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1.  Meta-analysis of randomised controlled trials comparing unipolar with bipolar hemiarthroplasty for displaced femoral-neck fractures 
International Orthopaedics  2014;38(8):1691-1696.
Unipolar and bipolar hemiarthroplasty (HA) are used to treat displaced femoral-neck fractures. However, which type is best for treating displaced femoral-neck fractures in elderly patients remains a subject for debate. Our aim was to review randomised controlled trials to establish which type provides superior clinical outcome for this patient population.
We searched PubMed, Embase and Cochrane Register of Controlled Trials databases and Web of Science for randomised controlled trials (RCTs) comparing unipolar with bipolar HA to treat femoral-neck fracture in the elderly. Risk ratios (RRs) and mean differences (MDs) from each trial were pooled using random-effects or fixed-effects models depending on study heterogeneity. Analysis was performed using RevMan5.2 from the Cochrane Collaboration.
A total of 1,100 patients from nine studies were assessed in this meta-analysis. Results showed no significant differences in function score [MD = −0.14, 95% confidence interval (CI) −2.42–2.13], mortality (RR = 0.97, 95% CI 0.65–1.46), dislocation (RR = 1.33, 95 % CI 0.53–3.34), deep infection (RR = 0.79, 95 % CI 0.35–1.79), acetabular erosion (RR = 1.99, 95 % CI 0.61–6.52), operating time (MD = 2.14, 95 % CI −9.85 to14.14), blood loss (MD = 13.40, 95 % CI −49.60 to 76.39) and length of hospital stay (MD = 0.12, 95 % CI −0.49to0.73) between unipolar and bipolar HA.
Unipolar and bipolar HA achieved similar clinical outcomes in patients with displaced femoral-neck fractures.
PMCID: PMC4115101  PMID: 24817022
Unipolar; Bipolar; Hemiarthroplasty; Displaced femoral-neck fractures
2.  Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study 
Nature Communications  2015;6:7633.
Graves' disease is the leading cause of hyperthyroidism affecting 1.0–1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B*38:02 (Armitage trend Pcombined=6.75 × 10−32) and HLA-DRB1*08:03 (Pcombined=1.83 × 10−9) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13–41.48) and 6.13 (95% confidence interval=3.28–11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined=3.32 × 10−21, 95% confidence interval=21.66–108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.
Graves' disease is the leading cause of hyperthyroidism but treatment options can cause life-threatening complications. Chen et al. conduct two-stage direct HLA genotyping and genome-wide association studies to identify HLA-B*38:02 and HLA-DRB1*08:03 as major pharmacogenetic determinants.
PMCID: PMC4506516  PMID: 26151496
3.  PPL2ab neurons restore sexual responses in aged Drosophila males through dopamine 
Nature Communications  2015;6:7490.
Male sexual desire typically declines with ageing. However, our understanding of the neurobiological basis for this phenomenon is limited by our knowledge of the brain circuitry and neuronal pathways controlling male sexual desire. A number of studies across species suggest that dopamine (DA) affects sexual desire. Here we use genetic tools and behavioural assays to identify a novel subset of DA neurons that regulate age-associated male courtship activity in Drosophila. We find that increasing DA levels in a subset of cells in the PPL2ab neuronal cluster is necessary and sufficient for increased sustained courtship in both young and aged male flies. Our results indicate that preventing the age-related decline in DA levels in PPL2ab neurons alleviates diminished courtship behaviours in male Drosophila. These results may provide the foundation for deciphering the circuitry involved in sexual motivation in the male Drosophila brain.
We currently lack a detailed understanding of the neurobiological basis for the decline of male sexual desire with age. Here the authors demonstrate that restoring impaired dopaminergic signalling in a specific cluster of neurons in the Drosophila brain increases sexual behaviour in ageing male flies.
PMCID: PMC4491191  PMID: 26123524
4.  Herbal formula, Scutellariae radix and Rhei rhizoma attenuate dimethylnitrosamine-induced liver fibrosis in a rat model 
Scientific Reports  2015;5:11734.
