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1.  Efficacy of Chinese Eye Exercises on Reducing Accommodative Lag in School-Aged Children: A Randomized Controlled Trial 
PLoS ONE  2015;10(3):e0117552.
Purpose
To evaluate the efficacy of Chinese eye exercises on reducing accommodative lag in children by a randomized, double-blinded controlled trial.
Methods
A total of 190 children aged 10 to 14 years with emmetropia to moderate myopia were included. They were randomly allocated to three groups: standard Chinese eye exercises group (trained for eye exercises by doctors of traditional Chinese medicine); sham point eye exercises group (instructed to massage on non-acupoints); and eyes closed group (asked to close their eyes without massage). Primary outcome was change in accommodative lag immediately after intervention. Secondary outcomes included changes in corrected near and distant visual acuity, and visual discomfort score.
Results
Children in the standard Chinese eye exercises group had significantly greater alleviation of accommodative lag (-0.10D) than those in sham point eye exercises group (-0.03D) and eyes closed group (0.07D) (P = 0.04). The proportion of children with alleviation of accommodative lag was significantly higher in the standard Chinese eye exercises group (54.0%) than in the sham point eye exercises group (32.8%) and the eyes closed group (34.9%) (P = 0.03). No significant differences were found in secondary outcomes.
Conclusion
Chinese eye exercises as performed daily in primary and middle schools in China have statistically but probably clinically insignificant effect in reducing accommodative lag of school-aged children in the short-term. Considering the higher amounts of near work load of Chinese children, the efficacy of eye exercises may be insufficient in preventing myopia progression in the long-term.
Trial Registration
ClinicalTrials.gov NCT01756287
doi:10.1371/journal.pone.0117552
PMCID: PMC4350838  PMID: 25742161
2.  High-resolution crystal structure of human Dim2/TXNL4B 
The high-resolution crystal structure of human Dim2/TXNL4B indicated that a region previously reported to be responsible for its interaction with Prp6 is unlikely to facilitate this interaction.
TXNL4A (thioredoxin-like 4A) is an essential protein conserved from yeast to humans and is a component of the pre-mRNA splicing machinery. TXNL4B was identified as a TXNL4-family protein that also interacts with Prp6, an integral component of the U4/U6·U5 tri-snRNP complex, and has been shown to function in pre-mRNA splicing. A crystal structure of TXNL4B was determined at 1.33 Å resolution and refined to an R work of 0.13 and an R free of 0.18 with one native dimer in the asymmetric unit. Residues 1–33 of TXNL4B have previously been reported to be responsible for its interaction with Prp6. However, this region extends to the β-sheet core of the thioredoxin-fold structure of TXNL4B. This suggests that the interpretation of the previously reported GST pull-down results without considering the structure and stability of TXNL4B is debatable.
doi:10.1107/S1744309113000973
PMCID: PMC3606563  PMID: 23519793
Dim2; TXNL4B; pre-mRNA splicing; human Dim1; U5-15kD
3.  Intermittent Hypoxia-induced Changes in Tumor-associated Macrophages and Tumor Malignancy in a Mouse Model of Sleep Apnea 
Rationale: An increased cancer aggressiveness and mortality have been recently reported among patients with obstructive sleep apnea (OSA). Intermittent hypoxia (IH), a hallmark of OSA, enhances melanoma growth and metastasis in mice.
Objectives: To assess whether OSA-related adverse cancer outcomes occur via IH-induced changes in host immune responses, namely tumor-associated macrophages (TAMs).
Measurements and Main Results: Lung epithelial TC1 cell tumors were 84% greater in mice subjected to IH for 28 days compared with room air (RA). In addition, TAMs in IH-exposed tumors exhibited reductions in M1 polarity with a shift toward M2 protumoral phenotype. Although TAMs from tumors harvested from RA-exposed mice increased TC1 migration and extravasation, TAMs from IH-exposed mice markedly enhanced such effects and also promoted proliferative rates and invasiveness of TC1 cells. Proliferative rates of melanoma (B16F10) and TC1 cells exposed to IH either in single culture or in coculture with macrophages (RAW 264.7) increased only when RAW 264.7 macrophages were concurrently present.
Conclusions: Our findings support the notion that IH-induced alterations in TAMs participate in the adverse cancer outcomes reported in OSA.
doi:10.1164/rccm.201310-1830OC
PMCID: PMC3977714  PMID: 24471484
sleep apnea; intermittent hypoxia; cancer; inflammation; tumor-associated macrophages
4.  Nonlinear Varying Coefficient Models with Applications to Studying Photosynthesis 
Motivated by a study on factors affecting the level of photosynthetic activity in a natural ecosystem, we propose nonlinear varying coefficient models, in which the relationship between the predictors and the response variable is allowed to be nonlinear. One-step local linear estimators are developed for the nonlinear varying coefficient models and their asymptotic normality is established leading to point-wise asymptotic confidence bands for the coefficient functions. Two-step local linear estimators are also proposed for cases where the varying coefficient functions admit different degrees of smoothness; bootstrap confidence intervals are utilized for inference based on the two-step estimators. We further propose a generalized F test to study whether the coefficient functions vary over a covariate. We illustrate the proposed methodology via an application to an ecology data set and study the finite sample performance by Monte Carlo simulation studies.
