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1.  New loci and coding variants confer risk for age-related macular degeneration in East Asians 
Cheng, Ching-Yu | Yamashiro, Kenji | Jia Chen, Li | Ahn, Jeeyun | Huang, Lulin | Huang, Lvzhen | Cheung, Chui Ming G. | Miyake, Masahiro | Cackett, Peter D. | Yeo, Ian Y. | Laude, Augustinus | Mathur, Ranjana | Pang, Junxiong | Sim, Kar Seng | Koh, Adrian H. | Chen, Peng | Lee, Shu Yen | Wong, Doric | Chan, Choi Mun | Loh, Boon Kwang | Sun, Yaoyao | Davila, Sonia | Nakata, Isao | Nakanishi, Hideo | Akagi-Kurashige, Yumiko | Gotoh, Norimoto | Tsujikawa, Akitaka | Matsuda, Fumihiko | Mori, Keisuke | Yoneya, Shin | Sakurada, Yoichi | Iijima, Hiroyuki | Iida, Tomohiro | Honda, Shigeru | Lai, Timothy Yuk Yau | Tam, Pancy Oi Sin | Chen, Haoyu | Tang, Shibo | Ding, Xiaoyan | Wen, Feng | Lu, Fang | Zhang, Xiongze | Shi, Yi | Zhao, Peiquan | Zhao, Bowen | Sang, Jinghong | Gong, Bo | Dorajoo, Rajkumar | Yuan, Jian-Min | Koh, Woon-Puay | van Dam, Rob M. | Friedlander, Yechiel | Lin, Ying | Hibberd, Martin L. | Foo, Jia Nee | Wang, Ningli | Wong, Chang Hua | Tan, Gavin S. | Park, Sang Jun | Bhargava, Mayuri | Gopal, Lingam | Naing, Thet | Liao, Jiemin | Guan Ong, Peng | Mitchell, Paul | Zhou, Peng | Xie, Xuefeng | Liang, Jinlong | Mei, Junpu | Jin, Xin | Saw, Seang-Mei | Ozaki, Mineo | Mizoguchi, Takanori | Kurimoto, Yasuo | Woo, Se Joon | Chung, Hum | Yu, Hyeong-Gon | Shin, Joo Young | Park, Dong Ho | Kim, In Taek | Chang, Woohyok | Sagong, Min | Lee, Sang-Joon | Kim, Hyun Woong | Lee, Ji Eun | Li, Yi | Liu, Jianjun | Teo, Yik Ying | Heng, Chew Kiat | Lim, Tock Han | Yang, Suk-Kyun | Song, Kyuyoung | Vithana, Eranga N. | Aung, Tin | Bei, Jin Xin | Zeng, Yi Xin | Tai, E. Shyong | Li, Xiao Xin | Yang, Zhenglin | Park, Kyu-Hyung | Pang, Chi Pui | Yoshimura, Nagahisa | Yin Wong, Tien | Khor, Chiea Chuen
Nature Communications  2015;6:6063.
Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10−22). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l−1 (P=5.82 × 10−21) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10−18), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10−11) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10−8). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.
Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Here, the authors carry out a two-stage genome-wide association study for AMD and identify three new AMD risk loci, highlighting the shared and distinct genetic basis of the disease in East Asians and Europeans.
doi:10.1038/ncomms7063
PMCID: PMC4317498  PMID: 25629512
2.  S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing 
Antioxidants & Redox Signaling  2014;20(6):937-951.
Abstract
Significance: Ion channels control membrane potential, cellular excitability, and Ca++ signaling, all of which play essential roles in cellular functions. The regulation of ion channels enables cells to respond to changing environments, and post-translational modification (PTM) is one major regulation mechanism. Recent Advances: Many PTMs (e.g., S-glutathionylation, S-nitrosylation, S-palmitoylation, S-sulfhydration, etc.) targeting the thiol group of cysteine residues have emerged to be essential for ion channels regulation under physiological and pathological conditions. Critical Issues: Under oxidative stress, S-glutathionylation could be a critical PTM that regulates many molecules. In this review, we discuss S-glutathionylation-mediated structural and functional changes of ion channels. Criteria for testing S-glutathionylation, methods and reagents used in ion channel S-glutathionylation studies, and thiol modification crosstalk, are also covered. Mechanotransduction, and S-glutathionylation of the mechanosensitive KATP channel, are discussed. Future Directions: Further investigation of the ion channel S-glutathionylation, especially the physiological significance of S-glutathionylation and thiol modification crosstalk, could lead to a better understanding of the thiol modifications in general and the ramifications of such modifications on cellular functions and related diseases. Antioxid. Redox Signal. 20, 937–951.
