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1.  Role of dopamine D2 receptors in ischemia/reperfusion induced apoptosis of cultured neonatal rat cardiomyocytes 
Background
Myocardial ischemia/reperfusion injury is the major cause of morbidity and mortality for cardiovascular diseases. Dopamine D2 receptors are expressed in cardiac tissues. However, the roles of dopamine D2 receptors in myocardial ischemia/reperfusion injury and cardiomyocyte apoptosis are unclear. Here we investigated the effects of both dopamine D2 receptors agonist (bromocriptine) and antagonist (haloperidol) on apoptosis of cultured neonatal rat ventricular myocytes induced by ischemia/reperfusion injury.
Methods
Myocardial ischemia/reperfusion injury was simulated by incubating primarily cultured neonatal rat cardiomyocytes in ischemic (hypoxic) buffer solution for 2 h. Thereafter, these cells were incubated for 24 h in normal culture medium.
Results
Treatment of the cardiomyocytes with 10 μM bromocriptine significantly decreased lactate dehydrogenase activity, increased superoxide dismutase activity, and decreased malondialdehyde content in the culture medium. Bromocriptine significantly inhibited the release of cytochrome c, accumulation of [Ca2+]i, and apoptosis induced by ischemia/reperfusion injury. Bromocriptine also down-regulated the expression of caspase-3 and -9, Fas and Fas ligand, and up-regulated Bcl-2 expression. In contrast, haloperidol (10 μM) had no significant effects on the apoptosis of cultured cardiomyocytes under the aforementioned conditions.
Conclusions
These data suggest that activation of dopamine D2 receptors can inhibit apoptosis of cardiomyocytes encountered during ischemia/reperfusion damage through various pathways.
doi:10.1186/1423-0127-18-18
PMCID: PMC3050795  PMID: 21324201
2.  A Promising Tool to Achieve Chemical Accuracy for Density Functional Theory Calculations on Y-NO Homolysis Bond Dissociation Energies 
A DFT-SOFM-RBFNN method is proposed to improve the accuracy of DFT calculations on Y-NO (Y = C, N, O, S) homolysis bond dissociation energies (BDE) by combining density functional theory (DFT) and artificial intelligence/machine learning methods, which consist of self-organizing feature mapping neural networks (SOFMNN) and radial basis function neural networks (RBFNN). A descriptor refinement step including SOFMNN clustering analysis and correlation analysis is implemented. The SOFMNN clustering analysis is applied to classify descriptors, and the representative descriptors in the groups are selected as neural network inputs according to their closeness to the experimental values through correlation analysis. Redundant descriptors and intuitively biased choices of descriptors can be avoided by this newly introduced step. Using RBFNN calculation with the selected descriptors, chemical accuracy (≤1 kcal·mol−1) is achieved for all 92 calculated organic Y-NO homolysis BDE calculated by DFT-B3LYP, and the mean absolute deviations (MADs) of the B3LYP/6-31G(d) and B3LYP/STO-3G methods are reduced from 4.45 and 10.53 kcal·mol−1 to 0.15 and 0.18 kcal·mol−1, respectively. The improved results for the minimal basis set STO-3G reach the same accuracy as those of 6-31G(d), and thus B3LYP calculation with the minimal basis set is recommended to be used for minimizing the computational cost and to expand the applications to large molecular systems. Further extrapolation tests are performed with six molecules (two containing Si-NO bonds and two containing fluorine), and the accuracy of the tests was within 1 kcal·mol−1. This study shows that DFT-SOFM-RBFNN is an efficient and highly accurate method for Y-NO homolysis BDE. The method may be used as a tool to design new NO carrier molecules.
doi:10.3390/ijms13078051
PMCID: PMC3430220  PMID: 22942689
Y-NO bond; homolysis bond dissociation energies; density functional theory; self-organizing feature mapping neural network; radial basis function neural network
3.  The functional expression of extracellular calcium-sensing receptor in rat pulmonary artery smooth muscle cells 
Background
The extracellular calcium-sensing receptor (CaSR) belongs to family C of the G protein coupled receptors. Whether the CaSR is expressed in the pulmonary artery (PA) is unknown.
Methods
The expression and distribution of CaSR were detected by RT-PCR, Western blotting and immunofluorescence. PA tension was detected by the pulmonary arterial ring technique, and the intracellular calcium concentration ([Ca2+]i) was detected by a laser-scanning confocal microscope.
Results
The expressions of CaSR mRNA and protein were found in both rat pulmonary artery smooth muscle cells (PASMCs) and PAs. Increased levels of [Ca2+]o (extracellular calcium concentration) or Gd3+ (an agonist of CaSR) induced an increase of [Ca2+]i and PAs constriction in a concentration-dependent manner. In addition, the above-mentioned effects of Ca2+ and Gd3+ were inhibited by U73122 (specific inhibitor of PLC), 2-APB (specific antagonist of IP3 receptor), and thapsigargin (blocker of sarcoplasmic reticulum calcium ATPase).