The bioactive components extracted from Scutellariae radix and Rhei rhizoma (SR) have been commonly used to treat liver diseases. The aim of this study was to verify the underlying mechanisms and antifibrotic effects of ethanol extract from the herbal combinatorial formula (SRE) in a dimethylnitrosamine (DMN)-administered rat model, with functional proteome tools. Our results indicated that the hepatic collagen content and alpha-smooth muscle actin expression were obviously alleviated by treatment with SRE. Comprehensive proteomics revealed global protein changes, and the network analysis implied that SRE application would attenuate oxidative stress and cytoskeleton dysregulation caused by DMN exposure. Next, marked downregulation of antioxidant enzymes mediated by DMN treatment was restored in the presence of SRE, while SRE treatment contributed to decreased MDA content. Moreover, protein carbonylation and DNA adduction induced by oxidative stress finally leading to liver injury were also reduced under SRE administration. These findings demonstrate that SRE could effectively prevent hepatic fibrosis mainly through regulating the redox status, and subsequently modulating the modification of intracellular molecules. Our experiments might help in developing novel therapeutic strategies against oxidation-caused liver diseases.
PMCID: PMC4488958  PMID: 26133262
5.  2-Deoxy-d-Glucose Can Complement Doxorubicin and Sorafenib to Suppress the Growth of Papillary Thyroid Carcinoma Cells 
PLoS ONE  2015;10(7):e0130959.
Tumor cells display a shift in energy metabolism from oxidative phosphorylation to aerobic glycolysis. A subset of papillary thyroid carcinoma (PTC) is refractory to surgery and radioactive iodine ablation. Doxorubicin and sorafenib are the drugs of choice for treating advanced thyroid cancer but both induce adverse effects. In this study, we assessed the anti-cancer activity of 2-deoxy-d-glucose (2-DG) alone and in combination with doxorubicin or sorafenib in PTC cell lines with (BCPAP) and without (CG3) the BRAFV600E mutation. BCPAP cells were more glycolytic than CG3 cells, as evidenced by their higher extracellular l-lactate production, lower intracellular ATP level, lower oxygen consumption rate (OCR), and lower ratio of OCR/extracellular acidification rate. However, dose-dependent reduction in cell viability, intracellular ATP depletion, and extracellular l-lactate production were observed after 2-DG treatment. Regression analysis showed that cell growth in both cell lines was dependent on ATP generation. 2-DG increased the chemosensitivity of BCPAP and CG3 cell lines to doxorubicin and sorafenib. These results demonstrate that the therapeutic effects of low combined doses of 2-DG and doxorubicin or sorafenib are similar to those of high doses of doxorubicin or sorafenib alone in PTC cell lines regardless of the BRAFV600E mutation.
PMCID: PMC4489888  PMID: 26134286
6.  Testing Gene-Gene Interactions in Genome Wide Association Studies 
Genetic epidemiology  2014;38(2):123-134.
Detection of gene-gene interaction has become increasingly popular over the past decade in genome wide association studies (GWAS). Besides traditional logistic regression analysis for detecting interactions between two markers, new methods have been developed in recent years such as comparing linkage disequilibrium (LD) in case and control groups. All these methods form the building blocks of most screening strategies for disease susceptibility loci in GWAS. In this paper, we are interested in comparing the competing methods and providing practical guidelines for selecting appropriate testing methods for interaction in GWAS. We first review a series of existing statistical methods to detect interactions, and then examine different definitions of interactions to gain insight into the theoretical relationship between the existing testing methods. Lastly, we perform extensive simulations to compare powers of various methods to detect either interaction between two markers at two unlinked loci or the overall association allowing for both interaction and main effects. This investigation reveals informative characteristics of various methods that are helpful to GWAS investigators.
PMCID: PMC4487553  PMID: 24431225
gene-gene interaction; GWAS; linkage disequilibrium; penetrance; logistic regression
7.  Archaeal Elp3 catalyzes tRNA wobble uridine modification at C5 via a radical mechanism 
Nature chemical biology  2014;10(10):810-812.
Approximately 25% of cytoplasmic tRNAs in eukaryotic organisms have the wobble uridine (U34) modified at C5 through a process that, according to genetic studies, is carried out by the eukaryotic Elongator complex. Here we show that a single archaeal protein, the homolog of the third subunit of the eukaryotic Elongator complex (Elp3), is able to catalyze the same reaction. The mechanism of action by Elp3 described here represents unprecedented chemistry performed on acetyl-CoA.
PMCID: PMC4479141  PMID: 25151136
8.  The Effects of Anti-Dementia and Nootropic Treatments on the Mortality of Patients with Dementia: A Population-Based Cohort Study in Taiwan 
PLoS ONE  2015;10(6):e0130993.
Few studies have examined the contribution of treatment on the mortality of dementia based on a population-based study.
To investigate the effects of anti-dementia and nootropic treatments on the mortality of dementia using a population-based cohort study.