doi:10.1007/s13253-013-0157-7
PMCID: PMC4070621  PMID: 24976756
Generalized F test; Local linear regression; Nonlinear regression model; Varying coefficient models
5.  Emergence of Multidrug-Resistant Campylobacter Species Isolates with a Horizontally Acquired rRNA Methylase 
Antibiotic-resistant Campylobacter constitutes a serious threat to public health, and resistance to macrolides is of particular concern, as this class of antibiotics is the drug of choice for clinical therapy of campylobacteriosis. Very recently, a horizontally transferrable macrolide resistance mediated by the rRNA methylase gene erm(B) was reported in a Campylobacter coli isolate, but little is known about the dissemination of erm(B) among Campylobacter isolates and the association of erm(B)-carrying isolates with clinical disease. To address this question and facilitate the control of antibiotic-resistant Campylobacter, we determined the distribution of erm(B) in 1,554 C. coli and Campylobacter jejuni isolates derived from food-producing animals and clinically confirmed human diarrheal cases. The results revealed that 58 of the examined isolates harbored erm(B) and exhibited high-level resistance to macrolides, and most were recent isolates, derived in 2011-2012. In addition, the erm(B)-positive isolates were all resistant to fluoroquinolones, another clinically important antibiotic used for treating campylobacteriosis. The erm(B) gene is found to be associated with chromosomal multidrug resistance genomic islands (MDRGIs) of Gram-positive origin or with plasmids of various sizes. All MDRGIs were transferrable to macrolide-susceptible C. jejuni by natural transformation under laboratory conditions. Molecular typing of the erm(B)-carrying isolates by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) identified diverse genotypes and outbreak-associated diarrheal isolates. Molecular typing also suggested zoonotic transmission of erm(B)-positive Campylobacter. These findings reveal an emerging and alarming trend of dissemination of erm(B) and MDRGIs in Campylobacter and underscore the need for heightened efforts to control their further spread.
doi:10.1128/AAC.03039-14
PMCID: PMC4135855  PMID: 24982085
6.  Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling 
Cancer research  2014;74(5):1329-1337.
Fragmented sleep (SF) is a highly prevalent condition and a hallmark of sleep apnea, a condition that has been associated with increased cancer incidence and mortality. In this study, we examined the hypothesis that SF promotes tumor growth and progression through pro-inflammatory TLR4 signaling. In the design, we compared mice that were exposed to SF one week before engraftment of syngeneic TC1 or LL3 tumor cells and tumor analysis three weeks later. We also compared host contributions through the use of mice genetically deficient in TLR4 or its effector molecules MYD88 or TRIF. We found that SF enhanced tumor size and weight compared to control mice. Increased invasiveness was apparent in SF tumors, which penetrated the tumor capsule into surrounding tissues including adjacent muscle. Tumor-associated macrophages (TAM) were more numerous in SF tumors where they were distributed in a relatively closer proximity to the tumor capsule, compared to control mice. Although tumors were generally smaller in both MYD88−/− and TRIF−/− hosts, the more aggressive features produced by SF persisted. In contrast, these more aggressive features produced by SF were abolished completely in TLR4−/− mice. Our findings offer mechanistic insights into how sleep perturbations can accelerate tumor growth and invasiveness through TAM recruitment and TLR4 signaling pathways.
doi:10.1158/0008-5472.CAN-13-3014
PMCID: PMC4247537  PMID: 24448240
7.  The mature anther-preferentially expressed genes are associated with pollen fertility, pollen germination and anther dehiscence in rice 
BMC Genomics  2015;16(1):101.
Background
The anthers and pollen grains are critical for male fertility and hybrid rice breeding. The development of rice mature anther and pollen consists of multiple continuous stages. However, molecular mechanisms regulating mature anther development were poorly understood.
Results
In this study, we have identified 291 mature anther-preferentially expressed genes (OsSTA) in rice based on Affymetrix microarray data. Gene Ontology (GO) analysis indicated that OsSTA genes mainly participated in metabolic and cellular processes that are likely important for rice anther and pollen development. The expression patterns of OsSTA genes were validated using real-time PCR and mRNA in situ hybridizations. Cis-element identification showed that most of the OsSTA genes had the cis-elements responsive to phytohormone regulation. Co-expression analysis of OsSTA genes showed that genes annotated with pectinesterase and calcium ion binding activities were rich in the network, suggesting that OsSTA genes could be involved in pollen germination and anther dehiscence. Furthermore, OsSTA RNAi transgenic lines showed male-sterility and pollen germination defects.
