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1.  Ascorbic Acid Protects against Hypertension through Downregulation of ACE1 Gene Expression Mediated by Histone Deacetylation in Prenatal Inflammation-Induced Offspring 
Scientific Reports  2016;6:39469.
Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Prenatal exposure to lipopolysaccharide (LPS) leads to hypertension in a rat offspring. However, the mechanism is still unclear. This study unraveled epigenetic mechanism for this and explored the protective effects of ascorbic acid against hypertension on prenatal inflammation-induced offspring. Prenatal LPS exposure resulted in an increase of intrarenal oxidative stress and enhanced angiotensin-converting enzyme 1 (ACE1) gene expression at the mRNA and protein levels in 6- and 12-week-old offspring, correlating with the augmentation of histone H3 acetylation (H3AC) on the ACE1 promoter. However, the prenatal ascorbic acid treatment decreased the LPS-induced expression of ACE1, protected against intrarenal oxidative stress, and reversed the altered histone modification on the ACE1 promoter, showing the protective effect in offspring of prenatal LPS stimulation. Our study demonstrates that ascorbic acid is able to prevent hypertension in offspring from prenatal inflammation exposure. Thus, ascorbic acid can be a new approach towards the prevention of fetal programming hypertension.
doi:10.1038/srep39469
PMCID: PMC5171640  PMID: 27995995
2.  Revalidation of a prognostic score model based on complete blood count for nasopharyngeal carcinoma through a prospective study 
Objective
In our previous work, we incorporated complete blood count (CBC) into TNM stage to develop a new prognostic score model, which was validated to improve prediction efficiency of TNM stage for nasopharyngeal carcinoma (NPC). The purpose of this study was to revalidate the accuracy of the model, and its superiority to TNM stage, through data from a prospective study.
Methods
CBC of 249 eligible patients from the 863 Program No. 2006AA02Z4B4 was evaluated. Prognostic index (PI) of each patient was calculated according to the score model. Then they were divided by the PI into three categories: the low-, intermediate-and high-risk patients. The 5-year disease-specific survival (DSS) of the three categories was compared by a log-rank test. The model and TNM stage (7th edition) were compared on efficiency for predicting the 5-year DSS, through comparison of the area under curve (AUC) of their receiver-operating characteristic curves.
Results
The 5-year DSS of the low-, intermediate-and high-risk patients were 96.0%, 79.1% and 62.2%, respectively. The low-and intermediate-risk patients had better DSS than the high-risk patients (P<0.001 and P<0.005, respectively). And there was a trend of better DSS in the low-risk patients, compared with the intermediate-risk patients (P=0.049). The AUC of the model was larger than that of TNM stage (0.726 vs. 0.661, P=0.023).
Conclusions
A CBC-based prognostic score model was revalidated to be accurate and superior to TNM stage on predicting 5-year DSS of NPC.
doi:10.21147/j.issn.1000-9604.2016.05.01
PMCID: PMC5101220  PMID: 27877005
Complete blood count; score model; revalidation; disease-specific survival; nasopharyngeal carcinoma
3.  Sustained elevation of NF-κB activity sensitizes offspring of maternal inflammation to hypertension via impairing PGC-1α recovery 
Scientific Reports  2016;6:32642.
Growing evidence has demonstrated that maternal detrimental factors, including inflammation, contribute to the development of hypertension in the offspring. The current study found that offspring subjected to prenatal exposure of inflammation by lipopolysaccharide (LPS) challenge during the second semester showed significantly increased systolic blood pressure. In addition, these offspring also displayed augmented vascular damage and reactive oxygen species (ROS) levels in thoracic aortas when challenged with deoxycorticosterone acetate and high-salt diet (DOCA-salt). Interestingly, the antioxidant N-acetyl-L-cysteine markedly reversed these changes. Mechanistically, prenatal LPS exposure led to pre-existing elevated peroxisome proliferators-activated receptor-γ co-activator (PGC)-1α, a critical master of ROS metabolism, which up-regulated the ROS defense capacity and maintained the balance of ROS generation and elimination under resting state. However, continued elevation of NF-κB activity significantly suppressed the rapid recovery of PGC-1α expression response to DOCA-salt challenge in offspring that underwent prenatal inflammatory stimulation. This was further confirmed by using a NF-κB inhibitor (N-p-Tosyl-L-phenylalanine chloromethyl ketone) that restored PGC-1α recovery and prevented blood pressure elevation induced by DOCA-salt. Our results suggest that maternal inflammation programmed proneness to NF-κB over-activation which impaired PGC-1α-mediated anti-oxidant capacity resulting in the increased sensitivity of offspring to hypertensive damage.
doi:10.1038/srep32642
PMCID: PMC5018852  PMID: 27616627
4.  Maternal inflammation activated ROS-p38 MAPK predisposes offspring to heart damages caused by isoproterenol via augmenting ROS generation 
Scientific Reports  2016;6:30146.
