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author:("Liu, banyan")
1.  Flowerlike CeO2 microspheres coated with Sr2Fe1.5Mo0.5Ox nanoparticles for an advanced fuel cell 
Scientific Reports  2015;5:11946.
Flowerlike CeO2 coated with Sr2Fe1.5Mo0.5Ox (Sr-Fe-Mo-oxide) nanoparticles exhibits enhanced conductivity at low temperatures (300–600 oC), e.g. 0.12 S cm−1 at 600 oC, this is comparable to pure ceria (0.1 S cm−1 at 800 oC). Advanced single layer fuel cell was constructed using the flowerlike CeO2/Sr-Fe-Mo-oxide layer attached to a Ni-foam layer coated with the conducting transition metal oxide. Such fuel cell has yielded a peak power density of 802 mWcm−2 at 550 oC. The mechanism of enhanced conductivity and cell performance were analyzed. These results provide a promising strategy for developing advanced low-temperature SOFCs.
PMCID: PMC4495617  PMID: 26154917
2.  Sch9 regulates intracellular protein ubiquitination by controlling stress responses 
Redox Biology  2015;5:290-300.
Protein ubiquitination and the subsequent degradation are important means by which aberrant proteins are removed from cells, a key requirement for long-term survival. In this study, we found that the overall level of ubiquitinated proteins dramatically decreased as yeast cell grew from log to stationary phase. Deletion of SCH9, a gene encoding a key protein kinase for longevity control, decreased the level of ubiquitinated proteins in log phase and this effect could be reversed by restoring Sch9 function. We demonstrate here that the decrease of ubiquitinated proteins in sch9Δ cells in log phase is not caused by changes in ubiquitin expression, proteasome activity, or autophagy, but by enhanced expression of stress response factors and a decreased level of oxidative stress. Our results revealed for the first time how Sch9 regulates the level of ubiquitinated proteins and provides new insight into how Sch9 controls longevity.
PMCID: PMC4477112  PMID: 26087116
SCH9; Yeast; Ubiquitination; Oxidation; Hydrogen peroxide
3.  The Efficacy of Shugan Jianpi Zhixie Therapy for Diarrhea-Predominant Irritable Bowel Syndrome: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials 
PLoS ONE  2015;10(4):e0122397.
Shugan Jianpi Zhixie therapy (SJZT) has been widely used to treat diarrhea-predominant irritable bowel syndrome (IBS-D), but the results are still controversial. A meta-analysis of randomized, double-blind, placebo-controlled trials was performed to assess the efficacy and tolerability of SJZT for IBS-D.
The MEDLINE, EMBASE, Cochrane Library, the China National Knowledge Infrastructure database, the Chinese Biomedical Literature database and the Wanfang database were searched up to June 2014 with no language restrictions. Summary estimates, including 95% confidence intervals (CI), were calculated for global symptom improvement, abdominal pain improvement, and Symptom Severity Scale (BSS) score.
Seven trials (N=954) were included. The overall risk of bias assessment was low. SJZT showed significant improvement for global symptom compared to placebo (RR 1.61; 95% CI 1.24, 2.10; P =0.0004; therapeutic gain = 33.0%; number needed to treat (NNT) = 3.0). SJZT was significantly more likely to reduce overall BSS score (SMD –0.67; 95% CI –0.94, –0.40; P < 0.00001) and improve abdominal pain (RR 4.34; 95% CI 2.64, 7.14; P < 0.00001) than placebo. The adverse events of SJZT were no different from those of placebo.
This meta-analysis suggests that SJZT is an effective and safe therapy option for patients with IBS-D. However, due to the high clinical heterogeneity and small sample size of the included trials, further standardized preparation, large-scale and rigorously designed trials are needed.
PMCID: PMC4390216  PMID: 25853241
4.  Self-Rated Health Status and Subjective Health Complaints Associated with Health-Promoting Lifestyles among Urban Chinese Women: A Cross-Sectional Study 
PLoS ONE  2015;10(2):e0117940.
This study aimed to investigate whether self-rated health status (SRH) and subjective health complaints (SHC) of urban Chinese women are associated with their health-promoting lifestyles (HPL).
We conducted a cross-sectional study on 8142 eligible Chinese participants between 2012 and 2013. Demographic and SHC data were collected. Each subject completed the SRH questionnaire and the Chinese version of the Health-Promoting Lifestyle Profile-II (HPLP-II). Correlation and binary regression analyses were performed to examine the associations of SRH and SHC with HPL.
