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1.  Patients Infected with CRF07_BC Have Significantly Lower Viral Loads than Patients with HIV-1 Subtype B: Mechanism and Impact on Disease Progression 
PLoS ONE  2014;9(12):e114441.
The circulating recombinant form (CRF) 07_BC is the most prevalent HIV-1 strain among injection drug users (IDUs) in Taiwan. It contains a 7 amino-acid deletion in its p6gag. We conducted a cohort study to compare viral loads and CD4 cell count changes between patients infected with subtype B and CRF07_BC and to elucidate its mechanism. Twenty-one patients infected with CRF07_BC and 59 patients with subtype B were selected from a cohort of 667 HIV-1/AIDS patients whom have been followed up for 3 years. Generalized estimated equation was used to analyze their clinical data and the results showed that patients infected with CRF07_BC had significantly lower viral loads (about 58,000 copies per ml less) than patients with subtype B infection (p = 0.002). The replicative capacity of nine CRF07_BC and four subtype B isolates were compared and the results showed that the former had significantly lower replicative capacity than the latter although all of them were CCR5- tropic and non-syncytium inducing viruses. An HIV-1-NL4-3 mutant virus which contains a 7 amino-acid deletion in p6gag (designated as 7d virus) was generated and its live cycle was investigated. The results showed that 7d virus had significantly lower replication capacity, poorer protease-mediated processing and viral proteins production. Electron microscopic examination of cells infected with wild-type or 7d virus demonstrated that the 7d virus had poorer and slower viral maturation processes: more viruses attached to the cell membrane and higher proportion of immature virions outside the cells. The interaction between p6gag and Alix protein was less efficient in cells infected with 7d virus. In conclusion, patients infected with CRF07_BC had significantly lower viral loads than patients infected with subtype B and it may due to the deletion of 7 amino acids which overlaps with Alix protein-binding domain of the p6gag.
PMCID: PMC4263662  PMID: 25502811
2.  A selfish DNA element engages a meiosis-specific motor and telomeres for germ-line propagation 
The Journal of Cell Biology  2014;205(5):643-661.
The yeast 2 micron plasmid engages a meiosis-specific motor that orchestrates telomere-led chromosome movements for its telomere-associated segregation during meiosis I.
The chromosome-like mitotic stability of the yeast 2 micron plasmid is conferred by the plasmid proteins Rep1-Rep2 and the cis-acting locus STB, likely by promoting plasmid-chromosome association and segregation by hitchhiking. Our analysis reveals that stable plasmid segregation during meiosis requires the bouquet proteins Ndj1 and Csm4. Plasmid relocalization from the nuclear interior in mitotic cells to the periphery at or proximal to telomeres rises from early meiosis to pachytene. Analogous to chromosomes, the plasmid undergoes Csm4- and Ndj1-dependent rapid prophase movements with speeds comparable to those of telomeres. Lack of Ndj1 partially disrupts plasmid–telomere association without affecting plasmid colocalization with the telomere-binding protein Rap1. The plasmid appears to engage a meiosis-specific motor that orchestrates telomere-led chromosome movements for its telomere-associated segregation during meiosis I. This hitherto uncharacterized mode of germ-line transmission by a selfish genetic element signifies a mechanistic variation within the shared theme of chromosome-coupled plasmid segregation during mitosis and meiosis.
PMCID: PMC4050733  PMID: 24914236
3.  STAT4: An Initiator of Meta-Inflammation in Adipose Tissue? 
Diabetes  2013;62(12):4002-4003.
PMCID: PMC3837030  PMID: 24264401
4.  Cancer incidence patterns among children and adolescents in Taiwan from 1995 to 2009: A population-based study 
Cancer  2014;120(22):3545-3553.
Currently, little information is available on childhood cancer incidence rates in Eastern Asia. The objective of this study was to report the first population-based cancer surveillance of children and adolescents in Taiwan.
Data from the Taiwan Cancer Registry were examined for cancer frequencies and incidence rates among individuals ages birth to 19 years from 1995 to 2009. Types of cancers were grouped according to the International Classification of Childhood Cancer. Rates were compared by sex and age. For further comparisons with other countries, rates were age standardized to the 2000 world standard population in 5-year age groups. Trends in incidence rates also were evaluated.
In total, 12,315 individuals were diagnosed with childhood cancers, for an age-standardized incidence rate (ASR) of 132.1 per million person-years from 1995 to 2009. The male-to-female incidence rate ratio was 1.19. Overall, leukemias were the most common cancer (ASR, 39.1 per million person-years), followed by central nervous system neoplasms (15.8 per million person-years), and lymphomas (15.3 per million person-years). During the 15-year study period, the incidence rates increased by 1% annually. Compared with other countries, the rate of hepatic tumors was 2 times greater in Taiwan. The rate of germ cell neoplasms in Taiwan was similar to that in the United States and was 1.3 to 1.9 times greater compared with Canada, Brazil, Israel, and Japan.