doi:10.1089/ars.2013.5483
PMCID: PMC3924852  PMID: 23834398
3.  Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma 
Vithana, Eranga N | Khor, Chiea-Chuen | Qiao, Chunyan | Nongpiur, Monisha E | George, Ronnie | Chen, Li-Jia | Do, Tan | Abu-Amero, Khaled | Huang, Chor Kai | Low, Sancy | Tajudin, Liza-Sharmini A | Perera, Shamira A | Cheng, Ching-Yu | Xu, Liang | Jia, Hongyan | Ho, Ching-Lin | Sim, Kar Seng | Wu, Ren-Yi | Tham, Clement C Y | Chew, Paul T K | Su, Daniel H | Oen, Francis T | Sarangapani, Sripriya | Soumittra, Nagaswamy | Osman, Essam A | Wong, Hon-Tym | Tang, Guangxian | Fan, Sujie | Meng, Hailin | Huong, Dao T L | Wang, Hua | Feng, Bo | Baskaran, Mani | Shantha, Balekudaru | Ramprasad, Vedam L | Kumaramanickavel, Govindasamy | Iyengar, Sudha K | How, Alicia C | Lee, Kelvin Y | Sivakumaran, Theru A | Yong, Victor H K | Ting, Serena M L | Li, Yang | Wang, Ya-Xing | Tay, Wan-Ting | Sim, Xueling | Lavanya, Raghavan | Cornes, Belinda K | Zheng, Ying-Feng | Wong, Tina T | Loon, Seng-Chee | Yong, Vernon K Y | Waseem, Naushin | Yaakub, Azhany | Chia, Kee-Seng | Allingham, R Rand | Hauser, Michael A | Lam, Dennis S C | Hibberd, Martin L | Bhattacharya, Shomi S | Zhang, Mingzhi | Teo, Yik Ying | Tan, Donald T | Jonas, Jost B | Tai, E-Shyong | Saw, Seang-Mei | Hon, Do Nhu | Al-Obeidan, Saleh A | Liu, Jianjun | Chau, Tran Nguyen Bich | Simmons, Cameron P | Bei, Jin-Xin | Zeng, Yi-Xin | Foster, Paul J | Vijaya, Lingam | Wong, Tien-Yin | Pang, Chi-Pui | Wang, Ningli | Aung, Tin
Nature genetics  2012;44(10):1142-1146.
Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10−12), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10−10) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10−9). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.
doi:10.1038/ng.2390
PMCID: PMC4333205  PMID: 22922875
5.  A Comparison between the Sixth and Seventh Editions of the UICC/AJCC Staging System for Nasopharyngeal Carcinoma in a Chinese Cohort 
PLoS ONE  2014;9(12):e116261.
Background
The International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) TNM staging system of nasopharyngeal carcinoma (NPC) is the most important system for survival prediction. The TNM 7th edition UICC/AJCC TNM staging system for NPC was adopted in January 2009, and is now internationally recommended. In comparison with the TNM 6th edition, there were several revisions in the new edition staging system. This study aims to evaluate the prognostic value of the TNM 7th edition for NPC patients in comparison with the TNM 6th edition.
Method
Clinical data of 2,629 NPC patients from the Sun Yat-sen University Cancer Center between January 2006 and December 2010 were retrospectively collected and all the patients were restaged according to the criteria of the TNM 6th edition and TNM 7th edition UICC/AJCC staging manual. Univariate and multivariate COX proportional hazards analyses were applied to evaluate the prognostic values between adjacent stage categories of the TNM 6th edition and TNM 7th edition.
Results
In comparison with the TNM 6th edition, a significant alteration of the distribution of N categories was observed when the TNM 7th edition was applied (χ2 = 20.589, P<0.001), with 119 (119/670, 17.8%) patients up-staging from N0 to N1. With regard to T and overall stage, 37 (37/561, 6.6%) patients were down-staged from T2a with the TNM 6th edition to T1 with the TNM 7th edition, and finally two patients were up-staged to overall stage II (2/118, 1.7%). Moreover, the survival curves were significantly segregated (P<0.05) between T1 and T2 as well as N1 and N2 with the TNM 7th edition.
Conclusions
The TNM 7th edition led to a significant alteration in the distribution of N categories and it is superior to the TNM 6th edition in predicting the frequency of overall survival and distant metastasis-free survival.
doi:10.1371/journal.pone.0116261
PMCID: PMC4275293  PMID: 25536307
6.  Long-Term Persistence of Functional Thymic Epithelial Progenitor Cells In Vivo under Conditions of Low FOXN1 Expression 
PLoS ONE  2014;9(12):e114842.
