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Search Results: 1 - 10 of 18854 matches for " Shu-Leong Ho "
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Mitochondrial neuronal uncoupling proteins: a target for potential disease-modification in Parkinson's disease
Philip WL Ho, Jessica WM Ho, Hui-Fang Liu, Danny HF So, Zero HM Tse, Koon-Ho Chan, David B Ramsden, Shu-Leong Ho
Translational Neurodegeneration , 2012, DOI: 10.1186/2047-9158-1-3
Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder and increasingly a major burden in an aging population. Although its pathogenesis is unknown, there is evidence to implicate common pathogenic processes towards eventual cell death in PD. These processes include mitochondrial dysfunction, oxidative stress, neuroinflammation, excitotoxicity, and ubiquitin proteasome dysfunction [1-4].There is considerable evidence to link mitochondrial dysfunction and PD. Mitochondrial Complex I activity is reduced in substantia nigra in PD [5]. Inhibition of Complex I activity using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone (both toxins used in experimental parkinsonian models) produce nigrostriatal dopaminergic degeneration in animal models [6,7]. Cybrid cell lines with normal nuclear genome but with mitochondrial DNA from PD patients have reduced Complex I activity and mitochondrial energy-dependent activities [8], have abnormal mitochondrial morphology [9], and are more susceptible to MPTP-induced toxicity. The process of aging involves the mitochondria [10]. Furthermore, dopamine metabolism and mitochondrial dysfunction generate oxidative stress. High basal levels of oxidative stress in substantia nigra are found in normal brain, and are increased in PD. Furthermore, antioxidant activity, such as glutathione (GSH), is reduced in substantia nigra of PD patients [11,12]. Based on the hypothesis that various genetic and environmental etiological factors converge on these common pathogenic processes in PD, targeting proteins which modulate mitochondria bioenergetics appears to be a logical approach in preserving neurons against mitochondrial dysfunction in PD.Mitochondria are rod-shaped cellular organelles, which range in size from between 1 and 10 microns in length. They provide cellular energy by converting oxygen and nutrients into adenosine triphosphate (ATP) via oxidative phosphorylation. Human cells have hundreds to thousands of mitochondria
Assessment of Cellular Estrogenic Activity Based on Estrogen Receptor-Mediated Reduction of Soluble-Form Catechol-O-Methyltransferase (COMT) Expression in an ELISA-Based System
Philip Wing-Lok Ho, Zero Ho-Man Tse, Hui-Fang Liu, Song Lu, Jessica Wing-Man Ho, Michelle Hiu-Wai Kung, David Boyer Ramsden, Shu-Leong Ho
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074065
Abstract: Xenoestrogens are either natural or synthetic compounds that mimic the effects of endogenous estrogen. These compounds, such as bisphenol-A (BPA), and phthalates, are commonly found in plastic wares. Exposure to these compounds poses major risk to human health because of the potential to cause endocrine disruption. There is huge demand for a wide range of chemicals to be assessed for such potential for the sake of public health. Classical in vivo assays for endocrine disruption are comprehensive but time-consuming and require sacrifice of experimental animals. Simple preliminary in vitro screening assays can reduce the time and expense involved. We previously demonstrated that catechol-O-methyltransferase (COMT) is transcriptionally regulated by estrogen via estrogen receptor (ER). Therefore, detecting corresponding changes of COMT expression in estrogen-responsive cells may be a useful method to estimate estrogenic effects of various compounds. We developed a novel cell-based ELISA to evaluate cellular response to estrogenicity by reduction of soluble-COMT expression in ER-positive MCF-7 cells exposed to estrogenic compounds. In contrast to various existing methods that only detect bioactivity, this method elucidates direct physiological effect in a living cell in response to a compound. We validated our assay using three well-characterized estrogenic plasticizers - BPA, benzyl butyl phthalate (BBP), and di-n-butyl phthalate (DBP). Cells were exposed to either these plasticizers or 17β-estradiol (E2) in estrogen-depleted medium with or without an ER-antagonist, ICI 182,780, and COMT expression assayed. Exposure to each of these plasticizers (10-9-10-7M) dose-dependently reduced COMT expression (p<0.05), which was blocked by ICI 182,780. Reduction of COMT expression was readily detectable in cells exposed to picomolar level of E2, comparable to other in vitro assays of similar sensitivity. To satisfy the demand for in vitro assays targeting different cellular components, a cell-based COMT assay provides useful initial screening to supplement the current assessments of xenoestrogens for potential estrogenic activity.
