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1.  Sox9 Gene Transfer Enhanced Regenerative Effect of Bone Marrow Mesenchymal Stem Cells on the Degenerated Intervertebral Disc in a Rabbit Model 
PLoS ONE  2014;9(4):e93570.
Objective
The effect of Sox9 on the differentiation of bone marrow mesenchymal stem cells (BMSCs) to nucleus pulposus (NP)-like (chondrocyte-like) cells in vitro has been demonstrated. The objective of this study is to investigate the efficacy and feasibility of Sox9-transduced BMSCs to repair the degenerated intervertebral disc in a rabbit model.
Materials and Methods
Fifty skeletally mature New Zealand white rabbits were used. In the treatment groups, NP tissue was aspirated from the L2-L3, L3-L4, and L4-L5 discs in accordance with a previously validated rabbit model of intervertebral disc degeneration and then treated with thermogelling chitosan (C/Gp), GFP-transduced autologous BMSCs with C/Gp or Sox9-transduced autologous BMSCs with C/Gp. The role of Sox9 in the chondrogenic differentiation of BMSCs embedded in C/Gp gels in vitro and the repair effect of Sox9-transduced BMSCs on degenerated discs were evaluated by real-time PCR, conventional and quantitative MRI, macroscopic appearance, histology and immunohistochemistry.
Results
Sox9 could induce the chondrogenic differentiation of BMSCs in C/Gp gels and BMSCs could survive in vivo for at least 12 weeks. A higher T2-weighted signal intensity and T2 value, better preserved NP structure and greater amount of extracellular matrix were observed in discs treated with Sox9-transduced BMSCs compared with those without transduction.
Conclusion
Sox9 gene transfer could significantly enhance the repair effect of BMSCs on the degenerated discs.
doi:10.1371/journal.pone.0093570
PMCID: PMC3972138  PMID: 24691466
2.  Expression of microRNA-454 in TGF-β1-stimulated hepatic stellate cells and in mouse livers infected with Schistosoma japonicum 
Parasites & Vectors  2014;7:148.
Background
In the process of hepatic fibrosis, hepatic stellate cells (HSCs) can be activated by many inflammatory cytokines. The transforming growth factor-β1 (TGF-β1) is one of the main profibrogenic mediators. Recently, some studies have also shown that microRNAs (miRNAs) play essential roles in the progress of liver fibrosis by being involved in the differentiation, fat metabolism and ECM production of HSCs.
Methods
The expression of miR-454 in LX-2 cells treated with TGF-β1 and in the fibrotic livers with Schistosoma japonicum infection was detected by qRT-PCR. The role of miR-454 on LX-2 cells was then analyzed by Western blot, flow cytometry and luciferase assay.
Results
The results showed that the expression of miR-454 was down-regulated in the TGF-β1-treated LX-2 cells and miR-454 could inhibit the activation of HSCs by directly targeting Smad4. However, we found that miR-454 had no effect on cell cycle and cell proliferation in TGF-β1-treated LX-2. Besides these, miR-454 was found to be regulated in the process of Schistosoma japonicum infection.
Conclusions
All the results suggested that miR-454 could provide a novel therapeutic approach for treating liver fibrosis, especially the liver fibrosis induced by Schistosoma japonicum.
doi:10.1186/1756-3305-7-148
PMCID: PMC3974749  PMID: 24685242
miR-454; TGF-β1; Hepatic stellate cell; Hepatic fibrosis; Schistosoma japonicum
3.  U4 at the 3′ UTR of PB1 Segment of H5N1 Influenza Virus Promotes RNA Polymerase Activity and Contributes to Viral Pathogenicity 
PLoS ONE  2014;9(3):e93366.
The viral RNA-dependent RNA polymerase has been found to contribute to efficient replication in mammalian systems and to the high pathogenicity of H5N1 influenza A virus in humans and other mammals. The terminal untranslated regions of the viral segments perform functions such as polyadenylation and contain signals for genomic packaging and initiation of RNA synthesis. These sequences are highly conserved, apart from a U/C polymorphism at position 4 of the 3′ end, most often seen in the polymerase gene segments. However, no study has yet tested whether the untranslated regions of H5N1 make any contribution to its high pathogenicity. Herein, the association of the fourth nucleotide at the 3′ end of the untranslated region in segment 2 (PB1), of A/Vietnam/1194/2004 (H5N1), with pathogenicity was examined in mice. To this end, an RNA polymerase reporter system was constructed, and viruses with mutations at this site were rescued. Results showed the U4 in PB1 was found to contribute to greater amounts of RNA-dependent RNA polymerase activity and differentially regulate genomic transcription and replication. Although a recombinant H5N1 virus with the rarer C4 sequence in all eight segments was viable and replicated to high titers in vitro, replacing a single U4 at the 3′ termini of the PB1 gene segment enhanced viral reproduction and more pathogenesis. In this way, these data showed the importance of untranslated regions of H5N1 influenza virus to pathogenicity.
doi:10.1371/journal.pone.0093366
PMCID: PMC3968160  PMID: 24676059
4.  Lipoxin A4 and Platelet Activating Factor Are Involved in E. coli or LPS-Induced Lung Inflammation in CFTR-Deficient Mice 
PLoS ONE  2014;9(3):e93003.