Conclusions
The results suggested that OsSTA genes function in rice male fertility, pollen germination and anther dehiscence and established molecular regulating networks that lay the foundation for further functional studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1305-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1305-y
PMCID: PMC4340671  PMID: 25765586
Mature anther; Microarray; Rice; RNA interference
9.  GeneChip Expression Profiling Reveals the Alterations of Energy Metabolism Related Genes in Osteocytes under Large Gradient High Magnetic Fields 
PLoS ONE  2015;10(1):e0116359.
The diamagnetic levitation as a novel ground-based model for simulating a reduced gravity environment has recently been applied in life science research. In this study a specially designed superconducting magnet with a large gradient high magnetic field (LG-HMF), which can provide three apparent gravity levels (μ-g, 1-g, and 2-g), was used to simulate a space-like gravity environment. Osteocyte, as the most important mechanosensor in bone, takes a pivotal position in mediating the mechano-induced bone remodeling. In this study, the effects of LG-HMF on gene expression profiling of osteocyte-like cell line MLO-Y4 were investigated by Affymetrix DNA microarray. LG-HMF affected osteocyte gene expression profiling. Differentially expressed genes (DEGs) and data mining were further analyzed by using bioinfomatic tools, such as DAVID, iReport. 12 energy metabolism related genes (PFKL, AK4, ALDOC, COX7A1, STC1, ADM, CA9, CA12, P4HA1, APLN, GPR35 and GPR84) were further confirmed by real-time PCR. An integrated gene interaction network of 12 DEGs was constructed. Bio-data mining showed that genes involved in glucose metabolic process and apoptosis changed notablly. Our results demostrated that LG-HMF affected the expression of energy metabolism related genes in osteocyte. The identification of sensitive genes to special environments may provide some potential targets for preventing and treating bone loss or osteoporosis.
doi:10.1371/journal.pone.0116359
PMCID: PMC4312085  PMID: 25635858
10.  Identification and Cytotoxic Activities of Two New Trichothecenes and a New Cuparane-Type Sesquiterpenoid from the Cultures of the Mushroom Engleromyces goetzii 
Abstract
Engleromyces goetzii is a traditional medicinal mushroom that is widely used to treat infection, inflammation and cancer in Tibet, Sichuan and Yunnan provinces of China. Two new trichothecenes, engleromycones A and B (1 and 2), one new cuparane-type sesquiterpenoid named infuscol F (11), eight known trichothecene analogs, sambucinol (3), 3-deoxysambucinol (4), trichothecolone (5), trichodermol (6), 8-deoxytrichothecin (7), trichothecin (8), trichothecinol B (9) and trichothecinol A (10), and one known cyclopentanoid sesquiterpene cyclonerodiol (12) were isolated from the cultures of E. goetzii. The new compounds were elucidated through spectroscopic analyses. The anticancer effects of trichothecenes 1–10 were examined in the HL-60, SMMC-7721, A549, MCF-7, and SW-480 human cancer cell lines using an MTT assay. Trichothecinol A (10) significantly inhibited the growth of MCF-7 cells, with an IC50 value of 0.006 µM, which was comparable to the cytotoxic activity of the positive control, paclitaxel, indicating that trichothecinol A (10) represents a potential anticancer agent.
Graphical Abstract
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-014-0051-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s13659-014-0051-1
PMCID: PMC4328002  PMID: 25633363
Engleromyces goetzii; Trichothecene; Engleromycone; Cuparane; Infuscol; Mycotoxin
11.  Identification and Cytotoxic Activities of Two New Trichothecenes and a New Cuparane-Type Sesquiterpenoid from the Cultures of the Mushroom Engleromyces goetzii 
Abstract
Engleromyces goetzii is a traditional medicinal mushroom that is widely used to treat infection, inflammation and cancer in Tibet, Sichuan and Yunnan provinces of China. Two new trichothecenes, engleromycones A and B (1 and 2), one new cuparane-type sesquiterpenoid named infuscol F (11), eight known trichothecene analogs, sambucinol (3), 3-deoxysambucinol (4), trichothecolone (5), trichodermol (6), 8-deoxytrichothecin (7), trichothecin (8), trichothecinol B (9) and trichothecinol A (10), and one known cyclopentanoid sesquiterpene cyclonerodiol (12) were isolated from the cultures of E. goetzii. The new compounds were elucidated through spectroscopic analyses. The anticancer effects of trichothecenes 1–10 were examined in the HL-60, SMMC-7721, A549, MCF-7, and SW-480 human cancer cell lines using an MTT assay. Trichothecinol A (10) significantly inhibited the growth of MCF-7 cells, with an IC50 value of 0.006 µM, which was comparable to the cytotoxic activity of the positive control, paclitaxel, indicating that trichothecinol A (10) represents a potential anticancer agent.
