis is the mechanism for maintaining protein homeostasis via modulation of protein translation, enhancement of chaperone capacity and the prompt clearance of misfolded protein by the ubiquitin proteasome system and autophagy. Deregulated protein translation and impaired capacities of chaperone or protein degradation can disturb proteostasis processes, leading to pathological protein aggregation and neurodegeneration in PD. In recent years, multiple molecular targets in the modulation of protein translation vital to proteostasis and dopaminergic neuron degeneration have been identified. The potential pathophysiological and therapeutic significance of these molecular targets to neurodegeneration in PD is highlighted.

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http://dx.doi.org/10.1186/s40035-019-0145-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360798PMC
February 2019
1 Read
5.534 Impact Factor

Correction: Superoxide drives progression of Parkin/PINK1-dependent mitophagy following translocation of Parkin to mitochondria.

Cell Death Dis 2018 Jul 19;9(8):794. Epub 2018 Jul 19.

Department of Neurology, National Neuroscience Institute, Singapore, Singapore.

The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information.

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http://dx.doi.org/10.1038/s41419-018-0832-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053442PMC
July 2018
6 Reads
5.959 Impact Factor

LRRK2 Interacts with ATM and Regulates Mdm2-p53 Cell Proliferation Axis in Response to Genotoxic Stress

Hum Mol Genet. 2017 Nov 15;26(22):4494-4505.

Human Molecular Genetics

Pathogenic leucine-rich repeat kinase 2 (LRRK2) mutations are recognized as the most common cause of familial Parkinson's disease in certain populations. Recently, LRRK2 mutations were shown to be associated with a higher risk of hormone-related cancers. However, how LRRK2 itself contributes to cancer risk remains unknown. DNA damage causes cancer, and DNA damage responses are among the most important pathways in cancer biology. To understand the role of LRRK2 in DNA damage response pathway, we induced DNA damage by applying genotoxic stress to the cells with Adriamycin. We found that DNA damage enhances LRRK2 phosphorylation at Serine 910, Serine 935 and Serine 1292. We further showed that LRRK2 phosphorylation is abolished in the absence of ATM, suggesting that LRRK2 phosphorylation requires ATM. It should also be noted that LRRK2 interacts with ATM. In contrast, overexpression or knockdown of LRRK2 does not affect ATM phosphorylation, indicating that LRRK2 is the downstream target of ATM in response to DNA damage. Moreover, we demonstrated that LRRK2 increases the expression of p53 and p21 by increasing the Mdm2 phosphorylation in response to DNA damage. Loss-of-function in LRRK2 has the opposite effect to that of LRRK2. In addition, FACS analysis revealed that LRRK2 enhances cell cycle progression into S phase in response to DNA damage, a finding that was confirmed by 5-bromo-2'-deoxyuridine immunostaining. Taken together, our findings demonstrate that LRRK2 plays an important role in the ATM-Mdm2-p53 pathway that regulates cell proliferation in response to DNA damage.

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November 2017

Impact Factor 6.393

Iron regulatory protein (IRP)-iron responsive element (IRE) signaling pathway in human neurodegenerative diseases.

Mol Neurodegener 2017 10 23;12(1):75. Epub 2017 Oct 23.

National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore.

The homeostasis of iron is vital to human health, and iron dyshomeostasis can lead to various disorders. Iron homeostasis is maintained by iron regulatory proteins (IRP1 and IRP2) and the iron-responsive element (IRE) signaling pathway. IRPs can bind to RNA stem-loops containing an IRE in the untranslated region (UTR) to manipulate translation of target mRNA. However, iron can bind to IRPs, leading to the dissociation of IRPs from the IRE and altered translation of target transcripts. Recently an IRE is found in the 5'-UTR of amyloid precursor protein (APP) and ?-synuclein (?-Syn) transcripts. The levels of ?-Syn, APP and amyloid ?-peptide (A?) as well as protein aggregation can be down-regulated by IRPs but are up-regulated in the presence of iron accumulation. Therefore, inhibition of the IRE-modulated expression of APP and ?-Syn or chelation of iron in patient's brains has therapeutic significance to human neurodegenerative diseases. Currently, new pre-drug IRE inhibitors with therapeutic effects have been identified and are at different stages of clinical trials for human neurodegenerative diseases. Although some promising drug candidates of chemical IRE inhibitors and iron-chelating agents have been identified and are being validated in clinical trials for neurodegenerative diseases, future studies are expected to further establish the clinical efficacy and safety of IRE inhibitors and iron-chelating agents in patients with neurodegenerative diseases.

