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1.  Charge Transfer in Dynamical Biosystems, or The Treachery of (Static) Images 
Accounts of Chemical Research  2014;48(2):474-481.
Conspectus
The image is not the thing. Just as a pipe rendered in an oil painting cannot be smoked, quantum mechanical coupling pathways rendered on LCDs do not convey electrons. The aim of this Account is to examine some of our recent discoveries regarding biological electron transfer (ET) and transport mechanisms that emerge when one moves beyond treacherous static views to dynamical frameworks.
Studies over the last two decades introduced both atomistic detail and macromolecule dynamics to the description of biological ET. The first model to move beyond the structureless square-barrier tunneling description is the Pathway model, which predicts how protein secondary motifs and folding-induced through-bond and through-space tunneling gaps influence kinetics. Explicit electronic structure theory is applied routinely now to elucidate ET mechanisms, to capture pathway interferences, and to treat redox cofactor electronic structure effects. Importantly, structural sampling of proteins provides an understanding of how dynamics may change the mechanisms of biological ET, as ET rates are exponentially sensitive to structure. Does protein motion average out tunneling pathways? Do conformational fluctuations gate biological ET? Are transient multistate resonances produced by energy gap fluctuations? These questions are becoming accessible as the static view of biological ET recedes and dynamical viewpoints take center stage.
This Account introduces ET reactions at the core of bioenergetics, summarizes our team’s progress toward arriving at an atomistic-level description, examines how thermal fluctuations influence ET, presents metrics that characterize dynamical effects on ET, and discusses applications in very long (micrometer scale) bacterial nanowires. The persistence of structural effects on the ET rates in the face of thermal fluctuations is considered. Finally, the flickering resonance (FR) view of charge transfer is presented to examine how fluctuations control low-barrier transport among multiple groups in van der Waals contact. FR produces exponential distance dependence in the absence of tunneling; the exponential character emerges from the probability of matching multiple vibronically broadened electronic energies within a tolerance defined by the rms coupling among interacting groups. FR thus produces band like coherent transport on the nanometer length scale, enabled by conformational fluctuations. Taken as a whole, the emerging context for ET in dynamical biomolecules provides a robust framework to design and interpret the inner workings of bioenergetics from the molecular to the cellular scale and beyond, with applications in biomedicine, biocatalysis, and energy science.
doi:10.1021/ar500271d
PMCID: PMC4333612  PMID: 25307316
2.  Dual inhibition of HCV and HIV by ring-expanded nucleosides containing the 5:7-fused imidazo[4,5-e][1,3]diazepine ring System. In vitro results and implications 
Examples of ring-expanded nucleosides (RENs), represented by general structures 1 and 2, exhibited dual anti-HCV and anti-HIV activities in both cell culture systems and the respective target enzyme assays, including HCV NTPase/helicase and human RNA helicase DDX3. Since HCV is a leading co-infection in late stage HIV AIDS patients, often leading to liver cirrhosis and death, the observed dual inhibition of HCV and HIV by the target nucleoside analogues has potentially beneficial implications in treating HIV patients infected with HCV.
doi:10.1016/j.bmcl.2013.12.121
PMCID: PMC3979313  PMID: 24461293
Ring-expanded nucleosides; imidazo[4,5-e][1,3]diazepines; organic synthesis; antiviral compounds; in vitro screening; hepatitis C virus (HCV); human immunodeficiency virus (HIV); dual inhibitors of HCV and HIV; inhibition of HCV NTPase/helicase; inhibition of RNA helicase DDX3
3.  New insights into the fungal community from the raw genomic sequence data of fig wasp Ceratosolen solmsi 
BMC Microbiology  2015;15(1):27.
Background
To date, biologists have discovered a large amount of valuable information from assembled genomes, but the abundant microbial data that is hidden in the raw genomic sequence data of plants and animals is usually ignored. In this study, the richness and composition of fungal community were determined in the raw genomic sequence data of Ceratosolen solmsi (RGSD-CS).
Results
To avoid the interference from sequences of C. solmsi, the unmapped raw data (about 17.1%) was obtained by excluding the assembled genome of C. solmsi from RGSD-CS. Comparing two fungal reference datasets, internal transcribed spacer (ITS) and large ribosomal subunit (LSU) of rRNA, the ITS dataset discovered a more diverse fungal community and was therefore selected as the reference dataset for evaluating the fungal community based on the unmapped raw data. The threshold of 95% sequence identity revealed many more matched fungal reads and fungal richness in the unmapped raw data than those by identities above 95%. Based on the threshold of 95% sequence identity, the fungal community of RGSD-CS was primarily composed of Saccharomycetes (88.4%) and two other classes (Agaricomycetes and Sordariomycetes, 8.3% in total). Compared with the fungal community of other reported fig wasps, Agaricomycetes and Eurotiomycetes were found to be unique to C. solmsi. In addition, the ratio of total fungal reads to RGSD-CS was estimated to be at least 4.8 × 10−3, which indicated that a large amount of fungal data was contained in RGSD-CS. However, rarefaction measure indicated that a deeper sequencing coverage with RGSD-CS was required to discover the entire fungal community of C. solmsi.
