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1.  Disparities in the Prevalence of Metabolic Syndrome (MS) and its Components Among University Employees by Age, Gender and Occupation 
Background: Metabolic Syndrome (MS), a known risk factor for Cardiovascular Disease (CVD) and type II diabetes is an emerging epidemic in China. Studies carried out on the general population indicate a varied clustering of cardiovascular risks in many parts of the country. However, there is limited data on its prevalence in the working population. Workplace can serve as an important place for prevention, control and management of CVD risks. The aim of this study was to investigate the prevalence of MS and its components among University workers, and determine how the prevalence varied according to sex and occupation.
Methods: This was a cross-sectional study of 2,428 University employees (22-60 years) who received an annual clinical examination at the University hospital. Anthropometric measurements, blood pressure, Fasting Plasma Glucose (FPG), and lipid profiles were measured. MS was defined according to the National Cholesterol Education Program Adult Treatment panel III modified criteria.
Results: Overall prevalence of MS was 6.1%, higher in males (5.1%) than females (1.1%), and increased with age. The most prevalent MS components in all workers were hypertension (37.9%) and hypertryglyceridemia (20.8%), corresponding rates in males were 28.3% and 16.1% while females had a prevalence of 9.6% and 4.7%. After adjustment for age, administrative work was associated (p<0.05) with increased hypertension (odds ratio (OR) =1.474; 95% confidence interval (CI), 1.146-1.896) and hyperglycemia (OR=1.469; 95% CI, 1.082-1.993) in male workers, and with hypertension (OR=1.492; 95% CI, 1.071-2.080) in females. However, prevalence of hypertryglyceridemia was lower (OR=0.390; 95% CI, 0.204-0.746) in female administrators compared to those in academics. Obesity, MS and reduced High Density Lipoprotein (HDL) cholesterol prevalence was not different (p>0.05) between the two occupations in both sexes.
Conclusions: Prevalence of MS and its components was higher in male workers than in females, increased with age, and were more common in administrative workers. The findings support the need for gender and occupation specific health interventions to prevent CVDs and type II diabetes in the workplace.
PMCID: PMC3972601
Obesity; Dyslipidemia; Hyperglycemia; Hypertension; Cardiovascular diseases
2.  Different Frequencies of Drug Resistance Mutations among HIV-1 Subtypes Circulating in China: A Comprehensive Study 
PLoS ONE  2014;9(3):e91803.
The rapid spreading of HIV drug resistance is threatening the overall success of free HAART in China. Much work has been done on drug-resistant mutations, however, most of which were based on subtype B. Due to different genetic background, subtypes difference would have an effect on the development of drug-resistant mutations, which has already been proved by more and more studies. In China, the main epidemic subtypes are CRF07_BC, CRF08_BC, Thai B and CRF01_AE. The depiction of drug resistance mutations in those subtypes will be helpful for the selection of regimens for Chinese. In this study, the distributions difference of amino acids at sites related to HIV drug resistance were compared among subtype B, CRF01_AE, CRF07_BC and CRF08_BC strains prevalent in China. The amino acid composition of sequences belonging to different subtypes, which were obtained from untreated and treated individuals separately, were also compared. The amino acids proportions of 19 sites in RT among subtype B, CRF01_AE and CRF08_BC have significant difference in drug resistance groups (chi-square test, p<0.05). Genetic barriers analysis revealed that sites 69, 138, 181, 215 and 238 were significantly different among subtypes (Kruskal Wallis test, p<0.05). All subtypes shared three highest prevalent drug resistance sites 103, 181 and 184 in common. Many drug resistant sites in protease show surprising high proportions in almost all subtypes in drug-naïve patients. This is the first comprehensive study in China on different development of drug resistance among different subtypes. The detailed data will lay a foundation for HIV treatment regimens design and improve HIV therapy in China.
PMCID: PMC3963863  PMID: 24663120
3.  MicroRNA-9 up-regulates E-cadherin through inhibition of NF-κB1–Snail1 pathway in melanoma 
The Journal of pathology  2011;226(1):61-72.
MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally regulate gene expression. Hsa-miR-9 has been shown to have opposite functions in different tumour types; however, the underlying mechanism is unclear. Here we show that hsa-miR-9 is down-regulated in metastatic melanomas compared to primary melanomas. Overexpression of miR-9 in melanoma cells resulted in significantly decreased cell proliferation and migratory capacity with decreased F-actin polymerization and down-regulation of multiple GTPases involved in cytoskeleton remodelling. miR-9 overexpression induced significant down-regulation of Snail1 with a concomitant increase in E-cadherin expression. In contrast, knockdown of miR-9 increased Snail1 expression as well as melanoma cell proliferation and migration capacity. Mechanistically, miR-9 expression down-regulated NF-κB1 in melanoma and the effect was abolished by mutations in the putative miR-9 binding sites within the 3′-untranslated region (UTR) of NF-κB1. Anti-miR-9 miRNA inhibitor also increased the expression of NF-κB1. The effects of miR-9 on Snail1 expression and melanoma cell proliferation and migration were rescued by overexpression of NF-κB1 in these cells. Furthermore, miR-9 overexpression resulted in significantly decreased melanoma growth and metastasis in vivo. In summary, miR-9 inhibits melanoma proliferation and metastasis through down-regulation of the NF-κB1-Snail1 pathway. This study finds a new mechanism that miR-9 utilizes to decrease E-cadherin expression and inhibit melanoma progression. The results suggest that function of microRNAs is context and tumour type-specific.