Normal thymus function reflects interactions between developing T-cells and several thymic stroma cell types. Within the stroma, key functions reside in the distinct cortical and medullary thymic epithelial cell (TEC) types. It has been demonstrated that, during organogenesis, all TECs can be derived from a common thymic epithelial progenitor cell (TEPC). The properties of this common progenitor are thus of interest. Differentiation of both cTEC and mTEC depends on the epithelial-specific transcription factor FOXN1, although formation of the common TEPC from which the TEC lineage originates does not require FOXN1. Here, we have used a revertible severely hypomorphic allele of Foxn1, Foxn1R, to test the stability of the common TEPC in vivo. By reactivating Foxn1 expression postnatally in Foxn1R/− mice we demonstrate that functional TEPCs can persist in the thymic rudiment until at least 6 months of age, and retain the potential to give rise to both cortical and medullary thymic epithelial cells (cTECs and mTECs). These data demonstrate that the TEPC-state is remarkably stable in vivo under conditions of low Foxn1 expression, suggesting that manipulation of FOXN1 activity may prove a valuable method for long term maintenance of TEPC in vitro.
doi:10.1371/journal.pone.0114842
PMCID: PMC4273964  PMID: 25531271
7.  Intercropping Enhances Productivity and Maintains the Most Soil Fertility Properties Relative to Sole Cropping 
PLoS ONE  2014;9(12):e113984.
Yield and nutrient acquisition advantages are frequently found in intercropping systems. However, there are few published reports on soil fertility in intercropping relative to monocultures. A field experiment was therefore established in 2009 in Gansu province, northwest China. The treatments comprised maize/faba bean, maize/soybean, maize/chickpea and maize/turnip intercropping, and their correspoding monocropping. In 2011 (the 3rd year) and 2012 (the 4th year) the yields and some soil chemical properties and enzyme activities were examined after all crop species were harvested or at later growth stages. Both grain yields and nutrient acquisition were significantly greater in all four intercropping systems than corresponding monocropping over two years. Generally, soil organic matter (OM) did not differ significantly from monocropping but did increase in maize/chickpea in 2012 and maize/turnip in both years. Soil total N (TN) did not differ between intercropping and monocropping in either year with the sole exception of maize/faba bean intercropping receiving 80 kg P ha−1 in 2011. Intercropping significantly reduced soil Olsen-P only in 2012, soil exchangeable K in both years, soil cation exchangeable capacity (CEC) in 2012, and soil pH in 2012. In the majority of cases soil enzyme activities did not differ across all the cropping systems at different P application rates compared to monocrops, with the exception of soil acid phosphatase activity which was higher in maize/legume intercropping than in the corresponding monocrops at 40 kg ha−1 P in 2011. P fertilization can alleviate the decline in soil Olsen-P and in soil CEC to some extent. In summary, intercropping enhanced productivity and maintained the majority of soil fertility properties for at least three to four years, especially at suitable P application rates. The results indicate that maize-based intercropping may be an efficient cropping system for sustainable agriculture with carefully managed fertilizer inputs.
doi:10.1371/journal.pone.0113984
PMCID: PMC4259307  PMID: 25486249
8.  Highly Compact Circulators in Square-Lattice Photonic Crystal Waveguides 
PLoS ONE  2014;9(11):e113508.
We propose, demonstrate and investigate highly compact circulators with ultra-low insertion loss in square-lattice- square-rod-photonic-crystal waveguides. Only a single magneto- optical square rod is required to be inserted into the cross center of waveguides, making the structure very compact and ultra efficient. The square rods around the center defect rod are replaced by several right-angled-triangle rods, reducing the insertion loss further and promoting the isolations as well. By choosing a linear-dispersion region and considering the mode patterns in the square magneto-optical rod, the operating mechanism of the circulator is analyzed. By applying the finite-element method together with the Nelder-Mead optimization method, an extremely low insertion loss of 0.02 dB for the transmitted wave and ultra high isolation of 46 dB∼48 dB for the isolated port are obtained. The idea presented can be applied to build circulators in different wavebands, e.g., microwave or Tera-Hertz.
doi:10.1371/journal.pone.0113508
PMCID: PMC4240590  PMID: 25415417
9.  Association between Reversal in the Expression of Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Channel and Age-Related Atrial Fibrillation 
Background
We compared cardiac electrophysiological indicators and regional expression levels of cardiac hyperpolarization-activated cyclic nucleotide-gated (HCN) channels between adult and aged dogs to identify possible mechanisms of age-related atrial fibrillation.