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http://dx.doi.org/10.1186/s13024-017-0218-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654065PMC
October 2017
5 Reads
8.274 Impact Factor

Superoxide drives progression of Parkin/PINK1-dependent mitophagy following translocation of Parkin to mitochondria.

Cell Death Dis 2017 10 12;8(10):e3097. Epub 2017 Oct 12.

Department of Neurology, National Neuroscience Institute, Singapore.

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http://www.nature.com/doifinder/10.1038/cddis.2017.463
Publisher Site
http://dx.doi.org/10.1038/cddis.2017.463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680585PMC
October 2017
12 Reads
5.014 Impact Factor

Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease.

Sci Signal 2017 Jul 18;10(488). Epub 2017 Jul 18.

Research Department, National Neuroscience Institute, Singapore General Hospital (SGH) Campus, Singapore 169856, Singapore.

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http://dx.doi.org/10.1126/scisignal.aam6790DOI Listing
July 2017
69 Reads
6.279 Impact Factor

F-box protein 7 mutations promote protein aggregation in mitochondria and inhibit mitophagy.

Hum Mol Genet 2015 Nov 26;24(22):6314-30. Epub 2015 Aug 26.

National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore, Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore, Singapore, Department of Neurology, Singapore General Hospital, Outram Road, Singapore, Singapore and

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http://dx.doi.org/10.1093/hmg/ddv340DOI Listing
November 2015
33 Reads
5 Citations
6.393 Impact Factor

Association Analysis of COQ2 Variant in Dementia and Essential Tremor.

Parkinsons Dis 2015 22;2015:926280. Epub 2015 Apr 22.

Department of Neurology, Singapore General Hospital, Singapore 169608 ; National Neuroscience Institute, Singapore 308433 ; Duke-NUS Graduate Medical School, Singapore 169857 ; Department of Clinical Research, Singapore General Hospital, Singapore 169608.

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http://dx.doi.org/10.1155/2015/926280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4421028PMC
May 2015
101 Reads

Thiol peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila.

Hum Mol Genet 2014 Jun 23;23(12):3157-65. Epub 2014 Jan 23.

Department of Neurology, Singapore General Hospital, Singapore, Singapore 169856 National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, Singapore 308433 Duke-NUS Graduate Medical School, 8 College Road, Singapore, Singapore 169857

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http://dx.doi.org/10.1093/hmg/ddu026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030771PMC
June 2014
28 Reads
9 Citations
6.393 Impact Factor

Mutant PINK1 upregulates tyrosine hydroxylase and dopamine levels, leading to vulnerability of dopaminergic neurons.

Free Radic Biol Med 2014 Mar 25;68:220-33. Epub 2013 Dec 25.

National Neuroscience Institute, Singapore 308433, Singapore; Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore; Department of Neurology, Singapore General Hospital, Singapore 169608, Singapore. Electronic address:

PINK1 mutations cause autosomal recessive forms of Parkinson disease (PD). Previous studies suggest that the neuroprotective function of wild-type (WT) PINK1 is related to mitochondrial homeostasis. PINK1 can also localize to the cytosol; however, the cytosolic function of PINK1 has not been fully elucidated. In this study we demonstrate that the extramitochondrial PINK1 can regulate tyrosine hydroxylase (TH) expression and dopamine (DA) content in dopaminergic neurons in a PINK1 kinase activity-dependent manner. We demonstrate that overexpression of full-length (FL) WT PINK1 can downregulate TH expression and DA content in dopaminergic neurons. In contrast, overexpression of PD-linked G309D, A339T, and E231G PINK1 mutations upregulates TH and DA levels in dopaminergic neurons and increases their vulnerability to oxidative stress. Furthermore transfection of FL WT PINK1 or PINK1 fragments with the PINK1 kinase domain can inhibit TH expression, whereas kinase-dead (KD) FL PINK1 or KD PINK1 fragments upregulate TH level. Our findings highlight a potential novel function of extramitochondrial PINK1 in dopaminergic neurons. Deregulation of these functions of PINK1 may contribute to PINK1 mutation-induced dopaminergic neuron degeneration. However, deleterious effects caused by PINK1 mutations may be alleviated by iron-chelating agents and antioxidant agents with DA quinone-conjugating capacity.