Conclusion
This study investigated the richness and composition of fungal community in RGSD-CS and provided new insights into the efficient study of microbial diversity using raw genomic sequence data.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-015-0370-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12866-015-0370-3
PMCID: PMC4329198
Fungal community; Unmapped raw data; Fig wasp; Fungal reference datasets
4.  Intracellular CD24 disrupts the ARF–NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation 
Nature Communications  2015;6:5909.
CD24 is overexpressed in nearly 70% human cancers, whereas TP53 is the most frequently mutated tumour-suppressor gene that functions in a context-dependent manner. Here we show that both targeted mutation and short hairpin RNA (shRNA) silencing of CD24 retard the growth, progression and metastasis of prostate cancer. CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A. CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen. In support of the functional interaction between CD24 and p53, in silico analyses reveal that TP53 mutates at a higher rate among glioma and prostate cancer samples with higher CD24 mRNA levels. These data provide a general mechanism for functional inactivation of ARF and reveal an important cellular context for genetic and viral inactivation of TP53.
P53 is a tumour suppressor that is frequently mutated or downregulated in cancer. Here, Wang et al. show that CD24, a molecule frequently overexpressed in cancer, promotes p53 degradation by disrupting a regulatory ARF–MDM2 interaction, and silencing CD24 prevents the downregulation of p53.
doi:10.1038/ncomms6909
PMCID: PMC4300525  PMID: 25600590
5.  Parameterizing the Morse Potential for Coarse-Grained Modeling of Blood Plasma 
Journal of computational physics  2014;257(Pt A):726-736.
Multiscale simulations of fluids such as blood represent a major computational challenge of coupling the disparate spatiotemporal scales between molecular and macroscopic transport phenomena characterizing such complex fluids. In this paper, a coarse-grained (CG) particle model is developed for simulating blood flow by modifying the Morse potential, traditionally used in Molecular Dynamics for modeling vibrating structures. The modified Morse potential is parameterized with effective mass scales for reproducing blood viscous flow properties, including density, pressure, viscosity, compressibility and characteristic flow dynamics of human blood plasma fluid. The parameterization follows a standard inverse-problem approach in which the optimal micro parameters are systematically searched, by gradually decoupling loosely correlated parameter spaces, to match the macro physical quantities of viscous blood flow. The predictions of this particle based multiscale model compare favorably to classic viscous flow solutions such as Counter-Poiseuille and Couette flows. It demonstrates that such coarse grained particle model can be applied to replicate the dynamics of viscous blood flow, with the advantage of bridging the gap between macroscopic flow scales and the cellular scales characterizing blood flow that continuum based models fail to handle adequately.
doi:10.1016/j.jcp.2013.09.040
PMCID: PMC4045626  PMID: 24910470
Morse potential; inverse problems; coarse-grained; blood plasma fluid
6.  Penicibrocazines A–E, Five New Sulfide Diketopiperazines from the Marine-Derived Endophytic Fungus Penicillium brocae 
Marine Drugs  2015;13(1):276-287.
Five new sulfide diketopiperazine derivatives, namely, penicibrocazines A–E (1–5), along with a known congener (6), were isolated and identified from the culture extract of Penicillium brocae MA-231, an endophytic fungus obtained from the fresh tissue of the marine mangrove plant Avicennia marina. The structures of these compounds were elucidated by detailed interpretation of NMR and mass spectroscopic data and the structures of compounds 1 and 3 were confirmed by single-crystal X-ray diffraction analysis. All these compounds were examined for cytotoxic and antimicrobial activities. Compounds 2–6 exhibited antimicrobial activity against some of the tested strains with MIC values ranging from 0.25 to 64 μg/mL.
doi:10.3390/md13010276
PMCID: PMC4306937  PMID: 25574740
mangrove plant; endophytic fungus; Pencillium brocae; secondary metabolites; antimicrobial activity
7.  Transferrin-conjugated doxorubicin-loaded lipid-coated nanoparticles for the targeting and therapy of lung cancer 
Oncology Letters  2014;9(3):1065-1072.