Material/Methods
Corrected sinus node recovery time (SNRTc) and effective refractory period (ERP) of the atrium and pulmonary veins were measured in 10 adult (3–6 years old) and 10 aged dogs (>9 years old). Expression levels of HCN2 and HCN4 channel mRNAs and proteins were measured in the sinoatrial node, atrium, and pulmonary veins by real-time PCR and Western blotting.
Results
Aged dogs exhibited a higher induction rate of atrial fibrillation (AF) in response to electrical stimulation, longer AF duration after induction, longer SNRTc, longer right atrial effective refractory period (AERP), shorter left AERP, and increased AERP dispersion compared to adults. Expression levels of HCN2 and HCN4 channel mRNAs and proteins were lower in the sinoatrial node but higher in the atrium and pulmonary veins of aged dogs.
Conclusions
Changes in atrial electrophysiological indicators in aged dogs revealed sinoatrial node dysfunction. There was a reversal in the local tissue distribution of HCN2 and HCN4 channel mRNA and protein, a decrease in sinoatrial node expression, and increase in atrial and pulmonary vein expression with age. Changes in atrial electrophysiological characteristics and regional HCN channel expression patterns were associated with the onset and maintenance of age-related atrial fibrillation.
doi:10.12659/MSM.892505
PMCID: PMC4242900  PMID: 25404650
Aging; Atrial Fibrillation; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
10.  Compound Danshen Dripping Pill Pretreatment to Prevent Contrast-Induced Nephropathy in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention 
Background. Contrast-induced nephropathy (CIN) limits the outcome of percutaneous coronary intervention (PCI). Objective. To investigate whether pretreatment with Compound Danshen Dripping Pills (CDDP) will decrease the incidence of CIN after PCI. Methods. A total of 229 patients with acute coronary syndrome (ACS) undergoing PCI were divided into the control group (n = 114) and the CDDP (containing salvia miltiorrhiza and sanqi) group (n = 115; given 20 CDDP pills, three times daily before PCI). Serum creatinine, creatinine clearance (CrCl), high-sensitivity C-reactive protein (hsCRP), P-selectin, and intercellular adhesion molecule-1 (ICAM-1) were measured at admission and 24 and 48 h after PCI. Results. CrCl decreased after PCI but recovered after 48 h. In the CDDP group, CrCl recovered more rapidly (P < 0.05). The procedure increased the hsCRP, P-selectin, and ICAM-1 levels, but these levels were less in the CDDP group (P < 0.05). Conclusions. Pretreatment with CDDP can decrease the occurrence of CIN in patients undergoing PCI, suggesting that the early use of CDDP is an appropriate adjuvant pharmacological therapy before PCI.
doi:10.1155/2014/256268
PMCID: PMC4216665  PMID: 25386219
11.  Hepatic arterial administration of sorafenib and iodized oil effectively attenuates tumor growth and intrahepatic metastasis in rabbit VX2 hepatocellular carcinoma model 
Aim: To investigate the therapeutic effect of the hepatic arterial administration of sorafenib in rabbit VX-2 hepatocellular carcinoma (HCC) model. Methods: Rabbit VX-2 HCC models were established via implanting VX-2 tumors into the livers, and randomly divided into four groups, respectively treated with (1) The hepatic arterial administration of iodized oil alone (TACE-i), (2) The hepatic arterial administration of iodized oil and pharmorubicin (TACE-ip), (3) The hepatic arterial administration of iodized and cis-DDP (TACE-ic), (4) The hepatic arterial administration of iodized and sorafenib (TACE-is). The growth rate and intrahepatic metastasis of implanted VX-2 tumor in each rabbit were measured. Microvessel density (MVD) in the adjacent tissues of implanted VX-2 tumor were estimated by detecting the expression of CD34 and VEGF level in tumor adjacent tissues were also examined by Immunohistochemistry. Results: Compared with other groups, TACE-is treatment group presented a better effect on inhibiting tumor growth rate and intrahepatic metastasis in rabbit VX-2 HCC model. The angiogenesis (assessed by MVD) in the adjacent tissues were suppressed more dramatically in TACE-is treated group. Moreover, TACE-is treatment did not significantly increase the levels of alanine transaminase and creatinine compared to the group with TACE-i treatment. Conclusion: The hepatic arterial administration of sorafenib and iodized oil (TACE-is) effectively attenuates tumor growth and intrahepatic metastasis in rabbit VX-2 HCC model without obvious hepatic and renal toxicity. One of the related mechanisms may be due to the inhibition of angiogenesis in the adjacent tissues. Our data indicated that TACE-is may be a secure and effective treatment for HCC.