CFTR (cystic fibrosis transmembrane conductance regulator) is expressed by both neutrophils and platelets. Lack of functional CFTR could lead to severe lung infection and inflammation. Here, we found that mutation of CFTR (F508del) or inhibition of CFTR in mice led to more severe thrombocytopenia, alveolar neutrocytosis and bacteriosis, and lower lipoxin A4/MIP-2 (macrophage inhibitory protein-2) or lipoxin A4/neutrophil ratios in the BAL (bronchoalveolar lavage) during acute E. coli pneumonia. In vitro, inhibition of CFTR promotes MIP-2 production in LPS-stimulated neutrophils; however, lipoxin A4 could dose-dependently suppress this effect. In LPS-induced acute lung inflammation, blockade of PSGL-1 (P-selectin glycoprotein ligand-1) or P-selectin, antagonism of PAF by WEB2086, or correction of mutated CFTR trafficking by KM11060 could significantly increase plasma lipoxin A4 levels in F508del relevant to wildtype mice. Concurrently, F508del mice had higher plasma platelet activating factor (PAF) levels and PAF-AH activity compared to wildtype under LPS challenge. Inhibiting hydrolysis of PAF by a specific PAF-AH (PAF-acetylhydrolase) inhibitor, MAFP, could worsen LPS-induced lung inflammation in F508del mice compared to vehicle treated F508del group. Particularly, depletion of platelets in F508del mice could significantly decrease plasma lipoxin A4 and PAF-AH activity and deteriorate LPS-induced lung inflammation compared to control F508del mice. Taken together, lipoxin A4 and PAF are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice, suggesting that lipoxin A4 and PAF might be therapeutic targets for ameliorating CFTR-deficiency deteriorated lung inflammation.
doi:10.1371/journal.pone.0093003
PMCID: PMC3966846  PMID: 24671173
5.  Quantification of Biomechanical Interaction of Transcatheter Aortic Valve Stent Deployed in Porcine and Ovine Hearts 
Annals of biomedical engineering  2012;41(3):577-586.
Success of the deployment and function in transcatheter aortic valve replacement (TAVR) is heavily reliant on the tissue-stent interaction. The present study quantified important tissue-stent contact variables of self-expanding transcatheter aortic valve (TAV) stents when deployed into ovine and porcine aortic roots, such as the stent radial expansion force, stent pullout force, the annulus deformation response and the coefficient of friction on the tissue-stent contact interface. Braided Nitinol stents were developed, tested to determine stent crimped diameter vs. stent radial force from a stent crimp experiment, and deployed in vitro to quantify stent pullout, aortic annulus deformation, and the coefficient of friction between the stent and the aortic tissue from an aortic root-stent interaction experiment. The results indicated that when crimped at body temperature from 26 mm to 19, 21 and 23 mm stent radial forces were approximately 30-40% higher than those crimped at room temperature. Coefficients of friction leveled to approximately 0.10 ± 0.01 as stent wire diameter increased and annulus size decreased from 23 to 19 mm. Regardless of aortic annulus size and species tested, it appeared that a minimum of about 2.5 mm in annular dilatation, caused by about 60N of radial force from stent expansion, was needed to anchor the stent against a pullout into the left ventricle. The study of the contact biomechanics in animal aortic tissues may help us better understand characteristics of tissue-stent interactions and quantify the baseline responses of non-calcified aortic tissues.
doi:10.1007/s10439-012-0694-1
PMCID: PMC3594518  PMID: 23161165
Transcatheter aortic valves; self-expanding; radial force; biomechanics
6.  A ‘hidden’ 18O-enriched reservoir in the sub-arc mantle 
Scientific Reports  2014;4:4232.
Plate subduction continuously transports crustal materials with high-δ18O values down to the mantle wedge, where mantle peridotites are expected to achieve the high-δ18O features. Elevated δ18O values relative to the upper mantle value have been reported for magmas from some subduction zones. However, peridotites with δ18O values significantly higher than the well-defined upper mantle values have never been observed from modern subduction zones. Here we present in-situ oxygen isotope data of olivine crystals in Sailipu mantle xenoliths from South Tibet, which have been subjected to a long history of Tethyan subduction before the India-Asia collision. Our data identify for the first time a metasomatized mantle that, interpreted as the sub-arc lithospheric mantle, shows anomalously enriched oxygen isotopes (δ18O = +8.03 ± 0.28 ‰). Such a high-δ18O mantle commonly does not contribute significantly to typical island arc basalts. However, partial melting or contamination of such a high-δ18O mantle is feasible to account for the high-δ18O signatures in arc basalts.