In the present study, a targetable vector was developed for the targeted delivery of anticancer agents, consisting of lipid-coated poly D,L-lactic-co-glycolic acid nanoparticles (PLGA-NP) that were modified with transferrin (TF). Doxorubicin (DOX) was used as a model drug for lung cancer therapy. The use of these NPs combined the advantages and avoided the disadvantages exhibited individually by liposomes and polymeric NPs during drug delivery. The lipid coating of the polymeric core was confirmed by transmission electron microscopy. The physicochemical characteristics of transferrin-conjugated lipid-coated NPs (TF-LP), including the particle size, zeta potential, morphology, encapsulation efficiency and in vitro DOX release, were also evaluated. The cellular uptake investigation in the present study found that TF-LP was more efficiently endocytosed by the A549 cells, than LP and PLGA-NPs. Furthermore, the anti-proliferative effect exhibited by DOX-loaded TF-LPs on A549 cells and the inhibition of tumor spheroid growth was stronger compared with the effect of DOX-loaded lipid-coated PLGA-NPs and PLGA-NPs. In the in vivo component of the present study, TF-LP demonstrated the best inhibitory effect on tumor growth in the A549 tumor-bearing mice. It was concluded that TF-LP may be an efficient targeted drug-delivery system for lung cancer therapy.
doi:10.3892/ol.2014.2840
PMCID: PMC4315058  PMID: 25663858
transferrin; tumor targeting; lung cancer; doxorubicin
8.  Cost-effectiveness analysis of colon cancer treatments from MOSIAC and No. 16968 trials 
World Journal of Gastroenterology : WJG  2014;20(47):17976-17984.
AIM: To compare XELOX and FOLFOX4 as colon cancer adjuvant chemotherapy based on MOSAIC and No. 16968 trails from Chinese cost-effectiveness perspective.
METHODS: A decision-analytic Markov model was developed to compare the FOLFOX4 and XELOX regimens based MOSAIC and No. 16968 trial. Five states were included in our Markov model: well (state 1), minor toxicity (state 2), major toxicity (state 3), quitting adjuvant chemotherapy (state 4), and death due to adjuvant chemotherapy (state 5). Transitions among the 5 states were assumed to be Markovian. Costs were calculated from the perspective of the Chinese health-care payer. The utility data were taken from published studies. Sensitivity analyses were used to explore the impact of uncertainty factors in this cost-effectiveness analysis.
RESULTS: Total direct costs of FOLFOX4 and XELOX per patient were $19884.96 ± 4280.30 and $18113.25 ± 3122.20, respectively. The total fees related to adverse events per patient during the entire treatment were $204.75 ± 16.80 for the XELOX group, and $873.72 ± 27.60 for the FOLFOX4 group, and the costs for travel and absenteeism per patient were $18495.00 for the XELOX group and $21,352.68 for the FOLFOX4 group. The base-case analysis showed that FOLFOX4 was estimated to produce an additional 0.06 in quality adjusted life years (QALYs) at an additional cost of $3950.47 when compared to the XELOX regimen over the model time horizon. The cost per QALY gained was $8047.30 in the XELOX group, which was $900.98 less than in the FOLFOX4 group ($8948.28). The one way sensitivity analysis demonstrated that the utility for the well state and minor toxicity state greatly influenced the incremental cost-effectiveness ratio of FOLFOX4.
CONCLUSION: In term of cost-comparison, XELOX is expected to dominate FOLFOX4 regimes; Therefore, XELOX provides a more cost-effective adjuvant chemotherapy for colon cancer patients in China.
doi:10.3748/wjg.v20.i47.17976
PMCID: PMC4273149  PMID: 25548497
Cost-effectiveness; Adjuvant chemotherapy; Colon cancer; FOLFOX; XELOX
9.  Bilirubin Modulates Acetylcholine Receptors In Rat Superior Cervical Ganglionic Neurons In a Bidirectional Manner 
Scientific Reports  2014;4:7475.
Autonomic dysfunction as a partial contributing factor to cardiovascular instability in jaundiced patients is often associated with increased serum bilirubin levels. Whether increased serum bilirubin levels could directly inhibit sympathetic ganglion transmission by blocking neuronal nicotinic acetylcholine receptors (nAChRs) remains to be elucidated. Conventional patch-clamp recordings were used to study the effect of bilirubin on nAChRs currents from enzymatically dissociated rat superior cervical ganglia (SCG) neurons. The results showed that low concnetrations (0.5 and 2 μM) of bilirubin enhanced the peak ACh-evoked currents, while high concentrations (3 to 5.5 µM) of bilirubin suppressed the currents with an IC50 of 4 ± 0.5 μM. In addition, bilirubin decreased the extent of desensitization of nAChRs in a concentration-dependent manner. This inhibitory effect of bilirubin on nAChRs channel currents was non-competitive and voltage independent. Bilirubin partly improved the inhibitory effect of forskolin on ACh-induced currents without affecting the action of H-89. These data suggest that the dual effects of enhancement and suppression of bilirubin on nAChR function may be ascribed to the action mechanism of positive allosteric modulation and direct blockade. Thus, suppression of sympathetic ganglionic transmission through postganglionic nAChRs inhibition may partially contribute to the adverse cardiovascular effects in jaundiced patients.