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http://dx.doi.org/10.1016/j.freeradbiomed.2013.12.015DOI Listing
March 2014
14 Reads
5.736 Impact Factor

LINGO-1 and Neurodegeneration: Pathophysiologic Clues for Essential Tremor.

Tremor Other Hyperkinet Mov (N Y) 2012 20;2. Epub 2012 Feb 20.

National Neuroscience Institute, Singapore 308433.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569903PMC
http://dx.doi.org/10.7916/D8PZ57JVDOI Listing
July 2013
3 Reads
2 Citations

Ring finger protein 146/Iduna is a poly(ADP-ribose) polymer binding and PARsylation dependent E3 ubiquitin ligase.

Cell Adh Migr 2011 Nov-Dec;5(6):463-71

National Neuroscience Institute, Singapore.

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http://dx.doi.org/10.4161/cam.5.6.18356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277779PMC
May 2012
9 Reads
9 Citations
4.505 Impact Factor

The roles of amyloid precursor protein (APP) in neurogenesis: Implications to pathogenesis and therapy of Alzheimer disease.

Cell Adh Migr 2011 Jul-Aug;5(4):280-92. Epub 2011 Jul 1.

National Neuroscience Institute; Singapore.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210295PMC
http://dx.doi.org/10.4161/cam.5.4.16986DOI Listing
December 2011
13 Reads
28 Citations
4.505 Impact Factor

Iron species-mediated dopamine oxidation, proteasome inhibition, and dopaminergic cell demise: implications for iron-related dopaminergic neuron degeneration.

Free Radic Biol Med 2010 Dec 18;49(12):1856-71. Epub 2010 Sep 18.

Department of Biological Science, National University of Singapore, Singapore.

Iron species have been suggested to be highly involved in the pathogenesis of Parkinson disease. However, the detailed mechanism of iron-induced dopaminergic degeneration is still unclear. In this study, we demonstrate that free iron ions (trivalent or bivalent) and iron ions in stable complex with cyanide ions (K(4)Fe(CN)(6) and K(3)Fe(CN)(6)) can induce dopamine (DA) oxidation with different profiles and subsequently lead to proteasome inhibition and even dopaminergic MN9D cell demise via different mechanisms. The free iron ions could mediate extensive DA oxidation in an iron-DA complex-dependent manner. However, iron ions in stable complex with cyanide ions could not induce, or could induce only brief, DA oxidation. Deferoxamine, a specific iron ion chelator, could disrupt iron-DA complex formation and thus abrogate free iron ion-catalyzed DA oxidation and subsequent cell toxicity. Glutathione could neither disrupt iron-DA complex formation nor influence free iron ion-catalyzed DA oxidation but could protect against iron-mediated toxicity via detoxification of toxic by-products of iron-mediated DA oxidation. The resulting DA oxidation could inhibit chymotrypsin-like, trypsin-like, and caspase-like proteasome activities. However, we demonstrated that oxidative damage was not the major toxic mechanism of MN9D cell degeneration, but it was the DA quinones derived from iron-induced DA oxidation that contributed significantly to proteasome inhibition and even dopaminergic cell demise.

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http://dx.doi.org/10.1016/j.freeradbiomed.2010.09.010DOI Listing
December 2010
4 Reads
5.736 Impact Factor

Glutathione conjugates with dopamine-derived quinones to form reactive or non-reactive glutathione-conjugates.

Neurochem Res 2010 Nov 19;35(11):1805-18. Epub 2010 Aug 19.

Department of Biological Science, National University of Singapore, Singapore, Singapore.