Maternal inflammation contributes to the increased incidence of adult cardiovascular disease. The current study investigated the susceptibility of cardiac damage responding to isoproterenol (ISO) in adult offspring that underwent maternal inflammation (modeled by pregnant Sprague-Dawley rats with lipopolysaccharides (LPS) challenge). We found that 2 weeks of ISO treatment in adult offspring of LPS-treated mothers led to augmented heart damage, characterized by left-ventricular systolic dysfunction, cardiac hypertrophy and myocardial fibrosis. Mechanistically, prenatal exposure to LPS led to up-regulated expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, antioxidant enzymes, and p38 MAPK activity in left ventricular of adult offspring at resting state. ISO treatment exaggerated ROS generation, p38 MAPK activation but down-regulated reactive oxygen species (ROS) elimination capacity in the left ventricular of offspring from LPS-treated mothers, while antioxidant N-acetyl-L-cysteine (NAC) reversed these changes together with improved cardiac functions. The p38 inhibitor SB202190 alleviated the heart damage only via inhibiting the expression of NADPH oxidases. Collectively, our data demonstrated that prenatal inflammation programs pre-existed ROS activation in the heart tissue, which switches on the early process of oxidative damages on heart rapidly through a ROS-p38 MAPK-NADPH oxidase-ROS positive feedback loop in response to a myocardial hypertrophic challenge in adulthood.
doi:10.1038/srep30146
PMCID: PMC4957145  PMID: 27443826
5.  Compound K Attenuates the Development of Atherosclerosis in ApoE−/− Mice via LXRα Activation 
Background: Atherosclerosis is a fundamental pathological process responded to some serious cardiovascular events. Although the cholesterol-lowering drugs are widely prescribed for atherosclerosis therapy, it is still the leading cause of death in the developed world. Here we measured the effects of compound K in atherosclerosis formation and investigated the probably mechanisms of the anti-antherosclerosis roles of compound K. Methods: We treated the atherosclerotic model animals (apoE−/− mice on western diet) with compound K and measured the size of atherosclerotic lesions, inflammatory cytokine levels and serum lipid profile. Peritoneal macrophages were collected in vitro for the foam cell and inflammasome experiments. Results: Our results show that treatment with compound K dose-dependently attenuates the formation of atherosclerotic plaques by 55% through activation of reverse cholesterol transport pathway, reduction of systemic inflammatory cytokines and inhibition of local inflammasome activity. Compound K increases the cholesterol efflux of macrophage-derived foam cells, and reduces the inflammasome activity in cholesterol crystal stimulated macrophages. The activation of LXRα may contribute to the athero-protective effects of compound K. Conclusion: These observations provide evidence for an athero-protective effect of compound K via LXRα activation, and support its further evaluation as a potential effective modulator for the prevention and treatment of atherosclerosis.
doi:10.3390/ijms17071054
PMCID: PMC4964430  PMID: 27399689
atherosclerosis; compound K; reverse cholesterol transport; inflammasome; LXRα
6.  Low molecular weight glutenin subunit gene Glu-B3h confers superior dough strength and breadmaking quality in wheat (Triticum aestivum L.) 
Scientific Reports  2016;6:27182.
Low molecular weight glutenin subunit is one of the important quality elements in wheat (Triticum aestivum L.). Although considerable allelic variation has been identified, the functional properties of individual alleles at Glu-3 loci are less studied. In this work, we performed the first comprehensive study on the molecular characteristics and functional properties of the Glu-B3h gene using the wheat cultivar CB037B and its Glu-B3 deletion line CB037C. The results showed that the Glu-B3h deletion had no significant effects on plant morphological or yield traits, but resulted in a clear reduction in protein body number and size and main quality parameters, including inferior mixing property, dough strength, loaf volume, and score. Molecular characterization showed that the Glu-B3h gene consists of 1179 bp, and its encoded B-subunit has a longer repetitive domain and an increased number of α-helices, as well as higher expression, which could contribute to superior flour quality. The SNP-based allele-specific PCR markers designed for the Glu-B3h gene were developed and validated with bread wheat holding various alleles at Glu-B3 locus, which could effectively distinguish the Glu-B3h gene from others at the Glu-B3 locus, and have potential applications for wheat quality improvement through marker-assisted selection.
doi:10.1038/srep27182
PMCID: PMC4895167  PMID: 27273251
7.  Widely tunable Tm-doped mode-locked all-fiber laser 
Scientific Reports  2016;6:27245.