PMCID: PMC4270620  PMID: 25550815
Hepatocellular carcinoma; TACE; sorafenib; MVD; VEGF
12.  The involvement of high mobility group 1 cytokine and phospholipases A2 in diabetic retinopathy 
Background
Diabetic retinopathy, the main microvascular complications of diabetes and one of the leading causes of blindness worldwide. Interesting reports on the role of inflammatory/proangiogenic high mobility group 1 (HMGB-1) cytokine and phospholipases A2 (PLA2) in neovascularization have diverted our concentration to reveal whether HMGB-1 and PLA2 plays role in diabetic retinopathy.
Methods
We performed our study in streptozotocin (STZ)-induced diabetic rat model. The expression levels of the cytokines, chemokines, and cell adhesion molecules in retinal tissues were evaluated by quantitative RT-PCR. HMGB-1 and PLA2 protein levels along with VEGF, TNF-α, IL-1β and ICAM-1 levels were also measured.
Results
We observed the retinal pericytes, endothelial injury/death and breakdown of blood–retinal barrier (BRB). The protein expression of HMGB-1, PLA2 and IL-1β were significantly increased in micro vessels from retina of diabetic rats. Diabetic rats had also high retinal levels of VEGF, ICAM-1 and TNF-α. Further investigation revealed that pericyte death is mediated by HMGB-1-induced cytotoxic activity of glial cells, while HMGB-1 can directly mediate endothelial cell death. Similarly, increased expression of PLA2 represents the diabetic mediated alteration of BRB, perhaps up regulating the VEGF.
Conclusions
Our data suggest that HMGB-1 and PLA2 involved in retinal pericyte and endothelial injury and cell death in diabetic retinopathy. From this study, we suggest that HMGB-1 and PLA2 may be interesting targets in managing diabetic retinopathy.
doi:10.1186/1476-511X-13-156
PMCID: PMC4287419  PMID: 25292258
Blood retinal barrier; Micro vessels; Retinal pericytes; Endothelial cells
13.  Study on Optimisation of Extraction Process of Tanshinone IIA and Its Mechanism of Induction of Gastric Cancer SGC7901 Cell Apoptosis 
The objective of this paper was to investigate the extraction process of tanshinone IIA and its mechanism of induction of gastric cancer SGC7901 cell apoptosis. Extraction process of tanshinone IIA was optimised by orthogonal experimental method, and its effect on gastric cancer SGC7901 cell apoptosis was observed using MTT assay and electron microscopy. The optimum extraction process of tanshinone IIA was as follows: addition of a 10-fold amount of 80% ethanol, one-time extraction, and extraction time of 45 minutes. The study concluded that tanshinone IIA can induce apoptosis of gastric cancer SGC7901 cells.
PMCID: PMC3847383  PMID: 24311868
Tanshinone IIA; MTT assay; gastric cancer SGC7901 cells
14.  Er-Xian Decoction, a traditional Chinese herbal formula, intervening early in hypothalamic-pituitary axis of male rats with delayed puberty 
Pharmacognosy Magazine  2014;10(40):517-521.
Background:
Er-Xian Decoction (EXD) is one of the traditional Chinese medicine (TCM) with unique effect on osteoporosis, menopausal syndrome and delayed puberty in China for many years.
Objective:
We aim to evaluate the potential activity of starting hypothalamic–pituitary–testicular (HPT) axis of male rats with delayed puberty.
Materials and Methods:
Delayed puberty model of male Sprague–Dawley (SD) rats were established with soy isoflavones (90 mg·kg-1) and were treated by EXD extract at doses of 5, 10 g·kg-1 or Testosterone undecanoate (TU) for 8 weeks. Body weight, body length, testis weight, T, E2 and luteinizing hormone (LH) in serum, gonadotropin releasing hormone (GnRH) in hypothalamus, follicle stimulating hormone (FSH) and LH in pituitary gland were determined by ELISA. Immunohistochemistry was used to detect LH in pituitary gland.
Results:
Soy isoflavones could significantly decrease body weight, body length, testicular organ coefficient T in serum, GnRH in hypothalamus, FSH and LH in pituitary gland. Both of EXD and TU could improve the condition. E2 and LH in serum of all groups were non-significance of difference (P > 0.05). The immunohistochemical results were well consistent with LH in pituitary gland.
Conclusion:
The results of the present research indicate that EXD extract is effective to start the HPT axis in puberty and can significantly improve sexual developmental inhibition caused by soy isoflavones.
doi:10.4103/0973-1296.141780
PMCID: PMC4239732  PMID: 25422555
Delayed puberty; Er-Xian Decoction; traditional Chinese medicine
15.  Study of Tetrapodal ZnO-PDMS Composites: A Comparison of Fillers Shapes in Stiffness and Hydrophobicity Improvements 
PLoS ONE  2014;9(9):e106991.