Both SRH and HPL of urban Chinese women were moderate. The most common complaints were fatigue (1972, 24.2%), eye discomfort (1571, 19.3%), and insomnia (1542, 18.9%). Teachers, highly educated subjects and elderly women had lower SRH scores, while college students and married women had better HPL. All items of HPLP-II were positively correlated with SRH (r = 0.127-0.533, P = 0.000) and negatively correlated with SHC to a significant extent (odds ratio [OR] = 1.40-11.37).
Aspects of HPL, particularly stress management and spiritual growth, are associated with higher SRH and lower SHC ratings among urban Chinese women. Physical activity and health responsibility are additionally related to reduced fatigue and nervousness. We believe that these findings will be instrumental in encouraging researchers and urban women to adopt better health-promoting lifestyles with different priorities in their daily lives.
PMCID: PMC4324778  PMID: 25671578
5.  Bu-Zhong-Yi-Qi pill alleviate the chemotherapy-related fatigue in 4 T1 murine breast cancer model 
Paclitaxel induced fatigue still remains underrecognized and undertreated, partly because of limited understanding of its pathophysiology and lack of effective treatments. This study is aim to evaluate the anti-fatigue effects and mechanism of Bu-Zhong-Yi-Qi pill in murine 4 T1 breast cancer mice were treated with paclitaxel.
Breast cancer mice established with murine 4 T1 cells were randomly and repectively divided into five groups: negative control group (NC), tumor control group (TC), paclitaxel group (PTX), Bu-Zhong-Yi-Qi pill group (BZYQ) and Bu-Zhong-Yi-Qi pill plus paclitaxel group (BZYQ + PTX). The mice were administered for 21 days. During this period, the tumor volume, body weight and the weight-loaded swimming time were measured. After the last administration, all mice were sacrificed, weighted the tumor, measured immune cell cytokines and oxidative stress indicator. The remaining 10 mice in each group were observed for survival analysis.
Treatments with BZYQ + PTX and PTX significantly reduced the rates of tumor volume in comparison with TC starting on the 9th day and the 18th day respectively (P < 0.05-0.01), and presented decreased tumor weight compared to TC (P < 0.05-0.01). Compared with mice in TC group, the median survival time and the average survival time in BZYQ + PTX group, BZYQ group and PTX group were significantly prolonged (P < 0.05-0.01). The swimming time of the BZYQ + PTX group gradually increased, which is longer than the PTX group on Day 14 and Day 21 (P < 0.01). The level of TNF-α was lower in BZYQ + PTX group than PTX group (P < 0.01). The level of SOD activity in BZYQ + PTX group was lower than the NC group (P <0.01), but much higher than the PTX group (P < 0.01). The level of MDA of BZYQ + PTX group was higher than the NC group (P < 0.01), but significant lower than the PTX group (P < 0.01).
BZYQ has the potential of alleviating paclitaxel chemotherapy-related fatigue in 4 T1 breast cancer mice by reducing the serum levels of TNF-α and modulating the level of MDA and the SOD activity.
PMCID: PMC4300826  PMID: 25511260
6.  Associations between breakfast eating habits and health-promoting lifestyle, suboptimal health status in Southern China: a population based, cross sectional study 
Suboptimal health status (SHS) is the intermediate health state between health and disease, refers to medically undiagnosed or functional somatic syndromes, and has been a major global public health challenge. However, both the etiology and mechanisms associated with SHS are still unclear. Breakfast eating behavior is a dietary pattern marker and previous studies have presented evidence of associations between failure to consume breakfast and increased diseases. Accordingly, in view of the significance of breakfast eating behaviors with respect to health status, the associations between breakfast eating habits and healthy lifestyle, SHS require further elucidation.
A cross-sectional survey was conducted within a clustered sample of 24,159 individuals aged 12–80 years in 2012–13 within the population of Southern China. Breakfast eating habits were categorically defined by consumption frequency (‘scarcely, sometimes or always’). Health-promoting lifestyle was assessed via the health-promoting lifestyle profile (HPLP-II). SHS was evaluated using the medical examination report and Sub-health Measurement Scale V1.0 (SHMS V1.0).