12,193 incident dementia patients were found from 2000 to 2010. Their data were compared with 12,193 age- and sex-matched non-dementia controls that were randomly selected from the same database. Dementia was classified into vascular (VaD) and degenerative dementia. Mortality incidence and hazard ratios (HRs) were calculated.
The median survival time was 3.39 years (95% confidence interval [CI]: 2.88–3.79) for VaD without medication, 6.62 years (95% CI: 6.24–7.21) for VaD with nootropics, 3.01 years (95% CI: 2.85–3.21) for degenerative dementia without medication, 8.11 years (95% CI: 6.30–8.55) for degenerative dementia with anti-dementia medication, 6.00 years (95% CI: 5.73–6.17) for degenerative dementia with nootropics, and 9.03 years (95% CI: 8.02–9.87) for degenerative dementia with both anti-dementia and nootropic medications. Compared to the non-dementia group, the HRs among individuals with degenerative dementia were 2.69 (95% CI: 2.55–2.83) without medication, 1.46 (95% CI: 1.39–1.54) with nootropics, 1.05 (95% CI: 0.82–1.34) with anti-dementia medication, and 0.92 (95% CI: 0.80–1.05) with both nootropic and anti-dementia medications. VaD with nootropics had a lower mortality (HR: 1.25, 95% CI: 1.15–1.37) than VaD without medication (HR: 2.46, 95% CI: 2.22–2.72).
Pharmacological treatments have beneficial effects for patients with dementia in prolonging their survival.
PMCID: PMC4476616  PMID: 26098910
9.  Prevalence and risk factors of posttraumatic stress disorder among survivors five years after the “Wenchuan” earthquake in China 
The aim of this study was to investigate the prevalence of posttraumatic stress disorder (PTSD) and its risk factors among survivors in a heavily-hit area five years after the Wenchuan earthquake in 2008, China.
684 survivors from Beichuan county, the center of the Wenchuan Earthquake in 2008, were evaluated using the PTSD Checklist-Civilian Version (PCL-C) questionnaire in 2013.
The prevalence of PTSD among survivors was 9.2% in 2013. Significant risk factors of PTSD included gender (females 12.1%, males 5.2%), age (18–35 y 0.8%, 36–59 y 9.7%, ≥60 y 12.9%), occupation (farmers 12.2%, non-farmers 1.6%), education (less than high school 11.0%; > = high school 0.8%) and family member loss (yes: 12.4%, no: 7.3%). Multivariate logistic regression showed that females, older people, farmers and those with family member loss were significantly more likely to develop PTSD.
Posttraumatic stress symptoms remained relatively common among survivors five years after the “5.12” Earthquake in Beichuan county, China. It is important to provide psychological aid and social support for survivors to decease health burden from PTSD, especially for females, farmers, old age survivors and those with family member loss.
PMCID: PMC4456058  PMID: 26040516
Posttraumatic stress disorder; Survivors; Risk factors; Wenchuan earthquake
10.  Association of Adiponectin Gene Polymorphism with Nonalcoholic Fatty Liver Disease in Taiwanese Patients with Type 2 Diabetes 
PLoS ONE  2015;10(6):e0127521.
Patients with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) have a higher prevalence of cardiovascular diseases. In this study we investigated the frequency of single nucleotide polymorphisms (SNPs) of several candidate genes associated with NAFLD in Taiwanese patients with type 2 diabetes mellitus (DM) and NAFLD and in those with DM but without fatty liver disease.
We enrolled 350 patients with type 2 DM and NAFLD and 209 patients with DM but without NAFLD. Body mass index (BMI), % body fat (% BF), glycated hemoglobin (HbA1c), high molecular weight (HMW) isoform of adiponectin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels were measured. Thirteen SNPs in 5 genes (adiponectin, leptin, peroxisome proliferator-activated receptor alpha, adiponutrin/patatin-like phospholipase domain-containing protein 3 and peroxisome proliferator-activated receptor γ co-activator 1α ) were measured.
Only adiponectin rs266729 polymorphism was associated with susceptibility to NAFLD (p = 0.001). Subgroup analysis revealed that the proportion of subjects with homozygous genotype GG was higher in patients with NAFLD (31%) than in controls (11%) and that the proportions of heterozygous CG and homozygous CC were higher in controls (37% and 52%, respectively) than in patients with NAFLD (33% and 36%, respectively). Patients with NAFLD carrying the GG genotype of rs266729 showed significantly lower serum HMW adiponectin levels than patients carrying the GC or CC genotype (3.75±0.37 vs. 3.99±0.66 vs. 4.79±0.58 μg/ml, p< 0.001). Body fat and serum HMW adiponectin levels were the strongest predictors of developing NAFLD (p < 0.001 and 0.004, respectively).