doi:10.1038/srep07475
PMCID: PMC4265787  PMID: 25503810
10.  Postoperative adjuvant transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond the Milan criteria: a retrospective analysis 
Objective: To clarify the value of postoperative adjuvant transcatheter arterial chemoembolization (TACE) for resectable multiple hepatocellular carcinoma beyond the Milan criteria. Background: Patients with multiple HCC have been shown to have a worse survival after a partial hepatectomy (PH) because of the high incidence of intrahepatic tumor recurrence. Postoperative adjuvant TACE is an optional strategy for HCC patients with a high recurrence risk. Its effects and range of applications are debatable. Methods: This retrospective study enrolled 135 HCC patients with resectable multiple hepatocellular carcinoma beyond the Milan criteria, and those patients underwent a hepatectomy with/without postoperative adjuvant TACE from Jan. 2004 to Dec. 2008. The patients were divided to the PH cohort or the PH+TACE cohort. The prognosis measures were the disease-free survival (DFS) and overall survival (OS) from the date of treatment. Univariate and multivariate analyses were used to assess the prognostic factors associated with DFS and OS, using the Cox proportional hazards model. Results: The 1-, 2-, and 5-year DFS and OS for the PH+TACE group differed significantly from the PH group (p = 0.004, p = 0.002, respectively). Multivariate analysis revealed that the significant independent risk factors associated with the DFS and OS were postoperative TACE treatment (p = 0.002, p = 0.001, respectively) and the number of tumors (p = 0.006, p = 0.037, respectively). Conclusions: Our results show that postoperative adjuvant treatment resulted in delayed intrahepatic recurrence and better survival for patients with resectable multiple hepatocellular carcinoma beyond the Milan criteria. Postoperative adjuvant TACE should be regarded as a common strategy for patients with resectable multiple HCC beyond the Milan criteria.
PMCID: PMC4300716  PMID: 25628953
TACE; multiple hepatocellular carcinoma; Milan criteria; recurrence; prognosis
11.  Design and Synthesis of 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (Citalopram) Analogues as Novel Probes for the Serotonin Transporter S1 and S2 Binding Sites 
Journal of medicinal chemistry  2013;56(23):9709-9724.
The serotonin transporter (SERT) is the primary target for antidepressant drugs. The existence of a high affinity primary orthosteric binding site (S1) and a low affinity secondary site (S2) has been described and their relation to antidepressant pharmacology has been debated. Herein, structural modifications to the N-, 4, 5, and 4’-positions of (±)citalopram (1) are reported. All of the analogues were SERT-selective and demonstrated that steric bulk was tolerated at the SERT S1 site, including two dimeric ligands (15 and 51.) In addition, 8 analogues were identified with similar potencies to S-1 for decreasing the dissociation of [3H]S-1 from the S1 site, via allosteric modulation at S2. Both dimeric compounds had similar affinities for the SERT S1 site (Ki=19.7 and 30.2 nM, respectively), whereas only the N-substituted analogue, 51, was as effective as S-1 in allosterically modulating the binding of [3H]S-1 via S2.
doi:10.1021/jm4014136
PMCID: PMC3894853  PMID: 24237160
12.  Accumulation of Oxidized LDL in the Tendon Tissues of C57BL/6 or Apolipoprotein E Knock-Out Mice That Consume a High Fat Diet: Potential Impact on Tendon Health 
PLoS ONE  2014;9(12):e114214.
Objective
Clinical studies have suggested an association between dyslipidemia and tendon injuries or chronic tendon pain; the mechanisms underlying this association are not yet known. The objectives of this study were (1) to evaluate the impact of a high fat diet on the function of load-bearing tendons and on the distribution in tendons of oxidized low density lipoprotein (oxLDL), and (2) to examine the effect of oxLDL on tendon fibroblast proliferation and gene expression.
Methods
Gene expression (Mmp2, Tgfb1, Col1a1, Col3a1), fat content (Oil Red O staining), oxLDL levels (immunohistochemistry) and tendon biomechanical properties were examined in mice (C57Bl/6 or ApoE -/-) receiving a standard or a high fat diet. Human tendon fibroblast proliferation and gene expression (COL1A1, COL3A1, MMP2) were examined following oxLDL exposure.
Results
In both types of mice (C57Bl/6 or ApoE -/-), consumption of a high fat diet led to a marked increase in oxLDL deposition in the load-bearing extracellular matrix of the tendon. The consumption of a high fat diet also reduced the failure stress and load of the patellar tendon in both mouse types, and increased Mmp2 expression. ApoE -/- mice exhibited more pronounced reductions in tendon function than wild-type mice, and decreased expression of Col1a1 compared to wild type mice. Human tendon fibroblasts responded to oxLDL by increasing their proliferation and their mRNA levels of MMP2, while decreasing their mRNA levels for COL1A1 and COL3A1.
Conclusion
The consumption of a high fat diet resulted in deleterious changes in tendon function, and these changes may be explained in part by the effects of oxLDL, which induced a proliferative, matrix-degrading phenotype in human tenocytes.
doi:10.1371/journal.pone.0114214
PMCID: PMC4264764  PMID: 25502628
13.  Cocirculation of Three Hemagglutinin and Two Neuraminidase Subtypes of Avian Influenza Viruses in Huzhou, China, April 2013: Implication for the Origin of the Novel H7N9 Virus 
Journal of Virology  2014;88(11):6506-6511.