Of the 24,159 participants, the prevalence rates for the ‘health’ , ‘SHS’ , and ‘disease’ were 18.8%, 46.0%, and 35.2%, respectively. Overall, 19.6% of participants reported ‘scarce’ breakfast eating habits, with frequent breakfast eaters scoring higher on both HPLP-II and SHMS V1.0. After demographic adjustment, regression analyses revealed a significant association between breakfast eating habits and healthy lifestyle (p <0.001). There were lower levels of breakfast consumption regularity amongst individuals with SHS than those with disease. Categorically ‘scarce’ breakfast eaters were approximately three times more likely to be assigned SHS (OR: 2.745, 95% CI: 2.468-3.053), while infrequent breakfast eaters (‘sometimes’) were just less than twice as likely to be assessed as being of SHS (OR: 1.731, 95% CI: 1.595-1.879).
Breakfast eating habits are significantly associated with a healthy lifestyle, and appear to be a useful predictor of a healthy lifestyle. Irregular breakfast eating habits are related to an increased risk of SHS; increased breakfast eating frequency may contribute to lowering the prevalence of SHS in Southern China.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0348-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4269950  PMID: 25496597
Breakfast eating habits; Suboptimal health status(SHS); Healthy lifestyle; Cross sectional study
8.  Increased susceptibility to pulmonary Pseudomonas infection in Splunc1 knockout mice 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(8):10.4049/jimmunol.1202340.
The airway epithelium is the first line of host defense against pathogens. The short PLUNC 1 (SPLUNC1) protein is secreted in respiratory tracts and a member of the BPI fold-containing (BPIF) protein family, which shares structural similarities with bactericidal/permeability-increasing (BPI)-like proteins. On the basis of its homology with BPIs and restricted expression of SPLUNC1 in serous cells of submucosal glands and surface epithelial cells of the upper respiratory tract, SPLUNC1 is thought to possess antimicrobial activity in host defense. SPLUNC1 is also reported to have surfactant properties, which may contribute to anti-biofilm defenses. The objective of this study was to determine the in vivo functions of SPLUNC1 following Pseudomonas aeruginosa infection and to elucidate the underlying mechanism, using a knockout (KO) mouse model with a genetic ablation of Splunc1. Splunc1 KO mice showed accelerated mortality and increased susceptibility to P. aeruginosa infection with significantly decreased survival rates, increased bacterial burdens, exaggerated tissue injuries, and elevated proinflammatory cytokine levels as compared to those of their wild-type (WT) littermates. Increased neutrophil infiltration in Splunc1 KO mice was accompanied by elevated chemokine levels including Cxcl1, Cxcl2, and Ccl20. Furthermore, the expression of several epithelial secretory proteins and antimicrobial molecules was considerably suppressed in the lungs of Splunc1 KO mice. The deficiencya of Splunc1 in mouse airway epithelium also results in increased biofilm formation of P. aeruginosa. Taken together, our results support that the ablation of Splunc1 in mouse airways affects the mucociliary clearance, resulting in decreased innate immune response during Pseudomonas-induced respiratory infection.
PMCID: PMC3839417  PMID: 24048904
splunc1; epithelium; mucociliary clearance; Pseudomonas infection
9.  Association of lifestyle factors and suboptimal health status: a cross-sectional study of Chinese students 
BMJ Open  2014;4(6):e005156.
Suboptimal health status (SHS) is considered to be an intermediate status between disease and health, and is characterised by a decline in vitality, in physiological function and in the capacity for adaptation. Although the incidence of SHS is high, the underlying causes remain unclear. Lifestyle is one of the most important factors affecting health status; however, the relationship between SHS and lifestyle has not been elucidated.
Cross-sectional survey.
A questionnaire, based on ‘Health Promoting Lifestyle Profile-II (HPLP-II)’ and ‘Sub-Health Measurement Scale V1.0 (SHMS V1.0)’, was sent to four colleges in four districts (Guangzhou, Foshan, Zhanjiang and Shaoguan) of China between May and July 2013.
A total of 12 429 questionnaires were distributed during the study period, and 11 144 completed responses were received.
The prevalence rates for the ‘healthy’, ‘SHS’ and ‘disease’ groups of respondents (students) were 22.81% (2542), 55.9% (6234) and 21.25% (2368), respectively. Most of the students reported a ‘moderate’ or ‘good’ lifestyle. There were significant differences in lifestyle and health status between the two genders. It was notable that health status was significantly positively correlated with lifestyle (r=0.563). For every dimension of the HPLP-II model, the mean values were lower for those participants who reported as ‘SHS’ or ‘disease’ than for those who reported that they were ‘healthy’. The individual dimensions of the HPLP-II model, including ‘spiritual growth’, ‘health responsibility’, ‘physical activity’, ‘interpersonal relations’ and ‘stress management’ were all related to SHS.