Graphical Abstract
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-014-0051-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s13659-014-0051-1
PMCID: PMC4328002  PMID: 25633363
Engleromyces goetzii; Trichothecene; Engleromycone; Cuparane; Infuscol; Mycotoxin
12.  An open-label, flexible-dose study of paliperidone extended-release in Chinese patients with first-onset psychosis 
Background
Antipsychotic medications facilitate the improvement of psychotic symptoms in patients with first-episode psychosis. Paliperidone extended-release (pali-ER), an atypical antipsychotic, was assessed for efficacy and safety in Chinese patients with first-episode psychosis.
Methods
In this 8-week, open-label, single-arm, multicenter study, patients with first-episode psychosis (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) and a Positive and Negative Syndrome Scale (PANSS) total score ≥70 were treated with flexible-dose pali-ER tablets (3–12 mg/day). The primary efficacy endpoint was the percentage of patients with an increase of ≥8 points in Personal and Social Performance (PSP) score from baseline to day 56 (8 weeks). Secondary endpoints included reduction in PANSS total score, improvement in Clinical Global Impression-Severity score, PSP score, Subjective Well-being under Neuroleptics Scale score, and relationship between duration of untreated psychosis and PANSS or PSP. Incidences of treatment-emergent adverse events were used to evaluate safety.
Results
Overall, 283 of 294 patients (96%) achieved a ≥8-point increase in PSP (primary endpoint, analysis set). For the secondary efficacy endpoints, 284/306 patients (93%) had a ≥30% reduction in PANSS total score; 266/306 patients (87%) achieved a ≤3 Clinical Global Impression-Severity scale score, and 218/294 patients (74%) had a PSP score ≥71. The Subjective Well-being under Neuroleptics Scale score was improved from a baseline mean of 72.7 to 94.7 at endpoint. There was a negative correlation between duration of untreated psychosis and posttreatment PSP score and a positive correlation with posttreatment PANSS total score. The most common treatment-emergent adverse events were extrapyramidal symptoms (12%), and agitation, somnolence, and xerostomia (4% each).
Conclusion
An 8-week, flexible-dose (3–12 mg/day) treatment with pali-ER resulted in significant improvements in psychotic symptoms and social functioning in Chinese patients with first-episode psychosis and was generally tolerable.
doi:10.2147/NDT.S70694
PMCID: PMC4295537  PMID: 25657581
paliperidone; first-episode psychosis; Personal and Social Performance score
13.  The Relationship Between Disability-Adjusted Life Years of Cataracts and Ambient Erythemal Ultraviolet Radiation in China 
Journal of Epidemiology  2015;25(1):57-65.
Background
Cataracts are one of the major public health problems worldwide. Ultraviolet radiation (UVR) is one of the risk factors for cataract development. We analyzed the relationship between disability-adjusted life year (DALY) rates of cataracts and UVR exposure in China.
Methods
DALY rates of cataracts and UVR exposure in 31 regions of China were calculated based on data from the Second China National Sample Survey on Disability and the United States’ National Aeronautics and Space Administration database. The relationship between the DALY rates of cataracts and UVR was estimated by Spearman rank correlation analysis and linear regression analysis.
Results
The elderly (≥65 years) had higher DALY rates of cataracts than the whole population. The DALY rate of cataracts in the agricultural population was higher than that observed in the non-agricultural population. The DALY rates of cataracts were positively associated with UVR The DALY rates of cataracts in regions with higher UVR were higher than those in regions with lower UVR. An increase in the daily ambient erythemal UVR of 1000 J/m2 was associated with an increase in the DALY rates of cataracts by 92 DALYs/100 000 (R2 = 0.676) among the whole population, 34 DALYs/100 000 among the population <65 years old (R2 = 0.423), 607 DALYs/100 000 among the population aged 65–74 years (R2 = 0.617), and by 1342 DALYs/100 000 among the population ≥75 years old (R2 = 0.758).
Conclusions
DALY rates of cataracts increased with increases in UVR exposure in 31 regions of China. Greater exposure to UVR increases the disease burden of cataracts in the whole population, especially in the elderly and among the agricultural population.
doi:10.2188/jea.JE20140017
PMCID: PMC4275439  PMID: 25263793
cataract; UVR exposure; disease burden; DALYs
14.  Human Connectome Module Pattern Detection Using A New Multi-Graph MinMax Cut Model 
Many recent scientific efforts have been devoted to constructing the human connectome using Diffusion Tensor Imaging (DTI) data for understanding the large-scale brain networks that underlie higher-level cognition in human. However, suitable computational network analysis tools are still lacking in human connectome research. To address this problem, we propose a novel multi-graph min-max cut model to detect the consistent network modules from the brain connectivity networks of all studied subjects. A new multi-graph MinMax cut model is introduced to solve this challenging computational neuroscience problem and the efficient optimization algorithm is derived. In the identified connectome module patterns, each network module shows similar connectivity patterns in all subjects, which potentially associate to specific brain functions shared by all subjects. We validate our method by analyzing the weighted fiber connectivity networks. The promising empirical results demonstrate the effectiveness of our method.