We demonstrated a widely tunable Tm-doped mode-locked all-fiber laser, with the widest tunable range of 136 nm, from 1842 to 1978 nm. Nonlinear polarization evolution (NPE) technique is employed to enable mode-locking and the wavelength-tunable operation. The widely tunable range attributes to the NPE-induced transmission modulation and bidirectional pumping mechanism. Such kind of tunable mode-locked laser can find various applications in optical communications, spectroscopy, time-resolved measurement, and among others.
doi:10.1038/srep27245
PMCID: PMC4893705  PMID: 27263655
8.  The Fabrication of Nanoimprinted P3HT Nanograting by Patterned ETFE Mold at Room Temperature and Its Application for Solar Cell 
Nanoimprinting lithography (NIL) is investigated as a promising method to define nanostructure; however, finding a practical method to achieve large area patterning of conjugated polymer remains a challenge. We demonstrate here that a simple and cost-effective technique is proposed to fabricate the nanoimprinted P3HT nanograting by solvent-assisted room temperature NIL (SART-NIL) method with patterned ETFE film as mold. The patterned ETFE template is produced by embossing ETFE film into a patterned silicon master and is used as template to transfer nanogratings during the SART-NIL process. It indicates that highly reproducible and well-controlled P3HT nanograting film is obtained successfully with feature size of nanogratings ranging from 130 to 700 nm, due to the flexibility, stiffness, and low surface energy of ETFE mold. Moreover, the SART-NIL method using ETFE mold is able to fabricate nanogratings but not to induce the change of molecular orientation within conjugated polymer. The conducting ability of P3HT nanograting in the vertical direction is also not damaged after patterning. Finally, we further apply P3HT nanograting for the fabrication of active layer of OBHJ solar cell device, to investigate the morphology role presented by ETFE mold in device performance. The device performance of OBHJ solar cell is preferential to that of PBHJ device obviously.
Electronic supplementary material
The online version of this article (doi:10.1186/s11671-016-1481-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s11671-016-1481-y
PMCID: PMC4875018  PMID: 27206643
ETFE film; Nanoimprint lithography; P3HT nanograting; Solar cell
9.  Inhibitory effect of Bailing capsule on hypoxia-induced proliferation of rat pulmonary arterial smooth muscle cells 
Saudi Medical Journal  2016;37(5):498-505.
Objectives:
To investigated the effects of Bailing capsule on hypoxia-induced proliferation of pulmonary arterial smooth muscle cells (PASMCs).
Methods:
This prospective study was performed at the Central Laboratory, Chengdu Medical College, Chengdu, China between April 2012 and November 2014. Ten healthy adult male Wistar rats were administrated with gastric perfusion of Bailing capsule to obtain serum containing the tested drugs. Proliferation of pulmonary arterial smooth muscle cells proliferation was measured using cell counting kit-8 assay. Production of reactive oxygen species (ROS) in rat PASMCs was determined through a fluorometric assay, whereas production of endothelin-1 (ET-1) was detected by ELISA and quantitative real-time PCR (qRT-PCR). Expression of proliferating cell nuclear antigen (PCNA), c-fos, and c-jun in PASMCs was also determined using immunohistochemistry staining and qRT-PCR.
Results:
We observed that the medicated serum obviously inhibited hypoxia-induced cell proliferation in a concentration-dependent manner. Moreover, the medicated serum significantly reduced hypoxia-induced production of ROS and ET-1, as well as expression of PCNA, c-fos, and c-jun, in PASMCs.
Conclusion:
Results demonstrated that Bailing capsule can inhibit hypoxia-induced PASMC proliferation possibly by suppressing ET-1 and ROS production and by inhibiting expression of PCNA, c-fos, and c-jun. These results suggest that Bailing possess antiproliferative property, which is probably one of the underlying mechanisms of Bailing capsule for the clinical treatment of chronic obstructive pulmonary disease.
doi:10.15537/smj.2016.5.14953
PMCID: PMC4880648  PMID: 27146611
10.  Single-wall carbon nanotubes and graphene oxide-based saturable absorbers for low phase noise mode-locked fiber lasers 
Scientific Reports  2016;6:25266.
Low phase noise mode-locked fiber laser finds important applications in telecommunication, ultrafast sciences, material science, and biology, etc. In this paper, two types of carbon nano-materials, i.e. single-wall carbon nanotube (SWNT) and graphene oxide (GO), are investigated as efficient saturable absorbers (SAs) to achieve low phase noise mode-locked fiber lasers. Various properties of these wall-paper SAs, such as saturable intensity, optical absorption and degree of purity, are found to be key factors determining the performance of the ultrafast pulses. Reduced-noise femtosecond fiber lasers based on such carbon-based SAs are experimentally demonstrated, for which the phase noise has been reduced by more than 10 dB for SWNT SAs and 8 dB for GO SAs at 10 kHz. To the best of our knowledge, this is the first investigation on the relationship between different carbon material based SAs and the phase noise of mode-locked lasers. This work paves the way to generate high-quality low phase noise ultrashort pulses in passively mode-locked fiber lasers.