Health status is significantly positively correlated with lifestyle. Poor lifestyle is a risk factor for SHS. Conversely, adopting a healthier lifestyle can improve SHS.
Trial registration number
PMCID: PMC4067885  PMID: 24951109
10.  The Effect of Chinese Herbal Medicine on Albuminuria Levels in Patients with Diabetic Nephropathy: A Systematic Review and Meta-Analysis 
To evaluate the effect of Chinese herbal medicine (CHM) on albuminuria levels in patients with diabetic nephropathy (DN), we performed comprehensive searches on Medline database, Cochrane Library, CNKI database, CBM database, Wanfang database, and VIP database up to December 2012. A total of 29 trials including 2440 participants with DN met the selection criteria. CHM was tested to be more effective in reducing urinary albumin excretion rate (UAER) (MD −82.95 μg/min, [−138.64, −27.26]) and proteinuria (MD −565.99 mg/24 h, [−892.41, −239.57]) compared with placebo. CHM had a greater beneficial effect on reduction of UAER (MD −13.41 μg/min, [−20.63, −6.19]) and proteinuria (MD −87.48 mg/24 h, [−142.90, −32.06]) compared with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Combination therapy with CHM and ACEI/ARB showed significant improvement in UAER (MD −28.18 μg/min, [−44.4, −11.97]), urinary albumin-creatinine ratio (MD −347.00, [−410.61, −283.39]), protein-creatinine ratio (MD −2.49, [−4.02, −0.96]), and proteinuria (MD −26.60 mg/24 h, [−26.73, −26.47]) compared with ACEI/ARB alone. No serious adverse events were reported. CHM seems to be an effective and safe therapy option to treat proteinuric patients with DN, suggesting that further study of CHM in the treatment of DN is warranted in rigorously designed, multicentre, large-scale trials with higher quality worldwide.
PMCID: PMC3770054  PMID: 24062795
11.  Surveillance of Antimicrobial Susceptibility Patterns among Shigella Species Isolated in China during the 7-Year Period of 2005-2011 
Annals of Laboratory Medicine  2013;33(2):111-115.
Shigella is a frequent cause of bacterial dysentery in the developing world. Treatment with antibiotics is recommended for shigellosis, but the options are limited due to globally emerging resistance. This study was conducted to determine the frequency and pattern of antimicrobial susceptibility of Shigella in China.
We studied the antimicrobial resistance profiles of 308 Shigella spp. strains (260 S. flexneri, 40 S. sonnei, 5 S. boydii, and 3 S. dysenteriae) isolated from fecal samples of patients (age, from 3 months to 92 yr) presenting with diarrhea in different districts of Anhui, China. The antimicrobial resistance of strains was determined by the agar dilution method according to the CSLI guidelines.
The most common serogroup in the Shigella isolates was S. flexneri (n=260, 84.4%), followed by S. sonnei (n=40, 13.0%). The highest resistance rate was found for nalidixic acid (96.4%), followed by ampicillin (93.2%), tetracycline (90.9%), and trimethoprim/sulfamethoxazole (80.8%). Among the isolates tested, 280 (91.0%) were multidrug resistant (resistant to ≥2 agents). The most common resistance pattern was the combination of ampicillin, tetracycline, and trimethoprim/sulfamethoxazole (70.8%). Resistance to ampicillin and tetracycline were more common among S. flexneri than among S. sonnei isolates.
S. flexneri is predominant in Anhui, China, and its higher antimicrobial resistance rate compared with that of S. sonnei is a cause for concern. Continuous monitoring of resistance patterns is necessary to control the spread of resistance in Shigella. The recommendations for antimicrobial treatment must be updated regularly based on surveillance results.