PMCID: PMC3959162  PMID: 22131135
miR-9; NF-κB1; E-cadherin; Snail1; melanoma
4.  Determination of carbohydrate-deficient transferrin in a Han Chinese population 
BMC Biochemistry  2014;15:5.
Carbohydrate-deficient transferrin (CDT) is a widely used alcohol biomarker. Because of the high prevalence of chronic alcohol abuse in many countries, CDT plays an important role in the areas of traffic, clinical, and forensic medicine. However, CDT levels have not been determined in the Han Chinese population. Therefore, we investigated the frequency of genetic transferrin variants and the relationship between CDT levels and alcohol consumption in this population. From this data, we established a CDT cut-off for Han Chinese and evaluated the analytical performance of the CDT capillary zone electrophoresis system.
The prevalence of transferrin variants was 4.14%. The mean CDT level of the reference group was 0.73%. We recommended CDT level >1.5% as cut off standard of alcohol intake to ensuring the specificity was best. The CDT test total precision for 0.5%, 0.7%, and 1.55% was 14.4%, 11.5%, and 7.2%, respectively. The data showed good linearity in the studied range of 0.6% to 8.2%.
These results demonstrate that CDT is a useful marker to detect heavy daily alcohol consumption. We proposed and evaluated the first CDT cut-off for the Han Chinese population, and we showed that the CDT capillary zone electrophoresis system is a reliable analytic method.
PMCID: PMC3945810  PMID: 24571498
CDT; Alcohol biomarker; Capillary electrophoresis; Han Chinese population
5.  Chemokine signaling involving chemokine (C-C motif) ligand 2 plays a role in descending pain facilitation 
Neuroscience bulletin  2012;28(2):193-207.
Despite accumulating evidence on a role of immune cells and their associated chemicals in mechanisms of pain, few studies have addressed the potential role of chemokines in the descending facilitation of persistent pain. The present study was undertaken to test the hypothesis that the chemokine (C-C motif) ligand 2 (CCL2) (commonly known as monocyte chemoattractant protein-1) signaling in the rostral ventromedial medulla (RVM), a pivotal structure in brainstem pain modulatory circuitry, is involved in descending pain facilitation in rats.
An L5 spinal nerve ligation (SNL) was produced in rats under pentobarbital anesthesia. Western blot and immunohistochemistry were used to detect the expression levels of CCL2 and CCL2 receptor (CCR2), and examine their distributions compared with the neuronal marker NeuN as well as glial markers glial fibrillary acidic protein (GFAP, astroglial) and CD11b (microglial), respectively.
SNL induced an increase in CCL2 expression in the RVM, and this returned to the control level at 4 weeks after injury. The induced CCL2 colocalized with NeuN, but not with GFAP and CD11b. CCR2 was also upregulated by SNL in the RVM, and this increase lasted for at least 4 weeks. CCR2 was colocalized with CD11b but not GFAP. Few RVM neurons also exhibited CCR2 staining. Neutralizing CCL2 with an anti-CCL2 antibody (0.2–20 ng) or injecting RS-102895 (0.1–10 pmol), a CCR2b chemokine receptor antagonist, into the RVM on day 1 after SNL, significantly attenuated the established thermal and mechanical hypersensitivity. In addition, injection of recombinant rat CCL2 (0.03–3 pmol) into the RVM induced dose-dependent hyperalgesia, which was prevented by pretreatment with RS-102895 (10 pmol). Interleukin-1β (IL-1β), a potent inducer of neuronal CCL2, was also selectively upregulated in RVM reactive astrocytes. Injection of IL-1β (120 fmol) into the RVM induced behavioral hyperalgesia, which was blocked by RS-102895 (10 pmol). However, an IL-1 receptor antagonist (3 pmol) did not prevent CCL2 (3 pmol)-induced hyperalgesia. These results suggest that the effect of CCL2 is downstream to IL-1β signaling.
The IL-1β and CCL2-CCR2 signaling cascades play a role in neuron-glia-cytokine interactions and the descending facilitation of neuropathic pain.