doi:10.1038/srep25266
PMCID: PMC4850480  PMID: 27126900
11.  Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error 
Fan, Qiao | Verhoeven, Virginie J. M. | Wojciechowski, Robert | Barathi, Veluchamy A. | Hysi, Pirro G. | Guggenheim, Jeremy A. | Höhn, René | Vitart, Veronique | Khawaja, Anthony P. | Yamashiro, Kenji | Hosseini, S Mohsen | Lehtimäki, Terho | Lu, Yi | Haller, Toomas | Xie, Jing | Delcourt, Cécile | Pirastu, Mario | Wedenoja, Juho | Gharahkhani, Puya | Venturini, Cristina | Miyake, Masahiro | Hewitt, Alex W. | Guo, Xiaobo | Mazur, Johanna | Huffman, Jenifer E. | Williams, Katie M. | Polasek, Ozren | Campbell, Harry | Rudan, Igor | Vatavuk, Zoran | Wilson, James F. | Joshi, Peter K. | McMahon, George | St Pourcain, Beate | Evans, David M. | Simpson, Claire L. | Schwantes-An, Tae-Hwi | Igo, Robert P. | Mirshahi, Alireza | Cougnard-Gregoire, Audrey | Bellenguez, Céline | Blettner, Maria | Raitakari, Olli | Kähönen, Mika | Seppala, Ilkka | Zeller, Tanja | Meitinger, Thomas | Ried, Janina S. | Gieger, Christian | Portas, Laura | van Leeuwen, Elisabeth M. | Amin, Najaf | Uitterlinden, André G. | Rivadeneira, Fernando | Hofman, Albert | Vingerling, Johannes R. | Wang, Ya Xing | Wang, Xu | Tai-Hui Boh, Eileen | Ikram, M. Kamran | Sabanayagam, Charumathi | Gupta, Preeti | Tan, Vincent | Zhou, Lei | Ho, Candice E. H. | Lim, Wan'e | Beuerman, Roger W. | Siantar, Rosalynn | Tai, E-Shyong | Vithana, Eranga | Mihailov, Evelin | Khor, Chiea-Chuen | Hayward, Caroline | Luben, Robert N. | Foster, Paul J. | Klein, Barbara E. K. | Klein, Ronald | Wong, Hoi-Suen | Mitchell, Paul | Metspalu, Andres | Aung, Tin | Young, Terri L. | He, Mingguang | Pärssinen, Olavi | van Duijn, Cornelia M. | Jin Wang, Jie | Williams, Cathy | Jonas, Jost B. | Teo, Yik-Ying | Mackey, David A. | Oexle, Konrad | Yoshimura, Nagahisa | Paterson, Andrew D. | Pfeiffer, Norbert | Wong, Tien-Yin | Baird, Paul N. | Stambolian, Dwight | Wilson, Joan E. Bailey | Cheng, Ching-Yu | Hammond, Christopher J. | Klaver, Caroline C. W. | Saw, Seang-Mei | Rahi, Jugnoo S. | Korobelnik, Jean-François | Kemp, John P. | Timpson, Nicholas J. | Smith, George Davey | Craig, Jamie E. | Burdon, Kathryn P. | Fogarty, Rhys D. | Iyengar, Sudha K. | Chew, Emily | Janmahasatian, Sarayut | Martin, Nicholas G. | MacGregor, Stuart | Xu, Liang | Schache, Maria | Nangia, Vinay | Panda-Jonas, Songhomitra | Wright, Alan F. | Fondran, Jeremy R. | Lass, Jonathan H. | Feng, Sheng | Zhao, Jing Hua | Khaw, Kay-Tee | Wareham, Nick J. | Rantanen, Taina | Kaprio, Jaakko | Pang, Chi Pui | Chen, Li Jia | Tam, Pancy O. | Jhanji, Vishal | Young, Alvin L. | Döring, Angela | Raffel, Leslie J. | Cotch, Mary-Frances | Li, Xiaohui | Yip, Shea Ping | Yap, Maurice K.H. | Biino, Ginevra | Vaccargiu, Simona | Fossarello, Maurizio | Fleck, Brian | Yazar, Seyhan | Tideman, Jan Willem L. | Tedja, Milly | Deangelis, Margaret M. | Morrison, Margaux | Farrer, Lindsay | Zhou, Xiangtian | Chen, Wei | Mizuki, Nobuhisa | Meguro, Akira | Mäkelä, Kari Matti
Nature Communications  2016;7:11008.
Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10−5), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
This report by the Consortium for Refractive Error and Myopia uses gene-environment-wide interaction study (GEWIS) to identify genetic loci that affect environmental influence in myopia development, and identifies ethnic specific genetic loci that attribute to eye refractive errors.
doi:10.1038/ncomms11008
PMCID: PMC4820539  PMID: 27020472
12.  Transcription Factor Foxo1 Is a Negative Regulator of NK Cell Maturation and Function 
Immunity  2015;42(3):457-470.