PMCID: PMC3589635  PMID: 23482897
Antimicrobial susceptibility; Antimicrobial resistance; Shigella
12.  Lack of Association between NLGN3, NLGN4, SHANK2 and SHANK3 Gene Variants and Autism Spectrum Disorder in a Chinese Population 
PLoS ONE  2013;8(2):e56639.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication, absence or delay in language development, and stereotyped or repetitive behaviors. Genetic studies show that neurexin-neuroligin (NRXN-NLGN) pathway genes contribute susceptibility to ASD, which include cell adhesion molecules NLGN3, NLGN4 and scaffolding proteins SHANK2 and SHANK3. Neuroligin proteins play an important role in synaptic function and trans-synaptic signaling by interacting with presynaptic neurexins. Shank proteins are scaffolding molecules of excitatory synapses, which function as central organizers of the postsynaptic density. Sequence level mutations and structural variations in these genes have been identified in ASD cases, while few studies were performed in Chinese population. In this study, we examined the copy numbers of four genes NLGN4, NLGN3, SHANK2, and SHANK3 in 285 ASD cases using multiplex fluorescence competitive polymerase chain reaction (PCR). We also screened the regulatory region including the promoter region and 5′/3′ untranslated regions (UTR) and the entire coding region of NLGN4 in a cohort of 285 ASD patients and 384 controls by direct sequencing of genomic DNA using the Sanger method. DNA copy number calculation in four genes showed no deletion or duplication in our cases. No missense mutations in NLGN4 were identified in our cohort. Association analysis of 6 common SNPs in NLGN4 did not find significant difference between ASD cases and controls. These findings showed that these genes may not be major disease genes in Chinese ASD cases.
PMCID: PMC3582503  PMID: 23468870
13.  Marginal Hazard Regression for Correlated Failure Time Data with Auxiliary Covariates 
Lifetime Data Analysis  2011;18(1):116-138.
In many biomedical studies, it is common that due to budget constraints, the primary covariate is only collected in a randomly selected subset from the full study cohort. Often, there is an inexpensive auxiliary covariate for the primary exposure variable that is readily available for all the cohort subjects. Valid statistical methods that make use of the auxiliary information to improve study efficiency need to be developed. To this end, we develop an estimated partial likelihood approach for correlated failure time data with auxiliary information. We assume a marginal hazard model with common baseline hazard function. The asymptotic properties for the proposed estimators are developed. The proof of the asymptotic results for the proposed estimators is nontrivial since the moments used in estimating equation are not martingale-based and the classical martingale theory is not sufficient. Instead, our proofs rely on modern empirical theory. The proposed estimator is evaluated through simulation studies and is shown to have increased efficiency compared to existing methods. The proposed methods are illustrated with a data set from the Framingham study.
PMCID: PMC3259288  PMID: 22094533
Marginal hazard model; Correlated failure time; Validation set; Auxiliary covariate
14.  Scavenger Receptor B1 is a Potential Biomarker of Human Nasopharyngeal Carcinoma and Its Growth is Inhibited by HDL-mimetic Nanoparticles 
Theranostics  2013;3(7):477-486.
Nasopharyngeal carcinoma (NPC) is a very regional malignant head and neck cancer that has attracted widespread attention for its unique etiology, epidemiology and therapeutic options. To achieve high cure rates in NPC patients, theranostic approaches are actively being pursued and improved efforts remain desirable in identifying novel biomarkers and establishing effective therapeutic approaches with low long-term toxicities. Here, we discovered that the scavenger receptor class B type I (SR-B1) was overexpressed in all investigated NPC cell lines and 75% of NPC biopsies, demonstrating that SR-B1 is a potential biomarker of NPC. Additional functional analysis showed that SR-B1 has great effect on cell motility while showing no significant impact on cell proliferation. As high-density lipoproteins (HDL) exhibit strong binding affinities to SR-B1 and HDL mimetic peptides are reportedly capable of inhibiting tumor growth, we further examined the SR-B1 targeting ability of a highly biocompatible HDL-mimicking peptide-phospholipid scaffold (HPPS) nanocarrier and investigated its therapeutic effect on NPC. Results show that NPC cells with higher SR-B1 expression have superior ability in taking up the core constituents of HPPS. Moreover, HPPS inhibited the motility and colony formation of 5-8F cells, and significantly suppressed the NPC cell growth in nude mice without inducing tumor cell necrosis or apoptosis. These results indicate that HPPS is not only a NPC-targeting nanocarrier but also an effective anti-NPC drug. Together, the identification of SR-B1 as a potential biomarker and the use of HPPS as an effective anti-NPC agent may shed new light on the diagnosis and therapeutics of NPC.
PMCID: PMC3706691  PMID: 23843895
Cancer theranostics; nasopharyngeal carcinoma; biomarker; SR-B1; lipoprotein nanocarrier.