ZnO particles of different size and structures were used as fillers to modify the silicone rubber, in order to reveal the effect of the filler shape in the polymer composites. Tetrapodal shaped microparticles, short microfibers/whiskers, and nanosized spherical particles from ZnO have been used as fillers to fabricate the different ZnO-Silicone composites. The detailed microstructures of the fillers as well as synthesized composites using scanning electron microscopy have been presented here. The tensile elastic modulus and water contact angle, which are important parameters for bio-mimetic applications, of fabricated composites with different fillers have been measured and compared. Among all three types of fillers, tetrapodal shaped ZnO microparticles showed the best performance in terms of increase in hydrophobicity of material cross-section as well as the stiffness of the composites. It has been demonstrated that the tetrapodal shaped microparticles gain their advantage due to the special shape, which avoids agglomeration problems as in the case for nanoparticles, and the difficulty of achieving truly random distribution for whisker fillers.
doi:10.1371/journal.pone.0106991
PMCID: PMC4160218  PMID: 25208080
16.  Basal Ganglia Subcircuits Distinctively Encode the Parsing and Concatenation of Action Sequences 
Nature neuroscience  2014;17(3):423-430.
Chunking allows the brain to efficiently organize memories and actions. Although basal ganglia circuits have been implicated in action chunking, little is known about how individual elements are concatenated into a behavioral sequence at the neural level. Using a task where mice learn rapid action sequences, we uncovered neuronal activity encoding entire sequences as single actions in basal ganglia circuits. Besides start/stop activity signaling sequence parsing, we found neurons displaying inhibited or sustained activity throughout the execution of an entire sequence. This sustained activity covaried with the rate of execution of individual sequence elements, consistent with motor concatenation. Direct and indirect pathways of basal ganglia were concomitantly active during sequence initiation, but behaved differently during sequence performance, revealing a more complex functional organization of these circuits than previously postulated. These results have important implications for understanding the functional organization of basal ganglia during the learning and execution of action sequences.
doi:10.1038/nn.3632
PMCID: PMC3955116  PMID: 24464039
17.  Structural Characterisation of a Polysaccharide from Radix Ranunculus Ternati 
A water soluble polysaccharide, HB-1, with a molecular weight of 23,930, was isolated from radix Ranunculi ternati. by hot water extraction, ethanol precipitation, deproteination,ultrafiltration and gel-filtration column chromatography. Its sugar composition was determined by GLC as Glc, Ara, and Gal in a molar ration of 16.071: 2.722: 1. And the absolute configuration of Glc was identified as D. Smith degradation and methylation reaction showed the proportion of —1Glc (A) was about 16%, —1Glc4— (B) about 62%, (C) about 14%, and —1Gal6— (D) about 8%. The repetitive unit was likely composed of 3 As, 3 Cs, 13 Bs and 1 D. Together with the average molecular weight, it was predictable that HB-1 consisted of about seven of the repetitive unit. The inhibition activity of HB-1 on human glioma cell line SF188 was also measured, only to find it inactive.
PMCID: PMC4232807  PMID: 25587330
Ranunculus ternatus Thunb; Polysaccharide; Ultrafiltration; Absolute configuration; Smith degradation; Methylation reaction; Anti-tumor activity
18.  Selection of Bone Metastasis Seeds by Mesenchymal Signals in the Primary Tumor Stroma 
Cell  2013;154(5):1060-1073.
Summary
How organ-specific metastatic traits arise in primary tumors remains unknown. Here we show a role of the breast tumor stroma in selecting cancer cells that are primed for metastasis in bone. Cancer-associated fibroblasts (CAFs) in triple-negative (TN) breast tumors skew heterogeneous cancer cell populations towards a predominance of clones that thrive on the CAF-derived factors CXCL12 and IGF1. Limiting concentrations of these factors select for cancer cells with high Src activity, a known clinical predictor of bone relapse and an enhancer of PI3K-Akt pathway activation by CXCL12 and IGF1. Carcinoma clones selected in this manner are primed for metastasis in the CXCL12-rich microenvironment of the bone marrow. The evidence suggests that stromal signals resembling those of a distant organ select for cancer cells that are primed for metastasis in that organ, thus illuminating the evolution of metastatic traits in a primary tumor and its distant metastases.
doi:10.1016/j.cell.2013.07.036
PMCID: PMC3974915  PMID: 23993096
19.  Activation of the Cl− Channel ANO1 by Localized Calcium Signals in Nociceptive Sensory Neurons Requires Coupling with the IP3 Receptor* 
Science signaling  2013;6(290):ra73.