SUMMARY
Little is known about the role of negative regulators in controlling natural killer (NK) cell development and effector functions. Foxo1 is a multifunctional transcription factor of the forkhead family. Using a mouse model of conditional deletion in NK cells, we found that Foxo1 negatively controlled NK cell differentiation and function. Immature NK cells expressed abundant Foxo1 and little Tbx21 relative to mature NK cells, but these two transcription factors reversed their expression as NK cells proceeded through development. Foxo1 promoted NK cell homing to lymph nodes through upregulating CD62L expression, and impaired late-stage maturation and effector functions by repressing Tbx21 expression. Loss of Foxo1 rescued the defect in late-stage NK cell maturation in heterozygous Tbx21+/− mice. Collectively, our data reveal a regulatory pathway by which the negative regulator Foxo1 and the positive regulator Tbx21 play opposing roles in controlling NK cell development and effector functions.
doi:10.1016/j.immuni.2015.02.006
PMCID: PMC4400836  PMID: 25769609
13.  A large animal model of Spinal Muscular Atrophy and correction of phenotype 
Annals of neurology  2015;77(3):399-414.
Objectives
Spinal muscular atrophy (SMA) is caused by reduced levels of SMN which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides or scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness and the response of clinically relevant biomarkers.
Methods
Using intrathecal delivery of scAAV9 expressing a shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN) and electrophysiology measures and pathology were performed.
Results
Knockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography (EMG) indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimates (MUNE), like human SMA. Neuropathology showed loss of motoneurons and motor axons. Pre-symptomatic delivery of scAAV9-SMN prevented SMA symptoms indicating all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures and pathology.
Interpretation
High SMN levels are critical in postnatal motoneurons and reduction of SMN results in a SMA phenotype which is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration and abrogation of phenotype can be achieved even after symptom onset.
doi:10.1002/ana.24332
PMCID: PMC4453930  PMID: 25516063
15.  High efficacy of intravesical treatment of metformin on bladder cancer in preclinical model 
Oncotarget  2016;7(8):9102-9117.
Anticancer potential of metformin has been extensively studied. However, its anticancer clinical use remains yet to be approved since sufficient concentration on target organs could not be achieved via conventional administration. To overcome this drawback, we aim to examine the efficiency of novel intravesical treatment of metformin on syngeneic orthotopic preclinical model. Three human and one murine bladder cancer cell lines were tested in vitro for inhibitory sensitivity by MTT and cologenic assays. AMPK pathway including AKT, Erk and S6K was examined by western blot and further explored by regulating activated levels using specific inhibitors. In vivo efficacy was determined by Kaplan-Meier survival curves and measurements of body and bladder weights plus tumor biomarkers. Lactic acid and metformin levels of plasma were measured by standard procedures. The results demonstrated that metformin activated AMPK and decreased phosphorylation of Akt and Erk. Furthermore, combinations of metformin with either Akt or Erk inhibitors synergistically diminished cancer proliferation, suggesting the involvement of Akt- and Erk- related pathways. Intravesical metformin 26 and 104 mg/kg, twice per week demonstrated a rapid elimination of the implanted tumor without any evidence of toxicity. In contrast, oral treatment at a dose of 800mg/kg/d exhibited little efficacy whereas severe toxicity existed if the dosage is higher. Collectively, intravesical metformin displays potent inhibition on bladder cancer in vitro and this preclinical study reveals the profound therapeutic application of metformin with durable tolerance via intravesical administration route.
doi:10.18632/oncotarget.6933
PMCID: PMC4891029  PMID: 26802022
metformin; bladder cancer; localized administration; AMPK; preclinical model
16.  Mechanical stretching stimulates collagen synthesis via down-regulating SO2/AAT1 pathway 
Scientific Reports  2016;6:21112.
The aim of the study was to investigate the role of endogenous sulfur dioxide (SO2)/ aspartate aminotransferase 1 (AAT1) pathway in stretch-induced excessive collagen expression and its mechanism. The mechanical stretch downregulated SO2/AAT1 pathway and increased collagen I and III protein expression. Importantly, AAT1 overexpression blocked the increase in collagen I and III expression, transforming growth factor-β1 (TGF- β1) expression and phosphorylation of Smad2/3 induced by stretch, but AAT1 knockdown mimicked the increase in collagen I and III expression, TGF- β1 expression and phosphorylation of Smad2/3 induced by stretch. Mechanistically, SB431542, a TGF-β1/Smad2/3 inhibitor, eliminated excessive collagen I and III accumulation induced by AAT1 knockdown, stretch or stretch plus AAT1 knockdown. In a rat model of high pulmonary blood flow-induced pulmonary vascular collagen accumulation, AAT1 expression and SO2 content in lung tissues of rat were reduced in shunt rats with high pulmonary blood flow. Supplement of SO2 derivatives inhibited activation of TGF- β1/Smad2/3 pathway and alleviated the excessive collagen accumulation in lung tissues of shunt rats. The results suggested that deficiency of endogenous SO2/AAT1 pathway mediated mechanical stretch-stimulated abnormal collagen accumulation via TGF-β1/Smad2/3 pathway.