PMCID: PMC3925328  PMID: 22466130
monocyte chemoattractant protein-1; chemokine (C-C motif) receptor 2; rostral ventromedial medulla; neuron-glial interaction; neuropathic pain; rat
6.  Rabies in Henan Province, China, 2010–2012 
Emerging Infectious Diseases  2014;20(2):331-333.
PMCID: PMC3901497  PMID: 24447764
rabies; rabies virus; viruses; zoonoses; China; Henan Province
7.  Impaired social decision making in patients with major depressive disorder 
BMC Psychiatry  2014;14:18.
Abnormal decision-making processes have been observed in patients with major depressive disorder (MDD). However, it is unresolved whether MDD patients show abnormalities in decision making in a social interaction context, in which decisions have actual influences on both the self-interests of the decision makers per se and those of their partners.
Using a well-studied ultimatum game (UG), which is frequently used to investigate social interaction behavior, we examined whether MDD can be associated with abnormalities in social decision-making behavior by comparing the acceptance rates of MDD patients (N = 14) with those of normal controls (N = 19).
The acceptance rates of the patients were lower than those of the normal controls. Additionally, unfair proposals were accepted at similar rates from computer partners and human partners in the MDD patients, unlike the acceptance rates in the normal controls, who were able to discriminatively treat unfair proposals from computer partners and human partners.
Depressed patients show abnormal decision-making behavior in a social interaction context. Several possible explanations, such as increased sensitivity to fairness, negative emotional state and disturbed affective cognition, have been proposed to account for the abnormal social decision-making behavior in patients with MDD. This aberrant social decision-making behavior may provide a new perspective in the search to find biomarkers for the diagnosis and prognosis of MDD.
PMCID: PMC3904421  PMID: 24450703
Ultimatum game; Major depressive disorder; Decision making; Fairness
8.  The chloride channel family gene CLCd negatively regulates pathogen-associated molecular pattern (PAMP)-triggered immunity in Arabidopsis  
Journal of Experimental Botany  2014;65(4):1205-1215.
It is shown that AtCLCd negatively regulates Arabidopsis PTI, probably by interacting with the PRR signalling pathway. Its sequence indicates that AtCLCd encodes a chloride/proton exchanger.
Chloride channel (CLC) family genes are ubiquitous from prokaryotes to eukaryotes and encode proteins with both channel and transporter activities. The Arabidopsis thaliana genome encodes seven CLC genes, and their products are found in a variety of cellular compartments and have various physiological functions. However, a role for AtCLCs in plant innate immunity has not previously been demonstrated. Here it is reported that AtCLCd is a negative regulator of pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI). T-DNA insertion mutants of AtCLCd exhibited enhanced responses to the elicitor, flg22. The PTI phenotypes of the clcd mutants were rescued by expression of AtCLCd. Overexpression of AtCLCd led to impaired flg22-induced responses. In line with a role for AtCLCd in PTI, the clcd mutants were more resistant to a virulent strain of the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 when spray inoculated, while AtCLCd-overexpressing lines displayed increased susceptibility to this pathogen. Interestingly, flg22 treatment was found to repress the expression of AtCLCd. In addition, its expression was elevated in mutants of the flg22 pattern recognition receptor (PRR) FLS2 and the PRR regulatory proteins BAK1 and BKK1, and reduced in an FLS2-overexpressing line. These latter findings indicate that FLS2 complexes regulate the expression of AtCLCd, further supporting a role for AtCLCd in PTI.
PMCID: PMC3935575  PMID: 24449384
Arabidopsis thaliana; AtCLCd; chloride channel; PAMP-triggered immunity.
9.  Mitotic phosphorylation of Exo84 disrupts exocyst assembly and arrests cell growth 
The Journal of Cell Biology  2013;202(1):97-111.
Mitotic phosphorylation of Exo84 disrupts the assembly of the exocyst complex, thereby inhibiting exocytosis of select secreted cargoes and cell surface expansion.
The rate of eukaryotic cell growth is tightly controlled for proper progression through each cell cycle stage and is important for cell size homeostasis. It was previously shown that cell growth is inhibited during mitosis when cells are preparing for division. However, the mechanism for growth arrest at this stage is unknown. Here we demonstrate that exocytosis of a select group of cargoes was inhibited before the metaphase–anaphase transition in the budding yeast Saccharomyces cerevisiae. The cyclin-dependent kinase, Cdk1, when bound to the mitotic cyclin Clb2, directly phosphorylated Exo84, a component of the exocyst complex essential for exocytosis. Mitotic phosphorylation of Exo84 disrupted the assembly of the exocyst complex, thereby affecting exocytosis and cell surface expansion. Our study demonstrates the coordination between membrane trafficking and cell cycle progression and provides a molecular mechanism by which cell growth is controlled during the cell division cycle.