PMCID: PMC4203411  PMID: 25320814
15.  Overexpression of copper/zinc superoxide dismutase from mangrove Kandelia candel in tobacco enhances salinity tolerance by the reduction of reactive oxygen species in chloroplast 
Na+ uptake and transport in Kandelia candel and antioxidative defense were investigated under rising NaCl stress from 100 to 300 mM. Salinized K. candel roots had a net Na+ efflux with a declined flux rate during an extended NaCl exposure. Na+ buildup in leaves enhanced H2O2 levels, superoxide dismutase (SOD) activity, and increased transcription of CSD gene encoding a Cu/Zn SOD. Sequence and subcellular localization analyses have revealed that KcCSD is a typical Cu/Zn SOD in chloroplast. The transgenic tobacco experimental system was used as a functional genetics model to test the effect of KcCSD on salinity tolerance. KcCSD-transgenic lines were more Na+ tolerant than wild-type (WT) tobacco in terms of lipid peroxidation, root growth, and survival rate. In the latter, 100 mM NaCl led to a remarkable reduction in chlorophyll content and a/b ratio, decreased maximal chlorophyll a fluorescence, and photochemical efficiency of photosystem II. NaCl stress in WT resulted from H2O2 burst in chloroplast. Na+ injury to chloroplast was less pronounced in KcCSD-transgenic plants due to upregulated antioxidant defense. KcCSD-transgenic tobacco enhanced SOD activity by an increment in SOD isoenzymes under 100 mM NaCl stress from 24 h to 7 day. Catalase activity rose in KcCSD overexpressing tobacco plants. KcCSD-transgenic plants better scavenged NaCl-elicited reactive oxygen species (ROS) compared to WT ones. In conclusion, K. candel effectively excluded Na+ in roots during a short exposure; and increased CSD expression to reduce ROS in chloroplast in a long-term and high saline environment.
doi:10.3389/fpls.2015.00023
PMCID: PMC4302849  PMID: 25657655
Kandelia candel; Na+ flux; superoxide anion; hydrogen peroxide; salt; catalase; superoxide dismutase
16.  Exploring HIV Prevention Strategies among Street-Based Female Sex Workers in Chongqing, China 
Background: Commercial sex plays an increasingly important role in China’s growing HIV and sexually transmitted infection (STI) epidemics. In China, street-based sex workers (SSWs) are a subgroup of female sex workers with a particularly high risk of HIV/STI infections but are neglected in responses to HIV. This study assesses changes in HIV voluntary counseling and testing (VCT) utilization and high-risk sexual behaviors following a three-month HIV preventive intervention among SSWs in Chongqing, China. Methods: A three-month intervention was conducted by a team of peer educators, outreach workers from community-based organizations and health professionals. It mainly included distribution of free pamphlets and condoms and delivery of onsite and clinic-based VCT. Cross-sectional surveys were conducted prior to (n = 100) and immediately following (n = 112) the intervention to assess its impact. In-depth interviews were conducted among 12 SSWs after the intervention to further explore potential barriers to HIV prevention. Results: The intervention significantly increased SSWs’ participation in VCT (from 2.0%–15.2%, P < 0.001). Despite participants’ improved HIV-related knowledge level (from 24.0%–73.2%, P < 0.001), there were minimal changes in the levels of condom use with clients. Qualitative research revealed that fear of police arrest and stigma were the main barriers to VCT utilization. Low condom use was associated with family financial constraints, inadequate power in condom negotiation, low awareness and misconceptions of HIV infection risks. Conclusion: HIV intervention improved VCT utilization and knowledge but we did not observe an increase in condom use after this short intervention. SSWs faced substantial economic, social and environmental barriers to VCT utilization and condom use.
doi:10.3390/ijerph120100855
PMCID: PMC4306897  PMID: 25602971
street-based sex worker; Human Immunodeficiency Virus; condom use; commercial sex; peer-based intervention
17.  Asymmetric Synthesis and Evaluation of Danshensu-Cysteine Conjugates as Novel Potential Anti-Apoptotic Drug Candidates 
We have previously reported that the danshensu-cysteine conjugate N-((R)-3-benzylthio-1-methoxy-1-oxo-2-propanyl)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanamide (DSC) is a potent anti-oxidative and anti-apoptotic agent. Herein, we further design and asymmetrically synthesize two diastereoisomers of DSC and explore their potential bioactivities. Our results show that DSC and its two diastereoisomers exert similar protective effects in hydrogen peroxide (H2O2)-induced cellular injury in SH-SY5Y cells, as evidenced by the increase of cell viability, superoxide dismutase (SOD), and reduced glutathione (GSH) activity, and glutathione peroxidase (GPx) expression, and the decrease of cellular morphological changes and nuclear condensation, lactate dehydrogenase (LDH) release, and malondialdehyde (MDA) production. In H2O2-stimulated human umbilical vein endothelial cells (HUVEC), DSC concentration-dependently attenuates H2O2-induced cell death, LDH release, mitochondrial membrane potential collapse, and modulates the expression of apoptosis-related proteins (Bcl-2, Bax, caspase-3, and caspase-9). Our results provide strong evidence that DSC and its two diastereoisomers have similar anti-oxidative activity and that DSC exerts significant vascular-protective effects, at least in part, through inhibition of apoptosis and modulation of endogenous antioxidant enzymes.