doi:10.1038/srep04232
PMCID: PMC3937801  PMID: 24577190
7.  Developing live vaccines against Yersinia pestis 
Three great plague pandemics caused by the gram-negative bacterium Yersinia pestis have killed nearly 200 million people and it has been linked to biowarfare in the past. Plague is endemic in many parts of the world. In addition, the risk of plague as a bioweapon has prompted increased research to develop plague vaccines against this disease. Injectable subunit vaccines are being developed in the United States and United Kingdom. However, the live attenuated Y. pestis-EV NIIEG strain has been used as a vaccine for more than 70 years in the former Soviet Union and in some parts of Asia and provides a high degree of efficacy against plague. This vaccine has not gained general acceptance because of safety concerns. In recent years, modern molecular biological techniques have been applied to Y. pestis to construct strains with specific defined mutations designed to create safe, immunogenic vaccines with potential for use in humans and as bait vaccines to reduce the load of Y. pestis in the environment. In addition, a number of live, vectored vaccines have been reported using attenuated viral vectors or attenuated Salmonella strains to deliver plague antigens. Here we summarize the progress of live attenuated vaccines against plague.
PMCID: PMC3932668  PMID: 21918302
Yersinia pestis; plague; live vaccines
8.  DPP6 regulation of dendritic morphogenesis impacts hippocampal synaptic development 
Nature communications  2013;4:2270.
Dipeptidyl-peptidase 6 (DPP6) is an auxiliary subunit of Kv4-mediated A-type K+ channels that, in addition to enhancing channel surface expression, potently accelerates their kinetics. The DPP6 gene has been associated with a number of human CNS disorders including ASDs and schizophrenia. Here we employ knockdown and genetic deletion of DPP6 to reveal its importance for the formation and stability of dendritic filopodia during early neuronal development. We find that hippocampal neurons lacking DPP6 show a sparser dendritic branching pattern along with fewer spines throughout development and into adulthood. In electrophysiological and imaging experiments we show that these deficits lead to fewer functional synapses and occur independently of the potassium channel subunit Kv4.2. We report that the extracellular domain of DPP6 interacts with a filopodia-associated myosin as well as with fibronectin in the extracellular matrix. DPP6 therefore plays an unexpected but important role in cell-adhesion and motility, impacting hippocampal synaptic development and function.
doi:10.1038/ncomms3270
PMCID: PMC3775611  PMID: 23912628
DPP6; filopodia; synapse development; hippocampus; cell adhesion; Myosin-X
9.  A Replication Study for the Association of rs726252 in PAPPA2 with Developmental Dysplasia of the Hip in Chinese Han Population 
BioMed Research International  2014;2014:979520.
Developmental dysplasia of the hip (DDH) is a common developmental hip disorder, which ranges from mild acetabulum malformation to irreducible hip dislocation. A previous study suggested a significant association of pregnancy-associated plasma protein-A2 (PAPPA2) with DDH susceptibility in Chinese Han population. But with the consideration of the sample size, the association was still debatable. To confirm the association of the reported single nucleotide polymorphism (SNP) in PAPPA2, rs726252 with DDH, we conducted a case-control study in a larger number of subjects. We genotyped rs726252 in 697 DDH subjects and 707 control subjects by TaqMan assay. The association between this SNP and DDH was evaluated statistically. No significant difference was found in any comparison of genotype distribution nor allele frequency between cases and controls. Our replication study indicated that the association between rs726252 and DDH in Chinese Han population was debatable. The association between PAPPA2 and DDH should be evaluated by additional studies.
doi:10.1155/2014/979520
PMCID: PMC3930137  PMID: 24672801
10.  CHARACTERIZATION OF AORTIC TISSUE CUTTING PROCESS: EXPERIMENTAL INVESTIGATION USING PORCINE ASCENDING AORTA 
Understanding biomechanical responses during soft tissue cutting is important for developing surgical simulators and robot-assisted surgery with haptic feedback. The biomechanics involved in the aortic tissue cutting process is largely unknown. In this study, porcine ascending aorta was selected as a representative aortic tissue, and tissue cutting experiments were performed using a novel tissue cutting apparatus. The tissue cutting responses under various cutting conditions were investigated, including differing initial tissue lateral holding force and distance, cutting speed, cutter inclination angle, tissue anatomical orientation and thickness. The results from this study suggest that a “break-in” cutting force of about 4 – 12 N, a cutter “break-in” distance of 5 – 15 mm, and a continuous cutting force of 2 – 4 N were needed to cut through the porcine ascending aorta tissue. For all testing conditions investigated in this study, the cutting force vs. the cutter displacement curves exhibited similar characteristics. More importantly, this study demonstrated that tissue cutting involving one or more of the following conditions: a larger lateral holding force, a smaller lateral hold distance, a higher cutting speed or a larger inclination angle, could result in a smaller “break in” cutting force and a smaller “break-in” distance. In addition, it was found that the cutting force in the vessel longitudinal direction was larger than that in the circumferential direction. There was a strong correlation between the tissue thickness and the cutting force. The experimental results reported in this study could provide a basis for understanding the characteristic response of aortic tissue to scalpel cutting, and offer insight into the development of surgical simulators.
doi:10.1016/j.jmbbm.2012.10.017
PMCID: PMC3557667  PMID: 23262306
Soft tissue; tissue cutting; ascending aorta; cutting variables; minimally invasive surgery
11.  Multicolor Fluorescent Semiconducting Polymer Dots with Narrow Emissions and High Brightness 
ACS nano  2013;7(1):376-384.
