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1.  The Compliance of Doctors with Viral Hepatitis B Screening and Antiviral Prophylaxis in Cancer Patients Receiving Cytotoxic Chemotherapy Using a Hospital-Based Screening Reminder System 
PLoS ONE  2015;10(2):e0116978.
Background and Aim
Screenings for hepatitis B surface antigen (HBsAg) and antiviral prophylaxis are recommended for HBsAg-positive patients before the start of cytotoxic chemotherapy; however, compliance with these recommendations varies among doctors. We investigated the compliance of doctors with these recommendations using a reminder system and assessed the outcomes of HBsAg-positive patients receiving cytotoxic chemotherapy.
Using a computer-assisted reminder system, doctors were alerted of both HBsAg screening and antiviral prophylaxis prior to prescribing chemotherapy. The compliance between different doctors and outcomes of patients were investigated during the period of execution of this system. The rates of compliance with both recommendations were compared among various cancer types.
A total of 1053 patients were enrolled, of which only 88 had previous data pertaining to HBsAg status. Using this reminder system, an overall screening rate of 85.5% (825/965) was achieved and did not significantly differ according to cancer type. However, the overall antiviral prophylactic rate was only 45.5% (61/134). The rates of antiviral prophylaxis were lower for doctors treating lung, breast and colorectal cancers than for those treating hematological malignancies (all p<0.05). Consequently, the rate of HBV reactivation was lower in patients who received antiviral prophylaxis than in those who did not (1.6% vs. 15.1%; p<0.01). Multivariate analysis revealed that male gender and antiviral prophylaxis were both related to reactivation of hepatitis B (p<0.05).
By using this reminder system, the overall screening rate for HBsAg was satisfactory, whereas the antiviral prophylaxis was inadequate in patients with solid tumors due to the varying compliance of the attending doctors. Further strategies to improve both screening and prophylaxis are needed to minimize HBV-related events during cytotoxic chemotherapy.
PMCID: PMC4319781  PMID: 25658926
2.  Effect of Cycloplegia on the Refractive Status of Children: The Shandong Children Eye Study 
PLoS ONE  2015;10(2):e0117482.
To determine the effect of 1% cyclopentolate on the refractive status of children aged 4 to 18 years.
Using a random cluster sampling in a cross-sectional school-based study design, children with an age of 4–18 years were selected from kindergardens, primary schools, junior and senior high schools in a rural county and a city. Auto-refractometry was performed before and after inducing cycloplegia which was achieved by 1% cyclopentolate eye drops.
Out of 6364 eligible children, data of 5999 (94.3%) children were included in the statistical analysis. Mean age was 10.0±3.3 years (range: 4–18 years). Mean difference between cycloplegic and non-cycloplegic refractive error (DIFF) was 0.78±0.79D (median: 0.50D; range: -1.00D to +10.75D). In univariate analysis, DIFF decreased significantly with older age (P<0.001;correlation coefficient r:-0.24), more hyperopic non-cycloplegic refractive error (P<0.001;r = 0.13) and more hyperopic cycloplegic refractive error (P<0.001;r = 0.49). In multivariate analysis, higher DIFF was associated with higher cycloplegic refractive error (P<0.001; standardized regression coefficient beta:0.50; regression coefficient B: 0.19; 95% confidence interval (CI): 0.18, 0.20), followed by lower intraocular pressure (P<0.001; beta: -0.06; B: -0.02; 95%CI: -0.03, -0.01), rural region of habitation (P = 0.001; beta: -0.04; B: -0.07; 95%CI: -0.11, -0.03), and, to a minor degree, with age (P = 0.006; beta: 0.04; B: 0.009; 95%CI: 0.003, 0.016). 66.4% of all eyes with non-cycloplegic myopia (≤-0.50D) remained myopic after cycloplegia while the remaining 33.6% of eyes became emmetropic (18.0%) or hyperopic (15.7%) under cycloplegia. Prevalence of emmetropia decreased from 37.5% before cycloplegia to 19.8% after cycloplegia while the remaining eyes became hyperopic under cycloplegia.
The error committed by using non-cycloplegic versus cycloplegic refractometry in children with mid to dark-brown iris color decreased with older age, and in parallel manner, with more myopic cycloplegic refractive error. Non-cycloplegic refractometric measures lead to a misclassification of refractive error in a significant proportion of children.
PMCID: PMC4319948  PMID: 25658329
3.  Corneal Curvature Radius and Associated Factors in Chinese Children: The Shandong Children Eye Study 
PLoS ONE  2015;10(2):e0117481.
To investigate the distribution of the (CCR) and its associated factors in children.
Using a random cluster sampling method, the school-based, cross-sectional Shandong Children Eye Study included children aged 4 to 18 years from the rural county of Guanxian and the city of Weihai in the province of Shandong in East China. CCR was measured by ocular biometry.