Conclusions
CaSR is expressed in rat PASMCs, and is involved in regulation of PA tension by increasing [Ca2+]i through G-PLC-IP3 pathway.
doi:10.1186/1423-0127-18-16
PMCID: PMC3050794  PMID: 21314926
4.  Discovery of a Potent, Covalent BTK Inhibitor for B-Cell Lymphoma 
ACS Chemical Biology  2014;9(5):1086-1091.
BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling and cellular assays to develop a potent, selective, and irreversible BTK kinase inhibitor, QL47, which covalently modifies Cys481. QL47 inhibits BTK kinase activity with an IC50 of 7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with an EC50 of 475 nM, and inhibits phosphorylation of a downstream effector PLCγ2 (Tyr759) with an EC50 of 318 nM. In Ramos cells QL47 induces a G1 cell cycle arrest that is associated with pronounced degradation of BTK protein. QL47 inhibits the proliferation of B-cell lymphoma cancer cell lines at submicromolar concentrations.
doi:10.1021/cb4008524
PMCID: PMC4027949  PMID: 24556163
5.  Vitamin E intake and the lung cancer risk among female nonsmokers: a report from the Shanghai Women’s Health Study 
Vitamin E includes several tocopherol isoforms which may reduce lung cancer risk, but past studies evaluating the association between vitamin E intake and lung cancer risk were inconsistent. We prospectively investigated the associations between tocopherol intake from diet and from supplements with lung cancer risk among 72,829 Chinese female nonsmokers aged 40-70 years and participating in the Shanghai Women’s Health Study (SWHS). Dietary and supplement tocopherol exposure was assessed by a validated food-frequency questionnaire at baseline, and also reassessed for change in intake during follow-up. Cox proportional hazards models with time-dependent covariates were used to calculate multivariate-adjusted hazard ratios (HRs) and 95% confidence interval (CIs) for lung cancer. After 12.02 years of follow-up, 481 women were diagnosed with lung cancer. Total dietary tocopherol was inversely associated with lung cancer risk among women meeting dietary guidelines for adequate intake (AI) of tocopherol (14 mg/day or more: HR: 0.78; 95% CI 0.60-0.99; compared to the category less than AI). The protective association between dietary tocopherol intake and lung cancer was restricted to women exposed to side-stream smoke in the home and workplace (HR=0.53 (0.29-0.97), p-trend = 0.04). In contrast, vitamin E supplement use was associated with increased lung cancer risk (HR: 1.33; 95% CI 1.01-1.73), more so for lung adenocarcinoma risk (HR: 1.79; 95% CI 1.23-2.60). In summary, dietary tocopherol intake may reduce the risk of lung cancer among female non-smokers, however supplements may increase lung adenocarcinoma risk and requires further investigation.
doi:10.1002/ijc.29016
PMCID: PMC4232456  PMID: 24916784
diet; dietary supplements; lung neoplasm; prospective study; tocopherols; women
6.  Associations between apolipoprotein E gene polymorphisms and Alzheimer’s disease risk in a large Chinese Han population 
Objective
Apolipoprotein E gene (APOE) polymorphisms contributing to the risk of sporadic Alzheimer’s disease (AD) have been identified for decades, but it has not been investigated in large AD samples of Chinese Han population.
Methods
We performed a cross-sectional study to explore the effect of APOE polymorphisms on sporadic AD in 875 sporadic AD patients and 1,195 cognitive normal controls of Chinese Han. Genotyping of APOE was determined by multiplex amplification refractory mutation system polymerase chain reaction.
Results
APOE ε3ε4 and ε4ε4 genotypes increased AD risk with dosage effect. The odds ratio (OR) of ε3ε4 was 1.89 and the OR of ε4ε4 was 15.64 compared with that of ε3ε3 in all the subjects. E2ε3 genotype decreased AD risk in all the subjects (OR=0.64), female subgroup (OR=0.57), and late-onset AD subgroup (OR=0.60). However, neither ε2ε2 nor ε2ε4 affected AD risk. About the age at onset (AAO), the influence of APOE ε4 was only exhibited in late-onset AD subgroup, with 1 year lower in ε4-positive ones than negative ones. Further analysis did not show the dosage effect of ε4 pertinent to AAO, though the AAO of ε4ε4 patients decreased by 2 years. E2 did not affect the AAO of AD.
Conclusion
APOE ε4 is a strong risk factor of AD risk in Chinese Han population, and APOE ε4ε4 genotype might be related to the AAO of late-onset AD.
doi:10.2147/CIA.S73396
PMCID: PMC4321568
sporadic; cross sectional study; dosage effect; age at onset
7.  The putative Na+/Cl−-dependent neurotransmitter/osmolyte transporter inebriated in the Drosophila hindgut is essential for the maintenance of systemic water homeostasis 
Scientific Reports  2015;5:7993.