Fluorescent semiconducting polymer dots (Pdots) have attracted great interest because of their superior characteristics as fluorescent probes, such as high fluorescence brightness, fast radiative rates, and excellent photostability. However, currently available Pdots generally exhibit broad emission spectra, which significantly limit their usefulness in many biological applications involving multiplex detections. Here, we describe the design and development of multicolor narrow emissive Pdots based on different boron-dipyrromethene (BODIPY) units. BODIPY-containing semiconducting polymers emitting at multiple wavelengths were synthesized and used as precursors for preparing the Pdots, where intra-particle energy transfer led to highly bright, narrow emissions. The emission full-width at half maximum (FWHM) of the resulting Pdots varies from 40 nm to 55 nm, which is 1.5~2 times narrower than those of conventional semiconducting polymer dots. BODIPY520 Pdots was about an order of magnitude brighter than commercial Qdot 525 under identical laser excitation conditions. Fluorescence imaging and flow cytometry experiments indicate the narrow emissions from these bright Pdots are promising for multiplexed biological detections.
doi:10.1021/nn304376z
PMCID: PMC3552064  PMID: 23282278
Polymer dots; fluorescence; semiconducting polymer; bioimaging; narrow emission
12.  Chemical signatures and new drug targets for gametocytocidal drug development 
Scientific Reports  2014;4:3743.
Control of parasite transmission is critical for the eradication of malaria. However, most antimalarial drugs are not active against P. falciparum gametocytes, responsible for the spread of malaria. Consequently, patients can remain infectious for weeks after the clearance of asexual parasites and clinical symptoms. Here we report the identification of 27 potent gametocytocidal compounds (IC50 < 1 μM) from screening 5,215 known drugs and compounds. All these compounds were active against three strains of gametocytes with different drug sensitivities and geographical origins, 3D7, HB3 and Dd2. Cheminformatic analysis revealed chemical signatures for P. falciparum sexual and asexual stages indicative of druggability and suggesting potential targets. Torin 2, a top lead compound (IC50 = 8 nM against gametocytes in vitro), completely blocked oocyst formation in a mouse model of transmission. These results provide critical new leads and potential targets to expand the repertoire of malaria transmission-blocking reagents.
doi:10.1038/srep03743
PMCID: PMC3894558  PMID: 24434750
13.  Protein Interactions and Regulation of EscA in Enterohemorrhagic E. coli 
PLoS ONE  2014;9(1):e85354.
Infections caused by enterohemorrhagic Escherichia coli (EHEC) can lead to diarrhea with abdominal cramps and sometimes are complicated by severe hemolytic uremic syndrome. EHEC secretes effector proteins into host cells through a type III secretion system that is composed of proteins encoded by a chromosomal island, locus for the enterocyte effacement (LEE). EspA is the major component of the filamentous structure connecting the bacteria and the host's cells. Synthesis and secretion of EspA must be carefully controlled since the protein is prone to polymerize. CesAB, CesA2, and EscL have been identified as being able to interact with EspA. Furthermore, the intracellular level of EspA declines when cesAB, cesA2, and escL are individually deleted. Here, we report a LEE gene named l0033, which also affects the intracellular level of EspA. We renamed l0033 as escA since its counterpart in enteropathogenic E. coli has been recently described. Similar to CesAB, EscL, and CesA2, EscA interacts with EspA and enhances the protein stability of EspA. However, EscA is also able to interact with inner membrane-associated EscL, CesA2, and EscN, but not with cytoplasmic CesAB. In terms of gene organizations, escA locates in LEE3. Expression of EscA is faithfully regulated via Mpc, the first gene product of LEE3. Since Mpc is tightly regulated to low level, we suggest that EscA is highly synchronized and critical to the process of escorting EspA to its final destination.
doi:10.1371/journal.pone.0085354
PMCID: PMC3890302  PMID: 24454847
14.  Multiple Response Regression for Gaussian Mixture Models with Known Labels 
Statistical analysis and data mining  2012;5(6):10.1002/sam.11158.
Multiple response regression is a useful regression technique to model multiple response variables using the same set of predictor variables. Most existing methods for multiple response regression are designed for modeling homogeneous data. In many applications, however, one may have heterogeneous data where the samples are divided into multiple groups. Our motivating example is a cancer dataset where the samples belong to multiple cancer subtypes. In this paper, we consider modeling the data coming from a mixture of several Gaussian distributions with known group labels. A naive approach is to split the data into several groups according to the labels and model each group separately. Although it is simple, this approach ignores potential common structures across different groups. We propose new penalized methods to model all groups jointly in which the common and unique structures can be identified. The proposed methods estimate the regression coefficient matrix, as well as the conditional inverse covariance matrix of response variables. Asymptotic properties of the proposed methods are explored. Through numerical examples, we demonstrate that both estimation and prediction can be improved by modeling all groups jointly using the proposed methods. An application to a glioblastoma cancer dataset reveals some interesting common and unique gene relationships across different cancer subtypes.
doi:10.1002/sam.11158
PMCID: PMC3885347  PMID: 24416092
Covariance estimation; GLASSO; Hierarchical penalty; LASSO; Multiple response; Regression; Sparsity
15.  Biomechanical characterization of aortic valve tissue in humans and common animal models 
Journal of biomedical materials research. Part A  2012;100(6):10.1002/jbm.a.34099.