CCR measurements were available for 5913 (92.9%) out of 6364 eligible children. Mean age was 10.0±3.3 years, and mean CCR was 7.84±0.27 mm (range: 6.98 to 9.35 mm). In multivariate linear regression analysis, longer CCR (i.e. flatter cornea) was significantly associated with the systemic parameters of male sex (P<0001;standardized regression coefficient beta: -0.08;regression coefficient B:-0.04; 95% Confidence Interval (CI):-0.05,-0.03), younger age (P<0.001;beta:-0.37;B:-0.03;95%CI:-0.04,-0.03), taller body height (P = 0.002;beta:0.06;B:0.001;95%CI:0.000,0.001), lower level of education of the father (P = 0.001;beta:-0.04;B:-0.01;95%CI:-0.02,-0.01) and maternal myopia (P<0.001;beta:-0.07;B:-0.04;95%CI:-0.06,-0.03), and with the ocular parameters of longer ocular axial length (P<0.001;beta:0.59;B:0.13;95%CI:0.12,0.14), larger horizontal corneal diameter (P<0.001;beta:0.19;B:0.13;95%CI:0.11,0.14), and smaller amount of cylindrical refractive error (P = 0.001;beta:-0.09;B:-0.05;95%CI:-0.06,-0.04).
Longer CCR (i.e., flatter corneas) (mean:7.84±0.27mm) was correlated with male sex, younger age, taller body height, lower paternal educational level, maternal myopia, longer axial length, larger corneas (i.e., longer horizontal corneal diameter), and smaller amount of cylindrical refractive error. These findings may be of interest for elucidation of the process of emmetropization and myopization and for corneal refractive surgery.
PMCID: PMC4319968  PMID: 25658095
4.  Characterization of a Null Allelic Mutant of the Rice NAL1 Gene Reveals Its Role in Regulating Cell Division 
PLoS ONE  2015;10(2):e0118169.
Leaf morphology is closely associated with cell division. In rice, mutations in Narrow leaf 1 (NAL1) show narrow leaf phenotypes. Previous studies have shown that NAL1 plays a role in regulating vein patterning and increasing grain yield in indica cultivars, but its role in leaf growth and development remains unknown. In this report, we characterized two allelic mutants of NARROW LEAF1 (NAL1), nal1-2 and nal1-3, both of which showed a 50% reduction in leaf width and length, as well as a dwarf culm. Longitudinal and transverse histological analyses of leaves and internodes revealed that cell division was suppressed in the anticlinal orientation but enhanced in the periclinal orientation in the mutants, while cell size remained unaltered. In addition to defects in cell proliferation, the mutants showed abnormal midrib in leaves. Map-based cloning revealed that nal1-2 is a null allelic mutant of NAL1 since both the whole promoter and a 404-bp fragment in the first exon of NAL1 were deleted, and that a 6-bp fragment was deleted in the mutant nal1-3. We demonstrated that NAL1 functions in the regulation of cell division as early as during leaf primordia initiation. The altered transcript level of G1- and S-phase-specific genes suggested that NAL1 affects cell cycle regulation. Heterogenous expression of NAL1 in fission yeast (Schizosaccharomyces pombe) further supported that NAL1 affects cell division. These results suggest that NAL1 controls leaf width and plant height through its effects on cell division.
PMCID: PMC4320051  PMID: 25658704
5.  Lack of association between the CDH1 polymorphism and gastric cancer susceptibility: a meta-analysis 
Scientific Reports  2015;5:7891.
E-Cadherin (CDH1) plays a key role in cell adhesion, which is vital to the normal development and maintenance of cells. Down regulation of CDH1, may lead to dysfunction of the cell-cell adhesion system, resulting in increased susceptibility to tumor development and subsequent tumor cell invasion and metastasis. The CDH1 C-160A polymorphism could decrease its transcription efficiency and may increase susceptibility to cancer development, but its relevance to gastric cancer is generally disputed. Consequently, we performed a meta-analysis of published case-control studies, including 4218 gastric cancer cases and 5461 controls. Overall, no significant association was observed between the CDH1 C-160A polymorphism and risk of gastric cancer in all genetic models. In the stratified analysis by total sample size, a significant association was observed in the small sample size subgroup (total sample size < 300), but the results should be interpreted with caution. In conclusion, this meta-analysis failed to confirm the association between the CDH1 C-160A polymorphism and risk of gastric cancer. Large-scale and well-designed studies are needed to confirm our findings.
PMCID: PMC4298742  PMID: 25599647
6.  Pharmacokinetics Interaction between Imatinib and Genistein in Rats 
BioMed Research International  2015;2015:368976.