We detected three avian influenza hemagglutinin (HA) subtypes (H7, H9, and H5) and two neuraminidase (NA) subtypes (N9 and N2), as well as H7N9-related H9N9 reassortant intermediates, cocirculating among poultry in Huzhou, China, during April 2013. The results of our study reveal not only that Huzhou is one of the geographic origins of the novel H7N9 virus but also that cocirculation poses a potential threat to humans in the future.
doi:10.1128/JVI.03319-13
PMCID: PMC4093899  PMID: 24623437
14.  Combination of specific single chain antibody variable fragment and siRNA has a synergistic inhibitory effect on the propagation of avian influenza virus H5N1 in chicken cells 
Virology Journal  2014;11(1):208.
Background
The avian influenza virus (AIV) causes frequent disease with high morbidity and mortality. RNA interference (RNAi) has been shown to provide an effective antiviral defense in animals, and several studies have focused on harnessing small interfering RNAs (siRNAs) to inhibit viral infections. In addition, single chain variable fragments (scFvs) contain the complete antigen binding site, and specific scFvs can bind to and neutralize viruses.
Results
Fourteen positive scFvs were selected by the yeast two-hybrid system. Using molecular docking technology, we selected the three highest affinity scFvs for further functional validation. Results of indirect ELISA and IFA showed that all three scFvs could bind to FJ13 strain and had neutralizing activity, decreasing the viral infectivity markedly. Chicken fibroblastic DF-1 cells were transfected with scFvs in combination with siRNA-NP604 (an siRNA of anti-AIV NP protein previously reported). Following infection with FJ13 virus, copy numbers of the virus were significantly reduced from 12 h to at least 60 h post-infection compared to that achieved in cells transfected with scFv or siRNA-NP604 separately.
Conclusions
A novel combination of antiviral siRNAs expressed in chicken cells and chicken antibody single-chain variable fragments (scFvs) secreted from the cells has a synergistic inhibitory effect on the avian influenza viral proliferation in vitro. Intracellular application of scFvs and anti-viral siRNA may provide a new approach to influenza prevention and treatment.
doi:10.1186/s12985-014-0208-x
PMCID: PMC4264339  PMID: 25471220
AIV H5N1; scFv; siRNA; Synergistic inhibitory effect
15.  Design and Evaluation of a PEGylated Lipopeptide Equipped with Drug-Interactive Motifs as an Improved Drug Carrier 
The AAPS Journal  2013;16(1):114-124.
Micelles are attractive delivery systems for hydrophobic drugs due to their small size and the ease of application. However, the limited drug loading capacity and the intrinsic poor stability of drug-loaded formulations represent two major issues for some micellar systems. In this study, we designed and synthesized a micelle-forming PEG-lipopeptide conjugate with two Fmoc groups located at the interfacial region, and two oleoyl chains as the hydrophobic core. The significance of Fmoc groups as a broadly applicable drug-interactive motif that enhances the carrier–drug interaction was examined using eight model drugs of diverse structures. Compared with an analogue without carrying a Fmoc motif, PEG5000-(Fmoc-OA)2 demonstrated a lower value of critical micelle concentration and three-fold increases of loading capacity for paclitaxel (PTX). These micelles showed tubular structures and small particle sizes (∼70 nm), which can be lyophilized and readily reconstituted with water without significant changes in particle sizes. Fluorescence quenching study illustrated the Fmoc/PTX π–π stacking contributes to the carrier/PTX interaction, and drug-release study demonstrated a much slower kinetics than Taxol, a clinically used PTX formulation. PTX/PEG5000-(Fmoc-OA)2 mixed micelles exhibited higher levels of cytotoxicity than Taxol in several cancer cell lines and more potent inhibitory effects on tumor growth than Taxol in a syngeneic murine breast cancer model (4T1.2). We have further shown that seven other drugs can be effectively formulated in PEG5000-(Fmoc-OA)2 micelles. Our study suggests that micelle-forming PEG-lipopeptide surfactants with interfacial Fmoc motifs may represent a promising formulation platform for a broad range of drugs with diverse structures.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-013-9536-9) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-013-9536-9
PMCID: PMC3889538  PMID: 24281690
drug-interactive motif; micelle; paclitaxel; slow release
16.  Patatin-related phospholipase pPLAIIIδ influences auxin-responsive cell morphology and organ size in Arabidopsis and Brassica napus 
BMC Plant Biology  2014;14(1):332.
Background
The members of the patatin-related phospholipase subfamily III (pPLAIIIs) have been implicated in the auxin response. However, it is not clear whether and how these genes affect plant and cell morphogenesis. Here, we studied the roles of the patatin-related phospholipase pPLAIIIδ in auxin-responsive cell morphology and organ size in Arabidopsis and Brassica napus.