Aortic valve disease develops in an escalating fashion in elderly patients. Current treatments including total valve replacement and valve repair techniques are still suboptimal. A thorough understanding of the animal and human valve tissue properties, particularly their differences, is crucial for the establishment of preclinical animal models and strategies for evaluating new valve treatment techniques, such as transcatheter valve intervention and tissue engineered valves. The goal of this study was to characterize and compare the biomechanical properties and histological structure of healthy ovine, porcine, and human aortic valve leaflets. The biaxial mechanical properties of the aortic valve leaflets of 10 ovine (~1 year), 10 porcine (6–9 months), and 10 aged human (80.6 ± 8.34) hearts were quantified. Tissue microstructure was analyzed via histological techniques. Aged human aortic valve leaflets were significantly less compliant than both ovine and porcine leaflets, with the ovine leaflets being the most compliant. Histological analysis revealed structural differences between the species: the human and porcine leaflets contained more collagen and elastin than the ovine leaflets. Significant mechanical and structural differences in the aortic valve tissues of 6- to 9-month-old porcine models and 1-year-old ovine models with respect to those of aged humans, suggest that these animal models may not be representative of the typical patient undergoing aortic valve replacement.
doi:10.1002/jbm.a.34099
PMCID: PMC3882754  PMID: 22447518
aortic valve; mechanical properties; animal trials; transcatheter aortic valve
16.  Effect of whole body vibration therapy on circulating serotonin levels in an ovariectomized rat model of osteoporosis 
Objective(s): Studies have reported that whole body vibration (WBV) played a vital role in bone remodeling. Circulating serotonin is also involved in negative regulating bone mass in rodents and humans. However, both WBV and inhibition of serotonin biosynthesis may suppress receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis in vitro. The purpose of the current study was to investigate the effect of WBV therapy on the levels of serum serotonin in ovariectomized rats.
Materials and Methods: Thirty-six-month-old female Sprague Dawley rats weighing 276.15±37.75 g were ovariectomized to induce osteoporosis, and another ten rats underwent sham operation to establish sham control (SHAM) group. After 3 months, ovariectomized rats were divided into three subgroups and then separately treated with WBV, Alendronate (ALN) and normal saline (OVX), SHAM group was given normal saline. After 6 weeks of treatment, rats were sacrificed. Serum serotonin, RANKL, bone turnover markers, and bone mineral density (BMD), bone strength were evaluated.
Results: The serum serotonin level was significantly lower in WBV group than OVX and ALN groups (P<0.05 and P<0.001). RANKL levels significantly decreased in WBV and ALN groups compared to OVX group (P<0.001 for both). BMD and biomechanical parameters of femur significantly increased (P<0.05 for both) and bone turnover levels decreased (P<0.001 for both) in WBV group compared to OVX group.
Conclusion: These data indicated that WBV enhanced the bone strength and BMD in ovariectomized rats most likely by reducing the levels of circulating serotonin.
PMCID: PMC3938888  PMID: 24592309
Osteoporosis; Ovariectomy; Serotonin; Whole body vibration
17.  Thoracoscopic Lobectomy versus Open Lobectomy in Stage I Non-Small Cell Lung Cancer: A Meta-Analysis 
PLoS ONE  2013;8(12):e82366.
The objective of the present meta-analysis was to evaluate the survival, recurrence rate, and complications in patients with stage I non-small cell lung cancer (NSCLC) who received video-assisted thoracoscopic surgery (VATS) or open lobectomy. A literature search was conducted on June 31, 2012 using combinations of the search terms video-assisted thoracic surgery, open thoracotomy, lobectomy, and non-small-cell lung cancer (NSCLC). Inclusion criteria were: 1) Compared video-assisted thoracic surgery (VATS) lobectomy with open lobectomy. 2) Stage I NSCLC. 2) No previous treatment for lung cancer. 4) Outcome data included 5-year survival rate, complication, and recurrence rate. Tests of heterogeneity, sensitivity, and publication bias were performed. A total of 23 studies (21 retrospective and 2 prospective) met the inclusion criteria. VATS was associated with a longer 5-year survival (odds ratio [OR] = 1.622, 95% confidence interval [CI] 1.272 to 2.069; P<0.001), higher local recurrence rate (OR = 2.152, 95% CI 1.349 to 3.434; P = 0.001), similar distant recurrence rate (OR = 0.91, 95% CI 0.33 to 2.48; P = 0.8560), and lower total complication rate (OR = 0.45, 95% CI 0.24 to 0.84; P = 0.013) compared to open lobectomy. VATS was also associated with lower rates arrhythmias, prolonged air leakage, and pneumonia but it did not show any statistical significance. Patients with stage I NSCLC undergoing VATS lobectomy had longer survival and fewer complications than those who received open lobectomy.
doi:10.1371/journal.pone.0082366
PMCID: PMC3877005  PMID: 24391716
18.  Predictive biomechanical analysis of ascending aortic aneurysm rupture potential 
Acta biomaterialia  2013;9(12):10.1016/j.actbio.2013.07.044.