doi:10.3390/ijms16010628
PMCID: PMC4307265  PMID: 25551606
Danshensu derivative; apoptosis; asymmetric synthesis; endothelial cells
18.  Wogonoside induces cell cycle arrest and mitochondrial mediated apoptosis by modulation of Bcl-2 and Bax in osteosarcoma cancer cells 
Osteosarcoma (OS) is the most common bone cancer with a great tendency for local invasion and distant metastasis. Restricted by the severe toxicity of conventional drugs, the therapeutic challenge of osteosarcoma still remains unconquered. The objective of the present research work was to investigate the antiproliferative activity of wogonoside against human osteosarcoma (SaOS-2) cell line. Cell viability after wogonoside treatment was evaluated by MTT assay. Phase contrast microscopy was used to evaluate the change in cell morphology following drug treatment. The effect of wogonoside on cell cycle phase distribution and mitochondrial membrane potential was investigated by flow cytometry using propidium iodide (PI) and rhodamine-123 DNA-binding fluorescent dyes respectively. Western blotting was used to evaluate the effect of wogonoside on cell cycle-related proteins as well as on the expression levels of Bcl-2, Bax, cytosolic and mitochondrial cytochrome c and apoptotic protease activating factor-1 (Apaf-1). Wogonoside induced a dose-dependent as well as time-dependent growth inhibitory effects on cell proliferation of SaOS-2 cancer cells. Wogonoside induced G2/M cell cycle arrest as well as loss in mitochondrial membrane potential in these cells. Within 48 h of incubation, approximately 4.36%, 6.72%, 11.54%, 21.88% and 15.54% of the cells underwent early apoptosis after treatment with 0, 5, 10, 25 and 75 μM of wogonoside respectively. Wogonoside led to reduced Bcl-2 expression and increased Bax expression, while as it led to s decrease in the levels of mitochondrial cytochrome c and an increase in cytosolic fraction and expressions of cytosolic apoptotic protease activating factor-1 (Apaf-1).
PMCID: PMC4348927  PMID: 25755693
Osteosarcoma; wogonoside; apoptosis; cell cycle; mitochondria
19.  Influence of morphology and hemodynamic factors on rupture of multiple intracranial aneurysms: matched-pairs of ruptured-unruptured aneurysms located unilaterally on the anterior circulation 
BMC Neurology  2014;14:253.
Background
The authors evaluated the impact of morphological and hemodynamic factors on the rupture of matched-pairs of ruptured-unruptured intracranial aneurysms on one patient’s ipsilateral anterior circulation with 3D reconstruction model and computational fluid dynamic method simulation.
Methods
20 patients with intracranial aneurysms pairs on the same-side of anterior circulation but with different rupture status were retrospectively collected. Each pair was divided into ruptured-unruptured group. Patient-specific models based on their 3D-DSA images were constructed and analyzed. The relative locations, morphologic and hemodynamic factors of these two groups were compared.
Results
There was no significant difference in the relative bleeding location. The morphological factors analysis found that the ruptured aneurysms more often had irregular shape and had significantly higher maximum height and aspect ratio. The hemodynamic factors analysis found lower minimum wall shear stress (WSSmin) and more low-wall shear stress-area (LSA) in the ruptured aneurysms than that of the unruptured ones. The ruptured aneurysms more often had WSSmin on the dome.
Conclusions
Intracranial aneurysms pairs with different rupture status on unilateral side of anterior circulation may be a good disease model to investigate possible characteristics linked to rupture independent of patient characteristics. Irregular shape, larger size, higher aspect ratio, lower WSSmin and more LSA may indicate a higher risk for their rupture.
doi:10.1186/s12883-014-0253-5
PMCID: PMC4301794  PMID: 25551809
Intracranial aneurysms; Multiple aneurysm; Anterior circulation; Rupture; Computational fluid dynamics
20.  Dopamine Receptors Antagonistically Regulate Behavioral Choice between Conflicting Alternatives in C. elegans 
PLoS ONE  2014;9(12):e115985.