The objective of this work was to investigate the effect of orally administered genistein on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Twenty-five healthy male SD (Sprague-Dawley) rats were randomly divided into five groups: A group (control group), B group (multiple dose of 100 mg/kg genistein for consecutive 15 days), C group (multiple dose of 50 mg/kg genistein for consecutive 15 days), D group (a single dose of 100 mg/kg genistein), and E group (a single dose of 50 mg/kg genistein). A single dose of imatinib is administered orally 30 min after administration of genistein (100 mg/kg or 50 mg/kg). The pharmacokinetic parameters of imatinib and N-desmethyl imatinib were calculated by DAS 3.0 software. The multiple dose of 100 mg/kg or 50 mg/kg genistein significantly (P < 0.05) decreased the AUC0−t and Cmax of imatinib. AUC0−t and the Cmax of N-desmethyl imatinib were also increased, but without any significant difference. However, the single dose of 100 mg/kg or 50 mg/kg genistein has no effect on the pharmacokinetics of imatinib and N-desmethyl imatinib. Those results indicated that multiple dose of genistein (100 mg/kg or 50 mg/kg) induces the metabolism of imatinib, while single dose of genistein has no effect.
PMCID: PMC4299555  PMID: 25629045
7.  Expression, purification, crystallization and preliminary X-ray diffraction analysis of Arabidopsis thaliana Deg8 
Crystals of Deg8, an ATP-independent serine endopeptidase from A. thaliana, were monoclinic, belonging to space group C2 with unit-cell parameters a = 129.5, b = 124.2, c = 93.3 Å, β = 132.4°, and diffracted to 2.0 Å resolution.
Arabidopsis thaliana Deg8, an ATP-independent serine endopeptidase, is involved in the repair of photosystem II (PSII), specifically the degradation of the photo-damaged PSII reaction centre D1 protein. To understand the molecular mechanism underlying the participation of Deg8 in the degradation of the photo-damaged D1 protein, the structure of Deg8 is needed. Until recently, however, no structure of Deg8 had been solved. In this study, Deg8 from A. thaliana was cloned, overexpressed and purified in Escherichia coli. Crystallization was performed at 277 K using tribasic sodium citrate as the precipitant and the crystals diffracted to 2.0 Å resolution, belonging to space group C2 with unit-cell parameters a = 129.5, b = 124.2, c = 93.3 Å, α = γ = 90, β = 132.4°. Assuming one trimer in the asymmetric unit, the Matthews coefficient and the solvent content were calculated to be 2.35 Å3 Da−1 and 47.6%, respectively.
PMCID: PMC3539708  PMID: 23295491
Deg8; photosystem II; Arabidopsis thaliana
8.  Some Statistical Strategies for DAE-seq Data Analysis: Variable Selection and Modeling Dependencies among Observations 
In DAE (DNA After Enrichment)-seq experiments, genomic regions related with certain biological processes are enriched/isolated by an assay and are then sequenced on a high-throughput sequencing platform to determine their genomic positions. Statistical analysis of DAE-seq data aims to detect genomic regions with significant aggregations of isolated DNA fragments (“enriched regions”) versus all the other regions (“background”). However, many confounding factors may influence DAE-seq signals. In addition, the signals in adjacent genomic regions may exhibit strong correlations, which invalidate the independence assumption employed by many existing methods. To mitigate these issues, we develop a novel Autoregressive Hidden Markov Model (AR-HMM) to account for covariates effects and violations of the independence assumption. We demonstrate that our AR-HMM leads to improved performance in identifying enriched regions in both simulated and real datasets, especially in those in epigenetic datasets with broader regions of DAE-seq signal enrichment. We also introduce a variable selection procedure in the context of the HMM/AR-HMM where the observations are not independent and the mean value of each state-specific emission distribution is modeled by some covariates. We study the theoretical properties of this variable selection procedure and demonstrate its efficacy in simulated and real DAE-seq data. In summary, we develop several practical approaches for DAE-seq data analysis that are also applicable to more general problems in statistics.
PMCID: PMC3963211  PMID: 24678134
High-throughput Sequencing; Hidden Markov Model; Mixture Regression; Autoregressive modeling; Variable Selection
9.  Relapse to Cocaine-seeking after Abstinence Is Regulated by cAMP-dependent Protein Kinase A in the Prefrontal Cortex 
Addiction biology  2013;19(1):77-86.