Most organisms are able to maintain systemic water homeostasis over a wide range of external or dietary osmolarities. The excretory system, composed of the kidneys in mammals and the Malpighian tubules and hindgut in insects, can increase water conservation and absorption to maintain systemic water homeostasis, which enables organisms to tolerate external hypertonicity or desiccation. However, the mechanisms underlying the maintenance of systemic water homeostasis by the excretory system have not been fully characterized. In the present study, we found that the putative Na+/Cl−-dependent neurotransmitter/osmolyte transporter inebriated (ine) is expressed in the basolateral membrane of anterior hindgut epithelial cells. This was confirmed by comparison with a known basolateral localized protein, the α subunit of Na+-K+ ATPase (ATPα). Under external hypertonicity, loss of ine in the hindgut epithelium results in severe dehydration without damage to the hindgut epithelial cells, implicating a physiological failure of water conservation/absorption. We also found that hindgut expression of ine is required for water conservation under desiccating conditions. Importantly, specific expression of ine in the hindgut epithelium can completely restore disrupted systemic water homeostasis in ine mutants under both conditions. Therefore, ine in the Drosophila hindgut is essential for the maintenance of systemic water homeostasis.
doi:10.1038/srep07993
PMCID: PMC4303880  PMID: 25613130
8.  Suppression of Mic60 compromises mitochondrial transcription and oxidative phosphorylation 
Scientific Reports  2015;5:7990.
Precise regulation of mtDNA transcription and oxidative phosphorylation (OXPHOS) is crucial for human health. As a component of mitochondrial contact site and cristae organizing system (MICOS), Mic60 plays a central role in mitochondrial morphology. However, it remains unclear whether Mic60 affects mitochondrial transcription. Here, we report that Mic60 interacts with mitochondrial transcription factors TFAM and TFB2M. Furthermore, we found that Mic60 knockdown compromises mitochondrial transcription and OXPHOS activities. Importantly, Mic60 deficiency decreased TFAM binding and mitochondrial RNA polymerase (POLRMT) recruitment to the mtDNA promoters. In addition, through mtDNA immunoprecipitation (mIP)-chromatin conformation capture (3C) assays, we found that Mic60 interacted with mtDNA and was involved in the architecture of mtDNA D-loop region. Taken together, our findings reveal a previously unrecognized important role of Mic60 in mtDNA transcription.
doi:10.1038/srep07990
PMCID: PMC4303897  PMID: 25612828
9.  The efficacy and mechanism of apoptosis induction by hypericin-mediated sonodynamic therapy in THP-1 macrophages 
Purpose
To investigate the sonoactivity of hypericin (HY), together with its sonodynamic effect on THP-1 macrophages and the underlying mechanism.
Materials and methods
CCK-8 was used to examine cell viability. Confocal laser scanning microscopy was performed to assess the localization of HY in cells, reactive oxygen species (ROS) generation, and opening of the mitochondrial permeability transition pore (mPTP) after different treatments. Apoptosis was analyzed using Hoechst–propidium iodide and transmission electron microscopy. Mitochondrial membrane potential (ΔΨm) collapse was detected via fluorescence microscopy. Lipoprotein oxidation was determined in malondialdehyde (MDA) assays. Western blotting was conducted to determine the translocation of BAX and cytochrome C and the expression of apoptosis-related proteins.
Results
HY was sublocalized among the nuclei and the mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosome in the cytosol of THP-1 macrophages. Under low-intensity ultrasound irradiation, HY significantly decreased cell viability and induced apoptosis. Furthermore, greater ROS generation, higher MDA levels, and greater ΔΨm loss were observed in the sonodynamic therapy (SDT) group. Both ROS generation and MDA levels were significantly reduced by the ROS scavenger N-acetyl cysteine (NAC) and the singlet oxygen scavenger sodium azide. Most of the loss of ΔΨm was inhibited by pretreatment with NAC, sodium azide, and the mPTP inhibitor cyclosporin A (CsA). mPTP opening was induced upon SDT but was reduced by pretreatment with bongkrekic acid, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid disodium, CsA, and NAC. Western blot analyses revealed translocation of BAX and cytochrome C, downregulated expression of Bcl-2, and upregulated expression of cleaved caspase-9, cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase in the SDT group, which were reversed by NAC.
Conclusion
HY mediated SDT-induced apoptosis in THP-1 macrophages via ROS generation. Then, the proapoptotic factor BAX translocated from the cytosol to the mitochondria, increasing the ratio of BAX/Bcl-2, and the mPTP opened to release cytochrome C. This study demonstrated the great potential of HY-mediated SDT for treating atherosclerosis.
doi:10.2147/IJN.S75398
PMCID: PMC4309797  PMID: 25653524
apoptosis; hypericin; sonodynamic therapy; mitochondria–caspase pathway; atherosclerosis
10.  Centralized isolation of Helicobacter pylori from multiple centers and transport condition influences 
AIM: To evaluate the efficacy of centralized culture and possible influencing factors.
METHODS: From January 2010 to July 2012, 66452 patients with suspected Helicobacter pylori (H. pylori) infection from 26 hospitals in Zhejiang and Jiangsu Provinces in China underwent gastrointestinal endoscopy. Gastric mucosal biopsies were taken from the antrum for culture. These biopsies were transported under natural environmental temperature to the central laboratory in Hangzhou city and divided into three groups based on their transport time: 5, 24 and 48 h. The culture results were reported after 72 h and the positive culture rates were analyzed by a χ2 test. An additional 5736 biopsies from H. pylori-positive patients (5646 rapid urease test-positive and 90 14C-urease breath test-positive) were also cultured for quality control in the central laboratory setting.