PMCID: PMC3704991  PMID: 23836930
10.  Multiscale geometric modeling of macromolecules I: Cartesian representation 
Journal of computational physics  2014;257(Pt A):10.1016/
This paper focuses on the geometric modeling and computational algorithm development of biomolecular structures from two data sources: Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) in the Eulerian (or Cartesian) representation. Molecular surface (MS) contains non-smooth geometric singularities, such as cusps, tips and self-intersecting facets, which often lead to computational instabilities in molecular simulations, and violate the physical principle of surface free energy minimization. Variational multiscale surface definitions are proposed based on geometric flows and solvation analysis of biomolecular systems. Our approach leads to geometric and potential driven Laplace-Beltrami flows for biomolecular surface evolution and formation. The resulting surfaces are free of geometric singularities and minimize the total free energy of the biomolecular system. High order partial differential equation (PDE)-based nonlinear filters are employed for EMDB data processing. We show the efficacy of this approach in feature-preserving noise reduction. After the construction of protein multiresolution surfaces, we explore the analysis and characterization of surface morphology by using a variety of curvature definitions. Apart from the classical Gaussian curvature and mean curvature, maximum curvature, minimum curvature, shape index, and curvedness are also applied to macromolecular surface analysis for the first time. Our curvature analysis is uniquely coupled to the analysis of electrostatic surface potential, which is a by-product of our variational multiscale solvation models. As an expository investigation, we particularly emphasize the numerical algorithms and computational protocols for practical applications of the above multiscale geometric models. Such information may otherwise be scattered over the vast literature on this topic. Based on the curvature and electrostatic analysis from our multiresolution surfaces, we introduce a new concept, the polarized curvature, for the prediction of protein binding sites.
PMCID: PMC3855405  PMID: 24327772
Protein characterization; Variational multiscale surfaces; Curvature analysis; High order geometric PDEs; Free energy functional; EMDataBank; Protein data bank
11.  A Multicenter Phase II Study of Ganetespib Monotherapy in Patients with Genotypically Defined Advanced Non–Small Cell Lung Cancer 
Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non–small cell lung cancer (NSCLC).
Experimental Design
Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m2 ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies.
Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia.
Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement.
PMCID: PMC3874465  PMID: 23553849
12.  High-order fractional partial differential equation transform for molecular surface construction 
Molecular based mathematical biology  2012;1:10.2478/mlbmb-2012-0001.
Fractional derivative or fractional calculus plays a significant role in theoretical modeling of scientific and engineering problems. However, only relatively low order fractional derivatives are used at present. In general, it is not obvious what role a high fractional derivative can play and how to make use of arbitrarily high-order fractional derivatives. This work introduces arbitrarily high-order fractional partial differential equations (PDEs) to describe fractional hyperdiffusions. The fractional PDEs are constructed via fractional variational principle. A fast fractional Fourier transform (FFFT) is proposed to numerically integrate the high-order fractional PDEs so as to avoid stringent stability constraints in solving high-order evolution PDEs. The proposed high-order fractional PDEs are applied to the surface generation of proteins. We first validate the proposed method with a variety of test examples in two and three-dimensional settings. The impact of high-order fractional derivatives to surface analysis is examined. We also construct fractional PDE transform based on arbitrarily high-order fractional PDEs. We demonstrate that the use of arbitrarily high-order derivatives gives rise to time-frequency localization, the control of the spectral distribution, and the regulation of the spatial resolution in the fractional PDE transform. Consequently, the fractional PDE transform enables the mode decomposition of images, signals, and surfaces. The effect of the propagation time on the quality of resulting molecular surfaces is also studied. Computational efficiency of the present surface generation method is compared with the MSMS approach in Cartesian representation. We further validate the present method by examining some benchmark indicators of macromolecular surfaces, i.e., surface area, surface enclosed volume, surface electrostatic potential and solvation free energy. Extensive numerical experiments and comparison with an established surface model indicate that the proposed high-order fractional PDEs are robust, stable and efficient for biomolecular surface generation.
PMCID: PMC3869418  PMID: 24364020
Molecular surface generation; High order fractional derivatives; Fractional calculus; Fractional PDE transform
13.  Correction: Therapeutic Effects of 15 Hz Pulsed Electromagnetic Field on Diabetic Peripheral Neuropathy in Streptozotocin-Treated Rats 
PLoS ONE  2013;8(12):10.1371/annotation/b162aa26-6251-4db6-af5f-35b4d9ee5055.
PMCID: PMC3868465
14.  Pathophysiological Defects and Transcriptional Profiling in the RBM20-/- Rat Model 
PLoS ONE  2013;8(12):e84281.