15.  Effects of second hand smoke on airway secretion and mucociliary clearance 
The airway acts as the first defense against inhaled pathogens and particulate matter from the environment. One major way for the airway to clear inhaled foreign objects is through mucociliary clearance (MCC), an important component of the respiratory innate immune defense against lung disease. MCC is characterized by the upward movement of mucus by ciliary motion that requires a balance between the volume and composition of the mucus, adequate periciliary liquid (PCL) volume, and normal ciliary beat frequency (CBF). Airway surface fluid (ASL) is a thin layer liquid that consists of the highly viscous mucus upper “gel” layer, and the watery lubricating lower “sol” layer. Mucus production, secretion and clearance are considered to play a critical role in maintenance of airway health because it maintains hydration in the airway and traps particulates, bacteria, and viruses. Different types of epithelial cells, including secretory cells, and ciliated cells, contribute to the MCC function. Cigarette smoke (CS) contains chemicals and particulates that significantly affect airway secretion. Active and passive CS-induced chronic obstructive pulmonary disease (COPD) is frequently associated with hyperplasia of goblet cells and submucosal glands (SMGs), thus increasing the secretory capacity of the airways that impairs MCC.
PMCID: PMC3428780  PMID: 22973232
epithelium; mucus; mucociliary clearance; smoke
16.  Semiparametric inference for a 2-stage outcome-auxiliary-dependent sampling design with continuous outcome 
Biostatistics (Oxford, England)  2011;12(3):521-534.
Two-stage design has long been recognized to be a cost-effective way for conducting biomedical studies. In many trials, auxiliary covariate information may also be available, and it is of interest to exploit these auxiliary data to improve the efficiency of inferences. In this paper, we propose a 2-stage design with continuous outcome where the second-stage data is sampled with an “outcome-auxiliary-dependent sampling” (OADS) scheme. We propose an estimator which is the maximizer for an estimated likelihood function. We show that the proposed estimator is consistent and asymptotically normally distributed. The simulation study indicates that greater study efficiency gains can be achieved under the proposed 2-stage OADS design by utilizing the auxiliary covariate information when compared with other alternative sampling schemes. We illustrate the proposed method by analyzing a data set from an environmental epidemiologic study.
PMCID: PMC3114654  PMID: 21252082
Auxiliary covariate; Kernel smoothing; Outcome-auxiliary-dependent sampling; 2-stage sampling design
17.  High Proportion of 22q13 Deletions and SHANK3 Mutations in Chinese Patients with Intellectual Disability 
PLoS ONE  2012;7(4):e34739.
Intellectual disability (ID) is a heterogeneous disorder caused by chromosomal abnormalities, monogenic factors and environmental factors. 22q13 deletion syndrome is a genetic disorder characterized by severe ID. Although the frequency of 22q13 deletions in ID is unclear, it is believed to be largely underestimated. To address this issue, we used Affymetrix Human SNP 6.0 array to detect the 22q13 deletions in 234 Chinese unexplained ID patients and 103 controls. After the Quality Control (QC) test of raw data, 22q13 deletions were found in four out of 230 cases (1.7%), while absent in parents of the cases and 101 controls. A review of genome-wide microarray studies in ID was performed and the frequency of 22q13 deletions from the literatures was 0.24%, much lower than our report. The overlapping region shared by all 4 cases encompasses the gene SHANK3. A heterozygous de novo nonsense mutation Y1015X of SHANK3 was identified in one ID patient. Cortical neurons were prepared from embryonic mice and were transfected with a control plasmid, shank3 wild-type (WT) or mutant plasmids. Overexpression of the Y1015 mutant in neurons significantly affected neurite outgrowth compared with shank3 WT. These findings suggest that 22q13 deletions may be a more frequent cause for Chinese ID patients than previously thought, and the SHANK3 gene is involved in the neurite development.
PMCID: PMC3324537  PMID: 22509352
18.  Identification of putative biomarkers for the serodiagnosis of drug-resistant Mycobacterium tuberculosis 
Proteome Science  2012;10:12.
Early diagnosis and treatment of Mycobacterium tuberculosis infection can prevent most deaths resulting from this pathogen; however, multidrug-resistant strains present serious threats to global tuberculosis control and prevention efforts. In this study, we identified antigens that could be used for the serodiagnosis of drug-resistant M. tuberculosis strains, using a proteomics-based analysis.