In patients with type 2 diabetes gene polymorphism of adiponectin rs266729 is associated with risk of NAFLD. G allele of rs266729 is associated with hypoadiponectinemia. Low serum adiponectin level may precipitate liver steatosis in patients with type 2 diabetes.
PMCID: PMC4456357  PMID: 26042596
11.  Biphasic Response of Mitochondrial Biogenesis to Oxidative Stress in Visceral Fat of Diet-Induced Obesity Mice 
Antioxidants & Redox Signaling  2014;20(16):2572-2588.
Aims: Studies in skeletal muscle demonstrate a strong association of mitochondrial dysfunction with insulin resistance (IR). However, there is still a paucity of knowledge regarding the alteration of mitochondria in adipose tissue (AT) in the pathogenesis of IR in obesity. We investigated the mitochondrial biogenesis in visceral fat (VF) and subcutaneous fat (SF) in C57BL/6J mice fed a high-fat high-sucrose diet for 12 months. Results: Impairment of glucose tolerance and insulin sensitivity developed after 1 month of the diet and was associated with a prompt increase of VF. The VF adipocytes were larger than those in the SF and had increased expressions of HIF-1α and p-NFκB p65. However, the alteration of mitochondrial biogenesis did not occur in the early stage when increased intracellular reactive oxygen species (ROS), mitochondrial oxygen consumption rate, and mitochondrial ROS emerged at the 1st, 2nd and 2nd month, respectively. Until the 6th month, the VF had markedly increased mitochondrial DNA content and expression of PGC-1α, Tfam, ATP5A, and MnSOD. This increase of mitochondrial biogenesis was followed by a generalized decrease at the 12th month and the mitochondrial morphology altered markedly. In the late stage, although mitochondrial ROS decreased, the increased expression of 8-OHdG in VF continued. Innovation and Conclusion: These data suggest that IR and ROS production occur before the biphasic changes of mitochondrial biogenesis in AT, and the VF plays a more crucial role. Antioxid. Redox Signal. 20, 2572–2588.
PMCID: PMC4025601  PMID: 24111683
12.  Fitz-Hugh-Curtis syndrome: clinical diagnostic value of dynamic enhanced MSCT 
Journal of Physical Therapy Science  2015;27(6):1641-1644.
[Purpose] This study aimed to investigate the clinical diagnostic value of dynamic enhanced multislice computed tomography (MSCT) for Fitz-Hugh-Curtis syndrome (FHCS). [Subjects and Methods] This study retrospectively analyzed the clinical features and manifestations of scanning and dynamic enhanced MSCT in 19 patients with FHCS. [Results] MSCT scans showed different degrees of liver capsule thickness in the lesion area: seven cases of sub-capsular effusion and three cases with a small amount of pleural effusion; thickness of the liver capsular arterial phase showing significant enhancement in 17 cases, and slight enhancement in two; portal venous and delayed phase enhancement decreased with no clear boundary of the liver parenchyma; and adjacent hepatic parenchymal involvement in five cases, in which the arterial phase appeared to have patchy or triangular enhancement, and unclear portal vein and delayed phase imaging findings. MSCT revealed pelvic inflammatory disease in 14 cases, peritonitis in two, endometritis combined with bilateral ovarian abscesses in two, and a tube-ovarian abscess in one. [Conclusion] Dynamic enhanced MSCT can accurately display liver capsule lesions and possible pelvic inflammatory diseases related to FHCS, suggest the infection source, and have high application value for making early, accurate diagnoses and improved prognosis.
PMCID: PMC4499951  PMID: 26180288
Tomography; X-ray compute; Perihepatitis
13.  Quantitative trait locus mapping of deep rooting by linkage and association analysis in rice 
Journal of Experimental Botany  2015;66(15):4749-4757.
Major quantitative trait loci (QTLs) of rice deep rooting were identified by combined linkage-based and linage disequilibrium-based QTL mapping in this study.