Based on the current data, the observed increase in overall incidence rates was attributable only marginally to improvements in case ascertainment and diagnostic procedures. The high rates of malignant hepatic tumors and germ cell neoplasms in Taiwan suggest variations in the background risk factors. Cancer 2014;120:3545–3553. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
The authors examine cancer incidence patterns in children and adolescents based on a national, population-based cancer registry of 12,315 individuals in Taiwan from 1995 to 2009. The high rates of malignant hepatic tumors and germ cell neoplasms in Taiwan suggest variations in background risk factors.
PMCID: PMC4232908  PMID: 25043411
adolescents; cancer; childhood; epidemiology; incidence; Taiwan
5.  Feature selection and classifier performance on diverse bio- logical datasets 
BMC Bioinformatics  2014;15(Suppl 13):S4.
There is an ever-expanding range of technologies that generate very large numbers of biomarkers for research and clinical applications. Choosing the most informative biomarkers from a high-dimensional data set, combined with identifying the most reliable and accurate classification algorithms to use with that biomarker set, can be a daunting task. Existing surveys of feature selection and classification algorithms typically focus on a single data type, such as gene expression microarrays, and rarely explore the model's performance across multiple biological data types.
This paper presents the results of a large scale empirical study whereby a large number of popular feature selection and classification algorithms are used to identify the tissue of origin for the NCI-60 cancer cell lines. A computational pipeline was implemented to maximize predictive accuracy of all models at all parameters on five different data types available for the NCI-60 cell lines. A validation experiment was conducted using external data in order to demonstrate robustness.
As expected, the data type and number of biomarkers have a significant effect on the performance of the predictive models. Although no model or data type uniformly outperforms the others across the entire range of tested numbers of markers, several clear trends are visible. At low numbers of biomarkers gene and protein expression data types are able to differentiate between cancer cell lines significantly better than the other three data types, namely SNP, array comparative genome hybridization (aCGH), and microRNA data.
Interestingly, as the number of selected biomarkers increases best performing classifiers based on SNP data match or slightly outperform those based on gene and protein expression, while those based on aCGH and microRNA data continue to perform the worst. It is observed that one class of feature selection and classifier are consistently top performers across data types and number of markers, suggesting that well performing feature-selection/classifier pairings are likely to be robust in biological classification problems regardless of the data type used in the analysis.
PMCID: PMC4248652  PMID: 25434802
6.  Genetic resistance to liver fibrosis on A/J mouse chromosome 17 
Because the histological and biochemical progression of liver disease is similar in alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH), we hypothesized that the genetic susceptibility to these liver diseases would be similar. To identify potential candidate genes that regulate the development of liver fibrosis, we studied a chromosome substitution strain (CSS-17) that contains chromosome 17 from the A/J inbred strain substituted for the corresponding chromosome on the C57BL/6J (B6) genetic background. Previously we identified quantitative trait loci (QTLs) in CSS-17, namely obesity resistant QTL13 and QTL 15 (Obrq13 and Obrq15, respectively), that were associated with protection from diet-induced obesity and hepatic steatosis on a high fat diet.
To test if these or other CSS-17 QTLs conferred resistance to alcohol-induced liver injury and fibrosis, B6, A/J, CSS-17 and congenics 17C-1 and 17C-6 were either fed Lieber DeCarli ethanol-containing diet or had carbon tetrachloride (CCl4) administered chronically.
The congenic strain carrying Obrq15 showed resistance from alcohol-induced liver injury and liver fibrosis, whereas Obrq13 conferred susceptibility to liver fibrosis. From published deep sequencing data for chromosome 17 in the B6 and A/J strains, we identified candidate genes in Obrq 13 and Obrq15 that contained single nucleotide polymorphisms (SNPs) in the promoter region or within the gene itself. NADPH oxidase organizer 1 (Noxo1) and NLR family, CARD domain containing 4 (Nlrc4) showed altered hepatic gene expression in strains with the A/J allele at the end of the ethanol diet study and after CCl4 treatment.
Aspects of the genetics for the progression of ASH are unique compared to NASH, suggesting that the molecular mechanisms for the progression of disease are at least partially distinct. Using these CSSs we identified two candidate genes, Noxo1 and Nlrc4, which modulate genetic susceptibility in ASH.
PMCID: PMC3796136  PMID: 23763294
C57BL/6J; A/J; congenic strains; liver fibrosis; Nlrc4 inflammasome; CCl4
7.  Scalable and Versatile Genome Editing Using Linear DNAs with Microhomology to Cas9 Sites in Caenorhabditis elegans 
Genetics  2014;198(4):1347-1356.