Prognostic implications of surrogate markers of atherosclerosis in low to intermediate risk patients with Type 2 Diabetes
Kui-Kai Lau, Yuen-Kwun Wong, Yap-Hang Chan, Kai-Hang Yiu, Kay-Cheong Teo, Leonard Li, Shu-Leong Ho, Koon-Ho Chan, Chung-Wah Siu, Hung-Fat Tse
Cardiovascular Diabetology , 2012, DOI: 10.1186/1475-2840-11-101
Abstract: We sought to determine the prognostic values of different non-invasive markers of atherosclerosis, including brachial artery endothelial function, carotid artery atheroma burden, ankle-brachial index, arterial stiffness and computed tomography coronary artery calcium score (CACS) in 151 T2DM Chinese patients that were identified low-intermediate risk from the FRS recalibrated for Chinese (<20% risk in 10?years). Patients were prospectively followed-up and presence of atherosclerotic events documented for a mean duration of 61?±?16?months.A total of 17 atherosclerotic events in 16 patients (11%) occurred during the follow-up period. The mean FRS of the study population was 5.0?±?4.6% and area under curve (AUC) from receiver operating characteristic curve analysis for prediction of atherosclerotic events was 0.59?±?0.07 (P?=?0.21). Among different vascular assessments, CACS?>?40 had the best prognostic value (AUC 0.81?±?0.06, P?<?0.01) and offered significantly better accuracy in prediction compared with FRS (P?=?0.038 for AUC comparisons). Combination of FRS with CACS or other surrogate vascular markers did not further improve the prognostic values over CACS alone. Multivariate Cox regression analysis identified CACS?>?40 as an independent predictor of atherosclerotic events in T2DM patients (Hazards Ratio 27.11, 95% Confidence Interval 3.36-218.81, P?=?0.002).In T2DM patients identified as low-intermediate risk by the FRS, a raised CACS?>?40 was an independent predictor for atherosclerotic events.Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing adverse atherosclerotic events including acute coronary syndrome (ACS) and ischemic stroke [1-3]. Various risk assessment algorithms, for example the Framingham Risk Score (FRS) and Systematic Coronary Risk Evaluation (SCORE), aim to predict the likelihood of developing cardiovascular events [4-6]. Some of these scores have also been recalibrated based on the ethnic differences in cardiovascul
Predicting Mendelian Disease-Causing Non-Synonymous Single Nucleotide Variants in Exome Sequencing Studies
Miao-Xin Li equal contributor ,Johnny S. H. Kwan equal contributor,Su-Ying Bao,Wanling Yang,Shu-Leong Ho,Yong-Qiang Song,Pak C. Sham
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003143
Abstract: Exome sequencing is becoming a standard tool for mapping Mendelian disease-causing (or pathogenic) non-synonymous single nucleotide variants (nsSNVs). Minor allele frequency (MAF) filtering approach and functional prediction methods are commonly used to identify candidate pathogenic mutations in these studies. Combining multiple functional prediction methods may increase accuracy in prediction. Here, we propose to use a logit model to combine multiple prediction methods and compute an unbiased probability of a rare variant being pathogenic. Also, for the first time we assess the predictive power of seven prediction methods (including SIFT, PolyPhen2, CONDEL, and logit) in predicting pathogenic nsSNVs from other rare variants, which reflects the situation after MAF filtering is done in exome-sequencing studies. We found that a logit model combining all or some original prediction methods outperforms other methods examined, but is unable to discriminate between autosomal dominant and autosomal recessive disease mutations. Finally, based on the predictions of the logit model, we estimate that an individual has around 5% of rare nsSNVs that are pathogenic and carries ~22 pathogenic derived alleles at least, which if made homozygous by consanguineous marriages may lead to recessive diseases.