Deep rooting is a very important trait for plants’ drought avoidance, and it is usually represented by the ratio of deep rooting (RDR). Three sets of rice populations were used to determine the genetic base for RDR. A linkage mapping population with 180 recombinant inbred lines and an association mapping population containing 237 rice varieties were used to identify genes linked to RDR. Six quantitative trait loci (QTLs) of RDR were identified as being located on chromosomes 1, 2, 4, 7, and 10. Using 1 019 883 single-nucleotide polymorphisms (SNPs), a genome-wide association study of the RDR was performed. Forty-eight significant SNPs of the RDR were identified and formed a clear peak on the short arm of chromosome 1 in a Manhattan plot. Compared with the shallow-rooting group and the whole collection, the deep-rooting group had selective sweep regions on chromosomes 1 and 2, especially in the major QTL region on chromosome 2. Seven of the nine candidate SNPs identified by association mapping were verified in two RDR extreme groups. The findings from this study will be beneficial to rice drought-resistance research and breeding.
PMCID: PMC4507776  PMID: 26022253
Drought avoidance; genome-wide association study (GWAS); quantitative trait locus (QTL); ratio of deep rooting (RDR); rice; root architecture; selective sweep.
14.  Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa 
Science translational medicine  2014;6(264):264ra163.
Patients with recessive dystrophic epidermolysis bullosa (RDEB) lack functional type VII collagen owing to mutations in the gene COL7A1 and suffer severe blistering and chronic wounds that ultimately lead to infection and development of lethal squamous cell carcinoma. The discovery of induced pluripotent stem cells (iPSCs) and the ability to edit the genome bring the possibility to provide definitive genetic therapy through corrected autologous tissues. We generated patient-derived COL7A1-corrected epithelial keratinocyte sheets for autologous grafting. We demonstrate the utility of sequential reprogramming and adenovirus-associated viral genome editing to generate corrected iPSC banks. iPSC-derived keratinocytes were produced with minimal heterogeneity, and these cells secreted wild-type type VII collagen, resulting in stratified epidermis in vitro in organotypic cultures and in vivo in mice. Sequencing of corrected cell lines before tissue formation revealed heterogeneity of cancer-predisposing mutations, allowing us to select COL7A1-corrected banks with minimal mutational burden for downstream epidermis production. Our results provide a clinical platform to use iPSCs in the treatment of debilitating genodermatoses, such as RDEB.
PMCID: PMC4428910  PMID: 25429056
15.  A Sparse Ising Model with Covariates 
Biometrics  2014;70(4):943-953.
There has been a lot of work fitting Ising models to multivariate binary data in order to understand the conditional dependency relationships between the variables. However, additional covariates are frequently recorded together with the binary data, and may influence the dependence relationships. Motivated by such a dataset on genomic instability collected from tumor samples of several types, we propose a sparse covariate dependent Ising model to study both the conditional dependency within the binary data and its relationship with the additional covariates. This results in subject-specific Ising models, where the subject’s covariates influence the strength of association between the genes. As in all exploratory data analysis, interpretability of results is important, and we use ℓ1 penalties to induce sparsity in the fitted graphs and in the number of selected covariates. Two algorithms to fit the model are proposed and compared on a set of simulated data, and asymptotic results are established. The results on the tumor dataset and their biological significance are discussed in detail.
PMCID: PMC4425428  PMID: 25099186
Binary Markov network; Graphical model; Lasso; Ising model; Pseudo-likelihood; Tumor suppressor genes
16.  Care Needs and Clinical Outcomes of Older People with Dementia: A Population-Based Propensity Score-Matched Cohort Study 
PLoS ONE  2015;10(5):e0124973.
To explore the healthcare resource utilization, psychotropic drug use and mortality of older people with dementia.
A nationwide propensity score-matched cohort study.
National Health Insurance Research database.
A total of 32,649 elderly people with dementia and their propensity-score matched controls (n=32,649).
Outpatient visits, inpatient care, psychotropic drug use, in-hospital mortality and all-cause mortality at 90 and 365 days.
Compared to the non-dementia group, a higher proportion of patients with dementia used inpatient services (1 year after index date: 20.91% vs. 9.55%), and the dementia group had more outpatient visits (median [standard deviation]: 7.00 [8.87] vs. 3.00 [8.30]). Furthermore, dementia cases with acute admission had the highest psychotropic drug utilization both at baseline and at the post-index dates (difference-in-differences: all <0.001). Dementia was associated with an increased risk of all-cause mortality (90 days, Odds ratio (OR)=1.85 [95%CI 1.67-2.05], p<0.001; 365 days, OR=1.59 [1.50-1.69], p<0.001) and in-hospital mortality (90 days, OR=1.97 [1.71-2.27], p<0.001; 365 days, OR=1.82 [1.61-2.05], p<0.001) compared to matched controls.