RESULTS: The positive culture rate was 31.66% (21036/66452) for the patient samples and 71.72% (4114/5736) for the H. pylori-positive quality control specimens. In the 5 h transport group, the positive culture rate was 30.99% (3865/12471), and 32.84% (14960/45553) in the 24 h transport group. In contrast, the positive culture rate declined significantly in the 48 h transport group (26.25%; P < 0.001). During transportation, the average natural temperature increased from 4.67 to 29.14 °C, while the positive culture rate declined from 36.67% (1462/3987) to 24.12% (1799/7459). When the temperature exceeded 24 °C, the positive culture rate decreased significantly, especially in the 48 h transport group (23.17%).
CONCLUSION: Transportation of specimens within 24 h and below 24 °C is reasonable and acceptable for centralized culture of multicenter H. pylori samples.
doi:10.3748/wjg.v21.i3.944
PMCID: PMC4299348  PMID: 25624729
Centralized isolation; Helicobacter pylori; Influencing factor; Multiple centers; Personalized treatment
11.  Elevated matrix metalloproteinase-7 expression promotes metastasis in human lung carcinoma 
Background
Matrix metalloproteinase 7 (MMP-7) promotes tumor invasion and metastasis in several cancers. However, its role in lung cancer progression is understudied. In this study, we investigated the correlation between MMP-7 expression and lung cancer pathology.
Methods
We searched the databases PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, China BioMedicine (CBM) and China National Knowledge Infrastructure (CNKI) for scientific literature relevant to MMP-7 and lung cancer. Carefully selected studies were pooled and ORs with 95% CI were calculated. Subgroup analyses and publication bias were analyzed to understand the retrieved data in greater detail. Version 12.0 STATA software was used for statistical analysis.
Results
We retrieved a total of 121 studies through database searches. Finally, 14 cohort studies satisfied our inclusion/exclusion criteria, and these 14 studies, published between 2004 and 2012, were selected for meta-analysis to understand the influence of MMP-7 expression in lung cancer progression. Our results showed consistent differences in MMP-7 expression when comparisons were made between TNM I-II versus III-IV (OR = 1.82, 95% CI: 1.19 to 2.78, P = 0.006); histologic grade 1 to 2 versus 3 to 4 (OR = 1.67, 95% CI: 1.14 to 2.42, P = 0.008); and lymph node-negative versus lymph node-positive samples (OR = 2.81, 95% CI: 1.73 to 4.58, P <0.001), with significantly higher MMP-7 expression levels found in the more advanced stages. Subgroup analysis showed that age was not the factor influencing the associations between histologic grade, LN metastasis and MMP-7 expression in lung cancer patients, as both under 60 and over 60 age groups showed strong correlations (all P <0.05). However, when TNM staging was analyzed for its association with MMP-7 expression, only patients under age 60 showed a statistically significant correlation.
Conclusions
Our meta-analysis results revealed that MMP-7 overexpression is associated with advanced TNM and histological grades, and is linked to aggressive LN metastasis in lung cancer patients; thus MMP-7 is a useful biomarker to assess the disease status in lung cancers.
doi:10.1186/1477-7819-13-5
PMCID: PMC4326471  PMID: 25588786
Matrix metalloproteinase 7; Protein expression; Lung cancer; Meta-analysis
12.  X-Ray Photoelectron Spectroscopy Investigation of the Nitrogen Species in Photoactive Perfluorophenylazide-Modified Surfaces 
X-ray Photoelectron Spectroscopy (XPS) was used to characterize the nitrogen species in perfluorophenylazide (PFPA) self-assembled monolayers. PFPA chemistry is a novel immobilization method for tailoring the surface properties of materials. It is a simple route for the efficient immobilization of graphene, proteins, carbohydrates and synthetic polymers onto a variety of surfaces. Upon light irradiation, the azido group in PFPA is converted to a highly reactive singlet nitrene species that readily undergoes CH insertion and C=C addition reactions. Here, the challenge of characterizing the PFPA modified surfaces was addressed by detailed XPS experimental analyses. The three nitrogen peaks detected in the XPS N1s spectra were assigned to amine/amide (400.5 eV) and azide (402.1 and 405.6 eV) species. The observed 2:1 ratio of the areas from the 402.1 eV to 405.6 eV peaks suggests the assignment of the peak at 402.1 eV to the two outer nitrogen atoms in the azido group and assignment of the peak at 405.6 eV to the central nitrogen atom in the azido group. The azide decomposition as the function of x-ray exposure was also determined. Finally, XPS analyses were conducted on patterned graphene to investigate the covalent bond formation between the PFPA and graphene. This study provides strong evidence for the formation of covalent bonds during the PFPA photocoupling process.
doi:10.1021/jp409338y
PMCID: PMC3923990  PMID: 24535931
PFPA; XPS; Surface Characterization; Graphene
13.  Cruciferous vegetables, glutathione S-transferase polymorphisms and the risk of colorectal cancer among Chinese men 
Annals of epidemiology  2013;24(1):10.1016/j.annepidem.2013.10.003.