Caenorhabditis elegans is a useful model to study the neuronal or molecular basis for behavioral choice, a specific form of decision-making. Although it has been implied that both D1-like and D2-like dopamine receptors may contribute to the control of decision-making in mammals, the genetic interactions between D1-like and D2-like dopamine receptors in regulating decision-making are still largely unclear. In the present study, we investigated the molecular control of behavioral choice between conflicting alternatives (diacetyl and Cu2+) by D1-like and D2-like dopamine receptors and their possible genetic interactions with C. elegans as the assay system. In the behavioral choice assay system, mutation of dop-1 gene encoding D1-like dopamine receptor resulted in the enhanced tendency to cross the Cu2+ barrier compared with wild-type. In contrast, mutations of dop-2 or dop-3 gene encoding D2-like dopamine receptor caused the weak tendency to cross the Cu2+ barrier compared with wild-type. During the control of behavioral choice, DOP-3 antagonistically regulated the function of DOP-1. The behavioral choice phenotype of dop-2; dop-1dop-3 triple mutant further confirmed the possible antagonistic function of D2-like dopamine receptor on D1-like dopamine receptor in regulating behavioral choice. The genetic assays further demonstrate that DOP-3 might act through Gαo signaling pathway encoded by GOA-1 and EGL-10, and DOP-1 might act through Gαq signaling pathway encoded by EGL-30 and EAT-16 to regulate the behavioral choice. DOP-1 might function in cholinergic neurons to regulate the behavioral choice, whereas DOP-3 might function in GABAergic neurons, RIC, and SIA neurons to regulate the behavioral choice. In this study, we provide the genetic evidence to indicate the antagonistic relationship between D1-like dopamine receptor and D2-like dopamine receptor in regulating the decision-making of animals. Our data will be useful for understanding the complex functions of dopamine receptors in regulating decision-making in animals.
doi:10.1371/journal.pone.0115985
PMCID: PMC4275273  PMID: 25536037
21.  Structural Basis of Chronic Beryllium Disease: Linking Allergic Hypersensitivity and Autoimmunity 
Cell  2014;158(1):132-142.
SUMMARY
T cell-mediated hypersensitivity to metal cations is common in humans. How the T cell antigen receptor (TCR) recognizes these cations bound to a major histocompatibility complex (MHC) protein and self-peptide is unknown. Individuals carrying the MHCII allele, HLA-DP2, are at risk for chronic beryllium disease (CBD), a debilitating inflammatory lung condition caused by the reaction of CD4 T cells to inhaled beryllium. We show here that the T cell ligand is created when a Be2+ cation becomes buried in an HLA-DP2/peptide complex, where it is coordinated by both MHC and peptide acidic amino acids. Surprisingly, the TCR does not interact with the Be2+ itself, but rather with surface changes induced by the firmly bound Be2+ and an accompanying Na+ cation. Thus, CBD, by creating a new antigen by indirectly modifying the structure of pre-existing self MHC-peptide complex, lies on the border between allergic hypersensitivity and autoimmunity.
doi:10.1016/j.cell.2014.04.048
PMCID: PMC4269484  PMID: 24995984
22.  Acupuncture promotes white adipose tissue browning by inducing UCP1 expression on DIO mice 
Background
To study the influence of acupuncture and its possible mechanism on white adipose tissue of high fat diet-induced obese.
Methods
Four-week-old C57BL/6 J mice were randomly divided into a normal diet group and a high-fat diet (HFD) group. After 8 weeks, the HFD mice were randomly divided into Electro-acupuncture (EA) group and control group. Mice in the EA group were electro-acupunctured, under physical restraint, on Zusanli (ST36) and Neiting (ST44) acupoints, while the mice in the control group were under physical restraint only. Body weight and food intake were monitored, and serum leptin, cholesterol and triglyceride levels were measured by using biochemistrical methods. The effect of EA on white adipose tissues (WAT) was assessed by qPCR, immunobloting, immunohistochemistry (IHC), immunoprecipitation and cold endurance experiment.
Results
The WAT/body weight ratio decreased (P < 0.05) in the EA group, albeit no significant difference on food consumption between EA and control groups. The difference in the darkness of Epi-WAT between EA and control groups could be distinguished visually. HE staining indicated that the EA mice had an increased number of UCP1-immunoreactive paucilocular adipocytes in their WAT. The expressions of brown adipose tissue (BAT) markers, including UCP1, COX4il and Nrtf1 were increased in the WAT of EA mice, acetylation of Pparγ was decreased by electro-acupuncture.
Conclusion
EA can remodel WAT to BAT through inducing UCP1 expression, and this may be one of the mechanisms by which acupuncture affects weight loss.
doi:10.1186/1472-6882-14-501
PMCID: PMC4301852  PMID: 25514854
Acupuncture; Browning; Obesity; UCP1; White adipose tissue
23.  Genes associated with thermosensitive genic male sterility in rice identified by comparative expression profiling 
BMC Genomics  2014;15(1):1114.
Background
Thermosensitive genic male sterile (TGMS) lines and photoperiod-sensitive genic male sterile (PGMS) lines have been successfully used in hybridization to improve rice yields. However, the molecular mechanisms underlying male sterility transitions in most PGMS/TGMS rice lines are unclear. In the recently developed TGMS-Co27 line, the male sterility is based on co-suppression of a UDP-glucose pyrophosphorylase gene (Ugp1), but further study is needed to fully elucidate the molecular mechanisms involved.