Serum from patients infected with drug-resistant or drug-susceptible M. tuberculosis strains and healthy controls was subjected to two-dimensional gel electrophoresis using a western blot approach. This procedure identified nine immunoreactive proteins, which were subjected to MALDI-TOF-MS analysis. Six recombinant proteins, namely rRv2031c, rRv0444c, rRv2145c, rRv3692, rRv0859c, and rRv3040, were expressed and used to determine the immuno-reactivity of 100 serum samples. Antibody reactivity against rRv2031c, rRv3692, and rRv0444c was consistently observed. Among them, the best sensitivity and specificity of rRv3692 were 37% and 95% respectively. Furthermore, when rRv2031c and rRv3692 or rRv2031c, rRv3692, and rRv0444c were combined in 2:1 or equal amounts, the assay sensitivity and specificity were improved to 56.7% and 100% respectively.
These results suggest that Rv2031c, Rv3692, and Rv0444c are possible candidate biomarkers for effective use in the serodiagnosis of drug-resistant tuberculosis infections, and a combined formula of these antigens should be considered when designing a subunit assay kit.
PMCID: PMC3305424  PMID: 22364187
Immunoproteomics; Mycobacterium tuberculosis; Drug-resistance; Serodiagnosis
19.  Additive–multiplicative rates model for recurrent events 
Lifetime data analysis  2010;16(3):353-373.
Recurrent events are frequently encountered in biomedical studies. Evaluating the covariates effects on the marginal recurrent event rate is of practical interest. There are mainly two types of rate models for the recurrent event data: the multiplicative rates model and the additive rates model. We consider a more flexible additive–multiplicative rates model for analysis of recurrent event data, wherein some covariate effects are additive while others are multiplicative. We formulate estimating equations for estimating the regression parameters. The estimators for these regression parameters are shown to be consistent and asymptotically normally distributed under appropriate regularity conditions. Moreover, the estimator of the baseline mean function is proposed and its large sample properties are investigated. We also conduct simulation studies to evaluate the finite sample behavior of the proposed estimators. A medical study of patients with cystic fibrosis suffered from recurrent pulmonary exacerbations is provided for illustration of the proposed method.
PMCID: PMC3199147  PMID: 20229314
Recurrent events; Rate regression; Additive–multiplicative rates model; Counting process; Empirical process
20.  Multivariate Failure Times Regression with a Continuous Auxiliary Covariate 
Journal of multivariate analysis  2010;101(3):679-691.
How to take advantage of the available auxiliary covariate information when the primary covariate of interest is not measured is a frequently encountered question in biomedical study. In this paper, we consider the multivariate failure times regression analysis in which the primary covariate is assessed only in a validation set but a continuous auxiliary covariate for it is available for all subjects in the study cohort. Under the frame of marginal hazard model, we propose to estimate the induced relative risk function in the nonvalidation set through kernel smoothing method and then obtain an estimated pseudo-partial likelihood function. The proposed estimated pseudo-partial likelihood estimator is shown to be consistent and asymptotically normal. We also give an estimator of the marginal cumulative baseline hazard function. Simulations are conducted to evaluate the finite sample performance of our proposed estimator. The proposed method is illustrated by analyzing a heart disease data from Studies of Left Ventricular Dysfunction (SOLVD).
PMCID: PMC3182102  PMID: 21966052
Multivariate Failure Times; Auxiliary Covariate; Pseudo-Partial Likelihood; Kernel Smoothing; Validation Sample
21.  Significance of differential expression of thymidylate synthase in normal and primary tumor tissues from patients with colorectal cancer 
The role of thymidylate synthase (TS) is essential as a key rate-limiting enzyme in DNA synthesis. It is the primary target of fluorouracil and its derivates in colorectal cancer. In this study, TS mRNA expression was examined in primary tumor and normal tissues from 76 patients with high- risk stage II/III colorectal cancer by laser capture microdissection and polymerase chain reaction. Thirty (39.47%) patients were found to have higher TS expression in primary tumors with earlier stage (P = 0.018), lower histological grades (P = 0.001) and high frequency microsatellite instability (P = 0.000). Multivariate analysis showed that microsatellite instability, histological grade and number of lymph nodes examined are independent prognostic markers.
PMCID: PMC3170281  PMID: 21824439
22.  Estimated Pseudo-Partial-Likelihood Method for Correlated Failure Time Data with Auxiliary Covariates 
Biometrics  2009;65(4):1184.
As biological studies become more expensive to conduct, statistical methods that take advantage of existing auxiliary information about an expensive exposure variable are desirable in practice. Such methods should improve the study efficiency and increase the statistical power for a given number of assays. In this paper, we consider an inference procedure for multivariate failure time with auxiliary covariate information. We propose an estimated pseudo-partial likelihood estimator under the marginal hazard model framework and develop the asymptotic properties for the proposed estimator. We conduct simulation studies to evaluate the performance of the proposed method in practical situations and demonstrate the proposed method with a data set from the Studies of Left Ventricular Dysfunction (SOLVD,1991).