When older people with dementia are admitted for acute illnesses, they may increase their use of psychotropic agents and their risk of death, particularly in-hospital mortality.
PMCID: PMC4425532  PMID: 25955163
17.  Macro- and microscale variables regulate stent haemodynamics, fibrin deposition and thrombomodulin expression 
Drug eluting stents are associated with late stent thrombosis (LST), delayed healing and prolonged exposure of stent struts to blood flow. Using macroscale disturbed and undisturbed fluid flow waveforms, we numerically and experimentally determined the effects of microscale model strut geometries upon the generation of prothrombotic conditions that are mediated by flow perturbations. Rectangular cross-sectional stent strut geometries of varying heights and corresponding streamlined versions were studied in the presence of disturbed and undisturbed bulk fluid flow. Numerical simulations and particle flow visualization experiments demonstrated that the interaction of bulk fluid flow and stent struts regulated the generation, size and dynamics of the peristrut flow recirculation zones. In the absence of endothelial cells, deposition of thrombin-generated fibrin occurred primarily in the recirculation zones. When endothelium was present, peristrut expression of anticoagulant thrombomodulin (TM) was dependent on strut height and geometry. Thinner and streamlined strut geometries reduced peristrut flow recirculation zones decreasing prothrombotic fibrin deposition and increasing endothelial anticoagulant TM expression. The studies define physical and functional consequences of macro- and microscale variables that relate to thrombogenicity associated with the most current stent designs, and particularly to LST.
PMCID: PMC3973357  PMID: 24554575
coronary stent thrombosis; haemodynamics; stent geometry; thrombomodulin; fibrin; stent streamlining
18.  Antimicrobial Resistance in Salmonella enterica Serovar Typhi Isolates from Bangladesh, Indonesia, Taiwan, and Vietnam 
Antimicrobial Agents and Chemotherapy  2014;58(11):6501-6507.
We characterized Salmonella enterica serovar Typhi isolates from Bangladesh, Indonesia, Taiwan, and Vietnam to investigate their genetic relatedness and antimicrobial resistance. The isolates from Bangladesh and Vietnam were genetically closely related but were distant from those from Indonesia and Taiwan. All but a few isolates from Indonesia and Taiwan were susceptible to all antimicrobials tested. The majority of isolates from Bangladesh and Vietnam were multidrug resistant (MDR) and belonged to the widespread haplotype H58 clone. IncHI1 plasmids were detected in all MDR S. Typhi isolates from Vietnam but in only 15% of MDR isolates from Bangladesh. Resistance genes in the majority of MDR S. Typhi isolates from Bangladesh should reside in the chromosome. Among the isolates from Bangladesh, 82% and 40% were resistant to various concentrations of nalidixic acid and ciprofloxacin, respectively. Several resistance mechanisms, including alterations in gyrase A, the presence of QnrS, and enhanced efflux pumps, were involved in the reduced susceptibility and resistance to fluoroquinolones. Intensive surveillance is necessary to monitor the spread of chromosome-mediated MDR and fluoroquinolone-resistant S. Typhi emerging in Bangladesh.
PMCID: PMC4249406  PMID: 25136011
19.  Beneficial Effect of Higher Dietary Fiber Intake on Plasma HDL-C and TC/HDL-C Ratio among Chinese Rural-to-Urban Migrant Workers 
Research has shown that high-dose supplemental dietary fiber intake has beneficial effects on cardiovascular risk factors. To clarify such a relationship, we examined the association between daily dietary fiber intake and plasma lipids using a cross-sectional design including 1034 (M 502, F 532) rural-to-urban workers in China. We found a dose-response relationship between increased dietary fiber intakes and increase of HDL cholesterol in male workers. There was also a dose-response relationship between increased dietary fiber intake and decreased total cholesterol to HDL cholesterol (TC/HDL-C) ratio in both male and female workers, after adjusting for potential confounders (p for trend, all p < 0.05). When the average dietary fiber intake increased from less than 18 g/day to over 30 g/day, the average HDL cholesterol level increased by 10.1%, and the TC/HDL-C ratio decreased by 14.4% for males (p = 0.020) and by 11.1% for females (p = 0.048). In conclusion, higher daily dietary fiber consumption is associated with beneficial effect on cholesterol for rural-to-urban workers in China, suggesting its potential beneficial effect on decreasing the risk of cardiovascular diseases.