Results
We show that overexpression of pPLAIIIδ inhibited longitudinal growth but promoted transverse growth in most organs of Arabidopsis and Brassica napus. Compared to wild-type plants, pPLAIIIδ-KO plants exhibited enhanced cell elongation in hypocotyls, and pPLAIIIδ-OE plants displayed broadened radial cell growth of hypocotyl and reduced leaf pavement cell polarity. For the hypocotyl phenotype in pPLAIIIδ mutants, which resembles the “triple response” to ethylene, we examined the expression of the ACS and ACO genes involved in ethylene biosynthesis and found that ACS4 and ACS5 were up-regulated by 2.5-fold on average in two OE lines compared with WT plants. The endogenous auxin distribution was disturbed in plants with altered pPLAIIIδ expression. pPLAIIIδ-OE and KO plants exhibited different sensitivities to indole-3-acetic acid-promoted hypocotyl elongation in both light and dark conditions. Gene expression analysis of auxin-induced genes in the dark showed that OE plants maintained a higher auxin response compared with WT and KO plants after treatment with 1 μM IAA for 12 h. Following treatment with 10 μM IAA for 30 min in the light, early auxin-induced genes were significantly up-regulated in two OE plant lines.
Conclusions
These data suggest that the PLAIIIδ gene plays an important role in cell morphology and organ size through its involvement in the regulation of auxin distribution in plants.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0332-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-014-0332-1
PMCID: PMC4253999  PMID: 25428555
Auxin; pPLAIIIδ; Cell morphology; Phospholipase; Ethylene; Phosphatidic acid
17.  Efficacy and prognostic analysis of chemoradiotherapy in patients with thoracic esophageal squamous carcinoma with cervical lymph nodal metastasis alone 
Background
The prognostic factors of thoracic esophageal squamous carcinoma with cervical lymph nodal metastasis (CLNM) have not been specifically investigated. This study was performed to analyze the efficacy and prognostic factors of chemoradiotherapy for thoracic esophageal carcinoma with CLNM alone.
Methods
From 2002 to 2011, 139 patients with inoperable esophageal cancer who underwent chemoradiotherapy at the Sun Yat-Sen University were retrospectively analyzed. Median radiation doses were 60 Gy (range: 50–68 Gy). Univariate and multivariate analyses were performed to compare overall survival (OS) and progression-free survival (PFS).
Results
The 1- and 3-year OS rates were 68.2% and 27.9%, respectively. The 1- and 3-year PFS rates were 51.9% and 20.1%, respectively. The multivariate analysis demonstrated that response to treatment, T stage, pathological grade, and laterality of cervical lymph nodal metastases were independent prognostic factors for thoracic esophageal carcinoma with CLNM.
Conclusions
Concurrent chemoradiotherapy is an important and hopeful treatment option for patients with esophageal cancer with CLNM alone. Our study has revealed that response to treatment, T stage, pathological grade and laterality of cervical lymph nodal metastases are significant prognostic factors for long-term survival.
doi:10.1186/s13014-014-0256-9
PMCID: PMC4251839  PMID: 25424871
Chemoradiotherapy; Esophageal cancer; Prognosis; Cervical lymph nodal metastasis
18.  Effect of fibroblast growth factor 9 on the osteogenic differentiation of bone marrow stromal stem cells and dental pulp stem cells 
Molecular Medicine Reports  2014;11(3):1661-1668.
The role of fibroblast growth factor 9 (FGF9) in bone formation may depend on gene dosage, developmental stage, cell type or interactions with other cytokines. In the present study bone marrow stromal stem cells (BMSCs) and dental pulp stem cells (DPSCs) were cultured and osteogenically induced in vitro, treated with exogenous FGF9 at varying concentrations. Alkaline phosphatase staining, alizarin red S staining, reverse transcription quantitative polymerase chain reaction and western blot analyses were performed in order to investigate the gene expression levels of osteogenic markers. The results of the present study demonstrated that FGF9 enhanced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) during osteogenic induction in BMSCs and DPSCs, which are derived from different tissues. FGF9 also inhibited the osteogenic differentiation of BMSCs and DPSCs through the activation of ERK1/2. These findings suggested that FGF9 may be an inhibitor of osteogenesis in mesenchymal stem cells in vitro and its application in vivo requires investigation in the future.
doi:10.3892/mmr.2014.2998
PMCID: PMC4270321  PMID: 25435023
fibroblast growth factor 9; osteogenic differentiation; bone marrow stromal stem cells; dental pulp stem cells
19.  Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis 
Nature Communications  2014;5:5209.