doi:10.1038/srep21112
PMCID: PMC4754767  PMID: 26880260
17.  Prenatal inflammation-induced NF-κB dyshomeostasis contributes to renin-angiotensin system over-activity resulting in prenatally programmed hypertension in offspring 
Scientific Reports  2016;6:21692.
Studies involving the use of prenatally programmed hypertension have been shown to potentially contribute to prevention of essential hypertension (EH). Our previous research has demonstrated that prenatal inflammatory stimulation leads to offspring’s aortic dysfunction and hypertension in pregnant Sprague-Dawley rats challenged with lipopolysaccharide (LPS). The present study found that prenatal LPS exposure led to NF-κB dyshomeostasis from fetus to adult, which was characterized by PI3K-Akt activation mediated degradation of IκBα protein and impaired NF-κB self-negative feedback loop mediated less newly synthesis of IκBα mRNA in thoracic aortas (gestational day 20, postnatal week 7 and 16). Prenatal or postnatal exposure of the IκBα degradation inhibitor, pyrollidine dithiocarbamate, effectively blocked NF-κB activation, endothelium dysfunction, and renin-angiotensin system (RAS) over-activity in thoracic aortas, resulting in reduced blood pressure in offspring that received prenatal exposure to LPS. Surprisingly, NF-κB dyshomeostasis and RAS over-activity were only found in thoracic aortas but not in superior mesenteric arteries. Collectively, our data demonstrate that the early life NF-κB dyshomeostasis induced by prenatal inflammatory exposure plays an essential role in the development of EH through triggering RAS over-activity. We conclude that early life NF-κB dyshomeostasis is a key predictor of EH, and thus, NF-κB inhibition represents an effective interventional strategy for EH prevention.
doi:10.1038/srep21692
PMCID: PMC4753429  PMID: 26877256
18.  The Enhanced Catalytic Activities of Asymmetric Au-Ni Nanoparticle Decorated Halloysite-Based Nanocomposite for the Degradation of Organic Dyes 
Janus particles (JPs) are unique among the nano-/microobjects because they provide asymmetry and can thus impart drastically different chemical or physical properties. In this work, we have fabricated the magnetic halloysite nanotube (HNT)-based HNTs@Fe3O4 nanocomposite (NCs) and then anchored the Janus Au-Ni or isotropic Au nanoparticles (NPs) to the surface of external wall of sulfydryl modified magnetic nanotubes. The characterization by physical methods authenticates the successful fabrication of two different magnetic HNTs@Fe3O4@Au and HNTs@Fe3O4@Au-Ni NCs. The catalytic activity and recyclability of the two NCs have been evaluated considering the degradation of Congo red (CR) and 4-nitrophenol (4-NP) using sodium borohydride as a model reaction. The results reveal that the symmetric Au NPs participated NCs display low activity in the degradation of the above organic dyes. However, a detailed kinetic study demonstrates that the employ of bimetallic Janus Au-Ni NPs in the NCs indicates enhanced catalytic activity, owing to the structurally specific nature. Furthermore, the magnetic functional NCs reported here can be used as recyclable catalyst which can be recovered simply by magnet.
doi:10.1186/s11671-016-1252-9
PMCID: PMC4744597  PMID: 26852228
Janus Au-Ni nanoparticle; Halloysite nanotube; Dye degradation; Magnetic nanocomposite
19.  Tomato SlERF.A1, SlERF.B4, SlERF.C3 and SlERF.A3, Members of B3 Group of ERF Family, Are Required for Resistance to Botrytis cinerea 
The Ethylene-Responsive Factors (ERFs) comprise a large family of transcriptional factors that play critical roles in plant immunity. Gray mold disease caused by Botrytis cinerea, a typical necrotrophic fungal pathogen, is the serious disease that threatens tomato production worldwide. However, littler is known about the molecular mechanism regulating the immunity to B. cinerea in tomato. In the present study, virus-induced gene silencing (VIGS)-based functional analyses of 18 members of B3 group (also called Group IX) in tomato ERF family were performed to identify putative ERFs that are involved in disease resistance against B. cinerea. VIGS-based silencing of either SlERF.B1 or SlERF.C2 had lethal effect while silencing of SlERF.A3 (Pit4) significantly suppressed vegetative growth of tomato plants. Importantly, silencing of SlERF.A1, SlERF.A3, SlERF.B4, or SlERF.C3 resulted in increased susceptibility to B. cinerea, attenuated the B. cinerea-induced expression of jasmonic acid/ethylene-mediated signaling responsive defense genes and promoted the B. cinerea-induced H2O2 accumulation. However, silencing of SlERF.A3 also decreased the resistance against Pseudomonas syringae pv. tomato (Pst) DC3000 but silencing of SlERF.A1, SlERF.B4 or SlERF.C3 did not affect the resistance to this bacterial pathogen. Expression of SlERF.A1, SlERF.A3, SlERF.B4, or SlERF.C3 was induced by B. cinerea and by defense signaling hormones such as salicylic acid, methyl jasmonate, and 1-aminocyclopropane-1-carboxylic acid (an ethylene precursor). SlERF.A1, SlERF.B4, SlERF.C3, and SlERF.A3 proteins were found to localize in nucleus of cells and possess transactivation activity in yeasts. These data suggest that SlERF.A1, SlERF.B4, and SlERF.C3, three previously uncharacterized ERFs in B3 group, and SlERF.A3, a previously identified ERF with function in immunity to Pst DC3000, play important roles in resistance against B. cinerea in tomato.