Homology-directed repair (HDR) of double-strand DNA breaks is a promising method for genome editing, but is thought to be less efficient than error-prone nonhomologous end joining in most cell types. We have investigated HDR of double-strand breaks induced by CRISPR-associated protein 9 (Cas9) in Caenorhabditis elegans. We find that HDR is very robust in the C. elegans germline. Linear repair templates with short (∼30–60 bases) homology arms support the integration of base and gene-sized edits with high efficiency, bypassing the need for selection. Based on these findings, we developed a systematic method to mutate, tag, or delete any gene in the C. elegans genome without the use of co-integrated markers or long homology arms. We generated 23 unique edits at 11 genes, including premature stops, whole-gene deletions, and protein fusions to antigenic peptides and GFP. Whole-genome sequencing of five edited strains revealed the presence of passenger variants, but no mutations at predicted off-target sites. The method is scalable for multi-gene editing projects and could be applied to other animals with an accessible germline.
PMCID: PMC4256755  PMID: 25249454
CRISPR; Cas9; genome editing; homology-directed repair; short homology arms; Caenorhabditis elegans
8.  Supervised Phase II Cardiac Exercise Therapy Shortens the Recovery of Exercise Capacity in Patients with Acute Myocardial Infarction 
Journal of Physical Therapy Science  2014;26(9):1503-1508.
[Purpose] To investigate the effects of Phase II cardiac exercise therapy (CET) on exercise capacity and changes in coronary risk factors (CRFs) of patients with acute myocardial infarction (AMI). [Subjects] Thirty male subjects with AMI were divided into an experimental group (EG) and a control group (CG). Another 30 age-matched subjects with patent coronary arteries served as a normal-control group (NCG). [Methods] Subjects in EG (n=20) trained using a stationary bicycle for 30 min at their target heart rate twice a week for 8 weeks. Exercise capacity was defined as the maximal metabolic equivalents (METs) that subjects reached during the symptom-limited maximal exercise test. HR, BP and RPP were recorded. Subjects in EG and CG received exercise tests and screening for CRFs at the beginning of, end of, and 3 months after Phase II CET, while subjects in NCG participated only in the 1st test. [Results] METs of CG did not improve until the 3rd test, while RPP at the 2nd test showed a significant increase. However, EG showed increased METs at the 2nd test without increase of RPP, and increased their high density lipoprotein cholesterol (HDL-C) during the follow-up period between the 2nd and 3rd tests. [Conclusion] Phase II CET shortens the recovery time of exercise capacity, helps to maintain the gained exercise capacity and increases HDL-C in phase III.
PMCID: PMC4175267  PMID: 25276046
Patent coronary artery; Exercise capacity; Phase II CET
9.  A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid utilization 
Nature  2013;502(7472):550-554.
Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or utilization. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding1,2 and is repressed by Rev-erbα/β and an HDAC3-containing complex3–5 during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes6–8, suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARδ-dependent de novo lipogenic pathway in the liver that modulates fat utilization by muscle via a circulating lipid. The nuclear receptor PPARδ controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARδ activation increases, while hepatocyte-Ppard deletion reduces, muscle fatty acid (FA) uptake. Unbiased metabolite profiling identifies PC(18:0/18:1), or 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC), as a serum lipid regulated by diurnal hepatic PPARδ activity. PC(18:0/18:1) reduces postprandial lipid levels and increases FA utilization through muscle PPARα. High fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy utilization in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPARδ-PC(18:0/18:1) signaling in metabolic disorders including obesity.
PMCID: PMC4141623  PMID: 24153306
10.  Stat3β mitigates development of atherosclerosis in apolipoprotein E-deficient mice 
The transcription factor Stat3 is an activator of systemic inflammatory genes. Two isoforms of Stat3 are generated by alternative splicing, Stat3α and Stat3β. The β isoform lacks the transactivation domain but retains other functions, including dimerization and DNA binding. Stat3β-deficient mice exhibit elevated expression of systemic inflammatory genes and are hyperresponsive to lipopolysaccharide, suggesting that Stat3β functions predominantly as a suppressor of systemic inflammation. To test whether Stat3β deficiency would provoke pathologic effects associated with chronic inflammation, we asked whether selective removal of Stat3β would exacerbate the development of atherosclerosis in apolipoprotein E-deficient mice. In apoE−/−Stat3β−/− mice atherosclerotic plaque formation was significantly enhanced relative to apoE−/−Stat3β+/+ controls. The ability of Stat3β deficiency to promote atherosclerosis was more pronounced in female mice, but could be unmasked in males by feeding a high fat diet. Infiltrating macrophages were not increased in aortas of apoE−/−Stat3β−/− mice. In contrast, the proportion of pro-inflammatory TH17 cells was significantly elevated in aortic infiltrates from apoE−/−Stat3β−/− mice, relative to paired apoE−/−Stat3β+/+ littermates. These observations indicate that Stat3β can suppress pathologic sequelae associated with chronic inflammation. Our findings further suggest that in Stat3β-deficient mice the unopposed action of Stat3α may enhance atherogenesis in part by promoting differentiation of TH17 cells.