Receptor protein tyrosine phosphatase sigma (RPTPσ) regulates neuronal extension and acts as a presynaptic nexus for multiple protein and proteoglycan interactions during synaptogenesis. Unknown mechanisms govern the shift in RPTPσ function, from outgrowth promotion to synaptic organization. Here, we report crystallographic, electron microscopic and small-angle X-ray scattering analyses, which reveal sufficient inter-domain flexibility in the RPTPσ extracellular region for interaction with both cis (same cell) and trans (opposite cell) ligands. Crystal structures of RPTPσ bound to its postsynaptic ligand TrkC detail an interaction surface partially overlapping the glycosaminoglycan-binding site. Accordingly, heparan sulphate and heparin oligomers compete with TrkC for RPTPσ binding in vitro and disrupt TrkC-dependent synaptic differentiation in neuronal co-culture assays. We propose that transient RPTPσ ectodomain emergence from the presynaptic proteoglycan layer allows capture by TrkC to form a trans-synaptic complex, the consequent reduction in RPTPσ flexibility potentiating interactions with additional ligands to orchestrate excitatory synapse formation.
Receptor protein tyrosine phosphatase sigma (RPTPσ) promotes both neurite outgrowth and synaptic organization. Here, Coles et al. present the structural basis for this switch in function, whereby TrkC on the postsynaptic membrane and heparan sulphate proteoglycans compete for the same binding surface on RPTPσ.
doi:10.1038/ncomms6209
PMCID: PMC4239663  PMID: 25385546
20.  piRBase: a web resource assisting piRNA functional study 
piRNAs are a class of small RNAs that is most abundantly expressed in the animal germ line. Presently, substantial research is going on to reveal the functions of piRNAs in the epigenetic and post-transcriptional regulation of transposons and genes. A piRNA database for collection, annotation and structuring of these data will be a valuable contribution to the field, and we have therefore developed the piRBase platform which integrates various piRNA-related high-throughput data. piRBase has the largest collection of piRNAs among existing databases, and contains at present 77 million piRNA sequences from nine organisms. Repeat-derived and gene-derived piRNAs, which possibly participate in the regulation of the corresponding elements, have been given particular attention. Furthermore, epigenetic data and reported piRNA targets were also collected. To our knowledge, this is the first piRNA database that systematically integrates epigenetic and post-transcriptional regulation data to support piRNA functional analysis. We believe that piRBase will contribute to a better understanding of the piRNA functions.
Database URL: http://www.regulatoryrna.org/database/piRNA/
doi:10.1093/database/bau110
PMCID: PMC4243270  PMID: 25425034
21.  Distinct Associations between Hypertension and Obstructive Sleep Apnea in Male and Female Patients 
PLoS ONE  2014;9(11):e113076.
Obstructive sleep apnea (OSA) is highly associated with hypertension. However, the correlation between hypertension and OSA at different levels of severity and the influence of gender on that correlation are unclear. A total of 996 patients (776 males and 190 females) with OSA were recruited. The influence of gender on the correlation between hypertension and OSA at different stratifications of severity, based on the apnea-hypopnea index (AHI), was fully evaluated together with the major health risk factors obesity, age, and diabetes. Females with OSA were significantly older on average than males with OSA. Moreover, females had milder degrees of OSA on average than the extent of severity seen in males. The proportion of females with diabetes or hypertension was higher than that of males. The proportion of males with hypertension and obesity increased significantly with OSA, and age also increased with OSA. The percentage of females with hypertension at different degrees of OSA severity was stable at about 26% in the mild, moderate, and severe OSA groups. Among females, age was increased significantly in the moderate relative to the mild OSA group. Moreover, the proportion of obese subjects was increased significantly in the severe compared with the moderate OSA group. The proportions of males and females with diabetes were not significantly different among all OSA severity groups. An ordinal multivariate logistic regression analysis confirmed that hypertension, age, and obesity were associated with OSA severity in males, whereas only age and obesity were associated with OSA severity in females. Although the proportion of subjects with hypertension was higher in females with OSA than in males with OSA, the proportion of subjects with hypertension increased as the severity of OSA increased in males but not in females.
doi:10.1371/journal.pone.0113076
PMCID: PMC4234651  PMID: 25402499
22.  Association between polymorphisms in the integrin gene predicted microRNA binding sites and bladder cancer risk 
Bladder cancer (BC) is the ninth most frequent malignancies in the world and the occurrence of this disease has dramatically increased in recent years. Integrins have been demonstrated to play an important role in the development and progression of BC. However, the association between polymorphisms in integrin genes and BC susceptibility was still unclear. A number of studies mainly focused on polymorphisms in the coding regions of integrin genes previously, while in this study, polymorphisms in the 3’ untranslated regions (3’UTR) were investigated in Chinese Han population. According to previous study, seven single-nucleotide polymorphisms (SNPs) in predicted microRNA (miRNA) target sites were chosen as potential targets. And four SNPs including rs11902171, rs2675, rs17664, and rs1062484, were finally examined for their effect on BC risk and clinical prognosis. These four polymorphisms were genotyped by using the high-resolution melting method (HRM) in 317 BC patients with long-time follow-up together with 317 age-matched healthy controls. AC carriers of rs2675 in ITGB5 were associated with an increased risk of BC (OR 1.44, 95% CI 1.02-2.03). No significant relationship was detected between these SNPs and the recurrence-free survival time of overall study population or non-muscle invasive BC subgroups in univariable analysis. In conclusion, rs2675 in miRNA binding sites of ITGB5 might be a potential target for BC susceptibility prediction.