doi:10.3389/fpls.2016.01964
PMCID: PMC5187353  PMID: 28083004
tomato (Solanum lycopersicum); ethylene-responsive factor (ERF); B3 group; Botrytis cinerea; defense response
20.  Hydrogen Sulfide Inhibits High-Salt Diet-Induced Renal Oxidative Stress and Kidney Injury in Dahl Rats 
Background. The study was designed to investigate if H2S could inhibit high-salt diet-induced renal excessive oxidative stress and kidney injury in Dahl rats. Methods. Male salt-sensitive Dahl and SD rats were used. Blood pressure (BP), serum creatinine, urea, creatinine clearance rate, and 24-hour urine protein were measured. Renal ultra- and microstructures were observed. Collagen-I and -III contents the oxidants and antioxidants levels in renal tissue were detected. Keap1/Nrf2 association and Keap1 s-sulfhydration were detected. Results. After 8 weeks of high-salt diet, BP was significantly increased, renal function and structure were impaired, and collagen deposition was abundant in renal tissues with increased renal MPO activity, H2O2, MDA, GSSG, and •OH contents, reduced renal T-AOC and GSH contents, CAT, GSH-PX and SOD activity, and SOD expressions in Dahl rats. Furthermore, endogenous H2S in renal tissues was decreased in Dahl rats. H2S donor, however, decreased BP, improved renal function and structure, and inhibited collagen excessive deposition in kidney, in association with increased antioxidative activity and reduced oxidative stress in renal tissues. H2S activated Nrf2 by inducing Keap1 s-sulfhydration and subsequent Keap1/Nrf2 disassociation. Conclusions. H2S protected against high-salt diet-induced renal injury associated with enhanced antioxidant capacity and inhibited renal oxidative stress.
doi:10.1155/2016/2807490
PMCID: PMC4707377  PMID: 26823949
21.  African Ancestry Analysis and Admixture Genetic Mapping for Proliferative Diabetic Retinopathy in African Americans 
Purpose.
To examine the relationship between proportion of African ancestry (PAA) and proliferative diabetic retinopathy (PDR) and to identify genetic loci associated with PDR using admixture mapping in African Americans with type 2 diabetes (T2D).
Methods.
Between 1993 and 2013, 1440 participants enrolled in four different studies had fundus photographs graded using the Early Treatment Diabetic Retinopathy Study scale. Cases (n = 305) had PDR while controls (n = 1135) had nonproliferative diabetic retinopathy (DR) or no DR. Covariates included diabetes duration, hemoglobin A1C, systolic blood pressure, income, and education. Genotyping was performed on the Affymetrix platform. The association between PAA and PDR was evaluated using logistic regression. Genome-wide admixture scanning was performed using ANCESTRYMAP software.
Results.
In the univariate analysis, PDR was associated with increased PAA (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.16–1.59, P = 0.0002). In multivariate regression adjusting for traditional DR risk factors, income and education, the association between PAA and PDR was attenuated and no longer significant (OR = 1.21, 95% CI = 0.59–2.47, P = 0.61). For the admixture analyses, the maximum genome-wide score was 1.44 on chromosome 1.
Conclusions.
In this largest study of PDR in African Americans with T2D to date, an association between PAA and PDR is not present after adjustment for clinical, demographic, and socioeconomic factors. No genome-wide significant locus (defined as having a locus-genome statistic > 5) was identified with admixture analysis. Further analyses with even larger sample sizes are needed to definitively assess if any admixture signal for DR is present.