Purpose
To assess the associations between cruciferous vegetable (CV) intake, GST gene polymorphisms and colorectal cancer (CRC) in a population of Chinese men.
Methods
Using incidence density sampling, CRC cases (N = 340) diagnosed prior to December 31, 2010 within the Shanghai Men’s Health Study were matched to non-cases (N = 673). CV intake was assessed from a food frequency questionnaire and by isothiocyanate (ITC) levels from spot urine samples. GSTM1 and GSTT1 were categorized as null (0 copies) versus non-null (1 or 2 copies). Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between CV intake and GST gene variants with CRC and statistical interactions were evaluated.
Results
CRC risk was not associated with CV intake, whether measured by self-report or by urinary ITC, nor with GST gene variants. No statistical interactions were detected between CV intake and GST gene variants on the odds of CRC. Stratifying by timing of urine sample collection and excluding CRC cases diagnosed in the first two years did not materially alter the results.
Conclusions
This study provides no evidence supporting the involvement of CV intake in the development of CRC in Chinese men.
doi:10.1016/j.annepidem.2013.10.003
PMCID: PMC3864981  PMID: 24238877
brassicaceae; China; colorectal neoplasms; glutathione S-transferase M1; glutathione S-transferase T1; men
14.  Mitochondrial Oxidative Stress in the Retinal Pigment Epithelium Leads to Localized Retinal Degeneration 
Purpose.
Oxidative stress in the RPE is widely accepted as a contributing factor to AMD. We have previously shown that ribozyme-mediated reduction in the antioxidant enzyme manganese superoxide dismutase (MnSOD) leads to some of the features of geographic atrophy in mice. To develop a mouse model independent of viral injection, we used a conditional knockout of the Sod2 gene in the RPE to elevate mitochondrial oxidative stress in that cell layer.
Methods.
Experimental mice in which exon 3 of Sod2 was flanked by loxP sites were also transgenic for PVMD2-rtTA and tetO-PhCMV cre, so that cre recombinase was expressed only in the RPE. Pups of this genotype (Sod2flox/floxVMD2cre) were induced to express cre recombinase by feeding doxycycline-laced chow to nursing dams. Controls included mice of this genotype not treated with doxycycline and doxycycline-treated Sod2flox/flox mice lacking the cre transgene. Expression of cre in the RPE was verified by immunohistochemistry, and deletion of Sod2 exon 3 in the RPE was confirmed by PCR. Mice were followed up over a period of 9 months by spectral-domain optical coherence tomography (SD-OCT), digital fundus imaging, and full-field ERG. Following euthanasia, retinas were examined by light and electron microscopy or by immunohistochemistry. Contour length of rod outer segments and thickness of the RPE layer were measured by unbiased stereology.
Results.
Following doxycycline induction of cre, Sod2flox/flox cre mice demonstrated increased signs of oxidative stress in the RPE and accumulation of autofluorescent material by age 2 months. They showed a gradual decline in the ERG response and thinning of the outer nuclear layer (by SD-OCT), which were statistically significant by 6 months. In addition, OCT and electron microscopy revealed increased porosity of the choroid. At the same interval, hypopigmented foci appeared in fundus micrographs, and vascular abnormalities were detected by fluorescein angiography. By 9 months, the RPE layer in Sod2flox/flox cre mice was thicker than in nontransgenic littermates, and the rod outer segments were significantly longer over most of the retina, although localized atrophy of photoreceptors was also obvious in some eyes.
Conclusions.
Conditional tissue-specific reduction in MnSOD induced oxidative stress in mouse RPE, leading to RPE dysfunction, damage to the choroid, and death of photoreceptor cells. The RPE oxidative stress did not cause drusen-like deposits, but the model recapitulated certain key aspects of the pathology of dry AMD and may be useful in testing therapies.
The RPE-specific deletion of mitochondrial superoxide dismutase in mice leads to oxidative stress in the RPE, accumulation of autofluorescent material, a decline in the ERG response, and localized death of photoreceptors. This model may be useful in understanding the mechanism of geographic atrophy.
doi:10.1167/iovs.14-14633
PMCID: PMC4112607  PMID: 24985474
retinal degeneration; mouse model; reactive oxygen species; manganese superoxide dismutase; retinal pigment epithelium
16.  Tracing children's vocabulary development from preschool through the school-age years: An 8-year longitudinal study 
Developmental science  2014;18(1):119-131.