Abstinence from cocaine self-administration (SA) is associated with neuroadaptations in the prefrontal cortex (PFC) and nucleus accumbens (NAc) that are implicated in cocaine-induced neuronal plasticity and relapse to drug-seeking. Alterations in cAMP-dependent protein kinase A (PKA) signaling are prominent in medium spiny neurons in the NAc after repeated cocaine exposure but it is unknown whether similar changes occur in the PFC. Because cocaine SA induces disturbances in glutamatergic transmission in the PFC-NAc pathway, we examined whether dysregulation of PKA-mediated molecular targets in PFC-NAc neurons occurs during abstinence and, if so, whether it contributes to cocaine seeking. We measured the phosphorylation of CREB (Ser133) and GluA1 (Ser845) in the dorsomedial (dm) PFC and the presynaptic marker, synapsin I (Ser9, Ser62/67, Ser603), in the NAc after 7 days of abstinence from cocaine SA with or without cue-induced cocaine-seeking. We also evaluated whether infusion of the PKA inhibitor, 8-bromo-Rp-cyclic adenosine 3′, 5′-monophosphorothioate (Rp-cAMPs), into the dmPFC after abstinence would affect cue-induced cocaine-seeking and PKA-regulated phosphoprotein levels. Seven days of forced abstinence increased the phosphorylation of CREB and GluA1 in the dmPFC and synapsin I (Ser9) in the NAc. Induction of these phosphoproteins was reversed by a cue-induced relapse test of cocaine-seeking. Bilateral intra-dmPFC Rp-cAMPs rescued abstinence-elevated PKA-mediated phosphoprotein levels in the dmPFC and NAc and suppressed cue-induced relapse. Thus, by inhibiting abstinence-induced PKA molecular targets, relapse reverses abstinence-induced neuroadaptations in the dmPFC that are responsible, in part, for the expression of cue-induced cocaine-seeking.
PMCID: PMC4110897  PMID: 23461423
CREB; AMPA receptor; nucleus accumbens; synapsin
10.  T helper cell dysregulation with hepatitis B and rebalance with glucocorticoids 
World Journal of Gastroenterology : WJG  2014;20(48):18354-18359.
AIM: To investigate T helper 17/regulatory T cell alterations in early severe hepatitis B and the effect of glucocorticoids.
METHODS: The study included 20 patients in the early stage of severe hepatitis B (SHB) and 11 healthy controls. All patients had elevated T helper 17 (Th17) levels, decreased regulatory T (Treg) cell levels, and significant Th17/Treg ratios.
RESULTS: After glucocorticoid treatment, 16 patients showed improvement with significant decreases in Th17 levels, increases in Treg, and rebalanced Th17/Treg ratios. The four patients who showed no improvement had increases in both Th17 and Treg levels and an even higher Th17/Treg ratio than before.
CONCLUSION: Glucocorticoid treatment can rectify Th17/Treg dysregulation in patients with SHB.
PMCID: PMC4277972  PMID: 25561802
Severe hepatitis B; T helper 17 cell; Regulatory T cell; Dysregulation; Glucocorticoid
11.  Efficacy of docetaxel combined with oxaliplatin and fluorouracil against stage III/IV gastric cancer 
World Journal of Gastroenterology : WJG  2014;20(48):18413-18419.
AIM: To investigate the clinical efficacy and toxic effects of neoadjuvant chemotherapy using docetaxel combined with oxaliplatin and fluorouracil for treating stage III/IV gastric cancer.
METHODS: A total of 53 stage III/IV gastric cancer patients were enrolled into the study and treated with neoadjuvant chemotherapy. Two of the cases were excluded. The program was as follows: 75 mg/m2 docetaxel and 85 mg/m2 oxaliplatin on day 1 and 1500 mg/m2 fluorouracil on days 1 to 3 for three weeks.
RESULTS: The tumour changes, postoperative remission rate, changes in the symptoms and adverse reactions were observed. The overall clinical efficacy (complete remission + partial remission) of the neoadjuvant chemotherapy was 62.7%. R0 radical resection was performed on 60.8% of the patients, with a remission rate (pathological complete response + pathological subtotal response + pathological partial response) of 74.2%. The Karnofksy score improved in 42 cases. The toxicity reactions mostly included myelosuppression, followed by gastrointestinal mucosal lesions, nausea, vomiting and diarrhoea.
CONCLUSION: Neoadjuvant chemotherapy consisting of docetaxel combined with oxaliplatin and fluorouracil is effective for stage III/IV gastric cancer. However, the treatment is associated with a high incidence of bone marrow suppression, which should be managed clinically.
PMCID: PMC4277980  PMID: 25561810
Gastric cancer; Neoadjuvant chemotherapy; Docetaxel; Oxaliplatin
12.  Comparative analysis of carotenoid accumulation in two goji (Lycium barbarum L. and L. ruthenicum Murr.) fruits 
BMC Plant Biology  2014;14(1):269.
The traditional Chinese medicinal plants Lycium barbarum L. and L. ruthenicum Murr. are valued for the abundance of bioactive carotenoids and anthocyanins in their fruits, respectively. However, the cellular and molecular mechanisms contributing to their species-specific bioactive profiles remain poorly understood.