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http://dx.doi.org/10.1007/s11064-010-0247-7DOI Listing
November 2010
6 Reads
2.593 Impact Factor

Notch as a molecular switch in neural stem cells.

IUBMB Life 2010 Aug;62(8):spcone

National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433.

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http://dx.doi.org/10.1002/iub.372DOI Listing
August 2010
43 Reads
1 Citation
3.143 Impact Factor

Dopamine (DA) induced irreversible proteasome inhibition via DA derived quinones.

Free Radic Res 2009 Apr 17;43(4):417-30. Epub 2009 Mar 17.

Department of Biological Science, National University of Singapore, 14 Science Drive 4, Singapore 117543.

This study demonstrated that DA and its oxidative metabolites: H2O2 and aminochrome (AM), cyclized DA quinones, could all directly inhibit proteasome activity. DA and AM, especially AM, could induce intensive and irreversible proteasome inhibition, whereas proteasome inhibition induced by H2O2 was weaker and GSH reversible. It was concluded that DA induced irreversible proteasome inhibition via DA-derived quinones, rather than through small molecular weight ROS. The AM was also more toxic than H2O2 to dopaminergic MN9D cells. Furthermore the cytotoxicity and proteasome inhibition induced by DA, AM and H2O2 could be abrogated by GSH, ascorbic acid (AA), Vitamin E, SOD (superoxidase dismutase) or CAT (catalase) with different profiles. Only GSH was potent to abrogate DA, AM or H2O2-induced cell toxicity and proteasome inhibition, as well as to reverse H2O2-induced proteosome inhibition. Therefore, therapeutic strategies to increase GSH level or to use GSH substitutes should function to control PD onset and development.

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http://dx.doi.org/10.1080/10715760902801533DOI Listing
April 2009
2 Reads
2.825 Impact Factor

Dopamine auto-oxidation aggravates non-apoptotic cell death induced by over-expression of human A53T mutant alpha-synuclein in dopaminergic PC12 cells.

J Neurochem 2009 Feb 27;108(3):601-10. Epub 2008 Nov 27.

Department of Biological Science, National University of Singapore, Singapore, Singapore.

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http://dx.doi.org/10.1111/j.1471-4159.2008.05795.xDOI Listing
February 2009
7 Reads
3 Citations
4.281 Impact Factor

Roles of glutathione (GSH) in dopamine (DA) oxidation studied by improved tandem HPLC plus ESI-MS.

Neurochem Res 2009 Feb 5;34(2):316-26. Epub 2008 Jul 5.

Department of Biological Science, National University of Singapore, 14 Science Drive 4, Singapore, Singapore, 117543.

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http://dx.doi.org/10.1007/s11064-008-9778-6DOI Listing
February 2009
4 Reads
3 Citations
2.593 Impact Factor

Chromium (III) enhanced diamine silver staining of proteins and DNA in gels.

Biotechnol Lett 2003 Nov;25(21):1801-4

State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, PR China.

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http://dx.doi.org/10.1023/a:1026280519327DOI Listing
November 2003
2 Reads
1 Citation
1.591 Impact Factor

Low content of protein S29 in ribosomes of human lung cancer cell line a549: detected by two-dimensional electrophoresis.

Protein Pept Lett 2003 Feb;10(1):91-7

State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.

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http://dx.doi.org/10.2174/0929866033408273DOI Listing
February 2003
6 Reads
1.070 Impact Factor

Top co-authors

Eng-King Tan
Eng-King Tan

Singapore General Hospital

8
Tit Meng Lim
Tit Meng Lim

National University of Singapore

7
Eng King Tan
Eng King Tan

National Neuroscience Institute

5
Dario C Angeles
Dario C Angeles

National Neuroscience Institute

3
Zhi-Cheng Xiao
Zhi-Cheng Xiao

Singapore General Hospital

2
Sushmitha Sathiyamoorthy
Sushmitha Sathiyamoorthy

National Neuroscience Institute of Singapore

2
Eng-King Tan
Eng-King Tan

Singapore General Hospital

2
Shao Ping Xie
Shao Ping Xie

National Neuroscience Institute

2
Christine Hui-shan Chan
Christine Hui-shan Chan

National Neuroscience Institute

2