In this 8-year longitudinal study, we traced the vocabulary growth of Chinese children, explored potential precursors of vocabulary knowledge, and investigated how vocabulary growth predicted future reading skills. Two hundred sixty-four (264) native Chinese children from Beijing were measured on a variety of reading and language tasks over 8 years. Between the ages of 4 to 10 years, they were administered tasks of vocabulary and related cognitive skills. At age 11, comprehensive reading skills, including character recognition, reading fluency, and reading comprehension were examined. Individual differences in vocabulary developmental profiles were estimated using the intercept-slope cluster method. Vocabulary development was then examined in relation to later reading outcomes. Three subgroups of lexical growth were classified, namely high-high (with a large initial vocabulary size and a fast growth rate), low-high (with a small initial vocabulary size and a fast growth rate) and low-low (with a small initial vocabulary size and a slow growth rate) groups. Low-high and low-low groups were distinguishable mostly through phonological skills, morphological skills and other reading-related cognitive skills. Childhood vocabulary development (using intercept and slope) explained subsequent reading skills. Findings suggest that language-related and reading-related cognitive skills differ among groups with different developmental trajectories of vocabulary, and the initial size and growth rate of vocabulary may be two predictors for later reading development.
doi:10.1111/desc.12190
PMCID: PMC4276547  PMID: 24962559
vocabulary development; growth rate; initial size; reading
17.  Tfap2a-dependent changes in mouse facial morphology result in clefting that can be ameliorated by a reduction in Fgf8 gene dosage 
Disease Models & Mechanisms  2014;8(1):31-43.
Failure of facial prominence fusion causes cleft lip and palate (CL/P), a common human birth defect. Several potential mechanisms can be envisioned that would result in CL/P, including failure of prominence growth and/or alignment as well as a failure of fusion of the juxtaposed epithelial seams. Here, using geometric morphometrics, we analyzed facial outgrowth and shape change over time in a novel mouse model exhibiting fully penetrant bilateral CL/P. This robust model is based upon mutations in Tfap2a, the gene encoding transcription factor AP-2α, which has been implicated in both syndromic and non-syndromic human CL/P. Our findings indicate that aberrant morphology and subsequent misalignment of the facial prominences underlies the inability of the mutant prominences to fuse. Exencephaly also occured in some of the Tfap2a mutants and we observed additional morphometric differences that indicate an influence of neural tube closure defects on facial shape. Molecular analysis of the CL/P model indicates that Fgf signaling is misregulated in the face, and that reducing Fgf8 gene dosage can attenuate the clefting pathology by generating compensatory changes. Furthermore, mutations in either Tfap2a or Fgf8 increase variance in facial shape, but the combination of these mutations restores variance to normal levels. The alterations in variance provide a potential mechanistic link between clefting and the evolution and diversity of facial morphology. Overall, our findings suggest that CL/P can result from small gene-expression changes that alter the shape of the facial prominences and uncouple their coordinated morphogenesis, which is necessary for normal fusion.
doi:10.1242/dmm.017616
PMCID: PMC4283648  PMID: 25381013
Craniofacial; TFAP2A; AP-2α; BOFS; Branchio-oculofacial syndrome; Cleft lip/palate; Geometric morphometrics; Fgf signaling pathway
18.  Draft genome sequence of Halomonas lutea strain YIM 91125T (DSM 23508T) isolated from the alkaline Lake Ebinur in Northwest China 
Species of the genus Halomonas are halophilic and their flexible adaption to changes of salinity and temperature brings considerable potential biotechnology applications, such as degradation of organic pollutants and enzyme production. The type strain Halomonas lutea YIM 91125T was isolated from a hypersaline lake in China. The genome of strain YIM 91125T becomes the twelfth species sequenced in Halomonas, and the thirteenth species sequenced in Halomonadaceae. We described the features of H. lutea YIM 91125T, together with the high quality draft genome sequence and annotation of its type strain. The 4,533,090 bp long genome of strain YIM 91125T with its 4,284 protein-coding and 84 RNA genes is a part of Genomic Encyclopedia of Type Strains, Phase I: the one thousand microbial genomes (KMG-I) project. From the viewpoint of comparative genomics, H. lutea has a larger genome size and more specific genes, which indicated acquisition of function bringing better adaption to its environment. DDH analysis demonstrated that H. lutea is a distinctive species, and halophilic features and nitrogen metabolism related genes were discovered in its genome.
doi:10.1186/1944-3277-10-1
PMCID: PMC4315136
Halomonas lutea; Aerobic; Gram-negative; Chemoorganotrophic; Moderately halophilic; Lake Ebinur
19.  Crystal structure of 1,7,8,9-tetra­chloro-4-(3,5-di­chloro­benz­yl)-10,10-dimeth­oxy-4-aza­tri­cyclo­[5.2.1.02,6]dec-8-ene-3,5-dione 
In the title compound, C17H11Cl6NO4, the configuration of the cyclo­alkene skeleton is endo,cis. The benzene ring is twisted by 58.94 (8)° from the attached pyrrolidine ring. Two carbonyl groups play a key role in the crystal packing. A short inter­molecular C⋯O distance of 3.017 (3) Å reveals that one carbonyl group is involved in dipole–dipole inter­actions, which link two adjacent enanti­omers into an inversion dimer. Another carbonyl group provides an acceptor for the weak inter­molecular C—H⋯O hydrogen bonds which link these dimers into layers parallel to (011).