PMCID: PMC3739303  PMID: 23619910
Stat3; Atherosclerosis; Inflammation; Acute phase response
11.  Discovery of selective inhibitors of Glutaminase-2, which inhibit mTORC1, activate autophagy and inhibit proliferation in cancer cells 
Oncotarget  2014;5(15):6087-6101.
Glutaminase, which converts glutamine to glutamate, is involved in Warburg effect in cancer cells. Two human glutaminase genes have been identified, GLS (GLS1) and GLS2. Two alternative transcripts arise from each glutaminase gene: first, the kidney isoform (KGA) and glutaminase C (GAC) for GLS; and, second, the liver isoform (LGA) and glutaminase B (GAB) for GLS2. While GLS1 is considered as a cancer therapeutic target, the potential role of GLS2 in cancer remains unclear. Here, we discovered a series of alkyl benzoquinones that preferentially inhibit glutaminase B isoform (GAB, GLS2) rather than the kidney isoform of glutaminase (KGA, GLS1). We identified amino acid residues in an allosteric binding pocket responsible for the selectivity. Treatment with the alkyl benzoquinones decreased intracellular glutaminase activity and glutamate levels. GLS2 inhibition by either alkyl benzoquinones or GLS2 siRNA reduced carcinoma cell proliferation and anchorage-independent colony formation, and induced autophagy via AMPK mediated mTORC1 inhibition. Our findings demonstrate amino acid sequences for selective inhibition of glutaminase isozymes and validate GLS2 as a potential anti-cancer target.
PMCID: PMC4171615  PMID: 25026281
AMPK; Autophagy; Glutaminase; mTOR; Raptor; ULK1
12.  Transcriptional Repression of Mitochondrial Function in Aging: A Novel Role for the Silencing Mediator of Retinoid and Thyroid Hormone Receptors Co-Repressor 
Antioxidants & Redox Signaling  2013;19(3):299-309.
Significance: Mitochondrial function plays an important role in metabolic homeostasis and has been implicated in aging. Although there is still ongoing debate regarding whether mitochondrion-derived oxidative stress is causative to the aging process, interventions that increase oxidative metabolism and antioxidant pathways in animal models protect against age-related deterioration, such as metabolic diseases and neurodegenerative disorders. Recent Advances: One of the well-characterized transcriptional networks known to improve mitochondrial activity is mediated by transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), which is activated by AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), two of the major energy sensing molecules that are responsible for the longevity effect of caloric restriction in certain model systems. PGC-1α co-activates several nuclear receptors, notably members of the peroxisome proliferator-activated receptor (PPAR) family, which are key regulators of mitochondrial oxidative metabolism. Critical Issues: Although the AMPK/SIRT1-PGC-1α-PPAR axis plays a prominent role in activating mitochondrial functions, their activities are down-regulated in older animals, suggesting the involvement of dominant negative regulatory mechanisms in the process of aging. Future Directions: In this review, we will discuss the role of a transcriptional co-repressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), whose activity and expression are increased with age, as a negative regulator of mitochondrial function that promotes aging and age-related metabolic diseases. Antioxid. Redox Signal. 19, 299–309.
PMCID: PMC3691917  PMID: 22703297
13.  Going-to-Scale with the Early Risers Conduct Problems Prevention Program: Use of a Comprehensive Implementation Support (CIS) System to Optimize Fidelity, Participation and Child Outcomes 
The present study is a descriptive report of a comprehensive implementation support (CIS) service that was used to promote high levels of program fidelity in a going-to-scale intervention trial of the Early Risers conduct problems prevention program. The program was delivered across 27 geographically-dispersed, elementary school sites over a two-year period. In this study we examined the level of fidelity achieved by program implementers across intervention components, the rate of child and parent participation across intervention components, and proximal child outcomes targeted by the intervention across two years of programming. Results showed that over the two-year intervention period the program was implemented with high fidelity, participation rates were acceptable, and children made positive gains on target outcomes similar to those found in previous randomized controlled trials. The results suggest that implementation support services may be advantageous in the wide-scale implementation of prevention programs that aim to achieve high implementation fidelity.
PMCID: PMC3602328  PMID: 23266400
prevention; going-to-scale; implementation support; implementation fidelity
14.  Conditional Ablation of Neuroprogenitor Cells in Adult Mice Impedes Recovery of Poststroke Cognitive Function and Reduces Synaptic Connectivity in the Perforant Pathway 
The Journal of Neuroscience  2013;33(44):17314-17325.