Aortic aneurysm is a leading cause of death in adults, often taking lives without any premonitory signs or symptoms. Adverse clinical outcomes of aortic aneurysm are preventable by elective surgical repair; however, identifying at-risk individuals is difficult. The objective of this study was to perform a predictive biomechanical analysis of ascending aortic aneurysm (AsAA) tissue to assess rupture risk on a patient-specific level. AsAA tissues, obtained intra-operatively from 50 patients, were subjected to biaxial mechanical and uniaxial failure tests to obtain their passive elastic mechanical properties. A novel analytical method was developed to predict the AsAA pressure-diameter response as well as the aortic wall yield and failure responses. Our results indicated that the mean predicted AsAA diameter at rupture was 5.6 ± 0.7 cm, and the associated blood pressure to induce rupture was 579.4 ± 214.8 mmHg. Statistical analysis showed significant positive correlation between aneurysm tissue compliance and predicted risk of rupture, where patients with a pressure-strain modulus ≥100 kPa may be nearly twice as likely to experience rupture than patients with more compliant aortic tissue. The mechanical analysis of pre-dissection patient tissue properties established in this study could predict the “future” onset of yielding and rupture in AsAA patients. The analysis results implicate decreased tissue compliance as a risk factor for AsAA rupture. The presented methods may serve as a basis for the development of a pre-operative planning tool for AsAA evaluation, a tool currently unavailable.
doi:10.1016/j.actbio.2013.07.044
PMCID: PMC3872822  PMID: 23948500
Ascending aortic aneurysm; Bicuspid aortic valve; Bovine aortic arch; Rupture potential
19.  DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-SIN1 association mediates ultraviolet B (UVB)-induced Akt Ser-473 phosphorylation and skin cell survival 
Molecular Cancer  2013;12:172.
Background
The exposure of skin keratinocytes to Ultraviolet (UV) irradiation leads to Akt phosphorylation at Ser-473, which is important for the carcinogenic effects of excessive sun exposure. The present study investigated the underlying mechanism of Akt Ser-473 phosphorylation by UVB radiation.
Results
We found that DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and mammalian target of rapamycin (mTOR) complex 2 (mTORC2) were both required for UVB-induced Akt Ser-473 phosphorylation in keratinocytes. Inhibition of DNA-PKcs activity via its inhibitor NU7026, a dominant-negative kinase-dead mutation, RNA interference (RNAi) or gene depletion led to the attenuation of UVB-induced Akt Ser-473 phosphorylation. Meanwhile, siRNA silencing or gene depletion of SIN1, a key component of mTORC2, abolished Akt Ser-473 phosphorylation by UVB. Significantly, we discovered that DNA-PKcs was associated with SIN1 in cytosol upon UVB radiation, and this complexation appeared required for Akt Ser-473 phosphorylation. Meanwhile, this DNA-PKcs-SIN1 complexation by UVB was dependent on epidermal growth factor receptor (EGFR) activation, and was disrupted by an EGFR inhibitor (AG1478) or by EGFR depletion. UVB-induced complexation between DNA-PKcs and mTORC2 components was also abolished by NU7026 and DNA-PKcs mutation. Finally, we found that both DNA-PKcs and SIN1 were associated with apoptosis resistance of UVB radiation, and inhibition of them by NU7026 or genetic depletion significantly enhanced UVB-induced cell death and apoptosis.
Conclusion
Taken together, these results strongly suggest that DNA-PKcs-mTORC2 association is required for UVB-induced Akt Ser-473 phosphorylation and cell survival, and might be important for tumor cell transformation.
doi:10.1186/1476-4598-12-172
PMCID: PMC3922905  PMID: 24365180
UV irradiation; Akt Ser-473 phosphorylation; DNA-PKcs; SIN1; Skin care
20.  Refractive Error, Visual Acuity and Causes of Vision Loss in Children in Shandong, China. The Shandong Children Eye Study 
PLoS ONE  2013;8(12):e82763.
Purpose
To examine the prevalence of refractive errors and prevalence and causes of vision loss among preschool and school children in East China.
Methods
Using a random cluster sampling in a cross-sectional school-based study design, children with an age of 4–18 years were selected from kindergartens, primary schools, and junior and senior high schools in the rural Guanxian County and the city of Weihai. All children underwent a complete ocular examination including measurement of uncorrected (UCVA) and best corrected visual acuity (BCVA) and auto-refractometry under cycloplegia. Myopia was defined as refractive error of ≤−0.5 diopters (D), high myopia as ≤−6.0D, and amblyopia as BCVA ≤20/32 without any obvious reason for vision reduction and with strabismus or refractive errors as potential reasons.