In this study, the red fruit (RF) of L. barbarum was found to accumulate high levels of carotenoids (primarily zeaxanthin), while they were undetectable in the black fruit (BF) of L. ruthenicum. Cytological and gene transcriptional analyses revealed that the chromoplast differentiation that occurs in the chloroplast during fruit ripening only occurs in RF, indicating that the lack of chromoplast biogenesis in BF leads to no sink for carotenoid storage and the failure to synthesize carotenoids. Similar enzyme activities of phytoene synthase 1 (PSY1), chromoplast-specific lycopene β-cyclase (CYC-B) and β-carotene hydroxylase 2 (CRTR-B2) were observed in both L. ruthenicum and L. barbarum, suggesting that the undetectable carotenoid levels in BF were not due to the inactivation of carotenoid biosynthetic enzymes. The transcript levels of the carotenoid biosynthetic genes, particularly PSY1, phytoene desaturase (PDS), ζ-carotene desaturase (ZDS), CYC-B and CRTR-B2, were greatly increased during RF ripening, indicating increased zeaxanthin biosynthesis. Additionally, carotenoid cleavage dioxygenase 4 (CCD4) was expressed at much higher levels in BF than in RF, suggesting continuous carotenoid degradation in BF.
The failure of the chromoplast development in BF causes low carotenoid biosynthesis levels and continuous carotenoid degradation, which ultimately leads to undetectable carotenoid levels in ripe BF. In contrast, the successful chromoplast biogenesis in RF furnishes the sink necessary for carotenoid storage. Based on this observation, the abundant zeaxanthin accumulation in RF is primarily determined via both the large carotenoid biosynthesis levels and the lack of carotenoid degradation, which are regulated at the transcriptional level.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0269-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4276078  PMID: 25511605
Carotenoids; Chromoplast; Fruit development; Gene expression; Lycium barbarum; L. ruthenicum
13.  Functional Conservation and Divergence of Four Ginger AP1/AGL9 MADS–Box Genes Revealed by Analysis of Their Expression and Protein–Protein Interaction, and Ectopic Expression of AhFUL Gene in Arabidopsis 
PLoS ONE  2014;9(12):e114134.
Alpinia genus are known generally as ginger–lilies for showy flowers in the ginger family, Zingiberaceae, and their floral morphology diverges from typical monocotyledon flowers. However, little is known about the functions of ginger MADS–box genes in floral identity. In this study, four AP1/AGL9 MADS–box genes were cloned from Alpinia hainanensis, and protein–protein interactions (PPIs) and roles of the four genes in floral homeotic conversion and in floral evolution are surveyed for the first time. AhFUL is clustered to the AP1lineage, AhSEP4 and AhSEP3b to the SEP lineage, and AhAGL6–like to the AGL6 lineage. The four genes showed conserved and divergent expression patterns, and their encoded proteins were localized in the nucleus. Seven combinations of PPI (AhFUL–AhSEP4, AhFUL–AhAGL6–like, AhFUL–AhSEP3b, AhSEP4–AhAGL6–like, AhSEP4–AhSEP3b, AhAGL6–like–AhSEP3b, and AhSEP3b–AhSEP3b) were detected, and the PPI patterns in the AP1/AGL9 lineage revealed that five of the 10 possible combinations are conserved and three are variable, while conclusions cannot yet be made regarding the other two. Ectopic expression of AhFUL in Arabidopsis thaliana led to early flowering and floral organ homeotic conversion to sepal–like or leaf–like. Therefore, we conclude that the four A. hainanensis AP1/AGL9 genes show functional conservation and divergence in the floral identity from other MADS–box genes.
PMCID: PMC4252096  PMID: 25461565
14.  Epigallocatechin-3-Gallate Reduces Myometrial Infiltration, Uterine Hyperactivity, and Stress Levels and Alleviates Generalized Hyperalgesia in Mice Induced With Adenomyosis 
Reproductive Sciences  2013;20(12):1478-1491.
In an effort to search for novel therapeutics for adenomyosis, we sought to determine whether treatment with epigallocatechin-3-gallate (EGCG) would suppress the myometrial infiltration, improve pain behavior, lower stress level, and reduce uterine contractility in a mice model of adenomyosis. Adenomyosis was induced in 28 female ICR mice neonatally dosed with tamoxifen, while another 12 (group C) were dosed with solvent only, which served as a blank control. Starting from 4 weeks after birth, hot plate test was administrated to all mice every 4 weeks. At the 16th week, all mice induced with adenomyosis were randomly divided into 3 groups: low-dose EGCG (5 mg/kg), high-dose EGCG (50 mg/kg), and untreated. Group C received no treatment. After 3 weeks of treatment, the hot plate test was administered again, a blood sample was taken to measure the plasma corticosterone level by enzyme-linked immunosorbent assay, and then all mice were sacrificed. The depth of myometrial infiltration and uterine contractility were also evaluated. We found that the induction of adenomyosis resulted in progressive generalized hyperalgesia, along with elevated amplitude and frequency of uterine contractions as well as elevated plasma corticosterone levels. The EGCG treatment dose dependently suppressed myometrial infiltration, improved generalized hyperalgesia, reduced uterine contractility, and lowered plasma corticosterone levels. These results suggest that induced adenomyosis causes pain and elevates stress levels in mice. Uterine hyperactivity may contribute to dysmenorrhea in women with adenomyosis who might also have elevated stress level due to pain. The EGCG appears to be a promising compound for treating adenomyosis.