The causal relationship between neurogenesis and the recovery of poststroke cognitive function has not been properly explored. The current study aimed to determine whether depleting neuroprogenitor cells (NPCs) affects poststroke functional outcome in nestin-δ-HSV-TK-EGFP transgenic mice, in which the expression of a truncated viral thymidine kinase gene and EGFP was restricted to nestin-expressing NPCs. Ganciclovir (GCV; 200 mg/kg/d) or saline was continuously administered via osmotic pumps in mice for 4 weeks before the induction of experimental stroke. Both baseline and stroke-induced type 1 and type 2 NPCs were conditionally ablated. GCV eliminated NPCs in a duration-dependent fashion, but it did not attenuate the genesis of astroglia or oligodendrocytes in the peri-infarct cortex, nor did it affect infarct size or cerebral blood reperfusion after stroke. Transgenic stroke mice given GCV displayed impaired spatial learning and memory in the Barnes maze test compared with saline control or wild-type stroke mice given GCV, suggesting a contributing role of stroke-induced neurogenesis in the recovery of cognitive function. However, there was no significant difference in poststroke motor function between transgenic mice treated with GCV and those treated with vehicle, despite a significant ablation of NPCs in the subventricular zone of the former. Furthermore, nestin-δ-HSV-TK-EGFP mice treated with GCV had fewer retrogradely labeled neurons in the entorhinal cortex (EC) when injected with the polysynaptic viral marker PRV614 in the dentate gyrus (DG), suggesting that there might be reduced synaptic connectivity between the DG and EC following ablation of NPCs, which may contribute to impaired poststroke memory function.
PMCID: PMC3812503  PMID: 24174664
15.  A Polymorphism of ORAI1 rs7135617, Is Associated with Susceptibility to Rheumatoid Arthritis 
Mediators of Inflammation  2014;2014:834831.
Rheumatoid arthritis (RA), a chronic inflammatory disease usually occurring in synovial tissues and joints, is highly associated with genetic and environmental factors. ORAI1, a gene related to cellular immune system, has been shown to be involved in the pathogenesis of chronic inflammatory diseases and immune diseases. To identify whether ORAI1 gene contributes to RA susceptibility, we enrolled 400 patients with RA and 621 healthy individuals for a case-control genetic association study. Five tagging single nucleotides polymorphisms (tSPNs) within ORAI1 gene were selected for genotyping. An SNP, rs7135617, showed a significant correlation with the risk of RA. Our results indicated that genetic polymorphism of ORAI1 gene is involved in the susceptibility of RA in a Taiwanese population.
PMCID: PMC3997980  PMID: 24808640
16.  Betel Chewing and Arecoline Affects Eotaxin-1, Asthma and Lung Function 
PLoS ONE  2014;9(3):e91889.
Betel nut is commonly used in many countries. Despite evidence suggesting an association with asthma, few studies have investigated the connection between betel nut use and asthma; thus, the underlying mechanism for the association with asthma is also unclear. The aim of this study was to investigate the association between betel chewing and asthma as well as the associations of plasma arecoline (a biomarker for exposure) and eotaxin-1 (a potential mediator) with asthma and lung function.
We recruited 600 hospital-based asthmatic patients and 1200 age- and gender-matched community controls in southern Taiwan. To clarify the mechanism of action for eotaxin-1 in the association between betel chewing and asthma, we also designed an in vitro experiment to study the functional associations between arecoline exposure and eotaxin-1 levels.
A significant association was found between asthma and current betel chewing (adjusted odds ratio 2.05, 95% CI = 1.12–3.76), which was independent of potential confounders but was attenuated following adjustment for eotaxin-1. Arecoline and eotaxin-1 levels were positively correlated (Spearman r = 0.303, p = 0.02), while arecoline and arecaidine were negatively correlated with lung function. Functionally, arecoline alone does not induce eotaxin-1 release in vitro from dermal and gingival fibroblasts. However, in the presence of IL-4 and TNF-alpha, arecoline at 100 μg/ml induced more eotaxin-1 release than arecoline at 0 μg/ml (2700±98 pg/ml vs 1850±142 pg/ml, p = 0.01 in dermal fibroblast cells, and 1489±78 pg/ml vs 1044±95 pg/ml, p = 0.03 in gingival fibroblast cells, respectively).
Betel chewing is associated with asthma in this population, with arecoline induction of eotaxin-1 supported as a plausible causal pathway.
PMCID: PMC3962362  PMID: 24658613
17.  Anti-Neuroinflammatory Effects of the Calcium Channel Blocker Nicardipine on Microglial Cells: Implications for Neuroprotection 
PLoS ONE  2014;9(3):e91167.
Nicardipine is a calcium channel blocker that has been widely used to control blood pressure in severe hypertension following events such as ischemic stroke, traumatic brain injury, and intracerebral hemorrhage. However, accumulating evidence suggests that inflammatory processes in the central nervous system that are mediated by microglial activation play important roles in neurodegeneration, and the effect of nicardipine on microglial activation remains unresolved.