PMCID: PMC4454936  PMID: 25938914
dietary fiber; high-density lipoprotein cholesterol; total cholesterol to high-density lipoprotein cholesterol ratio
20.  Reconstitution and structure of a bacterial Pnkp1–Rnl–Hen1 RNA repair complex 
Nature Communications  2015;6:6876.
Ribotoxins cleave essential RNAs for cell killing, and RNA repair neutralizes the damage inflicted by ribotoxins for cell survival. Here we report a new bacterial RNA repair complex that performs RNA repair linked to immunity. This new RNA repair complex is a 270-kDa heterohexamer composed of three proteins—Pnkp1, Rnl and Hen1—that are required to repair ribotoxin-cleaved RNA in vitro. The crystal structure of the complex reveals the molecular architecture of the heterohexamer as two rhomboid-shaped ring structures of Pnkp1–Rnl–Hen1 heterotrimer fused at the Pnkp1 dimer interface. The four active sites required for RNA repair are located on the inner rim of each ring. The architecture and the locations of the active sites of the Pnkp1–Rnl–Hen1 heterohexamer suggest an ordered series of repair reactions at the broken RNA ends that confer immunity to recurrent damage.
Bacterial ribotoxins target and cleave RNAs involved in translation, with target organism resistance being mediated by RNA repair systems. Here, Wang et al. identify, report the crystal structure, and characterize the activity of Pnkp1–Rnl–Hen1, a novel RNA repair complex from Capnocytophaga gingivalis.
PMCID: PMC4411300  PMID: 25882814
21.  Back focal plane imaging of Tamm plasmons and their coupled emission 
Laser & photonics reviews  2014;8(6):933-940.
The unique optical properties of TPs – such as flexible wavevector matching conditions including in-plane wavevector within the light line, existing both S- and P-polarized TPs and ability of populating with KR and RK illuminations – facilitate them for direct optical excitation. The Tamm plasmon Coupled emission (TPCE) from a combined photonic-plasmonic structure sustaining both surface plasmons (SPs) and Tamm plasmons (TPs) is described. The sensitivity of TPCE to the emission wavelength and polarization is examined with back focal plane imaging and verified with the numerical calculations. The results reveal that the excited probe can couple with both TPs and SPs, resulting in SPCE and TPCE, respectively. The TPCE angle is strongly dependent on the wavelength allowing for spectral resolution using different observation angles. These Tamm structures provide a new tool to control the optical emission from dye molecules and have many potential applications in fluorescence based-sensing and imaging.
PMCID: PMC4397660  PMID: 25893010
Tamm Plasmons; Surface Plasmons; Tamm Plasmon-Coupled Emission Fluorescence; Back Focal Plane Imaging
22.  Back focal plane imaging of directional emission from dye molecules coupled to one-dimensional photonic crystals 
Nanotechnology  2014;25(14):145202.
Bloch surface waves (BSWs) on one-dimensional photonic crystals (1DPC) have been used to beam the fluorescence emission from the dye molecules. All dielectric 1DPC displays its low propagating loss, narrow resonance and the absence of absorption or quenching. In this letter, back focal plane imaging reveals that in addition to the BSW mode, a guided mode and cavity mode also exist in the 1DPC which all couple with the excited dye molecules. The appearance of these modes is sensitive to the wavelength of the fluorescence and alters the beaming effect by the 1DPC. Numerical simulations verify the existence of these modes which are consistent with the experimental results. Comparisons between the Bloch surface wave-coupled emission (BWCE) and surface plasmon-coupled emission (SPCE) are also presented for a more clear understanding of the multilayered film-enabled directional emission.
PMCID: PMC4015633  PMID: 24621990
Bloch Surface waves; One-dimensional photonic crystals; Dye molecules; Fluorescence; Back focal plane imaging
23.  The anti-aging effects of Ludwigia octovalvis on Drosophila melanogaster and SAMP8 mice 
Age  2013;36(2):689-703.