PMCID: PMC3817672  PMID: 23703534
adenomyosis; corticosterone; EGCG; hyperalgesia; mouse; uterine contractility
Annals of biomedical engineering  2013;41(12):10.1007/s10439-013-0856-9.
Quantification of the age- and gender-specific in vivo mechanical characteristics of the ascending aorta (AA) will allow for identification of abnormalities aside from changes brought on by aging alone. Multiphase clinical CT scans of 45 male patients between the ages of 30 and 79 years were analyzed to assess age-dependent in vivo AA characteristics. The three-dimensional AA geometry for each patient was reconstructed from the CT scans for 9–10 phases throughout the cardiac cycle. The AA circumference was measured during each phase and was used to determine the corresponding diameter, circumferential strain, and wall tension at each phase. The pressure-strain modulus was also determined for each patient. The mean diastolic AA diameter was significantly smaller among young (42.6±5.2 years) at 29.9±2.8 mm than old patients (69.0±5.2 years) at 33.2±3.2 mm. The circumferential AA strain from end-diastole to peak-systole decreased from 0.092±0.03 in young to 0.056±0.03 in old patients. The pressure-strain modulus increased two-fold from 68.4±30.5 kPa in young to 162.0±93.5 kPa in old patients, and the systolic AA wall tension increased from 268.5±31.3 kPa in young to 304.9±49.2 kPa in old patients. The AA dilates and stiffens with aging which increases the vessel wall tension, likely predisposing aneurysm and dissection.
PMCID: PMC3823761  PMID: 23817767
ascending aorta; aging; mechanics; imaging; elasticity
16.  Transient Impact of Spike on Theta Rhythm in Temporal Lobe Epilepsy 
Experimental neurology  2013;250:10.1016/j.expneurol.2013.09.023.
Epileptic spike is an indicator of hyper-excitability and hyper-synchrony of neural networks. While cognitive deficit in epilepsy is a common observation, how spikes transiently influence brain oscillations, especially those essential for cognitive functions, remains obscure. Here we aimed to quantify the transient impacts of sporadic spikes on theta oscillations and investigate how such impacts may evolve during epileptogenesis. Longitudinal depth EEG data were recorded in the CA1 area of pilocarpine temporal lobe epilepsy (TLE) rat models. Phase stability, a measure of synchrony, and theta power were estimated around spikes as well as in the protracted spike-free periods (FP) at least one hour after spike bursts. We found that the change in theta power did not correlate with the change in phase stability. More importantly, the impact of spikes on theta rhythm was highly time-dependent. While theta power decreased abruptly after spikes both in the latent and chronic stages, changes of theta phase stability demonstrated opposite trends in the latent and chronic stages, potentially due to the substantial reorganization of neural circuits along epileptogenesis. During FP, theta phase stability was significantly higher than the baseline level before injections, indicating that hyper-synchrony remained even hours after the spike bursts. We concluded that spikes have transient negative effects on theta rhythm, however, impacts are different during latent and chronic stages, implying that its influence on cognitive processes may also change over time during epileptogenesis.
PMCID: PMC3857724  PMID: 24100023
Theta Rhythm; Temporal Lobe Epilepsy; Hippocampus; Epileptogenesis
17.  Hemodynamic Impact of Transcatheter Aortic Valve Deployment Configuration 
Journal of Medical Devices  2013;7(4):0409221-0409222.
PMCID: PMC4023853  PMID: 24895522
18.  Rapid prototyping of concave microwells for the formation of 3D multicellular cancer aggregates for drug screening 
Advanced healthcare materials  2013;3(4):609-616.
Microwell technology has revolutionized many aspects of in vitro cellular studies from 2-dimensional (2D) traditional cultures to 3-dimensional (3D) in vivo-like functional assays. However, existing lithography-based approaches are often costly and time-consuming. This study presents a rapid, low-cost prototyping method of CO2 laser ablation of a conventional untreated culture dish to create concave microwells used for generating multicellular aggregates, which can be readily available for general laboratories. Polymethylmethacrylate (PMMA), polydimethylsiloxane (PDMS), and polystyrene (PS) microwells were investigated, and each produced distinctive microwell features. Among these three materials, PS cell culture dishes produced the optimal surface smoothness and roundness. A549 lung cancer cells were grown to form cancer aggregates of controllable size from ~40 to ~80 μm in PS microwells. Functional assays of spheroids were performed to study migration on 2D substrates and in 3D hydrogel conditions as a step towards recapitulating the dissemination of cancer cells. Preclinical anti-cancer drug screening was investigated and revealed considerable differences between 2D and 3D conditions, indicating the importance of assay type as well as the utility of the present approach.