Results
Out of 6364 eligible children, 6026 (94.7%) children participated. Prevalence of myopia (overall: 36.9±0.6%;95% confidence interval (CI):36.0,38.0) increased (P<0.001) from 1.7±1.2% (95%CI:0.0,4.0) in the 4-years olds to 84.6±3.2% (95%CI:78.0,91.0) in 17-years olds. Myopia was associated with older age (OR:1.56;95%CI:1.52,1.60;P<0.001), female gender (OR:1.22;95%CI:1.08,1.39;P = 0.002) and urban region (OR:2.88;95%CI:2.53,3.29;P<0.001). Prevalence of high myopia (2.0±0.2%) increased from 0.7±0.3% (95%CI:0.1,1.3) in 10-years olds to 13.9±3.0 (95%CI:7.8,19.9) in 17-years olds. It was associated with older age (OR:1.50;95%CI:1.41,1.60;P<0.001) and urban region (OR:3.11;95%CI:2.08,4.66);P<0.001). Astigmatism (≥0.75D) (36.3±0.6%;95%CI:35.0,38.0) was associated with older age (P<0.001;OR:1.06;95%CI:1.04,1.09), more myopic refractive error (P<0.001;OR:0.94;95%CI:0.91,0.97) and urban region (P<0.001;OR:1.47;95%CI:1.31,1.64). BCVA was ≤20/40 in the better eye in 19 (0.32%) children. UCVA ≤20/40 in at least one eye was found in 2046 (34.05%) children, with undercorrected refractive error as cause in 1975 (32.9%) children. Amblyopia (BCVA ≤20/32) was detected in 44 (0.7%) children (11 children with bilateral amblyopia).
Conclusions
In coastal East China, about 14% of the 17-years olds were highly myopic, and 80% were myopic. Prevalence of myopia increased with older age, female gender and urban region. About 0.7% of pre-school children and school children were amblyopic.
doi:10.1371/journal.pone.0082763
PMCID: PMC3871613  PMID: 24376575
21.  Quantitative T2 mapping to characterize the process of intervertebral disc degeneration in a rabbit model 
Background
To investigate the potential of T2 mapping for characterizing the process of intervertebral disc degeneration (IDD) in a rabbit model.
Methods
Thirty-five rabbits underwent an annular stab to the L4/5 discs (L5/6 discs served as internal normal controls). Degenerative changes were graded according to the modified Thompson classification and quantified in T2 respectively at pre-operation, 1, 3, 6, 12 and 24 weeks postoperatively. After MRI analysis, expression analysis of aggrecan and type II collagen gene in nucleus pulposus (NP) was performed using real time polymerase chain reaction (real-time PCR). The longitudinal changes in NP T2 and gene expressions were studied by repeated measures and ANOVA, linear regression was performed for their correlations through the process of IDD. The reliability analysis of method of measurement of NP T2 was also performed.
Results
There was a strong inverse correlation between NP T2 and Thompson grades (r = -0.85). The decline of L4/5 NP T2 through 24 weeks was nonlinear, the most significant decrease was observed in 3 weeks postoperatively (P<0.05). The tendency was confirmed at gene expression levels. NP T2 correlated strongly with aggrecan (R2 = 0.85, P<0.01) and type II collagen (R2 = 0.78, P<0.01) gene expressions. The intraclass correlation coefficients for interobserver and intraobserver reliability were 0.963 and 0.977 respectively.
Conclusions
NP T2 correlates well with aggrecan and type II collagen gene expressions. T2 mapping could act as a sensitive, noninvasive tool for quantitatively characterizing the process of IDD in longitudinal study, help better understanding of the pathophysiology of IDD, assist us to detect the degenerative cascade, and develop a T2-based quantification scale for evaluation of IDD and efficacy of therapeutic interventions.
doi:10.1186/1471-2474-14-357
PMCID: PMC3878325  PMID: 24344686
Intervertebral disc; Degeneration; Animal model; MRI; T2 mapping
22.  Resolvin D1 Reverts Lipopolysaccharide-Induced TJ Proteins Disruption and the Increase of Cellular Permeability by Regulating IκBα Signaling in Human Vascular Endothelial Cells 
Tight Junctions (TJ) are important components of paracellular pathways, and their destruction enhances vascular permeability. Resolvin D1 (RvD1) is a novel lipid mediator that has treatment effects on inflammatory diseases, but its effect on inflammation induced increase in vascular permeability is unclear. To understand whether RvD1 counteracts the lipopolysaccharide (LPS) induced increase in vascular cell permeability, we investigated the effects of RvD1 on endothelial barrier permeability and tight junction reorganization and expression in the presence or absence of LPS stimulation in cultured Human Vascular Endothelial Cells (HUVECs). Our results showed that RvD1 decreased LPS-induced increased in cellular permeability and inhibited the LPS-induced redistribution of zo-1, occludin, and F-actin in HUVECs. Moreover, RvD1 attenuated the expression of IκBα in LPS-induced HUVECs. The NF-κB inhibitor PDTC enhanced the protective effects of RvD1 on restoration of occludin rather than zo-1 expression in LPS-stimulated HUVECs. By contrast, the ERK1/2 inhibitor PD98059 had no effect on LPS-induced alterations in zo-1 and occludin protein expressions in HUVECs. Our data indicate that RvD1 protects against impairment of endothelial barrier function induced by LPS through upregulating the expression of TJ proteins in HUVECs, which involves the IκBα pathway but not the ERK1/2 signaling.