We report that ANO1 (also known as TMEM16A) Ca2+-activated Cl− channels in small neurons from dorsal root ganglia are preferentially activated by particular pools of intracellular Ca2+. These ANO1 channels can be selectively activated by the G protein-coupled receptor (GPCR)-induced release of Ca2+ from intracellular stores, but not by Ca2+ influx through voltage-gated Ca2+ channels. This ability to discriminate between Ca2+ pools was achieved by the tethering of ANO1-containing plasma membrane domains, which also contained GPCRs such as bradykinin receptor-2 and protease-activated receptor-2, to juxtamembrane regions of the endoplasmic reticulum. Interaction of the C-terminus and the first intracellular loop of ANO1 with IP3R1 (inositol 1,4,5-trisphosphate receptor 1) contributed to the tethering. Disruption of membrane microdomains blocked the ANO1 and IP3R1 interaction and resulted in the loss of coupling between GPCR signaling and ANO1. The junctional signaling complex enabled ANO1-mediated excitation in response to specific Ca2+ signals rather than to global changes in intracellular Ca2+.
doi:10.1126/scisignal.2004184
PMCID: PMC4135425  PMID: 23982204
20.  Differential sensitivities of the vascular KATP channel to various PPAR activators 
Biochemical pharmacology  2013;85(10):1495-1503.
Several agonists of the peroxisome proliferator-activated receptors (PPARs) are currently used for the treatment of metabolic disorders including diabetes. We have recently shown that one of them, Rosiglitazone, inhibits the vascular ATP-sensitive K+ (KATP) channel and compromises the coronary vasodilation by the β-adrenoceptor agonist. Here, we show evidence for the channel inhibition by various PPAR agonists, information that may be useful for finding new therapeutical agents with less cardiovascular side-effects and more selective KATP channel blockers targeting at the Kir6.1 subunit. Structural comparison of these PPAR agonists may shed insight into the critical chemical groups for the channel inhibition.
Kir6.1/SUR2B channel was expressed in HEK293 cells and studied in whole-cell voltage clamp. The Kir6.1/SUR2B channel was strongly inhibited by several PPARγ agonists with potencies similar to, or higher than, that of Rosiglitazone, while other PPARγ agonists barely inhibited the channel. The Kir6.1/SUR2B channel was also inhibited by PPARα and PPARβ/δ agonists with intermediate potencies. The structure necessary for the channel inhibition appears to include the thiazole linked to an aromatic or furan ring. Additions of side groups such as small aliphatic chain increased the potency for channel inhibition, while additions of aromatic rings reduced it. These results indicate that the PPARγ agonists with weak KATP channel inhibition may be potential candidates as therapeutical agents, and those with strong channel inhibition may be used as selective KATP channel blockers. The structural information of the PPAR agonists may be useful for the development of new therapeutical modalities with less cardiovascular side-effects.
doi:10.1016/j.bcp.2013.02.039
PMCID: PMC4132832  PMID: 23500542
PPAR; thiazolidinedione; Type-2 diabetes mellitus; potassium channel; vascular tones; cardiovascular
21.  Design, synthesis, and anticancer activity of novel berberine derivatives prepared via CuAAC “click” chemistry as potential anticancer agents 
A series of novel derivatives of phenyl-substituted berberine triazolyls has been designed and synthesized via copper-catalyzed azide-alkyne cycloaddition click chemistry in an attempt to develop antitumor agents. All of the compounds were evaluated for anticancer activity against a panel of three human cancer cell lines, including MCF-7 (breast), SW-1990 (pancreatic), and SMMC-7721 (liver) and the noncancerous human umbilical vein endothelial cell (HUVEC) cell lines. The results indicated that most of the compounds displayed notable anticancer activities against the MCF-7 cells compared with berberine. Among these derivatives, compound 16 showed the most potent inhibitory activity against the SW-1990 and SMMC-7721 cell lines, with half-maximal inhibitory concentration (IC50) values of 8.54±1.97 μM and 11.87±1.83 μM, respectively. Compound 36 exhibited the most potent inhibitory activity against the MCF-7 cell line, with an IC50 value of 12.57±1.96 μM. Compound 16 and compound 36 exhibited low cytotoxicity in the HUVEC cell line, with IC50 values of 25.49±3.24 μM and 30.47±3.47 μM. Furthermore, compounds 14, 15, 16, 17, 18, 32, and 36 exhibited much better selectivity than berberine toward the normal cell line HUVEC.
doi:10.2147/DDDT.S63228
PMCID: PMC4128789  PMID: 25120353
berberine; anticancer; click chemistry; structure–activity relationship
22.  Deep brain optical measurements of cell type–specific neural activity in behaving mice 
Nature protocols  2014;9(6):1213-1228.