doi:10.1107/S2056989014025961
PMCID: PMC4331899
crystal structure; tri­cyclo­[5.2.1.02,6]dec-8-ene-3,5-dione; biological activity; cyclo­alkene skeleton; dipole–dipole inter­actions; hydrogen bonding
20.  Crystal structure of 1,7,8,9-tetra­chloro-4-(2-fluoro­benz­yl)-10,10-dimeth­oxy-4-aza­tri­cyclo­[5.2.1.02,6]dec-8-ene-3,5-dione 
In the title compound, C17H12Cl4FNO4, the configuration of the cyclo­alkene skeleton is endo,cis. The benzene ring is twisted by 71.01 (11)° from the attached pyrrolidine ring. In the crystal, one of the methine groups of the fused-ring system forms a weak C—H⋯O hydrogen bond. The other methine groups participates in a C—H⋯F inter­action to the same adjacent mol­ecule. Together, these generate [010] chains.
doi:10.1107/S2056989014026279
PMCID: PMC4331900
crystal structure; biochemical activity; tri­cyclo­[5,2,1,02,6]dec-8-ene-3,5-dione; hydrogen bonding; C—H⋯F inter­action
21.  CCR7 Expressing Mesenchymal Stem Cells Potently Inhibit Graft-versus-Host Disease by Spoiling the Fourth Supplemental Billingham’s Tenet 
PLoS ONE  2014;9(12):e115720.
The clinical acute graft-versus-host disease (GvHD)-therapy of mesenchymal stem cells (MSCs) is not as satisfactory as expected. Secondary lymphoid organs (SLOs) are the major niches serve to initiate immune responses or induce tolerance. Our previous study showed that CCR7 guide murine MSC line C3H10T1/2 migrating to SLOs. In this study, CCR7 gene was engineered into murine MSCs by lentivirus transfection system (MSCs/CCR7). The immunomodulatory mechanism of MSCs/CCR7 was further investigated. Provoked by inflammatory cytokines, MSCs/CCR7 increased the secretion of nitric oxide and calmed down the T cell immune response in vitro. Immunofluorescent staining results showed that transfused MSCs/CCR7 can migrate to and relocate at the appropriate T cell-rich zones within SLOs in vivo. MSCs/CCR7 displayed enhanced effect in prolonging the survival and alleviating the clinical scores of the GvHD mice than normal MSCs. Owing to the critical relocation sites, MSCs/CCR7 co-infusion potently made the T cells in SLOs more naïve like, thus control T cells trafficking from SLOs to the target organs. Through spoiling the fourth supplemental Billingham’s tenet, MSCs/CCR7 potently inhibited the development of GvHD. The study here provides a novel therapeutic strategy of MSCs/CCR7 infusion at a low dosage to give potent immunomodulatory effect for clinical immune disease therapy.
doi:10.1371/journal.pone.0115720
PMCID: PMC4280136  PMID: 25549354
22.  Universal Stem-Loop Primer Method for Screening and Quantification of MicroRNA 
PLoS ONE  2014;9(12):e115293.
RT-qPCR is the accepted technique for the quantification of microRNA (miR) expression: however, stem-loop RT-PCR, the most frequently used method for quantification of miRs, is time- and reagent-consuming as well as inconvenient for scanning. We established a new method called ‘universal stem-loop primer’ (USLP) with 8 random nucleotides instead of a specific sequence at the 3′ end of the traditional stem-loop primer (TSLP), for screening miR profile and to semi-quantify expression of miRs. Peripheral blood samples were cultured with phytohaemagglutinin (PHA), and then 87 candidate miRs were scanned in cultured T cells. By USLP, our study revealed that the expression of miR-150-5p (miR-150) decreased nearly 10-fold, and miR-155-5p (miR-155) increased more than 7-fold after treated with PHA. The results of the dissociation curve and gel electrophoresis showed that the PCR production of the USLP and TSLP were specificity. The USLP method has high precision because of its low ICV (ICV<2.5%). The sensitivity of the USLP is up to 103 copies/µl miR. As compared with the TSLP, USLP saved 75% the cost of primers and 60% of the test time. The USLP method is a simple, rapid, precise, sensitive, and cost-effective approach that is suitable for screening miR profiles.
doi:10.1371/journal.pone.0115293
PMCID: PMC4280144  PMID: 25548906
23.  Comparison of Combined General-Epidural Anesthesia with General Anesthesia Effects on Survival and Cancer Recurrence: A Meta-Analysis of Retrospective and Prospective Studies 
PLoS ONE  2014;9(12):e114667.
Objective
Animals underwent combined general-epidural anesthesia (EGA) is reported to have better long-time outcome than general anesthesia (GA). This study aimed to make overall evaluation of the association between these two anesthetic techniques and prognosis of cancer patients undergoing surgery.
Methods
Related databases such as PubMed and EMbase were searched for eligible studies that evaluated the influence of EGA and GA on the prognosis of cancer patients undergoing surgery. Selected studies were evaluated according to the inclusion criteria by two reviewers respectively, followed by data extraction and quality assessment. The odds ratio (OR) with their 95% confidence intervals (CIs) were calculated to assess the influence strength of EGA and GA on prognosis of cancer patients.