doi:10.1155/2013/185715
PMCID: PMC3870867  PMID: 24381712
23.  Bivariate Random Effects Models for Meta-Analysis of Comparative Studies with Binary Outcomes: Methods for the Absolute Risk Difference and Relative Risk 
Multivariate meta-analysis is increasingly utilized in biomedical research to combine data of multiple comparative clinical studies for evaluating drug efficacy and safety profile. When the probability of the event of interest is rare or when the individual study sample sizes are small, a substantial proportion of studies may not have any event of interest. Conventional meta-analysis methods either exclude such studies or include them through ad-hoc continuality correction by adding an arbitrary positive value to each cell of the corresponding 2 by 2 tables, which may result in less accurate conclusions. Furthermore, different continuity corrections may result in inconsistent conclusions. In this article, we discuss a bivariate Beta-binomial model derived from Sarmanov family of bivariate distributions and a bivariate generalized linear mixed effects model for binary clustered data to make valid inferences. These bivariate random effects models use all available data without ad hoc continuity corrections, and accounts for the potential correlation between treatment (or exposure) and control groups within studies naturally. We then utilize the bivariate random effects models to reanalyze two recent meta-analysis data sets.
doi:10.1177/0962280210393712
PMCID: PMC3348438  PMID: 21177306
clustered binary data; bivariate random effects models; Beta-binomial distribution; meta-analysis; bivariate generalized linear mixed models
24.  The Warburg Effect Dictates the Mechanism of Butyrate Mediated Histone Acetylation and Cell Proliferation 
Molecular cell  2012;48(4):612-626.
SUMMARY
Widespread changes in gene expression drive tumorigenesis, yet our knowledge of how aberrant epigenomic and transcriptome profiles arise in cancer cells is poorly understood. Here, we demonstrate that metabolic transformation plays an important role. Butyrate is the primary energy source of normal colonocytes and is metabolized to acetyl-CoA, which was shown to be important not only for energetics but also for HAT activity. Due to the Warburg effect, cancerous colonocytes rely on glucose as their primary energy source so butyrate accumulated and functioned as an HDAC inhibitor. Although both mechanisms increased histone acetylation, different target genes were upregulated. Consequently, butyrate stimulated the proliferation of normal colonocytes and cancerous colonocytes when the Warburg effect was prevented from occurring, whereas it inhibited the proliferation of cancerous colonocytes undergoing the Warburg effect. These findings link a common metabolite to epigenetic mechanisms that are differentially utilized by normal and cancerous cells because of their inherent metabolic differences.
doi:10.1016/j.molcel.2012.08.033
PMCID: PMC3513569  PMID: 23063526
Warburg effect; colorectal cancer; butyrate paradox; ATP citrate lyase; acetyl-CoA; HAT; HDAC; metaboloepigenetics
25.  Association of SERPINA9 gene variants with carotid artery atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study 
The SNP rs11628722 in the SERPINA9 gene was previously associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Centerin, the protein encoded by SERPINA9, is involved in maturation and maintenance of naïve B cells, which play a role in atherogenesis. We investigated whether 21 tag SNPs in the SERPINA9 gene are associated with features of carotid artery atherosclerotic plaque measured by magnetic resonance imaging (MRI). Carotid MRI data were obtained from 1,282 European Americans and 341 African Americans of the ARIC Carotid MRI study, which recruited participants from ARIC by a stratified sampling plan that over-sampled participants with carotid intima-media thickening. Five MRI measures, focused on carotid wall volume, wall thickness, and lipid core, were analyzed. Genetic associations between the MRI measurements and each of the 21 SNPs were analyzed in linear regression models with adjustment for sample weights and traditional risk factors. Rs11628722 was tested a priori. In African Americans, rs11628722 was significantly associated with carotid wall volume (p < 0.05). Among the other 20 SNPs, adjusted for multiple testing, rs4905204, which encodes an Ala to Val amino acid change, was significantly associated with maximum wall thickness (p < 0.000625) and suggestively associated with total wall volume (p < 0.0026) in European Americans. In conclusion, SNPs in the SERPINA9 gene showed race-specific associations with characteristics of carotid atherosclerotic plaques. Replications in other populations are needed to validate findings of this study and to establish the SERPINA9 gene as a candidate in the etiology of carotid atherosclerosis.
PMCID: PMC3852645  PMID: 24319541
SERPINA9 gene; carotid atherosclerosis; MRI; genetic association

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