PMCID: PMC4276218  PMID: 25550960
Integrin gene; polymorphisms; microRNA-binding sites; bladder cancer
23.  Reporting Quality of Systematic Reviews/Meta-Analyses of Acupuncture 
PLoS ONE  2014;9(11):e113172.
Background
The QUOROM and PRISMA statements were published in 1999 and 2009, respectively, to improve the consistency of reporting systematic reviews (SRs)/meta-analyses (MAs) of clinical trials. However, not all SRs/MAs adhere completely to these important standards. In particular, it is not clear how well SRs/MAs of acupuncture studies adhere to reporting standards and which reporting criteria are generally ignored in these analyses.
Objectives
To evaluate reporting quality in SRs/MAs of acupuncture studies.
Methods
We performed a literature search for studies published prior to 2014 using the following public archives: PubMed, EMBASE, Web of Science, the Cochrane Database of Systematic Reviews (CDSR), the Chinese Biomedical Literature Database (CBM), the Traditional Chinese Medicine (TCM) database, the Chinese Journal Full-text Database (CJFD), the Chinese Scientific Journal Full-text Database (CSJD), and the Wanfang database. Data were extracted into pre-prepared Excel data-extraction forms. Reporting quality was assessed based on the PRISMA checklist (27 items).
Results
Of 476 appropriate SRs/MAs identified in our search, 203, 227, and 46 were published in Chinese journals, international journals, and the Cochrane Database, respectively. In 476 SRs/MAs, only 3 reported the information completely. By contrast, approximately 4.93% (1/203), 8.81% (2/227) and 0.00% (0/46) SRs/Mas reported less than 10 items in Chinese journals, international journals and CDSR, respectively. In general, the least frequently reported items (reported≤50%) in SRs/MAs were “protocol and registration”, “risk of bias across studies”, and “additional analyses” in both methods and results sections.
Conclusions
SRs/MAs of acupuncture studies have not comprehensively reported information recommended in the PRISMA statement. Our study underscores that, in addition to focusing on careful study design and performance, attention should be paid to comprehensive reporting standards in SRs/MAs on acupuncture studies.
doi:10.1371/journal.pone.0113172
PMCID: PMC4232579  PMID: 25397774
24.  PRDI-BF1-RIZ domain of retinoblastoma protein-interacting zinc finger gene 1 induces apoptosis and exerts anticancer activity in esophageal squamous cell carcinoma cells 
Oncology Letters  2014;9(1):341-346.
The present study examined the role of the PRDI-BF1-RIZ (PR) domain of tumor suppressor retinoblastoma protein-interacting zinc finger gene 1 (RIZ1) as an anticancer domain and its ability to induce apoptosis in esophageal squamous cell carcinoma (ESCC) cells. The TE13 ESCC cell line was transfected with pcDNA3.1(+) eukaryotic expression vectors bearing the open reading frames of either the human RIZ1 gene or the PR domain, and the mRNA and protein expression levels were then detected using quantitative reverse transcription polymerase chain reaction and western blotting, respectively. The rate of apoptosis was determined by flow cytometry and the cell invasion ability was determined by an invasion assay. RIZ1 and the PR domain induced apoptosis and reduced the cell invasion ability (P<0.01). These findings indicate that the RIZ1 gene possesses anticancer activity in the PR domain, which may be important in inhibiting the development of ESCC.
doi:10.3892/ol.2014.2671
PMCID: PMC4246629  PMID: 25435989
retinoblastoma protein-interacting zinc finger gene 1; PRDI-BF1-RIZ domain; esophageal squamous cell carcinoma
25.  Satellite telemetry and social modeling offer new insights into the origin of primate multilevel societies 
Nature Communications  2014;5:5296.
Multilevel societies (MLS), in which polygynous reproductive units are nested in a larger social matrix, represent a highly complex social system documented only in a small number of mammalian species. Using long-term behavioural data, satellite telemetry and social network analysis, we present a new framework for understanding the function and social dynamics of the golden snub-nosed monkey MLS. Here we show that several one-male units form a cohesive breeding band that associates with one or more all-male units to form a herd. Herds seasonally aggregate and exchange members, thus facilitating gene flow and inbreeding avoidance. This MLS evolved from the aggregation of independent one-male, multifemale units that characterize ancestral Asian colobines; the evolutionary pathway leading to this MLS contrasts with that proposed for African papionins, which appear to have undergone internal fissioning of multimale–multifemale groups. The results suggest that both environmental and phylogenetic factors are important in the evolution of a primate MLS.
Multilevel societies (MLS) are a complex form of group organization found in mammals, yet the origin of MLS is poorly understood. Here the authors show that MLS of the golden snub-nosed monkey evolved from the aggregation of independent one-male, multifemale units found in ancestral Asian colobines.
doi:10.1038/ncomms6296
PMCID: PMC4220467  PMID: 25335993

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