PMCID: PMC4038742  PMID: 23983140
drug screening; microwell; multicellular cancer aggregate; multicellular spheroids
19.  Round window closure affects cochlear responses to supra-threshold stimuli 
The Laryngoscope  2013;123(12):E116-E121.
The round window acts as a vent for releasing inner ear pressure and facilitating basilar membrane vibration. Loss of this venting function affects cochlear function leading to hearing impairment. The current investigation was designed to examine how the cochlea responds to supra-threshold stimuli following round window closure in an effort to identify functional changes that might be used in clinical diagnosis of round window atresia.
Study Design
Prospective, controlled, animal study.
A rat model of round window occlusion was established. With this model, the thresholds of auditory brainstem responses and the input/output functions of distortion product otoacoustic emissions and acoustic startle responses were examined.
Round window closure caused a mild shift in the thresholds of the auditory brainstem response (13.5 ± 9.1 dB). It also reduced the amplitudes of the distortion product otoacoustic emissions and the slope of the input/output functions. This peripheral change was accompanied by a significant reduction in the amplitude, but not the threshold, of the acoustic startle reflex, a motor response to supra-threshold sounds.
In addition to causing mild increase in the threshold of the auditory brainstem response, round window occlusion reduced the slopes of both distortion product otoacoustic emissions and startle reflex input/output functions. These changes differ from those observed for typical conductive or sensory hearing loss, and could be present in patients with round window atresia. However, future clinical observations in patients are needed to confirm these findings.
PMCID: PMC4219855  PMID: 24114866
Round window; Atresia; Distortion production otoacoustic emission; Rats; Acoustic startle reflex
20.  Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs 
In light of the current outbreak of Ebola virus disease, there is an urgent need to develop effective therapeutics to treat Ebola infection, and drug repurposing screening is a potentially rapid approach for identifying such therapeutics. We developed a biosafety level 2 (BSL-2) 1536-well plate assay to screen for entry inhibitors of Ebola virus-like particles (VLPs) containing the glycoprotein (GP) and the matrix VP40 protein fused to a beta-lactamase reporter protein and applied this assay for a rapid drug repurposing screen of Food and Drug Administration (FDA)-approved drugs. We report here the identification of 53 drugs with activity of blocking Ebola VLP entry into cells. These 53 active compounds can be divided into categories including microtubule inhibitors, estrogen receptor modulators, antihistamines, antipsychotics, pump/channel antagonists, and anticancer/antibiotics. Several of these compounds, including microtubule inhibitors and estrogen receptor modulators, had previously been reported to be active in BSL-4 infectious Ebola virus replication assays and in animal model studies. Our assay represents a robust, effective and rapid high-throughput screen for the identification of lead compounds in drug development for the treatment of Ebola virus infection.
PMCID: PMC4317638
Antipsychotics; drug repurposing screen; Ebola virus; Ebola virus glycoprotein; estrogen receptor modulator; microtubule inhibitor; virus entry; VP40
21.  Trends in age-specific cerebrovascular disease in the European Union 
Although the mortality of cerebrovascular disease (CVD) has been steadily declined in the European Union (EU), CVD remains among the major causes of death in EU. As risk factors such asobesity and diabetes mellitus are increasing, the trends of European CVD mortality remains unknown. To understand the variation in CVD mortality of different EU countries, we studied the trends in CVD mortality in EU countries over the last three decades between males and females. Age- and sex-specific mortality rates between 1980 and 2011 were calculated by data from the WHO mortality database. Joinpoint software was used to calculate annual percentage changes and to characterize trends in mortality rates over time. Our study showed that between 1980 and 2011, CVD mortality significantly decreased in both men and women across all age groups. The specific mortality trends varied largely between EU countries. The plateau trend was observed in little regions at different age groups, however, the EU as a whole displayed declined trend CVD mortality. During the last three decades, CVD mortality decreased substantially in the entire population of EU. However, despite this overall decline in CVD mortality, several areas were identified as having no change in their CVD mortality rates at different period. The whole EU needs to establish strict prevention measures toreduce the incidence of CVD risk factors.
PMCID: PMC4276185  PMID: 25550927
Cerebrovascular disease; mortality; trends
22.  Association Studies with Imputed Variants Using Expectation-Maximization Likelihood-Ratio Tests 
PLoS ONE  2014;9(11):e110679.