Results
A total of ten studies involving 3254 patients were included. The overall results demonstrated that there was no significant difference between EGA and GA group (OR = 0.88, 95% CI 0.73 to 1.06, P = 0.187) concerning postoperative recurrence and metastasis rate. In regard to the following two factors: cancer category and time of follow-up, subgroup analysis identified significant differences between EGA and GA in the group of patients with prostate cancer and the group with follow-up less than or equal to two years (OR = 0.66, 95% CI 0.46 to 0.95, P = 0.027; OR = 0.70, 95% CI 0.51 to 0.98, P = 0.035; respectively) concerning postoperative recurrence and metastasis rate. However, no significant difference was found in the group of patients with colorectal cancer (OR = 1.06, 95% CI 0.84–1.33, P = 0.62).
Conclusions
This meta-analysis showed that EGA might be associated with improvement in prognosis of patients with operable prostate cancer and the cancer patients with follow-up less than or equal to two years. However, no obvious relationship between the improvement in prognosis of colorectal cancer and EGA were detected, comparing to GA. Furthermore, all the results should be interpreted cautiously, as heterogeneous data were used for analyzing.
doi:10.1371/journal.pone.0114667
PMCID: PMC4280190  PMID: 25548913
24.  Comparative study of mutations in SNP loci of K-RAS, hMLH1 and hMSH2 genes in neoplastic intestinal polyps and colorectal cancer 
World Journal of Gastroenterology : WJG  2014;20(48):18338-18345.
AIM: To clarify the molecular mechanism involved in pathogenesis of colorectal cancer as well as clinical significance of genetic analysis of histological samples.
METHODS: A total of 480 blood and tissue specimens were collected in our hospital from January 2011 to October 2012. In the observation group, there were 120 blood specimens and 120 intestinal tract tissue specimens collected from patients with neoplastic intestinal polyps. In the control group I there were 80 blood specimens and 80 intestinal tract tissue specimens collected from patients with colorectal cancer. In the control group II there were 40 blood specimens and 40 intestinal tract tissue specimens collected from healthy individuals. The gene segments were amplified using PCR and DNA gel electrophoresis along with DNA sequence analysis were employed for the detection of the following single nucleotide polymorphisms (SNPs): K-RAS codons 12 and 13; hMLH1 (human mutS homolog 1) gene missense mutation at Va1384Asp; hMSH2 (human mutS homolog 2) gene missense mutation at 2783C/A.
RESULTS: The mutation rate of the SNP at Va1384Asp locus of the hMLH1 gene from blood and tissue specimens in the observation group showed no statistical difference from those in the control group I. The mutation rates of SNPs in codons 12 and 13 of K-RAS and at 2783C/A locus of the hMSH2 gene were significantly lower in the observation group than in the control group I (χ2 = 15.476, 29.670, 10.811, 16.618, 33.538, 7.898, P < 0.05). The mutation rate of SNP at Va1384Asp locus of the hMLH1 gene was significantly higher in the observation group when compared to the control group II (χ2 = 10.486, 4.876, P < 0.05). The mutation rates of SNPs in codons 12 and 13 of K-RAS and at 2783C/A locus of the hMSH2 gene did not show any statistical difference from those in the control group II.
CONCLUSION: There may be important clinical significance and relevance between neoplastic intestinal polyps and colorectal cancer in terms of the mechanisms involved in the pathogenesis.
doi:10.3748/wjg.v20.i48.18338
PMCID: PMC4277970  PMID: 25561800
Neoplastic intestinal polyp; Colorectal cancer; Single nucleotide polymorphisms; K-RAS; hMLH1; hMSH2
25.  Cross-drug resistance to sunitinib induced by doxorubicin in endothelial cells 
Oncology Letters  2014;9(3):1287-1292.
Multiple drug resistance remains an unsolved problem in cancer therapy. A previous study has demonstrated that the chemotherapeutic drug doxorubicin (Dox) induced upregulation of P-glycoprotein in endothelial cells, resulting in a 20-fold increase in drug resistance and reduced efficiency of doxorubicin treatment in a mouse tumor model. In the present study, the cross-resistance and sensitivity of HMECd1 and HMECd2 established cell lines to anti-angiogenic drugs, particularly sunitinib, was explored. The results revealed that Dox treatment induced a significant increase in the breast cancer resistance protein (ABCG2) gene transcription and protein expression. This increase gave rise to a 4- to 5-fold increase in the half maximal inhibitory concentration of the HMECd1 and HMECd2 cells in response to sunitinib treatment in vitro. Functionally, the role of ABCG2 in the resistance to sunitinib was confirmed by the use of the ABCG2 inhibitors fumitremorgin C and diethylstilbestrol, which blocked cell resistance. The present study indicates that endothelial cells exhibit cross-resistance between cytotoxic drugs and anti-angiogenic drugs. This suggests that multiple drug resistance induced by chemotherapy in endothelial cells may affect the efficiency of anti-angiogenic drugs.
doi:10.3892/ol.2014.2819
PMCID: PMC4315062  PMID: 25663899
drug resistance; endothelial cells; cancer therapy; ABC family; sunitinib

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