PMCID: PMC2819485  PMID: 19432779
Auxiliary covariate; Marginal hazard model; Multivariate data; Pseudo-partial likelihood; Validation sample
23.  Zili Inhibits Transforming Growth Factor-β Signaling by Interacting with Smad4* 
The Journal of Biological Chemistry  2009;285(6):4243-4250.
Piwi proteins are required for germ cell proliferation, differentiation, and germ line stem cell maintenance. In normal tissues, human and mouse Piwil2 are primarily expressed in testis but widely expressed in tumors. However, the underlying mechanism remains largely unknown. In vertebrates, transforming growth factor (TGF)-β signaling plays an important role in patterning embryo and control of cell growth and differentiation. A previous study has shown a role for Zili, a Piwil2 gene in zebrafish, in germ cells in zebrafish. Here we report that zili functions in patterning the early embryo and inhibits TGF-β signaling. Whole mount expression analysis shows that zili expresses not only in PGCs but also in axis. Ectopic expression of zili causes fusion of the eyes and reduction of mesodermal marker genes expression, suggesting that zili functions to inhibit Nodal signaling and mesoderm formation. Genetic interaction shows that zili inhibits Nodal and bone morphogenetic protein signaling. The results of protein interaction assays identify that Zili binds to Smad4 via its N-terminal domain and prevents the formation of Smad2/3/4 and Smad1/5/9/4 complexes to antagonize TGF-β signaling. This work shows that zili plays a role in early embryogenesis beyond germ line as a novel negative regulator of TGF-β signaling, extending the function of Piwi proteins in vertebrates.
PMCID: PMC2823563  PMID: 20007318
Cytokines/TGF-β; Development Differentiation; Gene Regulation; Smad/Transcription Factor; Zebra fish; Smad4; TGF-β; Zili; Piwil2
24.  An Effective Amperometric Biosensor Based on Gold Nanoelectrode Arrays 
Nanoscale Research Letters  2008;4(3):210-215.
A sensitive amperometric biosensor based on gold nanoelectrode array (NEA) was investigated. The gold nanoelectrode array was fabricated by template-assisted electrodeposition on general electrodes, which shows an ordered well-defined 3D structure of nanowires. The sensitivity of the gold NEA to hydrogen peroxide is 37 times higher than that of the conventional electrode. The linear range of the platinum NEA toward H2O2 is from 1 × 10−6 to 1 × 10−2 M, covering four orders of magnitudes with detection limit of 1 × 10−7 M and a single noise ratio (S/N) of four. The enzyme electrode exhibits an excellent response performance to glucose with linear range from 1 × 10−5 to 1 × 10−2 M and a fast response time within 8 s. The Michaelis–Menten constant km and the maximum current density imax of the enzyme electrode were 4.97 mM and 84.60 μA cm−2, respectively. This special nanoelectrode may find potential application in other biosensors based on amperometric signals.
PMCID: PMC2893911  PMID: 20596449
Gold nanowires; Nanoelectrode arrays; Amperometric biosensor
25.  An Effective Amperometric Biosensor Based on Gold Nanoelectrode Arrays 
Nanoscale Research Letters  2008;4(3):210-215.
A sensitive amperometric biosensor based on gold nanoelectrode array (NEA) was investigated. The gold nanoelectrode array was fabricated by template-assisted electrodeposition on general electrodes, which shows an ordered well-defined 3D structure of nanowires. The sensitivity of the gold NEA to hydrogen peroxide is 37 times higher than that of the conventional electrode. The linear range of the platinum NEA toward H2O2is from 1 × 10−6to 1 × 10−2 M, covering four orders of magnitudes with detection limit of 1 × 10−7 M and a single noise ratio (S/N) of four. The enzyme electrode exhibits an excellent response performance to glucose with linear range from 1 × 10−5to 1 × 10−2 M and a fast response time within 8 s. The Michaelis–Menten constantkm and the maximum current densityimaxof the enzyme electrode were 4.97 mM and 84.60 μA cm−2, respectively. This special nanoelectrode may find potential application in other biosensors based on amperometric signals.
PMCID: PMC2893911  PMID: 20596449
Gold nanowires; Nanoelectrode arrays; Amperometric biosensor

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