Genotype imputation has become standard practice in modern genetic studies. As sequencing-based reference panels continue to grow, increasingly more markers are being well or better imputed but at the same time, even more markers with relatively low minor allele frequency are being imputed with low imputation quality. Here, we propose new methods that incorporate imputation uncertainty for downstream association analysis, with improved power and/or computational efficiency. We consider two scenarios: I) when posterior probabilities of all potential genotypes are estimated; and II) when only the one-dimensional summary statistic, imputed dosage, is available. For scenario I, we have developed an expectation-maximization likelihood-ratio test for association based on posterior probabilities. When only imputed dosages are available (scenario II), we first sample the genotype probabilities from its posterior distribution given the dosages, and then apply the EM-LRT on the sampled probabilities. Our simulations show that type I error of the proposed EM-LRT methods under both scenarios are protected. Compared with existing methods, EM-LRT-Prob (for scenario I) offers optimal statistical power across a wide spectrum of MAF and imputation quality. EM-LRT-Dose (for scenario II) achieves a similar level of statistical power as EM-LRT-Prob and, outperforms the standard Dosage method, especially for markers with relatively low MAF or imputation quality. Applications to two real data sets, the Cebu Longitudinal Health and Nutrition Survey study and the Women’s Health Initiative Study, provide further support to the validity and efficiency of our proposed methods.
PMCID: PMC4226494  PMID: 25383782
23.  Variations in Stable Carbon Isotope Composition and Leaf Traits of Picea schrenkiana var. tianschanica along an Altitude Gradient in Tianshan Mountains, Northwest China 
The Scientific World Journal  2014;2014:243159.
To understand the morphological and physiological responses of leaves to changes in altitudinal gradients, we examined ten morphological and physiological characteristics in one-year-old needles of Picea schrenkiana var. tianschanica at ten points along an altitudinal gradient from 1420 to 2300 m a.s.l. on the northern slopes of the Tianshan Mountains in northwest China. Our results indicated that LA, SD, LPC, and LKC increased linearly with increasing elevation, whereas leaf δ13C, LNC, Chla + b, LDMC, LMA, and Narea varied nonlinearly with changes in altitude. With elevation below 2100 m, LNC, Narea, and Chla + b increased, while LDMC and LMA decreased with increasing altitude. When altitude was above 2100 m, these properties showed the opposite patterns. Leaf δ13C was positively correlated with Narea and LNC and negatively correlated with SD and LA, suggesting that leaf δ13C was indirectly controlled by physiological and morphological adjustments along altitudinal gradients. Based on the observed maximum values in LNC, Narea, Chla + b, and LA and the minimum values in LMA and LDMC at the elevation of 2100 m, suggesting higher photosynthetic capacity and greater potential for fast growth under superior optimum zone, we concluded that the best growing elevation for P. schrenkiana var. tianschanica in the Tianshan Mountains was approximately 2100 m.
PMCID: PMC4235120  PMID: 25530993
24.  Heritability and Genomics of Gene Expression in Peripheral Blood 
Nature genetics  2014;46(5):430-437.
We assessed gene expression profiles in 2,752 twins, using a classic twin design to quantify expression heritability and quantitative trait loci (eQTL) in peripheral blood. The most highly heritable genes (~777) were grouped into distinct expression clusters, enriched in gene-poor regions, associated with specific gene function/ontology classes, and strongly associated with disease designation. The design enabled a comparison of twin-based heritability to estimates based on dizygotic IBD sharing and distant genetic relatedness. Consideration of sampling variation suggests that previous heritability estimates have been upwardly biased. Genotyping of 2,494 twins enabled powerful identification of eQTLs, which were further examined in a replication set of 1,895 unrelated subjects. A large number of local eQTLs (6,988) met replication criteria, while a relatively small number of distant eQTLs (165) met quality control and replication standards. Our results provide an important new resource toward understanding the genetic control of transcription.
PMCID: PMC4012342  PMID: 24728292
gene expression; peripheral blood; twin study; heritability; expression quantitative trait loci; eQTL
25.  Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance 
Cell Research  2013;23(11):1310-1321.
IRTKS encodes a member of the IRSp53/MIM homology domain family, which has been shown to play an important role in the formation of plasma membrane protrusions. Although the phosphorylation of IRTKS occurs in response to insulin stimulation, the role of this protein in insulin signaling remains unknown. Here we show that IRTKS-deficient mice exhibit insulin resistance, including hyperglycemia, hyperinsulinemia, glucose intolerance, decreased insulin sensitivity, and increased hepatic glucose production. The administration of ectopic IRTKS can ameliorate the insulin resistance of IRTKS-deficient and diabetic mice. In parallel, the expression level of IRTKS was significantly decreased in diabetic mouse model. Furthermore, DNA hypermethylation of the IRTKS promoter was also observed in these subjects. We also show that IRTKS, as an adaptor of the insulin receptor (IR), modulates IR-IRS1-PI3K-AKT signaling via regulating the phosphorylation of IR. These findings add new insights into our understanding of insulin signaling and resistance.
PMCID: PMC3817554  PMID: 23896986
insulin resistance; IRTKS; insulin receptor

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