Methodology/Principal Findings
In the present study, using murine BV-2 microglia, we demonstrated that nicardipine significantly inhibits microglia-related neuroinflammatory responses. Treatment with nicardipine inhibited microglial cell migration. Nicardipine also significantly inhibited LPS plus IFN-γ-induced release of nitric oxide (NO), and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, nicardipine also inhibited microglial activation by peptidoglycan, the major component of the Gram-positive bacterium cell wall. Notably, nicardipine also showed significant anti-neuroinflammatory effects on microglial activation in mice in vivo.
The present study is the first to report a novel inhibitory role of nicardipine on neuroinflammation and provides a new candidate agent for the development of therapies for inflammation-related neurodegenerative diseases.
PMCID: PMC3951295  PMID: 24621589
18.  Female Gender and Acne Disease Are Jointly and Independently Associated with the Risk of Major Depression and Suicide: A National Population-Based Study 
BioMed Research International  2014;2014:504279.
Acne is a common disease in adolescence with female preponderance. It could cause poor self-esteem and social phobia. Previous studies based on questionnaires from several thousands of adolescents showed that acne is associated with major depression and suicide. However, the gender- and age-specific risk of depression and suicide in patients with acne remain largely unknown. Using a database from the National Health Insurance, which included 98% of the population of Taiwan in 2006, we identified patients of acne, major depression, and suicide based on ICD-9-CM codes. Totally 47111 patients with acne were identified (16568 males and 30543 females) from 1 million subjects. The youths of 7–12 years had the highest prevalence of acne (14.39%). Major depression was more common in those with acne (0.77%) than controls (0.56% , P < 0.0001) regardless of gender. Multiple logistic regression showed an increased risk of major depression in women without acne (OR = 1.85, 95% CI 1.75–1.96). The risk is additive in women with acne (OR = 2.78, 95% CI 2.43–3.17). Similar additive risk of suicide was noticed in women with acne. In conclusion, acne and gender, independently and jointly, are associated with major depression and suicide. Special medical support should be warranted in females with acne for the risk of major depression and suicide.
PMCID: PMC3942337  PMID: 24678508
19.  Increased Tea Consumption Is Associated with Decreased Arterial Stiffness in a Chinese Population 
PLoS ONE  2014;9(1):e86022.
Tea has attracted considerable attention for its potential cardioprotective effects. The primary chemical components of tea are thought to have a beneficial effect by reducing arterial stiffness. The objective of this study was to assess the association between tea consumption and brachial–ankle pulse wave velocity (baPWV) in a relatively healthy Chinese population.
We enrolled 3,135 apparently healthy subjects from October 2006 to August 2009. Subjects taking medication for diabetes, hypertension, or hyperlipidemia, or with a history of cardiovascular disease, were excluded from the study. The subjects were categorized into three groups according to their tea-drinking habits: (1) none to low (n = 1615), defined as non-habitual tea drinkers, or drinking for <1 year, or drinking ≤150 mL per day for ≥1 year ; (2) moderate tea consumption, defined as drinking for ≥1 year and consumption between 151 and 450 mL per day; and (3) heavy tea consumption, defined as a drinking for ≥1 year and consumption >450 mL per day. Multiple logistic regression was used to determine whether different levels of consumption were independently associated with the highest quartile of baPWV values, defined as ≥1428.5 cm/s.
Of the 3,135 subjects, 48.5% had drunk >150 mL of tea per day for at least 1 year. In multivariate regression analysis with adjustment for co-variables, including, age, sex, current smoking, alcohol use, habitual exercise, total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratio >5, obesity, newly diagnosed hypertension and diabetes, subjects with high tea consumption had a decreased risk of highest quartile of baPWV by 22% (odds ratio = 0.78, 95% confidence interval = 0.62–0.98, p = 0.032), while subjects with moderate tea consumption did not (p = 0.742), as compared subjects with none to low tea consumption.
High, but not moderate, habitual tea consumption may decrease arterial stiffness.
PMCID: PMC3899106  PMID: 24465848
20.  Host metabolism regulates intracellular growth of Trypanosoma cruzi 
Cell host & microbe  2013;13(1):108-117.
Metabolic coupling of intracellular pathogens with host cells is essential for successful colonization of the host. Establishment of intracellular infection by the protozoan Trypanosoma cruzi leads to the development of human Chagas disease, yet the functional contributions of the host cell toward the infection process remain poorly characterized. Here, a genome-scale functional screen identified interconnected metabolic networks centered around host energy production, nucleotide metabolism, pteridine biosynthesis, and fatty acid oxidation as key processes that fuel intracellular T. cruzi growth. Additionally, the host kinase Akt, which plays essential roles in various cellular processes, was critical for parasite replication. Targeted perturbations in these host metabolic pathways or Akt-dependent signaling pathways modulated the parasite’s replicative capacity, highlighting the adaptability of this intracellular pathogen to changing conditions in the host. These findings identify key cellular process regulating intracellular T. cruzi growth and illuminate the potential to leverage host pathways to limit T. cruzi infection.