Our recent study indicated that RNA binding motif 20 (Rbm20) alters splicing of titin and other genes. The current goals were to understand how the Rbm20-/- rat is related to physiological, structural, and molecular changes leading to heart failure. We quantitatively and qualitatively compared the expression of titin isoforms between Rbm20-/- and wild type rats by real time RT-PCR and SDS agarose electrophoresis. Isoform changes were linked to alterations in transcription as opposed to translation of titin messages. Reduced time to exhaustion with running in knockout rats also suggested a lower maximal cardiac output or decreased skeletal muscle performance. Electron microscopic observations of the left ventricle from knockout animals showed abnormal myofibril arrangement, Z line streaming, and lipofuscin deposits. Mutant skeletal muscle ultrastructure appeared normal. The results suggest that splicing alterations in Rbm20-/- rats resulted in pathogenic changes in physiology and cardiac ultrastructure. Secondary changes were observed in message levels for many genes whose splicing was not directly affected. Gene and protein expression data indicated the activation of pathophysiological and muscle stress-activated pathways. These data provide new insights on Rbm20 function and how its malfunction leads to cardiomyopathy.
PMCID: PMC3868568  PMID: 24367651
15.  Upregulation of Cleavage and Polyadenylation Specific Factor 4 in Lung Adenocarcinoma and Its Critical Role for Cancer Cell Survival and Proliferation 
PLoS ONE  2013;8(12):e82728.
Cleavage and polyadenylation specific factor 4 (CPSF4), a member of CPSF complex, plays a key role in mRNA polyadenylation and mRNA 3′ ends maturation. However, its possible role in lung cancer pathogenesis is unknown. In this study, we investigated the biological role and clinical significance of CPSF4 in lung cancer growth and survival and elucidated its underlying molecular mechanisms. We found that CPSF4 was highly expressed in lung adenocarcinoma cell lines and tumor tissue but was undetectable in 8 normal human tissues. We also found that CPSF4 overexpression was correlated with poor overall survival in patients with lung adenocarcinomas (P<0.001). Multivariate survival analyses revealed that higher CPSF4 expression was an independent prognostic factor for overall survival of the patients with lung adenocarcinomas. Suppression of CPSF4 by siRNA inhibited lung cancer cells proliferation, colony formation, and induced apoptosis. Mechanism studies revealed that these effects were achieved through simultaneous modulation of multiple signaling pathways. Knockdown of CPSF4 expression by siRNA markedly inhibited the phosphorylation of PI3K, AKT and ERK1/2 and JNK proteins. In contrast, the ectopic expression of CPSF4 had the opposite effects. Moreover, CPSF4 knockdown also induced the cleavage of caspase-3 and caspse-9 proteins. Collectively, these results demonstrate that CPSF4 plays a critical role in regulating lung cancer cell proliferation and survival and may be a potential prognostic biomarker and therapeutic target for lung adenocarcinoma.
PMCID: PMC3865097  PMID: 24358221
16.  miR-451 regulates dendritic cell cytokine responses to influenza infection1 
MicroRNAs are important post-transcriptional regulators in immune cells, but how viral infection regulates microRNA expression to shape dendritic cell responses has not been well characterized. We identified 20 miRNAs that were differentially expressed in primary murine dendritic cells in response to the double-stranded RNA agonist poly(I:C), a subset of which were modestly regulated by influenza infection. miR-451 was unique because it was induced more strongly in primary splenic and lung dendritic cells by live viral infection than by purified agonists of pattern recognition receptors. We determined that miR-451 regulates a subset of pro-inflammatory cytokine responses. Three types of primary dendritic cells treated with anti-sense RNA antagomirs directed against miR-451 secreted elevated levels of IL-6, TNF, CCL5/RANTES, and CCL3/MIP1α, and these results were confirmed using miR-451null cells. miR-451 negatively regulates YWHAZ/14-3-3ζ protein levels in various cell types, and we measured a similar inhibition of YWHAZ levels in dendritic cells. It is known that YWHAZ can control the activity of two negative regulators of cytokine production: FOXO3, which is an inhibitory transcription factor, and ZFP36/Tristetraprolin, which binds to AU-rich elements within 3′-UTRs to destabilize cytokine mRNAs. Inhibition of miR-451 expression correlated with increased YWHAZ protein expression and decreased ZFP36 expression, providing a possible mechanism for the elevated secretion of IL-6, TNF, CCL5/RANTES, and CCL3/MIP1α. miR-451 levels are themselves increased by IL-6 and type I interferon, potentially forming a regulatory loop. These data suggest that viral infection specifically induces a miRNA that directs a negative regulatory cascade to tune dendritic cell cytokine production.