Recent advances in genetically encoded fluorescent sensors enable the monitoring of cellular events from genetically defined groups of neurons in vivo. In this protocol, we describe how to use a time-correlated single-photon counting (tcspc)–based fiber optics system to measure the intensity, emission spectra and lifetime of fluorescent biosensors expressed in deep brain structures in freely moving mice. When combined with cre-dependent selective expression of genetically encoded ca2+ indicators (GecIs), this system can be used to measure the average neural activity from a specific population of cells in mice performing complex behavioral tasks. as an example, we used viral expression of GcaMps in striatal projection neurons (spns) and recorded the fluorescence changes associated with calcium spikes from mice performing a lever-pressing operant task. the whole procedure, consisting of virus injection, behavior training and optical recording, takes 3–4 weeks to complete. With minor adaptations, this protocol can also be applied to recording cellular events from other cell types in deep brain regions, such as dopaminergic neurons in the ventral tegmental area. the simultaneously recorded fluorescence signals and behavior events can be used to explore the relationship between the neural activity of specific brain circuits and behavior.
doi:10.1038/nprot.2014.080
PMCID: PMC4100551  PMID: 24784819
24.  Anterior internal fixator versus a femoral distractor and external fixation for sacroiliac joint compression and single stance gait testing: a mechanical study in synthetic bone 
International Orthopaedics  2013;37(7):1341-1346.
Purpose
The purpose of this study was to evaluate the biomechanical stability and compressive forces across the sacroiliac (SI) joint of an anterior internal fixator compared to the femoral distractor and external fixator for vertically unstable pelvic fractures.
Methods
Five composite pelvises with a simulated APC type III injury fixed with a femoral distractor, external fixator, or anterior internal fixator were tested. A pressure-sensitive film (Tekscan) was placed in the disrupted SI joint recording the magnitude of force. Then, in a single-leg stance model (Instron machine), a load was applied through the sacrum. We recorded displacement at the pubic symphysis and SI joint using high-speed video. Peak load and displacement were measured, and axial stiffness was calculated. Values were compared using a Student’s t-test (p < 0.05).
Results
The SI joint was compressed significantly (p < 0.001) more using the anterior internal fixator (18.9 N) and femoral distractor (18.6 N) than the two-pin external fixator (2.5 N). There was no significant difference between the anterior internal fixator and the femoral distractor in displacement at the SI joint. The pubic symphysis displaced less with the femoral distractor than the anterior internal fixator (5.5 mm vs. 4.1 mm; p < 0.05).
Conclusions
The anterior pedicle screw internal fixator allows for indirect compression across the sacroiliac joint that is superior to two-pin external fixation and comparable to the femoral distractor. The anterior internal fixator may be an option for temporary anterior pelvic fixation in situations where external fixation or the femoral distractor have otherwise been used.
doi:10.1007/s00264-013-1890-9
PMCID: PMC3685661  PMID: 23645004
25.  Preparation and pharmacokinetics in beagle dogs of ganershu sustained-release pellets 
Pharmacognosy Magazine  2014;10(39):217-226.
Background:
The active ingredients of Ganershu compound recipe, which are effective for hepatitis treatment in liver protection and transaminase reduction. However, the active ingredients of Ganershu compound recipe are poor absorption, which conduct it has a low oral bioavailability.
Objective:
We prepared Ganershu sustained-release pellets (GSPs) by fluidized-bed on central composite design-response surface methodology and increase its bioavailability in beagle dogs.
Materials and Methods:
In this study, GSPs were successfully prepared. The Drug-loaded pellets and sustained-release coated were carried out in fluidized-bed machine. GSP was optimized for fitting release, roundness, and the overall desirability by central composite design-response surface methodology.
Results:
To optimize cumulative release profile, the outermost ethyl cellulose coating layer and the hydroxypropyl methyl cellulose (HPMC) swelling layer were employed, which were respectively given coating levels in terms of weight gain of 22% and 6%, the concentration of HPMC is 4.5% (g/ml). The pharmacokinetics of Ganershu normal pellets (GNPs) and GSP was studied in beagle dogs after oral administration. The naringenin as an index, the area under the curve0-∞ of naringenin in GSP was 1.38 times greater than that of GNP. Meanwhile, Tmax of GSP was prolonged for about 74%.
Conclusion:
This study can clearly indicate that we enhanced the oral bioavailability of Ganershu by preparing the GSP, which had the sustained dissolution and improved the potential of it for clinical application.
doi:10.4103/0973-1296.137360
PMCID: PMC4159913  PMID: 25210307
Beagle dogs; fluidized-bed; Ganershu sustained-release pellets; naringenin; pharmacokinetics

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