We investigated the anti-aging effects of Ludwigia octovalvis (Jacq.) P. H. Raven (Onagraceae), an extract of which is widely consumed as a healthful drink in a number of countries. Using the fruit fly, Drosophila melanogaster, as a model organism, we demonstrated that L. octovalvis extract (LOE) significantly extended fly lifespan on a high, but not a low, calorie diet, indicating that LOE may regulate lifespan through a dietary restriction (DR)-related pathway. LOE also attenuated age-related cognitive decline in both flies and in the senescence-accelerated-prone 8 (SAMP8) mouse, without causing any discernable negative trade-offs, including water intake, food intake, fecundity, or spontaneous motor activity. LOE contained high levels of polyphenols and flavonoids, which possess strong DPPH radical scavenging activity, and was shown to attenuate paraquat-induced oxidative damage and lethality in flies. Gas chromatography–mass spectrometry (GC-MS) analyses identified 17 known molecules, of which β-sitosterol and squalene were the two most abundant. We further demonstrated that β-sitosterol was capable of extending lifespan, likely through activating AMP-activated protein kinase (AMPK) in the fat body of adult flies. Taken together, our data suggest that LOE is a potent anti-aging intervention with potential for treating age-related disorders.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-013-9606-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4039272  PMID: 24338263
Ludwigia octovalvis; Dietary restriction; Lifespan; AMPK
24.  Comparison of the efficacy of aroma-acupressure and aromatherapy for the treatment of dementia-associated agitation 
One of the most common symptoms observed in patients with dementia is agitation, and several non-pharmacological treatments have been used to control this symptom. However, because of limitations in research design, the benefit of non-pharmacological treatments has only been demonstrated in certain cases. The purpose of this study was to compare aroma-acupressure and aromatherapy with respect to their effects on agitation in patients with dementia.
In this experimental study, the participants were randomly assigned to three groups: 56 patients were included in the aroma-acupressure group, 73 patients in the aromatherapy group, and 57 patients in the control group who received daily routine as usual without intervention. The Cohen-Mansfield Agitation Inventory (CMAI) scale and the heart rate variability (HRV) index were used to assess differences in agitation. The CMAI was used in the pre-test, post-test and post-three-week test, and the HRV was used in the pre-test, the post-test and the post-three-week test as well as every week during the four-week interventions.
The CMAI scores were significantly lower in the aroma-acupressure and aromatherapy groups compared with the control group in the post-test and post-three-week assessments. Sympathetic nervous activity was significantly lower in the fourth week in the aroma-acupressure group and in the second week in the aromatherapy group, whereas parasympathetic nervous activity increased from the second week to the fourth week in the aroma-acupressure group and in the fourth week in the aromatherapy group.
Aroma-acupressure had a greater effect than aromatherapy on agitation in patients with dementia. However, agitation was improved in both of the groups, which allowed the patients with dementia to become more relaxed. Future studies should continue to assess the benefits of aroma-acupressure and aromatherapy for the treatment of agitation in dementia patients.
Trial registration
ChiCTR-TRC-14004810; Date of registration: 2014/6/12
PMCID: PMC4381454  PMID: 25880034
Dementia; Agitation; Aroma-acupressure; Aromatherapy
25.  ARP2/3 complex is required for directional migration of neural stem cell-derived oligodendrocyte precursors in electric fields 
The loss of oligodendrocytes in a lesion of the central nervous system causes demyelination and therefore impairs axon function and survival. Transplantation of neural stem cell-derived oligodendrocyte precursor cells (NSC-OPCs) results in increased oligodendrocyte formation and enhanced remyelination. The directional migration of grafted cells to the target can promote the establishment of functional reconnection and myelination in the process of neural regeneration. Endogenous electric fields (EFs) that were detected in the development of the central nervous system can regulate cell migration.
NSCs were isolated from the brains of ARPC2+/+ and ARPC2−/− mouse embryo and differentiated into OPCs. After differentiation, the cultured oligospheres were stimulated with EFs (50, 100, or 200 mV/mm). The migration of OPCs from oligospheres was recorded using time-lapse microscopy. The cell migration directedness and speed were analyzed and quantified.
In this study, we found that NSC-OPCs migrated toward the cathode pole in EFs. The directedness and displacement of cathodal migration increased significantly when the EF strength increased from 50 to 200 mV/mm. However, the EF did not significantly change the cell migration speed. We also showed that the migration speed of ARPC2−/− OPCs, deficient in the actin-related proteins 2 and 3 (ARP2/3) complex, was significantly lower than that of wild type of OPCs. ARPC2−/− OPCs migrated randomly in EFs.
The migration direction of NSC-OPCs can be controlled by EFs. The function of the ARP complex is required for the cathodal migration of NSC-OPCs in EFs. EF-guided cell migration is an effective model to understanding the intracellular signaling pathway in the regulation of cell migration directness and motility.
Electronic supplementary material
The online version of this article (doi:10.1186/s13287-015-0042-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4404621  PMID: 25890209

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