PMCID: PMC3528339  PMID: 23169590
17.  Geometric modeling of subcellular structures, organelles, and multiprotein complexes 
Recently, the structure, function, stability, and dynamics of subcellular structures, organelles, and multi-protein complexes have emerged as a leading interest in structural biology. Geometric modeling not only provides visualizations of shapes for large biomolecular complexes but also fills the gap between structural information and theoretical modeling, and enables the understanding of function, stability, and dynamics. This paper introduces a suite of computational tools for volumetric data processing, information extraction, surface mesh rendering, geometric measurement, and curvature estimation of biomolecular complexes. Particular emphasis is given to the modeling of cryo-electron microscopy data. Lagrangian-triangle meshes are employed for the surface presentation. On the basis of this representation, algorithms are developed for surface area and surface-enclosed volume calculation, and curvature estimation. Methods for volumetric meshing have also been presented. Because the technological development in computer science and mathematics has led to multiple choices at each stage of the geometric modeling, we discuss the rationales in the design and selection of various algorithms. Analytical models are designed to test the computational accuracy and convergence of proposed algorithms. Finally, we select a set of six cryo-electron microscopy data representing typical subcellular complexes to demonstrate the efficacy of the proposed algorithms in handling biomolecular surfaces and explore their capability of geometric characterization of binding targets. This paper offers a comprehensive protocol for the geometric modeling of subcellular structures, organelles, and multiprotein complexes.
PMCID: PMC3568658  PMID: 23212797
macromolecules; geometric modeling; Laplace–Beltrami operator; high-order geometric PDEs; surface meshing; Gaussian curvature; mean curvature
18.  Case-Control Study on the Fibroblast Growth Factor Receptor 2 Gene Polymorphisms Associated with Breast Cancer in Chinese Han Women 
Journal of Breast Cancer  2013;16(4):366-371.
Genetic variation in fibroblast growth factor receptor 2 (FGFR2) is a newly described risk factor for breast cancer. This study aimed to evaluate the association of four single nucleotide polymorphisms (SNPs) in FGFR2 with breast cancer in Han Chinese women.
Two hundred three women with breast cancer and 200 breast cancer-free age-matched controls were selected. Four SNPs (rs2981579, rs1219648, rs2420946, and rs2981582) and their haplotypes were analyzed to test for their association with breast cancer susceptibility. The presence of the four FGFR2 SNPs was determined by polymerase chain reaction-restriction fragment length polymorphism analysis.
A statistically significant difference was observed in the frequency of rs2981582 in the FGFR2 gene (p<0.05) between case and control groups. In subjects stratified by menopausal status, rs2981582 TT, rs2420946 AA, and rs1219648 CC were significantly associated with the risk of breast cancer in postmenopausal subjects, but no significant associations between these four SNPs and the risk of breast cancer were identified in premenopausal subjects. Further, there was no significant association between hormone receptor status (estrogen receptor and progesterone receptor) and breast cancer risk. Six common (> 3%) haplotypes were identified. Three of these haplotypes, CGTC (odds ratio [OR], 0.613; 95% confidence interval [CI], 0.457-0.82; p=0.001), TGTC (OR, 6.561; 95% CI, 2.064-20.854; p<0.001), and CATC (OR, 12.645; 95% CI, 1.742-91.799; p=0.001) were significantly associated with breast cancer risk.
Our findings indicated that the SNP rs2981582 and haplotypes CGTC, TGTC, and CATC in FGFR2 may be associated with an increased risk of breast cancer in Han Chinese women.
PMCID: PMC3893337  PMID: 24454457
Breast neoplasms; Single nucleotide polymorphisms; Type 2 fibroblast growth factor receptor
19.  Pulsed Electromagnetic Fields Improve Bone Microstructure and Strength in Ovariectomized Rats through a Wnt/Lrp5/β-Catenin Signaling-Associated Mechanism 
PLoS ONE  2013;8(11):e79377.
Growing evidence has demonstrated that pulsed electromagnetic field (PEMF), as an alternative noninvasive method, could promote remarkable in vivo and in vitro osteogenesis. However, the exact mechanism of PEMF on osteopenia/osteoporosis is still poorly understood, which further limits the extensive clinical application of PEMF. In the present study, the efficiency of PEMF on osteoporotic bone microarchitecture and bone quality together with its associated signaling pathway mechanisms was systematically investigated in ovariectomized (OVX) rats. Thirty rats were equally assigned to the Control, OVX and OVX+PEMF groups. The OVX+PEMF group was subjected to daily 8-hour PEMF exposure with 15 Hz, 2.4 mT (peak value). After 10 weeks, the OVX+PEMF group exhibited significantly improved bone mass and bone architecture, evidenced by increased BMD, Tb.N, Tb.Th and BV/TV, and suppressed Tb.Sp and SMI levels in the MicroCT analysis. Three-point bending test suggests that PEMF attenuated the biomechanical strength deterioration of the OVX rat femora, evidenced by increased maximum load and elastic modulus. RT-PCR analysis demonstrated that PEMF exposure significantly promoted the overall gene expressions of Wnt1, LRP5 and β-catenin in the canonical Wnt signaling, but did not exhibit obvious impact on either RANKL or RANK gene expressions. Together, our present findings highlight that PEMF attenuated OVX-induced deterioration of bone microarchitecture and strength in rats by promoting the activation of Wnt/LRP5/β-catenin signaling rather than by inhibiting RANKL-RANK signaling. This study enriches our basic knowledge to the osteogenetic activity of PEMF, and may lead to more efficient and scientific clinical application of PEMF in inhibiting osteopenia/osteoporosis.