PMCID: PMC3560928  PMID: 23332160
21.  Acute kidney injury due to anti-tuberculosis drugs: a five-year experience in an aging population 
Patients on anti-tuberculosis treatment may develop acute kidney injury (AKI), but little is known about the renal outcome and prognostic factors, especially in an aging population. This study aimed to calculate the incidence of AKI due to anti-TB drugs and analyze the outcomes and predictors of renal recovery.
From 2006 to 2010, patients on anti-TB treatment were identified and their medical records reviewed. Acute kidney injury was defined according to the criteria established by the AKI Network, while renal recovery was defined as a return of serum creatinine to baseline. Predictors of renal recovery were identified by Cox regression analysis.
Ninety-nine out of 1394 (7.1%) patients on anti-TB treatment had AKI. Their median age was 68 years and there was male predominance. Sixty (61%) developed AKI within two months of anti-TB treatment, including 11 (11%) with a prior history of rifampin exposure. Thirty (30%) had co-morbid chronic kidney disease or end-stage renal disease. The median time of renal recovery was 39.6 days (range, 1–180 days). Factors predicting renal recovery were the presence of fever, rash, and gastro-intestinal disturbance at the onset of AKI. Sixty-two of the 71 (87%) patients who recovered from AKI had successful re-introduction or continuation of rifampin.
Renal function impairment is not a rare complication during anti-TB treatment in an elderly population. The presence of fever and rash may be associated with renal recovery. Rifampin can still be used in most patients who recover from AKI.
PMCID: PMC3898246  PMID: 24410958
Acute kidney injury; Anti-tuberculosis drug; Fever; Rash; Rifampin
22.  Meiotic Crossover Control by Concerted Action of Rad51-Dmc1 in Homolog Template Bias and Robust Homeostatic Regulation 
PLoS Genetics  2013;9(12):e1003978.
During meiosis, repair of programmed DNA double-strand breaks (DSBs) by recombination promotes pairing of homologous chromosomes and their connection by crossovers. Two DNA strand-exchange proteins, Rad51 and Dmc1, are required for meiotic recombination in many organisms. Studies in budding yeast imply that Rad51 acts to regulate Dmc1's strand exchange activity, while its own exchange activity is inhibited. However, in a dmc1 mutant, elimination of inhibitory factor, Hed1, activates Rad51's strand exchange activity and results in high levels of recombination without participation of Dmc1. Here we show that Rad51-mediated meiotic recombination is not subject to regulatory processes associated with high-fidelity chromosome segregation. These include homolog bias, a process that directs strand exchange between homologs rather than sister chromatids. Furthermore, activation of Rad51 does not effectively substitute for Dmc1's chromosome pairing activity, nor does it ensure formation of the obligate crossovers required for accurate homolog segregation. We further show that Dmc1's dominance in promoting strand exchange between homologs involves repression of Rad51's strand-exchange activity. This function of Dmc1 is independent of Hed1, but requires the meiotic kinase, Mek1. Hed1 makes a relatively minor contribution to homolog bias, but nonetheless this is important for normal morphogenesis of synaptonemal complexes and efficient crossing-over especially when DSB numbers are decreased. Super-resolution microscopy shows that Dmc1 also acts to organize discrete complexes of a Mek1 partner protein, Red1, into clusters along lateral elements of synaptonemal complexes; this activity may also contribute to homolog bias. Finally, we show that when interhomolog bias is defective, recombination is buffered by two feedback processes, one that increases the fraction of events that yields crossovers, and a second that we propose involves additional DSB formation in response to defective homolog interactions. Thus, robust crossover homeostasis is conferred by integrated regulation at initiation, strand-exchange and maturation steps of meiotic recombination.
Author Summary
Meiosis is the specialized cell division that produces gametes by precisely reducing the chromosome copy number from two to one. Accurate segregation of homologous chromosome pairs requires they be connected by crossing-over, the precise breakage and exchange of chromosome arms that is carried out by a process called recombination. Recombination is regulated so each pair of homologous chromosomes becomes connected by at least one crossover. We studied the roles of two recombination proteins, Rad51 and Dmc1, which can act directly to join homologous DNA molecules. Our evidence supports the idea that Dmc1 is the dominant joining activity, while Rad51 acts indirectly with other proteins to support and regulate Dmc1. Furthermore, Hed1, an inhibitor of Rad51's DNA joining activity, is also shown to enhance the efficiency of crossing-over. Cells in which Rad51 is activated to promote DNA joining in place of Dmc1 have unregulated and inefficient crossing-over that often leaves chromosome pairs without the requisite crossover. Despite these defects, most cells that use Rad51 in place of Dmc1 complete meiosis and produce high levels of crossovers. Our results indicate that compensatory processes ensure that meiotic cells accumulate high levels of crossover intermediates before progressing to the first round of chromosome segregation.