Uncoupling Protein-4 (UCP4) Increases ATP Supply by Interacting with Mitochondrial Complex II in Neuroblastoma Cells
Philip Wing-Lok Ho, Jessica Wing-Man Ho, Ho-Man Tse, Danny Hon-Fai So, David Chi-Wai Yiu, Hui-Fang Liu, Koon-Ho Chan, Michelle Hiu-Wai Kung, David Boyer Ramsden, Shu-Leong Ho
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032810
Abstract: Mitochondrial uncoupling protein-4 (UCP4) protects against Complex I deficiency as induced by 1-methyl-4-phenylpyridinium (MPP+), but how UCP4 affects mitochondrial function is unclear. Here we investigated how UCP4 affects mitochondrial bioenergetics in SH-SY5Y cells. Cells stably overexpressing UCP4 exhibited higher oxygen consumption (10.1%, p<0.01), with 20% greater proton leak than vector controls (p<0.01). Increased ATP supply was observed in UCP4-overexpressing cells compared to controls (p<0.05). Although state 4 and state 3 respiration rates of UCP4-overexpressing and control cells were similar, Complex II activity in UCP4-overexpressing cells was 30% higher (p<0.05), associated with protein binding between UCP4 and Complex II, but not that of either Complex I or IV. Mitochondrial ADP consumption by succinate-induced respiration was 26% higher in UCP4-overexpressing cells, with 20% higher ADP:O ratio (p<0.05). ADP/ATP exchange rate was not altered by UCP4 overexpression, as shown by unchanged mitochondrial ADP uptake activity. UCP4 overexpression retained normal mitochondrial morphology in situ, with similar mitochondrial membrane potential compared to controls. Our findings elucidate how UCP4 overexpression increases ATP synthesis by specifically interacting with Complex II. This highlights a unique role of UCP4 as a potential regulatory target to modulate mitochondrial Complex II and ATP output in preserving existing neurons against energy crisis.
Stroke Patients with a Past History of Cancer Are at Increased Risk of Recurrent Stroke and Cardiovascular Mortality
Kui-Kai Lau, Yuen-Kwun Wong, Kay-Cheong Teo, Richard Shek-Kwan Chang, Sonny Fong-Kwong Hon, Koon-Ho Chan, Raymond Tak-Fai Cheung, Leonard Sheung-Wai Li, Hung-Fat Tse, Shu-Leong Ho, Chung-Wah Siu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088283
Abstract: Background and Purpose Cancer patients are at increased risk of cardiovascular and cerebrovascular events. It is unclear whether cancer confers any additional risk for recurrent stroke or cardiovascular mortality after stroke. Methods This was a single center, observational study of 1,105 consecutive Chinese ischemic stroke patients recruited from a large stroke rehabilitation unit based in Hong Kong. We sought to determine whether patients with cancer are at higher risk of recurrent stroke and cardiovascular mortality. Results Amongst 1,105 patients, 58 patients (5.2%) had cancer, of whom 74% were in remission. After a mean follow-up of 76±18 months, 241 patients developed a recurrent stroke: 22 in patients with cancer (38%, annual incidence 13.94%/year), substantially more than those without cancer (21%, 4.65%/year) (p<0.01). In a Cox regression model, cancer, age and atrial fibrillation were the 3 independent predictors of recurrent stroke with a hazard ratio (HR) of 2.42 (95% confidence interval (CI): 1.54–3.80), 1.01 (1.00–1.03) and 1.35 (1.01–1.82) respectively. Likewise, patients with cancer had a higher cardiovascular mortality compared with those without cancer (4.30%/year vs. 2.35%/year, p = 0.08). In Cox regression analysis, cancer (HR: 2.08, 95% CI: 1.08–4.02), age (HR: 1.04, 95% CI 1.02–1.06), heart failure (HR: 3.06, 95% CI 1.72–5.47) and significant carotid atherosclerosis (HR: 1.55, 95% CI 1.02–2.36) were independent predictors for cardiovascular mortality. Conclusions Stroke patients with a past history of cancer are at increased risk of recurrent stroke and cardiovascular mortality.