PMCID: PMC3828367  PMID: 24244491
20.  Anti-Angiogenic Effect of Triptolide in Rheumatoid Arthritis by Targeting Angiogenic Cascade 
PLoS ONE  2013;8(10):e77513.
Rheumatoid arthritis (RA) is characterized by a pre-vascular seriously inflammatory phase, followed by a vascular phase with high increase in vessel growth. Since angiogenesis has been considered as an essential event in perpetuating inflammatory and immune responses, as well as supporting pannus growth and development of RA, inhibition of angiogenesis has been proposed as a novel therapeutic strategy for RA. Triptolide, a diterpenoid triepoxide from Tripterygium wilfordii Hook F, has been extensively used in treatment of RA patients. It also acts as a small molecule inhibitor of tumor angiogenesis in several cancer types. However, it is unclear whether triptolide possesses an anti-angiogenic effect in RA. To address this problem, we constructed collagen-induced arthritis (CIA) model using DA rats by the injection of bovine type II collagen. Then, CIA rats were treated with triptolide (11–45 µg/kg/day) starting on the day 1 after first immunization. The arthritis scores (P<0.05) and the arthritis incidence (P<0.05) of inflamed joints were both significantly decreased in triptolide-treated CIA rats compared to vehicle CIA rats. More interestingly, doses of 11∼45 µg/kg triptolide could markedly reduce the capillaries, small, medium and large vessel density in synovial membrane tissues of inflamed joints (all P<0.05). Moreover, triptolide inhibited matrigel-induced cell adhesion of HFLS–RA and HUVEC. It also disrupted tube formation of HUVEC on matrigel and suppressed the VEGF-induced chemotactic migration of HFLS–RA and HUVEC, respectively. Furthermore, triptolide significantly reduced the expression of angiogenic activators including TNF-α, IL-17, VEGF, VEGFR, Ang-1, Ang-2 and Tie2, as well as suppressed the IL1-β-induced phosphorylated of ERK, p38 and JNK at protein levels. In conclusion, our data suggest for the first time that triptolide may possess anti-angiogenic effect in RA both in vivo and in vitro assay systems by downregulating the angiogenic activators and inhibiting the activation of mitogen-activated protein kinase downstream signal pathway.
PMCID: PMC3810371  PMID: 24204851
21.  New insights into the genetic mechanism of IQ in autism spectrum disorders 
Frontiers in Genetics  2013;4:195.
Autism spectrum disorders (ASD) comprise a number of underlying sub-types with various symptoms and presumably different genetic causes. One important difference between these sub-phenotypes is IQ. Some forms of ASD such as Asperger’s have relatively intact intelligence while the majority does not. In this study, we explored the role of genetic factors that might account for this difference. Using a case–control study based on IQ status in 1657 ASD probands, we analyzed both common and rare variants provided by the Autism Genome Project (AGP) consortium via dbGaP (database of Genotypes and Phenotypes). We identified a set of genes, among them HLA-DRB1 and KIAA0319L, which are strongly associated with IQ within a population of ASD patients.
PMCID: PMC3799005  PMID: 24151499
GWAS; functional variants; rare variants; common variants; autism; cognitive development
22.  A molecular level prototype for mechanoelectrical transducer in mammalian hair cells 
The mechanoelectrical transducer (MET) is a crucial component of mammalian auditory system. The gating mechanism of the MET channel remains a puzzling issue, though there are many speculations, due to the lack of essential molecular building blocks. To understand the working principle of mammalian MET, we propose a molecular level prototype which constitutes a charged blocker, a realistic ion channel and its surrounding membrane. To validate the proposed prototype, we make use of a well-established ion channel theory, the Poisson-Nernst-Planck equations, for three-dimensional (3D) numerical simulations. A wide variety of model parameters, including bulk ion concentration, applied external voltage, blocker charge and blocker displacement, are explored to understand the basic function of the proposed MET prototype. We show that our prototype prediction of channel open probability in response to blocker relative displacement is in a remarkable accordance with experimental observation of rat cochlea outer hair cells. Our results appear to suggest that tip links which connect hair bundles gate MET channels.