PMCID: PMC3868528  PMID: 24367271
23.  Phenotypes and Genotypes of Patients with Pantothenate Kinase-Associated Neurodegeneration in Asian and Caucasian Populations: 2 Cases and Literature Review 
The Scientific World Journal  2013;2013:860539.
Objectives. Pantothenate kinase-associated neurodegeneration (PKAN) is a rare disease caused by pantothenate kinase 2 (PANK2, OMIM 606157) mutations. This study is aimed to investigate clinical presentations, pathologies, and genetics in patients with PKAN. Methods. Two patients with PKAN were reported. We reviewed the literature to include additional 19 patients with PKAN in Eastern Asia. These patients were divided into classic and atypical groups by the age of onset. We compared the data on PKAN patients of Asian and Caucasian populations. Results. We found iron deposits in the globus pallidus in our Patient 1 and a heterozygous truncating mutation (c.1408insT) in Patient 2. Literature review shows that generalized dystonia and bulbar signs are more common in classic PKAN patients, whereas segmental dystonia and tremors are more specific to atypical ones. Asian patients have less complex presentations—lower prevalence of pyramidal signs, mental impairment, and parkinsonism—than Caucasians. D378G in exon 3 is the most frequent mutation (28%) in Asians. Conclusions. Our study demonstrates that the distribution of dystonia is the major distinction between subgroups of PKAN. Caucasian patients have more complex presentations than Asians. Exon 3 and 4 are hot spots for screening PANK2 mutations in Asian patients.
PMCID: PMC3854131  PMID: 24348190
24.  Effects of Combined Phase III and Phase II Cardiac Exercise Therapy for Middle-aged Male Patients with Acute Myocardial Infarction 
Journal of Physical Therapy Science  2013;25(11):1415-1420.
[Purpose] To investigate the effects of cardiac exercise therapy (CET) on exercise capacity and coronary risk factors (CRFs) of patients with acute myocardial infarction (AMI). [Methods] Patients who participated in an 8-week supervised, hospital-based phase II and 6-month home-based phase III CET with monthly telephone and/or home visits were defined as the exercise group (EG) (n=20), while those who did not receive phase II or phase III CET were defined as the no-exercise group (NEG) (n=10). CRFs were evaluated pre- and post-phase II and eight months after discharge. One and two-way repeated measures ANOVA were used to perform intra- and inter-group comparisons. [Results] Thirty men with AMI aged 49.3 ± 8.3 years were studied. EG increased their exercise capacity (METs) (6.8 ± 1.6 vs.10.0 ± 1.9) after phase II CET and was able to maintain it at 8-month follow-up. Both groups had significantly fewer persons who kept on smoking compared to the first examination. High density lipoprotein cholesterol (HDL-C) increased from 38.1 ± 11.0 to 43.7 ± 8.7 mg/dl at follow-up in EG while no significant difference was noted in NEG. [Conclusion] After phase III CET subjects had maintained the therapeutic effects of smoking cessation, and increasing exercise capacity obtained in phase II CET. HDL-C in EG continued to improve during phase III CET.
PMCID: PMC3881468  PMID: 24396201
Acute myocardial infarction; Cardiac exercise therapy; Coronary risk factors
25.  Analysis for Distinctive Activation Patterns of Pain and Itchy in the Human Brain Cortex Measured Using Near Infrared Spectroscopy (NIRS) 
PLoS ONE  2013;8(10):e75360.
Pain and itch are closely related sensations, yet qualitatively quite distinct. Despite recent advances in brain imaging techniques, identifying the differences between pain and itch signals in the brain cortex is difficult due to continuous temporal and spatial changes in the signals. The high spatial resolution of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) has substantially advanced research of pain and itch, but these are uncomfortable because of expensiveness, importability and the limited operation in the shielded room. Here, we used near infrared spectroscopy (NIRS), which has more conventional usability. NIRS can be used to visualize dynamic changes in oxygenated hemoglobin and deoxyhemoglobin concentrations in the capillary networks near activated neural circuits in real-time as well as fMRI. We observed distinct activation patterns in the frontal cortex for acute pain and histamine-induced itch. The prefrontal cortex exhibited a pain-related and itch-related activation pattern of blood flow in each subject. Although it looked as though that activation pattern for pain and itching was different in each subject, further cross correlation analysis of NIRS signals between each channels showed an overall agreement with regard to prefrontal area involvement. As a result, pain-related and itch-related blood flow responses (delayed responses in prefrontal area) were found to be clearly different between pain (τ = +18.7 sec) and itch (τ = +0.63 sec) stimulation. This is the first pilot study to demonstrate the temporal and spatial separation of a pain-induced blood flow and an itch-induced blood flow in human cortex during information processing.
PMCID: PMC3789686  PMID: 24098378

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