Leveraging on Video Technology for High-Leverage Practices  [PDF]
Yew Hoong Leong, Foo Him Ho
Creative Education (CE) , 2012, DOI: 10.4236/ce.2012.38B025
Abstract: In redesigning a methods course for Singapore Secondary Mathematics prospective teachers, we leverage on video technology to help them learn about the instructional practice of going through textbook-type questions. We find that this innovation generates learning all round – both for the student teachers as well as teacher educators.
Erasure Coding for Real-Time Streaming
Derek Leong,Tracey Ho
Mathematics , 2012,
Abstract: We consider a real-time streaming system where messages are created sequentially at the source, and are encoded for transmission to the receiver over a packet erasure link. Each message must subsequently be decoded at the receiver within a given delay from its creation time. The goal is to construct an erasure correction code that achieves the maximum message size when all messages must be decoded by their respective deadlines under a specified set of erasure patterns (erasure model). We present an explicit intrasession code construction that is asymptotically optimal under erasure models containing a limited number of erasures per coding window, per sliding window, and containing erasure bursts of a limited length.
Symmetric Allocations for Distributed Storage
Derek Leong,Alexandros G. Dimakis,Tracey Ho
Mathematics , 2010,
Abstract: We consider the problem of optimally allocating a given total storage budget in a distributed storage system. A source has a data object which it can code and store over a set of storage nodes; it is allowed to store any amount of coded data in each node, as long as the total amount of storage used does not exceed the given budget. A data collector subsequently attempts to recover the original data object by accessing each of the nodes independently with some constant probability. By using an appropriate code, successful recovery occurs when the total amount of data in the accessed nodes is at least the size of the original data object. The goal is to find an optimal storage allocation that maximizes the probability of successful recovery. This optimization problem is challenging because of its discrete nature and nonconvexity, despite its simple formulation. Symmetric allocations (in which all nonempty nodes store the same amount of data), though intuitive, may be suboptimal; the problem is nontrivial even if we optimize over only symmetric allocations. Our main result shows that the symmetric allocation that spreads the budget maximally over all nodes is asymptotically optimal in a regime of interest. Specifically, we derive an upper bound for the suboptimality of this allocation and show that the performance gap vanishes asymptotically in the specified regime. Further, we explicitly find the optimal symmetric allocation for a variety of cases. Our results can be applied to distributed storage systems and other problems dealing with reliability under uncertainty, including delay tolerant networks (DTNs) and content delivery networks (CDNs).
Distributed Storage Allocations
Derek Leong,Alexandros G. Dimakis,Tracey Ho
Mathematics , 2010,
Abstract: We examine the problem of allocating a given total storage budget in a distributed storage system for maximum reliability. A source has a single data object that is to be coded and stored over a set of storage nodes; it is allowed to store any amount of coded data in each node, as long as the total amount of storage used does not exceed the given budget. A data collector subsequently attempts to recover the original data object by accessing only the data stored in a random subset of the nodes. By using an appropriate code, successful recovery can be achieved whenever the total amount of data accessed is at least the size of the original data object. The goal is to find an optimal storage allocation that maximizes the probability of successful recovery. This optimization problem is challenging in general because of its combinatorial nature, despite its simple formulation. We study several variations of the problem, assuming different allocation models and access models. The optimal allocation and the optimal symmetric allocation (in which all nonempty nodes store the same amount of data) are determined for a variety of cases. Our results indicate that the optimal allocations often have nonintuitive structure and are difficult to specify. We also show that depending on the circumstances, coding may or may not be beneficial for reliable storage.
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