PMCID: PMC3732576  PMID: 23625048
Mechanoelectrical transducer; Gating mechanism; Poisson-Nernst-Planck model; Ion channel
23.  Transition to persistent orofacial pain after nerve injury Involves supraspinal serotonin mechanisms 
The orofacial region is a major focus of chronic neuropathic pain conditions characterized by primary hyperalgesia at the site of injury and secondary hyperalgesia outside the injured zone. We have used a rat model of injury to the maxillary branch (V2) of the trigeminal nerve to produce constant and long-lasting primary hyperalgesia in the V2 territory and secondary hyperalgesia in territories innervated by the mandibular branch (V3). Our findings indicate that the induction of primary and secondary hyperalgesia depended on peripheral input from the injured nerve. In contrast, the maintenance of secondary hyperalgesia depended on central mechanisms. The centralization of the secondary hyperalgesia involved descending 5-HT drive from the rostral ventromedial medulla (RVM) and the contribution of 5-HT3 receptors in the trigeminal nucleus caudalis (Vc), the homolog of the spinal dorsal horn. Electrophysiological studies further indicate that after nerve injury spontaneous responses and enhanced post-stimulus discharges in Vc nociresponsive neurons were time-dependent on descending 5-HT drive and peripheral input. The induction phase of secondary hyperalgesia involved central sensitization mechanisms in Vc neurons that were dependent on peripheral input whereas the maintenance phase of secondary hyperalgesia involved central sensitization in Vc neurons conducted by a delayed descending 5-HT drive and a persistence of peripheral inputs. Our results are the first to show that the maintenance of secondary hyperalgesia and underlying central sensitization associated with persistent pain depend on a transition to supraspinal mechanisms involving the serotonin system in RVM-dorsal horn circuits.
PMCID: PMC3640487  PMID: 23516281
secondary hyperalgesia; serotonin; descending facilitation; RNA interference; trigeminal nucleus caudalis
24.  Multiscale geometric modeling of macromolecules II: Lagrangian representation 
Journal of computational chemistry  2013;34(24):2100-2120.
Geometric modeling of biomolecules plays an essential role in the conceptualization of biolmolecular structure, function, dynamics and transport. Qualitatively, geometric modeling offers a basis for molecular visualization, which is crucial for the understanding of molecular structure and interactions. Quantitatively, geometric modeling bridges the gap between molecular information, such as that from X-ray, NMR and cryo-EM, and theoretical/mathematical models, such as molecular dynamics, the Poisson-Boltzmann equation and the Nernst-Planck equation. In this work, we present a family of variational multiscale geometric models for macromolecular systems. Our models are able to combine multiresolution geometric modeling with multiscale electrostatic modeling in a unified variational framework. We discuss a suite of techniques for molecular surface generation, molecular surface meshing, molecular volumetric meshing, and the estimation of Hadwiger’s functionals. Emphasis is given to the multiresolution representations of biomolecules and the associated multiscale electrostatic analyses as well as multiresolution curvature characterizations. The resulting fine resolution representations of a biomolecular system enable the detailed analysis of solvent-solute interaction, and ion channel dynamics, while our coarse resolution representations highlight the compatibility of protein-ligand bindings and possibility of protein-protein interactions.
PMCID: PMC3760017  PMID: 23813599
Variational multiscale modeling; Multiresolution surface; Energy functional; Meshing; Curvature; Electrostatics
25.  First Definition of Reference Intervals of Liver Function Tests in China: A Large-Population-Based Multi-Center Study about Healthy Adults 
PLoS ONE  2013;8(9):e72916.
Reference intervals of Liver function tests are very important for the screening, diagnosis, treatment, and monitoring of liver diseases. We aim to establish common reference intervals of liver function tests specifically for the Chinese adult population.
A total of 3210 individuals (20–79 years) were enrolled in six representative geographical regions in China. Analytes of ALT, AST, GGT, ALP, total protein, albumin and total bilirubin were measured using three analytical systems mainly used in China. The newly established reference intervals were based on the results of traceability or multiple systems, and then validated in 21 large hospitals located nationwide qualified by the National External Quality Assessment (EQA) of China.
We had been established reference intervals of the seven liver function tests for the Chinese adult population and found there were apparent variances of reference values for the variables for partitioning analysis such as gender(ALT, GGT, total bilirubin), age(ALP, albumin) and region(total protein). More than 86% of the 21 laboratories passed the validation in all subgroup of reference intervals and overall about 95.3% to 98.8% of the 1220 validation results fell within the range of the new reference interval for all liver function tests. In comparison with the currently recommended reference intervals in China, the single side observed proportions of out of range of reference values from our study for most of the tests deviated significantly from the nominal 2.5% such as total bilirubin (15.2%), ALP (0.2%), albumin (0.0%). Most of reference intervals in our study were obviously different from that of other races.
These used reference intervals are no longer applicable for the current Chinese population. We have established common reference intervals of liver function tests that are defined specifically for Chinese population and can be universally used among EQA-approved laboratories located all over China.
PMCID: PMC3772807  PMID: 24058449

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