In African Americans with type 2 diabetes, proportion of African ancestry was associated with proliferative diabetic retinopathy (PDR) but the association was no longer present with adjustment for clinical/socioeconomic variables. No genome-wide significant loci were found with admixture scanning.
doi:10.1167/iovs.15-16674
PMCID: PMC4477259  PMID: 26098467
genetics; diabetic retinopathy; proliferative diabetic retinopathy; African Americans; admixture; ancestry
22.  High-power graphene mode-locked Tm/Ho co-doped fiber laser with evanescent field interaction 
Scientific Reports  2015;5:16624.
Mid-infrared ultrafast fiber lasers are valuable for various applications, including chemical and biomedical sensing, material processing and military applications. Here, we report all-fiber high-power graphene mode-locked Tm/Ho co-doped fiber laser at long wavelength with evanescent field interaction. Ultrafast pulses up to 7.8 MHz are generated at a center wavelength of 1879.4 nm, with a pulse width of 4.7 ps. A graphene absorber integrated with a side-polished fiber can increase the damage threshold significantly. Harmonics mode-locking can be obtained till to the 21th harmonics at a pump power of above 500 mW. By using one stage amplifier in the anomalous dispersion regime, the laser can be amplified up to 450 mW and the narrowest pulse duration of 1.4 ps can be obtained simultaneously. Our work paves the way to graphene Tm/Ho co-doped mode-locked all-fiber master oscillator power amplifiers as potentially efficient and economic laser sources for high-power laser applications, such as special material processing and nonlinear optical studies.
doi:10.1038/srep16624
PMCID: PMC4644976  PMID: 26567536
23.  Recombinant Hemagglutinin and Virus-Like Particle Vaccines for H7N9 Influenza Virus 
Cases of H7N9 human infection were caused by a novel, avian-origin H7N9 influenza A virus that emerged in eastern China in 2013. Clusters of human disease were identified in many cities in China, with mortality rates approaching 30%. Pandemic concerns were raised, as historically, influenza pandemics were caused by introduction of novel influenza A viruses into immunologically naïve human population. Currently, there are no approved human vaccines for H7N9 viruses. Recombinant protein vaccine approaches have advantages in safety and manufacturing. In this review, we focused on evaluation of the expression of recombinant hemagglutinin (rHA) proteins as candidate vaccines for H7N9 influenza, with the emphasis on the role of oligomeric and particulate structures in immunogenicity and protection. Challenges in preparation of broadly protective influenza vaccines are discussed, and examples of broadly protective vaccines are presented including rHA stem epitope vaccines, as well as recently introduced experimental multi-HA VLP vaccines.
doi:10.4172/2157-7560.1000287
PMCID: PMC4627708  PMID: 26523241
24.  Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium 
PLoS ONE  2015;10(10):e0140496.
Background
Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.
Methods
Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).
Results
Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.
doi:10.1371/journal.pone.0140496
PMCID: PMC4627813  PMID: 26516778
25.  A Method for Recording Urethral Pressure Profiles in Female Rats 
PLoS ONE  2015;10(10):e0140851.
Aims
Urethral pressure profile (UPP) and leak-point pressure (LPP) measurements as well as external urethral sphincter (EUS) electromyography (EMG) and videourodynamic analyses are the primary methods for evaluating urethral function in humans. However, UPP recording in female rats, a widely used animal model, is challenging due to their small body sizes. This study reports a novel method for recording UPP in female rats.
Materials and Methods
Seventeen anesthetized female rats were studied. LPP data for 14 rats were included. The other 3 rats were excluded because of death or abnormal urogenital organs. UPP curves were recorded using a modified water-perfusion catheter system, with the lateral hole facing the 3-, 6-, 9-, and 12-o’clock positions in a randomized sequence. LPP, functional urethral length (FUL) and maximum urethral closure pressure (MUCP) were analyzed.
Results
The mean LPP was 64.39 ± 20.29 cm H2O. The mean FUL and MUCP values at the 3-, 6-, 9-, and 12-o’clock positions were 12.90 ± 1.20, 16.70 ± 1.95, 13.90 ± 2.42, and 11.60 ± 0.97 mm, respectively, and 38.70 ± 11.85, 33.90 ± 11.82, 37.40 ± 11.95, and 71.90 ± 23.01 cm H2O, respectively. The FUL at the 6-o’clock position and MUCP at the 12-o’clock position were significantly greater than those at the other 3 positions. The FUL and MUCP of repeated UPP recordings were not significantly different than those of the first recordings.
Conclusions
UPP recording using a modified method based on a water-perfusion catheter system is feasible and replicable in female rats. It produces UPP curves that sensitively and appreciably reflect detailed pressure changes at different points within the urethra and thus provides opportunity to evaluate urethral structures, especially the urethral sphincter, in detail. These results may enhance the utility of female rat models in research of urinary sphincter mechanisms.
doi:10.1371/journal.pone.0140851
PMCID: PMC4621020  PMID: 26502072

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