Results
Microarray-based transcriptome profiling of TGMS-Co27 and wild-type Hejiang 19 (H1493) plants grown at high and low temperatures revealed that 15462 probe sets representing 8303 genes were differentially expressed in the two lines, under the two conditions, or both. Environmental factors strongly affected global gene expression. Some genes important for pollen development were strongly repressed in TGMS-Co27 at high temperature. More significantly, series-cluster analysis of differentially expressed genes (DEGs) between TGMS-Co27 plants grown under the two conditions showed that low temperature induced the expression of a gene cluster. This cluster was found to be essential for sterility transition. It includes many meiosis stage-related genes that are probably important for thermosensitive male sterility in TGMS-Co27, inter alia: Arg/Ser-rich domain (RS)-containing zinc finger proteins, polypyrimidine tract-binding proteins (PTBs), DEAD/DEAH box RNA helicases, ZOS (C2H2 zinc finger proteins of Oryza sativa), at least one polyadenylate-binding protein and some other RNA recognition motif (RRM) domain-containing proteins involved in post-transcriptional processes, eukaryotic initiation factor 5B (eIF5B), ribosomal proteins (L37, L1p/L10e, L27 and L24), aminoacyl-tRNA synthetases (ARSs), eukaryotic elongation factor Tu (eEF-Tu) and a peptide chain release factor protein involved in translation. The differential expression of 12 DEGs that are important for pollen development, low temperature responses or TGMS was validated by quantitative RT-PCR (qRT-PCR).
Conclusions
Temperature strongly affects global gene expression and may be the common regulator of fertility in PGMS/TGMS rice lines. The identified expression changes reflect perturbations in the transcriptomic regulation of pollen development networks in TGMS-Co27. Findings from this and previous studies indicate that sets of genes involved in post-transcriptional and translation processes are involved in thermosensitive male sterility transitions in TGMS-Co27.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1114) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-1114
PMCID: PMC4320516  PMID: 25512054
Transcriptome profiling; TGMS; Male sterility transition; Meiosis stage
24.  Hyperbaric oxygen therapy improves local microenvironment after spinal cord injury 
Neural Regeneration Research  2014;9(24):2182-2188.
Clinical studies have shown that hyperbaric oxygen therapy improves motor function in patients with spinal cord injury. In the present study, we explored the mechanisms associated with the recovery of neurological function after hyperbaric oxygen therapy in a rat model of spinal cord injury. We established an acute spinal cord injury model using a modification of the free-falling object method, and treated the animals with oxygen at 0.2 MPa for 45 minutes, 4 hours after injury. The treatment was administered four times per day, for 3 days. Compared with model rats that did not receive the treatment, rats exposed to hyperbaric oxygen had fewer apoptotic cells in spinal cord tissue, lower expression levels of aquaporin 4/9 mRNA and protein, and more NF-200 positive nerve fibers. Furthermore, they had smaller spinal cord cavities, rapid recovery of somatosensory and motor evoked potentials, and notably better recovery of hindlimb motor function than model rats. Our findings indicate that hyperbaric oxygen therapy reduces apoptosis, downregulates aquaporin 4/9 mRNA and protein expression in injured spinal cord tissue, improves the local microenvironment for nerve regeneration, and protects and repairs the spinal cord after injury.
doi:10.4103/1673-5374.147951
PMCID: PMC4316452  PMID: 25657740
nerve regeneration; spinal cord injury; hyperbaric oxygen; motor function; rats; microenvironment; aquaporin 4; aquaporin 9; neural regeneration
25.  Automation Practices in Large Molecule Bioanalysis: Recommendations from Group L5 of the Global Bioanalytical Consortium 
The AAPS Journal  2013;16(1):164-171.
In recent years, the use of automated sample handling instrumentation has come to the forefront of bioanalytical analysis in order to ensure greater assay consistency and throughput. Since robotic systems are becoming part of everyday analytical procedures, the need for consistent guidance across the pharmaceutical industry has become increasingly important. Pre-existing regulations do not go into sufficient detail in regard to how to handle the use of robotic systems for use with analytical methods, especially large molecule bioanalysis. As a result, Global Bioanalytical Consortium (GBC) Group L5 has put forth specific recommendations for the validation, qualification, and use of robotic systems as part of large molecule bioanalytical analyses in the present white paper. The guidelines presented can be followed to ensure that there is a consistent, transparent methodology that will ensure that robotic systems can be effectively used and documented in a regulated bioanalytical laboratory setting. This will allow for consistent use of robotic sample handling instrumentation as part of large molecule bioanalysis across the globe.
doi:10.1208/s12248-013-9551-x
PMCID: PMC3889521  PMID: 24311307
automation; documentation; large molecule bioanalysis; robotic system

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